Download Clinical management of secondary antibody deficiency (SAD)

Clinical management of secondary
antibody deficiency (SAD)
Sinisa Savic
Consultant clinical immunologist
Conflict of interest
• Research grants from BPL, Biotest, Baxter
• Advisory board: Biotest
• Travel grant: CSL Behring
Overview of the talk
• Causes
• Selection criteria
• Immunoglobulin replacement strategy
• Practical matters
• How to improve recognition and Rx of SAD
• Concluding remarks
Causes of SAD
• Malignancy: Haematological >>>others
• Chronic infections
• Drugs
• Protein-losing states, eg nephrotic syndrome
• Systemic inflammatory diseases
• Trauma
-IgG levelsHow low can we go?
Factors to consider
• Isolated low IgG, panhypogamma or
generalised immunosuppression
• Underlying disease: severity and activity
• Comorbidities bronchiectasis, CVD
• Duration-temporary eg secondary to
treatment
EURO Lupus cohort
• 36% presented with infection F/U
• 30% of deaths related to infection
Emery et al, Association between disease activity and risk of serious infection in subjects
with RA treated with etanercept or DMARDS’s 2014, accepted for publication CLL
• Infection cause of death between 25-50%
• Hypogammaglobulinaemia present in up to 85% of patients
• Common pathogens:
– S. pneumoniae,
– Haemophilus influenzae
Hamblin AD, Hamblin TJ. The immunodeficiency of chronic lymphocytic leukaemia. Br Med Bull. 2008;87:49–62.
Hypogamma 2nd to drugs
Low IgG pre Rituximab-outcomes
10
IgG levles g/l
8
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
6
4
2
RA
6
CTD
0
Vas
0
no infections
2
2
3
Infections
5
6
5
Dead
0
Pre R
N 29
Post R1
Post R2
Post R3
Post R
IgM has a protective role against sinopulmonary infections-evidence form PID
CVID patients who lacked IgM memory B-cells and failed
to produce anti-PnPS IgM had greater incidence of
respiratory infections and bronchiectasis
Study of 473 patients -low baseline IgA, IgM, and IgG levels
all correlate independently with chronic lung disease.
Multicenter prospective study- 201 patients with CVID over a 5-year period.
Mean IgA and IgM levels were significantly lower in patients who had more
than 1 episode of pneumonia compared with patients with only 1 episode or
no pneumonias.
Anti-PS23 IgM and/or IgA antibodies were detectable in a minority of
CVID patients. Antibody responses were correlated to B cell
subpopulations and serum immunoglobulin concentrations. The non
responders had a higher incidence of pneumonia and bronchiectasis
and responders had the lowest incidence of respiratory complications
Frequency and type of infections?
Sinopulmonary infections and encapsulated bacteria
Typical pathogens in PAD:
• S. pneumoniae,
• Streptococcus pyogenes
• Haemophilus influenzae
• Staphylococcus areus
Poor record of infective episodes (many ‘minor’ chest infections treated in community)
Challenge vaccination
Areas of controversy
• Adequate vaccine response and protective
titers
– Total vs serotype specific measurement
– >0.35μg/ml, or >1.3 (>70% of serotypes tested)
• Different methodologies for measuring Sp Ab
•
•
1.3 cutoff-27%(D28) and 40% (1yr)
>0.35 cutoff- 4%
Flow cytometry and Luminex
• Prevaccination (5/10)
• Postvaccination (3/10)
• 86% agreement on SPAD
SPAD
• 43.7% ELISA (23v)
• 32.8% Multiplex (>0.35)
• 76.5% Multiplex >1.3
Other considerations
• HiB titers do not correlate to non-typeable
H.influenzae
• Protective effects from pneumovax minimal at
the best(1)
• Role for other vaccine challenges- S. typhi (2)
2
1
M.A. J. Westerink et al
Pneumococcal vaccines in adults and children
Volume 3, Number 1; 51-67, February 2012
Review
Immune Responses to pneumococcal vaccines in children
and adults: Rationale for age-specific vaccination
M.A. Julie Westerink1, Harry W. Schroeder, Jr.2, and Moon H. Nahm3*
1
University of Toledo, Department of Medicine, Division of Infectious Diseases, Department of
Medical Microbiology and Immunology and Department of Pathology,Toledo OH 43614, USA
University of Alabama at Birmingham, Department of Medicine, Division of Immunology and
Rheumatology, Birmingham, AL 35294, USA
3
University of Alabama at Birmingham, Department of Pathology, Division of Laboratory Medicine,
Birmingham, AL 35294, USA
2
[Received April 12, 2011; Revised July 19, 2011; Accepted July 19, 2011]
ABSTRACT: Streptococcus pneumoniae is a significant human pathogen and currently available
Consideration of dosage, interval and route of
administration of immunoglobulin
Dosage
• 0.4-0.6 g/kg/month aiming to keep IgG >6 g/l
• Higher doses might be necessary in patients
with bronchiectasis
• Ideal body weight as a guide to dose
Evidence
Khan S, Grimbacher B, Boecking C, et al.
Serum trough IgG level and annual
intravenous immunoglobulin dose are
not related to body size in patients on
regular replacement therapy. Drug
Metabolism Letters. 2011;5(2):132-6.
Route
• IV or SC
• Duration of treatment
• Volume
• Patient related factors
– Comorbidities
– Preferences
• Hospital resources
IVIG
ScIG
Vox Sanguinis (2013) 105, 54–64
ORIGINAL ARTICLE
© 2013 International Society of Blood Transfusion
DOI: 10.1111/vox.12025
Thromboembolic events associated with immunoglobulin
treatment
M. B. Funk,1 N. Gross,2 S. Gross,2 A. Hunfeld,3 A. Lohmann,1 S. Guenay,1 K. M. Hanschmann 4 & B. Keller- Stanislawski 1
1
Department
Department
Department
4
Department
2
3
of
of
of
of
Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut, Langen, Germany
Immunology, Paul-Ehrlich-Institut, Langen, Germany
Haematology/Transfusion Medicine, Paul-Ehrlich-Institut, Langen, Germany
Biostatistics, Paul-Ehrlich-Institut, Langen, Germany.
Objective Due to an increasing number of reported thromboembolic events (TEE)
after the administration of one intravenous immunoglobulin (IVIG) and one subcutaneous immunoglobulin (SCIG), pharmacovigilance and laboratory data were
collected to analyse the root cause and assess the reporting frequency of TEEs for
various IG products.
Methods Paul-Ehrlich-Institut retrospectively analysed 228 reports of TEEs associated with six different IG products and estimated annual TEE-reporting rates
based on worldwide sale fi gures over a period of 6 years (2006–2011). In addition, non-activated partial thromboplastin time (NAPTT) testing was performed to
capture pro-coagulant potential of six IG products (four IVIG and two SCIG).
Received: 10 July 2012,
revised 10 December 2012,
accepted 13 December 2012,
published online 9 February 2013
Results For three IVIGs, the drug-related TEE-reporting rates remained stable
from 2006 to 2011 (0–0 83 cases per 1000 kg IVIG distributed). In contrast, the
TEE rate of one IVIG increased signifi cantly from 0 33 cases in 2006 to nearly
nine cases in 2010 (P < 0 001).
The NAPTT testing of IG products with a low TEE rate revealed a NAPTT time
>200 s and a NAPTT ratio >0 8, whereas TEE-associated batches of IG products
with an increased TEE rate had a NAPTT ratio <0 8. After modifi cations of manufacturing processes, a normalization of NAPTT results and a decrease in TEE rates
could be demonstrated.
Key words: frequency, immunoglobulin – severity, IVIG – corrective actions,
NAPTT, pharmacovigilance, Thromboembolic events.
Introduction
There is clinical evidence of an association between intravenous administration of immunoglobulin (IVIG) and thromboembolic events (TEEs) such as myocardial infarction,
stroke, pulmonary embolism and deep vein thrombosis,
which is assumed to be related to the relative increase in
blood viscosity through the high infl ux of IG in at-risk
patients [1]. An increased risk was found in patients with
pre-existing risk factors for thrombotic events such as
Correspondence: Markus B. Funk, Paul-Ehrlich-Institut, Division: Safety
of Medicinal Products and Medical Devices, Paul-Ehrlich-StraÔe 51-59,
63225 Langen, Germany
E-mail: [email protected]
54
advanced age, hypertension, diabetes mellitus, obesity
and a history of vascular diseases and thrombotic
episodes. The summary of product characteristics (core
SPC) also emphasized that thromboembolic reactions are
very rare undesirable effects [1].
In 2010, the Paul-Ehrlich-Institut (PEI) as the national
competent authority suspended the marketing authorization of an intravenous immunoglobulin (IVIG) Octagam,
which subsequently was also suspended by the European
Commission due to an unexpected high number of
reported TEEs and evidence of presence of pro-coagulant
activity [2] in certain batches. In 2011, cases of thromboembolic events, including strokes and pulmonary embolism were notifi ed to the PEI following treatment with a
subcutaneous immunoglobulin, (SCIG) Vivaglobin.
Monitoring
General considerations
• IgG trough levels
• Infection frequency
• 6-12 months assessment
• If trial of therapy- period of treatment
At diagnosis of SAD
J Clin Immunol
DOI 10.1007/s10875-014-9995-5
ASTUTE CLINICIAN REPORT
Antibody Deficiency Secondary to Chronic Lymphocytic
L eukemia: Should Patients be Treated with Prophylactic
Replacement I mmunoglobulin?
Fatima Dhalla &M ar y L ucas &Anna Schuh &
M alini Bhole &Rashmi Jain &Smita Y. Patel &
Sir aj M isbah &Helen Chapel
What is evidence for use of IVIG in
secondary antibody deficiencies?
Total :5119
SAD: 77 (1.5%)
No data on SAD
Total :6735
SAD: 430 (6.3%)
No specific information on the type or cause of SAD
2013-July
SAD:539
Leuk Lymphoma. 2009 May;50(5):764-72
Immunoglobulin prophylaxis in chronic lymphocytic
leukemia and multiple myeloma: systematic review and
meta-analysis.
Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O.
Conclusion made on:
• 1st randomized trial
• Prior to introduction of com Rx
• Different selection criteria
• Different costs
Commissioning
Figure 2.1.1 Change to the approval process
Red
Priority – High
Blue
Priority – Medium
Grey
Priority – Low
Black
Clinician completes immunoglobulin request form
Immunoglobulin Assessment Panel (IAP) review
signed off by Trust immunoglobulin designated person
Automatic IAP
approval
retrospective sign off by
Trust immunoglobulin
designated person
approved
by IAP
approved
by IAP
not approved
by IAP
Individual funding
request process
All applications for immunoglobulin to be registered on the immunoglobulin database (accepted or declined)
approved
Immunoglobulin given and release of funding
2.1.1 Change to the approval process in 2013
The resulting change to the approval process (Figure
not approved
Immunoglobulin not given/funding not approved
2.2 Commissioner’s Database
Information Service
Figure 2.4.1 The Immunoglobulin Key Performance Indicators Dashboar d
Prepared by Methods Insight Analytics for NHS England
Immunoglobulin Specialised Service Quality Dashboard
Winter 2013/14
S pine Charts
LEEDS TEACHING HOSPITALS NHS TRUST
Dom
Thm Quarterly Indicators (Q3 1314)
2
CO IVG06
Proportion of patients who are receiving immunoglobulin for a
grey/black indication who have outcomes entered on the national
database
5
CO IVG09
Rate of adverse events documented on the national database
4
CP IVG10
3
CO IVG11
2
CP IVG12
Rate of patients receiving immunoglobulin for designated short term
conditions who are re-registered on the national database
Rate of patients receiving immunoglobulin for designated short term
red/blue indication who have outcomes reported on the national
database
Patients receiving immunoglobulin for designated grey and grey unlisted
indications who have been reviewed and approved by a
multidisciplanary panel before commencing on immunoglobulin therapy
Rolling Year Indicators (RY Q3 1314)
Proportion of patients who are on long term immunoglobulin therapy for
PID who have 6 monthly trough immunoglobulin levels measured
IVG01
2
CP
5
CP IVG03
5
CP IVG04
5
CP IVG05
2
CP IVG07
2
CP IVG13
2
CP IVG15
Lower Limit
3SD 2SD
Acute
Trust
Value
Upper Limit
2SD 3SD
National
Mean
Num
Denom
Value
National
Mean
<5
<5
100.0%
38.5%
<5
<5
0.1%
0.5%
<5
<5
0.0%
4.3%
18
23
78.3%
45.5%
<5
<5
100.0%
100.0%
Num
Denom
Value
National
Mean
54
111
48.6%
73.4%
105
105
100.0%
83.3%
52
52
100.0%
81.3%
111
111
100.0%
102.9%
84
235
35.7%
29.7%
Rate of patients on long term immunoglobulin therapy for a neurological
condition who have oBjective measures of improvement documented
<5
<5
16.1%
35.3%
Rate of patients who are on immunoglobulin for a long term condition
who receive an annual review and a letter is sent to the GP
76
76
100.0%
96.9%
Proportion of patients receiving immunoglobulin for PID who are treated
via homecare
Proportion of patients receiving immunoglobulin for PID who are
receiving treatment at home who have received training from an
accredited home therapy centre
Proportion of patients receiving immunoglobulin who are entered on the
national database
Number of patients who are receiving immunoglobulin for a long term
condition who have documented evidence of dose reduction and/or
increased dosing interval
Trust Comments
IVG01 Figure from IVIG database. Higher percentage have had done and on results server but this data not easily accessible.
S PC Sparklines
Lower
3SD
Acute Trust
Value
National
Mean
Upper
3SD
Chart
Trend
Chart
Trend
Are we likely to see more cases of
secondary antibody deficiency
in the future?
Reduction in IgG serum levels post rituximab-RA
35
****
****
****
IgG levles g/l
**
*
**
16
Normal
range
6
5
N
517
379
261
167
103
59
17
Po
st
R
7
R
7
Pr
e
Po
st
R
6
R
6
Pr
e
Po
st
R
5
R
5
Pr
e
Po
st
R
4
R4
Pr
e
Po
st
R
3
R
3
Pr
e
Po
st
R
2
R
2
Pr
e
R
1
st
Po
Pr
e
R
1
0
Reduction in IgM serum levels post rituximab-RA
7
****
****
IgM levles g/l
****
****
***
*
2.5
Normal
range
0.6
N
517
379
261
167
103
59
17
7
R
Po
st
R
7
Pr
e
6
R
Po
st
R
6
Pr
e
5
R
Po
st
R
5
Pr
e
4
R
Po
st
R4
Pr
e
3
R
Po
st
R
3
Pr
e
2
R
Po
st
R
2
Pr
e
1
R
Po
st
Pr
e
R1
0
% of patients with reduced Ig’s following rituximab
80
70
60
RA
50
40
30
20
10
0
Pre Rx
C1
C2
C3
C4
C5
C6
C7
80
IgG
70
60
CTD
IgA
50
40
30
IgM
20
10
0
Pre Rx
C1
C2
C3
C4
C5
C6
100
80
Vasculitis
60
40
20
0
Pre-Rx
C1
C2
C3
C4
C5
Rate of infection post rituximab
60
50
40
30
20
10
0
Sinopulomonary
UTI
Other
Table 2 PI3K inhibitors in clinical trials
Drug
Target(s)
Tumors
Toxicities
Idelalisib (CAL-101)
p110-δ
Buparlisib (BKM-120)
p110-α,-β, -δ,-γ
CLL/SLL, iNHL,
MCL
breast, GBM, NSCLC
GDC-0941
p110-α,-β, -δ,-γ
pyrexia, nausea, decrease
appetite, fatigue
rash, hyperglycemia
diarrhea, anorexia
nausea, diarrhea, rash
vomiting, anorexia
PX-866
p110-α,-β, -δ,-γ
breast, NSCLC,
melanoma
endometrial,
pancreatic
ovarian, prostate,
GBM NSCLC
breast, NSCLC
Clinical
trials
III
References
[76,77,80,83,86,88-90]
IB/II
[103-109]
IB/II
[117-123]
fatigue, diarrhea
II
[126-129]
thromboembolism
GDC-0032
p110-α, -δ,-γ
diarrhea, hyperglycemia
I
[132]
fatigue, nausea, decreased
appetite
BAY 80-6946
p110-α,-β
NHL, esophageal, alopecia, dysgeusia anemia,
I
[135-137]
sarcoma pancreatic
mucositis
IPI-145
p110-δ,-γ
CLL/SLL, iNHL,
cytopenias liver enzyme
I
[138,139]
MCL
elevations
BEZ-235
p110-α,-β, -δ,-γ/mTOR
breast, GBM
mucositis
IB/II
[149-152]
BYL-719
p110-α
breast, cervical,
nausea, diarrhea
IB/II
[153-155]
endometrial ovarian,
hyperglycemia,vomiting
H&N
BGT-226
p110-α,-β, -δ,-γ/mTOR
solid tumors, breast nausea, vomiting diarrhea
I/II
[156]
PF-04691502
p110-α,-β, -δ,-γ/mTOR
endometrial
fatigue, nausea, vomiting
II
[162]
decreased appetite, rash
GDC-0980
p110-α,-β, -δ,-γ/mTOR
prostate
hyperglycemia, rash
IB/II
[167,168]
mucositis
GSK-2126458
p110-α,-β, -δ,-γ/mTOR
RCC, bladder
nausea, vomiting diarrhea
I
[169,170]
PF-05212384
p110-α,-γ/mTOR
solid tumor, CRC
rash, mucositis
II
[172]
transaminitis,
hyperglycemia
XL-765
p110-α,-β, -δ,-γ/mTOR
NSCLC, gliomas
nausea, diarrhea elevated
IB/II
[176-178]
liver enzymes
XL-147
p110-α,-β, -δ,-γ
solid tumor, GBM
nausea, vomiting diarrhea
I/II
[180-183]
Abbreviations: CLL/SLL chronic lymphocytic leukemia/small lymphocytic leukemia; CRC colorectal cancer; GBM
glioblastoma multiforme; H&N head and neck cancer; iNHL indolent non-Hodgkin’s lymphoma; MCL mantle cell lymphoma;
NHL non-Hodgkin’s lymphoma; NSCLC non-small cell lung cancer; RCC renal cell cancer.
Idelalisib (CAL-101, GS-1101)
Idelalisib (formerly CAL-101, GS-1101) is an oral, first-in-class, highly selective inhibitor of
How to improve management of SAD
• Improved recognition
– Patient infection/vaccination passport
– Improved testing of immune function
• Prospective studies of IgG replacement
• Better documentation of outcomes