Selective IgA Deficiency

The most frequent primary immunodeficiency, with a polygenic basis and a strong contribution from the HLA complex, defined by serum IgA below 0.07 g/L after 4 years of age with normal IgG and IgM; predominantly asymptomatic, it is associated with sinopulmonary and gastrointestinal infections, allergy, coeliac disease and other autoimmune diseases, and has a clinical and familial relationship with common variable immunodeficiency.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

Selective immunoglobulin A deficiency (sIgAD) is the most frequent primary immunodeficiency in populations of European ancestry but, unlike most inborn errors of immunity (IEIs), does not correspond to an identifiable monogenic defect and causes no disease in most affected people [3, 26]. The definition is laboratory-based: undetectable serum IgA or a level below 7 mg/dL (0.07 g/L) in an individual older than 4 years, with normal IgG and IgM, normal vaccine responses and exclusion of secondary causes of hypogammaglobulinaemia and T-cell defects [4, 26]. This definition rests on serum measurement, although most IgA in the body is secreted at mucosal surfaces and is not measured in clinical practice, helping to explain the weak correlation between serum levels and clinical expression [26].

The absence of IgA in healthy people was described in 1964 by Rockey, Hanson, Heremans and Kunkel, who reported two healthy men lacking what was then termed β2A globulin [1]. Four years later, Vyas, Perkins and Fudenberg associated anti-IgA antibodies with anaphylactoid transfusion reactions, an observation that shaped transfusion medicine for these patients for decades [29–31]. Subsequent clinical descriptions established the currently accepted picture: 85–90% asymptomatic carriers and a minority with infections, allergy and autoimmunity [10].

Molecular research followed two paths. In 2005, two simultaneously published articles identified variants in TNFRSF13B, the gene encoding the TACI receptor (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), in patients with common variable immunodeficiency (CVID) and sIgAD [32, 33]; in 2007, reassessment in large cohorts showed that these variants are risk factors for CVID but play a minimal or no role in sIgAD [9]. In 2010, the first genome-wide association study (GWAS) identified IFIH1 and CLEC16A outside the HLA region [7]; in 2012, fine mapping of the major histocompatibility complex (MHC) delineated several independent signals [6]; and in 2016 a European meta-analysis added four loci and estimated heritability [8].

Nomenclature has been revised. The 2024 International Union of Immunological Societies (IUIS) classification places sIgAD in the table of predominantly antibody deficiencies, with an unknown genetic defect and undetermined inheritance, separately from “IgG subclass deficiency with IgA deficiency”, specific polysaccharide antibody deficiency (SPAD) and transient hypogammaglobulinaemia of infancy [3]. The European Society for Immunodeficiencies (ESID) registry working definitions, in force since 2014 and revised in 2019, follow the same logic and now treat absent IgA with IgG subclass deficiency or a poor polysaccharide response as distinct entities [26, 34]. Orphanet retains sIgAD as a non-rare entity in Europe (ORPHA:69127) and has rendered the entries for isolated IgA1 deficiency, IgA2 deficiency and TACI-related IgAD obsolete [2, 12].

The scope of this article is primary sIgAD and the entities with which it can be confused. The general approach to IEIs and CVID, with which sIgAD shares familial clustering and to which it may progress, and the genetic syndromes in which low IgA is an accessory manifestation (22q11.2 deletion, ataxia-telangiectasia, Nijmegen, Kabuki, among others) are presented here only as context and differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. IgA: structure, subclasses and ontogeny

IgA accounts for more than 70% of total immunoglobulins in the body, but most does not circulate: it is secreted at mucosal surfaces in dimeric form, joined by the J chain and associated with the secretory component, and is found in saliva, tears and milk [5, 26]. The monomeric form predominates in serum, approximately 90% of which belongs to the IgA1 subclass, produced mainly by bone marrow plasma cells; secretory IgA is predominantly IgA2 and is produced in gut-associated lymphoid tissue (GALT) [5]. Mucosal IgA neutralises microorganisms and toxins without activating complement, whereas serum IgA acts through the FcαRI receptor [5]. IgA is virtually absent at birth and rises progressively until adolescence; the adult reference range cited by Swain and colleagues is 61–365 mg/dL [26]. This slow ontogeny is the reason for the diagnostic age threshold of 4 years [35].

2.2. Cellular mechanism

The central defect in sIgAD is failure of terminal B-cell differentiation into IgA-secreting plasma cells. Patients have immature IgA+ B cells that coexpress IgM and IgD, and the genes for the α1 and α2 constant regions on chromosome 14 are generally normal; the defect can be transferred by bone marrow or haematopoietic progenitor transplantation, demonstrating its haematopoietic origin [10, 26]. Abnormalities in helper T cells and the cytokine environment contribute: low transforming growth factor β (TGF-β) and changes in interleukin (IL)-4, IL-6, IL-7, IL-10 and IL-21; ex vivo IL-21 induces differentiation into IgA- and IgG-producing plasma cells in patients with sIgAD and CVID [8, 10, 26]. The serum concentration of a proliferation-inducing ligand (APRIL) is increased, interpreted as compensatory, and some patients have fewer FoxP3+ regulatory T cells, which has been associated with autoimmunity [26]. Secretory IgM increases compensatorily but does not distinguish symptomatic from asymptomatic patients [26].

More recent translational data add two aspects. In an Icelandic population-based cohort, adults with sIgAD had increased total IgG and IgG1, selectively reduced IgG4, a serum signature of five analytes (IL-18, soluble CD40L, thymic stromal lymphopoietin, CCL3 and TWEAK) associated with lower residual IgA and antinuclear antibodies, and reduced expression of IL-18 receptor components in B cells [36]. In Dutch children with recurrent respiratory infections, the gut microbiota differed in those with IgA deficiency, and faecal transfer to germ-free mice showed that a Bifidobacterium-dominated cluster induces serum, faecal and pulmonary IgA [37]. In IgA-deficient mice, gluten induced microbiota-dependent ileal villous atrophy, reproduced by monocolonisation with Streptococcus lutetiensis and prevented by a gluten-free diet [38]. These findings are preclinical or observational and currently have no therapeutic implications.

2.3. Genetic architecture: familial clustering and heritability

Familial clustering is well documented. Approximately 20–25% of patients have a family history of sIgAD or CVID [4, 39]. In Finland, 7.2% of first-degree relatives of 35 index cases had sIgAD, far above the proportion in blood donors; in a Swedish study of 12,600 twins, concordance was 31% in monozygotic and 13% in dizygotic twins (data cited by Swain and colleagues) [26]. In the Swedish cohort of the 2016 meta-analysis, heritability estimated from imputed variants was 0.49 (standard error 0.047), 0.39 after conditioning on association signals and 0.14 when the entire MHC was excluded, indicating that the HLA region explains most of the known genetic component and that the remainder is polygenic [8]. CVID and sIgAD occur in the same families, and the Oxford Desk Reference states that a family history of IgAD is frequent in patients with CVID [40].

2.4. The HLA region

The ancestral 8.1 haplotype (HLA-A1, B8, DR3, DQ2) is associated with sIgAD and, independently, with systemic lupus erythematosus (SLE), coeliac disease, dermatitis herpetiformis, type 1 diabetes (T1D), myasthenia gravis and scleroderma [26]. The risk conferred by the extended haplotype is multiplicative, and a substitution at amino acid 57 of the HLA-DQ β chain has been associated with susceptibility [10]. Initial estimates suggested sIgAD in 13% of B8/DR3 homozygotes (relative risk 77.8), but larger studies found more modest effects (relative risk 11.1 in homozygotes and 3.4 in heterozygotes) [35]. Some authors attribute the signal to an allele in the HLA class III region, based on comparisons of the haplotype in patients from Sardinia, northern Europe, Australia and the USA [35].

High-density mapping of 772 patients and 1976 controls from three European populations identified HLA-DQB1*02 as the primary signal (combined P 7.69×10⁻⁵⁷; odds ratio, OR, 2.80), explained by independent effects of the HLA-B*08:01-DRB1*03:01-DQB1*02 and DRB1*07:01-DQB1*02 haplotypes; secondary signals were DRB1*01:02 (P 5.86×10⁻¹⁷; OR 4.28) and the protective DRB1*15:01 allele (P 2.24×10⁻³⁵; OR 0.13), with effects conserved across ancestries [6]. The B*08:01/DRB1*03/DQB1*02:01 haplotype predominates in northern Europe (Sweden, Norway, Iceland, Finland, Germany), whereas the DRB1*01:02-DQB1*05:01 haplotype is more frequent in southern Europe (Spain, Italy) and Iran [35]. In the 2016 meta-analysis, the strongest signal lay 2.7 kb upstream of HLA-DQA1 (P = 3.3×10⁻⁹²) [8]. Risk haplotypes partly explain geographical variation: among Chinese donors with sIgAD, two-thirds carried the haplotypes described in Europeans, which are less frequent in the general Chinese population [26].

2.5. Loci outside the HLA region

The 2010 GWAS, with 430 patients from Sweden and Iceland and 1090 controls, replicated in two European cohorts, identified a non-synonymous IFIH1 variant (rs1990760, P = 7.3×10⁻¹⁰), already associated with T1D and SLE, and a suggestive association with CLEC16A (P = 1.8×10⁻⁷); autoimmunity loci were globally enriched among the signals (P = 9.0×10⁻⁴) [7]. The 2016 meta-analysis, with approximately 9.5 million polymorphisms, 1635 patients (excluding those with comorbid autoimmunity or anti-transglutaminase antibodies) and 4852 controls from seven European cohorts (Sweden and Iceland, Finland, Spain, Italy and the Czech Republic), confirmed the protective association of the common IFIH1 variant (P = 3.7×10⁻¹⁵; OR 0.62 in the previous GWAS), identified an association with the rare loss-of-function variant IFIH1 NM_022168.4:c.2767A>G p.(Ile923Val) (rs35667974; P = 2.6×10⁻⁸) and added four genome-wide significant loci: PVT1 (protective 1 bp deletion, P = 4.3×10⁻¹¹), ATG13–AMBRA1 (P = 6.7×10⁻¹⁰), AHI1 (P = 8.4×10⁻¹⁰) and CLEC16A (protective intronic insertion, P = 1.4×10⁻⁹) [8]. Three of these four loci overlap with autoimmunity markers; among 28 suggestive loci, half were autoimmune (FAS, GATA3, CD86, PTGER4, IKZF3, EGR2, FCRL3, IL2RA, PTPN2, IL2/IL21, CD28, among others) [8]. Pathway analysis showed enrichment of the “intestinal immune network for IgA production” (22 of 30 genes with P ≤0.05, including IL10, APRIL, B-cell activating factor (BAFF), TACI, CD40, ICOS, CCR9, MADCAM1 and AICDA) and of the regulatory T-cell signature, and a genetic architecture shared with T1D and rheumatoid arthritis even without the MHC; the non-MHC loci of sIgAD do not overlap with those of IgA nephropathy [8].

2.6. TNFRSF13B (TACI): from proposed cause to modifier

TNFRSF13B (17p11.2; HGNC:18153) encodes TACI, a lymphocyte-restricted tumour necrosis factor superfamily receptor that binds BAFF and APRIL and, through CAML, activates NF-AT, NF-κB and AP-1, regulating immunoglobulin class switching [11]. In 2005, Castigli and colleagues found a missense variant in one allele in 4 of 19 patients with CVID and 1 of 16 with sIgAD, absent in 50 controls, with cosegregation in relatives and inability of mutant B cells to produce IgG and IgA in response to APRIL [32]; in the same issue, Salzer and colleagues described homozygous and heterozygous variants in 13 patients with CVID, with abolition of APRIL binding by the S144X and C104R variants (historical designations, = NM_012452.3:c.431C>G p.(Ser144Ter) and NM_012452.3:c.310T>C p.(Cys104Arg)) [33].

The 2007 reassessment changed the interpretation. In patients with CVID from Sweden, Germany and the USA, C104R was present in 16 of 846 alleles versus 17 of 4208 in controls (OR 4.16; 95% confidence interval, 95% CI, 1.98–8.74) and A181E in 22 of 844 versus 20 of 3924 (OR 5.60; 95% CI 2.99–10.51) [9]. In 254 Swedish adults with sIgAD (sporadic cases or probands from multicase families), there was no excess of C104R (1/478 alleles versus 8/2038 in Swedish controls), A181E or ins204A, no homozygotes or compound heterozygotes were found, and sIgAD did not cosegregate with the variants in families; a sister of a CVID proband, heterozygous for A181E, had sIgAD, but the mother with the same variant had normal immunoglobulins [9]. The authors concluded that these heterozygous variants are risk factors for CVID, with a minimal role, if any, in sIgAD [9].

The 2025–2026 data consolidate this model. Rare deleterious heterozygous TNFRSF13B variants are present in approximately 10% of patients with predominantly antibody deficiency but also in approximately 1% of the healthy population; in 161 Iranian patients with these variants, disease required additional contributors (biallelic variants, the HLA class II marker DPA1*03, B-cell gene polymorphisms and pathogenic variants in other IEI genes in 16% of heterozygotes) [41]. In a Turkish series of 21 patients, the spectrum ranged from asymptomatic carrier status to CVID and combined immunodeficiency, with overlap between monoallelic and biallelic carriers and C104R as the most frequent variant (57%) [42]. The 2024 IUIS classifies TACI deficiency as autosomal recessive or dominant and notes that heterozygous variants are probably modifiers rather than causal [3]. Biallelic loss-of-function variants cause CVID2, a relationship classified as definitive by the Clinical Genome Resource (ClinGen) under a recessive model; ClinGen has no validity assertion for TNFRSF13B and sIgAD, although OMIM maps the IGAD2 locus (609529) to this gene [11]. Orphanet records only three cases or families with a CVID phenotype due to homozygous TACI deficiency (ORPHA:696907) [13]. A 2022 review cites at least one mutant allele in 13% of patients with sIgAD, but causality remains controversial and the same variant may occur in relatives with sIgAD or CVID [5].

2.7. Monogenic and chromosomal causes of low IgA

Although isolated sIgAD is polygenic, absent or low IgA forms part of the phenotype of several monogenic and chromosomal disorders [26, 43]. IFIH1 encodes melanoma differentiation-associated protein 5 (MDA5), a cytoplasmic viral RNA sensor that activates type I interferon production through mitochondrial antiviral signalling protein (MAVS) [44]. The clearest example of a Mendelian cause of IgAD with autoimmunity is the de novo gain-of-function variant IFIH1 p.(Arg779His), found by exome sequencing in a 16-year-old girl with severe, early-onset refractory SLE, IgAD and mild lower-limb spasticity, with elevated serum interferon α; the same variant causes Aicardi-Goutières syndrome type 7, illustrating the phenotypic heterogeneity of an identical variant [3, 45]. Other causes include RAC2 deficiency (autosomal recessive, with low IgG, IgA and IgM and IgAD mentioned by the IUIS), deletions of the immunoglobulin heavy-chain region at 14q32, which may remove IgA together with IgG subclasses and IgE, and large chromosomal rearrangements such as 18q deletion [3, 4, 10]. IL-10 and IL-6 polymorphisms and innate, phagocytic, complement and combined immune defects have been described in isolated cases [26]. A 2024 review summarises the genetic and epigenetic factors involved in B-cell development, IgA class-switch recombination and IgA+ plasma cell survival [46].

2.8. Variants of interest and standardised nomenclature

The TNFRSF13B and IFIH1 variants cited in the literature use historical protein names; the following table presents them in Human Genome Variation Society (HGVS) nomenclature, on the MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript, validated with VariantValidator, with the ClinVar classification consulted in October 2026 [47, 48]. The benign ClinVar classification of GWAS risk variants does not contradict their population association: these are small effects rather than Mendelian variants.

2.9. Pathophysiology of manifestations

The absence of secretory IgA reduces antigen exclusion at respiratory and digestive mucosal surfaces, explaining the predominance of sinopulmonary infections due to encapsulated bacteria and giardiasis; symptomatic giardiasis is associated with low intestinal secretory IgA independently of the serum level [26]. More severe infections are concentrated in patients with concomitant IgG2 or IgG4 deficiency or a poor response to pneumococcal polysaccharides, and reduced class-switched memory B cells are associated with pneumonia, bronchiectasis and autoimmunity [4, 26]. Autoimmunity results from shared risk loci (HLA, IFIH1, CLEC16A and others), reduced regulatory T cells and possibly greater mucosal antigen exposure [8, 26]. The association with coeliac disease may arise partly from linkage disequilibrium with HLA-DQB1*02, an allele present in at least 95% of children with coeliac disease [35]. Rare transfusion anaphylaxis depends on anti-IgA antibodies in the recipient and factors in the transfused component (section 7.7).

3. Clinical Spectrum and Manifestations by System

3.1. Overview and phenotypes

Most people with sIgAD have no disease attributable to the deficiency: reviews place the asymptomatic proportion at 85–90%, and fewer than 30% have evident clinical manifestations [10, 26, 35]. Swain and colleagues propose five phenotypes: asymptomatic, minor infections, allergic, autoimmune and severe disease [26]. Serum IgA levels do not correlate with severity, infections or autoimmunity [26]. Expression varies with age: allergy and infection predominate in childhood, whereas autoimmunity develops mainly in adulthood [26]. The estimated clinical burden depends strongly on how patients are identified, because blood donors identified through screening, immunology clinic patients and hospital registry patients represent different populations; the figures below should be read with this limitation in mind. In the tables and text, HR denotes the hazard ratio estimated in cohorts.

3.2. Infections

Infections are the most frequent manifestation in symptomatic patients and mainly involve the respiratory tract: recurrent sinusitis and pneumonia due to Streptococcus pneumoniae and Haemophilus influenzae, less frequently otitis media, and rare invasive disease [10, 26]. Up to one-third of symptomatic patients have recurrent infections (viral, otitis media, sinopulmonary and gastrointestinal); sepsis and meningitis are unusual [4]. In the Swedish national cohort of 2100 patients, the proportion with any infection recorded during inpatient or hospital outpatient care was 36.1% versus 18.8% in controls (prevalence ratio 2.4; 95% CI 2.2–2.6), with an excess of respiratory (17.8% vs 6.3%; 3.2), gastrointestinal (6.0% vs 1.8%; 3.5), skin (4.1% vs 2.2%; 1.9) and urinary infections (6.1% vs 3.4%; 1.8), otitis and mastoiditis (2.1% vs 1.1%; 2.0), sepsis (1.5% vs 0.45%; 3.4) and meningitis (0.38% vs 0.12%; 3.2) [24]. The absolute figures for sepsis and meningitis remain low, and the cohort includes only people whose IgA was measured in hospital.

In donors identified without complaints, the excess is smaller. In Iceland, both donors with incidentally discovered sIgAD and clinic patients had more infections than matched controls, with more respiratory viral infections, laryngitis and conjunctivitis [26]; in the 2025 Icelandic population-based cohort, adults had a greater burden of sinusitis and pneumonia [36]. In Denmark, 177 IgA-deficient donors showed only a trend towards more antimicrobial prescriptions (HR 1.19; p = 0.05), with no difference in hospital infections (HR 1.02), worse self-reported mental health in a subgroup of 28 and higher C-reactive protein in a subgroup of 10; the authors concluded that specific precautions were not justified in these donors [51]. In a Turkish series of 225 children with recurrent sinopulmonary infections, those with immunodeficiency, including sIgAD, tended to have more chronic lung damage, and bronchiectasis is a possible complication [10, 26].

The infectious pattern worsens when sIgAD coexists with IgG subclass deficiency (especially IgG2) or a poor polysaccharide response, although this association has not been consistently replicated [10, 26, 35]. In a study of children with respiratory infections, 9.3% had IgAD, 8.4% subclass deficiency and 1.4% both [4]. In two Turkish paediatric series, isolated IgG3 or IgG4 deficiency was not associated with a higher frequency of infections [52]. In an Israeli national cohort of 12,230 adults with sIgAD and 48,920 controls (2020–2022), first SARS-CoV-2 infection was not more frequent (13.0% vs 14.0%; adjusted OR 1.03), but reinfection (OR 1.15; 95% CI 1.09–1.22) and COVID-19 hospitalisation (OR 1.40; 95% CI 1.22–1.60) were more frequent, with the limitations of a study requiring measured IgA and not distinguishing incidental hospitalisations [53].

3.3. Gastrointestinal manifestations

Giardia lamblia is the most closely associated parasite, causing chronic diarrhoea, malabsorption and lymphoid hyperplasia; response to metronidazole may be incomplete, and defence against rotavirus appears adequate [26]. Other gastrointestinal diseases described include lactose intolerance, coeliac disease, ulcerative colitis, Crohn's disease, nodular lymphoid hyperplasia and neoplasia [5, 10]. Nodular lymphoid hyperplasia associated with giardiasis constitutes Herman syndrome and is considered a risk factor for gastrointestinal lymphoma [26]. Usually located in the small intestine, it may occur at atypical sites: subacute rectosigmoid obstruction due to nodular lymphoid hyperplasia has been described as the presentation of undiagnosed sIgAD [54].

Coeliac disease is the most extensively studied autoimmune association. In the Swedish cohort, 6.7% of patients with IgAD had coeliac disease versus 0.19% of controls, a prevalence ratio approaching 35 [22]. Conversely, sIgAD affects 2–3% of patients with coeliac disease (approximately 1:40 to 1:50), compared with 0.6% in a cited Spanish population [14, 26, 35, 55]. Estimates of coeliac disease in children with sIgAD range from 7.7% (Meini) and 8.7% (11 of 126 children aged 2–20 years, Lenhardt, all with HLA-DQ2 or DQ8) to 14% in an Italian series of 184 children and 15–30% when another autoimmune disease is already present [26, 35]; GeneReviews cites 2–10% according to the 2005 US National Institutes of Health (NIH) consensus [14]. In the USA, patients with coeliac disease and sIgAD had more other autoimmune diseases than those with coeliac disease without IgAD [26]. Patients do not produce IgA anti-gliadin, anti-transglutaminase or anti-endomysial antibodies, but may produce the corresponding IgG antibodies, affecting diagnosis (section 5.5) [10].

3.4. Allergy

Allergy is frequent, but its magnitude depends on the series. In a review of 21 studies with 534 patients, asthma was the most frequently described manifestation, followed by rhinitis and atopic dermatitis; allergy affected more than 30% and was the first manifestation in up to 40%, although an excess relative to the general population has not been demonstrated because of cohort heterogeneity [5]. Reported frequencies range from 13% (127 patients aged 2–67 years in the USA) and 48% (126 Brazilian children and adolescents) to 58% in an older study and 84% in a series aged 4–32 years, and total IgE is frequently increased [10, 26, 35]. In a Swedish prospective study, children with sIgAD had more pseudocroup in the first year and more reported food hypersensitivity at 4 years [10]. Among 4700 young applicants to the Italian air force, 0.34% had sIgAD and none had bronchial hyperresponsiveness to methacholine [26]. In Iceland, asthma was as frequent as in controls and allergic rhinoconjunctivitis more frequent in Swain's series; in the 2025 cohort, cutaneous atopy (eczema and urticaria) predominated [26, 36]. In Istanbul, 62.7% of 110 children aged 4–18 years had allergic sensitisation, associated with a family history of allergy, eosinophilia and elevated IgE, and less frequent in those with autoimmunity [56]; at two Turkish centres, 66.7% of 45 children had asthma, rhinitis or atopic dermatitis [52]. Allergic inflammation predisposes to sinusitis and otitis, so atopy control forms part of infection prevention [4].

3.5. Autoimmunity

Autoimmunity affects 3% to 79% of patients depending on the population and disease considered; reviews place most estimates between 5% and 30% [26, 35]. It is more frequent in adults and women: in a 2004 study, 28% had autoimmunity at a median age of 29 years, with immune thrombocytopenic purpura (ITP) the most common condition, followed by autoimmune haemolytic anaemia (AIHA), juvenile idiopathic arthritis (JIA), thyroiditis and SLE; in a younger population, the frequency was 19% [10]. First-degree relatives also have more autoimmunity (10% vs 5%) [26]. Autoantibodies without disease are frequent: in the Brazilian series, 60.7% had autoantibodies, mainly antinuclear antibodies (67.7% of positive patients), anti-thyroglobulin and anti-thyroid peroxidase (38.7% each), appearing from 3 years of age [10, 21]. The table summarises prevalence ratios in the Swedish cohort [22].

A geoepidemiology review classified the association with SLE, hyperthyroidism and hypothyroidism, T1D, inflammatory bowel disease, rheumatoid arthritis, JIA, ankylosing spondylitis and vitiligo as strong, the association with scleroderma, coeliac disease, autoimmune hepatitis, ITP and AIHA as weaker, and the association with myasthenia, lichen planus and multiple sclerosis as minimal or absent [57]. The classification of coeliac disease as a weak association differs from the prevalence ratio of 35 in the Swedish cohort and from coeliac disease guidelines, which include IgAD among risk groups; the difference probably reflects the way heterogeneous studies were aggregated, and the Swedish population-based cohort, despite selection bias, is the most robust quantitative source [22, 55, 57]. In paediatric series, autoimmunity affected 13.3% (Hashimoto thyroiditis, vitiligo, ITP) of 45 Turkish children and 17.3% in another Turkish series, and in Koskinen's long-term follow-up the mean age at onset was 31 years [21, 52]. Autoimmune cytopenias (neutropenia, thrombocytopenia) and lupus-like and arthritic diseases form part of the spectrum described by the US practice parameters [4].

3.6. Neoplasia

In a cohort of 386 Danish and Swedish patients, overall cancer incidence was not increased, with a non-significant increase in gastric cancer [26]. In the Swedish cohort of 2320 patients with IgA <0.07 g/L (1980–2010), cancer occurred at 61 per 10,000 person-years versus 47 in the 23,130 controls (HR 1.31; 95% CI 1.09–1.58), with an excess of gastrointestinal cancer (HR 1.64; 95% CI 1.07–2.50) and a non-significant increase in lymphoproliferative neoplasms (HR 1.68; 95% CI 0.89–3.19); the excess was concentrated in the first year after diagnosis (HR 2.80; 95% CI 1.74–4.49), suggesting surveillance bias, and was not explained by coeliac disease [23, 26]. In the Brazilian series, 3 of 51 children had neoplasia (two cases of Langerhans cell histiocytosis and one Hodgkin lymphoma) [21].

3.7. Other manifestations

In a US series of 15 renal biopsies with completely absent background IgA immunofluorescence, only one patient had a previous diagnosis of sIgAD; of the 10 with available immunoglobulin measurements, 9 were consistent with sIgAD, most with acute kidney injury with or without proteinuria and immune-mediated glomerulopathies, particularly lupus nephritis [58]. Pernicious anaemia and autoimmune atrophic gastritis have been described in association (section 10) [59]. Reactions to blood products and immunoglobulin are covered in section 7.

3.8. Paediatric natural history: the São Paulo series

The series from the Children's Institute of Hospital das Clínicas, Faculty of Medicine, University of São Paulo describes the natural history of 51 children with symptomatic sIgAD (IgA <0.07 g/L, normal IgG and IgM, age >4 years, excluding other IEIs, genetic syndromes and drug-induced causes), followed for a mean of 10 ± 2.8 years [21]. The median age at the first symptom was 1 year and at diagnosis 6 years. Almost all had infections (98%), particularly pneumonia (94%), sinusitis (approximately 70%) and gastrointestinal infections (54%), with a median onset at 1 year; 92.1% had allergy, with median onset at 5 years (rhinitis in 97.8% of allergic patients, asthma 67%, atopic dermatitis 19.1%); 19.6% had autoimmunity, with median onset at 8 years (thyroiditis in 60%, ITP and SLE), always associated with other manifestations [21]. The sequence infections → allergies → autoimmunity was statistically significant. Half the children had hypergammaglobulinaemia (IgG or IgM above the 97.5th percentile), associated with autoimmunity and autoantibodies, and 20 of 51 had elevated IgE without correlation with allergy; severe events (otomastoiditis, sepsis, osteomyelitis) were rare [21]. The evolution of IgA and progression to CVID in this series are described in section 11.

4. Clinical Recognition and Warning Signs

sIgAD is most often an incidental finding: it is discovered during blood donor screening, during coeliac disease investigation when total IgA is measured, or after a transfusion reaction [26, 59]. Clinical suspicion should arise with recurrent sinopulmonary infections, severe allergic rhinitis or asthma, coeliac disease, autoimmune thyroiditis, autoimmune cytopenias, JIA or SLE, and evaluation is mandatory after anaphylaxis to blood products and when there is a family history of immunoglobulin deficiencies [26]. Age guides interpretation: in a young child with recurrent infections, low IgA may merely reflect immaturity or transient hypogammaglobulinaemia of infancy, and definitive diagnosis is established only after 4 years [21, 35]. In the Netherlands, when IgA was standardised using age-specific percentiles, IgAD was found in 2.9% of children aged 2 or older with recurrent respiratory infections versus none of 189 controls [60].

Signs of deterioration requiring immunological reassessment include falling IgG or IgM, loss of vaccine responses, severe or invasive infections, bronchiectasis, autoimmunity and cytopenias, because they may herald progression to CVID [4, 63]. The emergency specific to this condition is an anaphylactic reaction to blood products or immunoglobulin, treated with intramuscular adrenaline (section 7.7) [25]. There is no newborn screening for sIgAD, and IgA is physiologically absent at birth [26].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The reference definitions agree on the essentials. The ESID registry working definition, reproduced by Swain and colleagues, requires undetectable serum IgA or a level below 7 mg/dL by nephelometry, age over 4 years, normal IgG and IgM, normal vaccine responses and exclusion of secondary causes of hypogammaglobulinaemia and T-cell defects [26, 34]. The 2015 US practice parameter of the American Academy of Allergy, Asthma and Immunology (AAAAI) and American College of Allergy, Asthma and Immunology (ACAAI) establishes the diagnosis after 4 years of age with IgA <7 mg/dL, normal IgG and IgM and exclusion of other causes of hypogammaglobulinaemia (statement SS96, grade C) [4]. The IUIS describes sIgAD as absent IgA with normal remaining isotypes, subclasses and specific antibodies [3]. The full text of the 2019 ESID definitions was not consulted; the secondary reproduction does not clarify whether the definition includes clinical entry criteria, so the version presented is used.

Source: reproduction of table 1 in Swain and colleagues, adapted from ESID definitions [26]. Applying these definitions in the ESID registry, with more than 25,000 patients, led to reclassification of 8% of adults and 27% of children initially registered as CVID into 22 other IEIs, demonstrating the utility of explicit criteria when no genetic diagnosis exists [34].

5.2. IgA measurement and analytical limits

The threshold of 7 mg/dL (0.07 g/L) was chosen because it corresponds to the lower detection limit of most clinical laboratories [10]. Only methods capable of detecting lower values distinguish absent from very low IgA: approximately two-thirds of people with IgA <7 mg/dL have detectable IgA at a lower level and approximately one-third appear to have complete absence [4]. Measured prevalence depends on the method and threshold (2 to 10 mg/dL depending on the laboratory) [26], and rare donor programmes use much lower thresholds, usually <0.05 mg/dL, to define absolute IgAD [31]. In the Brazilian series, IgA was measured outside infections and repeated throughout follow-up (mean nine samples per patient, with a minimum interval of one year) [21]; standardisation using age- and assay-specific percentiles, proposed in the Netherlands, allows IgAD in young children to be defined as IgA below the 2.5th percentile [60]. Rapid finger-prick tests have been developed for large-scale screening and, in Japan, a latex agglutination reagent with monoclonal antibodies and a detection limit of 0.4 mg/dL, with positive results confirmed by enzyme-linked immunosorbent assay (ELISA) [64, 65].

5.3. “Partial IgA deficiency”: a terminological divergence

Sources disagree on how to label IgA below −2 standard deviations for age but above 7 mg/dL. Yel and Cinicola and colleagues call it “partial IgA deficiency” and consider it frequent [5, 10]. The 2015 practice parameter recommends that these patients should not be diagnosed with IgAD, because there are no consistent clinical associations in this range (statement SS97, grade C) [4]. In practice, the difference is mainly one of labelling: a child with low but detectable IgA does not meet sIgAD criteria, but should be reassessed because IgA may rise or fall; in the Brazilian series, 9 of 51 children with sIgAD came to have only partially reduced IgA during follow-up [21].

5.4. Additional immunological evaluation

The initial investigation of suspected immunodeficiency includes a full blood count with differential, immunoglobulin measurement, T-lymphocyte subsets and antibody responses to previous immunisations (tetanus, diphtheria) [40]. In symptomatic patients with IgAD, IgG subclasses, responses to protein and polysaccharide (pneumococcal) antigens and immunophenotyping of class-switched memory B cells are added, because subclass deficiency, poor polysaccharide responses and reduced memory B cells are more frequent in symptomatic patients and define different entities or greater risk [4, 26]. Autoantibodies (antinuclear and anti-thyroid antibodies) are useful during follow-up given the frequency of autoimmunity [21]. Investigation of secondary causes (drugs, infections, protein loss) is a mandatory part of diagnosis [4, 26].

5.5. Coeliac disease in patients with IgAD

First-line coeliac serological tests (IgA anti-tissue transglutaminase, tTG-IgA; IgA anti-endomysial antibodies, EMA-IgA; IgA anti-deamidated gliadin peptides, DGP-IgA) depend on IgA and are falsely negative in sIgAD [14, 26]. All guidelines consulted recommend measuring total IgA and using IgG-based tests in IgAD, with differences in detail. TGA-IgA, TTG-IgA and IgA-TG2 denote the same test (IgA anti-transglutaminase 2), as do IgG-TG2, TTG-IgG and tTG-IgG for the IgG version.

Swain and colleagues consider IgG anti-tTG the most reliable serum marker in sIgAD, superior to IgG anti-DGP, whereas ESsCD favours combining the two and ACG expresses reservations about isolated DGP-IgG [26, 55, 61]. Duodenal biopsy (at least 4 specimens from the distal duodenum and 1 from the bulb, while on a gluten-containing diet) remains the diagnostic standard in patients with IgAD, because the paediatric biopsy-free pathway depends on IgA tests [26, 66]. HLA-DQ2/DQ8 typing has a high negative predictive value and, in ESsCD guidance, is the first step in an asymptomatic child at risk [14, 55]. During follow-up, IgG serology declines on a gluten-free diet but may not normalise despite strict adherence, limiting its value for assessing adherence [26, 55]. Multiplex assays with IgA verification beads detect IgAD without separate prescreening, although data remain limited [55].

5.6. Anti-IgA antibodies

Anti-IgA antibodies may be of the IgG or IgE class and directed against IgA in general (class-specific antibodies) or a subclass [67, 68]. They occur in 19% of 159 Finnish donors with severe IgAD (stable levels over 19 years of follow-up, unrelated to previous IgA exposure) and were not found in those with reduced but detectable IgA [69]. In a US series cited by Keller and colleagues, they were present in 79% of patients with absolute IgAD (<0.05 mg/dL) and 21% of those with very low but detectable IgA [31]; in Japan, approximately 32% of IgA-deficient individuals have anti-IgA, mainly naturally occurring [65]. In France, using a standardised commercial technique, IgG anti-IgA was found in 30% of 10 patients with sIgAD, 6% of 32 with other IEIs and 2% of 46 controls [70]. Available assays (ELISA, cytometry, fluorescence enzyme immunoassay, particle gel) are not standardised, there is no consensus on the clinically significant threshold or reference standard, and IgE-class anti-IgA testing, which would be most relevant to anaphylaxis, is not widely available [10, 30]. The predictive value of a positive anti-IgA result is limited: it is considered necessary but insufficient for a severe reaction [31].

5.7. Genetic tests and their limitations

There is no diagnostic genetic test for isolated sIgAD, which has a polygenic basis [8]. HLA typing is useful for coeliac disease, not for diagnosing sIgAD. Testing for TNFRSF13B variants should not be used as a stand-alone predictive test: a heterozygous C104R or A181E variant is a susceptibility factor to be interpreted alongside the immunological phenotype and does not establish a diagnosis, and no functional assay confirms disease attributable to TNFRSF13B [3, 11, 41]. Genetic analysis is indicated when the phenotype suggests another entity: low IgA with dysmorphism, intellectual disability, ataxia or heart disease (chromosomal and monogenic syndromes, section 6), IgAD with severe early-onset autoimmunity, as in IFIH1-related SLE, or antibody deficiency progressing to CVID, in which case the general approach to inborn errors of immunity applies [43, 45]. Abolhassani and colleagues propose clinical and immunological evaluation followed by targeted gene analysis [43]. A negative panel or exome does not exclude a rare monogenic cause, and detecting large deletions (14q32, 18q, 22q11.2) requires copy-number methods. When a variant is reported, the report should specify the gene, transcript with version, HGVS nomenclature, zygosity and classification according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP); ClinVar classification of TNFRSF13B variants is conflicting, which reinforces the need for caution [48].

5.8. Practical algorithm

5.9. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing have no application in isolated sIgAD because there is no identifiable causal variant. They are relevant only when low IgA forms part of a monogenic or chromosomal disorder with a known familial variant.

6. Differential Diagnosis

6.1. Other antibody deficiencies

The essential differential diagnosis comprises entities that share low IgA but have a different prognosis and management. Transient hypogammaglobulinaemia of infancy causes reduced IgG and IgA in young children and is the main reason for not diagnosing sIgAD before 4 years [3, 35]. CVID requires low IgG, markedly low IgA and poor vaccine responses or reduced memory B cells; sIgAD may progress to CVID, both occur in the same families, and CVID diagnosis is immunological and does not depend on the TNFRSF13B genotype [11, 26, 40]. CVID has its own genes, including ICOS, CD19, CD20, CD81, TNFRSF13C/BAFF-R and TNFRSF13B [40, 71, 72]. In the New Zealand CVID cohort, Māori patients had bronchiectasis in 79% versus 38% of Caucasian patients and more complete IgAD, a reminder that absent IgA in CVID is associated with more severe lung disease [73]. IgA deficiency with IgG subclass deficiency and SPAD are distinguished by subclasses and vaccine responses and alter the indication for immunoglobulin [26, 27].

6.2. Secondary causes

Acquired IgAD is associated with drugs, and medication review is recommended (SS99, grade C): phenytoin, carbamazepine, valproic acid, zonisamide, sulfasalazine, gold salts, penicillamine, hydroxychloroquine and non-steroidal anti-inflammatory drugs, with frequent reversibility after withdrawal [4]. Swain and colleagues add disease-modifying antirheumatic drugs and angiotensin-converting enzyme inhibitors, and broad-spectrum antibiotic-induced dysbiosis, with loss of APRIL and BAFF demonstrated in a murine model and bronchoalveolar lavage from intensive care patients [26]. Drug-induced IgAD is generally reversible, but persistent cases occur, as with ciclosporin, which may represent pre-existing sIgAD [26]. Other causes are hepatitis C virus and Epstein-Barr virus infections, myotonic dystrophy and protein-losing enteropathy [26]. Hereditary folate malabsorption (SLC46A1) causes low IgG, IgM and IgA in approximately 25% of patients, corrected by folate [74].

6.3. Genetic syndromes with low IgA

In syndromes, low IgA is usually an accessory manifestation: dysmorphism, developmental delay, ataxia or heart disease dominate the presentation, and diagnosis uses the appropriate cytogenetic or molecular test. In ataxia-telangiectasia, combined IgAD and IgG2 deficiency is associated with a poorer polysaccharide response, and the hyper-IgM phenotype identifies a subgroup with shorter survival [15]. In Nijmegen, subclass deficiency may occur with normal total IgG, and humoral surveillance is more intensive than in sIgAD (every 6 weeks in the first year and then every 3–6 months until IVIG is started) [16]. The frequency of IgAD in 3q29 deletion is based on a self-reported registry and should be interpreted cautiously [78]. The Wolf-Hirschhorn GeneReviews chapter has been retired and is of historical value only; the immunological data derive from a 1998 series [77].

7. Treatments and Risk Management Strategies

7.1. General principles

No treatment restores IgA production, and no IgA-enriched immunoglobulin preparation is available [39, 81]. Asymptomatic people or those diagnosed incidentally do not need treatment; they should be informed about the diagnosis, possible complications and its relevance to any future transfusion, and medical identification (a bracelet or alert card) is recommended by several sources [10, 26]. In symptomatic patients, treatment targets complications (infections, atopy, autoimmunity, coeliac disease), with monitoring over time to detect new complications and progression to another deficiency (SS98, grade C) [4, 26]. Patients with primary immunodeficiency should be followed by a clinical immunologist [40].

7.2. Infections

Acute infections are treated promptly and vigorously with targeted antibiotics [4, 26]. For recurrent sinopulmonary infections persisting despite control of allergy, asthma and rhinosinusitis, the US practice parameter recommends aggressive antimicrobial therapy and/or prophylaxis (SS100, grade C), and Swain and colleagues propose daily, possibly seasonal, antibiotic prophylaxis, continued if effective [4, 26]. The sources consulted do not define a prophylactic regimen (drug, dose and duration) specific to sIgAD; the regimens used in antibody deficiencies apply by analogy. Giardiasis is treated with metronidazole, with possible refractoriness, and reduced exposure to the parasite is recommended [26]. Bronchiectasis, when present, warrants surveillance and treatment specific to this complication [40].

7.3. Allergy and asthma

Atopy should be treated vigorously (SS101, grade C), because allergic inflammation predisposes to sinusitis and otitis and asthma and rhinitis are associated with more severe disease [4, 26]. Treatment follows general guidelines for each allergic disease; the sources consulted describe no pharmacological peculiarities in sIgAD.

7.4. Autoimmunity and coeliac disease

Autoimmune diseases are treated according to their respective guidelines. In coeliac disease, the ACG guideline recommends a strict gluten-free diet and lifelong follow-up [61]; in patients with IgAD, monitoring adherence through IgG serology is limited because these tests may not normalise despite a strict diet [55]. In SLE caused by the gain-of-function IFIH1 variant, disease remained active despite immunosuppression, placing these patients within the scope of interferonopathies [45].

7.5. Immunoglobulin replacement: indications

Immunoglobulin replacement is not indicated in isolated sIgAD. The 2017 AAAAI evidence review classifies it as “unlikely to be beneficial” (evidence IV, recommendation D), as for isolated IgE, IgG4 and IgM deficiencies; if poor specific IgG production coexists, with or without IgG2 deficiency, the phenotype should be treated as specific antibody deficiency [27]. The 2015 practice parameter acknowledges that rare patients may benefit (SS102, grade C): use is controversial and response minimal in most, and a therapeutic trial may be considered when recurrent infections affect quality of life despite aggressive antibiotic therapy and prophylaxis, or when there is antibiotic intolerance or hypersensitivity [4]. Swain and colleagues and the Immune Deficiency Foundation (IDF) restrict benefit to patients with specific antibody or IgG2 deficiency and recurrent severe infections, particularly with bronchiectasis [26, 39]; Yazdani and colleagues accept its use in a justified severe phenotype, using a product with minimal IgA content [81].

When used, the subcutaneous route is preferred by Swain and colleagues and the IDF because it may reduce the risk of clinically relevant anti-IgA antibodies and because patients who reacted to IVIG tolerated subcutaneous immunoglobulin (SCIG); if unavailable, IVIG with the lowest IgA content is used [4, 26, 27, 39]. The IDF statement that anaphylaxis to SCIG has not been reported derives from patient information material [39]. When IgG is low, IgAD is not a contraindication to immunoglobulin (SS12, grade C), and anaphylaxis to IVIG is very rare [4].

7.6. Immunoglobulin products: IgA content, dosing and labels

All immunoglobulin preparations contain some IgA, and the Gammagard S/D® label states that the IgA concentration that does not cause a reaction is unknown [82]. No product is indicated for isolated sIgAD; US Food and Drug Administration (FDA) labels refer to primary humoral immunodeficiency (PI), and the European Medicines Agency (EMA) European public assessment report (EPAR) to primary and secondary immunodeficiencies; use in a patient with IgAD associated with specific antibody or subclass deficiency is a specialist decision within the generic PI indication [82, 83]. The doses below are label doses for PI, rather than validated doses for sIgAD.

The adverse effect defining management in IgAD is hypersensitivity: IgA-depleted preparations (0.4–2.9 µg/mL) were better tolerated by patients who had reacted to products containing more IgA, but anaphylaxis occurred despite the low content [82]. Management consists of selecting a low-IgA product or the subcutaneous route, starting at a slow rate, having adrenaline available and observing the patient; severe reactions require discontinuation and specialist evaluation [27, 82, 85]. Other class effects (thrombosis, renal dysfunction) follow label warnings [83].

Table sources: labels and EPAR [82–86] and company announcement [87]. The Takeda announcement states that Gammagard Liquid ERC® is not specifically indicated for IgA sensitivity but may be considered on clinical judgement, and that the risk of anaphylaxis remains [87]. Deqsiga® trials included in the EPAR were conducted in patients with primary immunodeficiency and ITP, rather than sIgAD: in 22 patients with primary immunodeficiency, the non-serious infection rate was 0.48 per patient-month, with no serious infections, and in a 12-month study with 61 patients it was 0.07 per patient-year [84]. Access to these low-IgA formulations in Portugal and Brazil was not documented in the sources consulted.

7.7. Transfusion, anti-IgA antibodies and anaphylaxis

The relationship between IgAD, anti-IgA antibodies and transfusion reactions was described in 1968 and led for decades to the recommendation for components from IgA-deficient donors or washed components [29, 30]. Accumulated evidence shows that the actual risk is very low. Older estimates of anti-IgA-mediated anaphylaxis range from 1:20,000 to 1:47,000 transfusions [26]. In French haemovigilance from 2004–2014, among 9074 hypersensitivity reactions in more than 5.7 million transfused patients, 18 patients had possible IgAD or IgG anti-IgA, a maximum frequency of 1 per 871,911 transfusions; in a review of more than 10 million transfusions, only 3 of 229 anaphylactic or severe allergic reactions were confirmed as IgA-mediated (data cited by Keller and colleagues) [31]. The 2023 British Society for Haematology (BSH) guideline emphasises that haemovigilance does not show a greater incidence of IgAD in patients with anaphylaxis, that there is no evidence of a causal role for anti-IgA and that reactions in patients with IgAD more often have inflammatory features (fever, chills, myalgia) with rapid onset within the first 15 minutes [25].

The role of anti-IgA is debated. It is considered necessary but insufficient: in a US series, hypersensitivity reactions occurred in two-thirds of patients with anti-IgA and none without anti-IgA, and the current model combines recipient predisposition (activated basophils and mast cells, passive IgE, inflammation) with component mediators (IgA, haptoglobin, CCL5, complement fractions) [31]. For therapeutic immunoglobulin, Rachid and Bonilla concluded that the causal role of IgG or IgE anti-IgA remains controversial, depending on concentration, isotype, specificity, method, product IgA content and route [67]; Collet and colleagues assembled 38 patients with IgG anti-IgA and immunoglobulin hypersensitivity and 9 with anti-IgA and good tolerance, documented complement activation after infusion and proposed complement-mediated pseudoallergy as an alternative explanation [70]. The AAAAI review adds that IgE anti-IgA may cause anaphylaxis and IgG anti-IgA reactions through complement activation, but that the great majority of patients with low IgA, with or without IgG anti-IgA, receive IVIG without difficulty, and that in CVID IgG anti-IgA (10–22%) does not correlate with reactions [27]. In a Québec series of 272 components from IgA-deficient donors, the frequency of minor allergic reactions did not differ between donors with and without anti-IgA (1.15% vs 2.04%), and there was no anaphylaxis [88].

Recommendations differ. BSH 2023, which replaced the 2012 British Committee for Standards in Haematology guideline [89], adopts an approach based on reaction history, while Keller and colleagues, on behalf of the International Society of Blood Transfusion (ISBT) rare donor working group, propose an approach based on history and anti-IgA; the IDF and Yel recommend washed components or components from IgA-deficient donors for all patients with sIgAD needing transfusion; the US practice parameter considers the risk “unclear, probably small” and records variable practices [4, 10, 25, 31, 39].

Practice heterogeneity was documented in two international surveys published in 2026. In the Biomedical Excellence for Safer Transfusion (BEST) survey, 55% of physicians reported that local practice was to provide IgA-deficient products only to patients with a history of severe allergic reaction and confirmed anti-IgA (67% in the Americas, 44% in Europe); more than 80% test anti-IgA in confirmed IgA-deficient patients, but approximately 20% (30% in Europe) do not test before requesting products; there is no consensus on the anti-IgA threshold or reference standard; and 45% had requested at least one type of IgA-deficient product within five years [30]. In the ISBT survey of 35 rare donor programmes in 28 countries, 17 programmes in 11 countries (including Italy, Spain, Switzerland, the United Kingdom, the USA, Canada and Brazil) consider absolute IgAD a rare phenotype, 14 actively screen donors (most common threshold <0.05 mg/dL), 922 donors were registered in programmes using this threshold, and requests in 2019–2023 were few and mostly met with washed products [31]. In Brazil, Hospital Sírio-Libanês (active donor screening) and the Unicamp blood centre (family studies) responded [31]. Washed platelets have a shelf life of 4–6 hours and entail platelet loss, and alternatives include platelets in additive solution or with pathogen reduction, containing less plasma protein [31]. Approximately two-thirds of services would accept group A plasma or platelets with low-titre anti-B if group-identical or AB IgA-deficient components were unavailable [30].

Anaphylaxis is treated with intramuscular adrenaline, even in patients with thrombocytopenia or coagulopathy (1A), and transfusion should take place only where the patient can be observed by a trained team (1C) [25]. In a German series of 10 adults with anti-IgA (9 with CVID and 1 with IgAD and paroxysmal nocturnal haemoglobinuria), tolerance induction through controlled IgG infusions reduced or eliminated anti-IgA and allowed regular IVIG for up to 10 years and transfusion of normal components without complications; interruption and re-exposure caused reactions [90]. This approach is based on a small series and is not routine practice. Before chronic transfusion programmes, as in thalassaemia, GeneReviews recommends measuring immunoglobulins to identify IgAD, and the chapter on hereditary folate malabsorption mentions washed red cells in patients with IgAD [62, 74].

7.8. Vaccination

Sources agree that inactivated vaccines are safe and should be administered, including pneumococcal and influenza vaccines, and differ regarding live vaccines.

The best-supported position for sIgAD without another defect is that of IDSA, which contraindicates only oral poliovirus vaccine, no longer used in the USA; the CDC/ACIP list is more restrictive but acknowledges the lack of data for yellow fever, and the position of Swain and colleagues applies mainly to patients with associated defects [26, 91, 92]. Apparently minor antibody deficiencies may coexist with cellular immune defects, as in DiGeorge syndrome, which should be checked before live vaccines [91]. Household contacts should receive all vaccines, including measles-mumps-rubella, varicella, rotavirus and influenza [92]. In children with SPAD or ataxia-telangiectasia, IDSA recommends 13-valent pneumococcal conjugate vaccine and, from 2 years of age, 23-valent polysaccharide vaccine at least 8 weeks later, with a second dose 5 years later [91].

7.9. Special populations: pregnancy, lactation, perioperative care and transition

In the Swedish cohort of 613 mothers with IgAD (1172 singleton deliveries, 1973–2010) compared with 5758 controls, birth weight was 79 g lower, gestation 1.4 days shorter, preterm delivery did not differ significantly (5.8% vs 5.2%; OR 1.13), small-for-gestational-age birth was more frequent (4.3% vs 2.8%; OR 1.48; 95% CI 1.04–2.10), as was caesarean delivery (16.9% vs 11.9%; OR 1.51), with no difference in Apgar score; the excesses attenuated when women with autoimmune disease were excluded [93]. In 1985, isolated anti-IgA2 antibodies were found in 20% of 61 IgA-deficient pregnant women versus 7.5% of pregnant women without deficiency, declining after delivery, and children of IgA-deficient mothers (but not fathers) had below-average IgA, particularly when the mother had anti-IgA; the hypothesis of a transplacental effect was not replicated in the sources consulted [68]. Any peripartum transfusion follows the recommendations in section 7.7. The sources consulted describe no breastfeeding data in sIgAD.

In the perioperative setting, the IgAD diagnosis should be recorded in the medical record and communicated to the blood service when transfusion is anticipated, applying the recommendations in section 7.7 [25, 31]. During transition to adulthood, surveillance should shift from infections and allergy towards autoimmunity, which predominates in adults, and possible progression to CVID [10, 26].

7.10. Clinical trials

There are no ongoing therapeutic trials targeting sIgAD. The October 2026 ClinicalTrials.gov search found only one interventional trial targeting the condition, from 2001–2004, and one observational immunoglobulin hypersensitivity study with a cohort of patients with sIgAD; a negative search does not prove the absence of other studies [94, 95].

Therapeutic evidence in sIgAD therefore rests on observational studies and expert consensus with grades C and D. Recommendations on immunoglobulin, antibiotic prophylaxis and transfusion do not derive from randomised trials in this population, and immunoglobulin product trials were conducted in patients with primary immunodeficiency and low IgG. Associations in the Swedish and Israeli cohorts are prevalence or risk ratios that should be read in light of the absolute rates, which are low for severe outcomes.

7.11. Developments in the past 6–12 months (October 2025 to October 2026)

7.12. Guideline recommendations and divergences between sources

Recommendations from the guidelines and consensus documents consulted have been integrated into the preceding sections; the table brings together the six identified divergences and the interpretation adopted.

8. Reproductive Options and Family Counselling

8.1. Inheritance model and recurrence risk

sIgAD does not follow a Mendelian pattern in most families: it is usually sporadic, but autosomal recessive and dominant patterns have been observed, and overall inheritance is polygenic and multifactorial, with the largest known contribution in the HLA region [5, 8]. Counselling therefore rests on empirical risks. Approximately 20–25% of patients have a family history of sIgAD or CVID, and the IDF reports familial transmission in approximately 20% of cases [4, 39]. In Finland, 7.2% of first-degree relatives of 35 index cases had sIgAD, and in Sweden concordance was 31% in monozygotic and 13% in dizygotic twins [26]. Heritability was estimated at 0.49 in a Swedish cohort [8]. The US practice parameter reports possible male predominance [4].

In the only first-degree relative study included in the sources consulted, the observed risk (7.2%) was several times higher than donor prevalence and, as in the general sIgAD population, most affected relatives would be expected to be asymptomatic [10, 26]. The same family may include people with sIgAD and CVID, and a TNFRSF13B variant may be present in relatives with either phenotype and in healthy relatives [5, 9]. A 1985 study found below-average IgA in 21 of 27 children of IgA-deficient mothers, but not fathers, particularly when the mother had anti-IgA during pregnancy; the transplacental effect hypothesis was not confirmed by subsequent studies included in the sources consulted [68].

8.2. Testing relatives

There is no predictive or carrier genetic test for isolated sIgAD, and TNFRSF13B variant testing does not serve this purpose [3, 8, 41]. Immunoglobulin measurement in symptomatic relatives (recurrent infections, autoimmunity) is reasonable given the familial clustering of sIgAD and CVID, and the result has practical relevance to potential transfusions [4, 26]. Autoimmunity is more frequent in first-degree relatives of patients with sIgAD (10% vs 5%) [26].

8.3. Prenatal and preimplantation diagnosis and minors

Prenatal diagnosis and preimplantation genetic testing do not apply to isolated sIgAD; they are relevant only when low IgA forms part of a monogenic or chromosomal disorder with an identified familial variant (section 6). In minors, IgA measurement is interpretable only after 4 years and should be prompted by symptoms or a clinical need, such as coeliac disease investigation or preparation for transfusion [4, 35, 55].

8.4. Counselling content

Counselling should explain that sIgAD is frequent and almost always benign, that definitive diagnosis requires age over 4 years and exclusion of other causes, that recurrence risk is empirical and based on familial clustering, and that no useful genetic test exists for the isolated form. It should also explain the implications for transfusions and immunoglobulin and the importance of communicating the diagnosis to healthcare professionals, the need for surveillance for autoimmunity and coeliac disease, the possibility of progression to CVID and the fact that a heterozygous TNFRSF13B variant found on a panel is a risk factor rather than a diagnosis [11, 25, 26, 63].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each study measures

sIgAD prevalence varies with ancestry, the population studied (blood donors, pregnant women, schoolchildren, clinic patients or hospital registry patients), and the detection method and threshold, which range from less than 1 to 10 mg/dL [10, 26]. Donor studies measure a healthy adult population, underrepresenting more severely affected patients; clinic series overestimate the clinical burden; and hospital registry cohorts, such as the Swedish ones, include only people whose IgA was measured. Orphanet classifies the entity as non-rare in Europe and records no estimate [2]; prevalence is probably underestimated [10].

Outside the USA and Europe, estimates from the Arabian Peninsula, Spain and Nigeria are among the highest and those from East Asia among the lowest, partly related to the frequency of HLA risk haplotypes [10, 26]. The proportions of symptomatic patients vary between 10% and 35% depending on the series [21].

9.2. Founder populations and genetic variation

The HLA region explains most of the known variation. The 8.1 haplotype is more frequent in northern Europe, and the DRB1*01:02-DQB1*05:01 haplotype is more frequent in southern Europe and Iran [35]. In China, the lower frequency of risk haplotypes in the general population has been proposed as an explanation for lower prevalence [26]. Swedish and Icelandic populations, with national registries and historical donor screening, provide most genetic association and natural history data [7, 22, 36]. In New Zealand, Māori patients with CVID have more complete IgAD and bronchiectasis [73].

9.3. Portugal and Brazil

The sources consulted do not describe prevalence data for Portugal; this absence does not demonstrate that no published studies exist. In Brazil, prevalence among donors and pregnant women in São Paulo was 1:965, similar to other countries according to the authors [19]; the paediatric series from the Children's Institute of the University of São Paulo describes the natural history of 51 symptomatic children [21]; a Brazilian series of 126 children and adolescents found respiratory allergies and atopic dermatitis in 48% [10]; and two rare donor programmes (Hospital Sírio-Libanês and the Unicamp blood centre) responded to the international IgAD survey [31].

9.4. Special populations

In young children, low IgA is physiological and diagnosis is established only after 4 years [35]. In pregnant women, the Swedish cohort showed more small-for-gestational-age newborns and more caesarean deliveries, attenuated after excluding autoimmunity (section 7.9) [93]. In IgA-deficient blood donors, physical health does not differ from that of other donors and no specific precautions are justified [51]; their components, with or without anti-IgA, were safely transfused in a Canadian series [88]. Patients receiving chronic transfusions (thalassaemia) should have immunoglobulins measured before starting the programme [62].

9.5. Reference networks and patient associations

The relevant European reference network is ERN RITA (European Reference Network on Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases) [28]. ESID maintains the registry and working definitions [97]. Patient associations include the International Patient Organisation for Primary Immunodeficiencies (IPOPI) [98], the Portuguese Association of Patients with Primary Immunodeficiencies (APDIP) [99], the Immune Deficiency Foundation in the USA [39] and PID UK in the United Kingdom [40]. It was not possible to verify the website of the Brazilian immunodeficiency group.

10. Illustrative Clinical Case

Yoshino and Kosugi described in 2025 a 70-year-old Japanese man with a history of surgery for gastric carcinoid and sigmoid cancer who presented with two months of fatigue, malaise, anorexia and glossodynia [59]. At the local clinic, his haemoglobin was 5.2 g/dL, and upper gastrointestinal endoscopy showed neither ulcer nor neoplasia. At the hospital he was jaundiced, with macrocytic anaemia (haemoglobin 5.0 g/dL; mean corpuscular volume 113.5 fL; reticulocytes 3.21×10⁴/µL), platelets 5.8×10⁴/µL, lactate dehydrogenase 3220 U/L, total bilirubin 2.2 mg/dL (direct 0.8 mg/dL) and a negative direct Coombs test [59].

Packed red cells were transfused after crossmatching. Thirty minutes after starting, fever of 39.4 °C and chills developed, the transfusion was stopped and the episode interpreted as a febrile non-haemolytic reaction; blood cultures were negative and antibiotics were discontinued on the fourth day [59]. The blood film showed hypersegmented neutrophils and schistocytes, with low haptoglobin but normal ADAMTS13, C3 and C4, negative antinuclear and anticardiolipin antibodies and CT without lymphadenopathy or neoplasia, excluding thrombotic microangiopathy and leading to a diagnosis of pseudomicroangiopathy due to vitamin B12 deficiency. Endoscopy showed atrophic gastritis of the body and fundus (article figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC12257979/figure/f1-amjcaserep-26-e947678/), and biopsies revealed partial intestinal metaplasia in the antrum, loss of fundic glands (figure 2, haematoxylin-eosin: https://pmc.ncbi.nlm.nih.gov/articles/PMC12257979/figure/f2-amjcaserep-26-e947678/), hyperplasia of chromogranin A-positive cells (figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC12257979/figure/f3-amjcaserep-26-e947678/) and antral G-cell hyperplasia with loss of gastrin-producing cells in the body (figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC12257979/figure/f4-amjcaserep-26-e947678/). Anti-parietal cell and anti-intrinsic factor antibodies were negative, and pernicious anaemia was diagnosed histologically [59].

The patient received intravenous vitamin B12, 500 µg on alternate days, without further transfusions; haemoglobin rose to 7.4 g/dL at discharge (day 11) and 10.2 g/dL on day 28, and vitamin B12 was changed to weekly intramuscular administration in the first month and quarterly thereafter, with haemoglobin normalisation [59]. Serum IgA was below the assay limit, and on day 20 after discharge IgA <3 µg/dL with positive IgG-class anti-IgA antibodies was confirmed, establishing the sIgAD diagnosis. A medical alert bracelet was recommended, which the patient declined [59].

The case illustrates three aspects of this article. First, sIgAD is frequently diagnosed only after a transfusion reaction or during donor screening, even at an advanced age [26, 59]. Second, the described reaction was febrile rather than anaphylactic, the reaction type BSH 2023 more frequently associates with IgAD [25]. Third, the association with an autoimmune disease (atrophic gastritis with pernicious anaemia) is compatible with the autoimmune spectrum of sIgAD, although a causal relationship was not demonstrated and genetics were not investigated [59]. The authors recommend products from IgA-deficient donors or washed components when anti-IgA is present; this approach is more restrictive than BSH 2023, which reserves washed components for patients with a reaction history, and agrees with the ISBT proposal for patients with anti-IgA and a documented reaction, as this patient had [25, 31, 59].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis is good when sIgAD is not associated with significant disease [10, 39]. In the 20-year follow-up of 159 initially healthy Finnish donors with severe IgAD and 45 with reduced IgA, pneumonia, recurrent respiratory infections and autoimmune disease were more frequent in middle age (vitiligo, autoimmune hypothyroidism, milk intolerance and possibly rheumatoid arthritis associated with severe IgAD), and 80% (163 of 204) had infections, drug allergy, autoimmune or atopic disease, but IgAD in a healthy adult did not predict severe life-threatening disease [50]. In the Swedish cohort of 2495 patients identified through hospital IgA measurement (1980–2012), there were 102 deaths per 10,000 person-years versus 62 in the 24,509 controls (HR 1.8; 95% CI 1.6–2.1), with the greatest excess in the first year (HR 3.6), persistence in years 1–9 (HR 1.9), attenuation at 10–15 years (HR 1.5; p = 0.054) and no excess at 15–25 years (HR 1.1); relative mortality was greater in younger patients [49]. These figures reflect patients with a clinical reason for IgA measurement rather than the general sIgAD population.

IgA evolution is not fixed. In the Brazilian series, 9 of 51 children came to have only partial deficiency (mean age 10.6 years) and 4 of these normalised IgA (mean age 13 years); in children, the deficiency may resolve [10, 21]. Progression to CVID occurs in approximately 5% of patients according to one review, and occurred in 2 of 51 Brazilian children (at 12 and 18 years) [5, 21]. Aghamohammadi and colleagues described four patients with IgAD and autoimmunity who progressed to CVID and recommend monitoring all symptomatic patients, particularly those with IgG subclass deficiency or autoimmunity, to start immunoglobulin promptly and prevent severe infections and pulmonary insufficiency [63]. Progression to CVID entails a worse prognosis and a change in management [10]. In primary antibody deficiencies, delayed diagnosis, inadequate replacement or infection not treated vigorously favour bronchiectasis [40].

11.2. Surveillance

Sources do not define standardised surveillance intervals for sIgAD; they recommend regular reassessment tailored to symptoms [4, 26, 39]. The table organises surveillance from the recommendations and practice described.

12. Summary and Final Considerations

sIgAD is defined by serum IgA below 0.07 g/L after 4 years, with normal IgG and IgM, normal vaccine responses and exclusion of secondary causes and T-cell defects. It is the most frequent primary immunodeficiency in populations of European ancestry, with a prevalence of approximately 1:600 and variation from 1:143 in the Arabian Peninsula to approximately 1:18,500 in Japan, and has no identified monogenic cause: heritability of approximately 0.49 derives mainly from the HLA region (8.1 haplotype, DQB1*02, DRB1*01:02, with protective DRB1*15:01) and loci shared with autoimmunity (IFIH1, CLEC16A, PVT1, ATG13–AMBRA1, AHI1). Heterozygous TNFRSF13B variants are risk factors for CVID rather than causes of sIgAD and should not be used as a predictive test.

Most affected people are asymptomatic. In clinically identified patients, cohorts show more sinopulmonary and gastrointestinal infections, allergy, coeliac disease (6.7% versus 0.19% in the Swedish cohort) and other autoimmune diseases, a modest increase in gastrointestinal cancer and excess mortality concentrated in the first years after diagnosis; patients identified as healthy donors have a much smaller excess. Coeliac disease requires IgG-based serology whenever total IgA is deficient, and total IgA measurement should accompany any request for coeliac serology.

There is no specific treatment. Complications are treated according to their respective guidelines, with antibiotic prophylaxis for patients with recurrent infections and vigorous atopy control; immunoglobulin replacement is not indicated in isolated sIgAD and is reserved for patients with associated specific antibody or subclass deficiency and severe infections, preferring the subcutaneous route or low-IgA products, whose FDA and EMA labels differ regarding anti-IgA presence. The risk of anti-IgA transfusion anaphylaxis is very low, and more recent guidelines reserve washed components or components from IgA-deficient donors for patients with a reaction history, without delaying a life-saving transfusion, although international heterogeneity persists. Inactivated vaccines are recommended; contraindications to live vaccines vary between sources, with oral poliovirus vaccine the only common contraindication.

Follow-up aims to detect autoimmunity, coeliac disease and progression to CVID, which occurs in a minority and changes the prognosis, whereas IgA may normalise in some children. There are no therapeutic trials targeting sIgAD, and recent research focuses on microbiota, serum biomarkers and harmonising transfusion practices.

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