Follow-up and outcome of symptomatic partial or absolute IgA deficiency in children
Selective IgA deficiency is defined as absolute or partial when serum IgA level is < 7 mg/dl or 2 SD below normal for age, respectively. Few data are available on partial selective IgA deficiency, as probably most children with low serum IgA are seldom referred to a specialist clinic in common pediatric practice. The aim of our study was to better define the profile of both symptomatic forms and their clinical outcome in a pediatric immunology setting. Thus, clinical and immunological data from 103 symptomatic patients with selective IgA deficiency (53 absolute and 50 partial), 4–18 years of age, were collected at diagnosis and 80 patients (44 absolute and 36 partial) were monitored for a mean period of 5 years. Also, the prevalence of TNFRSF13B mutations has been assessed in 56 patients. The most common clinical features were infections (86/103; 83%), allergy (39/103; 38%), and autoimmunity (13/103; 13%). No significative differences were observed between absolute and partial selective IgA deficiency patients. However, a significative difference in the rate of IgA normalization between partial and absolute selective IgA deficiency patients (33 vs 9%, p = 0.01) was detected. Furthermore, a lower incidence of infections was associated to a normalization reversal compared to a final absolute or partial defect status (12 vs 53 and 64% respectively, p < 0.01).
What is Known:
● Selective IgA Deficiency is the most common primary immunodeficiency and is usually asymptomatic.
● Symptomatic pediatric patients with selective IgA deficiency mostly suffer with respiratory and gastrointestinal infections.
What is New:
● Symptomatic children with partial IgA defect may have similar clinical, immunological, and genetic features than symptomatic children with absolute IgA deficiency.
● Symptomatic children with partial IgA deficiency deserve accurate monitoring for associated diseases as per children with absolute IgA deficiency.
KeywordsTNFRSF13B Antibody deficiency Primary immunodeficiency Recurrent respiratory infections
Selective IgA deficiency
Primary immunodeficiency disease
Transmembrane activator and calcium modulator and cyclophilin ligand interactor
Common variable immunodeficiency
Absolute selective IgA deficiency
Partial selective IgA deficiency
We thank all patients and their referring nursing and medical staff of the Italian Primary Immunodeficiency Network Centers for their participation. This work was carried out in the tutorial framework of Master in Advanced Pediatric Allergy and Immunology at University of Rome Tor Vergata.
VM designed the study, analyzed and interpreted the data, wrote and critically reviewed the manuscript. LC and SG contributed to data interpretation and writing of the manuscript. CP, AP, FS critically reviewed and approved the final manuscript. MS, VG, EC contributed to the acquisition of data. SF, GDM, SDC performed all genetic and immunological analysis. VM designed the study, analyzed and interpreted the data, wrote and critically reviewed the manuscript. LC contributed to data interpretation and writing the manuscript. SG contributed to data interpretation and writing the manuscript. CP critically reviewed and approved the final manuscript. AP critically reviewed and approved the final manuscript. FS critically reviewed and approved the final manuscript. MS contributed to the acquisition of data. VG contributed to the acquisition of data. EC contributed to the acquisition of data. SF performed all genetic and immunological data. GDM performed all genetic and immunological data. SDC performed all genetic and immunological data.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Informed consent was obtained at diagnosis from all individual participants included in the study.
The approval for the study was obtained from the institutional review board. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 3.Aghamohammadi A, Abolhassani H, Biglari M, Abolmaali S, Moazzami K, Tabatabaeiyan M, Asgarian-Omran H, Parvaneh N, Mirahmadian M, Rezaei N (2011) Analysis of switched memory B cells in patients with IgA deficiency. Int Arch Allergy Immunol 156(4):462–468. https://doi.org/10.1159/000323903 Google Scholar
- 7.Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP Jr, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW, Bernstein DI, Blessing-Moore J, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D, Bonilla FA, Khan DA, Bernstein DI, Blessing-Moore J, Khan D, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D, Bonilla FA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP Jr, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW (2015) Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol 136(5):1186–1205. https://doi.org/10.1016/j.jaci.2015.04.049 Google Scholar
- 8.Bronson PG, Chang D, Bhangale T, Seldin MF, Ortmann W, Ferreira RC, Urcelay E, Pereira LF, Martin J, Plebani A, Lougaris V, Friman V, Freiberger T, Litzman J, Thon V, Pan-Hammarström Q, Hammarström L, Graham RR, Behrens TW (2016) Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Nat Genet 48(11):1425–1429. https://doi.org/10.1038/ng.3675 Google Scholar
- 9.Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, Geha RS (2005) TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 37(8):829–834. https://doi.org/10.1038/ng1601
- 10.Castigli E, Wilson S, Garibyan L, Rachid R, Bonilla F, Schneider L, Morra M, Curran J, Geha R (2007) Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet 39(4):430–431. https://doi.org/10.1038/ng0407-430
- 11.Cunningham-Rundles C (2001) Physiology of IgA and IgA deficiency. J Clin Immunol 21(5):303–309Google Scholar
- 15.Ferreira RC, Pan-Hammarström Q, Graham RR, Gateva V, Fontán G, Lee AT, Ortmann W, Urcelay E, Fernández-Arquero M, Núñez C, Jorgensen G, Ludviksson BR, Koskinen S, Haimila K, Clark HF, Klareskog L, Gregersen PK, Behrens TW, Hammarström L (2010) Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency. Nat Genet 42(9):777–780. https://doi.org/10.1038/ng.644 Google Scholar
- 16.Ferreira RC, Pan-Hammarström Q, Graham RR, Fontán G, Lee AT, Ortmann W, Wang N, Urcelay E, Fernández-Arquero M, Núñez C, Jorgensen G, Ludviksson BR, Koskinen S, Haimila K, Padyukov L, Gregersen PK, Hammarström L, Behrens TW (2012) High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency. PLoS Genet 8(1):e1002476. https://doi.org/10.1371/journal.pgen.1002476 Google Scholar
- 17.Freiberger T, Ravčuková B, Grodecká L, Pikulová Z, Štikarovská D, Pešák S, Kuklínek P, Jarkovský J, Salzer U, Litzman J (2012) Sequence variants of the TNFRSF13B gene in Czech CVID and IgAD patients in the context of other populations. Hum Immunol 73(11):1147–1154. https://doi.org/10.1016/j.humimm.2012.07.342 Google Scholar
- 19.Haimila K, Einarsdottir E, De Kauwe A et al (2009) The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. Genes Immun 10(2):151–161. https://doi.org/10.1038/gene.2008.89
- 21.Janzi M, Kull I, Sjöberg R, Wan J, Melén E, Bayat N, Östblom E, Pan-Hammarström Q, Nilsson P, Hammarström L (2009) Selective IgA deficiency in early life: association to infections and allergic diseases during childhood. Clin Immunol 133(1):78–85. https://doi.org/10.1016/j.clim.2009.05.014 Google Scholar
- 23.Jorgensen GH, Ornolfsson AE, Johannesson A, Gudmundsson S, Janzi M, Wang N, Hammarström L, Ludviksson BR (2011) Association of immunoglobulin A deficiency and elevated thyrotropin receptor antibodies in two Nordic countries. Hum Immunol 72(2):166–172. https://doi.org/10.1016/j.humimm.2010.10.014 Google Scholar
- 24.Koskinen S (1996) Long-term follow-up of health in blood donors with primary selective IgA deficiency. J Clin Immunol 16(3):165–170 https://www-ncbi-nlm-nih-gov/pubmed/8734360Google Scholar
- 25.Lim CK, Dahle C, Elvin K, Andersson BA, Rönnelid J, Melén E, Bergström A, Truedsson L, Hammarström L (2015) Reversal of immunoglobulin A deficiency in children. J Clin Immunol 35(1):87–91. https://doi.org/10.1007/s10875-014-0112-6
- 26.López-Mejías R, del Pozo N, Fernández-Arquero M, Ferreira A, García-Rodríguez MC, de la Concha EG, Fontán G, Urcelay E, Martínez A, Núñez C (2009) Role of polymorphisms in the TNFRSF13B (TACI) gene in Spanish patients with immunoglobulin a deficiency. Tissue Antigens 74(1):42–45. https://doi.org/10.1111/j.1399-0039.2009.01253.x Google Scholar
- 29.MacHulla HK, Schönermarck U, Schaaf A et al (2000) HLA-A, B, Cw and DRB1, DRB3/4/5, DQB1, DPB1 frequencies in German immunoglobulin A-deficient individuals. Scand J Immunol 52(2):207–211Google Scholar
- 31.Mohammadi J, Ramanujam R, Jarefors S, Rezaei N, Aghamohammadi A, Gregersen PK, Hammarström L (2010) IgA deficiency and the MHC: assessment of relative risk and microheterogeneity within the HLA A1 B8, DR3 (8.1) haplotype. J Clin Immunol 30(1):138–143. https://doi.org/10.1007/s10875-009-9336-2 Google Scholar
- 34.Pignata C, Monaco G, Ciccimarra F (1991) Heterogeneity of IgA deficiency in childhood. Pediatr Allergy Immunol 2:38–40. https://doi.org/10.1111/j.1399-3038.1991.tb00178.x Google Scholar
- 36.Rezaei N, Abolhassani H, Kasraian A et al (2013) Family study of pediatric patients with primary antibody deficiencies. Iran J Allergy Asthma Immunol 12(4):377–382Google Scholar
- 37.Rich RR et al (2008) Clinical immunology principles and practice, 3rd edn. Mosby Elsevier, Maryland HeightsGoogle Scholar
- 38.Salzer U, Bacchelli C, Buckridge S, Pan-Hammarstrom Q, Jennings S, Lougaris V, Bergbreiter A, Hagena T, Birmelin J, Plebani A, Webster ADB, Peter HH, Suez D, Chapel H, McLean-Tooke A, Spickett GP, Anover-Sombke S, Ochs HD, Urschel S, Belohradsky BH, Ugrinovic S, Kumararatne DS, Lawrence TC, Holm AM, Franco JL, Schulze I, Schneider P, Gertz EM, Schaffer AA, Hammarstrom L, Thrasher AJ, Gaspar HB, Grimbacher B (2009) Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113(9):1967–1976. https://doi.org/10.1182/blood-2008-02-141937 Google Scholar
- 40.Shakkottai A, Bupathi K, Patel AP, Chalom E, Chamarthi S, Lehman TJA, Peterson MGE, Gaur S, Moorthy LN (2012) Children with partial IgA deficiency: clinical characteristics observed in the pediatric rheumatology clinic. Clin Pediatr (Phila) 51(1):46–50. https://doi.org/10.1177/0009922811417287 Google Scholar