بیان سیتوکین پلاسما در سندرم خستگی مزمن نوجوان

Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescents. The pathophysiology is poorly understood, but low-grade systemic inflammation has been suggested as an important component. This study compared circulating levels of individual cytokines and parameters of cytokine networks in a large set of adolescent CFS patients and healthy controls, and explored associations between cytokines and symptoms in the CFS group. CFS patients (12–18 years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring three months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Thus, the case definition was broader than the Fukuda-criteria of CFS. Healthy controls having comparable distribution of gender and age were recruited from local schools. Twenty-seven plasma cytokines, including interleukins, chemokines and growth factors were assayed using multiplex technology. The results were subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and patients were subgrouped according to the Fukuda-criteria. A total of 120 CFS patients and 68 healthy controls were included. CFS patients had higher scores for fatigue (p < 0.001) and inflammatory symptoms (p < 0.001) than healthy controls. All cytokine levels and cytokine network parameters were similar, and none of the differences were statistically different across the two groups, also when adjusting for adherence to the Fukuda criteria of CFS. Within the CFS group, there were no associations between aggregate cytokine network parameters and symptom scores. Adolescent CFS patients are burdened by symptoms that might suggest low-grade systemic inflammation, but plasma levels of individual cytokines as well as cytokine network measures were not different from healthy controls, and there were no associations between symptoms and cytokine expression in the CFS group. Low-grade systemic inflammation does not appear to be a central part of adolescent CFS pathophysiology.

Chronic fatigue syndrome (CFS) is characterized by unexplained, long-lasting, disabling fatigue accompanied by pain, cognitive impairments, and other symptoms (Fukuda et al., 1994 and Royal College of Paediatrics and Child Health, 2004). CFS is an important cause of disability among adolescents, and may have detrimental effects on psychosocial and academic development (Kennedy et al., 2010), as well as family functioning (Missen et al., 2012). Adolescent CFS prevalence is estimated at 0.1–1.0% (Nijhof et al., 2011, Crawley et al., 2011 and Jason et al., 2006). The pathophysiology of CFS remains poorly understood. However, studies have reported alterations of homeostatic functions, such as enhanced sympathetic and attenuated parasympathetic cardiovascular nervous activity (Wyller et al., 2007, Wyller et al., 2008a and Wyller et al., 2008b), attenuation of the hypothalamus–pituitary–adrenal axis (HPA-axis) (Segal et al., 2005) and low-grade systemic inflammation (Klimas et al., 2012 and Raison et al., 2009). Inflammation might have a key role in the underlying pathophysiology, as assumed in the proposal for revised case definition of CFS (Carruthers et al., 2011). Accordingly, several studies have reported alterations in systemic cytokine expression in CFS, although the evidence is somewhat conflicting. For instance, Maes and co-workers (2012) reported increased levels of interleukin (IL)-1 and tumor necrosis factor (TNF), Fletcher and co-workers (2009) reported altered levels of several cytokines including IL-1α and IL-1β but normal levels of TNF, whereas Vollmer-Conna and co-workers (2007) did not find any alterations of cytokine expression. One reason for this discrepancy might be that CFS is associated with subtle alterations of cytokine networks rather than individual cytokines. Also, the mentioned pro-inflammatory cytokines are heavily influenced by pre-analytical factors and circulate at very low levels, requiring high sensitivity methods for reliable detection and making comparison between studies utilizing different assays difficult (Banks, 2000). Applying advanced mathematical methods on a large set of cytokine expression data in CFS patients and healthy controls, Broderick and co-workers (2010) found evidence of attenuated and Th1 and Th17 immune responses in the context of a well-established Th2 inflammatory environment in CFS. In adolescent CFS, cytokine expression has hardly been investigated. In a small study of fatigued adolescents (n = 9) following Epstein Barr virus infection, standard comparative analyses indicated increased levels of IL-8 and reduced levels of IL-23 as compared to recovered controls ( Broderick et al., 2012). In a previous report from the NorCAPITAL project, we reported slightly elevated levels of C-reactive protein (CRP) in adolescent CFS patients ( Sulheim et al., 2014). To the best of our knowledge, no other studies have specifically addressed circulating cytokine expression in adolescent CFS. Thus, the aims of this study were to compare individual cytokines and parameters of cytokine networks in plasma from a large set of adolescent CFS patients and healthy controls, and to explore associations between cytokines and symptoms in the CFS group. We hypothesized altered cytokine expression in CFS consistent with low-grade systemic inflammation, and a positive association between levels of proinflammatory cytokines and symptoms of inflammation.

Adolescent CFS patients are burdened by symptoms that might suggest low-grade systemic inflammation, but plasma levels of individual cytokines as well as cytokine network measures did not differ from healthy controls, and there were no associations between symptoms and cytokine expression in the CFS group. Low-grade systemic inflammation does not seem to be a central part of adolescent CFS pathophysiology.