Long COVID-19—it's not over until?

Abstract

Coronavirus disease-2019 (COVID-19) has swept through the world causing profound morbidity and mortality. Health organizations and governments are overwhelmed with the treatment and prevention of the acute disease. Meanwhile, evidence is gathering that surviving the acute disease is not the whole story, and many COVID-19 survivors experience ongoing symptoms and debilitation [1Xiong Q. Xu M. Li J. Liu Y. Zhang J. Dong W. et al.Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study.Clin Microbiol Infect. 2021; 27: 89-95https://doi.org/10.1016/j.cmi.2020.09.023Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 2Carfì A. Bernabei R. Landi F. Persistent symptoms in patients after acute COVID-19.JAMA. 2020; 324: 603-605Crossref PubMed Scopus (1885) Google Scholar, 3Townsend L. Dyer A.H. Jones K. Dunne J. Mooney A. Gaffney F. et al.Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection.medRxiv. 2020; https://doi.org/10.1101/2020.07.29.20164293Crossref PubMed Scopus (0) Google Scholar, 4Carvalho-Schneider C. Laurent E. Lemaignen A. Beaufils E. Bourbao-Tournois C. Laribi S. et al.Follow-up of adults with non-critical COVID-19 two months after symptoms’ onset.Clin Microbiol Infect. 2021; 27: 258-263https://doi.org/10.1016/j.cmi.2020.09.052Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar]. Recovered individuals continue to complain of a multitude of symptoms for months. Most of the patients will experience at least one symptom during their convalescent period [3Townsend L. Dyer A.H. Jones K. Dunne J. Mooney A. Gaffney F. et al.Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection.medRxiv. 2020; https://doi.org/10.1101/2020.07.29.20164293Crossref PubMed Scopus (0) Google Scholar, 4Carvalho-Schneider C. Laurent E. Lemaignen A. Beaufils E. Bourbao-Tournois C. Laribi S. et al.Follow-up of adults with non-critical COVID-19 two months after symptoms’ onset.Clin Microbiol Infect. 2021; 27: 258-263https://doi.org/10.1016/j.cmi.2020.09.052Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 5Mahase E. Covid-19: what do we know about “long covid”?.BMJ. 2020; 370: m2815https://doi.org/10.1136/bmj.m2815Crossref PubMed Scopus (240) Google Scholar, 6Dennis A. Wamil M. Kapur S. Alberts J. Badley A.D. Decker G.A. et al.Multi-organ impairment in low-risk individuals with long COVID.medRxiv. 2020; (ePub ahead of print)https://doi.org/10.1101/2020.10.14.20212555Crossref Scopus (0) Google Scholar]. The most prevalent ongoing symptoms are fatigue, dyspnoea, chest pain, joint pain, palpitations, anosmia and dysgeusia, hair loss, cognitive symptoms (memory and attention deficits) and psychosocial distress (loneliness, anxiety, depression and sleep disorders) [1Xiong Q. Xu M. Li J. Liu Y. Zhang J. Dong W. et al.Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study.Clin Microbiol Infect. 2021; 27: 89-95https://doi.org/10.1016/j.cmi.2020.09.023Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 2Carfì A. Bernabei R. Landi F. Persistent symptoms in patients after acute COVID-19.JAMA. 2020; 324: 603-605Crossref PubMed Scopus (1885) Google Scholar, 3Townsend L. Dyer A.H. Jones K. Dunne J. Mooney A. Gaffney F. et al.Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection.medRxiv. 2020; https://doi.org/10.1101/2020.07.29.20164293Crossref PubMed Scopus (0) Google Scholar, 4Carvalho-Schneider C. Laurent E. Lemaignen A. Beaufils E. Bourbao-Tournois C. Laribi S. et al.Follow-up of adults with non-critical COVID-19 two months after symptoms’ onset.Clin Microbiol Infect. 2021; 27: 258-263https://doi.org/10.1016/j.cmi.2020.09.052Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar] (see Table 1).Table 1Long COVID-19: proportions of main symptoms as reported in different cohortsXiong et al. [[1]Xiong Q. Xu M. Li J. Liu Y. Zhang J. Dong W. et al.Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study.Clin Microbiol Infect. 2021; 27: 89-95https://doi.org/10.1016/j.cmi.2020.09.023Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar]Carfi et al. [[2]Carfì A. Bernabei R. Landi F. Persistent symptoms in patients after acute COVID-19.JAMA. 2020; 324: 603-605Crossref PubMed Scopus (1885) Google Scholar]Townsend et al. [[3]Townsend L. Dyer A.H. Jones K. Dunne J. Mooney A. Gaffney F. et al.Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection.medRxiv. 2020; https://doi.org/10.1101/2020.07.29.20164293Crossref PubMed Scopus (0) Google Scholar]Carvalho-Schneider et al. [[4]Carvalho-Schneider C. Laurent E. Lemaignen A. Beaufils E. Bourbao-Tournois C. Laribi S. et al.Follow-up of adults with non-critical COVID-19 two months after symptoms’ onset.Clin Microbiol Infect. 2021; 27: 258-263https://doi.org/10.1016/j.cmi.2020.09.052Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar]Dennis et al. [[6]Dennis A. Wamil M. Kapur S. Alberts J. Badley A.D. Decker G.A. et al.Multi-organ impairment in low-risk individuals with long COVID.medRxiv. 2020; (ePub ahead of print)https://doi.org/10.1101/2020.10.14.20212555Crossref Scopus (0) Google Scholar]No. of recovered individuals538143128130201Median time of follow up (days)97 (IQR 95–102) from discharge60 (SD 14) from COVID-19 onset72 (IQR: 62-87) from discharge (or from 14 days following the diagnosis for outpatients)All individuals were evaluated at day 60 from COVID-19 onset140 (IQR 105-160) from COVID-19 onsetFatigue28.3%53.1%52.3%NA98.0%Dyspnoea26.0%43.4%NA7.7%87.1%Chest pain12.3%21.7%NA13.1%73.1%Joint pain7.6%27.3%NA16.3%78.1%Palpitations11.2%NANA10.9%NAAnosmia and disgeusiaNANANA22.7%NAHair loss28.6%NANANANACognitive symptomsNANANANANAPsychosocial distress22.7%NANANANAAbbreviations: COVID-19, coronavirus disease 2019; IQR, interquartile range; NA, not available; SD, standard deviation. Open table in a new tab Abbreviations: COVID-19, coronavirus disease 2019; IQR, interquartile range; NA, not available; SD, standard deviation. In some of the recovered patients, slow recovery is to be expected. Severe COVID-19 necessitates a prolonged intensive care unit (ICU) stay, and symptoms of ‘post-ICU syndrome’ are not unique to COVID-19 [[7]Lee M. Kang J. Jeong Y.J. Risk factors for post-intensive care syndrome: a systematic review and meta-analysis.Aust Crit Care. 2020; (ePub ahead of print)https://doi.org/10.1016/j.aucc.2019.10.004Abstract Full Text Full Text PDF Scopus (53) Google Scholar,[8]Jaffri A. Jaffri U.A. Post-Intensive care syndrome and COVID-19: crisis after a crisis?.Heart Lung. 2020; (ePub ahead of print)https://doi.org/10.1016/j.hrtlng.2020.06.006Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. However, a retrospective study by Carvalho-Schneider et al. shows that individuals who have recovered from mild and moderate COVID-19 are also experiencing post-COVID-19 symptoms, sometimes with disabling features and inability to return to their normal life [[4]Carvalho-Schneider C. Laurent E. Lemaignen A. Beaufils E. Bourbao-Tournois C. Laribi S. et al.Follow-up of adults with non-critical COVID-19 two months after symptoms’ onset.Clin Microbiol Infect. 2021; 27: 258-263https://doi.org/10.1016/j.cmi.2020.09.052Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar]. Similar persistent symptoms have been described following severe acute respiratory syndrome and Middle Eastern respiratory syndrome illnesses, although for the latter it was described in patients who had severe disease [[9]Ahmed H. Patel K. Greenwood D.C. Halpin S. Lewthwaite P. Salawu A. et al.Long-term clinical outcomes in survivors of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus outbreaks after hospitalisation or ICU admission: a systematic review and meta-analysis.J Rehabil Med. 2020; 52https://doi.org/10.2340/16501977-2694Crossref PubMed Scopus (295) Google Scholar]. In their study, Carvalho-Schneider et al. examined the effects of COVID-19 on a cohort of 150 recovering patients following mostly mild to moderate episodes who were treated as outpatients [[4]Carvalho-Schneider C. Laurent E. Lemaignen A. Beaufils E. Bourbao-Tournois C. Laribi S. et al.Follow-up of adults with non-critical COVID-19 two months after symptoms’ onset.Clin Microbiol Infect. 2021; 27: 258-263https://doi.org/10.1016/j.cmi.2020.09.052Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar]. Patients were contacted at 30 and 60 days after symptom onset and asked to answer a simple questionnaire regarding their symptoms and general well-being. The study shows that two-thirds of patients reported at least one symptom on both day 30 and day 60, and one-third of patients were feeling as bad or worse on day 60 as they had felt during the acute episode. The most prevalent symptoms were anosmia or ageusia (27.8% on day 30, 22% on day 60), followed by flu-like symptoms (36% on day 30, 21% on day 60). Ongoing symptoms on day 30 were associated with markers of more severe disease such as hospitalization, oxygen therapy and dyspnoea on presentation. Interestingly, the age group associated with ongoing symptoms was 40–60 years. Ongoing symptoms on day 60 retained significance only for hospitalization and the 40–49 years age group. The finding with the most impact was that about 1 in 9 (11%) were still on sick leave at day 60, a significant red flag for ongoing morbidity and disability following non-critical disease. It is important to note that half (75/150) of the cohort were health-care workers. This may be skewing the results either way as health-care workers tend to be (as a group) younger and healthier on the one hand, and more attuned to medical symptoms on the other. Xiong et al. [[1]Xiong Q. Xu M. Li J. Liu Y. Zhang J. Dong W. et al.Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study.Clin Microbiol Infect. 2021; 27: 89-95https://doi.org/10.1016/j.cmi.2020.09.023Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar] present a similar picture in their study of recovered hospitalized patients from Wuhan. The authors followed patients for a longer period, almost 4 months after symptom onset (median of 97 days following discharge, combined with median length of stay of approximately 2 weeks), showing that up to 50% of patients still had symptoms at that time period. The most frequent symptoms in this cohort were fatigue and dyspnoea. Another important feature of this study is the use of a control group from the general population under extreme lockdown in Wuhan. This helps to eliminate the psychological effects of the long and mandatory isolation period experienced by people with COVID-19, causing deconditioning, anxiety and depression. The study shows a significant difference between the two groups, and very few, if any, symptoms in the control group in general. These studies, and several others published so far, have focused on ascertaining that long COVID-19 exists and describing its early subjective features. It should be stated that less than a year has passed since the onset of the pandemic, and data regarding long-COVID pathogenesis, duration and treatments are still limited. The time has now come to shift the focus of ongoing research to several questions [[10]Yelin D. Wirtheim E. Vetter P. Kalil A.C. Bruchfeld J. Runold M. et al.Long-term consequences of COVID-19: research needs.Lancet Infect Dis. 2020; 20: 1115-1117Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar]. One of the most important questions we need to answer is for how long will the symptoms last? It is clear that there is a spectrum, i.e. some patients will return to their former life sooner than others. However, even 4 months from symptom onset, a substantial proportion of the patients are still suffering, and we still do not have a maximal cap. Will some patients never completely recover? And if so – who? And what will their natural history look like? Which patients need follow up? Risk factors for long COVID-19 are still pending. Carvalho-Schneider et al. have identified some risk factors for having symptoms in general, such as severity of the acute disease and being in the age group of 40–59 years. However, the relatively small cohort size was underpowered for risk factor assessment of the different symptoms. Treating the ‘mixed bag’ of symptoms as a single entity dilutes our ability to discern risk factors for their accrual, as they probably have different mechanisms and aetiologies. Gender, body mass index, co-morbidities, functional status and physical activity before the disease are good candidates for risk factors and need to be explored. In any case, long COVID-19 in individuals with co-morbidities might stem from exacerbation of the co-morbidity itself. Therefore, these patients need close scrutiny. In addition, the findings of Xiong et al. raise a point in favour of long-term follow up of recovered patients who are asymptomatic [[1]Xiong Q. Xu M. Li J. Liu Y. Zhang J. Dong W. et al.Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study.Clin Microbiol Infect. 2021; 27: 89-95https://doi.org/10.1016/j.cmi.2020.09.023Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar]. The incidence of new-onset diabetes [[11]Rubino F. Amiel S.A. Zimmet P. Alberti G. Bornstein S. Eckel R.H. et al.New-onset diabetes in COVID-19.N Engl J Med. 2020; (ePub ahead of print)https://doi.org/10.1056/NEJMc2018688Crossref PubMed Scopus (426) Google Scholar] or hypertension [[1]Xiong Q. Xu M. Li J. Liu Y. Zhang J. Dong W. et al.Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study.Clin Microbiol Infect. 2021; 27: 89-95https://doi.org/10.1016/j.cmi.2020.09.023Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar] is still anecdotal and needs to be explored but considering their long-term effects, it is imperative to identify and screen susceptible patients. Additional specific populations of interest for long-term follow up might be elderly patients, immunocompromised patients, and those living in developing countries. What is the cause of each of the ongoing symptoms? Mechanisms of direct viral invasion, thrombosis, hyperactivation of the immune system and hormonal dysregulation have all been suggested as causing the acute manifestations of COVID-19, but it is unclear which, if any, plays a part in long COVID-19. Dennis et al. have shown multi-organ dysfunction using MRI that is suggestive of an ongoing inflammatory process in recovering patients [[6]Dennis A. Wamil M. Kapur S. Alberts J. Badley A.D. Decker G.A. et al.Multi-organ impairment in low-risk individuals with long COVID.medRxiv. 2020; (ePub ahead of print)https://doi.org/10.1101/2020.10.14.20212555Crossref Scopus (0) Google Scholar], but its aetiology still needs to be ascertained. Additionally, certain rare syndromes such as Guillain–Barré syndrome [[12]Toscano G. Palmerini F. Ravaglia S. Ruiz L. Invernizzi P. Cuzzoni M.G. et al.Guillain-Barré syndrome associated with SARS-CoV-2.N Engl J Med. 2020; (ePub ahead of print)https://doi.org/10.1056/NEJMc2009191Crossref PubMed Scopus (787) Google Scholar], myasthenia gravis [[13]Restivo D.A. Centonze D. Alesina A. Marchese-Ragona R. Myasthenia gravis associated with SARS-CoV-2 infection.Ann Intern Med. 2020; (ePub ahead of print)https://doi.org/10.7326/l20-0845Crossref PubMed Google Scholar], postural–orthostatic tachycardia syndrome [[14]Miglis M.G. Prieto T. Shaik R. Muppidi S. Sinn D.I. Jaradeh S. A case report of postural tachycardia syndrome after COVID-19.Clin Auton Res. 2020; (0123456789): 1-3https://doi.org/10.1007/s10286-020-00727-9Crossref Scopus (78) Google Scholar] and others may account for some patients' symptoms. What control group should be used, if any? These are trying times for all of us. Lockdowns, unemployment, anxiety about the disease and the economy, and for many, grief may cause symptoms in the general population and therefore we must ascertain which of the symptoms we see are unique to recovering patients. Special consideration must be set for using and choosing a control group in describing long COVID-19. Xiong et al. used people under strict lockdown, but this group may not be available in many areas [[1]Xiong Q. Xu M. Li J. Liu Y. Zhang J. Dong W. et al.Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study.Clin Microbiol Infect. 2021; 27: 89-95https://doi.org/10.1016/j.cmi.2020.09.023Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar]. And last and most important—how can we help our patients? Reassurance and advice for patience is not enough for some of our patients. These are suffering people who are eager to return to their normal selves. Until we know more regarding the causes and possible treatments for long COVID-19 symptoms, recovering patients should be evaluated at designated multidisciplinary clinics, entered into systematic long-term follow up and linked to programmes aimed at specific physical and cognitive rehabilitation as well as emotional support systems. Further research is necessary to lay the foundations for these interventions aimed at addressing long COVID-19 symptoms. Individuals convalescing from COVID-19 seem to face a new challenge—recovering completely, and it is our duty to assist them in their recovery. All authors report no conflicts of interest relevant to this article. No external funding was received. All authors contributed to the writing of the manuscript and reviewed the final version.