Download ¹ Analytical-Diagnostic Laboratory and Immuno-allergology

SUBCUTANEOUS REPLACEMENT IN SYSTEMIC
IMMUNOGLOBULIN ADVERSE REACTIONS
Eštóková T.¹, Čižnár P.², Kužmová A.¹, Mlčochová D.¹
¹ Analytical-Diagnostic Laboratory and Immuno-allergology Outpatient Clinic, Prešov
² Pediatric Department, Comenius University Medical School, Bratislava
Years 2006-2008
Headache, fatigue
Aseptic meningitis
Serum sickness
Nausea, vomiting
Acute renal failure
Hemolytic anemia
Myalgias, arthralgias
Stroke
Pulmonary edema
Urticaria, rash, itching
Myocardial infarction
Leukopenia
Low-grade fever, chills
Severe wheezing
Neutropenia
Wheezing, chest pain
Bronchospasm
Multi-organ failure
Low back pain
Collapse
Abdominal pain, cramps
Anaphylactic reactions
Flushing, malaise
Dizziness, anxiety
Muscle cramps
Tachycardia
Blood pressure changes
Mild reactions require the infusion to be slowed and antihistamines and non-steroidal
anti-inflammatory drugs (NSAIDs) to be administered.
Moderate reactions include mild reactions worsening and require the infusion to be discontinued and antihistamines and NSAIDs to be administered.
Severe reactions include moderate reaction persisting or becoming worse; and serious
and potentially fatal side-effects requiring the administration of epinephrine and further
medical attention (Table 1).
Associated factors with adverse reactions caused by IVIG
- first administration
- infection
- rate of infusion
- change in preparations
- delay since the last infusion
- anti-IgA antibodies
Case report
Following data consist of the first experiences of initiation of home-based treatment with
subcutaneous immunoglobulin (SCIG) with the patient diagnosed with primary variable
immunodeficiency (CVID). While treating this patient mild, moderate, but also severe
adverse reactions occurred after previous administration of different intravenous and even
intramuscular preparations, in the past personal history.
Medical history
- grandfather died in older age of lung cancer
- father died at the age of 55 years of myocardial infarction
- mother and brother are healthy
- after a tonsillectomy at the age of 5
- after an appendectomy at the age of 16
The patient was treated by pediatric allergist/immunologist for recurrent respiratory infections from 2000-2004. Laboratory tests confirmed antibody deficiency (IgG, IgA,
IgM), parameters innate and adaptive cellular immunity were in the physiologic range.
The treatment was initiated by intramuscular immunoglobulin therapy (IMIG) – Norga®
(Imuna, Czech Republic). During this treatment were intermittently observed mild and
moderate side effects – malaise, low grade fever, dizziness, headache. Once after IMIG
was administered, severe adverse reaction occurred, accompanied by chills and syncope,
therefore this treatment was discontinued.
Adverse reactions to previous immunoglobulin therapy
The patient (age 30) has been treated at our immuno-allergy outpatient clinic since 2005
with the diagnosis of hypogammaglobulinaemia (IgG, IgA, IgM) with normal B cell count,
with susp. CVID (common variable immunodeficiency).
With the repeated administration of intramuscular and intravenous immunoglobulins
(IVIG, IMIG) repeatedly occurred slightly minor or moderate side-effects as well as serious
]adverse reactions, which resulted in discontinuation of the replacement therapy
(see the following information below).
Year 2006
Pasteurised Human Immunoglobulin Grifols® 16% solution (Instituto Grifols, S.A., Barcelona, Spain): IMIG – malaise occurred in the evening, followed by fatigue, fever, back
pain; lasted 2 to 3 days after administration.
5,00
4,00
Years 2009-2010
IgG
3,00
Years 2010-2011
Octagam® (Octapharma, Vienna, Austria): IVIG – during the administration of IVIG
pruritus of the infusion site, dizziness, nausea, tingling legs occurred.
Igamplia® 160mg/ml (Instituto Grifols, S.A., Barcelona, Spain): IMIG – the day of application, and three following days cramps and tingling legs, swollen ankles and feet,
facial erythema and swelling, headache, and myalgias occurred.
2,00
IgM
1,00
VI.10
II.10
X.09
Figure 1 Serum IgG,
IgA, IgM concentrations
(during intermittent IVIG/ IMIG therapy)
October 2005 – June 2010
g/l
3,5
3
2,5
Switch to subcutaneous immunoglobulin administration
Discussion
month/year
2
The most often reasons for switching to SCIG are systemic side effects under IVIG, poor
venous access and comorbid conditions. In February 2012 the health condition of the patient worsened due to recurrent bacterial respiratory infections. There was a progressive
decrease of serum concentrations of immunoglobulins (IgG 2,1 g/l, IgM 0,25 g/l, IgA
0,23 g/l). After the patient had been clinically and laboratory diagnosed with CVID complicated by chronic sinusitis, other ways of substitution were considered, i.e., a switch to
subcutaneous immunoglobulin administration (SCIG).
Due to the previous history of severe life threatening reactions and after the consent,
patient was admited to the intensive care unit of the 1st Internal Department, University
Hospital Bratislava, for a subcutaneous immunoglobulin replacement trial. On the day
1 she successfully completed an application of 10 ml Gammanorm® 165 mg/ml SC in a
sequential mode (1.. 2.. 3 ml), followed by 20 and 30 ml subsequently on days 2 and 3.
No clinicaly relevant side effects were observed. After she completed a course of theoretical
and practical training for SCIG home application, she was released. From this time ahead
she continues to apply 30 ml of Gammanorm® 165 mg/ml in a weekly periods. Reference
values of IgG were achieved after 5 applications.
VI.09
II.09
X.08
VI.08
II.08
0,00
X.07
Kiovig® (Baxter AG, Volketswil, Switzerland): IVIG – at a dose of 5 grams fever and
dizziness occurred in the evening hours. With the increasing of a dose to 6,5 grams occurred sudden chills, chest tightness, headache, nausea, hypotension, tachycardia, low back
pain, myalgias, muscle cramps, peripheral coldness and cyanosis, thread pulse, anxiety –
anaphylactoid reaction with the necessity of administration of epinephrine, hydrocortisone
and antihistamines (emergency transport).
IgA
VI.07
Rare
6,00
II.07
Severe
g/l
X.06
Mild / Moderate
Due to the good tolerability of this treatment, higher doses were administered, treatment
was not discontinued and therefore we have achieved higher and steady states of IgG levels using a subcutaneously administered doses at weekly intervals (Figure 1, 2, 3).
VI.06
Table 1: Adverse reactions to IVIG therapy
Flebogamma®5% (Instituto Grifols, S.A., Barcelona, Spain): IVIG – right at the initiation of infusion, at a dose of 1,5 gram, occurred chills, abdominal pain, diarrhea, headache,
back pain, muscle pain, low-grade fever, malaise. Followed by the administration at a
dose of 5 grams occurred chills, tachycardia, facial flushing, wheezing. In the evening,
the patient was examined in the emergency room for repeated complications – chills, facial flushing, swelling of the lips, arm pain. Despite premedication and reduction of the
prescribed rate of infusion, adverse reactions occurred repeatedly with increasing doses
over 5 grams, therefore the treatment was irregular and later discontinued.
II.06
Replacement of immunoglobulin IgG is a standard therapy for patients with primary
immunodeficiency disease (PIDD) characterized by primary antibody deficiency (PAD).
Administering IVIG reduces the incidence and severity of infection, improves healthrelated quality of life, and significantly reduces morbidity and mortality in patients with
PIDD. Since IVIG is a biological product derived from blood products, there are some
adverse reactions associated with its regular administration. The reported incidence of
adverse reactions varies widely, from 1% to 40% depending on the study and immunoglobulin used. The most common adverse events are immediate-type reactions, occurring
within 48-72 hours after initiation of the infusion. These reactions were classified as mild,
moderate, and severe (Brennan et al.), and were defined as follows:
Results
X.05
Introduction
IgG
1,5
IgA
1
IgM
0,5
0
month/year
Figure 2 Serum IgG, IgA, IgM concentrations (without replacement therapy)
August 2010 - April 2012
g/l
12
10
8
IgG
6
IgA
4
IgM
2
0
month/year
Despite initial concerns about possible adverse reactions at home, either by the patient
or physician, we evaluate the first months of treatment to be highly positive. There are
several advantages of SCIG over IVIG. The patient is satisfied with the current treatment,
as an advantage she considers reducing the number of doctor’s office visits, less frequent
contact with the patients in healthcare facilities, reducing the frequency and rate of infections, fewer needs of antibiotics, fewer absences from work, and limitations in daily
activities (Table 2).
Figure 3 Serum IgG, IgA, IgM concentrations (during SCIG therapy)
July 2012 - July 2014
Conclusion
Advantages
Disadvantages
Effective infection prevention
Increased infusion frequency
Convenience of administering at home
Self-infusion requires a reliable patient
No need for intravenous access
Localized reactions
In summary, systemic reactions rates with SCIG are low and reportedly occur less frequently than with IVIG infusions. SCIG systemic reactions rates are reported as 0% to
5%, generally occurring in less than 1% infusions. SCIG provides greater ease, flexibility and convenience than IVIG because it can be administered according to the patient´s
schedule and can be infused at home, without requiring venous access. Studies have suggested similar efficacy with SCIG compared with IVIG in preventing infections in patients with PIDD. Compared with IM or IV formulations and administration, for selected
patients, SCIG is better tolerated, clinically efficacious, safe, less costly, and appreciated
by the patients. Our initial clinical experience also shows that patients with serious side
effects to previous immunoglobulin therapy can be safely treated with subcutaneous replacement therapy.
Fewer side effects compared with IVIG
High level of patient motivation required
References
Rare systemic reactions
Contraindicated for patients with bleeding
More stable IgG concentrations
disorders, thrombocytopenia, receiving
Patients able to infuse themselves
anticoagulation therapy, or with severe skin diseases
Table 2 Advantages and disadvantages of subcutaneous administration
Despite serious adverse reactions with previous administration of several types of immunoglobulins (IVIG, IMIG), there have not occurred any systemic adverse reactions with
the current treatment (SCIG), except for mild local side effects – pain, swelling and redness at the infusion sites lasting for the period of first two months (Table 3).
Table 3 Side effects of subcutaneous immunoglobulin
Most common
Less Common
Rare
Localized swelling
Headache
Anaphylaxis
Localized erythema
Dizziness
Severe systemic
Localized itching
Fatigue
Localized pain
Chills
or discomfort
Localized induration
Fever
Cold sweats
infections
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