For patients affected by primary immunodeficiencies (PID), research has primarily concentrated on elucidating the pathophysiology of the disease, conducting epidemiological studies to define the prevalence in different populations, and determining the prognosis with different treatment modalities that are available. However, for patients, an important aspect of the disease is the impact it has upon daily living. An association between a reduced quality of life and chronic disease is well recognized [
16‐
18]. Previously, we have demonstrated improvements in quality of life in patients with CGD who had successfully undergone curative treatment with hematopietic stem cell transplantation, compared with those who continued with conservative prophylactic antimicrobial and anti-inflammatory treatment [
2]. Furthermore, we, and others, have demonstrated that many carriers of X-linked CGD experience significant inflammatory, autoimmune, and more rarely infectious symptoms as a result of lyonization, leading to dual neutrophil populations exhibiting normal and diminished or absent function associated with inflammation [
4,
5]. Our study is the first to investigate health-related quality of life and emotional health in any cohort of carriers of a primary immunodeficiency. Given that we now appreciate that X-linked CGD carriers have their own mutated gene–related disease issues, it is perhaps not surprising that many of them exhibit a reduced health-related quality of life, similar to that of adult CGD patients, and worse than UK normal controls.
There are many factors that may impact upon the psychological health of XL-CGD carriers, including being a caregiver for a child with chronic illness, genetic guilt, the presence of anxiety and depressive symptoms, and potential ill health of the subject themselves. Whilst there is no literature specifically about XL-CGD carriers in this area, there is literature from other conditions, which may be relevant to XL-CGD carriers. Caring for a child with a chronic illness increases levels of stress. It is less clear what that impact may be on other markers of psychological health including the presence of anxiety and depression. Having a child with a chronic condition impacts upon the psychological health of the family [
19]. Parental stress has been evaluated following HSCT of a child for malignant disease and primary immunodeficiency [
20]. Mothers were more prone to general stresses even 5 years after their child’s HSCT but do not report higher stress scores when compared with reference groups. Genetic guilt may account for some of the psychological distress seen in the carers of genetic disorders, but if this were the main cause, one would expect to see lower levels of distress in conditions where there is no such definitive inheritance. This does not appear to be true, as a study of pediatric inflammatory bowel disease patients and their parents found high levels of caregiver stress, with highest levels seen where the disease was most active [
21]. We have previously demonstrated that fatigue in carriers does not correlate with the disease status of the index case, as those with sons who had been successfully transplanted also exhibited symptoms [
6], suggesting that intrinsic factors also play a part. In this study, symptoms were found in siblings, which were no different to those in mothers or grandmothers, again suggesting that intrinsic factors play a role, rather than “genetic guilt.” Our findings of significantly reduced QoL in XL-CGD carriers compared with UK population norms, and comparable with that of adult CGD patients, are important, as it highlights an unrecognized and unmet need that needs to be addressed in these women. Whilst there are many factors that may have contributed to these findings, an increased awareness of these findings should aid clinicians in caring for the entire family, including female relative carriers, and to institute appropriate measures as indicated [
22]. It would be interesting to study QoL in other X-linked primary immunodeficiencies. In that respect, chronic granulomatous disease may be unique—to date, it seems to be the only disease where XL carriers may exhibit symptoms regardless of degree of lyonization. Furthermore, CGD is one of few diseases where there may be a reasonable mix between transplanted and non-transplanted patients—in Wiskott-Aldrich syndrome, common gamma chain–deficient severe combined immunodeficiency, and X-linked lymphoproliferative disease, the majority of patients are transplanted or deceased. Perhaps CD40L-deficiency is most similar in this regard, although carriers appear asymptomatic—it is however less common than XL-CGD, and gathering meaningful cohorts of patients and carriers will be more challenging.