Artigos

Conteúdo (article):

Fatores de risco para a Síndrome pós-COVID-19 em hospitalizados por Síndrome Respiratória Aguda Grave: revisão Sistemática e metanálise
Risk factors for Post-COVID Syndrome in patients hospitalized for severe acute respiratory syndrome: systematic review and meta-analysis
Factores de riesgo del síndrome post-COVID-19 en pacientes hospitalizados por síndrome respiratorio agudo severo: revisión sistemática y metanálisis

RESUMO

Introdução: Este estudo tem como objetivo identificar os fatores de risco associados ao desenvolvimento da síndrome pós-COVID-19 em egressos de internações por Síndrome Respiratória Aguda Grave. Metodologia: Foi realizada revisão sistemática de estudos observacionais publicados entre 2020 e 2023 em seis bases de dados. Os valores dos riscos relativos de cada fator investigado foram avaliados na metanálise através do modelo de efeitos aleatórios. Resultados: 1.010 publicações foram identificadas, sendo 45 estudos incluídos na análise qualitativa e sete estudos na metanálise. Estes estudos avaliaram a associação entre a síndrome pós-COVID-19 e fatores como a gravidade e o número de sintomas da doença na fase aguda, o sexo e comorbidades prévias. Os resultados apontaram que o sexo feminino (RR 1,52; IC 95% 1,26-1,85), a presença de hipertensão (RR 1,25; IC 95% 1,06-1,49) e um maior tempo de internação (RR 1,01; IC 95% 1.01-1,03) estavam associados ao desenvolvimento da síndrome. Conclusão: Egressos de internação por COVID-19 do sexo feminino, com maior tempo de internação e hipertensão deverão ser monitorados para identificar o desenvolvimento da síndrome pós-COVID-19, possibilitando intervenções em tempo oportuno.
Palavras-chave: Síndrome de COVID-19 Pós-Aguda; fatores de risco; hospitalização; pacientes internados; Síndrome Respiratória Aguda Grave.

ABSTRACT

Introduction: This study aims to identify the risk factors associated with the development of post-COVID-19 syndrome in patients discharged from hospitalizations due to severe acute respiratory syndrome. Methodology: A systematic review of observational studies published between 2020 and 2023 was carried out in six databases. The relative risk values of each investigated factor were evaluated in the meta-analysis using the random-effects model. Results: Our study identified 1,010 publications, with 45 studies included in the qualitative analysis and seven in the meta-analysis. These studies evaluated the association between post-COVID-19 syndrome and factors, such as the severity and number of symptoms of the disease in the acute phase, sex, and previous comorbidities. The results showed that the female gender (RR 1.52; 95% CI 1.26-1.85), the presence of hypertension (RR 1.25; 95% CI 1.06-1.49), and a longer hospital stay (RR 1.01; 95% CI 1.01-1.03) were associated with the development of the syndrome. Conclusion: Female patients discharged from hospital due to COVID-19, with longer hospital stays and hypertension should be monitored to identify the development of post-COVID-19 syndrome, thereby enabling timely interventions.
Keywords: Post-Acute COVID-19 Syndrome; risk factors; hospitalization; inpatients; severe acute respiratory syndrome

INTRODUCTION
COVID-19 infection was initially considered an acute pathology. However, by mid-2020, there were already reports of persistent symptoms in some individuals, which culminated in the creation of a new category in the international code of diseases to classify post-COVID-19 syndrome in September 2020.
Post-COVID-19 syndrome is defined by the World Health Organization (WHO) as the development of new symptoms for more than twelve weeks after the initial SARS-CoV-2 infection, with no other explanation. In 2021, the WHO estimated the prevalence of post-COVID-19 syndrome at 10% to 20%. However, in a systematic review of 57 studies involving 250,000 patients, more than half experienced post-acute sequelae six months after recovery. The most commonly reported symptoms were fever, fatigue, dyspnea, headache, cough, mental confusion, anxiety, depression, loss of smell and taste, joint pain, and arthralgia4. Another study that evaluated 1,007 participants found similar results5.
A meta-analysis of 20 studies and 13,340 patients reported that having a severe clinical condition during hospitalization increased the risk of post-COVID-19 syndrome6. However, there are still gaps in research into the risk factors for post-COVID-19 syndrome in hospitalized patients. Arnold et al.7 reported that 74% of the patients in their study presented at least one symptom three months after discharge, although lower prevalence rates have also been described7-9. Commonly reported risk factors were female gender, advanced age, and some medical comorbidities10.
Evidence suggests that individuals with this syndrome have higher mortality and healthcare use in the year following acute COVID-19 infection when compared to uninfected individuals11. This study aims to identify the risk factors associated with the development of post-COVID-19 syndrome in patients discharged from hospitalizations for Severe Acute Respiratory Syndrome (SARS).

METHODOLOGY
This review followed the PRISMA protocol and was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration CRD4202341351512. The research question was formulated in the PECO (population, exposure, comparison, and outcome) format, with the following final formulation: "What are the risk factors for the development of post-COVID-19 syndrome in patients discharged from a hospital for Severe Acute Respiratory Syndrome (SARS)?"
The review team received training on the review protocol and the process of article selection, data extraction, and synthesis, as well as on the use of the article’s quality assessment tool.
The criteria established for inclusion in the systematic review were longitudinal observational studies, such as cohorts and case-control studies, involving patients hospitalized for COVID-19 and followed up for at least 3 months. Articles published between January 1, 2020, and December 31, 2023, were analyzed. Clinical trials, editorials, systematic reviews, surveys, and commentaries were excluded.
Studies that evaluated exposure factors, such as sex, age, disease severity in the acute phase, nutritional status, medication exposure, comorbidities, smoking, alcoholism, obesity, sedentary lifestyle, presence of inflammatory changes, and genetic characteristics were included. The population that had not been exposed to the analyzed factors was considered a control group.
The search strategy combined MeSH (Medical Subject Headings) terms and keywords: "Post-Acute COVID-19 Syndrome" [MeSH] OR Long-COVID OR “Long Covid” OR “Post Covid syndrome” OR “Post Covid syndrome” OR “Long Covid-19” OR “Post-COVID conditions” OR “Covid Long”) AND ("Risk Factors" [MeSH] OR Risk Factors OR Predictor*) AND (Hospitalization OR Inpatients OR "Hospitalization" [MeSH] OR Hospitalized OR "Inpatients" [MeSH]).
Searches were conducted in Embase, PubMed, Cochrane Database of Systematic Reviews, LILACS, SciELO, and Web of Science databases in May 2023. No restrictions were placed on language or country of publication. No additional searches were performed in the references of the studies included in the review or in the gray literature.
The retrieved articles were imported into the Rayyan QCRI reference manager13. These references were distributed to two reviewers, SRS and RSNS, who independently evaluated the titles and abstracts. Discrepancies between the reviews were resolved by reviewer AMF. The articles selected at this stage were fully analyzed by two review teams: SRS and RSNS, and LULB and FMC.
SRS and RSNS systematized information on: article identification elements, year of publication, journal of publication, study design, statistical methods used, risk factors identified, number of participants, duration of observation and follow-up, outcome characterization, main results, and study funding sources. A narrative synthesis was then performed based on this information.
The reviewers analyzed the risk of bias using the National Heart, Lung, and Blood Institute\'s Study Quality Assessment tools14, developed for evaluating cohort and case-control studies. The studies were classified as good, fair, or poor quality. The evaluations were carried out independently by two pairs of reviewers and disagreements were resolved through discussions to reach a consensus.
The results of the analyses of the association between the evaluated factors and the development of post-COVID-19 syndrome were presented with Odds Ratio (OR) or Relative Risk (RR) values and their respective 95% confidence intervals (95% CI).
For the meta-analysis, studies with similar outcomes, follow-up time, study type, and populations were selected, thus ensuring homogeneity across the studies analyzed. Cohort studies of adult populations, with follow-up time ranging from three to seven months, of good or fair quality, and that considered post-COVID-19 syndrome as an outcome, were selected. Studies that considered only specific symptoms of the syndrome were excluded.
Despite the methodological similarities, the studies presented variations in the factors investigated. Therefore, the quantitative synthesis considered the analysis of each factor studied individually, including only the studies selected for the meta-analysis that evaluated the highlighted factor. Analyses were only performed when the factor studied was evaluated in at least four of the articles selected for the meta-analysis.
The meta-analysis was conducted in R 4.0.3 (2020-10-10) and RStudio 2024.12.1+563, using the metadat and metafor packages15. Heterogeneity was quantified by the heterogeneity index (I²), interpreted according to the criteria defined by Higgins et al.16 The heterogeneity index describes the percentage of the total variation between studies that is due to heterogeneity rather than chance. I² is calculated from the results using the formula: I² = 100% × (Q - df) / Q, where Q is the Cochran heterogeneity statistic and df is the degrees of freedom. An I² value equal to 0% indicates the absence of heterogeneity, and higher values indicate increasing heterogeneity15. The authors used the random effects methodology with a Restricted Maximum Likelihood (REML) estimator in all analyses. Metafor calculates the p-value by testing H0: combined effect = 0, using a z-test based on the effect estimate and its standard error. The p-value is calculated as follows: pj=2×P(∣Z∣>∣zj∣)≈2×(1−Φ(∣zj∣)) where Φ\PhiΦ is the Cumulative Distribution Function (CDF) of the standard normal15. The results were presented through forest plot graphs, generated by the metafor package.

RESULTS
A total of 1,010 publications were identified in the databases; 232 were duplicates (Figure 1). Screening the title and abstract of the remaining 778 publications resulted in the inclusion of 109 citations for full-article reading, with the exclusion of articles not relevant to the review, as described in Figure 1. After reviewing the complete articles, 64 articles were excluded (Figure 1). The 45 articles included consisted of 121,330 participants. After analysis, seven articles were selected for the meta-analysis (Figure 1). The following factors were evaluated as being associated with the development of a post-COVID-19 syndrome: female gender, length of hospital stay, intensive care unit (ICU) admission, and the presence of hypertension or diabetes as a comorbidity prior to SARS-CoV-2 infection. The heterogeneity index (I²) was 67.85% in the analysis of studies that considered the female sex (p = 0.0031), 30.60% in the evaluation of ICU admission as a predictor of the syndrome (p = 0.269), and 28.96% in the analysis regarding hypertension (p = 0.167), as can be seen in Figure 2. The I² index was 0.00% in the evaluation of the length of hospital stay (p = 0.751) and for the analysis of diabetes as a predisposing factor (p = 0.901), as can be seen in Figure 2. The results of the meta-analysis indicate the female sex (RR 1.52; 95% CI 1.26-1.85), the presence of hypertension (RR 1.25; 95% CI 1.06-1.49), and the longer length of hospital stay in the acute phase (RR 1.01; 95% CI 1.01-1.03) as risk factors, as can be seen in Figure 2.

Study Characteristics
The characteristics of the selected publications are described in Table 1. Cohort studies represented 93.33% of the publications. The review studies were conducted in twenty-one different countries, with 22.22% being developed in Spain.
Most studies (51.11%) had a mean follow-up time between 3 and 6 months (Table 1). As seen in Table 1, three studies analyzed risk factors only in children and adolescents under 18 years of age32,53,54. The largest available sample included 89,843 participants in a cohort of patients discharged from hospitals due to confirmed cases of COVID-19 in the United States.
The most common persistent symptoms were: fatigue, cough, dyspnea, yearsmia, musculoskeletal pain, ageusia, diarrhea, anxiety, depression, palpitations, arthralgia, and chest pain (Figure 3). More than half of the studies (57.77%) presented fair-quality analyses. The findings of the articles are summarized in Table 1 of the Supplementary Material.

Post-COVIA-19 syndrome and sex
Being female was a risk factor for developing anxiety, depression, fatigue, and sleep disorders as symptoms of post-COVID-19 syndrome. A 2022 study by Fenández-de-las-Peñas C. et al. associated being female with the presence of three or more symptoms of post-COVID-19 syndrome. In a cohort study conducted in Brazil, being female increased the likelihood of developing post-COVID-19 syndrome at three and six months of follow-up. There was a higher prevalence of skin problems, pain, neuropsychiatric symptoms, and fatigue at six months in the female population.

Post-COVID-19 syndrome and symptoms in the acute phase
Respiratory problems early in the illness or during hospitalization were predictors of post-COVID-19 syndrome in two Iranian studies18,19. The presence of vomiting, sore throat, diarrhea, dyspnea, and headache were associated with a higher number of long-term symptoms after COVID-1951. The development of symptoms, such as fatigue, headache, ageusia, and shortness of breath upon admission were considered independent predictors of the development of post-COVID-19 syndrome37.
Myalgia and headache in the acute phase have been described as risk factors for musculoskeletal pain associated with post-COVID-19 syndrome21,58. A higher number of symptoms during acute illness was a risk factor reported in seven articles.

Post-COVID-19 syndrome and severity of the acute conditions
The severity of COVID-19 in the acute phase has been associated with the development of post-COVID-19 syndrome17,25,39,46,53,54,56. Huang C. et al. report that severe COVID-19 is a risk factor for anxiety, depression, fatigue, and weakness17. Patients with moderate to severe COVID-19 had a 5.84-fold greater risk of post-COVID cognitive impairment when compared to patients with mild respiratory illness39. Sun LL et al. point out that severe patients have a higher risk of chest tightness, chest pain, and photophobia46. Shorter hospital stays are a protective factor against the development of post-COVID-19 syndrome symptoms19,21,25,26,28,35,48,51,55,58,59. Studies also suggest a relationship between longer hospital stays and the development of musculoskeletal pain21,58 and post-COVID-19 dyspnea26. Two cohort studies described a greater likelihood of fatigue and persistent dyspnea in people with more severe forms of COVID-1926,58. Length of hospital stay was a predictor of the development of post-COVID-19 syndrome and cardiopulmonary sequelae, such as dyspnea and fatigue59. Finally, only two studies found no statistical significance between length of hospital stay and symptoms of post-COVID-19 syndrome24,30.
Nine articles analyzed the relationship between Intensive Care Unit (ICU) admission and post-COVID-19 syndrome19,22,24,25,30,33,35,55,59. Of these, four studies showed no statistical difference in the risk of developing the syndrome between the groups admitted and not admitted to the ICU19,24,25,30. In the other studies, it was identified that ICU admission would be a risk factor for post-COVID-19 syndrome, with OR ranging from 1.68 to 5.6322,33,35,55,59. Ghosh P et al., Frontera J.A. et al., and Niebauer J.H. et al. identified that mechanical ventilation during hospitalization was a predictor of post-COVID-19 syndrome, with odds ratios of OR 2.29, OR 6.37, and OR 5.63, respectively33,34,59.

Post-COVID-19 syndrome, comorbidities, and age
Seven studies demonstrated that the number of comorbidities was a predictor of Post-COVID-19 Syndrome26,28,33,45,51,54,56. There was an association between a greater number of comorbidities and the development of fatigue and dyspnea26,44. A study by Ghosh P. et al. identified that the presence of at least one comorbidity was associated with Post-COVID-19 Syndrome33.
Regarding diabetes, three of the five studies evaluated found no association between this condition and Post-COVID-19 Syndrome20,24,27. A study in adults found that diabetes was a risk factor for the development of fatigue and anxiety as symptoms of Post-COVID-1945. A study in children demonstrated that diabetes was a risk factor for Post-COVID-19 Syndrome33.
Two articles found an association between systemic arterial hypertension and the development of Post-COVID-19 Syndrome41,49. Cardiovascular diseases were risk factors addressed in four articles27,38,45,53, and only in the study by Schouborg L.B. et al. was a relationship found between hypertension and the loss of functional status in heart disease patients38.
The absence of lung disease was a protective factor against post-COVID-19 functional status loss. A study by Gaspar P. et al., which evaluated the presence of post-COVID-19 symptoms for three, six, and nine months, only identified an association between lung disease and post-COVID-19 syndrome in the group with the longest follow-up time (OR 3.27). Seery V. et al. found that respiratory diseases are risk factors for post-COVID-19 syndrome, a result similar to those described by Pazukhina E. et al. regarding allergic respiratory diseases. Two studies have shown a relationship between COPD and the development of post-COVID-19 syndrome. No article identified smoking as a risk factor for the development of post-COVID-19 syndrome. Kidney disease was associated with post-COVID-19 syndrome. Only in the study by Pazukhina E. et al. were neurological diseases associated with the syndrome in children at six and twelve months of age41.
Excess weight can contribute to the development of fatigue or exertional dyspnea59. A body mass index (BMI) of between 35 and 40 kg/m² or greater than 40 kg/m² has been associated with post-COVID-19 syndrome36. Dias M.B. et al. reported that a higher BMI is a predictor of post-COVID-19 syndrome in patients over 50 years of age55.
Age was described as a risk factor for post-COVID-19 syndrome in hospitalized patients in five articles. In a case-control study by Azizi et al., age was associated with worse anxiety and depression scores in the three months following hospitalization44. In the cohort study by Osmanov et al., a difference was observed in the development of the syndrome between groups of older children as compared to children under 2 years of age32. There was no statistically significant difference between the groups in the other publications11,22,24,25,27,30,31.

Post-COVID-19 syndrome and immunological and genetic markers
Inflammatory, immunological, and genetic markers have been correlated in some articles with post-COVID-19 syndrome22,27,31. A proportional increase in anti-SARS-CoV-2 IgG 6 months after infection was a risk factor for the development of post-COVID-19 syndrome22. García-Abellán J. et al. identified a lower peak in anti-SARS-CoV-2 IgG as a protective factor31. Kurki et al. identified the presence of the APOE4 allele as a risk factor for mental fatigue.

Post-COVID-19 syndrome and social and economic factors.
Black individuals, with less than 12 years of schooling34,40 and the presence of stressors were independent predictors of neurocognitive outcomes related to post-COVID-19 syndrome34.

DISCUSSION
Studies indicate that female gender, clinical characteristics during the acute phase of the disease, length of hospital stay, and some medical comorbidities have been associated with the development of post-COVID-19 syndrome.
Studies indicate that men and women are equally likely to be infected with SARS-CoV-2, and that men have a higher risk of death during the acute phase of the disease10,61. A significant proportion of the studies in the systematic review (48.88%) demonstrated that being female represents a predisposition to the development of specific symptoms or post-COVID-19 syndrome50,56. These findings were also found in other systematic reviews that included non-hospitalized patients7,11,62.
It has been suggested that hormones may play a role in the continuation of the hyperinflammatory state of the acute phase of COVID-19 even after recovery, and that there is greater production of IgG antibodies in acute COVID-19 in women, which could trigger the post-COVID-19 syndrome63. The proportional increase in anti-SARS CoV-2 IgG was an independent risk factor for the development of post-COVID-19 syndrome. Another study found that the lower peak in anti-SARS CoV-2 IgG was a protective factor. Furthermore, biological differences between men and women in the expression of angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease-2 (TMPRSS2) receptors, as well as the lower production of pro-inflammatory interleukin-6 (IL-6) after viral infection in women, may explain the greater development of post-COVID-19 symptoms50.
Studies speculate that severe COVID-19 causes a more intense and significant immune response and cytokine release, causing damage to vital and non-vital organs. Furthermore, severe acute illness is treated more aggressively and is more commonly associated with iatrogenic damage (intubation, nosocomial infections, drug side effects, etc.) with lasting sequelae19. Glucocorticoid treatment during hospitalization was significantly associated with an increased risk of fatigue and anxiety in the study by Sun LL et al.46
The role of age in the development of post-COVID-19 syndrome is still controversial10. Most studies evaluating advanced age as a risk factor for post-COVID-19 syndrome have shown no association9,22-25,27,30,31,32,43,45,53,54,56.
A greater number of comorbidities acted as a predictor of the development of post-COVID-19 syndrome26,28,33,44,51,54,56. However, only some studies showed an association between specific pathologies and the development of post-COVID-19 syndrome23,33,38,41,45,49,53. The fact that the number of comorbidities showed a more consistent association with post-COVID-19 syndrome when compared to specific comorbidities indicates a more complex relationship between the syndrome and patients’ preconditions, which requires further study.
The risk of developing post-COVID-19 syndrome has also been associated with inflammatory markers22,31 and genetic elements27. The association between higher levels of inflammatory markers and the development of post-COVID-19 syndrome suggests that an exacerbated immune response may be related to this disease.
Socioeconomic and demographic factors also constituted predictors of the syndrome, highlighting the need to better evaluate the association of social determinants with post-COVID-19 syndrome.
This study has some limitations, the first of which is the possibility that not all studies on post-COVID-19 syndrome were selected due to the lack of gray literature searches or references of the included articles. More than half of the studies included in the meta-analysis were of fair quality. There is a concentration of studies in a few countries, and many of the studies were written by the same groups of authors. This lack of diversity among the studied populations may limit the analysis of factors associated with post-COVID-19 syndrome in global populations, reducing the external validity of the results found here. Even considering the use of a similar concept of post-COVID-19 syndrome, the list of symptoms used to characterize the syndrome may differ, as several of the studies evaluated in the qualitative analysis analyzed the role of participant characteristics and the development of specific symptoms or sets of symptoms. Another relevant limitation concerns the possibility of classification bias due to the wide range of nonspecific symptoms that characterize the syndrome, but which may be associated with other pathologies. Another notable limitation is the difficulty in evaluating factors, such as the number and type of symptoms as predictors of the syndrome in the meta-analysis due to differences in the measurement of these variables across studies.
The qualitative analysis identified individual studies that point to factors associated with the development of post-COVID-19 syndrome, such as female gender, clinical characteristics during hospitalization (number of symptoms, length of stay, disease severity), and previous comorbidities. Furthermore, the articles do not conclusively address the fact that age, socioeconomic and demographic factors, and some specific comorbidities, such as obesity and smoking, significantly influence the risk of developing post-COVID-19 syndrome in patients discharged from the hospital.
The risk factors identified in this review were female gender, hypertension, and length of hospital stay, and can be used as parameters to identify patients at greater risk of developing post-COVID-19 syndrome. Thus, a personalized monitoring strategy can be established, enabling improved care during the convalescence phase, especially for individuals with these characteristics. Furthermore, based on the data described here, it is clear that there is a need to restructure the healthcare network due to the new health needs defined by the post-pandemic scenario. Finally, we suggest conducting cohort studies to analyze risk factors for the development of post-COVID-19 syndrome in a wider range of countries, including Brazil. Considering the high prevalence of post-COVID-19 syndrome, it is imperative to expand the number of studies on interventions capable of reducing the impact of observed symptoms on people\'s lives.

REFERENCES
1. Katz A, Ekuma O, Enns JE, et al. Identifying people with post-COVID condition using linked, population-based administrative health data from Manitoba, Canada: prevalence and predictors in a cohort of COVID-positive individuals. BMJ Open. 2025;15(1):e087920.
2. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022 Apr;22(4):e102-e107.
3. World Health Organization. Post COVID-19 condition (Long COVID) [Internet]. 7 dezembro 2022 [Acesso em: 20 maio 2024]. Disponível em: https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition
4. 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 Netw Open 2021; 4(10):e2128568–8.
5. 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. J Med Virol 2021; 93(12):6566-6574.
6. Maglietta G, Diodati F, Puntoni M, Lazzarelli S, Marcomini B, Patrizi L, Caminiti C. Prognostic Factors for Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis. J. Clin. Med 2022; 11(6):1541.
7. Arnold DT, Hamilton FW, Milne A, Morley AJ, Viner J, Attwood M, Noel A, Gunning S, Hatrick J, Hamilton S, Elvers KT, Hyams C, Bibby A, Moran E, Adamali HI, Dodd JW, Maskell NA, Barratt SL. Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort. Thorax 2021; 76(4):399-401.
8. Moreno-Pérez O, Merino E, Leon-Ramirez JM, Andres M, Ramos JM, Arenas-Jiménez J, Asensio S, Sanchez R, Ruiz-Torregrosa P, Galan I, Scholz A, Amo A, González-delaAleja P, Boix V, Gil J; COVID19-ALC research group. Post-acute COVID-19 syndrome. Incidence and risk factors: A Mediterranean cohort study. J Infect 2021; 82(3):378-383.
9. Gaspar P, Dias M, Parreira I, Gonçalves HD, Parlato F, Maione V, Atalaia Barbacena H, Carreiro C, Duarte L. Predictors of Long-COVID-19 and its Impact on Quality of Life: Longitudinal Analysis at 3, 6 and 9 Months after Discharge from a Portuguese Centre. Acta Med Port 2023; 36(10):647-660.
10. Notarte KI, de Oliveira MHS, Peligro PJ, Velasco JV, Macaranas I, Ver AT, Pangilinan FC, Pastrana A, Goldrich N, Kavteladze D, Gellaco MML, Liu J, Lippi G, Henry BM, Fernández-de-las-Peñas C. Age, Sex and Previous Comorbidities as Risk Factors Not Associated with SARS-CoV-2 Infection for Long COVID-19: A Systematic Review and Meta-Analysis. J Clin Med 2022; 11(24):7314.
11. DeVries A, Shambhu S, Sloop S, Overhage JM. One-Year Adverse Outcomes Among US Adults With Post-COVID-19 Condition vs Those Without COVID-19 in a Large Commercial Insurance Database. JAMA Health Forum 2023; 4(3):e230010.
12. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372:n71.
13. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a web and mobile app for systematic reviews. Syst Rev 2016; 210:n5.
14. National Institute of Health. Study Quality Assessment Tools | National Heart, Lung, and Blood Institute (NHLBI) [Internet]. Nih.gov. Jul 2021 [Acesso em: 21 Maio 2024]. Disponível em: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
15. Viechtbauer, W. (2010). Conducting Meta-Analyses in R with the metafor Package. Journal of Statistical Software, 36(3), 1–48. https://doi.org/10.18637/jss.v036.i03
16. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
17. 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 2021; 397(10270):220-232.
18. Asadi-Pooya AA, Akbari A, Emami A, Lotfi M, Rostamihosseinkhani M, Nemati H, Barzegar Z, Kabiri M, Zeraatpisheh Z, Farjoud-Kouhanjani M, Jafari A, Sasannia S, Ashrafi S, Nazeri M, Nasiri S, Shahisavandi M. Long COVID syndrome-associated brain fog. J Med Virol 2022; 94(3):979-984.
19. Asadi-Pooya AA, Akbari A, Emami A, Lotfi M, Rostamihosseinkhani M, Nemati H, Barzegar Z, Kabiri M, Zeraatpisheh Z, Farjoud-Kouhanjani M, Jafari A, Sasannia F, Ashrafi S, Nazeri M, Nasiri S, Shahisavandi M. Risk Factors Associated with Long COVID Syndrome: A Retrospective Study. Iran J Med Sci 2021; 46(6):428-436.
20. Fernández-de-Las-Peñas C, Guijarro C, Torres-Macho J, Velasco-Arribas M, Plaza-Canteli S, Hernández-Barrera V, Arias-Navalón JA. Diabetes and the Risk of Long-term Post-COVID Symptoms. Diabetes 2021; 70(12):2917-2921.
21. Fernández-de-Las-Peñas C, de-la-Llave-Rincón AI, Ortega-Santiago R, Ambite-Quesada S, Gómez-Mayordomo V, Cuadrado ML, Arias-Navalón JA, Hernández-Barrera V, Martín-Guerrero JD, Pellicer-Valero OJ, Arendt-Nielsen L. Prevalence and risk factors of musculoskeletal pain symptoms as long-term post-COVID sequelae in hospitalized COVID-19 survivors: a multicenter study. Pain 2021; 163(9):e989-e996.
22. Peghin M, Palese A, Venturini M, De Martino M, Gerussi V, Graziano E, Bontempo G, Marrella F, Tommasini A, Fabris M, Curcio F, Isola M, Tascini C. Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients. Clin Microbiol Infect 2021; 27(10):1507-1513.
23. Fumagalli C, Zocchi C, Tassetti L, Silverii MV, Amato C, Livi L, Giovannoni L, Verrillo F, Bartoloni A, Marcucci R, Lavorini F, Fumagalli S, Ungar A, Olivotto I, Rasero L, Fattirolli F, Marchionni N; AOU Careggi COVID-19 Follow-up study Group. Factors associated with persistence of symptoms 1 year after COVID-19: A longitudinal, prospective phone-based interview follow-up cohort study. Eur J Intern Med 2022; 97:36-41.
24. Nune A, Durkowski V, Titman A, Gupta L, Hadzhiivanov M, Ahmed A, Musat C, Sapkota HR. Incidence and Risk Factors of Long Covid in the Uk: A Single-Centre Observational Study. J R Coll Physicians Edinb 2021; 51(4):338-343.
25. Becker C, Beck K, Zumbrunn S, Memma V, Herzog N, Bissmann B, Gross S, Loretz N, Mueller J, Amacher SA, Bohren C, Schaefert R, Bassetti S, Fux C, Mueller B, Schuetz P, Hunziker S. Long COVID 1 year after hospitalisation for COVID-19: a prospective bicentric cohort study. Swiss Med Wkly 2021; 151:w30091.
26. Fernández-de-Las-Peñas C, Palacios-Ceña D, Gómez-Mayordomo V, Palacios-Ceña M, Rodríguez-Jiménez J, de-la-Llave-Rincón AI, Velasco-Arribas M, Fuensalida-Novo S, Ambite-Quesada S, Guijarro C, Cuadrado ML, Florencio LL, Arias-Navalón JA, Ortega-Santiago R, Elvira-Martínez CM, Molina-Trigueros LJ, Torres-Macho J, Sebastián-Viana T, Canto-Diez MG, Cigarán-Méndez M, Hernández-Barrera V, Arendt-Nielsen L. Fatigue and Dyspnoea as Main Persistent Post-COVID-19 Symptoms in Previously Hospitalized Patients: Related Functional Limitations and Disability. Respiration 2021; 101(2):132-141.
27. Kurki SN, Kantonen J, Kaivola K, Hokkanen L, Mäyränpää MI, Puttonen H; FinnGen; Martola J, Pöyhönen M, Kero M, Tuimala J, Carpén O, Kantele A, Vapalahti O, Tiainen M, Tienari PJ, Kaila K, Hästbacka J, Myllykangas L. APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study. Acta Neuropathol Commun 2021; 9(1):199.
28. Fernández-de-Las-Peñas C, Palacios-Ceña D, Gómez-Mayordomo V, Rodríuez-Jiménez J, Palacios-Ceña M, Velasco-Arribas M, Guijarro C, de-la-Llave-Rincón AI, Fuensalida-Novo S, Elvira-Martínez CM, Cuadrado ML, Arias-Navalón JA, Florencio LL, Ortega-Santiago R, Molina-Trigueros LJ, Sebastián-Viana T, Torres-Macho J, Canto-Diez G, Plaza-Canteli S, Cigarán-Méndez M, Ambite-Quesada S, Hernández-Barrera V, Arias-Buría JL, Arendt-Nielsen L. Long-term post-COVID symptoms and associated risk factors in previously hospitalized patients: A multicenter study. J Infect 2021; 83(2):237-279.
29. Fernández-de-Las-Peñas C, Gómez-Mayordomo V, García-Azorín D, Palacios-Ceña D, Florencio LL, Guerrero AL, Hernández-Barrera V, Cuadrado ML. Previous History of Migraine Is Associated With Fatigue, but Not Headache, as Long-Term Post-COVID Symptom After Severe Acute Respiratory SARS-CoV-2 Infection: A Case-Control Study. Front Hum Neurosci 2021; 15:678472.
30. Fernández-de-Las-Peñas C, Guijarro C, Plaza-Canteli S, Hernández-Barrera V, Torres-Macho J. Prevalence of Post-COVID-19 Cough One Year After SARS-CoV-2 Infection: A Multicenter Study. Lung 2021; 199(3):249-253.
31. García-Abellán J, Padilla S, Fernández-González M, García JA, Agulló V, Andreo M, Ruiz S, Galiana A, Gutiérrez F, Masiá M. Antibody Response to SARS-CoV-2 is Associated with Long-term Clinical Outcome in Patients with COVID-19: a Longitudinal Study. J Clin Immunol 2021; 41(7):1490-1501.
32. Osmanov IM, Spiridonova E, Bobkova P, Gamirova A, Shikhaleva A, Andreeva M, Blyuss O, El-Taravi Y, DunnGalvin A, Comberiati P, Peroni DG, Apfelbacher C, Genuneit J, Mazankova L, Miroshina A, Chistyakova E, Samitova E, Borzakova S, Bondarenko E, Korsunskiy AA, Konova I, Hanson SW, Carson G, Sigfrid L, Scott JT, Greenhawt M, Whittaker EA, Garralda E, Swann OV, Buonsenso D, Nicholls DE, Simpson F, Jones C, Semple MG, Warner JO, Vos T, Olliaro P, Munblit D; and the Sechenov StopCOVID Research Team. Risk factors for post-COVID-19 condition in previously hospitalised children using the ISARIC Global follow-up protocol: a prospective cohort study. Eur Respir J 2022; 59(2):2101341.
33. Ghosh P, Niesen MJM, Pawlowski C, Bandi H, Yoo U, Lenehan PJ, M PK, Nadig M, Ross J, Ardhanari S, O\'Horo JC, Venkatakrishnan AJ, Rosen CJ, Telenti A, Hurt RT, Soundararajan V. Severe acute infection and chronic pulmonary disease are risk factors for developing post-COVID-19 conditions. medRxiv [Preprint] 2022; 2022.11.30.22282831.
34. Frontera JA, Sabadia S, Yang D, de Havenon A, Yaghi S, Lewis A, Lord AS, Melmed K, Thawani S, Balcer LJ, Wisniewski T, Galetta SL; NYU Neurology COVID-19 Study Team. Life stressors significantly impact long-term outcomes and post-acute symptoms 12-months after COVID-19 hospitalization. J Neurol Sci 2022; 443:120487.
35. Boglione L, Meli G, Poletti F, Rostagno R, Moglia R, Cantone M, Esposito M, Scianguetta C, Domenicale B, Di Pasquale F, Borrè S. Risk factors and incidence of long-COVID syndrome in hospitalized patients: does remdesivir have a protective effect? QJM 2022; 114(12):865-871.
36. Heubner L, Petrick PL, Güldner A, Bartels L, Ragaller M, Mirus M, Rand A, Tiebel O, Beyer-Westendorf J, Rößler M, Schmitt J, Koch T, Spieth PM. Extreme obesity is a strong predictor for in-hospital mortality and the prevalence of long-COVID in severe COVID-19 patients with acute respiratory distress syndrome. Sci Rep 2022; 12(1):18418.
37. Shah S, Bhattarai SR, Basnet K, Adhikari YR, Adhikari TB, Bhatta N, Chamlagain R, Aryal S, Sah SK, Bhandari G, Bhandari B, Poudel S, Pant P, Das SK. Post-COVID syndrome: A prospective study in a tertiary hospital of Nepal. PLoS One 2022; 17(8):e0272636.
38. Schouborg LB, Molsted S, Lendorf ME, Hegelund MH, Ryrsø CK, Sommer DH, Kolte L, Nolsöe RL, Pedersen TI, Harboe ZB, Browatzki A, Brandi L, Krog SM, Bestle MH, Jørgensen IM, Jensen TØ, Fischer TK, Pedersen-Bjergaard U, Lindegaard B. Risk factors for fatigue and impaired function eight months after hospital admission with COVID-19. Dan Med J 2022; 69(4):A08210633.
39. Cristillo V, Pilotto A, Cotti Piccinelli S, Bonzi G, Canale A, Gipponi S, Bezzi M, Leonardi M, Padovani A; Neuro Covid Next Study group. Premorbid vulnerability and disease severity impact on Long-COVID cognitive impairment. Aging Clin Exp Res 2022; 34(1):257-260.
40. Valdes E, Fuchs B, Morrison C, Charvet L, Lewis A, Thawani S, Balcer L, Galetta SL, Wisniewski T, Frontera JA. Demographic and social determinants of cognitive dysfunction following hospitalization for COVID-19. J Neurol Sci 2022; 438:120146.
41. Pazukhina E, Andreeva M, Spiridonova E, Bobkova P, Shikhaleva A, El-Taravi Y, Rumyantsev M, Gamirova A, Bairashevskaia A, Petrova P, Baimukhambetova D, Pikuza M, Abdeeva E, Filippova Y, Deunezhewa S, Nekliudov N, Bugaeva P, Bulanov N, Avdeev S, Kapustina V, Guekht A, DunnGalvin A, Comberiati P, Peroni DG, Apfelbacher C, Genuneit J, Reyes LF, Brackel CLH, Fomin V, Svistunov AA, Timashev P, Mazankova L, Miroshina A, Samitova E, Borzakova S, Bondarenko E, Korsunskiy AA, Carson G, Sigfrid L, Scott JT, Greenhawt M, Buonsenso D, Semple MG, Warner JO, Olliaro P, Needham DM, Glybochko P, Butnaru D, Osmanov IM, Munblit D; Sechenov StopCOVID Research Team. Prevalence and risk factors of post-COVID-19 condition in adults and children at 6 and 12 months after hospital discharge: a prospective, cohort study in Moscow (StopCOVID). BMC Med 2022; 20(1):244.
42. Bellan M, Apostolo D, Albè A, Crevola M, Errica N, Ratano G, Tonello S, Minisini R, D\'Onghia D, Baricich A, Patrucco F, Zeppegno P, Gramaglia C, Balbo PE, Cappellano G, Casella S, Chiocchetti A, Clivati E, Giordano M, Manfredi M, Patti G, Pinato DJ, Puricelli C, Raineri D, Rolla R, Sainaghi PP, Pirisi M; No-More COVID study group. Determinants of long COVID among adults hospitalized for SARS-CoV-2 infection: A prospective cohort study. Front Immunol 2022; 13:1038227.
43. Wong-Chew RM, Rodríguez Cabrera EX, Rodríguez Valdez CA, Lomelin-Gascon J, Morales-Juárez L, de la Cerda MLR, Villa-Romero AR, Arce Fernández S, Serratos Fernandez M, Bello HH, Castañeda LM, Avendaño MA, Hernández-Cruz JA, Álvarez Martínez N, Fernanda Contreras L, Rafael González de la Cerda L, Juárez Flores A, Martínez-Juarez LA, Álvarez-Hernández DA, Gallardo-Rincón H, Fajardo Dolci G, Tapia-Conyer R, Valdez-Vázquez RR. Symptom cluster analysis of long COVID-19 in patients discharged from the Temporary COVID-19 Hospital in Mexico City. Ther Adv Infect Dis 2022; 9:20499361211069264.
44. Magel T, Meagher E, Boulter T, Albert A, Tsai M, Muñoz C, Carlsten C, Johnston J, Wong AW, Shah A, Ryerson C, Mckay RJ, Nacul L. Fatigue presentation, severity, and related outcomes in a prospective cohort following post-COVID-19 hospitalization in British Columbia, Canada. Front Med (Lausanne) 2023; 10:1179783.
45. Azizi A, Achak D, Saad E, Hilali A, Youlyouz-Marfak I, Marfak A. Post-COVID-19 mental health and its associated factors at 3-months after discharge: A case-control study. Clin Epidemiol Glob Health 2022; 17:101141.
46. Sun LL, Wang J, Wang YS, Pan X, Luo J, Liu H, Jiang YR, Zhuang X, Lin L, Li GC, Zhao JW, Wang W, Wang YJ, Wang ZH, Shan HB, Chen SS, Chen JL, Xu ZW, Bai YH, Huang H, Xie WF. 15-Month Health Outcomes and the Related Risk Factors of Hospitalized COVID-19 Patients From Onset: A Cohort Study. Front Med (Lausanne) 2022; 9:854788.
47. Prestes GDS, Simon CS, Walz R, Ritter C, Dal-Pizzol F. Respiratory Outcomes After 6 Months of Hospital Discharge in Patients Affected by COVID-19: A Prospective Cohort. Front Med (Lausanne) 2022; 9:795074.
48. Chan Sui Ko A, Candellier A, Mercier M, Joseph C, Carette H, Basille D, Lion-Daolio S, Devaux S, Schmit JL, Lanoix JP, Andrejak C. No Impact of Corticosteroid Use During the Acute Phase on Persistent Symptoms Post-COVID-19. Int J Gen Med 2022; 15:6645-6651.
49. Chan Sui Ko A, Candellier A, Mercier M, Joseph C, Schmit JL, Lanoix JP, Andrejak C. Number of initial symptoms is more related to long COVID-19 than acute severity of infection: a prospective cohort of hospitalized patients. Int J Infect Dis 2022; 118:220-223.
50. Fernández-de-Las-Peñas C, Martín-Guerrero JD, Pellicer-Valero ÓJ, Navarro-Pardo E, Gómez-Mayordomo V, Cuadrado ML, Arias-Navalón JA, Cigarán-Méndez M, Hernández-Barrera V, Arendt-Nielsen L. Female Sex Is a Risk Factor Associated with Long-Term Post-COVID Related-Symptoms but Not with COVID-19 Symptoms: The LONG-COVID-EXP-CM Multicenter Study. J Clin Med 2022; 11(2):413.
51. Fernández-de-Las-Peñas C, Pellicer-Valero OJ, Navarro-Pardo E, Palacios-Ceña D, Florencio LL, Guijarro C, Martín-Guerrero JD. Symptoms Experienced at the Acute Phase of SARS-CoV-2 Infection as Risk Factor of Long-term Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study. Int J Infect Dis 2022; 116:241-244.
52. Bonyek-Silva I, Cerqueira-Silva T, Nunes S, Machado AFA, Cruz MRS, Pereira B, Estrela L, Silva J, Isis A, Barral A, Oliveira PRS, Khouri R, Serezani CH, Brodskyn C, Caldas JR, Barral-Netto M, Boaventura V, Tavares NM. Prediabetes Induces More Severe Acute COVID-19 Associated With IL-6 Production Without Worsening Long-Term Symptoms. Front Endocrinol (Lausanne) 2022; 13:896378.
53. Seery V, Raiden S, Penedo JMG, Borda M, Herrera L, Uranga M, Marcó Del Pont M, Chirino C, Erramuspe C, Alvarez LS, Lenoir M, Morales LD, Davenport C, Huespe Auchter S, Monsalvo L, Sastoque L, Gavazzi M, Russo C, Sananez I, Pando MLÁ, Laufer N, Muiños R, Ferrero F, Geffner J, Arruvito L. Persistent symptoms after COVID-19 in children and adolescents from Argentina. Int J Infect Dis 2023; 129:49-56.
54. Baptista de Lima J, Salazar L, Fernandes A, Teixeira C, Marques L, Afonso C. Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. Pediatr Infect Dis J 2023; 42(4):e109-e111.
55. Dias MB, Medeiros APV, de Melo SS, Fonseca CS, Jacob-Filho W, Avelino-Silva TJ, Aliberti MJR; CO-FRAIL Study Group. The long and winding road of COVID-19 in survivors of hospitalisation: Symptoms trajectory and predictors of long COVID. J Intern Med 2023; 293(2):264-268.
56. McAuley HJC, Evans RA, Bolton CE, Brightling CE, Chalmers JD, Docherty AB, Elneima O, Greenhaff PL, Gupta A, Harris VC, Harrison EM, Ho LP, Horsley A, Houchen-Wolloff L, Jolley CJ, Leavy OC, Lone NI, Man WD, Marks M, Parekh D, Poinasamy K, Quint JK, Raman B, Richardson M, Saunders RM, Sereno M, Shikotra A, Singapuri A, Singh SJ, Steiner M, Tan AL, Wain LV, Welch C, Whitney J, Witham MD, Lord J, Greening NJ; PHOSP-COVID Study Collaborative Group. Prevalence of physical frailty, including risk factors, up to 1 year after hospitalisation for COVID-19 in the UK: a multicentre, longitudinal cohort study. EClinicalMedicine 2023; 57:101896.
57. Mazurkiewicz I, Chatys-Bogacka Ż, Słowik J, Zdanecka M, Siwiec-Koźlik A, Słowik A, Drabik L, Wnuk M. Course of fatigue among patients previously hospitalised due to COVID-19. Neurol Neurochir Pol 2023; 57(1):101-110.
58. Fernández-de-Las-Peñas C, Cancela-Cilleruelo I, Moro-López-Menchero P, Rodríguez-Jiménez J, Pellicer-Valero OJ, Martín-Guerrero JD, Arendt-Nielsen L. Exploring the trajectory curve of long-term musculoskeletal post-COVID pain symptoms in hospitalized COVID-19 survivors: a multicenter study. Pain 2023; 164(2):413-420.
59. Niebauer JH, Binder-Rodriguez C, Iscel A, Schedl S, Capelle C, Kahr M, Cadjo S, Schamilow S, Badr-Eslam R, Lichtenauer M, Toma A, Zoufaly A, Valenta R, Hoffmann S, Charwat-Resl S, Krestan C, Hitzl W, Wenisch C, Bonderman D. Cardiopulmonary Long-Term Sequelae in Patients after Severe COVID-19 Disease. J Clin Med 2023; 12(4):1536.
60. Lapa J, Rosa D, Mendes JPL, Deusdará R, Romero GAS. Prevalence and Associated Factors of Post-COVID-19 Syndrome in a Brazilian Cohort after 3 and 6 Months of Hospital Discharge. Int J Environ Res Public Health 2023; 20(1):848.
61. Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero JJ, DeMeo DL, De Vries GJ, Epperson CN, Govindan R, Klein SL, Lonardo A, Maki PM, McCullough LD, Regitz-Zagrosek V, Regensteiner JG, Rubin JB, Sandberg K, Suzuki A. Sex and gender: modifiers of health, disease, and medicine. Lancet 2020; 396(10250):565-582.
62. Thompson EJ, Williams DM, Walker AJ, Mitchell RE, Niedzwiedz CL, Yang TC, Huggins CF, Kwong ASF, Silverwood RJ, Di Gessa G, Bowyer RCE, Northstone K, Hou B, Green MJ, Dodgeon B, Doores KJ, Duncan EL, Williams FMK; OpenSAFELY Collaborative; Steptoe A, Porteous DJ, McEachan RRC, Tomlinson L, Goldacre B, Patalay P, Ploubidis GB, Katikireddi SV, Tilling K, Rentsch CT, Timpson NJ, Chaturvedi N, Steves CJ. Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat Commun 2022; 13(1):3528.
63. Tsampasian V, Elghazaly H, Chattopadhyay R, Debski M, Naing TKP, Garg P, Clark A, Ntatsaki E, Vassiliou VS. Risk Factors Associated With Post-COVID-19 Condition: A Systematic Review and Meta-analysis. JAMA Intern Med 2023; 183(6):566-580.