Herpesvirus Antibody Response and Occurrence of Symptoms in Acute and Post-Acute COVID-19 Disease.

Knowledge about the underlying causes of the individual occurrence of symptoms during acute COVID-19 disease and during the post-acute sequelae of COVID-19 is limited. In a German COVID-19 follow-up study, we assessed whether elevated antibody responses to herpesviruses were associated with symptom occurrence in acute COVID-19 disease (n = 96 participants) and during 20 months of follow-up (n = 62 participants). Serum samples were analyzed for their antibodies to herpes simplex virus (HSV)-1 and -2, Epstein-Barr virus (EBV), and Cytomegalovirus (CMV) using fluorescent bead-based multiplex serology. The association of herpesvirus antibodies with symptom occurrence (fatigue, fever, dyspnea, decrease in taste, concentration problems) was assessed using multivariate logistic regression models. High EBV antibody levels were significantly associated with a more than fourfold increased odds of experiencing fatigue during acute COVID-19 disease and during follow-up. High CMV antibody levels were significantly associated with a more than threefold increased odds of experiencing concentration problems and a decrease in taste during the follow-up. The HSV-1 and -2 antibody levels were not elevated in the individuals that experienced symptoms. In conclusion, our findings indicate that herpesvirus infections, specifically EBV and CMV infections, might play a role in symptom development during acute and post-acute COVID-19 disease. It remains to be elucidated whether the elevated EBV and CMV antibodies determined in our study are indicators of herpesvirus reactivation.

Effects of age and gender on immunogenicity and reactogenicity of SpikoGen recombinant spike protein vaccine: a post-hoc analysis.

SpikoGen® COVID-19 vaccine is based on the spike protein extracellular domain of the ancestral Wuhan-Hu-1 strain modified by removal of the furin cleavage site and addition of stabilising mutations expressed as a recombinant protein in insect cells. It is formulated with Advax-CpG55.2™ adjuvant to ensure optimal immunogenicity. In this study, data from several SpikoGen® clinical trials was retrospectively analysed to assess for any effect of gender or age on seroconversion, neutralizing antibody levels or the incidence of adverse events. Following the 1st dose, older age was associated with a reduced rate of fatigue (RR 0.97, p < 0.001), headache (RR 0.98, p = 0.034) and myalgia (RR 0.97, p=0.016), following the 2nd dose, the rate of fatigue (RR 0.98, p = 0.017) but following the 3rd dose no effect of age on adverse events was evident. Similarly, following the 1st dose, men reported a 19% lower incidence of fatigue, 36% lower incidence of headache and 28% lower incidence of myalgia when compared to women. Interestingly, there was no relationship between age or gender and serum neutralizing antibody levels, although after each vaccine dose there was a consistent trend to women having a higher seroconversion rate. There was no correlation between neutralizing antibody levels and adverse events. Unlike what is seen with mRNA vaccines, reactogenicity trended lower after each subsequent SpikoGen® dose. Overall, SpikoGen® exhibited positive immunogenicity and low reactogenicity, indicating that a low incidence of adverse events does not equate to poor immunogenicity. SpikoGen® remains a promising protein-based vaccine platform for COVID-19 protection.

Long COVID or Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) and the Urgent Need to Identify Diagnostic Biomarkers and Risk Factors.

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), also known as post-COVID-19 condition or post-COVID syndrome, can affect anyone infected with SARS-CoV-2, regardless of age or the severity of the initial symptoms of COVID-19. Long COVID/PASC is the continuation or development of new symptoms after three months from the initial SARS-CoV-2 infection, which lasts for at least two months and has no other identifiable cause. Long COVID/PASC occurs in 10-20% of patients infected with SARS-CoV-2. The most common symptoms include fatigue, cognitive impairment (brain fog), and shortness of breath. However, more than 200 symptoms have been reported. No phenotypic or diagnostic biomarkers have been identified for developing long COVID/PASC, which is a multisystem disorder that can present with isolated or combined respiratory, hematological, immunological, cardiovascular, and neuropsychiatric symptoms. There is no cure. Therefore, individualized patient management requires a multidisciplinary clinical approach. Because millions of people have had and continue to have COVID-19, even in the era of vaccination and antiviral therapies, long COVID/PASC is now and will increasingly become a health and economic burden that the world must prepare for. Almost five years from the beginning of the COVID-19 pandemic, this article aims to review what is currently known about long COVID/PASC, the anticipated increasing global health burden, and why there is still an urgent need to identify diagnostic biomarkers and risk factors to improve prevention and treatment.

Self-reported immune status and COVID-19 associated subjective cognitive functioning in post-COVID-19 syndrome: Examination of an Irish cohort.

INTRODUCTION: Cognitive changes are very frequently reported by people with post-COVID-19 syndrome (PCS), but there is limited understanding of the underpinning mechanisms leading to these difficulties. It is possible that cognitive difficulties are related to immune status and/or low mood. The aim of the present study was to examine the relationship between immune status and cognitive functioning in PCS, while considering whether depression symptoms also influence this association. METHODS: Participants were recruited in an online study of cognitive and psychological consequences of PCS, involving individuals attending a post-COVID clinic in an acute general hospital in Ireland, and a comparison sample of age- and sex-matched community controls who had also been infected with COVID-19 but had not experienced PCS. Participants with PCS (n = 71) and community controls (n = 50) completed the immune status questionnaire, Cognitive Failures Questionnaire (CFQ), Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F). RESULTS: Significant differences were observed between groups in terms of perceived immune status, perceived cognitive function, depression scores, and fatigue, with the "PCS" group reporting lower immune status, more cognitive difficulties, and higher levels of depression and fatigue. Regression analysis in the PCS group indicated that immune status and depression significantly contributed to variance in subjective cognitive functioning, with immune status remaining a significant predictor of cognitive functioning scores even when accounting for depression, fatigue, and other covariates related to PCS, such as Body Mass Index (BMI). CONCLUSION: Our findings suggest that subjective cognitive functioning is influenced by self-reported immune status in PCS, emphasising the importance of immune status, cognitive, and mood screening as part of routine clinical care in PCS.

Mild Primary or Breakthrough SARS-CoV-2 Infection Promotes Autoantibody Production in Individuals with and without Neuro-PASC.

Patients with long COVID can develop humoral autoimmunity after severe acute SARS-CoV-2 infection. However, whether similar increases in autoantibody responses occur after mild infection and whether vaccination prior to SARS-CoV-2 breakthrough infection can limit autoantibody responses is unknown. In this study, we demonstrate that mild SARS-CoV-2 infection increases autoantibodies associated with rheumatic autoimmune diseases and diabetes in most individuals, regardless of vaccination status prior to infection. However, patients with long COVID and persistent neurologic and fatigue symptoms (neuro-PASC) have substantially higher autoantibody responses than convalescent control subjects at an average of 8 mo postinfection. Furthermore, high titers of systemic lupus erythematosus- and CNS-associated autoantibodies in patients with neuro-PASC are associated with impaired cognitive performance and greater symptom severity. In summary, we found that mild SARS-CoV-2 primary and breakthrough infections can induce persistent humoral autoimmunity in both patients with neuro-PASC and healthy COVID convalescents, suggesting that a reappraisal of mitigation strategies against SARS-CoV-2 is warranted to prevent transmission and potential development of autoimmunity.

"Do probiotics mitigate GI-induced inflammation and perceived fatigue in athletes? A systematic review".

BACKGROUND: Fatigue and gastrointestinal (GI) distress are common among athletes with an estimated 30-90% of athletes participating in marathons, triathlons, or similar events experiencing GI complaints. Intense exercise can lead to increased intestinal permeability, potentially allowing members of the gut microbiota to permeate into the bloodstream, resulting in an inflammatory response and cascade of performance-limiting outcomes. Probiotics, through their capacity to regulate the composition of the gut microbiota, may act as an adjunctive therapy by enhancing GI and immune function while mitigating inflammatory responses. This review investigates the effectiveness of probiotic supplementation on fatigue, inflammatory markers, and exercise performance based on randomized controlled trials (RCTs). METHODS: This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and PICOS (Population, Intervention, Comparison, Outcome, Study design) framework. A comprehensive search was conducted in Sportdiscus, PubMed, and Scopus databases, and the screening of titles, abstracts, and full articles was performed based on pre-defined eligibility criteria. Of the 3505 records identified, 1884 were screened using titles and abstracts, of which 450 studies were selected for full-text screening. After final screening, 13 studies met the eligibility criteria and were included for review. The studies contained 513 participants, consisting of 351 males and 115 females, however, two studies failed to mention the sex of the participants. Among the participants, 246 were defined as athletes, while the remaining participants were classified as recreationally active (n = 267). All trials were fully described and employed a double- or triple-blind placebo-controlled intervention using either a single probiotic strain or a multi-strain synbiotic (containing both pro- and pre-biotics). RESULTS: This review assesses the effects of daily probiotic supplementation, ranging from 13 to 90 days, on physical performance and physiological markers in various exercise protocols. Ten studies reported improvements in various parameters, such as, enhanced endurance performance, improved anxiety and stress levels, decreased GI symptoms, and reduced upper respiratory tract infections (URTI). Moreover, despite no improvements in maximal oxygen uptake (VO2), several studies demonstrated that probiotic supplementation led to amelioration in lactate, creatine kinase (CK), and ammonia concentrations, suggesting beneficial effects on mitigating exercise-induced muscular stress and damage. CONCLUSION: Probiotic supplementation, specifically at a minimum dosage of 15 billion CFUs daily for a duration of at least 28 days, may contribute to the reduction of perceived or actual fatigue.

Clinical significance of anti-mutated citrullinated vimentin antibodies in rheumatoid arthritis patients.

BACKGROUND: Anti-mutated citrullinated vimentin (MCV) antibodies have recently been recommended as a better arthritis diagnostic marker. OBJECTIVES: To investigate the association between anti-MCV antibodies and the clinical, functional, and radiographic characteristics of rheumatoid arthritis (RA) patients. METHODS: This case-control study was conducted on 40 RA patients and 40 healthy subjects. All patients were subjected to an assessment of disease using the 28-joint DAS (DAS28) and Clinical Disease Activity Index (CDAI), function by HAQ-DI, physical activity by International Physical Activity Questionnaire (IPAQ), fatigue by Functional Assessment of Chronic Illness Therapy (FACIT), serological tests as well as anti-MCV Abs measurement. A plain X-ray of both hands and wrists was done. RESULTS: The anti-MCV Abs level was significantly higher in RA patients than in healthy controls (P< 0.001). The anti-MCV Abs had a significant positive correlation with DAS, CDAI, HAQ, RF, Anti-CCP, and CRP (P= 0.006, 0.013, 0.005, < 0.001, < 0.001and 0.041 respectively) and a significant negative correlation with FACIT (p= 0.007). Positive anti-MCV RA patients had significantly higher erosions, JSN, and a total sharp score. CONCLUSIONS: Anti-MCV Abs may contribute to poor physical activity and more fatigue in RA patients beyond their established role in disease activity and erosion.

Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome.

Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which - combined with age, history of asthma bronchiale, and five symptoms during primary infection - is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.

Corticosteroid administration for cancer-related indications is an unfavorable prognostic factor in solid cancer patients receiving immune checkpoint inhibitor treatment.

OBJECTIVE: Immunotherapies targeting immune checkpoints have achieved encouraging survival benefits in patients with various solid cancers. Corticosteroids are frequently administrated for cancer/non-cancer related indications and immune-related adverse events (irAEs). This study aimed to clarify the prognostic significance of corticosteroid administration in solid cancer patients receiving immune checkpoint inhibitor (ICI) treatment. METHOD: First, a meta-analysis was performed using the literatures searched from PubMed, Cochrane Library, Web of Science, Embase, and Clinicaltrials.gov before January 2021. The Hazard ratios (HRs) coupled with 95% confidence intervals (CIs) were used to evaluate the correlation of corticosteroid administration with overall survival (OS) and progression-free survival (PFS). Then, a retrospective analysis enrolling 118 ICI-treated cancer patients was performed for validation, among which 26 patients received corticosteroids for cancer-related indications. RESULT: In the meta-analysis, corticosteroid administration for cancer-related indications was significantly correlated with worse PFS (HR = 1.735(1.381-2.180)) and OS (HR = 1.936(1.587-2.361)) of the ICI-treated patients. However, corticosteroid administration for non-cancer-related indications and irAEs was unrelated with PFS (non-cancer-related indications: HR = 0.830(0.645-1.067); irAEs: HR = 1.302(0.628-2.696)) and OS (non-cancer-related indications: HR = 0.786(0.512-1.206); irAEs: HR = 1.107(0.832-1.474)) of the ICI-treated patients. The following retrospective analysis identified corticosteroid administration for cancer-related indications was an independent unfavorable predictor for PFS (P = 0.006) and OS (P = 0.044) of the ICI-treated patients. The subgroup analysis based on non-small cell lung cancer (NSCLC) demonstrated the similar results (P = 0.002 for PFS and P = 0.047 for OS). CONCLUSION: Our study demonstrated corticosteroid administration for cancer-related indications is an unfavorable prognostic factor in solid cancer patients receiving ICI treatment. Therefore, careful selection of corticosteroid-treated patients for ICI therapy is quite necessary in individualized clinical management.

Understanding Fatigue in Sjögren's Syndrome: Outcome Measures, Biomarkers and Possible Interventions.

Sjögren's syndrome (SS) is an autoimmune disease affecting the salivary and lacrimal glands. Symptoms range from dryness to severe extra-glandular disease involving manifestations in the skin, lungs, nervous system, and kidney. Fatigue occurs in 70% of patients, characterizing primary SS (pSS) and significantly impacting the patient's quality of life. There are some generic and specific instruments used to measure fatigue in SS. The mechanisms involved with fatigue in SS are still poorly understood, but it appears fatigue signaling pathways are more associated with cell protection and defense than with pro-inflammatory pathways. There are no established pharmacological treatment options for fatigue in pSS. So far, exercise and neuromodulation techniques have shown positive effects on fatigue in pSS. This study briefly reviews fatigue in pSS, with special attention to outcome measures, biomarkers, and possible treatment options.

Oral Resveratrol supplementation attenuates exercise-induced Interleukin-6 but not Oxidative Stress after a high intensity cycling challenge in adults.

Previous studies demonstrated that resveratrol (RES) is able to enhance antioxidant, anti-inflammatory and insulin actions in humans. It is unclear whether RES can be used as ergogenic aids to enhance high-intensity cycling exercise performance and attenuate the high-intensity exercise-induced oxidative stress and inflammation. This study investigated the effect of RES supplementation on oxidative stress, inflammation, exercise-induced fatigue, and endurance performance. Eight male athletes participated in this single-blind crossover designed study and randomly instructed to receive four days of either oral RES (480 mg per day, totally 1920mg) or placebo supplementation. The cycling exercise challenge at 80% maximal oxygen consumption with 60 rpm was performed following 4 days of either RES or placebo supplementation. The total cycling performance time was recorded. In addition, blood samples were obtained to analyze the changes in blood glucose, plasma non-esterified fatty acid, serum lactate dehydrogenase, creatine kinase, uric acid, total antioxidant capacity, malondialdehyde, tumor necrosis factor-α, and interleukin-6. The exhausting time of cycling exercise challenge was not significantly increased in RES compared to that in placebo. However, IL-6 response was significantly decreased during exercise challenge in RES trial, and there were no differences in blood biomarkers, fatigue factors, and antioxidative response. Oral RES supplementation can attenuate exercise-induced IL-6 response but not fatigue and oxidative stress, inflammation response. However, we infer that 4-day oral RES supplementation has no ergogenic property on enhancing the high-intensity cycling exercise performance.

Fatigue Is Common in Immunoglobulin G Subclass Deficiency and Correlates With Inflammatory Response and Need for Immunoglobulin Replacement Therapy.

Purpose: Individuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT. Method: Thirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion. Results: QoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1. Conclusion: Fatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made.

Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial.

OBJECTIVES: Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS: 18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS: taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION: taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.

Regional microglial activation in the substantia nigra is linked with fatigue in MS.

OBJECTIVE: The goal of our study is to assess the role of microglial activation in MS-associated fatigue (MSAF) using [F-18]PBR06-PET. METHODS: Fatigue severity was measured using the Modified Fatigue Impact Scale (MFIS) in 12 subjects with MS (7 relapsing-remitting and 5 secondary progressive) and 10 healthy control participants who underwent [F-18]PBR06-PET. The MFIS provides a total fatigue score as well as physical, cognitive, and psychosocial fatigue subscale scores. Standardized Uptake Value (SUV) 60-90 minute frame PET maps were coregistered to 3T MRI. Voxel-by-voxel analysis using Statistical Parametric Mapping and atlas-based regional analyses were performed. SUV ratios (SUVRs) were global brain normalized. RESULTS: Peak voxel-based level of significance for correlation between total fatigue score and PET uptake was localized to the right substantia nigra (T-score 4.67, p = 0.001). Similarly, SUVRs derived from atlas-based segmentation of the substantia nigra showed significant correlation with MFIS (r = 0.76, p = 0.004). On multiple regression, the right substantia nigra was an independent predictor of total MFIS (p = 0.02) and cognitive MFIS subscale values (p = 0.007), after adjustment for age, disability, and depression. Several additional areas of significant correlations with fatigue scores were identified, including the right parahippocampal gyrus, right precuneus, and juxtacortical white matter (all p < 0.05). There was no correlation between fatigue scores and brain atrophy and lesion load in patients with MS. CONCLUSION: Substantia nigra microglial activation is linked to fatigue in MS. Microglial activation across key brain regions may represent a unifying mechanism for MSAF, and further evaluation of neuroimmunologic basis of MSAF is warranted.

Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study.

BACKGROUND: Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined. METHODS: We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology. RESULTS: 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%). CONCLUSIONS: Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.

Diagnosis and treatment of primary biliary cholangitis.

Primary biliary cholangitis is a cholestatic, chronic autoimmune liver disease with a wide individual variation in disease progression. The diagnosis is predominantly based on chronic elevation of alkaline phosphatase and the presence of anti-mitochondrial antibodies or other specific antinuclear antibodies (i.e. anti-gp210 and anti-sp100). Even in early-stage disease, health-related quality of life can be severely impaired by symptoms such as pruritus, fatigue, and sicca syndrome and metabolic bone disease should be assessed and treated. The prognosis of the disease is, however, largely determined by the development of cirrhosis and its complications. Ursodeoxycholic acid is associated with an improved prognosis and should be initiated and continued in all patients. Clinical outcome is related to the biochemical response to ursodeoxycholic acid, but the prognosis of those with an incomplete response is still better than those who remain untreated. Obeticholic acid was recently approved as second-line treatment and bezafibrate may serve as an adequate off-label alternative, particularly in patients with pruritus. Preliminary data suggest an additive effect of triple therapy with ursodeoxycholic acid, obeticholic acid, and bezafibrate, whereas other promising drugs are being evaluated in clinical trials.

The biological basis of chronic fatigue: neuroinflammation and innate immunity.

PURPOSE OF REVIEW: Chronic fatigue is common in cancer, neurodegenerative, and chronic inflammatory diseases and is regarded by many patients as their absolutely worst problem. Lately, fatigue is increasingly understood to have a genetic and molecular basis. RECENT FINDINGS: Biologically, fatigue occurs as part of the sickness behavior response, a complex and automated behavior triggered by the activation of innate immunity and neuroinflammation. IL-1ß causes neuronal activation in the brain and subsequent fatigue. In addition to proinflammatory molecules, potential partners in the complex brain signaling of fatigue include downregulatory mechanisms for inflammation and cellular stress responses and the neuropeptide hypocretin-1. These mechanisms all become constantly activated in chronic conditions. Genetic studies indicate that fatigue may have evolved to enhance survival during infection and injury. SUMMARY: Fatigue is a major clinical problem. Finding the right treatment is challenging, as no specific options exist and only a few of the mechanisms contributing to fatigue are known. Because fatigue is generated in the brain, further studies should focus on proteomics and specific candidate proteins in cerebrospinal fluid. Studies on genetic variants, gene activation, and epigenetics are also required.