Abstract
We present a serendipitous case of clinically significant pan-hypogammaglobulinaemia, diagnosed after routine serological testing for possible coeliac disease led first to identification of IgA deficiency (discovered as a low background in IgA-based routine serological screening), and subsequently to confirmed pan-hypogammaglobulinaemia (antibody immunodeficiency). Hypogammaglobulinaemia is a relatively rare diagnosis (estimated at 1 in 36,000), in which delayed diagnosis and treatment are associated with chronic organ damage including bronchiectasis. Routine serological testing for coeliac disease using the IgA anti-tissue transglutaminase (IgA TTG) test is in widespread use and provides an opportunity for early diagnosis of hypogammaglobulinaemia. Routine serological screening for coeliac disease may uncover IgA deficiency, and we suggest that all IgA-deficient cases identified should also be checked for antibody deficiency by quantifying the other immunoglobulins (IgG, IgM).
Introduction
Hypogammaglobulinaemia is a relatively rare diagnosis (estimated incidence of 1 in 36,000 person years 1 ) and may be primary or secondary. Diagnostic delay in antibody deficiency is common (i.e. median of two years in the UK 2 ) and increases the risk of chronic organ damage in antibody deficiency; there is a known correlation between delayed diagnosis in X-linked agammaglobulinaemia and chronic lung disease. 3 Infection frequency 4–6 and organ damage 7 can be prevented with appropriate and cost-effective 8 replacement immunoglobulin treatment. It is therefore important to diagnose and treat hypogammaglobulinaemic patients early.
With the introduction of new guidelines in 2009 on the indications for coeliac testing, 9 and an increased awareness of coeliac disease in patients and doctors, there has been an increase in serological screening (i.e. 6696 anti-tissue transglutaminase [TTG] tests done in our laboratory in 2008, and 11,356 in 2010). Incidental IgA deficiency may be discovered due to low-background optical density on TTG IgA enzyme-linked immunosorbent assay (ELISA), or low-background immunofluorescence on antiendomysial IgA 9,10 when serologically testing for coeliac disease. IgA deficiency is a relatively common condition with a prevalence of approximately one in 522, 11 and there is a higher prevalence in patients with coeliac disease (1 in 39). 12 Selective IgA deficiency is asymptomatic in 85–95% of patients 13 and of limited clinical significance, but carries more significance and a worse prognosis if it is part of pan-hypogammaglobulinaemia. Selective IgA deficiency is associated with many autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis and autoimmune hypothyroidism), sinopulmonary and gastrointestinal infections 14 (particularly when associated with IgG2 subclass deficiency 15 ) and may be associated with allergy. 16
Case history and results
A 28-year-old gentleman presented to his general practitioner (GP) with a seven-year history of altered bowel habit, with loose motions three times per day. Coeliac testing was requested with an anti-TTG IgA blood test. This revealed a very low optical density in IgA anti-TTG ELISA (INOVA Diagnostics, San Diego, CA, USA), and therefore his serum IgA concentration was measured by nephelometry (BN2 nephelometer; Siemens Healthcare Diagnostics, Frimley, UK) and found to be undetectable (<0.06 g/L; reference range 0.8–2.8 g/L). His other immunoglobulin classes were quantified, revealing a low IgG of 2.86 g/L (reference range 6–16 g/L) and low IgM of 0.26 g/L (reference range 0.5–1.9 g/L), indicating pan-hypogammaglobulinaemia. He had a normal serum albumin concentration which excludes secondary protein loss. Also, with protein loss, IgG is typically selectively low, whereas IgA and IgM remain normal or elevated due to their high molecular weight, unlike in this case where IgG, IgA and IgM were all low.
His GP was contacted, resulting in the prescription of azithromycin as prophylaxis for bacterial infection, and a referral to an immunology clinic was agreed. Further questioning at the clinic revealed a long history of recurrent minor upper respiratory illnesses requiring occasional antibiotics, and significant improvement of the altered bowel habit with the azithromycin, suggestive of bacterial overgrowth in the gut. No bronchiectasis was evident on high resolution computerized tomography.
Discussion
There are increasing numbers of patients who can be diagnosed with selective IgA deficiency resulting from screening for coeliac disease. In our laboratory, one of 190 IgA TTGs tested have IgA <0.1 g/L (Lock RJ, unpublished data). In our department, we inform patients with selective IgA deficiency that this is usually a benign diagnosis, but it can be associated with allergy, immunodeficiency and/or autoimmunity. We recommend routine testing of IgG and IgM in all patients with IgA deficiency documented incidentally as part of serological testing for coeliac disease, and in our laboratory, this would result in approximately 60 additional IgG and IgM tests per year. This case was discovered approximately two months after altering our laboratory protocol to perform this additional testing, and our first case was diagnosed in this manner. We recently similarly showed that a very low IgE concentration (deficiency) reported in the context of allergy testing can also be a missed clue to pan-hypogammaglobulinaemia. 17 This case highlights an additional opportunity for the early diagnosis of significant hypogammaglobulinaemia, allowing close patient monitoring and consideration of early antibody replacement therapy.
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