{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:16:57Z","timestamp":1790191017582,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Prospective cohort studies following individuals from acute infections have documented a prevalent post-infective fatigue state meeting diagnostic criteria for chronic fatigue syndrome (CFS) \u2013 that is, a post-infective fatigue syndrome (PIFS). The Dubbo Infection Outcomes Study (DIOS) was a prospective cohort following individuals from acute infection with Epstein-Barr virus (EBV), Ross River virus (RRV), or Q fever through to assessment of caseness for CFS designated by physician and psychiatrist assessments at 6 months. Previous studies in DIOS have revealed that functional genetic polymorphisms in both immunological (pro- and anti-inflammatory cytokines) and neurological (the purinergic receptor, P2X7) genes are associated with both the severity of the acute infection and subsequent prolonged illness. Principal components analysis was applied to self-report data from DIOS to describe the severity and course of both the overall illness and concurrent mood disturbance. Associations between demographics and acute infection characteristics, with prolonged illness course as well as the PIFS outcome were examined using multivariable statistics. Genetic haplotype-driven functional variations in the neuropeptide Y (NPY) gene previously shown to be associated with brain responses to stress, and to trait anxiety were also examined as predictors. The sample included 484 subjects (51% female, median age 32, IQR 19\u201344), of whom 90 (19%) met diagnostic criteria for CFS at 6 months. Participants with greater overall illness severity and concurrent mood disturbance in the acute illness had a more prolonged illness severity (HR = 0.39, 95% CI: 0.34\u20130.46, <jats:italic>p<\/jats:italic> &amp;lt; 0.001) and mood disturbance (HR = 0.36, 95% CI: 0.30\u20130.42, <jats:italic>p<\/jats:italic> &amp;lt; 0.001), respectively. Baseline illness severity and RRV infection were associated with delayed recovery. Female gender and mood disturbance in the acute illness were associated with prolonged mood disturbance. Logistic regression showed that the odds of an individual being diagnosed with PIFS increased with greater baseline illness severity (OR = 2.24, 95% CI: 1.71\u20132.94, <jats:italic>p<\/jats:italic> &amp;lt; 0.001). There was no association between the NPY haplotypes with overall illness severity or mood disturbance either during the acute illness phase or with prolonged illness (<jats:italic>p<\/jats:italic> &amp;gt; 0.05). Severe acute infective illnesses predicted prolonged illness, prolonged mood disturbance and PIFS. These factors may facilitate early intervention to manage both PIFS and mood disturbances.<\/jats:p>","DOI":"10.3389\/fneur.2022.935442","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T15:29:35Z","timestamp":1658762975000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Predictors of Chronic Fatigue Syndrome and Mood Disturbance After Acute Infection"],"prefix":"10.3389","volume":"13","author":[{"given":"Carolina X.","family":"Sandler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Cvejic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Braulio M.","family":"Valencia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian B.","family":"Hickie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1136\/bmj.38933.585764.AE","article-title":"Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study","volume":"333","author":"Hickie","year":"2006","journal-title":"BMJ."},{"key":"B2","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1080\/21641846.2018.1426086","article-title":"The international Collaborative on Fatigue Following Infection (Coffi)","volume":"6","author":"Katz","year":"2018","journal-title":"Fatigue."},{"key":"B3","doi-asserted-by":"publisher","first-page":"ofab440","DOI":"10.1093\/ofid\/ofab440","article-title":"Long COVID and post-infective fatigue syndrome: a review","volume":"8","author":"Sandler","year":"2021","journal-title":"Open Forum Infect Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1016\/S0140-6736(95)92537-6","article-title":"Postinfectious fatigue: prospective cohort study in primary care","volume":"345","author":"Wessely","year":"1995","journal-title":"Lancet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1017\/S0033291701003841","article-title":"Acute sickness behaviour: an immune system-to-brain communication?","volume":"31","author":"Vollmer-Conna","year":"2001","journal-title":"Psychol Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1177\/0004867413503718","article-title":"Mood disturbance after infection","volume":"47","author":"Gunaratne","year":"2013","journal-title":"Aust N Z J Psychiatry."},{"key":"B7","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.jpsychores.2017.06.013","article-title":"Biopsychosocial risk factors of persistent fatigue after acute infection: a systematic review to inform interventions","volume":"99","author":"Hulme","year":"2017","journal-title":"J Psychosom Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e3740","DOI":"10.1093\/cid\/ciaa1886","article-title":"Risks for developing Me\/Cfs in college students following infectious mononucleosis: a prospective cohort study","volume":"73","author":"Jason","year":"2020","journal-title":"Clin Infect Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jcv.2006.10.011","article-title":"Post-infectious fatigue syndrome in dengue infection","volume":"38","author":"Seet","year":"2007","journal-title":"J Clin Virol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1017\/S003329171000139X","article-title":"The pathway from glandular fever to chronic fatigue syndrome: can the cognitive behavioural model provide the map?","volume":"41","author":"Moss-Morris","year":"2011","journal-title":"Psychol Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1017\/S0033291703007554","article-title":"Predictors of fatigue following the onset of infectious mononucleosis","volume":"33","author":"Candy","year":"2003","journal-title":"Psychol Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/S0002-9343(00)00560-X","article-title":"Acute infectious mononucleosis: characteristics of patients who report failure to recover","volume":"109","author":"Buchwald","year":"2000","journal-title":"Am J Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"ofac127","DOI":"10.1093\/ofid\/ofac127","article-title":"Severe fatigue in the first year following SARS-CoV-2 infection: a prospective cohort study","volume":"9","author":"Verveen","year":"2022","journal-title":"Open Forum Infect Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1016\/j.bbi.2011.12.009","article-title":"Genetic associations of fatigue and other symptom domains of the acute sickness response to infection","volume":"26","author":"Piraino","year":"2012","journal-title":"Brain Behav Immun."},{"key":"B15","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1086\/500248","article-title":"Prolonged illness after infectious mononucleosis is associated with altered immunity but not with increased viral load","volume":"193","author":"Cameron","year":"2006","journal-title":"J Infect Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.bbi.2013.11.002","article-title":"Neurocognitive disturbances associated with acute infectious mononucleosis, ross river fever and q fever: a preliminary investigation of inflammatory and genetic correlates","volume":"36","author":"Cvejic","year":"2014","journal-title":"Brain Behav Immun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1017\/S0033291704001953","article-title":"Production of pro-inflammatory cytokines correlates with the symptoms of acute sickness behaviour in humans","volume":"34","author":"Vollmer-Conna","year":"2004","journal-title":"Psychol Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1086\/592967","article-title":"Cytokine polymorphisms have a synergistic effect on severity of the acute sickness response to infection","volume":"47","author":"Vollmer-Conna","year":"2008","journal-title":"Clin Infect Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1002\/jnr.24589","article-title":"Neuropeptide Y in Ptsd, Mdd, and chronic stress: a systematic review and meta-analysis","volume":"98","author":"Tural","year":"2020","journal-title":"J Neurosci Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.npep.2015.09.008","article-title":"Neuropeptide Y: a stressful review","volume":"55","author":"Reichmann","year":"2016","journal-title":"Neuropeptides."},{"key":"B21","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1001\/archgenpsychiatry.2010.197","article-title":"Emotion processing, major depression, and functional genetic variation of Neuropeptide Y","volume":"68","author":"Mickey","year":"2011","journal-title":"Arch Gen Psychiatry."},{"key":"B22","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.bbi.2021.01.005","article-title":"The severity of the pathogen-induced acute sickness response is affected by polymorphisms in genes of the nlrp3 inflammasome pathway","volume":"93","author":"Valencia","year":"2021","journal-title":"Brain Behav Immun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.bbi.2019.07.034","article-title":"Contribution of individual psychological and psychosocial factors to symptom severity and time-to-recovery after naturally-occurring acute infective illness: the Dubbo Infection Outcomes Study (Dios)","volume":"82","author":"Cvejic","year":"2019","journal-title":"Brain Behav Immun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.5694\/j.1326-5377.2001.tb143784.x","article-title":"Development of a simple screening tool for common mental disorders in general practice","volume":"175","author":"Hickie","year":"2001","journal-title":"Med J Aust."},{"key":"B25","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/0895-4356(95)00512-9","article-title":"Self-report disability in an international primary care study of psychological illness","volume":"49","author":"Von Korff","year":"1996","journal-title":"J Clin Epidemiol."},{"key":"B26","volume-title":"Manual Profile of Mood States","author":"McNair","year":"1971"},{"key":"B27","doi-asserted-by":"publisher","first-page":"953","DOI":"10.7326\/0003-4819-121-12-199412150-00009","article-title":"The chronic fatigue syndrome: a comprehensive approach to its definition and study. International chronic fatigue syndrome study group","volume":"121","author":"Fukuda","year":"1994","journal-title":"Ann Intern Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/nature06858","article-title":"Genetic variation in human npy expression affects stress response and emotion","volume":"452","author":"Zhou","year":"2008","journal-title":"Nature."},{"key":"B29","first-page":"2208","article-title":"Coxiella burnetti (q fever)","volume-title":"Principles and Practice of Infectious Diseases","author":"Marrie","year":"2015"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1016\/B978-1-4557-4801-3.00141-7","article-title":"Epstein-barr virus (infectious mononucleosis, epstein-barr virus-associated malignant diseases, and other diseases)","volume":"2","author":"Johannsen","year":"2015","journal-title":"Princ Pract Infect Dis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1128\/CMR.14.4.909-932.2001","article-title":"Ross river virus transmission, infection, and disease: a cross-disciplinary review","volume":"14","author":"Harley","year":"2001","journal-title":"Clin Microbiol Rev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1017\/S0950268818000031","article-title":"Rheumatism and chronic fatigue, the two facets of post-chikungunya disease: the telechik cohort study on Reunion Island","volume":"146","author":"Duvignaud","year":"2018","journal-title":"Epidemiol Infect."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1016\/S0140-6736(01)06961-6","article-title":"Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis","volume":"358","author":"White","year":"2001","journal-title":"Lancet."},{"key":"B34","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/sj.gene.6364162","article-title":"Heritability estimates of innate immunity: an extended twin study","volume":"6","author":"de Craen","year":"2005","journal-title":"Genes Immun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/1471-2377-11-62","article-title":"Evidence for a heritable predisposition to chronic fatigue syndrome","volume":"11","author":"Albright","year":"2011","journal-title":"BMC Neurol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1093\/infdis\/jiab027","article-title":"Regulation of the acute sickness response by the P2rx7 receptor","volume":"224","author":"Li","year":"2021","journal-title":"J Infect Dis."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.935442\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T15:29:40Z","timestamp":1658762980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.935442\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,25]]},"references-count":36,"alternative-id":["10.3389\/fneur.2022.935442"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.935442","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,25]]},"article-number":"935442"}}