Does this patient have an immunodeficiency?

Epidemiology and missed diagnoses

HIV infection is the most common cause of secondary immunodeficiency for which prevalence data are available. It is estimated that 0.2% of men and 0.1% of women in the UK are infected, approximately one-quarter of them undiagnosed.⁴ Neutropenia and other secondary and iatrogenic immunodeficiencies are common but their prevalence is difficult to quantify. The prevalence of common variable immunodeficiency (CVID), the most common primary antibody deficiency, is at least one in 50,000 in the UK but it is likely that many cases are unknown. International estimates of prevalence of CVID are as high as one in 10,000. Selective immunoglobulin A deficiency is common (1 in 500–700) but most of these individuals are asymptomatic and do not suffer from infections. Complement, primary T lymphocyte and neutrophil disorders are relatively rare.

There is also a significant delay in the diagnosis of immunodeficiency: 52% of adults with HIV infection are diagnosed late and 30% very late. In primary antibody deficiencies, delays of over seven years between first presentation and final diagnosis are common. For both diseases patients have often been reviewed by several physicians without the diagnosis having been considered. Delays in diagnosis and treatment are associated with poor outcomes.

When should immunodeficiency be considered?

Immunodeficiency should always be considered in patients with severe, persistent, unusual or recurrent infections. HIV testing should be specifically offered in a range of common conditions, including tuberculosis, atypical pneumonia, lymphoma, hepatitis B and C infection, as well as with well-known AIDS-defining illnesses (Kaposi's sarcoma, pneumocystis, cryptococcal or toxoplasma infections and oesophageal candida). In such circumstances, if HIV tests are negative, wider screening for immunodeficiency is often warranted. Infections and other presentations that should cause concern are included in Table 1.

Iatrogenic secondary immunodeficiency is often suspected from the clinical circumstances (eg recent chemotherapy or immunosuppression). Less well-known causes of secondary immunodeficiencies include hypogammaglobulinaemia with some anticonvulsants and antirheumatic drugs (eg sulphazalazine, gold). With some newer biological agents (eg antitumour necrosis factor drugs, rituximab), the infection risk may not be fully recognised for many years after they are licensed. Contrary to common perception, primary immunodeficiency often presents for the first time in adulthood. Recent UK guidelines for bronchiectasis specifically recommend testing for immunodeficiency in all cases. Other conditions such as sarcoid (or other granulomatous conditions), inflammatory bowel disease, lymphoma, immune thrombocytopenic purpura and neutropenia should also trigger immunodeficiency investigations.

Sometimes it is not the infection itself but the associated features which should prompt consideration of immunodeficiency. Paradoxically, autoimmunity is increased in immunodeficiency. Infections occurring in patients with splenomegaly, cytopenias (neutrophils, lymphocytes or platelets), chronic diarrhoea, sarcoid or coeliac disease should be investigated further (Fig 1). While recurrent meningitis is the hallmark of complement deficiency, not all complement disorders present with infections. Patients with a strong family history or early presentation of lupus or immune complex diseases should be investigated for complement defects with a CH50 functional complement test. Infections are not a feature of C1 inhibitor deficiency (inherited or acquired); these patients present with recurrent angio-oedema.

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Fig 1.

(a) Chest X-ray of a 26-year-old woman presenting with a dry cough showing bilateral hilar lymph node enlargement and perihilar parenchymal nodularity. (b) Computed tomography image better demonstrates the parenchymal nodules with a perilymphatic distribution consistent with granulomatous inflammation. Lung function tests show a restrictive pattern and reduced carbon monoxide transfer factor. (c) Transbronchial biopsy shows non-caseating granulomas, including some giant multinucleated cells of the Langerhans type. After exclusion of tuberculosis and HIV, sarcoidosis was diagnosed and she was treated with steroids. Four years later, after two episodes of lobar pneumonia, serum immunoglobulins (Igs) were measured and found to be reduced. A diagnosis of common variable immunodeficiency was made and she was commenced on Ig replacement therapy. It was revealed that she was non-immune to rubella during her pregnancies at ages 20 and 22, suggesting that a significant immunodeficiency had been present for at least 10 years (images courtesy of Drs John Reynolds and Zbigniew Rudzki).

Testing for immunodeficiency: go ‘FISHing’

The tests indicated depend on the most likely diagnosis. This is suggested by a combination of the presenting features and prevalence of the condition. For example, meningococcal meningitis is a classic presentation of a complement deficiency, but antibody deficiencies are more likely to be identified because they are commoner. Fortunately, the most common immunodeficiencies can be identified on simple and widely available tests. In a busy clinical environment, the acronym FISH (full blood count, immunogloblins, serum complement C3/C4, HIV test) is a mnemonic for the common first-line investigations. These initial tests are occasionally diagnostic but usually only provide pointers to the problem (Table 2a). Scrutiny of the results with follow-up of any abnormality is essential (Table 2b).

Box 1.

Useful sources of information about immunodeficiency.

Further investigations

A comprehensive algorithm for investigation of immunodeficiency has been published⁵ and is also available as a web-based tool (www.ukpin.org.uk). Discussion with an immunologist is recommended for cases where abnormalities of uncertain significance are found or immunodeficiency is strongly suspected despite normal investigations.⁶ Immunodeficiency disorders not identified on routinely available tests include specific antibody deficiency, complement deficiency, chronic granulomatous disease or type 1 cytokine deficiency. These can be identified only by requesting the specific diagnostic test on the basis of a high index of suspicion and knowledge of the typical presentations of the individual diseases.

When the investigation of immunodeficiency is being considered, discussion of appropriate microbiological investigations should take place at the same time. Specialised culture or molecular tests for a wider range of organisms may be indicated. It is worth noting that viral and bacterial serology will be unreliable in patients with antibody deficiency. Similarly, interferon-gamma release assays (eg to investigate tuberculosis) may also be falsely negative in immunosuppressed patients. Finally, some patients clearly have abnormal susceptibility to infection but do not fall into any currently known disease pattern. These patients should be referred for immunology specialist follow-up. It is in this environment that rare and new diseases will continue to be investigated, and where the interface of the basic science and clinical practice of immunology helps to advance understanding and therapy of the immune system.