Coronavirus disease 2019 (COVID-19) is a highly contagious novel viral infection first identified in Wuhan, China in late 2019. As the outbreak developed into a pandemic, there was a global rush to generate rapid evidence to understand the natural history of the disease to help combat it. There is currently an abundance of literature on the early natural history of the disease whereas limited synthesis of evidence exists on the late sequelae of the disease. A rapid review of the literature was conducted to synthesize evidence on the late sequelae of COVID-19 to highlight the health burden experienced by a proportion of COVID-19 survivors and make recommendations for public health measures and/or further research. References were searched on PubMed and three COVID-19 literature hubs (Lit Covid, COVID-19 L-OVE, WHO COVID-19 database) that were anticipated to yield the broadest evidence. Screening of studies was performed on the Covidence Platform and were strictly included based on laboratory-confirmed COVID-19 cases, and reporting of negative RT-PCR and/or positive serology test results after initial diagnosis to be able to best distinguish between acute COVID-19 and post-acute COVID-19 sequelae. Information was extracted on study characteristics, population or patient characteristics, initial COVID-19 diagnosis, and post-acute COVID-19 presentation. This rapid review yielded a total of 20 eligible studies: 7 cross-sectional studies, 2 cohort studies, 1 case-control study, 2 case series. and 8 case reports. There was significant evidence of persistent post-acute clinical manifestations, and extrapulmonary and multisystem involvement been reported. A total of 49 persistent post-acute clinical manifestations and 10 new onset diagnoses post-acute COVID-19 were identified. Systemic/general, otolaryngological, cardiothoracic, gastrointestinal, hepatobiliary, renal, neurological, psychosocial, dermatological, radiological, and immune-mediated clinical manifestations have been described. Most authors of included studies discussed that post-acute illness of COVID-19 is likely immune-mediated, however, further research is needed. Post-acute COVID-19 has serious impact on people’s daily functioning. Evidence suggests that COVID-19 can cause persistent illness resulting in prolonged recovery. Numerous planned or ongoing studies are in place in many parts of the world that are investigating the long-term sequelae of COVID-19, however, there is inadequate organized responses from health systems globally.
Recommendations
Keywords
COVID-19, coronavirus disease 2019, SAR-CoV-2, severe acute respiratory syndrome coronavirus 2, post-COVID-19, post-COVID syndrome, long covid.
In December 2019, an outbreak of pneumonia cases of unknown origin was reported in Wuhan, China, which later developed into a pandemic in 2020 (World Health Organization [WHO], 2020a) (Esakandari et al, 2020). The pathogen responsible was found to be a novel coronavirus called the 'severe acute respiratory syndrome coronavirus 2' (SARS-CoV-2) (Esakandari et al, 2020). WHO named this novel disease 'coronavirus disease 2019' and abbreviated it as ‘COVID 19’ (Centers for Disease Control and Prevention, 2020). As of April 27, 2021, there have been nearly 146 million cases and 3 million deaths reported worldwide (WHO, 2021a). There is a global rush to generate rapid evidence to combat this highly contagious novel coronavirus. Scientists continue to learn more about the natural history of this disease every day since the outbreak in China.
This novel coronavirus usually affects the respiratory system and symptoms commonly noted to occur were fever, dry cough, and fatigue (WHO, 2020b). Less commonly, some patients experienced a loss of taste or smell, nasal congestion, conjunctivitis, sore throat, headache, muscle or joint pain, skin rashes, nausea or vomiting, chills or dizziness, and diarrhea (WHO, 2020b). Furthermore, several reports also describe extra-pulmonary effects of COVID-19 (Gupta et al, 2020) (Sarkesh et al, 2020). Patients with severe COVID-19, experienced shortness of breath, loss of appetite, confusion, persistent pain or pressure in the chest, and high fever above 38 °C. Early reports state that the presence of preexisting comorbidities was more common in patients with severe disease than in those with non-severe disease (Guan et al, 2020).
As the pandemic evolved throughout 2020, several reports describing a proportion of survivors who were experiencing long-term effects beyond the initial acute course of illness regardless of disease severity began to surface. Some emerging terminology used to describe this condition
include ‘post-COVID syndrome’, ‘post-acute COVID-19 syndrome’, ‘long COVID’, and ‘long haulers.' (Lopez-Leon et al, 2021) (Al-Jahdhami et al, 2021) (Higgins et al 2020) (Seyed Alinaghi et al, 2021). However, there is no clear international consensus yet on these terms (WHO, 2021b). Defining the phases of COVID-19 has been an evolving process but suggestions have been made based on the detection of SARS-CoV-2 with RT-PCR, onset of symptoms, and presence of persistent symptoms, or long-term complications. (Figure 1.)
Figure 1. Timeline of COVID-19. Adapted from Nalbandian et al (2021).
1.1 Rationale
Currently, there is an abundance of literature on the early natural history of the disease i.e., on clinical manifestations of acute COVID-19 (Huang, 2020) (Zhang, 2020) (Fu, 2020), whereas there is limited synthesis on the late sequelae of the disease – clinical manifestations of post-acute COVID-19. This rapid review was performed to synthesize evidence on post-acute COVID-19 clinical manifestations to highlight the health burden experienced by a proportion of COVID-19 survivors. This may provide evidence to guide public health measures as well as help identify gaps in research related to long-term effects of COVID-19.
1.2 Goals & Objectives
This rapid review was completed in six months between October 2020 and April 2021. The review was conducted in accordance with the PRISMA statement (Page, M. et al, 2021). The methodology used in this review was adapted with reference to the Rapid Review Guidebook by NCCMT (Dobbins, n.d.), and the Practical Guide for Rapid Reviews to Strengthen Health Policy and Systems by WHO (Tricco, Langlois, & Straus, n.d.).
2.1 Eligibility criteria
No restrictions were imposed on the design of primary studies, and whether an article was published and externally peer reviewed.
Inclusion criteria:
1. Examined laboratory confirmed COVID-19 cases.
2. Examined cases where recovery from acute phase is ascertained by reporting either negative RT-PCR test result for SARS-Cov-2 and/or positive serology test for IgG antibodies for SARS-Cov-2.
3. Describes persistent clinical manifestations in patients after the acute course of COVID 19 illness.
4. Describes new-onset clinical manifestations in patients after the acute course of COVID 19 illness.
5. Published in December 2019 and later (i.e., 12/01/2019 onwards).
Exclusion criteria:
6. Does not indicate recovery from acute phase by reporting either negative RT-PCR test result for SARS-Cov-2 and/or positive serology test for IgG antibodies for SARS-Cov-2.
7. Describes clinical manifestations during the acute course of COVID-19 illness.
8. Describes worsening of pre-existing comorbidities after COVID-19 diagnosis.
9. Review articles, editorials, and letters.
10. Did not publish in English language.
2.2 Information sources
Given the limited timeframe that was available for this rapid review, the search was restricted to four information sources that were anticipated to yield the broadest evidence – PubMed and three COVID-19 literature hubs (Lit Covid, COVID-19 L-OVE, WHO COVID-19 database).
2.3 Search strategy
Using relevant keywords, the search query below was used to search for studies on PubMed filtered for publication dates starting from 1st December 2019. The COVID-19 literature hubs were explored using the keywords from the same search query followed by using database specific filters to find studies.
(“COVID-19” OR “SARS-Cov-2”) AND ("persistent" OR "persisting" OR "persistent symptoms" OR "persisting symptoms" OR “chronic symptoms” OR "post-covid" OR "post-infection" OR “post-viral” OR "new-onset")
The initial search was only conducted on the COVID-19 literature hubs on October 27, 2020. A second search was conducted on PubMed on January 14, 2021.
2.4 Study selection
The Covidence Platform was used for conducting this rapid review. All retrieved records from the search strategy were imported on Covidence Platform, and on processing of the records, duplicates were removed. According to the eligibility criteria, screening of titles and abstracts were largely performed by the author, and around 14% were screened by a peer student.
Articles deemed potentially eligible were then retrieved for full-text assessment by the author.
2.5 Data collection process
A data extraction template was designed on the Covidence Platform for the purpose of initial data extraction by the author. Extracted data was then downloaded and curated onto a table for further extraction and analysis.
2.6 Data items
The following data was extracted by the author: study characteristics (first author’s names, country, study design, study setting, sample size), population or patient characteristics (age, gender, comorbidities, time of hospitalization), initial COVID-19 diagnosis (method of diagnosis , presentation, severity), and post-acute COVID-19 presentation (method of ascertainment of recovery from acute infection (negative RT-PCR and/or positive IgG antibody), persistent or new-onset clinical manifestations, diagnoses).
2.7 Study appraisal
Since this is a rapid review conducted during a limited timeframe largely by a single reviewer, risk of bias assessment of included studies was not performed.
Figure 2. PRISMA flow diagram – study selection.
The search retrieved 3311 publications, of which 1135 were duplicates. After excluding most publications at the title and abstract screening stage (n=2075), 101 records were selected for full-text assessment. Twenty studies met the eligibility criteria and were included for narrative synthesis. (Figure 2.) Eligible studies included 10 observational studies (7 cross-sectional studies, 2 cohort studies, 1 case-control study) and 2 case series. and 8 case reports. This review includes 4598 COVID-19 patients with post-acute illness, with only one case report reporting a death. (Dono et all, 2020)(Table 1.)
3.1 Observational studies
Four observational studies included in the review were published in 2020 and six observational studies were published in 2021. The largest included study (n=2581; 233 patients with post-acute illness) is a cross-sectional study with patients from 18 hospitals from various European countries. Other included studies were from China (n=2), Bangladesh (n=2), Pakistan (n=1), Egypt (n=1), Nigeria (n=1), Italy (n=1), and USA (n=1). 7 observational studies included hospitalized patients, except one retrospective study (Osikomaiya et al, 2021) and cross- sectional study (Iqbal et al, 2021) that included patients from an outpatient follow-up clinic, and based on records from a diagnostic laboratory, respectively. Included studies involved patient populations of both genders with a greater proportion comprising of young adults. Severity of acute COVID-19 ranged from mild to moderate to severe, with 44.7% (2057/4598) having comorbidities. The time between initial COVID-19 diagnosis and first negative swab result was only reported by Yan et al (2020) as 16.2 (IQR 9.0-22.3). Recovery from acute COVID-19 was ascertained by negative RT-PCR testing in all studies, except in one cross-sectional study (Lechien et al, 2021) where patients were included in the study based on positive serology IgG test. (Supplementary Material: Table 2.)
Figure 3. Persistent post-acute sequelae of COVID-19 identified in this rapid review.
3.1.1 Post-acute clinical manifestations reported in observational studies
Forty-six clinical manifestations post-SARS-CoV-2 were reported by included observational studies. (Figure 3.) Studies described 4577 COVID-19 survivors experiencing persistent post acute sequelae, with over 76% experiencing general/systemic clinical manifestations such as fever, fatigue, myalgia, joint pain, pain/discomfort/malaise, limited mobility, night sweats, weight loss, hair fall, skin rash, loss of appetite, and sleep difficulties. Persistent clinical manifestations with the highest prevalence included fatigue (30.9%), anxiety/depression (23.9%), sleep difficulties (23.7%), and pain/discomfort/malaise (21.9%). 52.6% and 26.8% of COVID-19 survivors experienced psychosocial and neurologic clinical manifestations, respectively. Less than 1% of patients were found with radiological evidence of persistent lung fibrotic changes and myocardial edema. One cross-sectional study (Kamal et al.) reported new-onset diabetes mellitus. (Supplementary Material: Table 3).
3.2 Case series and case reports
All included case series and case reports were published in 2020, except for one case report that was published in 2021. Included case reports were from Italy (n=3), USA (n=2), Qatar (n=1), Pakistan (n=1), and UK (n=1); case series were from India and China. All case series and case reports included 13 hospitalized patients (male=5; female=9), except for one case report of a female patient (Buselli et al, 2021) who was from an outpatient clinic. Ages of these patients ranged from 28-85 with some comorbidities. Not all studies reported the severity of illness. Studies that reported the time between initial COVID-19 diagnosis and first negative swab result were more than 14 days. Recovery from acute COVID-19 was ascertained by negative RT-PCR testing in all studies, except in one case series (Chandrashekara et al, 2020) where the patients had positive serology IgG tests. (Supplementary Material: Table 4).
3.2.1 Post-acute diagnoses reported in case series and case reports
Post-SARS-CoV-2 diagnoses were reported by all 8 case reports, and 1 case series. These included early interstitial lung disease, new-onset systemic lupus erythematosus, hyperinflammatory syndrome (multisystem inflammatory syndrome), polyarthritis, psychogenic dysphonia, autoimmune encephalitis presenting as new-onset refractory status epilepticus, recurring antibiotic resistant bacterial pneumonia, new-onset pustular psoriasis, and post COVID-19 associated orthostatic cerebral hypoperfusion syndrome and small fiber neuropathy. Additionally, Wang et al (2020) reported a case series of three COVID-19 patients with persistent gastrointestinal symptoms and persistently detectable SARS-CoV-2 in stool after resolution of respiratory illness and viral clearance in the throat. (Supplementary Material: Table 5.)
The author took a rapid review approach to gather evidence of post-acute sequelae of COVID 19. A total of 20 studies and 4598 COVID-19 patients experiencing post-acute illness were included in this review. (Table 1.) All included studies examined laboratory confirmed COVID-19 cases, and recovery from acute COVID-19 was ascertained by undetectable SARS-CoV-2 via RT-PCR and/or positive IgG serology for SARS-CoV-2.
This rapid review yielded the greatest evidence on persistent post-acute COVID-19 consequences (> 99% of the COVID-19 patients), including extrapulmonary and multisystem involvement. (Figure 2.) Included studies described systemic/general, otolaryngological, cardiothoracic, gastrointestinal, hepatobiliary, renal, neurological, psychosocial, dermatological, radiological, and immune-mediated clinical manifestations. (Supplementary Material: Tables 3 and 5). Most authors discussed that post-COVID-19 illness to be primarily immune-mediated, leading to extrapulmonary clinical manifestations, however, further investigation on long term consequences of COVID-19 is necessitated.
A major limitation in this rapid review is that every stage of the review was conducted by a single reviewer, except for a small proportion of title and abstract screening. A second limitation is that included studies were not evaluated for risk of bias. In addition, only 2.6% of the patients in this study were in the age group 0-19. Hence, this review did not yield significant evidence on post acute COVID-19 clinical manifestations among children and adolescents who are now also known to experience long-term consequences of the disease (Osmanov, 2021).
After several early reports of COVID-19 patients experiencing prolonged illness, some policy and other responses have been made by health organizations, health systems, health service providers, and patients globally. Some identified calls to action made thus far to address long term effects of COVID-19 have been reviewed below.
4.1 Patient and Public Responses
The Long Covid Support is a patient-led peer support and advocacy group that was created to support struggling COVID-19 survivors in the UK. At present, it is an International Facebook group (LongCovid, n.d.). Similarly, Long Covid Kids is a UK-based International parent and patient-led campaign and support group for parents and children affected with COVID-19 and its long-term consequences. They also promote participation in An Investigative Study in collaboration with PeopleWith, a smartphone app that helps monitor symptoms, diagnosis, medications, and other health related factors that influence one’s overall health. PeopleWith provides anonymized data to scientists, health, and government leaders to understand the progression of COVID-19 illness. (PeopleWith, n.d.). The Covid-19 Research Involvement Group is another UK-based Facebook group created as a platform for investigators to connect with patients for involvement, participation, and engagement in COVID-19 related research. Additionally, the UK arm of a queer feminist wellness collective, event series, and media company called Body Politic has set up a campaign called LongCovidSOS calling for recognition, research, and rehabilitation of COVID-19 survivors among the public and employers who are suffering from long-term effects of the infection (LongCovidSOS, n.d.).
4.2 Health Systems and Service Provider Responses
The National Institute for Health and Care Excellence together with the Scottish Intercollegiate Guidelines Network, and the RCGP Royal College of General Practitioners have produced guidelines for managing the long-term effects of COVID-19 to assist with post-COVID efforts by the English National Health Service (NHS). The post-COVID efforts set out by the NHS prior to the publication of these guidelines included setting up a care pathway for patients with long term effects of COVID-19. Once any serious underlying pathology is excluded by an initial assessment at primary or secondary care, a referral is made to one of three pathways for those who experienced persisting symptoms beyond 12 weeks: any of the 40 post-COVID assessment clinics launched by NHS, local rehabilitation clinics or the “Your COVID Recovery” NHS digital program. The NHS digital program provides patients with self-management advice on tackling daily activities, returning to work, and seeking help (WHO, 2021b).
The Royal Australian College of General Practitioners (RACGP) also has published guidelines (National COVID-19 Clinical Evidence Taskforce, 2021) for coordinated care of patients with post-acute COVID-19 infection with a person-centered care approach coordinated primarily by the general practitioner and primary health care nurse while other expertise in the care team when necessitated. In Italy, a multidisciplinary health care service called the Post-COVID 19 Day-Hospital has been developed by a tertiary care center in Rome. Similarly, in Czechia, a specialized Post-COVID Care Center has been setup by a local teaching hospital to take care of COVID-19 patients experiencing residual symptoms three months after their acute illness. In Belgium, programs have been developed specifically for intensive care unit patients for the management of post intensive care syndrome (PICS) that includes services from a multidisciplinary team either at home or at a specialized or geriatric hospital (WHO, 2021b).
4.3 National Surveillance Systems
To support the process of implementing a surveillance system, WHO has introduced three emergency use ICD codes to the list of ICD codes for COVID-19: “Personal history of COVID 19”, “Post COVID-19 condition”, and “Multisystem inflammatory syndrome associated with COVID-19” (WHO, n.d.).
4.4 Research
In February 2021, the National Institutes of Health (NIH) announced (Collins, 2021) the Post Acute Sequelae of SARS-CoV-2 Infection (PASC) Initiative after congress provided $1.15 billion in funding over four years to support research into long-term health consequences of COVID 19. In collaboration with a health science company called ZOE, a group of physicians and scientists at Massachusetts General Hospital, the Harvard T.H. Chan School of Public Health, King's College London, and Stanford University School of Medicine have created a smartphone based app called the COVID symptom tracker. This app provides data for the largest global study called the COVID Symptom Study and it is said that new work is underway from this study aiming to shed more light on long-term effects of COVID-19. In the UK, currently, there are several research studies already setup and running related to long-term effects of the disease, such as the Post-Hospitalization COVID-19 study and the prevalence study called UK_REACH (WHO, 2021b). Likewise, with the intent to explore ongoing symptoms in COVID-19 patients, the Spanish Society of General Practitioners have launched an online anonymous survey. Scientists in Italy are also investigating outcomes in hospitalized COVID-19 patients after their discharge. In a study in Czechia, researchers would be performing physical examinations twice over a year to investigate the resolution of lung function in COVID-19 patients, and additionally assess their immune functions. The COVIMMUNE study in France is also investigating immune responses in COVID-19 patients (WHO, 2021b).
Although case definitions related to post-infection are still not elaborate, there is significant evidence that COVID-19 can cause persistent illness resulting in prolonged recovery. Post acute COVID-19 has serious impact on people’s daily functioning leading to potentially significant economic consequences for themselves, their families, and society at large. There are numerous planned or ongoing studies in place in many parts of the world that are investigating the long-term sequelae of COVID-19. However, there is inadequate organized responses from health systems globally.
Following recommendations are some key first steps to take to address post-acute COVID-19.
Click here to open the supplementary material to view tables.
I would like to thank the CEO and Co-founder of BroadStreet, Tracy Flood M.D., Ph.D. for providing the opportunity for students in the U.S. and around the world to collaborate on The COVID-19 Data Project. I would like to recognize my advisor Katherine Mills, Ph.D. (Tulane University School of Public Health and Tropical Medicine) for reviewing the article. In the Research group, I would like to thank fellow intern McKenzie Yerkes for assisting with screening of titles and abstracts, and fellow interns/team leads Imani Kigamwa and Sara Nishijima for reviewing the article and providing feedback. Finally, I would also like to express my appreciation for the encouragement and feedback from Natacha Wathieu, M.D. (Tulane University School of Medicine; Brown University/Rhode Island Hospital).
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