Immunodeficiency

Introduction

Immunodeficiency is impaired immune function that predisposes to infection, and in some conditions also to autoimmunity and malignancy. It is divided into primary immunodeficiency (PID) - usually genetic, congenital, and rare - and secondary immunodeficiency, which is acquired and vastly more common in everyday clinical practice.

The exam value of this topic lies less in memorising every named syndrome and more in a structured way of thinking: which arm of the immune system is affected predicts which infections occur, and recognising a suspicious pattern of infection (rather than any single infection) is what should prompt investigation.

Primary immunodeficiency

Primary immunodeficiencies are classified by which component of the immune system is defective, and each category produces a recognisably different infection pattern.

Antibody (B-cell) deficiencies - the largest category

• X-linked agammaglobulinaemia (Bruton's) - absent B cells from a BTK gene mutation; affects boys, presenting with recurrent bacterial infections from around 6 months of age, once protective maternal antibody has waned
• Common variable immunodeficiency (CVID) - the commonest symptomatic PID presenting in adulthood; low immunoglobulin levels with recurrent sinopulmonary infections, an increased risk of autoimmune disease, and a risk of progressive bronchiectasis from repeated chest infections if unrecognised
• Selective IgA deficiency - the commonest primary immunodeficiency overall, often entirely asymptomatic, but with an important safety implication: patients can develop anti-IgA antibodies and are at risk of anaphylaxis if given blood products containing IgA

T-cell and combined deficiencies

• Severe combined immunodeficiency (SCID) - absent or severely impaired T- and B-cell function, presenting in early infancy with severe, recurrent and opportunistic infections and failure to thrive; a paediatric emergency, since live vaccines can cause fatal disseminated infection and the only curative treatment is bone marrow/stem cell transplant
• DiGeorge syndrome (22q11 deletion) - thymic aplasia or hypoplasia causing T-cell deficiency, alongside congenital cardiac defects, hypocalcaemia (from parathyroid aplasia) and characteristic facial features - remembered by the mnemonic CATCH-22: Cardiac abnormality, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcaemia, chromosome 22q11 deletion

Phagocyte defects

• Chronic granulomatous disease (CGD) - a defect in the NADPH oxidase respiratory burst, so phagocytes cannot kill certain organisms once ingested; causes recurrent infection with catalase-positive organisms (Staphylococcus aureus, Aspergillus, Serratia, Burkholderia) and granuloma formation; diagnosed with a nitroblue tetrazolium or dihydrorhodamine test
• Leukocyte adhesion deficiency - neutrophils cannot migrate to sites of infection; classically causes delayed umbilical cord separation and recurrent infections that fail to form pus, despite a markedly raised neutrophil count in the blood

Complement deficiencies

Deficiency of the terminal complement components (C5-C9), which form the membrane attack complex, causes a striking and specific susceptibility to recurrent Neisseria infections - meningococcal and gonococcal disease - and should be considered in anyone with more than one episode of invasive meningococcal disease.

Secondary immunodeficiency

Secondary immunodeficiency is acquired rather than inherited, and is encountered far more often in everyday clinical practice than any primary immunodeficiency.

When to suspect immunodeficiency: the SPUR criteria

A useful screening framework for deciding when a pattern of infection warrants investigation for an underlying immunodeficiency, primary or secondary.

• Serious infections - requiring hospital admission or IV antibiotics
• Persistent infections - not clearing fully with standard treatment
• Unusual infections - opportunistic organisms, or infection at an unusual site
• Recurrent infections - for example two or more pneumonias in a year, four or more new ear infections in a year, or two or more serious sinus infections in a year

Other features that should raise suspicion include failure to thrive in an infant, a family history of primary immunodeficiency or unexplained early infant death, persistent oral thrush beyond infancy, recurrent deep-seated abscesses, and infections needing prolonged or repeated courses of antibiotics with a poor response.

Investigations

• FBC with differential - looking for lymphopenia or neutropenia
• Immunoglobulin levels (IgG, IgA, IgM) - the first-line screen for antibody deficiency
• Lymphocyte subsets (flow cytometry) - CD4/CD8 T cells, B cells and NK cells, to characterise a suspected T-cell or combined defect
• Complement levels (CH50/AP50) - screening for classical and alternative pathway deficiency
• Specific (functional) antibody response to vaccination (e.g. pneumococcal or tetanus) - tests whether the immune system can actually mount a protective response, which raw immunoglobulin levels alone do not show
• HIV test - always excluded as a cause of secondary immunodeficiency
• Neutrophil function testing (nitroblue tetrazolium or dihydrorhodamine test) - for suspected chronic granulomatous disease
• Genetic testing - for suspected specific primary immunodeficiency syndromes

Management

• Prompt, aggressive treatment of infection, with a lower threshold for antibiotics and specialist input than in an immunocompetent patient
• Immunoglobulin replacement therapy (IV or subcutaneous) for significant antibody deficiency, such as CVID or X-linked agammaglobulinaemia
• Prophylactic antibiotics in selected conditions to reduce infection frequency
• Optimised vaccination, particularly pneumococcal, Hib and meningococcal vaccination in asplenia/hyposplenism
• Avoid live vaccines wherever T-cell function is significantly impaired (SCID, advanced HIV, significant immunosuppression), given the risk of disseminated vaccine-strain infection
• Bone marrow/stem cell transplant - curative for SCID and some other severe primary immunodeficiencies, ideally before serious infection has already caused irreversible harm
• Treat the underlying cause where secondary - optimise diabetic control, stop or reduce a causative drug where possible, treat the underlying malignancy, or start antiretroviral therapy for HIV
• Genetic counselling for families affected by an inherited primary immunodeficiency
• Ongoing multidisciplinary input from clinical immunology

Complications

• Recurrent or chronic infection causing cumulative organ damage - for example bronchiectasis from repeated chest infections in antibody deficiency
• Autoimmune disease, particularly associated with CVID
• Increased risk of certain malignancies, particularly lymphoma, in some primary immunodeficiencies
• Growth failure and developmental impact in affected children
• Death from overwhelming infection if a significant immunodeficiency, especially SCID, is not recognised and treated promptly

Red flags

Prognosis

Outcome depends heavily on the specific condition and how early it is recognised. SCID is rapidly fatal in infancy without transplantation, but has an excellent prognosis if treated before serious infection occurs, which is why some countries have introduced newborn screening for it. Antibody deficiencies such as CVID generally respond well to immunoglobulin replacement, though established bronchiectasis from delayed diagnosis is not reversible. Secondary immunodeficiency generally improves, sometimes substantially, once the underlying cause is treated or removed - control of HIV, resolution of neutropenia, or optimisation of diabetes are all examples where the immune defect itself can be reversed rather than simply managed around.