Date Published: September 15, 2017
Publisher: BioMed Central
Author(s): Przemyslaw Zdziarski, Andrzej Gamian, Jacek Majda, Agnieszka Korzeniowska-Kowal.
Allergic, especially anaphylactic, reactions during immunoglobulin replacement therapy are rare, but their pathophysiology and classification remain ambiguous. Recent findings show positive results of skin tests with commercially available immunoglobulins, but target antigens and responsible compounds of the tested immunoglobulins have not been strictly identified.
Four adult patients with recently diagnosed common variable immunodeficiency qualified for standard subcutaneous immunoglobulin replacement therapy regimen. They had no history of receiving immunoglobulins, blood or blood product transfusions. Edema, confluent wheals and erythema were observed at the site of subcutaneous immunoglobulin infusion: typical early and late phase reaction. A transient increase in various passively transferred IgG and IgE antibodies was responsible for misleading positive outcome of the serological testing for active humoral response such as type I allergy, anti-Rh, isohemagglutinins and rheumatoid factor (RF). Although the clinical presentation was very unusual and severe, the retrospective analysis showed no isohemagglutinins, RF and IgE in the patients’ serum before but it was positive after the infusion (median IgE = 18 IU/ml, RF = 8 IU/ml). Type I allergic reaction (laryngeal edema, rhinoconjuctivitis) came out at +14 days of replacement therapy when the patient visited countryside. In the second patient anaphylactic reaction was observed 5 days after ScIg administration, and only when the patient consumed peanuts. Therefore, IgE concentration was measured retrospectively in a series of commercial preparations used in the initial subcutaneous immunoglobulin replacement therapy that caused the adverse event (AE) and it was determined between 138 and 232 IU/ml (kU/l), i.e. 690–2100 IU per g of protein. Specific IgE was within a wide range from 198 (mix of food) to 2809 kUA/l (mix of grass) but many of the tested allergen-specific IgE were class 2 or 3 (i.e. 0.71–17.5 kUA/l).
The case resembles passive cutaneous anaphylaxis and Prausnitz–Küstner reaction but clinical significance of the classical phenomena has not yet been described. This observation indicates that anaphylactic reactions during immunoglobulin replacement therapy may result from IgE or pathological IgG content. Such IgE presence was sporadically reported (34.5–105 IU/ml, i.e. 862.5–1450 IU/g of protein) in intravenous immunoglobulins that are used and monitored by healthcare professionals. In clinical practice the definition of adverse events is inadequate since individual batches of immunoglobulins come with different specificity therefore, they should be classified as transfusion products (not bioequivalents). Such new approach implies establishing (1) new control methods and strategies to ensure introduction of the safety regulations for subcutaneous home self-administration of immunoglobulins as well as (2) guidelines for the prevention of anaphylaxis in patients receiving immunoglobulins (for example peanut).
The choice of methods of drug production, their further purification, sterilization, distribution and storage are critical to pharmacovigilance. Immunoglobulin preparations are of a paramount importance to management of the primary humoral immunodeficiency. Subcutaneous immunoglobulin (ScIg) infusion as replacement therapy is frequently chosen for patients with primary antibody deficiencies (PAD). Although a routine immunoglobulin therapy involves intramuscular injections, it has nowadays been replaced by subcutaneous infusion. Commercially available immunoglobulin preparations contain IgG antibodies, pooled from >3000 donors, with heterogeneous specificity and physicochemical properties  as well as trace amounts of IgA, sometimes human albumin, but according to product specifications they should be free of IgM and IgE. Therefore, purification, standardization and quality control of the therapeutic antibodies are of a great importance.
Adult patients (aged 30–50 years) with diagnosed common variable immunodeficiency (CVID) according to ESID criteria and clinical characteristics  were referred for standard immunoglobulin replacement therapy. Due to professional activity (frequent traveling) or poor venous access, four of them were qualified for subcutaneous (ScIg) infusion (following recommendations in the product specification of Subcuvia®). They had no history of receiving immunoglobulins, blood or blood product transfusions. Neither hypersensitivity reactions nor allergy (especially to latex, amoxicillin, benzyl penicillin, grass pollens and peanuts) were observed in the natural history of the disease. Antibody of the IgE class was not detected even in patients with the giardiasis, that normally prompts a very high level of IgE in immunocompetent subjects . If IgE is shown to be absent in such cases, active IgE-mediated immune response and anaphylactic reactions can essentially be excluded. Three of the patients, before being diagnosed in our center with CVID, showed negative results for common allergens, when using skin prick test. Delayed hypersensitivity test with PPD was negative for all four patients. Patients received ScIg daily dose of 0.15 g/kg body weight (i.e. maximal daily dose of Subcuvia®), what corresponds to recommended dose of 400 mg/kg body weight per month according to the International Union of Immunological Societies Scientific Committee Guidelines, EMEA [7, 8] and to cumulative monthly dose in the order of 0.4–0.8 g/kg, as recommended in the product specification. Twelve minutes after the first ScIg injection (different batch of the product for each patient) edema, confluent wheal and erythema occurred (Fig. 1, top panel). The same reaction was observed in another area of the subcutaneous injection. A typical late phase reaction occurred 4–6 h later (Fig. 1, bottom panel, different batch of the product for each patient). One patient exhibited type I allergic reaction but 5 days after ScIg administration, rapid rhinoconjunctivitis and stridor (laryngeal edema) occurred after patient’s exposure to grass pollens (when patient visited countryside) (first representative patient after consent for SPT and further evaluation—Fig. 2a).Fig. 1Early (EPR, top panel) and late (LPR, bottom panel) phase reaction respectively 0, 5 and 6 h after injection of IgE-contained ScIgFig. 2Passive type I (anaphylactic) reaction after ongoing sensitization during initial subcutaneous immunoglobulins repacement therapy. Timeline of two CVID patients receiving initial ScIg therapy. Negative skin test before, but positive after replacement therapy with Subcuvia® was presented. a Patient with rhinoconjunctivitis and laryngeal edema occurring after exposure to grass pollens. Serum IgE level fluctuation was presented. It was tested retrospectively every 2 days when ScIg loading dose was given over the course of 2 weeks. Serum IgE level and short serum half-life do not reflect IgE elimination, but FcƐR expression and opsonization of immune cells that are source positive skin tests. b Patient with anaphylaxis after peanut exposition during home-based self-administration of ScIg. ScIg home administration, and “take peanut home” messages of guidelines  may be the cause of anaphylactic complication. Noteworthy, still positive test with the gradual decrease of wheal was observed after switching ScIg product (Subcuvia® withdrawal) to another one (Hizentra®). The first product contains IgE, the other—does not
To achieve the highest level of safety and quality of drugs the regulation experts recommend a stepwise approach. Unfortunately, immunoglobulins and other blood-derived products are not typical drugs, since plasma processing into various types of products is highly specialized. Large-scale processing (fractionation) is very important for ensuring quality and safety profiles of the products .
Our observation of passive transfer of hypersensitivity indicates that rigorous blood donor screening for allergies should be considered and the blind-spot testing for IgE as part of ScIg quality control should be performed. Furthermore, until now late manifestation of immediate type hypersensitivity after ScIg (positive ICT remains detectable for weeks to months (Fig. 2) has not been described in medical literature nor as product characteristics. Therefore, there are no strict safety regulations for home-based self-administration of immunoglobulins. The ScIg are non-bioequivalent products (Table 2; Fig. 2) and are misnamed as a medication. IgE has a short serum half-life (i.e. days, Fig. 2a), but after binding to Fc it resides in tissues for months (Fig. 2). Due to prolonged risk of anaphylaxis after IgE passive transfer, switching from in-hospital administration to home self-administration should be done with an extreme care, and screening for allergy by SPT/ICT is recommended. In pharmaceutical process testing of immunoglobulin products for IgE content is not part of routine practice but could be considered. Testing for newly-acquired IgE sensitivities should be considered in patients receiving IgE-containing immunoglobulin products, particularly in those patients who develop new allergic sensitivities, and would be an interesting area to study prospectively (Table 5).Table 5Difference between immunoglobulins (ScIg, IVIg) and typical drugsFeatureDrug/medicineImmunoglobulinSourceChemical (for example catalytic, enzymatic) reaction “IN VITRO”Plasma obtained from blood donorsa “IN VIVO”Chemical composition, doseKnown(standardization following pharmacopeia)Dose [g] describe active compound contentNot precisely definedProtein (in reality proteins complex)Dose [g] describe total protein contentClinical pharmacologyMechanism of actionDefined (by strict receptors)Multifactorial (depends on antigenic specificity)Elimination and half-life (T½)Renal intestinal etc. after easy diffusion from tissue compartmentStrictly defined T½Not knownSerum T½ does not reflect immunoglobulin elimination, but FcR opsonizationbUnpredictable adrsImmunogenicityUsually low (in general haptenic formula)Pathological anti—IgAcImmunoreactivity (immune reaction to pharmaceutical product)Rare, but ever probable (e.g. benzylpenicillin allergy)Physiological tolerance or antiidiotypic immune responsedImmunoglobulins are a pharmaceutical product with unique technology, contrary to bio-synthetic drugsaImmunoglobulin preparation is plasma fractionation: plasma is obtained in accordance with WHO guidelines from at least 1000 donorsbAfter immunoglobulin distribution to tissue compartment FcR opsonization occurs (see Figs. 2a, 3). It blocks inverse diffusion to serumcIn clinical practice immunoglobulins are used as replacement therapy in patients with primary and secondary immunodeficiencies. Lack of active immune response after antigenic stimulation (e.g. vaccination) in such patients is one crucial mechanism of low immunogenicity. Contrary to CVID, patients with selective IgA deficiency may produce IgG that reacts with IgA in immunoglobulins (product characteristic of many immunoglobulins as well as Subcuvia® does not contain essential contraindication—selective IgA deficiency)dWhen immunoglobulin is used in immunomodulatory therapy (autoimmune disease) the immune response to immunoglobulins and hyperreactivity may be observed. For example Rheumatoid factor from patients with autoimmune disease and IgG from pharmaceutical product