Association of anti-IgA antibodies with adverse reactions to γ-globulin infusion
2011; Elsevier BV; Volume: 128; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2011.01.061
ISSN1097-6825
AutoresRima Rachid, Mariana Castells, Charlotte Cunningham‐Rundles, Francisco A. Bonilla,
Tópico(s)Blood groups and transfusion
ResumoTo the Editor:Serum IgG anti-IgA antibody has been associated with the development of adverse reactions (including non-IgE mediated anaphylaxis) to intravenous immunoglobulin (IVIG) in patients with undetectable IgA (here defined as 7 mg/dL.2Sandler S.G. Eckrich R. Malamut D. Mallory D. Hemagglutination assays for the diagnosis and prevention of IgA anaphylactic transfusion reactions.Blood. 1994; 84: 2031-2035PubMed Google Scholar Subclass-specific (or limited specificity) anti-IgA reacts with only 1 subclass (IgA1, IgA2m[1], or IgA2m[2]).2Sandler S.G. Eckrich R. Malamut D. Mallory D. Hemagglutination assays for the diagnosis and prevention of IgA anaphylactic transfusion reactions.Blood. 1994; 84: 2031-2035PubMed Google Scholar It is estimated that up to 40% of patients with selective IgA deficiency and 9% to 25% of patients with common variable immunodeficiency (CVID) may have IgG anti-IgA.3de Albuquerque Campos R. Sato M.N. da Silva Duarte A.J. IgG anti-IgA subclasses in common variable immunodeficiency and association with severe adverse reactions to intravenous immunoglobulin therapy.J Clin Immunol. 2000; 20: 77-82Crossref PubMed Scopus (57) Google Scholar IgE anti-IgA has been found much less frequently. Three of 4 patients with IgE anti-IgA had anaphylaxis to γ-globulin or other blood products.4Ferreira A. Garcia Rodriguez M.C. Fontan G. Follow-up of anti-IgA antibodies in primary immunodeficient patients treated with gamma-globulin.Vox Sang. 1989; 56: 218-222Crossref PubMed Scopus (14) Google Scholar, 5Burks A.W. Sampson H.A. Buckley R.H. Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia: detection of IgE antibodies to IgA.N Engl J Med. 1986; 314: 560-564Crossref PubMed Scopus (305) Google ScholarWe conducted a retrospective and prospective observational study to evaluate the possible association with adverse reactions of IgG and/or IgE anti-IgA in IgA-deficient patients receiving IVIG or subcutaneous immunoglobulin (SCIG) at Children's Hospital Boston, Boston, Mass, and Brigham and Women's Hospital, Boston, Mass. All investigations were conducted according to the policies and procedures of the institutional review boards of both institutions.Among 425 immunodeficient patients receiving IgG therapy, we identified 35 (8.2%) with undetectable IgA; 22 were enrolled. Twenty of these were studied retrospectively (medical record review for 1 year before enrollment) and prospectively (6 months) for symptoms related to IgG infusion. Thirteen patients (11 with CVID, 2 with IgA deficiency) were excluded because of an increase in IgA level (3), lack of consent (7), or nonadherence with the study procedure (3). Blood was collected at enrollment and after the 6-month observation period. Subjects 22 and 23 were studied only prospectively because they did not receive IgG in the year before obtaining the serum specimens. Data were collected with respect to the IgG product, lot number, dose, rate of infusion, use of premedications, and symptoms recorded within 1 hour after the end of the infusion (acute) or up to 72 hours later (delayed). Symptoms were graded as mild (treated by the patients or medical staff without discontinuing the infusion), moderate (requiring telephone contact with, or a visit to an outpatient setting for assistance from, a health care provider, or requiring cessation of the infusion), or severe (requiring an emergency department visit or hospitalization, or resuscitation).We measured serum levels of IgA1, IgA2, and IgG anti-IgA1 and anti-IgA2 by ELISA using myeloma controls to establish approximate concentration standard curves. Serum specimens were also studied at the Mayo Clinic Laboratory (Rochester, Minn) by using a Luminex-based assay system and in the Red Cross Laboratory (Philadelphia, Pa) by passive hemagglutination. IgE anti-IgA1 and anti-IgA2 were measured by ImmunoCAP assays at ViraCor-IBT Laboratories (Lenexa, Kan).In all patients throughout the study, only mild symptoms were reported, including headache, fatigue, and malaise. These were of a nature and frequency commonly seen in many clinical trials of IgG therapy that routinely exclude IgA-deficient patients. Therefore, no attempt was made to correlate these symptom data with results of immunoassays.Results of the immunochemical analyses are shown in Table E1 (see this article's Online Repository at www.jacionline.org). Background levels for IgG anti-IgA1 or IgA2 ELISA ranged from 51 to 240 ng/mL (lower limit of assay detection, sera diluted 1:100). Three subjects had levels well above this range (504-4528 ng/mL; Table I). Two individuals (subjects 23 and 32) had class-specific IgG anti-IgA by ELISA. One subject (33) had subclass-specific IgG anti-IgA2. Subjects 32 and 33 have only ever received SCIG and have never had adverse reactions. Their ability to tolerate IVIG is unknown. Seven years before enrollment, patient 23 had anaphylaxis requiring epinephrine during infusion of an IVIG product containing 1000 arbitrary units, and in the Red Cross Laboratory, IgG anti-IgA was detected. Her IgG anti-IgA level repeated 2½ years later at the Mayo Clinic Laboratory was still >1000 arbitrary units.Table ICharacteristics of patients with positive anti-IgA antibodiesSubject no.SexAge∗Age when first serum specimen obtained.(y)Dx, SC/IV†Therapy at time when serum specimen obtained; IV, intravenous infusion; SC, subcutaneous infusion.Specno.IgA1 (ng/mL)IgA2 (ng/mL)CHBIgG anti-IgA1(ng/mL)CHBIgG anti-IgA2(ng/mL)Mayo IgG anti-IgA(AU)‡AU, Arbitrary units; 200 = positive; maximum result reported >1000.RC IgG anti-IgA§Qualitative test, results reported as type of anti-IgA detected, or not detected (ND).23F26CVID, IV1522045283363>1000Anti-IgA32F60CVID, SC11503228211859684ND21212043983563>1000ND33M60CVID, SC1204116167755172Anti-IgA2225371130504133Anti-IgA2CHB, Children's Hospital Boston; Dx, diagnosis; F, female; M, male; Spec, specimen.∗ Age when first serum specimen obtained.† Therapy at time when serum specimen obtained; IV, intravenous infusion; SC, subcutaneous infusion.‡ AU, Arbitrary units; 200 = positive; maximum result reported >1000.§ Qualitative test, results reported as type of anti-IgA detected, or not detected (ND). Open table in a new tab The two patients who had class-specific IgG anti-IgA in our assay also tested positive in the Mayo Clinic Laboratory. The 1 individual with subclass-specific IgG anti-IgA2 did not test positive in the Mayo Clinic Laboratory (result in the "equivocal" range). Subject 23 also tested positive in the Red Cross Laboratory; subject 32 did not. The test was repeated with the same result. The reason for the discrepancy is unknown. The Red Cross Laboratory did detect the subclass-specific IgG anti-IgA2 that was also found by our ELISA in patient 33. Overall, there is good agreement between our results and these 2 clinical reference laboratories. IgE anti-IgA was not detected in any patient.Anaphylaxis is very rare among patients receiving IVIG.6Brennan V.M. Salome-Bentley N.J. Chapel H.M. Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin.Clin Exp Immunol. 2003; 133: 247-251Crossref PubMed Scopus (111) Google Scholar Therefore, a possible increased risk associated with IgG anti-IgA remains very difficult to quantify. None of the patients evaluated developed a significant reaction during the study period. We could not address the potential clinical significance of the subclass-specific anti-IgA2 with respect to IVIG, because the only such patient we identified had only ever received SCIG.Is IgG anti-IgA a "biomarker" of increased risk of non–IgE-mediated anaphylaxis to γ-globulin infusion containing IgA? Several anecdotal reports (including this one) suggest this may be the case. The mechanism whereby anti-IgA antibodies might cause an adverse reaction to IgG that contains some IgA is open to speculation. It has been reported that some individuals react to products with "high" IgA and tolerate products with "low" IgA.7Hedderich U. Kratzsch G. Stephen W. Dichtelmuller H. Olischlager K. Heimpel H. Immunoglobulin substitution therapy in a patient with primary hypogammaglobulinaemia and anti-IgA antibodies.Clin Allergy. 1986; 16: 339-344Crossref PubMed Scopus (11) Google Scholar, 8Cunningham-Rundles C. Wong S. Bjorkander J. Hanson L.A. Use of an IgA-depleted intravenous immunoglobulin in a patient with an anti-IgA antibody.Clin Immunol Immunopathol. 1986; 38: 141-149Crossref PubMed Scopus (16) Google Scholar This could be interpreted as an indication that the reaction mechanism involves interaction of IgG anti-IgA with infused IgA. However, patient 23 appears not to tolerate IVIG products containing even trace amounts of IgA, and some patients with IgG anti-IgA tolerate IVIG without symptoms.9Ferreira A. Garcia Rodriguez M.C. Lopez-Trascasa M. Pascual Salcedo D. Fontan G. Anti-IgA antibodies in selective IgA deficiency and in primary immunodeficient patients treated with gamma-globulin.Clin Immunol Immunopathol. 1988; 47: 199-207Crossref PubMed Scopus (50) Google ScholarGiven the rarity of anaphylaxis to IVIG, much larger prospective studies are required to establish more clearly any possibility of increased risk associated with IgA deficiency. It is not clear that class-specific or subclass-specific IgG anti-IgA antibodies have clinical relevance. Our data and others' suggest that further study of a possible association is warranted. In an individual patient, the presence of IgG anti-IgA may indicate a need for closer monitoring, or consideration of alternative therapy such as SCIG, which appears to be tolerated in many of these patients. To the Editor: Serum IgG anti-IgA antibody has been associated with the development of adverse reactions (including non-IgE mediated anaphylaxis) to intravenous immunoglobulin (IVIG) in patients with undetectable IgA (here defined as 7 mg/dL.2Sandler S.G. Eckrich R. Malamut D. Mallory D. Hemagglutination assays for the diagnosis and prevention of IgA anaphylactic transfusion reactions.Blood. 1994; 84: 2031-2035PubMed Google Scholar Subclass-specific (or limited specificity) anti-IgA reacts with only 1 subclass (IgA1, IgA2m[1], or IgA2m[2]).2Sandler S.G. Eckrich R. Malamut D. Mallory D. Hemagglutination assays for the diagnosis and prevention of IgA anaphylactic transfusion reactions.Blood. 1994; 84: 2031-2035PubMed Google Scholar It is estimated that up to 40% of patients with selective IgA deficiency and 9% to 25% of patients with common variable immunodeficiency (CVID) may have IgG anti-IgA.3de Albuquerque Campos R. Sato M.N. da Silva Duarte A.J. IgG anti-IgA subclasses in common variable immunodeficiency and association with severe adverse reactions to intravenous immunoglobulin therapy.J Clin Immunol. 2000; 20: 77-82Crossref PubMed Scopus (57) Google Scholar IgE anti-IgA has been found much less frequently. Three of 4 patients with IgE anti-IgA had anaphylaxis to γ-globulin or other blood products.4Ferreira A. Garcia Rodriguez M.C. Fontan G. Follow-up of anti-IgA antibodies in primary immunodeficient patients treated with gamma-globulin.Vox Sang. 1989; 56: 218-222Crossref PubMed Scopus (14) Google Scholar, 5Burks A.W. Sampson H.A. Buckley R.H. Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia: detection of IgE antibodies to IgA.N Engl J Med. 1986; 314: 560-564Crossref PubMed Scopus (305) Google Scholar We conducted a retrospective and prospective observational study to evaluate the possible association with adverse reactions of IgG and/or IgE anti-IgA in IgA-deficient patients receiving IVIG or subcutaneous immunoglobulin (SCIG) at Children's Hospital Boston, Boston, Mass, and Brigham and Women's Hospital, Boston, Mass. All investigations were conducted according to the policies and procedures of the institutional review boards of both institutions. Among 425 immunodeficient patients receiving IgG therapy, we identified 35 (8.2%) with undetectable IgA; 22 were enrolled. Twenty of these were studied retrospectively (medical record review for 1 year before enrollment) and prospectively (6 months) for symptoms related to IgG infusion. Thirteen patients (11 with CVID, 2 with IgA deficiency) were excluded because of an increase in IgA level (3), lack of consent (7), or nonadherence with the study procedure (3). Blood was collected at enrollment and after the 6-month observation period. Subjects 22 and 23 were studied only prospectively because they did not receive IgG in the year before obtaining the serum specimens. Data were collected with respect to the IgG product, lot number, dose, rate of infusion, use of premedications, and symptoms recorded within 1 hour after the end of the infusion (acute) or up to 72 hours later (delayed). Symptoms were graded as mild (treated by the patients or medical staff without discontinuing the infusion), moderate (requiring telephone contact with, or a visit to an outpatient setting for assistance from, a health care provider, or requiring cessation of the infusion), or severe (requiring an emergency department visit or hospitalization, or resuscitation). We measured serum levels of IgA1, IgA2, and IgG anti-IgA1 and anti-IgA2 by ELISA using myeloma controls to establish approximate concentration standard curves. Serum specimens were also studied at the Mayo Clinic Laboratory (Rochester, Minn) by using a Luminex-based assay system and in the Red Cross Laboratory (Philadelphia, Pa) by passive hemagglutination. IgE anti-IgA1 and anti-IgA2 were measured by ImmunoCAP assays at ViraCor-IBT Laboratories (Lenexa, Kan). In all patients throughout the study, only mild symptoms were reported, including headache, fatigue, and malaise. These were of a nature and frequency commonly seen in many clinical trials of IgG therapy that routinely exclude IgA-deficient patients. Therefore, no attempt was made to correlate these symptom data with results of immunoassays. Results of the immunochemical analyses are shown in Table E1 (see this article's Online Repository at www.jacionline.org). Background levels for IgG anti-IgA1 or IgA2 ELISA ranged from 51 to 240 ng/mL (lower limit of assay detection, sera diluted 1:100). Three subjects had levels well above this range (504-4528 ng/mL; Table I). Two individuals (subjects 23 and 32) had class-specific IgG anti-IgA by ELISA. One subject (33) had subclass-specific IgG anti-IgA2. Subjects 32 and 33 have only ever received SCIG and have never had adverse reactions. Their ability to tolerate IVIG is unknown. Seven years before enrollment, patient 23 had anaphylaxis requiring epinephrine during infusion of an IVIG product containing 1000 arbitrary units, and in the Red Cross Laboratory, IgG anti-IgA was detected. Her IgG anti-IgA level repeated 2½ years later at the Mayo Clinic Laboratory was still >1000 arbitrary units. CHB, Children's Hospital Boston; Dx, diagnosis; F, female; M, male; Spec, specimen. The two patients who had class-specific IgG anti-IgA in our assay also tested positive in the Mayo Clinic Laboratory. The 1 individual with subclass-specific IgG anti-IgA2 did not test positive in the Mayo Clinic Laboratory (result in the "equivocal" range). Subject 23 also tested positive in the Red Cross Laboratory; subject 32 did not. The test was repeated with the same result. The reason for the discrepancy is unknown. The Red Cross Laboratory did detect the subclass-specific IgG anti-IgA2 that was also found by our ELISA in patient 33. Overall, there is good agreement between our results and these 2 clinical reference laboratories. IgE anti-IgA was not detected in any patient. Anaphylaxis is very rare among patients receiving IVIG.6Brennan V.M. Salome-Bentley N.J. Chapel H.M. Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin.Clin Exp Immunol. 2003; 133: 247-251Crossref PubMed Scopus (111) Google Scholar Therefore, a possible increased risk associated with IgG anti-IgA remains very difficult to quantify. None of the patients evaluated developed a significant reaction during the study period. We could not address the potential clinical significance of the subclass-specific anti-IgA2 with respect to IVIG, because the only such patient we identified had only ever received SCIG. Is IgG anti-IgA a "biomarker" of increased risk of non–IgE-mediated anaphylaxis to γ-globulin infusion containing IgA? Several anecdotal reports (including this one) suggest this may be the case. The mechanism whereby anti-IgA antibodies might cause an adverse reaction to IgG that contains some IgA is open to speculation. It has been reported that some individuals react to products with "high" IgA and tolerate products with "low" IgA.7Hedderich U. Kratzsch G. Stephen W. Dichtelmuller H. Olischlager K. Heimpel H. Immunoglobulin substitution therapy in a patient with primary hypogammaglobulinaemia and anti-IgA antibodies.Clin Allergy. 1986; 16: 339-344Crossref PubMed Scopus (11) Google Scholar, 8Cunningham-Rundles C. Wong S. Bjorkander J. Hanson L.A. Use of an IgA-depleted intravenous immunoglobulin in a patient with an anti-IgA antibody.Clin Immunol Immunopathol. 1986; 38: 141-149Crossref PubMed Scopus (16) Google Scholar This could be interpreted as an indication that the reaction mechanism involves interaction of IgG anti-IgA with infused IgA. However, patient 23 appears not to tolerate IVIG products containing even trace amounts of IgA, and some patients with IgG anti-IgA tolerate IVIG without symptoms.9Ferreira A. Garcia Rodriguez M.C. Lopez-Trascasa M. Pascual Salcedo D. Fontan G. Anti-IgA antibodies in selective IgA deficiency and in primary immunodeficient patients treated with gamma-globulin.Clin Immunol Immunopathol. 1988; 47: 199-207Crossref PubMed Scopus (50) Google Scholar Given the rarity of anaphylaxis to IVIG, much larger prospective studies are required to establish more clearly any possibility of increased risk associated with IgA deficiency. It is not clear that class-specific or subclass-specific IgG anti-IgA antibodies have clinical relevance. Our data and others' suggest that further study of a possible association is warranted. In an individual patient, the presence of IgG anti-IgA may indicate a need for closer monitoring, or consideration of alternative therapy such as SCIG, which appears to be tolerated in many of these patients. We are very grateful to Drs Michelle Altrich and John F. Halsey of ViraCor-IBT Laboratories (Lenexa, Kan) for performing ImmunoCAP assays for IgE anti-IgA antibodies. We acknowledge the technical assistance of Ms Donna-Lee Destouche, the expert advice of Ms Haifa Jabara (both from Children's Hospital Boston), and the assistance of clinical coordinator Mary Lou Hogan (Brigham and Women's Hospital). We are very thankful to our patients who participated in the study. Table E1. Tabled 1Results of immunochemical analysisSubject no.SexAge∗Age when first serum specimen obtained.(y)Dx, SC/IV†CID, Combined immunodeficiency; G2, IgG2 deficiency; G4, IgG4 deficiency; Hypogam, unspecified hypogammaglobulinemia, consisting of low total IgG level with apparent adequate vaccine antibodies; therapy at time when serum specimen obtained, IV, intravenous infusion, SC, subcutaneous infusion.Specno.IgA1(ng/mL)IgA2 (ng/mL)CHBIgG anti-IgA1(ng/mL)CHBIgG anti-IgA2(ng/mL)MayoIgG anti-IgA(AU)‡AU, Arbitrary units; 200 = positive; maximum result reported >1000.Red CrossIgG anti-IgA§Qualitative test, results reported as type of anti-IgA detected, or not detected (ND).01F8CID, IV1983126112717091ND28243449816467ND02F43CVID, IV11030632606324ND2445275636833ND03F43CVID, IV143622013812684ND237529717012863ND04F31CVID, SC11859653ND25502861039267ND06F40IGAD, IV132730512913556ND231828712615555ND07F37CVID, IV1263159689345ND2469330241232114ND08F17CVID, IV1459165679335ND2380150789648ND13F15G4/IGAD, IV13424189716436ND14M13Hypogam, IV134317512410852ND15M35CVID, IV166123214517473ND2393109595822ND18M17CVID, IV1245827181ND223875878945ND19M6Hypogam, IV124736219110041ND211667641186525ND20F23CVID, IV1236110821062225114809368ND21F55CVID, IV118559607357ND22M6Hypogam, IV119053495814ND222289747526ND23F26CVID, IV1522045283363>1000Anti-IgA30F53CVID, SC1101732311510982ND277333712511575ND31M55CVID, IV1954977554ND2580757046ND32F60CVID, SC11503228211859684ND21212043983563>1000ND33M60CVID, SC1204116167755172Anti-IgA2225371130504133Anti-IgA234F80CVID, IV113064519880ND212747919477ND35F29Hypogam, SC112484798165ND212092635255NDCHB, Children's Hospital Boston; Dx, diagnosis; F, female; IGAD, IgA deficiency; M, male; Spec, specimen.An empty cell indicates the test was not done.∗ Age when first serum specimen obtained.† CID, Combined immunodeficiency; G2, IgG2 deficiency; G4, IgG4 deficiency; Hypogam, unspecified hypogammaglobulinemia, consisting of low total IgG level with apparent adequate vaccine antibodies; therapy at time when serum specimen obtained, IV, intravenous infusion, SC, subcutaneous infusion.‡ AU, Arbitrary units; 200 = positive; maximum result reported >1000.§ Qualitative test, results reported as type of anti-IgA detected, or not detected (ND). Open table in a new tab CHB, Children's Hospital Boston; Dx, diagnosis; F, female; IGAD, IgA deficiency; M, male; Spec, specimen. An empty cell indicates the test was not done.
Referência(s)