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Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos (URJC), Avenida de Atenas s/n, Madrid, Alcorcón 28922 Spain
Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos (URJC), Avenida de Atenas s/n, Madrid, Alcorcón 28922 Spain
Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos (URJC), Avenida de Atenas s/n, Madrid, Alcorcón 28922 Spain
Department of Neurology, Hospital Clínico San Carlos, Madrid, SpainDepartment of Medicine, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
Department of Radiology, Rehabilitation and Physiotherapy, Universidad Complutense de Madrid, Madrid, SpainInstituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain
This meta-analysis quantitively analysed data from 29 peer-reviewed studies and 4 preprints.
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The results showed that 63.2, 71.9 and 45.9% of the sample exhibited ≥one post-COVID symptoms 30, 60, or ≥90days after onset or hospitalization.
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Fatigue and dyspnea were the most prevalent symptoms (pooled prevalence from 35% to 60%) depending on the follow-up period.
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The prevalence of each post-COVID symptom in isolation dropped off 30days after (10–15%) but increased at 60days or longer after (40–60%) onset.
Abstract
Background
Single studies support the presence of several post-COVID-19 symptoms; however, no meta-analysis differentiating hospitalized and non-hospitalized patients has been published to date. This meta-analysis analyses the prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized patients recovered from COVID-19
. Methods
MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were searched up to March 15, 2021. Peer-reviewed studies or preprints reporting data on post-COVID-19 symptoms collected by personal, telephonic or electronic interview were included. Methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. We used a random-effects models for meta-analytical pooled prevalence of each post-COVID-19 symptom, and I² statistics for heterogeneity. Data synthesis was categorized at 30, 60, and ≥90 days after
. Results
From 15,577 studies identified, 29 peer-reviewed studies and 4 preprints met inclusion criteria. The sample included 15,244 hospitalized and 9011 non-hospitalized patients. The methodological quality of most studies was fair. The results showed that 63.2, 71.9 and 45.9% of the sample exhibited ≥one post-COVID-19 symptom at 30, 60, or ≥90days after onset/hospitalization. Fatigue and dyspnea were the most prevalent symptoms with a pooled prevalence ranging from 35 to 60% depending on the follow-up. Other post-COVID-19 symptoms included cough (20–25%), anosmia (10–20%), ageusia (15–20%) or joint pain (15–20%). Time trend analysis revealed a decreased prevalence 30days after with an increase after 60days
. Conclusion
This meta-analysis shows that post-COVID-19 symptoms are present in more than 60% of patients infected by SARS-CoV‑2. Fatigue and dyspnea were the most prevalent post-COVID-19 symptoms, particularly 60 and ≥90 days after.
The world is suffering a dramatic situation of catastrophic proportions due to the rapid worldwide spread of the coronavirus disease 2019 (COVID-19) caused by the pathogen acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [
]. Symptoms associated with SARS-CoV-2 infection are heterogeneous and affect different systems such as respiratory (cough, sore throat, rhinorrhea, dyspnea), musculoskeletal (myalgias), gastrointestinal (diarrhoea, vomiting), and neurological (headaches, myopathy, ageusia, anosmia) [
Understandably, most literature has concentrated on the potential pathophysiology of the disease and on the management of acute cases at hospitalization periods. However, a second pandemic has emerged: post-COVID-19 sequalae and “long-haulers” [
]. Since millions of people will survive to SARS-CoV-2 infection; the number of individuals suffering COVID-19 sequelae, i.e., long hauler, will dramatically increase with time [
]. Therefore, identification of the COVID-19 aftermaths will be crucial for healthcare professionals.
Current evidence suggests the presence of a plethora of symptoms in subjects recovered from COVID-19. However, literature investigating the symptoms after SARS-CoV-2 infection is on its infancy in comparison with the literature available on the acute COVID-19 phase. Different terms are currently used for describing the presence of post-COVID-19 symptoms (e.g., post-COVID-19 syndrome, persistent post-COVID), being “long COVID” probably the most expanded term [
]. “Long COVID” is used to describe illness in people who have recovered from COVID-19 but still exhibit symptoms for far longer than would be expected [
]. In the last months, an increasing number of studies assessing the presence of post-COVID-19 symptoms have been published. In fact, a meta-analysis has been recently published as a preprint [
]. This meta-analysis found that 80% of COVID-19 survivors exhibited at least one post-COVID-19 symptom, being fatigue (58%), headache (44%), attention disorders (27%), hair loss (25%), and dyspnea (24%) the most frequent [
]. However, this review pooled prevalence rates without considering follow-up periods after symptoms and did not differentiate between hospitalized and non-hospitalized patients [
This study presents a systematic review and meta-analysis pooling prevalence data of post-COVID-19 symptoms differentiating between hospitalized and non-hospitalized COVID-19 survivors and analysing the prevalence of post-COVID-19 symptoms at different timepoints. The research questions of this systematic review and meta-analysis were: what is the prevalence of post-COVID-19 symptoms in individuals recovered from SARS-CoV-2 infection?, is there any difference in post-COVID-19 between hospitalized and non-hospitalized patients? and, what is the time-course of post-COVID-19 symptoms in the next months following SARS-CoV-2 infection?
2. Methods
This systematic review and meta-analysis adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement as appropriate [
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
]. It was also prospectively registered in the Open Science Framework Registry database with the following link https://doi.org/10.17605/OSF.IO/ESWQZ.
2.1 Systematic literature search
Electronic literature searches were conducted on MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as on preprint servers medRxiv and bioRxiv, for studies published to March 20, 2021. We also screened the reference list of the identified papers. Database search strategies were conducted with the assistance of an experienced health science librarian. Searches were limited to human studies by using the following terms: “long COVID syndrome”, “long COVID symptoms”, “long haul COVID”, “long hauler COVID”, “chronic COVID syndrome”, “chronic COVID symptoms”, “post-acute COVID syndrome”, “post-acute COVID symptoms”, “persistent COVID syndrome”, “post-COVID”, “COVID sequalae” OR “persistent COVID symptoms”. The inclusion/exclusion criteria were formulated by using the Population, Intervention, Comparison, Outcome (PICO) questions:
Population: Adults (>18 years), positively diagnosed of SARS-CoV-2 infection with real-time reverse transcription-polymerase chain reaction (PCR) assay of nasopharyngeal/oral swab samples, during the first wave of the pandemic (from January 1 to June 30, 2020). We included both hospitalized and non-hospitalized patients.
Intervention: Not applicable
Comparison: Not applicable
Outcomes: Monitorization or collection of the presence of multiple symptoms in COVID-19 survivors after SARS-CoV-2 infection, i.e., hospital discharge or symptoms onset, by either personal, telephonic, or electronical interview. Studies monitoring just changes in immunological, serological or radiological outcomes without assessment of post-COVID −19 symptoms were excluded.
2.2 Screening process, study selection and data extraction
This review/meta-analysis considered original research including observational cohort or case-control studies where samples of COVID-19 survivors, either hospitalized or non-hospitalized, were followed for the presence of symptoms for more than two weeks after infection. Based on pre-existing data and timeframes [
], we selected 30, 60, and ≥90 days after symptoms onset as pre-endpoints selected for the analysis. Editorials, opinion, and correspondence articles were excluded.
Two authors reviewed the title and abstract of publications identified in the databases. First, the duplicates were removed. Second, title and abstract of the articles were screened for potential eligibility and posterior full-read text. Data including authors, country, sample size, clinical data, settings (hospitalization/no hospitalization), symptoms at onset, and post-COVID-19 symptoms at different follow-up periods were extracted from each study. Both authors had to achieve a consensus on data-extraction. Discrepancies between the reviewers at any stage of the screening process were resolved by asking a third author, if necessary.
2.3 Methodological quality
The methodological quality of the studies was independently assessed by two authors using the Newcastle-Ottawa Scale, a star rating system that evaluates the risk of bias of case-control and cohort studies [
Wells G.A., Tugwell P., O'Connell D., Welch V., Peterson J., Shea B., et al. The newcastle-ottawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses 2015.
]. This scale, when applied to cohort studies, includes the following sections: case selection, comparability, and exposure. Case selection includes representativeness of cohort, selection of non-exposed cohort, ascertainment of exposure (case definition), and outcome of interest no present at start. Comparability evaluates the analysis of comparison (e.g., controlled for age, gender, or other factors) between groups (exposed and non-exposed). Exposure includes outcome assessment, long enough follow-up period, and adequate follow-up. In longitudinal cohort studies or case-control studies, a maximum of 9 stars can be awarded. In cross-sectional cohort studies, a maximum of 3 stars can be awarded. Studies scoring 3 are considered of good quality, those scoring 2 are of fair quality and studies scoring 1 are of poor quality [
Wells G.A., Tugwell P., O'Connell D., Welch V., Peterson J., Shea B., et al. The newcastle-ottawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses 2015.
]. Methodological quality of the included studies was determined by two authors and the differences, if existed, were discussed. In the case of disagreement, a third researcher arbitrated a consensus decision.
2.4 Data synthesis and analysis
The meta-analysis was conducted with the R software 4.0.0 using meta and dmetar packages. Percentages and frequencies of each symptom at onset/hospitalization and each symptom were extracted from studies and an overall proportion was calculated reporting a single proportion using the metaprop function. We used a random-effects model because potential heterogeneity was expected. An I2 value ≥75% was considered to indicate serious heterogeneity. We were not able to assess funnel plot asymmetry due to an insufficient number of studies investigating the same post-COVID-19 symptom at a particular follow-up. We calculated sample size-weighted mean scores for each study reporting data alongside 95% confidence intervals (95%CI) in addition to any potential meta-analytical summary effect on the pooled prevalence data for each post-COVID-19 symptom. Data synthesis was categorized by time after onset/hospitalization into three follow-up periods (symptoms at 30 days, 60 days, and ≥90 days). To determine the time-course of post-COVID-19 symptoms over time (from onset to ≥90 days after), Freeman-Tukey double arcsine transformation was conducted using the escalc function in the metafor package. The rma.mv (meta-analytic multilevel random effect model with moderators via linear mixed-effect models) was used to carry out a multilevel metanalysis with three levels to identify time and time *subgroup effect. For meta-analyses of studies reporting outcomes at multiple time points, it may be reasonable to assume that the true effects are correlated over time according to an autoregressive structure; therefore, a heteroscedastic autoregressive (HAR) model was adopted. Grouping by gender was not possible due to lack of data (see discussion section).
For quantitative data (age, days at hospital), overall means and standard deviations (SD) were calculated using the pool.groups function from the dmetar package. Median and interquartile range (IQR) were converted to mean and SD as described by Luo et al. [
]. When necessary, data were estimated from graphs with the GetData Graph Digitizer v.2.26.0.20 software.
2.5 Role of the funding source
There was no funding source for this study.
2.6 Patient and public involvement
Patients were not involved in the study since this was a meta-analysis of the literature.
3. Results
3.1 Study selection
The selection process is shown in Fig. 1. The electronic search identified 15,577 potential titles. After removing duplicates and papers not directly related to post-COVID-19 symptoms, 64 studies remained. Twenty-six (n = 26) were excluded after title/abstract examination. One preprint was excluded because it analysed risk factors and clusters but not detailed specific post-COVID-19 symptoms [
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Risk factors for long-term consequences of COVID-19 in hospitalised adults in moscow using the isaric global follow-up protocol: stopcovid cohort study.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Risk factors for long-term consequences of COVID-19 in hospitalised adults in moscow using the isaric global follow-up protocol: stopcovid cohort study.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
] were included in the systematic review and meta-analysis.
3.2 Sample characteristics
The characteristics of the COVID-19 populations of the included studies are shown in Table 1. The total sample comprised 24,255 COVID-19 survivors (52.26% female; mean ± SD age: 47.8 ± 16.6 years); 15,244 were hospitalized (42.7% female; age: 48.6 ± 17.4) whereas 9011 (70.2% female; age: 44.3 ± 14.8) were non-hospitalized patients. The mean length of hospital stay due to SARS-CoV-2 infection was 12.5 days (SD 6.8). From those hospitalized, 402 patients (8%) required ICU admission (mean stay: 15 ± 14.6 days).
Table 1Characteristics of the included studies investigating post-COVID-19 symptoms.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Risk factors for long-term consequences of COVID-19 in hospitalised adults in moscow using the isaric global follow-up protocol: stopcovid cohort study.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Almost 50% of the total sample exhibited at least one pre-existing comorbidity (one: 26.3%, 95%CI 25.3–28.0%; two: 17.6%, 95%CI 15.1–20.5%; ≥ three: 25.6%, 95%CI 11.4 −47.8%) with hypertension (22.9%, 95%CI 16.2–31.5%) and obesity (22.2%, 95%CI 13.9 −33.5%) being the most prevalent. Pre-existing comorbidities were, in general, more prevalent in hospitalized patients than in non-hospitalized patients. Table 2 summarizes the pooled prevalence of demographic and clinical data of COVID-19 survivors separated by hospitalization. Hospitalization data were collected from medical records in all studies.
Table 2Pooled means of demographic and clinical data differentiated by hospitalized (n=15,244) and non-hospitalized (n=9,011) COVID-19 patients.
Thirty studies (88%) were cross-sectional, just one was of good quality (3/3 stars), 28 were considered of fair quality (2/3 stars), and two of poor quality (1/3 stars). One was a longitudinal cohort study with high methodological quality (8/9 stars), and two were case-control studies of poor quality (5/9 stars, with 0 stars in the comparability domain). No disagreement between authors was observed. Table 3 presents the Newcastle-Ottawa Scale scores for each study and a summary of every item.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Risk factors for long-term consequences of COVID-19 in hospitalised adults in moscow using the isaric global follow-up protocol: stopcovid cohort study.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
3.4 Symptoms at onset or hospital admission experienced by COVID-19 patients
Supplementary Table summarizes which study assessed each COVID-19 onset symptom and each post-COVID-19 symptom. Sixteen studies (48.5%) collected the post-COVID-19 data by telephonic interviews, whereas ten studies (30%) collected data face-to-face interviews.
Pooled data of symptoms at onset and post-COVID-19 symptoms experienced by the total sample, including both hospitalized and non-hospitalized COVID-19 patients, are shown in Table 4. In the total sample, the most common symptoms experienced at SARS-CoV-2 infection were fatigue (63.4%), cough (60.2%), fever (55.3%), ageusia (46.0%), anosmia (45.7%) and dyspnea (44.1%). Among hospitalized patients, the most common onset symptoms at hospital admission included cough (65.2%), fever (59.45%), fatigue (48.0%), dyspnea (50.9%), anosmia (34.3%) and ageusia (34.0%). In non-hospitalized patients, the most common onset symptoms were fatigue (71.89%), myalgia (59%), cough (56%), fever (52.5%), anosmia (51.9%), and ageusia (51.8%). Most pooled data showed high level of heterogeneity (I2≥75%).
Table 4Pooled prevalence of symptoms at onset, and Post-COVID-19 Symptoms 30, 60, and ≥90 days after Onset/Hospitalization.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- united states.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.
Peluso M.J., Kelly J.D., Lu S. et al. Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19. medRxiv. 2021 Mar 12;2021.03.11.21252311.