Bulk RNA sequencing for analysis of post COVID-19 condition in adolescents and young adults.

BACKGROUND: Post COVID-19 condition (PCC) is a complication of SARS-COV-2 infection and can lead to long-term disability. METHODS: The present study was designed to analyse the gene expression patterns of PCC through bulk RNA sequencing of whole blood and to explore the potential molecular mechanisms of PCC. Whole blood was collected from 80 participants enrolled in a prospective cohort study following SARS-CoV-2 infected and non-infected individuals for 6 months after recruitment and was used for bulk RNA sequencing. Identification of differentially expressed genes (DEG), pathway enrichment and immune cell deconvolution was performed to explore potential biological pathways involved in PCC. RESULTS: We have found 13 differentially expressed genes associated with PCC. Enriched pathways were related to interferon-signalling and anti-viral immune processes. CONCLUSION: The PCC transcriptome is characterized by a modest overexpression of interferon-stimulated genes, pointing to a subtle ongoing inflammatory response.

Hair cortisol and self-perceived stress in adolescents with multi-system functional somatic disorders.

BACKGROUND: Long-term stress causing altered hypothalamic-pituitary-adrenal (HPA) axis dynamics with cortisol dysfunction may be involved in the pathophysiology of functional somatic disorders (FSD), but studies on adolescents with multi-system FSD are lacking. Therefore, we investigated: 1) whether hair cortisol concentration (HCC) differentiates adolescents with multi-system FSD from a) a population-based sample and b) a subgroup derived from the sample reporting a high physical symptom load, and 2) whether FSD population HCC is associated with primary symptom presentations and self-perceived stress. METHODS: We used data from a clinical sample with multi-system FSD (N = 91, age 15-19 years) and a population-based sample (N = 1,450, age 16-17 years) including a subgroup with top 10% total scores on physical symptoms (N = 147). Density plots and multiple linear regression were applied to compare HCC between groups. In the clinical sample, multiple linear regression was employed to assess the association between HCC and primary symptom clusters and self-perceived stress. RESULTS: Median HCC was lower in the clinical sample than in the population-based sample (ß = 0.80 (95%CI: 0.66, 0.97)), but not significantly different from median HCC in the derived subgroup (ß = 0.84 (95%CI: 0.66, 1.07)). In the clinical sample, HCC was not significantly associated with primary symptom clusters (F(2, 82) = 0.13, p = 0.88) or self-perceived stress (F(4, 83) = 1.18, p = 0.33). CONCLUSION: Our findings indicate that HCC is lowered in adolescents with multi-system FSD but not significantly associated with primary symptom presentations or self-perceived stress. Future studies including multiple measures of HPA axis dynamics alongside psychological measures may further elucidate the role of long-term stress in FSD. TRIAL REGISTRATION: The AHEAD study was pre-registered at ClinicalTrials.gov (NCT02346071), 26/01/2015.

Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers.

BACKGROUND: Chronic fatigue syndrome (CFS) is defined according to subjective symptoms only, and several conflicting case definition exist. Previous research has discovered certain biological alterations. The aim of the present study was to explore possible subgroups based on biological markers within a widely defined cohort of adolescent CFS patients and investigate to what extent eventual subgroups are associated with other variables. METHODS: The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) has previously performed detailed investigation of immunological, autonomic, neuroendocrine, cognitive and sensory processing functions in an adolescent group of CFS patients recruited according to wide diagnostic criteria. In the present study, hierarchical cluster analyses (Ward's method) were performed using representative variables from all these domains. Associations between clusters and constitutional factors (including candidate genetic markers), diagnostic criteria, subjective symptoms and prognosis were explored by standard statistical methods. RESULTS: A total of 116 patients (26.7% males, mean age 15.4 years) were included. The final cluster analyses revealed six clusters labelled pain tolerant & good cognitions, restored HPA dynamics, orthostatic intolerance, low-grade inflammation, pain intolerant & poor cognitions, and high vagal (parasympathetic) activity, respectively. There was substantial overlap between clusters. The pain intolerant & poor cognitions-cluster was associated with low functional abilities and quality of life, and adherence to the Canada 2003 diagnostic criteria for CFS. No other statistically significant cluster associations were discovered. CONCLUSION: Within a widely defined cohort of adolescent CFS patients, clusters could be delineated, but no distinct subgroups could be identified. Associations between clusters and constitutional factors, subjective symptoms and prognosis were scarce. These results question the clinical usefulness of searching for CFS subgroups, as well as the validity of the most "narrow" CFS diagnostic criteria. TRIAL REGISTRATION: Clinical Trials NCT01040429.

Functional evidence of low-pressure cardiopulmonary baroreceptor reinnervation 1 year after heart transplantation.

PURPOSE: Heart transplantation (HTx) implies denervation of afferent neural connections. Reinnervation of low-pressure cardiopulmonary baroreceptors might impact the development and treatment of hypertension, but little is known of its occurrence. The present prospective study investigated possible afferent reinnervation of low-pressure cardiopulmonary baroreceptors during the first year after heart transplantation. METHODS: A total of 50 heart transplant recipients (HTxRs) were included and were evaluated 7-12 weeks after transplant surgery, with follow-up 6 and 12 months later. In addition, a reference group of 50 healthy control subjects was examined once. Continuous, non-invasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 20° head-up tilt, during Valsalva maneuver and during 1 min of 30% maximal voluntary handgrip. In addition, routine clinical data including invasive measurements were used in the analyses. RESULTS: During the first year after HTx, the heart rate (HR) response to 20° head-up tilt partly normalized, a negative relationship between resting mean right atrial pressure and HR tilt response developed, low-frequency variability of the RR interval and systolic blood pressure at supine rest increased, and the total peripheral resistance response to Valsalva maneuver became stronger. CONCLUSION: Functional assessments suggest that afferent reinnervation of low-pressure cardiopulmonary receptors occurs during the first year after heart transplantation, partially restoring reflex-mediated responses to altered cardiac filling.

Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome.

BACKGROUND: Chronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology. METHODS: We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients). RESULTS: A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score. CONCLUSION: We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study.

INTRODUCTION: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls. MATERIALS AND METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents). RESULTS: The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p = 0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 × 106 cells/L, p = 0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p = 0.01) and plasma epinephrine (363 vs 237 nmol/L, p = 0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p = 0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p = 0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B = 4.5 × 10-4, p < 0.001), urine norepinephrine (B = 9.6 × 10-2, p = 0.044) and high-frequency power of heart rate variability (B = -3.7 × 10-2, p = 0.024). CONCLUSIONS: In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.

Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study.

INTRODUCTION: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue and Chronic Fatigue Syndrome (CFS). This study investigated baseline predictors of chronic fatigue six months after an acute EBV infection. MATERIALS AND METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively. We performed linear regression to assess possible associations between baseline predictors and fatigue (Chalder Fatigue Questionnaire total score) six months after the acute EBV infection. A total of 70 healthy controls were included for cross-sectional reference. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents). RESULTS: In the final multiple linear regression model, fatigue six months after acute EBV infection was significantly and independently predicted by the following baseline variables (regression coefficient B[95% CI]): Sensory sensitivity (0.8[0.09-1.6]), pain severity (0.2[0.02-0.3]), functional impairment (1000 steps/day) (-0.3[-0.5 to -0.08]), negative emotions (anxiety) (0.4[0.2-0.6]), verbal memory (correct word recognition) (1.7[0.1-3.3]), plasma C-reactive protein (2.8[1.1-4.4] for CRP values >0.86) and plasma Vitamin B12 (-0.005[-0.01 to -0.001]). CONCLUSIONS: Development of fatigue after acute EBV infection is to a larger extent predicted by baseline variables related to symptoms and functions than to baseline variables reflecting infectious and immune processes. TRIAL REGISTRATION: ClinicalTrials, ID: NCT02335437, https://clinicaltrials.gov/ct2/show/NCT02335437.

The Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo-controlled trial.

OBJECTIVES: The aim of this double-blinded randomised placebo-controlled trial was to investigate the efficacy of clonidine for delirium in medical inpatients greater than 65 years. METHODS: Acutely admitted medical patients greater than 65 years with delirium or subsyndromal delirium were eligible for inclusion. Included patients were given a loading dose of either placebo or clonidine; 75 µg every third hour up to a maximum of four doses to reach steady state and further 75 µg twice daily until delirium free for 2 days, discharge or a maximum of 7 days of treatment. The primary endpoint was the trajectory of the Memorial Delirium Assessment Scale (MDAS) for the 7 days of treatment. Presence of delirium according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria and severity measured by MDAS were assessed daily until discharge or a maximum of 7 days after end of treatment. RESULTS: Because of slower enrolment than anticipated, the study was halted early. Ten patients in each group were studied. The low recruitment rate was mainly due to the presence of multiple patient exclusion criteria for patient safety. There was no significant difference between the treatment group in the primary endpoint comparing the trajectory of MDAS for the 7 days of treatment using mixed linear models with log transformation, (P = .60). The treatment group did not have increased adverse effects. CONCLUSIONS: No effect of clonidine for delirium was found, although the study was under powered. Further studies in less frail populations are now required.

Autonomic cardiovascular control in older patients with acute infection and delirium: a pilot study of orthostatic stress responses.

BACKGROUND: Alterations in autonomic nervous system (ANS) activity might be involved in the pathophysiology of delirium. The aim was to explore autonomic cardiovascular control in older patients with and without delirium. METHODS: Fourteen patients (five with delirium) acutely admitted to the geriatric ward with an infection were enrolled in the study. Patients with atrial fibrillation, a pacemaker, or on treatment with beta-blockers, calcium channel blockers or acetylcholinesterase inhibitors were not eligible. Continuous, non-invasive hemodynamic variables were measured during supine rest (5 min) and head-up tilt (HUT) to 15 degrees (10 min). Heart rate (HR), blood pressure (BP) and stroke volume (SV) were recorded beat-to-beat. Cardiac output (CO), total peripheral resistance (TPR), end-diastolic volume (EDV) and heart rate variability (HRV) values were calculated. RESULTS: Median age was 86 years. HR, BP, SV, CO, TPR and EDV were similar across the two groups at rest, but there was a trend towards a greater increase in systolic BP and HR during HUT in the delirium group. At rest, all HRV indices were higher in the delirium group, but the differences were not statistically significant. During HUT, the delirium group had higher power spectral density (PSD) (representing total variability) (p = 0.06) and a lower low frequency (LF)/high frequency (HF)-ratio (an index of sympathovagal balance) than the control group (p = 0.06). Also, delirious patients had a significantly greater reduction in standard deviation of RR-intervals (SDNN) (representing total variability) from baseline than controls (p = 0.01) during HUT. CONCLUSIONS: This explorative pilot study on autonomic cardiovascular control in delirium suggests that there may be differences in HRV that should be further investigated in larger samples.

Autonomic cardiovascular control changes in recent heart transplant recipients lead to physiological limitations in response to orthostatic challenge and isometric exercise.

PURPOSE: Heart transplantation causes denervation of the donor heart, but the consequences for cardiovascular homeostasis remain to be fully understood. The present study investigated cardiovascular autonomic control at supine rest, during orthostatic challenge and during isometric exercise in heart transplant recipients (HTxR). METHODS: A total of 50 HTxRs were investigated 7-12 weeks after transplant surgery and compared with 50 healthy control subjects. Continuous, noninvasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 60° head-up tilt and during 1 min of 30% of maximal voluntary handgrip. Plasma and urine catecholamines were assayed, and symptoms were charted. RESULTS: At supine rest, heart rate, blood pressures and total peripheral resistance were higher, and stroke volume and end diastolic volume were lower in the HTxR group. During tilt, heart rate, blood pressures and total peripheral resistance increased less, and stroke volume and end diastolic volume decreased less. During handgrip, heart rate and cardiac output increased less, and stroke volume and end diastolic volume decreased less. Orthostatic symptoms were similar across the groups, but the HTxRs complained more of pale and cold hands. CONCLUSION: HTxRs are characterized by elevated blood pressures and total peripheral resistance at supine rest as well as attenuated blood pressures and total peripheral resistance responses during orthostatic challenge, possibly caused by low-pressure cardiopulmonary baroreceptor denervation. In addition, HTxRs show attenuated cardiac output response during isometric exercise due to efferent sympathetic denervation. These physiological limitations might have negative functional consequences.

Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later.

AIM: Acute Epstein-Barr virus (EBV) infection is a trigger of prolonged fatigue. This study investigated baseline predictors of physical activity six months after an acute EBV infection. METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively. In this exploratory study, we performed linear regression analysis to assess possible associations between baseline predictors and steps per day at six months. RESULTS: In the final multiple linear regression model, physical activity six months after acute EBV infection was significantly and independently predicted by baseline physical activity (steps per day), substance use (alcohol and illicit drugs) and human growth hormone (adjusted R2  = 0.20). CONCLUSION: Baseline physical activity, substance use and plasma growth hormone are independent predictors of physical activity six months after an acute EBV infection in adolescents, whereas markers of the infection and associated immune response do not seem to be associated with physical activity six months later.

Transforming growth factor beta (TGF-ß) in adolescent chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescent. The disease mechanisms are unknown. Previous studies have suggested elevated plasma levels of several cytokines, but a recent meta-analysis of 38 articles found that of 77 different cytokines measured in plasma, transforming growth factor beta (TGF-ß) was the only one that was elevated in patients compared to controls in a sufficient number of articles. In the present study we therefore compared the plasma levels of the three TGF-ß isoforms in adolescent CFS patients and healthy controls. In addition, the study explored associations between TGF-ß levels, neuroendocrine markers, clinical markers and differentially expressed genes within the CFS group. METHODS: CFS patients aged 12-18 years (n = 120) 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 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls (n = 68) were recruited from local schools. The three isoforms of TGF-ß (TGF-ß1, TGF-ß2, TGF-ß3) were assayed using multiplex technology. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. Whole blood gene expression was assessed by RNA sequencing in a subgroup of patients (n = 29) and controls (n = 18). RESULTS: Plasma levels of all three isoforms of TGF-ß were equal in the CFS patients and the healthy controls. Subgrouping according to the Fukuda and Canada 2003 criteria of CFS did not reveal differential results. Within the CFS group, all isoforms of TGF-ß were associated with plasma cortisol, urine norepinephrine and urine epinephrine, and this association pattern was related to fatigue score. Also, TGF-ß3 was related to expression of the B cell annotated genes TNFRSF13C and CXCR5. CONCLUSIONS: Plasma levels of all TGF-ß isoforms were not altered in adolescent CFS. However, the TGF-ß isoforms were associated with neuroendocrine markers, an association related to fatigue score. Furthermore, TGF-ß3 might partly mediate an association between plasma cortisol and B cell gene expression. Trial registration Clinical Trials NCT01040429.

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival.

BACKGROUND: Chronic fatigue syndrome (CFS) is a prevalent and disabling condition affecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group. METHODS: CFS patients (12-18 years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. RESULTS: A total of 29 CFS patients and 18 healthy controls were included. We identified 176 genes as differentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell differentiation and survival, as well as enhancement of innate antiviral responses and inflammation in the CFS group. A pattern of co-expression could be identified, and this pattern, as well as single gene transcripts, was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated. CONCLUSION: Adolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise. Trial registration Clinical Trials NCT01040429.

Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: a cross-sectional study.

BACKGROUND: Chronic fatigue syndrome (CFS) is a common and disabling disorder, and a major threat against adolescent health. The pathophysiology is unknown, but alteration of neuroendocrine control systems might be a central element, resulting in attenuation of the hypothalamus-pituitary-adrenalin (HPA) axis and enhancement of the sympathetic/adrenal medulla (SAM) system. This study explored differences in neuroendocrine control mechanisms between adolescent CFS patients and healthy controls, and whether characteristics of the control mechanisms are associated with important clinical variables within the CFS group. METHODS: CFS patients 12-18 years of age were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied. A comparable group of healthy controls were recruited from local schools. A total of nine hormones were assayed and subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and daily physical activity was recorded by an accelerometer. RESULTS: A total of 120 CFS patients and 68 healthy controls were included. CFS patients had significantly higher levels of plasma norepinephrine, plasma epinephrine and plasma FT4, and significantly lower levels of urine cortisol/creatinine ratio. Subgrouping according to other case definitions as well as adjusting for confounding factors did not alter the results. Multivariate linear regression models as well as network analyses revealed different interrelations between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls. Also, single hormone degree centrality was associated with clinical markers within the CFS group. CONCLUSION: This study reveals different interrelation between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls, and an association between hormone control characteristics and important clinical variables in the CFS group. These results add to the growing insight of CFS disease mechanisms. Trial registration Clinical Trials NCT01040429.

Plasma cytokine expression in adolescent chronic fatigue syndrome.

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 (12-18years 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.

Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study.

AIM: To study health related quality of life (HRQOL) and depressive symptoms in adolescents with chronic fatigue syndrome (CFS) and to investigate in which domains their HRQOL and depressive symptoms differ from those of healthy adolescents. BACKGROUND AND OBJECTIVE: Several symptoms such as disabling fatigue, pain and depressive symptoms affect different life domains of adolescents with CFS. Compared to adolescents with other chronic diseases, young people with CFS are reported to be severely impaired, both physiologically and mentally. Despite this, few have investigated the HRQOL in this group. METHOD: This is a cross-sectional study on HRQOL including 120 adolescents with CFS and 39 healthy controls (HC), between 12 and 18 years. The Pediatric Quality of Life Inventory™, 4.0 (PedsQL) was used to assess HRQOL. The Mood and Feelings Questionnaire assessed depressive symptoms. Data were collected between March 2010 and October 2012 as part of the NorCAPITAL project (Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial). Linear and logistic regression models were used in analysis, and all tests were two-sided. RESULTS: Adolescents with CFS reported significantly lower overall HRQOL compared to HCs. When controlling for gender differences, CFS patients scored 44 points lower overall HRQOL on a scale from 0-100 compared to HCs. The domains with the largest differences were interference with physical health (B = -59, 95 % CI -54 to -65) and school functioning (B = -52, 95 % CI -45 to -58). Both depressive symptoms and being a patient were independently associated with lower levels of HRQOL CONCLUSION: The difference in HRQOL between CFS patients and healthy adolescents was even larger than we expected. The large sample of adolescents with CFS in our study confirms previous findings from smaller studies, and emphasizes that CFS is a seriously disabling condition that has a strong impact on their HRQOL. Even though depressive symptoms were found in the group of patients, they could not statistically explain the poor HRQOL.

Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial.

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A-adrenoceptor agonist clonidine. METHODS: A total of 176 adolescent CFS patients (12-18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 µg or 50 µg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model. RESULTS: A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period. CONCLUSIONS: Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance. TRIAL REGISTRATION: Clinical Trials ID: NCT01040429, date of registration 12/28/2009.

Study findings challenge the content validity of the Canadian Consensus Criteria for adolescent chronic fatigue syndrome.

AIM: The 2003 Canadian Consensus Criteria for chronic fatigue syndrome (CFS) are often assumed to suggest low-grade systemic inflammation, but have never been formally validated. This study explored the content validity of the Criteria in a sample of adolescents with CFS selected according to a wide case definition. METHODS: A total of 120 patients with CFS with a mean age of 15.4 years (range 12-18 years) included in the NorCAPITAL project were post hoc subgrouped according to the Canadian Consensus Criteria. Those who satisfied the criteria (Criteria positive) and those who did not (Criteria negative) were compared across a wide range of disease markers and markers of prognosis. RESULTS: A total of 46 patients were classified as Criteria positive, 69 were classified as Criteria negative, and five could not be classified. All disease markers were equal across the two groups, except the digit span backward test of cognitive function, which showed poorer performance in the Criteria-positive group. Also, the prognosis over a 30-week period was equal between the groups. CONCLUSION: This study questions the content validity of the Canadian Consensus Criteria, as few differences were found between adolescent patients with CFS who did and did not satisfy the Criteria.

Fit elderly men can also stand: orthostatic tolerance and autonomic cardiovascular control in elderly endurance athletes.

BACKGROUND AND AIMS: Endurance training may reduce orthostatic tolerance. Elderly people are prone to orthostatic intolerance, but the impact of endurance training in old age has been insufficiently explored. METHODS: 54 healthy men; 30 endurance athletes and 24 controls, free from medication and chronic diseases, were subjected to head-up tilt tests: 30º for 10 min and 70º for 40 min. Non-invasive recordings of blood pressures, heart rate, stroke volume, end diastolic volume, total peripheral resistance, heart rate variability, blood pressure variability, and baroreflex sensitivity were obtained. We registered terminations of test due to frank syncope or unbearable presyncopal symptoms. RESULTS: Mean age 71 years (range 65-84); athletes had lower body mass index (23.4 versus 24.8, p < 0.05) and lower resting heart rate (50 versus 61, p < 0.01). Blood pressures and total peripheral resistance were equal. End diastolic volume index, baroreflex sensitivity, and heart rate variability were higher among athletes, both HF-RRI (high-frequency variability, reflecting parasympathetic activity) and LF-RRI (low-frequency variability, reflecting both sympathetic and parasympathetic activity). Syncope or presyncopal symptoms occurred in 11 persons, 4 athletes and 7 controls (p = 0.2). Cox Regression analysis showed that higher heart rate at rest was the only variable associated with syncope. DISCUSSION: Orthostatic tolerance was not reduced among elderly endurance athletes. Rather, there was a trend towards better orthostatic tolerance, which might be attributed to stronger parasympathetic cardiovascular control and larger blood volume. CONCLUSIONS: Better orthostatic tolerance might be an additional benefit of physical activity in older age.