Plebiani A, Soresina A, Rondelli R, et al. Clin Immunol. 2002;104:221–230
Purpose of the Study.
This large Italian study was designed to investigate the natural history of X-linked agammaglobulinemia (XLA). Although it is among the more common of the primary immunodeficiencies, there is surprisingly little information on optimal management and outcome. This study was designed to characterize the long-term issues facing this patient population.
Seventy-three males with a definite diagnosis of XLA constitute the study population. Thirty-nine Italian centers participated. This group is relatively old with a mean age of 14 years, and this allows the authors to perform certain longitudinal studies.
All male patients at the 39 centers with hypogammaglobulinemia and B cell numbers <1% were initially included. Mutation analysis of Bruton’s tyrosine kinase (BTK) was performed and 73 were identified as having “definite XLA” on this basis. These patients constitute the study population. An enrollment questionnaire was sent in 1994 and annual reports have been filed on each patient since that time.
There are several surprises in this article. The immunoglobulin G (IgG) levels at enrollment ranged from a low of 7 mg/dL to a high of 891 mg/dL. Most patients, but not all, had very low immunoglobulin A (IgA) levels, and the 10 patients who had an IgA >20 mg/dL typically had normal or near normal immunoglobulin M (IgM) levels, but there was no correlation between IgA/IgM levels and IgG levels. All patients had <1% B cells because that was required for entry into the study. As one would expect, respiratory tract infections were observed in a majority of patients at the time of diagnosis. Other common infections were skin infections, gastrointestinal infections, and sepsis. These authors describe a high rate of chronic lung disease in their patients rising to 100% at 30 years of follow-up. There is a sharp increase in chronic lung disease between 12 and 20 years of follow-up, perhaps reflecting the introduction of intravenous immune globulin (IVIG) 15–20 years ago. The chance of having chronic lung disease also increases with delay in diagnosis. Half of the patients diagnosed at 10 years or age or later had chronic lung disease at the time of diagnosis. There was a single death and no malignancies, which is better than has been previously published.
The spectrum of XLA is clearly broader than was once imagined. Although patients have improved survival in this study compared with earlier studies of XLA patients, there are significant health issues for these patients. Chronic lung disease and sinusitis remain persistent problems.
This is a wonderful study that will lead many people to revise their diagnostic work-up of patients with hypogammaglobulinemia. Questions yet to be addressed are how to improve management and eliminate chronic infections.