SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine. The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis. In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.

Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Czech Republic

Department of Epidemiology Columbia University Mailman School of Public Health New York NY USA

Department of Epidemiology of Microbial Diseases Yale School of Public Health New Haven CT USA

Department of Immunobiology Yale University School of Medicine New Haven CT USA

Department of Molecular Cellular and Developmental Biology Yale University New Haven CT USA

Howard Hughes Medical Institute Chevy Chase MD USA

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Nat Med. 2022 Aug;28(8):1723. doi: 10.1038/s41591-022-01952-7. PubMed

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Stefano, G. B. Historical insight into infections and disorders associated with neurological and psychiatric sequelae similar to long COVID. Med. Sci. Monit. 27, e931447 (2021). PubMed DOI PMC

Huang, C. et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 397, 220–232 (2021). PubMed DOI PMC

Sigfrid, L. et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg. Heal. Eur. 8, 100186 (2021). DOI

Evans, R. A. et al. Clinical characteristics with inflammation profiling of long-COVID and association with one-year recovery following hospitalisation in the UK: a prospective observational study. Preprint at medRxiv https://doi.org/10.1101/2021.12.13.21267471 (2021).

Taquet, M. et al. Incidence, co-occurrence, and evolution of long-COVID features: a 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLoS Med. 18, e1003773 (2021). PubMed DOI PMC

Estiri, H. et al. Evolving phenotypes of non-hospitalized patients that indicate long COVID. BMC Med. 19, 249 (2021). PubMed DOI PMC

Caspersen, I. H., Magnus, P. & Trogstad, L. Excess risk and clusters of symptoms after COVID-19 in a large Norwegian cohort. Eur. J. Epidemiol. https://doi.org/10.1007/s10654-022-00847-8 (2022).

Havervall, S. et al. Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers. J. Am. Med. Assoc. 325, 2015–2016 (2021). DOI

Blomberg, B. et al. Long COVID in a prospective cohort of home-isolated patients. Nat. Med. 27, 1607–1613 (2021). PubMed DOI PMC

Logue, J. K. et al. Sequelae in adults at 6 Months after COVID-19 infection. JAMA Netw. Open 4, e210830 (2021). PubMed DOI PMC

Amin-Chowdhury, Z. et al. Characterising long COVID more than 6 months after acute infection in adults; prospective longitudinal cohort study, England. Preprint at medRxiv https://doi.org/10.1101/2021.03.18.21253633 (2021).

Frontera, J. A. et al. Prevalence and predictors of prolonged cognitive and psychological symptoms following COVID-19 in the United States. Front. Aging Neurosci. 13, 357 (2021). DOI

Søraas, A. et al. Persisting symptoms three to eight months after non-hospitalized COVID-19, a prospective cohort study. PLoS ONE 16, e0256142 (2021). PubMed DOI PMC

Ayoubkhani, D. & Pawelek, P. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 3 February 2022. UK Office for National Statistics https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/3february2022 (2022).

Groff, D. et al. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review. JAMA Netw. Open 4, e2128568 (2021). PubMed DOI PMC

Crook, H., Raza, S., Nowell, J., Young, M. & Edison, P. Long COVID — mechanisms, risk factors, and management. Br. Med. J. 374, n1648 (2021). DOI

Michelen, M. et al. Characterising long COVID: a living systematic review. BMJ Glob. Heal. 6, e005427 (2021). DOI

Malik, P. et al. Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)—a systematic review and meta-analysis. J. Med. Virol. 94, 253–262 (2022). PubMed DOI

Korompoki, E. et al. Epidemiology and organ specific sequelae of post-acute COVID19: a narrative review. J. Infect. 83, 1–16 (2021). PubMed DOI PMC

Nalbandian, A. et al. Post-acute COVID-19 syndrome. Nat. Med. 27, 601–615 (2021). PubMed DOI PMC

Proal, A. D. & VanElzakker, M. B. Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front. Microbiol. 12, 1494 (2021). DOI

Balcom, E. F., Nath, A. & Power, C. Acute and chronic neurological disorders in COVID-19: potential mechanisms of disease. Brain 144, 3576–3588 (2021). PubMed DOI PMC

Mehandru, S. & Merad, M. Pathological sequelae of long-haul COVID. Nat. Immunol. 23, 194–202 (2022). PubMed DOI PMC

Morroy, G. et al. Fatigue following acute Q-fever: a systematic literature review. PLoS One 11, e0155884 (2016). PubMed DOI PMC

Hung, T. M., Wills, B., Clapham, H. E., Yacoub, S. & Turner, H. C. The uncertainty surrounding the burden of post-acute consequences of dengue infection. Trends Parasitol. 35, 673–676 (2019). PubMed DOI

PREVAIL III Study Group et al. A longitudinal study of Ebola sequelae in Liberia. N. Engl. J. Med. 380, 924–934 (2019).

Rojas, M. et al. Ebola virus disease: an emerging and re-emerging viral threat. J. Autoimmun. 106, 102375 (2020). PubMed DOI

Carod-Artal, F. J. Post-Ebola virus disease syndrome: what do we know? Expert Rev. Anti. Infect. Ther. 13, 1185–1187 (2015). PubMed DOI

Rodríguez-Morales, A. J., Cardona-Ospina, J. A., Fernanda Urbano-Garzón, S. & Sebastian Hurtado-Zapata, J. Prevalence of post-chikungunya infection chronic inflammatory arthritis: a systematic review and meta-analysis. Arthritis Care Res. 68, 1849–1858 (2016). DOI

Paixão, E. S. et al. Chikungunya chronic disease: a systematic review and meta-analysis. Trans. R. Soc. Trop. Med. Hyg. 112, 301–316 (2018). PubMed DOI

Hickie, I. et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: Prospective cohort study. Br. Med. J. 333, 575–578 (2006). DOI

Harley, D., Bossingham, D., Purdie, D. M., Pandeya, N. & Sleigh, A. C. Ross River virus disease in tropical Queensland: evolution of rheumatic manifestations in an inception cohort followed for six months. Med. J. Aust. 177, 352–355 (2002). PubMed DOI

Mylonas, A. D. et al. Natural history of Ross River virus-induced epidemic polyarthritis. Med. J. Aust. 177, 356–360 (2002). PubMed DOI

Condon, R. J. & Rouse, I. L. Acute symptoms and sequelae of Ross River virus infection in south-western Australia: a follow-up study. Clin. Diagn. Virol. 3, 273–284 (1995). PubMed DOI

Shing, S. L. H. et al. Post-polio syndrome: more than just a lower motor neuron disease. Front. Neurol. 10, 773 (2019). DOI

Patel, H., Sander, B. & Nelder, M. P. Long-term sequelae of West Nile virus-related illness: a systematic review. Lancet Infect. Dis. 15, 951–959 (2015). PubMed DOI

Katz, B. Z., Shiraishi, Y., Mears, C. J., Binns, H. J. & Taylor, R. Chronic fatigue syndrome after infectious mononucleosis in adolescents. Pediatrics 124, 189–193 (2009). PubMed DOI

Jason, L. A., Cotler, J., Islam, M. F., Sunnquist, M. & Katz, B. Z. Risks for developing myalgic encephalomyelitis/chronic fatigue syndrome in college students following infectious mononucleosis: a prospective cohort study. Clin. Infect. Dis. 73, e3740–e3746 (2021). PubMed DOI

Pedersen, M. et al. Predictors of chronic fatigue in adolescents six months after acute Epstein–Barr virus infection: a prospective cohort study. Brain. Behav. Immun. 75, 94–100 (2019). PubMed DOI

Petersen, I., Thomas, J. M., Hamilton, W. T. & White, P. D. Risk and predictors of fatigue after infectious mononucleosis in a large primary-care cohort. QJM 99, 49–55 (2006). PubMed DOI

White, P. D. et al. Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever. Br. J. Psychiatry 173, 475–481 (1998). PubMed DOI

Naess, H., Nyland, M., Hausken, T., Follestad, I. & Nyland, H. I. Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence. BMC Gastroenterol. 12, 13 (2012). PubMed DOI PMC

Litleskare, S. et al. Prevalence of irritable bowel syndrome and chronic fatigue 10 years after Giardia infection. Clin. Gastroenterol. Hepatol. 16, 1064–1072.e4 (2018). PubMed DOI

Hunskar, G. S. et al. Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: a controlled prospective cohort study. Scand. J. Pain 22, 348–355 (2021).

Rebman, A. W. & Aucott, J. N. Post-treatment Lyme disease as a model for persistent symptoms in Lyme disease. Front. Med. 7, 57 (2020). DOI

Mac, S. et al. Long-term sequelae and health-related quality of life associated with lyme disease: a systematic review. Clin. Infect. Dis. 71, 440–452 (2020). PubMed DOI

Aucott, J. N. et al. Risk of post-treatment Lyme disease in patients with ideally-treated early Lyme disease: a prospective cohort study. Int. J. Infect. Dis. 116, 230–237 (2022). PubMed DOI

Shadick, N. A. et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann. Intern. Med. 131, 919–926 (1999). PubMed DOI

Shadick, N. A. et al. The long-term clinical outcomes of Lyme disease: a population-based retrospective cohort study. Ann. Intern. Med. 121, 560–567 (1994). PubMed DOI

Rebman, A. W. et al. The clinical, symptom, and quality-of-life characterization of a well-defined group of patients with posttreatment lyme disease syndrome. Front. Med. 4, 224 (2017). DOI

Fallon, B. A. et al. The General Symptom Questionnaire-30 (GSQ-30): a brief measure of multi-system symptom burden in Lyme disease. Front. Med. 6, 283 (2019). DOI

Ursinus, J. et al. Prevalence of persistent symptoms after treatment for Lyme borreliosis: a prospective observational cohort study. Lancet Reg. Heal. Eur. 6, 100142 (2021). DOI

Bechtold, K. T., Rebman, A. W., Crowder, L. A., Johnson-Greene, D. & Aucott, J. N. Standardized symptom measurement of individuals with early Lyme disease over time. Arch. Clin. Neuropsychol. 32, 129–141 (2017). PubMed DOI

Seltzer, E. G., Gerber, M. A., Cartter, M. L., Freudigman, K. & Shapiro, E. D. Long-term outcomes of persons with Lyme disease. J. Am. Med. Assoc. 283, 609–616 (2000). DOI

Wormser, G. P. et al. Prospective evaluation of the frequency and severity of symptoms in Lyme disease patients with erythema migrans compared with matched controls at baseline, 6 months, and 12 months. Clin. Infect. Dis. 71, 3118–3124 (2020). PubMed DOI PMC

Cerar, D., Cerar, T., Ružić-Sabljić, E., Wormser, G. P. & Strle, F. Subjective symptoms after treatment of early Lyme disease. Am. J. Med. 123, 79–86 (2010). PubMed DOI

Magnus, P. et al. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. Vaccine 33, 6173–6177 (2015). PubMed DOI

Tsai, S. Y. et al. Increased risk of chronic fatigue syndrome following herpes zoster: a population-based study. Eur. J. Clin. Microbiol. Infect. Dis. 33, 1653–1659 (2014). PubMed DOI

Chia, J., Chia, A., Voeller, M., Lee, T. & Chang, R. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. J. Clin. Pathol. 63, 165–168 (2010). PubMed DOI

O’Neal, A. J. & Hanson, M. R. The enterovirus theory of disease etiology in myalgic encephalomyelitis/chronic fatigue syndrome: a critical review. Front. Med. 8, 908 (2021).

Shantha, J. G., Crozier, I. & Yeh, S. An update on ocular complications of Ebola virus disease. Curr. Opin. Ophthalmol. 28, 600–606 (2017). PubMed DOI PMC

Shantha, J. G. et al. Ophthalmic manifestations and causes of vision impairment in Ebola virus disease survivors in Monrovia, Liberia. Ophthalmology 124, 170–177 (2017). PubMed DOI

Steptoe, P. J. et al. Novel retinal lesion in Ebola survivors, Sierra Leone, 2016. Emerg. Infect. Dis. 23, 1102–1109 (2017). PubMed DOI PMC

Fukuda, K. et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann. Intern. Med. 121, 953–959 (1994). PubMed DOI

Carruthers, B. M. et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J. Chronic Fatigue Syndr. 11, 7–115 (2003). DOI

Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome et al. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness (National Academies Press, 2015).

Sharpe, M. C. A report — chronic fatigue syndrome: guidelines for research. J. R. Soc. Med. 84, 118–121 (1991). PubMed DOI PMC

Moss-Morris, R., Spence, M. J. & Hou, R. The pathway from glandular fever to chronic fatigue syndrome: can the cognitive behavioural model provide the map? Psychol. Med. 41, 1099–1107 (2011). PubMed DOI

Buchwald, D. S., Rea, T. D., Katon, W. J., Russo, J. E. & Ashley, R. L. Acute infectious mononucleosis: Characteristics of patients who report failure to recover. Am. J. Med. 109, 531–537 (2000). PubMed DOI

Murray, K. O. et al. Survival analysis, long-term outcomes, and percentage of recovery up to 8 years post-infection among the Houston West Nile virus cohort. PLoS ONE 9, e102953 (2014). PubMed DOI PMC

Balakrishnan, A., Thekkekara, R. J. & Tandale, B. V. Outcomes of West Nile encephalitis patients after 1 year of West Nile encephalitis outbreak in Kerala, India: a follow-up study. J. Med. Virol. 88, 1856–1861 (2016).

Sejvar, J. J. et al. Neurocognitive and functional outcomes in persons recovering from West Nile virus illness. J. Neuropsychol. 2, 477–499 (2008). PubMed DOI

Ayres, J. G. et al. Post-infection fatigue syndrome following Q fever. QJM 91, 105–123 (1998). PubMed DOI

Wildman, M. J. et al. Chronic fatigue following infection by Coxiella burnetii (Q fever): ten-year follow-up of the 1989 UK outbreak cohort. QJM 95, 527–538 (2002). PubMed DOI

Ayres, J. G. et al. Long-term follow-up of patients from the 1989 Q fever outbreak: no evidence of excess cardiac disease in those with fatigue. QJM 95, 539–546 (2002). PubMed DOI

Van Woerden, H. C., Healy, B., Llewelyn, M. B. & Matthews, I. P. A nested case control study demonstrating increased chronic fatigue six years after a Q fever outbreak. Microbiol. Res. 2, 19 (2011). DOI

Marmion, B. P., Shannon, M., Maddocks, I., Storm, P. & Penttila, I. Protracted debility and fatigue after acute Q fever. Lancet 347, 977–978 (1996). PubMed DOI

Ankert, J., Frosinski, J., Weis, S., Boden, K. & Pletz, M. W. Incidence of chronic Q fever and chronic fatigue syndrome: a 6 year follow-up of a large Q fever outbreak. Transbound. Emerg. Dis. https://doi.org/10.1111/tbed.14224 (2021).

Bronner, M. B. et al. Long-term impact of a Q-fever outbreak: an evaluation of health symptoms, health-related quality of life, participation and health care satisfaction after ten years. J. Psychosom. Res. 139, 110258 (2020). PubMed DOI PMC

Mørch, K. et al. Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course. BMC Gastroenterol. 13, 28 (2013). PubMed DOI PMC

Canavan, C., West, J. & Card, T. The epidemiology of irritable bowel syndrome. Clin. Epidemiol. 6, 71–80 (2014). PubMed PMC

Lim, E. J. et al. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J. Transl. Med. 18, 100 (2020). PubMed DOI PMC

Weitzner, E. et al. Long-term assessment of post-treatment symptoms in patients with culture-confirmed early Lyme disease. Clin. Infect. Dis. 61, 1800–1806 (2015). PubMed DOI PMC

Dinerman, H. & Steerc, A. C. Lyme disease associated with fibromyalgia. Ann. Intern. Med. 117, 281–285 (1992). PubMed DOI

Rowe, A. K. et al. Clinical, virologic, and immunologic follow-up of convalescent Ebola hemorrhagic fever patients and their household contacts, Kikwit, Democratic Republic of the Congo. J. Infect. Dis. 179, S28–S35 (1999). PubMed DOI

Jagadesh, S. et al. Disability among Ebola survivors and their close contacts in Sierra Leone: a retrospective case-controlled cohort study. Clin. Infect. Dis. 66, 131–133 (2018). PubMed DOI

Clark, D. V. et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect. Dis. 15, 905–912 (2015). PubMed DOI

Bond, N. G. et al. Post-Ebola syndrome presents with multiple overlapping symptom clusters: evidence from an ongoing cohort study in eastern Sierra Leone. Clin. Infect. Dis. 73, 1046–1054 (2021). PubMed DOI PMC

Soumahoro, M. K. et al. Impact of chikungunya virus infection on health status and quality of life: a retrospective cohort study. PLoS ONE 4, e7800 (2009). PubMed DOI PMC

Duvignaud, A. et al. Rheumatism and chronic fatigue, the two facets of post-chikungunya disease: the TELECHIK cohort study on Reunion island. Epidemiol. Infect. 146, 633–641 (2018). PubMed DOI

Gérardin, P. et al. Perceived morbidity and community burden after a chikungunya outbreak: the TELECHIK survey, a population-based cohort study. BMC Med. 9, 1–11 (2011). DOI

Marimoutou, C., Vivier, E., Oliver, M., Boutin, J. P. & Simon, F. Morbidity and impaired quality of life 30 months after chikungunya infection: comparative cohort of infected and uninfected french military policemen in Reunion island. Medicine 91, 212–219 (2012). PubMed DOI

Ramachandran, V. et al. Impact of chikungunya on health related quality of life Chennai, South India. PLoS ONE 7, e51519 (2012). PubMed DOI PMC

Kularatne, S. A. M. et al. Epidemiology, clinical manifestations, and long-term outcomes of a major outbreak of chikungunya in a hamlet in Sri Lanka, in 2007: a longitudinal cohort study. J. Trop. Med. 2012, 639178 (2012). PubMed DOI PMC

Rogers, J. P. et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiat. 7, 611–627 (2020). DOI

Lam, M. H. B. et al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors long-term follow-up. Arch. Intern. Med. 169, 2142–2147 (2009). PubMed DOI

Moldofsky, H. & Patcai, J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. 11, 37 (2011). PubMed DOI PMC

Keita, A. K. et al. A 40-month follow-up of Ebola virus disease survivors in Guinea (Postebogui) reveals long-term detection of Ebola viral ribonucleic acid in semen and breast milk. Open Forum Infect. Dis. 6, ofz482 (2019). PubMed DOI PMC

Fischer, W. A. et al. Ebola virus ribonucleic acid detection in semen more than two years after resolution of acute Ebola virus infection. Open Forum Infect. Dis. 4, ofx155 (2017). PubMed DOI PMC

Lavergne, S. M. et al. Ebola-Specific CD8 PubMed DOI PMC

Wiedemann, A. et al. Long-lasting severe immune dysfunction in Ebola virus disease survivors. Nat. Commun. 11, 3730 (2020). PubMed DOI PMC

Adaken, C. et al. Ebola virus antibody decay–stimulation in a high proportion of survivors. Nature 590, 468–472 (2021). PubMed DOI PMC

Keita, A. K. et al. Resurgence of Ebola virus in 2021 in Guinea suggests a new paradigm for outbreaks. Nature 597, 539–543 (2021). PubMed DOI

Diallo, B. et al. Resurgence of Ebola virus disease in Guinea linked to a survivor with virus persistence in seminal fluid for more than 500 days. Clin. Infect. Dis. 63, 1353–1356 (2016). PubMed DOI PMC

Murray, K. et al. Persistent infection with West Nile virus years after initial infection. J. Infect. Dis. 201, 2–4 (2010). PubMed DOI

Gaebler, C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 591, 639–644 (2021). PubMed DOI PMC

Cheung, C. C. L. et al. Residual SARS-CoV-2 viral antigens detected in GI and hepatic tissues from five recovered patients with COVID-19. Gut 71, 226–229 (2022). PubMed DOI

Fernández-Castañeda, A. et al. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain. Preprint at bioRxiv https://doi.org/10.1101/2022.01.07.475453 (2022).

Rojas, M. et al. Molecular mimicry and autoimmunity. J. Autoimmun. 95, 100–123 (2018). PubMed DOI

Lanz, T. V. et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 603, 321–327 (2022). PubMed DOI

Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein–Barr virus associated with multiple sclerosis. Science 375, 296–301 (2022). PubMed DOI

Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370, eabd4585 (2020).

Wang, E. Y. et al. Diverse functional autoantibodies in patients with COVID-19. Nature 595, 283–288 (2021). PubMed DOI

Combes, A. J. et al. Global absence and targeting of protective immune states in severe COVID-19. Nature 591, 124–130 (2021). PubMed DOI PMC

Zuo, Y. et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci. Transl. Med. 12, eabd3876 (2020). PubMed DOI PMC

Woodruff, M. C. et al. Relaxed peripheral tolerance drives broad de novo autoreactivity in severe COVID-19. Preprint at medRxiv https://doi.org/10.1101/2020.10.21.20216192 (2021).

Zhou, Y. et al. Clinical and autoimmune characteristics of severe and critical cases of COVID-19. Clin. Transl. Sci. 13, 1077–1086 (2020). PubMed DOI PMC

Song, E. et al. Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms. Cell Rep. Med. 2, 100288 (2021). PubMed DOI PMC

Zuniga, M. et al. Autoimmunity to annexin A2 predicts mortality among hospitalised COVID-19 patients. Eur. Respir. J. 58, 2100918 (2021). PubMed DOI PMC

Chang, S. E. et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat. Commun. 12, 1–15 (2021). DOI

Wallukat, G. et al. Functional autoantibodies against G-protein coupled receptors in patients with persistentlLong-COVID-19 symptoms. J. Transl. Autoimmun. 4, 100100 (2021). PubMed DOI PMC

Su, Y. et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell 185, 881–895 (2022).

Iijima, N. & Iwasaki, A. Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Nature 533, 552–556 (2016). PubMed DOI PMC

Manfredo Vieira, S. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359, 1156–1161 (2018). PubMed DOI

Kaminska, B., Mota, M. & Pizzi, M. Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation. Biochim. Biophys. Acta Mol. Basis Dis. 1862, 339–351 (2016). DOI

Matthay, M. A. et al. Acute respiratory distress syndrome. Nat. Rev. Dis. Prim. 5, 18 (2018). DOI

Pretorius, E. et al. Persistent clotting protein pathology in Long COVID/post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc. Diabetol. 20, 172 (2021). PubMed DOI PMC

Angum, F., Khan, T., Kaler, J., Siddiqui, L. & Hussain, A. The prevalence of autoimmune disorders in women: a narrative review. Cureus 12, e8094–e8094 (2020). PubMed PMC

Tozay, S. et al. Long-term complications of ebola virus disease: prevalence and predictors of major symptoms and the role of inflammation. Clin. Infect. Dis. 71, 1749–1755 (2020). PubMed DOI

Etard, J. F. et al. Multidisciplinary assessment of post-Ebola sequelae in Guinea (Postebogui): an observational cohort study. Lancet Infect. Dis. 17, 545–552 (2017). PubMed DOI

Kibadi, K. et al. Late ophthalmologic manifestations in survivors of the 1995 Ebola virus epidemic in Kikwit, Democratic Republic of the Congo. J. Infect. Dis. 179, S13–S14 (1999). PubMed DOI

Wilson, H. W. et al. Post-Ebola syndrome among ebola virus disease survivors in montserrado county, Liberia 2016. Biomed. Res. Int. 2018, 1909410 (2018). PubMed DOI PMC

Mattia, J. G. et al. Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. Lancet Infect. Dis. 16, 331–338 (2016). PubMed DOI

Qureshi, A. I. et al. Study of Ebola virus disease survivors in Guinea. Clin. Infect. Dis. 61, 1035–1042 (2015). PubMed DOI

Tiffany, A. et al. Ebola virus disease complications as experienced by survivors in Sierra Leone. Clin. Infect. Dis. 62, 1360–1366 (2016). PubMed DOI PMC

Nanyonga, M., Saidu, J., Ramsay, A., Shindo, N. & Bausch, D. G. Sequelae of Ebola virus disease, Kenema District, Sierra Leone. Clin. Infect. Dis. 62, 125–126 (2016). PubMed DOI

Howlett, P. J. et al. Case series of severe neurologic sequelae of ebola virus disease during epidemic, Sierra Leone. Emerg. Infect. Dis. 24, 1412–1421 (2018). PubMed DOI PMC

Halsey, E. S. et al. Occurrence and correlates of symptom persistence following acute dengue fever in Peru. Am. J. Trop. Med. Hyg. 90, 449–456 (2014). PubMed DOI PMC

Sigera, P. C. et al. Dengue and post-infection fatigue: findings from a prospective cohort — the Colombo Dengue Study. Trans. R. Soc. Trop. Med. Hyg. 115, 669–676 (2021). PubMed DOI

Seet, R. C. S., Quek, A. M. L. & Lim, E. C. H. Post-infectious fatigue syndrome in dengue infection. J. Clin. Virol. 38, 1–6 (2007). PubMed DOI

Teixeira, L. A. S., Nogueira, F. P. D. S. & Nascentes, G. A. N. Prospective study of patients with persistent symptoms of dengue in Brazil. Rev. Inst. Med. Trop. Sao Paulo 59, e65 (2017). PubMed DOI PMC

García, G. et al. Long-term persistence of clinical symptoms in dengue-infected persons and its association with immunological disorders. Int. J. Infect. Dis. 15, e38–e43 (2011). PubMed DOI

Kularatne, S. Survey on the management of dengue infection in Sri Lanka: opinions of physicians and pediatricians. Southeast Asian J. Trop. Med. Public Health 36, 1198–1200 (2005). PubMed

Umakanth, M. Post dengue fatigue syndrome (PDFS) among dengue IgM-antibody positive patients at Batticaloa Teaching Hospital, Sri Lanka. OALib 05, 1–6 (2018).

González, D. et al. Evaluation of some clinical, humoral and imagenological parameters in patients of dengue haemorrhagic fever six months after acute illness. Dengue Bull. 29, 79–84 (2005).

Chang, A. Y. et al. Frequency of chronic joint pain following chikungunya virus infection: a Colombian cohort study. Arthritis Rheumatol. 70, 578–584 (2018). PubMed DOI PMC

Couturier, E. et al. Impaired quality of life after chikungunya virus infection: a 2-year follow-up study. Rheumatology 51, 1315–1322 (2012). PubMed DOI

Bouquillard, E. et al. Rheumatic manifestations associated with chikungunya virus infection: a study of 307 patients with 32-month follow-up (RHUMATOCHIK study). Joint Bone Spine 85, 207–210 (2018). PubMed DOI

Moro, M. L. et al. Long-term chikungunya infection clinical manifestations after an outbreak in Italy: a prognostic cohort study. J. Infect. 65, 165–172 (2012). PubMed DOI

Manimunda, S. P. et al. Clinical progression of chikungunya fever during acute and chronic arthritic stages and the changes in joint morphology as revealed by imaging. Trans. R. Soc. Trop. Med. Hyg. 104, 392–399 (2010). PubMed DOI

Schilte, C. et al. Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study. PLoS Negl. Trop. Dis. 7, e2137 (2013). PubMed DOI PMC

Javelle, E. et al. Specific management of post-chikungunya rheumatic disorders: a retrospective study of 159 cases in Reunion Island from 2006–2012. PLoS Negl. Trop. Dis. 9, e0003603 (2015). PubMed DOI PMC

Sissoko, D. et al. Post-epidemic chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period. PLoS Negl. Trop. Dis. 3, 389 (2009). DOI

Rahim, A. A., Thekkekara, R. J., Bina, T. & Paul, B. J. Disability with persistent pain following an epidemic of chikungunya in rural south India. J. Rheumatol. 43, 440–444 (2016). PubMed DOI

Blettery, M. et al. Brief report: management of chronic post-chikungunya rheumatic disease: the Martinican experience. Arthritis Rheumatol. 68, 2817–2824 (2016). PubMed DOI

Dupuis-Maguiraga, L. et al. Chikungunya disease: infection-associated markers from the acute to the chronic phase of arbovirus-induced arthralgia. PLoS Negl. Trop. Dis. 6, e1446 (2012). PubMed DOI PMC

Jason, L. A. et al. Predictors of post-infectious chronic fatigue syndrome in adolescents. Heal. Psychol. Behav. Med. 2, 41–51 (2014). DOI

Katz, B. Z., Stewart, J. M., Shiraishi, Y., Mears, C. J. & Taylor, R. Autonomic symptoms at baseline and following infectious mononucleosis in a prospective cohort of adolescents. Arch. Pediatr. Adolesc. Med. 165, 765 (2011). PubMed DOI PMC

Katz, B. Z. et al. A validated scale for assessing the severity of acute infectious mononucleosis. J. Pediatr. 209, 130–133 (2019). PubMed DOI PMC

Ragonese, P. et al. Prevalence and risk factors of post-polio syndrome in a cohort of polio survivors. J. Neurol. Sci. 236, 31–35 (2005). PubMed DOI

Ramblow, J., Alexander, M., Laporte, R., Kaufmann, C. & Kuller, L. Epidemiology of the post-polio syndrome. Am. J. Epidemiol. 136, 769–786 (1992). DOI

Berlly, M. H., Strauser, W. W. & Hall, K. M. Fatigue in postpolio syndrome. Arch. Phys. Med. Rehabil. 72, 115–118 (1991). PubMed

Nollet, F. et al. Disability and functional assessment in former polio patients with and without postpolio syndrome. Arch. Phys. Med. Rehabil. 80, 136–143 (1999). PubMed DOI

Romigi, A. et al. Restless legs syndrome and post polio syndrome: a case–control study. Eur. J. Neurol. 22, 472–478 (2015). PubMed DOI

On, A. Y., Oncu, J., Atamaz, F. & Durmaz, B. Impact of post-polio-related fatigue on quality of life. J. Rehabil. Med. 38, 329–332 (2006). PubMed DOI

Takemura, J., Saeki, S., Hachisuka, K. & Aritome, K. Prevalence of post-polio syndrome based on a cross-sectional survey in Kitakyushu, Japan. J. Rehabil. Med. 36, 1–3 (2004). PubMed DOI

Marin, L. F., Carvalho, L. B. C., Prado, L. B. F., Oliveira, A. S. B. & Prado, G. F. Restless legs syndrome is highly prevalent in patients with post-polio syndrome. Sleep. Med. 37, 147–150 (2017). PubMed DOI

Nolan, M. S., Hause, A. M. & Murray, K. O. Findings of long-term depression up to 8 years post infection from West Nile virus. J. Clin. Psychol. 68, 801–808 (2012). PubMed DOI PMC

Loeb, M. et al. Prognosis after West Nile virus infection. Ann. Intern. Med. 149, 232–241 (2008). PubMed DOI

Yeung, M. W., Tomlinson, G., Loeb, M. & Sander, B. Health-related quality of life in persons with West Nile virus infection: a longitudinal cohort study. Health Qual. Life Outcomes 15, 1–10 (2017). DOI

Garcia, M. N. et al. Evaluation of prolonged fatigue post-west nile virus infection and association of fatigue with elevated antiviral and proinflammatory cytokines. Viral Immunol. 27, 327–333 (2014). PubMed DOI PMC

Carson, P. J. et al. Long-term clinical and neuropsychological outcomes of West Nile virus infection. Clin. Infect. Dis. 43, 723–730 (2006). PubMed DOI

Klee, A. L. et al. Long-term prognosis for clinical West Nile virus infection. Emerg. Infect. Dis. 10, 1405–1411 (2004). PubMed DOI PMC

Patnaik, J. L., Harmon, H. & Vogt, R. L. Follow-up of 2003 human West Nile virus infections, Denver, Colorado. Emerg. Infect. Dis. 12, 1129–1131 (2006). PubMed DOI PMC

Cook, R. L. et al. Demographic and clinical factors associated with persistent symptoms after West Nile virus infection. Am. J. Trop. Med. Hyg. 83, 1133–1136 (2010). PubMed DOI PMC

Samaan, Z. et al. Neuropsychological impact of west nile virus infection: an extensive neuropsychiatric assessment of 49 cases in Canada. PLoS One 11, e0158364 (2016). PubMed DOI PMC

Sadek, J. R. et al. Persistent neuropsychological impairment associated with West Nile virus infection. J. Clin. Exp. Neuropsychol. 32, 81–87 (2010). PubMed DOI

Kuberski, T., Brown, C. B. & Robinson, L. Clinical observations on West Nile virus infections. Infect. Med. 25, 430–434 (2008).

Leis, A. A. et al. Tumor necrosis factor-alpha signaling may contribute to chronic West Nile virus post-infectious proinflammatory state. Front. Med. 7, 164 (2020). DOI

Tansey, C. M. et al. One-year outcomes and health care utilization in survivors of severe acute respiratory syndrome. Arch. Intern. Med. 167, 1312–1320 (2007). PubMed DOI

Guo, L. et al. Long-term outcomes in patients with severe acute respiratory syndrome treated with oseltamivir: a 12-year longitudinal study. Int J. Clin. Exp. Med 12, 12464–12471 (2019).

Vallings, R. A case of chronic fatigue syndrome triggered by influenza H1N1 (swine influenza). J. Clin. Pathol. 63, 184–185 (2010). PubMed DOI

Van Loenhout, J. A. F. et al. Q-fever patients suffer from impaired health status long after the acute phase of the illness: results from a 24-month cohort study. J. Infect. 70, 237–246 (2015). PubMed DOI

Hatchette, T. F., Hayes, M., Merry, H., Schlech, W. F. & Marrie, T. J. The effect of C. burnetii infection on the quality of life of patients following an outbreak of Q fever. Epidemiol. Infect. 130, 491–495 (2003). PubMed DOI PMC

Leung-Shea, C. & Danaher, P. J. Q fever in members of the United States armed forces returning from Iraq. Clin. Infect. Dis. 43, e77–e82 (2006). PubMed DOI

Smith, R. P. et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann. Intern. Med. 136, 421–428 (2002). PubMed DOI

Nowakowski, J. et al. Long-term follow-up of patients with culture-confirmed lyme disease. Am. J. Med. 115, 91–96 (2003). PubMed DOI

Aucott, J. N., Rebman, A. W., Crowder, L. A. & Kortte, K. B. Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here? Qual. Life Res. 22, 75–84 (2013). PubMed DOI

Adrion, E. R., Aucott, J., Lemke, K. W. & Weiner, J. P. Health care costs, utilization and patterns of care following lyme disease. PLoS ONE 10, e0116767 (2015). PubMed DOI PMC

Klempner, M. S. et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N. Engl. J. Med. 345, 85–92 (2001). PubMed DOI

Stormorken, E., Jason, L. A. & Kirkevold, M. From good health to illness with post-infectious fatigue syndrome: a qualitative study of adults’ experiences of the illness trajectory. BMC Fam. Pract. 18, 1–15 (2017). DOI

Ayoubkhani, D. & Gaughan, C. Technical article: Updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK: 26 April 2020 to 1 August 2021. UK Office for National Statistics https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021 (2021).

Smith, M. P. Estimating total morbidity burden of COVID-19: relative importance of death and disability. J. Clin. Epidemiol. 142, 54–59 (2022). PubMed DOI

Morin, L. et al. Four-month clinical status of a cohort of patients after hospitalization for COVID-19. J. Am. Med. Assoc. 325, 1525–1534 (2021). DOI

Komaroff, A. L. & Lipkin, W. I. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends Mol. Med. 27, 895–906 (2021). PubMed DOI PMC

Wong, T. L. & Weitzer, D. J. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) — a systemic review and comparison of clinical presentation and symptomatology. Medicina 57, 418 (2021). PubMed DOI PMC

Torjesen, I. COVID-19: middle aged women face greater risk of debilitating long term symptoms. Br. Med. J. 372, n829 (2021). DOI

Peghin, M. et al. Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients. Clin. Microbiol. Infect. 27, 1507–1513 (2021). PubMed DOI PMC

Visconti, A. et al. Diagnostic value of cutaneous manifestation of SARS-CoV-2 infection. Br. J. Dermatol. 184, 880–887 (2021). PubMed DOI PMC

Caress, J. B. et al. COVID-19-associated Guillain–Barré syndrome: the early pandemic experience. Muscle Nerve 62, 485–491 (2020). PubMed DOI PMC

Blitshteyn, S. & Whitelaw, S. Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients. Immunol. Res. 69, 205–211 (2021). PubMed DOI PMC

Fahd Qadir, M. M. et al. SARS-CoV-2 infection of the pancreas promotes thrombofibrosis and is associated with new-onset diabetes. JCI Insight 6, e151551 (2021). DOI

Li, P. et al. Factors associated with risk of postdischarge thrombosis in patients with COVID-19. JAMA Netw. Open 4, e2135397(2021). PubMed DOI PMC

Xie, Y., Xu, E. & Al-Aly, Z. Risks of mental health outcomes in people with COVID-19: cohort study. Br. Med. J. 376, e068993 (2022). DOI

World Health Organization. A clinical case definition of post COVID-19 condition by a Delphi consensus. https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1 (2021).

US Centers for Disease Control and Prevention. Post-COVID conditions. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/ (2021).

National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. https://www.nice.org.uk/guidance/ng188 (2020).