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Does this patient have an immunodeficiency?

Aarnoud P Huissoon and Mamidipudi Thirumala Krishna
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DOI: https://doi.org/10.7861/clinmedicine.11-4-380
Clin Med August 2011
Aarnoud P Huissoon
Birmingham Heartlands Hospital
Roles: Consultant immunologist
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  • For correspondence: aarn.huissoon@nhs.net
Mamidipudi Thirumala Krishna
Birmingham Heartlands Hospital
Roles: Consultant allergist and immunologist
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Key points

Patients with immunodeficiency often present with infections but these need not be unusual or severe

Immunodeficiency presenting in adults may be secondary (eg HIV, lymphoma, drugs) or primary (usually antibody deficiency)

FISHing (full blood count, immunoglobulins, serum complement, HIV test) will identify the most common immunodeficiencies

Adults with normal initial investigations may nonetheless have significant immunodeficiency: referral to an immunologist is recommended where there is a high index of suspicion

Non-infectious features such as splenomegaly, granulomata or autoimmunity (eg idiopathic thrombocytopenic purpura) increase the likelihood of identifying an immunodeficiency

KEY WORDS: common variable immunodeficiency, HIV infection, immunoglobulins, primary immunodeficiency, secondary immunodeficiency

There is a good chance that most physicians will have seen a patient with an immune deficiency in the past year. This brief review aims to help decide when a patient needs to be investigated for immunodeficiency, what tests should be done and what to do with the results. Detailed descriptions of individual immunodeficiency disorders can be found in reviews listed.1–3 Children with suspected immunodeficiency require special consideration and are outside the scope of this article.

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.

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Table 1.

Reasons to go FISHing.5

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.

Fig 1.
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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).

Laboratory investigations

Laboratory evidence of immunodeficiency may be identified indirectly during the course of routine testing for vague clinical presentations. Neutropenia, and especially lymphopenia, are often ignored or attributed to other causes and not further investigated. Low serum globulins (total protein minus albumin should be >20 g/l) may be seen in hypogammaglobulinaemia. Similarly raised globulins (>40 g/l) can occur in HIV infection and myeloma and should prompt further tests. Failure to produce an antibody response to vaccination or infection, or absent isohaemagglutinins (blood group antibodies) may also be pointers to antibody deficiency.

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).

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Table 2a.

Investigation of possible immunodeficiency (ID): FISHing for immunodeficiency. This will identify many primary and secondary IDs but other important conditions require further tests (see Table 2b).

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Table 2b.

Investigation of possible immunodeficiency: results of FISHing normal, nothing significant, or follow-up testing. A guide to possible second- and third-line investigations (it is often helpful to consult an immunologist at this stage). Adapted from reference 6.

Box 1.

Useful sources of information about immunodeficiency.


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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.

Conclusions

The question ‘Does this patient have an immune deficiency?’ should be asked in a wide range of clinical scenarios in which infection need not be a prominent feature. The situation is analogous to cystic fibrosis, coeliac or thyroid disease which are increasingly diagnosed in patients who lack the classic features of the condition. Widely available, simple tests can often suggest the diagnosis, but further tests and specialist referral are indicated where there is a high index of suspicion. There remains a perception that HIV testing is awkward and patients (and many doctors) still avoid discussing it. Until the HIV test becomes an ‘ordinary’ investigation in routine practice, this condition will remain underdiagnosed to the detriment of the patient and the public. We recommend immunodeficiency testing in a wider range of disease-specific diagnostic protocols. FISHing is encouraged, but it is important to examine the results critically and to recognise the potential significance of results which might suggest an immunodeficiency only indirectly.

  • © 2011 Royal College of Physicians

References

  1. ↵
    1. Baggaley R
    . HIV for non-HIV specialists. Medical Foundation for AIDs and Sexual Health, 2008. www.medfash.org.uk/publications/documents/HIV_for_non_HIV_specialists.pdf
  2. ↵
    1. Boxer L,
    2. Dale DC
    . Neutropenia: causes and consequences. Semin Hematol 2002; 39: 75–81doi:10.1053/shem.2002.31911
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  3. ↵
    1. Notarangelo LD,
    2. Fischer A,
    3. Geha RS,
    4. et al
    . International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol 2009; 124: 1161–78
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  4. ↵
    Health Protection Agency. HIV in the United Kingdom: 2010 report. Health Protection Report 2010;4:no.47. www.hpa.org.uk/Publications/InfectiousDiseases/HIVAndSTIs/1011HIVUK2010Report
  5. ↵
    British HIV Association, British Association of Sexual Health and HIV, British Infection Society. UK national guidelines for HIV testing 2008 2008. London: BHIVA
  6. ↵
    1. de Vries E
    . Clinical Working Party of the European Society for Immunodeficiencies (ESID). Patient-centred screening for primary immunodeficiency: a multi-stage diagnostic protocol designed for non-immunologists. Clin Exp Immunol 2006; 145: 204–14
    OpenUrlCrossRefPubMed
    1. Wood P
    . UK Primary Immunodeficiency Network. Primary antibody deficiencies: recognition, clinical diagnosis and referral of patients. Clin Med 2009; 9: 595–9
    OpenUrlAbstract/FREE Full Text
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Does this patient have an immunodeficiency?
Aarnoud P Huissoon, Mamidipudi Thirumala Krishna
Clinical Medicine Aug 2011, 11 (4) 380-384; DOI: 10.7861/clinmedicine.11-4-380

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Does this patient have an immunodeficiency?
Aarnoud P Huissoon, Mamidipudi Thirumala Krishna
Clinical Medicine Aug 2011, 11 (4) 380-384; DOI: 10.7861/clinmedicine.11-4-380
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