Vegard Bruun Bratholm Wyller

• Sommen, Silke Lauren; Segtnan, Sunniva; Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Stiansen-Sonerud, Tonje & Gjerstad, Johannes [Show all 11 contributors for this article] (2026). Long COVID: Deep single-cell immunophenotyping and machine learning reveal a general signature for fatigue. Journal of Translational Medicine. 24(1). doi: 10.1186/s12967-026-08149-3. Full text in Research Archive
• Brodwall, Elias Myrstad; Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Sommen, Silke Lauren; Lund-Berven, Lise & Cvejic, Erin [Show all 8 contributors for this article] (2026). Correlates of fatigue in SARS-CoV-2-positive and -negative adolescents and young adults: Repeated cross-sectional analyses from a prospective cohort study. Journal of Psychosomatic Research. ISSN 0022-3999. 209. doi: 10.1016/j.jpsychores.2026.112885. Full text in Research Archive
• Kongsnes, Berit Elise Bergem; Asprusten, Tarjei Tørre; Wyller, Vegard Bruun Bratholm & Pedersen, Maria (2026). The association between hair cortisol levels, Epstein-Barr virus infections and chronic fatigue in adolescents. Stress. ISSN 1025-3890. 29(1). doi: 10.1080/10253890.2026.2638303. Full text in Research Archive
• Nerli, Tom Farmen; Selvakumar, Joel Pradeepkumar; Heier, Ingar; Johnsen, Tone Langjordet; Wyller, Vegard Bruun Bratholm & Wisløff, Torbjørn (2026). Cost-effectiveness of a brief cognitive-behavioral outpatient rehabilitation program for patients with post-COVID-19 condition within a pragmatic randomized controlled trial. Cost Effectiveness and Resource Allocation. 24. doi: 10.1186/s12962-026-00748-7. Full text in Research Archive
• Nørgaard, Nikolai Nordberg; Holstad, Isabelle Aria Johanna Boere; Jess, Moritz Schneider; Wyller, Vegard Bruun Bratholm & Nestaas, Eirik (2026). Dynamic adaptive changes in heart function first 10 days after birth in healthy term neonates. Early Human Development. ISSN 0378-3782. 219, p. 106553–106553. doi: 10.1016/j.earlhumdev.2026.106553. Full text in Research Archive
• Raijmakers, Ruud P.H.; Lund-Berven, Lise; Keijmel, Stephan P.; Rodrigo, Chaturaka; Wyller, Vegard Bruun Bratholm & Katz, Ben Z. [Show all 20 contributors for this article] (2025). Immunological associations in post-infective fatigue syndromes including Long COVID—a systematic review and meta-analysis. EBioMedicine. 121. doi: 10.1016/j.ebiom.2025.105970. Full text in Research Archive Show summary

  Background The pathophysiology of post-infective fatigue syndromes (PIFS), including Long COVID, is unknown. This systematic review and meta-analysis aimed to investigate if PIFS is associated with persistent immune activation. Methods PubMed, EMBASE, and Web of Science were searched for terms related to infection, fatigue, persistent symptoms, and immunological markers. Population: adults and adolescents; Exposure: documented acute infection; Comparator: those who developed PIFS vs. recovered controls from the same exposure; and Outcomes: immunological biomarkers. Studies which documented acute infection, applied diagnostic criteria for PIFS, and assayed circulating immunologic markers were eligible. Findings From 14,985 studies screened, 30 articles were included (n = 5102 participants; 833 PIFS/PIFS-like cases, n = 4269 recovered control participants) with many studies excluded by inadequate quality in eligibility criteria. The meta-analysis (11 studies; n = 413 PIFS cases, analysed with random-effects models) showed PIFS cases had increased: white cell counts at 3–6 months (Cohen's d: 0.41, 95% CI 0.09–0.74); and circulating levels of RANTES and TNFα at 6–12 months (Cohen's d: 0.45 [95% CI 0.16–0.73] and 0.30 [95% CI 0.04–0.57], respectively) compared to controls recovered from the same exposure. Interpretation These findings provide cautious support for persistent immune activation in PIFS, but warrant further replication. Future studies should include better documentation of acute infection and PIFS case characterisation. Funding ARL is supported by a National Health and Medical Research Council Practitioner Fellowship (Grant 1041897). CXS is supported by a Cancer Institute New South Wales Early Career Fellowship (2021/ECF1310). BZK is supported by the National Institute of Allergy and Infectious Diseases (AI 105781). RAE is supported by the National Institute for Health and Care.

• Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Brodwall, Elias Myrstad; Sommen, Silke Lauren; Lund-Berven, Lise & Stiansen-Sonerud, Tonje [Show all 8 contributors for this article] (2025). Risk factors for fatigue severity in the post-COVID-19 condition: A prospective controlled cohort study of nonhospitalised adolescents and young adults. Brain, Behavior, and Immunity - Health (BBI - Health). 44. doi: 10.1016/j.bbih.2025.100967. Full text in Research Archive Show summary

  Long COVID is a global health concern, leading to persistent symptoms and disability long after the acute SARS-CoV-2 infection in most age groups. The condition can manifest even following mild COVID-19, and in young people, it may have serious adverse consequences for educational attainment and transition to adulthood. Fatigue is the most prevalent symptom, but the underlying mechanisms remain poorly understood. In this prospective study of 404 SARS-CoV-2-positive and 105 SARS-CoV-2 negative, non-hospitalised youth (ages 12–25, female 62%), we investigated which factors in the early convalescent stage (<28 days since test) were associated with the severity of persistent fatigue at 6 months after infection. Participants completed questionnaires regarding clinical symptoms, social factors and psychological traits, and were subject to clinical and functional testing and biomarker analyses. Variables with significant (p < 0.2) associations to the outcome in simple linear regression were chosen for multivariable modelling, together with potential confounders. In the final multivariable model, SARS-CoV-2-positivity was a minor risk factor for fatigue severity at six months. Baseline severity of symptoms was the main risk factor and correlated with psychosocial factors such as loneliness and neuroticism, rather than biomarkers. Our results suggest that factors not related to infection are major risk factors for persistent fatigue in this age group.

• Brodwall, Elias Myrstad; Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Sommen, Silke Lauren; Lund-Berven, Lise & Cvejic, Erin [Show all 8 contributors for this article] (2025). Predictors of fatigue progression in long COVID among young people. Brain, Behavior, and Immunity - Health (BBI - Health). 45. doi: 10.1016/j.bbih.2025.100982. Full text in Research Archive Show summary

  Long COVID, or post-COVID-19 condition (PCC), has emerged as a significant health concern, with fatigue being the most prevalent persistent symptom among young people. However, research on predictors of fatigue progression in young populations is limited. This study aimed to investigate factors during acute SARS-CoV-2 infection that could predict fatigue progression between six and 12 months post-infection in a cohort of young people with chronic fatigue following COVID-19. Data from the Long-Term Effects of COVID-19 in Adolescents (LoTECA) project were analyzed. A total of 93 participants (mean age 18.5 years, 84 % female) with chronic fatigue at six months, completed the 12-month follow-up. Multivariate analyses identified non-European ethnicity, higher interferon gamma (IFN-γ) levels, and lower RR-interval (higher resting heart rate) during acute infection as significant predictors of fatigue progression from six to 12 months. These three factors explained 21 % of the variance in the fatigue score, highlighting the importance of ethnicity, immune response, and autonomic function in the trajectory of long COVID fatigue. Early identification and targeted interventions, particularly for ethnic minorities and those with specific immune or autonomic markers during acute infection, may be helpful in reducing long-term fatigue. Further research is needed to explore treatment strategies for affected young populations.

• Nyengaard, Rebecca; Kallesøe, Karen Hansen; Rimvall, Martin Køster; Ørnbøl, Eva; Wellnitz, Kaare Bro & Olsen, Else Marie [Show all 8 contributors for this article] (2024). Hair cortisol and self-perceived stress in adolescents with multi-system functional somatic disorders. BMC Psychiatry. 24(1), p. 1–12. doi: 10.1186/s12888-024-05518-4. Full text in Research Archive Show summary

  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 (β = 0.80 (95%CI: 0.66, 0.97)), but not significantly different from median HCC in the derived subgroup (β = 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

• Havdal, Lise Beier; Selvakumar, Joel Pradeepkumar; Lund-Berven, Lise; Stiansen-Sonerud, Tonje; Zetterberg, Henrik & Blennow, Kaj [Show all 8 contributors for this article] (2024). Neurological involvement among non-hospitalized adolescents and young adults 6 months after acute COVID-19. Frontiers in Neurology. 15. doi: 10.3389/fneur.2024.1345787. Full text in Research Archive Show summary

  Introduction: The post-COVID-19 condition (PCC) is characterized by debilitating persistent symptoms, including symptoms suggesting neurological aberrations such as concentration difficulties, impaired memory, pain, and sleep disturbances. The underlying mechanisms remain elusive. This study aimed to investigate brain injury biomarkers, neurocognitive test performance, and self-reported neurological and neuropsychological symptoms in young people with PCC. Methods: A total of 404 non-hospitalized adolescents and young adults aged 12–25 years who tested positive for SARS-CoV-2, along with 105 matched SARS-CoV-2 negative individuals, were prospectively enrolled and followed-up for 6 months (Clinical Trials ID: NCT04686734). All participants underwent comprehensive assessment encompassing clinical examinations, questionnaires, neurocognitive testing and blood sampling. Serum samples were immunoassayed for the brain injury biomarkers neurofilament light chain (Nfl) and glial fibrillary acidic protein (GFAp). At 6 months, cross-sectional analyses of serum Nfl/GFAp, neurocognitive test results and symptom scores were performed across groups based on adherence to PCC criteria as well as initial SARS-CoV-2 test results. Also, associations between Nfl/GFAp, neurocognitive test results, and symptom scores were explored. Results: A total of 381 SARS-CoV-2 positive and 85 SARS-CoV-2 negative were included in the final analysis at 6 months, of whom 48% and 47%, respectively, adhered to the PCC criteria. Serum levels of Nfl and GFAp were almost equal across groups and did not differ from reference values in healthy populations. Also, neurocognitive test results were not different across groups, whereas symptom scores were significantly higher in patients fulfilling PCC criteria (independent of initial SARS-CoV-2 status). No significant associations between Nfl/GFAp, neurocognitive test results, and symptom scores were found. Conclusion: Normal brain injury biomarkers and neurocognitive performance 6 months after mild COVID-19 implies that the persistent symptoms associated with PCC are not concurrent with ongoing central nervous system damage or permanent disruption of cognitive functions. This finding contradicts the notion of neuroinflammation as a likely explanation for the persistent symptoms.

• Nerli, Tom Farmen; Selvakumar, Joel Pradeepkumar; Cvejic, Erin; Heier, Ingar; Pedersen, Maria & Johnsen, Tone Langjordet [Show all 7 contributors for this article] (2024). Brief Outpatient Rehabilitation Program for Post-COVID-19 Condition: A Randomized Clinical Trial. JAMA Network Open. 7(12), p. 1–16. doi: 10.1001/jamanetworkopen.2024.50744. Full text in Research Archive Show summary

  Importance Post–COVID-19 condition (PCC) is emerging as a common and debilitating condition with few treatment options. Objective To assess the effectiveness of a brief outpatient rehabilitation program based on a cognitive and behavioral approach for patients with PCC. Design, Setting, and Participants Patients with mild to moderate PCC were randomized 1:1 to an established transdiagnostic rehabilitation program or care as usual at a single referral center recruiting from the region of the South-Eastern Norway Regional Health Authority. Participants were followed up after treatment completion and 12 months after enrollment using participant-reported outcome measures. Data were collected from February 22, 2022, until April 15, 2024. Intention-to-treat analysis was performed. Intervention The program consisted of 2 to 8 outpatient encounters with approximately 2 to 6 weeks between each encounter. The intervention was theoretically grounded in the cognitive activation theory of stress, and physicians and physiotherapists were trained in cognitive and behavioral approaches with targeted negative stimuli and response outcome expectancies being particularly important. Main Outcomes and Measures Participant-reported physical function assessed by the Short-Form Health Survey 36 Physical Function Subscale (SF-36-PFS) served as the primary outcome. Secondary outcome measures were the remaining subscales of the SF-36, return to work self-efficacy and symptom scores on fatigue, postexertional malaise, breathlessness, cognitive difficulties, sleep problems, anxiety and depression symptoms, and smell and taste abnormalities. Safety measures included primary health care contacts; hospital admissions; initiation of pharmacologic and/or nonpharmacologic therapy; occurrence of novel disease, illness, or other health problems; worsening of selected key symptoms; working abilities; and thoughts of suicide. Results A total of 473 patients with mild to moderate PCC were assessed for eligibility (n = 364 physician referred; n = 109 self-referred); 314 were included (225 females [72%]; mean [SD] age, 43 [12] years) and 231 completed the primary end point evaluation. The SF-36-PFS scores improved statistically and clinically significantly in the intervention group (score difference between groups, 9.2; 95% CI, 4.3-14.2; P < .001; Cohen d = 0.43; intention-to-treat analysis). The effect was sustained over time. Most secondary and safety measures favored the intervention. Conclusions and Relevance In this randomized clinical trial, a brief outpatient rehabilitation program with a cognitive and behavioral approach in patients with PCC was effective and safe. This trial adds to the evidence supporting such interventions in routine clinical care. Future research should investigate which elements of this approach are the most effective and identify subgroups for which the current treatment is most relevant. Trial Registration ClinicalTrials.gov Identifier: NCT05196451

• Sommen, Silke Lauren; Zhao, Zhi; Segtnan, Sunniva; Stiansen-Sonerud, Tonje; Selvakumar, Joel Pradeepkumar & Havdal, Lise Beier [Show all 9 contributors for this article] (2024). Bulk RNA sequencing for analysis of post COVID-19 condition in adolescents and young adults. Journal of Translational Medicine. 22(1). doi: 10.1186/s12967-024-05117-7. Full text in Research Archive Show summary

  Background Post COVID19 condition (PCC) is a complication of SARSCOV2 infection and can lead to longterm 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 SARSCoV2 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 antiviral immune processes. Conclusion The PCC transcriptome is characterized by a modest overexpression of interferon-stimulated genes, pointing to a subtle ongoing inflammatory response.

• Olbjørn, Christine; Hagen, Milada; Moen, Aina Elisabeth Fossum; Havdal, Lise Beier; Sommen, Silke Lauren & Lund-Berven, Lise [Show all 10 contributors for this article] (2024). Longitudinal Fecal Microbiota Profiles in A Cohort of Non-Hospitalized Adolescents and Young Adults with COVID-19: Associations with SARS-CoV-2 Status and Long-Term Fatigue. Pathogens. ISSN 2076-0817. 13(11). doi: 10.3390/pathogens13110953. Full text in Research Archive Show summary

  Adolescents most often experience mild acute COVID-19, but may still face fatigue and persistent symptoms such as post-COVID-19 condition (PCC) and post-infective fatigue syndrome (PIFS). We explored the fecal microbiota of SARS-CoV-2 positive and negative non-hospitalized adolescents and young adults (12–25 years of age) in the “Long-Term Effects of COVID-19 in Adolescents” (LoTECA) project, a longitudinal observational cohort study. With a targeted qPCR approach, the quantities of 100 fecal bacterial taxa were measured at baseline (early convalescent stage) in 145 SARS-CoV-2-positive and 32 SARS-CoV-2 negative participants and after six months in 107 of the SARS-CoV-2-positive and 19 of the SARS-CoV-2 negative participants. Results: Faecalibacterium prausnitzii M21.2 and Gemmiger formicilis (both p < 0.001) were enriched in the SARS-CoV-2-positive participants compared to negative controls at baseline. In SARS-CoV-2-positive participants, lower baseline abundance of Faecalibacterium prausnitzii M21/2 (p = 0.013) and higher abundance of Clostridium spiroforme (p = 0.006), Sutterella wadsworthensis (p < 0.001), and Streptococcus thermophilus (p = 0.039) were associated with six-month fatigue. Sutterella wadsworthensis and Streptococcus thermophilus enrichment was additionally associated with PCC in the SARS-CoV-2-positive group (p < 0.001 and 0.042 respectively). Conclusions: Adolescents and young adults with mild acute COVID-19 infection had increased fecal abundance of the beneficial Faecalibacterium prausnitzii M21/2 and Gemmiger formicilis compared to SARS-CoV-2 negative controls in the early convalescent stage. Additionally, the abundance of both known (Faecalibacterium prausnitzii, Streptococcus thermophilus) and new (Clostridium spiroforme, Sutterella wadsworthensis) bacteria were associated with persistent symptoms such as fatigue in the COVID-19 infected group, warranting further exploration of the role of these bacteria in COVID-19 disease and PCC pathophysiology.

• Christensen, Anders Haugom; Wyller, Vegard Bruun Bratholm; Nygaard, Sissel; Rolid, Katrine; Nytrøen, Kari & Gullestad, Lars [Show all 10 contributors for this article] (2023). Factors Associated with Sinoatrial Reinnervation after Heart Transplantation. Transplantation direct. 9(12). doi: 10.1097/TXD.0000000000001553. Full text in Research Archive Show summary

  Background. Factors associated with sympathetic and parasympathetic sinoatrial reinnervation after heart transplantation (HTx) are inadequately studied. Methods. Fifty transplant recipients were examined at 7 to 12 wk (index visit), 6, 12, 24, and 36 mo after HTx. Supine rest heart rate variability in the low-frequency (LF) domain (sympathetic and parasympathetic sinoatrial reinnervation) and the high-frequency (HF) domain (parasympathetic sinoatrial reinnervation) were measured repeatedly and related to selected recipient, donor, and perisurgical characteristics. We primarily aimed to identify index visit factors that affect the sinoatrial reinnervation process. Secondarily, we examined overall associations between indices of reinnervation and repeatedly measured recipient characteristics to generate new hypotheses regarding the consequences of reinnervation. Results. LF and HF variability increased time dependently. In multivariate modeling, a pretransplant diagnosis of nonischemic cardiomyopathy (P = 0.038) and higher index visit handgrip strength (P = 0.028) predicted improved LF variability. Recipient age, early episodes of rejection, and duration of extracorporeal circulation were not associated with indices of reinnervation. Study average handgrip strength was positively associated with LF and HF variability (respectively, P = 0.005 and P = 0.029), whereas study average C-reactive protein was negatively associated (respectively, P = 0.015 and P = 0.008). Conclusions. Indices of both sympathetic and parasympathetic sinoatrial reinnervation increased with time after HTx. A pretransplant diagnosis of nonischemic cardiomyopathy and higher index visit handgrip strength predicted higher indices of mainly sympathetic reinnervation, whereas age, rejection episodes, and duration of extracorporeal circulation had no association. HTx recipients with higher indices of reinnervation had higher average handgrip strength, suggesting a link between reinnervation and improved frailty. The more reinnervated participants had lower average C-reactive protein, suggesting an inhibitory effect of reinnervation on inflammation, possibly through enhanced function of the inflammatory reflex. These potential effects of reinnervation may affect long-term morbidity in HTx patients and should be scrutinized in future research.

• White, Peter; Abbey, Susan; Angus, Brian; Ball, Harriet A; Buchwald, Dedra S & Burness, Christine [Show all 51 contributors for this article] (2023). Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050. 94(12), p. 1056–1063. doi: 10.1136/jnnp-2022-330463. Full text in Research Archive
• Alme, Tomas Nordheim; Andreasson, Anna; Asprusten, Tarjei Tørre; Bakken, Anne Karen; Beadsworth, Michael BJ & Boye, Birgitte [Show all 51 contributors for this article] (2023). Chronic fatigue syndromes: real illnesses that people can recover from. Scandinavian Journal of Primary Health Care. ISSN 0281-3432. 41(4), p. 372–376. doi: 10.1080/02813432.2023.2235609. Full text in Research Archive Show summary

  The ‘Oslo Chronic Fatigue Consortium’ consists of researchers and clinicians who question the current narrative that chronic fatigue syndromes, including post-covid conditions, are incurable diseases. Instead, we propose an alternative view, based on research, which offers more hope to patients. Whilst we regard the symptoms of these conditions as real, we propose that they are more likely to reflect the brain's response to a range of biological, psychological, and social factors, rather than a specific disease process. Possible causes include persistent activation of the neurobiological stress response, accompanied by associated changes in immunological, hormonal, cognitive and behavioural domains. We further propose that the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation.Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities. Finally, we call for a much more open and constructive dialogue about these conditions. This dialogue should include a wider range of views, including those of patients who have recovered from them.

• Fløtten, Kjersti Johanne Østrem; Aujoulat, Isabelle; Wyller, Vegard Bruun Bratholm & Solevåg, Anne Lee (2023). “I can’t pose a whole heap of questions that I know I don’t have time to follow up”—Exploring perceptions of an adolescent transition program. PLOS ONE. 18(11). doi: 10.1371/journal.pone.0293947. Full text in Research Archive Show summary

  Internal solitary waves (ISWs) of large amplitude moving in the coastal ocean induce sizeable horizontal velocities above the sea bed. In turn, these give rise to instability and vortex formation in the bottom boundary layer (BBL), and sediment resuspension and concentration maintenance in the water column. We present two-dimensional laminar simulations in a numerical tank suitable for internal wave motion, including the processes of the BBL. The combined wave and vorticity field encounters a cloud of tracer particles near the bottom. The tracer particles are moved vertically because of the vorticity field during a first encounter. The reflected wave intercepts a second time with the tracer particles, which are then moved further vertically. Numerical experiments with a kinematic viscosity of 1/100 cm2 s−1 or 1/1000 cm2 s-1 are used to manipulate the scale of the Reynolds number at a moderate and great laboratory scale. The final vertical position of the tracer particles is found below a vertical level of approximately 0.23 times the water depth (H) after the second passage. The result is independent of the scale. This vertical position matches available field measurements of a summer benthic nepheloid layer reaching a height of 0.19H. The laminar model predictions compare very well to the ISW-driven vortex formation measured in a three-dimensional laboratory wave tank. Convergence of the calculated vortex formation is documented.

• Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Drevvatne, Martin Solstrand; Brodwall, Elias Myrstad; Lund-Berven, Lise & Stiansen-Sonerud, Tonje [Show all 19 contributors for this article] (2023). Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults. JAMA Network Open. 6(3). doi: 10.1001/jamanetworkopen.2023.5763. Full text in Research Archive Show summary

  Importance The prevalence and baseline risk factors of post–COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19. Objectives To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors. Design, Setting, and Participants This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription–polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to the World Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed. Exposures SARS-CoV-2 infection. Main Outcomes and Measures The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2–positive and SARS-CoV-2–negative groups, and the risk difference with corresponding 95% CIs. Results A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2–positive and 4 of the SARS-CoV-2–negative individuals were lost to follow-up, and 16 SARS-CoV-2–negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2–positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2–negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5% in the SARS-CoV-2–positive group and 47.1% in the control group (risk difference, 1.5%; 95% CI, −10.2% to 13.1%). SARS-CoV-2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95% CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95% CI, 1.27-1.56). Low physical activity (RR, 0.96; 95% CI, 0.92-1.00) and loneliness (RR, 1.01; 95% CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits. Conclusions and Relevance The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of the World Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.

• Nygaard, Sissel; Christensen, Anders Haugom; Sletner, Line; Rolid, Katrine; Nytrøen, Kari & Gullestad, Lars [Show all 11 contributors for this article] (2022). Predictors of Hypertension Development 1 Year after Heart Transplantation. Transplantation. ISSN 0041-1337. 106(8), p. 1656–1665. doi: 10.1097/TP.0000000000004068. Full text in Research Archive
• Sommen, Silke Lauren; Havdal, Lise Beier; Selvakumar, Joel Pradeepkumar; Einvik, Gunnar; Leegaard, Truls Michael & Lund-Johansen, Fridtjof [Show all 12 contributors for this article] (2022). Inflammatory markers and pulmonary function in adolescents and young adults 6 months after mild COVID-19. Frontiers in Immunology. 13, p. 1–12. doi: 10.3389/fimmu.2022.1081718. Full text in Research Archive Show summary

  Introduction: Both public and scientific attention have shifted from the acute COVID-19 illness to the chronic disability experienced by a proportion of COVID-19 convalescents. Post COVID-19 condition, a term used for long-lasting symptoms after COVID-19, can affect individuals across all disease severity and age groups. Data on post-COVID-19 symptomatology, epidemiology and pathophysiology in adolescents and young adults are scarce. To date, little is known on the immunological and pulmonary trends in these patients after COVID-19. This study investigated immunological markers and pulmonary function in non-hospitalized patients in this group at 6 months after initial mild COVID-19 infection. Methods: Non-hospitalized SARS-CoV-2 positive (n = 405) and SARS-CoV-2 negative (n = 111) adolescents and young adults (aged 12-25 years) were followed prospectively for six months after SARS-CoV-2 PCR testing. At baseline and at six months follow-up, all participants underwent an assessment including clinical examination, questionnaires, spirometry, and blood sampling. Cross-sectional comparisons of blood biomarkers; including white blood cell counts, CRP, GDF-15, a 27-multiplex cytokine assay, complement activation products and SARS-CoV-2 antibodies; and spirometry measures were performed after classification of all participants according to their COVID-19 status and adherence to post-COVID-19 case criteria. Associations between biomarkers and COVID-19 symptoms were explored. Results: No difference in pulmonary function was detected between the groups. COVID-19 convalescents had higher levels of chemokines eotaxin, MCP-1 and IP-10 than non-infected controls. The increase was modest and not associated with long-lasting COVID-19 symptoms. Discussion: Elevated inflammatory mediators were found in adolescents and young adults six months after mild COVID-19, but there was no association with post-COVID-19 condition.

• Fløtten, Kjersti Johanne Østrem; Aujoulat, Isabelle; Wyller, Vegard Bruun Bratholm & Solevåg, Anne Lee (2022). But what do we mean by “health”? A critical perspective on the concept of health in the adolescent transition program of a Norwegian university hospital. BMC Health Services Research. 22(1), p. 1–9. doi: 10.1186/s12913-022-08903-5. Full text in Research Archive Show summary

  Background To understand better what influences the practice of our transition program, we wanted to explore the underlying theory of health. Methods We performed a qualitative content analysis of the written material that guides the program, comprising a quality system guideline, two checklists, a guide to health professionals and managers, and three patient brochures. Results The analysis resulted in the formulation of three themes; “Being on top of medical management”, “Ability to promote own health” and “Awareness of own goals and expectations”. Conclusion Our analysis indicates that the program content revolves mainly around medical management and that other dimensions of health are not emphasised. We question what the goals of the program are and if these goals are explicit and shared among the program stakeholders. An explicit program theory is vital and needs to be evident in material supporting transition programs.

• Havdal, Lise Beier; Berven, Lise; Selvakumar, Joel Pradeepkumar; Stiansen-Sonerud, Tonje; Leegaard, Truls Michael & Tjade, Trygve Olav [Show all 9 contributors for this article] (2022). Neurological Involvement in COVID-19 Among Non-Hospitalized Adolescents and Young Adults. Frontiers in Neurology. 13. doi: 10.3389/fneur.2022.915712. Full text in Research Archive Show summary

  Introduction Coronavirus disease 2019 (COVID-19) is prevalent among young people, and neurological involvement has been reported. We investigated neurological symptoms, cognitive test results, and biomarkers of brain injury, as well as associations between these variables in non-hospitalized adolescents and young adults with COVID-19. Methods This study reports baseline findings from an ongoing observational cohort study of COVID-19 cases and non-COVID controls aged 12–25 years (Clinical Trials ID: NCT04686734). Symptoms were charted using a standardized questionnaire. Cognitive performance was evaluated by applying tests of working memory, verbal learning, delayed recall, and recognition. The brain injury biomarkers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp), were assayed in serum samples using ultrasensitive immunoassays. Results A total of 405 COVID-19 cases and 111 non-COVID cases were prospectively included. Serum Nfl and GFAp concentrations were significantly elevated in COVID-19 cases as compared with non-COVID controls ( p = 0.050 and p = 0.014, respectively). The COVID-19 cases reported more fatigue ( p &amp;lt; 0.001) and post-exertional malaise (PEM) ( p = 0.001) compared to non-COVID-19 controls. Cognitive test performance and clinical neurological examination did not differ across the two groups. Within the COVID-19 group, there were no associations between symptoms, cognitive test results, and NfL or GFAp levels. However, fatigue and PEM were strongly associated with older age and female sex. Conclusions Non-hospitalized adolescents and young adults with COVID-19 reported more fatigue and PEM and had slightly elevated levels of brain injury markers, but showed normal cognitive performance. No associations were found between symptoms, brain injury markers, and cognitive test results, but fatigue and PEM were strongly related to female sex and older age.

• Berven, Lise; Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Stiansen-Sonerud, Tonje; Einvik, Gunnar & Leegaard, Truls Michael [Show all 10 contributors for this article] (2022). Inflammatory Markers, Pulmonary Function, and Clinical Symptoms in Acute COVID-19 Among Non-Hospitalized Adolescents and Young Adults. Frontiers in Immunology. 13:837288, p. 1–11. doi: 10.3389/fimmu.2022.837288. Full text in Research Archive Show summary

  Summary: Mild, subacute COVID-19 in young people show inflammatory enhancement, but normal pulmonary function. Inflammatory markers are associated with age and male sex, whereas clinical symptoms are associated with age and female sex, but not with objective disease markers. Background: Coronavirus Disease 2019 (COVID-19) is widespread among adolescents and young adults across the globe. The present study aimed to compare inflammatory markers, pulmonary function and clinical symptoms across non-hospitalized, 12 – 25 years old COVID-19 cases and non-COVID-19 controls, and to investigate associations between inflammatory markers, clinical symptoms, pulmonary function and background variables in the COVID-19 group. Methods: The present paper presents baseline data from an ongoing longitudinal observational cohort study (Long-Term Effects of COVID-19 in Adolescents, LoTECA, ClinicalTrials ID: NCT04686734). A total of 31 plasma cytokines and complement activation products were assayed by multiplex and ELISA methodologies. Pulmonary function and clinical symptoms were investigated by spirometry and questionnaires, respectively. Results: A total of 405 COVID-19 cases and 111 non-COVID-19 controls were included. The COVID-19 group had significantly higher plasma levels of IL-1β, IL-4, IL-7, IL-8, IL-12, TNF, IP-10, eotaxin, GM-CSF, bFGF, complement TCC and C3bc, and significantly lower levels of IL-13 and MIP-1α, as compared to controls. Spirometry did not detect any significant differences across the groups. IL-4, IL-7, TNF and eotaxin were negatively associated with female sex; eotaxin and IL-4 were positively associated with age. Clinical symptoms were positively associated with female sex and age, but not with objective disease markers. Conclusions: Among non-hospitalized adolescents and young adults with COVID-19 there was significant alterations of plasma inflammatory markers in the subacute stage of the infection. Still, pulmonary function was normal. Clinical symptoms were independent of inflammatory and pulmonary function markers, but positively associated with age and female sex.

• Øie, Merete Glenne; Buer, Sofie; Bølgen, Maria Sletten; Pedersen, Maria; Asprusten, Tarjei Tørre & Wyller, Vegard Bruun Bratholm (2022). Subjective and objective cognitive function in adolescent with chronic fatigue following Epstein-Barr virus infection. Journal of Psychosomatic Research. ISSN 0022-3999. 163, p. 1–6. doi: 10.1016/j.jpsychores.2022.111063. Full text in Research Archive Show summary

  Objective Cognitive difficulties are among the most disruptive and disabling problems reported by chronic fatigue syndrome (CFS) sufferers. Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and CFS. The aim of this study was to investigate subjectively reported and objectively measured cognitive functioning in fatigued and non-fatigued adolescents six months after EBV infection. Methods A total of 195 adolescents (12–19 years) with acute EBV infection were followed prospectively for six months, after which they were grouped as chronically fatigued (CF+) and non-fatigued (CF−) cases based on questionnaire score; the CF+-group was further subgrouped according to CFS diagnosis. A group of 70 healthy controls was also included. Groups were cross-sectionally compared on objective measures of processing speed, executive functions and memory, and subjective cognitive functioning. Results There were no group differences regarding objective cognitive measures, but the CF+-group reported significantly (p < 0.001) more cognitive problems (cognitive symptoms sum score = 9.5) compared to the CF−-group (cognitive symptoms sum score = 5.3) and the healthy control group (cognitive symptoms sum score = 6.4). The CFS subgroup rated symptoms scores even higher but did not differ on cognitive performance tests. Conclusion Subjective experiences of cognitive difficulties characterize adolescents with CF and CFS six months after acute EBV infection, whereas objective measures of cognitive impairment are inconspicuous.

• Christensen, Anders Haugom; Nygaard, Sissel; Rolid, Katrine; Nytrøen, Kari; Gullestad, Lars & Fiane, Arnt Eltvedt [Show all 10 contributors for this article] (2021). Strong evidence for parasympathetic sinoatrial reinnervation after heart transplantation. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. p. 1–12. doi: 10.1016/j.healun.2021.11.005. Full text in Research Archive Show summary

  Background Heart transplantation (HTx) surgically denervates the heart. We examined indices of sinoatrial reinnervation, with emphasis on (1) the occurrence and timing of parasympathetic reinnervation, and (2) the consequences of reinnervation for heart rate (HR) responsiveness and arterial baroreceptor sensitivity. Methods Fifty HTx recipients were prospectively followed for 36 months after surgery. Hemodynamic variables and heart rate variability were continuously recorded at supine rest, 60 degrees head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. Results Suggesting parasympathetic reinnervation: at baseline rest, root of the mean squared differences of successive RR intervals increased from median 3.9(5.9) to 7.1(5.1) ms (p < 0.001); high-frequency power increased from 4.0(12) to 5.7(18.9) ms2 (p = 0.018); and baroreceptor sensitivity increased from 0.04(0.36) to 1.3(2.4) ms/mmHg (p < 0.001). Suggesting sympathetic reinnervation: at baseline rest low-frequency power increased from 0.49(2.5) to 7.5(18.1) ms2 (p < 0.001); and HR responses to sympathetic stimulation during (1) head-up tilt increased from 1.9(4.2) to 9.1(8.2) bpm (p < 0.001), (2) Valsalva increased from 1.6(1.4) to 8.3(10.8) bpm (p < 0.001) and (3) handgrip increased from 0.3(0.6) to 1.9(5.1) bpm (p < 0.001). Signs of sympathetic reinnervation emerged within 6 months, while signs of parasympathetic reinnervation emerged by 24 months. Conclusions Root of the mean squared differences of successive RR intervals, high-frequency and low-frequency variability, HR responsiveness and arterial baroreflex sensitivity all increased after HTx, suggesting functional parasympathetic and sympathetic sinoatrial reinnervation. Accordingly, the pathological regulatory state present in heart transplant recipients, which is responsible for a host of functional and clinical abnormalities, is being partially offset over time by restored autonomic control of the heart in many heart transplant recipients.

• Fevang, Børre; Wyller, Vegard Bruun Bratholm; Mollnes, Tom Eirik; Pedersen, Maria; Asprusten, Tarjei Tørre & Michelsen, Annika Elisabet [Show all 8 contributors for this article] (2021). Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.715102. Full text in Research Archive Show summary

  Background: Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics. Methods: Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively. Results: Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group. Conclusion: Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months.

• Christensen, Anders Haugom; Nygaard, Sissel Irene; Rolid, Katrine; Nytrøen, Kari; Gullestad, Lars & Fiane, Arnt [Show all 10 contributors for this article] (2021). Early Signs of Sinoatrial Reinnervation in the Transplanted Heart. Transplantation. ISSN 0041-1337. 105(9), p. 2086–2096. doi: 10.1097/TP.0000000000003580. Full text in Research Archive
• Asprusten, Tarjei Tørre; Sletner, Line & Wyller, Vegard Bruun Bratholm (2021). Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers. Journal of Translational Medicine. 19, p. 1–12. doi: 10.1186/s12967-021-02713-9. Full text in Research Archive Show summary

  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

• Sandler, Carolina X; Wyller, Vegard B. B; Moss-Morris, Rona; Buchwald, Dedra; Crawley, Esther & Hautvast, Jeannine [Show all 12 contributors for this article] (2021). Long COVID and post-infective fatigue syndrome: A review. Open Forum Infectious Diseases. 8(10). doi: 10.1093/ofid/ofab440. Full text in Research Archive Show summary

  Fatigue is a dominant feature of both acute and convalescent coronavirus disease 2019 (COVID-19) (sometimes termed “long-COVID”), with up to 46% of patients reporting fatigue that lasts from weeks to months. The investigators of the international Collaborative on Fatigue Following Infection (COFFI) conducted a systematic review of post-COVID fatigue and a narrative review on fatigue after other infections, and made recommendations for clinical and research approaches to assessing fatigue after COVID-19. In the majority of COVID-19 cohort studies, persistent fatigue was reported by a significant minority of patients, ranging from 13% to 33% at 16–20 weeks post-symptom onset. Data from the prospective cohort studies in COFFI and others indicate that fatigue is also a prevalent outcome from many acute systemic infections, notably infectious mononucleosis, with a case rate for clinically significant Post-infective fatigue after exclusion of recognized medical and psychiatric causes, ranging from 10%–35% at 6 months. To better characterize post-COVID fatigue, the COFFI investigators recommend the following: application of validated screening questionnaires for case detection; standardized interviews encompassing fatigue, mood, and other symptoms; and investigative approaches to identify end-organ damage and mental health conditions.

• Wyller, Vegard Bruun Bratholm; Nygaard, Sissel; Christensen, Anders Haugom; Rolid, Katrine; Nytrøen, Kari & Gullestad, Lars [Show all 10 contributors for this article] (2021). Functional evidence of low-pressure cardiopulmonary baroreceptor reinnervation 1 year after heart transplantation. European Journal of Applied Physiology. ISSN 1439-6319. 121(3), p. 915–927. doi: 10.1007/s00421-020-04586-0. Full text in Research Archive Show summary

  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.

• Malik, Sadaf; Asprusten, Tarjei Tørre; Pedersen, Maria; Mangersnes, Julie; Trondalen, Gro & Roy, Betty Van [Show all 8 contributors for this article] (2020). Cognitive–behavioural therapy combined with music therapy for chronic fatigue following Epstein-Barr virus infection in adolescents: a randomised controlled trial. BMJ Paediatrics Open. 4:e000797, p. 1–10. doi: 10.1136/bmjpo-2020-000797. Full text in Research Archive Show summary

  Abstract Background Cognitive–behavioural therapy (CBT) is effective in chronic fatigue (CF) syndrome. However, CBT has not been investigated in postinfectious CF, nor is it known whether addition of therapeutic elements from other disciplines might be useful. We explored combined CBT and music therapy intervention for CF following Epstein-Barr virus (EBV) infection in adolescents. Methods Adolescents (12–20 years old) participating in a postinfectious cohort study who developed CF 6 months after an acute EBV infection were eligible for the present study. A combined CBT and music therapy programme (10 therapy sessions and related homework) was compared with care as usual in a randomised controlled design. Therapists and participants were blinded to outcome evaluation. Endpoints included physical activity (steps/day), symptom scores, recovery rate and possible harmful effects, but the study was underpowered regarding efficacy. Total follow-up time was 15 months. Power analyses suggested that 120 participants would be needed in order to detect a moderate effect size. Results A total of 91 individuals with postinfectious CF were eligible, and a total of 43 were included (21 intervention group, 22 control group). Concern regarding school absence due to therapy sessions was the main reason for declining participation. Seven individuals left the study during the first 3 months, leaving 15 in the intervention group and 21 in the control group at 3 months follow-up. No harmful effects were recorded, and compliance with appointment was high. In intention-to-treat analyses, the primary endpoint (number of steps/day) did not differ significantly between the intervention group and the control group (difference (95% CI) =–1298 (–4874 to 2278)). Secondary outcome measures were also not significantly different among the two groups. Conclusion An intervention study of combined CBT and music therapy in postinfectious CF is feasible. A fully powered trial is needed to evaluate efficacy; participants’ concern regarding school absence should be properly addressed to secure recruitment. Trial registration number ClinicalTrials ID: NCT02499302, registered July 2015. http://dx.doi.org/10.1136/bmjpo-2020-000797

• Nygaard, Sissel Irene; Rolid, Katrine; Nytrøen, Kari; Fiane, Arnt E; Wyller, Vegard Bruun Bratholm & Gullestad, Lars [Show all 7 contributors for this article] (2020). Heart Rate Response after Heart Transplantation. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. 39(4), p. S285–S286. doi: 10.1016/j.healun.2020.01.630. Full text in Research Archive
• Trondalen, Gro; Mangersnes, Julie; Bonde, Lars Ole; Malik, Sadaf; Asprusten, Tarjei Tørre & Rødevand, Linn Nilsen [Show all 8 contributors for this article] (2020). Music therapy for chronic fatigue following epstein-barr virus infection in adolescents. Music and Medicine. 12(2), p. 84–91. doi: 10.47513/mmd.v12i2.679. Full text in Research Archive
• Brodwall, Elias Myrstad; Pedersen, Maria; Asprusten, Tarjei Tørre & Wyller, Vegard Bruun Bratholm (2020). Pain in adolescent chronic fatigue following Epstein-Barr virus infection. Scandinavian Journal of Pain. ISSN 1877-8860. doi: 10.1515/sjpain-2020-0031. Full text in Research Archive
• Nguyen, Chinh BKrong; Kumar, Surendra; Zucknick, Manuela; Kristensen, Vessela N.; Gjerstad, Johannes & Nilsen, Hilde Loge [Show all 7 contributors for this article] (2019). Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. ISSN 0889-1591. 76, p. 82–96. doi: 10.1016/j.bbi.2018.11.008. Full text in Research Archive Show summary

  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.

• Asprusten, Tarjei Tørre; Pedersen, Maria; Skovlund, Eva & Wyller, Vegard Bruun Bratholm (2019). EBV-requisitioning physicians' guess on fatigue state 6 months after acute EBV infection. BMJ Paediatrics Open. 3(1). doi: 10.1136/bmjpo-2018-000390. Full text in Research Archive Show summary

  We assessed referring medical practitioner’s ability to predict chronic fatigue development in adolescents presenting with acute infectious mononucleosis. Compared with ‘not fatigued’ being predicted as ‘unsurely fatigued’ and ‘likely fatigued’ were both strongly associated with developing fatigue 6 months later (OR 2.5, 95% CI 1.16% to 5.47% and 3.2, 95% CI 1.19% to 8.61%, respectively, P=0.012). The positive and negative predictive values were 66% and 62%, respectively. Disentangling the physician’s intuition may be of interest in further investigations of risk factors and prophylactic factors for fatigue development.

• Pedersen, Maria; Asprusten, Tarjei Tørre; Godang, Kristin; Leegaard, Truls Michael; Osnes, Liv T. N. & Skovlund, Eva [Show all 9 contributors for this article] (2019). Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later. Acta Paediatrica. ISSN 0803-5253. 108(8), p. 1521–1526. doi: 10.1111/apa.14728. Full text in Research Archive Show summary

  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.

• Kristiansen, Miriam Skjerven; Stabursvik, Julie; O'Leary, Elise Catriona Solberg; Pedersen, Maria; Asprusten, Tarjei Tørre & Leegaard, Truls Michael [Show all 11 contributors for this article] (2019). Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study. Brain, Behavior, and Immunity. ISSN 0889-1591. 80, p. 551–563. doi: 10.1016/j.bbi.2019.04.040. Full text in Research Archive Show summary

  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.

• Neerland, Bjørn Erik; Wyller, Torgeir Bruun & Wyller, Vegard Bruun Bratholm (2019). Autonomic cardiovascular control in older patients with acute infection and delirium: a pilot study of orthostatic stress responses. BMC Geriatrics. 19(23), p. 1–8. doi: 10.1186/s12877-019-1035-0. Full text in Research Archive Show summary

  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.

• Nygaard, Sissel Irene; Christensen, Anders Haugom; Rolid, Katrine; Nytrøen, Kari; Gullestad, Lars & Fiane, Arnt E [Show all 11 contributors for this article] (2019). Autonomic cardiovascular control changes in recent heart transplant recipients lead to physiological limitations in response to orthostatic challenge and isometric exercise. European Journal of Applied Physiology. ISSN 1439-6319. 119(10), p. 2225–2236. doi: 10.1007/s00421-019-04207-5. Full text in Research Archive Show summary

  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.

• Pedersen, Maria; Asprusten, Tarjei Tørre; Godang, Kristin; Leegaard, Truls Michael; Osnes, Liv T. N. & Skovlund, Eva [Show all 9 contributors for this article] (2019). Fatigue in Epstein-Barr virus infected adolescents and healthy controls: A prospective multifactorial association study. Journal of Psychosomatic Research. ISSN 0022-3999. 121, p. 46–59. doi: 10.1016/j.jpsychores.2019.04.008. Full text in Research Archive
• Hov, Karen Roksund; Neerland, Bjørn Erik; Undseth, Øystein; Wyller, Vegard Bruun Bratholm; MacLullich, Alasdair M.J. & Qvigstad, Eirik [Show all 8 contributors for this article] (2019). The Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo-controlled trial. International Journal of Geriatric Psychiatry. ISSN 0885-6230. 34(7), p. 974–981. doi: 10.1002/gps.5098. Full text in Research Archive Show summary

  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.

• Valenza, Gaetano; Citi, Luca; Wyller, Vegard Bruun Bratholm & Barbieri, Riccardo (2018). ECG-derived sympathetic and parasympathetic activity in the healthy: An early lower-body negative pressure study using adaptive Kalman prediction. IEEE Engineering in Medicine and Biology Society. Conference Proceedings. ISSN 1557-170X. 2018:8513512-July, p. 5628–5631. doi: 10.1109/EMBC.2018.8513512. Full text in Research Archive
• Katz, Ben Z; Collin, Simon M.; Murphy, Gabrielle; Moss-Morris, Rona; Wyller, Vegard Bruun Bratholm & Wensaas, Knut-Arne [Show all 15 contributors for this article] (2018). The international collaborative on fatigue following infection (COFFI). Fatigue: Biomedicine, Health & Behavior. ISSN 2164-1846. 6(2), p. 106–121. doi: 10.1080/21641846.2018.1426086. Full text in Research Archive
• Hov, Karen Roksund; Neerland, Bjørn Erik; Andersen, Anders Mikal; Undseth, Øystein; Wyller, Vegard Bruun Bratholm & MacLullich, Alasdair M.J. [Show all 9 contributors for this article] (2018). The use of clonidine in elderly patients with delirium; pharmacokinetics and hemodynamic responses. BMC Pharmacology and Toxicology. 19(29). doi: 10.1186/s40360-018-0218-1. Full text in Research Archive Show summary

  Background The Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is an RCT investigating the effect of clonidine in medical patients > 65 years with delirium. To assess the dosage regimen and safety measures of this study protocol, we measured the plasma concentrations and hemodynamic effects of clonidine in the first 20 patients. Methods Patients were randomised to clonidine (n = 10) or placebo (n = 10). The treatment group was given a loading dose (75μg every 3rd hour up to a maximum of 4 doses) to reach steady state, and further 75μg twice daily until delirium free for 2 days, discharge or a maximum of 7 days. Blood pressure (BP) and heart rate (HR) were measured just before every dose. If the systolic BP was < 100 mmHg or HR < 50 beats per minute the next dose was omitted. Plasma concentrations of clonidine were measured 3 h after each drug intake on day 1, just before intake (day 2 and at steady state day 4–6) and 3 h after intake at steady state (Cmax). Our estimated pre-specified plasma concentration target range was 0.3–0.7μg/L. Results 3 h after the first dose of 75μg clonidine, plasma concentration levels rose to median 0.35 (range 0.24–0.40)μg/L. Median trough concentration (C0) at day 2 was 0.70 (0.47–0.96)μg/L. At steady state, median C0 was 0.47 (0.36–0.76)μg/L, rising to Cmax 0.74 (0.56–0.95)μg/L 3 h post dose. A significant haemodynamic change from baseline was only found at a few time-points during the loading doses within the clonidine group. There was however extensive individual BP and HR variation in both the clonidine and placebo groups, and when comparing the change scores (delta values) between the clonidine and the placebo groups, there were no significant differences. Conclusions The plasma concentration of clonidine was at the higher end of the estimated therapeutic range. Hemodynamic changes during clonidine treatment were as expected, with trends towards lower blood pressure and heart rate in patients treated with clonidine, but with dose adjustments based on SBP this protocol appears safe.

• Pedersen, Maria; Asprusten, Tarjei Tørre; Godang, Kristin; Leegaard, Truls Michael; Osnes, Liv T. N. & Skovlund, Eva [Show all 9 contributors for this article] (2018). Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: a prospective cohort study. Brain, Behavior, and Immunity. ISSN 0889-1591. 75, p. 94–100. doi: 10.1016/j.bbi.2018.09.023. Full text in Research Archive Show summary

  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.

• Asprusten, Tarjei Tørre; Sulheim, Dag; Fagermoen, Frode Even; Winger, Anette; Skovlund, Eva & Wyller, Vegard Bruun Bratholm (2018). Systemix exertion intolerance disease diagnostic criteria Applied on an adolescent chronic fatigue syndrom cohort: evaluation of subgroup differences and prognostic utility. BMJ Paediatrics Open. 2:e000233(1), p. 1–8. doi: 10.1136/bmjpo-2017-000233. Full text in Research Archive Show summary

  Objective Existing case definitions for chronic fatigue syndrome (CFS) all have disputed validity. The present study investigates differences between adolescent patients with CFS who satisfy the systemic exertion intolerance disease (SEID) diagnostic criteria (SEID-positive) and those who do not satisfy the criteria (SEID-negative). Methods 120 adolescent patients with CFS with a mean age of 15.4 years (range 12–18 years) included in the NorCAPITAL project (ClinicalTrials ID: NCT01040429) were post-hoc subgrouped according to the SEID criteria based on a comprehensive questionnaire. The two subgroups were compared across baseline characteristics, as well as a wide range of cardiovascular, inflammatory, infectious, neuroendocrine and cognitive variables. Data from 30-week follow-up were used to investigate prognostic differences between SEID-positive and SEID-negative patients. Results A total of 45 patients with CFS were SEID-positive, 69 were SEID-negative and 6 could not be classified. Despite the fact that clinically depressed patients were excluded in the NorCAPITAL project, the SEID-positive group had significantly higher score on symptoms suggesting a mood disorder (Mood and Feelings Questionnaire): 23.2 vs 13.4, difference 9.19 (95% CI 5.78 to 12.6). No other baseline characteristics showed any group differences. When accounting for multiple comparisons, there were no statistically significant differences between the groups regarding cardiovascular, inflammatory, infectious, neuroendocrine and cognitive variables. Steps per day and Chalder Fatigue Questionnaire at week 30 showed no differences between the groups. Conclusion The findings question the discriminant and prognostic validity of the SEID diagnostic criteria in adolescent CFS, and suggest that the criteria tend to select patients with depressive symptoms.

• Nordin, Succora; Donkor, Hilde Mjell; Wyller, Vegard Bruun Bratholm; Farstad, Teresa; Borthne, Arne Sigmund & Moen, Atle [Show all 7 contributors for this article] (2018). Pericarditis in a newborn child. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 138(5). doi: 10.4045/tidsskr.17.0555. Full text in Research Archive
• Bakke, Laura A Wortinger; Endestad, Tor; Melinder, Annika Maria D; Øie, Merete Glenne; Sulheim, Dag & Fagermoen, Frode Even [Show all 7 contributors for this article] (2017). Emotional conflict processing in adolescent chronic fatigue syndrome: A pilot study using functional magnetic resonance imaging. Journal of Clinical and Experimental Neuropsychology. ISSN 1380-3395. 39(4), p. 355–368. doi: 10.1080/13803395.2016.1230180. Full text in Research Archive Show summary

  Introduction: Studies of neurocognition suggest that abnormalities in cognitive control contribute to the pathophysiology of chronic fatigue syndrome (CFS) in adolescents, yet these abnormalities remain poorly understood at the neurobiological level. Reports indicate that adolescents with CFS are significantly impaired in conflict processing, a primary element of cognitive control. Method: In this study, we examine whether emotional conflict processing is altered on behavioral and neural levels in adolescents with CFS and a healthy comparison group. Fifteen adolescent patients with CFS and 24 healthy adolescent participants underwent functional magnetic resonance imaging (fMRI) while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect labeled words. Results: Adolescent CFS patients were less able to engage the left amygdala and left midposterior insula (mpINS) in response to conflict than the healthy comparison group. An association between accuracy interference and conflict-related reactivity in the amygdala was observed in CFS patients. A relationship between response time interference and conflict-related reactivity in the mpINS was also reported. Neural responses in the amygdala and mpINS were specific to fatigue severity. Conclusions: These data demonstrate that adolescent CFS patients displayed deficits in emotional conflict processing. Our results suggest abnormalities in affective and cognitive functioning of the salience network, which might underlie the pathophysiology of adolescent CFS.

• Nguyen, Chinh Bkrong Thi Thuy; Alsøe, Lene; Lindvall, Jessica Margareta; Sulheim, Dag; Fagermoen, Frode Even & Winger, Anette [Show all 9 contributors for this article] (2017). Whole blood gene expression in adolescent chronic fatigue syndrome: An exploratory cross-sectional study suggesting altered B cell differentiation and survival. Journal of Translational Medicine. 15. doi: 10.1186/s12967-017-1201-0. Full text in Research Archive Show summary

  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.

• Feiring, Berit; Laake, Ida; Bakken, Inger Johanne; Greve-Isdahl, Margrethe; Wyller, Vegard Bruun Bratholm & Håberg, Siri Eldevik [Show all 8 contributors for this article] (2017). HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway. Vaccine. ISSN 0264-410X. 35(33), p. 4203–4212. doi: 10.1016/j.vaccine.2017.06.031. Full text in Research Archive
• Pedersen, Maria; Ekstedt, Mirjam; Småstuen, Milada C; Wyller, Vegard Bruun Bratholm; Sulheim, Dag & Fagermoen, Frode Even [Show all 9 contributors for this article] (2017). Sleep-wake rhythm disturbances and perceived sleep in adolescent chronic fatigue syndrome. Journal of Sleep Research. ISSN 0962-1105. 26(5), p. 595–601. doi: 10.1111/jsr.12547. Full text in Research Archive Show summary

  Chronic fatigue syndrome (CFS) is characterized by long-lasting, disabling and unexplained fatigue that is often accompanied by unrefreshing sleep. The aim of this cross-sectional study was to investigate sleep–wake rhythm and perceived sleep in adolescent CFS patients compared to healthy individuals. We analysed baseline data on 120 adolescent CFS patients and 39 healthy individuals included in the NorCAPITAL project. Activity measures from a uniaxial accelerometer (activPAL) were used to estimate mid-sleep time (mid-point of a period with sleep) and time in bed. Scores from the Karolinska Sleep Questionnaire (KSQ) were also assessed. The activity measures showed that the CFS patients stayed significantly longer in bed, had a significantly delayed mid-sleep time and a more varied sleep–wake rhythm during weekdays compared with healthy individuals. On the KSQ, the CFS patients reported significantly more insomnia symptoms, sleepiness, awakening problems and a longer sleep onset latency than healthy individuals. These results might indicate that disrupted sleep–wake phase could contribute to adolescent CFS; however, further investigations are warranted.

• Wyller, Vegard Bruun Bratholm; Nguyen, Chinh Bkrong Thi Thuy; Ludviksen, Judith K & Mollnes, Tom Eirik (2017). Transforming growth factor beta (TGF‑β)in adolescent chronic fatigue syndrome. Journal of Translational Medicine. 15(1). doi: 10.1186/s12967-017-1350-1. Full text in Research Archive Show summary

  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-β) 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-β isoforms in adolescent CFS patients and healthy controls. In addition, the study explored associations between TGF-β 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-β (TGF-β1, TGF-β2, TGF-β3) 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-β 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-β were associated with plasma cortisol, urine norepinephrine and urine epinephrine, and this association pattern was related to fatigue score. Also, TGF-β3 was related to expression of the B cell annotated genes TNFRSF13C and CXCR5. Conclusions Plasma levels of all TGF-β isoforms were not altered in adolescent CFS. However, the TGF-β isoforms were associated with neuroendocrine markers, an association related to fatigue score. Furthermore, TGF-β3 might partly mediate an association between plasma cortisol and B cell gene expression.

• Bakke, Laura A. Wortinger; Øie, Merete Glenne; Endestad, Tor & Wyller, Vegard Bruun Bratholm (2017). Altered right anterior insular connectivity and loss of associated functions in adolescent chronic fatigue syndrome. PLOS ONE. 12(9). doi: 10.1371/journal.pone.0184325. Full text in Research Archive Show summary

  Abstract Impairments in cognition, pain intolerance, and physical inactivity characterize adolescent chronic fatigue syndrome (CFS), yet little is known about its neurobiology. The right dorsal anterior insular (dAI) connectivity of the salience network provides a motivational context to stimuli. In this study, we examined regional functional connectivity (FC) patterns of the right dAI in adolescent CFS patients and healthy participants. Eighteen adolescent patients with CFS and 18 aged-matched healthy adolescent control participants underwent resting-state functional magnetic resonance imaging. The right dAI region of interest was examined in a seed-to-voxel resting-state FC analysis using SPM and CONN toolbox. Relative to healthy adolescents, CFS patients demonstrated reduced FC of the right dAI to the right posterior parietal cortex (PPC) node of the central executive network. The decreased FC of the right dAI–PPC might indicate impaired cognitive control development in adolescent CFS. Immature FC of the right dAI–PPC in patients also lacked associations with three known functional domains: cognition, pain and physical activity, which were observed in the healthy group. These results suggest a distinct biological signature of adolescent CFS and might represent a fundamental role of the dAI in motivated behavior.

• Wyller, Hedda Bratholm; Wyller, Vegard Bruun Bratholm; Crane, Catherine & Gjelsvik, Bergliot (2017). The relationship between sensory processing sensitivity and psychological distress: A model of underpinning mechanisms and an analysis of therapeutic possibilities. Scandinavian Psychologist. p. 16–16. doi: 10.15714/scandpsychol.4.e15. Full text in Research Archive
• Wyller, Vegard Bruun Bratholm (2017). The bedside rationing paradigm and the shortcomings of modernist ethics. Clinical Ethics. ISSN 1477-7509. 12(2), p. 70–75. doi: 10.1177/1477750917691888. Full text in Research Archive
• Wyller, Vegard Bruun; Vitelli, Valeria; Sulheim, Dag; Fagermoen, Frode Even; Winger, Anette & Godang, Kristin [Show all 7 contributors for this article] (2016). Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: a cross-sectional study. Journal of Translational Medicine. 14(121). doi: 10.1186/s12967-016-0873-1. Full text in Research Archive Show summary

  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.

• Bakke, Laura A Wortinger; Endestad, Tor; Melinder, Annika Maria D; Øie, Merete Glenne; Nilsen, Andre Sevenius & Wyller, Vegard Bruun (2016). Aberrant resting-state functional connectivity in the Salience Network of adolescent Chronic Fatigue Syndrome. PLOS ONE. 11(7). doi: 10.1371/journal.pone.0159351. Full text in Research Archive Show summary

  Abstract Neural network investigations are currently absent in adolescent chronic fatigue syndrome (CFS). In this study, we examine whether the core intrinsic connectivity networks (ICNs) are altered in adolescent CFS patients. Eighteen adolescent patients with CFS and 18 aged matched healthy adolescent control subjects underwent resting-state functional magnetic resonance imaging (rfMRI). Data was analyzed using dual-regression independent components analysis, which is a data-driven approach for the identification of independent brain networks. Intrinsic connectivity was evaluated in the default mode network (DMN), salience network (SN), and central executive network (CEN). Associations between network characteristics and symptoms of CFS were also explored. Adolescent CFS patients displayed a significant decrease in SN functional connectivity to the right posterior insula compared to healthy comparison participants, which was related to fatigue symptoms. Additionally, there was an association between pain intensity and SN functional connectivity to the left middle insula and caudate that differed between adolescent patients and healthy comparison participants. Our findings of insula dysfunction and its association with fatigue severity and pain intensity in adolescent CFS demonstrate an aberration of the salience network which might play a role in CFS pathophysiology.

• Hall, Karhryn T.; Kossowsky, Joe; Oberlander, Tim F.; Kaptchuk, Ted J.; Saul, J. Philip & Wyller, Vegard Bruun [Show all 11 contributors for this article] (2016). Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome. The Pharmacogenomics Journal. ISSN 1470-269X. 16(5), p. 454–460. doi: 10.1038/tpj.2016.53. Full text in Research Archive Show summary

  Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene–drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine–COMT interaction effects in other conditions.

• Meyer, Benedicte; Nguyen, Chinh Bkrong Thi Thuy; Moen, Aurora; Fagermoen, Frode Even; Sulheim, Dag & Nilsen, Hilde [Show all 8 contributors for this article] (2015). Maintenance of Chronic Fatigue Syndrome (CFS) in young CFS patients is associated with the 5-HTTLPR and SNP rs25531 A > G Genotype. PLOS ONE. 10(10). doi: 10.1371/journal.pone.0140883. Full text in Research Archive Show summary

  Earlier studies have shown that genetic variability in the SLC6A4 gene encoding the serotonin transporter (5-HTT) may be important for the re-uptake of serotonin (5-HT) in the central nervous system. In the present study we investigated how the 5-HTT genotype i.e. the short (S) versus long (L) 5-HTTLPR allele and the SNP rs25531 A > G affect the physical and psychosocial functioning in patients with chronic fatigue syndrome (CFS). All 120 patients were recruited from The Department of Paediatrics at Oslo University Hospital, Norway, a national referral center for young CFS patients (12–18 years). Main outcomes were number of steps per day obtained by an accelerometer and disability scored by the Functional Disability Inventory (FDI). Patients with the 5-HTT SS or SLG genotype had a significantly lower number of steps per day than patients with the 5-HTT LALG, SLA or LALA genotype. Patients with the 5-HTT SS or SLG genotype also had a significantly higher FDI score than patients with the 5-HTT LALG, SLA or LALA genotype. Thus, CFS patients with the 5-HTT SS or SLG genotype had worse 30 weeks outcome than CFS patients with the 5-HTT LALG, SLA or LALA genotype. The present study suggests that the 5-HTT genotype may be a factor that contributes to maintenance of CFS.

• Mellingsæter, Marte; Wyller, Torgeir Bruun; Ranhoff, Anette Hylen & Wyller, Vegard Bruun (2015). Fit elderly men can also stand: orthostatic tolerance and autonomic cardiovascular control in elderly endurance athletes. Aging Clinical and Experimental Research. ISSN 1594-0667. 27(4), p. 499–505. doi: 10.1007/s40520-014-0303-2. Full text in Research Archive
• Mellingsæter, Marte; Wyller, Torgeir Bruun; Ranhoff, Anette Hylen; Bogdanovic, Nenad & Wyller, Vegard Bruun (2015). Reduced sympathetic response to head-up tilt in subjects with mild cognitive impairment or mild Alzheimer's dementia. Dementia and Geriatric Cognitive Disorders Extra. 5(1), p. 107–115. doi: 10.1159/000375297. Full text in Research Archive Show summary

  Background: Hemodynamic control was compared in patients with mild cognitive impairment (MCI) or mild Alzheimer's dementia (AD) as well as in healthy elderly subjects. Methods: Noninvasive, continuous hemodynamic recordings were obtained from 14 patients and 48 controls during supine rest (tilt of 30 and 70°). Cardiac output, end-diastolic volume, total peripheral resistance, heart rate variability (HRV), systolic blood pressure variability (SBPV), and baroreceptor sensitivity were calculated. Results: At 70° tilt, the HRV indices differed significantly, with higher high-frequency (HF) variability as well as lower low-frequency (LF) variability and LF/HF ratios in the patients. The patients had significantly lower SBPV in the LF range at 30° tilt. Conclusions: The results indicate a poorer sympathetic response to orthostatic stress in MCI and mild AD.

• Winger, Anette; Kvarstein, Gunnvald; Wyller, Vegard Bruun; Ekstedt, Mirjam; Sulheim, Dag & Fagermoen, Frode Even [Show all 8 contributors for this article] (2015). Health related quality of life in adolescents with chronic fatigue syndrome: A cross-sectional study. Health and Quality of Life Outcomes. 13:96. doi: 10.1186/s12955-015-0288-3. Full text in Research Archive Show summary

  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. <br>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. <br>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. <br>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 <br>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.

• Neerland, Bjørn Erik; Hov, Karen Roksund; Wyller, Vegard Bruun; Qvigstad, Eirik; Skovlund, Eva & MacLullich, AM [Show all 7 contributors for this article] (2015). The protocol of the oslo study of clonidine in elderly patients with delirium; LUCID: A randomised placebo-controlled trial. BMC Geriatrics. 15:7, p. 1–14. doi: 10.1186/s12877-015-0006-3. Full text in Research Archive Show summary

  Background Delirium affects 15% of hospitalised patients and is linked with poor outcomes, yet few pharmacological treatment options exist. One hypothesis is that delirium may in part result from exaggerated and/or prolonged stress responses. Dexmedetomidine, a parenterally-administered alpha2-adrenergic receptor agonist which attenuates sympathetic nervous system activity, shows promise as treatment in ICU delirium. Clonidine exhibits similar pharmacodynamic properties and can be administered orally. We therefore wish to explore possible effects of clonidine upon the duration and severity of delirium in general medical inpatients. Methods/Design The Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is a randomised, placebo-controlled, double-blinded, parallel group study with 4-month prospective follow-up. We will recruit 100 older medical inpatients with delirium or subsyndromal delirium in the acute geriatric ward. Participants will be randomised to oral clonidine or placebo until delirium free for 2 days (Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria), or after a maximum of 7 days treatment. Assessment of haemodynamics (blood pressure, heart rate and electrocardiogram) and delirium will be performed daily until discharge or a maximum of 7 days after end of treatment. The primary endpoint is the trajectory of delirium over time (measured by Memorial Delirium Assessment Scale). Secondary endpoints include the duration of delirium, use of rescue medication for delirium, pharmacokinetics and pharmacodynamics of clonidine, cognitive function after 4 months, length of hospital stay and need for institutionalisation. Discussion LUCID will explore the efficacy and safety of clonidine for delirium in older medical inpatients. Trial registration ClinicalTrials.gov NCT01956604 . EudraCT Number: 2013-000815-26

• Sulheim, Dag; Fagermoen, Frode Even; Sivertsen, Øyvind Stople; Winger, Anette; Wyller, Vegard Bruun & Øie, Merete Glenne (2015). Cognitive dysfunction in adolescents with chronic fatigue: a cross-sectional study. Archives of Disease in Childhood. ISSN 0003-9888. 100(9), p. 838–844. doi: 10.1136/archdischild-2014-306764. Full text in Research Archive Show summary

  Objective To compare cognitive function in adolescents with chronic fatigue with cognitive function in healthy controls (HC). Study design Cross-sectional study. Setting Paediatric department at Oslo University Hospital, Norway. Participants 120 adolescents with chronic fatigue (average age 15.4 years; range 12–18) and 39 HC (average age 15.2 years; range 12–18). Methods The adolescents completed a neurocognitive test battery measuring processing speed, working memory, cognitive inhibition, cognitive flexibility, verbal learning and verbal memory, and questionnaires addressing demographic data, depression symptoms, anxiety traits, fatigue and sleep problems. Parents completed the Behaviour Rating Inventory of Executive Function (BRIEF), which measures the everyday executive functions of children. Results Adolescents with chronic fatigue had impaired cognitive function compared to HC regarding processing speed (mean difference 3.3, 95% CI 1.1 to 5.5, p=0.003), working memory (−2.4, −3.7 to −1.1, p<0.001), cognitive inhibition response time (6.2, 0.8 to 11.7, p=0.025) and verbal learning (−1.7, −3.2 to −0.3, p=0.022). The BRIEF results indicated that everyday executive functions were significantly worse in the chronic fatigue group compared to the HC (11.2, 8.2 to 14.3, p<0.001). Group differences remained largely unaffected when adjusted for symptoms of depression, anxiety traits and sleep problems. Conclusions Adolescents with chronic fatigue had impaired cognitive function of clinical relevance, measured by objective cognitive tests, in comparison to HC. Working memory and processing speed may represent core difficulties

• Fagermoen, Frode Even; Sulheim, Dag; Winger, Anette; Andersen, Anders Mikal; Gjerstad, Johannes & Godang, Kristin [Show all 10 contributors for this article] (2015). Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: A randomized controlled trial. BMC Pediatrics. 15. doi: 10.1186/s12887-015-0428-2. Full text in Research Archive Show summary

  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.

• Wyller, Vegard Bruun; Sørensen, Øystein; Sulheim, Dag; Fagermoen, Frode Even; Ueland, Thor & Mollnes, Tom Eirik (2015). Plasma cytokine expression in adolescent chronic fatigue syndrome. Brain, Behavior, and Immunity. ISSN 0889-1591. 46, p. 80–86. doi: 10.1016/j.bbi.2014.12.025. Full text in Research Archive Show summary

  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.

• Asprusten, Tarjei Tørre; Fagermoen, Frode Even; Sulheim, Dag; Skovlund, Eva; Sørensen, Øystein & Mollnes, Tom Eirik [Show all 7 contributors for this article] (2015). Study findings challenge the content validity of the Canadian Consensus Criteria for adolescent chronic fatigue syndrome. Acta Paediatrica. ISSN 0803-5253. 104(5), p. 498–503. doi: 10.1111/apa.12950. Full text in Research Archive
• Sulheim, Dag; Fagermoen, Frode Even; Winger, Anette; Andersen, Anders Mikal; Godang, Kristin & Müller, Fredrik [Show all 11 contributors for this article] (2014). Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome: A Combined Cross-sectional and Randomized Clinical Trial. JAMA pediatrics. ISSN 2168-6203. 168(4), p. 351–360. doi: 10.1001/jamapediatrics.2013.4647. Full text in Research Archive
• Winger, Anette; Kvarstein, Gunnvald; Wyller, Vegard Bruun; Sulheim, Dag; Fagermoen, Frode Even & Småstuen, Milada Cvancarova [Show all 7 contributors for this article] (2014). Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study. BMJ Open. 4(10). doi: 10.1136/bmjopen-2014-005920. Full text in Research Archive Show summary

  Objectives: Although pain is a significant symptom in chronic fatigue syndrome (CFS), pain is poorly understood in adolescents with CFS. The aim of this study was to explore pain distribution and prevalence, pain intensity and its functional interference in everyday life, as well as pressure pain thresholds (PPT) in adolescents with CFS and compare this with a control group of healthy adolescents (HC). Methods: This is a case–control, cross-sectional study on pain including 120 adolescents with CFS and 39 HCs, aged 12–18 years. We measured pain frequency, pain severity and pain interference using self-reporting questionnaires. PPT was measured using pressure algometry. 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. Results: Adolescents with CFS had significantly lower PPTs compared with HCs (p<0.001). The Pain Severity Score and the Pain Interference Score were significantly higher in adolescents with CFS compared with HCs (p<0.001). Almost all adolescents with CFS experienced headache, abdominal pain and/or pain in muscles and joints. Moreover, in all sites, the pain intensity levels were significantly higher than in HCs (p<0.001). Conclusions: We found a higher prevalence of severe pain among adolescents with CFS and lowered pain thresholds compared with HCs. The mechanisms, however, are still obscure. Large longitudinal population surveys are warranted measuring pain thresholds prior to the onset of CFS.

• Kristensen, Hanne; Ørbeck, Beate; Torgersen, Halvor; Hansen, Berit Marina Hjelde & Wyller, Vegard Bruun (2014). Somatic symptoms in children with anxiety disorders: an exploratory cross-sectional study of the relationship between subjective and objective measures. European Child and Adolescent Psychiatry. ISSN 1018-8827. 23(9), p. 795–803. doi: 10.1007/s00787-013-0512-9. Full text in Research Archive Show summary

  Symptoms of childhood anxiety disorders include activation of bodily stress systems to fear stimuli, indicating alterations of the autonomic nervous system (ANS). Self-reported somatic symptoms are frequently reported, while studies including objective measures of ANS are scarce and show inconsistent results. Even less studied is the relationship between subjective and objective measures of somatic symptoms in anxious children. Increased knowledge of this relationship may have relevance for treatment programmes for anxiety disorders. This cross-sectional study examined subjective and objective measures of ANS responsiveness in a clinical sample of children with anxiety disorders (7–13 years; n = 23) and in healthy controls (HC; n = 22) with equal distributions of gender and age. The subjective measure used was the Multidimensional Anxiety Scale for Children (MASC), which includes a subscale on somatic symptoms. The objective measures consisted of an orthostatic challenge (head-up tilt test, HUT), and an isometric muscular exercise (handgrip) while the participants were attached to the Task Force Monitor, a combined hardware and software device used for continuous, non-invasive recording of cardiovascular variables. The anxiety disorder group reported significantly more somatic symptoms than HCs (both by mother and child reports). In contrast, no relevant differences in cardiovascular variables were demonstrated between the anxiety group and HCs. Finally, there were no significant correlations between subjective and objective measures in either group. Because of the small sample size, the findings must be interpreted carefully, but the results do not support previous reports of functional alterations of the ANS in anxious children.

• Wyller, Vegard Bruun; Fagermoen, Frode Even; Sulheim, Dag; Winger, Anette; Skovlund, Eva & Saul, J. Philip (2014). Orthostatic responses in adolescent chronic fatigue syndrome: Contributions from expectancies as well as gravity. BioPsychoSocial Medicine. 8. doi: 10.1186/1751-0759-8-22. Full text in Research Archive Show summary

  Background: Orthostatic intolerance is common in chronic fatigue syndrome (CFS), and several studies have documented an abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli. The aim of this study was to explore whether the expectancies towards standing are contributors to autonomic responses in addition to the gravitational stimulus itself. Methods: A total of 30 CFS patients (12–18 years of age) and 39 healthy controls underwent 20° head-up tilt test and a motor imagery protocol of standing upright. Beat-to-beat cardiovascular variables were recorded. Results: At supine rest, CFS patients had significantly higher heart rate, diastolic blood pressure, and mean arterial blood pressure, and lower stroke index and heart rate variability (HRV) indices. The response to 20° head-up tilt was identical in the two groups. The response to imaginary upright position was characterized by a stronger increase of HRV indices of sympathetic predominance (power in the low-frequency range as well as the ratio low-frequency: high-frequency power) among CFS patients. Conclusions: These results suggest that in CFS patients expectancies towards orthostatic challenge might be additional determinants of autonomic cardiovascular modulation along with the gravitational stimulus per se.

• Zeller, Bernward; Loge, Jon Håvard; Kanellopoulos, Adriani; Hamre, Hanne Mari; Wyller, Vegard Bruun & Ruud, Ellen (2014). Chronic fatigue in long-term survivors of childhood Lymphomas and Leukemia: Persistence and associated clinical factors. Journal of Pediatric Hematology/Oncology. ISSN 1077-4114. 36(6), p. 438–444. doi: 10.1097/MPH.0000000000000051. Full text in Research Archive
• Wyller, Vegard Bruun; Gisvold, Sven Erik; Hagen, Egil Ragnar; Heggedal, Rune; Heimdal, Arnulf & Karlsen, Kjetil [Show all 10 contributors for this article] (2013). Reclaim the profession! Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. doi: 10.4045/tidsskr.13.0238. Full text in Research Archive
• Mellingsæter, Marte; Wyller, Vegard Bruun; Wyller, Torgeir Bruun & Ranhoff, Anette Hylen (2013). Gender differences in orthostatic tolerance in the elderly. Aging Clinical and Experimental Research. ISSN 1594-0667. 25(6), p. 659–665. doi: 10.1007/s40520-013-0092-z. Full text in Research Archive
• Wyller, Vegard Bruun & Helland, Ingrid B (2013). Relationship between autonomic cardiovascular control, case definition, clinical symptoms, and functional disability in adolescent chronic fatigue syndrome: an exploratory study. BioPsychoSocial Medicine. doi: 10.1186/1751-0759-7-5. Full text in Research Archive
• Elsais, Ahmed; Wyller, Vegard Bruun; Loge, Jon Håvard & Kerty, Emilia (2013). Fatigue in myasthenia gravis: is it more than muscular weakness? BMC Neurology. 13. doi: 10.1186/1471-2377-13-132. Full text in Research Archive Show summary

  Background Few studies have focused on fatigue in myasthenia gravis (MG), and fatigue in relation to the autonomic system has never been systematically explored in these patients. The study aimed to document the prevalence of MG-related fatigue in ethnic Norwegians and to examine whether MG severity is associated with symptoms of autonomic disturbance, which in turn is associated with fatigue and functional disability. Methods Eighty two of the 97 who fulfilled the study inclusion criteria participated in the study. Controls were 410 age- and sex-matched subjects drawn from a normative sample (n?=?2136) representative of the Norwegian population. Bivariate analyses and multivariate linear regression analyses were used to assess associations between questionnaire-reported MG severity, symptoms of autonomic disturbance, fatigue (mental and physical) and functional disability. Results Forty-four per cent (36/82) of patients fulfilled the criteria for fatigue compared with 22% (90/410) of controls (odds ratio 2.0; p?=?0.003). Twenty-one per cent of patients (17/82) met the criteria for chronic fatigue versus 12% (48/410) of controls (odds ratio 1.96; p?=?0.03). MG patients had higher total fatigue scores than controls (p?<?0.001) and a high prevalence of autonomic symptoms, especially poor thermoregulation and sleep disturbance. According to multivariate analyses controlled for MG score, symptoms of autonomic disturbances were independently positively associated with fatigue (p?<?0.001), and fatigue was independently negatively associated with functional level (p?<?0.001). Conclusion Norwegian ethnic patients with MG have higher levels of fatigue and a higher prevalence of chronic fatigue than controls, even in patients in full remission. MG severity is highly suggestive to be associated with symptoms of autonomic disturbance, which in turn is associated with fatigue and the level of functional disability.

• Winger, Anette; Ekstedt, Mirjam; Wyller, Vegard Bruun & Helseth, Sølvi (2013). Sometimes it feels as if the world goes on without me: adolescents' experiences of living with chronic fatigue syndrome. Journal of Clinical Nursing (JCN). ISSN 0962-1067. doi: 10.1111/jocn.12522. Full text in Research Archive Show summary

  AIMS AND OBJECTIVES: To explore the experience of being an adolescent with chronic fatigue syndrome. BACKGROUND: Despite ample research, chronic fatigue syndrome is still poorly understood, and there are still controversies related to the illness. Adolescents with chronic fatigue syndrome are often unable to attend school and lose social relations with friends. The challenges they face will affect their quality of life. DESIGN: A qualitative, phenomenological hermeneutical design. METHOD: Six boys and twelve girls, aged 12-18, were interviewed, emphasising their own experiences living with chronic fatigue syndrome. Analyses were performed using a phenomenological hermeneutical method. RESULTS: The core theme, 'Sometimes it feels as if the world goes on without me', encompasses the feelings an adolescent living with chronic fatigue syndrome might have about life. The core theme was supported by four subthemes: 'On the side of life - locked in and shut out'; 'the body, the illness and me'; 'if the illness is not visible to others, does it exist?'; and 'handling life while hoping for a better future'. The subthemes reflect the experience of social isolation, their own and others' understanding of the illness and hope for the future. CONCLUSIONS: Not being able to be with friends, or attend school, made the adolescents feel different and forgotten. They felt alienated in their own bodies and were struggling to be visible to themselves and to their surroundings. Spending less time with friends and more time with their parents constituted a threat to independence and development. Yet they managed to envision a better future despite all the difficulties. RELEVANCE FOR CLINICAL PRACTICE: To provide effective support and constructive relations to adolescents with chronic fatigue syndrome, all health professions involved need insight from the persons who are themselves ill. Health centres could function as resource centres for patients and healthcare professionals

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• Reme, Silje Endresen; Landmark, Live; Asprusten, Tarjei Tørre; Suvatne, Christer; Herner, Linn Breen & Drivenes, Elin [Show all 63 contributors for this article] (2026). Gi pasientene livet tilbake. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 146. doi: 10.4045/tidsskr.26.0480. Full text in Research Archive Show summary

  Vi vet nok til å kunne hjelpe langt flere pasienter med langvarige symptomer. Likevel holder vi tilbake håpet, av frykt for å skuffe. Det kan koste pasientene store deler av livet. Denne kronikken er et faglig opprop fra 63 klinikere, forskere og fagpersoner fra hele landet. Vi har klinisk og forskningsmessig erfaring med vedvarende fysiske symptomer, som smerter, utmattelse, «hjernetåke», svimmelhet og mageplager og har samlet oss om et felles budskap: Ny kunnskap om hvordan slike symptomer oppstår og opprettholdes gir grunn til langt større håp om bedring enn mange pasienter får formidlet i dag.

• Grødeland, Gunnveig; Pettersen, Frank O. & Wyller, Vegard Bruun Bratholm (2026). Vaksinepodden - Episode 41 - Long Covid. Full text in Research Archive Show summary

  Media forteller jevnlig om personer med langvarige ettervirkninger etter smitte med koronaviruset SARS-CoV-2. Hva er long covid, og er det unikt etter smitte med koronavirus? Kan man bli frisk om man opplever long covid, og hva er status på forskning i dag? I denne episoden har vi besøk av Vegard Bruun Bratholm Wyller, som er professor ved Institutt for klinisk medisin og spesialist i barnesykdommer. Han er også forskningsleder ved Barne- og ungdomsklinikken, Akershus Universitetssykehus. Wyller har i over 20 år forsket på ettervirkninger som utmattelse etter smitte med ulike virus, og har gjennomført flere interessante studier av long covid etter smitte med koronaviruset SARS-CoV-2. I studio er ellers som vanlig overlege Frank Olav Pettersen fra Infeksjonsmedisinsk avdeling ved Ullevål, og Gunnveig Grødeland som er professor i immunologi og leder for Senter for pandemi- og en-helseforskning ved Universitetet i Oslo.

• Selvakumar, Joel Pradeepkumar & Wyller, Vegard Bruun Bratholm (2025). ME patient experiences: Sampling bias limits the external validity of findings. Journal of Health Psychology. ISSN 1359-1053. 30(5), p. 1136–1141. doi: https:/journals.sagepub.com/doi/10.1177/13591053241310320. Full text in Research Archive
• Wyller, Vegard Bruun Bratholm (2025). CFS/ME-pasienter blir hørt – og det finnes behandling som hjelper mange. 145. doi: 10.4045/tidsskr.25.0086. Full text in Research Archive
• Wyller, Vegard Bruun Bratholm & Hem, Erlend (2023). Failure to thrive = sviktende utvikling. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(13). doi: 10.4045/tidsskr.23.0096. Full text in Research Archive
• Verveen, Anouk; Müller, Fabiola; Lloyd, Andrew; Moss-Morris, Rona; Omland, Torbjørn & Penninx, Brenda [Show all 14 contributors for this article] (2022). A research agenda for post-COVID-19 fatigue. Journal of Psychosomatic Research. ISSN 0022-3999. 154. doi: 10.1016/j.jpsychores.2022.110726. Full text in Research Archive
• Wyller, Vegard Bruun Bratholm (2019). Pain is common in chronic fatigue syndrome-current knowledge and future perspectives. Scandinavian Journal of Pain. ISSN 1877-8860. 19(1), p. 5–8. doi: 10.1515/sjpain-2018-2007. Full text in Research Archive
• Wyller, Vegard Bruun Bratholm (2019). Autonomic and inflammatory disturbances do not seem to explain symptoms in chronic fatigue. Brain, Behavior, and Immunity. ISSN 0889-1591. 80, p. 901–901. doi: 10.1016/j.bbi.2019.05.037. Full text in Research Archive
• Wyller, Vegard Bruun Bratholm (2019). Chronic fatigue is characterized by a relative lack of abnormalities in biological markers. Brain, Behavior, and Immunity. ISSN 0889-1591. 80, p. 902–902. doi: 10.1016/j.bbi.2019.05.043. Full text in Research Archive
• Bratholm, Hedda & Wyller, Vegard Bruun Bratholm (2018). Feilinformasjon om kronisk utmattelsessyndrom. Tidsskrift for Norsk psykologforening (Psykologtidsskriftet). ISSN 0332-6470. 55(2), p. 126–127. Full text in Research Archive
• Wyller, Vegard Bruun Bratholm; Vitelli, Valeria; Sulheim, Dag; Fagermoen, Frode Even; Winger, Anette & Godang, Kristin [Show all 7 contributors for this article] (2017). Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: A cross-sectional study. Journal of Translational Medicine. 15(157). doi: 10.1186/s12967-017-1261-1. Full text in Research Archive
• Wyller, Vegard Bruun Bratholm (2016). Den brysomme samvittigheten. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(7), p. 595–595. doi: 10.4045/tidsskr.16.0268. Full text in Research Archive
• Vogt, Henrik; Ulvestad, Elling & Wyller, Vegard Bruun Bratholm (2016). Metabolic features of chronic fatigue syndrome revisited. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 113(46), p. E7140–E7141. doi: 10.1073/pnas.1615143113. Full text in Research Archive
• Wyller, Vegard Bruun; Jacobsen, Kristine; Dahl, Mai Britt; Nilsen, Hilde; Proske, Simone & Horter, Thorsten [Show all 7 contributors for this article] (2016). Interferon gamma may improve cardiac function in Friedreich's ataxia cardiomyopathy. International Journal of Cardiology. ISSN 0167-5273. 221, p. 376–378. doi: 10.1016/j.ijcard.2016.06.288. Full text in Research Archive
• Wyller, Vegard Bruun; Reme, Silje & Mollnes, Tom Eirik (2016). Kronisk utmattelsessyndrom/myalgisk encefalopati - sykdomsmekanismer, diagnostikk og behandling. 83(2), p. 24–27. Full text in Research Archive
• Wyller, Vegard Bruun (2015). Re: Hva er egentlig myalgisk encefalopati? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 135(22), p. 2020–2020. doi: 10.4045/tidsskr.15.1184. Full text in Research Archive
• Wyller, Vegard Bruun; Reme, Silje & Mollnes, Tom Eirik (2015). Kronisk utmattelsessyndrom/myalgisk encefalopati – sykdomsmekanismer, diagnostikk og behandling. 135(23/24), p. 2172–2175. doi: 10.4045/tidsskr.15.1180. Full text in Research Archive
• Wyller, Vegard Bruun (2015). Re: Hva er egentlig myalgisk encefalopati? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 135(22), p. 2021–2021. doi: 10.4045/tidsskr.15.1186. Full text in Research Archive
• Wyller, Vegard Bruun (2015). Elefanten i rommet. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 135(6), p. 507–507. doi: 10.4045/tidsskr.15.0343. Full text in Research Archive
• Wyller, Vegard Bruun (2015). Helsepolitikk – mer ideologi enn fornuft? :. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 135(16), p. 1423–1423. doi: 10.4045/tidsskr.15.0882. Full text in Research Archive
• Winger, Anette; Ekstedt, Mirjam; Wyller, Vegard Bruun & Helseth, Sølvi (2013). "Sometimes it Feels as if The World Goes on Without Me" Adolescents experiences of living with chronic fatigue syndrome. Full text in Research Archive
• Landmark, Live; Kennair, Leif Edward Ottesen; Bendixen, Mons; Fors, Egil Andreas; Wyller, Vegard Bruun Bratholm & Reme, Silje Endresen [Show all 7 contributors for this article] (2026). Towards an integrative model of persistent physical symptoms: Studies in a specialised pain setting. Norges teknisk-naturvitenskapelige universitet. ISSN 9788235300089. Full text in Research Archive Show summary

  Persistent physical symptoms such as pain, sleep problems, and fatigue are common and among the leading causes of functional impairment. Patients referred to specialised pain care often present with symptom profiles that extend far beyond pain alone, raising fundamental questions about whether pain-focused classifications adequately capture the full extent of these presentations. This thesis addresses these questions in a large clinical cohort of approximately 4,000 patients referred to specialised pain services, examining overall symptom burden, psychosocial mechanisms, and prognostic factors within a transdiagnostic framework. Study I showed that insomnia symptoms showed associations with functioning that were comparable to or stronger than pain intensity, while fatigue and psychological distress contributed independently but with smaller effects. Study II demonstrated that insomnia symptoms were pronounced across all ICD-11 chronic pain categories, and that baseline levels of insomnia symptoms predicted both pain intensity and pain bothersomeness at 12-month follow-up, independent of baseline pain and psychosocial factors. Study III found that more than 90% of the cohort met criteria for moderate or severe Bodily Distress Syndrome (BDS), and that greater extent of multisystem symptoms at baseline predicted poorer function and lower perceived improvement at 12-month follow-up. Taken together, the findings indicate that this specialised pain population is characterised by high overall symptom burden in addition to pain. The findings support a transdiagnostic and integrated approach that moves beyond both organ-based classifications and a narrow focus on pain alone, and instead targets factors associated with functional impairment.

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