ORIGINAL RESEARCH
Microbes, Infection and Chemotherapy ISSN: 2789 - 4274 https://doi.org/10.54034/mic.e1981
Rate of post Covid-19 symptoms: a systematic review and meta-analysis
Nesma Nabil Ahmed Elgohary1,a, Mohamed Nazmy Farres2, Diaa Marzouk Abdelhamid1, Salwa Mostafa Mohamed3, Mohamed Farouk Allam1,b
1Department of Family Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
2Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Corresponding author: E-mail:farouk.allam@med.asu.edu.eg
Orcid ID: ahttps:/orcid.org/0009-0004-5080-4151, bhttps:/orcid.org/0000-0001-5954-8909
Submitted: october 12, 2023
Reviewed: february 25, 2024
Approved: may 04, 2024
Abstract
Background. Covid-19 pandemic has led to global pandemic and substantial health, economic and social impact. The causative agent is coronavirus-2 (SARS-CoV-2) which belongs to the coronavirus family. The clinical picture of the infection ranges from a flu-like symptoms to severe pneumonia and mortality. Till January 2022, the cumulative number of cases exceeded 600 million worldwide with mortality rate of more than 6 million. Objective: to identify rate of total and individual presentations of post COVID-19 conditions. Methodology: the literature was reviewed till 1st July 2022, in six databases, we identified 5486 articles; after removal of duplicates and screening for eligible studies according to inclusion criteria, 17 studies were included for further qualitative and quantitative analysis. Results: the results showed high rate of post COVID-19 condition among patients. With prevalence rate of 5 to 10%, fatigue was the most reported symptom with prevalence of 34% among patients (RE: 0.33%, 95%CI: 0.32-0.35). The second highest common symptom was breathlessness with prevalence of 31% (RE: 0.31, 95%CI: 0.20-0.43). Mental health symptoms including anxiety and depression were also distinctly frequent. We also reported on different neurocognitive symptoms including attention and memory problems with rate of 16% (RE: 0.16, 95%CI: 0.11-0.22) and 19% (RE: 0.19, 95%CI: 0.14-0.26) respectively. Conclusion: it is apparent that a significant percentage of individuals with COVID-19 (45%) continue to grapple with a variety of persistent symptoms. Among these, fatigue and dyspnea emerge as highly prevalent issues consistently reported across various groups of patients. However, it is evident that a considerable portion of patients also contend with a diverse array of other lingering symptoms, displaying variability both in number and severity.
Keyword: Sars-CoV-2, Covid-19, post Covid-19, prevalence, dyspnea, fatigue, mental health.
Introduction
In 2019, a novel coronavirus was identified in Wuhan, China to cause a severe type of pneumonia namely severe acute respiratory distress syndrome coronavirus 2 (SARS-COV-2) (1). The swift spread of SARS-COV-2 led to an international public health emergency causing unprecedented rates of both morbidity and mortality (2). In addition to the emerging data of extrapulmonary manifestations of COVID-19 that included pro-thrombotic states, myocardial, gastro-intestinal, hepatic, endocrinologic, renal and dermatological manifestations (3). These extrapulmonary manifestations could be caused by extrapulmonary dissemination and replication of the virus as described in other coronaviruses or due to an outcome of an immunological reaction to the infection (4).
Describing themselves as “long-haulers”, the number of recovering patients was increasing and there were evolving reports of varying persistent multi-organ symptoms after the acute phase of the disease. Post COVID-19 condition occurs as a spectrum of symptoms that present four or more weeks after acute infection with SARS-CoV-2. Most published data to date state 50-70% of hospitalized patients experienced at least one post-acute COVID-19 symptom up to 3 months after discharge. Commonly reported symptoms include; neurocognitive post COVID-19 (fatigue, dizziness, inattention and brain fog), respiratory post COVID-19 (dyspnea, chest pain and cough), mental health related symptoms (insomnia, depression, post-traumatic stress disorder). Additionally, gastro-intestinal post COVID-19 (diarrhea, vomiting, abdominal pain) along with decline in quality of life and decreased ability to perform activities of daily living (ADL) were reported (5). Among non-hospitalized patients, similar symptoms presenting up to two to six months were documented with fatigue and dyspnea being most reported (6).
Till date, the specific cause of post COVID-19 symptoms has not been established. However, multiple reports of similar symptoms were released following prior coronavirus pandemics such as SARS in 2003 and MERS in 2012 (7). It has been proposed the spike subunit of these viruses engage with ACE2 (angiotensin-converting enzyme) as an entry receptor that is present in different body tissues (8). Other mechanisms may involve; host inflammatory and immune response to the acute infection (9). Patient-related causes; age, gender, pre-existing comorbidities and illness-related causes; severity of illness, hospitalization and its duration are factors that seem to influence the spectrum of symptoms and duration to resolution of post-acute COVID-19 symptoms. Early data show a longer recovery period for older patients, patients who required hospitalization and those who suffered from medical complications such as secondary bacterial infection and thromboembolic events (10).
However, the response to post COVID-19 symptoms is still in its infancy despite being an emerging crisis as scientific evidence and robust data are nonetheless required for clear definition, identification of time frame, classification and management of the condition (11). The aim of the current systematic review/meta-analysis was to identify total and individual incidence/prevalence rates of different clinical presentations of post COVID-19 symptoms.
Materials and methods
Criteria for considering studies for this review
Types of studies: the review was restricted to observational cohort and cross-sectional studies which investigated the frequency of post COVID conditions.
Types of participants: participants were adult patients with the definitive diagnosis of COVID-19. Patients were considered to have a definite diagnosis of COVID-19 if they were laboratory-confirmed using reverse transcription polymerase chain reaction (RT-PCR) and/or high-resolution CT chest with CO-RADS 4 or 5.
Types of outcome measures
At least one of the following outcomes was considered: Post COVID fatigue. Post COVID memory problems. Post COVID inattention. Post COVID chest pain. Post COVID dyspnea. Post COVID cough. Post COVID anosmia. Post COVID GIT symptoms; diarrhea and vomiting. Post COVID mental health symptoms; anxiety, depression post-traumatic stress disorder (PTSD) and insomnia. Post COVID decline in quality of life.
Inclusion Criteria: Cohort studies. Cross-sectional studies. Studies conducted on adult human subjects. Studies conducted on patients diagnosed with COVID-19 confirmed with positive reverse transcription polymerase chain reaction (RT-PCR) and/or high-resolution CT chest with CO-RADS 4 or 5. Studies published in Arabic, English, French or Spanish languages.
Exclusion Criteria: Review and opinion studies. Studies conducted during acute phase of COVID-19 infection. Studies conducted on animals.
Search strategy for identification of studies
Literature search was conducted electronic databases; PubMed, MEDLINE and Web of Science databases, as well as on preprint servers medRxiv and bioRxiv, for studies published to July 1st, 2022. References in the identified papers were also screened. Searches were limited to human studies by using the following terms: “long COVID-19 syndrome”, “long COVID-19 symptoms”, “persistent COVID symptoms”, “long hauler COVID-19”, “chronic COVID-19 syndrome”, “chronic COVID-19 symptoms”, “post-acute COVID-19 syndrome”,“post-COVID-19 condition”, and “COVID-19 sequelae”. The study was limited to articles published in English, French, German, Italian, Spanish and Arabic languages.
Methods of the review
Locating and selecting studies: Abstracts of articles identified using the search strategy were viewed and articles that appeared to fulfill the inclusion criteria were retrieved in full. Data on at least one of the outcome measures was included in the study. Each article identified was reviewed and categorized into one of the following groups: Included: Cross-sectional or Cohort studies that met the described inclusion criteria and those where it was impossible to tell from the abstract, title or MESH headings. Exclusion criteria comprised studies with follow up period less than 4 weeks or studies with patients having important comorbidities such as cancer, diabetes, neurodegenerative problems, and pregnant women.
When there was a doubt, A second reviewer (MFA) assessed the article, and a consensus was reached. The literature was reviewed till July 1st, 2022, and yielded 318 articles after ranking the articles according to authors and year of publication. Articles fulfilling the inclusion criteria were included (17 articles) for further steps of data collection, analysis, and reporting. Of the studies that met our inclusion criteria 16 were in English language and only one study in Spanish. There were no available studies published in Arabic, German, Italian or French languages.
Data extraction: the title and abstract of publications identified in the databases were reviewed. 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, symptoms at onset, and post-COVID 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 when necessary.
Statistical considerations: data were abstracted from every study in the form of a risk estimate and its 95% confidence interval. Pooled estimates of frequencies were obtained by weighing each study by the inverse variance of the effect measure on a logarithmic scale. This approach to pool the results assumed that the study populations being compared were similar and hence corresponded to a fixed effect analysis. The validity of pooling the frequencies was tested (test of homogeneity) using chi square test. A violation of this test suggested that the studies being pooled differed from one another. In case of noticeable heterogeneity of the effect measure among the compared studies, we performed a random effect analysis based on the method described by DerSimonian and Laird. The random effect analysis accounted for the interstudy variation. Because the test of homogeneity had low power, we reported the figures of the random effect analysis even with the absence of significant heterogeneity. All statistical analyses for pooling the studies were performed on the MetaXL Software.
Ethical Considerations: systematic reviews and Meta-analysis are exempted from Ethical Committees Approvals.
Results
In six databases, we identified 5486 articles; 4329 duplicates were removed. Out of the remaining 1158 abstracts, we excluded 1112 after screening. Thus, 46 full-text studies were assessed for eligibility and 28 were excluded. Finally, 17 studies were included for further qualitative and quantitative analysis.
Figure 1 PRISMA flow diagram showing selection of studies. PRISMA; Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Characteristics of included studies
Out of the 17 included studies, 6 studies were cross-sectional, while the other remaining 11 studies were prospective cohort.
Four studies were conducted in Italy (12,13,14,15), 3 studies in the United Kingdom (16,17), 2 studies were conducted in China (18,19), two studies in United States of America (20,21). The studies included patients in various healthcare settings including community care and hospitalized patients.
Table 1. List of included studies
| Cross-sectional Study | ||
|---|---|---|
| 1 | Italy | Carfì et al., 2020 |
| 2 | United Kingdom | Mandal et al., 2020 |
| 3 | Ireland | Townsend et al., 2020 |
| 4 | France | Garrigues et al., 2020 |
| 5 | Italy | Janiri et al., 2021 |
| 6 | Spain | Taboada et al., 2021 |
| Prospective cohort Study | ||
| 1 | United Kingdom | Arnold et al., 2020 |
| 2 | China | Xiong et al., 2020 |
| 3 | USA | Jacobs et al., 2020 |
| 4 | United Kingdom | Halpin et al., 2020 |
| 5 | USA | Jacobson et al., 2021 |
| 6 | Netherlands | Morin et al., 2021 |
| 7 | USA | Huang et al., 2021 |
| 8 | USA | Kayaaslan et al., 2021 |
| 9 | Turkey | Nehme et al., 2021 |
| 10 | Italy | Colizzi et al., 2022 |
| 11 | Italy | Comelli et al., 2022 |
Table 2 Characteristics of included studies evaluating frequency of post COVID-19 symptoms, by countries
| Author | Year | Type of study | Country | Number of participants |
|---|---|---|---|---|
| Carfìet al. | 2020 | Cross-sectional | Italy | 143 |
| Janiriet al. | 2021 | Cross Sectional study | Italy | 381 |
| Colizzi et al. | 2022 | Cohort study | Italy | 479 |
| Comelli et al. | 2022 | Cohort study | Italy | 456 |
| Halpin et al. | 2020 | Cohort study | United Kingdom | 100 |
| Arnold et al. | 2020 | Cohort study | United Kingdom | 110 |
| Mandal et al. | 2020 | Cross-sectional | United Kingdom | 384 |
| Xiong et al. | 2020 | Cohort study | China | 538 |
| Huang et al. | 2021 | Cohort study | China | 1655 |
| Jacobs et al. | 2020 | Cohort Study | USA | 149 |
| Jacobson et al. | 2021 | Cohort Study | USA | 118 |
| Garrigues et al. | 2020 | Cross sectional Study | France | 120 |
| Townsend et al. | 2020 | Cross-sectional study | Ireland | 128 |
| Taboada et al. | 2021 | Cross sectional | Spain | 183 |
| Nehme et al. | 2021 | Cohort Study | Switzerland | 669 |
| Kayaaslan et al. | 2021 | Cohort study | Turkey | 1007 |
| Morin et el. | 2021 | Cohort study | Netherlands | 431 |
Table 3 Studies showing frequency of fatigue among patients with post COVID-19
| No. | Author | Year | Type of study | Frequency | 95%CI | |
|---|---|---|---|---|---|---|
| Lower limit | Upper limit | |||||
| 1 | Arnold et al. | 2020 | Cohort study | 43/110 (39%) | 30 | 48 |
| 2 | Carfì et al. | 2020 | Cross-sectional | 76/143 (53.1%) | 45 | 61 |
| 3 | Garrigues et al. | 2020 | Cross sectional | 66/120 (55%) | 46 | 64 |
| 4 | Halpin et al. | 2020 | Cohort study | 64/100 (64%) | 49 | 72 |
| 5 | Jacobs et al. | 2020 | Cohort study | 82/149 (55%) | 47 | 63 |
| 6 | Mandal et al. | 2020 | Cross-sectional | 265/384 (69%) | 64 | 74 |
| 7 | Townsend et al. | 2020 | Cross-sectional | 67/128 (52.3%) | 44 | 61 |
| 8 | Xiong et al. | 2020 | Cohort study | 152/538 (28.3%) | 24 | 32 |
| 9 | Kayaaslan et al. | 2021 | Cohort study | 244/1007 (24.3%) | 22 | 27 |
| 10 | Jacobson et al. | 2021 | Cohort study | 36/118 (30.8%) | 22 | 39 |
| 11 | Morin et al. | 2021 | Cohort study | 134/431 (31%) | 27 | 35 |
| 12 | Nehme et al. | 2021 | Cohort study | 60/669 (9%) | 7 | 11 |
| 13 | Comelli et al. | 2022 | Cohort study | 230/456 (54.6%) | 46 | 55 |
| Total | 1519/4353 (34%) | 32 | 35 | |||
Figure 2 Forest plot for the frequency of fatigue amongst post COVID-19 patients
Pooling of all included studies showed fatigue frequency of almost 34% amongst post covid-19 patients. (RE: 0.33%, 95%CI: 0.32 – 0.35)
Table 4 Studies showing frequency of memory problems among patients with post COVID-19 conditions
| No | Author | Year | Type of study | Frequency | 95% CI | |
|---|---|---|---|---|---|---|
| Lower limit | Upper limit | |||||
| 1 | Garrigues et al. | 2020 | Cross-sectional | 41/120 (34.2%) | 26 | 43 |
| 2 | Del Brutto et al. | 2021 | Cohort | 12/93 (12.9%) | 6 | 20 |
| 3 | Jacobson et al. | 2021 | Cohort | 20/118 (17.1%) | 10 | 24 |
| 4 | Morin et al. | 2021 | Cohort | 73/416 (17.5%) | 14 | 21 |
| 5 | Sarah Weihe et al. | 2022 | Cohort | 27/ 105 (26%) | 17 | 34 |
| Total | 162/842 (19%) | 14 | 26 | |||
Pooling of all included studies showed memory frequency of almost 19% amongst post COVID-19 patients. (RE: 0.19, 95%CI: 0.14 – 0.26).
Figure 3 Forest plot for the frequency of memory problems amongst post COVID-19 patients
Table 5 Studies showing frequency of inattention among patients with post COVID-19 conditions
| No | Authors | Year | type of study | Risk Estimate | 95% CI | |
|---|---|---|---|---|---|---|
| Lower Limit | Upper Limit | |||||
| 1 | Garrigues et al. | 2020 | Cross-sectional | 32/120 (26.7%) | 19 - 35 | |
| 2 | Kayaaslan et al. | 2021 | Prospective | 163/1007 (16.2%) | 14 -18 | |
| 3 | Morin et al. | 2021 | Cohort | 41/412 (10%) | jul-13 | |
| 4 | Heesakkers et al. | 2022 | Cohort | 39/241 (16.2%) | dic-21 | |
| Total | 275/1780 (15%) | nov-22 | ||||
Pooling of all included studies showed inattention of 16% amongst post COVID-19 patients. (RE: 0.16, 95% CI: 0.11 – 0.22)
Figure 4 Forest plot for the frequency of inattention amongst post COVID-19 patients
Table 6 Studies showing frequency of dyspnea among patients with post COVID-19 conditions
| No | Authors | Year | Type of study | Frequency | 95% CI | |
|---|---|---|---|---|---|---|
| Lower limit | Upper limit | |||||
| 1 | Arnold et al. | 2020 | Cohort | 42.9/110 (39%) | 30 | 48 |
| 2 | Carfì et al. | 2020 | Cohort | 62/143 (43.4%) | 35-51 | 51 |
| 3 | Garrigues et al. | 2020 | Cross-sectional | 50/120 (41.7) | 33 | 50 |
| 4 | Halpin et al. | 2020 | Cohort | 50/100 (50%) | 40 | 60 |
| 5 | Jacobs et al. | 2020 | Cohort | 58/128 (45.3%) | 37 | 54 |
| 6 | Mandal et al. | 2020 | Cohort | 203/384 (53%) | 48 | 58 |
| 7 | Schneider et al. | 2020 | Cohort | 10/130 (7.7%) | 3 | 12 |
| 8 | Xiong et al. | 2020 | Case/control | 115/538 (21.4%) | 18-25 | 25 |
| 9 | Kayaaslan et al. | 2021 | Cohort | 207/1007 (20.5%) | 18 | 23 |
| 10 | Jacobson et al. | 2021 | Cohort | 31/118 (26.5%) | 19 | 35 |
| 11 | Morin et al. | 2021 | Cohort | 78/478 (16.3%) | 13-20 | 20 |
| 12 | Nehme et al. | 2021 | Cohort | 40/669 (6%) | 4 | 8 |
| 13 | Comelli et al. | 2022 | Cohort | 324/456 (71.7%) | 67-75 | 75 |
| 14 | Heesakkers et al. | 2022 | Cohort | 51/245 (20.8%) | 16 | 26 |
| Total | 1322/4626 | 20 | 43 | |||
Pooling of all included studies showed dyspnea frequency of 31% amongst post covid-19 patients. (RE: 0.31, 95%CI: 0.20 – 0.43)
Figure 5 Forest plot for the frequency of dyspnea amongst post COVID-19 patients
Table 7 Studies showing frequency of chest pain among patients with post COVID-19 conditions
| No. | Year | Year | Type of study | Risk Estimate | 95% CI | |
|---|---|---|---|---|---|---|
| Lower limit | Upper limit | |||||
| 1 | Arnold et al. | 2020 | Cohort | 18/110 (16%) | 9 | 23 |
| 2 | Carfì et al. | 2020 | Cross-sectional | 32/143 (22%) | 16 | 29 |
| 3 | Garrigues et al. | 2020 | Cross-sectional | 13/120 (10.8%) | 5 | 16 |
| 4 | Schneider et al. | 2020 | Cohort | 17/130 (13.1%) | 7 | 19 |
| 5 | Xiong et al. | 2020 | Cohort | 66/538 (12.3%) | 9 | 15 |
| 6 | Kayaaslan et al. | 2021 | Cohort | 58/1007 (5.8%) | 4 | 7 |
| 7 | Jacobson et al. | 2021 | Cohort | 16/118 (13.7%) | 7 | 20 |
| 8 | Morin et al. | 2021 | Cohort | 34/418 (8.1%) | 6 | 11 |
| Total | 254/2584 | 9 | 16 | |||
Pooling of all included studies showed chest pain frequency of 9% among post COVID-19 patients. (RE: 0.121, 95%CI: 0.085 – 0.162)
Figure 6 Forest plot for the frequency of chest pain among post covid-19 patients
Pooling of all included studies showed chest pain frequency of 12% among post covid-19 patients. (RE: 0.121, 95%CI: 0.085 – 0.162)
Table 8 Studies showing frequency of cough among patients with post COVID-19 conditions
| No. | Authors | Year | Type of study | Frequency | 95% CI | |
|---|---|---|---|---|---|---|
| Lower Limit | Upper Limit | |||||
| 1 | Carfì et al. | 2020 | Cohort | 24/143 (17%) | 11 | 23 |
| 2 | Garrigues et al. | 2020 | Cohort | 20/120 (16.7%) | 10 | 23 |
| 3 | Jacobs et al. | 2020 | Cohort | 46/110 (41.8%) | 33 | 51 |
| 4 | Mandal et al. | 2020 | Cross-sectional | 130/384 (34%) | 29 | 39 |
| 5 | Xiong et al. | 2020 | Case-control | 38/538 (7%) | 5 | 9 |
| 6 | Kayaaslan et al. | 2021 | Cohort | 45/1007 (4.5%) | 3 | 6 |
| 7 | Jacobson et al. | 2021 | Cohort | 10/118 (8.5%) | 3 | 18 |
| 8 | Morin et al. | 2021 | Cohort study | 21/420 (8.1%) | 3 | 7 |
| 9 | Nehme et al. | 2021 | Cohort | 19/583 (3%) | 2 | 5 |
| Total | 353/3423 (13%) | 6 | 23 | |||
Figure 7 Forest plot for the frequency of cough among post covid-19 patients
Pooling of all included studies showed cough frequency of 13% among post covid-19 patients. (RE: 0.13, 95%CI: 0.06 – 0.22)
Table 9 Studies showing frequency of GIT symptoms among patients with post COVID-19 conditions
| No. | Authors | Year | Type of study | Frequency | 95% CI | |
|---|---|---|---|---|---|---|
| Lower Limit | Upper Limit | |||||
| 1 | Carfì et al. (diarrhea) | 2020 | Cohort | 5% (7/143) | 0,01 | 0,08 |
| 2 | Jacobs et al. | 2020 | Cohort | 10.9% (20/183) | 0,06 | 0,15 |
| 3 | Jacobson et al. | 2021 | Cohort | 8/118 (6.8%) | 0,02 | 0,11 |
| 4 | Comelli et al. (altered bowel habits and bloating) | 2022 | Cohort | 149/456 (32.8%) | 0,28 | 0,37 |
| 5 | Heesakkers (bowel Problems) | 2022 | Cohort | 9/ 245 (3.7%) | 0,01 | 0,06 |
| Total | 193/1145 (9%) | 1 | 23 | |||
Figure 8 Forest plot for the frequency of GIT symptoms among post covid-19 patients
Pooling of all included studies showed GIT symptoms frequency of 9% among post COVID-19 patients. (RE: 0.09, 95%CI: 0.01 – 0.2)
Table 10 Studies showing frequency of anosmia among patients with post COVID-19 conditions
| Study No | Authors | Year | Type of study | Frequency | 95% CI | |
|---|---|---|---|---|---|---|
| Lower Limit | Upper Limit | |||||
| 1 | Arnold et al. | 2020 | Cohort | 42.9/110 (39%) | 30 | 48 |
| 2 | Carfì et al. | 2020 | Cohort | 62/143 (43.4%) | 35-51 | 51 |
| 3 | Garrigues et al. | 2020 | Cross-sectional | 50/120 (41.7) | 33 | 50 |
| 4 | Halpin et al. | 2020 | Cohort | 50/100 (50%) | 40 | 60 |
| 5 | Jacobs et al. | 2020 | Cohort | 58/128 (45.3%) | 37 | 54 |
| 6 | Mandal et al. | 2020 | Cohort | 203/384 (53%) | 48 | 58 |
| 7 | Schneider et al. | 2020 | Cohort | 10/130 (7.7%) | 3 | 12 |
| 8 | Xiong et al. | 2020 | Case/control | 115/538 (21.4%) | 18-25 | 25 |
| 9 | Kayaaslan et al. | 2021 | Cohort | 207/1007 (20.5%) | 18 | 23 |
| 10 | Jacobson et al. | 2021 | Cohort | 31/118 (26.5%) | 19 | 35 |
| 11 | Morin et al. | 2021 | Cohort | 78/478 (16.3%) | 13-20 | 20 |
| 12 | Nehme et al. | 2021 | Cohort | 40/669 (6%) | 4 | 8 |
| 13 | Comelli et al. | 2022 | Cohort | 324/456 (71.7%) | 67-75 | 75 |
| 14 | Heesakkers et al. | 2022 | Cohort | 51/245 (20.8%) | 16 | 26 |
| Total | 1322/4626 | 20 | 43 | |||
Pooling of all included studies showed anosmia frequency of 12% among post covid-19 patients. (RE: 0.12, 95%CI: 0.09 – 0.17)
Figure 9 Forest plot for the frequency of anosmia among post COVID-19 patients
Table 11 Studies showing frequency of mental health symptoms among patients with post COVID-19 conditions
| Study No | Authors | Year | Type of study | Frequency | 95% CI | |
|---|---|---|---|---|---|---|
| Lower Limit | Upper Limit | |||||
| 1 | Arnold et al. | 2020 | Cohort | 32/110 (29%) | 21 | 38 |
| 2 | Garrigues et al. (Sleep disorder) |
2020 | Cross-sectional | 37/120% (30.8%) | 22 | 39 |
| 3 | Halpin et al. | 2020 | Cohort | 31/100 (31%) | 22 | 40 |
| 4 | Mandal et al. | 2020 | Cohort | 56/384 (14.6%) | 11 | 18 |
| 5 | Xiong et al. | 2020 | Cohort | 275/538 (51.1%) | 46 | 55 |
| 6 | Heesakkers et al. | 2021 | Cohort | 64/244 (26.2%) | 20 | 32 |
| 7 | Huang et al. | 2021 | Cohort | 437/1655 (26%) | 24 | 29 |
| 8 | Kayaaslan et al. | 2021 | Cohort | 122/1007 (12.11%) | 10 | 14 |
| 9 | Janiri et al. | 2021 | Cross-sectional | 212/381 (55.6%) | 50 | 60 |
| 10 | Colizzi et al. | 2022 | Cohort | 49/479 (10.2%) | 7 | 13 |
| Total | 1315/5018 (26%) | 18 | 38 | |||
Pooling of all included studies showed mental health symptoms frequency of 27% among post COVID-19 patients. (RE: 0.27, 95% CI: 0.18 – 0.38)
Figure 10 Forest plot for the frequency of mental health symptoms among post COVID-19 patients
Table 12 Studies investigating decline of quality of life among patients with post COVID-19 conditions
| Study No | Authors | Year | Type of study | Tool Used | Measured Outcome | |
|---|---|---|---|---|---|---|
| 1 | Garrigues et al. | 2020 | Cross-sectional | EQ-5D-5L | Mean EQ-VAS: 70.3% | |
| Mean EQ-5D index: 0.86 | ||||||
| 2 | Huang et al. | 2021 | Cohort | EQ-5D-5L | 176/1655 (10%) | |
| 3 | Jacobson et al. | 2021 | Cohort | 6-min-walk-distance in meters | Mean distance: 416.4 (84.8) | |
| 4 | 2021 | Cross-sectional | PCFS scale | Frequency of decreased functional status: | ||
| Taboada et al. | 87/183 (47.5%) | |||||
Due to different QoL assessment tools and various outcomes among the included studies, pooling of results could not be obtained.
Discussion
In this systematic review, the progression of clinical symptoms reported by patients after a period of 30 days post–acute infection phase and beyond was examined. The current review involved 7051 COVID-19 survivors out of the 17 included studies and suggests that rates of post COVID-19 symptoms are common; 45% of survivors of COVID-19 develop at least one unresolved or relapsing symptoms within a follow up duration ranging 4 weeks to 12 months following the viral infection.
These results highlight the increasing possibility of pathological sequelae after exposure to the SARS-CoV-2 virus. Ten studies collected information from patients using self-reported surveys. Four studies collected data from medical records and three studies obtained data by clinical evaluation. Six out of the 17 studies included only hospitalized patients for COVID-19. The remaining studies had mixed samples with mild, moderate and severe COVID-19 patients.
Fatigue, dyspnea and psychiatric symptoms; anxiety and disturbed sleep, were highly prevalent symptoms. These findings correspond with other systematic reviews (22,23,24) that report post COVID-19 condition as a multifaceted, complex condition with a range of symptoms affecting multiple systems. It was noted that 2 of the most common symptoms; fatigue and dyspnea are consistent with the symptoms included in the WHO's definition of post COVID-19 condition (25).
Different study designs, population, varying follow-up duration and assessment tools led to an evident heterogeneity between studies. This could be explained by the low number of published studies, the lack of standardized data collection tools and scarce systematic strategies on assessment, diagnosis and patient follow up beyond their acute COVID-19 infection. In addition to a high degree of between-study heterogeneity in defining post COVID-19 condition which has been observed in this systematic review and hindered pooling the data in a formal meta-analytic model. Similarly, in a recent systematic review to emphasize their inability to perform meta-analysis beyond pooling of data due to the above mentioned reasons (22,26).
Regarding pooled results that evaluated frequency of post COVID-19 fatigue; thirteen studies evaluated the frequency of post COVID-19 fatigue. These studies were pooled and showed frequency of 34% among patients 30 days or more after acute phase (27) reported that fatigue could be present even after 100 days of the first symptom of acute COVID-19. This result corresponds to a recent systematic review and meta-analysis which found that fatigue is one of the three most common presenting symptoms in patients 3 months following the acute infection (28). The symptoms observed in post COVID-19 patients partially resemble the chronic fatigue syndrome (CFS). CFS includes the occurence of severe incapacitating fatigue, neurocognitive decline, pain, disturbed sleep, symptoms suggestive of autonomic dysfunction along with worsening global symptoms after minor increases in physical and/or cognitive activity. Myalgic encephalomyelitis (ME) or CFS is a complex clinical condition without established causes. Possible causes of CFS include viruses, immune dysfunction, endocrine-metabolic dysfunction, and neuropsychiatric factors (29). The reported infectious agents related to CFS are Epstein-Barr virus, enterovirus, cytomegalovirus, and herpesvirus. Symptoms must occur at least 50% of the time for a minimum of 6 months (30). Cognitive behavioral therapy (CBT) in association with gradual physical exercise can be an effective treatment in CFS. Pharmacological agents such as anti-depressants, steroids, and vitamin supplements have shown mixed results in small-scale clinical trials (31). Given that the symptoms of post COVID-19 bear a strong resemblance to CFS, CBT with gradual exercise should be explored in future studies as a possible treatment modality in post COVID-19 condition.
With regard to pooled studies evaluating frequency of post COVID-19 memory problems, 5 pooled studies assessed the prevalence of memory problems following acute phase infection (32,33,34,35,36) and demonstrated frequency of 19% of memory loss as a post COVID-19 condition. The etiology of neurological symptoms in COVID-19 patients is complex and multifactorial. Similarly, present reports of symptoms involving cognition and memory persist despite improvement in other clinical symptoms (11). One proposed theroy is neurotropism using a transsynaptic spread mechanism (37). These results in hemorrhagic and hypoxic driven neuronal apoptosis where widespread acute insult to subcortical, cortical and white matter fiber bundles may impact brain function and hinder brain connectivity, consecutively, resulting in symptoms such as those identified within our study.
Four pooled studies evaluated the frequency of post COVID-19 inattention (33,35,38,39) and showed prevalence of 15% of inattention among post COVID-19 patients. This is slightly lower than the results reported with frequency of 17% among post COVID-19 patients (23).
A reported trial of identifying biomarkers associated with post COVID-19 condition through plasma concentration of viral antigen and inflammatory markers (40). Their results revealed higher prevalence of viral antigen among post COVID-19 patients presenting with neuropsychiatric symptoms than those with other system symptoms.
Neuroinflammation has been proposed as an outcome of the viral spread into the brain tissue through nasal cavity or blood stream. The effect of persistent neuroinflammation during the onset of symptoms is reported as a cause of neurocognitive impairment: through either an auto-immune reaction or activation of microglia (41,42).
One study highlighted structural alterations of the brain in symptomatic patients who recovered from COVID-19, based on MRI findings (diffusion tensing imaging and 3 dimensional T1-weighted sequences and pseudo-continuous arterial spin labeling) (43). Structural modifications were reported in several brain regions, including hippocampus, insular lobe, and olfactory cortex. Grey matter volume in various brain regions like hippocampus and cingulate gyrus was found correlated with memory loss. Additionally, a decrease in cortical thickness, combined with modifications in white matter microstructure, along with a decrease in regional cerebral blood flow in frontal and limbic regions. In this line, It was identified that neuronal dysfunction markers were increased in patients who recovered from COVID-19, in comparison with healthy controls (44). In addition, two autopsy studies provided additional support in favor of the neuro-inflammation hypothesis, too.
As for pooled results that evaluated frequency of post COVID-19 dyspnea; fourteen pooled studies investigated frequency of post COVID-19 dyspnea and resulted in frequency of 20%. The occurrence of respiratory symptoms following SARS-CoV-2 infection is similar to that present in SARS survivors, which also exhibit symptoms 6–12 months after the infection. Radiological changes following acute infection are commonly reported, in one follow-up study conducted among non-critical hospitalized COVID-19 patients, imaging and radiographic changes remained in nearly two-thirds of patients ninety days after hospital discharge. Additionally, It was found that the estimate of abnormal lung function and radiological abnormality reached 53% in COVID-19 survivors (45). Nevertheless, the study did not report on clinical correlation of these radiological findings.
It was pointed out that dyspnea, in the absence of pulmonary lesion, could hypothetically be related to inappropriate ventilation regulation resulting from autonomous nervous system disorders (potential damages in the intrathoracic reflex receptors) (23).
In regard to pooled results that evaluated frequencies of post COVID-19 cough 9 pooled studies investigated frequency of cough and our results demonstrated lower prevalence than reported in another systematic review (23) as it showed higher rate of cough. Additionally in a recent systematic review (46) a prevalence of 6.5 was reported. The study provided information on the prevalence of burdensome cough following COVID-19, defined as a cough with a numerical rating scale of 4. It indicated that 710 patients who had recovered from COVID-19 pneumonia might experience burdensome cough two months after discharge. However, noticeable variability in results and estimated prevalence between studies remains high. The frequency of post-COVID-19 chest pain was assessed in eight studies, with a frequency rate of 12. Additionally, studies concerning autopsies reported rare instances of direct myocardial injury by SARS-CoV-2. Several syndromes, such as myocarditis, pericarditis, and postural orthostatic tachycardia syndrome (POTS), have been reported in post-COVID-19 (44,47). A study (48) revealed cardiovascular involvement on cardiac MRI and was observed in 78 of individuals after recovery from acute covid-19 infection however correlation to clinical symptoms was not reported additionally hospitalized patients with evident biomarkers of myocardial injury may have underlying coronary artery disease revealed by the physiological stress of acute COVID-19 infection and could benefit from medical optimization.
Mast Cell Activation Syndrome (MCAS) is a one of the proposed theories for post COVID-19 chest pain (49). MCAS is a multisystem, inflammatory disease caused by mast cell hyperactivity and release of inflammatory cytokines (50). Symptoms experienced in MCAS largely overlap with those seen in post COVID-19 condition, including chest pain and palpitations. Mast cells express surface proteins for pathogen recognition in addition to ACE2 which causes them to be susceptible to a direct attack from SARS-CoV-2. However, this potential mechanism remains theoretical since to date experimental studies linking MCAS and post COVID-19 condition are lacking.
Five pooled studies examined frequency of post COVID-19 gastro-intestinal symptoms. We observed neither enumeration nor specification of GIT symptoms among the included studies. Additionally, no classified symptoms among other meta-analyses (51,52).
COVID-19 has the potential to alter the gut microbiome, including enrichment of opportunistic infectious organisms and depletion of beneficial commensals (53).
Thus, it could attribute to persistence of GIT symptoms beyond the acute infection phase. The ability of the gut microbiota to alter the course of respiratory infections (gut–lung axis) has also been recognized previously in influenza and other respiratory infections (54).
The prevalence of post COVID-19 anosmia was evaluated in 7 studies. Higher frequency of loss of smell among non-hospitalized patients than hospitalized patients was reported (23,51). Similar finding was reported where follow up of patients after 30 and 60 days post-acute infection revealed higher incidence between non hospitalized patients after day 60 (51).
Before the emergence of SARS-CoV-2, 18 to 42% of patients with olfactory dysfunction were associated with a preceding viral upper respiratory infection (55).
It is currently unclear to what extent the etiology of post-COVID-19 anosmia is similar to or different from post-viral olfactory dysfunction (PVOD) associated with other viruses (56). However covid-19 is recognized to more frequently and distinctly induce olfactory dysfunction compared with other viral infections with incomplete recovery of smell. A report (57) on the role of neuroepithelial viral invasion and subsequent inflammation as possible mechanisms contributing to olfactory dysfunction similarly it was found through histological assessment a persistent inflammation within the olfactory neuroepithelium along with viral persistence (32).
prevalence of mental health symptoms was observed in our study in correspondence with results from other systematic reviews (22,23,51,52) these symptoms include depression anxiety and sleep difficulties (13) revealed higher frequency of anxiety and sleeping problems after twelve months of follow up anxiety and/or depression were reported by 8 studies. In one study (53) the lowest frequency of depression 43 despite an overall high frequency of symptoms however this study did not use a questionnaire or psychometric scale and queries were limited to individuals who were willing and able to describe their symptoms. Three studies (5,16,38) reported a combined prevalence of anxiety and depression of 211 216 and 230 respectively. A large-scale dataset analysis of 62354 covid-19 survivors from 54 health facilities in the United States evaluated the incidence of first and recurrent psychiatric illness between 14 and 90 days of diagnosis to be 181 (58). Additionally it reported the estimated overall probability of diagnosis of a new psychiatric illness within 90 days after covid-19 diagnosis to be 58 anxiety disorder 47 mood disorder 2 insomnia 19 four studies evaluated quality of life however they could not be pooled as different tools were used in two studies (5,33) used eq-5d-5l questionnaire nevertheless different outcomes were obtained which hindered us from pooling prevalence. Furthermore an additional tool for quality of life assessment (EuroQol) visual analogue scale was used (5).
A retrospective cohort study (36) reported frailty in 20 and 18 of the participants at 6 and 12 months respectively.
Conclusions
Post COVID-19 condition is a multisystem disease, with high prevalence both in short and long term. These long-term post COVID-19 conditions can overwhelm existing health care capacity, particularly in resource-constrained health systems. Hence, high prevalence and long-term health effects of post COVID-19 condition. It is apparent that a significant percentage of individuals with COVID-19 (45%) continue to grapple with a variety of persistent symptoms. Among these, fatigue and dyspnea emerge as highly prevalent issues consistently reported across various groups of patients. However, it is evident that a considerable portion of patients also contend with a diverse array of other lingering symptoms, displaying variability both in number and severity. Our findings indicate that effective clinical management of post-COVID-19 conditions will necessitate a comprehensive understanding of the patient's perspective.
Authors' contributions
Nesma Nabil Ahmed Elgohary: study design, analysis and interpretation of data, manuscript writing, collection of data, critical revision. Mohamed Nazmy Farres: analysis and interpretation of data, manuscript writing, collection of data, critical revision. Diaa Marzouk Abdelhamid: analysis and interpretation of data, collection of data, critical revision. Salwa Mostafa Mohamed: study design, manuscript writing, collection of data, critical revision. Mohamed Farouk Allam: study design, analysis and interpretation of data, manuscript writing, collection of data, critical revision.
Ethical considerations
Systematic reviews and Meta-analysis are exempted from Ethical Committees Approvals.
Funding
None.
Conflicts of interest
None.
Availability of data
Data supporting the results reported in the article can be found in the supplementary Excel File.
References
1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DS, Du B. Clinical characteristics of coronavirus disease 2019 in China. New England Journal of Medicine 2020;382(18):1708-20.
2. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. The Lancet Infectious Diseases 2020;20(5):533-4.
3. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, Bikdeli B, Ahluwalia N, Ausiello JC, Wan EY, Freedberg DE. Extrapulmonary manifestations of COVID-19. Nature Medicine 2020;26(7):1017-32.
4. Holmes KV. SARS coronavirus: a new challenge for prevention and therapy. The Journal of Clinical Investigation 2003;111(11):1605-9.
5. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, Kang L, Guo L, Liu M, Zhou X, Luo J, Huang Z, Tu S, Zhao Y, Chen L, Xu D, Li Y, Li C, Peng L, Li Y, Xie W, Cui D, Shang L, Fan G, Xu J, Wang G, Wang Y, Zhong J, Wang C, Wang J, Zhang D, Cao B. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2023 Jun 17;401(10393):e21-e33.
6. Del Brutto OH, Wu S, Mera RM, Costa AF, Recalde BY, Issa NP. Cognitive decline among individuals with history of mild symptomatic SARS‐CoV‐2 infection: A longitudinal prospective study nested to a population cohort. European Journal of Neurology 2021;28(10):3245-53.
7. Goërtz YM, Van Herck M, Delbressine JM, Vaes AW, Meys R, Machado FV, Houben-Wilke S, Burtin C, Posthuma R, Franssen FM, Van Loon N. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-COVID-19 syndrome?. ERJ Open Research 2020;6(4).
8. Hui DS, Joynt GM, Wong KT, Gomersall CD, Li TS, Antonio G, Ko FW, Chan MC, Chan DP, Tong MW, Rainer TH. Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors. Thorax 2005;60(5):401-9.
9. Wong TL, Weitzer DJ. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a systemic review and comparison of clinical presentation and symptomatology. Medicina 2021;57(5):418.
10. Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. New England Journal of Medicine 2014;370(17):1626-35.
11. Shanley JE, Valenciano AF, Timmons G, Miner AE, Kakarla V, Rempe T, Yang JH, Gooding A, Norman MA, Banks SJ, Ritter ML. Longitudinal evaluation of neurologic‐post acute sequelae SARS‐CoV‐2 infection symptoms. Annals of Clinical and Translational Neurology 2022;9(7):995-1010.
12. Carfì A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. JAMA 2020;324(6):603-5.
13. Colizzi M, Peghin M, De Martino M, Bontempo G, Gerussi V, Palese A, Isola M, Tascini C, Balestrieri M. Mental health symptoms one year after acute COVID-19 infection: Prevalence and risk factors. Revista de Psiquiatría y Salud Mental 2023;1;16:38-46.
14. Comelli A, Viero G, Bettini G, Nobili A, Tettamanti M, Galbussera AA, Muscatello A, Mantero M, Canetta C, Martinelli Boneschi F, Arighi A. Patient-reported symptoms and sequelae 12 months after COVID-19 in hospitalized adults: a multicenter long-term follow-up study. Frontiers in Medicine 2022;9:834354.
15. Janiri D, Carfì A, Kotzalidis GD, Bernabei R, Landi F, Sani G, COVID GA, Post-Acute Care Study Group. Posttraumatic stress disorder in patients after severe COVID-19 infection. JAMA Psychiatry 2021;78(5):567-9.
16. Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O, McLean L, Walshaw C, Kemp S, Corrado J, Singh R, Collins T. Postdischarge symptoms and rehabilitation needs in survivors of COVID‐19 infection: A cross‐sectional evaluation. Journal of Medical Virology 2021;93(2):1013-22.
17. Mandal S, Barnett J, Brill SE, Brown JS, Denneny EK, Hare SS, Heightman M, Hillman TE, Jacob J, Jarvis HC, Lipman MC. 'Long-COVID': a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax 2021;76(4):396-8.
18. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, Kang L, Guo L, Liu M, Zhou X, Luo J. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. The Lancet 2021;397(10270):220-32.
19. Xiong Q, Xu M, Li J, Liu Y, Zhang J, Xu Y, Dong W. Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study. Clinical Microbiology and Infection 2021;27(1):89-95.
20. Jacobs LG, Gourna Paleoudis E, Lesky-Di Bari D, Nyirenda T, Friedman T, Gupta A, Rasouli L, Zetkulic M, Balani B, Ogedegbe C, Bawa H. Persistence of symptoms and quality of life at 35 days after hospitalization for COVID-19 infection. PloS One 2020;15(12):e0243882.
21. Jacobson KB, Rao M, Bonilla H, Subramanian A, Hack I, Madrigal M, Singh U, Jagannathan P, Grant P. Patients with uncomplicated coronavirus disease 2019 (COVID-19) have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic. Clinical Infectious Diseases 2021;73(3):e826-9.
22. Groff D, Sun A, Ssentongo AE, Ba DM, Parsons N, Poudel GR, Lekoubou A, Oh JS, Ericson JE, Ssentongo P, Chinchilli VM. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review. JAMA Network Open 2021;4(10):e2128568.
23. Lopez-Leon S, Wegman-Ostrosky T, Ayuzo Del Valle NC, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, Villapol S. Long-COVID in children and adolescents: a systematic review and meta-analyses. Sci Rep 2022;12(1):9950.
24. O'Mahoney LL, Routen A, Gillies C, Ekezie W, Welford A, Zhang A, Karamchandani U, Simms-Williams N, Cassambai S, Ardavani A, Wilkinson TJ. The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis. EClinicalMedicine 2023;55.
25. Diaz JV, Herridge M, Bertagnolio S, Davis HE, Dua T, Kaushic C, Marshall JC, del Rosario Pérez M, Strub-Wourgaft N, Soriano JB. Towards a universal understanding of post COVID-19 condition. Bulletin of the World Health Organization 2021;99(12):901.
26. Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, Shchendrygina A, Escher F, Vasa-Nicotera M, Zeiher AM, Vehreschild M. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiology 2020;5(11):1265-73.
27. Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F, O'Connor L, Leavy D, O'Brien K, Dowds J, Sugrue JA. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PloS One 2020;15(11):e0240784
28. Hanson SW, Abbafati C, Aerts JG, Al-Aly Z, Ashbaugh C, Ballouz T, Blyuss O, Bobkova P, Bonsel G, Borzakova S, Buonsenso D. Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA 2022;328(16):1604-15.
29. Shaheen N, Shaheen A. Long-term sequelae of COVID-19 (myalgic encephalomyelitis): An international cross-sectional study. Medicine 2022;101(45):e31819.
30. Wong TL, Weitzer DJ. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a systemic review and comparison of clinical presentation and symptomatology. Medicina 2021;57(5):418.
31. Jason LA, Islam MF, Conroy K, Cotler J, Torres C, Johnson M, Mabie B. COVID-19 symptoms over time: comparing long-haulers to ME/CFS. Fatigue: Biomedicine, Health & Behavior 2021;9(2):59-68.
32. De Melo GD, Lazarini F, Levallois S, Hautefort C, Michel V, Larrous F, Verillaud B, Aparicio C, Wagner S, Gheusi G, Kergoat L. COVID-19–related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters. Science Translational Medicine 2021;13(596):eabf8396.
33. Garrigues E, Janvier P, Kherabi Y, Le Bot A, Hamon A, Gouze H, Doucet L, Berkani S, Oliosi E, Mallart E, Corre F. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. Journal of Infection 2020;81(6):e4-6.
34. Jacobs LG, Gourna Paleoudis E, Lesky-Di Bari D, Nyirenda T, Friedman T, Gupta A, Rasouli L, Zetkulic M, Balani B, Ogedegbe C, Bawa H. Persistence of symptoms and quality of life at 35 days after hospitalization for COVID-19 infection. PloS One 2020;15(12):e0243882.
35. Morin L, Savale L, Pham T, Colle R, Figueiredo S, Harrois A, Gasnier M, Lecoq AL, Meyrignac O, Noel N, Baudry E. Four-month clinical status of a cohort of patients after hospitalization for COVID-19. JAMA 2021;325(15):1525-34.
36. Weihe S, Mortensen CB, Haase N, Andersen LP, Mohr T, Siegel H, Ibsen M, Jørgensen VR, Buck DL, Pedersen HB, Pedersen HP. Long‐term cognitive and functional status in Danish ICU patients with COVID‐19. Acta Anaesthesiologica Scandinavica 2022;66(8):978-86.
37. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host–virus interaction, and proposed neurotropic mechanisms. ACS Chemical Neuroscience 2020;11(7):995-8.
38. Kayaaslan B, Eser F, Kalem AK, Kaya G, Kaplan B, Kacar D, Hasanoglu I, Coskun B, Guner R. Post‐COVID syndrome: A single‐center questionnaire study on 1007 participants recovered from COVID‐19. Journal of Medical Virology 2021;93(12):6566-74.
39. Morin L, Savale L, Pham T, Colle R, Figueiredo S, Harrois A, Gasnier M, Lecoq AL, Meyrignac O, Noel N, Baudry E. Four-month clinical status of a cohort of patients after hospitalization for COVID-19. JAMA 2021;325(15):1525-34.
40. Swank Z, Senussi Y, Manickas-Hill Z, Yu XG, Li JZ, Alter G, Walt DR. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clinical Infectious Diseases 2023;76(3):e487-90.
41. Boucas AP, Rheinheimer J, Lagopoulos J. Why severe COVID-19 patients are at greater risk of developing depression: a molecular perspective. The Neuroscientist 2022;28(1):11-9.
42. Dani M, Dirksen A, Taraborrelli P, Torocastro M, Panagopoulos D, Sutton R, Lim PB. Autonomic dysfunction in 'long COVID': rationale, physiology and management strategies. Clinical Medicine 2021;21(1):e63.
43. Lu Y, Li X, Geng D, Mei N, Wu PY, Huang CC, Jia T, Zhao Y, Wang D, Xiao A, Yin B. Cerebral micro-structural changes in COVID-19 patients–an MRI-based 3-month follow-up study. EClinicalMedicine 2020;25.
44. Sun B, Tang N, Peluso MJ, Iyer NS, Torres L, Donatelli JL, Munter SE, Nixon CC, Rutishauser RL, Rodriguez-Barraquer I, Greenhouse B. Characterization and biomarker analyses of post-COVID-19 complications and neurological manifestations. Cells 2021;10(2):386.
45. Huang Y, Tan C, Wu J, Chen M, Wang Z, Luo L, Zhou X, Liu X, Huang X, Yuan S, Chen C. Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase. Respiratory Research 2020;21:1-0.
46. O'Mahoney LL, Routen A, Gillies C, Ekezie W, Welford A, Zhang A, Karamchandani U, Simms-Williams N, Cassambai S, Ardavani A, Wilkinson TJ. The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis. EClinicalMedicine 2023;55.
47. D'Cruz RF, Waller MD, Perrin F, Periselneris J, Norton S, Smith LJ, Patrick T, Walder D, Heitmann A, Lee K, Madula R. Chest radiography is a poor predictor of respiratory symptoms and functional impairment in survivors of severe COVID-19 pneumonia. ERJ Open Research 2021;7(1).
48. Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, Shchendrygina A, Escher F, Vasa-Nicotera M, Zeiher AM, Vehreschild M. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiology 2020;5(11):1265-73.
49. Afrin LB, Weinstock LB, Molderings GJ. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. International Journal of Infectious Diseases 2020;100:327-32.
50. Frieri M. Mast cell activation syndrome. Clinical Reviews in Allergy & Immunology 2018;54:353-65.
51. Groff D, Sun A, Ssentongo AE, Ba DM, Parsons N, Poudel GR, Lekoubou A, Oh JS, Ericson JE, Ssentongo P, Chinchilli VM. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review. JAMA Network Open 2021;4(10):e2128568.
52. Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F, O'Connor L, Leavy D, O'Brien K, Dowds J, Sugrue JA. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PloS One 2020;15(11):e0240784
53. Zuo T, Zhang F, Lui GC, Yeoh YK, Li AY, Zhan H, Wan Y, Chung AC, Cheung CP, Chen N, Lai CK. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology 2020;159(3):944-55
54. Bradley KC, Finsterbusch K, Schnepf D, Crotta S, Llorian M, Davidson S, Fuchs SY, Staeheli P, Wack A. Microbiota-driven tonic interferon signals in lung stromal cells protect from influenza virus infection. Cell Reports 2019;28(1):245-56.
55. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367(6483):1260-3.
56. Xiong Q, Xu M, Li J, Liu Y, Zhang J, Xu Y, Dong W. Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study. Clinical Microbiology and Infection 2021;27(1):89-95.
57. Iadecola C, Anrather J, Kamel H. Effects of COVID-19 on the nervous system. Cell 2020;183(1):16-27.
58. Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. The Lancet Psychiatry 2021;8(5):416-27.
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