While most people infected with SARS-CoV-2 recover within 2-4 weeks with limited complications, some adults and children continue to face persistent symptoms long after the initial infection (1). This condition, commonly referred to as “long COVID,” is of critical concern due to the sheer number of affected individuals, the significant health challenges it places on those affected, and the impact it has on health systems and economies (2).
According to the World Health Organization (WHO), long COVID, or post-COVID-19 condition, manifests as a variety of symptoms persisting in individuals with a confirmed case of COVID-19:
- Symptoms continuing (or starting again) three months after the initial SARS-CoV-2 diagnosis;
- The symptoms last at least 2 months; and
- Symptoms which cannot be explained by an alternative diagnosis (3)
Commonly reported symptoms include persistent loss of smell/taste, fatigue, shortness of breath, chest pain, cognitive disturbances or “brain fog”, anxiety, and depression(4). The wide range of reported symptoms reflects the impact this disease may have on multiple organ systems. While the underlying cause remains largely unknown, it is evident that this condition can affect individuals of all ages and is not predicated on how severe the initial COVID-19 case was. Early evidence suggests that vaccination may have a protective effect against developing long COVID (5-7).
It is now estimated that nearly 1 in 10 people affected by COVID-19 (hospitalized and non-hospitalized individuals) may develop long COVID, which amounts to a global burden of over 16 million people worldwide (8).
Evaluating the mechanisms of long COVID:
The exact mechanism leading to long COVID is still unclear, but scientists have implicated the persistence of viral antigens months after infection, and aberrant or abnormal immune responses as potential causes for this condition (2, 9, 10). It is apparent, however, that patients may suffer from a range of symptoms (4). A patient-driven study – involving 3,762 long COVID survey respondents from 56 countries – described the largest collection of symptoms (203 symptoms relating to 10 organ systems), organized in three clusters of symptoms based on severity and persistence for as long as seven months (11).
Few studies have demonstrated potential links between this condition and the immune system. A large cohort study of COVID-19 hospitalized individuals suggested that long COVID may be associated with lower anti-SARS-CoV-2 antibodies at two- and six-months post-discharge for hospitalized patients (8). Some have also suggested that auto-antibodies generated after SARS-CoV-2 infection attack “self” i.e. elements within one’s immune system or cells, which may lead to cellular damage (12, 13) It has been suggested that this condition may exhibit hallmarks found in other autoimmune diseases, such as increased concentrations of cytokines in serum lasting more than eight months post-infection, causing persistent inflammation (14, 15). Collectively, these studies suggest the involvement of both viral and immune components in the pathophysiology of long COVID.
Interestingly, the presentation of long-lasting symptoms is strikingly like that of chronic fatigue syndrome, or myalgic encephalitis, seen following other viral or bacterial infections. For instance, there are several similarities between Chikungunya and COVID-19, with both infections associated with varied and long-lasting symptoms (1). Hence, lessons learnt from other diseases may help better unravel mechanisms and identify potential treatment strategies.
Observational cohort studies such as the PHOSP-COVID in the UK (14) have indicated that Long COVID is more common in females than in males. In a UK study published by Nature (16), researchers tracked COVID-19 symptoms in 4,182 people who had previously tested positive for SARS-CoV-2. Nearly 13.3% of patients experienced symptoms that lasted over 28 days, and these individuals were generally more likely to be female, older, and tended to exhibit a greater number of symptoms in the first week following acute SARS-CoV-2 infection (16). Recently, another large multicenter cohort study of nearly 2,000 patients from four hospitals in Madrid, Spain corroborated these observations (10). Finally, while COVID-19 in children is usually associated with mild symptoms, a large prospective cohort study by public health officials in the UK found that some children may also experience prolonged symptoms (17). Ultimately, more studies are needed to determine if certain populations are disproportionately affected by long COVID.
Vaccination and long COVID:
It is largely unclear whether vaccination can improve this condition, or whether breakthrough infections in fully vaccinated individuals could also lead to long COVID. In a preliminary study from the UK, 57% of people with long COVID reported an improvement in symptoms, 24% reported no changes and nearly 19% reported deterioration in their condition after one dose of vaccine (5). Another study, published in Lancet Infectious Diseases, evaluated the disease profile of breakthrough infections in people from the UK and found that the odds of lingering COVID-19 symptoms for 28 days or more were reduced by ~50% in people who had received two vaccine doses (6). Likewise, a recent pre-print from Israel, therefore not peer-reviewed, evaluated the incidence of post-COVID-19 symptoms (such as fatigue, headache, weakness, and muscle pain) post-vaccination in a cohort of 951 infected and 2,437 uninfected individuals. Generally, vaccination with at least two doses was associated with a substantial decrease in most of these symptoms (7). Collectively, early evidence suggests that vaccination may have a protective effect against developing long COVID, however, more studies, specifically considering mix and match schedules (as administered in Canada), are needed.
The serious impact of long COVID on various facets of an individual’s health (18), and the overall global health and economic burden, ensures that research on Long COVID and potential therapeutics will continue to remain a key priority for the foreseeable future. As such, health and research organizations worldwide are rapidly mobilizing efforts to understand and address long COVID. For instance, the National Health Services (NHS) in the UK has invested over £10M towards building a network of 69 post-COVID-19 specialty clinics. Likewise, the UK’s National Institute for Health Research (NIHR) and UK Research and Innovation (UKRI) have invested ~£25M to better understand long-term effects of COVID-19 on the physical and mental health of patients, and another ~£20M to focus on research related to non-hospitalized adults and children with long COVID. One study (HEAL-COVID) is testing therapeutic options by examining the efficacy of two drugs (an anticoagulant to reduce risk of blood clots and an anti-inflammatory drug to control inflammation) in patients discharged from the hospital. Meanwhile in the USA, the National Institutes of Health has dedicated $1.15B USD to create the “Post-Acute Sequelae of SARS-CoV-2 Infection Initiative” (NIH PASC), focused on understanding the biological basis of long COVID and factors contributing to vulnerability (14).
In Canada, the overall incidence of long COVID remains largely unknown. An early prospective cohort study from Vancouver (November 2020), reported that over 75% of hospitalized patients had abnormal outcomes three months after symptom onset, with one-third reporting at least a moderate level of impairment in quality of life (19). The Canadian Institutes of Health Research (CIHR) and the COVID-19 Immunity Task Force (CITF) have recently funded 41 studies (20) that are currently underway to evaluate the broader impact of long COVID on Canadians. This includes the Canadian COVID-19 Prospective Cohort Study (CanCOV), which follows 2,000 (1,000 non-hospitalized and 1,000 hospitalized) patients who have had SARS-CoV-2 infection and 500 family caregivers from across Canada (Quebec, Ontario, Alberta, and British Columbia) for up to one year. CanCOV is examining a wide range of factors related to long COVID (genomics, epigenomics, antibody testing and immune analyses) (22). The list of studies funded by the CITF investigating potential mechanisms and therapies of Long COVID have been published on their website (23).
The Public Health Agency of Canada (PHAC) recently released a statement acknowledging the impact of long COVID and current initiatives to support affected individuals (21). Providing patients with adequate support has been repeatedly listed as a top priority by research, health, and patient organizations. While there are some clinics established across Canada providing dedicated care to long COVID patients, more multidisciplinary care facilities are needed to meet the increasing demand. Overall, efforts to better understand this condition within a Canadian context are critical, so that patients can receive the care and support they deserve.
- Carson, G., Long Covid Forum Group. Research priorities for Long Covid: refined through an international multi-stakeholder forum. BMC Med 19, 84 (2021). https://doi.org/10.1186/s12916-021-01947-0
- Selina Rajan et al., In the wake of the pandemic: Preparing for Long COVID. WHO, ISSN: 19978073
- Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, Group WC. A clinical case definition of post-COVID-19 condition by a Delphi consensus. The Lancet Infectious Diseases. 2021 Dec 21.
- Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, Cook JR, Nordvig AS, Shalev D, Sehrawat TS, Ahluwalia N. Post-acute COVID-19 syndrome. Nature medicine. 2021 Apr;27(4):601-15.
- Strain WD, Sherwood O, Banerjee A, van der Togt V, Hishmeh L, Rossman J. The impact of COVID vaccination on symptoms of Long COVID. An international survey of people with lived experience of long COVID.
- Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E, Berry S, Canas LS, Graham MS, Klaser K, Modat M, Murray B. 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. The Lancet Infectious Diseases. 2022 Jan 1;22(1):43-55.
- Kuodi P, Gorelik Y, Zayyad H, Wertheim O, Wiegler KB, Jabal KA, Dror A, Nazzal S, Glikman D, Edelstein M. Association between vaccination status and reported incidence of post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients infected between March 2020 and November 2021. medRxiv. 2022 Jan 1.
- García-Abellán J, Padilla S, Fernández-González M, García JA, Agulló V, Andreo M, Ruiz S, Galiana A, Gutiérrez F, Masiá M. Antibody response to SARS-CoV-2 is associated with long-term clinical outcome in patients with COVID-19: a longitudinal study. Journal of clinical immunology. 2021 Oct;41(7):1490-501.
- Gaebler C, Wang Z, Lorenzi JC, Muecksch F, Finkin S, Tokuyama M, Cho A, Jankovic M, Schaefer-Babajew D, Oliveira TY, Cipolla M. Evolution of antibody immunity to SARS-CoV-2. Nature. 2021 Mar;591(7851):639-44.
- Fernández-de-Las-Peñas C, Pellicer-Valero OJ, Navarro-Pardo E, Palacios-Ceña D, Florencio LL, Guijarro C, Martín-Guerrero JD. Symptoms Experienced at the Acute Phase of SARS-CoV-2 Infection as Risk Factor of Long-term Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study. International Journal of Infectious Diseases. 2022 Jan 10.
- Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, Redfield S, Austin JP, Akrami A. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. Available at SSRN 3820561. 2021 Apr 6.
- Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515).
- Zuo Y, Estes SK, Ali RA, Gandhi AA, Yalavarthi S, Shi H, Sule G, Gockman K, Madison JA, Zuo M, Yadav V. Prothrombotic autoantibodies in serum from hospitalized patients with COVID-19. Science translational medicine. 2020 Nov 18;12(570).
- Marshall M. The four most urgent questions about long COVID. Nature. 2021 Jun 1;594(7862):168-70.
- Alwan NA. The road to addressing Long Covid. Science. 2021 Jul 30;373(6554):491-3.
- Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, Pujol JC, Klaser K, Antonelli M, Canas LS, Molteni E. Attributes and predictors of long COVID. Nature medicine. 2021 Apr;27(4):626-31.
- Molteni E, Sudre CH, Canas LS, Bhopal SS, Hughes RC, Antonelli M, Murray B, Kläser K, Kerfoot E, Chen L, Deng J. Illness duration and symptom profile in symptomatic UK school-aged children tested for SARS-CoV-2. The Lancet Child & Adolescent Health. 2021 Oct 1;5(10):708-18.
- Selina Rajan et al., In the wake of the pandemic: Preparing for Long COVID. WHO, ISSN: 19978073
- Wong AW, Shah AS, Johnston JC, Carlsten C, Ryerson CJ. Patient-reported outcome measures after COVID-19: a prospective cohort study. European Respiratory Journal. 2020 Nov 1;56(5).
- CIHR Funding Decisions Database. Op Grant Emerging COVID-19 Research Gaps Priorities – Post COVID-19 condition.
- PHAC. Statement from the Chief Public Health Officer of Canada on July 7, 2021.
- CANCOV: Research program pillars: link here
- CITF: List of funded research on Long COVID: here