Michel Goldman- Institute for Interdisciplinary Innovation in Healthcare (I3h), Université Libre de Bruxelles, Brussels, Belgium
Introduction
As a syndrome which can take multiple forms and mimic different diseases, long Covid can be considered as a novel “Great Imitator,” a nickname attributed to syphilis more than a century ago (1). Indeed, there is a body of evidence that infection with SARS-CoV-2 can result in protean pathological changes which persist after the virus has been cleared, a clinical situation qualified as long Covid or post-COVID-19 condition (2). The impact of long COVID-19 on public health is expected to be huge since more than half of COVID-19 survivors develop post-acute sequelae according to systematic review studies (3–6). The real burden of long Covid is however not established due to the elusive definition of the condition (7) and the emergence of the Omicron variants. Although the risk of developing long Covid after infection with an Omicron variant has been found to be reduced by half as compared to previous strains, the absolute numbers will clearly remain high (8). It is therefore important to rapidly address the several challenges related to long Covid.
Making the right diagnosis, the clinical challenge
According to the World Health Organization, the diagnosis of long Covid is merely a diagnosis of exclusion that is made in individuals with a history of probable or confirmed SARS CoV-2 infection, who develop long-lasting symptoms that cannot be explained by another cause (2). The list of symptoms that have been attributed to long Covid is very long and most probably not closed. As a matter of fact, post-acute sequelae of COVID-19 may affect almost every system of the human body, with respiratory and neuropsychiatric conditions at the forefront (9, 10). Strikingly, a recent study revealed that the increased risk for seizures, psychosis, dementia and epilepsy persists for at least 2 years (11).
In view of the wide range of symptoms and the lack of biomarkers, the diagnosis of long Covid requires experienced physicians with broad clinical knowledge. The first step in the work-up of a patient suspect to suffer from this condition is to carefully look at his/her past medical history before he/she was infected with the SARS-CoV-2 virus. Indeed, it is not unusual to identify somatic symptoms which have occurred before the acute COVID-19 phase (12). In such cases, one can assume that these symptoms were not primary caused but rather exacerbated by the infection. The next step is to get a precise description of the acute phase of the infection. This might allow to distinguish lingering symptoms following the acute disease from new symptoms that appear after resolution of the acute disease (9). In most cases, appropriate clinico-biological and imaging explorations will be needed to exclude diagnoses unrelated to COVID-19.
When cognitive dysfunction, depression, fatigue associated with musculoskeletal pain, post-exertional malaise, sleep disturbances or orthostatic intolerance are present, long Covid might be confounded with myalgic encephalomyelitis, chronic fatigue or fibromyalgia (13). Although the pathophysiology of these conditions is unclear, there is evidence that viral infections might represent contributing factors. Indeed, they might develop after infectious mononucleosis/ glandular fever caused by the Epstein Barr virus as well as after the Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) caused by β-coronaviruses closely related to SARS-CoV-2 (14). Long Covid can be considered as a post-viral syndrome of a similar type.
Deciphering the pathophysiological determinants, the research challenge
Whereas, the immunoinflammatory processes elicited by the SARS-CoV-2 virus in the acute phase of COVID-19 have been reasonably well characterized (15), the pathophysiology of long Covid remains obscure although a number hypothetical mechanisms have been proposed (16, 17). Viral persistence might be an important factor as suggested by a study demonstrating persistence of viral RNA and viral antigens in the gut mucosa of patients with long Covid (18). Despite experimental evidence that the SARS-CoV-2 virus might enter the central nervous system (CNS), there so far no demonstration that neuro-psychiatric symptoms of long Covid are caused by infection of brain cells (19).
Incomplete healing of early inflammatory or thrombotic lesions elicited by the virus might certainly explain several persistent symptoms, especially in the lungs (9). There is indeed suggestive evidence that early events increase the risk to develop long Covid, even in patients who were not hospitalized (20–22). Among these events, reactivation of the Epstein Barr virus deserves special attention (22).
Immune dysregulation could also play an important role in the pathogenesis of long Covid, First and foremost, a diverse range of autoantibodies were detected in the serum of COVID-19 patients (23). Anti-nuclear antibodies and antibodies neutralizing interferon-α might be especially important to consider as their production was found to correlate with the development of long Covid features (22). Besides humoral autoimmunity, there is suggestive evidence that T lymphocytes either virus-specific or activated by bystander mechanisms could also contribute to the pathology of long Covid (22, 24).
Taking care of long Covid patients, the therapeutic challenge
Given the heterogeneity of long Covid and the poor knowledge on its pathogenesis, it is not surprising that its treatment is merely symptomatic. Pain medications including opioids, antidepressant drugs and anxiolytic drugs are frequently used (10), often without adequate surveillance. Although guidelines have been proposed by several learned societies, certain therapeutic modalities remain a matter of debate such as behavioral therapy and grade exercise therapy for symptoms suggestive of myalgic encephalomyelitis or chronic fatigue (17).
Since viral persistence might contribute to long Covid, it is important to delineate the impact of anti-SARS-CoV-2 vaccination and antiviral drugs in patients suffering from post-Covid conditions. There is evidence that vaccination might reduce symptoms in some patients suffering from long Covid but these beneficial effects are limited (25, 26). Likewise, when acute Covid occurs despite vaccination, the risk of developing long Covid is only moderately reduced after breakthrough infection (27–29). Regarding antiviral drugs, the observation of viral rebounds after a 5-day course of nirmatrelvir-ritonavir (30) raises significant concerns about the effect of this treatment on long Covid. Undoubtedly, additional research is needed to efficiently tackle long Covid. In the meantime, it is important to make healthcare professionals and patients savvy about the several uncertainties that we are facing.
Concluding remarks
Long covid is a highly heterogeneous condition with multiple clinical presentations of variable severity and multiple factors contributing to its pathogenesis. There is an urgent need to foster new interdisciplinary research to stratify long Covid patients according to phenotypic and molecular criteria with the ultimate goal to provide each of them with the right treatment at the right time.
Author contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Funding
This work was supported by a grant of the Université libre de Bruxelles to the I3h Institute.
Acknowledgments
MG serves on the Civil Society Forum of the Health Emergency Preparedness and Response Agency of the European Commission.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
2. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. (2022) 22:e102–7. doi: 10.1016/S1473-3099(21)00703-9
3. Phillips S, Williams MA. Confronting our next national health disaster — long-haul Covid. N Engl J Med. (2021) 385:577–9. doi: 10.1056/NEJMp2109285
4. Groff D, Sun A, Ssentongo AE, Ba DM, Parsons N, Poudel GR, et al. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review. JAMA Netw Open. (2021) 4:e2128568. doi: 10.1001/jamanetworkopen.2021.28568
5. Salamanna F, Veronesi F, Martini L, Landini MP, Fini M. Post-COVID-19 syndrome: the persistent symptoms at the post-viral stage of the disease. a systematic review of the current data. Front Med. (2021) 8:653516. doi: 10.3389/fmed.2021.653516
6. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis. (2022). doi: 10.1093/infdis/jiac136. [Epub ahead of print].
7. Ledford H. How common is long covid? why there's still no answer. Nature. (2022) 606:852–3. doi: 10.1038/d41586-022-01702-2
8. Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet. (2022) 399:2263–4. doi: 10.1016/S0140-6736(22)00941-2
9. Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol. (2022) 23:194. doi: 10.1038/s41590-021-01104-y
10. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequalae of COVID-19. Nature. (2021) 594:259–64. doi: 10.1038/s41586-021-03553-9
11. Taquet M, Sillett R, Zhu L, Mendel J, Camplisson I, Dercon Q, Harrison PJ. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry. (2022). doi: 10.1016/S2215-0366(22)00260-7. [Epub ahead of print].
12. Ballering AV, van Zon SKR, olde Hartman TC, Rosmalen JGM. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. Lancet. (2022) 400:452–61. doi: 10.1016/S0140-6736(22)01214-4
13. Poenaru S, Abdallah SJ, Corrales-Medina V, Cowan J. COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review. Ther Adv Infect Dis. (2021) 8:20499361211009384. doi: 10.1177/20499361211009385
14. Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli 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 Psychiatry. (2020) 7:611–27. doi: 10.1016/S2215-0366(20)30203-0
15. Vabret N, Britton GJ, Gruber C, Hegde S, Kim J, Kuksin M, et al. Immunology of COVID-19: current state of the science. Immunity. (2020) 52:910–41. doi: 10.1016/j.immuni.2020.05.002
16. Proal AD, VanElzakker MB. Long COVID or Post-acute Sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front Microbiol. (2021) 12:698169. doi: 10.3389/fmicb.2021.698169
17. Crook H, Raza S, Nowell J, Young M, Edison P. Long covid—mechanisms, risk factors, and management. BMJ. (2021) 374:n1648. doi: 10.1136/bmj.n1648
18. Zollner A, Koch R, Jukic A, Pfister A, Meyer M, Rössler A, Kimpel J, Adolph TE, Tilg H. Postacute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases. Gastroenterology. (2022) 163:495–506. doi: 10.1053/j.gastro.2022.04.037
19. Spudich S, Nath A. Nervous system consequences of COVID-19. Science. (2022) 375:267–9. doi: 10.1126/science.abm2052
20. Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, et al. Attributes and predictors of long COVID. Nat Med. (2021) 27:1116. doi: 10.1038/s41591-021-01361-2
21. Subramanian A, Nirantharakumar K, Hughes S, Myles P, Williams T, et al. Symptoms and risk factors for long COVID in non-hospitalized adults. Nat Med. (2022) 28:1706–14. doi: 10.1038/s41591-022-01909-w
22. Su Y, Yuan D, Chen DG, Ng RH, Wang K, Choi J, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. (2022) 185:881–95. doi: 10.1016/j.cell.2022.01.014
23. Wang EY, Mao T, Klein J, Dai Y, Huck JD, Jaycox JR, et al. Diverse functional autoantibodies in patients with COVID-19. Nature. (2021) 595:283–8. doi: 10.1101/2020.12.10.20247205
24. Littlefield KM, Watson RO, Schneider JM, Neff CP, Yamada E, Zhang M, et al. SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2. PLoS Pathog. (2022) 18:e1010359. doi: 10.1371/journal.ppat.1010359
25. Ayoubkhani D, Bermingham C, Pouwels KB, Glickman M, Nafilyan V, Zaccardi F, et al. Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study. BMJ. (2022) 377:e069676. doi: 10.1136/bmj-2021-069676
26. Sivan M, Greenhalgh T, Milne R, Delaney B. Are vaccines a potential treatment for long covid? BMJ. (2022) 377:o988. doi: 10.1136/bmj.o988
27. Azzolini E, Levi R, Sarti R, Pozzi C, Mollura M, Mantovani A, et al. Association between BNT162b2 vaccination and long COVID after infections not requiring hospitalization in health care workers. JAMA. (2022) 328:676–8. doi: 10.1001/jama.2022.11691
28. Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E, Berry S, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID symptom study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis. (2022) 22:43–55. doi: 10.1016/S1473-3099(21)00460-6
29. Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med. (2022) 28:1461–7. doi: 10.1038/s41591-022-01840-0
Keywords: long Covid, chronic fatigue, fibromyalgia, myalgic encephalomyelitis, COVID-19 vaccine, Epstein Barr virus
Citation: Goldman M (2022) Long Covid, a great imitator of the 21th century. Front. Med. 9:1026425. doi: 10.3389/fmed.2022.1026425
Received: 23 August 2022; Accepted: 31 August 2022;
Published: 15 September 2022.
Edited by:
Ondrej Viklicky, Institute for Clinical and Experimental Medicine (IKEM), CzechiaReviewed by:
Ivan Zahradka, Institute for Clinical and Experimental Medicine (IKEM), CzechiaCopyright © 2022 Goldman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Michel Goldman, mgoldman@i3health.eu