The health status and quality of life of adults with X-linked agammaglobulinemia

Abstract

Forty-one adults (mean age 33) with a definitive diagnosis of X-linked agammaglobulinemia (XLA) completed a questionnaire concerning current and past medical problems and quality of life. Thirty-six of the 41 were working full time or were full time students; 18 had not missed any work or school due to infection in the previous year. Their quality of life was equivalent to that of the general US male population. Thirteen of the 41 reported that they had chronic lung disease, and 33 indicated that they had one or more episodes of sinusitis in the preceding year. Arthritis, diarrhea and skin infections were common but not debilitating. The 41 study subjects were more likely to have a prior family history of XLA, and they were more likely to have milder mutations in Btk, the gene responsible for XLA. These results indicate that most adults with XLA are moderately healthy and lead productive lives.

Introduction

X-linked agammaglobulinemia (XLA) is a rare genetic disorder of the immune system resulting in the early onset of recurrent infections, profound hypogammaglobulinemia and markedly decreased or absent B cells [1], [2], [3], [4], [5], [6]. The patients are most vulnerable to infections with encapsulated bacteria, particularly S. pneumoniae and H. influenzae, and they generally begin to have frequent episodes of otitis by 4 to 8 months of life. The majority of patients with XLA are recognized to have immunodeficiency at less than 5 years of age when they are hospitalized for severe infection [7]. Currently, patients are treated with aggressive use of antibiotics and monthly infusions of intravenous gammaglobulin, a therapy that became widely available in the mid-1980s. Prior to that time, patients were treated with intramuscular injections of gammaglobulin or plasma therapy, neither of which provided optimal amounts of gammaglobulin.

Recurrent pneumonias, otitis and sinusitis in patients with XLA have been reported to cause chronic lung disease and hearing loss [2], [8], [9]. In addition to their increased susceptibility to infections with encapsulated bacteria, patients with XLA have an elevated risk of infection with giardia, mycoplasma and enteroviruses [10], [11], [12], [13], [14]. Giardia infections in these patients are sometimes associated with the development of inflammatory bowel disease. Chronic pneumonitis and/or arthritis can result from infection with mycoplasmas [12]. Most viral infections do not cause unusual problems in patients with XLA; however, the enteroviruses, including echo virus, coxsackie and wild type and vaccine associated polio, can cause chronic, progressive, devastating enteroviral meningoencephalitis, arthritis or enteritis [13], [14], [15], [16], [17], [18]. In the late 1980s and early 1990s, some patients with XLA acquired hepatitis C through contaminated preparations of intravenous gammaglobulin [19], [20], [21]. Because hepatitis C infection can remain asymptomatic for 10 to 20 years, the long-term outlook for these patients has been uncertain.

XLA was first described by Bruton in 1952 [1], and, between 1950 and 1980, most affected patients died at less than 20 years of age. Some patients died of their first major infection, about 20% died of chronic enteroviral infection and a significant proportion died of chronic lung disease or cor pulmonale secondary to chronic lung disease [2]. In 1985, Lederman and Winkelstein published a comprehensive survey of 96 patients with XLA [2]. Sixteen of the patients died at a mean of 17 years of age, and the oldest patient was 28 years old. In that series, 41% of patients between 10 and 20 years of age and 76% of patients over 20 years of age had chronic lung disease. In a more recent study, Plebani et al. reported that 80% of patients who had been followed more than 17 years had chronic lung disease [4]. Because of improvements in diagnosis and therapy in the last 20 to 30 years, an increasing number of patients with XLA are now surviving into adulthood; however, other than case reports, there is very little information in the medical literature about the health status of adults with XLA.

In 1993 two groups demonstrated that XLA was caused by mutations in a hematopoietic-specific signal transduction molecule called Btk (for Bruton's tyrosine kinase) [22], [23]. In addition to clarifying the requirements for normal B cell development, this finding made it possible to make a definitive diagnosis of XLA in patients with atypical findings and to exclude the diagnosis of XLA in individuals who had clinical findings similar to those seen in XLA. To determine the health status and quality of life of adults with a definitive diagnosis of XLA, we asked adults with proven mutations in Btk to fill out a questionnaire that addressed past and current medical problems, psycho-social functioning, employment status and financial concerns.