In May 2023, with evidence of a significant decline in the weekly number of COVID-19 related deaths, hospitalizations, and Intensive Care Units (ICU) admissions, the World Health Organization (WHO) determined the end of the Public Health Emergency of International Concern for COVID-19.1 Despite the end of the pandemic, individuals who have had COVID-19 may experience sustained post-infection sequelae. This condition, known by various names such as long COVID, post-acute COVID-19, post-acute sequelae of SARS-CoV-2 infection, post-COVID conditions, long-term effects of COVID, chronic COVID, is classified in the International Classification of Diseases, 11th Revision (ICD-11) as post-COVID-19 condition.2

Major international public health agencies have standardized the definitions and terminology of this condition. The National Institute for Health and Care Excellence (NICE), in their COVID-19 rapid guideline on managing the long-term effects of COVID-19, categorizes post-COVID-19 syndrome as signs and symptoms developing during or after an infection consistent with COVID-19, persisting for more than 12-weeks and not explained by an alternative diagnosis.3 The World Health Organization, in October 2021, established a clinical case definition for post-COVID-19 condition: “post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3-months from the onset of COVID-19, with symptoms that last for at least 2-months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction, but also others, and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time”.4

Post-COVID-19 syndrome can cause symptoms across multiple systems, such as respiratory (shortness of breath, cough), cardiovascular (chest tightness, palpitations), general symptoms (fatigue, fever, pain), neurological symptoms (cognitive impairment, headache, sleep disturbances, musculoskeletal symptoms (joint and muscle pain), as well as psychological/psychiatric symptoms (depression, anxiety).3 Over 200 symptoms have been reported, with an estimated 65 million individuals worldwide experiencing long COVID, with cases increasing daily.5

The prevalence of long COVID varies widely in literature due to different definitions and symptom duration considerations. A 2022 study found 21.8 % of adults had symptoms lasting more than 3-months, with younger age, women, low income, overweight or obesity, smokers or ex-smokers, individuals with depression, and unvaccinated adults being more likely to experience long COVID.6 O’Mahoney and colleagues found that in a 2023 systematic review the pooled prevalence of COVID-19 survivors experiencing at least one symptom at follow-up was 52.6 % in hospitalized patients and 34.5 % in the non-hospitalized group.7 A 2025 systematic review and meta-analysis estimated that more than half of the COVID-19 survivors (56.5 %) reported experiencing one or more symptoms from 12- to 26-weeks. Fatigue and dyspnea were the most common symptoms reported, followed by headaches, myalgia, and chest pain. Limitations in returning to work were the most reported outcomes related to functional impairment in studies.8

The present study aims to estimate the frequency and assess the factors associated with post-COVID-19 syndrome in the population residing in municipalities in Paraiba and in the municipality of Rio de Janeiro. The results may help in the clinical investigation and management of nonspecific signs and symptoms that comprise the syndrome and thus provide more effective support to people with the condition. Additionally, identifying groups that may be at higher risk can contribute to the development of strategies and guide specific care for those who might suffer long-term effects.

The results of 1.350 participants were analyzed, divided into 734 cases and 616 controls, resulting in a post-COVID-19 syndrome frequency of 54 %. Most of the sample were from the state of Paraíba (Fig. 1).

Fig. 1.

Consort diagram.

Females, middle-aged, black/brown, and less educated individuals comprised higher proportions of participants. Nevertheless, females, middle-aged, white and more educated appeared more likely to have post-COVID-19 condition (Table 1).

Regarding the clinical conditions prior to COVID-19, participants were asked about the diagnosis by a doctor, or in the case of mental illnesses, by a doctor or psychologist. The most prevalent clinical condition in cases and controls before COVID-19 was hypertension (28.6 % in cases and 16.2 % in controls), followed by hypercholesterolemia (27 % in cases and 13.5 % in controls), and mental illness such as anxiety disorder and panic disorder (16.5 % in cases and 6.7 % in controls). Almost 23 % of cases had chronic long-term illnesses whereas almost 14 % of controls lived with chronic health conditions. Overweight and obesity were frequent and appeared somewhat more likely to develop post-COVID-19 condition. Chronic lung diseases (other than asthma), coagulation disorders, depression, and chronic kidney disease were more strongly associated with post-COVID-19 condition (Table 1).

Almost 50 % of cases and controls engaged in some form of physical activity before contracting the COVID-19 infection. A small proportion were smokers, and one-quarter consumed alcoholic beverages. None of those lifestyle elements appeared associated with post-COVID-19 condition. More than half of cases and controls considered their health to be good before the COVID-19 infection and were less likely to develop post-COVID-19 condition. A substantial proportion of participants reported a family history of post-COVID-19 symptoms (30.6 %) or hospitalization (20.6 %), which appeared to increase the odds of developing that syndrome (Table 2).

Nearly four times as many cases as controls were hospitalized due to COVID-19 and the frequency of post-COVID-19 conditions was 85 % among these participants who needed hospital care. Participants who required hospitalization had higher odds of presenting symptoms lasting longer than twelve weeks (Table 2). Besides, more than three-fourths of both cases and controls had not been vaccinated before the infection and vaccination showed no association to post-COVID-19 condition.

The most frequent circulating variants at the onset of symptoms among cases were Beta and Gama that were reported in Brazil in 2020 and the first half of 2021 respectively.11 In the univariable logistic regression analysis, it was observed that when the onset of COVID-19 symptoms coincided with the circulation of pre-Delta and pre-Omicron variants, the chance of developing post-COVID-19 syndrome increased by 1.5 times for the Beta variant, 1.69 times for Alpha, and 1.71 times for Gamma (Table 2).

As shown in Fig. 2, the highest frequencies were observed in the following symptoms in case participants: fatigue (70 %), cough (62 %), headache (57 %), memory loss (54 %), joint pain (51 %), loss of appetite (50 %), and difficulty concentrating (49 %). It was also noted that fatigue, joint pain, and difficulty concentrating caused significant limitations in daily activities for those who experienced these symptoms. Overall, general, respiratory and neurological symptoms were the most frequent.

Fig. 2.

Distribution of leading symptoms and their impact on daily functional capacity.

The multivariate logistic regression (Table 3) demonstrated that the variables most strongly associated with post-COVID-19 condition were hospitalization and chronic lung disease. Mental illness, family history of post-COVID-19 condition, age above 40-years and female sex were also significant predictors. Race, self-perception of health before COVID-19 and hypercholesterolemia showed association of low magnitude. Chronic kidney disease showed a marginal association. Vaccination status before COVID-19 infection was not associated to post-COVID-19 condition.

In a sample of individuals who had been diagnosed with COVID-19 in several municipalities in the state of Paraíba and in the city of Rio de Janeiro, we found that 54 % developed the post-COVID-19 condition. History of chronic diseases, mental illness, hospitalization for COVID-19, female sex, age of 40-years or more and family history of post-COVID-19 condition were the factors most strongly associated with post-COVID-19 condition after multivariable adjustment.

The frequency of post-COVID-19 syndrome observed in this study is consistent with findings from meta-analysis and systematic reviews.12,13 Reported prevalence varies widely in the literature, depending on case definition, the timing of data collection, follow-up duration, severity of acute infection, methods of symptom ascertainment and sample characteristics.14,15

This relatively high frequency may be explained by several factors. First, the case definition adopted followed WHO and NICE criteria, which prioritize sensitivity and consider the presence of at least one persistent symptom. In addition, markers of greater severity of acute COVID-19 such as the need for hospitalization, were associated with post-COVID-19 condition in this cohort, suggesting that the disease severity may have contributed to the overall burden of persisting symptoms. Finally, most infections occurred during the circulation of more virulent variants, which may have further influenced the observed frequency.

Post-COVID-19 condition is a multisystem disorder involving pathophysiological mechanisms, including microthrombi, direct virus-induced damage, and immune-mediated injurie.14 In this study fatigue was the most frequent reported symptom, consistent with previous literature.13,14,16 Persistent fatigue is a well-recognized sequela of infectious diseases and likely reflects a complex interaction of immunological and psychosocial factors.17 It impacts daily functioning, word capacity, and quality of life.

Consistent with findings from systematic reviews and meta-analyses13,18 respiratory, neurological, and psychological symptoms were among the most frequently reported manifestations. In this study, fatigue, respiratory symptoms, and cognitive complaints predominated.

Female sex has been consistently associated with post-COVID-19 condition in the literature.18–24 This association may reflect sex-related differences in immune and hormonal responses ‒ such as higher IgG antibody production during the acute response, which may result in a more favorable outcome during the disease onset, but could be associated with the persistence of disease manifestations – as well as social and behavioral factors, including greater symptom awareness and disproportionate psychosocial burden during the pandemic.24–26 In line with what has been observed in the literature, in this study, female sex had a higher likelihood of developing post-COVID-19 condition.

Statistically significant association of post-COVID-19 condition was observed among middle aged (40‒60-years) and over 60. Although evidence regarding age remains heterogeneous, several studies report higher frequencies of persistent symptoms in middle-aged and older adults,27–32 possibly reflecting cumulative comorbidities. Several studies pointed out that post-COVID-19 condition impacted quality of life, loss of work capacity, and functionality of individuals.33–35 In this perspective, the involvement of groups within the economically active population, such as middle-aged individuals, points to the social and economic consequences of the syndrome that need further analysis.

It is described in literature that the COVID-19 pandemic has disproportionately affected minority groups, including African American, Native American, and Latin communities, due to factors like chronic conditions, limited healthcare, and poor living conditions.36,37 In this study we found a higher risk in white race. These results resemble those found in large retrospectives studies,27,30 but it should be interpreted cautiously, as residual confounding, differential access to diagnosis, and reporting bias that cannot be excluded.

A systematic review and meta-analysis, Tsampasian and colleagues reported that comorbidities were associated with a higher risk of developing post-COVID-19 condition.28 Anxiety and other mental illnesses have also been consistently associated with the condition22,27,38,39 and frequently persist as long-term symptoms.22,23 The pandemic itself could affect mental health due to its significant impact on the societies and economies of countries, increasing risk factors such as unemployment, grief, and financial insecurity.40

The Pan American Health Organization, through its High-Level Commission on Mental Health and COVID-19, has provided guidance to countries to improve mental health care, such as integrating mental health into all policies, improving and expanding mental health services throughout the life cycle, and enhancing data and research in mental health.41 Therefore, this work provides further evidence on the need for all government sectors to ensure that mental health is addressed at all levels of care and prevention.

Poorer self-rated health prior to COVID-19, although only the “good” category showed a statistically significant association, suggests that self-perceived health status may play a role in vulnerability to the outcome. Consistent with previous studies, a prior history of chronic lung disease and hypercholesterolemia were associated with the condition22,27,28,42,43, however the former finding should be interpreted with caution due to the small number of exposed participants.

To our knowledge, the association between family history and post-COVID-19 have not been previously reported. In this study, having first-degree relatives with persistent post-COVID-19 symptoms was associated with a higher likelihood of developing the condition. This finding is biologically plausible and may reflect genetic susceptibility,44 which could bring this familial tendency to the disease, such as the association of certain HLA-I alleles that have lower affinity for SARS-CoV-2 antigens and could contribute to the development of post-COVID-19 condition by inducing less effective immune responses.45

Hospitalization during acute COVID-19 was strongly associated with post-COVID-19 condition. These data are consistent with previous studies,22,28,46 which highlighted that patients with prior critical illnesses are a high-risk population that should be monitored and have prevention and rehabilitation strategies implemented.

Vaccination status prior to SARS‑CoV‑2 infection was not significantly associated with the outcome in this study in contrast to findings from multiple systematic reviews indicating that full vaccination reduces the risk of long COVID compared to unvaccinated individuals.47 This result may be explained by the high proportion of unvaccinated participants at the time of infection and by infections occurring predominantly during earlier pandemic waves, when clinical protocols were less developed, and many participants being infected before widespread of vaccine availability ‒ potentially confounding the observed null association and limiting the ability to detect a protective effect.

Some limitations should be acknowledged. Because data on symptoms, lifestyle factors, and pre-COVID health status were self-reported, some degree of recall bias and misclassification cannot be excluded, particularly given the interval between infection and interview for some participants. Although the possibility that some controls may have developed symptoms after the assessment period cannot be excluded, this issue was considered in the interpretation of the findings and is unlikely to have materially influenced the results. In addition, changes in the magnitude of associations after multivariable adjustment highlight the importance of cautious interpretation of univariate findings. Finally, the use of a convenience sampling strategy may limit generalizability.

Post-COVID-19 condition was a sequela left by the pandemic, and it will be the subject of studies for a long time to better understand its etiology, the correlation between selected symptoms and the condition, factors associated, markers, treatment, and impacts on global public health.

This case-control study identified factors statistically associated with post-COVID-19 condition. Female sex, middle age, and white race were associated with a higher likelihood of the syndrome. Pre-existing conditions such as hypercholesterolemia, chronic lung diseases, and mental health disorders also were associated with an increased likelihood of the condition. Furthermore, a family history of the condition and previous hospitalization due to COVID-19 emerged as significant contributing factors.

These findings are in line with the most recent literature and suggest that these groups may benefit from closer follow-up after recovery, considering the impact on quality of life and long-term health. Moreover, the history of COVID-19 should be considered in the clinical investigation and management of the nonspecific signs and symptoms shared by multiple etiologies.

Furthermore, the factors associated identified in this study may contribute to developing strategies to reduce the impact on patient’s quality of life and on the health system.