The physical and psychological health of x-linked carriers of chronic granulomatous disease in the United Kingdom

Abstract

Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency in which there is a defect in one of the subunits of NADPH oxidase resulting in recurrent, severe infection, inflammation and autoimmunity. In the UK, 70% of cases are inherited in an X-linked (XL) manner, with the remainder being autosomal recessive (AR). Patients with CGD have an absent, or significantly reduced, neutrophil oxidative burst (NOB). XL-CGD carriers have a dual population of cells, those that function normally and produce an oxidative burst, and those that do not. XL-CGD carriers have been reported to have higher rates of discoid lupus, but there is little literature about other significant medical problems. Anecdotally, XL-CGD carriers suffer from more significant medical problems akin to that seen in CGD patients. Methods XL-CGD carriers were identified from the UK CGD Registry and through consultants caring for patients at the main centres in the UK; Great North Children’s Hospital, Newcastle upon Tyne, Great Ormond Street Hospital and the Royal Free Hospital, London. A control group of carriers of Muscular Dystrophy (MD) were recruited from the Great North Children’s Hospital. XL-CGD carriers completed questionnaires about their medical and psychological health. Blood samples were taken for neutrophil oxidative burst, autoantibody panel and cytokine measurement. MD carriers completed psychological health questionnaires. Questionnaires were compared with population data, where available, and published works about comparable groups. Psychological health questionnaires were compared to the recruited MD carrier control group. Results 81 XL-CGD carriers were recruited from 62 families, 2 were deceased. iii The mean NOB at enrolment was 47% with the majority of XL-CGD carriers falling in the range of 21-60%. Photosensitivity was reported in 74% of the recruited XL-CGD carriers and 40% reported a DLE-type malar rash. 26% of XL-CGD carriers met 4 or more of the ARA SLE criteria, whilst a further 30% met 3 or more criteria. 23% suffered recurrent or significant infection. 53% suffered from gastrointestinal symptoms and 59% suffered joint symptoms. Other autoimmune phenomena including Raynaud’s phenomenon were reported. 66% XL-CGD carriers suffered greater than normal levels of anxiety and 27% suffered depression. The XL-CGD carriers had significantly higher anxiety scores than parents of children with Cystic Fibrosis and had similar anxiety scores to published data about patients with SLE. 50% XL-CGD carriers suffered excessive fatigue. IL-8 levels were significantly higher in XL-CGD carriers compared to healthy controls. IL-8 levels were significantly higher in XL-CGD carriers reporting excessive fatigue than XL-CGD carriers who did not report significant fatigue. Quality of Life (QoL) Scores were reduced in all domains and significantly worse than UK population data. The XL-CGD carriers had poorer QoL than CGD patients in the social function, vitality and bodily pain domains. Conclusions This is the first study to have evaluated the health of XL-CGD carriers, and has demonstrated that XL-CGD carriers experience similar problems to CGD patients, with infection, inflammation and autoimmunity all demonstrated in this study. Excessive fatigue was reported in approximately half of the XL-CGD carriers and was associated with higher levels of IL-8. The aetiology for the symptoms seen in the XL-CGD carriers in this study is unclear. There was a lack of consistent correlation with degree of residual NOB function, with only recurrent skin abscesses, diarrhoea and abdominal pain being significantly associated with lower values. The raised IL-8 in the fatigued XL-CGD carriers supports the hypothesis of an inflammatory process but further work is required to investigate this. The lack of association with degree of iv residual NOB function means identifying XL-CGD carriers at risk of medical symptoms is not possible simply by assessing their NOB function. Psychological health has also been affected with the high rates of anxiety in the XL-CGD carrier population and significantly reduced QoL scores in comparison to UK population data. This has not been previously demonstrated. The psychological health problems are likely to be multifactorial in aetiology. This study has clearly demonstrated that XL-CGD carriers must now be considered as potential patients and should be pro-actively assessed and managed. It is not yet clear what the optimal medical management is, and this now needs to be investigated.