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D. Kumararatne



Classification of primary immunodeficiency states.

Immunoglobulin replacement therapy—discussion of dosage.

Mendelian susceptibility to mycobacterial disease—molecular basis of novel immunodeficiency characterized by monocytopenia and dendritic cell deficiency.

Clinical consequences of complement deficiency.

Chronic mucocutaneous candidiasis—clinical description and recent advances in understanding of pathogenesis.

Updated on 30 Nov 2011. The previous version of this content can be found here.
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date: 24 April 2017

Immunodeficiency is caused by failure of a component of the immune system and results in increased susceptibility to infections. The possibility that a patient has an underlying immunodeficiency should be considered in the following circumstances: (1) serious, persistent, unusual or recurrent infections; (2) failure to thrive in infancy; (3) known family history of immunodeficiency; (4) unexplained lymphopenia in infancy; (5) combination of clinical features characteristic of a particular immunodeficiency syndrome. The nature of the microbial infection in a particular patient provides a clue to the likely cause of immunodeficiency.

Primary immunodeficiency diseases are heritable disorders which result in defects in an intrinsic component of the immune system. Secondary immunodeficiencies are caused by conditions which impair the normal function of the immune system and include viral infections, myelomatosis, non-Hodgkin’s lymphoma, severe renal or liver failure, and use of therapeutic agents which impair immunity.

Defects in anatomical and physiological barriers to infection

These are some the commonest predisposing causes of infection, e.g. obstruction of the biliary tract, urinary tract, or bronchi; presence of foreign bodies or avascular areas. Recurrent infections within the same anatomical locations are a characteristic feature, with typical organisms including pyogenic bacteria such as staphylococci, commensal organisms from the skin or intestinal tract, and fungi, especially candida.

Antibody deficiency

Clinical features—typical presentation is with recurrent infections by encapsulated bacteria, e.g. Streptococcus pneumoniae, Haemophilus influenzae type B; most patients suffer from repeated sinopulmonary infections, eventually resulting in structural lung damage; arthritis occurs in a few patients; diarrhoea and malabsorption may occur in a few patients; due to chronic infection with intestinal pathogens or bacterial overgrowth in the small intestine.

Causes—major forms of antibody deficiency include (1) common variable immune deficiency—the commonest primary immunodeficiency disease; underlying molecular defect usually unknown; clinically defined by susceptibility to infection accompanied by low serum IgG and evidence of impaired specific antibody production in response to natural microbial exposure or vaccination. (2) X-linked agammaglobulinaemia—caused by a defect in a cytoplasmic tyrosine-kinase that results in the arrest of B-cell maturation; affected boys usually develop recurrent infections typical of antibody deficiency from around 6 months of age. (3) Other conditions—including (a) antibody deficiency associated with severe B lymphopenia; (b) hyper-IgM syndrome; (c) X-linked lymphoproliferative syndrome; (d) selective antibody deficiency with normal immunoglobulins; (e) antibody deficiency associated with thymoma; (f) IgA deficiency, (g) IgG subclass deficiency.

Treatment—immunoglobulin replacement therapy through the intravenous (IVIG) or subcutaneous (SCIG) routes is the mainstay of therapy.

Impaired T-cell-mediated immunity

Clinical features—these include increased susceptibility to infections caused by (1) viruses—e.g. children may develop fatal infection with common exanthematous viruses; adults may have considerable morbidity and mortality from reactivation of latent viruses, e.g. cytomegalovirus, herpes simplex, and varicella-zoster; (2) Pneumocycstis jiroveci—pulmonary infection is pathognomonic for T-cell deficiency; (3) fungal infections—e.g. mucocutaneous infection with candida; invasive infection caused by filamentous fungi like aspergillus and mucor; (4) intracellular bacteria—e.g. tuberculosis.

Causes—these may be inherited (rare) or acquired. Commonest causes of acquired T-cell deficiency include HIV infection or immunosuppressive therapy. Severe combined immunodeficiency, characterized by profound T- and B-cell failure, is caused by a variety of molecular defects. These patients present in early infancy with failure to thrive and recurrent, severe, potentially life-threatening bacterial, viral, and fungal infections, often including infections by organisms of low-grade virulence.

Treatment—(1) severe inherited T-cell disorders—invariably fatal unless treated with bone marrow stem cell transplantation or (in a very few instances) with gene therapy; (2) secondary T-cell deficiency—requires supportive therapy with antiviral and antibacterial chemotherapy agents.

Phagocyte deficiency

Clinical features—these typically include repeated visceral abscesses caused by Staphylococcus aureus or some species of Gram-negative bacteria, and invasive fungal infections are a particular risk.

Causes—these include (1) neutropenia—the commonest phagocyte deficiency seen in clinical practice; a neutrophil count <0.5 × 109/litre is associated with a high risk of life-threatening bacterial sepsis; (2) defects in bacterial killing—the best-characterized condition is chronic granulomatous disease, which is due to faulty postphagocytic activation of the NADPH oxidase complex; (3) defects in leucocyte migration.

Treatment—this requires prophylactic antibacterial and antifungal agents, with the aggressive use of antibiotic chemotherapy of infections when they occur. Bone marrow transplantation is required for patients with defective leucocyte migration.

Other causes of immunodeficiency

These include (1) Mendelian susceptibility to mycobacterial disease; (2) Wiskott–Aldrich syndrome—characterized by eczema, thrombocytopenic purpura, with small, defective platelets and variable immunodeficiency; (3) DNA repair defects associated with immunodeficiency—e.g. ataxia telangiectasia; (4) defects in innate immunity—e.g. inherited deficiencies of components of complement system or impairment of the function of microbial pattern recognition receptors.

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