Abstract

Introduction

The COVID-19 pandemic, caused by the novel coronavirus (SARS-CoV-2), is a public health emergency of global impact ¹1. Ministério da Saúde. Boletim Epidemiológico Especial. Doença pelo Novo Coronavírus COVID-19 2021; (86). https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/covid-19/2021/boletim_epidemiologico_covid_86-final-_29out.pdf.
https://www.gov.br/saude/pt-br/centrais-... . By January 2023, it had affected more than 600 million people worldwide ²2. World Health Organization. WHO COVID-19 dashboard. https://covid19.who.int/ (accessed on 23/Jan/2023).
https://covid19.who.int/... ; more than 35 million in Brazil, representing a cumulative incidence of 17.35 per 10,000 inhabitants ³3. Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde, Ministério da Saúde. Diretrizes para diagnóstico e tratamento da COVID-19: versão 3. Brasília: Ministério da Saúde; 2020.. Specifically in the state of Mato Grosso, this number has exceeded 838,000 contaminated people, with 15,246 deaths due to the disease ⁴4. Ministério da Saúde. Painel interativo COVID-19. https://covid.saude.gov.br/ (accessed on 09/Jan/2023).
https://covid.saude.gov.br/... . With the progression of the COVID-19 pandemic, there is a growing awareness of its long-term impacts on the population health ⁵5. Kim Y, Ha B, Kim SW, Chang HH, Kwnom KT, Bae S, et al. Post-acute COVID-19 syndrome in patients after 12 months from COVID-19 infection in Korea. BMC Infect Dis 2022; 22:93-127.. Currently, SARS-CoV-2 is recognized as a condition that causes not only pulmonary issues, but also a multiple organ syndrome ⁶6. Ramakrishnan RK, Kashour T, Hamid Q, Halwani R, Tleyjeh IM. Unraveling the mistery surrounding post-acute sequelae of COVID-19. Front Immunol 2021; 12:686029..

After the initial acute infection, like many other viral disorders, a variety of long-lasting and new symptoms of COVID-19 has been described using the following terminologies: post-COVID-19 syndrome, long COVID, and post-COVID-19 conditions ⁷7. Centers for Disease Control and Prevention. Long COVID or post-COVID conditions. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html#:~:text=People%20with%20post%2DCOVID%20conditions%20(or%20long%20COVID)%20may,away%20or%20come%20back%20again (accessed on 23/Jan/2023).
https://www.cdc.gov/coronavirus/2019-nco... . These terminologies refer to symptoms that develop during or after a SARS-CoV-2 infection and that last more than 12 weeks after the infection is diagnosed ⁸8. National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. https://www.nice.org.uk/guidance/ng188 (accessed on 23/Jan/2023).
https://www.nice.org.uk/guidance/ng188... ^,99. Baig AM. Chronic COVID syndrome: need for an appropriate medical terminology for long COVID and COVID long haulers. J Med Virol 2021; 93:2555-6.^,1010. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review. J Infect Dis 2022; 16:136..

According to estimates, persistent COVID-19 symptoms are observed in about one out of ten cases of the disease ¹⁰10. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review. J Infect Dis 2022; 16:136.; however, in Brazil, a study conducted in São Paulo showed that 68% of hospitalized patients had at least one recurrent symptom related to COVID-19 11 months after diagnosis ¹¹11. Freire MP, Oliveira MS, Magri MMC, Tavares BM, Marinho I, Nastri ACSS, et al. Frequency and factors associated with hospital readmission after COVID-19 hospitalization: the importance of post-COVID diarrhea. Clinics (Sao Paulo) 2022; 77:100061..

The frequency of persistent symptoms depends on the extension and severity of the infection and organs affected ¹²12. Gamberini L, Mazzoli CA, Gordini G, Prediletto I, Sintonen H, Scaramuzzo G, et al. Health-related quality of life profiles, trajectories, persistent symptoms and pulmonary function one year after ICU discharge in invasively ventilated COVID-19 patients, a prospective follow-up study. Respir Med 2021; 189:106665.. According to a systematic review of longitudinal studies, the most frequently reported symptoms were fatigue, dyspnea, memory loss, and being unable to concentrate up to one year after recovery from COVID-19 ¹³13. Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: a systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens 2022; 19:2-269.. The same review also showed that female patients, older age, comorbidities, and disease severity in the acute phase of the disease are risk factors for developing post-COVID-19 syndrome ¹³13. Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: a systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens 2022; 19:2-269..

Also, post-COVID-19 syndrome should be evaluated in relation to the dominant variant of the SARS-CoV-2. Since the first case, several variants have been identified, with new waves and mortality caused by the disease ¹⁴14. Moura EC, Cortez-Escalante J, Cavalcante FV, Barreto ICHC, Sanchez MN, Santos LMP. Covid-19: evolução temporal e imunização nas três ondas epidemiológicas, Brasil, 2020-2022. Rev Saúde Pública 2022; 56:105.. COVID-19 vaccines also follow the pace of variant identification for their improvement ¹⁵15. Menni C, Klaser K, May A, Polidori L, Capdevilla J, Louca P, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis 2021; 21:939-49.. In late 2021, the Omicron variant (PANGO B.1.1.529) caused a sudden increase in cases worldwide, but according to a recent study, the chance of post-COVID-19 syndrome was lower among cases due to Omicron variant when compared to the Delta variant (the one identified before Omicron) ¹⁶16. Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet 2022; 399:2263-4..

In this dynamic context of the COVID-19 pandemic, post-COVID-19 syndrome should be characterized over time, as well as the factors associated with this condition. In addition to many patients requiring specialized monitoring, a number of patients need to be readmitted to hospitals ¹⁰10. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review. J Infect Dis 2022; 16:136., which means an increase in healthcare treatments ³3. Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde, Ministério da Saúde. Diretrizes para diagnóstico e tratamento da COVID-19: versão 3. Brasília: Ministério da Saúde; 2020.. These results agree with findings of a systematic review ¹⁰10. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review. J Infect Dis 2022; 16:136., which also highlighted that a considerable number of participants reported losses in professional, social/family, and mental health areas.

Considering the above, this study aimed to analyze post-COVID-19 syndrome among hospitalized COVID-19 patients 6 and 12 months after hospital discharge.

Methods

This is an ambidirectional cohort study that assessed patients with a diagnosis of COVID-19 living in Cuiabá (capital of Mato Grosso) and Várzea Grande (a municipality near the capital), and who were admitted to public and private hospitals in Cuiabá, with cases ending up with hospital discharge between October and December 2021 and January and March 2022. The cases were identified by IndicaSUS, a system implemented by the government of Mato Grosso ⁴4. Ministério da Saúde. Painel interativo COVID-19. https://covid.saude.gov.br/ (accessed on 09/Jan/2023).
https://covid.saude.gov.br/... , accessed through the Cuiabá Municipal Health Department. After collecting data from medical records, individuals were interviewed by telephone 6 and 12 months after hospital discharge.

Of all seven hospitals in Cuiabá, only three allowed access to patient records. Individuals aged 18 or over, with COVID-19 confirmed through PCR, rapid test or antigen test, and who were discharged from hospital according to information recorded in IndicaSUS were considered eligible. Exclusion criteria were patients living in a nursing home and patients who have communication difficulties (aphasia, cognitive impairment, and severe hearing loss).

From October 2021 to March 2022, 998 patients with confirmed COVID-19 living in Cuiabá and Várzea Grande had their cases closed in hospitals in the capital; of these, 689 were discharged (69%), with 277 in the three hospitals selected for the study (40.2% of the total adult patients who were discharged during the period). During data collection from medical records, 10 patients were excluded because they lived in nursing homes and 8 were excluded because, despite being registered in IndicaSUS as hospital discharges, they died during hospitalization. Therefore, 259 individuals remained eligible for the study (Figure 1).

Participants were contacted via telephone and messaging application and invited to participate in the study, scheduled according to the interviewee’s preferences. During data collection, the study objective, informed consent form, free decision to participate, privacy guarantee, and the possibility of withdrawal from the study were explained to participants.

To identify deaths after hospital discharge, a search was conducted in the Brazilian Mortality Information System for individuals not found through telephone contact 12 months after hospital discharge. The search was performed by technicians from the Cuiabá Municipal Health Department using personal information from medical records (name, taxpayer identification number, birth date, and mother’s name). In addition to these, patients who refused to participate and who reported impossibility to be contacted by telephone and inability to answer the questionnaire due to communication difficulties such as aphasia, cognitive impairment or severe hearing loss, in addition to deaths after hospital discharge, were considered losses.

Individual telephone interviews were conducted with participants and lasted about 20 to 35 minutes. The questions referred to demographic and socioeconomic characteristics, housing and living conditions, health and hospitalization characteristics, and persistent symptoms since the acute phase of COVID-19 or new symptoms at the time of the interview.

The variables about sociodemographic and economic characteristics were: sex, age group in years (18-29, 30-49, 50-59, and 60 or more), ethnicity/skin color (white, mixed-race, black, yellow/Indigenous), education (completed elementary school, completed high school, completed higher education or more), monthly income in minimum wages (up to 2, 2-3, and 3 or more), whether the patient had a job at the time of hospital admission and at the time of the interview (among those who reported a job when they were admitted).

The variables about health and hospitalization characteristics were: diagnosis of COVID-19 prior to the infection that caused hospitalization, number of vaccine doses received before hospitalization (1, 2, 3, or 4), self-reported comorbidities (high blood pressure, diabetes mellitus, obesity, heart disease), number of comorbidities (no comorbidity, 1 or 2, and 3 or more). The variables obtained from medical records were: length of stay (average days classified into tertiles), intensive care unit (ICU) hospitalization (yes/no), days in the ICU (average days classified into tertiles), and mechanical ventilation required (yes/no).

The following comorbidities: high blood pressure, diabetes mellitus, obesity, and heart disease were considered in the data analysis, as they were the most frequent among reported comorbidities. However, only 11 patients reported obesity. When body mass index (BMI) was calculated using weight and height data, 46 individuals presented 30kg/m² or more, characterizing obesity ¹⁷17. World Health Organization. Obesity: preventing and managing the global epidemic. Report of a World Health Organization Consultation. Geneva: World Health Organization; 2000. (WHO Obesity Technical Report Series, 284)., with this information considered in data analysis.

Participants were also asked about 24 classes of symptoms present in the acute phase of COVID-19 and 6 and 12 months after hospital discharge - this list of symptoms was developed according to the literature ¹⁸18. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med 2021; 27:601-15.. A blank field was provided for the patient to report symptoms that were not mentioned during the interview.

Symptoms were classified as: muscular (tiredness/fatigue, joint pain, asthenia/muscle weakness, dysphoria/indisposition); neuropsychiatric (memory problems, anxiety, attention deficit/concentration problems, dizziness, depression, headache, taste and smell disorders, sleep disorders, low mood, post-traumatic stress disorder); dermatological (hair loss), cardiovascular (palpitation, dyspnea, chest pain); and pulmonary (dyspnea, cough, mechanical ventilation required). Other symptoms were also investigated: sore throat, runny nose, fever, sweating, nausea ¹⁸18. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med 2021; 27:601-15.. Also, the ten most frequent symptoms in the acute phase of the disease were evaluated regarding the presence of persistent symptoms six months after hospital discharge. Post-COVID-19 syndrome was defined as the presence of persistent or new symptoms 6 and 12 months after hospital discharge, as reported in previous studies ⁵5. Kim Y, Ha B, Kim SW, Chang HH, Kwnom KT, Bae S, et al. Post-acute COVID-19 syndrome in patients after 12 months from COVID-19 infection in Korea. BMC Infect Dis 2022; 22:93-127.^,1010. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review. J Infect Dis 2022; 16:136.^,1919. Moreno-Pérez O, Merino E, Leon-Ramirez MJ, Andres M, Ramos JM, Arenas-Jiménez J, et al. Post-acute COVID-19 syndrome. Incidence and risk factors: a Mediterranean cohort study. J Infect 2021; 82:378-83.. The number of symptoms (none, 1 or 2, 3 or more) was also evaluated.

The analyses were performed in Stata, version 16 (https://www.stata.com). Variables were described using absolute and relative frequency, with the chi-square test or Fisher’s exact test applied to assess differences between proportions, considering the statistical significance level of 5% (p-value < 0.05).

All ethical aspects in research were respected, in compliance with Resolution n. 466/2012 of the Brazilian National Health Council. This study was approved by the Research Ethics Committee with Human Beings in the Health Area of the Mato Grosso Federal University, Cuiabá Campus (report n. 5,415,255/2022 of May 18, 2022). All participants signed the informed consent form.

Results

In total, 190 patients were evaluated six months after hospital discharge (mean: 6.29 months, standard deviation - SD: 1.24) and 160 patients 12 months after hospital discharge (mean: 13.17 months, SD: 1.11), representing 73.3% and 62.2% of the eligible population, respectively. Among the losses and exclusions at 6 and 12 months, the highest proportions referred to impossibility to be contacted by telephone (n = 48), refusal to participate (n = 11), inability to answer the questionnaire due to communication difficulties such as of aphasia, cognitive impairment or severe hearing loss (n = 13), in addition to deaths after hospital discharge (n = 28) (Figure 1).

Of all 190 individuals assessed six months after hospital discharge, 59% were female patients, 40% were 60 years old or over, 63.2% reported mixed-race skin, 55.8% had completed elementary education, and 57.4% had a job when they were hospitalized but only 41.6% had a job when the interview was conducted. When asked about the presence of symptoms, 87.4% reported COVID-19 symptoms at the time of the interview, conducted six months after hospital discharge, and 83.2% did not think they were recovered from COVID-19. At the evaluation of 24 symptoms, 88.4% reported at least one symptom and 36.3% had three or more symptoms (Table 1).

At the 12-month interview, 160 individuals were evaluated. Of these, 58.7 were female patients, with similar sociodemographic characteristics to the 6-month interview. When asked about the symptoms, 67.5% reported COVID-19 symptoms at the time of the interview, conducted 12 months after hospital discharge, and 66.8% did not think they were recovered from COVID-19. At the evaluation of 24 symptoms, 68.7% reported at least one symptom and 8.13% had three or more symptoms (Table 1).

No significant difference was found in the presence of post-COVID-19 syndrome according to sex at the 6-month assessment; however, at the 12-month assessment, the prevalence of three or more symptoms was higher among female patients (11.6%) when compared to male patients (3.1%). No significant difference was observed in the following variables: ethnicity/skin color, education, and employment at the time of hospitalization. The frequency of post-COVID-19 syndrome was higher among individuals of older age, mixed-race skin color, and lower family income, and among those who had no job when the interview was conducted 6 and 12 months after hospital discharge. When evaluated after 12 months, the prevalence of persistent symptoms did not present a statistically significant difference. The presence of three or more symptoms was significantly higher among patients who reported no job (46%) when compared to those who had a job (22.8%) (Table 1).

Only 9.4% of individuals had already been diagnosed with COVID-19 prior to the infection that caused hospitalization, with no significant difference with the presence of post-COVID-19 syndrome 6 and 12 months after hospital discharge. However, among patients who were hospitalized due to recurrent COVID-19 infection, 64.7% had three or more symptoms after six months versus 34.4% of patients who had been hospitalized due to the first infection, with a borderline significance level (p-value = 0.05); but this difference was not observed 12 months after discharge. More than 70% of interviewers had received at least two doses of the vaccine against SARs-CoV-2 before hospitalization (41.6% received two doses and 32.6% received 3 or 4 doses), with no significant difference in relation to post-COVID-19 syndrome after 6 and 12 months (Table 2).

The prevalence of post-COVID-19 syndrome was higher among patients with high blood pressure (98.2%) and diabetes (98.4%), when compared to individuals without these comorbidities (74.7% and 83.3%, respectively; p-value < 0.01) six months after discharge, and 81.6% among patients with high blood pressure and 77.1% among patients with diabetes when compared to individuals without these comorbidities (53.4% and 65.2%, respectively) 12 months after discharge, with a significant difference only for high blood pressure at the second prospective follow-up. No significant difference was observed between patients with obesity and heart disease. The prevalence of post-COVID-19 syndrome and the presence of three or more symptoms were higher among patients with a higher number of comorbidities six months after discharge (p-value < 0.01) (Table 2).

The average length of stay of patients was 12.7 days; it was longer among patients who had at least one symptom six months after discharge (13.6 days) when compared to those who had no symptoms (5.6 days). Similar results were observed after 12 months. The prevalence of post-COVID-19 syndrome and the presence of three or more symptoms were also higher 6 and 12 months after discharge among patients in the tertile with the longest length of stay. Of the patients evaluated, 30.0% required admission to an ICU, with an average of 13.8 days in the ICU, and 6.5% required invasive mechanical ventilation and presented post-COVID-19 syndrome, with no statistically significant difference in post-COVID-19 syndrome and number of symptoms in relation to these variables (Table 2).

More than half of the patients presented muscular symptoms (58.9%) and neuropsychiatric symptoms (55.3%) six months after hospital discharge. These percentages remained high also after 12 months: 44.4% for muscular symptoms and 30.6% for neuropsychiatric symptoms. Fatigue was the most common symptom 6 and 12 months after hospital discharge (55.3% and 40.6%, respectively), followed by memory or decision-making problems (36.8%; 20%), hair loss (26.8%; 11.2%), dyspnea (16.3%; 7.5%), anxiety (14.2%; 8.1%), joint pain (12.1%; 6.8%), and attention deficit/concentration problems (10%; 1.2%) at 6 and 12 months, respectively (Table 3). When compared to sex, hair loss was the only symptom presenting a significant difference (p-value < 0.01), with a higher prevalence among female patients.

A higher prevalence of post-COVID-19 syndrome was observed six months after discharge among patients who reported a higher number of symptoms in the acute phase of COVID-19 (p-value < 0.01). When assessing each symptom specifically, a higher prevalence of post-COVID-19 syndrome was observed among patients who reported cough (92.2%), fever (92.4%), and body aches (95.9%), when compared to patients without these symptoms (77.5%, 79.3%, and 80.6%, respectively; p-value < 0.05). A higher number of persistent symptoms after hospital discharge was also observed among patients with these symptoms at the 6-month assessment (Table 4).

When evaluated 12 months after hospital discharge, the proportion of post-COVID-19 syndrome was higher among patients who reported more than two symptoms in the acute phase of COVID-19 (68.7%). When comparing each symptom specifically, a higher prevalence of post-COVID-19 syndrome was observed among patients who reported cough (71.6%), fever (73.7%), and dyspnea (74.4%) when compared to patients without these symptoms (60%, 56.5%, and 61.4%, respectively; with no statistically significant difference) (Table 5).

Discussion

The results of this study showed that 88.4% and 67.5% of patients who recovered from the acute phase of COVID-19 still had at least one symptom at the 6-month and 12-month assessments, respectively, and more than 30% had three or more symptoms of the disease at both interviews, with fatigue, dyspnea, joint pain, hair loss, and anxiety as the most common symptoms. The prevalence of post-COVID-19 syndrome was higher among older patients, with comorbidities, and lower per capita income. The results highlighted that post-COVID-19 syndrome affected more patients who presented higher severity in the acute phase, considering the length of stay and required admission to the ICU.

The prevalence of post-COVID-19 syndrome between 6 and 12 months after recovery from the acute phase ranges from 61% to 87% in international ¹³13. Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: a systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens 2022; 19:2-269. and national literature ²⁰20. 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; 2:848., in agreement with the findings of our study. In Brazil, few studies have evaluated the presence of persistent symptoms of COVID-19 ²⁰20. 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; 2:848.^,2121. Bonifácio LP, Csizmar VNF, Barbosa-Júnior F, Pereira APS, Koenigkam-Santos M, Wada DT, et al. Long-term symptoms among COVID-19 survivors in prospective cohort study, Brazil. Emerg Infect Dis 2022; 28:730-3.^,2222. Silva KM, Freitas DCA, Medeiros SS, Miranda LVA, Carmo JBM, Silva RG, et al. Prevalence and predictors of COVID-19 long-term symptoms: a cohort study from the Amazon Basin. Am J Trop Med Hyg 2023; 26:220362.^,2323. Talhari C, Criado PR, Castro CCS, Ianhez M, Ramos PM, Miot HA. Prevalence of and risk factors for post-COVID: results from a survey of 6,958 patients from Brazil. An Acad Bras Ciênc 2023; 95:e20220143.; this is the first study conducted in Mato Grosso, a state with a high cumulative number of deaths due to COVID-19, ranking second among the states of Brazil ¹1. Ministério da Saúde. Boletim Epidemiológico Especial. Doença pelo Novo Coronavírus COVID-19 2021; (86). https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/covid-19/2021/boletim_epidemiologico_covid_86-final-_29out.pdf.
https://www.gov.br/saude/pt-br/centrais-... .

The frequency of symptoms in our study was higher than that reported in a prospective study conducted in Brazil with hospitalized patients; of these, 61% presented at least one symptom after six months, with fatigue and memory loss as the most frequent symptoms ²⁰20. 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; 2:848.. This result can be attributed to the fact that in our study, 83.2% of respondents do not think they are recovered from COVID-19.

Although the 6-month assessment found no significant difference in the proportion of patients with post-COVID-19 syndrome according to sex, the 12-month assessment showed a higher number of female patients with three or more symptoms when compared to male patients. This result is similar to that found in a cohort in the Amazon Region that identified female patients, non-white skin color, and high BMI as independent predictors of a higher number of symptoms in post-COVID-19 syndrome ²²22. Silva KM, Freitas DCA, Medeiros SS, Miranda LVA, Carmo JBM, Silva RG, et al. Prevalence and predictors of COVID-19 long-term symptoms: a cohort study from the Amazon Basin. Am J Trop Med Hyg 2023; 26:220362., in agreement with other studies ¹¹11. Freire MP, Oliveira MS, Magri MMC, Tavares BM, Marinho I, Nastri ACSS, et al. Frequency and factors associated with hospital readmission after COVID-19 hospitalization: the importance of post-COVID diarrhea. Clinics (Sao Paulo) 2022; 77:100061.^,1313. Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: a systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens 2022; 19:2-269.^,2323. Talhari C, Criado PR, Castro CCS, Ianhez M, Ramos PM, Miot HA. Prevalence of and risk factors for post-COVID: results from a survey of 6,958 patients from Brazil. An Acad Bras Ciênc 2023; 95:e20220143..

A higher prevalence of post-COVID-19 syndrome among individuals of older age, lower income, and without a job six weeks after discharge was consistent with the findings of studies conducted in other countries ¹³13. Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: a systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens 2022; 19:2-269. and in Brazil assessing this theme ²⁰20. 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; 2:848.. Also, the impact on physical and cognitive functions in individuals with post-COVID-19 syndrome can prevent them from returning to work, which consequently affects the family income ²⁰20. 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; 2:848.. This difference in relation to the current job was not observed 12 weeks after discharge, which can be explained by the time from discharge to the 12-month interview, with consequent decrease in persistent symptoms among patients. Also, progress was seen with the economic growth in the country ²⁴24. Buonsenso D, Gualano MR, Rossi MF, Gris AV, Sisti LG, Borrelli I, et al. Post-acute COVID-19 sequelae in a working population at one year follow-up: a wide range of impacts from an Italian sample. Int J Environ Res Public Health 2022; 19:11093..

It should be noted that post-COVID-19 syndrome has disproportionately affected social groups; and social, economic, environmental, and political factors preceding the pandemic may have possibly contributed to health disparities ²⁵25. Goldin I, Muggah R. Viral inequality. Project Syndicate 2020; 27 mar. https://www.project-syndicate.org/onpoint/viral-inequality-by-ian-goldin-and-robert-muggah-2020-03.
https://www.project-syndicate.org/onpoin... . Then, inequality acts as a “threat enhancer”, interacting with the post-COVID-19 syndrome to increase the vulnerability of society as a whole ²⁵25. Goldin I, Muggah R. Viral inequality. Project Syndicate 2020; 27 mar. https://www.project-syndicate.org/onpoint/viral-inequality-by-ian-goldin-and-robert-muggah-2020-03.
https://www.project-syndicate.org/onpoin... .

Regarding comorbidities, prospective studies correlate preexisting comorbidities with post-COVID-19 syndrome, such as high blood pressure, cardiovascular disease, acute heart injury, and diabetes mellitus ⁵5. Kim Y, Ha B, Kim SW, Chang HH, Kwnom KT, Bae S, et al. Post-acute COVID-19 syndrome in patients after 12 months from COVID-19 infection in Korea. BMC Infect Dis 2022; 22:93-127.^,2626. Zhu Z, Wang M, Lin W, Cai Q, Zhang L, Chen D, et al. Cardiac biomarkers, cardiac injury, and comorbidities associated with serious illness and mortality in coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Immun Inflamm Dis 2021; 9:1071-100., consistent with the findings of our study. This relationship may be related to the fact that SARS-CoV-2 infection can cause an excessive release of cytokines (proinflammatory, profibrotic, and immune response regulator proteins), which results in aggravation of inflammatory mechanisms. Also, virus infection in the endothelial cell and consequent endothelial dysfunction is among the explanations for a more frequent occurrence of severe cases and post-COVID-19 syndrome among patients with comorbidities related to blood vessels ²⁷27. Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodríguez L. SARS-CoV-2 infection: the role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev 2020; 54:62-75.. Also, patients hospitalized due to COVID-19 may experience worsening of preinfection comorbidities, including high blood pressure and diabetes mellitus ⁵5. Kim Y, Ha B, Kim SW, Chang HH, Kwnom KT, Bae S, et al. Post-acute COVID-19 syndrome in patients after 12 months from COVID-19 infection in Korea. BMC Infect Dis 2022; 22:93-127..

As expected, the presence of symptoms after 6 and 12 months was higher among patients who were hospitalized for a longer period, which may be related to the greater severity of the disease in the acute phase. Studies found in the literature have reported a higher risk of long-term symptoms in patients requiring ICU admission and/or ventilatory support than in non-severe patients in terms of acute infection status ²⁸28. Huang L, Qun Y, Gu X, Wang Q, Ren L, Wang Y, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet 2021; 398:747-58.^,2929. Zhang X, Wang F, Shen Y, Zhang X, Cen Y, Wang B, et al. Symptoms and health outcomes among survivors of COVID-19 infection 1 year after discharge from hospitals in Wuhan, China. JAMA Netw Open 2021; 4:e2127403.. A recent study conducted in Brazil found a higher frequency of persistent symptoms among critical patients in the acute phase when compared to patients with mild and moderate levels ²¹21. Bonifácio LP, Csizmar VNF, Barbosa-Júnior F, Pereira APS, Koenigkam-Santos M, Wada DT, et al. Long-term symptoms among COVID-19 survivors in prospective cohort study, Brazil. Emerg Infect Dis 2022; 28:730-3..

Among the persistent symptoms among studied patients, muscular and neuropsychiatric symptoms were more frequent, with fatigue and dyspnea presenting similar results in other studies ⁵5. Kim Y, Ha B, Kim SW, Chang HH, Kwnom KT, Bae S, et al. Post-acute COVID-19 syndrome in patients after 12 months from COVID-19 infection in Korea. BMC Infect Dis 2022; 22:93-127.^,2828. Huang L, Qun Y, Gu X, Wang Q, Ren L, Wang Y, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet 2021; 398:747-58.^,3030. Augustin M, Schommers P, Stecher M, Dewald F, Gieselmann L, Gruell H, et al. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg Health Eur 2021; 6:100122., and may be associated with recurrent visits to the health service ³¹31. Günster C, Busse R, Spoden M, Rombey T, Schillinger G, Hoffmann W, et al. 6-month mortality and readmissions of hospitalized COVID-19 patients: a nationwide cohort study of 8,679 patients in Germany. PLoS One 2021; 16:e0255427.. A possible explanation for these symptoms would be the persistence of residual fibrotic lung areas, resulting from an ineffective healing stage after the initial acute inflammatory response of the disease ³²32. Duarte AR, Izquierdo MR, Fernández de Alba IG, Contreras MP, Fernández-Martínez NF, Ruiz-Montero R, et al. Sequelae, persistent symptomatology and outcomes after Covid-19 hospitalization: the ANCOHVID multicentre 6-month follow up study. BMC Med 2021; 19:129..

The COVID-19 pandemic has an impact on the mental health of infected and noninfected people ³³33. Rogers JP, Chesney E, Oliver D. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry 2020; 7:611-27.. Survivors are at high risk of psychiatric outcomes, such as anxiety and depression ³⁴34. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature 2021; 594:259-64., with the frequency of depressive symptoms more than 12 weeks after SARS-CoV-2 infection ranging from 11% to 28% ³⁵35. Renaud-Charest O, Lui LM, Eskander S, Ceban F, Ho R, Di Vincenzo JD, et al. Onset and frequency of depression in post-COVID-19 syndrome: a systematic review. J Psychiatr Res 2021; 144:129-37.. Our study found 55.3% of patients with neuropsychiatric conditions at the 6-month assessment and 30.6% at the 12-month assessment, with 14.2% of patients reporting anxiety and 2.1% depression at six months and 8,1% reporting anxiety and 1.2% depression at 12 months. Symptoms of depression can be at least partially explained by the exacerbation of inflammatory mechanisms mentioned above, given the evidence of association between inflammation and depression and that symptoms of depression in post-COVID-19 syndrome is proportional to the systemic inflammation measured in acute phase of the infection ³⁵35. Renaud-Charest O, Lui LM, Eskander S, Ceban F, Ho R, Di Vincenzo JD, et al. Onset and frequency of depression in post-COVID-19 syndrome: a systematic review. J Psychiatr Res 2021; 144:129-37.. Also, psychological symptoms may be caused by an indirect effect of virus infection, such as fear of dying from the disease, reduced social contact, loneliness, incomplete recovery of physical health, and job loss ³⁴34. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature 2021; 594:259-64..

Memory problems are among the neuropsychiatric symptoms reported by the patients ³⁶36. Duarte Junior SS, Guarnier GFF, Cardoso IBR, Felicio FC, Pereira JS, Silva ACS, et al. Recuperação de déficit de memória pós-COVID-19: uma revisão. Revista de Ciências Biológicas e da Saúde 2021; 4(3). https://unignet.com.br/wp-content/uploads/10_RECUPERACAO-DE-DEFICIT-DE-MEMORIA-POS-COVID-19.pdf.
https://unignet.com.br/wp-content/upload... . These results indicate that individuals who have recovered from COVID-19 have a worse performance in cognitive tests in several domains than it would be expected. This impairment is proportional to the severity of symptoms and more commonly found among patients who were hospitalized ³⁶36. Duarte Junior SS, Guarnier GFF, Cardoso IBR, Felicio FC, Pereira JS, Silva ACS, et al. Recuperação de déficit de memória pós-COVID-19: uma revisão. Revista de Ciências Biológicas e da Saúde 2021; 4(3). https://unignet.com.br/wp-content/uploads/10_RECUPERACAO-DE-DEFICIT-DE-MEMORIA-POS-COVID-19.pdf.
https://unignet.com.br/wp-content/upload... . Also, memory problems after SARS-CoV-2 infection are possibly not due to exclusively neurological damage, but may be associated with psychiatric disorders and worsening of pre-existing cognitive issues. Further research is needed to provide a better understanding of all neurological disorders associated with COVID-19 and their cognitive manifestations ³⁶36. Duarte Junior SS, Guarnier GFF, Cardoso IBR, Felicio FC, Pereira JS, Silva ACS, et al. Recuperação de déficit de memória pós-COVID-19: uma revisão. Revista de Ciências Biológicas e da Saúde 2021; 4(3). https://unignet.com.br/wp-content/uploads/10_RECUPERACAO-DE-DEFICIT-DE-MEMORIA-POS-COVID-19.pdf.
https://unignet.com.br/wp-content/upload... ^,3737. Miskowiak KW, Johnsen S, Sattler SM, Nielsen S, Kunalan K, Rungby J, et al. Cognitive impairments four months after COVID-19 hospital discharge: pattern, severity and association with illness variables. Eur Neuropsychopharmacol 2021; 46:39-48..

Our findings report hair loss among the main symptoms identified 6 and 12 months after discharge, and among the dermatological symptoms of post-COVID-19 syndrome listed in the literature ¹⁸18. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med 2021; 27:601-15., possibly due to its pathogenesis, clinical course, and treatment ³²32. Duarte AR, Izquierdo MR, Fernández de Alba IG, Contreras MP, Fernández-Martínez NF, Ruiz-Montero R, et al. Sequelae, persistent symptomatology and outcomes after Covid-19 hospitalization: the ANCOHVID multicentre 6-month follow up study. BMC Med 2021; 19:129.^,3838. Nguyen BS, Tosti A. Alopecia in patients with COVID-19: a systematic review and meta-analysis. JAAD Int 2022; 7:67-77.. A study by Saceda-Corralo et al. ³⁹39. Saceda-Corralo D, Pindado-Ortega C, Moreno-Arrones OM, Ortega-Quijano D, Fernández-Nieto D, Jiménez-Cauhe J, et al. Association of inflammation with progression of hair loss in women with frontal fibrosing alopecia. JAMA Dermatol 2020; 156:700-2. identified that hair loss may be a sequela in COVID-19 survivors, observed almost exclusively in women, in agreement with our findings that also identified a higher prevalence of hair loss hair among women when compared to men. The result of a study by Zheng et al. ⁴⁰40. Zeng F, Dai C, Cai P, Wang J, Xu L, Li J, et al. A comparison study of SARS-CoV-2 IgG antibody between male and female COVID-19 patients: a possible reason underlying different outcome between sex. J Med Virol 2020; 92:2050-4. indicated that women develop stronger humoral immune and cellular responses to COVID-19, which can extend symptom manifestations and cause sequelae such as hair loss. A higher prevalence of hair loss among women can also be explained by hormonal changes and stress that can be caused by the disease ⁴¹41. Banka N, Mubki T, Bunagan MJK, McElwee K, Shapiro J. Frontal fibrosing alopecia: a retrospective clinical review of 62 patients with treatment outcome and long-term follow-up. Int J Dermatol 2014; 53:1324-30..

The results obtained in our study highlight a higher prevalence of post-COVID-19 syndrome among patients who had symptoms such as cough, fever, and body aches in the acute phase of the disease, which can be explained by the relationship between these symptoms and disease severity. These results agree with findings in the literature that report an association between disease severity in the acute phase and persistent symptoms, such as fatigue, dyspnea, muscle weakness, and stress ²⁸28. Huang L, Qun Y, Gu X, Wang Q, Ren L, Wang Y, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet 2021; 398:747-58.^,4242. Ioannou GN, Baraff A, Fox A, Shahoumian T, Hickok A, O&apos;Hare AM, et al. Rates and factors associated with documentation of diagnostic codes for long COVID in the national veterans affairs health care system. JAMA Netw Open 2022; 5:e2224359..

Although fever is a common symptom in the acute phase, it usually improves over time and has not been observed among the main symptoms after recovery from the acute phase. A meta-analysis study on long-term symptoms in COVID-19 survivors found higher frequency of fatigue, dyspnea, cough, body aches, depression, anxiety, memory loss, and insomnia at one-year follow-up, but did not report fever among persistent symptoms ¹³13. Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: a systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens 2022; 19:2-269.^,4343. Shang YF, Liu T, Yu JN, Xu XR, Zahid KR, Wei YC, et al. Half-year follow-up of patients recovering from severe COVID-19: analysis of symptoms and their risk factors. J Intern Med 2021; 290:444-50..

In our study, less than half of the patients had completed the immunization schedule before admission, with no significant difference in the number of persistent symptoms according to the vaccine doses. However, the important role of vaccination to promote a significant reduction of the number of infection, reinfection, and serious cases must be considered ⁴⁴44. World Health Organization. Update on Omicron. https://www.who.int/news/item/28-11-2021-update-on-omicron (accessed on 23/Jan/2023).
https://www.who.int/news/item/28-11-2021... . The fact that our study only analyzed patients who required hospitalization and did not evaluate the last dose date in relation to the hospitalization date may have prevented the analysis of this information, since studies have attempted to explain a lower probability of long-term symptoms among immunized individuals ¹⁶16. Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet 2022; 399:2263-4.^,4545. Rosenblat JD, Cha DS, Mansur RB, McIntyre RS. Inflamed moods: a review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry 2014; 53:23-4..

Among the limitations of our study, in addition to those mentioned above, convenience sampling should be highlighted, which prevents generalization of findings, and the failure to assess post-COVID-19 syndrome by differentiating virus variants. The definition of post-COVID-19 syndrome adopted should also be considered, based on the interviewee’s report of the presence of one or more symptoms from the list of 24 symptoms in the questionnaire applied 6 and 12 months after hospital discharge, according to other observational studies ⁵5. Kim Y, Ha B, Kim SW, Chang HH, Kwnom KT, Bae S, et al. Post-acute COVID-19 syndrome in patients after 12 months from COVID-19 infection in Korea. BMC Infect Dis 2022; 22:93-127.^,99. Baig AM. Chronic COVID syndrome: need for an appropriate medical terminology for long COVID and COVID long haulers. J Med Virol 2021; 93:2555-6.. Our study did not adopt the definition of the World Health Organization (WHO) issued in October 2021, which characterizes post-COVID-19 syndrome as the presence of symptoms three months from the onset of COVID-19 with symptoms that last for at least two months and cannot be explained by an alternative diagnosis. However, the WHO recognizes that 15.1% of individuals infected by SARS-CoV-2 present persistent symptoms 12 months after the onset of the infection, with the main symptoms including fatigue, dyspnea, and cognitive issues, such as that observed in our study ⁴⁶46. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 2023; 21:133-46.. Also, with the variety of symptoms mentioned in the literature for post-COVID-19 syndrome, the list of 24 symptoms used in the questionnaire may have been a limitation, considering that more than 200 symptoms have been identified, affecting multiple organs ⁴⁶46. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 2023; 21:133-46.. Also, a possible memory bias cannot be ignored for some retrospective questions and symptoms in the acute phase during hospital admission.

Future studies with representative sample and identification of virus lineage can contribute to knowledge about post-COVID-19 syndrome and how the COVID-19 pandemic evolves over time.

Our results suggest that a high number of patients may present post-COVID-19 syndrome within one year of hospitalization, being more frequent among patients of older age, with comorbidities, lower per capita family income, without a job, and among those with more serious COVID-19 in the acute phase. Our study can provide information about the prevalence of persistent symptoms, requiring a broad assessment of primary care about the long-term effects and impact on quality of life of symptoms and, if possible, support patients who may need treatment of high complexity.

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