11th February 2024

Primary Immunodeficiencies

Primary immunodeficiencies cause an increased susceptibility to “SPUR” Infections:

Serious, Persistent, Unusual and Recurring infections

Primary immunodeficiencies can be classified based on which part of the immune system is affected.

Neutrophil disorders

Examples

Chronic granulomatous disease

A hereditary condition (either X-linked or autosomal recessive) which reduces the ability of neutrophils and macrophages to phagocytose bacteria and fungi, leading to recurrent infection and the formation of post-infective granulomas throughout the body. The diagnosis is made with neutrophil-function testing and genotyping for specific mutations. Treatment is with antibiotic prophylaxis and early recognition of infection.

Leukocyte adhesion deficiency

A rare autosomal recessive condition which affects the ability of B and T cells to migrate from the blood to affected tissue, which has pathogenic bacteria. Severe disease often has a high mortality rate in infanthood. Causes recurrent bacterial infections, frequently from Staph aureus and Pseudomonas aeruginosa. Diagnosis is made with flow cytometry and genetic testing.

References

• Angel A, Vaillant J, Ahmad F (2022). Leukocyte Adhesion Deficiency Available from https://www.ncbi.nlm.nih.gov/books/NBK539770/
• National Institute of Allergy and Infectious Diseases (2022) Chronic Granulomatous Disease
• Available from: https://www.niaid.nih.gov/diseases-conditions/chronic-granulomatous-disease-cgd

Complement deficiency

Summary

This refers to a deficiency in any part of the complement cascade (C1 – C9). These are usually hereditary, but some are not clinically significant and do not lead to recurrent infections. There is, however, a strong association between complement deficiency, SLE and hereditary angioedema. Patients with deficiencies in the early components of the classical complement pathway, such as C1, C2 and C4, will get recurrence of infection with encapsulated bacteria, such as Strep. Pneumoniae and Haemophilus Influenza. A deficiency in components of the final common pathway, C5 – C9, causes an increased susceptibility to infections from Neisseria spp.

Image Source: Wikimedia Commons (2019). Complement pathway, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/0/0b/Complement_pathway.png  (Accessed: 9 January 2024).

References

Fatema M, Shucman T (2022). Complement deficiency. Available from https://www.ncbi.nlm.nih.gov/books/NBK557581/

B cell/antibody deficiency

Examples

Common variable immunodeficiency (CVID)

Consists of a group of diseases characterised by a deficiency in immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM). The clinical presentation can vary depending on which immunoglobulins are affected, but some patients have a deficiency of all three. Patients with CVID are more susceptible to sinuses and respiratory tract bacterial and viral infections. There is also an increased susceptibility to GI infections such as Campylobacter and Giardia. Patients often respond poorly to vaccines as they cannot produce adequate antibodies. Diagnosis is made by measuring immunoglobulin levels, and the primary treatment is with intravenous or subcutaneous immunoglobulin infusions.

X-linked agammaglobulinaemia

An X-linked disorder caused by failure of B cell maturation resulting in a complete absence of B cells and, therefore, no antibodies. Patients suffer recurrent pyogenic sinus, lung and skin infections, particularly from encapsulated bacteria and viral central nervous system infections. The diagnosis is made by confirming low immunoglobulin levels and the absence of B cells on flow cytometry. Treatment is with immunoglobulin replacement and prompt initiation of antibiotics in infection. Live virus vaccines are contraindicated.

Selective IgA deficiency

It is the most common primary antibody deficiency defined by undetectable IgA levels with normal levels of other immunoglobulins. 85 – 90% of patients with Selective IgA deficiency are asymptomatic, whereas the remainder have an increased propensity to recurrent sinusitis, respiratory infections, allergies and autoimmune disorders. Recurrent infections tended to be bacterial, and there was an association between IgA deficiency and autoimmunity with idiopathic thrombocytopenic purpura, haemolytic anaemia and systemic lupus erythematosus (SLE) as well as Coeliac disease and thyroid disease. Diagnosis is made by confirming undetectable IgA compared with normal other subclasses of immunoglobulins. Treatment is not indicated for asymptomatic patients, and those with recurrent infections should be treated promptly or considered for prophylactic antibiotics.

References

• Justiz Vaillant AA, Qurie A. Immunodeficiency. [Updated 2022 Jul 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK500027/
• Lackey AE, Ahmad F. X-linked Agammaglobulinemia. [Updated 2022 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549865/
• Pescador Ruschel MA, Vaqar S. Common Variable Immunodeficiency. [Updated 2022 Nov 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549787/

T-cell deficiency

Examples

DiGeorge syndrome

Also known as 22q11.2 deletion syndrome, it is named due to a deletion on a small part of chromosome 22. It is an autosomal dominant condition whose clinical symptoms are due to a defect in the development of pharyngeal arches in the embryonic stage. Clinical manifestations can vary, but the classic triad is a hypoplastic thymus, hypocalcaemia and cardiac anomalies. The immunodeficiency comes from the hypoplastic thymus, the site of T cell maturation. Patients are noted to have recurrent sinus and respiratory infections. There is no specific treatment, but prompt administration of antibiotics is advised when indicated. Diagnosis is with genetic studies, usually via fluorescence in situ hybridisation (FISH).

Ataxia telangiectasia

A rare autosomal recessive condition leading to early onset ataxic gait and cutaneous telangiectasia due to mutations in the ataxia telangiectasia mutated (ATM) gene. ATM is involved in immunoglobulin production and T cell proliferation, so two-thirds will also experience immune system involvement, typically with low IgG and IgA levels and low CD4 counts. They are predisposed to recurrent sinopulmonary infections. Typically, neurological features are noticed first, followed by telangiectasia, usually seen in the eye. The diagnosis is clinical but confirmed by demonstrating high alfa-fetoprotein levels; a brain MRI demonstrates cerebellar atrophy and low immunoglobulin levels. The treatment is supportive and often involves a multi-disciplinary team.

Severe common immune deficiency (SCID)

The most severe of the primary immunodeficiencies affecting both B and T cell formation. It was known as the “bubble boy disease” after the child with SCID who was raised in a sterile environment. Mortality rates are high without treatment, and patients are vulnerable to recurrent infections from opportunistic pathogens such as Pneumocystis Jirovecii and Cryptosporidium. Antibiotic and antiviral prophylaxis is usually indicated. The definitive treatment is stem cell transplantation.