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Clinical significance of hyper-IgA in a paediatric laboratory series
  1. Valentina Copetti1,
  2. Serena Pastore1,2,
  3. Carlo De Pieri2,
  4. Oriano Radillo3,
  5. Andrea Taddio1,2,
  6. Alessandro Ventura1,2,
  7. Alberto Tommasini2
  1. 1University of Trieste, Trieste, Italy
  2. 2Institute of Maternal and Child Health—IRCCS Burlo Garofolo, Trieste, Italy
  3. 3Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health—IRCCS Burlo Garofolo, Trieste, Italy
  1. Correspondence to Dr Serena Pastore, University of Trieste, Institute of Maternal and Child Health—IRCCS Burlo Garofolo Trieste, via dell'Istria 65/1, Trieste, 34137 Italy; pastore_serena{at}libero.it

Abstract

The causes of extremely elevated IgA, whether isolated or associated with an increase in other classes of immunoglobulin, are poorly defined in paediatrics. We reviewed the diagnostic significance of very high IgA levels (greater than 3 SD above the mean for age) in a cohort of patients referred to a tertiary care children's hospital. Hyper-IgA was found in 91 of 6364 subjects (1.4%) and in 68 cases was not associated with an increased IgG and/or IgM level. Most subjects with hyper-IgA (73.5%) had a severe immune defect, a chronic rheumatic disease or inflammatory bowel disease, while these conditions were very rare in a control group with normal IgA values (8%). Although our results may in part reflect the experience of a tertiary care centre, we suggest that hyper-IgA in children should always arouse suspicion of a serious disease.

  • General Paediatrics
  • Immunology
  • Paediatric Practice

https://doi.org/10.1136/archdischild-2014-306607

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    Introduction

    Very high levels of one or more classes of immunoglobulin can be found in children with various clinical conditions.1 Diagnostic protocols have been developed for defined forms of IgG, IgM or IgE hypergammaglobulinaemia, which could be the expression of chronic inflammatory disease and/or primary immunodeficiency syndromes.2 ,3 In contrast, except for well described conditions such as IgA nephropathy and Henoch Schönlein purpura, less is known about hyper-IgA.

    We reviewed the diagnostic significance of very high IgA levels in the clinical practice of a tertiary care children's hospital.

    Samples and methods

    We collected data on all IgA levels measured in children aged less than 16 years, at the immunopathology laboratories of the Institute for Maternal and Child Health, IRCCS Burlo Garofolo, from 2009 to 2013. IgA values greater than 3 SD above the mean, based on the local reference values for three age groups, were considered as ‘hyper-IgA’ (0–12 months, IgA>1.13 g/L; 1–3 years, IgA>2.25 g/L; 3–16 years, IgA>3.68 g/L).

    For subjects with repeated hyper-IgA measured on different occasions, only the first value was recorded.

    To identify the diseases associated with hyper-IgA, an age-matched control group of 200 subjects with normal IgA values was randomly selected from the same laboratory series.

    Physicians caring for each patient were asked to fill out a questionnaire regarding the clinical diagnosis and the interpretation of increased values of IgA. In addition, levels of IgG and IgM more than 2 SD above the mean were also recorded when available. Subjects whose clinical records were not available were excluded from the analysis.

    Control randomisation was performed using a algorithm in Microsoft Excel. Statistical analysis between cases and controls was carried out using the χ2 test.

    Results

    A total of 12 650 measurements of serum IgA were taken from 6364 subjects during the study period. Ninety-one subjects (48 males, 43 females, mean age 9.1 years) had one or more hyper-IgA values (mean IgA value 4.27 g/L, range 0.114–10.51 g/L). Clinical records were available for 83/91 subjects with hyper-IgA and 173/200 age-matched controls with normal IgA. All the subjects were divided into six groups based on the referring sub-specialty (table 1).

    View this table:
    Table 1

    Referring medical specialties for patients with hyper-IgA and controls

    Most subjects with hyper-IgA had a serious disorder (61/83). In particular, a number of different monogenic rare disorders were found: mevalonate kinase deficiency (2 cases), dyskeratosis congenita (1), IPEX and IPEX-like syndrome (2), anhidrotic ectodermal dysplasia (1), autoimmune lymphoproliferative syndrome (ALPS; 1) and chronic granulomatous disease (1). Overall, primary immune defects were significantly more common in the hyper-IgA group than in controls (9/83 vs 0/173, p<0.0001). Similarly, rheumatic fever (4 cases) and vasculitis (2 cases of Kawasaki disease and 2 Henoch-Schönlein purpura) were found in subjects with hyper-IgA, but not in controls (8/83 vs 0/173, p<0.0001). Among other chronic disorders, juvenile idiopathic arthritis (9/83 vs 6/173, p=0.0187) and inflammatory bowel disease (9/83 vs 4/173, p=0.0036) were significantly more common among hyper-IgA subjects than in controls.

    Infectious diseases associated with hyper-IgA included infections by mycobacteria or Bartonella (4 cases), Epstein Barr virus or cytomegalovirus infections (3 cases), septic arthritis, infective endocarditis, HIV infection and renal abscess, while only four pneumococcal infections were found in controls.

    Conversely, there was a higher proportion of healthy subjects among controls with normal IgA.

    Median IgA values do not differ significantly among the various paediatric specialties, although children with immunological disorders tended to have higher values (figure 1). The highest IgA values were found in cases with rheumatic fever and retroperitoneal fibrosis, mevalonate kinase deficiency and dyskeratosis congenita, coeliac disease, lymphatic leukaemia, bone marrow transplantation, HIV infection and infective endocarditis.

    Figure 1
    Figure 1

    IgA values in different paediatric specialties. Green circles indicate patients aged <1 year, orange circles 1–3 years, and blue circles >3 years. Dotted lines represent the cut-off of 3 SD above the mean in the three age groups. The median values for each group are presented as black lines.

    Sixty-eight out of 83 subjects with hyper-IgA had normal IgG and IgM values. Increased IgM levels were present together with hyper-IgA in four patients, all of whom had infectious diseases (infectious mononucleosis, cytomegalovirus infection, respiratory infection in cystic fibrosis, HIV-1 infection). Increased IgG values were measured in 11 subjects with rheumatological, gastrointestinal and infectious disorders. In contrast, no patient in the control group had increased IgG or IgM values.

    Discussion

    Hyper-IgA is not a rare finding in a third level paediatric hospital. We showed that in most cases hyper-IgA was not associated with a general increase in other immunoglobulin classes. Thus, the finding of hyper-IgA can play a specific role as a diagnostic marker. Notably, in our series, a simultaneous increase in IgA and IgM levels was found only in infections. In contrast, isolated hyper-IgA, sometimes with extremely high values, was mostly found in serious inflammatory or immune disorders. No subject with a primary immune defect was found in the control group; this is not surprising given the low prevalence of immune deficiency diseases in overall paediatric practice. Furthermore, the selection of a control group with normal IgA values meant that most antibody deficiencies were excluded.

    Careful consideration of the finding of hyper-IgA could be very helpful in the differential diagnosis of some specific conditions. For example, hyper-IgA in patients with periodic fevers is highly suspicious of a familial auto-inflammatory disorder, in particular mevalonate kinase deficiency.4 In some patients with complex clinical pictures, high IgA values may help the clinician diagnose some rare defects of immunity, including dyskeratosis congenita and immune dysregulations.5–7

    Indeed in our series, in almost all chronic disease cases, hyper-IgA was present at the first clinical evaluation. In particular, subjects with an inborn immune defect already had hyper-IgA in their first years of life. In many subjects, hyper-IgA preceded other disease-associated symptoms, such as teeth abnormalities in ectodermal dysplasia, lung disease in dyskeratosis congenita, diabetes in IPEX, autoimmune manifestations in ALPS, and gastrointestinal symptoms in mevalonate kinase deficiency. It is thus likely that in some of these patients, taking note of hyper-IgA might have contributed to earlier diagnosis.

    Our study does not provide a comprehensive list of disorders associated with hyper-IgA, but does highlight the potential role of hyper-IgA in the diagnostic process, in particular in patients with an incomplete clinical picture at disease onset.

    However, in other cases, hyper-IgA developed during the course of the disease, reflecting either a flare of an inflammatory rheumatological or gastrointestinal disorder, or a chronic infection.8 ,9 For example, this was seen in a patient with cystic fibrosis, in whom IgA progressively increased after lung colonisation by an antibiotic resistant bacterium, as previously reported by other authors.10

    In conclusion, the potential role of hyper-IgA in paediatric diagnostics may be greater than previously recognised, even though our finding of a high prevalence of serious disease with high IgA levels may not apply to the general population. We suggested that hyper-IgA in children should always raise the suspicion of a serious immune defect, a chronic rheumatic disease or an inflammatory gastrointestinal disorder.

    References

    1. ↵
      1. Stiehm ER,
      2. Fudenberg HH
      . Serum levels of immune globulins in health and disease: a survey. Pediatrics 1966;37:715–27.
      OpenUrlAbstract/FREE Full Text
    2. ↵
      1. Buckley RH,
      2. Wray BB,
      3. Belmaker EZ
      . Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 1972;49:59–70.
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. Geha RS,
      2. Hyslop N,
      3. Alami S,
      4. et al
      . Hyper immunoglobulin M immunodeficiency. (Dysgammaglobulinemia). Presence of immunoglobulin M-secreting plasmacytoid cells in peripheral blood and failure of immunoglobulin M-immunoglobulin G switch in B-cell differentiation. J Clin Invest 1979;64:385–91.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Klasen IS,
      2. Goertz JH,
      3. van de Wiel GA,
      4. et al
      . Hyper-immunoglobulin A in the hyperimmunoglobulinemia D syndrome. Clin Diagn Lab Immunol 2001;8:58–61.
      OpenUrlPubMed
    5. ↵
      1. Knudson M,
      2. Kulkarni S,
      3. Ballas ZK,
      4. et al
      . Association of immune abnormalities with telomere shortening in autosomal-dominant dyskeratosis congenita. Blood 2005;105:682–8.
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Hanson EP,
      2. Monaco-Shawver L,
      3. Solt LA,
      4. et al
      . Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol 2008;122:1169–77.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Le Deist F,
      2. Emile JF,
      3. Rieux-Laucat F,
      4. et al
      . Clinical, immunological, and pathological consequences of Fas-deficient conditions. Lancet 1996;348:719–23.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Badcock LJ,
      2. Clarke S,
      3. Jones PW,
      4. et al
      . Abnormal IgA levels in patients with rheumatoid arthritis. Ann Rheum Dis 2003;62:83–4.
      OpenUrlFREE Full Text
    9. ↵
      1. Bolton PM,
      2. James SL,
      3. Newcombe RG,
      4. et al
      . The immune competence of patients with inflammatory bowel disease. Gut 1974;15:213–19.
      OpenUrlAbstract/FREE Full Text
    10. ↵
      1. Moss RB
      . Hypergammaglobulinemia in cystic fibrosis. Role of Pseudomonas endobronchial infection. Chest 1987;91:522–6.
      OpenUrlCrossRefPubMed

    Footnotes

    • Contributors VC, CDP: obtained the clinical data of each patient; SP: conceptualised and wrote the article; OR: obtained the laboratory data of each patient; ATa: revised the English and critically reviewed the manuscript; AV: helped to write the article, and critically reviewed and revised the manuscript; ATo: analysed data, and conceptualised and wrote the article. All authors approved the final manuscript as submitted.

    • Competing interests None.

    • Ethics approval The local Institution Research Board approved this study.

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.