Immune deficiency in Ataxia-Telangiectasia: a longitudinal study of 44 patients

Abstract

SummaryAtaxia-Telangiectasia (A-T) is a genetic condition leading to neurological defects and immune deficiency. The nature of the immune deficiency is highly variable, and in some cases causes significant morbidity and mortality due to recurrent sinopulmonary infections. Although the neurological defects in A-T are progressive, the natural history of the immune deficiency in A-T has not been evaluated formally. In this study we analyse the clinical history and immunological data in 44 patients with A-T who attended the National Ataxia-Telangiectasia clinic in Nottingham between 2001 and 2011. Using patient medical records and Nottingham University Hospitals (NUH) National Health Service Trust medical IT systems, data regarding clinical history, use of immunoglobulin replacement therapy, total immunoglobulin levels, specific antibody levels and lymphocyte subset counts were obtained. T cell receptor spectratyping results in some patients were already available and, where possible, repeat blood samples were collected for analysis. This study shows that subtle quantitative changes in certain immunological parameters such as lymphocyte subset counts may occur in patients with A-T over time. However, in general, for the majority of patients the severity of immune deficiency (both clinically and in terms of immunological blood markers) does not seem to deteriorate significantly with time. This finding serves to inform the long-term management of this cohort of patients because, if recurrent respiratory tract infections present later in life, then other contributory factors (e.g. cough/swallowing difficulties, underlying lung disease) should be investigated aggressively. Our findings also offer some form of reassurance for parents of children with A-T, which is otherwise a progressively severely debilitating condition.

Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia

“…Diseases of the respiratory system cause significant morbidity and are a frequent factor or cause of death in the A-T population [20,30-32]. Several factors contribute to the increased susceptibility to respiratory infections.…”

ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia

“…If recurrent respiratory tract infections present later in life, then other contributory factors (e.g. cough/swallowing difficulties, neuromuscular abnormalities or underlying lung disease) are a more likely explanation [27].…”

“…A high proportion (74%) of children with A-T are prescribed prophylactic antibiotics [24] on inconsistent and non-evidence-based criteria. A longitudinal follow-up study (mean duration of follow-up 5 years) found that 30 (68%) out of 44 patients were commenced early on prophylactic antibiotics with an aim to reduce the frequency and severity of bacterial respiratory infections [27]. The proportion of patients with A-T who had chronic respiratory symptoms and were using chronic macrolide antibiotics was lower in the patients in the USA (12 out of 36 A-T patients alive and 0 out of 65 A-T patients who died secondary to lung disease); however comparative data for patients with A-T who did not have chronic respiratory symptoms were not available [17].…”

Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis

“…1 Until now, immune dysfunction in AT has been characterized by improper B-and T-cell maturation, [2][3][4][5] immunoglobulin deficiencies, and impaired antibody responses observed in about two-thirds of patients. 6,7 Patients often have recurring respiratory tract infections and chronic interstitial inflammatory lung disease, although opportunistic infections are uncommon. 8,9 Many symptoms in AT patients, including increased incidence of autoimmunity, 10 oxidative stress, 11 cardiovascular disease, insulin resistance, and elevated serum levels of inflammatory cytokines, 12,13 suggest that they also suffer from pathologic inflammation.…”