Dexamethasone attenuates interferon-related cytokine hyperresponsiveness in COVID-19 patients.

Background: Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated. Objective: We combined functional immunological assays and an omics-based approach to investigate the in vitro and in vivo effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients. Methods: Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed. Results: Dexamethasone efficiently inhibited SARS-CoV-2-induced in vitro expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated ex vivo with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses. Conclusion: We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.

Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

The role of trained immunity in COVID-19: Lessons for the next pandemic.

Trained immunity is a long-term increase in responsiveness of innate immune cells, induced by certain infections and vaccines. During the last 3 years of the COVID-19 pandemic, vaccines that induce trained immunity, such as BCG, MMR, OPV, and others, have been investigated for their capacity to protect against COVID-19. Further, trained immunity-inducing vaccines have been shown to improve B and T cell responsiveness to both mRNA- and adenovirus-based anti-COVID-19 vaccines. Moreover, SARS-CoV-2 infection itself induces inappropriately strong programs of trained immunity in some individuals, which may contribute to the long-term inflammatory sequelae. In this review, we detail these and other aspects of the role of trained immunity in SARS-CoV-2 infection and COVID-19. We also examine the learnings from the trained immunity studies conducted in the context of this pandemic and discuss how they may help us in preparing for future infectious outbreaks.

[Chronic fatigue syndrome: source of controversy]. / Het chronische-vermoeidheidsyndroom: bron van ophef.

Chronic fatigue syndrome (CFS) remains a controversial medical disorder. A combination of poorly executed studies using variable case definitions and diagnostic criteria have led to controversial results. These controversies cloud our vision on CFS, and lead to scepticism and frustration among patients, doctors and researchers. For future perspective, interdisciplinary studies of high quality with large well-defined patient groups and adequate controls are needed.

Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome.

BACKGROUND: Q fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences. The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC). METHODS: The study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach. RESULTS: Inflammatory markers, including 4E-BP1 (P = 9.60-16 and 1.41-7) and MMP-1 (P = 7.09-9 and 3.51-9), are significantly more expressed in both QFS and CFS patients compared to HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism. When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobacteria (with emphasis on Ruminococcus and Bifidobacterium spp.). When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found. CONCLUSIONS: We show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

Mediation analysis shows that a decline in self-efficacy mediates the increase in fatigue severity following an initial positive response to cognitive behavioural therapy in Q fever fatigue syndrome.

OBJECTIVE: Q fever fatigue syndrome (QFS) is characterized by chronic fatigue following acute Q fever. Previously, it was shown that cognitive behavioural therapy (CBT), and not doxycycline, was significantly more effective than placebo in reducing fatigue severity in QFS patients. However, this effect was not maintained after one year. The aim of this study is to elucidate the cognitive and behavioural variables which mediate the positive effect of CBT on fatigue during the treatment and the relapse of fatigue after completion of CBT, by using multiple mediation analysis. METHODS: Additional analyses were performed on data of a randomized controlled trial that investigated the efficacy of CBT and antibiotics compared to placebo for QFS [1]. Only those patients in the CBT group who completed the allocated CBT treatment, and those patients in the medication group who did not follow additional CBT during follow-up, were included in this study. Two mediation models were tested, using respectively assessments at baseline and end-of-treatment (EOT), and EOT and follow-up, comparing the CBT group (n = 43) with the medication group (n = 89). RESULTS: During treatment, the decrease in fatigue brought on by CBT was completely mediated by an increase in self-efficacy with respect to fatigue. A reduction in self-efficacy partly mediated the increase in fatigue at follow-up in the CBT group. CONCLUSIONS: Given the decline in self efficacy, booster sessions focussing on restoration and maintenance of self-efficacy with respect to fatigue, may lead to elongation of the initial positive effects of CBT for QFS.

A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and chronic fatigue syndrome.

BACKGROUND: Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. It has been hypothesized that low grade inflammation plays a role in its aetiology. In this study, we aimed to identify transcriptome profiles that could aid to better understand the pathophysiology of QFS. METHODS: RNA of monocytes was collected from QFS patients (n = 10), chronic fatigue syndrome patients (CFS, n = 10), Q fever seropositive controls (n = 10), and healthy controls (n = 10) who were age- (± 5 years) and sex-matched. Transcriptome analysis was performed using RNA sequencing. RESULTS: Mitochondrial-derived peptide (MDP)-coding genes MT-RNR2 (humanin) and MT-RNR1 (MOTS-c) were differentially expressed when comparing QFS (- 4.8 log2-fold-change P = 2.19 × 10-9 and - 4.9 log2-fold-change P = 4.69 × 10-8), CFS (- 5.2 log2-fold-change, P = 3.49 × 10-11 - 4.4 log2-fold-change, P = 2.71 × 10-9), and Q fever seropositive control (- 3.7 log2-fold-change P = 1.78 × 10-6 and - 3.2 log2-fold-change P = 1.12 × 10-5) groups with healthy controls, resulting in a decreased median production of humanin in QFS patients (371 pg/mL; Interquartile range, IQR, 325-384), CFS patients (364 pg/mL; IQR 316-387), and asymptomatic Q fever seropositive controls (354 pg/mL; 292-393). CONCLUSIONS: Expression of MDP-coding genes MT-RNR1 (MOTS-c) and MT-RNR2 (humanin) is decreased in CFS, QFS, and, to a lesser extent, in Q fever seropositive controls, resulting in a decreased production of humanin. These novel peptides might indeed be important in the pathophysiology of both QFS and CFS.

Cytokine profiles in patients with Q fever fatigue syndrome.

BACKGROUND: Q fever fatigue syndrome (QFS) is a state of prolonged fatigue following around 20% of acute Q fever cases. It is thought that chronic inflammation plays a role in its etiology. To test this hypothesis we measured circulating cytokines and the ex-vivo cytokine production in patients with QFS and compared with various control groups. MATERIALS/METHODS: Peripheral blood mononuclear cells (PBMCs), whole blood, and serum were collected from 20 QFS patients, 19 chronic fatigue syndrome (CFS) patients, 19 Q fever seropositive controls, and 25 age- and sex-matched healthy controls. Coxiella-specific ex-vivo production of tumor necrosis factor (TNF)α, interleukin (IL)-1ß, IL-6, and interferon (IFN) was measured, together with a total of 92 circulating inflammatory proteins. RESULTS: PBMCs of QFS patients produced more IL-6 (P = 0.0001), TNFα (P = 0.0002), and IL-1ß (P = 0.0005) than the various control groups when stimulated with Coxiella antigen. QFS patients had distinct differences in circulating inflammatory markers compared to the other groups, including higher concentrations of circulating IL-6 and IFNγ. CONCLUSION: QFS patients showed signs of chronic inflammation compared to asymptomatic Q fever seropositive controls, CFS patients, and healthy controls, of which the monocyte-derived cytokines TNFα, IL-1ß, and especially IL-6, are likely crucial components.

Long-term effect of cognitive behavioural therapy and doxycycline treatment for patients with Q fever fatigue syndrome: One-year follow-up of the Qure study.

BACKGROUND: Previously, we reported a randomized placebo-controlled trial, the Qure study, showing that cognitive behavioural therapy (CBT), and not doxycycline, was significantly more effective than placebo in reducing fatigue severity in Q fever fatigue syndrome (QFS) patients. This follow-up study evaluates the long-term effect of these treatment regimens, 1 year after completion of the original trial. METHODS: All patients who completed the Qure study, CBT (n = 50), doxycycline (n = 52), and placebo (n = 52), were included in this follow-up study. Between twelve and fifteen months after end of treatment (EOT), patients filled out web-based questionnaires including the main outcome measure fatigue severity, assessed with the Checklist Individual Strength (CIS), subscale fatigue severity. RESULTS: Fatigue severity in the CBT, but not doxycycline or placebo, group was significantly increased at follow-up compared to EOT (respective means 39.5 [95% CI, 36.2-42.9] and 31.3 [95% CI, 27.5-35.1], mean difference 8.2 [95% CI, 4.9-11.6]; P < .001). Fatigue severity scores of CBT (adjusted mean 39.8 [95% CI, 36.1-43.4]) and doxycycline (adjusted mean 41.0 [95% CI, 37.5-44.6]) groups did not significantly differ from the placebo group (adjusted mean 37.1 [95% CI, 33.6-40.7]; P = .92 and P = .38, respectively). CONCLUSION: The beneficial effect of CBT on fatigue severity at EOT was not maintained 1 year thereafter. Due to its initial beneficial effect and side effects of long-term doxycycline use, we still recommend CBT as treatment for QFS. We suggest further investigation on tailoring CBT more to QFS, possibly followed by booster sessions.

Hair and salivary cortisol in a cohort of women with chronic fatigue syndrome.

Hypocortisolism has been found in CFS patients in blood, urine, and saliva. It is unclear if hypocortisolism can also be demonstrated using long-term cortisol measurements, such as cortisol in hair. In addition, the interaction between the HPA axis and the immune system, both expected to play an important role in CFS, is unclear. The objective of the current study was to compare hair and salivary cortisol concentrations in a cohort of female CFS patients to those in healthy controls, and to test the effect of an interleukin-1 receptor antagonist (anakinra) on the HPA axis. Salivary cortisol concentrations of 107 CFS patients were compared to 59 healthy controls, with CFS patients showing a decreased cortisol awakening response (4.2 nmol/L ±â€¯5.4 vs 6.1 nmol/L ±â€¯6.3, p = 0.036). Total cortisol output during the day did not differ significantly in saliva, but there was a trend to lower hair cortisol in a subset of 46 patients compared to 46 controls (3.8 pg/mg ±â€¯2.1 vs 4.3 pg/mg ±â€¯1.8, p = 0.062). After four weeks of treatment with either daily anakinra (100 mg/day) or placebo, there was a slight decrease of hair cortisol concentrations in the anakinra group compared to an increase in the placebo group (p = 0.022). This study confirms the altered dynamics of the HPA axis in a group of CFS patients, and for the first time shows that this might also be present for long-term cortisol measures.

Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome.

Approximately 20% of patients with acute Q fever develop Q fever fatigue syndrome (QFS), a debilitating fatigue syndrome. This study further investigates the role of C. burnetii-specific IFNγ, but also IL-2, CXCL9, CXCL10, and CXLC11 production in QFS patients. C. burnetii-specific IFNy, IL-2, CXCL9, CXCL10, and CXCL11 production were tested in ex vivo stimulated whole blood of QFS patients who recovered from their complaints (n = 8), QFS patients with persisting complaints (n = 27), and asymptomatic Q fever seropositive controls (n = 10). With the exclusion of one outlier, stimulation with C. burnetii revealed significantly higher IFNy and CXCL10 production in QFS patients with persisting complaints (medians 288.0 and 176.0 pg/mL, respectively) than in QFS patients who recovered from their complaints (medians 93.0 and 85.5 pg/mL, respectively) (p = 0.041 and 0.045, respectively). No significant differences between groups were found for C. burnetii-specific IL-2, CXCL9, and CXCL11 production. These findings point towards a difference in cell-mediated immunity in QFS patients with persisting complaints compared to those who recovered from their complaints. Such a difference may aid to eventually diagnose QFS more objectively and might serve as an indicator of its underlying etiology.

Fatigue Is Associated With Altered Monitoring and Preparation of Physical Effort in Patients With Chronic Fatigue Syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is characterized by disabling fatigue, which is suggested to be maintained by dysfunctional beliefs. Fatigue and its maintenance are recently conceptualized as arising from abnormally precise expectations about bodily inputs and from beliefs of diminished control over bodily states, respectively. This study used functional neuroimaging to identify the neural correlates of fatigue and its maintenance by beliefs during a physical effort task. METHODS: We isolated behavioral adjustments and cerebral activity during feedback processing and motor preparation, in the context of a task in which patients with CFS (n = 85) and healthy control subjects (n = 29) produced 30%, 50%, and 70% of their right-hand maximal voluntary contraction, and received directional feedback on performance (e.g., too little force). RESULTS: Patients with CSF showed an effort-dependent behavioral bias toward less effort investment in response to directional feedback for the highest effort level as compared with healthy control subjects. This bias was associated with reduced feedback-related activity in the dorsolateral prefrontal cortex. These effects were proportional to state-related fatigue and prior beliefs about CFS patients' ability to perform the task. Patients with CFS also showed higher activity in the supplementary motor area, proportional to their state-related fatigue, and reduced connectivity between the supplementary motor area and sensorimotor cortex during motor preparation as compared with control subjects. CONCLUSIONS: These findings link fatigue symptoms to alterations in behavioral choices on effort investment, prefrontal functioning, and supplementary motor area connectivity, with the dorsolateral prefrontal cortex being associated with prior beliefs about physical abilities.

Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment.

BACKGROUND: Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades. METHODS: Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 µL samples using a 'proximity extension assay' (PEA) based immunoassay. Since Transforming growth factor beta (TGF-ß) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA. RESULTS: In CFS/ME patients, the 'normalized protein expression' value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-ß did not differ between patients and controls. CONCLUSIONS: In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014.

Hypothesis: stimulation of trained immunity as adjunctive immunotherapy in cancer.

Cancer immunotherapy has steadily progressed during the past decades, with checkpoint inhibitor therapy becoming the latest and one of the most promising treatments. Despite the progress, most of the patients do not respond or develop resistance, and novel additional approaches are needed to improve the clinical effectiveness of immunotherapy. Trained immunity (TI) has been described recently as a process of epigenetic and metabolic reprogramming that induces a long-term enhanced function of innate immune cells. TI is considered to have beneficial effects in improving host response to infections and vaccination, and increasing evidence suggests that TI-mediated mechanisms also have useful and potent antitumor effects. We hypothesized that novel and more effective approaches for immunotherapy in cancer may involve induction of TI, alone or in combination with current immunotherapies.

Long-term follow-up after cognitive behaviour therapy for chronic fatigue syndrome.

OBJECTIVE: Cognitive behaviour therapy (CBT) is an effective treatment for chronic fatigue syndrome (CFS). Main aim was to determine whether treatment effects were maintained up to 10years after treatment. METHODS: Participants (n=583) of previously published studies on the effects of CBT for CFS were contacted for a long-term follow-up assessment. They completed questionnaires on main outcomes fatigue severity (CIS) and physical functioning (SF-36). The course of these outcomes since post-treatment assessment was examined using mixed model analyses. RESULTS: Between 21 and 125months after finishing CBT, 511 persons (response rate 88%) completed a follow-up assessment. At follow-up, mean fatigue severity was significantly increased to 37.60 (SD=12.76) and mean physical functioning significantly decreased to 73.16 (SD=23.56) compared to post-treatment assessment. At follow-up still 37% of the participants had fatigue scores in the normal range and 70% were not impaired in physical functioning. CONCLUSION: Positive effects of CBT for CFS on fatigue and physical functioning were partly sustained at long-term follow-up. However, a subgroup of patients once again reported severe fatigue, and compromised physical functioning. Further research should elucidate the reasons for this deterioration to facilitate the development of treatment strategies for relapse prevention.

Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial.

Background: Approximately 20% of patients with acute Q fever will develop chronic fatigue, referred to as Q fever fatigue syndrome (QFS). The objective of this randomized controlled clinical trial was to assess the efficacy of either long-term treatment with doxycycline or cognitive-behavioral therapy (CBT) in reducing fatigue severity in patients with QFS. Methods: Adult patients were included who met the QFS criteria according to the Dutch guideline: a new onset of severe fatigue lasting ≥6 months with significant disabilities, related to an acute Q fever infection, without other somatic or psychiatric comorbidity explaining the fatigue. Using block randomization, patients were randomized between oral study medication and CBT (2:1) for 24 weeks. Second, a double-blind randomization between doxycycline (200 mg/day, once daily) and placebo was performed in the medication group. Primary outcome was fatigue severity at end of treatment (EOT; week 26), assessed with the Checklist Individual Strength subscale Fatigue Severity. Results: Of 155 patients randomized, 154 were included in the intention-to-treat analysis (doxycycline, 52; placebo, 52; CBT, 50). At EOT, fatigue severity was similar between doxycycline (40.8 [95% confidence interval {CI}, 37.3-44.3]) and placebo (37.8 [95% CI, 34.3-41.2]; difference, doxycycline vs placebo, -3.0 [97.5% CI, -8.7 to 2.6]; P = .45). Fatigue severity was significantly lower after CBT (31.6 [95% CI, 28.0-35.1]) than after placebo (difference, CBT vs placebo, 6.2 [97.5% CI, .5-11.9]; P = .03). Conclusions: CBT is effective in reducing fatigue severity in QFS patients. Long-term treatment with doxycycline does not reduce fatigue severity in QFS patients compared to placebo. Clinical Trials Registration: NCT01318356.

Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial.

BACKGROUND: Interleukin-1 (IL-1), an important proinflammatory cytokine, is suspected to play a role in chronic fatigue syndrome (CFS). OBJECTIVE: To evaluate the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with CFS. DESIGN: Randomized, placebo-controlled trial from July 2014 to May 2016. Patients, providers, and researchers were blinded to treatment assignment. (ClinicalTrials.gov: NCT02108210). SETTING: University hospital in the Netherlands. PATIENTS: 50 women aged 18 to 59 years with CFS and severe fatigue leading to functional impairment. INTERVENTION: Participants were randomly assigned to daily subcutaneous anakinra, 100 mg (n = 25), or placebo (n = 25) for 4 weeks and were followed for an additional 20 weeks after treatment (n = 50). MEASUREMENTS: The primary outcome was fatigue severity, measured by the Checklist Individual Strength subscale (CIS-fatigue) at 4 weeks. Secondary outcomes were level of impairment, physical and social functioning, psychological distress, and pain severity at 4 and 24 weeks. RESULTS: At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in CIS-fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, -4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]). LIMITATION: Small sample size and wide variability in symptom duration; inclusion was not limited to patients with postinfectious symptoms. CONCLUSION: Peripheral IL-1 inhibition using anakinra for 4 weeks does not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue. PRIMARY FUNDING SOURCE: Interleukin Foundation and an independent donor who wishes to remain anonymous.