X-Linked Agammaglobulinemia

Excerpt

X-linked agammaglobulinemia or XLA is one of the most common pediatric primary immunodeficiencies that prevent affected individuals from making antibodies and requires lifelong immunoglobulin replacement therapy for survival.

The molecular basis for XLA is a disruption in B cell development due to mutation in Bruton's tyrosine kinase (Btk). Affected individuals inherit a defect that prevents precursor B cells in the bone marrow from forming mature, circulating B-lymphocytes that would otherwise be capable of proliferating and differentiating into antibody-producing plasma cells in secondary lymphoid organs like the tonsils and lymph nodes. This dysfunction results in dangerously low, clinically undetectable levels of all immunoglobulin isotypes in the serum.

Without immunoglobulins (or antibodies), XLA patients are rendered vulnerable to invasive infections from encapsulated bacteria (such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae), have an increased incidence of enterovirus infections (e.g., poliovirus, coxsackievirus, echovirus), and chronic diarrhea (from Giardia lamblia).

XLA patients commonly present with a history of recurrent upper respiratory tract infections, including sinusitis and otitis media, beginning after 6 to 9 months when most of the maternal antibodies have been exhausted. However, hospitalization for bacterial pneumonia, requiring intravenous antibiotics for resolution, is usually what prompts the diagnostic work-up for immune deficiency disease. The average age of diagnosis is 2.5 years, and almost all cases of XLA get diagnosed before 5 years of age. Notably, late-onset forms of XLA also exist.

There is currently no cure for XLA; however, early management with immunoglobulin replacement therapy and antibiotics to prevent and treat infections. Although this lifelong avenue is costly, it has been the mainstay of treatment for the past fifty years. Any significant delay in diagnosis poses the danger of developing chronic, treatment-resistant infections, and end-organ damage that cannot be corrected.