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O1 Functionally Distinct HMGB1 Isoforms Correlate With Physiological
Processes In Drug-Induced SJS/TEN.
Daniel F Carr1, Wen-Hung Chung2, Rosalind E Jenkiins1, Mas Chaponda1, Gospel
Nwikue1, Elena M Cornejo Castro1, Daniel J Antoine1, Munir Pirmohamed1
1. University of Liverpool, Liverpool, United Kingdom
2. Chang Gung Memorial Hospital, Taipei, Taiwan
Keywords: Stevens Johnson Syndrome, HMGB1, Biomarker, Hypersensitivity
Introduction
Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are
serious, life threatening severe immune-mediated cutaneous reactions with
mortality ranging from 10-30%. The commonest causes are drugs. SJS/TEN is
characterised by widespread epidermal detachment due to keratinocyte cell
death. Increased concentrations of cytotoxic molecules may act as potential
serum biomarkers of SJS/TEN. However, to date no mechanism based biomarker
has been validated for diagnostic utility in this field. HMGB1 is a well-validated
biomarker of cell death and inflammation. This study investigated whether
HMGB1 represents a valid, utilisable biomarkers for drug-induced SJS/TEN.
Method
Serum samples from nevirapine-treated Malawian HIV patients (27 MPE, 12
DRESS, 12 SJS/TEN cases and matched tolerant controls) were analysed for total
HMGB1 by ELISA. Novel mass-spectrometric protocols were also used to analyse
post-translationally modified forms of HMGB1. In addition serum from 20
Taiwanese SJS patients (5 carbamazepine, 8 allopurinol, 5 phenytoin, 2
sulfamethoxazole) both during and post-reaction were analysed for HMGB1
isoforms.
Results
There was a significant elevation of mean total serum HMGB1at time of reaction
in patinets with nevirapine-induced MPE (6.0ng/ml), HSS (6.3ng/ml) and
SJS/TEN (15.9ng/ml) comapred to tolerant controls at weeks (1.3ng/ml)
(p<0.001). Analysis of post-translationally modified isoforms of the HMGB1 in
the different phenotypes (Fig. 1) showed patients with MPE and DRESS had
elevation the acetylated form of HMGB1 which is a marker of innate
immunity. By contrast, SJS/TEN patient sera contained comparable levels of
acetylated HMGB1, but also had very high levels of the non-acetylated form,
which is associated with cell death/ tissue injury. The tolerant control patients
had low levels of the unacetylated form. This pattern of HMGB1 isoform elevation
was replicated in the Taiwanese SJS cohort. As patients recovered, the total
HMGB1 concentrations went down, although there was still significant elevation
of the suphonyl (partially reduced) HMGB1 isoform which has no known immune
function and may represent a marker of innate immunity returning to "steady
state".
Conclusion
In conclusion, our data suggest that post-translationally modified HMGB1 may
represent mechanism-based diagnostic and prognostic markers for drug-induced
SJS/TEN. This needs to be studied in more patients.
O2 Hypersensitivity Reactions To Beta-Lactams, Does The T Cell
Recognition Pattern Influence The Clinical Picture?
Natascha Wuillemin, Dolores Dina, Klara K Eriksson, Daniel Yerly
University Hospital Bern, Bern, Switzerland
Keywords: Hapten, PI, Amoxcillin
Introduction
Worldwide, beta-lactam antibiotics can commonly cause hypersensitivity
reactions (HR) with various clinical pictures from minor affections like
maculopapular exanthema (MPE) and urticaria to severe cutaneous adverse
reactions (SCAR) and anaphylaxis. Currently, two different concepts provide
rational explanations how a drug can initiate a drug HR by activating human T
cells – the hapten concept and the pharmacological interaction with immune
receptor (p-i) concept. In this study, we investigated the relationship between
the reactivity pattern of drug-reacting T cells found in the peripheral blood of
allergic patients and their clinical picture.
Method
We expanded beta-lactams reacting T cells from drug allergic individuals,
including patients with typically IgE mediated hypersensitivity reactions such as
urticaria or anaphylaxis as well as patients with T cell mediated reactions such as
MPE and SCAR. The drug-reacting T cells were analyzed in terms of their
phenotype (CD4+/CD8+) and the recognition pattern of AMX, e.g. hapten or p-i.
Results
From patients with type I HR to amoxicillin, T cell clones (TCC) could be
generated and analysed. They showed amoxicillin reactivity according to the
hapten mechanism: antigenic complexes were stably presented and antigen
presentation machinery was essential for T cell activation. TCC from patients
suffering from MPE showed similar features. Three patients with DRESS to
amoxicillin or ceftriaxone could be included. Drug reacting T cells from those
patients showed exclusively reactivity according to pi-concept. Stimulatory
antigenic complexes were not stably presented for T cell activation and addition
of drug to TCC in the presence of antigenic presenting cells lead to immediate
activation, measured by calcium intake.
Conclusion
We conclude that T cells from type I HR and MPE patients recognize beta-lactams
according to the hapten mechanism. In contrast, in patients with SCAR, the p-i
concept might also be relevant for beta-lactams recognition. Consequently, the
current preclinical risk evaluation of new drugs to cause severe HR, which is
solely based on their ability to form haptens, might be insufficient.
O3 Specific Binding Characteristics Of HLA Alleles Associated With
Nevirapine Hypersensitivity
Rebecca Pavlos1, Elizabeth Mckinnin1, David Ostrov2, Bjoern Peters3, Soren
Buus4, David Koelle5, Abha Chopra1, Craig Rive1, Alec Redwood1, Susana
Restrepo6, Austin Bracey6, Jing Yuan7, Silvana Gaudieri8, Mary Carrington9, David
Haas10, Simon Mallal10, Elizabeth Phillips10
1. Murdoch University, Perth, Australia
2. University of Florida, Gainesville, United States
3. La Jolla Institute for Allergy and Immunology, La Jolla, United States
4. University of Copenhagen, Copenhagen, Denmark
5. University of Washington, Seattle, United States
6. Univesrity of Florida, Gainesville, United States
7. Boehringer Ingelheim Inc, Ridgefield, United States
8. Univesrity of Western Australia, Perth, Australia
9. Ragon Insitute, Cambridge, United States
10.Vanderbilt University, Nashville, United States
Keywords: Nevirapine, HLA, Peptide Binding Groove
Introduction
Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI)
associated with a hypersensitivity syndrome (HSR) in approximately 5% of
patients. Multiple class I/II HLA associations have been described in association
with NVP hypersensitivity reaction (HSR) phenotypes. Based on the established
models of drug HSR which highlight the significance of the HLA peptide binding
groove for specific drug interactions, we compared NVP HSR-associated alleles
across ethnic groups for similarities in peptide binding specificities and HLA
binding pocket structure.
Method
HLA typing was performed on DNA from ClinicalTrials.gov
NCT00310843. Univariate and multivariate analyses stratified for race were
performed according to HLA class I/II alleles, MHCcluster groups and key HLA
peptide binding groove amino acids.
Results
Examination of HLA allele peptide binding characteristics, together with structure
of the B and F pockets in the peptide binding cleft identified a group of HLA-C
alleles with common binding properties, and the same F pocket structure as HLAC*04:01 that were predictive of cutaneous NVP HSR (HLA-C*04:(03/06/07),C*05:(01/09),-C*18:01) (OR [95%CI] 2.9 [1.6-5.23], p=0.005). Similarly, a
group of protective HLA-B alleles with a characteristic B pocket was identified
(HLA-B*15:(01/12/24/25/27/32/35),-B*52:01)( OR [95%CI] =0.2 [0.07-0.5],
p=0.0003). HLA-DRB1 alleles DRB1*01:(01/02/03), DRB1*04:(04/05/08/10),DRB1*14:02) which share the DRB1-P4 pocket were found to associate with
cutaneous NVP HSR (OR [95%CI] 2.15 [1.23-3.24], p = 0.0013). Molecular
docking suggests that NVP is able to bind to the B pocket in both HLA-B and
HLA-C as well as the P4 residues in HLA-DRB1
Conclusion
The cutaneous phenotypes of NVP HSR associates with different HLA-C, HLA-B
and DR-alleles respectively that share peptide binding characteristics and binding
pocket structure. Models suggest that NVP may bind directly to multiple HLA
within the antigen binding cleft in the site normally occupied by peptide. The
identified HLA-NVP interactions will have consequences for peptide binding and T
cell receptor recognition in NVP HSR.
O4 Do We Need To Measure Total IgE For The Interpretation Of
Analytical Results Of ImmunoCAP And 3gAllergy Specific IgE?
Douwe De Boer1, Paul Menheere1, Chris Nieuwhof2, Judith Bons1
1. Central Diagnostic Laboratory, MUMC+, Maastricht, Netherlands, The
2. Internal Medicine, MUMC+, Maastricht, Netherlands, The
Keywords: Total IgE, Penicillin, Chlorhexidine, ImmunoCAP, 3gAllergy
Introduction
Non-specific binding of IgE in in-vitro IgE allergy tests contributes to falsepositive results. For ImmunoCAP it is stated that very low levels of allergen
specific IgE (sIgE) should be evaluated with caution when total IgE (tIgE) > 1000
kU/L. For β-lactams and chlorhexidine sIgE the warning limit is 500 kU/L. For
3gAllergy no such alerts are known. These warnings imply to measure tIgE for an
interpretation of analytical results of at least ImmunoCAP sIgE. Goal of this study
is to verify such warning limits for ImmunoCAP as well as 3gAllergy.
Method
Relationship between sIgE and tIgE was investigated for ImmunoCAP (Thermo
Fisher) and 3gAllergy (Siemens) penicillin V sIgE as well as for ImmunoCAP
chlorhexidine sIgE. Ves v 5 sIgE was taken as the 1000 kU/L limit control. All
tests were performed according the manufacturers’ instructions. Because
ImmunoCAP and 3gAllergy tIgE have a very strong correlation (r = 0.995), sIgE
of both tests were graphically plotted against ImmunoCAP tIgE only. An iterative
polynomial regression procedure, which excluded outliers when those after fitting
were outside the 95% confidence interval, was applied to check for the nature of
a relationship.
Results
For ImmunoCAP penicillin V (r = 0.900) and chlorhexidine (r = 0.888) strong
polynomial relations were observed, while for ImmunoCAP Ves v 5 only very
weak relations (r < 0.500) were noticed. For tIgE > 500 kU/L most of the
penicillin V and chlorhexidine sIgE values were > 0.10 kU/L and with increasing
tIgE the number of sIgE values > 0.35 kU/L increased. For 3gAllergy some
results were > 0.35 kU/L, but the majority of results was < 0.10 kU/L and
consequently insufficient data points were obtained for adequate
regression. ImmunoCAP is based on high-capacity binding cellulose and at
relatively high concentrations of tIgE, the frequency of possible false-positive
results increases, especially for penicillin V and chlorhexidine sIgE. 3gAllergy is
based on non-specified polymers attached to a bead, which is also subjected to
false-positive results for penicillin V sIgE, but only at lower levels and frequency.
Conclusion
The warning limit of 500 kU/L of tIgE for ImmunoCAP penicillin V and
chlorhexidine sIgE is valid and above the limit false-positive results are likely. For
3gAllergy penicillin V sIgE a limit is also needed but at a higher level.
Consequently, for the respective tests we do need to measure tIgE for any sIgE
result > 0.10 kU/L.
O5 Neutrophil Activation In Systemic Anaphylaxis: Results From The
Multicentric NASA Study
Friederike Jonsson1, Luc De Chaisemartin2, Vanessa Granger2, Caitlin Gillis1,
Aurelie Gouel1, Catherine Neukirch2, Fadia Dib2, Pascale Roland Nicaise2, Dan
Longrois2, Florence Tubach2, Sylvie Martin2, Pierre Bruhns1, NASA Study Group3
1. Institut Pasteur, France, France
2. Hopital Bichat, France, France
3. Institut Pasteur & Hopital Bichat, France, France
Keywords: Anaphylaxis, Drug, Curare, IgG, Neutrophils
Introduction
Anaphylaxis is a severe systemic allergic reaction that can be life-threatening. In
about 85% of cases evidence for the activation of the classical anaphylaxis
pathway involving IgE and IgE receptors can be detected. Recently, an
alternative pathway involving IgG and IgG receptors (FcγRs) on neutrophils has
been suggested by animal models. We hypothesized that such a mechanism may
also exist in humans and studied this possibility in a multicentric prospective
cohort of patients suspected of perioperative anaphylaxis to neuromuscular
blocking agents (NMBA).
Method
Consecutive patients suspected of perioperative anaphylaxis (n=86 cases) were
recruited and paired with 86 control patients. Blood samples were collected for
cases and controls promptly after anesthesia induction. Extensive allergological
testing was performed 6-8 weeks after the reaction for cases. Circulating
elastase, neutrophil extracellular traps (NETs), tryptase, histamine, and IgG and
IgE anti-NMBA were measured by ELISA. FcγR expression on the major cell
populations in the blood was analyzed by flow cytometry.
Results
We found higher circulating NETs and elastase levels during an anaphylactic
reaction compared to controls. IgG anti-NMBA were found in both cases and
controls, however for cases the IgG titer was associated with anaphylaxis
severity. Finally, we show a significant decrease of FcγR expression specifically
on neutrophils, pointing towards their engagement by immune complexes. This
decrease not only correlated significantly with NET release but also with the
severity of the anaphylactic reaction. Together, our results strongly suggest an
activation of neutrophils by NBMA-IgG complexes during anaphylaxis.
Conclusion
We reveal for the first time the existence of an IgG-dependent neutrophil
activation pathway during anaphylaxis in human. This additional mechanism
opens potential applications in anaphylaxis diagnostics and treatment.
O6 Purpuric Drug Eruptions Due To Epidermal Growth Factor Receptor
Tyrosine Kinase Inhibitors (EGFR-TKIs) For Non-Small-Cell Lung Cancer
(NSCLC): A Clinic-Pathological Study Of 32 Cases
Kai-Lung Chen1, Shu-Ling Liao1, Yi-Shuan Sheen1, Yung-Tsu Cho1, Che-Wen
Yang1, Jau-Yu Liau2, Chia-Yu Chu1
1. Department of Dermatology, National Taiwan University Hospital and
National Taiwan University College of Medicine, Taipei, Taiwan, Taipei,
Taiwan
2. Department of Pathology, National Taiwan University Hospital and National
Taiwan University College of Medicine, Taipei, Taiwan, Taipei, Taiwan
Keywords: EGFR-TKIs, Purpura, Vasculitis, Staphylococcus
Introduction
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have
been widely used to treat non-small-cell lung cancer (NSCLC). Skin toxicities
related to EGFR-TKIs are common, such as acneiform eruptions, pruritus,
xerosis, and paronychia. However, purpuric eruptions are rarely seen and only
few cases reported. We conducted this study to classify the purpuric drug
eruptions due to EGFR-TKIs (gefitinib, erlotinib, or afatinib) for NSCLC with clinicpathological correlations.
Method
During January 2012 to August 2015, 32 patients were included in this study. We
recorded the characteristic, lag period, and also the peripheral platelet counts
while biopsy. Skin biopsies with tissue culture were undertaken in every patients.
DIF studies were performed in most of them.
Results
We classified the clinical presentations into four different types: purpura only
(n=7, 21.9%), eczema craquelé-like (n=5, 15.6%), pustulosis (n=16, 50%), and
necrolytic migratory erythema (NME)-like patches (n=8, 25%). Different types
could be presented on the same patient concomitantly. 93% (15/16) of
pustulosis type specimens grew Staphylococcus aureus, whereas only 25%
(5/20) among other types. Most of the histopathology showed parakeratosis,
hypogranulosis, perivascular lymphocytic and neutrophilic infiltration, endothelial
cell swelling and RBC extravasation. Typical leukocytoclastic vasculitis (LCV) was
found in 13-29% of patients. Most of the DIF showed negative finding. Most of
the patients were responsive to one-week systemic cefazolin treatment with or
without discontinuing the EGFR-TKI.
Conclusion
There are four types of the purpuric drug eruptions due to EGFR TKIs: purpura,
eczema craquelé-like, pustulosis, and NME-like patches. No significant
histopathological differences between each group, and less than one third of
patients presented typical LCV. Staphylococcus aureus was the most common
pathogen identified. Most of the patients showed dramatic improvement by the
treatment of systemic antibiotics, especially those with pustulosis type.
Poster presentations
Poster Walk 1: Anaphylaxis (P01 – P09)
P01 Anaphylactic Reactions During Anaesthesia And The Perioperative
Period
Rita Aguiar, Anabela Lopes, Natália Fernandes, Leonor Viegas, MA PereiraBarbosa
Immunoallergology Department.Hospital de Santa Maria-Centro Hospitalar Lisboa
Norte, Lisbon, Portugal
Keywords: Anaphylatic Reactions, Anaesthesia
Introduction
Anaphylaxis incidence in the perioperative setting varies between 1:10000 and
1:20000. Although this value is yet to be determined in Portugal, an increase in
the number of reactions has been reported. Clinical evaluation is important in
order to identify risk factors and drugs that cause anaphylaxis, so that
alternative options can be found.
The aim of this study was to characterize the reactions of patients (pts) with
perioperative anaphylaxis and for conducting medical techniques requiring
sedation.
Method
Retrospective analysis of medical records of 57 pts with perioperative
anaphylaxis and anaphylaxis undergoing medical procedures with sedation,
observed in the immunoallergologic outpatient clinic (2009-2015).
The diagnostic investigation was carried out 6-8 weeks after the reaction,
included detailed medical history, specific IgE assay to betalactams and latex,
skin tests (ST) with the culprit drug and evidence of provocation when
necessary, according to the recommendations of the SFAR / ENDA.
Results
: We studied 56 pts (41 females) with mean age of 50 ± 18 years.
Regarding the severity of anaphylaxis and according to Mertes classification,
24 cases (42.8%) had stage I reaction and 24 cases (42.8%) had II reaction, 7
cases (12.5%) grade III and 1 case (1.8%) grade IV.
An IgE-mediated mechanism has been established in 34 pts (60.7%). The major
etiologic agents causing IgE-mediated reactions were muscle relaxants in 7 pts
(12.5%), antibiotics in 6 cases (10.7%; 4 cefazolin, 1 aminopenicillin, 1
ciprofloxacin), metamizole in 3 pts (5.4 %), 2 pts latex (3.6%), 7 pts (12.5%)
reacted with less representative agents.
On 10 pts (17,8%) drugs responsible for the reactions were associated with nonIgE-mediated mechanisms, anti-inflammatory (NSAIDs) are the most frequent
agents (5 pts).
In 14 pts (25%) it was not possible to determine a pharmacological aetiology of
the reaction.
Conclusion
More than half of perioperative events (60.7%) have an IgE-mediated
mechanism. Muscle relaxants, antibiotics and patent blue dye were the most
frequently identified agents. In 17.8% of the reactions was involved a non-IgEmediated mechanism, namely NSAIDs. It is important to determine the aetiology
of perioperative reactions for guidance in future surgery, either because the
identified agents are often used outside the perioperative setting.
P02 Anaphylaxis To Chlorhexidine: Is There A Cross-Reactivity To
Alexidine?
Antonia Bünter1, Nisha Gupta2, Tatjana Pecaric Petkovic1, Nicole Wirth1, Werner
J Pichler1, Oliver Hausmann3
1. ADR-AC GmbH, Bern, Switzerland
2. Teleflex Incorporated, Bern, Switzerland
3. Dep. of Rheumatology, Immunology and Allergology, University Hospital
and University of Bern, Bern, Switzerland
Introduction
Chlorhexidine (CHX) and its diacetate derivative (CHA) are two forms of the
same disinfectant for skin and mucosal surfaces as well as medical devices.
CHX/CHA are bivalent compounds with biguanide groups and chlorophenyl
endings. CHX/CHA can cause IgE-mediated anaphylaxis. Alexidine (ALX), a
related biguanide without aromatic end groups, has similar bactericidal
properties and represents a potential substitute for CHX/CHA. The allergic
potential of ALX is unknown.
Method
We investigated whether patients sensitized to CHX/CHA also react with ALX. We
used blood of CHX/CHA-allergic donors for basophil activation testing (BAT for
CD63 and CD203a as activation markers) with CHA and ALX. In addition, we
performed inhibition assays with CHA, chlorguanide (CG) and ALX using a
commercial IgE assay for CHX (ImmunoCAP, ThermoFisher Scientific, Uppsala).
Results
13 patients from a single tertiary care center with allergic reactions to CHX within
the last 8 years were included. 9/13 patients had still elevated CHX-specific IgE
(>0.35 kU/l), although mostly substantially lower compared to the time of
anaphylaxis. In 6/13 patients with CHX-specific IgE >0.7 kU/l CAP inhibition
studies were performed. CG showed a strong inhibitory effect in 6/6 and CHA in
3/6 tested sera. ALX induced partial inhibition of CHX positivity in 2/6 sera but at
much higher concentrations compared to CHA. 3/13 patients showed a positive
BAT with CHA, one of them with additional positivity to ALX.
Conclusion
Both, CAP inhibition studies as well as BAT analysis show that patients with
documented CHX/CHA allergy do not or only partially react with ALX in these
IgE-based assays. Based on this limited cross-reactivity of CHX/CHA and ALX,
ALX may be potential alternative for CHX-allergic patients. More patients need to
be included to substantiate this assumption. An ALX-specific IgE assay would
help to differentiate CHX/CHA- and ALX-specific sensitization.
P03 Cefotaxime-Induced Severe Anaphylaxis In A Neonate
Mehtap Yazicioglu1, Pinar G Ozdemir1, Gokce Ciplak2, Ozkan Kaya3
1. Trakya University Department of Pediatric Allergy, Edirne, Turkey
2. Trakya University Department of Pediatrics, Edirne, Turkey
3. Trakya Hospital, Edirne, Turkey
Introduction
Anaphylaxis is defined as a serious generalized allergic or hypersensitivity
reaction that is rapid in onset and might cause death. It is very rare in infancy.
In this case report, we present a neonate who developed anaphylaxis during
infusion of first dose of cefotaxime.
Case Description
A-one month infant was referred to our Pediatric Emergency Department
because of anaphylactic reaction with rash, cyanosis and respiratory arrest
developed after first dose of cefotaxime treatment. She was intubated
immediately, then extubated after 10 minutes. Pyhsical examination on
admission showed prolonged expirium bilaterally, and rales at the right lung
base. Other findings were unremarkable. She was hospitalized and treatment
with salbutamol nebules (0,15mg/kg/dose, q 6hr) was started. Vital findings
were observed closely. On the 4th day of admission, before discharge, she was
consulted with our pediatric allergy department. She was born full term by
Cesarean delivery, weighing 3,180 g. Her personal and family history was
unremarkable, except her mother described rash and swelling of the lips and face
after spraying cologne. Laboratory investigations on admission: CBC with white
blood cell differential was within normal range; C-reactive protein (CRP): 1,35
mg/dl (0-0,34); serum total IgE:2,4 U/ml (0-170). Serum tryptase: 17,7ng/ml
(on the 4th day of admission); serum tryptase 12,3ng/ml (after 2 months). Skin
prick tests with cefotaxime (2 mg/ml), and cefotaxime (10 mg/ml) were both
negative. We did not perform intradermal tests and drug provocation test with
cefotaxime. The patient was discharged to be followed with prescription
of epinephrine autoinjector to use in case of anaphylactic emergency, and the
family was educated about about signs and symptoms of anaphylaxis and about
when and how to use the EpiPen.
How this report contributes to current knowledge
Anaphylaxis in newborn period is very rare. Our case was interesting that to our
knowledge this is the first case of anaphylaxis in a newborn induced by first dose
of an antibiotic. We wished to attract attention that severe drug reactions can
also be seen in early life.
P04 Clinical Features And Diagnosis Of Anaphylaxis Resulting From
Exposure To Chlorhexidine
Peter John Cooke
Auckland City Hospital, Auckland, New Zealand
Keywords: Chlorhexidine, Skin Prick Testing, Specific IgE, Anaphylaxis
Introduction
The Auckland Anaesthetic Allergy Clinic is jointly provided by the Departments of
Anaesthesia and Immunology. All patients referred following perioperative
anaphylaxis are skin prick tested with chlorhexidine 2%. This review describes
the clinical features of the cases in which a diagnosis of allergic anaphylaxis to
chlorhexidine was made during the period January 2012 to December 2015.
Method
Patient data and clinic test results were archived on a simple Excel
spreadsheet. These were reviewed by the author and a chart review of the
chlorhexidine anaphylaxis cases was undertaken.
Results
A total of 14 patients were diagnosed with chlorhexidine allergy during the
period. (11 male and 3 female).
The following manifestations of anaphylaxis were documented: hypotension (12
patients), tachycardia (9), flushing (7), facial swelling (4), urticaria (3),
bronchospasm (2), piloerection (2), agitation (1), generalized swelling (1). Four
patients had CPR during their anaphylaxis, 9 patients had a grade 3 reaction and
one patient had a grade 1 reaction. Twelve of the 14 patients received
adrenaline. Anaphylaxis followed the insertion of a chlorhexidine impregnated
central venous line in 7 cases, urethral catheterization with chlorhexidine
containing gel in 3 and following topical exposure only in 4 cases.
Skin testing was performed 30-130 days after the anaphylaxis event.
All of the patients diagnosed with chlorhexidine allergy developed a
wheal >3mm after a s prick test with 2% chlorhexidine (range 3-20mm). The
specific IgE for Chlorhexidine was obtained in 11 of the 14 cases and in 10 of the
11 it was elevated.
During the same period 219 other patients were seen at our clinic and all
received skin prick tests for chlorhexidine 2%. All of these patients had
completely negative tests with a no wheal and no flare.
Conclusion
This data shows that patients with chlorhexidine anaphylaxis demonstrate typical
signs but that hypotension is the most common manifestation. Convincing skin
testing results along with specific IgE testing and the clinical history provided the
basis of the diagnosis. Chlorhexidine is used in our region for skin preparation
prior to anaesthetic and surgical procedures and four anaphylaxis cases resulted
from topical exposure to chlorhexidine.
Our data also suggests that a skin prick test with 2% chlorhexidine in alcohol is a
satisfactory method of skin testing.
P05 Drug-Induced Anaphylaxis: Five-Year Single-Center Survey
Inês Mota, Ângela Gaspar, Filipe Benito-Garcia, Marta Chambel, Mário MoraisAlmeida
Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal
Keywords: Anaphylaxis, Drug Allergy, NSAID, Antibiotics
Introduction
Drug-induced anaphylaxis (DIA) is the most common cause of fatal anaphylaxis.
Anaphylaxis related to nonsteroidal anti-inflammatory drugs (NSAID) is typically
drug-specific or class-specific, as well as with beta-lactams (BL) antibiotics (AB).
Although skin testing and drug provocation tests (DPT) can confirm the
diagnosis, in severe cases the diagnosis is mostly based on clinical history. The
aim of this study was to characterize patients (pts) with DIA and their drug
allergy work-up.
Method
Systematic review of all pts with clinical history compatible with DIA reported to
our drug allergy center in the last five years. All pts were investigated according
to ENDA/EAACI recommendations, through skin testing and in vitro tests
(whether standardized tests available) and DPT (when indicated).
Results
A total of 114 pts were included: mean age 41.5 (SD±16.8) yrs, 10% <18 yrs,
68% female, 72% atopic and 23% had asthma. Median age of first anaphylactic
episode was 36.5 yrs [1;74], and 19 pts had recurrent DIA. The main causes
were NSAID (50 pts) [acetylsalicylic acid (15), ibuprofen (13), metamizol (13),
diclofenac (9), paracetamol (3), etodolac, ketorolac and clonixin (1 each)] and
AB (46 pts) [BL (37), quinolones (4), macrolides (3), fosfomycin (1) and
minocycline (1)]. Other drug agents found: neuromuscular blocking drugs (5
pts), proton pump inhibitors (5 pts), carboplatin (3 pts), corticosteroids (2 pts),
local anesthetics (2 pts), ranitidine, midazolam and patent blue (1pt each). There
was a predominance of mucocutaneous manifestations (96%), followed by
respiratory (80%) and cardiovascular (45%) symptoms. In 25% of pts the
reaction occurred in hospital setting and 12% had intraoperative anaphylaxis.
DIA was supported in 72 pts (63%), through skin tests in 62 and the remaining
by in vitro tests or DPT. Considering the severity of reactions and the lack of
standardized tests for some drugs, patients whose DIA was based on clinical
history were successfully challenged with alternative drugs.
Conclusion
NSAID and AB were responsible for the majority of DIA. Anaphylactic reactions
were reported at any age. The heterogeneity of mechanisms involved, the
severity of clinical reactions and the lack of standardized in vivo and/or in vitro
tests do not allow to confirm the diagnosis in all cases. Patients with DIA should
be evaluated in specialized centers in order to perform accurate diagnosis, to
prevent recurrence and to find safe alternatives.
P06 Intraoperative Severe Anaphylactic Reaction Due To Patent Blue V
Dye
Luis Marques, Eva Alcoceba, Silvia Lara
Hospitals Universitaris Santa Maria - Arnau de Vilanova, Lleida, Spain
Introduction
Intraoperative anaphylactic reactions are a diagnostic challenge. The chronology
of the administration of the multiple drugs and the beginning of the reaction are
important in identifying the culprit drug.
Patent blue V is a well known cause of perioperative anaphylaxis
This dye is a member of the triarylmethane family, which also includes isosulfan
blue and methylene blue. Is used for staging breast cancer, identifying sentinel
lymph nodes. The frequency of reactions is around 0,24 to 1,1%. It can be also
found in food (food additive E-131) and cosmetics.
Case Description
We describe the case of a woman 65 years-old with a ductal carcinoma of the left
breast, who suffered hypotension (85/60), bronchospasm with hypoxemia,
urticaria, angioedema of the face, tongue and epiglottis after the administration
through the nipple of colorant patent blue V. Anaesthetic induction was done with
fentanyl, propofol and rocuronium. Adrenaline, bronchodilators, antihistamines,
corticosteroids and vasopressive drugs were administered, being admitted in the
ICU. The levels of tryptase were 8’5 µg/mL 20 min after the beginning of the
reaction, 16’6 µg/mL at 2h and 3,23µg/mL at 48h.
One month after the reaction cutaneous tests were done, being positive for
patent blue V (intradermal reaction at 1/10) and negative for suxamethonium,
cis-atracurium, rocuronium, fentanyl, propofol, midazolam, povidone-iodine and
latex.
It was the first time the patient received this dye or any similar dye as a drug.
Intraoperative anaphylactic shock due to allergy to patent blue V was diagnosed.
The future use of this dye was prohibited and an advise to avoid stuff which
contains this product was given to the patient.
A suspicion of sensitization through foods or cosmetics is possible as the patient
reacted the first time she received this drug.
How this report contributes to current knowledge
This case confirms previous descriptions of reactions with patent blue V: reaction
with the first exposition and severe allergic reactions, with hypotension and raise
in tryptase levels. Cutaneous test are useful in the diagnostic and standardized
concentrations have been described by ENDA.
P07 Kounis Syndrome In The Setting Of Anaphylaxis To Diclofenac
Leonor Carneiro-Leão, Carmen Botelho, Eunice Dias-Castro, Josefina Cernadas
Serviço de Imunoalergologia, Centro Hospitalar de São João, Porto, Portugal
Introduction
Kounis Syndrome (KS), the occurrence of acute coronary events as consequence
of allergic or hypersensitivity reactions has been described for years. It is still
relatively unknown and consequently underdiagnosed, leading to inadequate
treatment and subsequent morbidity. There are three subtypes of KS: type I
which occurs in patients without predisposing cardiovascular factors; type II
which occurs in patients with cardiovascular risk factors; and type III by stent
thrombosis.
Case Description
A 55 year old man, a smoker with type II Diabetes, was admitted to our hospital
for myocardial infarction (MI) after taking 2 pills of diclofenac 75mg for left leg
pain. He complained of immediate generalized pruritus, malaise, constrictive
radiating chest pain, dyspnea, dizziness and sweating. He was assessed by the
mobile medical team on site as being agitated, hypotensive (BP: 96/74mmHg)
and with generalized wheezing on chest auscultation. Aggressive fluid
resuscitation, nebulized salbutamol and IV corticosteroids improved his status on
route to the ER; he was also treated with acetylsalicylic acid 250mg and
sublingual isosorbide dinitrate 5mg. Epinephrine was not given. ECG confirmed
NSTEMI with an elevated troponin I (0.59ng/ml). Serum tryptase was not
measured. He was admitted to the Coronary ICU and cardiac catheterization
showed mild coronary artery disease. He recalled a previous reaction to
diclofenac, with immediate generalized pruritus. The patient recovery was
uneventful. He was then referred to our Drug Allergy Unit. Oral challenge with
meloxicam 15mg was negative and he was instructed to avoid NSAID’s other
than meloxicam.
How this report contributes to current knowledge
MI in the setting of anaphylaxis is underreported. Clinicians should be aware of
this possible complication even in patients without cardiovascular risk factors in
order to diagnose and treat it early. Also, the WAO Anaphylaxis guidelines
recommend a minimum 4 hours observation period after anaphylaxis, 8-10 hours
if there is respiratory or cardiovascular compromise during the reaction. This
allows not only for detection and treatment of biphasic reactions, but also of
secondary cardiovascular events.
P08 Perioperative Anaphylaxis Audit: Royal Melbourne Hospital
Katherine Nicholls1, William Lay2, Olivia Smith2, Christine Collins1, Gary
Unglik1, Kymble Spriggs1, Priscilla Auyeung1, Jeremy McComish1, Jo A Douglass1
1. Department of Immunology and Allergy, The Royal Melbourne Hospital,
Parkville, Australia
2. Department of Medicine, University of Melbourne, Parkville, Australia
Introduction
Perioperative anaphylaxis (PA) is a medical emergency, with potential for
mortality. Skin testing (ST) of agents used in the perioperative period is
considered the gold standard for the identification of likely causative agents1.
Neuromuscular blocking agents (NMBA) (58%), antibiotics (12-15%) and latex
(16-19%) are the most commonly implicated causative agents1,2. Chlorhexidine
allergy is also described although its prevalence is not well established and likely
underreported3,4.
We conducted a retrospective audit of all patients who underwent ST and specific
IgE testing (SpIgE) for investigation of a perioperative allergic event. We sought
the proportion of patients who had a likely agent detected and the prevalence of
likely causative agents in our cohort.
Method
Medical histories were reviewed for all patients referred for PA who underwent
testing in our centre over a 2-year period from September 2013 to August
2015. Data collected included severity grading5, acute elevation in Mast cell
tryptase (MCT) (>12ng/mL or >135% basal level), and causative agent indicated
by the presence of a positive ST or SpIgE to NMBA, latex, antibiotics or
chlorhexidine. Results are expressed as n (%) and comparisons performed by
Fisher’s exact test.
Results
Of 47 patients identified during this period, ST was positive in 22 (47%), with
NMBA and beta-lactam antibiotics accounting for 10 (42%) and 7 (29%) of
positive results respectively. Of the 27 patients with MCT results, 14/19 (73%)
patients with an acute MCT rise had positive skin or SpIgE tests, compared with
only 1 (13%) of 8 patients with no reported MCT rise (P<0.01). Over the same
period, 4 patients (18%) had positive SpIgE to chlorhexidine (range 0.4355.8kUa/L). Reactions graded as severe (Grade 3) were associated with an
increased proportion of positive ST (16/31, 52%) compared with Grades 1 and 2
(6/16, 38%), however this result did not reach statistical significance.
Conclusion
The prevalence of causative agents reflects current literature, with an increased
proportion of reactions to antibiotics, and decreased proportion to latex. Our
audit indicated a significantly higher proportion of positive ST in those with
acutely elevated MCT. In our cohort, chlorhexidine appeared to be a common
allergen.
References: 1 Mertes et al. JACI 2011;128:366-73, 2 Ebo et al. Allergy
2007;62:471-87, 3 Garvey et al. JACI 2007;120:409-415, 4 Calogiuri et al. J
Allergy Ther. 2013;4, 5 Brown et al. JACI 2004;114:371-6
P09 Recurrent peri-operative anaphylaxis - a perfect storm
Jonny G Peter, Paul Potter
University of Cape Town, Cape Town, South Africa
Introduction
Allergy work-up to identify the causative agent in patients experiencing perioperative anaphylaxis is challenging. Patients have multiple exposures over a
short time period; Paper-based records from remote hospitals are often
unavailable to the allergist; and diagnostic testing for many drugs is either
unavailable or sub-optimal.
Case Description
A 56-year-old man with debilitating osteoarthritis required hip replacements in
order to work. He had no chronic medical co-morbidities, but labeled penicillin
allergy following a childhood reaction during prolonged antibiotics for
osteomyelitis. He was referred for testing after three operations in a remote
private South African hospital. Peri-operative anaphylaxis, confirmed with serial
tryptase measurement, occurred in the 1st and 3rd surgeries. Possible offending
agents included: propofol, midazolam, bupivacaine, fentanyl, clindamycin and
cyclokapron. Apparently, in the uneventful 2nd surgery, the drugs were the same
except cyclokapron was omitted. Cleaning agents used were unknown. In vitro
specific IgE testing was negative to latex but elevated (5.49kUA/l) for
chlorhexidine; Skin testing was positive with chlorhexidine and intradermal
testing generated systemic symptoms and required treatment. CAST ELISA
testing was negative to propofol and bupivacaine. Clindamycin in vitro testing
was unavailable and in vivo testing is not recommended. The likely offending
agent was chlorhexidine, and the patient was anxious to return to work, thus,
although each anesthetic chart was not available for detailed review, repeat
surgery proceeded. Unfortunately, he experienced recurrent anaphylaxis despite
a chlorhexidine free theatre. Several months later the anesthetic charts from all
four operations were acquired, and it was clear that an additional offending agent
was likely clindamycin. Avoidance of both clindamycin and chlorhexidine resulted
in a safe surgery. Subsequent testing allowed the patient to be ‘de-labeled’ as
penicillin allergic.
How this report contributes to current knowledge
Dual sensitivity is described in about 2% of peri-operative anaphylaxis cases.
Thus, even if a possible causative agent is identified, it remains mandatory a
conduct a detailed review of all anesthetic charts; however, this can pose a
major challenge in countries were records remain paper-based. The use of
alternative drugs in patients carrying a penicillin allergy label can carry
significant morbidity.
Poster Walk 2: DH regions and patient groups
(P10 – P19)
P10 A Rare Presentation Of Amoxicillin Allergy In A Young Child
Fabrícia Carolino, Eunice Dias De Castro, Josefina R Cernadas
Serviço de Imunoalergologia, Centro Hospitalar São João E.P.E., Porto, Portugal
Introduction
Fixed drug eruptions (FDE) are characterized by well-demarcated skin and/or
mucosal lesions beginning a few minutes to several hours after drug exposure
and that reappear at the exact location on re-exposure to the offending drug.
Aminopenicillins are among those drugs most commonly associated with FDE.
Non-pigmenting FDE (NPFDE) is an FDE type that leaves no residual
pigmentation.
Case Description
The authors report the case of a non-atopic 5 years-old boy, presenting two
reproducible episodes of cutaneous lesions (erythematous pruritic plaques)
located to the genital area, occurring a few hours after medication with
amoxicillin for upper airways infection. The antibiotic was changed to a non-betalactam drug with progressive symptoms resolution, leaving no residual skin
pigmentation. There was a previous exposure to amoxicillin with tolerance. After
the second episode, the child has already been medicated with a second
generation cephalosporin (cefaclor) and tolerated this drug. Following the first
evaluation in our Allergy Department, the child was assessed in the Drug Allergy
Unit. No skin tests (intradermal with late reading) were performed due to agerelated constraints. A controlled re-challenge with oral amoxicillin in the agerecommended intake-dose was performed. Five hours after the end of oral
challenge, the child began to develop a cutaneous exanthema and returned to
the hospital for medical assessment as it was recommended. On physical
examination, we observed swelling and erythematous plaques affecting the
inferior part of penis, the scrotum and the perianal region; the child’s mother
confirmed that the lesions presented the same location as that of the two
previous episodes. Taking these findings into account, the final diagnosis was
multiple fixed drug eruption. The child was treated with oral antihistamine
and corticosteroid, with complete resolution in 3 days.
How this report contributes to current knowledge
To the authors’ knowledge, this is the third case reported of this type of drug
eruption in the paediatric age.
P11 Adverse Drug Reactions In Children: Antibiotics Or Virus?
Ana Sofia Moreira1, Carmo Abreu2, Eva Gomes2
1. Centro Hospitalar Vila Nova Gaia e Espinho, Vila Nova Gaia, Portugal
2. Centro Hospitalar do Porto, Porto, Portugal
Keywords: Children, Drug Reactions
Introduction
About 10% of portuguese children report to have had at least one adverse
reaction to drugs and 6% to be allergic to at least one drug, being the antibiotics
the most frequent medication implicated. The diagnostic investigation reveals that
in 90% of cases drug hypersensitivity is not confirmed, what is thought to be
related to the high prevalence of infectious/viral rashes in childhood. Our aim was
to evaluate the main reasons for referral to our pediatric drug allergy clinic,
characterize the reactions mentioned by patients, particularly with regard to their
sazonality and to analyse the results of the diagnostic investigation performed.
Method
Retrospective analysis of medical records from the pediatric patients followed in
our department, in the last 6 years, due to suspected drug hypersensitivity.
Results
We studied 364 children of whom 200 (55%) were male. The median age at the
time of the suspected reaction was 3.5 years (6 months-17 years). Antibiotics
were the suspected drug in 84% of cases (n=305). In 75% (n=274) of patients
the symptoms reported were only cutaneous (maculopapular eruptions or
urticaria) and in 72% (n=262) of cases the reaction was nonimmediate. Drug
hypersensivity was confirmed in 10 patients (3%). The month in which the drug
reaction occurred was identified by 51% (n=184) of patients. Sixty % of the
reactions occurred during winter-spring months. Viral serologies were performed
on 74 patients who reported a recent reaction and positive results for at least one
of the viruses studied were obtained in 14 patients (19% - IgM) and 48 patients
(65% - IgG).
Conclusion
The majority of children studied due to suspected drug hypersensitivity reported
cutaneous symptoms and nonimmediate reactions. Most reactions occurred before
3 years of age, which according to the literature, concerns the age when
infectious rashes are more frequent. We verified a seasonal pattern in the
occurrence of the suspected drug reactions that is similar to that described for the
most common viral infections in childhood, while the peak for antibiotic
consumption has been reported in autumn. Confirmation of hypersentisitivity to
the suspected drug was possible in 10 of 364 patients, while a possible viral
etiology was documented in 14 of 74 patients. Our findings reinforce the idea that
many of the cutaneous reactions which motivate the study in our department are
probably caused by infections and not by drug hypersensitivity.
P12 Allergic Reactions In Invasive Medical Procedures
Bárbara Kong Cardoso, Elza Tomaz, Sara Correia, Filipe Inácio
Hospital de S.Bernardo - Centro Hospitalar de Setúbal, Setúbal, Portugal
Keywords: Perioperative Allergy, Invasive Medical Procedures, Drug
Hypersensitivity
Introduction
Surgery associated allergic reactions have been extensively studied and culprit
agents have been pointed on several reports. Nevertheless last decade changes in
pharmacological protocols resulted in the increase of possible implicated drugs. In
the other hand, other invasive procedures (diagnostic/therapeutic) have been
increasing in frequency and are also related to allergic events. Our aim was to
seek for new agents involved in perioperative allergy as well as characterize
reactions occurring due to other invasive procedures
Method
We reviewed the medical records of 28 patients referred to our clinic for allergic
reaction associated to an invasive procedure in the last two years regarding
administered drugs, type of reaction and results of the allergological workup.
Results
In our study group, 21 were female and 7 male, mean age was 54.7 years (2 84).
Fourteen were studied for procedures with general anesthesia related adverse
events: 6 anaphylatic reactions, 6 urticaria/angioedema, 1 bronchospasm and 1
hypotension. Positive relevant results were obtained in 13 patients: 1 skin prick
test (SPT) to metamizol, 2 intradermal skin tests (IDT) to midazolam, 1 to
tramadol, 3 to ondansetron, 1 to rocuronium, 1 to atracurium, 2 to vecuronium, 2
to metamizol, 1 basophil activation test (BAT) to metamizol. One patient was
positive to both to atracurium and vecuronium and one patient had no positive
tests.
In 9 patients reactions were associated to invasive procedures with local
anesthesia. Positive results were one IDT and BAT to verapamil (anaphylaxis) and
one patch test to iodixanol (maculopapular rash) in 2 patients submitted to
coronary angiography. Six patients with adverse reactions during dental
treatment and one during a carpal tunnel surgery had no positive tests.
Five patients had been submitted to procedures without use of any anesthetic: 1
with local erythema after an esteroid intra-articular infiltration had a positive
patch test to betamethasone dipropionate; 1 with an anaphylactic reaction during
a colonoscopy had a positive BAT to metamizol used as analgesic; 1 with acute
urticaria after contrast injection for a thyroid TC had IDT positive to iomeprol.
Two patients had a negative workup.
Conclusion
Comparing to previous published series ondansetron seems to be emerging as an
important agent in perioperative allergy.
Invasive procedures other than major surgeries are associated to allergic
reactions both immediate and non-immediate, some of them being severe.
P13 Antibiotic Allergy In Children: Room For Improvement
Annabelle Arnold1, Natasha Bear2, Kristina Rueter3, Grace Gong4, Michael
O'Sullivan5, Saravanan Muthusamy1, Valerie Noble1, Michaela Lucas6
1. Department of Immunology, Princess Margaret Hospital, Perth, Australia
2. Telethon Kids Institute, Department of Clinical Research and Education,
Princess Margaret Hospital, Perth, Australia
3. Department of Immunology, Department of Clinical Research and
Education, Princess Margaret Hospital, Telethon Kids Institute, Perth,
Australia
4. Department of Immunology, PathWest Laboratory Medicine WA, Princess
Margaret Hospital, Perth, Australia
5. Department of Immunology, Princess Margaret Hospital, PathWest
Laboratory Medicine WA, Fiona Stanley Hospital, School of Pathology and
Laboratory Medicine, University of Western Australia, Perth, Australia
6. Department of Immunology, Princess Margaret Hospital, Sir Charles
Gairdner Hospital, PathWest Laboratory Medicine WA, School of Medicine
and Pharmacology, School of Pathology and Laboratory Medicine, University
of Western Australia, Institute of Immunology and Infectious Diseases,
Murdoch University, Perth, Australia
Keywords: Allergy, Antibiotic, Anaphylaxis
Introduction
Beta-lactam antibiotics remain one of the most effective treatments of bacterial
infections and are the most frequently prescribed antibiotic in children. Allergic
reactions to these antibiotics are common. Nevertheless, strategies for peadiatric
antibiotic allergy testing and management remain poorly defined, including issues
around the need for skin testing prior to oral provocation challenges (OPC; 2dose) and the value of prolonged courses with the culprit antibiotic after the
successful administration of an initial supervised dose.
Method
To address these issues, we performed a retrospective cross-sectional analysis of
children (6m-16yrs) with an antibiotic allergy label who presented to a tertiary
pediatric hospital in Western Australia from 2006 to 2015. Data collection
included results of skin prick (SPT), intradermal testing (IDT) and OPCs, outcome
of 5-day antibiotic courses, type of initial reaction, confounding illnesses and coexisting allergies. The data was analysed using Mann-Whitney U for continuous
data and Fishers exact test for categorical data.
Results
We performed 207 beta lactam antibiotic tests in 172 children. In 82 (39.6%)
cases OPCs were performed without preceding skin testing (Group 1); three OPCs
(3.7%) were unsuccessful with 1 child with anaphylaxis. In 125 (60.4%) cases
skin testing was performed (Group 2). Of these, 22 cases (17.6%) were positive
by SPT or IDT; these children were deemed to have confirmed antibiotic
allergy. The remaining 103 cases proceeded to OPC; 4 (3.8%) reacted to OPC,
including 2 children with anaphylaxis. Finally, 152 cases (from Group 1 or 2)
received a 5 day course with the culprit antibiotic. This resulted in a rash in 9
children (5.9%) during the course. In both groups confounding illnesses, initial
reaction, gender and co-existing allergies did not predict testing outcome.
Conclusion
In our cohort, the rate of allergy confirmed by skin testing was significantly higher
than for those who underwent a direct challenge (17.6% versus 3.7%). The rate
of reactivity to OPC was comparable for Group 1 and 2. These data further
supports that performing direct supervised OPC with the culprit drug in children
may be safe and potentially may avoid the need for resource intensive skin
testing. Extended courses with the culprit drug should be considered, allowing
confirmation of non-immediate reactions such as cutaneous reactions.
P14 Drug Hypersensitivity Reactions In Children And Results Of
Diagnostic Evaluation
Neringa Buterleviciute, Odilija Rudzeviciene
Vilnius University Faculty of Medicine Centre of Children Pulmonology and
Allergology, Vilnius, Lithuania
Keywords: Drug Hypersensitivity, Chidren, Clinical Pattern, Diagnostics
Introduction
Patients or parents reported drug allergy in children is more common than the
true drug allergy incidence. The aim of our study was to evaluate the clinical
pattern of patient/parent reported drug hypersensitivity reactions and results of
diagnostic evaluation.
Method
15 children who were tested for drug allergy in 2015 were included in the study:
8 boys (53.3%) and 7 girls (46.7%), age range 1-15 years. We analysed causes,
clinical pattern of reported drug hypersensitivity reactions and results of
diagnostic evaluation.
Results
26 drug hypersensitivity reactions were reported. Three drug hypersensitivity
reactions were reported in 4 children, two reactions – in 3 children. The main
suspected drugs were antibiotics 17 (65.4%), NSAIDs – 5 (19.2%) cases, local
anaesthetics – 4 (15.4%) cases. Amoxicillin was the most frequently suspected
drug (6 (23.1%) cases). 8 (30.8%) reactions appeared during 1 hour. Skin
symptoms were reported in 24 (92.3%) cases: maculopapular rash – 20 (76.9%),
angioedema – 5 (19.2%) cases. Respiratory and cardiovascular symptoms were
reported in 2 cases (7.7%). Drug provocation test was positive only for 1 child,
who experienced angioedema after nimesulide and ibuprofen intake, and drug
provocation test was positive to ibuprofen.
Conclusion
The most common suspected drugs were antibiotics, especially amoxicillin. Skin
was the most frequently affected and maculopapular rash was the most common
symptom. Drug provocation test was positive only for 1 patient.
P15 Nonimmediate Cutaneous Drug Reactions In Children: Are Skin Tests
Required?
Ana Sofia Moreira1, Carmo Abreu2, Eva Gomes2
1. Centro Hospitalar Vila Nova Gaia e Espinho, Vila Nova Gaia, Portugal
2. Centro Hospitalar do Porto, Porto, Portugal
Keywords: Skin Tests, B-Lactams, Diagnosis
Introduction
Delayed urticaria and maculopapular eruptions associated with antibiotics are the
most common reasons for referral to our pediatric drug allergy clinic. In this
context, several studies point to the limited usefulness of skin tests, even to blactam antibiotics, with some authors advocating the use of drug provocation test
without the need for other previous diagnostic procedures. Our aim was to
describe the cases followed in our department in which this diagnostic approach
was used (exclusive drug provocation test).
Method
Retrospective analysis of medical records from children referred to our drug
allergy clinic due to suspected hypersensitivity to antibiotics, who reported
nonimmediate cutaneous reactions (urticaria or maculopapular eruption) without
signs of severity or systemic involvement. All children underwent provocation test
with the suspected drug without conducting previous skin tests. The drug
provocation test was extended to include the number of days of treatment
reported at index reaction. Data was collected regarding gender of patients, age
at the drug reaction, drug involved, symptoms reported on the reaction and
results of the drug provocation test.
Results
We evaluated 213 children of which 50% (n= 107) were male, with a median age
of 3 years (6 months-17 years) at the time of reaction. In 97% (n=206) of the
cases the involved antibiotics were b-lactam (amoxicillin-clavulanic acid in 92
patients, amoxicillin in 89 and cephalosporins in 5 cases). Only 3 children had
positive drug provocations tests. In all cases the symptoms were similar to those
previously reported and easily controlled with oral antihistamine.
Conclusion
Performing an exclusive drug provocation test in children with suspected
hypersensitivity to antibiotics, who present with nonimmediate cutaneous
reactions without signs of severity, proved to be a safe and effective approach.
P16 Pediatric Patients With A History Of Penicillin Allergy And A Positive
Penicillin Skin Test May Not Be At An Increased Risk For Multiple Drug
Allergies
Sara May1, Thanai Pongdee2, Miguel Park3
1. University of Nebraska Medical Center, Omaha, United States
2. Mayo Clinic, Jacksonville, United States
3. Mayo Clinic, Rochester, United States
Keywords: Penicillin Allergy, Multiple Drug Allergies, Risk
Introduction
Patients with a sulfonamide allergy or penicillins (PCN) may be at increased risk
for reactions to other drugs. However, the studies were conducted in adults
without PCN skin testing (PST) to confirm a PCN allergy. We conducted a study to
determine if pediatric patients with a history of PCN allergy and a positive PST
were at an increased risk for multiple drug allergies.
Method
Children (< 18 years) with a history of PCN allergy were evaluated with PST and
reviewed for basic demographic, PST results, and other medication allergies listed
in the allergy module in the electronic medical record. A univariate logistic
regression analysis was employed to calculate the odds ratio (OR) and the 95%
confidence interval (CI). P-value of 0.05 or less was considered statistically
significant. The Institutional Review Board (IRB) approved the study.
Results
778 children underwent penicillin skin test. 703 (90.4%) of 778 patients had a
negative PST, 66 (8.5%) were positive, and 9 (1.1%) were equivocal. The overall
mean ± standard deviation (SD) age of the study group was 5 ± 3.5
years. Three hundred and sixty seven (47.1%) were females. 703 children
(90.4%) had a negative PST, 66 patients (8.5%) positive PST, and 9 (1.1%)
equivocal PST. 181 (23%) of 778 patients reported a history of multiple drug
allergies. Among the 181 patients reporting a history of multiple drug allergies,
81 (45%) were female and 100 (55%) were male. Males were 1.6 times (95% CI
.8-1.6, p = 0.5) more likely than females to report multiple drug allergies,
although not statistically significant. 14 (21%) of 66 patients with a positive PST
reported multiple drug allergies compared to 167 (23%) of 712 (p = 0.76)
patients with a negative PST. Those patients with multiple drug allergies and a
history of PCN allergy, cephalosporin [15% (114 of 778)] was the most common
medication listed in the allergy module. Other medication listed in the medication
allergy modules were 10% (79) macrolide antibiotics, 9% (71) sulfonamides,
0.4% (3) quinolones, and 1% (9) nonsteroidal anti-inflammatory drug (NSAIDS).
Conclusion
PCN allergic pediatric patients may not be at an increased risk for multiple drug
allergies. Among patients with a history of PCN allergy, cephalosporin, macrolide
antibiotics and sulfonamide antibiotics were the most common drug allergies
listed in the medication allergy module.
P17 Proved Hypersensitivity To Drugs According Data Of Vilnius
University Hospital Santariskiu Klinikos
Linas Griguola1, Arturas Vinikovas1, Simona Kašinskaite2, Violeta Kvedariene2
1. Vilnius University, faculty of Medicine, Vilnius, Lithuania
2. Center of Pulmonology and Allergology, Clinic of Infectious, Chest diseases,
Dermatology and Allergology, Vilnius University Hospital Santariskiu
Klinikos, Vilnius, Lithuania
Keywords: Drug, Hypersensitivity
Introduction
Adverse reactions to drugs are common problem, but true hypersensitivity to
drug is rare.
Aim of the study: to investigate true hypersensitivity reactions among female
and male with suspicion of drug allergy.
Method
755 patients with suspicion of allergic reactions to drugs were addressed to
consultations in Pulmonology and Allergology center by general practitioners.
Patients were divided into groups by sex and suspected drugs: I – Antibiotics
(AB), II – NSAID, III – Other. Each category was divided into subcategories: IA
beta-lactam AB, IB Other AB; IIA ASA, IIB acetaminophen, IIC other NSAID; IIIA
local anesthetics (LA), IIIB iodine containing contrasts (ICC), IIIC Other.
Results
755 patients with 980 cases of suspected drug allergy were investigated:
618(81.85%) females with average age 48.4(SD ± 15.2) and 137(18.15%) males
with average age 47.6(SD ± 18).
Female group had 821(83.8%) adverse reactions to drugs. 199(24.2%) reactions
to I (AB): 151(75.9%) were to beta-lactams, from all tested 36(16.9%) were true
hypersensitivity; 46(23.1%) reactions were to other-AB, from all tested reactions
4(9.1%) were proved. 2(1%) cases were not tested. Accordingly: II (NSAID) had
306(37.3%) reactions: to aspirin - 56(18.3%), 4(9.6%) were proved; to
acetaminophen - 47(15.3%), 12(40%) were proved; IIC (Other-NSAID) – 203
(66.3%), 29(19.2%) were proved. III (Other) had 316(38.5%) reactions: IIIA
(LA) – 99(31.3%), 1(1.5%) was proved; IIIB (ICC) – 20(6.3%), 2(15.5%) were
proved; IIIC (Other) – 197(24%), proved - 19(15.4%).
Male group had 159(16.2%) adverse reactions to drugs. I (AB) had 30(18.8%)
reactions: IA (beta-lactam) - 25(83.3%), from all tested reactions 7(21.2%) were
proved. Accordingly: IB (other-AB) – 5(16.6%), all negatives. II category had
77(48.4%) reactions: to aspirin - 17(22%), 2(16.6%) were proved; IIB
(acetaminophen) – 18(23.4%), 2(11.8%) were proved; IIC (other-NSAID) –
42(54.5%), DPTs proved 2(6.9%). III category had 48(30.2%) reactions: IIIA
(LA) – 16(33.3%), 1(7.7%) was proved; IIIB (ICC) – 6(12.5, all negatives; IIIC
(Other) – 26(54.2%), DPTs proved 4(22.2%). NA - 4(2.5%).
Conclusion
Of all reactions true hypersensitivity were proved for: antibiotics – 15.6%,
NSAIDs – 20.2%, other drugs - 11.1% in female group and 20% for AB, 10.3%
for NSAIDs, 13.8% for other drugs in male group.
P18 Self-Reported Prevalence Of Drug Hypersensitivity Reactions Among
Students In Celal Bayar University, Turkey
Ayse Aktas, Suheyla Rahman, Huseyin Elbi, Beyhan Cengiz Ozyurt
celal bayar university, Manisa, Turkey
Keywords: Drug Hypersensitivity, Prevalence,
Introduction
Drug hypersensitivity reactions (DHR) is defined "unwanted and harmful
reactions occurring to drugs prescribed dose" by World Health Organization
(WHO). DHR is an important health problem because of causing life-threatening
condition, extending the length of stay in hospital and increasing the cost of
treatment.
The aim of this study was to determine the prevalence of self-reported DHR
among students at the university.
Method
A structured questionnaire was carried out to students of Celal Bayar University in
Manisa, Turkey.
Results
2086 students have participated in our study. 1217 (58.3%) of them were
women, 869 (41.7%) were male. The mean prevalance of self-reported DHR was
5.3% (111/2086). Drug allergy incidence of students (male / female) was 3.5%
and 6.7%, respectively (p<0.001). The most common allergic reactions were rash
52.2%, cardiovascular reactions 12.6% and respiratory reactions 11.7%.
Aforementioned two systems involvement were %23.4. The most frequently
involved drugs were antibiotics 52.2% (n:58) and analgesics 24.3% (n:27).
Conclusion
The diagnosis of drug allergy is based on a detailed history of the onset of
symptoms/signs’ relationship between the appearance of symptoms and drug
use. Misinterpretations just based on the DHR story can effect the individual
treatment options. A definitive diagnosis can be easily reachable with a complete
clinical history, standardized skin tests and drug provocation tests. Therefore we
can recommend that doctors should be more informed about the managements of
DHR due to self-reported DHR is highly prevalant just like shown in this study.
P19 Severe Drug Hypersensitivity Reactions In Pediatric Age
Ozlem Cavkaytar, Betul Karaatmaca, Pinar Gur Cetinkaya, Saliha Esenboga, Umit
M. Sahiner, Bulent E. Sekerel, Ozge Soyer
Hacettepe University School of Medicine Department of Pediatric Allergy, Ankara,
Turkey
Keywords: Drug Hypersensitivity, Anaphylaxis, Child, Pediatric
Introduction
Epidemiologic data on drug induced anaphylaxis (DIA) in pediatric age is lacking.
The aim of this study is to define the actual rate of drug induced anaphylactic
reactions in childhood together with the severity and culprit drug patterns.
Method
Patients with a history of drug hypersensitivity reaction (DHR) referred between
January 2012-December 2015 were included. After filling out an European
Network for Drug Allergy (ENDA) questionnaire, initial skin tests and/or
provocation tests were performed for the offending drug. The severity of
anaphylactic reactions was determined as mild, moderate and severe according to
EAACI guidelines on anaphylaxis in childhood.
Results
Among 627 children and adolescents referred due to a DHR, diagnostic work-up
was completed in 532 patients. 103 (19.3%) of them [54.4% male, median age
(interquartile range; 9.6 years (5.3-13.3)] had anaphylaxis in the history and
diagnostic tests revealed that 75 (14.1% of all evaluated patients, 72.8% of all
patients with a DIA) of them were actually hypersensitive to the offending drug.
The culprit drugs responsible from actual DIA were antibiotics (36%), NSAIDs
(22.7%), chemotherapeutics (20%), biologicals(6.7), anesthetic agents(5.3%),
enzyme therapy(4%) and others. Majority of the patients with actual DIA
reported moderate (38.7%) and severe (37.3%) drug induced anaphylactic
reactions. History of chronic disease (44% vs. 17.9%, p=0.014), concomitant
intake of other drugs regularly (40% vs. 7.1%, p=0.001), cyanosis (23% vs.
3.6%, p=0.022) and hospitalization (56.2 vs. 17.9, p=0.001) due to the
suspected DIA and use of chemotherapeutics as the culprit drug (20% vs. 0,
p=0.01) were more frequent, whereas use of antibiotics was less frequent (71.4%
vs. 36%, p=0.001) in patients with actual DIA compared to nonhypersensitive
patients. Atopic disease, atopy or family history of atopy or drug hypersensitivity
did not have an impact on actual DIA. It is important to note that actual DIA was
more frequent in children younger than 10 years of age compared to older
adolescents (81.5% vs. 63.3%, p=0.038).
Conclusion
During childhood, any history of DIA reaction may not be an actual DHR, however
young age, existence of chronic disease and use of chemotherapeutics might
point out the actual drug induced anaphylaxis in children and adolescents.
Poster Walk 3: Desensitisation (P20 – P28)
P20 A Protocol For Desensitisation To Valaciclovir
Celia Zubrinich, Bianca Tong, Mittal Patel, Michelle Giles, Robyn O'Hehir, Robert
Puy
Alfred Health, Melbourne, Australia
Introduction
We report a protocol for desensitisation to valaciclovir.
Case Description
A woman in her 40s developed generalised urticaria on the second or third day of
her initial course of acyclovir (administered five times daily) for newly diagnosed
genital herpes. The urticaria continued to cause distress despite substitution to
valaciclovir for a further few days. Antiviral medication was ceased. The rash
resolved over two weeks with the use of anti-histamines. For more than a decade
since then, she has experienced frequent and prolonged confirmed herpetic
recurrences, more often present than not. The attacks had a marked viral
prodrome and significantly affected her lifestyle.
Recurrent genital herpes may be treated with suppressive antiviral therapy if
frequent. Supervised direct challenge to valaciclovir was an option but
desensitisation was favoured because it required a single clinic visit and, of
relevance to the patient, likely entailed less risk. We identified reports of
desensitisation to acyclovir but not valaciclovir. The final treatment dose of
acyclovir (usually 400 mg) differs from that of valaciclovir (500 mg). Acyclovir
therapy requires multiple doses per day, whereas valaciclovir requires only a
single daily dose. We developed and present a 14-dose oral desensitisation
protocol that was administered over 3.5 hours (Figure 1). The first 10 doses were
valaciclovir in suspension and the final four doses were prepared from a 500mg
tablet. The patient tolerated the procedure with no ill effect. There has not been
a single herpetic recurrence in the twelve months since the treatment
commenced.
How this report contributes to current knowledge
Desensitisation to valaciclovir may be performed where suppressive therapy for
herpes is indicated.
P21 A Rare Case Of Desensitization To Modafinil
Josefina Cernadas, Luís Amaral, Fabrícia Carolino
Serviço de Imunoalergologia, Centro Hospitalar de São João E.P.E., Porto,
Portugal
Introduction
Modafinil is a 2-benzhydrylsulfinylethanamide molecule, belonging to a class of
medications called wakefulness promoting agents used to treat excessive
sleepiness caused by narcolepsy (a condition that causes excessive daytime
sleepiness) or shift work sleep disorder. Another use is to prevent excessive
sleepiness caused by obstructive sleep apnea/hypopnea syndrome. It acts as a
blocker of a type of molecule called the dopamine transporter. Rare occurrences
including severe cutaneous adverse reactions, as erythema multiforme, SJS, TEN
and DRESS, affecting adults and children and probably allergic, have been
reported. Rare cases of angioedema and multi-organ hypersensitivity reactions
have also been described.
Case Description
The authors describe a case of a 27 year-old male with the diagnosis of
narcolepsy medicated with modafinil 100 mg in an increasing dosage. Four days
after beginning the medication, he complained of generalized pruritus,
maculopapular exanthema and angioedema of upper and lower limbs. No
analytical changes were found in the acute phase. He was treated with
intravenous corticosteroid and antihistamines and, four days after complete
recovery, the drug was re-introduced with reproducible signs and symptoms
arising twelve hours after the intake of 100 mg of modafinil. Because this was
the only therapeutic option for the patient he was referred to our Allergy
Department for desensitization. A suspension of 1mg/ml (100mg/100ml) was
prepared and a “tailor made” desensitization protocol was started with an initial
dose of 1 mg, followed by doubling doses, taken with one hour intervals. The
cumulative dose reached on the first day was 15 mg, 85 mg on the second and
100 mg on the third and fourth days. For safety reasons, 100 mg/day were taken
in the first week followed by an increase, to the intended doses (Neurology
prescription) in the following weeks: 100+100 mg on the second week,
100+200 mg on the third week and 200+200 mg on the fourth and on, as
chronic treatment. After we have achieved tolerance to a dose of 100 mg, the
slowly increase to the targeted dose of 200 mg twice a day was well tolerated.
The patient is still on the same therapeutic scheme with no further reactions.
How this report contributes to current knowledge
As far as we know this is the first case describing a desensitization protocol to
modafinil.
P22 A Sixteen-Day Desensitization Protocol In Delayed Type
Hypersensitivity Reactions To Oral Drugs
Semra Demir, Asli Gelincik, Muge Olgac, Raif Caskun, Derya Unal, Bahauddin
Colakoglu, Suna Buyukozturk
Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
Keywords: Delayed Type Hypersensitivity Reactions, Desensitization
Introduction
Although desensitization in immediate type hypersensitivity reactions due to
chemotherapeutics is well described and standardized for many drugs, common
protocols in delayed type hypersensitivity reactions (DHR) are not standardized.
Our aim is to evaluate the usefulness of the 16-day desensitization protocol
which we had recently described for capasitabine in DHRs caused by various oral
chemotherapeutic drugs.
Method
We applied our slow desensitization protocol which started with 1/100 of the
target dose and was completed in 16 days with slow incremental doses in
patients who had experienced DHR due to various oral chemotherapeutic drugs.
Results
Four patients (2 female, 2 male) who were referred to our clinic for
desensitization were included. The mean age was 55±22,25 years. The culprit
drugs were pazopanib, nilotinib and lenalidomide. The mean reaction time after
the initiation of the drug was 7,5±2,08 days and the reaction types were
maculopapular rush (MPR) in 2 patients and generalized morbiliform rushes
(GMR) in 2 patients. Two patients who had experienced MPR caused by
lenalidomide completed the protocols without any reactions. However, the other
two patients developed pruritus and rush on the 9th and the 15th days of the
desensitization protocols. After the reactions were treated with
methylprednisolone, the doses were decreased to the last tolerated doses and
gradually increased afterwards. One of them completed the desensitization in 28
days. However, the second patient could tolerate almost the ¾ of the targeted
dose.
Conclusion
This sixteen-day protocol seems to be a useful guide for the desensitization in
delayed type hypersensitivity reactions especially in MPR in oral
chemotherapeutics. However, the protocol can be modified in some patients.
P23 Desensitization To Intravenous Etoposide Using A 12 And A 13-Step
Protocol. Two Cases Report.
Olga Vega Matute1, Amalia Bernad1, Gabriel Gastaminza1, Roselle Madamba1,
Carlos Lacasa2, MJ Goikoetxea1, Carmen D'Amelio1, Jose Rifón3, Nicolas
Martínez3, Marta Ferrer1
1. Departament of Allergy and Immunology Clínica Universidad de Navarra,
Pamplona, Spain
2. Department of Pharmacy Clínica Universidad de Navarra, Pamplona, Spain
3. Departament of Hematology Clínica Universidad de Navarra, Pamplona,
Spain
Introduction
Etoposide is a chemotherapy agent used to treat malignant conditions. Because
of the repeated use of this drug in within time intervals for cancer treatment,
there is a high chance as with any chemotherapeutic agent to induce
hypersensitivity reactions (HSR). It is reported to induce HSR in 6% of the
patients.
Case Description
We present two cases. First is a 7 year old female patient with acute myeloid
leukemia (AML). She had previously received 2 courses of treatment with
etoposide. In the second course, with the first administration she had a reaction
consisted with facial erythema and severe dyspnea. When evaluated in our
hospital, she needed treatment with etoposide for autologous stem-cell
transplantation. The second patient was an 8 year old male with refractory acute
lymphoid leukemia (ALL-B) that had received 6 doses of treatment with
etoposide. In the last dose, he reported pharyngeal obstruction and chest
erythema. When evaluated in our hospital, he needed salvage chemotherapy
containing etoposide followed by allogenic stem-cell transplantation.
We performed skin prick test with Etoposide, using commercially available drug
solution for intravenous use. In both patients the test was negative.
Because Etoposide was the most suitable chemotherapeutic option for both
patients, we decided to administer the drug using a desensitization
protocol. Castells (2) developed a protocol for desensitization to drugs with a 12
steps infusion of the target dose. In the first case we had to add 1 step to this
protocol because of the dose needed. She received premedication treatment and
400mg of Etoposide in a 13 steps protocol, twice in consecutive days. She had no
HSR, the transplantation went well and she is now in complete remission. In the
second patient we followed the 12 step protocol with premedication treatment
and the patient was able to receive the target dose (150mg). We did 3
desensitization protocols with the total dose, in 3 consecutive days. He had no
HSR and he continues in follow up in our hospital.
How this report contributes to current knowledge
Patients with HSR to etoposide, in which this drug is the most adequate
chemotherapeutic option for such a severe disease, the desensitization protocol
is a treatment that proved to be effective in order to administer the treatment.
P24 Drug Desensitisation In Oncology: The Experience Of An
Immunoallergology Department For 5 Years
Carmelita Ribeiro1, Emília Faria1, Cristina Frutuoso2, Anabela Barros2, Rosário
Lebre2, Alice Pego2, Ana Todo Bom1
1. Allergy and Clinical Immunology Department, Coimbra University Hospital
Center, Coimbra, Portugal
2. Oncology Department, Coimbra University Hospital Center, Coimbra,
Portugal
Keywords: Drug Desensitisation, Oncology,Chemotherapy Agents,
Platins,Taxanes
Introduction
Any cancer drug can potentially trigger a hypersensitivity reaction (HSR),
particularly chemotherapy agents and monoclonal antibodies. The more frequent
drugs inducing HSR are the platins (IgE-mediated reactions) and taxanes (nonimmunological reactions). Desensitisation protocols must be considered when
there is no valid and effective alternative treatment. This is especially relevant
for cancer patients who are thus able to continue their first line treatment.The
aim was to describe the experience of an Immunoallergology Department with
desensitization to chemotherapy agents.
Method
Retrospective review of charts of oncology patients desensitized in the
Immunoallergology Department of CHUC in the last 5 years.
Results
There were a total of 72 desensitisation procedures corresponding to 15 patients
treated (11 female) during the period in question, with a mean age of 56 years
(range: 28-73 years). The patients had ovarian cancer (8 patients), lung cancer
(3 patients), colon cancer (2), rectal cancer (1) and breast cancer (1). The HSR
were all with moderate to severe immediate reactions: rash, urticaria, laryngeal
stridor, bronchospasm, syncope and anaphylaxis (6 patients). Eleven patients
were desensitized to platins (carboplatin n=6, cisplatin=3, oxaliplatin n=2), three
to taxanes (docetaxel n=2, nabpaclitaxel n=1) and one to monoclonal antibodies
(panitumumab). In the total of 72 desensitisation procedures, the range of
desensitisation procedures for patient was 17 (maximum) to 2 (minimum)
treatmens with carboplatin. There were 5 desensitisation procedures in 2011, 12
in 2012, 19 in 2013, 18 in 2014 and also in 2015. In the 72 desensitisation did
not have any reaction in 59 procedures (82%) and in the others, the reactions
were milder than the initial HSR (only 1 patient had anaphylaxis in the third
desensitization with cisplatin). All patients received their daily programmed dose.
Five patients discontinued the desensitization programme (3 patients due to
progression of the oncological disease, 1 patient due to neurological toxicity and
another for anaphylaxis during de desensitization).
Conclusion
In the majority of patients, desensitization procedures allowed safe
reintroduction of chemotherapy agents in Immunoallergology centers with
experience. This approach must be considered by Oncologic doctors in the
treatment of specific oncologic patients with previous history of HSR to these
drugs.
P25 Filgrastim Anaphylaxis: A Successful Desensitization Protocol
Luis Amaral, Josefina Cernadas
Serviço de Imunoalergologia, Centro Hospitalar de São João E.P.E., Porto,
Portugal
Introduction
Filgrastim is a recombinant human granulocyte colony-stimulating factor (G-CSF)
and is used to prevent or treat neutropenia that is generally associated with
chemotherapy. Anaphylatic reactions to filgrastim are rarely reported and there
is only one published successful desensitization protocol in a patient with
immediate hypersensitivity to filgrastim.
Case Description
We describe a case of a 47-year-old woman with ductal breast carcinoma
receiving chemotherapy with doxorubicin, cyclophosphamide and docetaxel. She
developed chemotherapy induced neutropenia for which she was started on SC
filgrastim [300mcg] days after the chemotherapy cycle, given once a day, for 4
consecutive days. Ten minutes after the 4th dose of filgrastim, she developed
facial erythema, labial angioedema, dyspnea and colicky abdominal pain. These
symptoms quickly reversed spontaneously in 48h. Subsequently, filgrastim was
withdrawn and anaphylaxis work-up was done.
A 5-step desensitization protocol was performed using sequential doses
intravenously: 15, 30, 60, 80, 115 to a cumulative dose of 300 mcg diluted in
20mL of saline over approximately 3 hours. In the following day she received
300mcg in two steps with success and in 3rd day in one without any reaction.
How this report contributes to current knowledge
In summary, we present a successful desensitization protocol for filgrastim in a
patient with a previous life-threatening immediate hypersensitivity reaction.
P26 Galsulfase Hypersensitivity And Desensitization Of A
Mucopolysaccharidosis VI Patient
Luis Felipe Ensina, Carolina Aranda, Ines Camelo Nunes, Ana Maria Martins,
Dirceu Solé
Federal University of São Paulo, São Paulo, Brazil
Keywords: Omalizumab, Desensitization
Introduction
Mucopolysaccharidosis VI or Maroteaux-Lamy Syndrome (MPS VI) is a lysosomal
storage disorder caused by deficiency of arylsulfatase B. The enzyme
replacement therapy (ERT) with galsulfase is so far the only specific treatment
for MPS VI. Infusion-related reactions (IRR) to ERT can occur and can be severe,
precluding further ERT. However, the interruption of ERT can accelerate the
disease progression and precipitate earlier death. The aim of this study is to
report IRR to galsulfase in a MPS VI Brazilian patient, and his treatment
reestablishiment after desensitization.
Method
a 7y-old male started presenting symptoms such ias dyspnea and itch during his
44th infusion. No improvement was observed with premedication (corticosteroids
and antihistamines) in the folowing infusion. ERT were stopped for four weeks
and the patient underwent skin tests (prick and intradermal). Skin prick test was
performed using the straight concentration of galsulfase and Intradermal tests
with progressive dilutions. Skin tests were also performed in 10 healthy subjects
and in a MPS VI patient without IRR, to rule out a skin irritant effect, since skin
tests with galsulfase have not been standardized.
Results
Patient presented a positive skin prick test, suggesting an IgE-mediated reaction.
Therefore, a rapid desensitization protocol was generated. Three solutions ( each
250 mL 0.9% sodium chloride – 1:100, 1:10 and 1:1 respectively) were
delivered in 12 consecutive steps at an increasing infusion rate. Pre-medications
were used to block different allergy pathways. This protocol has succeeded for
six months, when during the 22th infusion he started to present wheals in the
beginning of the third bag. A new protocol was developed (four bags -16 steps),
but the patient still had symptoms. A 75mg omalizumab (Omab) monthly was
introduced. Ten days after the Omab, a new infusion using the same
desensitization protocol was performed with no reaction.
Conclusion
To our knowledge, we are the first group to use an adapted 12-step
desensitization protocol to galsufase with omalizumab. The protocol has shown to
be safe and effective for the patient receiving the enzyme in the recommended
dose. Management of these reactions with desensitization can provide first line
therapy and permit continued ERT.
P27 RAPID DRUG DESENSITIZATION WITH BIOLOGICALS: ONE-CENTER
EXPERIENCE WITH FOUR BIOLOGICALS
Sevim Bavbek, Resat Kendirlinan, Pamir Çerçi, Seda Tutluer, Sadan Soyyigit,
Zeynep Çelebi Sözener, Ömür Aydin, Reyhan Gümüsburun
Ankara University, Ankara, Turkey
Keywords: Biologicals, Rituximab, Infliximab, Rapid Drug Desensitization
Introduction
Rapid drug desensitization (RDD) induces a temporary tolerance to biological
drugs inducing hypersensitivity reactions (HSRs) but data are limited regarding
use of this outside of the USA.Therefore in this study we aimed to report our
data with RDD to rituximab, infliximab, cetuximab and trastuzumab.
Method
The study was conducted as a retrospective chart review of patients with
symptoms of HSRs to biological agents to which RDD have been performed
between January 2012 and January 2016.. HSRs were classified as Grade I, II
and III based on their severity. Skin prick/intradermal tests were performed with
implicated biologicals. The 12-step RDD protocol developed at Brigham and
Women Hospital was used
Results
Study group consisted of 11 female and four men ( mean age: 54, 21±11 years).
Majority of the study subjects (66.6%) were using the biological agents for the
treatment of malign diseases. Twelve subjects had experienced HSR to
rituximab, three had HSR to cetuximab, infliximab and trastuzumab respectively.
HSR to cetuximab, infliximab and trastuzumab occurred during first infusion and
all were Grade III, 11 of 12 subjects with rituximab hypersensitivity had reaction
during first infusion, nine had Grade II and three had Grade III. Of the 15
patients, 86,6% had respiratory symptoms, 66,6% had cardiovascular, 60% had
cutaneous symptoms, and 40% had gastrointestinal symptoms. Skin tests with
rituximab were done on eight patients, only three resulted in positive in 1/100
dilutions of intradermal tests, and skin tests were negative on either prick or
intradermal tests with other biologicals. Of 88 RDD, 81 desensitizations with
rituximab, five desensitizations with cetuximab, and one desensitization with
infliximab and one desensitization with trastuzumab were done. There were nine
breakthrough reactions (10.1 %) in seven subjects, which were all associated
with rituximab and less severe than initial reactions. Of breakthrough reactions,
55.5% were cutaneous, followed by cardiovascular (33%), respiratory (22,2%),
and gastrointestinal (11,1%) symptoms. Reactions mainly occurred at step 12,
and all were successfully under-controlled and except single desensitization, all
desensitization procedures were completed with full target dose.
Conclusion
We found RDD is safe and effective, to our knowledge, in the largest series of
biological including Rituximab in our country.
P28 Successful Desensitization To A High Dose Of Methotrexate In A
Delayed Type Hypersensitivity Reaction
Josefina Cernadas1, Leonor Carneiro-Leão1, Fabrícia Carolino1, Marta Almeida2
1. Serviço de Imunoalergologia, Centro Hospitalar de São João, Porto,
Portugal
2. Serviço de Pediatria, Instituto Português de Oncologia do Porto Francisco
Gentil, Porto, Portugal
Introduction
Delayed type hypersensitivity reactions are mediated by cells rather than by
antibodies. They can be life-threatening and classically constitute a
contraindication to desensitization (DZT). However, in selected cases of
uncomplicated exanthemas, when the culprit drug is irreplaceable or more
effective, this option might be considered. Methotrexate (MTX) is a folic acid
antagonist with a major role in the treatment of B cell acute lymphoblastic
leukemia (ALL). The authors describe a successful DZT to a high dose of IV MTX
associated to inthrathecal administration, following a delayed-type
hypersensitivity reaction.
Case Description
We report a case of a 12 year old boy under B cell ALL treatment. He was
scheduled to receive 4 cycles of MTX 8000mg IV perfusion over 24h (10% on the
1st hour, 90% over the remaining 23h hours, with a constant concentration),
followed by inthrathecal administration of MTX 12mg, cytarabine 30mg and
prednisolone 10mg. He complained of an intensely pruritic morbilliform
exanthema in his abdomen arising 72h after completion of the first treatment.
The rash resolved with anti histamines and oral and topic corticosteroids, over a
period of 10 days with severe residual hyperpigmentation. No renal or liver
function analytical changes were found during this episode. Because no
alternative treatment was available for his specific type of leukemia, a decision to
perform DZT was made.
The patient (60Kg) was pretreated with montelukaste 10mg, starting 2 days
before chemotherapy (QT); prednisolone 60mg was started the day before QT
and maintained over 4 days in decreasing doses. He was admitted and a 14 step
DZT protocol to MTX was performed. The doses administered were doubled in
each step until the 14th step, with a cumulative dose of 1671mg of MTX infused
over a period of 4.5 hours. The remaining dose, until the target dose of 8000mg
was infused at a small rate during 24.5h. This procedure was followed by triple
inthrathecal treatment, including MTX. The patient was able to reach the target
dose without any reaction. He has now completed 3 of the 4 scheduled cycles.
How this report contributes to current knowledge
To our knowledge this is the first description of a successful DZT to such a high
dose of MTX in a delayed type reaction. The IV DZT protocol also made possible
the administration of inthrathecal MTX. Our findings support that DZT protocols
might be suitable in selected cases, allowing these patients to safely continue
with first line therapy.
Poster Walk 4: SJS (P29 – P38)
P29 Assessment Of Impact Of Infection On Drug-Induced Severe
Cutaneous Adverse Reactions And Rhabdomyolysis Using The Japanese
Adverse Drug Event Report Database
Kimie Sai1, Takuya Imatoh1, Ryosuke Nakamura1, Chisato Fukazawa2, Yasushi
Hinomura2, Yoshiro Saito1
1. National Institute of Health Sciences, Tokyo, Japan
2. Japan Pharmaceutical Information Center, Tokyo, Japan
Keywords: Severe Cutaneous Adverse Reactions, Rhabdomyolysis, Infection,
Database
Introduction
Involvement of immune-mediated mechanism has been demonstrated in a
certain type of serious adverse drug reactions (ADRs), such as severe cutaneous
adverse reactions (SCAR) or rhabdomyolysis (RM), and thus, a possible
potentiation of these ADRs by infection via activating immune reactions is
postulated. In this study, to assess a role of infection in occurrence and severity
of SCAR and RM in Japanese cases, we analyzed a relation of infection to
reporting rates of these ADRs and severe outcomes or periods to onsets using
the Japanese Adverse Drug Event Report database (JADER).
Method
A total of 302,641 reports regarding primary suspected drugs from 2009 to 2013
in JADER were used in our analysis. Of these, a total of 3,167 SCAR reports
(Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), or
mucocutaneous ocular syndrome) and 1,847 RM reports were
included. Infection-Positive (Infect-P) was defined if the individual case report
included data on anti-infectious drugs or infection-related diseases, either as a
primary suspected drug (PS) or concomitant drugs/diseases (CO). Rates of
infections for SCAR or RM among total reports, and ratios of severe phenotype
(TEN for SCAR) and severe outcomes (no recovery, permanent damage and
death) and period to onset of SCAR or RM were compared between Infect-P and
Infection-Negative (Infect-N).
Results
The reporting ratios for Infect–P (vs. Infect-N) were significantly higher in SCAR
(adjusted odds ratio [95%CI]: 1.8 [1.7-2.0] for PS and 2.0 [1.8-2.2] for CO,
respectively) and lower in RM (0.6 [0.5-0.7] for PS and 0.8 [0.7-0.9] for
CO). The rate of TEN in SCAR was significantly higher in Infect-P (vs. Infect-N)
(1.3[1.1-1.6] for PS and 2.2 [1.8-2.7] for CO). Higher rates of severe outcomes
by Infect-P (vs. Infect-N) were observed for SCAR (1.6 [1.2-2.1] for PS and
1.9[1.4-2.5] for CO) and RM (1.3 [0.8-2.2] for PS and 1.7 [1.0-2.3] for
CO). The mean period to onset of SCAR was shorter for PS (25 days) but
marginal for CO (40 days) in Infect-P comparing with Infect-N (36 days), and
earlier onset of RM was evident in Infect-P (47 days for PS and 191 days for CO)
comparing with Infect-N (250 days).
Conclusion
This study indicated a substantial association between infection and
occurrence/severity in SCAR as well as RM, showing much larger impacts on
SCAR.
P30 Characterization Of Erythema Multiforme And Severe Cutaneous
Adverse Reactions Hospitalizations
Bernardo Sousa-Pinto, Cláudia Correia, Lídia Gomes, Sara Gil-Mata, Luís
Araújo, Luís Delgado
Immunology Laboratory - Basic and Clinical Immunology. Faculty of Medicine,
Porto, Portugal
Keywords: Erythema Multiforme, Severe Cutaneous Adverse Reactions,
Epidemiology, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis
Introduction
Erythema multiforme (EM) and severe cutaneous adverse reactions (SCARs) are
immunologically-mediated delayed hypersensitivity reactions triggered after
exposition to external agents such as drugs. We aim to characterize
hospitalizations occurring in Portuguese public hospitals with associated diagnosis
of drug-related EM and SCARs concerning patients’ demographic and clinical
characteristics, in-hospital mortality and most frequently associated drug classes.
Method
We used a database containing all hospitalizations occurred in mainland Portugal
public hospitals and analyzed all episodes with associated diagnosis of drugrelated EM or SCARs - Stevens-Johnson syndrome (SJS), toxic epidermal
necrolysis (TEN) and SJS/TEN overlap syndrome. These hospitalizations were
compared concerning patients’ demographic and clinical characteristics (gender,
age and comorbidities), length of stay, and in-hospital mortality. We also
evaluated the drug classes most frequently associated with these diagnoses,
estimating the number of episodes per million drug packages sold. A logistic
regression was performed to evaluate for factors significantly associated with inhospital mortality among SCARs.
Results
Between 2009 and 2014, there were 122 hospitalizations with associated
diagnosis of EM and 132 with associated diagnosis of SCARs. Most EM (65%) and
SCARs (55%) episodes occurred in women. The median age was 63 years old for
both EM and SCARs. The frequency of HIV co-infection was higher among SCARs
episodes (9% versus 2%; p=0.009). In-hospital mortality varied between 7%
(EM) and 44% (TEN). Advanced age (OR=1.06; 95% CI: 1.02-1.45), heart
failure (OR=4.93; 95% CI: 1.01-23.99), liver disease (OR=7.39; 95% CI: 1.0751.02) and TEN diagnosis (OR=14.66; 95% CI: 1.73-124.31) were all
significantly associated with higher risk of in-hospital mortality among SCARs
episodes. The highest numbers of EM and SCARs episodes per million drug
packages sold concerned antiviral (1.5 and 8.7, respectively) and uric acid
metabolism drugs (2.4 and 5.0, respectively).
Conclusion
SCARs are associated with higher mortality than EM. Advanced age, heart failure,
liver disease and TEN diagnoses are associated with higher in-hospital mortality
among SCARs episodes. Antiviral and uric acid metabolism drugs are the drug
classes most frequently associated with SCARs hospitalizations.
P31 Effects Of Infection On Incidence/Severity Of SJS/TEN And
Myopathy In Japanese Cases Analyzed By Voluntary Case Reports
Ryosuke Nakamura1, Kimie Sai1, Takuya Imatoh1, Yoshimi Okamoto-Uchida1,
Koji Kajinami2, Kayoko Matsunaga3, Michiko Aihara4, Yoshiro Saito1
1. National Institute of Health Sciences, Tokyo, Japan
2. Kanazawa Medical University, Ishikawa, Japan
3. Fujita Health University, Aichi, Japan
4. Yokohama City University, Kanagawa, Japan
Keywords: SJS, TEN, Myopathy, Infection, Adverse Reaction
Introduction
Immunological mechanisms are supposed to be involved in the pathogenesis of
certain types of serious adverse reactions (ADRs), such as severe cutaneous
adverse reactions or rhabdomyolysis. Therefore, infection which activates
immune system may affect incidence and severity of ADRs. In this study, we
analyzed an association of concomitant infectious diseases with
incidence/severity of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis
(TEN) and myopathy, based on Japanese voluntary case reports.
Method
Patients who experienced SJS/TEN (259 cases) or myopathy (a total of 129
cases) were recruited through a nationwide blood sampling network in Japan
operated by the National Institute of Health Sciences under a cooperation of the
Ministry of Health, Labour and Welfare, Pharmaceuticals and Medical Devices
Agency, and Federation of Pharmaceutical Manufacturers’ Association of Japan.
Written informed consent was obtained from all recruited patients. Using the
case report data, we analyzed rates for concomitant infectious disease
(tuberculosis, hepatitis, AIDS, influenza infection, and herpes simplex infection,
etc.), and compared the severity (severe phenotypes or outcomes) and the mean
period to onset of the ADRs between patients with and without infectios diseases.
Results
For SJS/TEN cases, the rate of infectious diseases was 51%, of which 31% was
the cases caused by a primary suspected drug. The rates of severe phenotype
TEN, ocular involvement and permanent damage were significantly higher
(p<0.05) and the mean period of onset of SJS/TEN was significantly shorter in
the infectious patients’ group compared with non-infectious group. The rate of
infectious diseases in myopathy was 23%, of which 12 % was the cases caused
by a primary suspected drug. The rates of severe phenotype and permanent
damage were higher and the mean period of onset of myopathy was shorter in
the myopathy patients with infectious disease than those without infection,
although these differences were not statistically significant.
Conclusion
This study indicated that the incidence and the severity of SJS/TEN and
myopathy are associated with the concomitant infectious disease, especially in
the cases of SJS/TEN, which might reflect a greater contribution of immune
system as a mechanism of occurrence.
P32 Efficacy Of Tumor Necrosis Factor–a Antagonists In StevensJohnson Syndrome And Toxic Epidermal Necrolysis: A Randomized
Controlled Trial And Immunosuppressive Effects Evaluation
Chuang-Wei Wang1, Shih-Chi Su1, Shuen-Iu Hung2, Hsin-Chun Ho1, Chih-Hsun
Yang1, Wen-Hung Chung1
1. Department of Dermatology, Drug Hypersensitivity Clinical and Research
Center, Chang Gung Memorial Hospital, Linkou And Keelung, Taiwan
2. Department and Institute of Pharmacology, School of Medicine, Infection
and Immunity Research Center, National Yang-Ming University, Linkou,
Taiwan
Introduction
Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare,
but life-threatening adverse drug reactions. While the clinical manifestations of
SJS/TEN are well-defined, the optimal treatment for these diseases remains
unavailable. We aim to evaluate the efficacy and safety of etanercept (anti-TNF-α
agent) in patients with SJS/TEN.
Method
We enrolled 98 patients with SJS/TEN to perform an open, prospective, doubleblind and randomized comparison trial of etanercept versus corticosteroid. We
further investigated the immunologic effects of etanercept in SJS/TEN patients.
Results
This study demonstrated that etanercept had clinical improvements in patients
with SJS/TEN. Etanercept revealed to be more decreased the SCORTEN-based
predicted mortality rate (predicted rate=17.47%; observed rate=8.33%) than in
corticosteroid use (predicted rate=20.13%; observed rate=15.91%). Compared
with corticosteroid, etanercept also showed a shorter skin healing time (The
median times are 14 days for etanercept and 17 days for corticosteroid;
P<0.05*) and less side effect for gastrointestinal hemorrhage (0% after
etanercept use and 11.8% after corticosteroid use; P <0.05*) in total SJS/TEN
patients. For mechanism study, etanercept significantly decreased the granulysin
and TNF-α expression in blister fluids and plasma (In blister fluids:
granulysin=62.5% and TNF-α=50.0% decrease after 2 days treatment; in
plasma: granulysin=54.7% and TNF-α=69.2% decrease after 15 days treatment,
all P<0.05*) and increased Treg cells population (2-fold percentage increase
after 15 days treatment, P<0.01**).
Conclusion
This study indicates that etanercept (anti-TNF-α agent) not only has
immunosuppressive effects but also serves as an alternative medicine for
SJS/TEN treatment.
P33 Evolution Of Drug Causality In Stevens-Johnson Syndrome And
Toxic Epidermal Necrolysis In Europe: Analysis Of 10 Years RegiSCARStudy
Maren Paulmann1, Ariane Dunant2, Maja Mockenhaupt1, Peggy Sekula3, Martin
Schumacher3, Sylvia Kardaun4, Luigi Naldi5, Teresa Bellón6, Daniel Creamer7,
Cynthia Haddad8, Bruno Sassolas9, Bénédicte Lebrun-Vignes10, Laurence
Valeyrie-Allanore8, Jean-Claude Roujeau8
1. Dokumentationszentrum schwerer Hautreaktionen, University Medical
Center, Freiburg, Germany
2. Department of Biostatistics and Epidemiology Unit, Institut GustaveRoussy, Villejuif, France
3. Institute of Medical Biometry and Medical Informatics, University Medical
Center, Freiburg, Germany
4. Reference Center for Cutaneous Adverse Reactions, University Medical
Center, Groningen, Netherlands, The
5. Department of Dermatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
6. Institute for Health Research, University Hospital La Paz–IdiPAZ, Madrid,
Spain
7. Department of Dermatology, King's College Hospital, London, United
Kingdom
8. Reference Center for Toxic and Autoimmune Blistering Diseases, Hopital
Henri Modor, University Paris-Est, Créteil, France
9. Department of Internal medicine and Respiratory Diseases, Hôpital Cavale
Blanche, Brest, France
10.Department of pharmacology, Hôpital Pitié-salpétrière, Paris, France
Introduction
Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) is rare, but
the most severe of all adverse drug reactions due to a high mortality, which is
almost 50% in TEN. Good evaluation of risk factors is essential for efficient
pharmacovigilance.
Method
From January 2003 to December 2012 the international Registry of Severe
Cutaneous Adverse Reactions (RegiSCAR) included 1096 cases of SJS/TEN
collected in seven countries (France, Germany, Israel, Italy, Netherlands, Spain,
United Kingdom). The diagnoses and dates of onset were validated by an expert
group, blinded for any information on exposures. Causality was established by
using the specific algorithm ALDEN that had previously shown a good correlation
with the results of a case-control analysis in an earlier systematic collection of
several hundred cases.
Results
In terms of overall causality assessment, at least one medication was evaluated
as the «probable» or «very probable» cause in 744/1096 cases (68 %). A
medication cause was determined as «possible» in 209 cases (19%), as
«unlikely» in 68 cases (6,2%) and “very unlikely” in 57 cases (5,2%). 18
patients (1.6%) denied any exposure to medications. The 5 medications most
often incriminated («probable» or «very probable» causality) were allopurinol
(n=187; 17%), sulfamethoxazole (n=80), lamotrigine (n=76), carbamazepine
(n=51), phenytoin (n=42). There were substantial differences between reactions
developing among hospitalized and community patients, e.g. older age, exposure
to a substantially higher number of drugs and a noticeable role for metamizole
among inhospital cases in Germany. In both groups (inhospital and community
cases) we identified a signal for proton pump inhibitors.
Conclusion
In spite of prior warnings in medical journals and towards regulatory agencies,
allopurinol is still the principal cause of SJS/TEN in Europe, as it was 10 years
ago. Off-label prescription of allopurinol for asymptomatic hyperuricemia has not
decreased. Sulfamethoxazole and other anti-infective sulfonamides are still
frequent inducers of SJS/TEN. Lamotrigine is now the third cause and the first
one among antiepileptic drugs, independent of new indications such as bipolar
disorder. Finally, it is important to note that at least 13% of SJS/TEN-cases have
no drug cause.
Investigation of other possible causes of such «idiopathic cases», e.g. infections,
should be a priority.
P34 Long-Term Sequelae In Patients With Stevens-Johnson Syndrome
And Toxic Epidermal Necrolysis: A 5-Year Analysis
Maren Paulmann1, Carmen Kremmler1, Peggy Sekula2, Laurence ValeyrieAllanore3, Luigi Naldi4, Sylvia Kardaun5, Maja Mockenhaupt1
1. Dokumentationszentrum schwerer Hautreaktionen, University Medical
Center, Freiburg, Germany
2. Institute of Medical Biometry and Medical Informatics, University Medical
Center, Freiburg, Germany
3. Reference Center for Toxic and Autoimmune Blistering Diseases, Hopital
Henri Modor, University Paris-Est, Créteil, France
4. Department of Dermatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
5. Reference Center for Cutaneous Adverse Reactions, University Medical
Center, Groningen, Netherlands, The
Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare,
but severe reactions with blisters and erosions of skin and mucosae. Most often
SJS/TEN is induced by drugs, less frequently by infections, whereas some cases
are “idiopathic”. Severity is determined by skin detachment related to the body
surface area (BSA): SJS <10%, TEN >30%, and SJS/TEN-overlap 10-30% of
BSA. The high mortality rate is due to severity as well as age of the patient.
Survivors frequently suffer from long-term sequelae, particularly of the mucosae.
Method
In order to evaluate frequency and extent of late sequelae in patients with
SJS/TEN, a cohort study was performed. Patients with a validated diagnosis of
SJS/TEN, who were included in the international Registry of Severe Cutaneous
Adverse Reactions (RegiSCAR) between 2003 and 2007, were asked to answer a
follow-up questionnaire.
Results
112/233 completed follow-up questionnaires could be analyzed. 62 patients were
diagnosed with SJS, 35 with SJS/TEN-overlap, and 15 with TEN. The mean age is
44 years, and approx. 60% are women. More than 90% of the patients suffer
from sequelae after 5 years, while the percentage increases with severity of the
reaction. Less than 50% were able to completely return to their normal daily
activities. Sequelae mainly affect skin (73%), mucosa (57%) and nails (52%).
Chronic sequelae of the eyes (67%) are the main issue for the patients. They
include increased photosensitivity, dry eyes, ingrowing eyelashes (trichiasis),
excessive watery eyes (epiphora), inflammatory cicatrization up to blindness.
Furthermore, patients describe sleep disturbances and nightmares (29%). In
addition, they are afraid of drug use (65%), and 56% of the patients avoid
taking drugs, which may have a negative impact on their health. Although many
patients consider professional psychological support helpful (54%), only 9% had
received it.
Conclusion
This evaluation shows that the majority of patients who survived SJS/TEN suffer
from long-term sequelae. An interdisciplinary approach is not only important in
the acute stage of the disease, but also after discharge from the hospital,
including regular check-ups by specialists for these rare severe reactions.
P35 Major Emotional Complications And Decreased Health Related
Quality Of Life Among Survivors Of Stevens-Johnson Syndrome And
Toxic Epidermal Necrolysis
Roni P. Dodiuk-Gad1, Cristina Olteanu2, Anthony Feinstein3, Rena Hashimoto4,
Raed Alhusayen4, Sonia Whyte-Croasdaile5, Yaron Finkelstein6, Marjorie Burnett7,
Shachar Sade8, Robert Cartotto7, Marc Jeschke7, Neil H. Shear4
1. Department of Dermatology, Ha’emek Medical Center, Afula, Israel
2. Faculty of Medicine, University of Toronto, Toronto, Canada
3. Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto,
Canada
4. Division of Dermatology, Department of Medicine, Sunnybrook Health
Sciences Centre, Toronto, Canada
5. SJS and TENS Group Canada-CAST International, Toronto, Canada
6. Paediatric Emergency Medicine, Clinical Pharmacology and Toxicology, The
Hospital for Sick Children, Toronto, Canada
7. Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto,
Canada
8. Department of Pathology, Sunnybrook Health Sciences Centre, Toronto,
Canada
Keywords: Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, Emotional
Complications, SJS/TEN
Introduction
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are lifethreatening mucocutaneous reactions, predominantly drug-induced. In addition
to these high mortality rates, early and late physical complications are common.
No studies were conducted on the emotional status or the general Health-Related
Quality of Life among survivors of SJS/TEN. We aimed to characterize the longterm emotional complications and health-related quality of life among SJS/TEN
survivors.
Method
Patients older than 18 years who survived SJS/TEN were assessed using various
parameters. Emotional assessment was conducted by three validated
questionnaires: Impact of Events Scale-Revised, General Health Questionnaire,
and Hospital Anxiety and Depression Scale. Health-Related Quality of Life was
assessed by three validated questionnaires: Dermatology Life Quality Index, EQ5D, Skindex-29 and one specially designed for the study.
Results
Our cohort consists of 17 patients with mean 51.6±74.7 months (median=9,
range=1-228) following SJS/TEN. Eleven out of 17 (65%) were found to have
symptoms of post-traumatic stress (Impact of Events Scale-Revised,
mean=22.4±19.9) and 5 (29%) met the criteria for post-traumatic stress
disorder, 12 (71%) had psychological distress (General Health Questionnaire,
mean total score=4.6±4.2) and 11 (65%) had symptoms of a psychiatric clinical
disorder (Hospital Anxiety and Depression Scale, mean total score=14.5±8.4).
The Dermatology Life Quality Index indicated a moderate to extremely large
effect on the lives of 9 (53%) participants (mean total score=6.9±7.6). Skindex29 indicated a mild-severe effect on Health-Related Quality of Life in 10 (59%)
participants (mean=24.6±21.5). Participants rated their general health at a
mean of 66.2/100±18.1 (EQ-5D VAS). Fourteen (82%) participants reported that
SJS/TEN decreased their current quality of life. Twelve (71%) reported that
SJS/TEN influenced their current emotional status. Eleven (65%) reported that
SJS/TEN influenced their current everyday activities.
Conclusion
Survivors of SJS/TEN suffer from severe long-term emotional complications and
decreased health-related quality of life.
P36 Retrospective Analysis Of Stevens-Johnson Syndrome And Toxic
Epidermal Necrolysis In Japanese Patients - Treatment And Outcome
Naoko Takamura1, Yumiko Yamane1, Setsuko Matsukura2, Kazuko Nakamura2,
Yuko Watanabe1, Yukie Yamaguchi1, Takeshi Kambara2, Zenro Ikezawa1, Michiko
Aihara1
1. Department of Environmental Immuno-Dermatology## Yokohama City
University, Yokohama, Japan
2. Department of Dermatology## Yokohama City University Medical Center,
Yokohama, Japan
Keywords: SJS, TEN
Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare
but severe adverse drug reactions with high mortality.
Method
To present the clinical characteristics of SJS and TEN in Japan and evaluate the
efficacy of treatments, we retrospectively analyzed cases of SJS and TEN treated
in Yokohama City University Hospital and Yokohama City University Medical
Center between January 2000 and December 2015.
Results
60 cases of SJS (24 males and 36 females; average age, 54.2 years) and 40
cases of TEN (19 males and 21 females; average age, 56.2 years) were included
in this study.
31 cases of SJS (51.6%) and all cases of TEN were caused by drugs. Hepatitis
was the most common organ involvement in both SJS and TEN. Renal
dysfunction, intestinal disorder, and respiratory disorder were also involved in
some cases. The major complication was pneumonia and sepsis. All cases except
for 4 cases were treated systemically with corticosteroids. In SJS 40 cases
(66.6%) were treated with corticosteroid alone, Steroid pulse therapy was
performed in 40% of SJS and 90% of TEN. Plasmapheresis and/or
immunoglobulin therapy was combined with steroid therapy performed 17 cases
in SJS (42%) and 26 cases in TEN (65%). Average SCORTEN score was 1.13 in
SJS and 2.32 in TEN. The mortality rate was 6% and the rates for SJS and TEN
were 1.7% and 12.5%, respectively. The mortality rate was 0% treated with
combination of corticosteroid, plasmapheresis and immunoglobulin therapy in
SJS and TEN. These were much lower than predicted mortality according to a
severity-of-illness scoring system fot TEN prognosis (SCORTEN) socre.
Conclusion
Treatment with steroid pulse therapy in combination with plasmapheresis and/or
immunoglobulin therapy seems to have contributed to prognostic improvement
in SJS/TEN.
P37 Severe Physical Complications Among Survivors Of Stevens-Johnson
Syndrome And Toxic Epidermal Necrolysis
Roni P. Dodiuk-Gad1, Cristina Olteanu2, Rena Hashimoto3, Hall Chew4, Raed
Alhusayen3, Sonia Whyte-Croasdaile5, Yaron Finkelstein6, Marjorie Burnett7,
Shachar Sade8, Robert Cartotto7, Marc Jeschke7, Neil H. Shear3
1. Department of Dermatology, Ha’emek Medical Center, Afula, Israel
2. Faculty of Medicine, University of Toronto, Toronto, Canada
3. Division of Dermatology, Department of Medicine, Sunnybrook Health
Sciences Centre, Toronto, Canada
4. Department of Ophthalmology and Vision Sciences, Sunnybrook Health
Sciences Centre, Toronto, Canada
5. SJS and TENS Group Canada-CAST International, Toronto, Canada
6. Paediatric Emergency Medicine, Clinical Pharmacology and Toxicology, The
Hospital for Sick Children, Toronto, Canada
7. Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto,
Canada
8. Department of Pathology, Sunnybrook Health Sciences Centre, Toronto,
Canada
Keywords: Physical Complications, Stevens-Johnson Syndrome, Toxic Epidermal
Necrolysis, Long-Term Complications
Introduction
Stevens–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are
considered the most severe types of cutaneous adverse reactions to drugs, with
high morbidity and mortality rates. We aimed to characterize the long-term
physical complications among SJS/TEN survivors.
Method
Patients older than 18 years who survived SJS/TEN were assessed by an
interview and by skin, oral mucous membrane and detailed ophthalmic exam.
Results
Our cohort consists of 17 patients with mean 51.6±74.7 months (median=9,
range=1-228) following SJS/TEN. The most commonly reported symptom among
survivors was chronic fatigue/weakness (76%). The most common cutaneous
signs were post-inflammatory dyspigmentation in 77% of participants, scars
(46%), and milia (15%). The most common cutaneous symptoms were pruritus
(53%), photosensitivity (35%), and dry skin (24%). In the ophthalmic exam, dry
eyes were the most common finding in 44%. Other identified signs were: lid
adhesions/symblepharon (33%), chronic ocular surface inflammation (33%), loss
of visual acuity (22%), chronic conjunctivitis (22%), keratinization of the tarsal
conjunctiva (22%), lachrymal duct scarring (22%), blindness (11%),
photophobia (11%), ectropian and trichiasis (11%), corneal abrasions/ulcers
(11%), conjunctival synechiae (11%), and corneal neovascularization (11%).
The most commonly reported ocular symptoms were dry eyes in 47% of
participants; other symptoms included photophobia (35%), loss of visual acuity
(35%), and ocular pain (24%). Hair loss and nail loss were reported in 53% and
35% of participants a few months after TEN, respectively. Other less common
complications included genital synechiae in 18% of female survivors, lupus
(12%), renal dysfunction (12%), and fibromyalgia (6%). Tinnitus, tenderness on
soles of feet, abnormal ECG, and vocal cord dysfunction were each reported in
6% of participants.
Conclusion
Survivors of SJS/TEN suffer from severe, long-term physical complications and
require ongoing longitudinal medical follow-up.
P38 Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Combined
With Haemophagocytic Lymphohistiocytosis: A Case Report
Brittany Knezevic1, Una Nic Ionmhain1, Allison Barraclough1, Michaela Lucas2,
Matthew Anstey1
1. Sir Charles Gairdner Hospital, Perth, Australia
2. Pathwest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth,
Australia
Introduction
The combination of Stevens-Johnson syndrome/toxic epidermal necrolysis
(SJS/TEN) with haemophagocytic lymphohistiocytosis (HLH) is life-threatening
and usually fatal in adults. We report a rare case of a 36 year old male who
survived these concomitant illnesses.
Case Description
The patient presented with a one week history of fevers and flu-like symptoms,
with onset of a mucocutaneous rash on day five. He was admitted to a tertiary
intensive care unit (ICU) with a diagnosis of SJS/TEN (20-25% of total body
surface area). The potentially implicated drugs (ibuprofen, codeine and
amoxicillin) were promptly withdrawn, and he received immunosuppressive
therapy with methylprednisolone, intravenous immunoglobulin and cyclosporin
combined with supportive ICU care. He continued to systemically deteriorate at
a time when his skin lesions stabilised. Recognition of hyperferritinemia (40900
ug/L), unremitting fevers and pancytopenia in a critically ill patient, clinched the
diagnosis of HLH which was confirmed on bone marrow biopsy. He received
treatment with the HLH-94 chemotherapy protocol (including etoposide and
dexamethasone). Sequential skin patch tests to ibuprofen and amoxicillin,
performed six months post-discharge, were negative (codeine patches were not
available). The patient’s negative patch tests were interpreted with caution, due
to previous chemotherapy and the unavoidable delays to testing, both of which
may have led to T lymphocyte depletion and false negative patch test
results. The patient was advised to strictly avoid all non-steroidal antiinflammatories, aspirin, codeine and amoxicillin (he had tolerated other opiates
and beta-lactams in hospital).
How this report contributes to current knowledge
To our knowledge, this is the first report of an adult surviving a severe episode of
HLH and SJS/TEN overlap (rather than SJS alone). This case highlights (i) the
potential for HLH to coexist with SJS/TEN and the importance of early recognition
and treatment, (ii) the difficulties in interpreting patch tests in patients who have
received marrow ablative therapies, and (iii) the complexities of providing
recommendations on drug avoidance to patients with severe cutaneous adverse
drug reactions and negative patch test results. In vitro lymphocyte proliferation
assays may be a useful alternative diagnostic tool in this clinical setting.
Poster Walk 5: Other organs / Unexpected
immune reactions (P39 – P47)
P39 A Case Report Of Patient With Anti-Tuberculosis Drug-Related
Severe Liver Failure
Toru Usui1, Xiaoli Meng1, John Farrell1, Paul Whitaker2, John Watson2, Neil
French1, Kevin Park1, Dean Naisbitt1
1. MRC Centre for Drug Safety Science, Dept Molecular & Clinical
Pharmacology, University of Liverpool, Liverpool, United Kingdom
2. Regional Adult Cystic Fibrosis Unit, St James’s Hospital, Leeds, United
Kingdom
Keywords: Isoniazid, Drug-Induced Liver Injury
Introduction
Exposure to anti-tuberculosis drugs (ATDs) isoniazid (INH), ethambutol (ETB),
pyrazinamide (PZA) and/or rifampicin (RIF) is associated with a mild elevation of
liver enzymes that occasionally develops into severe liver injury. We have
reported that INH-specific CD4+ T-cell clones circulate in patients with ATDrelated liver injury, which suggests that the adaptive immune system is involved
in the disease pathogenesis. This study details the nature of the drug antigenspecific T-cell response that develops in a fatal case of ATD-related liver failure.
Method
Peripheral blood mononuclear cells were isolated from a patient who had a
severe liver reaction to ATD medications, ALT 514 IU/L and Bilirubin 30
mg/dL. A lymphocyte transformation test (LTT) and IFNγ-ELISPOT assay using
ATDs were performed and clones were generated from ATDs by serial dilution.
Drug-specific clones were identified in terms of cross-reactivity and doseresponsiveness and then characterized in terms of CD phenotype and cytokine
secretion.
Results
Positive LTT against multiple drugs (INH, ETB, PZA, RIF, and activated ester of
isonicotinic acid which forms isonicotinic amide adducts in the cell culture
system) was observed. Over 700 T-cell clones were generated from INH, ETB,
PZA, RIF or activated ester of isonicotinic acid treated peripheral blood
mononuclear cells. Antigen-specific proliferative responses of CD4+/CD8+ clones
were identified with only ETB and RIF. Clones were highly specific and did not
crossreact with other ATDs. Clones are activated to proliferate and secrete
cytotoxic mediators (granzyme B, perforin) and effector cytokines (IFN-γ, Il-13).
Conclusion
In conclusion, cytotoxic ETB and RIF-specific T-cell clones have been identified in
patient with ATD-related severe liver failure.
P40 Acute Interstitial Nephritis Induced By Ibuprofen
Ana Castro Neves, Susana Cadinha, Ana Moreira, JP Moreira Da Silva
Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova De Gaia, Portugal
Introduction
Acute Interstitial Nephritis (AIN) is often drug induced and the most frequently
implicated drugs are Non-steroidal anti-inflamatory drugs (NSAIDs) and
antibiotics. We report the case of a patient with AIN induced by Ibuprofen.
Case Description
A 74 year-old-female was admitted at emergency department with a 10-day
history of malaise, anorexia, nausea, diffuse myalgias, fever (38ºC) and flank
pain, treated with Paracetamol, Ibuprofen and Ciprofloxacin for suspected
Pyelonephritis, by her attending physician. At admission she was febrile (38ºC)
and prostrated. Laboratory studies revealed: leukocytosis, acute kidney injury
(serum creatinine 5,8 mg/dL, blood urea nitrogen 178 mg/dL) and positive Creactive Protein; urinalysis with leucocituria, proteinuria and hematuria; negative
blood culture. Chest X-ray and ultra sound of kidneys were normal. Treatment
with Paracetamol, Ibuprofen and Ciprofloxacin was discontinued and she started
Meropenem and intravenous fluids. Renal function improved and she was
discharged after 3 days. One year later she was admitted to hospital with similar
clinical presentation and diagnosed with AIN. Ten days prior to this admission
she was treated with Ciprofloxacin and Ibuprofen for Phlebitis. After these 2
episodes she was again treated with Ciprofloxacin with good tolerance. She was
then referred to our Drug Allergy Clinic for suspected hypersensitivity to
Ibuprofen. Lymphocyte transformation test (LTT) with Ibuprofen was positive
(stimulation index of 13,4 at 10ug/mL). Drug provocation test (DPT) with the
suspected drug was not performed. DPT and long-term challenge with alternative
drugs (Paracetamol and Etoricoxib) were both negative.
How this report contributes to current knowledge
Renal biopsy is the only definitive method to establish the diagnosis of AIN.
However, when diagnosis seems likely, a probable precipitating drug can be
easily withdrawn or patient improves readily after withdrawal of the suspected
drug, biopsy can be avoidable. Challenge with the suspected drug remains the
gold standard for diagnosis of drug hypersensitivity. Since AIN is a severe
hypersensitivity reaction, DPT with the suspected drug is contra-indicated. The
obvious time relationship between Ibuprofen treatment and reaction
development in both episodes, the reproducible clinical presentation and positive
LTT, suggests Ibuprofen has been the culprit drug. In cases of severe reactions
LTT seems to be a valuable diagnostic tool.
P41 Cetuximab Induced Acneiform Rash – Two Case Reports
Daniela Ledic Drvar1, Sandra Jerkovic Gulin2, Suzana Ljubojevic Hadzavdic1,
Romana Ceovic1
1. Department of Dermatology and Venereology, University Hospital Center
Zagreb and School of Medicine, Zagreb, Croatia
2. Department of Dermatology and Venereology, General Hospital Sibenik,
Sibenik, Croatia
Introduction
Epidermal growth factor receptor inhibitors (EGFRIs) are used for treatment of
advanced lung, pancreatic, colorectal, and head and neck cancers. Cetuximab is
a monoclonal antibody that competitively binds to the extracellular domain of
EGFR and blocks cytoplasmic-domain phosphorilation. It is characterized by
frequent cutaneous adverse reactions (CARs) including acneiform rash (AR),
desquamation, xerosis, pruritus, hair abnormalities, paronychia, changes in nails,
mucositis, increased growth of facial hair and eyelashes, and teleangiectasias. AR
usually appears between day 2 to week 6 after cetuximab introduction. According
to the National Cancer Institute Common Toxicity Criteria, severity of toxicity of
AR is graded into five grades, and according to EGFRI-induced AR severity score
into mild, moderate and severe toxicity.
Prophylactic antibiotic treatment with doxycycline 100 mg bid for the first 6
weeks is recommended. Therapeutic plan includes use of grade-based skin
treatment algorithm: a) mild toxicity - local therapy with corticosteroids or
antibiotics, b) moderate toxicity - local therapy with addition of oral antibiotic,
and c) severe toxicity - cetuximab dose lowering and therapy for moderate
toxicity with an addition of a methyprednisolone dose pack. If therapy is
ineffective within 2-4 weeks, it is necessary to discontinue cetuximab
treatment.
Case Description
We present two male patients with metastatic colorectal cancer who developed
papulopustular lesions on the sebum-rich areas of the face, scalp and trunk
accompanied by pruritus and burning sensations (grade 2/3 or moderate
toxicity), one to three weeks after introduction of cetuximab. One patient
developed desquamation of the palms. Comedones, primary acne lesions, were
lacking. There was no sign of superinfection. Patients were treated with
doxycycline 2x100 mg bid for two weeks, followed by 1x100 mg, until the end of
cetuximab therapy. Local therapy included clindamycin lotion, hydrocortisone
/oxytetracycline ointment, benzoyl peroxide suspension and emollients. After
three weeks of treatment, significant improvement of AR severity was achieved
and there was no need for cetuximab dose reduction.
How this report contributes to current knowledge
Studies have demonstrated positive correlation between treatment efficacy and
CARs for EGFRI. Since frequency and severity of skin lesions are dosedependent, a gradual increase in dose until CARs develop might be a good
strategy to maximize the efficacy of EGFRI.
P42 Enteropathy Associated With Losartan
Ana Montoro De Francisco, Talía De Vicente Jiménez, Amelia García Luque,
Natalia Rosado David, José Mª Mateos Galván
Hospital Central de la Defesa, IMIDEF, Madrid, Spain
Introduction
On August 2012 Rubio-Tapia et al reported an association of olmesartan therapy
with an unexplained enteropathy symptomatically resembling celiac disease or
sprue. Olmesartan is an Angiotensin II Receptor Antagonist (ARA II) widely used
in high blood pressure, heart disease and diabetics. On July 2013 the Food Drug
Administration (FDA) approves label changes to include intestinal problems,
Severe Spruelike Enteropathy (SSE) linked to blood pressure medicine
olmesartan.
Losartan was the first ARA II commercialized in 1995 and it seems to produce
similar Adverse Drug Reactions (ADR) that olmesartan.
Case Description
Method
Desing: Case report of enteropathy associated with losartan
Scope: Allergy Service, Hospital Central de la Defensa, Madrid.
Period: May 2015
Main variables assessed: demographic and clinical variables, diagnostic criteria,
treatment, evolution, causal relationship between drug and enteropathy
according to the modified Karch Lasagna algorithm.
The patient has given written informed consent for the publication research.
Results
A 81 years old woman, diagnosed of hypertension, treated for three years with
losartan 100 mg/d. After starting treatment she refers chronic diarrhea and since
two years ago worsening diarrhea, abdominal pain and weight loss. The patient
was treated at the emergency service twice for 3-4 daily episodes of watery,
nonbloody diarrhea associated with abdominal bloating. The patient failed
conservative management including gluten-free diet, oral antibiotic and
corticosteroid. Additionally to diarrheal syndrome, the patient showed hoarseness
and cough.
Allergologic study: immediate and delayed prick test and specific IgE were
negative for food.
A colonoscopy with colonic biopsies revealed evidence of microscopic colitis.
Treatment: Losartan withdrawal, achieving complete remission in four weeks.
The case has been reported to Spanish Postmarketing Surveillance System.
How this report contributes to current knowledge
The allergist should keep in mind this possible and rare ADR in patients treated
with losartan (ARA II) showing enteropathy, as discontinuing losartan leads to
clinical improvement.
This enteropathy case is very similar to SSE described in 2012 related to
olmesartan.
P43 Granuloma Annulare After Therapy With Canakinumab
Razvigor Darlenski
Tokuda Hospital Sofia, Sofia, Bulgaria
Introduction
Granuloma annulare (GA) is a benign inflammatory dermatosis affecting
predominantly females. The disease etiology and pathophysiology remain
unclear. Trauma, association with diabetes mellitus and medicamentous genesis
have been suspected. Pathogenic mechanisms include cell-mediated immunity
(type IV), macrophage activation, and cytokine-mediated degradation of
connective tissue.
Case Description
Herein we present a 56-years-old male Caucasian patient who developed skin
lesions on the back of the hand 3 months after initiation of therapy with
canakinumab as a part of a clinical trail for treatment of coronary artery disease.
Upon admission the skin changes involved the dorsum of the hand and were
presented by annular papules and plaques, the largest 3 cm in diameter with
depressed center and elevated and infiltrated borders. The patient had no other
relevant history of present or past disease beyond the coronary artery diseases
and elevated serum cholesterol levels. He took no other medication prior or
during the disease onset.
Based on the clinical findings the diagnosis of GA was coined. Cryotherapy with
liquid nitrogen was performed. Canakinumab was withdrawn. Skin lesions
resolved within the 2 weeks later. No new lesions appeared during the 6 months
follow up.
How this report contributes to current knowledge
Canakinumab is a IL-1 beta monoclonal antibody used in rheumatology and in
the treatment of autoinflammatory syndrome. Recently it was tested in coronary
artery disease, gout and COPD. As a new drug, its safety profile and unwanted
adverse events are still to be challenged. In the described case we present the
development of cutaneous reaction coinciding with the drug introduction. Druginduced GA has been described in the literature, e.g. after allopurinol,
amlodipine, TNF-alpha inhibitors, gold, and interferon therapy. As far as we are
aware no previous reports exist on the association between canakinumab
therapy and GA.
P44 Hypersensitivity Eosinophilic Myocarditis Or Acute Coronary
Syndrome? – Case Report
Dario Gulin1, Jozica Sikic1, Jasna Cerkez Habek1, Sandra Jerkovic Gulin2,
Edvard Galic1
1. University Hospital Sveti Duh, Zagreb, Croatia
2. General Hospital Sibenik, Sibenik, Croatia
Introduction
Eosinophilic myocarditis (EM) is a potentially fatal disease if left untreated. There
are numerous drugs that have been implicated in causing the hypersensitivity
(HS) form of EM but frequently the cause of the disease remains unknown as it
could have a delayed presentation for up to two years. In this case report we
present an atypical clinical presentation of HS EM, possibly caused by
hydrochlorothiazide (HCT), and significant coronary artery disease (CAD).
Case Description
A 63-year-old man presented to the emergency department with flu-like
symptoms. He had a history of chronic bronchitis and arterial hypertension
treated with budesonide/formoterol and HCT. His general physical examination
was unremarkable, without any signs of heart failure. Complete blood count
(CBC) revealed leucocytosis with slightly eosinophilia and elevated troponin and
CRP. ECG showed no changes in ST/T segment. Echocardiography revealed
minimal pericardial effusion for up to 4 mm. Initial right pneumonia was
observed on X-ray. He was treated with amoxicillin/clavulanic acid, azithromycin
and ibuprofen. Fifth day of hospitalization the signs of disease became more
prominent: CBC revealed 19.2x10^9/L leucocytes with 11.2x10^9/L eosinophils
and troponin level was doubled. Pulse doses of corticosteroids (CS)
(methylprednisolone 500 mg i.v.) were started and other therapy was
discontinued. Seven hours later patient was asymptomatic, leucocytes were
normal with slightly eosinophilia. Pulse doses of CS were continued up to three
days when converted to oral CS. Endomyocardial biopsy showed no
inflammation. Coronarography revealed two-vessel CAD, treated with
percutaneous coronary intervention.
How this report contributes to current knowledge
One of the most common cause of EM reported in literature is drug HS. In our
patient HCT is a potential cause. Symptoms, levels of troponin, ECG and
echocardiographic changes were more suggestive for EM than CAD.
Endomyocardial biopsy revealed no EM but it was performed third day after pulse
dosage of intra-venous CS, when symptoms completely vanished. It should be
also noted that EM is a focal disease and biopsy doesn’t have to prove the
diagnosis. It is more obvious that CAD was co-finding, as symptoms of CAD
could not be resolved using CS, and troponin levels would not fall second day
after initiating therapy. CBC with eosinophilic drop powers that hypothesis. Early
administration of systemic CS is necessary regardless of underlying causes, as
delayed treatment may result in fatal outcomes.
P45 Piperacillin-Induced Immune Haemolytic Anaemia - A Severe And
Frequent Complication Of Antibiotic Treatment In Patients With Cystic
Fibrosis.
Philip Specht1, Doris Staab1, Beate Mayer2, Jobst Roehmel1
1. Division of Cystic Fibrosis, Pediatric Pneumology and Immunology,
Charité-Universitätsmedizin Berlin, Berlin, Germany
2. Institute for Transfusion Medicine, Charité - Universitätsmedizin Berlin,
Berlin, Germany
Keywords: Piperacillin, Autoimmune, Haemolysis, Cystic Fibrosis,
Introduction
Two mechanisms of drug-induced haemolysis have been described. Usually both,
extravascular and intravascular haemolysis, are caused by drug dependent
antibodies (ddAb). Extravascular haemolysis presents with mild and less severe
clinical symptoms of anaemia, whereas intravascular haemolysis usually
manifests with a rapid destruction of red blood cells caused by antibodymediated complement activation leading to acute clinical symptoms.
Interestingly more than 50% of all piperacillin-induced immune haemolytic
anaemia (PIHA) cases investigated at a reference laboratory in Germany were
patients with cystic fibrosis (CF). Therefore the investigated hypothesis of this
study is a higher prevalence for PIHA in patients with CF as for the general
population. Additionally risk factors for PIHA are systematically assessed.
Method
Included were all patients with CF older than 12 years who were admitted to the
hospital for antibiotic treatment. Past transplantation was an exclusion criterion.
Blood samples were obtained in the beginning and at the end of a given
intravenous treatment. Direct antiglobulin test (DAT) and indirect antiglobulin
test (IAT) were performed using standard techniques. For positive samples an
antibody differentiation was done. DdAb were investigated using gel technique.
Thus we prepared a 1mg/mL drug solution or used ex-vivo antigens, respectively
and incubated it for 30 minutes in presence of patients’ plasma and group O
RBCs. The individual prior exposure to piperacillin and information concerning
atopy and microbiology are documented.
Results
In the ongoing trial 2 out of 20 patients developed a PIHA. This is a high
prevalence compared to the general expectation of approximately 1:1000000.
Both had ddAb but no complement activation. This is typical for extravascular
haemolysis. Clinical symptoms of haemolysis were mild but there was a drop of
haemoglobin by 4 mg/dL. The study will be finished by April 2016.
Conclusion
These results suggest a higher prevalence of PIHA in patients with CF than
expected in the general population. This is backed by several case reports.
Possibly this is due to the exposure to piperacillin. Therefore PIHA should be
considered when treating patients with CF.
P46 Progesterone Triggered Pemphigus Foliaceus - Case Report
Sandra Jerkovic Gulin1, Caius Solovan2, Anca Chiriac3
1. Department of Dermatology and Venereology, General Hospital Sibenik,
Sibenik, Croatia
2. Department of Dermatology, University of Medicine and Pharmacy,
Tamisoara, Romania
3. Dermatology Department, Nicolina Medical Centre, Apollonia University,
„P.Poni“ Research Institute of Macromolecular Chemistry, Iasi, Romania
Introduction
Pemphigus foliaceus (PF) is a benign variety of pemphigus (P) characterized by
acantholysis in the upper part of epidermis, induced by immunoglobulin G (IgG)
autoantibodies (mainly IgG4 subclass) targeting desmoglein -1 (dsg-1). Clinical
expression of PF is based on the presence of scaly and crusted erosions on an
erythematous base, flaccid blisters, minor or no involvement of mucous
membranes and with seborrheic distribution and aspect of the lesions in early
stages of the disease. PF is classified into four types: endemic (fogo selvagem),
idiopathic, erythematosus (Senear-Usher syndrome) and drug-induced. Drugs
triggering or inducing PF reported in literature are penicillamine, bucilamine,
captopril, lisinopril, enalapril, fosinopril, candesartan, tipronin and rifampicin.
Case Description
A 45-year-old woman presented with facial erythema, multiple erythematous
papules and plaques, few scaly plaques, shallow erosions and superficial blisters
on an erythematous base localized on the upper chest and upper back in „V“
distribution, acompanied by pain and burning sensation. Mucous membranes
were spared. Lesions appeared two months after initiating systemic therapy with
medroxyprogesterone acetate 10mg daily for 14 days per month for
metrorrhagia. Biopsy revealed subcorneal cleft within the upper epidermis with
acantholytic keratynocytes. Direct immunofluorescence (DIF) of perilesional skin
showed intercellular, intraepithelial IgG. Indirect immunofluorescence (IIF)
showed intercellular, intraepithelial IgG, with higher fluorescent intensity in the
upper dermis. The diagnosis of possible drug induced PF was presumed based on
clinical, histological and immunological grounds. The suspected culprit drug –
progesterone was discontinued. Treatment with high-potency topical
corticosteroid (betamethasone) in combination with gentamicin ointment twice
daily was started. After 4 weeks of treatment, lesions resolved almost
completely. Close follow-up was recommended.
How this report contributes to current knowledge
Although PF often occurs spontaneously, it may be triggered by certain
medications. A case of localized PF induced by topical imiquimod treatment has
been recently reported, based on an unknown mechanism of acantholysis,
probably due to antibodies to dsg-1. Drug as a trigger must be suspected in
every newly diagnosed P. Indentification and elimination of triggering drug may
soothe the clinical symptoms and shorten the treatment.
P47 Ramipril - Triggered Generalized Pustular Psoriasis
Paola Djurinec1, Kresimir Kostovic1, Mirna Bradamante1, Sandra Jerkovic
Gulin2, Romana Ceovic1
1. Department of Dermatology and Venereology, University Hospital Center
Zagreb and School of Medicine Zagreb, Zagreb, Croatia
2. Department of Dermatology and Venereology, General Hospital Sibenik,
Sibenik, Croatia
Introduction
Generalized pustular psoriasis (GPP) is an extreme and serious form of
psoriasis (P) with tiny, sterile, yellow pustules on an erythematous base. The
clinical presentation of drug-provoked P include more often generalized plaque P
and erythroderma, and rarely palmoplantar pustulosis or GGP. Drugs can cause
a) precipitation of P de novo in predisposed or nonpredisposed individuals; b)
exacerbation of pre-existing psoriatic lesions; c) induction of lesions in clinically
normal skin in patients with P; and d) development of treatment-resistant
P. Angiotensin-converting enzyme inhibitors (ACEIs) are widely used to control
hypertension and are considered to be possible triggering, exacerbating or
inducing agents of P. Rarely, ACEIs have been reported in the literature as
inductors of GPP. We present our first case of ramipril-triggered GPP.
Case Description
46-year-old women presented with low-grade fever, erythema, small pustules 12 mm in size and exfoliation involving skin on trunk, extremities, palms and
soles. She had no previous history of P or family history of P. She began taking
the new antihypertensive – ramipril two months before the onset of symptoms.
Laboratory findings showed elevated erythrocyte sedimentation rate and Creactive peptide with other biochemical findings within normal limits. Gram
stained smear examination of pustules were negative and the pus culture was
sterile. We set up a working diagnosis of GPP based on history, laboratory
findings and clinical picture and the main differential diagnosis was acute
generalized exanthematous pustulosis. Biopsy was performed. Ramipril as
suspected culprit drug was discontinued and replaced with valsartan. We started
the treatment with acitretin 50mg/day which resulted in good initial therapeutic
response. On the basis of clinical picture, biopsy and satisfactory therapeutic
outcome, the diagnosis of GPP was confirmed.
How this report contributes to current knowledge
Only one case of ramipril-induced GPP in patient with psoriatic arthritis has been
published in the literature. According to our knowledge, we present a first case of
ramipril-triggered GPP in an individual without personal and family history of P.
As P is a common skin disorder, knowledge of the factors that are inducers,
triggers, or aggravators of the disease is of utmost importance for clinicians.
Drug cessation or replacement may play a crucial role in the treatment outcome
so taking a detailed history is decisive.
Poster Walk 6: NSAIDs (P48 – P56)
P48 Aspirin Desensitization In Cardiovascular Disease – Portuguese
Experience
Jose Pedro Almeida1, Joana Caiado1, Elisa Pedro1, Pedro Canas Da Silva2,
Manuel Pereira Barbosa1
1. Immunoallergology Department, Centro Hospitalar Lisboa Norte/Hospital
Santa Maria, Lisbon, Portugal
2. Cardiology Department, Centro Hospitalar Lisboa Norte/Hospital Santa
Maria, Lisbon, Portugal
Keywords: Aspirin Hypersensitivity, Drug Desensitization, Anaphylaxis
Introduction
Several studies have demonstrated a reduction in adverse cardiovascular events
with the administration of dual antiplatelet therapy (aspirin and clopidogrel) to
patients (pts) with coronary artery disease, especially in the prevention of
thrombosis after implantation of bare-metal and drug-eluting stents. However,
when pts have aspirin hypersensitivity (AH) this treatment is limited, and they
are maintained on monotherapy with clopidogrel. Aspirin desensitization (AD) is
the alternative for these individuals. The aim is to describe the experience of a
Portuguese Allergy Department in AD on cardiovascular pts, between April 2006
and January 2016.
Method
Thirty pts with previous history of AH who needed dual antiplatelet therapy due
to cardiovascular disease (female-14;male-16), mean age 64 years-old, were
desensitized to aspirin. The clinical presentation of AH was asthma (6 pts),
anaphylaxis (4 pts), cutaneous rash (7 pts), angioedema (13 pts), in some cases
with very remote reactions (>20 years ago). In most pts (22 out of 30), AD was
performed immediately after percutaneous coronary intervention (PCI). Most AD
were performed in Cardiology Department (27); 3 pts with planned AD were
desensitized at the Allergy Day-Care Unit ; oral doses were increased every 3060 minutes (target dose 152.5mg) under a 4.5-hour protocol. Pre-medication
was not administered.
Results
All pts successfully completed AD, although there were 2 reactions 30 minutes
after the procedure: a 63 year-old man who developed acute rhinitis and
conjuntivitis, eyelid angioedema and dry cough; and a 75 year-old man who
developed acute generalized urticaria. All pts were monitored after AD, and are
still on daily aspirin 100 mg (there were neither hypersensitivity reactions nor
drop-outs).
Conclusion
Despite positive clinical history of AH, some pts had a remote reaction, and due
to the emergency of the procedure we were not able to confirm their AH. This
fact could in part explain the low incidence of reactions during AD; another
reason could be the smaller dose of aspirin used as antiplatelet (100-150mg)
compared with the dose to which they previously reacted (>500mg). Some
authors advocate that AD should be performed before PCI, but PCI could provide
greater hemodynamic stability and therefore allow a safer AD. Based on our
experience, AD is safe and efficacious, even when performed after PCI, with all
pts responding to the desensitization procedure.
P49 Astma And/Or Rhinitis To NSAIDs With Good Tolerance To ASA.
Gador Bogas1, Natalia Blanca-López2, Diana Pérez-Alzate2, Inmaculada Doña1,
José Augusto Agúndez3, Elena García-Martín3, José Antonio Cornejo-García4,
Cristobalina Mayorga4, María José Torres1, Gabriela Canto2, Miguel Blanca5
1. Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga,
Spain
2. Allergy Service, Infanta Leonor University Hospital, Madrid, Spain
3. Department of Pharmacology, University of Extremadura, Caceres, Spain
4. Research Laboratory and Allergy Unit, IBIMA, Regional University Hospital
of Malaga, UMA, Malaga, Spain
5. Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA,, Malaga,
Spain
Introduction
Subjects with hypersensitivity reactions to NSAIDs with airways involvement can
develop rhinitis and or asthma after the intake of ASA and other NSAIDs that are
strong COX-1 inhibitors. Some cases may also respond to weak COX-1 and
selective COX-2 inhibitors. The hallmark characteristic is that symptoms are
triggered by asthma and that in most instances subjects have a pre-existing
respiratory disease. We studied if subjects can be selective responders to some
NSAIDs including weak COX-1 or selective COX-2 inhibitors having good
tolerance to ASA.
Method
Subjects reporting rhinitis and/or asthma to a single NSAID with good tolerance
to ASA were evaluated. An allergological evaluation was carried out plus a
controlled challenge with ASA for verifying tolerance. In a second step we
proceed to a controlled challenge with the culprit drug involved. FEV1 and
acoustic nasal rhynomanometry were measured with values lower that 12% and
30% respectively considered as a positive response. Also nasal and bronchial
symptoms were recorded.
Results
We confirmed in 21 cases the appearance of nasal and/or bronchial symptoms by
objective parameters (decrease in FEV1 and/or decrease in nasal volume cavity)
after the administration of the drug. The drugs involved were ibuprofen in 4
cases, paracetamol in 4 cases, desketoprofen in 1 and etoricoxib in another.
Conclusion
Selective respiratory responses to a single NSAID with good tolerance to ASA
occur. Although the underlying mechanism is not known, the classical
involvement of the leukotriene’s pathway occurring is aspirin exacerbated
respiratory disease seems to be discarded. This constitutes a new phenotype
within the category of hypersensitivity reactions to NSAIDs.
P50 Clinical Characteristics Of 196 Patients With Non-Steroidal AntiInflammatory Drug (NSAIDs) Hypersensitivity
Sengül Aksakal1, Aytül Zerrin Sin2, Zeynep Peker Koç2, Fatma Düsünür
Günsen2, Ömür Ardeniz2, Emine Nihal Mete Gökmen2, Okan Gülbahar2, Ali
Kokuludag2
1. Karadeniz Technical University Medical Faculty Department of Clinical
Immunology, Trabzon, Turkey
2. Ege University Medical Faculty Department of Allergy and Clinical
Immunology, Izmir, Turkey
Keywords: Non-Steroidal Anti-Inflammatory Drug Hypersensitivity
Introduction
Nonsteroidal antiinflammatory drugs (NSAIDs) as the most frequently prescribed
classes of drugs have been reported to be the second most common cause of
drug hypersensitivity reactions after beta-lactam antibiotics. In this study we
aimed to evaluate the clinical characteristics of NSAID hypersensitivity based on
European Network for Drug Allergy (ENDA)’s classification.
Method
196 patients diagnosed as NSAIDs hypersensitivity between the years of 20132014 were enrolled to the study. The patients were questioned about the other
allergic diseases (rhinitis, asthma, urticarial, personal and familial drug allergy)
besides the demographic features. NSAID reactions were classified as follow :
NSAID induced urticaria/ angioedema (NIUA), single NSAID induced
urticaria/angioedema, anaphylaxis or both (SNIUAA), NSAID exacerbated
cutaneous disease (NECD), NSAIDs exacerbated respiratory disease (NERD),
single NSAID induced delayed hypersensitivity reactions (SNIDR). Acetylsalicylic
acid, diclofenac, paracetamol and meloxicam were the most frequently preferred
drugs for oral provocation test to distinguish of cross-reactive and IgE-mediated
reactions.
Results
Hypersensitivity to NSAIDs was 3 times common in female (%77) than male
(%23). The patients with NERD had atopic history the most frequently (%50). %
6.6 of patients have drug allergy in their family. The frequency of
hypersensitivities was found respectively as follows: NIUA (%46), SNIUAA
(%24), NECD (%15), NERD (%8), SNIRD (%7). The patients who had crossreactive hypersensitivity to many of NSAIDs could be tolerated paracetamol,
meloxicam and nimesulid. Diclofenac (11 cases %23), Flurbiprofen (7 cases %
15), Metamizol (7 cases %15) were induced SNIUAA respectively, But according
to their chemical structure propionic acid derivatives had been caused severe
anaphylaxis mostly. Commonly seen delayed reactions due to NSAIDs are
maculopapular eruptions and fixed drug eruption.
Conclusion
NSAIDs were caused NIUA, SNIUAA and NECD most frequently (%85) although
NERD and delayed reactions were quite rare. There are still unexplained points in
these cases. Therefore there are needed more clinical studies.
P51 Development Of Immediate Hypersensitivity To Several NSAIDs
Maintaining Good Tolerance To ASA
Natalia Pérez-Sánchez1, Natalia Blanca-López2, Diana Pérez-Alzate2, Gador
Bogas1, Inmaculada Doña1, María Salas1, María José Torres1, Miguel Blanca1,
Gabriela Canto2
1. Allergy Unit, Malaga Regional University Hospital-IBIMA, Malaga, Spain
2. Allergy Service, Infanta Leonor Hospital, Madrid, Spain
Introduction
Subjects responding to several NSAIDs including ASA are considered crosshypersensitive, whereas those responding to only one NSAID with tolerance to
other chemically unrelated NSAIDs are considered selective responders.
However, in some cases, patients that develop immediate reactions to several
NSAIDs are classified as cross-hypersensitive without assessing ASA tolerance.
Case Description
A 70 year-old woman, without allergic history, referred that in 1996 she
developed two episodes of urticaria less than an hour after paracetamol intake.
Three years after, she had developed three episodes of urticaria 90 minutes after
dipyrone intake. At that time she was allergologically evaluated: intradermal test
(ID) with dipyrone (2 mg/ml) and paracetamol (0.1 mg/ml) were positive. She
was challenged with ASA showing tolerance at full therapeutic doses (500 mg).
In 2012, she suffered from an episode of facial angioedema and pruritus in the
tongue after celecoxib intake. She reported previous tolerance to this drug on
many occasions. In September 2014, she was re-evaluated: ID to paracetamol
was negative (0.1 mg/ml), and ID and basophil activation test (BAT) to dipyrone
were positive. Drug challenges: 60 minutes after achieving a cumulative dose of
paracetamol 300 mg, she developed generalized pruritus and urticaria. Two
weeks later, she presented pruritus in the tongue and ears, nasal itching and
obstruction, and wheals in the neck after provocation with a cumulative dose of
100 mg of celecoxib, with no changes in FEV1 values. After another interval of
two weeks tolerance to etoricoxib was observed at full therapeutic doses. Two
weeks later the patient tolerated ASA and ibuprofen during controlled challenge
until therapeutic doses. In addition, around two months later the patient received
two independent two day treatment courses with these drugs, separated by a
two week time interval.
How this report contributes to current knowledge
Subjects may develop an immediate response to a number of different NSAIDs,
including some COX-1 and/or selective COX-2 inhibitors but tolerate strong COX1 inhibitors. This case shows the importance of testing for ASA tolerance when
confronted by a patient who responds to several chemically unrelated NSAIDs.
P52 Diagnosis Of Hypersensitivity Reactions To Paracetamol In A Large
Serie Of Cases
Inmaculada Doña1, Maria Salas1, Francisca Gomez1, Natalia Blanca-Lopez2,
Diana Perez-Alzate2, Gador Bogas3, Esther Barrionuevo1, Maria Jose Torres1,
Inmaculada Andreu4, Miguel Ángel Miranda4, Gabriela Canto2, Miguel Blanca1
1. Regional Hospital of Málaga-IBIMA, Málaga, Spain
2. Infanta Leonor Hospital, Madrid, Spain
3. Regional Hospital of Málaga, Málaga, Spain
4. Dpto. Química /Instituto de Tecnología Química –UPV-CSIC, Valencia,
Spain
Introduction
The most important drug involved in hypersensitivity drug reactions (HDR) are
NSAIDs. Two mechanisms are involved: immunological sensitization (specific
IgE or T-cell) and pharmacological (COX-1 inhibition). Paracetamol, one of the
drug most highly consumed all over the world, has been implicated in HDR. The
contribution these mechanisms in HDR to paracetamol is not well known. We
studied a large group of patients who developed one/several episodes indicative
HDR to paracetamol.
Method
Patients with reactions to paracetamol were classified as cross-hypersensitivity
(CH) if they responded to two others NSAIDS not chemically related including
ASA. If only paracetamol was implicated, drug provocation test (DPT) with ASA
was required: if positive, they were included as CH and if negative, as selective
responders (SR). In cases who reported respiratory symptoms, nasal provocation
test with L-ASA were performed. Atopy status was also assessed with prick test
to inhalant allergens.
Results
A total of 350 patients with confirmed diagnosis of HDR to paracetamol were
included: 288 (82.28%) resulted to be CH and 62 SR (17.71%). Within the CH
group, following the ENDA classification, 181 (62.84%) were NIUA, 25 (8.68%)
NERD, 16 (5.55%) NECD, and in 60 (20.83%) blended reactions. A total of 46
(25.41%) patients required a positive DPT for diagnosis. Nasal challenge with LASA was positive in 19 (82.6%) patients with clinical history suggestive of NERD.
Within SR group, 56 cases (90.32%) were SNIUAA ( reaction less than 24),
being anaphylaxis the most frequent clinical entity (29 (51.78%), followed by
urticaria/angioedema (16; 28.57%), angioedema (6; 10.71%), urticaria (4;
7.14%) and fixed drug eruption (1; 1.78%). A total of 18 (32.14%) patients
required a positive DPT to paracetamol for diagnosis. The remaining 6 (9.67%)
cases were SNIDHR as they had the reaction more than 24 hours after
paracetamol administration: 4 (66.66%) maculopapular exanthema and 2
(33.33%) exanthema with desquamation. One patient had respiratory symptoms
and was confirmed as SR.
Conclusion
These data indicate that when patients develop a HDR to paracetamol after
carried out the allergological work-up, the 80% of patients who developed a
positive response were CH with a lower proportion being SR. DPT was needed in
more than 20% of cases to achieve the diagnosis.
P53 Hypersensitivity To Paracetamol According To The New
Classification Of Hypersensitivity To NSAIDs
Gabija Didžiokaite1, Olesia Gaidej2, Simona Kašinskaite3, Violeta Kvedariene3
1. Vilnius University, Faculty of Medicine, Vilnius, Lithuania
2. Vilnius University Hospital Santariskiu Klinikos, Centre of Internal
Medicine, Vilnius, Lithuania
3. Center of Pulmonology and Allergology, Clinic of Infectious, Chest
diseases, Dermatology and Allergology, Vilnius University Hospital
Santariskiu Klinikos, Vilnius, Lithuania
Keywords: Paracetamol, Diagnostics, Provocation Tests, Drug Hypersensitivity
Introduction
Paracetamol is often proposed as a safe alternative to the patients with
hypersensitivity to NSAIDs. However, reactions induced by this drug can
manifest in a wide variety of symptoms.
Aim: To evaluate hypersensitivity to paracetamol in Lithuanian adult population
according to the new classification of hypersensitivity to NSAIDS.
Method
We followed 183 adult patients (211 clinical histories) of suspected
hypersensitivity to paracetamol in the Pulmonology and Allergology Centre of
Vilnius University Hospital Santariskiu Klinikos. The median age of patients was
42.5 [32.75 – 53.25] years. Most of the patients were females 144 (78.7%).
14 medications containing paracetamol were reported. ENDA questionnaires
were completed, patch and drug provocation tests (DPTs) were performed to
confirm the diagnosis.
Results
We adapted our clinical cases to the new classification of hypersensitivity to
NSAIDs and divided our patients into 5 categories. 53 cases (47 patients) were
nonimmunologically mediated (cross-reactive) hypersensitivity reactions to
NSAIDs: 4 cases of “NSAIDs-exacerbated respiratory disease”, 4 cases of
“NSAIDs-exacerbated cutaneous disease” and other 45 cases (39 patients) of
“NSAIDs-induced urticaria/angioedema (NIUA)”. 86 cases (75 patients) were
immunologically mediated (non-cross-reactive) hypersensitivity reactions to
NSAIDs: 63 cases (55 patients) of “Single-NSAID-induced urticaria/angioedema
or anaphylaxis (SNIUAA)” and 23 cases (20 patients) of “Single-NSAID-induced
delayed hypersensitivity reactions (SNIRD)”. 10 cases of bronchospasm without
underlying chronic airway respiratory diseases and 62 cases of anaphylaxis,
maculopapular rash and other hypersensitivity reactions induced not only by
paracetamol but also by other NSAIDs could not be classified according to the
criteria of this classification.
Only 25 (13,7%) patients (mostly SNIUAA (10 patients) and SNIRD (7 patients))
underwent further allergological work-up with suspected causative drug. Only 7
(28 %) of them (3 SNIUAA, 2 NIUA and 2 SNIRD), had true paracetamol
hypersensitivity. For 1 patient hypersensitivity was demonstrated by patch
test, and for 6 by DPTs. 6 out of 7 positive test results occurred as skin
reactions.
Conclusion
True hypersensitivity to paracetamol is rare. In our research, only patients with
skin reactions in their clinical history, mostly SNIUAA, were confirmed to be
hypersensitive to this drug.
P54 Ibuprofen And Other Aryl Propionic Derivates Can Induce
Immediate Selective Hypersensitivity Responses.
Diana Perez-Alzate1, Natalia Blanca-López1, Maria Isabel Garcimartin1,
Inmaculada Doña2, Maria Luisa Somoza1, Cristobalina Mayorga3, Maria Jose
Torres4, Gador Bojas2, Jose Antonio Cornejo-Garcia3, Maria Gabriela Canto1,
Miguel Blanca5
1. Allergy Unit, Infanta Leonor University Hospital, Madrid, Spain
2. Allergy Unit, Regional University Hospital of Malaga, Malaga, Spain
3. Research Laboratory and Allergy Unit, IBIMA, Regional University Hospital
of Malaga, Malaga, Spain
4. Allergy Unit, Regional University Hospital of Malaga, Madrid, Spain
5. Allergy Unit, Regional University Hospital of Malaga, Malaga, Spain,
Malaga, Spain
Keywords: Aryl-Propionic Derivates, Ibuprofen, Immediate Selective Responses
Introduction
Arylpropionic acid derivatives are the most commonly prescribed and consumed
NSAIDs and very often obtained without medical prescription. From these the
most common is ibuprofen. Within the group of hypersensitivity reactons to
NSAIDs, these drugs are progressivelly involved and include those mediated by
specific immunological mechansims and those classically classified as crossintolerance reactions. Within the first category, IgE mediates or T cell specific
responses may occur. We present a serie of cases with an immediate selective
response to ibuprofen and other arylpropionic derivatives confirmed by drug
provocation tests (DPT). In addition to demostrate selectivity of the response to
these drugs we assesed cross-reactivity between them.
Method
Subjects who reported symptoms indicative of an hypersensitivity reaction to an
NSAIDs were evalauted. A DPT with ASA was carried out to rule out crossintolerance (non allergic hypersensitivity). Imputability of the different aryl
propionic derivatives and assesement of cross-reactivity was carried out by drug
provocation tests. Serum tryptase was quantized in peripheral blood at 2 and 24
hours post episode and in the affected skin by immunohistochemistry at the
momment of the appearance of the reaction.
Results
All subjects included had good tolerance to ASA. After proceeding with the aryl
propionic acid derivative challenge, 42 cases were classified as selective
immediate responders. Ibuprofen was the drug most frequently involved,
followed by naproxen and desketoprofen. We found cases than only responded
to one sngle drug and others who responded to several, confirming crossreactivity. Quantitation of tryptase levels in peripheral blood and skin biopsies
were indicative of an immediate selective response with the involvement of mast
cell activation.
Conclusion
Ibuprofen and other aryl propionic acid derivatives can induce selective
responses in subjects with NSAIDs hypersensitivity. Further studies are in
progress for identifiyng the possible adducts (hapten-carrier complexes)
implicated and the existence of cross-reactivity.
P55 Subjects Developing Immediate Responses To Several NSAIDs Can
Be Selective With Good Tolerance To ASA.
Natalia Blanca-Lopez1, Diana Pérez-Alzate1, Francisco Javier Ruano Perez1,
Inmaculada Doña2, Maria Luisa Somoza1, Inmaculada Andreu3, Miguel Angel
Miranda3, Cristobalina Mayorga4, Maria Jose Torres2, Jose Antonio CornejoGarcia4, Miguel Blanca2, Maria Gabriela Canto1
1. Allergy Unit, Infanta Leonor University Hospital, Madrid, Spain
2. Allergy Unit, Regional University Hospital of Malaga, Malaga, Spain
3. Universidad Politécnica de Valencia, Valencia, Spain
4. Research Laboratory and Allergy Unit, IBIMA, Regional University Hospital
of Malaga, UMA,, Malaga, Spain
Keywords: NSAIDs, Immediate Reactions, Selective Response
Introduction
Hypersensitivity reactions to NSAIDs can be classified as cross-intolerance where
vasoactive mediators are released by nonspecific immunological mechanisms,
and selective responders mediated by IgE antibodies or T cells. Those responding
to several no chemically-related NSAIDs are considered cross-intolerants. The
existence of responders to several NSAIDs with good tolerance to ASA was
studied
Method
We searched in the dabase of the National Spanish Network for the Study of
Adverse Reactions to Drugs and Allergens the possible existence of cases with
immediate reactions to different NSAIDs and good tolerance to ASA confirmed by
drug provocation tests (DPT). In these the selective response to the culprit
NSAIDs was confirmed.
Results
We found 20 cases that acomplished these criteria. The higher number of
episodes occurred with a pyrazolone derivative (dipyrone) followed by ibuprofen
and other arylpropionic acid derivatives (ketoprofen and naproxen), diclofenac,
paracetamol and COX-2 inhibitors. A total of 60 episodes were reported, being 3
NSAIDs involved in 15 cases, and more than 3 drugs in 5 patients.
Conclusion
Subjects with reactions to different NSAIDs but good tolerance to ASA exist. In
patients with multiple responses to NSAIDs if tolerance to ASA is not known it
should be assessed before being considered as cross-intolerants. This study adds
a new phenotype to hypersensitivity reactions to NSAIDs. Further studies are in
progress to determine how many cases with NSAIDs hypersensitivity belong to
these category.
P56 Utility Of Low-Dose Oral Aspirin Challenges For Diagnosis Of Aspirin
Exacerbated Respiratory Disease
Elina Jerschow1, Teresa Pelletier2, Zhen Ren3, Golda Hudes4, Marek Sanak5,
Esperanza Morales6, Victor Schuster1, Simon D Spivack4, David Rosenstreich7
1. Albert Einstein College of Medicine/Montefiore Medical Center, Bronx,
United States
2. Albert Einstein College of Medicine, Bronx, United States
3. Jacobi Medical Center, Ny, United States
4. Albert Einstein College of Medicine/Montefiore Medical Center, Ny, United
States
5. Jagiellonian University Medical College, Bronx, Poland
6. Ferkauf Graduate School of Psychology at Yeshiva University, Ny, United
States
7. Albert Einstein College of Medicine/Montefiore Medical Center, Krakow,
United States
Keywords: Aspirin Exacerbated Respiratory Disease, Fraction Of Exhaled Nitric
Oxide, Leukotriene E4, Oral Graded Aspirin Challenge, Prostaglandin D2
Introduction
Aspirin exacerbated respiratory disease (AERD) is diagnosed through graded
aspirin challenges that induce hypersensitivity reactions and eicosanoid level
changes. It is not known whether diagnostically useful changes also occur after
low dose aspirin challenges that do not induce hypersensitivity reactions. We
investigated the utility of low dose oral aspirin challenges for diagnosing AERD by
measuring different clinical parameters and eicosanoid changes.
Method
Sixteen AERD and thirteen aspirin-tolerant asthma patients (ATA) underwent oral
challenges with low dose (20, 40 mg) aspirin, and diagnostic oral graded aspirin
challenges (up to 325 mg aspirin). Forced expiratory volume in 1 second (FEV1),
nasal peak flow (NPF), the fraction of exhaled nitric oxide (FeNO), and eicosanoid
levels in plasma and urine were analyzed.
Results
In AERD but not in ATA subjects, 40 mg aspirin challenges induced a significant
decrease from baseline in FeNO (19% (±5.1), p=0.001) without causing any
hypersensitivity reaction. The FeNO decrease also occurred after higher dose
aspirin challenges (27.8% (±4.9) (p<0.001)). The sensitivity and specificity of
40-mg-aspirin-induced FeNO changes for identifying AERD were 90% and 100%
with an area under the curve (AUC) of 0.98 (95%CI 0.92-1.00). The low dose
challenge also induced a significant leukotriene E4 urine increase in AERD patients
(from 6.32 (±0.08) to 6.91 (±0.15) log-pg/mg creatinine (p<0.001)) but the
sensitivity and specificity of these changes were less than for the FeNO changes.
Conclusion
The low dose aspirin-induced decrease in FeNO in AERD patients may be useful
for the diagnosis of aspirin allergy without inducing a hypersensitivity reaction.
Poster Walk 7: NSAID 2 (P57 – 65)
P57 Alternate Regulation Of Cyclooxygenase-2 (COX-2) MRNA
Expression May Predispose Patients To Aspirin-Induced Exacerbations
Renato Erzen, Mira Silar, Nissera Bajrovic, Matija Rijavec, Mihaela Zidarn, Peter
Korosec
University hospital for respiratory diseases and allergy Golnik, Golnik, Slovenia
Keywords: Asthma/Rhinitis, Hypersensitivity To Acetylsalicylic Acid, COX-2 MRNA
Expression
Introduction
Exposure to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory
drugs (NSAID) may exacerbate respiratory disease (asthma, rhinitis), cutaneous
diseases (urticaria and angioedema in patients with chronic urticaria, trigger
urticaria, angioedema and anaphylaxis in patients without underlying diseases.
We made a hypothesis that alternate regulation of cyclooxigenase-2 (COX-2)
mRNA expression may predispose patients to ASA-induced exacerbations.
Method
We performed a prospective study of 40 subjects (mean age 49 years, 27
women) who had suspected hypersensitivity to ASA or other NSAID. 20 subjects
had asthma (10 of them also nasal polyposis). We performed provocation tests
(nasal and/or oral) with ASA in all of them. In 14 subjects tests were positive (8
nasal). Gene expression was analyzed in whole blood sample using real-time RT
PCR just before ASA provocation and 4 hours after provocation. We also included
6 Hymenoptera venom allergic patients which were followed after systemic
reaction (SR) during VIT failure and 4 healthy control subjects.
Results
We found significantly important increase of COX-2 mRNA expression in patients
with ASA provocation test (p=0.004). There was no difference in ASA tolerant
patients. COX-1 expression was comparable between ASA tolerant and
hypersensitive patients and showed no dynamic during provocation. There were
no changes in COX-2 expression in subjects with SR during VIT or in healthy
control subjects.
Conclusion
Main findings in our study are: (1) after provocation with ASA COX-2 expression
is increased in subjects with Aspirin intolerance in comparison with subjects who
tolerate Aspirin; (2) during allergic reaction like SR in VIT failure we found no
differnce in COX-2 expression; (3) all subjects that were positive on ASA
provocation test had asthma and/or nasal polyposis.
P58 Anaphylaxis To Diclofenac: What About The Underlying Mechanism?
Leonor Carneiro-Leão, Fabrícia Carolino, Luís Amaral, Carmen Botelho, Eunice
Dias-Castro, Josefina Cernadas
Serviço de Imunoalergologia, Centro Hospitalar de São João, Porto, Portugal
Keywords: Diclofenac Anaphylaxis Mechanism
Introduction
Diclofenac is a phenylacetic acid derivative belonging to the group of
arylcarboxylic acids. NSAIDs have been reported as the 2nd most frequent cause
of drug-induced anaphylaxis and diclofenac was the only NSAID significantly
associated with anaphylaxis. However, some doubts remain about the
pathophysiology of these reactions. Here we describe a case series of
anaphylaxis probably induced by diclofenac.
Method
Retrospective analysis of patients with suspected anaphylaxis to diclofenac
studied in our DAU, who underwent skin tests (ST). Records were analyzed for
clinical signs and symptoms, severity of reactions, ST and oral challenges
(OC). ST were performed with commercially available IV formulation of
diclofenac, in a concentration of 25 mg/ml, diluted from 1x10-4 to 1/1 for IDT
and 1/1 for SPT.
Results
A total of 33 patients were enrolled in the final analysis. Mean age was 50(±
12.75) years, 22(68.8%) were women, 6(18.2%) were atopic. The time elapsed
until the reaction was less than 1 hour in 26(83.2%) cases. Seventeen patients
had grade 4 anaphylaxis and 10 had history of re-exposure with reproducible
symptoms.
Nineteen patients (62.7%) reported reactions only to diclofenac (single-reactors)
and 12 to other NSAIDs (multiple reactors) (8 to acetylsalicylic acid, 2 to
aceclofenac). Twelve single-reactors (63.2%) had positive ST (two with systemic
symptoms during the procedure). Only 4 multiple reactors (33.3%) had positive
tests.
Only 1 diagnostic OC was performed in order to clarify a doubtful history and it
was positive. OC with alternative drugs were performed in 29 patients, with
meloxicam in 17 and etoricoxib in 9. Two patients had skin symptoms during the
alternative OC and both were from the multiple reactors group.
Conclusion
We report a large series of anaphylaxis to diclofenac assessed by skin tests. As
the majority of NSAIDs hypersensitivity reactions are considered to be due to a
non-immunologic mechanism, non-irritative concentrations to IDT and specific
IgE’s are not available. Characteristics such as the severity and time of reaction,
single-reactor status and systemic symptoms during skin tests suggest IgEdependent hypersensitivity in this sudy. The value of intradermal tests and their
non-irritative concentrations remain to be determined.doubtful history and it was
positive.
P59 COX-2 Inhibitors - Are They Always A Safe Alternative In
Hypersensitivity To Nonsteroidal Anti-Inflammatory Drugs?
Luis Amaral, Fabricia Carolino, Eunice Castro, Josefina Cernadas
Serviço de Imunoalergologia, Centro Hospitalar de São João E.P.E., Porto,
Portugal
Introduction
Nonsteroidal anti-inflammatory drugs (NSAID) are one of the most frequent
causes of drug-induced hypersensitivity reactions worldwide. It is generally
assumed that inhibition of cycloxygenase 1 (COX-1) enzyme by the offending
drugs plays a relevant pathogenic role in multiple NSAID reactors. It is generally
expected tolerability to preferential/selective COX-2 inhibitors among patients
with NSAIDs hypersensitivity.
Method
We reviewed the medical records and selected patients referred to our drug
allergy unit in the past five years, with history of reproducible hypersensitivity
reactions to NSAIDs COX-1 inhibitors and positive oral challenge (OC) with
etoricoxib, a selective COX-2 inhibitor, and/or to meloxicam, a preferential COX2 inhibitor.
Results
Inclusion criteria were met in 15 patients, aged 28 to 68 (47±13 years-old), 12
females. Seven patients were atopic. Eight patients had asthma, 5 chronic
rhinosinusitis and nasal polyposis and 3 patients had chronic urticaria. The
primary NSAIDs hypersensitivity reactions were: 8 urticaria and angioedema; 4
anaphylaxis and 3 asthma exacerbation. Eight patients presented a positive OC
with meloxicam: 4 with immediate urticaria and angioedema; 3 with late-onset
of angioedema and 1 with asthma exacerbation. One patient with late-onset
angioedema to meloxicam also had a late-onset of angioedema with etoricoxib.
Eight subjects had positive OC with etoricoxib: 5 with immediate urticarial, 2
with late-onset angioedema and 1 with anaphylactic reaction.
Conclusion
Based on the results of previous studies, it could be tempting to prescribe COX-2
inhibitors in cases of multiple reactors to NSAIDs COX-1 inhibitors, without
establishing its tolerance in a proper setting. However, these data strongly
suggest that, before prescribing an alternative NSAIDs, a provocation test should
always be performed.
P60 Management Of Patients With History Of NSAIDs Reactions Prior To
Coronary Angioplasty
Mona Al-Ahmad1, Tito Rodriguez2
1. Microbiology Department, Faculty of Medicine, Kuwait University, Kuwait,
Kuwait
2. Al Rashed Allergy Center, Kuwait, Kuwait
Keywords: Aspirin , Desensitization , Coronary ,
Introduction
History of NSAIDs hypersensitivity is common in some patients with coronary
artery disease who are in need for coronary angioplasty. These patients require
dual antiplatelet therapy to avoid in-stent thrombosis, and full evaluation of
NSAIDs allergy. We present a cohort of patients with acute coronary syndrome
undergoing aspirin desensitization to evaluate the short- and long-term efficacy
and safety
Method
We developed a dynamic protocol that is based on both the patient
characteristics and onset of reaction after NSAIDs. This challenge/desensitization
protocol is shorter than previously published ones. The objective is to asses short
and long-term efficacy and safety prior to stent placement
Results
A total of 19 patients with history of NSAIDs allergy were challenged with
different doses of Aspirin. All patients tolerated the oral protocol at different
timings of 30-45-90-120 minutes. The dosage given ranges between (21, 41, 81
and 162 mg) of aspirin given by mouth after premedication with montelukast.
We had two patients reacting during the procedure and one during a 6 hourfollow-up. All reactions were limited to the skin. All patients tolerated the
required dose of aspirin within 60-150 min. Those requiring urgent
catheterization were desensitized within 90 min.
Conclusion
Our protocol provide an effective and safe short and long-time administration of
Aspirin 81mg dose in patients with history of NSAIDs allergy
P61 Oral Drug Challenge With Non-Steroidal Anti-Inflammatory Drug
Under Spirometric Control - Clinical Series Of 110 Patients
João Pedro Azevedo, Emília Faria, Beatriz Tavares, Frederico Regateiro, Ana
Todo-Bom
Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
Keywords: NSAID; NSAID-Exacerbated Respiratory Disease; Asthma
Introduction
Oral drug challenge (ODC) is the gold standard for the diagnosis of
hypersensitivity reactions to non-steroidal anti-inflammatory (NSAIDs). If
suspicion of respiratory symptoms, the ODC might include a lung function
evaluation (LFE). Aim: To evaluate the lung function volumes during ODC to
NSAIDs performed in our department between 2010 and 2015.
Method
One-hundred and ten ODCs with NSAIDs under LFE were performed. An
alternative drug was tested in 77 of the patients (70%) whereas 33 were
diagnostic tests (30%). The drugs tested were meloxicam (n=46, 41.8%);
acetylsalicylic acid (19, 17.4%); etoricoxib (16, 14.6%); nimesulide (15,
13.6%); ibuprofen (4, 3.6%); celecoxib (3, 2.7%); metamizol (3, 2.7%);
acetaminophen (3, 2.7%) and diclofenac (1, 0.9%). The criteria for a positive
ODC were: a decrease in FEV1>/=20% of baseline, a decrease of
MMEF75/25>/=25% of baseline or when major symptoms occurred. Statistical
analysis based on independent sample t test and paired t test.
Results
Seventy-nine patients were female (71.8%) (44.8±15.6 years) and 31 were
male (28.2%) (40.5±16.4 years). Sixty-two patients had a previous diagnosis of
asthma (56.4%), 18 of which with diagnosis of NSAID-exacerbated respiratory
disease (NERD) (16.4%).
ODC was positive in 7 cases (4 by decrease of volumes and 3 by reported
symptoms): 5 alternatives and 2 diagnostic (4 with meloxicam; 1 ibuprofen, 1
metamizol; 1 etoricoxib), 2 patients with no previous asthma diagnosis.
Taking into consideration the whole population tested, we observed statistically
significant decreases in FEV1 and FVC values at 30 and 120 minutes after
medication versus baseline; and also a decrease in volumes at 30, 60, 120, 180
and 240 minutes after the second dose vs baseline (p<0.05).
When comparing alternative versus diagnostic ODCs, we found statistically
significant differences in the measurement of FEV1 at one hour after the second
dose (p<0.05).
Conclusion
The number of positive ODCs was low (6.36%). Patients with asthma have an
increased risk of reaction even with alternative NSAIDs. There was a statistically
significant decrease in FEV1 at almost all timepoints after NSAIDs compared to
baseline, even including negative challenges in the analysis. This suggests that
NSAIDs might have a general effect to reduce FEV1.
P62 PREVALENCE AND INCIDENCE OF ANALGESIC HIPERSENSITIVITY
REACTIONS IN COLOMBIA
Pablo Andrés Miranda1, Bautista De La Cruz Hoyos2
1. Universidad Nacional de Colombia, Cartagena, Colombia
2. Centro de Especialistas Santo Domingo - Alergologia, Cartagena, Colombia
Keywords: ANALGESIC, ALLERGY, HIPERSENSITIVITY
Introduction
The most common drug hypersensitivity reactions (DHR) involve analgesic such
as aspirin and other non steroidal anti-inflammatory drugs.
Method
Records with personal history of allergy analgesics diagnosis (ICD-10 code Z886)
of Information System of Social Protection (SISPRO) between 2010 and 2014
were included. To determine the prevalence and incidence of AHR, population
estimates from the National Statistics Department of Colombia (DANE) were
used.
Results
1657 cases with personal history of AHR between 2010 and 2015 were identified.
223 cases were confirmed news diagnoses in the same period. On average 331
cases of AHR per year were estimated. The estimated annual prevalence AHR
were 7 cases per million (2010= 6; 2011= 7.1; 2012=8.1; 2013= 6.8 and
2014= 7.2). The estimated annual incidence AHR were 0.9 cases per million
(2010= 0.8; 2011= 1.1; 2012= 0.9; 2013= 0.8 and 2014= 1). Most cases range
between 19 and 59 years age.
Conclusion
Both under-diagnosis and over-diagnosis AHR are common in the world.
Population studies with confirmatory tests AHR in Colombia are required.
PREVALENCE AHR
COLOMBIA
Cases per million
1-5 años
6-9 años
10-14 años
15-18 años
19-26 años
27-44 años
45-59 años
> 60 años
Total
INCIDENCE AHR
2010
COLOMBIA
% (n)
Cases per million
1-5 años
0 (0)
6-9 años
5.4 (3)
10-14 años
8 (4)
15-18 años
8.3 (2)
2010
%(n)
2011
%(n)
2012
%(n)
2013
%(n)
0.4 (1)
5.4 (15)
8 (22)
8.3 (23)
14.9
(41)
34.8
(96)
19.2
(53)
9.1 (25)
100
(276)
5.1 (17)
6.9 (23)
6.3 (21)
6.9 (23)
13.9
(46)
2.4 (9)
4 (15)
9.2 (35)
7.4 (28)
2011
% (n)
2012
% (n)
2013
% (n)
2014
% (n)
0 (0)
0 (0)
9.3 (5)
7.4 (4)
0 (0)
2.4 (1)
9.5 (4)
7.1 (3)
2.5 (1)
5 (2)
2.5 (1)
10 (4)
8.2 (4)
10.2 (5)
10.2 (5)
18.4 (9)
5.2 (17)
5.2 (17)
10.8 (35)
7.7 (25)
18.8
19.8 (75)
(61)
29.8
26.2
32 (106)
(113)
(85)
16.6
19 (63) 16.4 (62)
(54)
9.7 (32) 11.1 (42) 9.5 (31)
100
100
100
(331)
(379)
(325)
2014
%(n)
3.8 (13)
3.2 (11)
12.1 (42)
10.8 (37)
16.8
(58)
27.7
(96)
14.5
(50)
11.3 (39)
100
(346)
19-26 años
27-44 años
45-59 años
> 60 años
Total
14.9 (4) 20.4 (11) 21.4 (9) 22.5 (9) 20.4 (10)
34.8 (10) 35.2 (19) 26.2 (11) 25 (10) 16.3 (8)
19.2 (8) 18.5 (10) 23.8 (10) 22.5 (9) 8.2 (4)
9.1 (7)
9.3 (5)
9.5 (4)
10 (4)
8.2 (4)
100 (38) 100 (54) 100 (42) 100 (40) 100 (49)
P63 Recent Endoscopic Sinus Surgery Lessens Reactions During Aspirin
Challenge In Patients With Aspirin Exacerbated Respiratory Disease
Teresa Pelletier1, Waleed Abuzeid2, Nadeem Akbar2, Marc Gibber2, Marvin Fried2,
Weiguo Han1, Taha Keskin2, Robert Tamayev2, Golda Hudes2, Simon D Spivack2,
David Rosenstreich2, Elina Jerschow2
1. Albert Einstein College of Medicine, Bronx, United States
2. Albert Einstein College of Medicine/ Montefiore Medical Center, Bronx,
United States
Keywords: Aspirin Exacerbated Respiratory Disease, Oral Graded Aspirin
Challenge, Endoscopic Sinus Surgery, Silent Challenge
Introduction
Aspirin-exacerbated respiratory disease (AERD) is diagnosed clinically through a
positive oral graded aspirin challenge. Upon confirming aspirin hypersensitivity,
aspirin desensitization and treatment has been proven to reduce recurrence of
nasal polyposis and asthma symptoms. However, negative aspirin challenges
have been reported to occur in otherwise aspirin allergic individuals (“silent
challenges”) after intake of antihistamines, leukotriene blockers, or oral
corticosteroids. We sought to determine whether recent endoscopic sinus surgery
(ESS) also affects reactions to aspirin challenge in patients with AERD.
Method
19 AERD patients underwent two aspirin challenges: one before and the other
after (within eight weeks) their most recent ESS. Reactions to aspirin were
evaluated by changes in forced expiratory volume in 1 second (FEVl, percent
predicted), nasal peak flow (NPF), and fraction of exhaled nitric oxide (FeNO).
Results
Decreased time between ESS and challenge was associated with decreased
frequency of positive reactions: all 19 patients with a history averaging 32
months (IQR 9-72) since last ESS, reacted to aspirin. In contrast, only 10
(52.6%) of these patients, challenged on average of 1.1 months (IQR 0.8-1.4)
after ESS, reacted to aspirin. Nine patients (47.4%) had no clinically apparent
reaction to aspirin challenge after recent ESS. In the 10 patients who had a
positive challenge after recent ESS, the decrease in FEV1 during this challenge
was less than during the baseline challenge before ESS: -8.9±1.2% vs. 19.7±3.7% (p<0.01), respectively. NPF decrease was also smaller during the
challenge after recent ESS than before recent ESS, -11.1± 5.1% vs. -25.5±6.2%
(p<0.01), respectively. FeNO significantly decreased in all patients during the
first challenge (-22.2% (IQR -50.6 to -20.9)) and decreased only in those who
had positive challenges after recent ESS (-32.5% (IQR -35.1 to -22.6)), (p=0.3).
Conclusion
Recent ESS could contribute to a false-negative aspirin challenge. Patients who
reacted to aspirin during the challenge after recent ESS had milder reactions
comparing to the challenge before ESS. This presents a clinical dilemma: while
appearing safer, aspirin challenges after a recent ESS may have a decreased
diagnostic sensitivity so that some AERD patients could be misclassified as
aspirin-tolerant. Clinicians should consider the possibility of false-negative
challenges after recent ESS.
P64 Safe Use Of Imidazol Salycilate In A Case Of Multiple NSAIDs
Induced Urticaria-Angioedema
Elisa Boni, Marina Russello, Marina Mauro
Hospital Sant'Anna, Como, Italy
Introduction
Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) has been
classified by Ayuso et al. into different phenotypes. Multiple NSAID-induced
urticaria-angioedema (MNSAID-UA) is presumably related to cyclo-oxygenase 1
(COX -1) inhibition. Patients with MNSAID-UA have reactions to multiple
chemically unrelated molecules while usually they tolerate low COX-1 inhibitors.
Case Description
We report the case of a 32 years old man who experienced several episodes of
angioedema of lips and face after intake of acetyilsalicylic acid (ASA), in one
occasion associated to the intake of paracetamol. Diagnosis of MNSAID-UA was
confirmed by oral drug provocation test (DPT) to ibuprofen, a strong COX-1
inhibitor chemically unrelated to ASA, that induced labial angioedema. DPT with
alternative drugs, defined as low COX-1 inhibitors, was then performed.
Angioedema also appeared with nimesulide and paracetamol. Instead, the
patient tolerated imidazole salicylate.
How this report contributes to current knowledge
Low COX-1 inhibitors as paracetamol and nimesulide not always are tolerated by
patients with MNSAID-UA. This report confirms the safe use of imidazol salicylate
in patients with hypersensitivity to ASA presumably due to non-interference with
the cyclo-oxygenase pathway.
P65 Selective Hypersensitivity Reactions To Ibuprofen – Seven Years
Experience
Marta Ferreira Neto
CHLN-HSM, Lisbon, Portugal
Keywords: Selective, Ibuprofen, Oral Challenges
Introduction
Immunologically mediated (non cross-reactive) hypersensitivity reactions to
nonsteroidal anti-inflammatory drugs(NSAIDs) are classified in two groups:
Single NSAID-induced urticaria/angioedema or anaphylaxis and Single NSAIDinduced delayed hypersensitivity reactions. In these entities patients have
hypersensitivity to NSAIDS belonging to the same chemical group and tolerate
chemically nonrelated ones. Usually there isn’t an underlying chronic disease like
asthma or urticaria. Ibuprofen(Ib), belonging to Propionic acid derivatives(Pad)
group, is one of the most frequently used NSAIDs, with frequent hypersensitivity
drug reactions reports.
Method
We retrospectively analysed all patients(Pt) referred to our drug outpatient visit,
from January 2008 to december 2015, with a selective history of hypersensitivity
reaction to Ib. Oral drug challenges(ODC) were performed, in order to establish
the diagnosis.
Results
<span lang="EN-US" style="line-height: 107%; font-family:; font-size: 11pt;
mso-bidi-font-size: 16.0pt;" en-us;mso-fareast-language:en-us;mso-bidilanguage:ar-sa"="" mso-hansi-theme-font:minor-latin;mso-bidi-fontfamily:arial;mso-ansi-language:="" minor-latin;mso-fareast-fontfamily:calibri;mso-fareast-theme-font:minor-latin;="">A total of 10 Pt, aged
between 18 and 79, 90% female were included. After intake of Ib, 10(100%) Pt
reported cutaneous symptoms: 2(20%) Urticaria (U) and 8(80%) U/Angioedema.
Besides Ib, Flurbiprofen, Dexcetoprofen and Naproxen were also the culprit drugs
in 3 different Pt. All 10 Pt tolerated Acetaminophen after the reaction.
Hypersensitivity reactions were immediate in 3(30%) Pt (<1h), late (1-6h) in
1(10%) and accelerated (8-24h) in 6(60%). ODC were performed with
Ibuprofen, Acetylsalicylic acid (ASA) and Nimesulide (N) in 6(60%) patients, and
in the remaining 4(40%) only with ASA and N. All ODC (100%) with Ib were
positive, with reproductible symptoms, even in the non immediate reactions.
All Pt (100%) had negative ODC with ASA and N.
Conclusion
Single NSAID-induced urticaria/angioedema to Ib was established in 10 (100%)
Pt and to chemically related compounds of Pad group in 3 (30%) Pt. Women
represent the majority, cutaneous symptoms are the only clinical presentation
and 70% are non-immediate reactions. Other strong Cox1 inhibitors (except Pad
group), Nimesulida and Acetaminophen are the alternatives in the 10 patients.
Poster Walk 8: Epidemiological Methods
(P66 – P72)
P66 Allopurinol Hypersensitivity: A 7-Year Review
Lise Brosseron, Daniela Malheiro, Susana Cadinha, Patrícia Barreira, JP Moreira
Da Silva
Centro Hospitalar Vila Nova de Gaia/Espinho, EPE, Vila Nova De Gaia, Portugal
Introduction
Allopurinol, an antihyperuricaemic agent, is used as first-line treatment of
chronic gout. Allopurinol hypersensitivity (AH) is a rare but important cause of
hypersensitivity reactions, ranging from mild cutaneous manifestations to lifethreatening severe cutaneous adverse reactions (SCAR). Despite several risk
factors have been proposed, the underlying mechanisms remain unknown. Our
aim was to characterize a series of patients with suspected AH referred to our
drug allergy department during a 7-year period (2009-2015).
Method
A retrospective analysis was performed, assessing demographic and clinical data.
AH was confirmed by a positive drug provocation test (DPT), positive lymphocyte
transformation test (LTT) or reaction upon desensitization, and considered
probable based only on a suggestive clinical history.
Results
Among a total of 954 patients, 29 (3%) had suspected AH. The mean age was
69±10 years and 16 (55%) were male. Allopurinol was prescribed for gout in 14
(48%), asymptomatic hyperuricemia in 12 (41%) and malignancies in 3 (10%)
patients; 20 (69%) were polymedicated (≥4 drugs). Cutaneous reactions were
reported by 27 (93%) subjects (14 exanthema, 5 urticaria/angioedema, 2 fixed
drug eruption, 3 vasculitis and 3 DRESS). Twenty-six (90%) reported delayed
reactions (DR), 1 reported immediate reaction and 2 were unable to recall onset.
SPT (3) and patch tests (25) were negative in all patients tested. LTT performed
in 12 patients (5 exanthema, 1 urticaria/angioedema, 3 vasculitis and 3 DRESS)
was positive in 4, negative in 5, doubtful in 2 and undetermined in 1. DPT was
positive in 2 out of 11 and long term challenge in 2 out of 8. Four patients were
submitted to desensitization: 3 developed reaction during the procedure,
confirming diagnosis; 2 were able to tolerate treatment. AH was confirmed in 10
(35%), considered probable in 6 (21%), excluded in 7 (24%) and inconclusive in
6 patients. Among confirmed AH patients, all were DR and 80% had started
Allopurinol recently (≤10 days).
Conclusion
As previously described in the literature, our study suggests that AH is rare,
usually presents with delayed cutaneous symptoms and can be related to recent
introduction of Allopurinol. In the diagnostic workup of suspected AH, DPT
remains the gold-standard while patch tests appear to be unhelpful. We discuss
the usefulness of TTL, which seems promising, especially in SCAR where DPT is
contraindicated.
P67 Antibiotic Allergy Labelling Is Associated With Increased Hospital
Readmission Rates In Australia
Brittany Knezevic1, Dustin Sprigg1, Michelle Trevenen2, Jason Seet1, Jason
Trubiano3, William Smith4, Yogesh Jeelall2, Sandra Vale5, Richard Loh6, Andrew
Mclean-Tooke7, Michaela Lucas7
1. Sir Charles Gairdner Hospital, Perth, Australia
2. The University of Western Australia, Perth, Australia
3. Austin Health, Melbourne, Australia
4. Royal Adelaide Hospital, Adelaide, Australia
5. Australian Society of Clinical Immunology and Allergy, Balgowlah, Australia
6. Princess Margaret Hospital, Perth, Australia
7. Pathwest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth,
Australia
Keywords: Antibiotic, Allergy, Adverse Drug Reactions, Delabelling
Introduction
Patients frequently report antibiotic allergies, however only about 10% of
labelled patients have a true allergy. This study investigates the documentation
of antibiotic “allergy” labels (AALs) and the effect of labelling on clinical outcomes
in an adult tertiary hospital in Australia.
Method
We performed a retrospective single-centre cross-sectional analysis of 737
inpatients in a major teaching hospital in Western Australia. All patients were
captured in the 2013 and 2014 National Antimicrobial Prescribing Surveys
(NAPS). NAPS is an annual audit of Australian health services, led by The
Australian Commission on Safety and Quality in Health Care, to assess volume
and appropriateness of antimicrobial prescribing. Data collected by detailed chart
review, included antibiotic adverse drug reactions (ADRs), antibiotic cost,
prescribing appropriateness, prevalence of multi-drug resistant organisms, length
of stay, intensive care admission and readmissions.
Results
Complete data were captured for 687 patients. 278 (40%) were aged 70 or
above, 322 (47%) were female and 279 (41%) were prescribed antibiotics at the
time of audit. AALs were recorded in 122 (18%) of all patients. The majority of
AALs were penicillin labels (n=87; 71%). Details of the clinical reactions to the
culprit antibiotic were documented for 80 of 141 (57%) individual allergy labels:
61 described symptoms consistent with drug allergies and 19 were non-specific
symptoms. Five patients were receiving an antibiotic that would be considered
contraindicated according to their documented allergy status. Females and older
patients were significantly more likely to have an AAL (gender: OR=2.54, 95%
CI=1.69-3.82, p<0.001; for a one standard deviation (19.6 years) increase in
age: OR=1.31, 95% CI=1.06-1.60, p=0.007). Patients with AALs had
significantly more hospital readmissions within 4 weeks (p=0.001) and 6 months
(p=0.025) of discharge, compared with unlabelled patients independent of age
and gender. The majority of patients with AALs (84%) who were readmitted had
a diagnosis of an infection.
Conclusion
This first Australian study shows that purported AALs are common but poorly
documented in hospital records. Patients with AALs are significantly more likely
to require readmissions. There may be a role for antibiotic allergy delabelling to
mitigate the clinical and associated economic burdens for patients with invalid
allergy labels.
P68 Experts' Opinions On Severe Cutaneous Adverse Drug ReactionsReport Of A Survey From The 9th International Congress On Cutaneous
Adverse Drug Reactions 2015
Roni P. Dodiuk-Gad1, Cristina Olteanu2, Wen-Hung Chung3, Neil H. Shear4
1. Department of Dermatology, Ha’emek Medical Center, Afula, Israel
2. Faculty of Medicine, University of Toronto, Toronto, Canada
3. Department of Dermatology, Drug Hypersensitivity Clinical and Research
Center, Chang Gung Memorial Hospitals, Taipei, Taiwan
4. Division of Dermatology, Department of Medicine, Sunnybrook Health
Sciences Centre, Linkou, Canada
Keywords: SJS/TEN, DRESS, AGEP
Introduction
On June 8th, 2015, the 9th International Congress on Cutaneous Adverse Drug
Reactions (cADR) was held at the 23rd World Congress of Dermatology. Eighty
participants attended the congress from 23 countries; a variety of specialists
with different areas of expertise included dermatology, regulatory agencies and
public health, clinical pharmacology, immunology, infectious disease, oncology,
pediatrics, etc. During the Congress, surveys were conducted to learn about the
participants’ experiences and perspectives regarding four major topics:
Pharmacogenomics and Severe Cutaneous Adverse Drug Reactions (SCAR), Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Drug-Induced
Hypersensitivity Syndrome (DIHS), Stevens-Johnson Syndrome and Toxic
Epidermal Necrolysis (SJS/TEN), and Acute Generalized Exanthematous
Pustulosis (AGEP).
Method
Participants answered survey questions anonymously through an electronic
voting system.
Results
In a survey of the pharmacogenomics of SCAR, 21% of participants regularly
conducted genetic screening prior to treatment with carbamazepine (N=53) and
15% of participants regularly conducted genetic screening prior to administration
with allopurinol (N=52). Seventy-eight percent reported that there is a lack of
knowledge among physicians regarding genetic screening for Human Leukocyte
Antigens (HLAs) for preventing SCAR in their country (N=51). In a survey of
SJS/TEN, systemic corticosteroids was the preferred treatment in 45% followed
by only supportive treatment in 18%, intravenous immunoglobulin in 16%, and
cyclosporine in 14% (N=51). In a survey of DRESS/DIHS, 36% regularly assess
reactivation of human herpesvirus-6 (HHV-6) in their management of patients
with DRESS/DIHS (N=53), and 33% monitor late autoimmune complications in
these patients (N=54). In a survey of AGEP, 67% of participants always conduct
assessment for systemic involvement (N=47).
Conclusion
There is a lack of implementation of regulatory agencies recommendations’
regarding genetic screening prior to treatment with carbamazepine or allopurinol.
There is still no international consensus for the management of patients with
SJS/TEN. Assessing reactivation of HHV-6 and monitoring late autoimmune
complications in patients with DRESS/DIHS is not commonly done. Assessing
systemic involvement in patients with AGEP was found to be commonly
conducted.
P69 HLA-A*31-Positive AGEP With Carbamazepine Use And Other Severe
Cutaneous Adverse Drug Reactions (SCARs) Detected By Electronic
Medical Records Screening
Sabine Müller1, Ursula Amstutz2, Lukas Jörg3, Nikhil Yawalkar4, Stephan
Krähenbühl1
1. Department of Clinical Pharmacology and Regional Pharmacovigilance
Center, Inselspital, University Hospital Bern, Bern, Switzerland
2. University Institute of Clinical Chemistry, Inselspital, University Hospital
Bern and University of Bern, Bern, Switzerland
3. Department of Rheumatology, Clinical Immunology and Allergology,
Inselspital, University Hospital Bern, Bern, Switzerland
4. Department of Dermatology, Inselspital, University Hospital Bern, Bern,
Switzerland
Introduction
Pharmacovigilance (PV) programs based on spontaneous reporting of adverse
drug reactions (ADRs) are compromised by underreporting and inconstant data
quality. Underreporting of severe adverse drug reactions by hospitals is in the
range of 95% (Drug Saf 2006;29:385-96). This study aims to assess
underreporting and to evaluate the potential of electronic chart screening for
SCARs in two departments (dermatology and allergology) as a proactive case
detection method regarding detection rate and data quality.
Method
Electronic reports from January 2014 - December 2015 of the allergology and
dermatology units at the Inselspital Bern (Switzerland) were reviewed monthly
for diagnosis of SCARs (AGEP, SJS/TEN, DRESS) and compared to SCARs
reported to the PV service of the clinical pharmacology unit. Cases were
evaluated for standard PV parameters and results of allergologic and HLA testing
if available.
Results
During this 2-year period, 27 SCARs were registered at our PV unit. 2 SCAR
cases were reported spontaneously (1 DRESS, 1 SJS), while 25 SCARs were
detected proactively (13 AGEP, 9 DRESS, 3 SJS). Interestingly, among the
screened charts, a patient with carbamazepine-induced AGEP was a carrier for
HLA-A*31 (HLA-A*3101 to be confirmed), possibly associated with
carbamazepine-induced AGEP (Epilepsia 2014;55:496-506).
Conclusion
Spontaneous reporting is insufficient, even for severe ADRs with well-established
causality. Combination of chart screening with standard PV programs is a
promising method to enhance detection rate and signal quality for rare
idiosyncratic ADRs.
P70 Patients With Suspected Drug Allergy: A Specific Psychological
Profile?
Eunice Dias-Castro1, Ana Leblanc1, Laura Ribeiro2, Josefina R. Cernadas1
1. Allergy and Clinical Immunology Department, Centro Hospitalar S. João
EPE, Porto, Portugal
2. Biochemistry Department. Medical Education and Simulation Department.
Faculty of Medicine, University of Porto, Porto, Portugal
Introduction
There are several studies demonstrating an important association between
allergic diseases and the psychological characteristics of the patients. The
majority involves skin or respiratory diseases and only a few drug allergy (DA).
Patients with adverse reactions to drugs appear to have more psychological
disturbances than those with asthma/rhinitis.
Method
We evaluated psychological characteristics of 115consecutively patients
>16years-old, studied in our Department for suspected DA. Four self-completed
validated questionnaires (anxiety, depression, alexithymia, personality type)
were used. Evaluation of patient emotions at the time of the reaction was also
performed based on a numerical scale to quantify fear/panic and an open
question. The control group included 55 patients from the outpatient clinic
without any history of DA. Description of variables was done through absolute
and relative frequencies. Chi-square and Fisher test were used to evaluate the
association between variables and groups. The magnitude of the associations
was measured by the Odds Ratios. The significance of the difference between the
medium intensity of fear/panic at the time of the reaction by gender was
evaluated by a student t-test for independent samples. All the variables with a
proof value <=0.20 in the univariate analysis were considered for the
multivariate analysis. The level of significance was considered 5%. Statistical
analysis used the SPSS,version 20.0.
Results
There were no significant differences between the 2 groups concerning
demographic or social characteristics, except for age (p=0.025). Allergic diseases
were significantly more prevalent in the control group (51.1%vs.87.3;p<0.001)
but other diseases were significantly higher in the patient group
(67.5%vs.27.8%;p<0.001). The majority of the controls were on regular
medication (68.4%vs.94.2%;p<0.001), although psychiatric medication was
more frequently used in the case group (32.0%vs.5.8%;p<0.001). After
adjustment for age, allergic disease, other diseases and daily medication, the
suspicion of DA did not show any association with psychological characteristics.
The differences between the medium intensity of fear/panic at the time of the
reaction by gender were statistically significant (p=0.022), with males having a
lower result (2.7points vs.3.6).
Conclusion
The suspicion of DA did not show any association with psychological
characteristics of the patients. The analysis of those with confirmed DA is still
ongoing.
P71 Use Of An Electronic Device And A Computerized Mathematic
Algorithm To Detect The Allergic Drug Reactions Through The Analysis
Of Heart Rate Variability.
Arantza Vega1, Raquel Gutierrez Rivas2, Ana Alonso1, Juan Maria Beitia1, Belén
Mateo1, Remedios Cárdenas1, Juan Jesus Garcia-Dominguez2
1. Hospital Universitario de Guadalajara, Guadalajara, Spain
2. Universidad de Alcalá, Alcalá De Henares, Spain
Keywords: Challenge Test, Heart Rate Variability, Electronic Device,
Introduction
Challenge test (CT) is the gold-standard for the diagnosis of drug allergy. Its
implementation involves a high consumption of time and resources and implies
the risk of severe adverse reactions apparence.
Currently there is not a diagnostic tool able to perform an early detection of the
allergic reactions, thus reducing the length of the challenge test and decreasing
the onset of severe allergic reactions.
Heart rate variability has been used for help to the diagnosis of several illnesses.
It has been recently used for the detection of allergic reactions. We explore the
use of a heart rate variability monitoring device to detect in real time the allergic
reactions in patients undergoing a CT.
Method
Patients, older than 12 years, with suspected drug allergy that, following the
normal diagnostic protocol, were undergoing a CT and agreed to participate. A
remote monitoring device called Shimmer was placed from10 minutes before the
star of the test until Its completion. Increasing doses of the drug were
administered at 30 or 60 minutes interval untill the end of the test or until the
onset of allergic symptoms. Heart rate variability was analysed by the proposed
mathematic algorithm, and Its results were compared to the CT results.
Results
One hundred and twenty thee patients were studied: 81 women, 42 men, mean
age 41,8y (14-92). Drugs tested included NSAID (50), Betalactamics (40), other
antibiotics (8) and others (25). The drug CT was positive in seven of them
(5,6%).
The algorithm detection showed a positive result in nineteen patients and a
negative one in 104. Its sensitivity and specificity were 57% and 87%
respectively. When NSAIDs CT were ruled out the results improved reaching
100% sensitivity and 96% specificity. The global negative predictive value was
97%.
The detection took place at least 90 minutes before the onset of symptoms.
Conclusion
The use of a heart rate variability device with a mathematic algorithm can be a
useful tool in drug allergy diagnosis. Further studies are needed.
P72 Variation In ERAP Influences Risk For HLA-B*57:01 Positive
Abacavir Hypersensitivity
Rebecca Pavlos1, Kaija Strautins1, Ian James1, Simon Mallal2, Alec Redwood1,
Elizabeth Phillips2
1. Murdoch University, Perth, Australia
2. Vanderbilt University, Nashville, United States
Keywords: ERAP, Abacavir, HLA-B*57:01
Introduction
Abacavir (ABC) binds non-covalently to the floor of the peptide-binding groove of
HLA-B*57:01, altering the chemistry and shape of the antigen binding cleft. This
allows previously untolerized self-peptides to be presented by HLA-B*57:01 to T
cells. Endoplasmic reticulum aminopeptidases (ERAPs) trim peptides for MHC
Class I presentation, influencing the degree and specificity of the CD8+ T-cell
response. Genetic variation within ERAP adds to the positive predictive value
(PPV) of the HLA class I risk allele in autoimmune diseases such as HLA-B27
positive ankylosing spondylitis. Considering the altered peptide repertoire
mechanism of ABC HSR we hypothesize that variation in ERAP may help explain
why 45% of patients carrying HLA-B*57:01 can tolerate ABC.
Method
3’UTR, intron and exon encoded SNPs which characterise gene haplotypes were
examined for ERAP1 in HLA-B*57:01+ ABC patch test positive (PT+) patients
[n=53] and HLA-B*57:01+ ABC tolerant controls [n=22] with sequence-based
typing. Rs2248374, a tag SNP for functional ERAP2 haplotypes was also
examined. Haplotype A is tagged by the (A) allele, while haplotype B is tagged
by rs2248374(G). Fisher exact tests and multiple logistic regressions were used
to compare genotypes between ABC HSR PT+ and tolerant groups.
Results
HLA-B*57:01+ ABC tolerance was associated with rs27434(GG) (18/22(82%) vs
24/53(45%) in ABC HSR PT+, p=0.005). This SNP maps to the active site within
ERAP1 (AA356). For an HLA-B*57:01 positive population, with 45% of cases
tolerant to abacavir, the estimated chances of tolerance given rs27434 genotype
are AA(0%), AG(13%) and GG(43%). A missense mutation within the domain
junction (rs30187(C)) important in conformational change of ERAP1 (AA528),
was overrepresented in HLA-B*57:01+ ABC tolerant individuals
(p=0.04). Analysis indicated linkage between rs27044 and rs30187, rs17482078
and rs2287987, and between rs30187 and rs27434 (all p < 0.0001). In a
multivariable model with rs27434(GG), the ERAP2 SNP (rs2248374(G)) that tags
haplotype B, characterized by a truncated protein, was decreased in tolerant
individuals (p = 0.005).
Conclusion
ERAP variants are important in the development of ABC HSR. ERAP activity may
influence the repertoire of peptides presented by HLA-B*57:01 or influence early
changes in immunodominant epitope selection. This provides a potential
pathogenic mechanism for the development of ABC HSR or ABC tolerance in HLAB*57:01 carriers.
Poster Walk 9: DRESS / AGEP (P73 – P81)
P73 A Clinical Case Of DRESS Syndrome In A Child After Administration
Of Amoxicillin-Clavulanic Acid
Rita Aguiar1, Anabela Lopes1, Ana Neves2, Maria Do Céu Machado2, MA PereiraBarbosa1
1. Immunoallergology Department.Hospital de Santa Maria-Centro Hospitalar
Lisboa Norte, Lisbon, Portugal
2. Pediatrics Department.Hospital de Santa Maria-Centro Hospitalar Lisboa
Norte, Lisbon, Portugal
Keywords: DRESS Syndrome, Amoxicillin-Clavulanate, Patch Testing
Introduction
Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an
uncommon but serious hypersensitivity drug reaction. It is characterized by a
polymorphic disseminated eruption with fever and multiple organ dysfunction.
DRESS syndrome is a rare entity in children.
The authors describe a case of a children admitted to our hospital for amoxicillinclavulanate induced DRESS syndrome.
Method
CASE REPORT:
Male, 31 months-old, presented to the emergency department with diffuse
erythema involving trunk and extremities, sparing palms of hands and feet,
angioedema of the tongue and fever after treatment with amoxicillin/clavulanate
for cutaneous infection.
Laboratory findings revealed lymphocytosis, eosinophilia (600/µL), and elevated
serum transaminases AST 139 U/L, ALT 440 U/L, LDH 976U/L. No previous drug
allergies were reported at the time of presentation.
On the second day of hospitalization, the patient’s rash was still persistent ant it
appeared petechiae and hemorrhagic suffusion suggestive of vasculitis on the
face, forehead and periorbital without worsening throughout the hospitalization.
Infectious markers and serological tests were negative. Corticosteroid treatment
was started after exclusion of other potentially serious conditions including
infections and hematologic malignancies. The results of the skin biopsy taken
from the lesions revealed superficial perivascular dermatitis involving spongiotic
eosinophils compatible with spongiotic drug eruption. A dramatic improvement
was observed and his clinical and laboratory findings were recovered on the
5th day of the treatment.
The high fever, lymphocytosis and eosinophilia were resolved (eosinophilia rate
was 1,8%). ALT 114, AST 57, without changes of cholestasis
(GGT 28, LDH 567, total bilirubin 0,2 mg/dL). Abdominal ultrasound unchanged.
Specific IgE β-lactams were negative.
Patch tests with β-lactams revealed positive reaction to amoxicillin.
Results
.
Conclusion
Given the significant morbidity early recognition of drug reaction with
eosinophilia and systemic symptoms syndrome and initiation of appropriate
therapy are imperative in limiting morbidity.
In this study, patch testing was a safe and useful method in confirming the
culprit drug in DRESS induced β-lactam. The pathogenesis of DRESS is not yet
entirely clarified, but positive patch tests suggest a drug-dependent delayed
hypersensitivity mechanism.
P74 Acute Generalized Exanthematous Pustulosis (AGEP) Induced By
Mesalazine, Reliable And Oftenly Used Drug To Treat Inflammatory
Bowel Disease
Ceyda Tunakan Dalgiç, Emine Nihal Mete Gökmen, Fatma Düsünür Günsen,
Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Ali Kokuludag, Aytül Zerrin
Sin
Ege University Medical Faculty, Department of Allergy and Clinical Immunology,
Izmir, Turkey
Introduction
Acute generalized exanthematous pustulosis (AGEP) is a rare eruption
characterized by acute, extensive formation of sterile nonfollicular pustules on
edematous- erythematous skin. It is accompanied by fever, peripheral blood
leucocytosis neutrophilia, and sometimes by facial edema, hepatitis and
eosinophilia. Most cases of AGEP (90%) is caused by drugs and acute infections.
Case Description
34 year- old female patient with ulserative colitis had been taken mesalazine
tablets 2400 mg per day for one month. After one month therapy, a cutaneous
reaction characterized by disseminated pustules on an erythematous base
happened and mesalazine was stopped. During the period, lesions was localised
to extremites, so topical therapy used. After the reaction was recovered, because
of severe ulserative colitis, 15 days later mesalazine was restarted. Due to the
second therapy, after the first dosage, she developed multiple disseminated
sterile pustules on an erythematous background, associated with fever and
neutrophilia. Laboratory examinations showed the elevation of white blood cells,
neutrophils, erythrocyte sedimentation rate and C-reactive protein (white blood
cells,9110/mm3; (64.2% neutrophils, 21.4% lymphocytes, 2.7% eosinophils,
11.4% monocytes), erythrocyte sedimentation rate 13 mm/h, C-reactive
protein level 3.27mg/dl). Punch biopsy from pustules revealed subcorneal
pustular formation, perivascular infiltration rich in leukocyte in dermis and
acanthosis in epidermis. No accumulation was detected in immunofluorescence
analyses. Clinical and histopathological findings were considered as AGEP. She
was treated with intravenous corticosteroids, oral antihistamines and topical
corticosteroids. The patient’s rashes decreased within the following 7 days and
then diminished with desquamation.Consent: Written informed consent was
obtained from the patient.
How this report contributes to current knowledge
We report a patient with AGEP after the use of mesalazine. It’s important to
consider AGEP in the differential diagnosis of acute pustular rashes and drugs
should be investigated as causative agents. Knowledge of the clinical features
are necessary to be distinguished from other entities . It’s the first AGEP case
due to 5-ASA derived mesalazine in the literature. As mesalazine has been
oftenly using for inflammatory bowel diseases, clinicians should be aware of its
potential about developing AGEP and be careful about it.
P75 Changes Of Blood Plasmacytoid Dendritic Cells, Myeloid Dendritic
Cells, And Basophils During The Acute Stage Of Drug Reaction With
Eosinophilia And Systemic Symptoms (DRESS) And Other Drug Eruptions
Shao-Hsuan Hsu, Yung-Tsu Cho, Che-Wen Yang, Kai-Lung Chen, Chia-Yu Chu
Department of Dermatology, National Taiwan University Hospital and National
Taiwan University College of Medicine, Taipei, Taiwan
Keywords: Drug Reaction With Eosinophilia And Systemic Symptoms,
Plasmacytoid Dendritic Cell, Myeloid Dendritic Cell, Basophil, Human Herpes
Simplex Virus-6
Introduction
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe
cutaneous drug reaction characterized by exanthematous skin rash, fever,
lymphadenopathies, eosinophilia, atypical lymphocytosis and internal organ
involvement. Reactivation of human herpes virus (HHV)-6 and decreased
plasmacytoid dendritic cell (pDC) in the peripheral blood were putatively related
to the disease, though the causality remained inconclusive.
Method
We recruited 18 patients from July 2013 to May 2014 with the diagnosis of drug
eruptions including maculopapular eruptions (MPE), Stevens-Johnson syndrome
(SJS), fixed drug eruption (FDE) and DRESS. The peripheral blood pDC (linCD123+CD11c-), myeloid DC (mDC, lin-CD123-CD11c+) and basophils (lin-HLADR-CD123+CD11c+) were simultaneously labeled and processed by 4-color assay
method, with the frequencies of such cells counted by flow cytometry. HHV-6
reactivation was determined by the presence of viral DNA in the whole blood
sample or the elevation of anti-HHV-6 IgG in the serum during the convalescent
stage.
Results
Decreased frequencies of pDC were significantly associated with the diagnosis of
DRESS (p = 0.004), presence of atypical lymphocytosis (p = 0.023) and HHV-6
reactivation (p = 0.043), while those of mDC and basophils were unrelated to the
type of drug eruption, presence of atypical lymphocytosis, eosinophilia or HHV-6
reactivation. The reactivation of HHV-6 was only found in DRESS patients, in
which the pDC frequencies consistently showed a decreasing trend.
Conclusion
In this study, we found that decreased pDC in the peripheral blood during the
acute stage is more common in DRESS patients than the other drug eruptions,
while only part of the patients demonstrated measurable HHV-6 reactivation.
mDC and basophils did not show remarkable trend among different drug
eruptions. The decrement of peripheral blood pDC might be the preceding, or
might be the causative, event before HHV-6 reactivation.
P76 Characterization Of Isoniazid/Rifampicin-Specific T-Cell Responses
In Patients With DRESS Syndrome
Young-Min Ye1, Gyu-Young Hur2, Hae-Sim Park1, Seung-Hyun Kim1
1. Department of Allergy & Clinical Immunology, Ajou University School of
Medicine, Suwon, South Korea
2. Department of Internal medicine, College of Medicine, Korea University,
Seoul, South Korea
Keywords: Antituberculosis Drugs, Drug Rash With Eosinophilia And Systemic
Symptoms, T Cell Response, HLA
Introduction
Antituberculosis drugs (ATDs) including isoniazid, rifampicin, pyrazinamide and
ethambutol are commonly used for the treatment of tuberculosis, but
occasionally associated with drug- induced hypersensitive reactions such as
drug rash with eosinophilia and systemic symptoms (DRESS) syndrome and
hepatitis. The culprit drug and mechanistic basis of the hypersensitive reaction
has not been defined. The aim of this study was to find whether drug-responsive
T cell response was detectable in patients with ATD-related DRESS and
characterize the mechanistic features of the T-cell response.
Method
A lymphocyte transformation test (LTT) was performed using peripheral blood
mononuclear cells (PBMCs) from ATD-induced DRESS patients. Subsequently,
drug-specific T-cell clones were generated from the hypersensitive patients. We
measured the drug-specific proliferative responses and interferon-gamma (IFNγ) secretion. Anti-human class I and class II blocking antibodies were used to
analyze HLA-restricted T-cell response.
Results
Strong proliferative responses to isoniazid or rifampicin were detectable in the
patient with DRESS by LTT. Isoniazid/rifampicin- specific T-cell clones were
generated from blood of the patients, but not pyrazinamide or ethambutol. The T
cell clones proliferated and secreted IFNγ when stimulated with isoniazid or
rifampicin. They did not cross-react with each other. T-cell responses were
blocked in the presence of anti-human class II antibodies.
Conclusion
This study identifies isoniazid/rifampicin- responsive T-cells in peripheral blood of
certain patients with ATD-induced DRESS. It highlights an important role of drugresponsive T-cell immune responses in ATD-induced DRESS syndrome.
P77 DRESS Syndrome Secondary To Sulfasalazine With Delayed TEN: A
Case Presentation
Syed . Ali1, Michaela . Lucas2, Peter N Hollingsworth3, Andrew P C Mclean-Tooke3
1. Department of Immunology, Perth, Australia
2. Department of Immunology, Pathwest; QE2 Medical Centre; SMP, PALM,
UWA; IIID, Murdoch University, Perth, Australia
3. Department of Immunology, Pathwest; QE2 Medical Centre, Perth,
Australia
Introduction
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and
potentially life threatening condition. DRESS preceding toxic epidermal necrolysis
(TEN) has only been reported with 3 cases to date.
Case Description
A 31 year old lady presented with a 3 day history of fever, morbilliform rash,
cervical lymphadenopathy and facial oedema. 5 weeks prior she had been
diagnosed with rheumatoid arthritis (RA) and commenced on hydroxychloroquine
and sulfasalazine. Investigations showed an eosinophilia, elevated liver function
tests (LFTs) and high inflammatory markers. Infectious screen including viral
tests was negative. A clinical diagnosis of DRESS was made, all RA drugs were
ceased and she was started on high dose oral corticosteroids. During admission
she developed a marked lymphocytosis, neutrophilia and eosinophilia with
worsening LFTs and coagulopathy. The rash, LFTs and leukocytosis gradually
improved and she was discharged on day 9 to continue on high dose oral
steroids.
She presented 3 days later with worsening of her rash, high fevers and right
upper quadrant abdominal pain associated with worsening of LFTs, anaemia and
thrombocytopenia. 3 doses of IV methylprednisolone were administered.
Haemophagocytic lymphohistiocytosis was considered given a high ferritin and
hypofibrinogenaemia although bone marrow examination showed reactive
changes but no evidence of haemophagocytosis. There was again improvement
in rash, facial swelling and laboratory markers, and she was discharged to
continue high dose steroids.
She re-presented 7 days later with return of fevers, rash, jaundice and
deterioration in her LFTs. Cyclosporin was added but ceased after 4 days due to
concerns regarding worsening LFTs. Liver biopsy showed submassive central
necrosis and prominent bile duct damage. Ganciclovir was added following an
equivocal PCR for HHV-6 on the liver biopsy tissue and she was considered for
liver transplant if her liver failure worsened. On day 40 her LFTs had improved
but she developed mucosal ulceration involving the mouth, eyes and genitals
with bullous skin lesions involving 80% of the body surface which was Nikolsky
sign positive. Skin biopsy was consistent with TEN. She was transferred to the
ICU for aggressive management and intravenous immunoglobulin but
deteriorated and passed away the next day.
How this report contributes to current knowledge
Here, we present a fatal case of DRESS with fulminant liver failure followed by
extensive TEN despite immunosuppression and broad anti-microbial cover.
P78 Drug Rash With Eosinophilia And Systemic Symptoms (DRESS)
Features According To The Culprit Drug
Zohra Chadly, Nadia Ben Fredj, Karim Aouam, Haifa Ben Romdhane, Naceur A
Boughattas, Amel Chaabane
Faculty of Medicine/University hospital/University of Monastir, Monastir, Tunisia
Introduction
The aim of this study was to evaluate the clinical and chronological Drug Rash
with Eosinophilia and Systemic Symptoms (DRESS) characteristics according to
the culprit drug.
Method
We carried out a retrospective study including all cases of DRESS notified to the
Pharmacovigilance Unit of Monastir during 11 years. Diagnosis of DRESS was
based on European RegiSCAR criteria. Imputability was established according to
Begaud’s method. Skin tests were performed according ENDA recommendations.
Results
Fourty seven cases of DRESS were included in our study: 27 men and 20
women, with a mean age of 47 years ±19. Antiepileptics drugs (18 cases: 15
carbamazepine, 2 phenobarbital, and 1 lamorigine) were the most frequent
responsible drugs in our study followed by antibiotics (12: 6 betalactams, 4
glycopeptides, 1 cotrimoxazole and 1 ethambutol), allopurinol (10) and
salazopyrin (7). All patients had pruritic maculopapular rash involving more than
50% of their body surface area. Mucosal involvement was observed mainly with
antiepileptics drugs (5 cases) and allopurinol (4 cases). Lymphadenopathy was
more frequent with salazopyrin and antiepileptics drugs (55% each). Eosinophilia
was observed in 90% of cases with allopurinol, 66% with antibiotics and
antiepileptics drugs, and 57% with salazopyrin. Atypical lymphocytosis was
observed only in 8 cases. Liver was the most common organ affected (74.5%) in
our series. The most frequent type of liver injury was: cytolytic with antibiotics
and allopurinol (58% and 30% respectively) and mixed with salazopyrin and
allopurinol (57% and 50% respectively). Renal failure was observed in all cases
induced by allopurinol. Pulmonary involvement was observed in 5 cases (3with
salazopyrin and 2 with antiepileptic drugs). The mean incubation period was
similar in the four groups of incriminated drugs. The outcome was favorable after
drug withdrawal in 95.7% of cases. Two patients with DRESS induced by
allopurinol died because of multiple organ failure. Skin tests (patch or
intradermal tests) were done in 33 cases. 75% of skin tests with antiepileptics
drugs and antibiotics were positive. Skin tests with salazopyrin and allopurinol
were all negative.
Conclusion
Throughout this study, we point out the variability of DRESS clinical
characteristics according to the culprit drug in one hand and the unsefulness of
skin tests with salazopyrin and allopurinol in the other hand.
P79 Drug Reaction With Eosinophilia And Systemic Symptoms Induced
By Allopurinol: Not Always Easy To Diagnose.
Marina Lluncor Salazar1, Beatriz Pola1, Ana Fiandor2, Teresa Bellón3, Elena
Ramírez4, Javier Domínguez Ortega2, Santiago Quirce5, Rosario Cabañas2
1. Allergy Department. La Paz Hospital Institute for Health Research
(IdiPAZ)., Madrid, Spain
2. Allergy Department. La Paz Hospital Institute for Health Research
(IdiPAZ). Consorcio Piel en RED, Madrid, Spain
3. Immunology Department. La Paz Hospital Institute for Health Research
(IdiPAZ). Consorcio Piel en RED, Madrid, Spain
4. Department of Clinical Pharmacology, Hospital La Paz Health Research
Institute (IdiPAZ), School of Medicine, Universidad Autónoma de Madrid,
Madrid, Spain. Consorcio Piel en RED, Madrid, Spain
5. Allergy Department. La Paz Hospital Institute for Health Research
(IdiPAZ), Madrid, Spain
Keywords: DRESS, Allopurinol, Oxypurinol, LTT
Introduction
DRESS is a life threatening hypersensitivity reaction. Allopurinol is a frequent
cause. Lymphocyte transformation test(LTT) and epicutaneous tests with
allopurinol are usually negative. We report a case with positive LTT to allopurinol
and its metabolite, oxypurinol.
Method
A 37-year-old female attended the emergency room complaining of asthenia,
cough, and generalized edema. She had a history chronic renal insufficiency
stage 4 secondary to focal segmental glomerulosclerosis, high blood pressure
and migraine. She was admitted with respiratory infection, acute kidney injury,
and desquamative skin lesions that had appeared 20 days before. Initially she
had erythema and face swelling, difficulty swallowing, painful papular lesions on
face, scalp and upper trunk, abdomen and thighs. She had been treated with
antihistamines, topical and systemic low dose corticosteroids with clinical
improvement. She was on treatment with omeprazole, valsartan, prednisone,
acetazolamide, allopurinol and ezetimibe/simvastatin. DRESS was suspected. A
team of specialists (dermatologist, allergologist, pharmacologist, nephrologist)
evaluated the patient. Laboratory tests and herpes virus serology were
performed. After discharge she was evaluated on Allergy Unit. LTT was
performed two months later according to Pichler et al. LTT is positive if
stimulation index(SI)≥2
Results
Tests revealed WBC 11,400, 700 eosinophils/mm3(6,2%), creatinine 4,38mg/dl
(baseline 2,8mg/dl), CRP 49,8, GPT 483, GGT 1264 and hyperamilasemia.
Serology was only positive for herpes 6(1/320). According to Kardaun score,
“probable” DRESS diagnosis was established(4 points). She was included in Piel
en Red Registry. Causality assessment according the Spanish Pharmacovigilance
System Algorithm(SFEV) results were: allopurinol +7(probable) and
Conditional(Unrelated) the other drugs. Allopurinol treatment was stopped. She
received a bolus of metylprednisolone intravenously 3 consecutive days,
antihistamines and antibiotics with improvement. She was discharged 15 days
later with corticosteroid treatment (reducing dose) during 14 weeks. Patch tests
were negative with allopurinol, ezetimibe and simvastatine. LTT was positive to
allopurinol and to its metabolite oxypurinol at different concentrations with the
highest stimulation index for oxypurinol(SI 14,84)
Conclusion
We report a case of DRESS by allopurinol in which the diagnosis was difficult to
establish. LTT has been useful to identify the etiological agent.
P80 Drug Reaction With Eosinophilia And Systemic Symptoms Syndrome
Induced By Two Drugs Simultaneously: A Case Report.
Krasimira Baynova, Marina Labella, Manuel Prados
HUVR Seville, Seville, Spain
Introduction
Drug reaction with eosinophylia and systemic symptoms ( DRESS) is a severe
potentially life-threatening druh hypersensitivity reaction with delayed onset( two
to eight weeks after beggining a drug intake). It is characterized by rash, fever,
blood abnormalities and/or internal organ involvement. Most frequently
implicated drugs in DRESS are anti-epileptic drugs. We present a case of DRESS
induced by carbamzepine and paracetamol simultaneously.
Case Description
A 84 year-old cauacsian woman with no previous drug hypersnsitivity history,
complained of generalized maculopapular itchy purplish rash( trunk, abdomen,
upper and lower extremities), peeling skin, fever and general weakness. A month
before she was diagnosed of trigeminal neuralgia and started a treatment with
pregabalin, carbamazepine and paracetamol.Previously the patient had used
paracetamol without adverse reactions. Pregabalin and carbamazepine were used
for the first time. Symptoms disppeared when the three drugs were interrupted
and oral corticoid treament was established.
Peripheral blood test was done when patient was symptomatic. Skin patch test
and lymphocyte activation test ( LAT)with paracetamol, carbamazepine and
pregabalin were performed four weeks after complete recovering. In blood test
was observed eosinophylia( 1000/mm3) and leucocytosis( > 11
000/mm3). Kidney and liver function were normal. Skin patch test(
interpretation in 48 and 96 hours) and lymphocyte activation test were positive
to paracetamol and carbamazepine, and negative to pregabalin.
Pregabalin treatment was continued without adverse reactions. A few months
later our patient took a pill of paracetamol and experienced eosinophylia
and maculopapular rush in abdomen and lower extremities.
How this report contributes to current knowledge
DRESS is a type IV drug hypersensitivity reaction and is commonly induced by
aromatic anticonvulsnts as carbamazepine. Nevertheless any drug intake could
induce this severe reaction , including
" innocuous" drugs as
paracetamol. The allergy work-out should be carried out 4 to 6 weeks after the
complete recovering and should include all involved drugs.
P81 The Drug Reaction With Eosinophilia And Systemic Symptoms
(DRESS) Induced By The Second-Line Antituberculosis Drugs And
Epstein-Barr Virus Infection
Agne Ramonaite, Ieva Bajoriuniene, Brigita Sitkauskiene, Raimundas
Sakalauskas
Department of Pulmonology and Immunology, Lithuanian University of Health
Sciences, Kaunas, Lithuania
Introduction
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe
drug-induced reaction that involves both skin and viscera. Antiepileptic agents,
allopurinol and sulfonamides are the most frequently reported causes. Other
causal factors such as drug metabolites, genetic factors and viral infections have
been also reported.
Case Description
31-year-old female was admitted to the hospital for the treatment of multidrugresistant pulmonary tuberculosis. She was treated with second-line
antituberculosis drugs: moxifloxacin, kanamycin, cycloserine, prothionamide,
para-aminosalicylic acid. After three weeks of therapy she developed high fever
(>39°C), lymphadenopathy in the cervical and axillary regions and pruritic
maculopapular eruption all over the body. Hematologic abnormalities such as
leukocytosis with eosinophilia (1,81x 109/l) and monocytosis (1,85x 109/l) were
detected in peripheral blood of the patient. Hepatitis was asymptomatic and
detected using the liver function tests: serum aspartate aminotransferase (AST
1379 IU/l) and alanine aminotransferase (ALT 1221 IU/l) levels were increased
by approximately 30-40 fold above the normal limits. The positive diagnosis of
Ebstein-Barr infection was based on an increase in the anti Ebstein-Barr
immunoglobulin G titer, implicating an Ebstein-Barr virus reactivation. Based on
the clinic and laboratory findings diagnosis of DRESS was suspected, and all the
drugs were discontinued. Patient’s condition improved after 8 weeks. The skin
patch tests with moxifloxacin, kanamycin, cycloserine, prothionamide and paraaminosalicylic acid were done 2 months after the hypersensitivity syndrome
resolved. The patch tests showed a positive reaction to prothionamide and paraaminosalicylic acid.
How this report contributes to current knowledge
This case reports the development of DRESS caused by late type of
hypersensitivity to second-line antituberculosis drugs (prothionamide and paraaminosalicylic acid) in association with Epstein-Barr virus infection.
Poster Walk 10: Miscellaneous drug
hypersensitivity (P82 – P91)
P82 A Case Of Cycloserine-Induced Lichenoid Drug Eruption Confirmed
With A Lymphocatye Transformation Test
Jae-Woo Kwon1, Shinyoung Park2
1. Department of Allergy and Clinical Immunology, Kangwon National
University School of Medicine, Chuncheon, Korea
2. The research department, Kangwon regional cancer center, Kangwon
national university hospital, Chuncheon, Korea
Introduction
LDE (Lichenoid drug eruption) is a rare form of delayed type drug eruptions.
Among anti-Tb (antituberculosis) drugs, ethambutol is one of the most common
causative drugs to induce LDEs and cycloserine has been reported known as a
rare causative drug of the LDEs.
Case Description
38 years old man presented with pururitus, lichenoid skin lesion on whole body,
and blood eosinophilia (16,824 /ul). He had been treated with isoniazid,
rifampicin, ethambutol, and pyrazinamide for 2 months and then with
ethambutol, levofloxacin, cycloserine for next 2 months because of elevated liver
enzymes. Mild pruritus developed at the start of anti-Tb medications and
aggrevated with development of lichenoid skin lesion 1 month ago. pruritus, skin
lesions, and eosinophilia were improved since anti-Tb medications were
stoped. Patch test showed mild reaction for ethambutol and strong reaction
for cycloserine. Then we performed an LTT (lymphocyte transformation test) and
successfully comfirmed cycloserine as the offending drug.
How this report contributes to current knowledge
This suggests that the cycloserine should be considered as a possible causative
drug of LDE and an LTT could be an option for the diagnosis of lichenoid drug
eruption due to cycloserine.
P83 Allergic Reaction To Topical Eye Drops: 5 Years’ Retrospective Study
In A Drug Allergy Unit
Diana Silva1, Leonor Carneiro Leão1, Fabricia Carolino2, Eunice Castro2, Josefina
Cernadas2
1. Allergy and Clinical Immunology Department, São João Medical Center;
Laboratory of Basic & Clinical Immunology, Faculty of Medicine, Porto
University, Porto, Portugal
2. Allergy and Clinical Immunology Department, São João Medical Center,
Porto, Portugal
Keywords: Drug Allergy; Ocular Allergy
Introduction
Ophthalmic products are widely used and long-term application is frequently
needed. This might lead to ocular surface changes and increase the frequency of
adverse reactions. However, the underlying mechanisms and the causal agent
are usually difficult to ascertain. We aimed to evaluate the patients referred to
our drug allergy unit with suspected hypersensitivity reaction to topical eye
drops.
Method
A cross-sectional, retrospective analysis of the clinical files of all patients studied
in the Drug Allergy Unit of a University Hospital, in the last five years (January
2010 to December 2015) was made. Those with a suspected hypersensitivity
reaction to topical eye drops were selected. Demographic, clinical history and
diagnostic procedures data were collected.
Results
Four patients, two children (2 and 11 years of age) and two adults (49 and 72
years), were referred due to a suspicion of hypersensitivity reaction to topical
eye drops. Both children reacted after atropine conjunctival application. The two
adults reacted with each of the following topical drugs: timolol and moxifloxacin
with tobramycin. All showed local symptoms of conjunctival erythema and
ocular/facial edema immediately after drug administration. The patient who
reacted to timolol presented dyspnea. For diagnostic study, the 2-year-old child
performed conjunctival provocation test (CPT) with increasing doses of atropine
(1mg/ml; 5 mg/ml and 10 mg/ml), with positive reaction with facial erythema at
10mg/ml dose; the 11-year-old child was submitted to skin prick and intradermal
tests with atropine, which were negative, and waits for CPT to complete the
study. The two adult patients performed only diagnostic CPT. The 49-year-old
woman, which reacted with timolol, did CPT with spirometry control, without a
significant change in FEV1 or any clinical symptoms; the 72-year-old male
performed two separate CPT with moxifloxacin and tobramycin, both with
negative results.
Conclusion
Hypersensitivity reactions to topical eye drops are probably underreported in our
clinical practice. In three out of four patient’s hypersensitivity reaction was
excluded after diagnostic work-up. Facial erythema is a frequent dose-dependent
adverse effect to topical atropine, graded conjunctival challenge is important for
establishing the diagnosis. Awareness should be increased for unneeded
avoidance of topical eye drops.
P84 ALLERGY TO HEPARINS
Diana Perez-Alzate, Natalia Blanca-López, Maria Luisa Somoza Alvarez, Maria
Garcimartin, Maria Vazquez De La Torre, Francisco Javier Ruano Pérez, Elisa
Haroun, Gabriela Canto Diez
Hospital Universitario Infanta Leonor, Madrid, Spain
Keywords: Allergy, Hipersensitivity, Unfractionated Heparin And Low Molecular
Weight Heparins,Cross-Reactivity
Introduction
The Incidence of reactions to heparins may be higher than previously
thought. Extensive cross-reactivity among unfractionated heparin and low
molecular weight heparins (LMWH) has been described.
Aim: To characterize the patients with hypersensitivity to Heparins and the
cross-reactivity among heparins in our clinical practice
Method
Retrospective study was performed in our Allergy Unit from 2013-2015. Clinical
data were registered from all patients who developed heparins hypersensitivity.
Skin/challenge test were performed with the heparin involved and with others
LMWH.
Results
From a total of 20 patients, 10 were finally diagnosed of allergy to at least one
heparin. Mean age: 61,25y.o. From these, 37.5% had other drug allergies
(NSAID, Contrast agents) and 37.55% were atopic. Nine out of 10 cases
developed cutaneous symptoms and one anaphylaxis.
Patch test with the suspected drug was positive in one case to Bemiparin and
Enoxaparin. Prick/ID were performed in all patients, with one positive result in
delayed reading.
Positive Subcutaneous challenge were: Enoxaparin in 40%, Bemiparin in 10%,
Enoxaparin and Bemiparin i30%, Enoxaparin, Bemiparin, Nadroparin, Tinzaparin
and Heparin in 10% and Heparin in10%.
Intravenous provocation with heparin was not performed because of the severity
of the episodes developed by the patient (4 anaphylaxis).
Conclusion
- In this study the frequency of heparin allergy is low but increasing, being the
most common type of reaction delayed-type hypersensitivity (DTH).
- We observed a high cross-reactivity among LMWHs and Heparin.
- Challenge is considered the gold standard for the diagnose, being the clinical
findings similar to previous reported.
P85 Allopurinol-Induced Adverse Drug Reactions
Katinka Ónodi-Nagy1, Ágnes Kinyó2, Lajos Kemény1, Zsuzsanna Bata-Csörgo1
1. Department of Dermatology and Allergology, Szeged, Hungary
2. Department of Dermatology, Venereology and Oncodermatology, Pécs,
Hungary
Keywords: Allopurinol, Adverse Reactions, Clinical Characteristics
Introduction
Allopurinol, a xanthine oxidase inhibitor, is the most widely administered urate
lowering drug in the long-term management of chronic hyperuricemia and gout.
In 2% of the treated patients adverse drug reactions, life-threatening cutaneous
and systemic symptoms can develop. Human leukocyte antigen (HLA) genes play
central role in immune reactions. Important association between HLA-B*5801
allele and allopurinol-induced severe cutaneous adverse drug reactions have
been reported.
Method
In the past few years an increase in allopurinol-induced adverse drug reaction
have been experienced among patients at our clinic (University of Szeged).
Therefore we decided to investigate the clinical characteristics of these patients.
Results
Between 2002 and 2008 81 patients were sent to our laboratory center with
suspected allopurinol hypersensitivity for Lymphocyte Transformation Test (LTT).
This number rose to 222 between 2009 and 2015. LTT was positive in 4 cases
out of the 81 patients and in 20 cases out of the 222 patients respectively,
indicating 4.9% and 9% sensitivity. Of all these patients we were able to obtain a
complete clinical history of 35 patients (mean age 68 years), 4 patients in the
first period and 31 patients in the second period. They presented generalized
maculopapular exanthems in 37.14%, drug reaction with eosinophilia and
systemic symptoms in 31.43%, Stevens-Johnson syndrome in 8.57%, erythema
multiforme in 5.71%, vasculitis in 5.71%, bullous drug exanthems in 2.86%,
toxic epidermal necrolysis in 2.86%, acute generalized exanthematous pustulosis
in 2.86% and erythroderma in 2.86%. The primary indication of the treatment
was asymptomatic hyperuricemia in 88.6% of the patients. We concluded that
the concomitant use of allopurinol and certain diuretics, furosemide and/or
hydrochlorothiazide in 28 cases of our 35 patients, and impaired renal function
enhance allopurinol toxicity increasing the risk of adverse drug reaction
developments. Evaluation of the HLA-B*5801 studies are in progress.
Conclusion
Our data show that the use of allopurinol and thus the number of the resulting
hypersensitivity reactions is increasing. The more and more common
hypersensitivity reactions may be the result of the improper drug prescription,
indication and advanced age. Based on our results LTT is not sensitive enough in
proving allopurinol-induced adverse drug reactions.
P86 Analysis Of A Population With Immediate Hypersensitivity To
Corticosteroids - An 11 Year Review
Joana Sofia Pita1, Emília Faria1, Rosa Anita Fernandes1, Ana Moura1, Nuno
Sousa2, Carmelita Ribeiro1, Carlos Loureiro1, Ana Todo Bom1
1. Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
2. Centro Hospitalar de Leiria, Leiria, Portugal
Keywords: Hypersensitivity, Corticosteroids, Skin Tests
Introduction
Due to their anti-inflammatory and immunomodulatory properties,
corticosteroids are highly prescribed. The prevalence of hypersensitivity (HS)
reactions is estimated at <1%. The aim of our study was to characterize a
population of patients referred to our outpatient clinic for suspected immediate
HS to corticosteroids.
Method
Retrospective analysis including 61 patients sent to our Drug Allergy consultation
for suspected corticosteroid HS, from January 2005 to December 2015. We
proceeded to the patients’ clinical evaluation and analysis of the results of skin
prick (SPT) and intradermal tests (IDT) of the following drugs: prednisolone
succinate 125mg/ml, dexamethasone sodium phosphate 5mg/ml,
methylprednisolone sodium succinate 40mg/ml, hydrocortisone 100mg/ml,
betamethasone diopropionate 5mg/ml. IDT were performed with the following
dilutions: 1:1000, 1:100 and 1:10. The tests were read at 20 minutes, and at
24-48h.
Results
We analysed 61 patients with suspected immediate HS to corticosteroids, in
which 77% was female, with a median age of 47 years. Twelve patients had
positive tests results (19%). The population with positive results was mainly
female, 58%, with a median age of 39 (± 16 years). Half of this population had
associated atopic disease (asthma and/or rhinitis). The clinical manifestations
after the drug administration were: anaphylactic reactions in 50%, urticaria
and/or angioedema in 41% and syncope in 8%. In these 12 patients we obtained
6% of positive SPT, and 12% of positive IDT. Thirty percent of positive reactions
occurred with methylprednisolone, followed by dexamethasone (26%),
prednisolone (17%), hydrocortisone (13%) and betamethasone (13%). Eight
patients (66%) presented HS to more than one corticosteroid.
Conclusion
We obtained 19% positive prick and intradermal tests to corticosteroids, being
anaphylaxis the most common reaction in these patients. There was a high
frequency of sensitization to methylprednisolone and dexamethasone. 66% of
patients had HS to more than one corticosteroid, which probably correlates with
the presence of cross-reactivity among these drugs.
P87 Anaphylaxis Against Mivacurium In A 12-Months Old Boy At FirstTime Exposure
Wolfgang Pfützner
Department of Dermatology and Allergology, Philipps University Marburg,
Marburg, Germany
Keywords: Anaphylaxis, Mivacurium, Infant, Anaesthesia
Introduction
Since sensitization against an allergen is an important requirement for the
development of anaphylaxis, drug hypersensitivity reactions are very uncommon
in infants. We report on a 12-months old boy who experienced a severe
anaphylactic reaction during perioperative anaesthesia.
Method
About 5 minutes after receiving fentanyl, propofol and mivacurium for the
induction of anaesthesia, a persistent rush was noticed, followed by a fall of
blood pressure down to 70/40 mm Hg, tachycardia (f = 150/min) and respiratory
distress. Emergency treatment was initiated by i.v.-application of epinephrine,
after which the little boy fully recovered. Two months later he was referred to
our department for allergological evaluation, including both laboratory analysis
and skin tests with different drugs.
Results
Total IgE was 25.5 kU/l with no allergen-specific IgE-antibodies detectable
against pholcodine, latex, egg white and soja, and basal serum mast cell
tryptase was 2.77 µg/l (Thermo Fisher, Germany). Skin prick tests revealed a
positive result to mivacurium but showed negative reactions against fentanyl,
remifentanyl, propofol, rocuronium, and cis-atracurium. Thus, diagnosis of drug
allergy against mivacurium was established, together with cross-reactive
sensitization against another neuromuscular blocking agent (NMBA), cisatracurium. Surgery was rescheduled utilizing rocuronium for muscle relaxation,
which was well tolerated.
Conclusion
NMBAs are the major cause of perioperative anaphylaxis, accounting for about
70% of all cases, with IgE-antibodies directed against quaternary ammonium
compounds (QAC). Hypersensitivity reactions against NMBAs without prior
exposure to this drug class have been reported previously, suggesting
sensitization induced by other QAM-containing substances like disinfectants, food
or industrial materials. However, we are not aware about reports of anaphylaxis
against NMBAs in infants of such a young age. Thus, this case underlines both
the risk of allergic reactions against NMBAs at first exposure and the necessity of
comprehensively testing these drugs even in very small children with the history
of perioperative anaphylaxis.
P88 Antihistamine-Exacerbated Chronic Spontaneous Urticaria:
A Paradox?
Nadine Marrouche, Clive Grattan
Norfolk and Norwich University Hospital, Norwich, United Kingdom
Introduction
Histamine released from mast cells plays a key role in the pathogenesis of
chronic spontaneous urticaria (CSU). However, it is unlikely that histamine alone
is the only mediator of the disease. From clinical experience we know that H1antihistamines, even at high doses, are ineffective in at least 30% of patients.
Antihistamine hypersensitivity has been reported in the literature but CSU
exacerbation by multiple antihistamines in the same patient is rare.
Case Description
A 38-year old female patient presented with a one-year history of recurrent itchy
hives. The clinical history was suggestive of CSU. She was prescribed various
antihistamines including chlorphenamine, loratadine, fexofenadine, and
cetirizine. The patient noticed significant worsening of her urticaria within an
hour of taking any antihistamine. Her urticaria exacerbations responded well to
systemic steroids. The patient was re-challenged with cetirizine when her CSU
was in remission. Within 90 minutes, she developed generalized itchy wheals
which lasted several days. A skin biopsy showed typical urticaria with unusual
prominence of eosinophils suggestive of urticaria with superimposed drug
reaction (Figure 1). The patient was subsequently challenged with oral
acrivastine and a similar reaction was observed.
How this report contributes to current knowledge
The underlying mechanism of antihistamine hypersensitivity remains unclear.
Our patient had a positive oral challenge to multiple antihistamines with at least
a 90-minute delay which suggests that the underlying mechanism is likely nonimmunological. In one case report it was suggested that, in some patients,
antihistamines could paradoxically shift the H1 histamine receptor to the active
confirmation leading to adverse reactions after dosing [*]. Our case highlights
the rare possibility of a drug most commonly used to treat urticaria acting as the
causal agent itself.
*Urticaria induced by antihistamines. González de Olano D et al. J Investig
Allergol Clin Immunol. (2006)
P89 Anti-Osteoporotic Agents-Induced Cutaneous Adverse Drug
Reactions In Asians
Yu-En Chen1, Chun-Bing Chen2, Wen-Hung Chung2, Yu-Ping Hsiao3, Chia-Yu
Chu4
1. College of Medicine, Chung Shan Medical University Hospital and Chung
Shan Medical University, Taichung, Taiwan
2. Department of Dermatology, Drug hypersensitivity clinical and research
center, Chang Gung Memorial Hospitals, Linkou,Taipei And Keelung,
Taiwan
3. Department of Dermatology, Chung Shan Medical University Hospital and
Chung Shan Medical University College of Medicine, Taichung, Taiwan
4. Department of Dermatology, National Taiwan University Hospital and
National Taiwan University College of Medicine, Taipei, Taiwan
Keywords: Severe Cutaneous Adverse Reactions,Anti-Osteoporotic Agents,
Bisphosphonates,Strontium Ranelate, Denosumab
Introduction
New medications such as bisphosphonates and strontium ranelate (a strontium
salt of ranelic acid) have been introduced in the market for the treatment of
osteoporosis and there are few case reports of severe cutaneous adverse
reactions (SCAR) related to anti-osteoporotic agents.Therefore,we tried to
identify the association between anti-osteoporotic agents and cutaneous adverse
drug reaction(cADR) and the appropriate selection of alternative drugs.
Method
We retrospectively analyzed cADRs, including maculopapular
exanthema(MPE),Stevens-Johnson syndrome (SJS) , drug rash with eosinophilia
and systemic symptoms (DRESS), related to use of anti-osteoporotic agents in
Taiwan and Hong Kong from 2011 to 2015. We analyzed the causative antiosteoporotic agents, clinical characteristics, outcomes and further assessed
patients’ tolerability to alternative anti-osteoporotic agents after the development
of anti-osteoporotic agents-related cADRs. We also review the literatures of antiosteoporotic agents-related SCAR.
Results
There were 14 cases of anti-osteoporotic agents-related cADRs, including 6 SJS,
1 DRESS and 7 MPE. The most common causative agents were strontium
ranelate and bisphosphonates. Strontium ranelate was found to be related to
most SCAR cases, including 6 SJS and 1 DRESS. For MPE, there were 3 cases
caused by bisphosphonates, 3 cases caused by strontium ranelate and 1 case
caused by teriparatide. There was no mortality and long-term sequelae of all
SCAR cases. There was no cross hypersensitivity among strontium ranelate,
bisphosphonates, and denosumab (a monoclonal antibody). Patients with
strontium ranelate-related cADRs were tolerant of alternative bisphosphonates
and denosumab. One case of bisphosphonate-induced MPE was also tolerant of
denosumab.
Conclusion
Most of the anti-osteoporotic agents-related cADRs are usually mild. In Asia,
strontium ranelate seems to cause more SJS/TEN than DRESS in comparison
with that in Europe. No mortality was reported among patient with SCARs. Owing
to the structural difference in anti-osteoporotic agents, denosumab was well
tolerated in patients allergic to either strontium ranelate or bisphosphonates as
alternative drug.
Table 2. Strontium ranelate–induced severe cutaneous adverse reactions
Region
Asia
Europe
Tan et
Case series
This study al.[1]/ Lee Cacoub et al.[3]
et al.[2]
Taiwan
Country
and Hong Singapore
France etc
Kong
Culprit anti-osteoporotic agent
SR1
SR
SR
2
Indication to anti-osteoporotic agent OPO
PM OPO
OPO
Ethnicity
Chinese
Chinese
Caucasian
Patients’
Gender
F (83.3)
F (100.0)
F (100.0)
profile
68.7 (in DRESS
Average age (year)
64.7
69.5
group)
No. of SCARs patients
7
2
52
Total case No. 6 (85.7)
2 (100.0)
5 (9.6)
Average latent
29.2
16
Not mentioned
period (days)
SJS/TEN3 Eye
1 (16.7)
1 (50)
Not mentioned
involvementa
Orogenital
Phenotype
5 (83.3 ) 2 (100.0)
Not mentioned
involvement
Total case No. 1 (14.3)
0
47(90.4)
Average latent
90.0
0
33.5
DRESS4 period (days)
Liver
0 (0)
0 (0)
37 (79.0)
involvementb
Kidney
involvementc
Eosinophiliad
0 (0)
0 (0)
1(100.0)
0 (0)
12 (25.0)
43 (91.0)
Persistent DRESS
symptoms (21.3)
Clinical sequelae
Nil
Nil
and relapse of
DRESS (2.0)
8.5 % (in DRESS
Mortality rate
0%
0%
group)
Abbreviation: 1.SR, strontium ranelate; 2.PM OPO, postmenopausal osteoporosis;
3. SJS/TEN, Stevens-Johnson syndrome/Toxic epidermal necrolysis;
4.DRESS, drug rash with eosinophilia and systemic symptoms
*data are n(%) of patients unless otherwise specified
a. Eye involvement : corneal ulcer or symblepharon
b. Liver involvement : 2-fold increase from normal or baseline levels of
serum glutamic oxaloacetic transaminase(GOT),glutamic pyruvate
transaminase(GPT)
or total bilirubin
c. Kidney involvement : >1.5-fold elevation of serum creatinine from the normal
range
d. Eosinophilia : eosinophils count > 500/μL
Ref.
1.Tan, K.W., Y.S. Wang, and Y.K. Tay,Stevens-Johnson syndrome due to
strontium ranelate.
Ann Acad Med Singapore, 2011. 40(11): p. 510-1.
2.Lee, H.Y., et al.Strontium ranelate-induced toxic epidermal necrolysis
in a patient with post-menopausal osteoporosis. Osteoporos Int, 2009. 20(1): p.
161-2.
3.Cacoub, P., et al.,Drug rash with eosinophilia and systemic symptoms (DRESS)
in patients receiving strontium ranelate. Osteoporos Int, 2013. 24(5): p. 1751-7.
P90 DIAGNOSIS OF ALLERGIC REACTIONS TO EYE DROPS
Maria Vazquez De La Torre, Natalia Blanca-Lopez, Diana Perez-Alzate, Maria
Isabel Garcimartin, Francisco Javier Ruano, Maria Luisa Somoza, Elisa Haroun,
Gabriela Canto
Hospital Infanta Leonor, Madrid, Spain
Keywords: Allergy, Eye Drops,
Introduction
Allergic reactions to eyedrops are rare in spite of the extensive use of these
drugs by ophthalmologists. The percentage of this kind of adverse drug reactions
(ADR) is reported to be less than 6 %.
Method
A total of 62 patients with suspect of ADR to eyedrops were evaluated in a period
of 6 years (2008-2014). The allergological evaluation included: clinical history,
patch tests (PTs) and conjunctival drug provocation test (CDPT). PTs with
delayed readings at 48 and 96 hours were performed with the culprit eyedrops,
alternative eyedrops and, in addition, the preservatives of the drugs. The culprit
drugs used were: mydriatics (phenylephrine 100mg/ml, tropicamide 10mg/ml,
cyclopentolate 10mg/ml and atropine 10mg/ml), local anesthetics (tetracaine
1mg/ml, oxibuprocaine 4mg/ml), solutions for glaucoma theraphy (brimatroprost
0.3mg/ml, travoprost 0.4mg/ml, brinzolamide 10mg/ml and timolol 5mg/ml) and
fluorescein 20mg/ml. The preservatives included were: benzalkonium chloride
0.1%, ethylenediamine 1%, phenylmercuric acetate 0.01%, parabens 16%,
polymixin B 3% and thimerosal 0.1%. The CDPT was carried out by instilling one
drop of the ophthalmic solution in the eye, with readings made at 20 minutes
and 24h later.
Results
From the total group, 40 patients (64.5%) were finally diagnosed of allergy to
eyedrops. In 67.5% several mydriatics were involved in the reaction, and in
17.5% of these, a local anesthetic was also implicated. The clinical history
reported by these 40 patients was: blepharoconjunctivitis in 23 cases (57.5%),
conjunctivitis in 16 (40%) and cutaneous erythema only in one case. PTs were
positive in 32 (80%) patients: 100% to phenylephrine and, in only one subject
cyclopentolate in addition to phenylephrine. The CDPT was necessary for the
diagnosis in the remaining 8 (20%) patients, being 7 positive to phenylephrine,
and one to timolol. Phenylephrine was positive in 95% of patients finally
diagnosed of eyedrop allergy. All patients with allergy to phenylephrine tolerated
tropicamide, atropine, and cyclopentolate, except one that had a positive PT with
cyclopentolate.
Conclusion
Phenylephrine is responsible for most of the allergic reactions induced by
eyedrops. PTs are a safe and useful tool for the diagnosis. Tropicamide, atropine
and cyclopentolate seems to be good mydriatic alternatives for these patients.
P91 Diagnostic Approach In Suspected Hypersensitivity Reactions To
Corticosteroids
Fabrícia Carolino, Eunice Dias De Castro, Josefina R Cernadas
Serviço de Imunoalergologia, Centro Hospitalar São João E.P.E., Porto, Portugal
Keywords: Drug Hypersensitivity, Corticosteroids, Skin Tests
Introduction
Hypersensitivity reactions (HSR) to corticosteroids (CS) are rare although there
are a growing number of reports both to systemic and topical CS. There are no
standardized procedures for diagnostic skin testing with these drugs but a panel
is recommended to assess cross-reactivity between steroids. Incremental drug
challenge is still necessary for diagnostic or tolerance assessment purposes, but
in this point safety issues may overcome.
Method
Retrospective analysis of consecutive patients evaluated in our Drug Allergy Unit
for suspected CS HSR, during a 5-years-period. Skin prick tests (SPT) and
intradermal tests (IDT) were performed with commercially available sterile CS
formulations – betamethasone (7 mg/ml), budesonide (0.5 mg/ml),
dexamethasone (4 mg/ml), hydrocortisone (100 mg/ml), methylprednisolone
(62.5 mg/ml) and/or prednisolone (25 mg/ml). Oral solution of deflazacort
(22.75 mg/ml) and nasal-spray suspension of fluticasone (27.5 μg/dose) were
also used for SPT. Patch tests (PT) with a standard and/or complementary CS
series were performed. Drug challenges (DC) used a selected-CS dose ranging
between approximately 0.5 and 1.5 mg/kg/day.
Results
A total of 31 patients were assessed (74.2% females, mean±SDage 36.8±23.2
years) for suspected CS HSR. The main implicated CS were oral deflazacort
(n=11) and oral betamethasone (n=5). 45.2% had immediate reactions and
38.2% late-onset symptoms; 51.6% presented skin/mucosal manifestations. IDT
were performed in 12 patients and were positive to at least one of the tested
drugs in 4 (2 with anaphylaxis and 2 with late-onset skin/mucosal involvement);
2 patients tested positively in IDT for more than 1 CS
(dexamethasone/hydrocortisone and methylprednisolone/hydrocortisone). IDT
were also performed in non-atopic controls. Patch tests in 10 patients revealed
positive results (including the suspected CS) in 2 of them. DC was undertaken
with the suspected systemic CS in 8 patients (no positive challenges and 2
doubtful); the remaining patients were tested for an alternative CS.
Conclusion
Proper validated skin tests may provide the necessary diagnostic evidence in
drug allergy. They are particularly useful in more severe index reactions when
re-challenging is not an option. The accuracy of skin tests needs to be further
established with larger studies.
Poster Walk 11: Miscellaneous drug
hypersensitivity 2 (P92 – P94, P96 – P101)
P92 16 Years Of Experience With Proton Pump Inhibitors (PPIs)
Javier Dionicio Elera, Cosmin Boteanu, Maria Aranzazu Jimenez Blanco,
Rosario Gonzalez-Mendiola, Irene Carrasco García, Antonio Alvarez, Jose Julio
Laguna Martinez
Hospital de la Cruz Roja Madrid, MADRID, Spain
Introduction
Proton Pump Inhibitors (PPIs) are commonly used for the treatment of acidrelated disorders. They are generally well tolerated, with a low incidence of
adverse effects (1%). Omeprazole is the most common PPIs used and its intake
has tripled from 2003 to 2012 in spain. Although hypersensitivity reactions to
PPIs are rare, they are being more reported in recent years maybe due to the
growing use of these drugs.
The aim of this study was to review our experience with the use of PPIs in the
last 16 years.
Method
We undertook a retrospective analysis of 10 858 patients who attended to the
Drug Allergy Unit of Hospital de la Cruz Roja-Madrid, from 1999 to 2014.
We devided our patients in 2 groups according to the increase of intake of PPIs.
Group 1 from 1999 to 2008 and Group 2 from 2009 to 2014.
We consider positive cases those who had Positive skin Prick test or positive
drug provocation test or positive basophil activation test or suggestive history of
PPIs allergy. We excluded patients who quit or refused the study.
Results
A total of 253 patients (2,3%) were attended in the Allergy Unit with suspected
history of PPIs allergy in the last 16 years . From those, 16 (6,3%) were positive
cases.
In group 1, we included 5563 patients, from those, 91 were suspected cases,
and 4 (4,4%) of them were positive
In group 2, we included 5295 patients, from those 162 were suspected cases,
and 12 (7.4%) of them were positive
Conclusion
In our experience, we found an increase in the number of reactions due to PPIs
in the last years. Our results are according to the literature: Hypersensitivity
reactions to PPIs are rare.
P93 ALLERGY EVALUATION OF QUINOLONE INDUCED ADVERSE
REACTIONS
Jaume Martí Garrido, Carla Torán Barona, Carolina Perales Chorda, Ramón
López Salgueiro, Miguel Díaz Palacios, Dolores Hernández Fernández De Rojas
IIS La Fe, Valencia, Spain
Keywords: Quinolone, Allergy.
Introduction
The increasing use of quinolone antibiotics is associated with an increase in
hypersensitivity reactions. The objective of this study is to analyse the cases of
suspected allergy to quinolones referred to an allergy department in a tertiary
level centre during 2015.
Method
We performed a descriptive, retrospective study. Cases were identified from the
medical record administrator programme by searching the terms “quinolone,
norfloxacin, moxifloxacin, levofloxacin or ciprofloxacin”. We collected
demographic and medical data, information of the adverse events, results of the
allergy evaluation and the recommendations for the future use of quinolones.
Results
We analysed 60 cases (26 male/34 female) with an average age of 60,5 years
(6-88). The most frequent clinical manifestations were cutaneous (70%), 11%
digestive, 7% respiratory, 7% neurological, 4% cardiovascular and 1% renal.
The most common symptom were pruritus (25%) and erythema (24%). The
reaction was immediate (within minutes) in 37% and delayed in 45%. The type
of reaction was not described in 18% of cases. The involved quinolones were
ciprofloxacin (40%), levofloxacin (37%), norfloxacin (8%) and moxifloxacin
(8%). The most frequent route of administration was oral (66%), followed by
intravenous (30%), topical (2%) and otic (2%). In two cases quinolones were
directly banned after the adverse event due to the patient clinical condition or it
was not considered necessary due to the lack of evidence on the reliability of the
tests. Skin tests were performed in 40% of cases, with positive results for
ciprofloxacin 78%, moxifloxacin 77%, levofloxacin 57% and none for norfloxacin.
In a case of a generalized delayed reaction, patch tests were negative. In one
case a fixed drug erythema due to norfloxacin was diagnosed without further
check. In 10 cases of severe immediate reactions, BAT was performed 17 times
with 4 positive results for ciprofloxacin and 3 for levofloxacin. In these cases
quinolones were banned. All patients tolerated alternative quinolones to the one
eliciting the adverse event, even when skin tests were positive.
Conclusion
Ciprofloxacin and levofloxacin were the most frequently involved quinolones. Skin
symptoms were the most common clinical manifestations. Allergy evaluation
included skin tests, BAT and controlled exposure in order to identify the
responsible quinolones and search for safe alternatives. The sensitivity and
specificity of these tests are still undetermined.
P94 Bupropion-Induced Acute Urticaria And Angioedema, A Case Report
Emre Ali Acar1, Ayse Aktas2, Aylin Türel Ermertcan3, Peyker Temiz4
1. Celal Bayar University, Faculty of Medicine, Department of Internal
Medicine, Manisa, Turkey
2. Celal Bayar University, Faculty of Medicine, Department of Allergy and
Immunology, Manisa, Turkey
3. Celal Bayar University, Faculty of Medicine, Department of Dermatology,
Manisa, Turkey
4. Celal Bayar University, Faculty of Medicine, Department of Pathology,
Manisa, Turkey
Introduction
Bupropion is a new-generation antidepressant, while its sustained release (SR)
formulation is used in smoking cessation for a long time successfully. Urticaria,
pruritus and rashes can be seen in 1-4% of the patients and anaphylactoid
reactions like angioedema and dyspnea can be seen in 0,1-0,3% of the patients
using bupropion. We wanted to report a case with urticaria and angioedema due
to SR bupropion treatment.
Case Description
A-27-year-old woman without any disease history admitted to a hospital for
smoking cessation. She had 15-pack-year of smoking history and she had
started using 150 mg of SR bupropion. In first 3 days, she had used it once a
day, then she started using twice a day. On tenth day of treatment, generalized
rash with pruritus had been developed. In physical examination, she had
generalized plaques and papules with edema and erythema on his neck, trunk,
upper and lower extremites (Picture 1). She had swelling on her lips as well. With
suspicion of adverse drug reaction, skin biopsy was made. Other physical
examination, blood and urinary laboratory findings were normal. With these
clinical and histopathological findings, urticaria and angioedema diagnosis were
made. She was hospitalized and bupropion treatment was stopped. Systemic
corticosteroid and antihistaminic treatments were started. On third day of
treatment, her skin lesions were regressed.
How this report contributes to current knowledge
Buproprion is a commonly used drug in smoking cessation clinics. Although it is
rare, physicians should be cautious about urticaria, angioedema and anaphylaxis
as adverse drug reactions of bupropion treatment.
P96 Delayed Type Hypersensitivity And Study Of Cross-Reactivity
Between Proton-Pump Inhibitors
Chien-Yio Lin1, Chung-Yee Rosaline Hui2, Ya-Ching Chang2, Chih-Hsun Yang2,
Wen-Hung Chung2
1. Department of Dermatology, Chang Gung Memorial Hospital, Linkou,
Taiwan
2. Department of Dermatology, Drug Hypersensitivity Clinical and Research
Center, Chang Gung Memorial Hospital, Linkou, Taiwan
Introduction
There are six PPIs available for clinical use, which could be set into two groups,
omeprazole/esomeprazole/pantoprazole vs.
lansoprazole/dexlansoprazole/rabeprazole, based on the same basic skeleton,
but differed by virtue of substitutions on both rings. The former three have
changes in their benzimidazole ring, whereas the latter three have changes in
their pyridine ring. Although proton-pump inhibitors (PPI) are relatively well
tolerated, some patients may develop hypersensitivity reactions, which vary from
mild symptoms to life-threatening severe cutaneous adverse reactions (SCARs),
such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN),
acute generalized exanthematous pustulosis (AGEP), and drug rash with
eosinophilia and systemic symptoms (DRESS). Clinicians often overlook the
potential of PPI-related SCARs.
Method
We retrospectively analyzed patients of PPI-related cutaneous adverse reactions
from Chang Gung Memorial Hospital health system during January 2003 to
December 2015. We analyzed the causative PPIs, cutaneous manifestation,
organ involvement, treatment, and complications. We also assessed the crosshypersensitivity to other PPI after the hypersensitivity episode. The causality of
the culprit drugs was further confirmed by in vitro lymphocyte activation test
(LAT) and patch test in some cases.
Results
There were 48 cases of PPI-related cutaneous adverse reactions, with
maculopapular eruption (MPE, n=20), DRESS (n=10), and SJS/TEN (n=9),
contributing the most. Esomeprazole was the most common causative PPI
(n=23, 47.9%), and the liver was the most frequently involved internal organ
(26.7%). One patient (2.1%) died of esomeprazole-induced TEN. Seven patients
allergic to one group of PPI would able to tolerate the other different structured
PPI group, whereas two patients showed cross-hypersensitivity when shifting to
alternative PPI of the same group with similar structure. The drug causality and
cross-reactivity were confirmed by lymphocyte activation test in 53.8% patient of
whom tested; besides, 2 of 5 patient with patch test performed showed
corresponding result to the LAT.
Conclusion
The clinicians should be cautious of PPI-related SCARs. The potential of crosshypersensitivity to similar structured PPI should be aware of, and shifting to
different structured PPI could be considered when PPI is the treatment of choice.
P97 Diagnostic Work-Up In Suspected Hypersensitivity To Proton-Pump
Inhibitors: Looking At Cross-Reactivity
Fabrícia Carolino1, Diana Silva2, Eunice Dias De Castro1, Josefina R Cernadas1
1. Serviço de Imunoalergologia, Centro Hospitalar São João E.P.E., Porto,
Portugal
2. Serviço de Imunoalergologia, Centro Hospitalar São João E.P.E.;
Laboratório de Imunologia, Faculdade de Medicina, Universidade do Porto,
Porto, Portugal
Keywords: Drug Hypersensitivity, Proton-Pump Inhibitors, Skin Tests, CrossReactivity
Introduction
Proton-pump inhibitors (PPI) are widely used in clinical practice and there are
multiple reports of hypersensitivity reactions (HSR), most of them immediate,
and cross-reactivity (CR) between PPI. Specificity of skin tests has to be
determined and there are currently no specific recommendations from the ENDA
group. Aim: We present a consecutive case series of patients with suspected PPI
HSR.
Method
The present study is a case series of patients evaluated in our Drug Allergy Unit
for suspected PPI HSR, in an 8-year period. CR in skin prick tests (SPT) and
intradermal tests (IDT) was assessed using the commercially available parenteral
PPI formulations (esomeprazole 20mg/ml, omeprazole 4mg/ml, pantoprazole
4mg/ml) and crushed tablets in saline (lansoprazole 15mg/ml, rabeprazole
10mg/ml) for SPT. IDT were only performed with parenteral formulations
(1/1000-1/1 dilutions), due to safety and accuracy reasons.
Results
In the studied period, 19 patients (11 female; mean±SD age 50.7±14.2 years)
were assessed for the suspected HSR. PPI were mainly prescribed for
dyspepsia/stomach ache (n=11) or Helicobacter pylori eradication (n=4).
Implicated PPI were omeprazole (n=13), esomeprazole (n=4), pantoprazole
(n=2), lansoprazole (n=2), with 2 patients reacting to different PPI
(omeprazole/lansoprazole and omeprazole/pantoprazole). Eight patients had
immediate reactions (6 anaphylaxis and 2 urticaria) and 3 of them had positive
SPT (one had positive SPT to both omeprazole and pantoprazole). Seven patients
(5 urticaria, 1 anaphylaxis and 1 MPE) had positive IDT to omeprazole only
(undiluted) and 1 patient (anaphylaxis) had a positive IDT to pantoprazole alone
(1/100). Cutaneous CR (this is, positive IDT for >1 PPI) was present in 3
patients, as described below:
- one patient with anaphylaxis to omeprazole and positive IDT to omeprazole
(1/1000) plus esomeprazole (1/10);
- another patient with anaphylaxis to omeprazole and positive IDT to omeprazole
(1/10) plus pantoprazole (1/1);
- and a patient with urticaria to esomeprazole and positive IDT to esomeprazole
(1/10) plus pantoprazole (1/10).
Non-atopic controls were also tested for PPI.
Conclusion
Cross-reactivity in 4 patients can be explained by the similar chemical structure
of PPI. Additional multicentre studies are needed to standardize procedures for
skin tests with PPI. Oral challenges are also important to increase the diagnostic
accuracy to this pharmacological group.
P98 Management Of Infusion-Related Hypersensitivity Reactions To
Enzyme Replacement Therapy For Lysosomal Diseases
Luis Felipe Ensina1, Carolina Aranda1, Ines Camelo Nunes1, Alex Lacerda1, Ana
Maria Martins1, Ekaterini Goudouris2, Marcia Ribeiro2, José Francisco Da Silva
Franco3, Leandra Queiroz4, Dirceu Solé1
1. Federal University of São Paulo, São Paulo, Brazil
2. Federal University of Rio de Janeiro, Rio De Janeiro, Brazil
3. Pontificia Universidade Católica de Campinas, Campinas, Brazil
4. Private Practice, Goiania, Brazil
Keywords: Desensitization, Lysosomal Diseases
Introduction
Enzyme replacement therapy (ERT) has been used in the treatment of lysosomal
diseases (LD). ERT with human recombinant enzymes has shown to slow
disease progression and improve the quality of life. Infusion-related reactions
(IRR) to ERT can occur and be severe, including hypersensitivity reactions
(HSRs) such as anaphylaxis. A diagnostic and treatment protocol was proposed
to manage those reactions.
Method
Patients under ERT for Mucopolysaccharidosis (I, II and VI), Gaucher, Fabry and
Pompe diseases under treatment in 7 centers from Brazil were assessed from
January 2011 through December 2015. In the presence of suggestive signs or
symptoms of an adverse reaction, ERT was stopped and skin tests for specific
IgE assay were performed. In patients with symptoms of acute infection after
infusion and with negative skin tests, ERT was maintained at the same infusion
rate. In patients without a history of infection and with negative tests, ERT was
maintained with an increased infusion rate. For those patients with positive ST
that continued reacting after adjustments in the IR, a 3 bags 12-steps
desensitization protocol was generated.
Results
Thirteen patients presented a suggestive HSR with positive skin tests, during
treatment with laronidase (n=3), galsulfase (n=2), betagalsidase (n=7),
imiglucerase (n=1). Urticaria was the most commom symptom observed (50%),
followed by fever (20%), chills (10%), cough (10%) and anaphylaxis (10%). Of
the 911 desensitizations performed, 20% induced mild reactions, but all patients
received their full target dose. No severe, life-threatening HSRs or deaths
occurred during the procedure.
Conclusion
Considering the importance of ERT in the treatment of LD, a standardized
diagnostic protocol for IRR allows us to establish a correct diagnosis and propose
an efficient treatment algorithm, which includes infusion rate modification and
desensitization
P99 Management Of Insulin Allergy With Continuous Subcutaneous
Insulin Infusion
Ceyda Tunakan Dalgiç, Aytül Zerrin Sin, Fatma Düsünür Günsen, Gökten
Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Emine Nihal Mete Gökmen, Ali
Kokuludag
Ege University Medical Faculty, Department of Allergy and Clinical Immunology,
Izmir, Turkey
Introduction
Insulin allergy is uncommon, particularly in patients with Type 2 diabetes
mellitus (DM). Management of the condition can be difficult. We report a patient
with Type 2 DM and insulin allergy successfully managed with continuous
subcutaneous insulin infusion (CSII).
Case Description
35 years old woman diagnosed as type 2 diabetes mellitus used detemir insulin
at first. On the third day of detemir, 12 hours after the dose, a pruriginous
papule occured at the site of injection area. Local reaction was continued. On
the seventh day, detemir was changed with NPH. Local reaction occured at first
dose of NPH. All of the local reactions were late onset. Therapy was changed to
glargine. One hour after the first dose of glargine, local reaction and generalize
pruritus were occurred. All insulin types were stopped and four weeks later, skin
tests were performed. Prick tests were negative. Intradermal tests were positive
with the dilutions of 1/100 detemir, 1/100 glargine, 1/1000 NPH, 1/1000 regular
insulin. Glulisin, aspart and lispro were negative. Insulin specific IgE (194 Ku/L
(0-87)) and anti-insulin antibody %47.8 (reference <8.2) were high and
specific Ig G4 was normal (35 mg/ dL (0-125)). The therapy started with glulisin
and there wasn’t any reaction at first. Therefore, since blood glucose and serum
glycated hemoglobin A1c levels (10%) were still higher, as a long acting insulin,
NPH had to be added together with antihistaminic. No reaction was observed
with NPH. At the 20th day of glulisin, late onset local reactions were seen
again. Glulisin was changed to aspart. Similar reactions were seen with those
insulins. Finally, the only insulin which has never been used before was lispro.
We suggested CSII pump with lispro. After this method, insulin hypersensitivity
was successfully treated and glycemic control was achieved.Consent: Written
informed consent was obtained from the patient.
How this report contributes to current knowledge
Allergy to insulin analogues is rare and requires early diagnosis, leading to a
major therapeutic challenge. In this case, local reactions continued although
types of insulins and application areas were changed. Interestingly, blood
glucose was increasing to uncontrolled levels always following by the cutaneous
reactions, also. As we consider anti-insulin antibodies and late onset local
reactions, insulin allergy is thought to be mediated by type 1 and type
2 hypersensitivity reactions in this case.
P100 Off-Label Use Of Icatibant For Management Of Serious
Angioedema Associated With Angiotensin Inhibitors
Ana M Montoro De Francisco, Talía Mª De Vicente Jiménez, Adriana M
Mendoza Parra, Angella M Burgos Pimentel, Amelia García Luque
Hospital Central de la Defensa, IMIDEF, Madrid, Spain
Keywords: Angioedema, Angiotensin Inhibitors, Icatibant
Introduction
Angioedema is a serious, infrequent and well-known Adverse Drug Reaction
(ADR) to antihypertensive drugs: Inhibitors of Angiotensin Converting Enzyme
(ACEI), Angiotensin II Receptor Blocker (ARB) and Direct Inhibitor of Renin
(DIR). ACEI/ARB/DIR are largely used worldwide, therefore, the morbidity and
mortality from ADR could be considerable. No medications are currently
approved for management of this ADR.
Icatibant, a bradykinin receptor type 2 antagonist, is a potential treatment for a
serious bradykinin-mediated angioedema associated with angiotensin inhibitors.
Method
Design: A case series of 100 patients with angioedema associated with
ACEI/ARB/IDR.
Scope: Allergy service, Hospital Central de la Defensa, Madrid.
Period: March 2009 to December 2015.
Main Variables assessed: demographic and clinical variables, treatment, and
evolution.
The patients have given written informed consent for the publication research.
Results
One hundred patients with episodes of angioedema all of them associated with
ACEI/ARB/DIR. In addition to angioedema, patients showed cough,
conjunctivitis, pruritus and rhinitis.
Twenty had severe angioedema with airway compromise, speech impairment
and hoarseness and poor response to antihistamines and corticosteroids which
required hospitalization. They were treated with icatibant 30mg subcutaneous
injection improving in their symptoms after 20 minutes-3 three hours. All
patients experienced complete resolution of angioedema and avoidance of
intubation and tracheotomy.
Age 66,3 years (37-90), 12 females and 8 males. Ten patients had previously
experienced serious angioedema attacks.
Eight drugs were involved: ACEI 15 (enalapril, captopril and lisinopril), ARBII 4
(valsartan, losartan, olemesartan and ibersartan) and DIR 1 (aliskiren). More
frequently involved drug was enalapril (9 cases).
Conclusion
Angioedema associated to angiotensin inhibitors is a serious ADR, it is rare but
not unusual due to the widespread use of this class of drugs. Icatibant used offlabel helped to improve the acute angioedema attacks and avoidance of
intubation and tracheotomy.
P101 Thiocolchicoside Anaphylaxis: An Unusual Suspect?
Luis Amaral, Fabricia Carolino, Leonor Carneiro Leão, Eunice Castro, Josefina
Cernadas
Serviço de Imunoalergologia, Centro Hospitalar de São João E.P.E., Porto,
Portugal
Introduction
Thiocolchicoside is a sulfureted semi-synthetic molecule derived from
colchicoside and is used frequently as adjuvant treatment for acute muscle
contractures in spinal pathology. Immediate hypersensitivity reactions are
rarely reported and only two documented cases of immediate anaphylaxis are
described in the literature. Moreover, the allergy diagnosis with validated skin
tests is lacking.
Method
We describe a first case of a 56-year-old woman that reported generalized
pruritus, a rash involving palms and soles, dyspnea and colicky abdominal pain,
5 minutes after intramuscular (IM) administration of thiocolchicoside. These
symptoms quickly reversed with IM adrenaline and intravenous (IV)
hydrocortisone. A few months later we received a second case of a 52-year-old
man who experienced dizziness, malaise and hypotension, 40 minutes after IM
administration of thiocolchicoside and diclofenac. This clinical scenario was
inverted with volume reposition with saline, IV hydrocortisone and adrenaline
wasn’t administered.
Results
In the first case the emergency lab results showed serum tryptase 47 mcgr/L.
Skin Prick test (SPT) [2 mg/ml] was negative and 5 minutes after performing
intradermal test (IDT) [2 mg/ml] the patient experienced throat tightness that
was reversed with ebastine 20mg. In the second case the SPT [2 mg/ml] was
negative and IDT [2 mg/ml] was positive with a 7mm wheal diameter. The skin
tests and oral provocation with diclofenac were negative.
SPT and IDT with the same concentration were also negative in 6 patients with
suspected immediate reaction to thiocolchicoside, confirmed by negative drug
provocation test.
Conclusion
Thiocolchicoside is often administered as an adjuvant therapy with nonsteroidal anti-inflammatory drugs and is probably underestimated as a cause of
immediate hypersensitivity reactions. Since the skin tests are not yet validated,
many times it can be forgotten on the diagnostic workup. To our knowledge,
this is the third study reporting documented anaphylaxis to thiocolchicoside and
the first to support this diagnosis with intradermal tests.
Poster Walk 12: Betalactam hypersensitivity
(P102 – P111)
P102 A Curious Delayed Reading- A Case Report Of A ß-Lactam Allergy
In A Child
Nicole Pinto, Joana Belo, João Marques, Pedro Carreiro- Martins, Paula LeiriaPinto
Hospital de Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon,
Portugal
Introduction
β-lactam antibiotics are commonly prescribed drugs worldwide and the most
frequent cause of adverse drug reaction mediated by immunological
mechanisms. Nonimmediate reactions, specially maculopapular and urticarial
exanthems, are common. Skin tests are used to evaluate drug hypersensitivity
and delayed reading might be useful in the diagnosis.
Case Description
A 2,5 year old girl, with no relevant past medical history, was referred to our
outpatient clinic for suspected drug allergy to β-lactams. The patient had been
admitted to the hospital for acute mastoiditis. Upon admission, amoxicillinclavulanic acid (Ax/C), which she had been taking for 4 days, was discontinued
due to vomiting and she was started on triple IV antibiotherapy with
ceftriaxone, vancomycin and metronidazole. On the 15th day of treatment,
physical examination revealed a diffuse pruriginous maculopapular rash and
fever, without palpable adenopathies. C-reactive protein was increased,
eosinophil count was within normal range values and serologies for EBV and
CMV were negative. An allergic reaction to ceftriaxone was suspected and the
drug was discontinued by the 23rd day of treatment. Due to persistence of
symptoms, the remaining 2 antibiotics were also discontinued 3 days later.
Skin biopsy was suggestive of erythema multiforme and a course of systemic
corticotherapy was started with resolution of symptoms. Skin prick tests and
intradermal tests (IDT) with Ax/C, penicillin, cefuroxime and ceftriaxone were
performed, using the maximal non-irritant dose, all of which were negative on
immediate reading. 48 hours later, both the prick and IDT were positive for
Ax/C as well as the IDT for ceftriaxone.
How this report contributes to current knowledge
Few nonimmediate reactions to cephalosporin are confirmed, due to the fact
that most are caused by infections. Nonetheless, allergic reactions can occur
even in young children, and in our case, the culprit agents were confirmed by a
positive skin prick test on delayed reading. Skin prick tests and IDT with
delayed readings seem to be useful in the evaluation of these reactions.
P103 Betalactam-Induced Hypersensitivity: A 10-Years’ Experience
Amel Chaabane, Haifa Ben Romdhane, Nadia Ben Fredj, Zohra Chadly, Naceur
A Boughattas, Karim Aouam
Faculty of Medicine/University hospital/University of Monastir, Monastir, Tunisia
Keywords: Betalactam, Skin Tests, Diagnosis, Cross Reactivity
Introduction
Betalactams hypersensitivity remains overestimated because of the lack of an
objective diagnosis tool leading to unjustified therapeutic alternatives
This study has been performed in order to analyze the epidemiological, clinical
and chronological features of betalactams hypersensitivity, to evaluate the skin
tests value, and to establish a practical approach exploring such drug
hypersensitivity.
Method
We included all adverse effects suspected to be induced by betalactams and
notified to the pharmacovigilance unit of Monastir during 11 years. The drug
imputability was established according to Begaud et al. method. Skin tests
were performed as recommended by ENDA.
Results
Betalactms hypersensitivity was diagnosed in 168 patients. Almost all reactions
were cutaneous mainly maculo-papular rashes. The severity was estimated at
11.3%. The delayed reactions occurred in 60.7% of cases. All reactions
resolved after drug withdrawal. We identified 19 positive rechallenges. Skin
tests were performed in 386 cases and were positive in 26.2% of them.
Penicillins were implicated in 62.5% of cases. Almost all of immediate reactions
were induced by penicillins. The hypersensitivity was selective to one
betalactam in nearly half of cases. Cross-reactivity was objectified among
penicillins in one third of cases, between cefotaxime and cefazolin in one case,
between penicillins and cephalosporins in 19% of cases, involving piperacillintazobactam in two cases and imipenem in one case.
Conclusion
Through the current study, we have demonstrated that the betalactam
hypersensitivity reactions are mostly delayed and non severe. The diagnosis
was confirmed using skin tests which were useful not only in identifying the
culprit drug but also in assessing cross reactivity. These findings have to be
improved by the drug provocation test which is still not performed in our
centre.
P104 Cefazolin Hypersensitivity: Towards Optimized Diagnosis
Astrid P. Uyttebroek1, Chris H. Bridts1, Antonino Romano2, Didier G. Ebo1,
Vito Sabato1
1. University of Antwerp, Faculty of Medicine and Health Sciences,
Department of Immunology, Allergology, Rheumatology and Antwerp
University Hospital, Immunology, Allergology, Rheumatology, Antwerp,
Belgium
2. Allergy Unit, Complesso Integrato Columbus, Rome, Italy; IRCCS Oasi
Maria S.S., Troina, Italy
Keywords: Drug Hypersensitivity, Cefazolin, Diagnosis, Skin Testing
Introduction
Correct diagnosis of cefazolin hypersensitivity is not straightforward, mainly
because of the absence of in vitro tests and uncertainties associated with the
optimal skin test concentrations. Cross-reactivity patterns involving cefazolin
suggest that cefazolin hypersensitivity is an isolated hypersensitivity.
Objectives: As a first objective of this study, we sought to confirm whether
the application of a higher than 2 mg/mL test concentration could increase skin
test sensitivity, and add to the diagnosis of cefazolin hypersensitivity. A second
part of our study aimed at investigating the cross-reactivity between cefazolin
and other β-lactam antibiotics.
Method
66 patients referred to our outpatients’ clinic for diagnostic evaluation after
experiencing perioperative anaphylaxis, and exposed to cefazolin, underwent
skin testing with cefazolin up to 20 mg/mL. Patients exhibiting a positive skin
test with cefazolin had a panel of skin tests with other β-lactams and, if
indicated, graded drug challenges in order to study cross-reactivity.
Results
Increasing the skin test concentration from 2 mg/mL to 20 mg/mL identified an
additional 7/19 (27%) patients, who would otherwise have displayed negative
skin testing. The concentration was proven to be non-irritating in 30 cefazolin
exposed control individuals in which an alternative culprit for peri-operative
anaphylaxis was identified. Graded challenge testing, following negative skin
testing, displayed that all the patients tolerated alternative β-lactam antibiotics.
Of them, 11 individuals also tolerated an alternative cephalosporin, suggesting
that cefazolin hypersensitivity (generally) is a selective allergy.
Conclusion
Increasing cefazolin skin test concentration up to 20 mg/mL benefits the
sensitivity of diagnosis. Furthermore, our data further confirm that cefazolin
hypersensitivity seems to be a selective allergy with good tolerance to other βlactam antibiotics.
P105 Clavulanic Acid Allergy – Two Cases Report
Anabela Lopes1, Joana Cosme1, Rita Aguiar1, Tatiana Lourenço1, Maria-João
Paes1, Amélia Spínola-Santos1, Manuel Pereira-Barbosa2
1. Immunoallergy Department - Hospital de Santa Maria – Centro
Hospitalar Lisboa Norte, Lisbon, Portugal
2. Immunoallergy Department - Hospital de Santa Maria – Centro
Hospitalar Lisboa Norte; Faculdade de Medicina de Lisboa, Lisbon,
Portugal
Keywords: Clavulanic Acid, Delayed Reactions, Selective Reactions, ß-Lactams
Introduction
Beta-lactams (BL) are frequently prescribed antibiotics. Allergic reactions to BL
can be immediate (IgE reactions) and non-immediate reactions (T cell
reactions). There are two major types of BL allergic patients: cross-reactive
patients that are allergic to common BL ring and selective patients, allergic to
side chains. In the last years, several cases of clavulanic allergic patients were
described. Frequently, the reactions to clavulanic acid (CL) are immediate and,
until now, there are only reports of selective reactions to CL.
Method
The authors report two cases of unusual CL allergic patients. The patients were
submitted to skin tests (ST) with penicilloylpolylysine (PPL), minor determinant
mixture (MDM), amoxicillin (AX), CL (Diater laboratory), benzylpenicillin,
ampicillin, cefuroxime, ceftriaxone, cefipime, determination of specific IgE to BL
and oral provocation tests to alternative and culprit drugs.
Results
1st case: male, 45 years old, presented to our allergy clinic with maculopapular
rash, seven days after beginning treatment with amoxicillin-clavulanic acid
(AX/CL) and ibuprofen for pharygintis. He had previously received AX/CL with
good tolerance. Drug provocation with ibuprofen was performed with negative
results. Specific IgE to BL were negative. ST with PPL, MDM, AX,
benzylpenicillin and AX/CL were negative and the patient was performed an
oral AX/CL drug provocation. On the 5th day after drug provocation, he
developed a generalized maculopapular rash. ST with CL was performed with a
positive late reaction in the intradermal test (20mg/mL) and a new drug
provocation only with AX was negative then.
2nd case: female, 40 years old described 2 previous allergic reactions:
generalized urticaria 10 minutes after the intake of one AX tablet at 36 years
and an episode of anaphylaxis 5 minutes after one AX/CL tablet at 39 years.
Specific IgE to BL were negative. ST with PPL, MDM, AX and CL and
benzylpenicillin revealed positive results with a positive immediate prick test to
AX and a intradermal test to CL (20mg/mL). ST and drug provocation with
cefuroxime and ceftriaxone were negative.
Conclusion
The first case concerns a rare delayed reaction to CL. To the best of our
knowledge, the second case describes the first case of positivity to both AX and
CL.
P106 Diagnosis Of Betalactam Allergy In An Allergy Department
Cíntia Rito Cruz, Rute Pereira Dos Reis, Elza Tomaz, Ana Paula Pires, Filipe
Inácio
Serviço de Imunoalergologia, Hospital de São Bernardo, Setúbal, Portugal
Keywords: Betalactam Allergy, Immediate Hipersensitivity
Introduction
Betalactams (BL) are still the most frequent drugs implicated in allergic
reactions. All BL currently available may cause these reactions. Immediate
hypersensitivity (IH) reactions usually appear within 1 h of drug intake and are
mediated by specific IgE (sIgE) antibodies. They can be evaluated by different
methods: clinical history, skin tests (ST), in vitro quantification of sIgE and
drug provocation tests (DPT). The determination of sIgE has safety advantages
over ST and DPT, but has low sensitivity. ST should be performed with PPL,
MDM, penicillin G, amoxicillin and ampicillin. If these are all negative, a DPT
should be executed to ultimately confirm or exclude allergy.
Method
Retrospective study that included patients who had undergone ST with PPL and
MDM for investigation of BL allergy in 2014 and 2015. Data were then collected
regarding the results of ST (PPL, MDM, penicillin G, amoxicillin, ampicillin and a
cephalosporin), sIgE (penicillin G, penicillin V, ampicillin, amoxicillin and
cefaclor) and DPT (to amoxicillin and/or a cephalosporin).
Results
One hundred and one patients (24% male), with a mean age of 42 years old.
The suspected BL was: penicillin G (40), amoxicillin (37), cephalosporins (6),
ampicillin (2) and unknown (16). Eleven percent of the patients had positive ST
to PPL or MDM, with only 1 having positive sIgE. Five of these patients
underwent ST with an alternative cephalosporin (cefuroxime): 2 were positive
and 3 were negative. Two of these underwent DPT, that were negative. Out of
90 patients with negative ST to PPL and MDM, 55 were submitted to ST with
ampicillin and/or penicillin G and/or amoxicillin, being positive in 7% of the
patients; they all had negative sIgE. ST with amoxicillin didn’t add any extra
information. Out of 84 patients with negative ST, 36 proceeded to DPT, which
were positive in 6% of the cases. Twelve patients underwent ST with a
cephalosporin, being positive in 2 (when the suspected BL was also a
cephalosporin). IH to BL was confirmed in 19% of the cases.
Conclusion
Of the 19 cases of confirmed IH to BL, only 1 had positive sIgE, corroborating
the extremely low sensitivity of the method. Only 19% of the suspected cases
of BL IH were confirmed, emphasizing the importance to refer patients to an
Allergy Centre for investigation. Some patients never concluded the BL allergy
study, and some are still undergoing. We highlight the need for new less
expensive and time consuming tests, which would also reduce the number of
dropouts.
P107 Diagnostic Work-Up Of 410 Patients With Suspicion Of
Betalactam Antibiotic Hypersensitivity
Filipe Benito-Garcia, Inês Mota, Magna Correia, Ângela Gaspar, Marta
Chambel, Susana Piedade, Mário Morais-Almeida
CUF Descobertas Hospital, Lisboa, Portugal
Keywords: Adults, Beta-Lactams, Drug Allergy, Children, Skin Tests
Introduction
The aim of this study was to characterize the activity developed at our drug
allergy outpatients’ center with patients (pts) referred with suspicion of
hypersensitivity (HS) to betalactam antibiotics (BL).
Method
Retrospective analysis of clinical files, in vivo / in vitro test results and drug
provocation tests (DPT) from January 2011 to December 2015. All pts were
studied according to standardized diagnostic procedures of ENDA/EAACI: serum
specific IgE (sIgE) (ImmunoCAP®,ThermoFisher) to penicillin G/V, amoxicillin
and ampicillin; skin prick and intradermal tests (IDT) to PPL/MD (DAP®,Diater),
penicillin G, amoxicillin and cefuroxime with immediate and delayed reading.
Other penicillin derivatives / cephalosporins were tested if they were the culprit
drug. DPT with culprit drug was performed if previous investigation was
negative. In confirmed cases an alternative BL was tested.
Results
410 pts with suspicion of HS to BL were included: mean age was 34.6 (SD±18)
yrs, 21% had <18yrs and 68% were female. Penicillins/derivatives were the
main culprit drugs (314 pts), mostly amoxicillin (229 pts), 149 in association
with clavulanic acid. Cephalosporins were mentioned by 42 pts, namely
cefazolin (15 pts). Mucocutaneous symptoms were the most frequent
manifestations (81%); anaphylaxis occurred in 54 pts, 18 with loss of
consciousness. HS to BL was confirmed in 88 pts (21.5%), all with a DPT
negative to an alternative BL. HS was excluded in 289 pts (70.5%); 33 pts are
under study. Confirmation of HS was made by: sIgE in 10 pts; skin testing in
65 pts and DPT in 13 pts (amoxicillin-11, clavulanic acid-2). Skin tests were
positive to: amoxicillin-33, penicillin-16, PPL-15, MD-3, flucloxacilin-1 cefazolin5, cefuroxime-1. Delayed reading of IDT was positive in 7 pts: penicillin-3,
amoxicillin-4. A systemic reaction during skin testing occurred in 13 pts, in 3
with anaphylaxis: one child during IDT with amoxicillin (2.5mg/mL) and 2
adults during IDT with amoxicillin (25mg/mL).
Conclusion
To investigate the suspicion of HS to BL is of outmost importance because in
most of these pts allergological workup is negative and HS to BL is excluded.
Although the majority of confirmed cases are IgE-mediated, in about one fourth
a non-IgE mediated mechanism seems to be involved (positive DPT or positive
delayed reading of IDT). Systemic reactions during IDT and DPT also reinforce
the need of referral these pts to specialized centers.
P108 Immediate Selective Hypersensitivity Reactions To Clavulanic
Acid
Alla Nakonechna1, Yurij Antipkin2, Tetiana Umanets2, Fernando Pineda3,
Francisca Arribas3, Volodymyr Lapshyn2
1. Royal Liverpool and Broadgreen University Hospitals NHS Trust,
Liverpool, United Kingdom
2. Institute of Pediatrics, Obstetrics and Gynaecology, Kiev, Ukraine
3. Diater Laboratorios, Madrid, Spain
Introduction
Clavulanic acid (CLV) is b-lactamases inhibitor with weak antibacterial activity
and low immunogenic capacity widely used in combination with beta-lactam
antibiotics. Despite there is a number of reports of allergy to CVL in the
combination with amoxicillin (AX-CVL), it is important to distinguish this kind of
hypersensitivity as of the clinical implications of an amoxicillin allergy diagnosis.
Method
We present here 23 patients (14 women and 9 men, aged 23-62) with
immediate hypersensitivity reactions to amoxicillin-clavulanic acid. Clinical
symptoms occured within 30-60 minutes after AX-CLV intake and included
urticaria/angioedema, bronchospasm and anaphylaxis.
Skin prick and intradermal tests with: major determinant benzylpenicilloyl polyL-lysine (PPL-0.04 mg/mL), minor determinant mixture (MDM-0.5 mg/ml), CLV
(20mg/ml) and amoxicillin (20mg/ml), all provided by Diater (Madrid, Spain),
along with benzylpenicillin (10,000IU/mL; Normon SA), ampicillin and
cefuroxime (20mg/ml; GlaxoSmithKline Beecham) were performed. In those
cases with a positive skin test to CLV the AX-CLV (20/4 mg/ml)
(GlaxoSmithKline Beecham) was also tested. Specific IgE antibodies against
penicillin V, penicillin G, amoxicillin and ampicillin were measured by ELISA.
Drug provocation test (DPT) with amoxicillin was performed in selective CLV
hypersensitivity patients group.
Results
Specific IgE antibodies against penicillin V, penicillin G, amoxicillin and
ampicillin were less than 0.35 UI/mL in all patients.
Among 23 patients with immediate hypersensitivity reactions to AX-CLV only 2
patients (8.7%) had a positive skin test to benzylpenicillin determinants and 14
patients (60.8%) to amoxicillin.
Among 7patients (30.4%) who had a positive intradermal test to selective CLV
component and good tolerance to amoxicillin in DPT only 4 patients (17.4%)
were detected by AX-CLV.
Conclusion
Our investigation show:
Immediate selective hypersensitivity reactions to CLV found in around 30% of
patients with immediate allergic reactions to AX-CLV combination.
Although allergy to clavulanic acid is infrequent, this molecule should be used
in diagnostic assessment when evaluating an immediate reaction to AX-CLV
and conventional skin testing with benzylpenicillin and amoxicillin determinants
are negative.
Testing with selective CLV component is more sensitive and reliable than
detection by AX-CLV for proving allergy to clavulanic acid.
P109 PREVALENCE AND INCIDENCE OF PENICILLIN
HYPERSENSITIVITY REACTIONS IN COLOMBIA
Pablo Andrés Miranda, Bautista De La Cruz Hoyos
Universidad Nacional de Colombia, Cartagena, Colombia
Keywords: PENICILLIN, ALLERGY, HIPERSENSITIVITY
Introduction
Penicillin remains one of the most widely used antibiotics in the world.
Hypersensitivity reactions are more common adverse effects to this antibiotic.
Method
Records with allergy status of penicillin (ICD-10 code Z880) and adverse effects
to penicillin (ICD-10 code Y400) of Information System of Social Protection
(SISPRO) between 2010 and 2014 were included. To determine the prevalence
and incidence of AHR, population estimates from the National Statistics
Department of Colombia (DANE) were used.
Results
781 cases with allergy status of penicillin and adverse effects to penicillin (PHR)
between 2010 and 2015 were identified. 148 cases were confirmed news
diagnoses in the same period. On average 156 cases of PHR per year were
estimated. The estimated annual prevalence PHR were 3.3 cases per million
(2010= 4.3; 2011= 3.3; 2012=3.8; 2013= 2.7 and 2014= 2.7). The estimated
annual incidence PHR were 0.4 cases per million (2010= 0.53; 2011= 0.43;
2012= 0.60; 2013= 0.55 and 2014= 0.25). Most cases it presenting in adult
aged 60 years or younger, in children aged 5 years or younger and between 19
and 26 years age in 2010-2011; and in adult aged 60 years or younger
and between 19 and 26 years age in 2012-2014.
Conclusion
Both under-diagnosis and over-diagnosis PHR are common in the world.
Population studies with confirmatory tests PHR in Colombia are required.
PREVALENCE PHR
COLOMBIA
Cases per million
1-5 años
6-9 años
10-14 años
15-18 años
19-26 años
27-44 años
45-59 años
> 60 años
Total
INCIDENCE PHR
2010
COLOMBIA
% (n)
Cases per million
1-5 años
0.47 (2)
6-9 años
0.58 (2)
2010
%(n)
2011
%(n)
2012
%(n)
2013
%(n)
2014
%(n)
20.4
(12)
3.0 (35)
4.1 (13)
5.4 (14)
12.7
(24)
6.1 (45)
1.2 (39)
28.5
(13)
4.3
(195)
13.9
(17)
1.4 (24)
1.5 (6)
3.2 (5)
10.2
(14)
4.8 (36)
1.5 (31)
21.3
(17)
3.3
(150)
2011
% (n)
2012
% (n)
2013
% (n)
2014
% (n)
0.47 (2)
0.58 (2)
1.17 (5)
1.46 (5)
0.93 (4)
1.17 (4)
0.47 (2)
0.59 (2)
3.5 (26) 6.9 (33) 2.9 (32)
2.1 (6)
2.6 (9)
4.1 (9)
12.5
(18)
4.9 (44)
3.0 (32)
24.5
(34)
3.8
(178)
0.5 (12) 3.0 (5)
1.5 (2)
1.8 (13)
2.3 (5)
3.3 (6)
7.7 (10) 7.7 (14)
2.8 (27)
1.6 (19)
17.0
(19)
2.7
(127)
2.8 (27)
1.3 (19)
17.2
(15)
2.7
(131)
10-14 años
15-18 años
19-26 años
27-44 años
45-59 años
> 60 años
Total
1.36 (6) 0.91 (4) 0.23 (1) 0.92 (4) 0.00 (0)
1.70 (6) 1.13 (4) 0.28 (1) 1.14 (4) 0.00 (0)
0.16 (1) 0.31 (2) 0.46 (3) 0.15 (1) 0.30 (2)
0.09 (1) 0.18 (2) 0.26 (3) 0.09 (1) 0.17 (2)
0.44 (3) 0.28(2)
0.69 (5) 0.54 (4) 0.26 (2)
0.67 (3) 0.43 (2) 1.04 (5) 0.81 (4) 0.39 (2)
0.53 (24) 0.43 (20) 0.60 (28) 0.55 (26) 0.25 (12)
P110 Selective Sensitization To Amoxicilin And Clavulanic Acid
Jose Julio Laguna Martinez, Aranzazu Jimenez Blanco, Javier Dionicio Elera,
Cosmin Boteanu, Rosario Gonzalez-Mendiola, Marta Del Pozo
Allergy Unit.Hospital Central Cruz Roja, Madrid, Spain
Introduction
Beta-lactam (BL) antibiotics are the drugs most frequently involved in IgEmediated allergic reactions.
Differences in the pattern of consumption are related with the specific BL
involved in the allergic reactions and vary among countries and over the time.
Since specific recognition of the amoxicillin (AX) side chain was described, a
significant increase in the number of selective immediate reactions to AX and
more recently selective reactions to Clavulanic acid (CLV) have been reported.
Patients with allergic reactions after AX-CLV administration can react to either AX
or CLV. No evidence of cross reactivity between CLV and other BL has been
reported.
Case Description
We present an atopic 44 year-old man referred to our allergy unit due in 2008 he
took amoxicillin 500mg/day as treatment for respiratory infection, 30 minutes
after the first tablet he developed pharyngeal pruritus, cutaneous erythema and
flushing following generalised itching and erythema.
Method
Skin prick test (SPT) and intradermal test (IDT) were performed using classic
penicillin determinants, amoxicillin, ampicillin and clavulanic acid determinants
according ENDA protocol.
Total IgE and specific IgE (Thermo Fisher Scientific) with penicillin determinants
(penicilloyl G, amoxicilloy, penicilloyl V and ampicilloyl) were performed
Drug provocation Test (DPT) if skin and in vitro test were negatives
As reaction was several years before, we performed second work up 1 month
later.
Results
Total IgE 270 KU/L, Specific IgE with penicillin determinants were negative.
Skin tests show positive results only to CLV (20 mg/ml IDT)
DPT was positive to AX, 30 minutes after first dose (125 mg) patient developed
pruritus, facial erythema and cutaneous rash in thorax and back
DPT with BP following 3 days domiciliary intake was negative
Second work up
Skin tests show positive results only to CLV 20 mg/ml IDT
DPT and with BP following 3 days domiciliary intake was negative again
How this report contributes to current knowledge
Conclusions
We present a double selective sensitization to clavulanic acid and amoxicillin with
tolerance to BP.
We confirm that tolerance to BP is a stable phenomenon performing a second BP
administration one month later, according recently studies, where selective
patients tolerate subsequent administrations of other BL.
Our exceptional case highlights the need to be aware of new patterns of betalactams sensitization.
We recommend using AX and CLV separately for skin test
P111 Infliximab-Specific T Cells Are Detectable Also In Treated Patients
Who Have Not Developed Anti-Drug Antibodies
Alessandra Vultaggio1, Francesca Nencini2, Sara Pratesi2, Andrea Matucci1,
Enrico Maggi2
1. AOU careggi, Florence, Italy
2. Dept of Internal Medicine, Florence, Italy
Introduction
Infliximab (IFX) carries potential risk of immunogenicity, with the expansion of
memory T cells and the production of anti-drug antibodies (ADA). Little is known
about the possibility that sensitization to IFX may occur also in treated ADApatients. This study was aimed to evaluate whether IFX may be immunogenic in
the latter group of patients.
Method
Seventy-one IFX-treated patients, including both ADA+ and ADA- patients were
enrolled. Untreated patients and healthy donors were also selected as controls.
Memory T cells was evaluated by the proliferation of drug-stimulated PBMC or
co-cultures of IFX-pulsed DC plus autologous CD4+ T cells. Measurement of
drug-induced cytokines production was performed in the culture supernatants by
ELISA. Cytokines mRNA expression was also studied.
Results
T cell proliferation and cytokine production were mainly detectable in ADA+
patients, but cytokines were observed in about 25% of non-proliferating cultures
as well. IL-10 was the most frequently detectable cytokine. Additionally, the
proportion of patients expressing IL-10 mRNA in IFX-stimulated PBMC was
significantly higher in ADA- than in ADA+ patients. IL-10 mRNA levels resulted
higher in ADA- than in ADA+ patients. Anti-IL-10 mAbs were able to significantly
increase both IFX-driven proliferation and expression of T cell-related cytokines
in PBMC.
Conclusion
Cell sensitization to IFX may be detectable in a proportion of ADA- treated
patients. Proliferation assay combined with cytokines evaluation may work better
than the single test in evaluating cell sensitization. In ADA- patients IFX-induced
IL-10 may overcome the effects of other T cell-related cytokines
Poster Walk 13: Biologicals, Local anesthetics,
others (P112 – P118)
P112 A Case Report Of Allergic Immediate Systemic Reaction To
Adalimumab And Certolizumab
Ceyda Tunakan Dalgiç, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür
Ardeniz, Okan Gülbahar, Emine Nihal Mete Gökmen, Aytül Zerrin Sin, Ali
Kokuludag
Ege University Medical Faculty,Department of Allergy and Clinical Immunology,
Izmir, Turkey
Introduction
Adalimumab, recombinant fully humanized anti-tumor necrosis factor (anti-TNF)
antibody, had been using for the patients with inflammatory artritis and bowel
diseases. Adverse reactions to adalimumab are limited mainly to injection site,
immediate systemic reactions are very rare. Generalise skin reactions to this
antibody are around 1%. Certolizumab is humanized from mouse, anti-TNF
recombinant antibody with the same indications. Systemic adverse reactions to
certolizumab is very rare, also.
Case Description
We report a 59-year-old woman with spondylartritisi (SpA) who was treated with
adalimumab every two weeks for 4 years. At the 4th year, adalimumab was
changed to prefilled ready to use form. 30 minutes after the first application of
this form, local reaction and also vomiting, dispnea, laryngeal edema,
hipotension with generalise itching happened. Than adalimumab was stopped.
Therapy was changed to certolizumab pegol. 30 minutes after the first injection
of certolizumab , she had nause, dizziness and visual disturbances without skin
reactions. 15 days later she injected the second certolizumab dosage and the
same reactions repeated. She was referred to allergy clinic. Skin prick test with
50 mg/mL of adalimumab was found negative. Intradermal test with (5
mg/ml) 1/10 dilusion was 10 /45 mm and 1/100 dilusion was 8/40 mm
(histamin intradermal : 10 /50 mm).Both skin prick and intradermal tests with
certolizumab pegol were negative. Depending on the uncertainty of her history
about certolizumab, drug provocation test was administered with total therapy
dose. No adverse or allergic reaction occured during provocation. The patient
was continued certolizumab therapy seamlessly.
Consent: Written informed consent was obtained from the patient for publication
of this case report and any accompanying images.
How this report contributes to current knowledge
Although adverse systemic reactions to adalimumab are rare , we describe a
immediate systemic reaction to adalimumab; fully humanized recombinant
biological. We thought the reaction was not due to the new form, because the
contents are completely same. Allergic reaction after changing the form seems to
be coinsidental. Alternative monoclonal antibodies should be searched for those
patients.
P113 Allergy To Local Anesthetics: Negative Predictive Value Of Skin
Tests
Ivana Cegec, Danica Juricic Nahal, Viktorija Erdeljic Turk, Matea Radacic
Aumiler, Ksenija Makar Ausperger, Iva Kraljickovic, Iveta Simic
University Hospital Zagreb, Zagreb, Croatia
Keywords: Local Anesthetics, Skin Test, Hypersensitivity, Negative Predictive
Value
Introduction
Although true allergy to local anesthetics (LA) is rare, patients often report
unwanted reactions after the administration of LA, requiring allergy
consultations. Diagnosis of hypersensitivity reaction to LA is made after skin
tests followed by exposition tests. The aim of this study was to determine the
negative predictive value (NPV) of skin tests to LA.
Method
A retrospective chart review was performed on patients undergoing local
anesthetic skin testing. A total of 50 patients tested for hypersensitivity to LA in
the period from January to August 2015 at the Division of Clinical pharmacology
at the University Hospital Zagreb were enrolled in this study. All patients
underwent skin tests (‘prick’ and intradermal tests with 1:100 dilution) followed
by incremental subcutaneous challenge with undiluted LA. Skin tests were
performed with lidocaine, articaine, bupivacaine or articaine+adrenaline, while
exposition was performed using mainly lidocaine. Telephone follow-up visits were
performed during December 2015. On the basis of the follow-up results, the NPV
of skin tests was calculated.
Results
Skin tests were performed using two or more LA (lidocaine in 50 patients,
articaine in 35 patients, bupivacaine in 27 patients, articaine+adrenaline in 11
patients). All skin tests were negative. Subcutaneous challenge was performed
with lidocaine in 41 pts, articaine in 7pts, bupivacaine in1pt, and
articaine+adrenaline in1pt. All patients had negative subcutaneous challenge. In
the follow-up period 20 pts received LA, 20 pts have not received LA while 10 pts
were unavailable for follow-up. Of the patients who received LA after testing, 19
had no reactions during exposure while 1 pt experienced a severe hypertensive
reaction with generalized exanthema. The NPV of skin tests to LA was 95%.
NPV for subcutaneous challenge tests was not calculated due to incomplete data
on specific LAs used in subsequent exposures.
Conclusion
Skin tests to LA are safe and have an excellent negative predictive value which
allows the selection of a local anesthetic that can be safely administered in the
future.
P114 Cutaneous Adverse Reactions Of Molecular Targeted Agents -A
Retrospective Analysis In 150 Patients In Our DepartmentYukie Yamaguchi, Tomoya Watanabe, Megumi Satoh, Tomohiko Tanegashima,
Kayoko Oda, Hidefumi Wada, Michiko Aihara
Yokohama City University Graduate School of Medicine, Yokohama, Japan
Keywords: Molecular Targeted Agents, Biologics
Introduction
Molecular targeted agents are widely used in various inflammatory and immune
diseases and tumors. Differently from adverse reactions induced by conventional
drugs, these drugs demonstrate various new types of adverse reactions. Some of
events may be induced by cross-reactions related to the expression of the same
antigen on different tissue. Immune imbalance caused by a depletion of specific
antigen may be a trigger of unpredictable reactions. It is important to know the
prevalence, clinical types, and severity of the side-effects in each drugs.
Method
We retrospectively analyzed patients who visited our department due to
cutaneous adverse reactions caused by molecular targeted agents from 2010 to
2015. Types of drugs, clinical features of cutaneous adverse reactions, and
subsequent outcome were evaluated.
Results
One hundred and fifty patients were evaluated in this study. High frequency
agents were EGFR inhibitors (63%), multikinase inhibitors (8%), TNF-a inhibitors
(6%), and programmed death-1 (PD-1) inhibitors (5%). Regarding clinical
phenotypes, acneiform eruptions and perionychia were highly observed (68%)
mainly caused by EGFR inhibitors as the target antigen EGFR is also involved in
skin homeostasis. Maculopapular drug eruption (10%) and hand-foot syndrome
(7%) were observed in users of multikinases inhibitors and EGFR inhibitors. Of
note, systemic drug eruption (erythroderma, erythema multiforme,
maculopapular) was highly observed in patients treated with multikinase
inhibitors. Psoriasis-like and palmoplantar pustulosis-like eruptions (5%) were
caused by TNF-a inhibitors and IL-6R inhibitors. Although the frequency was low,
lupus-like reaction, vitiligo, and other unexpected reactions were caused by
inhibitors of TNF-a or PD-1, supposedly those inhibitors lead to immune
imbalance further causing autoimmunity and inflammatory reactions. As for the
outcome, 85% of patients continued molecular targeted agents, while 15% of
patients required discontinuation of the drug.
Conclusion
Predicteable cutaneous reaction, like acneiform eruptions by EGFR inhibitors,
would be possible to manage without discontinuation of the drug. Some drugs,
such as immune checkpoint inhibitors, may cause unexpected immune
responses. Since adverse reactions of molecular targeted agents are variable
depending on drugs. It is important to recognize the function of targeted antigen,
and close monitoring is recommended
P115 Generalized Paralysis Induced By Local Lidocaine Injection
Jaechun Jason Lee, Jay Chol Choi, Hwa Young Lee
Jeju National University School of Medicine, Jeju, South Korea
Introduction
Local anesthetics, such as lidocaine, are widely used for numbing. Adverse drug
reactions related to lidocaine are variable, unpredictable, and rarely reproducible,
with the exception of some typical cases.
Case Description
A 42-year-old female who had shown a bizarre neurological reaction after
lidocaine injection for dental procedures was referred for diagnosis and safe
anesthetic alternatives. Within a few minutes after exposure to lidocaine, she
was unable to move any extremity, or to speak, while sensory and high cranial
nerve functions were preserved. She was alert and able to communicate with eye
blinks. This reaction was repeatedly reproduced after intradermal injection of 2%
lidocaine, with complete recovery within 1 h without treatment. No crossreactivity with mepivacaine and bupivacaine was observed.
How this report contributes to current knowledge
This is the first report of immediate and transient generalized paralysis related to
lidocaine.
P116 HYPERSENSITIVITY TO LOCAL ANAESTHETICS – A TEN YEAR
REVIEW
Rosa-Anita Rodrigues Fernandes1, Emília Faria1, Joana Pita1, Nuno Sousa2,
Carmelita Ribeiro3, Isabel Carrapatoso1, Ana Todo Bom1
1. Allergy and Clinical Immunology Department, Coimbra University Hospital
Center, Coimbra, Portugal
2. Allergy and Clinical Immunology Consult, Leiria Hospital Center, Leiria,
Portugal
3. Coimbra University Hospital Centre, Coimbra, Portugal
Keywords: Local Anaesthetics, Hypersensitivity
Introduction
True allergy to local anaesthetics (LA) is uncommon. Allergic reactions account
for less than 1% of all adverse reactions. Immediate reactions are rare. The aim
of this study was to describe the main characteristics of the population with
confirmed LA allergy among patients referred to our outpatient clinic for
suspected hypersensitivity (HS) to LA.
Method
Retrospective analysis of the medical files of patients with suggestive history of
immediate HS reactions to LA, referred to our outpatient centre between January
2006 and December 2015. In order to confirm the diagnosis, we conducted skin
prick tests and subcutaneous drug provocation test (DPT) with the undiluted
commercial solution of the culprit or an alternative LA. DPT was performed in
increasing doses, every 15 minutes, up to a cumulative dose of 3.6ml.
Sensitization to latex was excluded.
Results
A total of 65 patients with history of an adverse reaction to LA underwent DPT,
75% female with a median age of 44 years (±17.4). Only 5 patients (7.7%) had
positive DPT (lidocaine in 2 patients, mepivacaine in 2 patients and ropivacaine
in 1 patient). Of those patients, 60% were female and the median age was 35
years (±20.6 years). Sixty percent of the patients had past history of multiple
surgical interventions (with general anesthesia) and allergic diseases, asthma
and rhinitis being the most frequent. Cutaneous symptoms (urticaria and
angioedema) were the main manifestation, in 4 patients (66%). There was no
registry of severe adverse reactions. All reactions started within 2 hours following
LA application and regressed spontaneously without any treatment. Sensitization
to both lidocaine and mepivacaine was determined in 2 patients. Comorbidities
such as hypertension (2 patients), diabetes (1 patient) and thyroid disease (1
patient) were also seen. Eighty three percent of these reactions occurred during
dental procedures and 60% of these after administration of lidocaine.
Conclusion
As stated in other studies, we find a low positivity rate to DPT. And our findings
were similar to those found in the literature: adverse reactions to LA are more
prevalent in the mid-age and with cutaneous symptoms being the most frequent
manifestation of HS. Although rare, consequences of true allergy to local
anaesthetics can be serious, considering a patient’s future management and
therapy.
P117 Local Anaesthetics: A Rare Culprit In Hypersensitivity Reactions
Ana Rodolfo, Eunice Dias-Castro, Josefina Cernadas
Centro Hospitalar de São João, Porto, Portugal
Keywords: Local Anaesthetics, Local Anaesthetics Hypersensitivity
Introduction
Local anaesthetics (LA) are widely used drugs with an exceptional benefit-risk
profile. Adverse reactions are scarce. Hypersensitivity reactions are especially
rare, accounting for less than 1% of all adverse reactions. When a reaction
occurs, an allergy work-up should be performed in order to exclude an allergic
reaction or to identify an alternative drug.
Method
Retrospective analysis of data from patients referred to our drug allergy unit with
suspected LA allergy in the past 5 years. The analysis was performed using
SPSS, version 21.
Results
We studied 47 patients for suspected LA allergy (83% females, with median age
49, and interquartile range 23). Six patients were atopic. Thirty six % of patients
were referred by their family physician and 26% by dentists.
Of the 47 patients, 38% had a suspected reaction during a
dental procedure, 14% had positive patch tests with LA and 13% had peroperative anaphylaxis. Considering the patients who had a suspected
reaction,74% had immediate reactions. In 49% of these cases, there was
mucocutaneous involvement, 33% had respiratory symptoms and 33%
vasovagal response. The LA used was known in 70% of these cases, none of
them were an ester. Lidocaine was the culprit in 20 cases, mepivacaine in 5,
articaine in 5 and ropivacaine in 4.
Skin prick tests (SPT) and intradermal tests (ID) were performed with validated
concentrations, without vasoconstrictor. Only 2 patients had positive tests: 1
positive SPT to mepivacaine and one positive ID to procaine; the other patient
had a positive ID to ropivacaine. All 45 patients with negative skin tests were
submitted to subcutaneous challenges that were negative.
None of the patients referred because of positive patch tests to LA had a
positive study.
Conclusion
The majority of adverse reactions to LA may be attributed to non-immune
mediated mechanisms, pharmacologic, psycho or neuro-vegetative reactions.
When LA are used, the patients are usually under stress. Our experience is in
agreement with literature since hypersensitivity was excluded in the majority of
the patients with suspected LA reactions.
P118 Stevens-Johnson Syndrome In Clinical Practice: A Variant Of
Clinical Course
MARINA Voronova
State Hospital 52, Moscow, Russia
Keywords: Stevens-Johnson Syndrome, Clinical Case
Introduction
A 44 year-man was urgently admitted to our allergy clinic with complaints of pain
in the area of scrotum, painfulness in oral cavity, rash on hands, eyelids and
foot. Anamnesis excerption: Alcohol abuse for a long time. About two years ago,
following one of patient’s drinking-bouts, episode with loss of consciousness
emerged, qualified as secondary epilepsy; carbamazepine was administered. The
patient described vesicular rash on lips and hands following the carbamazepine
medication; he did not seek medical attention, though. The therapy was
cancelled. Within two weeks the skin rash passed. The present episode had also
been related with a prolonged period of alcohol ingestion, whereupon a
detoxification treatment was administered, and, taking into account the
possibility of episyndrome, carbamazepine was ordered, too. On the second day
vesicular rash appeared on hands, thereupon in the scrotum area, on eyelids and
on mucous tunic of mouth, forcing the patient to seek medical attention.
Condition on admittance: of moderate gravity. Rash on hands with big serous
fluid-filled vesicles; negative Nikolsky symptom. There were erosion with
diapedetic bleeding and scrotal oedema in the area of scrotum and penis.
Cheilitis, multiple aphthae on the internal surface of cheeks, on hard and soft
palate and on tong were revealed, as well as haemorrhagic crustings on eyelids,
moderate injection in scleral vessels. Physical state: with no specific findings.
Systemic glucocorticoids and antihistamine preparations were administrated, as
well as antibacterial, infusion therapy and topical treatment. On the second day a
total relief of diapedetic bleeding in the scrotal area was achieved. To the end of
the 10th day a total epithelization in the area of penis and scrotum occurred.
Aphtae on hard and soft palate relieved totally within the first three days.
Laboratory results have shown increasing levels in circulating thrombocytes
according to the relief of diapedetic bleeding. Maximal levels were attained by
the 6th day (667 *109/L) with the following return to normal values. On
admission C-reactive protein levels were elevated up to 136.65 mg/L, by the 7th
day they returned to normal values.
No eosinophilia or leukocytosis had been revealed. The described case represents
a favorable variant of clinical course of carbamazepine intolerance, with a quick
epithelisation, and no injury in liver, kidneys or blood islands.
Method
Results
Conclusion
-
Poster Walk 14: RCM (P119 – P128)
P119 13 CASES OF SEVERE ANAPHYLACTIC REACTIONS DUE TO
RADIOCONTRAST MEDIA
Jaume Martí Garrido, Ramon Lopez Salgueiro, Diana Kury Valle, Verónica
Pacheco Coronel, Carolina Perales Chordá, Dolores Hernandez Fernandez De
Rojas
IIS La Fe, Valencia, Spain
Introduction
The increasing use of radiocontrast media (RCM) is associated with an increase in
adverse reactions with these preparations.
Method
We revised a total of 249 cases referred during 2012-2014 for allergic evaluation
due to adverse with RCM. We collected information about the radiological
procedures, adverse reactions and results of allergy study of patients who
developed severe anaphylactic reactions.
Results
We analysed 5 men and 8 women with an average age of 63 years (37-86). In
69% respiratory symptoms were reported, 62% neurological, 54% cutaneous,
31% cardiovascular and 31% digestive symptoms. 31% complaint of subjective
symptoms (general discomfort, heat or flushing). The reaction was immediate
(within minutes) in 69% of cases. One patient required admission to the
intensive care unit and another had a repeated episode of anaphylaxis after
readministration of RCM despite of the premedication. In 4 cases the reaction
occurred during a computed tomography (CT), in 4 with intravenous urography
(IVU), and 3 with magnetic resonance (MR). In 2 cases the radiological
procedure was not specified. In 2 of the 13 patients (15%), intradermal tests
were positive with the RCM involved: iomeprol and dimeglumine gadopentetate.
The basophil activation test (BAT) with the RCM was positive in 4 cases: 2 with
iomeprol and iodixanol, 1 with iopamidol and 1 with gadobenate and
gadopentate.
Conclusion
TC and IVU were the most frequently involved radiological procedures.
Respiratory symptoms were the most common clinical manifestations. Skin tests
and BAT helped to identify the agents responsible for the reactions. The
sensitivity and specificity of these tests are still undetermined.
P120 Anaphylactic Shock After Administration Of Iodinated Contrast
Medium During Cardiac Catheterization
Roselle Catherine Yu Madamba, Marta Ferrer, Maria Jose Goikoetxea, Carmen D´
Amelio, Amalia Bernad, Olga Vega, Gabriel Gastaminza
Clinica Universidad de Navarra, Pamplona, Spain
Introduction
Iodinated contrast media (ICM) are one of the most commonly used in the field
of diagnostic medicine today. Though considered generally safe, they can cause
hypersensitivity reactions that can either be immediate or nonimmediate. Anaphylactic shock reactions to ICM are rare but serious and could
be life threatening. Hence, urgent and timely treatment should be
administered.
Case Description
We present a case of a 64 year old hypertensive patient with ischemic
cardiopathy who presented with intense cephalic heat, tachycardia, hypoxemia
and hypotension of 50/30mmHg without any cutaneous lesions immediately after
the administration of 35 grams of Iomeprol contrast medium for cardiac
catheterization. Epinephrine IM, Dexchlorpheneramine and corticosteroid IV and
intravenous fluid therapy were administered which afforded the reversal of the
hypotension. The tryptase at the time of the reaction and 2 hours post reaction
were both elevated, 85.70ug/L and 88.70ug/L respectively. Baseline tryptase
was normal (6.86ug/L). Skin prick test and basophil activation test to different
contrast media were negative while intradermal test to Iomeprol showed a
positive result and negative to Iohexol, Iodixanol and Meglumine. Thus,
challenge test to Iodixanol reaching a total dose of 47 grams as an alternative
medium was done which he tolerated well. One month later, the patient
underwent another cardiac catheterization. However, 10 minutes after the
administration of 15 grams of Iodixanol, he presented another episode of
anaphylactic shock. He was given the same medications he had received
previously which reversed the anaphylactic shock. Tryptase level was positive
(30.20 ug/L). Due to the episode of anaphylactic shock, the contemplated
cardiac catheterization was discontinued. Skin tests the next day resulted
positive to Iohexol, Iodixanol and Iomeprol.
How this report contributes to current knowledge
Despite that the patient tolerated well the challenge test with Iodixanol and skin
test was negative, possible hypersensitivity reactions can still occur. Although
challenge test is considered the gold standard in drug allergy, it can also provoke
sensitisation to the drug or increase the sensitivity that could not be detected
prior due to cross reaction. As of the present, the pathophysiological mechanism
of these allergic reactions still needs to be exemplified.
P121 ANAPHYLACTIC SHOCK AND CARDIAC ARREST INDUCED BY
GADOLINIUM-BASED CONTRAST AGENTS
Beatriz Pola Bibián, Marina Lluncor Salazar, Gemma Vilà Nadal, Ana María
Fiandor Roman, Javier Dominguez Ortega, Miguel Gonzalez Muñoz, Santiago
Quirce Gancedo, Maria Rosario Cabañas Moreno
La Paz Hospital, Madrid, Spain
Keywords: Paramagnetic Contrast Agents, Anaphylaxis
Introduction
Gadobenate Dimeglumine and Gadoteric Acid are two gadolinium-based contrast
agents that enhance the contrast images obtained by magnetic resonance
imaging. Allergic reactions to them are rare.
Method
We report two cases of IgE-mediated anaphylactic shock, induced by these
gadolinium-based contrast agents and documented by positive allergy
assessment. The first case is a 26-year-old woman with no previous drug allergy
who developed dizziness, generalised erythrodermia and throat tightness, when
a nuclear magnetic resonance with MultiHance (Gadobenate Dimeglumine) was
being performed. On physical examination, she had hypotension, tachycardia,
tachypnea, 69% of basal oxygen saturation and generalized pulmonary
hypoventilation. She recovered after treatment with corticosteroids and
adrenaline. Nine months later the patient was referred to the allergy unit. The
second case is a 51-year-old woman with a history of high blood pressure treated
with betablockers, rhinoconjunctivitis and asthma due to sensitization to house
dust mites and dog dander. Immediately after the intravenous infusion of
Dotarem (Gadoteric Acid) she developed dizziness, loss of consciousness and
cardiac arrest. On physical examination, she had universal rash without wheals,
90% of basal oxygen saturation and generalized wheezing. CPR was started and
1mg of Adrenaline was administrated. She recovered after 15 minutes and was
admitted to the ICU. Two months later she was referred to the allergy unit.
Results
Case 1: Basal serum tryptase was normal. Skin prick tests (SPTs) were positive
with Gadobenate Dimeglumine and negative with other paramagnetic contrasts
agents and latex. The patient tolerated a MRI with Gadobutrol two years later.
Case 2: Basal serum tryptase was normal. Basophil activation test (BAT) was
positive with Gadoteric Acid, and negative with other paramagnetic and iodinated
contrast agents.
Conclusion
We report two cases of an anaphylactic shock, one with cardiac arrest,
immediately after the intravenous infusion of a paramagnetic contrast agent.
Positive SPTs to Gadobenate Dimeglumine and positive BAT to Gadoteric Acid
suggest an IgE-mediated mechanism. Hypersensitivity reactions with
paramagnetic contrasts are very unusual. There are few cases with positive SPTs
or BAT reported in literature. We should take into account that SPTs and BAT can
be helpful to identify the responsible agent and the alternative contrasts that
could be administered safely to the patient in the future.
P122 Anaphylaxis To Gadobenate And Cross-Reactivity To Other
Gadolinium-Based Contrast Agents In Two Patients
Kathrin Scherer Hofmeier
Allergy Unit, Department of Dermatology, University Hospital Basel, Basel,
Switzerland
Keywords: Anaphylaxis, Gadolinium, Gadobenate
Introduction
The frequency of adverse reactions to gadolinium-based contrast media is
estimated to be 0.07%-2.4%. True allergic hypersensitivity reactions are very
rare, presenting usually as urticarial exanthems of minor severity. The reported
incidence is 0.004%-0.007%. Severe life-threatening reactions were extremely
rare (0.001%-0.01%). Prior allergic reactions to gadolinium contrast media
(GCM) are considered risk factors for new sensitizations to other GCM. We report
on two female patients with severe immediate type reactions to Gadobenate,
with cross reactivity to other GCM.
Method
Patient 1 (48 yrs): An MRI with Gadobenate was performed for diagnosis of
pancreatitis. Immediately after application of the GCM she developed generalized
itch and erythema, dyspnoea and cardiac arrest after 10 min. Mechanical and
drug resuscitation was successfully performed. No definite prior exposure.
Patient 2 (74 yrs): MRI with Gadobenate was performed for cardiac diagnostics.
Within few minutes after application of the drug she developed a generalized
sensitization of head, erythema, dysphagia, dyspnoea and swelling of the
tongue. Prior exposure to an unknown GCM.
Results
Pricktests were negative for Gadoterate, Gadobutrol, Gadoxetate and
Gadopentetat in both patients. Gadobenate was postive in patient 2.
Intradermaltests were positive for Gadobenate and Gadobutrol in both patients,
and Gadoxetate, Gadoterat and Gadopentetat in patient 1. Mastcell tryptase and
Basophil activation tests were normal/negative in both patients.
Conclusion
We report on two cases of rare severe hypersensitivity reactions to Gadobenate
with skin test cross-reactivity to Gadobutrol in both patients, and further GCM in
one patient. Gadopentetat, a linear non-ionic GCM, was skin test negative in both
patients, whereas the linear ionic culprit Gadobenate was cross-reactive with the
cyclic Gadobutrol in both patients, and cross-reactive to other linear ionic and
cyclic GCM in patient 1.
P123 Anaphylaxis To Glatiramer Acetate In A Patient With Multiple
Sclerosis
Fabrícia Carolino1, Vladyslava Barzylovych2, Josefina R Cernadas1
1. Serviço de Imunoalergologia, Centro Hospitalar São João E.P.E., Porto,
Portugal
2. Serviço de Imunoalergologia, Centro Hospitalar São João E.P.E., Porto,
Portugal; Drug Allergy Diagnostics Centre, Institute of Paediatrics,
Obstetrics and Gynaecology of NAMS, Kiev, Ukraine
Introduction
Glatiramer acetate (GA) or Copaxone®(marketed by Teva Pharmaceuticals
Europe B.V.) is an injectable immunomodulatory treatment approved for
relapsing-remitting multiple sclerosis (MS) in preventing relapses and slowing the
disability progression. Rare cases of hypersensitivity reactions to this drug have
been published in the literature. The authors describe a case of systemic
symptoms associated with GA and the diagnostic workup of the patient.
Case Description
The authors report the case of a 34 year-old woman diagnosed with MS in 2008,
initially treated with interferon-β1a (Avonex®). As relapses were frequent
despite treatment, this was changed in January/2013 to natalizumab (Tysabri®),
which is a monoclonal antibody (α4-integrin antagonist) with similar therapeutic
indications to those described for GA. After 12 months of treatment, natalizumab
was stopped because the patient developed persistent anti-drug antibodies.
Considering that the patient was planning a pregnancy a new treatment (with
GA) was started in March/2015. Four months later, the patient presented a
generalized skin-burning sensation, dyspnoea and palpitations, 1 minute after GA
administration with no additional signs or symptoms. At this point, the patient
was referred to our Drug Allergy Department for assessment. Skin tests were
performed with GA plus the inactive ingredient of Copaxone® with allergenic
potential, mannitol; the dilutions were prepared with saline solution. For skin
prick tests we used GA 20 mg/ml in the 1/100, 1/10 and 1/1 dilutions, and
mannitol 100 mg/ml (undiluted). Intradermal tests were performed with 1/1 000
000 to 1/10 dilution of GA (20 mg/ml), with a strong positive result at 1/10
concentration. Intradermal test to mannitol (1/10 dilution) was negative.
How this report contributes to current knowledge
We also tested three (2 atopic and 1 non-atopic) controls for GA at 1/10 dilution
with negative results. These results point to an underlying immunological
mechanism in this case. A desensitization approach with GA might be considered
for this patient.
P124 Delayed Hypersensitivity Reaction To Radiocontrast Media
Fabrícia Carolino1, Diana Silva2, Leonor Leão1, Josefina R Cernadas1
1. Serviço de Imunoalergologia, Centro Hospitalar São João E.P.E., Porto,
Portugal
2. Serviço de Imunoalergologia, Centro Hospitalar São João E.P.E.;
Laboratório de Imunologia, Faculdade de Medicina, Universidade do Porto,
Porto, Portugal
Introduction
Iodinated contrast media (ICM) may associate with different types of adverse
events including allergic and non-allergic hypersensitivity reactions as defined by
the European Academy of Allergy and Clinical Immunology. Immune-mediated
reactions are either immediate or non-immediate reactions that become
apparent later than 1 h (and up to several days) after exposure and these are
less frequently reported.
Case Description
The authors report the case of a 46 year-old woman, with history of Hodgkin’s
lymphoma, evaluated in our Drug Allergy Unit for two suspected hypersensitivity
reactions to ICM. In 2014, the patient underwent a contrasted CT scan with
iomeprol (Iomeron®) and 72h later developed a generalized pruritic
micropapular exanthema that resolved completely in a week (with antihistamine
and corticosteroid medication). She had been previously exposed to ICM with
tolerance. In 2015, a new high-resolution CT scan was performed using the same
ICM (iomeprol), and again a diffuse pruritic exanthema developed (6h later) but
this time with facial angioedema and fever (39ºC); the symptoms resolved in 4
days under medication (antihistamine and corticosteroid), leaving residual
purplish lesions that eventually disappeared (after weeks). Skin prick tests with
idopovidone (Betadine®), and undiluted ioversol (Optiray®), iobitridol
(Xenetix®), iopromide (Ultravist®) and iomeprol (Iomeron®) were negative.
Intradermal tests were performed with 1/100 and 1/10 dilutions of ioversol
(Optiray®), iobitridol (Xenetix®), iopromide (Ultravist®) and iomeprol
(Iomeron®); immediate reading was negative for all tested ICM but late reading
(at 48h) was positive to ioversol (Optiray®) and iomeprol (Iomeron®) in both
dilutions.
How this report contributes to current knowledge
The results confirmed a delayed hypersensitivity to ICM, with cutaneous crossreactivity between ioversol and iomeprol.
P125 Drug Reaction With Eosinophilia And Systemic Symptoms Induced
By Iodixanol
Gemma Vilà-Nadal1, Beatriz Pola1, Marina Lluncor1, Ana Fiandor2, Teresa
Bellón3, Javier Domínguez2, Santiago Quirce2
1. Allergy Department. La Paz Hospital Institute for Health Research
(IdiPAZ), Madrid, Spain
2. Allergy Department. La Paz Hospital Institute for Health Research
(IdiPAZ), Consorcio Piel en RED, Madrid, Spain
3. Immunology Department. La Paz Hospital Institute for Health Research
(IdiPAZ), Consorcio Piel en RED, Madrid, Spain
Introduction
We describe a case of a Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS) following a coronary catheterization with iodixanol.Late reactions to
iodinated contrast media are frequent.We describe the tests used for the
diagnosis in this case.
Case Description
Method:We report a case of a 74-year-old man admitted to the coronary unit
with cardiac arrest.A cardiac catheterization was performed without
complications.Three days later he received another cardiac catheterization and
within 24 hours he presented a generalized maculopapular exanthema with
pruritus and facial angioedema. Over the next few days the body temperature
rose up to 38,5º C. Blood tests showed eosinophilia (1200 per mcL), total white
blood cell count 19000/mcL, neutrophils 16700/mcL, renal impairment
(creatinine 1,89mg/dL, previously being normal).The contrast used for
catheterization was iodixanol. The patient also received ticagrelor, carvedilol,
enalapril, furosemide, fondaparinux and lorazepam. Assessment of causality was
established using the Spanish Pharmacovigilance System Algorithm. Results were
(+6) “probable” for iodixanol and (+4) “possible” for carvedilol and ticagrelor. A
multidisciplinary group composed by a dermatologist; a pharmacologist and an
allergist evaluated the patient. This case was included in the Piel en RED
registry. Six months after the reaction the patient was referred to the allergy unit
and tests were performed. The allergy study included epicutaneous tests and the
lymphocyte transformation test (LTT) according to Pichler et al. An stimulation
index (SI) was calculated. Results: The diagnosis of a “probable” DRESS was
established according to the scoring system described by Kardaun et al. Our
patient received a score of 4. A skin biopsy showed spongiotic dermatitis with
eosinophils. The patient had a positive LTT to iodixanol; the SI was over 8 in two
concentrations. LTT showed also positive results for other iodinated contrast
media. We also tested carvedilol and ticagrelor with a lightly positive result.
Epicutaneous test showed remarkable positivity to iodixanol beginning at the 48
h reading. The test was negative to carvedilol, iobitridol and iomeprol.
How this report contributes to current knowledge
LTT and patch test were useful to identify this agent as responsible for the
reaction. DRESS requires a multidisciplinary approach and an allergy study is
essential to determine the etiology of the disease.
P126 Electronic Consultation Support System For Radiocontrast Media
Hypersensitivity Changes Clinician’s Behavior
Min-Suk Yang1, Sun-Sin Kim2, Sae-Hoon Kim3, Hye-Ryun Kang4, Heung-Woo
Park4, Sang-Heon Cho5, Kyung-Up Min5, Yoon-Seok Chang3
1. Seoul National University Borame Hospital, Seoul, South Korea
2. Seoul National University Hosptial Healthcare System Gangnam Center,
Seoul, South Korea
3. Seoul National University Bundang Hospital, Seongnam, South Korea
4. Seoul National University Hosptial, Seoul, South Korea
5. Seoul National University College of Medicine, Seoul, South Korea
Keywords: Drug Hypersensitivity, Radiocontrast Media, Clinical Decision
Supporting System
Introduction
Patients with a previous history of radiocontrast media (RCM) hypersensitivity
could be overlooked, resulting in repeated reactions. To avoid this, 'consultation
support system for RCM hypersensitivity' has been embedded to Seoul National
University Bundang Hospital (SNUBH) since Dec 2011. We analyzed the influence
of this system on doctors' practice pattern.
Method
A retrospective study was conducted with the patients with previous RCM
reactions (Dec 1st 2010-Nov 30th 2012). Control period was between Dec 2010
and Nov 2011 and intervention period was Dec 2011 and Nov 2012. Primary
outcome was composite outcome of premedication and consultation.
Premedication was defined as the preventive medication prescribed by the doctor
who ordered RCM enhanced CT (CT) at the same time. Secondary outcomes
were the recurrence rate after the consultation support system and ther rate of
premedication using systemic steroid for those with previous history of moderate
to severe RCM reactions.
Results
In the control period, 189 clinicians prescribed 913 CT scans and 225 clinicians
did 1,153 examinations in the intervention period. The odds of achieving
composite outcome increased significantly after the consultation support system
(OR 1.54, 95% CI 1.15-2.05). Clinicians in both medical (OR=1.48, 95% CI
1.06-2.07) and surgical (OR=2.07, CI 1.24-3.46) part showed significant
changes in their behavior, but emergency department did not (OR=1.07, 95% CI
0.41-2.78). Professors (OR=1.47, 95% CI 1.06-2.04) and trainees (OR=1.97,
95% CI 1.22-3.18) showed significant changes in their behavior to the patients
with previous RCM reactions. The rate of premedication using systemic steroid
for the patients with previous history of moderate to severe RCM reactions did
not changed significantly (OR=1.68, 95% CI 0.70-0.404). The results of analyses
with 86 clinicians who ordered CT scans during both control and intervention
periods were not altered.
Conclusion
The consultation support system for those with previous RCM hypersensitivity
reactions changed doctor's practice patterns and decreased recurrent
RCM hypersensitivity reactions as well.
P127 Hypersensitivity Reactions To Iodinated Contrast Media: Skin
Testing And Follow-Up
Danica Juricic Nahal, Ivana Cegec, Viktorija Erdeljic Turk, Iva Kraljickovic,
Matea Radacic Aumiler, Ksenija Makar Ausperger, Iveta Simic
University Hospital Zagreb, Zagreb, Croatia
Keywords: Iodinated Contrast Media, Hypersensitivity, Skin Test, Follow-Up
Introduction
Iodinated contrast media (ICM) are frequently used to enhance radiological
procedures. Hypersensitivity reactions to ICM can be classified as immediate or
nonimmediate. Skin tests have been performed in the diagnosis of both types of
reactions to ICM. The sensitivity of skin tests has not been adequately validated.
Method
A retrospective chart review was performed on patients (pts) undergoing ICM
skin testing. A total of 45 pts tested for ICM allergy at the Division of Clinical
Pharmacology at the University Hospital Zagreb between July 2014 and October
2015 were enrolled. All pts underwent skin tests (prick test and intradermal test
with immediate and delayed reading) to iohexole and/or iodixanole. Pts were
contacted during December 2015 and questioned about exposure to ICM after
testing. Eligible pts (n=40) were classified into 3 groups: nonimmediate or
immediate hypersensitivity reaction to ICM, and previously unexposed group.
Results
The nonimmediate group comprised 15 pts with hystory of exanthema (53.3%),
urticaria (20%), angioedema (13.3%) and pruritus (6.7%) to ICM. One pt had
positive skin tests to iodixanole and negative to iohexole. All other performed
tests were negative. In the follow-up period 4 pts were exposed to ICM without
adverse reactions; 10 pts were not exposed to ICM; 1 pt was unavailable for
follow up.
The immediate group comprised 11 pts with hystory of gastrointestinal
symptoms (27.3%), urticaria (27.3%), angioedema (18.2%), general symptoms
(18.2%) and flush (9.1%) to ICM. One pt tested positive to iohexole. All other
performed tests were negative. In the follow-up period 7 pts were exposed to
ICM; 6 pts experienced no adverse reactions; 4 pts were not exposed to ICM and
1 pt developed angioedema.
The previously unexposed group comprised 14 pts. All skin tests were negative.
The reason for referral to ICM testing was a hystory of serious allergic reaction to
different allergens. In the follow-up period 5 pts were exposed to ICM without
adverse reactions; 4 pts were not exposed to ICM; 5 pts were not available for
follow up.
Conclusion
Overall, 16 pts were exposed to ICM in the follow-up period and of those, 1 pt
developed an immediate reaction. The calculated negative predictive value in this
study is thus 93.8%.
This study adds further knowledge to the field of ICM hypersensitivity. Studies
including follow-up data on sebsequent ICM exposure are needed in order to
adequately validate ICM skin tests.
P128 Would Iodine Allergy Exist?
Clémence Delahaye, Jenny Flabbee, Julie Waton, Olivia Bauvin, Annick Barbaud
Dermatology and Allergy department, Brabois hospital, University hospital of
Nancy, Lorraine University, 54500 Vandoeuvre-Lès-Nancy, France
Keywords: Allergy - Iodine - Multiples Reactivity
Introduction
Allergies to povidone iodine (PVI) are related to povidone (PV), those due to
radio contrast media (RCM) to cyclic structures and those with seafood related to
animal protein such as tropomyosin. The iodine allergy is a mythical entity, but
nevertheless !
Method
A 39 year old diabetic man, with end stage renal disease undergoing peritoneal
dialysis, was referred for immediate hypersensitivity (IH) reactions. Betadine
dermique® containing povidone iodine triggered an immediate contact pruritic
rash disappearing in 30 minutes (mns). Angioedema and urticaria occurred a few
mns after ingestion of shrimps, mussels, oysters, whelks, trout and salmon.
Awaiting kidney transplant, having never received RCM, a predictive assessment
of RCM IH was required. Patch and prick tests (pt), IDT, specific IgE and RCM
reintroduction were performed under hospital supervision.
Results
While all patch tests were negative, pt were positive for pure Betadine
dermique® and iodized alcohol at 1% in water but negative for Lugol 2%
(potassium iodide) and PV. Pt to a native oyster was positive but negative for
crab, mussel and shrimp. IgEs were negative for salmon, mussel, oyster and
shrimp. Pt and IDR were negative for iobitridol, ioxaglate and iodixanol in pure
form (use concentration), but the intravenous administration of 1 ml iobitridol
induced a generalized pruritus, a trunk and face erythema with ear edema,
occurring after 30 mns and resolution in 60 mns after treatment with intravenous
methylprednisolone and antihistamines.
Conclusion
This exceptional case of multiple reactivities to iodine products and oyster
suggests that for this patient iodine itself could be the common allergen. The
positive pt to oyster is probably not related to a tropomyosin sensitization. Unlike
previous published cases of allergy to povidone iodine, in this case the IH does
not appear due to PV. While IDT was negative, iobitridol induced an immediate
reaction. We emphasize 1) in case of PVI IH, the need to do a pt to PVI and PV
before concluding to the lack of iodine sensitization and thus allow RCM; 2) if
negative IDT with RCM, we must continue investigations by an intravenous
introduction test with a limited volume of RCM and 3) even if it is exceptional, an
iodine allergy may exist. Investigations are continued with in vitro tests.
Poster Walk 15: MPE /Type 4 (P129 - P137)
P129 Delayed Hypersensitivity Cutaneous Reactions: A Case/Control
Study From A Tunisian Database
Karim Aouam, Najah Ben Fadhel, Zohra Chadly, Nadia Ben Fredj, Naceur A
Boughattas, Amel Chaabane
Faculty of Medicine/University hospital/University of Monastir, Monastir, Tunisia
Keywords: Case/Noncase, Drug Allergy, Delayed Reactions, Epidemiology
Introduction
Drug hypersensitivity reactions represent a heterogeneous clinical entity with
diverse pathogenesis and result in a considerable burden of morbidity and
mortality. Diagnostic procedures rely on clinical history, skin testing and in some
cases, provocation tests. Drug imputability is still difficult to establish due to the
weakness of sensitivity of some skin tests and the impossibility to perform
provocation test in case of severe reactions. The aim of our study is to evaluate
delayed-type cutaneous allergic reactions associated with drug use.
Method
The data were obtained from a Tunisian pharmacovigilance database of adverse
drug reactions (ADRs). Analyzed reports were retrieved from the
pharmacovigilance unit of Monastir (Tunisia) database collected from 2004 to
2015. The association between drugs and skin reactions was assessed using the
case/non-case method, calculating the adverse reaction reporting odds ratio
(ROR) and their 95% confidence intervals as a measure of disproportionality. The
“cases” were defined as reports of type III and IV skin allergic reactions
(according to gelle and Coombs classifications). The “non-cases” were all other
reports.
Results
Overall 1800 reports of adverse reactions related to drug use were analyzed; of
which 1523 (84%) were judged as type III and IV skin allergic reactions (cases)
and the remaining were considered non-cases. Drug classes associated with a
significant increase of ROR were anticonvulsive agents (ROR=2.2, 95% CI [1.43.3], p<10-3) and antibacterial drugs (ROR=1.6, 95% CI [1.3-2], p<10-3).
Among antibacterial agents, betalactams were associated with a significant ROR
(1.5; 95% CI [1.2-1.8], p<10-3). Regarding betalactams, only oxacilline and the
third generation cephalosporins were associated with a significant risk (ROR=1.9;
95% CI [1.1-3.2], p=0.01) and (ROR=1.81; 95% CI [1.3-2.4], p<10-3),
respectively, while only carbamazepine (ROR=3; 95% CI [1.6-5.7], p<10-3) and
phenobarbital (ROR=2.3; 95% CI [1.1-5.2], p=0.03) have shown a significant
ROR values among anticonvulsive agents.
Conclusion
Results highlight the frequency of association of delayed hypersensitivity skin
reactions with betalactams, carbamazepine and phenobarbital. Given the
widespread use of these drugs, awareness should be raised among patients and
prescribers about these risks.
P130 Delayed Hypersensitivity Reactions To Cephalosporins: A Review
Of Seven Cases
Joana Cosme1, Anabela Lopes1, Amélia Spínola-Santos1, Manuel PereiraBarbosa2
1. Immunoallergy Department - Hospital de Santa Maria – Centro Hospitalar
Lisboa Norte, Lisbon, Portugal, Lisboa, Portugal
2. Immunoallergy Department - Hospital de Santa Maria – Centro Hospitalar
Lisboa Norte, Lisbon, Portugal; Faculdade de Medicina de Lisboa, Lisboa,
Portugal
Keywords: ß-Lactams, Cephalosporins, Cross-Reactivity, Delayed
Hypersensitivity Reactions
Introduction
Delayed hypersensitivity reactions to cephalosporins are poorly described
reactions that occur more than 1 h after drug administration. The mechanisms
involved seem to be heterogeneous and not totally characterized. Objectives:
To characterize the delayed hypersensitivity to cephalosporins and determine the
clinical profile of these patients and the cross reactivity with other antibiotics.
Method
Retrospective review from the patients with delayed confirmed hypersensitivity
reactions to cephalosporins between 2013-2014. The patients were submitted to
skin tests with penicilloylpolylysine (PPL), minor determinant mixture (MDM),
benzylpenicillin, ampicillin, amoxicillin, cefuroxime, ceftriaxone, cefipime and
other antibiotics that were eventually involved. Results for specific IgE to βlactams and oral provocation challenge tests (OPT) with the alternative and/or
culprit β-lactms were also reviewed.
Results
Within the 7 patients that were reviewed 71% were female, with a median age of
56 [32.5-66] years and 43% had personal history of atopy. The clinical
manifestations reported by these patients were delayed urticaria in 57% of the
cases and 43% described delayed rash. In all cases the symptoms appeared
more than 24 hours after the beginning of the antibiotic. In 6(85.7%) the
episodes occurred after cephalosporins intake. One patient had an adverse event
with amoxicillin and the sensitization to cephalosporins was only found after
investigation. All had negative specific IgE for β-lactams. Four (57.1%) had
sensitization only to cephalosporins. The cephalosporins involved and the delayed
results of the IDT and OPT are summarized on table 1. All the suspected
cephalosporins were confirmed: 6 (85.7%) on the basis delayed IDT, in 1
(14.3%) cephalosporins' sensitization was determined after OPT. Regarding cross
reactivity with other β-lactams 3 (42.9%) patients had reactivity to
aminopenicillins.
Conclusion
Delayed reactions to cephalosporins are associated with delayed clinical
manifestations and all had only skin involvement. The reactivity with other βlactams, within the patients with delayed cephalosporins hypersensitivity, was
heterogeneous.
P131 Diclofenac Induced Allergic Contact Dermatitis - Case Series Of
Four Patients
Sandra Jerkovic Gulin1, Anca Chiriac2
1. Department of Dermatology and Venereology, General Hospital Sibenik,
Sibenik, Croatia
2. Dermatology Department, Nicolina Medical Centre, Apollonia University,
„P.Poni“ Research Institute of Macromolecular Chemistry, Iasi, Romania
Introduction
Allergic contact dermatitis is an immune-mediated antigen-specific skin reaction
to an allergenic chemical that corresponds to a delayed-type hypersensitivity
response (type IV reaction). Allergic contact dermatitis should be suspected
when skin lesions are localized to the site of previous applications of the culprit
drug. The gold standard for diagnosis is patch testing; identification and removal
of any potential causal agents is crucial.
Diclofenac cream/gel contains propylene glycol, diclofenac, dimethyl sulfoxide,
ethanol and glycerin. It is a widely used non-steroidal anti-inflammatory drug,
known to cause especially photoalergic contact reactions.
Case Description
We present four cases of diclofenac induced allergic contact dermatitis,
diagnosed based on clinical grounds: intensly itchy eczematous lesions on the
sites of drug application, after several days of treatment. No allergic history, no
other drug intake were reported by the patients. The application of topical
diclofenac was strictly avoided in all cases, potent topical steroids proved to be
effective in all cases within two weeeks of therapy.
Patch tests were performed in all cases with european standard batery and with
patients' own cream or gel three weeks after completion of local steroid therapy.
Reading was performed at 96 hours and proved to be positive only to diclofenac.
No sun exposure was allowed during the testing, any other treatments were
forbidden.
How this report contributes to current knowledge
Patients and physicians must be aware of the risk of cutaneous sensitization
induced by topical diclofenac, a drug extensively used also as self medication.
P132 Late-Onset Maculopapular Rash To Irbesartan
Bárbara Kong Cardoso, Elza Tomaz, Regina Viseu, Filipe Inácio
Hospital de S.Bernardo - Centro Hospitalar de Setúbal, Setúbal, Portugal
Introduction
Hypertension is one of the most common worldwide diseases. Angiotensin II
receptor blocker are one of antihypertensive drugs most prescribed. Some wellknown adverse effects of irbesartan are dizziness, urticaria and angioedema.
Irbesartan cutaneous non-immediate reactions have been reported previously in
a limited number of case reports.
Case Description
Sixty years old female patient referred to our clinic with a three week history of
an itchy erythematous maculopapular eruption affecting the torso (thorax and
abdomen) and proximal part of upper and lower limbs which resolved with
hyperpigmentation. The patient reported since then similar but short-lasting
lesions that she related to atorvastatin intake.
The patient current medications were: atorvastatin, irbesartan, chlordiazepoxide,
levothyroxine, estradiol patch, olanzapine and paroxetine. All of them but
irbesartan and paroxetine had been taken for several years. Irbesartan was the
latest drug introduced, approximately 2 months before the exanthematous rash
beginning and paroxetine was only introduced after the symptoms appearance.
There was no history of any infectious disease. Previously performed
histopathologic examination of the lesions showed lymphocytic infiltrate and
eosinophils in the dermis, compatible to drug reaction.
Irbesartan was changed to diltiazem in patient therapy. Patch tests (PT) to
irbesartan, candesartan and atorvastatin (5% in petrolatum) were performed and
a lymphocyte transformation test (LTT) to irbesartan was executed.
Results: PT to irbesartan was positive at 48 and 96 hour. LTT (irbesartan
100µg/mL) showed 6.3 stimulation index.
The patient did not refer new lesions after stopping irbesartan and was
diagnosed as non-immediate drug reaction due to irbesartan based in clinical,
histopathologic and analytic features.
Three months later candesartan was introduced in patient therapy, without skin
reaction after 3 months.
How this report contributes to current knowledge
There are few reports about non immediate cutaneous side effects due to
irbesartan. PT and LTT proved useful in the diagnosis. In spite of the similarity of
chemical structure, candesartan may be tried in patients allergic to irbesartan.
P133 Nonimmediate Hypersensitivity Reactions To Betalactams – A
Retrospective Analysis
Ana Moreira, Susana Cadinha, Ana Castro Neves, Patricia Barreira, Daniela
Malheiro, JP Moreira Da Silva
Centro Hospitalar Vila Nova Gaia e Espinho, Vila Nova Gaia, Portugal
Keywords: Betalactams, Hypersensitivity, Nonimmediate Reactions
Introduction
Betalactams (BL) are the most widely prescribed antibiotics and the most
frequent cause of drug allergic reactions. Benzylpenicillin, the major responsible
for BL drug allergic reactions, has been progressively replaced by amoxicillin and
to a lesser extent by cephalosporins or other BL. Our aim was to characterize a
series of subjects with suspected nonimmediate hypersensitivity (NIH) to natural
penicillins and aminopenicillins/clavulanic acid (CA) and evaluate the usefulness
of different diagnostic procedures in the study of these reactions.
Method
A total of 391 patients with suspected betalactam hypersensitivity (BH) were
referred to our department from 2009 to 2015 and those with suspected NIH to
natural penicillins and aminopenicillins/CA were evaluated. Demographic data,
atopy, allergic diseases, comorbidities, clinical manifestations and diagnostic
procedures were assessed. BH was confirmed by positive skin tests (ST), drug
provocation test (DPT) or long term-challenge (LTC) and considered probable
based on a suggestive history and/or positive lymphocytic transformation test
(LTT). ST were performed with PPL, MDM, Amoxicillin, Amoxicilin/CA, Ampicillin
and Penicillin G; DPT was performed with Amoxicillin, Amoxicilin/CA and
Penicillin.
Results
169 (43%) patients had suspected NIH to natural penicillins and
aminopenicillins/CA: 67% female; median age 37 years (1-81); 34% atopic;
16% had rhinitis/rhinoconjunctivitis, 14% asthma/rhinitis and 8% chronic
urticaria/angioedema. Cutaneous reactions were reported by 84% of patients.
Skin prick tests were negative in all patients tested (129). Intradermal tests were
performed in 110 patients and 11 had positive late-reading. Patch tests were
positive in 7 out of 111 patients. LTT was positive in 5 out of 11 patients. DPT
performed in 120 patients was positive in 10. LTC performed in 86 patients was
positive in 8. BH was confirmed in 29 patients (11 by ST, 10 by DPT and 8 by
LTC), considered probable in 7 patients, excluded in 103 and inconclusive in 30.
Conclusion
As previously reported in the literature, our study suggests that BH usually
presents with cutaneous symptoms and affects mainly adults. BH was
established in 17% of the patients, 38% by ST, 34% by DPT and 28% by LTC.
According to the ENDA guidelines, DTP is the gold-standard for definitive
diagnosis of BH. Nevertheless, 8 patients would not have been diagnosed if LTC
was not included in the diagnostic work-up.
P134 OCCUPATIONAL AIRBORNE CONTACT DERMATITIS TO
OMEPRAZOLE
Ružica Jurakic-Toncic1, Suzana Ljubojevic1, Petra Turcic2
1. Department of Dermatology and Venereology, University Hospital Center
Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia
2. Department of Pharmacology, Faculty of Pharmacy and Biochemistry,
University of Zagreb, Zagreb, Croatia
Keywords: Omeprasole, Proton Pump Inhibitor, Eczema
Introduction
Omeprazole is a proton pump inhibitor for the treatment of gastric acid-related
disorders. It is administered orally.
Method
We present 52-years-old chemist who worked in a pharmaceutical company for 5
years and she was exposed to omeprazole during the manufacturing process.
When working in the laboratory, she was wearing protective latex free gloves.
Whenever they were manufacturing omeprazole she had eczema with scaling on
the eyelids face and neck, later hands were also affected. When she was on sick
leave or when she was on vacation she had completely regression of skin
dermatitis. The patient was treated with topical corticosteroids, which resulted
with temporally regression of skin symptoms.
Results
We preformed lymphocyte transformation test (LTT) which was negative. Patch
test to baseline series was negative, but patch test to omeprazole (0.1% and
0.5% in saline solution) was positive at day 2 (+) and day 3 (++).
Conclusion
Omeprazole constitute a high-sensitizing chemical. Although direct contact with
the skin is not always present, distribution of dust containing omeprazole
through the air and deposition on exposed areas may result in an airborne
pattern of contact dermatitis. Our case confirms the risk of sensitization to
omeprazole from occupational exposure.
P135 Ornidazole-Induced Fixed Drug Eruption Confirmed By Positive
Patch Test On A Residual Pigmented Lesion
Liesbeth Gilissen, Sara Huygens, An Goossens
University Hospitals Leuven, Leuven, Belgium
Keywords: Fixed Drug Eruption; Ornidazole; Patch Testing
Introduction
Ornidazole is a 5-nitroimidazole derivative commonly prescribed for the
treatment of diarrhea caused by anaerobic bacteria. Previous cases of fixed drug
eruptions (FDE) from ornidazole were reported in the literature (1-6), however,
in only one of them the diagnosis has been confirmed by a positive patch test
(5); their patient had also shown a FDE following oral intake of fluconazole (5).
In another case (6) cross-reactivity occurred following oral intake with
secnidazole.
A 40-year-old male patient presented with two pigmented lesions, one on the
upper arm, and one with a central erosion on the glans penis. These had
occurred since the intake of ornidazole (Tiberal®, Laboratoires SERB, Paris,
France) and budesonide (Entocort®, AstraZeneca, Brussels, Belgium), 2 weeks
previously. The provisional diagnosis of FDE was put forward.
Method
Five weeks later, patch tests with ornidazole (tablet crushed and diluted 30% in
petrolatum) and budesonide (0.01% in petrolatum) were performed on a residual
pigmented lesion on the upper arm, and also on a non-lesional skin site as a
control, using vander Bend Chambers® (vander Bend, Brielle, The Netherlands).
Results
Only the patch test with ornidazole on the residual pigmented lesion showed a
positive reaction at day 4, while the control on the non-lesional skin remained
negative. Discontinuation of ornidazole resulted in clearance of the lesions.
Conclusion
In the unlikely event of a fixed drug eruption, clear identification of the culprit
may be difficult, in particular when multiple medications are administered. Patch
testing in a previously affected lesion may identify the causative agent, as in the
present case.
References:
1. Gupta R. Fixed drug eruption due to ornidazole. Indian J Dermatol 2014:
59(6): 635.
2. Marya C et al. Mucosal fixed drug eruption in a patient treated with ornidazole.
J Dermatol 2012: 27: 6(1): 21-24.
3. Gupta S et al. Fixed drug eruption caused by ornidazole. Contact Dermatitis
2005: 53: 300–301.
4. Gupta S et al. Multiple fixed drug eruption caused by ornidazole. Dermatitis
2010: 21: 330–333.
5. Bavbek S et al. Fixed drug eruption caused by ornidazole and fluconazole but
not isoconazole, itraconazole, ketoconazole and metronidazole. J Dermatol 2013:
40(2): 134-135.
6. Sanmukhani J et al. Fixed drug eruption with ornidazole having crosssensitivity to secnidazole but not to other nitro-imidazole compounds: A case
report. Br J Clin Pharmacol 2010: 69: 703–704
P136 REPEATED DELAYED REACTION INDUCED BY AMOXICILLIN AND
AMOXICILLIN CLAVULANATE
Inmaculada Andreu1, Ramon Lopez-Salgueiro1, Alicia Martinez Romero2, Pau
Gomez Cabezas2
1. IIS La Fe, Valencia, Spain
2. CIPF, Valencia, Spain
Introduction
There are no techniques validated for the diagnosis of drug induced delayed
allergic reactions. In vivo tests are inconvenient and in vitro tests are neither
sensitive nor validated.
We describe a case of recurrent delayed reactions related to therapy with
amoxicillin and amoxicillin clavunalate by in vivo and in vitro tests.
Method
The patient developed repeated episodes of generalized skin rash, pruritus,
malaise, chest pain and dysphagia after 5-7 days of therapy with amoxicillin
clavunalate or amoxicillin. Blood tests showed an elevation in CRP, GGT,
fibrinogen and monocytosis during the acute phase. The reactions resolved with
corticosteroids and antihistamines.
Intradermal and patch tests were performed with amoxicillin and amoxicillinclavunalate. Total IgE and specific IgE and IgG to amoxicillin were measured by
ImmunoCAP®. Cell activation analysis by the culprit drugs and clavulanate was
performed by flow cytometry. Basophil Activation Test (BASOTEST®) was
considered positive if activation > 5% or SI (stimulation index) >2. Mononuclear
cell activation was evaluated by the expression of CD69 after drug exposure for
48 hours. Antibodies anti-CMV, Herpes, Epstein-Barr and parvovirus were
analyzed.
Results
Intradermal and patch tests with amoxicillin and amoxicillin clavunate acid were
negative. Total IgE: 198 kUI/l. Specific IgE for amoxicillin and penicillin were
negative (0,07 kUI/l). Specific IgG was 3,42 mgA/L. Basophil activation test was
positive for amoxicillin (1/160: 10,87%;SI:16,73 - 1/40: 48,55%;SI:35,69) and
amoxicillin clavunalate (1/160: 22,76%;SI:16,73 - 1/40: 74,68%;SI:54,91),
but negative for clavunalate (100 microgr/ml: 3,55%;SI: 1,26 – 200 microgr/ml:
3,98%;SI:1,41). A 3-fold increase occurred when the mononuclear cells were
treated with amoxicillin, 2.5-fold increase with clavulanate and 10-fold increase
when the samples were treated with amoxicilline clavunalate. Serologies showed
positive IgG for Epstein-Barr, herpes and parvovirus.
Conclusion
Delayed adverse reactions to amoxicillin and amoxicillin clavulanate may be
diagnosed by alternative tests such as basophil and lymphocyte activation tests
when conventional in vivo and vitro tests show negative results. We hypothesize
that specific IgG may induce anaphylactic reactions through basophil activation.
Although the role of T cell activation is not clear, we observed a synergic effect of
both drugs.
P137 Systemic Photosensitivity From Fenofibrate In A Patient PhotoSensitized To Ketoprofen
Liesbeth Gilissen, An Goossens
University Hospitals Leuven, Leuven, Belgium
Keywords: Fenofibrate; Patch Testing; Photo-Allergic Contact Dermatitis;
Systemic Contact Dermatitis
Introduction
Fenofibrate is widely used in the treatment of hypercholesterolemia and
hypertriglyceridemia. Cutaneous side effects such as pruritus, rash, urticarial
lesions, but also cases of photosensitivity have been previously described (1-3).
A 47-year old female patient presented with a severe vesicular eruption involving
the sun-exposed body areas, except under the wristwatch. The face was only
slightly affected to which she had applied a sunscreen. She had been taken
several medications, i.e., fenofibrate (Lipanthyl®, Mylan EPD, Wavre, Belgium),
metformine (Metformax®, Menarini, Zaventem, Belgium), spironolactone, and
allopurinol (Zyloric®, Laboratoires SMB, Brussels, Belgium).
Method
Patch tests with the European baseline series and photo-patch tests with the
European photo-patch test series were performed, using IQ Ultra® Chambers
(Chemotechnique Diagnostics, Vellinge, Sweden).
Results
A strong positive photo-patch test to ketoprofen (D2 -, D4 +++, D8 +++) and
also a positive patch test to benzophenone-3 (D2 +, D4 ++) were obtained.
Conclusion
Photo-allergic contact dermatitis from ketoprofen often gives rise to
simultaneous reactions to other nonsteroidal anti-inflammatory drugs (NSAIDs),
sunscreens, and fragrance components (4), as well as to fenofibrate (5), which,
administered systemically, may induce photosensitivity. The benzophenone
moiety is responsible for the photosensitization reaction (3,5).
References
1. Gardeazabal J, Gonzalez M, Izu R, Gil N, Aguirre A, Diaz-Perez J. Phenofibrateinduced lichenoid photodermatitis. Photodermatol Photoimmunol Photomed
1993: 9(4):156-158.
2. Barbaud A, Schmutz J, Trechot P, et al. Photoallergie au fenofibrate
(Lipanthyl®): à propos de 3 cas. Lett GERDA 1992: 9: 6–10.
3. Serrano G, Fortea J, Latasa J, Millan F, Janes C, Bosca F, Migual A
Photosensitivity induced by fibric acid derivatives and its relation to photocontact
dermatitis to ketoprofen. J Am Acad Dermatol 1992: 27(2): 204-208.
4. Matthieu L, Meuleman L, Van Hecke E, Blondeel A, Dezfoulian B, Constandt L,
Goossens A. Contact and photocontact allergy to ketoprofen. The Belgian
experience. Contact Dermatitis 2004: 50(4): 238–241.
5. Leroy D, Dompmartin A, Szczurko C, Michel M, Louvet S. Photodermatitis from
ketoprofen with cross-reactivity to fenofibrate and benzophenones.
Photodermatol Photoimmunol Photomed 1997:13(3): 93-97.
Poster Walk 16: HLA Genetics (P138 – P146)
P138 A Copy Number Variation In ALOX5 And PTGER1 Is Associated With
Nonsteroidal Anti-Inflammatory Drugs Induced Urticaria And/Or
Angioedema.
Pedro Ayuso Parejo1, Maria Del Carmen Plaza-Serón1, Inmaculada Doña2, Natalia
Blanca López1, Carlos Flores3, Luisa Galindo2, Ana Molina4, James Richard
Perkins4, Jose Antonio Cornejo-García4, José Augusto García-Agúndez5, Elena
García-Martín6, Paloma Campo2, María Gabriela Canto1, Miguel Blanca2
1. Allergy service, Infanta Leonor Hospital, Madrid, Spain, Madrid, Spain
2. Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga,
Spain, Málaga, Spain
3. Research Unit and Centro de Investigación Biomédica en Red de
Enfermedades Respiratorias de Enfermedades Respiratorias, Instituto de
Salud Carlos III, Madrid, Spain, Madrid, Spain
4. Research Laboratory, IBIMA, Malaga Regional University Hospital, UMA,
Malaga, Spain, Málaga, Spain
5. Department of Pharmacology, University of Extremadura, Cáceres, Spain,
Cáceres, Spain
6. Department of Biochemistry and Molecular Biology, University of
Extremadura, Cáceres, Spain., Caceres, Spain
Keywords: NSAIDs Hypersensitivity, Genetic Association Study,
Cyclooxygenases, Prostaglandin E Receptors, Arachidonate 5-Lypoxygenase.
Introduction
Cross-intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs) is a class of
hypersensitivity reaction in which NSAIDs-induced urticaria and/or angioedema
(NIUA) is the most frequent entity. It is thought to involve dysregulation of the
arachidonic acid (AA) pathway. However, this mechanism has not been
confirmed for NIUA. In this work we assessed copy number variations (CNVs) in
8 of the main genes involved in the AA pathway and their possible genetic
association with NIUA.
Method
CNVs in ALOX5, LTC4S, PTGS1, PTGS2, PTGER1, PTGER2, PTGER3 and PTGER4
were analyzed using TaqMan copy number assays. Genotyping was carried out
by real time quantitative PCR. Individual genotypes were assigned using the
CopyCallerTM Software. Statistical analysis was carried out using GraphPad prism
5, PLINK, EPIDAT and R version 3.1.2.
Results
151 cases and 139 controls were analyzed during the discovery phase and 148
cases and 140 controls were used for replication. CNVs in open reading frames
were found for ALOX5, PTGER1, PTGER3 and PTGER4. Statistically significant
changes in CNVs between NIUA and controls were found for ALOX5 (pc=0.017)
and PTGER1 (pc=1.22E-04). Moreover, we described that there was not a
correlation between the presence of a deletion in ALOX5 with the presence of a
deletion in PTGER1 (R2 = 0.274).
Conclusion
This study represents the first analysis showing an association between CNVs in
exonic regions of ALOX5 and PTGER1 and NIUA. This suggests an important role
of CNVs in this pathology that should be further explored in future studies.
P139 Association Of Galectin-3 (LGALS3) Single Nucleotide
Polymorphisms With Non-Steroidal Anti-Inflammatory Drugs-Induced
Urticaria/Angioedema
José Antonio Cornejo-Garcia1, Inmaculada Doña2, Rosa María GuéantRodríguez3, Natalia Blanca-López4, María Carmen Plaza-Serón5, Raquel JuradoEscobar5, Esther Barrionuevo2, María Salas2, María Luisa Galindo2, Gabriela
Canto4, Miguel Blanca2, Jean-Louis Guéant3
1. Research Laboratory and Allergy Unit, IBIMA, Regional University Hospital
of Malaga, UMA, Malaga, Spain
2. Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga,
Spain
3. University of Lorraine and University Hospital Center (CHU) of Nancy,
INSERM U-954, Faculty of Medicine, Vandoeuvre-Les-Nancy, France
4. Allergy Service, Infanta Leonor University Hospital, Madrid, Spain
5. Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA,
Malaga, Spain
Introduction
NSAIDs are the first cause of drug hypersensitivity reactions (DHRs), being those
mediated by non-specific immunological mechanisms (cross-intolerance, CI) the
most frequent. Skin is the most commonly affected organ and NSAIDs-induced
urticaria/angioedema (NIUA) the most frequent clinical entity. Galectin-3 plays
an important role in the biological responses of skin cells, and it is being
regarded as a novel therapeutic target for a variety of skin disorders. We
analyzed the association of several nonsynonymous single nucleotide
polymorphisms (SNPs) in LGALS3 with CI in a large group of patients with
different clinical entities, including NIUA, NSAIDs-exacerbated respiratory disease
and a mixed pattern of response that includes both skin and respiratory
involvement.
Method
The population studied was obtained from two Allergy Services integrated into
the Spanish network RIRAAF. Cases included had to develop more than two
episodes of CI after the intake of two or more NSAIDs from different chemical
groups. We studied several SNPs in LGALS3 using TaqMan® probes. s both skin
and respiratory involvement.
Results
A total of 504 subjects with CI to NSAIDs were included and 271 age and sexmatched healthy controls. Statistically significant associations were found
between NIUA and LGALS3 rs11125 (p<0.001) and rs4644 (p=0.032).
Conclusion
Our results suggest a role for SNPs in LGALS3 in NIUA, the most important
clinical entity induced by HRDs. The association of such genetic variants with
NIUA provides us with new clues for understanding their underlying mechanisms.
Further studies are required to analyze the potential role of other genetic
variants in galectins and related genes in HRDs to NSAIDs.
P140 Detection Of T-Cell Responses To Ticlopidine Using Peripheral
Blood Mononuclear Cells From HLA-A*33:03+ Healthy Donors.
Toru Usui, Arun Tailor, Lee Faulkner, John Farrell, Ana Alfirevic, B Kevin Park,
Dean J Naisbitt
University of Liverpool, Liverpool, United Kingdom
Introduction
Ticlopidine is an anti-platelet drug used in the treatment of atherothrombosis and
is known to cause idiosyncratic drug induced liver injury (DILI). The recent
identification of human leukocyte antigen (HLA)-A*33:03 as a susceptibility
factor and the delayed nature of the liver injury are both indicative of an immune
pathogenesis. However, the role of the adaptive immune system in ticlopidineinduced DILI has not yet been defined.
The aim of this study was to investigate whether drug-specific T cell responses
could be detected in healthy volunteers who expressed HLA-A*33:03. Any T cell
responses would then be fully characterized for drug specificity, HLA restriction
and the mechanism(s) of antigen presentation
Method
Peripheral blood mononuclear cells were isolated from HLA-typed healthy
volunteers who did or did not express the risk allele: HLA-A*33:03.
Subsequently, naïve T-cells were separated and co-cultured with autologous
monocyte-derived dendritic cells (DCs) in the presence of the ticlopidine for a
period of 8 days, to expand the number of drug-responsive T-cells. T-cells were
then harvested and incubated with freshly prepared dendritic cells and drug to
test their antigen specificity using readouts for cell proliferation and cytokine
secretion. T-cell clones were also generated following priming and drug-specific T
cell clones analysed for cytokine secretion and HLA restriction.
Results
Using the DC priming assay all four HLA-A*33:03 positive donors showed
ticlopidine-specific proliferation and IFNγ secretion. However, no ticlopidinespecific responses were detected in HLA-A*33:03 negative donors. Around one
thousand CD8 positive clones were generated from three HLA-A*33:03 positive
donors, but ticlopidine specific clones were only obtained from one donor. These
CD8 positive clones showed ticlopidine-specific IFNγ secretion. This response was
restricted by HLA-A*33:03 and was not dependent on the presence of antigen
presenting cells.
Conclusion
In conclusion, ticlopidine-specific T-cells were detected in healthy volunteers
expressing the risk allele HLA-A*33:03 using the DC priming assay.
P141 Epistasis Approaches To Identify Novel Genes Potentially Involved
In NSAIDs Hypersensitivity
James Richard Perkins1, Jose Antonio Cornejo García1, Oswaldo Trelles2,
Inmaculada Doña3, Esther Barrionuevo3, María Salas3, María Auxiliadora
Guerrero3, Miguel Blanca3, Alex Upton2
1. Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA,
Malaga, Spain
2. Department of Computer Architecture, University of Malaga, Malaga, Spain
3. Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga,
Spain
Keywords: NSAIDs-Hypersensitivity, GWAS, Genetics, Epistasis, Systems Biology
Introduction
A handful of genome wide association studies (GWASs) have been performed to
detect genetic variation associated with NSAID hypersensitivity, by comparing
the frequencies of hundreds of thousands of single nucleotide polymorphisms
(SNPs) between NSAIDs hypersensitive subjects and control individuals. This is
done on a SNP-by-SNP basis, meaning that each variant is considered
independently. However, the effect of a single SNP on phenotype is influenced by
other factors, including the individual’s genetic background. An alternative
approach to analyse this data is the use of epistasis methods, which look for
associations between pairs of SNPs and a phenotype that are stronger than the
sum of the individual SNP-phenotype associations, suggesting an interaction
between the SNPs.
Method
We analysed data from an NSAIDs hypersensitivity GWAS using an epistasis
detection method, MBMDR. The resulting pairs of interacting SNPs were used to
build networks, both at the SNP level and at the gene level, by mapping SNPs to
their closest protein coding gene (within 500kb). These networks were analysed
to identify SNPs and genes with a potential role in NSAIDs hypersensitivity using
graph metrics. This approach identifies important hub nodes based on the
strength and number of connections they have, which can be interpreted as the
number of distinct pair-wise interactions they are involved in.
Results
Our approach identified a number of genes with potential roles in NSAIDs
hypersensitivity, including genes potentially involved in asthma (KCNB2,
PPP1R3C and CSMD1), rhinitis (SCN11A) and immune system functioning
(TSPAN33). It also found a number of genes with a potential role in lipid related
processes, such as SGSM2 and BUB3. The gene CGNL1, whose expression has
been shown to change following aspirin intake, was also identified. Additionally,
pathway analysis of the networks found enrichment for ALK1 and TGF-beta
signalling.
Conclusion
The study presented here shows how weighted epistatic analysis approaches can
complement traditional SNP-by-SNP analyses. Additional studies are necessary to
replicate these findings, and they should be applied to other NSAIDs
hypersensitivity pathologies. Moreover, the mechanisms by which the SNPs and
genes identified here affect NSAIDs hypersensitivity must be investigated
further.
P142 Genetic Predisposition Of Cold Medicine Related SJS/TEN With
Severe Ocular Complications
Mayumi Ueta1, Hiromi Sawai2, Chie Sotozono3, Katushi Tokunaga2, Shigeru
Kinoshita1
1. Department of Frontier Medical Science and Technology for
Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
2. Department of Human Genetics, Graduate School of Medicine, The
University of Tokyo, Tokyo, Japan
3. Department of Ophthalmology, Kyoto Prefectural University of Medicine,
Kyoto, Japan
Keywords: Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN),
Severe Ocular Complications (SOC), Cold Medicines (CM), Genetic Predisposition
Introduction
Stevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous
reaction of the skin and mucosa such as the ocular surface, oral cavity, and
genitals. In patients with extensive skin detachment and a poor prognosis, the
condition is called toxic epidermal necrolysis (TEN). Severe ocular complications
(SOC) appear in about 40% of SJS/TEN patients diagnosed by dermatologists.
Among SJS- and TEN patients, especially those with SJS/TEN with SOC, cold
medicines (CM) including multi-ingredient cold medications and non-steroidal
anti-inflammatory drugs were the main causative drugs. We reported that in the
Japanese, CM-SJS/TEN with SOC was strongly associated with HLA-A*02:06 and
significantly associated with HLA-B*44:03; in Indian and Brazilian caucasian
populations it was associated with HLA-B*44:03, and in Koreans with HLAA*02:06. In our 1st genome-wide association study, we analyzed our SJS/TEN
with SOC patients using the Affymetrix GeneChip Mapping 500K array set, and
found an association between prostaglandin E receptor 3 (PTGER3) and SJS/TEN
with SOC, and subsequently found that this association was stronger in patients
with CM-SJS/TEN with SOC than in patients with all SJS/TEN with SOC. In this
study, we performed the 2nd genome-wide association study using the Japanese
CM-SJS/TEN with SOC.
Method
We performed a genome-wide association study of Japanese 117 CM-SJS/TEN
with SOC patients and 691 controls using the Affymetrix AXIOM Genome-Wide
ASI 1 array. For the examination of 17 SNPs in regions near TSHZ2, we
genotyped 101 of the patients and 200 of the 691 controls.
Results
Manhattan plots showed that the HLA-A region was most strongly associated with
the susceptibility for CM-SJS/TEN with SOC. Outside of the HLA region, there
were 60 SNPs with a value of p < 10-3 in either allele frequency, the dominant-,
or the recessive model. Among the 11 SNPs of 8 genes with p < 10-5, IKZF1
manifested particularly low p-values [rs897693 (CC+CT vs TT), OR = 5.0, p =
2.1×10-8]. Among the 11 SNPs of 8 genes whose value in our second genomewide association study was p < 10-5, TSHZ2 also had especially low p-values
[rs4809905 (AA+AG vs GG), OR=0.3, p = 1.5×10-7]. Furthermore, we have
examined 17 SNPs in regions near TSHZ2 using 101 CM-SJS/TEN patients and
200 controls, and found that 8 SNPs exhibited a significant genome-wide
association with CM-SJS/TEN with SOC.
Conclusion
TSHZ2 is one of the susceptibility gene for CM-SJS/TEN with SOC in the
Japanese.
P143 HLA-B*13:01 And Dapsone Induced Hypersensitivity In Thai
Population.
Chonlaphat Chonlaphat Sukasem1, Patompong Satapornpong2, Therdpong
Tempark3, Pawinee Rerknimitr4, Kulprapat Pairayayutakul5, Jettanong
Klaewsongkram6
1. Ramathibodi hospital, Mahidol university, Bangkok, Thailand
2. Division of Pharmacogenomics and Personalized Medicine, Department of
Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University,
Bangkok, Thailand
3. Division of Pediatric Dermatology, Department of Pediatrics, Faculty of
Medicine, Chulalongkorn University, Bangkok, Thailand
4. Division of Dermatology, Department of Medicine, Faculty of Medicine,
Chulalongkorn University, Bangkok, Thailand
5. 6Raj Pracha Samasai Institute, Department of disease control, ministry of
public health, Nonthaburi, Thailand
6. Division of Allergy and Clinical Immunology, Department of Medicine,
Faculty of Medicine, Allergy and Clinical Immunology Research Group,
Chulalongkorn University,, Bangkok, Thailand
Keywords: HLA-B*13:01, Dapsone, Thai, Dapsone Induced Hypersensitivity
Reactions, DISH
Introduction
Background: Dapsone is regarded as the treatment of choice for infections,
various dermatological diseases and inflammatory diseases. Drug
hypersensitivity syndrome is considered as a severe cutaneous adverse drug
reaction which is commonly precipitated by dapsone. A previous publication
showed that the HLA-B*13:01 allele is a strong marker for dapsone-induced
hypersensitivity syndrome of leprosy patients in China. Although dapsoneinduced hypersensitivity reactions is common, however there are no data
describing whether HLA-B*13:01 could be used as a genetic marker for
prediction of dapsone-induced hypersensitivity reactions in Thai.
Objective: The aim of this study was to investigate the predisposition of
dapsone-induced DHS, conferred by HLA-B*13:01 in a Thai population.
Method
A total of 22 patients, included 11 patients in dapsone-induced hypersensitivity
syndrome, 11 patients in dapsone-tolerant control group (dapsone treatment for
more than 6 months but without any episode of dapsone-induced
hypersensitivity syndrome) and 986 healthy Thai population group. HLA-B
genotype were determined by two-stage sequence-specific oligonucleotide probe
system (SSOP). This study was approved by the Ethics Committee of
Ramathibodi hospital.
Results
The results presented HLA-B*13:01 allele in patients of dapsone-induced
hypersensitivity syndrome, dapsone tolerant controls and healthy Thai population
were 63.64% (7/11), 18.18% (2/11) and 13.59% (134/986) respectively. The
HLA-B*13:01 allele were not significantly different between DIHS cases and
dapsone tolerant controls (p-value = 0.0805, OR = 7.88, 95% CI = 1.11 –
56.13), but there were significant different between DIHS cases and healthy Thai
population (p-value = 0.0002, OR = 11.13, 95% CI = 3.21 – 38.52).
Conclusion
Discussion: Although the samples size of DIHS cases and dapsone tolerant
controls in this research were limited, there were found the HLA-B*13:01 allele
could predisposition toward to dapsone-induced hypersensitivity in Thailand.
P144 HLA-B*15:02 Alleles And Lamotrigine-Induced Cutaneous Adverse
Drug Reactions In Thai
Chonlaphat Sukasem1, N Koomdee1, T Jantararoungtong1, S Santon1, A
Puangpetch1, U Intusoma2, W Tassaneeyakul3, V Theeramoke4
1. 1Division of Pharmacogenomics and Personalized Medicine, Department of
Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University,
Bangkok, Thailand
2. .Department of Pediatrics, Faculty of Medicine, Prince of Songkla
University, Songkla, Thailand
3. Department of Pharmacology, Faculty of Medicine, Khon Kaen University,
Khon Kaen, Thailand
4. Manarom Hospital, Bangkok, Thailand
Keywords: Lamotrigine; HLA-B*1502; Cutaneous Adver Sereactions; StevensJohnsonsyndrome; Toxic Epidermal Necrolysis
Introduction
Background: Lamotrigine (LTG) is one of the antiepileptic drugs (AEDs)
commonly used in the treatment of epilepsy for partial seizures and psychiatric
patients in clinical practice. Several HLA alleles have been associated with
Lamotrigene-induced cutaneous adverse drug reactions (cADRs) in different
populations, however, this has not been investigated in Thai.
Objective: The aims of this study were to determine the possible associations of
lamotrigine-induced cADRs with the HLA-B alleles in Thai patients.
Method
A total of 645 patients, including 16 patients with lamotrigine-induced cADRs,
vary from maculopapular exanthema (MPE) to Stevens-Johnson syndrome/toxic
epidermal necrolysis (SJS/TEN), 50 lamotrigine-tolerant controls and 580 healthy
controls were included in this study. HLA-B genotyping was performed. This
case-control study was approved by the Ethics Committee of Ramathibodi
Hospital.
Results
The differences in the starting dosage of LTG among the SJS/TEN, MPE, and LTGtolerant control groups were not statistically significant. HLA-B*15:02 allele was
present in 33.3% (1/3; LTG-induced SJS/TEN group), 38.5% (5/13; LTG-induced
MPE group) of Thai patients but only 12.0% (6/50) of lamotrigine-tolerant
controls and 14.8% of 580 healthy controls. There was significant difference in
the frequency of subjects with the HLA-B*1502 allele between SJS/TEN and LTGtolerant groups (p < 0.05, OR = 3.559, 95% CI 1.71-7.40), and healthy controls
(p = 0.003, OR = 2.75, 95% CI 1.38-5.47). Significant difference between the
MPE group and LTG-tolerant group (p < 0.05, OR = 4.613, 95% CI 2.23-9.51),
and healthy controls (p < 0.05, OR = 3.565, 95% CI 1.80-7.03).
Conclusion
In conclusion, In this study, we found a statistically significant association
between the HLA-B*1502 allele and LTG-induced cADRs in Thai population.
Therefore, an application of HLA-B*1502 as a screening test before prescribing
LTG will help to prevent LTG-induced cADRs in Thailand.
Table 1. Clinical characteristics of LTG-induced cADRs group and LTG-tolerant
group.
LTG-induced cADRs
LTG-tolerant group (n=50) p-Value
group (n=16)
6:10
12:38
0.340
Gender
1:2 (SJS/TEN)
1.000
(male: female)
5:8 (MPE)
0.353
35.5±21.7
38.2±19.0
0.646
Mean age (years) 52.3±24.0 (SJS/TEN)
0.415
32.0±20.9 (MPE)
0.353
51.6±26.6
77.6±62.0
0.109
Starting dosage of
41.7±14.4 (SJS/TEN)
0.325
LTG (mg/day)
53.8±28.6 (MPE)
0.186
No significant differences were observed in gender, mean age, and mean starting
dosage of LTG between cases and LTG-tolerant controls.
Table 2. Comparison of HLA-B*15:02 frequency among groups.
Group1 ( frequency of HLA- Group2 ( frequency of HLA- pORa
B*15:02)
B*15:02)
Value
LTG-induced SJS/TEN
LTG-tolerant group
LTG-induced SJS/TEN
Healthy control
LTG-induced SJS/TEN
LTG-induced MPE
LTG-induced MPE
LTG-tolerant group
95% CIb
1.717.40
1.380.003 2.750
5.47
0.061.000 0.800
11.29
<0.05 4.613 2.230.0004 3.559
LTG-induced MPE
a
b
9.51
1.81<0.05 3.565
7.03
Healthy control
OR: odds ratio.
CI: confidence interval.
Table 3 The association of individual HLA-B allele with Lamotrigine induced
Cutaneous Adverse Drug Reactions (cADR)
cADR cases versus
cADR cases versus
Lamotrigine
Healthy control
HLA- Lamotrigine Lamotrigine Healthy
tolerant control
B
induced
tolerant
control
OR
allele cADR (n=16) (n=50)
(n=580) OR (95%
P value (95%
P value
CI)
CI)
1301 2 (12.5)
6 (12)
1502 6 (37.5)
6 (12)
1513 1 (6.3)
0 (0)
1535 1 (6.3)
1 (2)
3901 1 (6.3)
1 (2)
4001 3 (18.8)
13 (24)
4403 4 (25)
2 (4)
4601 5 (31.3)
11 (22)
5101 2 (12.5)
2 (4)
5201 1 (6.3)
1 (2)
5801 2 (12.5)
5 (10)
OR: odds ratio.
CI: confidence interval.
1.083
(0.4682.505)
4.423
86 (14.8) (2.1429.134)
2.064
10 (1.7) (1.7852.386)
3.128
12 (2.1) (0.61615.886)
3.128
11 (1.9) (0.61615.886)
0.743
109
(0.377(18.8)
1.464)
8.000
48 (8.3) (2.66923.982)
1.539
101
(0.844(17.4)
3.006)
3.545
43 (7.4) (1.11411.280)
3.128
16 (2.8) (0.61615.886)
1.330
116 (20) (0.5543.190)
81 (14)
0.907
(0.4032.043)
3.418
0.000026 (1.7306.751)
3.128
0.029
(0.61615.886)
3.128
0.279
(0.61615.886)
3.128
0.279
(0.61615.886)
1.000
0.389
(0.4932.027)
3.833
0.000025 (1.6348.991)
2.194
0.149
(1.1204.296)
1.963
0.024
(0.7495.146)
2.064
0.279
(0.5028.493)
0.591
0.523
(0.2761.265)
0.852
0.814
0.000273
0.279
0.279
0.279
1.000
0.001
0.020
0.164
0.498
0.173
P145 HLA-B*38:01 And HLA-A*24:02 Allele Frequencies In Spanish
Patients With Lamotrigine-Induced SCARs
Teresa Bellón1, Elena Ramirez2, Alberto Manuel Borobia2, Hoi Tong3, Jose Luis
Castañer4, Francisco José De Abajo5
1. IdiPAZ, Madrid, Spain
2. Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
3. Hospital Universitario La Paz, Madrid, Spain
4. Hospital Universitario Ramón y Cajal, Madrid, Spain
5. Hospital Universitario Príncipe de Asturias, Alcalá De Henares, Madrid,
Spain
Introduction
Some HLA-I alleles are risk factors for the development of severe cutaneous
adverse drug reactions (SCARs). HLA-B1502 is strongly associated with the
development of Stevens Johnson syndrome /toxic epidermal necrolysis
(SJS/TEN) to carbamazepine (CBZ) in Southeast Asian populations where the
allele is prevalent. On the other hand, HLA-A3101 has been found to be a risk
factor for (CBZ)-induced drug reaction with eosinophilia and systemic symptoms
(DRESS) in European and Asian patients. HLA-A3101 has been weakly associated
to CBZ-induced SJS/TEN in Europeans, and no association has been found with
other aromatic antiepileptic drugs (AEDs). No HLA-I alleles have been definitely
associated with lamotrigine (LTG)- or phenytoine (PHE)- induced SCARs in
Europeans
Method
To explore the association of HLA-I allele frequencies with SCARs to AEDs in our
population, 12 patients with DRESS and 14 cases with SJS/TEN included in the
Spanish registry PIELenREd were studied. Six cases were related to LTG (3
SJS/TEN; 3 DRESS), 6 were related to CBZ (2 SJS/TEN; 4 DRESS), and 14 cases
were induced by PHE (9 SJS/TEN; 5 DRESS). DNA was prepared from total blood
and four digits HLA typing was performed. The frequencies of HLA-I alleles in
patients with LTG-induced SCARs were compared with frequencies in patients
within the other groups, and with previously published HLA-I frequencies in 253
Spanish individuals (Balas et al Tissue Antigens, 2010).
Results
HLA-B3801 allele was present in all 3 cases of LTG-induced SJS/TEN suggesting
a strong association (OR=37.92; 95% CI: 5.4-269.53; p<0.0001). Only 2 out of
9 SJS/TEN cases induced by PHE were carriers of HLA-B3801 (OR=4.74; 95%CI:
0.67-25.12; p=0.09). None of the 12 DRESS cases analyzed were carriers of
HLA-B3801. On the other hand, the 3 LTG-induced DRESS patients were carriers
of HLA-A2402 showing a significant association as compared to the control
sample (OR=5.25; 95%CI: 1.0-24.75; p=0.04). HLA-A2402 was found in 3 out
of 5 cases of PHE-induced DRESS (OR=4.5; 95%CI: 0.88-20.27; p=0.054) and
was absent in all CBZ cases and in SJS/TEN cases to PHE.
Conclusion
Our results suggest that HLA-B3801 may be a risk factor for LTG-induced
SJS/TEN, in agreement with previous data (Lonjou et al, Pharmacogenetics and
Genomics 2008). On the other hand HLA-A2402 might be related with LTGinduced DRESS or exantematic reactions, as recently published in the Norwegian
population (Shirzadi et al Epilepsy Research 2016).
P146 Overrepresentation Of A Class II HLA Haplotype In Severe
Hypersensitivity Type I Reactions To Carboplatin
Violeta Régnier Galvao1, Rebecca Pavlos2, Elizabeth Mckinnon2, Kristina
Williams3, Alicia Beeghly-Fadiel4, Alec Redwood2, Elizabeth Phillips3, Mariana
Castells1
1. Brigham and Women`s Hospital, Division of Rheumatology, Immunology
and Allergy, Harvard Medical School, Boston, United States
2. Institute for Immunology and Infectious diseases, Murdoch University,
Perth, Australia
3. Vanderbilt University Medical Center, Nashville, United States
4. Vanderbilt Epidemiology Center, Institute for Medicine and Public Health;
Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center,
Nashville, United States
Keywords: HLA Genotyping, Rapid Drug Desensitization, Carboplatin, IgEMediated Reaction, Drug Allergy
Introduction
HLA class I and class II genotyping has identified patients at risk for both T-cell
mediated and IgE/mast cell mediated severe drug hypersensitivity (HSR). Class
II HLA-DRA variants have been associated with immediate allergic reactions to
beta-lactams and the HLA-DRB1*07:01 allele has been associated with IgEmediated reactions to asparagine. Up to 27% of women exposed to 6 or more
cycles of carboplatin present with immediate HSR and 50% of these reactions are
anaphylactic. BRCA1/2 mutations have been found to be more common among
patients who develop immediate reactions to carboplatin and these reactions,
including anaphylaxis, have been successfully addressed by rapid drug
desensitization (RDD).We sought to evaluate the HLA profile of patients who
presented an initial carboplatin-induced severe hypersensitivity reaction including
anaphylaxis, had a positive skin test and were treated with the BWH rapid drug
desensitization 3-4 bags protocol.
Method
HLA ABC DR DQ DP typing was conducted for a cohort of Caucasian ovarian
cancer patients (n=11) with a history of grade 2 or 3 type I HSR to carboplatin
undergoing RDD and a control group of Caucasian ovarian cancer patients
treated with carboplatin, who tolerated 8 or more cycles (n=12). Allele carriage
amongst cases and controls was compared using Fisher’s exact test. The
Haploblocks program was used to generate cobygram visuals of HLA cocarriage.
Results
Among allergic patients, 36% (4/11) had grade 2 and 64% (7/11) grade 3 initial
HSR. All successfully tolerated the RDD and were able to complete their
treatment plans. We found that the HLA-DRB1*15:01 allele was more prevalent
among allergic patients (5/11, 45%) than among the control group (1/12, 8.3%)
(p=0.06). Cobygram analysis suggests that the HLA class II association may
extend to the DQA1*01:02-DQB1*06:02-DRB1*15:01 haplotype (Figure 1).
Conclusion
In this Caucasian cohort of ovarian cancer patients, a specific HLA class II allele,
DRB1*15:01, was suggested to be associated with immediate hypersensitivity to
carboplatin. Further carboplatin HSR cases and carboplatin tolerant controls are
currently been accrued to verify the validity of this association and assess its
extension to the DQA1*01:02-DQB1*06:02-DRB1*15:01 haplotype.
Poster Walk 17: in vivo Diagnosis + sIgE
(P147 – P154)
P147 Absence Of Specific Ig-E Against Beta-Lactams Nine Months After
An Allergic Reaction To Amoxicillin-Clavulanic Acid
Elisa Boni, Marina Russello, Marina Mauro
Hospital Sant'Anna, Como, Italy
Introduction
In case of immediate reactions to beta-lactams, allergological work up consists of
detection of specific Immunoglobulin-E (Ig-E) against beta-lactams in serum and
skin tests, i.e. prick test and intradermal tests with major and minor antigenic
determinants of penicillin, amoxicillin, ampicillin and benzilpenicillin. Levels of
specific Ig-E decrease after the reaction and they are no more detectable after
some years. It is recommended to perform in vivo and in vitro tests after 3
weeks and no later than 6-12 months after the reaction. Sensitivity of tests then
decreases and false negative result may occur. In case of remote history of
immediate reaction to beta-lactam, if tests are negative, a provocation test with
the culprit drug is necessary and should be followed by repetition of skin tests.
Case Description
We report the case of a woman aged 61 years who experienced a systemic
reaction (urticaria, vomit, diarrhea, fatigue) 15 minutes after intake of
amoxicillin/clavulanic acid. Four months later, she underwent a visit in our
Allergy Unit and serological and skin tests were scheduled.
Serological specific Ig-E against penicilloyl G, penicilloyl V, ampicillin, amoxicillin,
cefaclor as well as skin tests gave negative result. They were performed
respectively 5 and 9 months after the reaction. A drug provocation test (DPT)
with amoxicillin was then performed and was considered positive for the
occurrence of generalized pruritus 20 minutes after the intake of the last dose
(cumulative dose 875 mg). Skin tests were repeated with positive results to both
amoxicillin and ampicillin, at the concentration of of 1 mg/ml and 20 mg/ml,
respectively.
How this report contributes to current knowledge
Specific Ig-E levels against beta-lactams decrease after immediate-type
reactions. Guidelines recommend to perform allergological work up within 6-12
months. Our case shows how this period might be too long and false negative
tests can occur even if performed within one year. DPT should always follow
negative skin tests to obtain a correct diagnosis.
P148 Drug Provocation Tests In Suspected Opioid Allergy
Kok Loong Ue, Krzysztof Rutkowski
Department of Allergy, Guy’s and St Thomas’ NHS Foundation Trust, London,
United Kingdom
Keywords: Anaphylaxis, Codeine, Drug Provocation Test, Morphine, Opiod Allergy
Introduction
There are no good epidemiological data regarding opioid allergy (OA). Many side
effects can occur with this group of drugs. These are often misinterpreted as an
IgE-mediated OA. As a consequence, many patients receive an unsubstantiated
diagnosis of OA and avoid opioid unnecessarily. Diagnosis of OA can be
challenging as skin tests (ST) and opioid-specific IgE have a poor predictive
value. Drug provocation tests (DPT) remain the gold standard for the diagnosis
of OA. However, there are almost no studies of opioid DPT and no validated
opioid DPT protocols.
Method
30 suspected cases of OA (12 morphine, 18 codeine) were studied using detailed
history and oral DPT. Opioid ST and specific IgE were not performed.
Standardised local protocols were used. For morphine: 2, 3, and 5mg morphine
sulphate oral solution (10mg/5mls) was administered at 30min interval with
120min monitoring. For codeine:10, 20 and 30mg codeine phosphate syrup
(25mg/5mls) was administered at 30min interval with 60min of monitoring. All
DPT were performed on a specialist allergy unit.
Results
25 females and 5 males (median age of 46.5) experienced various symptoms
reported as OA. Opioids were prescribed mainly for analgesia. 20 patients (67%)
had cutaneous symptoms: angioedema: 5, urticaria: 4, angioedema and
urticaria: 2, unspecified rash: 5, angioedema, unspecified rash and pruritus: 3,
angioedema and unspecified rash: one. 11 patients (37%) experienced
symptoms suggestive of anaphylaxis: dyspnoea, tachycardia, hypotension,
dizziness and collapse. 2 of these (18%) experienced cutaneous symptoms too.
Other non-specific symptoms included nausea: 2, paraesthesia: 2, tremor: 1,
anxiety: 1. DPT were negative in 23 patients (77%). 6 patients (20%) had
symptoms of intolerance: pruritus, nausea, dizziness, tremor to morphine (2)
and codeine (4). Only 3% of DPT were positive: 1 patient experienced
angioedema with codeine.
Conclusion
DPT-confirmed OA appears to be very rare (3%). Most symptoms misinterpreted
as OA could be due to a dose-dependent mast cell degranulation, genetic
polymorphism of CYP2D6 gene or the underlying acute illness. Morphine and
codeine DPT are a safe and reliable diagnostic tool. Our ongoing multi-centre
study will endeavour to validate this approach in a larger cohort of suspected OA
patients (including other opioids) and produce standardised DPT protocols to
improve the diagnosis of OA in Europe and worldwide.
P149 IMPROVEMENT TO THE SPECIFIC IgE CUT-OFF IN THE ASSESS OF
ß-LACTAMIC ALLERGY
Victor Soriano Gomis, Jorge Frances Ferre, Angel Esteban Rodriguez, Vicente
Cantó Reig, Javier Fernandez Sanchez
Universitary General Hospital of Alicante, Alicante, Spain
Introduction
Specific IgE against β-lactams by CAP FEIA system (Thermo Scientific®) used to
use the cut-off of 0.35 kU/L, but now we can get a detection limit of the assay of
0.10 kU/L. We pretend to evaluate if this change of cut-off from 0.35 to 0.10
kU/L improves the sensitivity without compromise its specificity.
Method
74 patients older than 18 years evaluated in the allergy outpatient clinic since
January 2011 to April 2014 were studied. They were classified as allergic by
history and skin tests positive to β-lactamic antibiotics. Specific IgE against
penicilloyl G, penicilloyl V, amoxicilloyl and ampicilloyl were analyzed by CAP
FEIA system (Thermo Scientific®). With these IgE values and positive or
negative diagnosis of allergy, sensitivity and specificity of both cut-offs (0.35 and
0.10 kU/L), the ROC curves were obtained. In addition, the AUC value (with their
confidence interval) was calculated. The SPSS (v19.0) and “Analyse-it”- Excel
were used.
Results
ROC results
Specific IgE
Penicilloyl G
Penicilloyl V
Ampicilloyl
Amoxicilloyl
AUC value
0.780
0.748
0.783
0.844
CI 95%
0.66-0.90
0.638-0.858
0.674-0.892
0.758-0.930
Sensitivity and specificity with the 0.10 kU/L cut-off
Specific IgE
Sensitivity (%)
Specificity (%)
Penicilloyl G
55.6
85.7
Penicilloyl V
47.1
80.0
Ampicilloyl
74.2
69.0
Amoxicilloyl
74.2
74.4
Sensitivity and specificity with the 0.35 kU/L cut-off
Specific IgE
Sensitivity (%)
Specificity (%)
Penicilloyl G
33.3
94.6
Penicilloyl V
23.5
97.5
Ampicilloyl
35.5
97.6
Amoxicilloyl
45.2
93.0
Conclusion
The cut-off of 0.10 kU/L may be more appropriate to use in the clinical practice
because it improves the correct classification of b-lactams allergy patients. The
amoxicilloyl obtains the best performance with this new cut-off.
P150 Initial False Negative Specific IgE To Gelatin In A Patient With
Gelatin-Induced Anaphylaxis.
Christine Breynaert1, Erna Van Hoeyveld2, Rik Schrijvers1
1. Laboratory of clinical immunology, department of microbiology and
immunology, KU Leuven, Leuven, Belgium
2. Laboratory medicine, Immunology, University Hospitals, KU Leuven,
Belgium, Leuven, Belgium
Introduction
The time of determination of specific IgE (sIgE) to potential culprit drugs, as an
aid in the diagnosis of peri-operative anaphylaxis, is not well defined for all
drugs.
Case Description
A 62-year old man experienced an anaphylaxis within 15 minutes after receiving
a gelatin-containing plasma expander during general anesthesia for hip surgery
after a high velocity trauma. Decontamination was performed with chlorhexidine,
and propofol, lidocaine, sufentanil, rocuronium, dexamethasone, was
adminstered 2h15 and cephazolin 1h45 prior to the event. The gelatin infusion
was stopped and treatment with epinephrine, norepinephrine, promethazine,
hydrocortisone, and saline fluid expansion installed. Serum tryptase was
transiently increased (95.7 ng/dl 1h30 after the onset of the reaction versus 6.0
ng/dl > 24 h after the event). ImmunoCAP sIgE (Thermofisher - Phadia,
Sweden) to gelatin, galactose-alpha-1,3-galactose, ethylene oxide, latex, and
chlorhexidine was negative on the sample obtained 1h30 after the event, and
independently confirmed. However, repeat sampling 16 days after the event with
a serial dilution of the gelatin-containing plasma expander, mimicking the timing
of the initial testing, demonstrated the inhibition of sIgE determination with a
50% inhibitory concentration (IC50) of 0.02% (Fig. 1). No serum before the
anaphylaxis was available to confirm a pre-existing sensitization. Skin testing 4
weeks after the event was positive for the 4% gelatin-containing plasma
expander (3 mm and 5 mm wheal diameter after skin prick testing at a 1:10 and
1:1 dilution respectively) and negative for chlorhexidine, latex, and cephazoline.
How this report contributes to current knowledge
A rare case of IgE-mediated gelatin allergy is reported. We hypothesized that the
initial sIgE for gelatin was false negative due to competition of infused gelatin
with the gelatin-immunoCAP assay rather than a boostin phenomenon had taken
place, suggesting careful interpretation of sIgE determinations very early after
the event, at least in the case of gelatin-sIgE.
P151 Inmediate Reactions To Beta-Lactam Antibiotics. Pattern Of Skin
Test Response Over The Time
Jose Julio Laguna Martinez1, Rosario Gonzalez Mendiola1, Javier Dionicio
Elera1, Cosmin Boteanu1, Aranzazu Jimenez Blanco1, Marta Del Pozo1, Raquel
Fuentes Irigoyen2
1. Allergy Unit. Hospital Central de la Cruz Roja, Madrid, Spain
2. Pharmacy Service. Hospital Central de la Cruz Roja, Madrid, Spain
Keywords: Beta-Lactams, Amoxicillin, Skin Test, Allergy,Inmediate Reaction
Introduction
Beta-lactam (BL) antibiotics are the drugs most frequently involved in IgEmediated allergic reactions. Skin testing is the most widely used diagnostic
method to evaluate IgE mediated reactions to BL. Skin test respond to penicillin
determinants vary in different populations over time related with pattern of
consumption. but precise studies The aim of our work is to study the variation of
the skin response over long time in a well-defined series of allergic to BL.
Method
All patients submitted to our centre, in ten year period (1999-2009) with a
compatible history of beta-lactam allergy underwent allergy work-up according to
the ENDA protocols for immediate reactions.
Skin tests (prick and intradermal) with the classical penicillin reagents
(Allergopharma Reinbeck, Germany (1999 to 2005) and from 2005 (Diater
reagents DAP, Madrid, Spain): penicilloyl polylysine (PPL), minor determinants
mixture (MDM :benzylpenicillin and sodium benzylpenicilloate) and
benzylpenicillin (penicillin G) and Semi-synthetic penicillins (amoxicillin,
amoxicilin/clavulanic acid and ampicillin) were also systematically tested, as well
as any other suspected beta-lactam. In the case of negative results, we perform
provocation tests with the suspected drug. Considering the temporal variation for
immediate reactions in terms of skin test positivity, Patients were classified
according to the year they referred the reaction, in four periods (>1980, 19801990, 1991-2000 and >2001-2009)
Results
From a total of 2716 patients initially evaluaed, 296 were finale confirmed as
inmediate reactions to Betalactamic. A total of 247 were diagnosed by skin
testing, this represents 83% of total (247/296).
Considering the temporal variation for immediate reactions in terms of skin test
positivity, the analysis of the AX determinants showed that there was a gradual
increase over the years that varied from 38,5% to 81,2%. Statistical analysis
confirm a strong signification p< 0,0001. In parallel a decreased of antigenic
determinants of penicillin (including PPL, MDM and Benzylpenicillin) from 30,8 %
to 12,7% also statistic significance p<0,007.
Conclusion
Our study confirm that the variation of beta-lactam pattern consumption modify
the skin test response in a long series over 10 years.
Strong statistical significance of amoxicillin skin tests rising p < 0.001 correlates
with the progressive increase in amoxicillin consumption since 2001.
P152 New Fluorescent Dendrimeric Antigens For The Evaluation Of
Dendritic Cell Maturation As A Test To Detect Allergy Reactions To
Amoxicillin
Daniel Collado1, Yolanda Vida1, Francisco Najera1, Ezequiel Perez-Inestrosa1,
Pablo Mesa-Antunez1, Cristobalina Mayorga2, María José Torres2, Miguel Blanca2
1. University of Malaga, Malaga, Spain
2. Allergy Service, Carlos Haya, Malaga, Spain
Keywords: Confocal Microscopy; Dendritic Cell; Maturation
Introduction
ln order to emulate the recognition process working in vivo, much effort have
been made to prepare hapten(drug)-carrier(protein) conjugates attempting to
work like the antigen responsible for the allergic drug reaction.
Method
In our efforts to exploit the dendrimer properties in the interaction with the
immunological system, we have prepared a series of Dendrimeric:Antigens
(DeAn), to study the dendritic cell (DC) maturation as a test to detect allergy
reactions to amoxicillin.
Recently our research group developed a new kind of dendrimer, called BAPAD,
that we have used in this work to obtain the dendrimeric moiety of the target
molecule. To this avail we synthesized a generation two BAPAD dendrimer using
cystamine as core. Then, the free amine groups on the surface of the dendrimer
were functionalized with an amoxiciloyl group (AXO). The fluorescent DeAn has
been fully characterized by NMR and MS techniques, and their fluorescent
properties well established in aqueous biological media using confocal
microscopy. The fluorescent dendron (De) without the haptenic moieties at the
periphery has been also obtained and fully characterized as a control assay. The
fluorescent DeAn and De was used in dissolution and supported in solid surface
(cellulose disk). The solid conjugates were immunologically evaluated by RAST
inhibition using sera from 7 patients allergic to amoxicillin. DC from four
amoxicillin allergic patients have been incubated with fluorescent DeAn and De
and studied with a flow cytometer to determine whether or not the cells were
able to uptake both compounds.
Results
Flow cytometry and confocal microscopy show that these dendrimeric structures
interact with DC and are internalized by them to the cellular cytoplasm. The
maturation of DC was tracked by by flow cytometry. In all cases, low maturation
induced by DeAn in allergic patients is observed. This effect can be due to two
factors: 1) that the concentration of compound that enters the DC is low and 2)
that the hapten density presented in DeAn is low. The RAST inhibition studies of
solid supported DeAn showed a higher RAST inhibitions values for allergic
patients compare with negatives controls. This value was also compared with
solid surfaces conjugated with PLL-AXO showing similar results.
Conclusion
These dendrimeric structures assayed in RAST inhibition studies letting us check
that inhibition occurred, so recognition existed between IgE of patients allergic to
amoxicillin and DeAn structures.
P153 Positive Skin Test Or Positive Specific IgE To Penicillin Does Not
Predict Penicillin Allergy
Line K Tannert1, Charlotte G Mortz2, Per Stahl Skov3, Carsten Bindslev-Jensen2
1. Odense Research Center for Anaphylaxis, Odense C, Denmark
2. Department of Dermatology and Allergy Center, Odense C, Denmark
3. Odense Research Center for Anaphylaxis, Odense C/Copenhagen,
Denmark
Introduction
Diagnosis of penicillin allergy is based on case history, skin testing (ST, prick and
intracutaneous tests) and measurement of specific IgE (s-IgE) to a penicillin and
challenge with penicillin. If ST or s-IgE is positive, the patient is classified as
allergic to penicillin according to the European Network of Drug Allergy guidelines
and challenge is omitted. Therefore, the true sensitivity and specificity of ST and
s-IgE are presently not known.
The aim of this study was to investigate the clinical relevance of a positive skin
test and s-IgE to penicillin.
Method
Forty-four patients with a positive ST and/or s-IgE were included; ST with
penicillin was done and s-IgE was measured in all 44 patients at the time point
designated T0. Challenge with the culprit penicillin was performed immediately
hereafter although abstained in patients with recent anaphylaxis to penicillin
(n=8), systemic reactions to ST (n=3) or development of delayed positive ST
(n=8). These were classified as allergic to penicillin; thus, 25 patients were
challenged.
18 of the patients had been evaluated previously (T-1) and reproducibility of the
results were compared to T0 and again four weeks post challenge (T1).
Results
Nine of the 25 challenged patients were positive. There was a significantly
increased probability of being allergic to penicillin if both skin test and s-IgE were
positive at T0 (p=0.007). Positive ST or s-IgE alone did not predict penicillin
allergy (p=0.313/p=0.051).
Among the 18 patients repeatedly tested, only 12/26 (46.2%) of positive skin
tests at T-1 were reproducibly positive at T0, and only one further ST became
positive at T1. For s-IgE, 14/24 (58.3%) of positive measurements were still
positive at T0 and seven further became positive at T1, although s-IgE levels at
T0 and T1 did not differ significantly (p=0.599).
Conclusion
In this study, the best predictor for a positive penicillin challenge was history
combined with both positive ST and s-IgE. There was a relatively low
reproducibility of a previously positive ST and s-IgE.
P154 Significance Of Skin Testing And In-Vitro-Analysis Of
Neuromuscular Blocking Agents In Diagnosis Of Perioperative Drug
Hypersensitivity: Evaluation Of A Negative Control Population
Wolfgang Pfützner, Hannah Dörnbach, Johanna Visse, Michele Rauber,
Christian Möbs
Department of Dermatology and Allergology, Philipps University Marburg,
Marburg, Germany
Keywords: Perioperative Anaphylaxis, Anaesthesia, Neuromuscular Blocking
Agents, Skin Test, Basophil Activation Test
Introduction
Perioperative drug hypersensitivity (PDH) presents a major problem resulting in
unexpected, often severe anaphylactic reactions. Diagnosis of anaphylaxis during
anaesthesia mainly relies on skin testing, since assays for the detection of IgEantibodies are not available and provocation tests are not feasible for most of the
involved drugs. Neuromuscular blocking agents (NMBAs) are recognized as the
most prevalent elicitors of PDH, however, skin tests with NMBAs might result in
false-positive results due to unspecific, non-IgE-mediated release of histamine.
Method
To further investigate this subject, we evaluated the potential of NMBAs eliciting
positive results in individuals with known NMBA-tolerance in both skin prick
(SPT) and intracutaneous tests (ICT) and compared these with the reactivity in
basophil activation tests (BAT). Eleven individuals (5 females, 6 males; 25-60
years old, median (m) = 50) without known allergy to NMBAs, but tolerant to a
recently perioperative applied NMBA were included in this study. The NMBAs
Suxamethonium, Rocuronium, Cis-Atracurium and Mivacurium were tested by
both titrated SPT and ICT, and NMBAs eliciting a positive skin reaction were
further analyzed by BAT with the individuals’ serum.
Results
SPT yielded positive results in 0/11 participants for Suxamethonium, Rocuronium
and Cis-Atracurium and in 2/11 for Mivacurium. ICT was positive in 2/11 for
Suxamethonium, 9/11 for Rocuronium, 8/11 for Cis-Atracurium and in 11/11 for
Mivacurium. BAT analysis confirmed the positive skin tests in only one individual,
while it was negative for the NMBAs in all others.
Conclusion
These findings show that skin test results with NMBAs have to be carefully
interpreted regarding their clinical relevance and the implementation of more
reliable test systems would be helpful for diagnosis of PDH.
Poster Walk 18: in vitro /ex vivo (P155 – P158,
P160 – P164)
P155 Diagnostic Value Of The Lymphocyte Toxicity Assay (LTA) And The
In Vitro Platelet Toxicity Assay (IPTA) For ß-Lactam Allergy
Abdelbaset A Elzagallaai, Lindsey Chow, Awatif M Abuzgaia, Michael J Rieder
Western University, London, Canada
Keywords: Drug Allergy, Drug Hypersensitivity, In Vitro Diagnosis
Introduction
β-lactam antibiotics (BLAs) are the drugs most associated with immune-mediated
hypersensitivity reactions (drug allergy). They can elicit all types of allergic
reactions i.e., types I, II, III and IV. Although the immediate IgE-mediated
reaction has been well studied, the pathophysiology of non-immediate
hypersensitivity reactions is not well understood. Cross-reactions among BLAs
with different side chains are variable. The diagnosis and prediction of BLAsinduced allergic reactions is challenging and based mostly on clinical history. The
lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (iPTA) are
in vitro tests with a potantial value for diagnosis and prediction of drug allergy.
Their value in diagnosis of reactions to BLAs, however, is still unknown. This
work is an attempt to evaluate the performance of in vitro toxicity testing for
diagnosis of different types of allergy to BLAs and to investigate the their
different underlying pathophysiology.
Method
One hundred and seventy individuals (85 drug allergy-suspected patients and 85
healthy volunteers) were included in this study. Patients were identified from
clinical records and included using a rigorous internationally recognized inclusion
criteria based on their clinical presentation and available diagnostic investigations
(i.e., skin testing and RAST). The LTA and iPTA tests were performed after
resolution of the reaction symptoms. Data was expressed as percentage of cell
death compared to control (vihicle without the drug) after incubation with the
suspected drug in presence of rat microsomes (MICs).
Results
Patients were grouped according to their exhibited symptoms into 3 groups
constituted of 8 patients type I, 28 patients type III and 49 patients type IV.
Patients with type IV reactions exhibited higher degrees of cell death than the
other 2 groups (p<0.05) with type I patients exhibiting the lowest degree of cell
death among all groups.
Conclusion
Using the in vitro toxicity testing (LTA and iPTA) we were able to identify patients
susceptible to develop allergy to BLAs. In addition, cells isolated from patients
with different types of reactions exhibit variable degrees of cell death, which
indicate possible distinct pathophysiological mechanisms. The LTA and iPTA can
be a useful tool to both diagnose drug allergy to BLAs and investigate its
underlying pathophysiology.
Characteristic
Sex (female/male; n[%])
Age (mean; y [range])
Type of reaction (n [%])
Type I
Type III
Type IV
Total
Value
53/31 [63.1/36.9]
24 [1-88]
8 [9.4]
28 [32.9]
49 [57.6]
85 [100]
P156 Enzyme Linked Immunospot Assay Used In The Diagnosis Of
Severe Cutaneous Adverse Reactions To Antimicrobials
Alec Redwood1, Jason Trubiano2, Rebecca Pavlos1, Emily Woolnough2, Kaija
Stautins1, Christina Cheng2, Elizabeth Phillips3
1. Institute of Immunology and Infectious Diseases, Murdoch University,
Perth, Australia
2. Department of Infectious Diseases, Alfred Health, Melbourne, Australia
3. Vanderbilt University Medical Center, Nashville, United States
Introduction
The ability to define drug causality in cases of Severe Cutaneous Adverse
Reactions (SCAR) where multiple antimicrobials are implicated remains
problematic. We describe a case of toxic epidermal necrolysis (TEN) in the
setting of multiple implicated antimicrobials and the utility of T-cell enzyme
linked immunospot assay (ELISpot) to define antimicrobial causality
Case Description
A 20-year old man was admitted to a tertiary referral trauma centre for
management of wound sepsis and femoral stump osteomyelitis in the setting of
recent below-knee amputation following a high-speed motorbike accident. Whilst
receiving escalating antimicrobial treatment, for bacteraemia and fevers >
38.3°C, he developed a blistering rash involving greater than 30% of body
surface area (BSA) associated with a positive Nikolsky sign, consistent with TEN.
Multiple antimicrobials were administered prior to onset of TEN, four of whichvancomycin, meropenem, linezolid and teicoplanin - were temporally associated
with the onset of TEN.
How this report contributes to current knowledge
We sought to use cellular assays, IFN-gamma ELISpot and flow cytometry, to
identify the causative agent of TEN in a patient receiving multiple
antibiotics. Following informed consent, patient whole blood was collected on
day 4 post onset of TEN. PBMCs were extracted and cryopreserved. HLA ABC
DR DQ DP typing was performed and the PBMCs were used for ex vivo ELISpot
testing. PBMCs were also incubated with candidate drugs for 18-20 hours at
37°C in 5% CO2 and assessed by flow cytometry for upregulation of the T cell
activation marker CD137.
Patient HLA was HLA-A*01:01 and 02:02, HLA-B*37:01 and 41:01, HLAC*10:01 and 17:01, HLA-DPB1*10:01, HLA-DQA1*01:01 and 02:01, HLADQB1*02:02 and 05:01, HLA-DRB1*07:01 and 10:01. Positive ELISpot
responses were reproducibly produced only to the glycopeptide antibiotic
teicoplanin, with up to 300 SFU/million cells. ELISpot data were confirmed by
flow cytometry analysis, where only teicoplanin induced up-regulation of the
activation marker CD137 (0.3% of total CD8+ T-cells). All other antibiotics
including vancomycin and meropenem were negative by ELISpot and flow
cytometry.
We believe this to be the first reported use of T-cell ELISpot to assign isolated
teicoplanin causality to TEN.
P157 Evaluation Of In-Vitro Diagnostic Methods For Identifying The
Culprit Drugs In Drug Hypersensitivity
Kenichi Kato1, Hiroaki Azukizawa2, Takaaki Hanafusa3, Ichiro Katayama1
1. Department of Dermatology, Osaka University, Osaka, Japan
2. Department of Dermatology, Nara Medical University, Nara, Japan
3. Department of Dermatology, Tokyo Medical and Dental University, Tokyo,
Japan
Introduction
The drug-induced lymphocyte stimulation test (DLST), or lymphocyte
transformation test (LTT), is used to identify the culprit drug in cases of
cutaneous adverse drug reactions (cADR). While DLST is widely used as in-vitro
diagnostic tool, its sensitivity and specificity are unsatisfactory. Determination of
antigen-specific IFN-γ production by enzyme-linked immunospot assay
(conventional IFNγ-ELISpot) is well-established diagnostic method for
tuberculosis infection, and recent reports suggested that drug-induced
conventional IFNγ-ELISpot is useful for identifying the culprit drug of cADR cases.
The aim of this study was to establish a novel diagnostic method for identifying
the culprit drug in cADR patients through the efficient detection of the drugspecific IFN-γ production by IFNγ-ELISpot.
Method
Ten cases of cADR caused by clinically convincing culprit drugs were enrolled in
this study. Peripheral blood mononuclear cells (PBMCs) from all 10 patients were
used for both DLST and drug-induced conventional IFNγ-ELISpot. In addition,
drug-induced IFNγ-ELISpot was also performed by using PBMCs which were nonspecifically stimulated with monoclonal antibodies for 7 days before exposing
culprit drugs (modified IFNγ-ELISpot) in all cases.
Results
Drug-induced IFN-γ production was detected by modified IFNγ-ELISpot in 5
patients of which DLST and conventional IFNγ-ELISpot were both negative.
Moreover, IFN-γ secretion was observed by modified IFNγ-ELISpot in all 4
patients of which DLST were positive.
Conclusion
Modified IFNγ-ELISpot using expanded PBMCs is more sensitive than
conventional IFNγ-ELISpot for detecting drug-induced IFN-γ production.
Therefore, this novel IFNγ-ELISpot could be a useful in-vitro tool for identifying
culprit drugs in cADR cases.
P158 Ex-Vivo Expanded Skin-Infiltrating T Cells From Severe Drug
Eruptions Are Reactive With Causative Drugs: A Possible Novel Method
For Determination Of Causative Drugs
Toshiharu Fujiyama1, Hideo Hashizume2, Takatsune Umayahara1, Taisuke Ito1,
Yoshiki Tokura1
1. Hamamatsu University School of Medicine, Hamamatsu, Japan
2. Shimada City Municipal Hospital, Shimada, Japan
Keywords: T Cells, IFN-Gamma,
Introduction
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and druginduced hypersensitivity syndrome/ drug reaction with eosinophilia and systemic
symptoms (DIHS/DRESS) are life-threatening adverse drug reactions. For
prevention of relapse, it is mandatory to determine the causative drug. Patch
test and lymphocyte stimulation test (LST; also known as DLST in Japan) are
frequently used for this purpose, but their positivity ratios are not sufficiently
high. We sought to explore a novel method using skin-infiltrating T cells for
determination of causative drugs because it is considered that antigen-specific T
cells infiltrate in skin lesions of the severe drug eruptions and participate in its
pathogenesis.
Method
We expanded skin-infiltrating T cells from 4-mm biopsied lesional skin samples of
severe drug eruption using anti-CD3/CD28 antibodies and IL-2. More than 107 T
cells/specimen were obtained by two-week cultivation. To investigate their
cytokine production by in vitro stimulation with causative drugs, the expanded T
cells were co-cultured with drugs peripheral blood mononuclear cells (PBMCs)
from the same patient, and IFN-g production was assessed by ELISpot assay.
Moreover, to see the drug-induced T-cell proliferation, the expanded T cells were
labeled with CFSE and cultured with drugs and X-ray-irradiated PBMCs for a
week, and the proliferation was assessed by flow cytometry. The cytokine profile
of the cells which proliferated in response to drugs was also assessed by flow
cytometry.
Results
The ELISpot assay showed a significantly high number of T cells produced IFN-g
by drug stimulation as compared to no addition control. The CFSE assay revealed
that both CD8+ and CD4+ T cells proliferated in response to causative drugs in
SJS/TEN and DIHS/DRESS. Notably, the majority of CD8+ T cells proliferating to
causative drugs expressed IFN-g in SJS/TEN.
Conclusion
Our study suggests that the use of ex-vivo expanded skin-infiltrating T cells can
yield a novel method for determination of causative drugs in the severe drug
eruptions.
P160 In Vitro Release Of IL-2, IL-5 And IL-13 In Diagnosis Of Patients
With Delayed-Type Nickel Hypersensitivity
Mira Silar1, Mihaela Zidarn1, Helena Rupnik2, Peter Korosec1
1. University Clinic for Respiratory and Allergic Diseases, Golnik, Slovenia
2. ARSDERMA, Ljubljana, Slovenia
Introduction
T cells play a major role in delayed-type of hypersensitivity reactions. Their
reactivity can be assessed by lymphocyte transformation test or upregulation of
cell surface activation markers, and those tests are of limited practicability or
diagnostic sensitivity. Some previous report suggested that in vitro secretion of
cytokines by peripheral blood mononuclear cells (PBMC) could be a promising
tool for improved detection of T-cell sensitization. For that reason we wanted to
test this methodology in patients with well-defined delayed-type nickel
hypersensitivity.
Method
PBMC of 10 nickel hypersensitive patients and 9 healthy controls were incubated
for 48 hours with two different concentration of NiSO4x6H2O (0.5 to 5 μg/ml).
IL-2, IL-5, IL-13 and IFN-γ concentrations were measured in supernatants with
multiplex flow cytometry CBA Flex Array.
Results
We showed a significantly increased secretion of IL-2 (median 182 vs 3 ng/ml),
IL-5 (9 vs 0 ng/ml), IL-13 (36 vs 0.5 ng/ml) in response to NiSO4x6H2O in
patients nickel hypersensitivity when compared with healthy controls. The
response in the patients was concentration dependent. No difference was evident
for IFN-γ . The ROC curve analysis demonstrated the highest AUC of 0.99 for IL2 and IL-13, followed by AUC of 0.91 for IL-5.
Conclusion
The measurement of IL-2 and IL-13 appearing to be a superb approach to
identify antigen reactive T cells in the peripheral blood of patients with the
hypersensitivity reactions. This cytokine approach could be now tested on the
clinical important issue of the diagnosis of the delayed-type hypersensitivity
reactions to drugs.
P161 Single Cell Analysis Of Drug Responsive T Cells; Identification Of
Candidate Drug Reactive T Cell Receptors In Abacavir And
Carbamazepine Hypersensitivity
Alec James Redwood1, Kaija Strautins1, Katie White2, Abha Chopra1, Katherine
Konvinse2, Shay Leary1, Rebecca Pavlos1, Simon Mallal2, Elizabeth Phillips2
1. Institute for Immunology and Infectious Diseases, Murdoch University,
Perth, Australia
2. Vanderbilt University Medical Center, Nashville, United States
Keywords: T Cell Receptor, Abacavir, Carbamazepine
Introduction
T cell mediated drug hypersensitivity requires three essential components, a
target drug, a scaffold for the drug (MHC class I or class II) and a pathogenic T
cell receptor (TCR). For several drugs including, abacavir and carbamazepine,
two components of this trimolecular complex have been defined. For abacavir
hypersensitivity reaction (HSR) the associated MHC is HLA-B*57:01 and for
carbamazepine induced Stevens-Johnson syndrome/toxic epidermal necrolysis
(SJS/TEN), the associated MHC is HLA-B*15:02. In the former instance the
association of drug with MHC has been further defined with the successful
resolution of the crystal structure of the abacavir complexed to HLA B57:01.
To fully understand T cell mediated hypersensitivity reactions the nature of the T
cells involved and ultimately the mechanism by which the TCR interacts with
MHC plus drug must be elucidated. This study seeks to sequence and clone the
TCR mediating drug hypersensitivity in response to a series of drugs.
Method
Working from a cohort of cryopreserved PBMCs on HLA-typed patients with
confirmed histories of T-cell mediated drug hypersensitivities (abacavir
hypersensitivity and carbamazepine SJS/TEN and DRESS) we performed flow
cytometry, single cell cloning and single cell TCR sequencing and used these to
develop and interrogate T-cell responses. PBMC samples with confirmed T-cell
reactivity (ELISpot) were treated with drug for 18-20 hours. Upregulation of the
activation marker CD137 was used to sort drug reactive CD8+ or CD4+ T
cells. T-cells lines or clones were produced and individual T-cells were sorted for
single or bulk TCR sequencing.
Results
We have developed a pipeline for the identification of pathogenic TCRs. T-cell
lines maintained reactivity to candidate drugs. TCR sequencing from abacavir
HSR patients (n=3) identified no public TCR, rather multiple putative pathogenic
TCRs have been identified. For carbamazepine induced SJS/TEN (n=1) and
DRESS (n=1) we have also identified multiple putative pathogenic TCR.
Conclusion
Several candidate pathogenic TCRs have been identified in patients with
hypersensitivity to abacavir or carbamazepine. These putative TCRs will be
cloned into Jurkat T-cell lines to determine if multiple T-cell clones contribute to
hypersensitivity or if only a single clone in each patient is pathogenic. Ultimately
these cloned TCR will be used to define the crystal structure of the trimolecular
complex of drug/MHC/TCR.
P162 Specificity And Sensitivity Of LTT In DRESS: Analysis Of Agreement
With The Spanish Pharmacovigilance System Probability Algorithm
Rosario Cabañas1, Elena Ramirez2, Ana María Fiandor3, Teresa Bellón4
1. Servicio de Alergia, Hospital Universitario La Paz, Madrid, Spain
2. Servicio de Farmacología Clínica, Hospital Universitario La Paz, Madrid,
Spain
3. Servicio de Alergia , Hospital Universitario La Paz, Madrid, Spain
4. IdiPAZ, Madrid, Spain
Introduction
DRESS (drug reaction with eosinophilia and systemic symptoms) is a severe
cutaneous adverse reaction (cADR). Causality assessment is often a problem in
polymedicated patients. The probability algorithm of the Spanish
Pharmacovigilance System (Capellá & Laporte, 1993) establishes different
categories of causality after scoring of chronology, bibliography, drug withdrawal,
re-exposure, and alternative causes (unlikely: <0, conditional: 1-3; possible 4-5,
probable: 6-7, definite: >8). LTT has been used as a tool to determine the
causality of cADR. LTT specificity and sensitivity are difficult to ascertain as the
gold standard (re-challenge) is not acceptable in severe cases
Method
A total of 34 LTT assays were performed with suspected drugs in 15 DRESS
cases included in the Spanish registry PIELenRED. Results were considered
positive if stimulation indexes (S.I.) were ≥2, except for betalactam antibiotics
(S.I. ≥3) or iodinated contrast media (S.I. ≥4). The Spanish Pharmacovigilance
System algorithm (SPA) was applied and suspected drugs were divided into two
categories: unrelated (SPA score ≤3) and related (SPA score ≥4).
Results
Positive LTT results were obtained in all patients. In 19 out of 23 positive LTT
assays the drugs were related to the adverse reaction (SPA score ≥4). Ten out of
the 11 drugs that tested negative were predicted to be unrelated to the adverse
reaction (SPA score ≤3). A contingency table was built (Table 1). Fisher’s exact
test was used to analyze the data. There was a significant agreement between
the two methods (OR=47.5; 95% IC: 3.9-1342.94). If the pharmacovigilance
algorithm was considered as gold standard, 95%sensitivity and 71% specificity
were obtained for LTT assays, with a positive predictive value (PPV)=82% and
negative predictive value (NPV)= 90% (p<0.001). On the other hand, if LTT was
considered as gold standard, 82% sensitivity and 90% specificity was obtained
for the SPA, with a PPV=90% and NPV=70% (p<0.001).
Conclusion
Although this is a small case series, the results indicate that LTT is a sensitive
tool for causality assessment in DRESS. Moreover, the probability algorithm of
the Spanish pharmacovigilance system can be useful to identify the culprit drug
during the acute disease.
Table 1. Drug causality data in DRESS patients
Pharmacovigilance algorithm (SPA) results
Related drug (SPA ≥4) Unrelated drug (SPA≤3)
Positive LTT
19
4
Negative LTT
1
10
Total
20
14
Total
23
11
34
P163 The Role Of Interleukin-22 In ß-Lactam Hypersensitivity.
Andrew Sullivan1, Paul Whitaker2, Daniel Peckham2, B Kevin Park1, Dean J
Naisbitt1
1. University of Liverpool, Liverpool, United Kingdom
2. St James’s Hospital, Leeds, United Kingdom
Introduction
Antigen-specific T cells are important in the aetiology of cutaneous drug
hypersensitivity. Classical Th1/Th2 phenotypes are used to classify drug
hypersensitivity reactions, though these do not fully characterise the function of
immune cells as the newer Th subsets such as Th9, Th17 and Th22 have not been
studied.
Method
The aim of this study was to use the β-lactam antibiotic piperacillin as a
paradigm to fully characterise the phenotype and function of drug-specific T cells.
T cells were cloned from both blood and inflamed skin of hypersensitive patients
and naïve T cells from healthy donors were primed to piperacillin using dendritic
cells.
Results
Drug-specific clones were generated from both blood (n=570, 84% CD4) and
skin (n=96, 83% CD4) from patients hypersensitive to piperacillin. All clones
secreted high levels of IFNγ and IL13 following drug stimulation. Interleukin-22,
perforin and granzyme B were also secreted by over 50% of clones. In contrast,
IL17A secretion was not detected. Naïve T cells primed to piperacillin using
autologous dendritic cells, proliferated in the presence of drug (p=0.001, SI>2)
and had a similar pattern of cytokine secretion to clones generated from
hypersensitive patients. Significant differences in chemokine receptor expression
were observed between the different populations of T cell clones. CLA, CXCR6
and CCR1 expression was higher on piperacillin-specific skin-derived clones when
compared to non piperacillin-specific skin-derived clones (P=0.01). CCR2, CCR4,
CXCR1 and E-cadherin were higher on skin-specific clones when compared to
blood-specific clones (P=0.01). Piperacillin-specific clones isolated from blood
and skin of hypersensitive patients, as well as piperacillin-specific T cells
from healthy donors migrated in the presence of chemokines specific to their
respective cell surface receptors, with migration to CCR4 and CCR10 most
prevalent. Finally, regulation of the cytokine secretion through modulation of
nuclear receptor signalling was studied. Inhibition of the aryl hydrocarbon
receptor during naïve T cell priming abrogated the drug-specific cytokine
response.
Conclusion
Our data describe a subset of piperacillin-specific T-cells that secrete IL-22, IFNγ,
perforin and granzyme B, but not IL-17, in response to antigen challenge. Taken
together this suggests that IL-22 is important in the progression of β-lactam
hypersensitivity.
P164 Vancomycin-Specific T Cell Responses And Teicoplanin CrossReactivity
Wei Yann Haw, Marta E Polak, Carolann Mcguire, Michael R Ardern-Jones
University of Southampton, Southampton, United Kingdom
Keywords: Drug Hypersensitivity Reactions, T Cell, Vancomycin, In-Vitro
Diagnostic Tests
Introduction
Glycopeptide antibiotics, vancomycin and teicoplanin, share a similar structure
and are the mainstay of therapy for severe gram-positive organisms.
Hypersensitivity responses to vancomycin are well recognised but the risk of
cross-reactivity with teicoplanin is unclear. Our study aims to examine the role of
T cell responses in vancomycin hypersensitivity reactions and explore the
potential for cross-reactivity between vancomycin and teicoplanin.
Method
Our cohort comprised of vancomycin exposed allergics who had suffered delayed
skin drug hypersensitivity reactions n=17; non-allergic previously vancomycin
exposed controls n=5; and vancomycin naïve controls n=12. We tested ex-vivo
drug induced lymphocyte proliferation and cytokine release. Vancomycin-specific
T cell lines were grown to test for teicoplanin cross-reactivity.
Results
In our cohort of vancomycin allergics, vancomycin hypersensitivity reaction
patterns were drug exanthems (47.1%), DRESS (29.4%), or SJS/TEN (23.5%).
Circulating IFN-γ vancomycin-specific T cells were identified at higher frequency
than naïve controls: (IFN-γ p<0.0001; SI p=0.042). Interestingly, detectable
frequencies in vancomycin exposed controls were higher than naïve controls
(p<0.0001; SI p=0.12) suggesting that low frequency responses were the result
of vancomycin priming even in the context of a non-allergic individual. This was
confirmed by the expansion of short term T cell lines in vancomycin exposed
controls (IFN-γ p=0.008; SI p=0.016). Cross-reactivity against teicoplanin was
found to be minimal (42.7 x10-4% IFN-γ and SI 1.0 in vancomycin-specific T-cell
lines compared to 48 x10-4% IFN-γ and SI 1.3 in non-vancomycin-specific T-cells
lines).
Conclusion
Circulating vancomycin specific-T cell frequencies were found to be higher in
vancomycin allergics than vancomycin exposed controls, which in turn were
higher than naïve controls. Using vancomycin-specific T cell lines we did not see
any evidence of teicoplanin cross-reactivity despite the similar molecular
structures of the two drugs. We also showed that low-level of vancomycinspecific responses identified ex-vivo in exposed controls were able to efficiently
expand on short term culture, confirming that they were genuine vancomycinspecific T cells. This suggests both immune predisposition and potentially
adaptive regulation may be important in regulating the development of
hypersensitivity reactions to vancomycin.
Poster Walk 19: BAT and Biomarkers
(P165 – P173)
P165 A Combination Of Early Biomarkers Useful For The Prediction Of
Severe ADRs
Yumi Aoyama1, Tetsuo Shiohara2
1. Kawasaki Hospital Kawasaki Medical School, Okayama, Japan
2. Kyorin University School of Medicine, Tokyo, Japan
Keywords: Biomarker, Cytokines,Stevens-Johnson Syndrome,Toxic Epidermal
Necrolysis, Drug-Induced Hypersensitivity Syndrome
Introduction
Severe adverse drug reactions (ADR) including Stevens-Johnson syndrome
(SJS)/toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity
syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms
(DRESS) are acute life-threatening conditions. Although previous studies
demonstrated the pathogenic role of soluble mediators including
cytokines/chemokines secreted by different immune cells including TNF-a, IFN-g,
IL10, perforin/granzyme B, FasL and granulysin, there are few biomarkers or
prognostic tests available to predict disease progression that can be used in
clinical routine for diagnosis and to monitor patients with ADRs.
Method
We therefore, measured serum levels of cytokines/chemokines as well as other
biological markers in patients who presented with clinical symptoms suggestive
of ADRs at their initial presentation.
Results
The results show that sFasL represents a useful early biomarker that can predict
the subsequent progression to TEN, but not SJS, particularly when combined
with the increase in IL-6 and IFN g-induced protein 10 (IP-10). Granulysin was
increased in severe ADRs. Interestingly, the IL-17 level was significantly
increased in patients with viral exanthema but not in severe ADRs and rather
decreased in DiHS/DRESS patients. Increased IL-10 levels were observed in SJS
and DiHS/DRESS, but not in TEN. One surprising finding was that serum IL-10
levels in SJS were much higher than those in TEN despite clinical similarities
between the two diseases. Increased IL-10 levels associated with increased
levels of IL-2, IL-5 and IFN-g at the initial presentation may be a useful predictor
of SJS patients who will not progress to TEN. Alternatively, relatively low levels
of IL-10 associated with increased IL-6 and IP-10 levels could be interpreted as
suggesting the subsequent progression to TEN. The increased levels of IL-6 and
IP-10 are reliable biomarkers predictive of the progression to severe ADRs, such
as SJS/TEN and DiHS/DRESS.
Conclusion
The use of a combination of several early biomarkers, although not sufficiently
sensitive or specific on its own when used alone, could increase the diagnostic
and prognostic utility for the prediction of severe ADRs.
P166 Basophil Activation Test In The Diagnostic Approach Of Reactions
During General Anaesthesia
Ana Moreira1, Susana Cadinha1, Patrícia Barreira1, Ana Castro Neves1, Daniela
Malheiro1, Sara Correia2, JP Moreira Da Silva1
1. Centro Hospitalar Vila Nova Gaia, Vila Nova Gaia, Portugal
2. Centro Hospitalar de Setúbal, Setúbal, Portugal
Keywords: Basophil Activation Test, General Anaesthesia
Introduction
Neuromuscular blocking agents (NMBAs), latex and antibiotics are the most
frequent agents causing hypersensitivity reactions (HR) in the perioperative
setting, followed by hipnotics and opioid analgesics. The diagnostic approach is
complex and relies on suggestive history and skin tests (ST), since basophil
activation test (BAT) has not yet been validated and drug provocation test has
limited indications because of the pharmacological effects of these drugs. Our
aim was to characterize a series of subjects with suspected HR during general
anaesthesia (GA) and to evaluate the concordance between ST and BAT in
patients submitted to both diagnostic procedures with the suspected drugs:
fentanyl (F), propofol (P) and rocuronium (R).
Method
Retrospective analysis of medical records from patients referred to our
department, from 2009 to 2015, with suspected HR during GA. The data
collected were: demographic data, atopy, clinical manifestations, results from ST
and BAT. ST and BAT were performed in the following concentrations: 0,05
mg/ml for F and 10 mg/ml for P and R (SPT); 1/100 dilution for R and 1/10 for F
and P (ID); 25, 12.5 and 6.25 ug/ml for F; 100, 50 and 10 ug/ml for P; 10, 5,
2.5 ug/ml for R (BAT).
Results
From a total of 34 patients referred to our department, we enrolled 15: mean
age 44 (± 21) years; 8 female; 5 atopic; 1 had asthma and 3 had hypertension.
Cutaneous reactions were reported by 7 patients, anaphylaxis by 6 and isolated
respiratory symptoms by 2. BAT and ST to F were performed in 12 patients, to P
in 13 and to R in 12. SPT and ID performed with F (12) and P (13) were all
negative. In the case of R SPT were positive in 1 out of 12 tests and ID were
positive in 2 out of 11. TAB performed with F (12) was negative in 10 cases,
positive in 1 and indetermined in another one. TAB performed with P (13) was
negative in 9, positive in 3 and indetermined in 1. In the case of R (12) TAB was
negative in 10 and positive in 3. Results to ST and BAT were concordant in 83%
of patients tested with F, 69% with P and 67% with R. Allergy was excluded by
subsequently administration of the suspected drugs in 5 patients (1 F, 4 P). One
of them had negative ST and positive BAT (P).
Conclusion
ST and BAT to the suspected drug were concordant in the majority of cases
(83% F, 69% P, 67% R). According to this results BAT seems to be a valuable
contribution in the diagnostic approach of these patients.
P167 IL-10 Can Be Related To Successful Desensitization
Asli Gelincik, Semra Demir, Fatma Sen, Hamza Ugur Bozbey, Muge Olgac,
Derya Unal, Raif Coskun, Bahauddin Colakoglu, Suna Buyuozturk, Esin ÇatinAktas, Gunnur Deniz
Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
Keywords: IL-10, Desensitization
Introduction
The mechanism of drug desensitization is scarcely understood. The aim of the
study is to observe the cytokine levels in the serum of patients who underwent a
successful drug desensitization.
Method
Patients with a hypersensitivity reaction to any culprit drug and therefore has to
be desensitized with the drug were included into the study. IL-4, IL-5, IFN γ and
IL-10 levels were determined with ELISA in the peripheral serum samples of the
patients before the desensitization to any culprit drug and within 24 hours after
the procedure. The results were compared with the serum samples of patients
who could tolerate the same drugs and healthy subjects who were not exposed
to these drugs.
Results
26 patients who experienced allergic reactions due to various drugs and
therefore had to be desensitized, 10 patients who could tolerate the same drugs
and 5 healthy subjects were included. The diagnosis of the patients were as
follows: malignancy (14 patients), multiple sclerosis (2 patients), metabolic
storage disorders (2 patients), iron salt deficiency (2 patients) and Basedow
Graves disease (1 patient), coronary heart disease ( 1 patient), and congenital
adrenal hyperplasia (1 patient). The drugs used for desensitization in the order of
the most frequent to the least were as follows: parenteral or per oral
chemotherapeutics, aspirin, corticosteroids, storage enzymes, iron salts and antithyroidal drugs. Skin prick tests were positive in 5 patients with parenteral
chemotherapeutics, 2 patients with iron salts, 2 patients with storage enzymes
and in one patient with methylprednisolone. The baseline cytokine levels were
not statistically different between the three groups. The desensitization was not
successful in 4 of the patients and because of this insufficient patient number
their cytokine levels were not further analyzed. The IL-10 levels after the
successful desensitization procedure in 22 patients significantly increased when
compared to their baseline levels (p: 0,006). The rise in IL-10 levels were
greater in chemotherapeutic desensitizations than the desensitizations with other
drugs (p: 0.005) whereas the other three cytokines did not significantly change.
Conclusion
Successful desensitization can be related with increase in IL-10. In order to
further elucidate the mechanism of successful desensitization, cells secreting IL10 should be examined.
P168 Immediate Reactions To Proton Pump Inhibitors: Value Of Basophil
Activation Test.
Maria Salas1, Jose Julio Laguna2, Esther Barrionuevo3, J Dionicio2, Tahia
Fernandez4, R Gonzalez-Mendiola2, I Olazabal5, Maria Dolores Ruiz1, Miguel
Blanca1, Cristobalina Mayorga6, Maria José Torres1
1. Regional Hospital of Málaga-IBIMA, Málaga, Spain
2. Hospital de la Cruz Roja, Madrid, Spain
3. Regional Hospital of Málaga-IBIMA, Mdálaga, Spain
4. Research Laboratory, IBIMA, Málaga, Spain
5. Inmunology Department. Alfonso X el Sabio University, Madrid, Spain
6. Research Laboratory-IBIMA, Málaga, Spain
Introduction
The incidence of allergic reactions to proton pump inhibitors (PPI) has increased
in recent years. Most publications describe isolated cases and limited data are
available about the value of skin tests. Therefore, the diagnostic approach is the
drug provocation test (DPT), which is not risk free, especially for severe
reactions. The aim of the study was to assess the value of the basophil activation
test (BAT) for the diagnosis of immediate allergic reactions to PPI.
Method
We evaluated 49 patients with immediate allergic reactions to PPI. Twenty two
subjects with good tolerance to PPI were included as controls. Patients with
anaphylaxis or shock were diagnosed by clinical history, once other possible
causes were ruled out, and those with urticaria-angioedema or pruritus, by DPT.
BAT with omeprazole and pantoprazole at 3 different concentrations (2, 0.2 and
0.02 mg/ml) using CD193 (CCR3) and CD203c for basophil selection and CD63
as activation marker, was performed in all patients and controls.
Results
The PPIs involved were omeprazole (N=43), pantoprazole (N=1) lansoprazole
(N=2) and esomeprazole (N=2), one patient had two reactions, one with
omeprazole and other one with pantoprazole. A total of 20 cases (40.81%)
reported anaphylaxis, 12 (24.48%) anaphylactic shock,13 (26.53%) urticariaangioedema, and 4 (8.16%) pruritus. BAT was positive in 36 cases (73.46%): 14
to omeprazole and pantoprazole (28.5%), 19 to omeprazole (38.7%) and 3 to
pantoprazole (6%). BAT was negative in control patients, indicating a specificity
of 100%. BAT sensitive was 82%.
Conclusion
Immediate hypersensitivity reactions to PPI do occur, with omeprazole being the
most frequently involved. Anaphylaxis is the most common clinical entity. BAT is
a useful method for diagnosing these patients with a good sensitivity and
specificity.
P169 Improvement Of The Elevated Tryptase Criterion To Discriminate
IgE From Non-IgE Mediated Allergic Reactions.
Gabriel Gastaminza, Alberto Lafuente, Carmen D'Amelio, Amalia Bernad, Olga
Vega, Roselle Catherine Madamba, M Jose Goikoetxea, Marta Ferrer, Jorge Núñez
Clinica Universidad de Navarra, Pamplona, Spain
Keywords: Anaphylaxis, Tryptase
Introduction
There is no consensus on an optimal cutoff point (COP) of blood tryptase during
the reaction (TDR) to discriminate IgE- from non-IgE-mediated reactions. We
aimed to compare the diagnostic accuracy between TDR and TDR/basal tryptase
(TDR/BT) index for discriminating IgE- from non-IgE-mediated reactions, and to
estimate a COP for the best of these tests.
Method
Patients with an immediate allergic reaction treated in Clínica Universidad de
Navarra (Spain) from 2009-2015. Allergological study was performed to classify
the reaction into IgE- or non-IgE-mediated. The area under de curve (AUC) of
the receiver operating characteristic (ROC) analysis was calculated to indicate
the discriminative power of each test.
Results
We included 102 patients (45% men; aged 3-99 years; 48% with IgE-mediated
reaction; 54% with anaphylaxis criteria) who had an allergic reaction (emergency
room, n=27; hospitalization, n=15; perioperative, n=44; other hospital areas,
n=16).
The median TDR for the IgE-mediated reactions was 7.6 µg/L (p25-75: 4.9- 13.8
µg/L) and 5.2 µg/L (p25-75: 3.6- 7.5 µg/L) for the non-IgE-mediated reactions
(p=0.047).
The median TDR/BT ratio was 2.6 (p25-75: 1.7- 4.3) in IgE-mediated reactions
and 1.2 (p25-75: 1.0- 1.6) in non-IgE-mediated reactions (p=0.001).
The TDR/BT ratio showed the greatest ability to discriminate IgE from non-IgE
meditated reactions compared with TDR (AUC TDR/BT=0.78 and AUC TDR=0.65;
p=0.003). The optimal COP for TDR/BT to discriminate between IgE and non-IgE
reactions was 1.66.
Conclusion
TDR/BT ratio showed a significantly better diagnostic performance than TDR to
discriminate IgE from non-IgE mediated allergic reactions. An optimal TDR/BT
ratio threshold around 1.7 may be useful in clinical practice to classify allergic
reactions as IgE or non-IgE mediated.
P170 Low Expression Of Tim-3 Could Serve As A Biomarker For Control
And Diagnose Maculopapular Exanthema Induced By Drugs
Tahia Diana Fernández1, Inmaculada Doña2, Francisca Palomares1, Rubén
Fernández1, Maria Salas2, Esther Barrionuevo2, Maria Isabel Sanchez2, Miguel
Blanca2, Maria José Torres2, Cristobalina Mayorga1
1. Research Unit for Allergic Diseases. IBIMA-Regional University Hospital of
Malaga-UMA, Málaga, Spain
2. Allergy Unit. IBIMA-Regional University Hospital of Malaga-UMA, Málaga,
Spain
Keywords: Skin, Peripheral Blood, Lymphocytes, Tim3,Maculopapular Exanthema
Introduction
Previous studies have been showed that in cutaneous non-immediate reactions
to drugs, like maculopapular exanthema (MPE), several lymphocyte subtypes are
involved, mainly CD4 lymphocytes with a Th1-phenotype. However the
involvement of other lymphocyte subtypes, that have shown effector activity in
autoimmune diseases such as rheumatoid arthritis, multiple sclerosis or psoriasis
like Th17-cells has not been studied yet. Moreover, numbers of both lymphocyte
subsets can be controlled by the interaction of the receptor Tim3 with Gal9
inducing their apoptosis and the differentiation of regulatory T cells. The aim of
the study was to analyse the expression of Tim3 in patients with drug induced
MPE during the acute phase and after resolution of the reaction.
Method
Peripheral blood cells (PBMC) and skin biopsies were obtained from 18 allergic
patients and 10 tolerant subjects. Immunohistochemical staining and flow
cytometry were carried out to determine the presence of Th1 (CXCR3+) and Th17
(RORgt+IL17+) CD4-cells and the expression of Tim3.
Results
The involvement of Th1-CD4-cells in EMP were confirmed, with higher levels
compared to controls in both, skin (p<0.0001) and PBMC (p=0.032 during the
acute phase and p=0.039 after resolution). However, we could not find any
difference in the frequencies of Th17-cells between patients and controls in any
of the conditions. The expression of Tim3, was strongly decreased in patients
mainly in the skin (p<0.0001) and in Th1-CD4-cells (p<0.0001) during the acute
phase, but, interestingly, also after resolution (p=0.039). The expression of Tim3
in Th17-cells was similar in patients and controls.
Conclusion
The low expression of Tim3 in the effector cells during the acute phase could be
the responsible of the impaired regulation of these cells in MPE affecting their
homeostasis in these patients. The low expression of Tim3 after resolution could
serve as a biomarker for this type of reactions and could be a target to develop
strategies to control and diagnose the disease.
P171 Role Of Basophil Activation Test Using Two Different Activation
Markers For The Diagnosis Of Allergy To Fluoroquinolones
Esther Barrionuevo1, Tahía Fernandez2, Arturo Ruiz1, Adriana Ariza2, Maria
Salas1, Inmaculada Doña1, Ana Molina2, Miguel Blanca1, Maria Jose Torres1,
Cristobalina Mayorga2
1. Regional Hospital of Málaga, Málaga, Spain
2. Research Laboratory-IBIMA, Málaga, Spain
Introduction
Fluoroquinolones (FQ) are the second most frequent cause of hypersensitivity to
antibiotics after betalactams. Most reactions induced by FQ were immediate. For
the in vitro diagnosis only the basophil activation test (BAT) has shown to be
useful although with suboptimal sensitivity. The aim of our study was to analyze
the BAT to FQ using two different activations markers, CD63 and CD203c, in the
evaluation of patients with immediate allergic reactions to these drugs.
Method
Seventeen patients with confirmed immediate allergic reactions to FQ (6 to
Ciprofloxacin and 11 to Moxifloxacin) were included in the study. Eighteen
controls with tolerance to FQ were also included. BAT was performed with
Moxifloxacin and Ciprofloxacin at 2 and 0.2 mg/mL using CD203c and CD63 as
activation markers. Positive results were considered when SI > 3 to at least one
of the concentrations used in the test.
Results
Data indicated that although both Ciprofloxacin and Moxifloxacin are able to
induce both activation marker expression (CD63 and CD203c), there is a
predominance in the expression of each one depending on the drug included in
the test. Thus Ciprofloxacin was able to mainly increase the expression of CD63
(40%, p=0.0053) whereas Moxifloxacin mainly increase the expression of
CD203c (10%). In addition, analyzing the expression of both markers in
basophils from Moxifloxacin allergic patients stimulated with the culprit drug, we
found a higher expression of CD203c in patients suffering anaphylactic shock
(7%), whereas was CD63 the marker that showed a higher up-regulation in
patients with anaphylaxis (17%). When we analyzed the sensitivity and
specificity of the test using these activation markers we can see that the best
results were observed using the culprit drug and CD203c as activation marker for
Moxifloxacin (S= 36.4% and E= 94.4%) and CD63 for Ciprofloxacin (S=83.3%
and E= 88.9%).
Conclusion
The BAT must be performed using the culprit drug and CD203c for Moxifloxacin
or CD63 for Ciprofloxacin as activation marker to diagnose Quinolone Allergy.
Although this differential expression of both activation markers seems to be also
related with the culprit drug and clinical entity.Using this criteria and a cut-off of
3, we have obtained a better sensitivity for Ciprofloxacin.
P172 The Importance Of Basophil Activation Test In Anaphylaxis Due To
Celecoxib
Amalia Bernad Alonso, Carmen D'Amelio Garófalo, Olga Vega Matute, Marta
Ferrer Puga, María José Goikoetxea Lapresa, Roselle Catherine Yu Madamba,
Gabriel Gastaminza Lasarte
Clínica Universidad de Navarra, Pamplona, Spain
Introduction
Celecoxib, is a specific COX-2 inhibitor which is an alternative treatment for
patients with intolerance to NSAIDs.
Case Description
We present two cases of anaphylaxis due to Celecoxib. The first is a 57 year old
male who was taking Celecoxib as an alternative medication for sciatic pain since
he had poor gastric tolerance with NSAIDs. He had a history of idiopathic
recurrent urticaria. He had an episode of anaphylactic shock 30 minutes after
taking 1 tablet of Celecoxib which prompted him to sought consult at the
emergency room wherein he was administered with Epinephrine IM. On follow
up after one month, prick test with Celecoxib revealed negative. Because the
suspicion that the reaction was caused by allergy to Anisakis, a challenge test
with Celecoxib was done that resulted positive, and epinephrine was
administered. Basophil activation test was positive with Celecoxib and negative
to Parecoxib. Two months later, he presented with hives two hours after taking
750 mg of acetylsalicylic acid (ASA). Tolerance test with Meloxicam and
Nabumetone were performed which the patient tolerated well.
The second case is a 58 year old male who had an episode of anaphylaxis three
hours after taking Celecoxib for headache. Tryptase was elevated, 19.9 ug/L. A
month earlier, he had generalized itching after taking one tablet of celecoxib. He
took Metamizol previously which he tolerated well. No history of atopy nor
allergy to medications. Skin tests to NSAIDs were negative. Basophil activation
test was positive with celecoxib and negative to ASA, Metamizole, Paracetamol,
Parecoxib and Dexketoprofen. He underwent challenge test with Aspirin with
positive result. Both patients were diagnosed with intolerance to NSAIDs and
anaphylaxis secondary to Celecoxib.
How this report contributes to current knowledge
Anaphylaxis due to Celecoxib is considered a rare entity as patients with
intolerance to NSAIDs usually tolerate Celecoxib and other COX-2 inhibitors. The
positive result in the basophil activation test together with a compatible clinical
history makes us hypothesize that these are cases of a selective hypersensitivity
to Celecoxib, instead of the fact that both patients were finally NSAIDs
intolerant. Hence, BAT can be useful for the diagnosis, given the low
sensitivity of skin tests.
P173 The Role Of Basophil Activation Test In The Diagnosis Of
Immediate Type Drug Hypersensitivity To Betalactam Antibiotics.
Antonia Thinnes, Hans F. Merk, Jens Malte Baron, Martin Leverkus, Galina
Balakirski
Department for Dermatology and Allergology, University Hospital of Aachen,
Aachen, Germany
Keywords: Basophil Activation Test, Betalactam Antibiotics, Immediate Type
Drug Hypersensitivity
Introduction
Basophil activation test (BAT) is reported to be a useful and very promising
technique in the diagnosis of immediate type drug hypersensitivity reactions. It is
used in combination with in vivo and in vitro diagnostic tools and may contribute
to the sensitivity of the diagnostic work out.
Method
In order to investigate the role of BAT in the diagnosis of immediate type drug
hypersensitivity to betalactam antibiotics we analyzed all BATs performed with
betalactam antibiotics in our department during the period from 2009 to 2012.
We compared the results of in vivo diagnostics (skin prick test, intracutaneous
test, patch test) and in vitro diagnostics (specific IgE) with the results of the BAT
under the aspect, if BAT represent a useful tool for assessment of the individual
risk of the patient to experience another immediate type drug hypersensitivity
reaction on reexposure to the tested drug.
Results
We performed BAT with betalactam antibiotics in 64 cases: 20% (n=13) with
penicillin (PEN), 38% (n=24) with aminopenicilins (AMP) and 42% (n=27) with
cephalosporins (CPH).
In the PEN-group 23% (n=3) of the patients had at least one positive in vivo
test, but negative BAT and 15% (n=2) had positive BAT, but negative in vivo
tests.
In the AMP-group 17% (n=4) of patients had at least one positive in vivo test,
but negative BAT and 17% (n=4) had positive BAT, but negative in vivo tests.
Only 8% (n=2) of patients had positive both BAT und at least one in vivo test.
4% (n=1) of patients had both positive at least one in vivo test and specific IgE,
but negative BAT.
In the CPH-group 22% (n=6) of the patients had positive BAT, but no other
positive test results and 4% (n=1) had positive both BAT und at least one in vivo
test.
Conclusion
In case of the negative in vivo and in vitro test results (inclusive BAT) the
individual risk of the patient to experience another immediate type drug
hypersensitivity reaction on reexposure to the tested drug was considered to be
low, so drug provocation test (DPT) as the next diagnostic step was
recommended: from overall of 41 such cases DPT was performed in 32% (n=13)
and was unremarkable in 100% (n=13).
Our results confirm that BAT may be an important tool to increase the sensitivity
of the diagnostic and make the better risk assessment possible. However, the
limitation of this study is that we didn’t perform DPT in patients with positive in
vivo or in vitro results and therefore are not able to estimate the frequency of
false positive BATs.
Frequency of positive in vivo and in vitro results in the diagnostic work out of
immediate type drug hypersensitivity reactions to betalactam antibiotics in
Department of Dermatology and Allergology at the University Hospital of Aachen,
Germany during the period from 2009 to 2012.
Positive BAT results in patients with negative in vivo tests and specific IgE may
provide important information for assessment of the individual risk of the patient
to experience another immediate type drug hypersensitivity reaction on
reexposure to the tested drug.
Penicillin
Aminopenicillins Cephalosporins Total
20%
38% (n=24)
42% (n=27) 100%(n=64)
(n=13)
positive in vivo results
23%
17% (n=4)
11% (n=7)
and negative BAT
(n=3)
negative in vivo results
as well as absence of
15%
19%
17% (n=4)
22% (n=6)
specific IgE and
(n=2)
(n=12)
positive BAT
positive in vivo results
8% (n=2)
4% (n=1)
4,5% (n=3)
and positive BAT
positive in vivo results,
positive specific IgE and 4% (n=1)
1,5% (n=1)
negative BAT
negative in vivo results
62%
54% (n=13)
74% (n=20) 64% (n=41)
and negative BAT
(n=8)
Poster Walk 20: TCR recognition, cellular
(P174 – P183)
P174 Characterisation Of The Effect Of Co-Inhibitory Signalling On The
Activation Of Drug-Derived Antigen-Specific T-Cells.
Andrew Gibson, Monday Ogese, Lee Faulkner, B Kevin Park, Dean J Naisbitt
University of Liverpool, Liverpool, United Kingdom
Introduction
The factors governing inter-individual susceptibility to drug hypersensitivity
remain ill-defined. Although the association of specific HLA alleles with
hypersensitivity is important, for most drugs, the majority of individuals who are
positive for an HLA risk allele do not develop a reaction. Thus, predisposition is
likely mediated by other parameters, which may include T-cell co-inhibitory
pathways. As polymorphisms in co-inhibitory pathways are associated with
dysregulated immune responses, we investigated the role of these pathways
during drug (SMX-NO)-specific T-cell responses. Programmed death-1 (PD-1)
and cytotoxic T-lymphocyte associated protein 4 (CTLA4) are considered to be
key immune checkpoints, and TIM-3 is of current interest due to its reported
upregulation alongside PD-1.
Method
Naïve and memory T-cells from healthy donors were incubated for 8 days with
SMX-NO and dendritic cells ±PD-L1, CTLA4, TIM-3 blocking antibody. Antigenreactivity was then assessed by T-cell cytokine secretion and proliferation. Cell
phenotype was assessed by flow cytometry. T-cell clones were then generated
from these cultures.
Results
While blockade of PD-L1 or CTLA4 enhanced the activation of SMX-NO-primed
naïve T-cells, only the blockade of CTLA4 enhanced the proliferative response of
antigen-stimulated memory T-cells suggesting a greater regulatory role for
CTLA4 during secondary T-cell responses. Blockade of TIM-3 had no effect on Tcell activation of either naïve or memory cells. While all receptors were
upregulated on T-cells after antigen exposure, PD-1 was upregulated at earlier
time points than CTLA4 and TIM-3 indicating a differential role for these
receptors during early and late stage T-cell activation. High expression of
individual co-inhibitory receptors has previously been associated with exhausted
T-cells, while other studies indicate that these cells are highly functional. We
found no correlation between the level of individual co-inhibitory receptor
expression and the strength of T-cell activation in the T-cell clones.
Conclusion
Drug-induced stimulation of naïve T-cells was significantly enhanced by blocking
PD-L1 or CTLA4. However, the co-inhibitory pathways did not have a great
effect on memory T-cell responses. Any differences in the control of the different
T-cell co-inhibitory pathways may be important in determining whether a
particular individual develops a hypersensitivity response to a drug.
P175 Characterization Of Drug Hapten-Specific T Cell Responses In
Piperacillin Hypersensitive Patients.
Zaid Al-Attar1, Fiazia Yaseen1, Xiaoli Meng1, Rozalind Jenkins1, Paul Whitaker2,
Daniel Peckham2, Lee Faulkner1, John Farrel1, Kevin Park1, Dean Naisbitt1
1. MRC Centre for Drug Safety Science, Dept Molecular & Clinical
Pharmacology, University of Liverpool, Liverpool, United Kingdom
2. Regional Adult Cystic Fibrosis Unit, St James’s Hospital, Leeds, United
Kingdom
Introduction
Piperacillin is a b-lactam frequently used to combat bacterial infections in
patients with cystic fibrosis. However, its use is associated with high incidence of
delayed-type hypersensitivity reactions. Previous studies have identified
lymphocyte proliferative responses and cytokine secretion from PBMCs isolated
from approximately 75% of hypersensitive patients but not from tolerant
controls. The drug forms a hapten that binds covalently to specific lysine residues
on serum albumin (HSA).
Aim: To generate a synthetic piperacillin-HSA conjugate and to quantify the level
of modification at specific lysine residues. Furthermore, the activation of T-cells
with free drug and the drug-protein conjugate was assessed.
Method
Piperacillin was incubated with HSA at different molar ratios (10:1–250:1
drug:protein). Mass spectrometry was used to characterize modification at
specific lysine residues. PBMCs from hypersensitive patients were cultured in the
presence of parent drug and the piperacillin-HSA conjugate and T-cell clones
generated by serial dilution. T cell clones were analysed for antigen-specific
proliferative responses, cytokine release and TCR-Vb usage.
Results
Cyclised and hydrolysed forms of piperacillin hapten were detected on over 10
lysine residues of HSA. Quantitative analysis revealed that 3-23% of lysine 541
was modified with piperacillin haptens. Sixty CD4+ clones displayed reactivity
against piperacillin-modified HSA but did not respond to free piperacillin or to
other b-lactam HSA adducts. T cell activation was dependent on protein
processing by antigen presenting cells and the level of modification with the
piperacillin hapten, as low levels of modification failed to activate the clones. A
further sixty CD4+ clones were responsive to free piperacillin and were not
activated with the piperacillin-HSA conjugates. T-cell clones secreted a variety of
molecules: IFN-γ (72% of clones), IL5 (48%), IL13 (37%), perforin (48%),
granzyme B (26%) & FasL (52%) and showed a restricted expression of TCR-Vb9
(68%).
Conclusion
We have shown that drug hapten-responsive CD4+ T-cells with divergent antigen
specificities circulate in hypersensitive patients. These data have important
implications for studies investigating the nature of the drug antigen. It is
necessary to synthesize conjugates with different drug haptens to fully
investigate the antigen specificity of the T-cell repertoire.
P176 Characterization Of The Response Of T-Cells To Telaprevir And Its
Metabolite In Normal Volunteers
Zaid Al-Attar, Khetam Alhilali, Yanni Xue, John Farrell, Lee Faulkner, Kevin
Park, Dean Naisbitt
MRC Centre for Drug Safety Science, Dept Molecular & Clinical Pharmacology,
University of Liverpool, Liverpool, United Kingdom
Introduction
Telaprevir is antiretroviral drug developed for the treatment of hepatitis C.
Human exposure is associated with a high frequency of cutaneous side effects
varying in severity from mild rash (56%) to Stevens Johnson syndrome/toxic
epidermal necrolysis (<1%). Telaprevir interconverts to an R-diastereomer (VRT127394), which is the major metabolite. There is no known HLA risk allele
associated telaprevir hypersensitivity. However, this does not rule out a role for
antigen-specific T-cells in mediating hypersensitivity.
Aim: The aims of this study were to (1) generate T-cell clones with specificity
for telaprevir and/or its metabolite and (2) explore the nature of the induced
response.
Method
The optimal T-cell priming concentration of telaprevir and its metabolite was
identified using a PBMC toxicity assay. Naïve T-cells from 3 normal volunteers
were primed with autologous dendritic cells (DCs) and telaprevir or VRT-127394
for 10 days. Alternatively, PBMCs from 3 normal volunteers were cultured with
telaprevir or VRT-127394 for 14 days. T-cells from both experimental procedures
were cloned by serial dilution and repetitive mitogen stimulation. T-cell
proliferative responses were assessed using [3H] thymidine incorporation and
IFN-γ. Antigen-specific clones were phenotyped for CD4, CD8 and TCR Vb
expression.
Results
T-cell responses to telaprevir or VRT-127394 were not detected using the DC
priming assay. However, 13 telaprevir-responsive T-cell clones were isolated
from PBMC cultures from one volunteer. All 13 clones were stimulated to
proliferate in the presence of telaprevir and its metabolite in a dose-dependent
manner at a similar concentration range. Clones were not activated in the
presence of antigen presenting cells pulsed with telaprevir for 1-16 hr. 11 clones
secreted IFN-γ when activated with telaprevir. 10 clones were CD4+ and 3 were
CD8+. Clones expressed a restricted pattern of TCR-Vb which was dominated by
Vb2 and Vb22.
Conclusion
The data presented here shows that telaprevir-responsive T-cells were detected
in healthy volunteers. CD4+ and CD8+ clones were activated with both telaprevir
and the major metabolite VRT-127394. Future work will focus on assessing the
nature of the T-cell response in hypersensitive patients.
P177 Characterization Of The T Cell Receptor Signatures Of DrugResponsive T Cells
Patricia Illing1, Nicole Mifsud1, Heidi Fettke1, Jeffrey Lai1, Rebecca Ho1, Patrick
Kwan2, Anthony Purcell1
1. Infection and Immunity Program, Monash Biomedicine Discovery Institute
and Department of Biochemistry and Molecular Biology, Monash
University, Clayton, Australia
2. Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
Keywords: Human Leukocyte Antigen, Carbamazepine, Allopurinol, Abacavir
Introduction
The strongest associations reported to date between adverse drug reactions and
specific Human Leukocyte Antigen (HLA) allotypes are between HLA-B*57:01
and abacavir hypersensitivity syndrome, HLA-B*58:01 and allopurinol
hypersensitivities, and HLA-B*15:02 and carbamazepine induced StevensJohnson Syndrome/Toxic Epidermal Necrolysis. A lesser association also exists
between HLA-A*31:01 and carbamazepine induced hypersensitivities. In this
study we examined the diversity of the T cell response to these drugs (and
metabolites) by characterising the T cell receptor (TCR) signatures of drugresponsive CD8+ T cells at a single cell level in patients and healthy
donors. These studies were complimented by analyses of the diversity and
perturbation of the HLA peptide repertoire following drug/metabolite exposure.
Method
To characterise drug responsive TCR signatures, peripheral blood mononuclear
cells were stimulated with the parent drug or metabolite in vitro and drugresponsive T cells characterized (phenotype and function) by flow cytometry.
Single-cell flow cytometric sorting of drug-responsive CD8+ T cells was
performed prior to a paired analysis of TCR alpha and beta chain variable regions
using a novel multiplex nested RT-PCR methodology. To assess the influence of
drugs/metabolites on peptide presentation by HLA molecules, HLA transfected BLymphoblastoid cell lines were grown to high density in the presence of the
molecule of interest. 5-10x108 cells were harvested, the HLA molecules
immunoaffinity purified, and the peptide/small molecule ligands dissociated and
analysed using Liquid Chromatography Tandem Mass Spectrometry.
Results
Our data demonstrated that the TCR signatures for abacavir-responsive CD8+ T
cells were oligoclonal, correlating with previous reports of a large and diverse
perturbation in HLA-B*57:01 peptide repertoire during abacavir exposure.
Interestingly, whilst both carbamazepine and allopurinol hypersensitivities are
postulated to occur via a direct interaction of the HLA-peptide-drug-TCR at the
cell surface, and cause minimal change of the HLA peptide repertoire, their TCR
usage profiles are divergent with carbamazepine being more restricted and
allopurinol/oxypurinol exhibiting greater diversity.
Conclusion
These data suggest a spectrum of diversity in the T cell response that may
correlate with altered modes of drug presentation in HLA associated drug
hypersensitivity.
P178 Defining The Signals Between Hepatocytes And Immune Cells In
Idiosyncratic Drug-Induced Liver Injury (DILI)
Monday O Ogese1, Lee Faulkner2, B. Kevin Park2, Catherine Betts1, Dean J
Naisbitt2
1. AstraZeneca R&D, Cambridge, United Kingdom
2. University of Liverpool, Liverpool, United Kingdom
Keywords: DILI, Hepatocytes, Idiosyncratic, Cytokines
Introduction
An association between HLA genotype and the development of certain forms of
DILI is well established. Furthermore, it is now apparent that drug-specific T-cells
are activated in certain patients with DILI. The cross-talk signals between
hepatocytes and the immune cells resident in the liver and circulation are likely
to be critical in determining the outcome of drug exposure and development of
immune-mediated DILI. However, tissue-specific immune signalling with respect
to human DILI remains largely unexplored. Thus, the aim of this study was to
profile the signals released by fresh human hepatocytes upon drug exposure and
to characterise the impact of these molecules (cytokines and chemokines) on the
phenotype and function of antigen presenting cells (APC).
Method
Fresh human hepatocytes were exposed to three test compounds implicated in
DILI (flucloxacillin, amoxicillin and isoniazid) and one reactive metabolite,
nitroso-sulphamethoxazole (SMX-NO), and end-points of hepatocyte toxicity, cell
viability and oxidative stress assessed.
Results
HMGB1 and LDH release as well as ATP depletion occurred in a drug- and
concentration-dependent manner. Furthermore, compound-specific activation of
Nrf2 marker genes was observed with each of the test drugs. SMX-NO
differentially induced the expression of NQO1, TXNRD1 and SRXN1 responsible
for cytoprotection against chemically reactive metabolites. Also, the expression
of AKR1B10, SRXN1 and LOC344887 were significantly increased by all the test
compounds. Hepatocytes cultured with test drugs released a mixture of proinflammatory (IFN-gamma, GM-CSF, IL-12p40, IL-12p70, IL-1β, TNF-α, TNF-β,
IL-8 and MCP-1) and anti-inflammatory cytokines (IL-1RA, IL-10 and IL-13). Coculture of APC with supernatant from drug treated hepatocytes resulted in a
highly drug-dependent release of cytokines as well as significant changes in
expression of MHC class II and CD86 on the cell surface of dendritic cells.
Conclusion
In conclusion, our study begins to define the various factors that might be
important in determining whether drug exposure in patients results in an
immune response and tissue injury. We found that cross-talk signals were highly
drug specific. The development of a liver/immune cell culture system will be an
important step forward in advancing our understanding of the molecular
mechanisms underlining the development of idiosyncratic DILI.
P179 Development Of Novel Chemicals That Do Not Bind To HLA-B*57:01
Or Activate CD8+ T-Cells Through Modification Of The 6-Amino
Cyclopropyl Group Of Abacavir.
Paul Thomson, John Farrell, Mohammad Alhaidari, Neill Berry, Paul M O'Neill, B
Kevin Park, Dean J Naisbitt
University of Liverpool, Liverpool, United Kingdom
Introduction
Exposure to the reverse transcriptase inhibitor abacavir has been associated with
hypersensitivity reactions mediated by CD8+ T-cells in individuals carrying the
human leukocyte antigen (HLA-B*57:01) risk allele. It has been shown that
abacavir can interact directly with the antigen binding cleft of HLA-B*57:01,
altering its conformation and thereby causing an alteration of the peptides
displayed on the cell surface. It has been hypothesized that these alternative
self-peptide sequences trigger the CD8+ T-cell response in abacavir
hypersensitive patients.
We examined whether it is possible to synthesize compounds that retain antiviral
activity, but do not bind to HLA-B*57:01 and activate CD8+ T-cells.
Method
Twenty five abacavir analogues were synthesized with modifications around the
cyclopropyl group with compounds divided into three main groups. Abacavir
responsive CD8+ T-cell clones were generated from healthy donors positive for
the HLA-B*57:01 risk allele. IFN-g secretion was measured when the clones
were cultured in the presence of autologous antigen presenting cells and
abacavir or abacavir analogues using an ELISpot assay. Anti-viral activity of the
analogues was assessed using a range of established assays. In silico docking
studies were carried out to find potential binding orientations of the abacavir
analogues within the F-pocket of HLA-B*57:01.
Results
CD8+ T-cell clones proliferated and secreted IFN-g in response to abacavir.
Several analogues in groups 1 and 2 displayed some antiviral activity without
triggering CD8+ T-cell responses. Molecular docking studies of these analogues
to HLA-B*57:01 demonstrated a quantitative relationship between the protein
binding and the T-cell response. These data prompted us to synthesize a
3rd group of compounds where the NH-cyclopropyl group of abacavir was
replaced with substituted cyclic amine derivatives. This third series was
subjected to additional antiviral activity and T-cell response assays and several
molecules were shown to be devoid of T-cell activity, whilst maintaining a
favourable antiviral profile.
Conclusion
These studies demonstrate that modification of the cyclopropyl moiety of
abacavir may result in compounds that retain the antiviral activity, without
generating an unwanted T-cell response. This approach represents an exciting
approach to the design of safe antiviral drugs eliminating the need for
personalised medicine therapy regimes.
P180 Generation And Characterization Of Dapsone- And NitrosoDapsone-Specific T-Cell Clones Using Lymphocytes From Healthy
Volunteers
Abdulaziz Alzahrani1, Monday O Ogese2, John Farrell1, Lee Faulkner1, Andrew
Gibson1, Arun Tailor1, B Kevin Park1, Dean J Naisbitt1
1. University of Liverpool, Liverpool, United Kingdom
2. AstraZeneca R&D, Cambridge, United Kingdom
Keywords: Dapsone, Hypersensitivity, T-Cells, Dendritic Cells,Cytokines
Introduction
Dapsone is an antibiotic commonly used in the treatment of leprosy. Its use is
associated with development of hypersensitivity in 0.5-3.6% patients. HLAB*13:01 is associated with an increased susceptibility to dapsone
hypersensitivity but no studies have been carried out to determine the
immunological mechanism(s) underlying the reactions and/or the role of the HLA
risk allele in antigen presentation. The aims of this study were to: (i) Prime naive
T-cells to dapsone and nitroso-dapsone (ii) Generate dapsone-and nitrosodapsone-specific T-cell clones from healthy donors and (iii) Characterize the
pathways of drug-specific T-cell activation.
Method
Peripheral blood mononuclear cells (PBMCs) were isolated from healthy
volunteers, and CD14+ monocytes and naïve T-cells were isolated by magnetic
bead separation. Monocyte-derived dendritic cells (DC) were used to prime naïve
T-cells in the presence of either dapsone or nitroso dapsone using an established
DC priming assay. Drug-specific T-cell clones were generated by serial dilution
and repetitive mitogen stimulation. Antigen specificity was assessed by
measurement of proliferation and cytokine release using [3H]-thymidine release
and IFN-gamma Elispot, respectively.
Results
Moderate priming of naive T-cells to both dapsone-and nitroso-dapsone was
detected but only five dapsone-specific T-cell clones were generated from one
out of three donors tested. No nitroso-dapsone-specific T-cell clones were
detected in any of the 3 donors. The dapsone-responsive clones were stimulated
to proliferate is a dose-dependent manner, but showed no cross reactivity with
nitroso-dapsone or three closely related structures. The clones secreted
IFNgamma, IL-5 and IL-13 alongside the cytolytic molecule granzyme B. All of
the dapsone-specific clones were CD4+, and showed MHC class II-restricted
activation. Use of fixed or pulsed antigen presenting cells suggested that
activation of T cell clones by dapsone did not require antigen processing.
Conclusion
: Naïve T cells were primed to both dapsone and nitroso dapsone. Dapsonespecific T-cell clones were activated via a processing independent pathway, thus
suggesting a non-covalent interaction between drug, MHC and T cell receptor.
On-going studies using PBMCs from volunteers ezxpressing HLA-B*13:01 will
investigate the role of HLA*B13:01 in the activation of dapsone- and nitrosodapsone-specific T cells.
P181 Identification Of Benzylpenicillin-Hapten Peptides Responsible For
Naïve T-Cell Activation And Immunization Of Allergic Patients To
Penicillin
Marie Eliane Azoury1, Lucia Fili2, Rami Bechara1, Noémie Scornet3, Cathy Nhim1,
Richard Weaver4, Nancy Claude4, Delphine Joseph3, Bernard Maillere5, Paola
Parronchi2, Marc Pallardy1
1. University Paris-Saclay, Univ Paris-Sud, INSERM UMR996, ChâtenayMalabry, France
2. University of Florence, Department of Experimental and Clinical medicine,
Florence, Italy
3. University Paris-Saclay, Univ Paris-Sud, UMR CNRS8076, ChâtenayMalabry, France
4. Institut de Recherches Internationales Servier, Suresnes, France
5. SIMOPRO, IBiTecS, CEA, Saclay, France
Introduction
Allergic reactions to drugs are often unpredictable and may have many side
effects including anaphylaxis. According to the hapten hypothesis, drug of low
molecular weight can bind to proteins and form immunogenic complexes. Antigen
presenting cells, such as dendritic cells (DCs), recognize and internalize drug
hapten complexes, and digest them into benzylpenicillin-hapten peptides (BP-P),
which are presented on HLA molecules to drug-specific T-cells. This lead to the
immunization of the exposed person. There is in vitro evidence that T-cells from
allergic patients react to benzylpenicillin-Human Serum Albumin (BP-HSA)
bioconjugate and our group has recently shown the existence of naïve CD4+ T
lymphocytes specific to BP-HSA in healthy donors. In this context, we were
interested in identifying BP-P from HSA able to immunize patients to BP thus
contributing to hypersensitivity reactions.
Method
We have considered HSA as a good model for BP haptenization since BP is known
to bind covalently to HSA and because HSA is the most abundant protein in the
sera. We have synthetized BP-HSA bioconjugate, investigated BP-HSA-specific
naïve CD4+ T-cell responses in healthy donors and identified BP binding positions
on HSA using mass-spectrometry. Twelve 15-mer BP-P were identified as
potential T-cell epitopes using the predictive IEDB computational approach and
were synthesized using an original BP-lysine monomer. Naïve CD4+ T cells from
non-allergic donors were stimulated once a week with autologous DCs loaded
with BP-HSA or BP-P to amplify BP-HSA- or BP-P-specific T-cells respectively.
Activation of specific CD4+ T-cells was detected using interferon-γ ELISpot and
their frequency was calculated using the Poisson distribution.
Results
In this study, BP-HSA- and BP-P-specific naïve CD4+ T cells were detected in
15/16 and 11/14 of the tested healthy donors respectively. Most donors
responded to 3 peptides with BP covalently bound on lysines 159, 212 and 525
respectively. Two of these benzylpenicillinoylated peptides (lysines 159 and 525)
were found to induce peripheral blood mononuclear cells (PBMC) proliferation in
patients with allergic reaction to BP using the lymphocyte transformation test.
Conclusion
This study showed the capacity of BP-HSA to be recognized by naïve T-cells from
multiple healthy donors and allowed the identification for the first time of BP-P
responsible for naïve T-cell activation and immunization of allergic patients to BP.
P182 Massive Expansion Of Clonotypic And Polycytotoxic CD8+ T Cells In
Toxic Epidermal Necrolysis
Axel Patrice Villani1, Aurore Rozières2, Benoît Bensaïd3, Mathilde Tardieu3,
Floriane Albert3, Virginie Mutez3, Tugba Baysal3, Marc Pallardy4, Janet
Maryanski5, Jean-François Nicolas6, Osami Kanagawa3, Marc Vocanson3
1. Inserm U1111 - CIRI, Lyon I University, Edouard Herriot Hospital, Lyon,
France
2. Inserm U1111 - CIRI, Lyon I University, Lyon, France
3. Inserm U1111 - CIRI, Lyon, France
4. INSERM UMR 996, Université Paris-Sud, Châtenay-Malabry, Lyon, France
5. Unité de Thérapie Cellulaire et Génique (UTCG) and URE 004 (ImCelVir),
Université Nice Sophia Antipolis, Nice, France
6. Inserm U1111 - CIRI, Lyon I University, Lyon-Sud Hospital, Lyon, France
Keywords: Toxic Epidermal Necrolysis, CD8+ T Cells, Polycytotoxicity, Clonotypic
Introduction
Toxic epidermal necrolysis (TEN) is a life-threatening and blistering adverse drug
reaction, characterized by an acute epidermal necrolysis. Diverse studies have
reported that the onset of TEN correlates with skin infiltration by cytotoxic
lymphocytes (T, NK cells) and inflammatory monocytes.
Method
To further characterize the phenotype of skin-infiltrating lymphocytes at the
acute phase of TEN, we conducted a prospective study on the blood and blister
fluids from 11 TEN patients, using flow and mass cytometry, as well as next
generation TCR sequencing.
Results
Our results confirm that conventional CD8+ T cells (CD45+TCRab+CD8b+) and,
at a lesser extend CD4+ T cells, were the main leucocyte subsets found in recent
TEN blisters. Consequently, the CD4/CD8 ratio was inversed in blisters (mean:
0.8) compared to blood (mean: 2). However, we failed to repeatedly detect NK
(CD45+TCRab+NKP46+) or NKT cells (CD45+TCRab+TCRVa24+) in TEN blisters.
Strikingly, deep sequencing of the T cell receptor CDR3 repertoire revealed
massive clonal expansions of T cells in blister cells of 6 TEN patients, which were
confirmed at TCR-Vb usage level by flow cytometry. Over-represented TCR-Vb+
blister cells were mainly effector memory CD8+CD45RA-CD27+ T cells and
displayed a poly-cytotoxic phenotype since they co-expressed Granulysin,
Granzyme B, Granzyme A, Perforin and TWEAK, as demonstrated by mass
cytometry.
Conclusion
Our results highlight a massive skin recruitment of clonotypic and poly-cytotoxic
CD8+ T cells in TEN patients, which could explain the severity of this lifethreatening disease.
P183 Pharmaco-Immunological Synapse Of HLA-Drug-TCR In SCAR
Shuen-Iu Hung
National Yang-Ming University, Taipei, Taiwan
Keywords: Immune Synapse, TCR, HLA, Drug Antigen,SCAR
Introduction
Life-threatening severe cutaneous adverse reactions (SCAR), including drug
reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN) are known as T cellsmediated drug hypersensitivity, some of which showed strong HLA genetic
predisposition. Our previous studies have discovered that HLA-B*15:02, HLAA*31:01, and HLA-B*58:01, are the genetic markers of carbamazepine-induced
SJS/TEN, -DRESS, and allopurinol-SCAR, respectively. Although we recently also
have identified that HLA can directly interact with the drugs and metabolites
(JACI 2012; JACI 2015), the role of TCR and immune synapse of HLA-drug-TCR
in SCAR remain unclear.
Method
We enrolled patients with SCAR caused by carbamazepine, allopurinol,
phenytoin, lamotrigine or antibiotics, and collected the blister cells from skin
lesions or PBMC from patients in the acute or recovery stage. We applied the
technology of next-generation sequencing to investigate the TCR repertoire of
SCAR. Real-time quantitative PCR was used to measure and validate the gene
expression of TCR. We generated the recombinant TCRalpha/beta fusion protein,
TCRalpha/beta transfectants, and used in vitro cell cultures to examine the
molecular interaction of HLA-drug-TCR in drug hypersensitivity.
Results
We found that different drugs-induced SCAR showed various profiles of TCR
usage. Particularly, limited and shared drug-specific CDR3 clonotypes were
predominantly expressed in the blister cells and PBMC of SCAR patients. The in
vitro drug-expanded T cells highly expressed the specific CDR3 clonotypes and
produced granulysin upon drug stimulation. Furthermore, we generated drugspecific TCRalpha/beta recombinant protein, and found it could directly interact
with the drug antigen and show cross-reactivity to the structure-related
compounds or metabolites. Using in vitro cell culture and ELISPOT assays, we
found that the specific TCRalpha/beta transfectants were activated upon drug
stimulation, and the response was facilitated by the co-culture of antigenpresenting cells with the expression of matched HLA transgene.
Conclusion
Our data suggest that clonotype-specific TCRalpha/beta directly interacts with
drug antigens presented by HLA in the T cells-mediated drug hypersensitivity.
This study provides a new insight into the pharmaco-immunological synapse of
HLA-drug-TCR in SCAR.
Poster Walk 21: New in vitro methods, Haptens,
etc. (P184 - P194)
P184 Amoxicillin-Clavulanate Forms Distinct Multiple Haptenic
Structures On Human Serum Albumin In Patients
Xiaoli Meng1, Arun Tailor1, Caroline J Harrison1, Rosalind E Jenkins1, Paul
Whitaker2, Neil S French1, Dean J Naisbitt1, B Kevin Park1
1. University of Liverpool, Liverpool, United Kingdom
2. St James’s Hospital, Leeds, United Kingdom
Keywords: Covalent Binding, Haptenic Structures, Albumin
Introduction
Amoxicillin-clavulanate (AC) is one of the most common causes of drug induced
liver injury (DILI) in Europe and the US. The mechanisms of amoxicillinclavulanate–induced liver injury (AC-DILI) remain to be defined, however, recent
studies have shown that AC-DILI is associated with both HLA class I and class II
alleles, indicating immune-mediated mechanisms have been involved.
Method
In order to investigate the molecular basis involved in AC-DILI, we have
characterized the binding of AC to proteins in vitro and in patients receiving
amoxicillin-clavulanate therapy using novel mass spectrometric methods.
Clavulanic acid was incubated with N-acetyl lysine in phosphate buffer and the
structures of adducts were characterised by mass spectrometry. In addition,
amoxicillin and clavulanic acid were incubated with human serum albumin (HSA)
in vitro to identify possible adducts formed on proteins, and the protein adducts
formed in cell culture medium and in patients were also characterised by mass
spectrometric methods.
Results
Amoxicillin formed adducts with lysine residues on HSA in vitro, with K190, K199
and K525 being the most reactive sites. In addition, amoxicillin-modified K190
and K525, and novel adducts derived from amoxicillin dimmer were also detected
in plasma samples from patients, and more extensive modification was observed
in patients that had been administered higher doses of amoxicillin. The binding of
clavulanic acid to HSA was rather complicated compared to amoxicillin. A total of
seven types of adducts were identified when clavulanic acid was incubated with
HSA at high concentration in vitro, including that formed by direct binding of
clavulanic acid to lysine residues, novel pyrazine adducts derived from binding to
the degradation products of clavulanic acid, and a cross-linking adduct.
Importantly, stable adducts derived from formylacetic acid and pyrazine were
also detected in all patients.
Conclusion
The finding of distinct novel types of AC haptens formed in patient is vital for
further exploration of the immunological consequences to define the mechanisms
of drug hypersensitivity exemplified by AC.
P185 Dendrimeric Antigens For Studying The Influence Of Penicillin
Determinants Orientation On IgE Recognition
Maria Isabel Montañez1, Cristobalina Mayorga2, Francisco Najera3, Adriana
Ariza1, Tahia D Fernandez1, Maria Salas2, Angela Martin-Serrano1, Miguel Blanca2,
Ezequiel Perez-Inestrosa3, Maria Jose Torres2
1. Research Laboratory. IBIMA, Regional University Hospital of Malaga, UMA,
Malaga, Spain
2. Allergy Unit. IBIMA, Regional University Hospital of Malaga, UMA, Malaga,
Spain
3. Department of Organic Chemistry, University of Malaga, IBIMA, BIONAND,
Malaga, Spain
Keywords: Dendrimer, IgE, Penicillin
Introduction
Benzylpenicilloyl-dendrimer conjugates are recognized by IgE specific to BP
(benzylpenicillin). Dendrimers are monodisperse synthetic carriers, which
chemical structure can be perfectly characterized. Their use compared to the
conventional poly-L-lysine carrier improves the reproducibility and sensibility of
in vitro tests to diagnose allergy. Moreover, increasing understanding of the
immunological recognition of drug-carrier conjugates in vitro would help to
improve diagnostic tests. Herein we include other penicillin epitope, AX
(amoxicillin), and study Dendrimeric Antigen (DeAn) conjugates that contain two
types of epitopes, BP and AX, in the same carrier dendrimer molecule. We
hypothesize that the orientation and tridimensional disposition of the peripheral
epitopes in the DeAn may play key roles in the IgE recognition.
Method
Synthesis of DeAn conjugates was accomplished by reaction of generation 4
PAMAM (PolyAMidoAMine) dendrimers with either one kind of penicillin (BP or AX)
or both penicillins (BP and AX). Their chemical and tridimensional structures
were studied by mono- and bi-dimensional NMR (Nuclear Magnetic Resonance)
and MDS (Molecular Dynamic Simulation). The conjugates were immunologically
evaluated by RAST (Radio-Allergo-Sorbent-Test) inhibition using sera from 6
patients allergic to penicillins (selective and cross-reactive).
Results
Spatial conformation showed differences between benzylpenicilloyl, with a hidden
side chain, and amoxicilloyl, exposing the entire molecule outside the
dendrimeric skeleton. Concerning immunological assays, at the maximum
conjugate concentration, serum allergic to BP showed 80% of RAST inhibition to
both BP-DeAn and biepitope-DeAn, and negative to AX-DeAn. Sera allergic to AX
showed 90% of inhibition to both AX-DeAn and biepitope-DeAn, with no
inhibition to BP-DeAn. All sera with cross-reactivity to both penicillins inhibited
above 90% to both AX-DeAn and biepitope-DeAn and above 60% to BP-DeAn.
Conclusion
Experimental data show less recognition of benzylpenicilloyl compared to
amoxicilloyl units in those biepitope-DeAn, probably due to the different
accessibility of the side chain of both penicillins to IgE recognition. Therefore
there is a correlation between the tridimensional chemical structures of penicillin
epitopes and the way DeAn are recognized by sIgE. Moreover, the biepitope
DeAn conjugates could represent the basis of a novel method for screening a
wider proportion of allergic patients with a single test.
P186 Dendrimeric Antigens On Solid Supports: Designed Materials For
IgE Quantification.
Yolanda Vida1, Maria Isabel Montañez2, Noemi Molina1, Daniel Collado1,
Francisco Najera1, Adriana Ariza3, Maria Jose Torres4, Cristobalina Mayorga2,
Ezequiel Perez-Inestrosa1
1. Universidad de Malaga-IBIMA, Department of Organic Chemistry.
Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Malaga,
Spain
2. Research Laboratory Carlos Haya Hospital-IBIMA. Andalusian Centre for
Nanomedicine and Biotechnology-BIONAND, Malaga, Spain
3. Research Laboratory Carlos Haya Hospital-IBIMA., Malaga, Spain
4. Allergy Service, Carlos Haya Hospital, Malaga, Spain. Andalusian Centre
for Nanomedicine and Biotechnology-BIONAND, Malaga, Spain
Keywords: IgE Quantification, Dendrimers, Dendrimeric Antigens,
Introduction
Complex functional materials consisting of bioactive molecules immobilized on
solid supports present potential applications in biosensoring. Advances in the
fabrication of these surface materials are of growing interests in antibody-based
diagnostic. We describe recent progress in the preparation of new materials for
biosensor applications where Dendrimeric Antigens (DeAn), synthetic antigens
where the role of the carrier protein is performed by a dendrimer, were
supported on silica particles to assemble DeAn@SiO2 composites. DeAn@SiO2
containing the allergenic determinant to amoxicillin (AXO) has been studied for
quantifying IgE specific to Amoxicillin.
Method
We report on the use of silica particles as a solid support for RAST (RadioAllergo-Sorbent-Test) with a view to its use as a complementary diagnostic
method for identifying allergic responses to penicillin. We prepared
nanoconjugated Dendrimeric Antigens (DeAn) consisting of second-generation
PAMAM dendrimers (PAMAM-G2) peripherally decorated with the suspected
amoxicillin hapten (AXO). These organic-inorganic hybrid materials were
carefully characterized and the preparation methodology was checked to be
highly reproducible. To study the potential of those composites in the detection
and quantification of antibodies, they were clinically tested by RAST using sera
from allergic patients and control individuals tolerant to this drug, according to
conventional protocols applied in the clinical practice.
Results
: 0.4 mg of DeAn@SiO2 composites were used in each assay, producing positive
RAST results (7%) in sera from three allergic patients. No signal was obtained in
the RAST on two control individuals (even though being one of them with
diagnosed immediate allergic reaction to benzylpenicillin), ensuring a high
specificity in the detection of antibodies. Additionally, larger amounts of
composites (1 and 1.6 mg) were used in the assays, increasing the RAST level
for patients allergic (14% and 18% respectively), which successfully improves
the sensitivity of the test. The percentage of RAST obtained with the control gave
negatives values, maintaining the specificity of the test.
Conclusion
DeAn@SiO2 composites, containing the allergenic determinant to AXO, proved
effective in detecting and quantifying IgE in sera from patients allergic to
amoxicillin, in a specific and selective way. This new material is thus promising
candidate for improving in vitro clinical diagnostic practice.
P187 Development Of A Screening Assay For Drug Hypersensitivity Using
Naïve T Cells From Donors With Seven Different HLA Class I Risk Alleles.
Lee Faulkner, Sally Wood, Ana Alfirevic, Munir Pirmohamed, Dean J Naisbitt, B
Kevin Park
University of Liverpool, Liverpool, United Kingdom
Introduction
A small proportion of adverse drug reactions (ADRs) are due to drug
hypersensitivity where the immune response causes an unexpected and
sometimes severe clinical reaction. Genome-wide screens have identified many
different genetic associations between drugs and ADRs. Of particular interest to
hypersensitivity reactions are the HLA Class I and Class II risk alleles. Not all
individuals with a HLA risk allele will develop hypersensitivity. Thus, the
frequency/severity of a reaction is a function of the chemistry of the drug, the
biology of the immune system, the genotype of the individual and the underlying
medical condition.
Drug hypersensitivity reactions are rare and are rarely detected during clinical
trials. It is only once the drug is widely prescribed that these reactions become
apparent. Since hypersensitivity reactions that target skin and liver are a major
cause of drug withdrawal from the market, there is a need to develop a
screening assay which could potentially detect these reactions during drug
development.
Method
We have established a biobank of lymphocytes isolated from 1000 HLA-typed
volunteers and have developed a DC priming assay which can prime naïve T cells
to various drugs. The current form of the DC assay is labour intensive, requires
large numbers of cells, uses different plate formats, has multiple readouts and
takes 3-4 weeks to run. The aim is to modify this into a screening assay using a
single plate with a single readout. We have selected up to 5 donors expressing
seven different HLA Class I risk alleles: A*3101, A*3303, A*6801, B*1301,
B*1502, B*5701 and B*5801. Ten donors without the HLA risk alleles will be
included as negative controls and a unique donor exposed to nitrososulfamethoxazole (SMX-NO) will be used as a positive control.
Results
Initial development has concentrated on using the SMX-NO and 2 β-lactam
antibiotics as positive controls to optimise the assay conditions, to assess the
frequency of T-cell responses and to measure the strength of the response
induced. Early results show that proliferative responses to SMX-NO have been
detected in the screening assay at a similar intensity to that detected in the
existing form of the assay. Further work will concentrate on reproducibility and
inter-donor variation.
Conclusion
Once established, the screening assay will be used to investigate responses to
ticlopidine, dapsone, carbamazepine, flucloxacillin allopurinol and abacavir.
P188 Different Patterns Of Recognition Of Structures Derived From
Amoxicillin By IgE Antibodies From Patients With Immediate
Hypersensitivity Reactions To Betalactams
Adriana Ariza1, Cristobalina Mayorga1, María Isabel Montañez2, María Salas3,
Inmaculada Doña3, Ángela Martín-Serrano2, Ezequiel Pérez-Inestrosa4, Dolores
Pérez-Sala5, Miguel Blanca3, Antonio E Guzmán6, María José Torres3, María José
Torres3
1. Research Laboratory, IBIMA – Regional University Hospital of Malaga –
University of Malaga, Málaga, Spain
2. Research Laboratory, IBIMA – Regional University Hospital of Malaga –
University of Malaga; BIONAND, Málaga, Spain
3. Allergy Unit, IBIMA – Regional University Hospital of Malaga – University of
Malaga, Málaga, Spain
4. Department of Organic Chemistry, IBIMA – University of Malaga;
BIONAND, Málaga, Spain
5. Department of Chemical and Physical Biology, Centro de Investigaciones
Biológicas, Madrid, Spain
6. Pharmacy Unit, Regional University Hospital of Malaga, Málaga, Spain
Keywords: Amoxicillin, IgE, Carrier Molecule, Hypersensitivity
Introduction
Amoxicillin (AX) is the most frequent antibiotic elicitor of allergic reactions to
drugs. It is widely accepted the requirement of the binding of the AX to a carrier
molecule for its optimal IgE recognition. Although the carrier molecule seems to
form part of the antigenic determinant, its contribution in the pattern of response
is not fully known. The aim of this work was to study the recognition of different
structures derived from AX by IgE antibodies from allergic patients to this drug.
Method
Patients (N=21) with an immediate allergic reaction to AX and
radioallergosorbent test (RAST) values >7% were included. The IgE recognition
study was performed by RAST inhibition using on the solid phase AX bound to
poly-L-lysine and in the fluid phase the following inhibitors: AX, amoxicilloic acid,
AX bound to butylamine (AXO-BA) and to human serum albumin (AXO-HSA), and
fractions of different molecular weights of human serum modified with AX.
Results
Two well-defined patterns of recognition were observed: A group of patients in
whom AX itself was significantly higher recognized (Group A, N=8) and another
group of patients who preferentially recognized AXO-BA and AXO-HSA (Group B,
N=13). No significant differences were observed for amoxicilloic acid, being
significantly the lowest recognized structure in both groups. Regarding the
pattern of recognition of different fractions from AX-modified human sera, groups
A and B showed differences, with a higher recognition of the lowest molecular
weight fraction (<3 kDa) in Group A and no differential recognition in Group B.
Interestingly, all patients classified as Group A had selective allergic reactions to
AX, and all those in Group B had cross-reactive reactions.
Conclusion
Although both AX derivatives and carrier molecules are important for the IgE
recognition, differences exist between patients with a selective or a crossreacting response. In selective patients, it is necessary that the side chain of the
AX was preserved in the AX-carrier adducts and exposed to the IgE, and this fact
is influenced by the conditions in the formation of adducts. However, for crossreactive patients, whose IgE antibodies recognize the AX side chain and part of
the common structure of penicillins, the conditions for the generation of AXcarrier adducts seem not to be relevant for their recognition. The poor
recognition of the amoxicilloic acid reinforces the need for binding the AX to a
carrier molecule for an optimal recognition.
P189 High-Resolution Typing Of HLA Polymorphism And T-Cell Receptor
Repertoire For Severe Adverse Drug Reactions Based On The CostEffective Next-Generation Sequencing Approaches
Tai-Ming Ko, Yuan-Tsong Chen, Jer-Yuarn Wu
Academia Sinica, Taipei, Taiwan
Introduction
Immune-related severe adverse drug reaction (ADR) is widely hypothesised
triggered by the combination of HLA, drugs, peptides, and T-cell receptor (TCR)
molecules. Currently, numerous types of severe ADRs are reported to be related
to particular HLA polymorphisms, such as HLA-B*15:02 allele associated with
carbamazepine-induced Steven’s Johnson syndrome (SJS) and HLA-B*58:01
allele associated with allopurinol-induced severe cutaneous adverse reactions
(SCARs). The use of TCR by drug-specific T cells is also considered a co-factor
responsible for severe ADR. The major challenges of using Sanger sequencing,
for high-throughput typing of HLA and TCR gene in large cohort studies, is the
high cost involved. Moreover, it is unknown whether CBZ-SJS or allopurinolSCARs is linked to more specified HLA types. Our aim was to identify which
specified HLA types and TCR profiling correlated with CBZ-SJS or allopurinolSCARs based on using cost-effective next-generation sequencing approaches.
Method
We enrolled patients with CBZ-SJS, CBZ-tolerant subjects, patients with
allopurinol-SCARs, allopurinol-tolerant subjects, and healthy controls. For HLA
typing, we developed an analysis pipeline for illumina Miseq or PacBio sequencing
platform. For TCR typing, a widely used primer set was used and an analysis
pipeline for illumina Miseq or Hiseq sequencing platform was developed. Sanger
sequencing for the validation of HLA and TCR was performed.
Results
We genotyped all major HLA regions, including HLA-A, HLA-B, HLA-C, HLA-DPB1,
HLA-DQB1, and HLA-DRB1, in all the subjects. Compared with sequence-based
typing ($400 per sample) for HLA typing, the cost based on next-generation
sequencing ($240 per sample) was reduced. CBZ-SJS patients or allopurinolSCAR patients were HLA-B*15:02:01-positive or HLA-B*58:01:01-positive,
respectively. For TCR, we genotyped all the V beta subfamilies. Dominant CDR3
sequences were verified by Sanger sequencing. Compared with Sanger
sequencing ($500 per sample), the cost based on next-generation sequencing
($50 per sample) was much lower. Additionally, novel TCR clonotypes, possibly
associated with SJS patients, were identified.
Conclusion
A cost-effective method for high-throughput and high-resolution typing of HLA
and TCR was developed. HLA-B*15:02:01 and HLA-B*58:01:01 were found as
more specified HLA genotypes for developing CBZ-SJS and allopurinol-SCARs,
respectively.
P190 Identification And Fate Of Intracellular Proteins Haptenated By
Amoxicillin
Francisco J. Sánchez-Gómez1, Juan M. González-Morena1, Yolanda Vida2,
Ezequiel Pérez-Inestrosa2, Miguel Blanca3, María J. Torres3, Dolores Pérez-Sala1
1. Department of Chemical and Physical Biology, Centro de Investigaciones
Biológicas-CSIC, Madrid, Spain
2. Department of Organic Chemistry, University of Málaga, Málaga, Spain
3. Allergy Unit, IBIMA-Regional Hospital of Málaga, Málaga, Spain
Keywords: Allergy, Amoxicillin, Haptenation, Exosomes, Intercellular
Communication
Introduction
The common use of beta-lactams during the last decades is leading to an
increase in the prevalence of allergic responses. In the allergic response, the
adduct formation between small drugs and proteins, called haptenation, allows
drugs to be recognized as antigens by the immune system. Moreover, it has
been hypothesized that structures from target proteins can also contribute to the
formation of the antigenic determinants. Identification of protein targets for
haptenation is relevant for their potential use in novel diagnostic tools as well as
for understanding the complete mechanisms involved in antigen presentation and
the role played by the cells that participate in allergy induction. In recent years
our lab has undertaken the identification of targets proteins for the haptenation
by beta-lactams.
Method
We have attempted the identification of protein targets for covalent modification
by amoxicillin (AX) and a biotinylated analogue (AX-B) as model compounds. To
accomplish these aims, we decided to use a B-lymphocyte cell line as cellular
model. The identification of the proteins haptenated by AX and AX-B has been
approached with mass spectrometry experiments. In addition, intercellular
communication mediated by vesicular delivery of molecular messages has been
explored by microscopy techniques.
Results
In our experiments we have observed a complex pattern of proteins modified by
amoxicillin. Among them, we have isolated and identified several novel targets
for haptenation by AX in B-lymphocytes. In addition, these haptenated proteins
have been observed both intracellularly and in the conditioned medium, where
they were found both in soluble and vesicular fractions.
Conclusion
Our results indicate that intracellular proteins may be haptenated by beta-lactam
antibiotics and reach the extracellular medium. The importance of these targets
in the development of allergic reactions will be the subject of further
investigations.
Funding: MINECOSAF2012-36519; ISCIII RD12/0013/0008
P191 In Vitro Detection Of Terbinafine Protein Adducts.
Arun Tailor, Toru Usui, Yanni Xue, Xiaoli Meng, Dean J Naisbitt, B Kevin Park
University of Liverpool, Liverpool, United Kingdom
Introduction
Idiosyncratic drug induced liver injury (iDILI) is a severe adverse reaction which
manifests in some, but not all drug recipients. The incidence of these reactions is
so low that these adverse events cannot be attributed to the normal
pharmacological action of a drug, but are probably due to the individual biology
of a patient. To support this claim, an increasing number of genetic associations
have been found in cases of iDILI, and many of these are with HLA alleles. This
indicates that iDILI may have an immunological aetiology and there is increasing
evidence to support this. For example: the detection of T-cells in liver biopsies
from iDILI patients and the isolation of drug specific T-cells in patients suffering
from flucloxacillin and co-amoxiclav induced liver injury. This sets a precedence
to investigate other iDILI drugs such as terbinafine in the context of drug
hypersensitivity reactions. Terbinafine can form a chemically reactive metabolite
and like β-lactam antibiotics, may form drug-protein haptens to activate an
immune response. Although the hapten model for drug hypersensitivity is well
established, the precise nature of the drug antigen is unclear. The aim of this
study is to investigate the formation of terbinafine adducts using a chemically
reactive metabolite of terbinafine: allylic aldehyde, 7,7-dimethylhept-2-ene-4ynal (TBF-A).
Method
TBF-A was incubated for 24 hours at a 10:1 molar ratio for synthetic peptides
and a 1:1 ratio for other molecules. Mass spectrometric analysis was conducted
using an API 4000 or an QTRAP 5500 hybrid quadrupole-linear ion trap mass
spectrometer (AB Sciex). Conjugates were detected using multiple reaction
monitoring and also enhanced product ion scanning methods
Results
TBF-A showed binding to N-acetyl cysteine and glutathione but not to N-acetyl
lysine. Additionally, TBF-A was shown to bind covalently to glutathione stransferase pi. Following incubation with human serum albumin, no conjugates
were detected. Synthetic cysteine containing peptides were also generated and
shown to bind TBF-A.
Conclusion
TBF-A binds to cysteine residues in small molecules, larger proteins and also in
synthetic peptides. Thus, we are now conducting additional studies to isolate
TBF-A specific T-cells in order to investigate whether formation of this metabolite
is important for the activation of the adaptive immune system in patients with
iDILI.
P192 MicroRNAs Dysregulation In PBMCs From Drug Hypersensitivity
Patients During Drug Challenge In Vitro.
Alejandra Monroy Arreola1, Jesus Agustin Badillo Corona1, Silvia Mendez
Flores2, Judith Dominguez Cherit2, Dean J Naisbitt3, Noe Valentin Duran
Figueroa1, Jose Luis Castrejon Flores1
1. Instituto Politecnico Nacional, Mexico, Mexico
2. Instituto Nacional de Ciencias Medicas y Nutricion, Mexico, Mexico
3. University of Liverpool, Liverpool, United Kingdom
Keywords: MicroRNAs, Drug Hypersensitivity, Mechanisms.
Introduction
Drug hypersensitivity reactions account for approximately 15% of all adverse
drug reactions, where the skin is the main organ affected generating an
important health problem. During the last twenty years, we have gained insight
in to the immunological mechanism(s) behind different forms of cutaneous
hypersensitivity, but our knowledge of post-transcriptional immune regulators
remains poorly understood. MicroRNAs (miRNAs) play a key role in several
immunological processes and in the pathogenesis of several diseases including
severe skin conditions; nonetheless, their cellular origin and the changes in the
expression as a result of drug exposure needs to be further investigated.
Method
Two allergic patients to sulfamethoxazole (SMX1 & SMX2) and one allergic
patient to levofloxacin (LFV1) were enrolled in the study. Approval for the study
was obtained from local research ethics committee, and informed written consent
was obtained from each donor. The presence of drug specific T-cells was
determined by LTT. Additionally, PMBCs (1.5x105 cells/mL) from each patient
were incubated by triplicate in cell culture alone or in the presence of the culprit
drugs at different concentrations. The change in the pattern of expression of the
miRNAs was compare between drug free cells and drug incubated cells at 0, 12,
24 & 48 h by RT-PCR using commercial specific probes for miR-18a, -21, -142 &
-155. The U6 gene was used as reference, and the relative expression was
calculated using the delta Cq method.
Results
Positive stimulation indexes were obtained from the three patients at different
concentrations. Moreover, a significant increase in the expression of miR-18a, 21, -142 & -155 was detected after 12-48 h in the PBMCs of all the patients.
Quantitative relative expression of the different miRNAs showed a fold change
between 2 to 100 during the incubation time when compared with cells without
drug. When a different drug, not related with the reaction, was used, the change
in the pattern of expression was reduced or similar to basal levels.
Conclusion
Our findings clearly show that the incubation of the culprit drugs with PBMCs
from hypersensitive patients modify the expression of miRNAs in a dose and time
dependent manner. At the presence, we are evaluating the change in the pattern
of expression of miRNAs in PBMCs of hypersensitive patients caused by
anticonvulsants and in patients with severe cutaneous reactions.
Table 1. Clinical information and functional assays results from three
hypersensivity patients to antibiotics.
Lymphocyte
Patient
transformation
Change in the pattern of
information.
test
expresion of miRNAs with drugs.
Skin
Drug
Relative
Code SexAge
S.I. / Drug [ug/mL] miRNA
Time
reaction
[ug/mL]
Expression
142
SMX [400] 153 ± 28
12 h
SMX-NO
5.0 / SMX [200]
18a
71.6 ± 1.21 24 h
SMX1F 60 MPE
[12]
5.2 / SMX-NO [20]
SMX-NO
155
5.6 ± 1.1
24 h
[12]
18a
SMX [400] 2.5 ± 0.6
24 h
2.0 / SMX [400]
SMX-NO
SMX2M 35 MPE
21
6.3 ± 3.2
24 h
3.0 / SMX-NO [20]
[12]
142
SMX [400] 3.9 ± 0.7
24 h
142
LVF [10]
12.2 ± 0.9 24 h
LVF1 M 47 MPE
2.0 / LVF [10]
18a
LVF [10]
4.0 ± 0.4
48 h
155
LVF [10]
5.1 ± 1.1 48 h
SMX, Sulfamethoxazole; SMX-NO, Sulfamethoxazole Nitroso; LVF, Levofloxacin;
MPE, Maculopapular Exanthema. Relative expression results are presented as the
Mean ± S.D. obtained by the delta Cq method.
P193 NSAIDs-Exacerbated Cutaneous Disease: High Throughput Gene
Expression Profiling
José Antonio Cornejo-García1, James Perkins2, Natalia Blanca-López3, Diana
Pérez-Alzate3, Raquel Jurado-Escobar2, Inmaculada Doña4, Gador Bogas4, María J
Torres4, Gabriela Canto3, Miguel Blanca4
1. Research Laboratory and Allergy Unit, IBIMA, Regional University Hospital
of Malaga, UMA, Malaga, Spain
2. Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA,
Malaga, Spain
3. Allergy Service, Infanta Leonor University Hospital, Madrid, Spain
4. Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga,
Spain
Keywords: Drug Hypersensitivity, NSAIDs, NECD, Gene Expression
Introduction
Some patients with a history of chronic spontaneous urticaria may suffer from an
exacerbation of this pathology after aspirin and other non-steroidal antiinflammatory drugs (NSAIDs) intake, a condition termed NSAIDs-exacerbated
cutaneous disease (NECD). In addition to the participation of COX-1 inhibition
the underlying mechanism may be influenced by differential gene expression. To
assess the genetic mechanisms potentially implicated in NECD we analysed gene
expression patterns using microarrays technology.
Method
Total RNA was obtained during the acute phase from skin biopsies in 3 patients
with NECD, and 14 heathy controls. After quality control evaluation, gene
expression patterns were compared through the GeneChip Human Gene 2.0 ST
microarrays system (Affymetrix).
echanism may be influenced by differential gene expression. To assess the
genetic mechanisms potentially implicated in NECD we analysed gene expression
patterns using microarrays technology.
Results
We found 163 differentially expressed transcripts in NECD patients from a total of
48227 analysed (FDR p value <0.05, and a log fold change >1 or < 1). Top
upregulated transcripts were related to the structural integrity of epithelial cells
(KRT16, KRT17), the HLA system (HLA-DQB1) and microRNAs (MIR4427). Some
downregulated transcripts were also related to microRNAs (MIR3127) and
microRNA-mediated gene repression (DND1), adhesion and migration of
epithelial cells (POSTN), transcription factors (ZNF667), and collagen integrity
(COL6A5).
Conclusion
We described a differential expression pattern in NECD suggesting intricate
interactions in gene regulation affecting skin structural integrity, cell adhesion
and migration, and the HLA system. Our results shed new light for understanding
the mechanisms underlying this entity.:normal'>KRT16, KRT17), the HLA system
(HLA-DQB1) and microRNAs (MIR4427). Some downregulated transcripts were
also related to microRNAs (MIR3127) and microRNA-mediated gene repression
(DND1), adhesion and migration of epithelial cells (POSTN), transcription factors
(ZNF667), and collagen integrity (COL6A5).
P194 Utility Of Skin Tests In Non-Immediate Reactions To Amoxicillin
Luis Mario Tubella Marti1, Fernando Pineda De La Losa2, Francisca Arribas
Poves2, Jaime Tubella Lopez1, Teodora Lopez Santiago1
1. Alergology Service. Hospital Delfos., Barcelona, Spain
2. DIATER Laboratorios, Madrid, Spain
Keywords: Diagnostic, Skin Test, Amoxicillin, Non-Immediated
Introduction
Allergy to beta-lactam antibiotics, specifically penicillins, is presented differently
depending on the time spent from administration of the drug until the reaction.
Thus we can classify these manifestations as immediate, accelerated or delayed,
or simply as immediate or not immediate.
Method
Patient who comes to be attended after having suffered 2 episodes of RAM after
taking amoxicillin. Both episodes coursed with generalized skin rash, eight days
after taking amoxicillin 500 per a picture of tonsillitis and the second 5 days after
taking amoxicillin 500 per a tooth extraction. On both occasions the picture is
manifested after a latency period of 48-72 hours after the last intake.
Skin tests with amoxicillin (DAP DIATER kit) by prick test and ID to 1:10 and 1:
100 and undiluted. Oral challenge test against Cefuroxime increasing doses up to
the maximum cumulative dose of 500 mg.
RAST tests against penicilloyl G and V, ampicillin, amoxicillin and cefaclor
Results
The skin tests were positive for amoxicillin ID undiluted, 1:10 and 1: 100 at 72
hours. The oral food challenge to cefuroxime at the doses administered was
negative. RAST tests against penicilloyl G and V, Ampicillin, Amoxicillin and
negative cefaclor.
Conclusion
We report a case of delayed reaction to amoxicillin with tolerance to cefuroxime,
where the history and skin tests were essential in the diagnosing of this case.