The present study assessed the prevalence of long COVID and its associated factors 6–10 months after initial infection in adults and the elderly in southern Brazil. It was observed that almost half of the individuals developed long COVID. The most prevalent residual symptoms were fatigue, memory loss, loss of attention, headache, loss of smell, muscle pain and loss of taste. Female individuals who had anxiety, previous morbidities, and who were admitted to a hospital were more likely to develop long-standing COVID, while those with a good and very good self-perception of health were less likely to develop long-standing COVID.
Internationally, studies find the prevalence of long COVID to be 26.0% and 38.2% after six months (21,22) and 12.8% (6) after seven months of the acute phase of infection, with few studies investigating long COVID using a longer time frame in nonhospitalized individuals, both in the international and Brazilian literature. Regarding residual symptoms, the proportion of persistent symptoms among those infected with the mild form of acute infection may be as high as 50.0%, corroborating the data from our study (23). Fatigue, memory loss, loss of attention, headache, loss of smell, myalgia and loss of taste were not considered the most common symptoms presented in the literature (23). Fatigue is one of the main persistent symptoms after six months of acute infection, and some authors suggest that this fact is related not only to the inflammatory response associated with acute COVID-19 infection, which may promote this prolonged convalescence but also to the possibility of posttraumatic stress disorder after COVID-19, which could contribute to a more prolonged experience of this type of symptom (24,25).
Similar to the findings of this research, some authors suggest that memory and attention loss can also be experienced by individuals after infection by COVID-19, showing prevalence rates of 11.0% and 13.0%, respectively (26), and another study showed a prevalence of 10.7% with symptoms evaluated as "concentration or memory deficit" (7). The cause of these sequelae can be explained by the affinity and ease of the virus replicating in neural cells (27), which can cause lesions in the hippocampus, and there is also a psychosomatic effect caused by the disease. Many people who have recovered from COVID-19 have reported that they do not feel like themselves: experiencing short-term memory loss, confusion, difficulty concentrating and just feeling different than before contracting the infection due to the traumatic event of contracting the virus (28).
Olfactory and gustatory dysfunctions are described in the literature as the main acute symptoms of infection (5); however, anosmia and ageusia are symptoms that remain for four to seven months after infection (6). One of the theories for this could be that the targets of the virus may be nonneuronal cells and stem cells that express angiotensin-converting enzyme 2 (ACE2) receptors, while another theory is that there is involvement of infection of the sustaining cells and vascular pericytes of the olfactory epithelium and bulb (29,30).
Unlike the results of our study, headache as a neuropsychiatric symptom is a common persistent symptom after recovery from the acute phase of COVID-19 (44.0%) (23), but it is more commonly found in patients who have been hospitalized (32,33). The etiology of this type of residual symptom is complex and multifactorial and may be related to the direct effect of infection, cerebrovascular disease (including hypercoagulation)(34), physiological impairment (hypoxia), side effects of medication and social aspects of having a potentially fatal disease (35).
In our study, female subjects showed a 1.76 times higher probability of developing long COVID-19 than males, and this association has been previously discussed in the literature in nonhospitalized patients (9,16,21,36–38). There are several hypotheses that explain this association, including biological, immunological and behavioral hypotheses. First, there are biological differences in the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) between women and men. Immunological differences, for example, lower production of proinflammatory interleukin-6 (IL-6) after viral infection in women, could explain the greater development of post-COVID symptoms (39–42). The literature shows that factors such as higher psychological stress (depression and poor sleep quality) can play an important role in the development of long-term symptoms, and in our study, the prevalence of depression and poor sleep quality (data not presented in the article) were higher in women, supporting this hypothesis (43,44).
Furthermore, female sex is associated with a higher occurrence of several autoimmune diseases, and the preponderance of these diseases in the long COVID may be a result of their similarity (45). Additionally, women are more likely to report their symptoms to a physician (46). Finally, it is possible that pandemic-related factors of COVID-19, such as physical inactivity, isolation and stress, may promote the triggering of this outcome (44).
Our study showed that people with anxiety are more likely to develop long COVID. Other authors confirm this hypothesis by showing that anxiety is among the psychiatric disorders with the highest prevalence in people who had COVID-19, as well as being one of the symptoms that persist (7,47), which shows that an increasing number of mental health problems, such as anxiety and depression, have been associated with the development of COVID-19 and consequently long COVID-19 (48). Another study conducted in the United States found that individuals with a diagnosis of a psychiatric disorder in the year before the COVID-19 pandemic had a 65% increased risk of developing the disease compared to a cohort matched for physical risk factors without a psychiatric diagnosis (49). The association between anxiety and the increased likelihood of developing COVID-19 and long COVID-19 may be related to behavioral factors, symptomatology, comorbidities, vulnerability of the anxious state and even be connected with other symptoms (50,51).
Individual-morbidity interactions are complex and interfere with the clinical management of patients with COVID-19 (52). A previous study showed that the greater the number of preexisting comorbidities, the greater the presence of long COVID (53), because healthy people, in general, have efficient innate immunity that, in addition to intact cellular and humoral immunity, limits the progression of infection and promotes recovery in a few weeks, unlike people with chronic diseases (54). Both in individuals who were hospitalized and those who were not, the presence of previous morbidities seems to be an important determinant to be considered when evaluating long COVID (55).
Our findings showed an association between hospitalizations in both wards and/or intensive care units and long COVID, which is consistent with several studies (16,32,56) that observed impairments to health even after the cessation of symptoms. In a cohort by Rigoni et al., 2022 that evaluated 413 individuals who had COVID-19 through remote and ambulatory monitoring, approximately 30% suffered from persistence of at least two symptoms even after six months of infection. Tenforde et al., (2020) observed that the development of long-lasting COVID-19 symptoms in hospitalized individuals was associated with length of stay in the hospital, with the duration of symptoms among those who were not hospitalized being approximately four weeks, while for hospitalized individuals, the duration was at least eight weeks after discharge.
Having a good and very good self-perception of health was associated with a lower likelihood of developing long COVID in our study. Between the prepandemic period and the 1st quarter of 2022, an estimated that 91.6% of Brazilians rated their health status as poor (59). Seeking health care due to COVID-19 symptoms during the pandemic was a major predictor of perceived poor health. Furthermore, negative individual feelings create a perception of poor health status even before the medical diagnosis of the disease. The worsening in overall health status is greater among those who have a self-perception of poor health than among those who rate their health as good or very good (60). Infected people who negatively rate their general health status have a higher risk of developing long COVID and are strongly linked to residual symptoms (61).
However, the results found in this study should be interpreted in the context of its limitations and strengths. Among the limitations, this design does not allow for inferring causality, as it is a cross-sectional study, but we tried to minimize this problem by including temporality in the questions. In addition, symptoms were self-reported, and our questions related to only 19 out of more than 200 symptoms reported in the literature; however, we our questions addressed the most frequent symptoms (62). Survival bias should be considered, as only surviving individuals from COVID-19 were analyzed, which may have underestimated the occurrence of symptoms.
As a strength, our study provides information from a representative sample of COVID-19-infected individuals, regardless of disease severity, diagnosed with the gold standard test (RT‒PCR), with a response rate above 75%. We also highlight that we interrogated the presence of symptoms, which decreases potential reporting bias. Moreover, this study reveals unpublished data on the characteristics of long COVID in the Brazilian population, which is especially important given that the literature on this subject is scarce. In fact, the few existing studies evaluated hospitalized patients and most evaluated small samples in developed countries, especially in Europe.