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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 1. Carbone J Adverse reactions and pathogen safety of intravenous immunoglobulin, Current Drug Safety 2007;2:9-18. 2. Čižnár P, Smutková M Prvé skúsenosti s domácou liečbou subkutánnymi imunoglobulínmi, Pediatria pre prax 2011;12(6):254-256. 3. Dashti-Khavidaki et al. Adverse reactions of prophylactic intravenous immunoglobulin; a 13-year experience with 3004 infusions in Iranian patients with primary immunodeficiency diseases, J Investig Allergol Clin Immunol. 2009;19(2):139-145. 4. Eijkhout HW et al. Substitution therapy in immunodeficient patients with anti-IgA antibodies or severe adverse reactions to previous immunoglobulin therapy, The Journal of Medicine 2003;6:61. 5. Feldmeyer L et al. Not all intravenous immunoglobulin preparations are equally well tolerated, Acta Derm Venereo 2010;90:494-497. 6. Jolles S et al. New frontiers in subcutaneous immunoglobulin treatment, Biol Ther 2011;1(1):003. 7. Kirmse J Subcutaneous administration of immunoglobulin, Journal of Infusion Nursing 2006;29:15-20. 8. Kobrynski L Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases, Biologics: Targets and Therapy 2012;6:277-287. 9. Moore ML et al. Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century, Ann Allergy Asthma Immunol. 2008;101:114-121. 10. Orange JS et al. Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy, Clin Exp Immunol. 2012;169:172-181. 11. Palabrica Frances Rose R et al. Adverse events of intravenous immunoglobulin infusions: a ten-year retrospective study, Asia Pac Allergy 2013;3:249-256. 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