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Daniel A P de Miranda, Sarah V C Gomes, Priscilla S Filgueiras, Camila A Corsini, Nathalie B F Almeida, Raphael A Silva, Maria Izabella V A R C Medeiros, Raquel V R Vilela, Gabriel R Fernandes, Rafaella F Q Grenfell, Long COVID-19 syndrome: a 14-months longitudinal study during the two first epidemic peaks in Southeast Brazil, Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 116, Issue 11, November 2022, Pages 1007–1014, https://doi.org/10.1093/trstmh/trac030
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Abstract
A growing number of long COVID cases after infection have been reported. By definition, long COVID is the condition whereby affected individuals do not recover for several weeks or months following the onset of symptoms suggestive of COVID-19, the profile and timeline of which remains uncertain.
In this work, in-home, outpatient and hospitalized COVID-19 positive patients were monitored for up to 14 mo to establish the prevalence of long COVID symptoms and their correlation with age, pre-existing comorbidities and course of acute infection. The longitudinal study included 646 positive patients who were monitored once a month.
From the whole population, 50.2% presented with long COVID syndrome. Twenty-three different symptoms were reported. Most frequent were fatigue (35.6%), persistent cough (34.0%), dyspnea (26.5%), loss of smell/taste (20.1%) and frequent headaches (17.3%). Mental disorders (20.7%), change in blood pressure (7.4%) and thrombosis (6.2%) were also reported. Most patients presented with 2–3 symptoms at the same time. Long COVID started after mild, moderate and severe infection in 60, 13 and 27% of cases, respectively, and it was not restricted to specific age groups.
Older patients tended to have more severe symptoms, leading to a longer post-COVID-19 period. The presence of seven comorbidities was correlated with the severity of infection, and severity itself was the main factor that determined the duration of symptoms in long COVID cases.
Introduction
Globally, there have been >298 million confirmed cases of coronavirus disease 2019 (COVID-19), including 5 469 303 deaths, as reported by the WHO on 7 January 2022.1 In Brazil, one of the countries most affected by the pandemic, >22 million confirmed cases were notified, with 619 513 deaths since 3 January 2020,1 although the reality may be different, as Brazil has low testing capacity.2 As the accumulated incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increases, a growing number of multiorgan symptoms persisting after acute infection have been reported. Post-COVID-19 condition, or long COVID syndrome, is the condition whereby affected individuals do not recover for several weeks or months following the onset of symptoms suggestive of COVID-19.1,3 Recent studies show that a growing number of patients will experience prolonged symptoms,4,5 the profile and timeline of which remain uncertain. Based on limited and observational data, patients who require admission to the ICU and/or ventilatory support during severe cases seem to be at an increased risk of developing long COVID syndrome,6 although the occurrence of sequelae is also observed in patients with mild to moderate symptoms.7,8
Long COVID is a complex and increasingly recognized condition with prolonged heterogeneous symptoms and secondary complications that are poorly understood at this time.9 Alterations to the respiratory function, mental disorders and the appearance of heart disease may indicate an overview of the impacts caused by COVID-19 on the wellness, mobility and longevity of recovering patients.10 The prognosis of this new clinical entity is not known and is likely dependent on the severity of clinical symptoms, underlying comorbid conditions and response to treatment. The WHO estimated that 10 to 20% of COVID-19 patients experienced lingering symptoms for months following infection and recognized that the condition is clearly of public health concern, given the substantial impact it has on society, ranging from increased healthcare costs to economic and productivity losses.1 Failure to recognize that the long-term ramifications of COVID-19 also include the development of new onset chronic disease will leave us yet again unprepared to deal with the huge after-effects of the infection.
All the knowledge concerning the infection mentioned is a necessary step for humankind to get through this pandemic, therefore, lack of information surrounding how the human body will recover from long COVID syndrome is a modern challenge for science itself. To this end, and considering the rapidly growing number of patients describing COVID-19 sequalae, identification, documentation and investigation of these long-term consequences represent an imperative need. Furthermore, in a world with increasing vaccine coverage leading to increased notifications of mild and moderate acute infections, or even asymptomatic ones, it is necessary to understand that even infections with milder symptoms lead to the development of long COVID syndrome and its sequelae. Here, we present clinical and demographic data from in-home, outpatient and hospitalized COVID-19 positive patients who were monitored for up to 14 mo while long COVID symptoms were recorded.
Materials and Methods
Participants and procedure
A longitudinal study was conducted among 646 patients with confirmed acute SARS-CoV-2 infection. Patients were enrolled after being attended by emergency room clinicians of the Hospital da Baleia or the Hospital Metropolitano Dr Celio de Castro, hospitals with referral care for COVID-19 in Belo Horizonte, Brazil. All of them were tested by reverse transcription quantitative real-time PCR (RT-qPCR) using a nasopharyngeal swab according to WHO recommendations11 and had a COVID-19 positive diagnosis. Monitoring of persistent symptoms and sequelae was performed through interviews conducted in person or through a virtual platform once a month for each patient for up to 14 mo after confirmatory diagnosis, from March 2020 to November 2021 during the two epidemic peaks. Some volunteers presented to the health services. All thrombosis and changes in blood pressure cases were diagnosed by physicians. Individual patient information was collected by the questionnaire and from the hospital electronic medical records and included demographic aspects (age and gender), primary symptoms, persistent symptoms, comorbidities, RT-qPCR results, clinical course of acute infection and dates of symptoms onset and vaccination. The clinical course of COVID-19 was classified based on the WHO classification and was categorized as mild, moderate or severe. Mild COVID-19 was defined as respiratory symptoms without evidence of pneumonia or hypoxia, while moderate or severe COVID-19 was defined as the presence of clinical and radiological evidence of pneumonia. In moderate cases, the blood oxygen saturation level (SpO2) was ≥90% in room air, while one of the following was required to define a case as severe: a respiratory rate >30 breaths/min or SpO2<90% in room air or requiring ICU hospitalization.12
Statistical analyses
Analyses were carried out using the statistical programming language R. Comparisons between age and duration of symptoms in long COVID syndrome were performed using Pearson correlation, and the t-test (p<0.05) indicated differences between the groups. The OR of severe COVID-19 in patients with comorbidities was calculated by Fisher's exact test.
Results
The baseline characteristics including demographic status, pre-COVID-19 comorbidities and COVID-19 course of the 646 patients are listed in Table 1. Briefly, volunteers were aged 18–91 y. The mean age of the study sample was 50.26±15.78 y. Most of the volunteers were females (348; 53.9%). A minority of the study population reported no pre-existing comorbidities (245; 37.9%). For the 62.1% reporting pre-existing comorbidities, most common were chronic arterial hypertension (223; 34.5%), diabetes (114; 17.6%), chronic kidney disease (92; 14.2%) and cancer (83; 12.8%). According to the WHO classification,12 most of the patients reported COVID-19 with mild symptoms (329; 50.9%), while moderate and severe infection courses were respectively registered in 57 (8.8%) and 260 (40.2%) of cases. Among the whole study population, 641 patients (99.2%) (aged 18–91 y) had COVID-19 prior to vaccination, while only five patients (0.8%) (aged 44–65 y) had the infection after the complete protocol of vaccination, a group that was monitored for 7 mo since vaccination started in January 2021. Of the unvaccinated patients, half (321; 50.1%) developed long COVID syndrome. Three patients from the vaccinated group (60.0%) (aged 44–65 y) presented with long COVID syndrome. Details are presented in Figure 1.
. | Total (n=646) . | With long COVID syndrome (n=324) . | Without long COVID syndrome (n=322) . | |||
---|---|---|---|---|---|---|
. | n . | % . | n . | % . | N . | % . |
Age, y | ||||||
<20 | 13 | 2.0 | 4 | 1.2 | 9 | 2.8 |
21–40 | 180 | 27.9 | 102 | 31.5 | 78 | 24.2 |
41–60 | 274 | 42.4 | 138 | 42.6 | 136 | 42.2 |
61–80 | 160 | 24.8 | 69 | 21.3 | 91 | 28.3 |
>81 | 19 | 2.9 | 11 | 3.4 | 8 | 2.5 |
Gender | ||||||
Female | 348 | 53.9 | 205 | 63.3 | 143 | 44.4 |
Male | 298 | 46.1 | 119 | 36.7 | 179 | 55.6 |
Comorbidities | ||||||
Chronic arterial hypertension | 223 | 34.5 | 97 | 29.9 | 126 | 39.1 |
Previous stroke | 15 | 2.3 | 8 | 2.5 | 7 | 2.2 |
Heart disease | 44 | 6.8 | 22 | 6.8 | 22 | 6.8 |
Asthma | 37 | 5.7 | 20 | 6.2 | 17 | 5.3 |
Chronic obstructive pulmonary disease | 31 | 4.8 | 19 | 5.9 | 12 | 3.7 |
Chronic kidney disease | 92 | 14.2 | 45 | 13.9 | 47 | 14.6 |
Diabetes | 114 | 17.6 | 51 | 15.7 | 63 | 19.6 |
Cancer | 83 | 12.8 | 37 | 11.4 | 46 | 14.3 |
Obesity | 64 | 9.9 | 33 | 10.2 | 31 | 9.6 |
Dyslipidemia | 19 | 2.9 | 8 | 2.5 | 11 | 3.4 |
Alzheimer's disease | 2 | 0.3 | 2 | 0.6 | 0 | 0.0 |
Depression | 11 | 1.7 | 9 | 2.8 | 2 | 0.6 |
Smoker or alcoholic | 77 | 11.9 | 29 | 9.0 | 48 | 14.9 |
Hypothyroidism | 11 | 1.7 | 1 | 0.3 | 10 | 3.1 |
Thromboembolic disorders | 4 | 0.6 | 1 | 0.3 | 3 | 0.9 |
Hypothyroidism | 13 | 2.0 | 2 | 0.6 | 11 | 3.4 |
HIV | 2 | 0.3 | 1 | 0.3 | 1 | 0.3 |
Clinical course of COVID-19 | ||||||
Mild | 329 | 50.9 | 195 | 60.2 | 134 | 41.6 |
Moderate | 57 | 8.8 | 43 | 13.3 | 14 | 4.3 |
Severe | 260 | 40.2 | 86 | 26.5 | 174 | 54.0 |
. | Total (n=646) . | With long COVID syndrome (n=324) . | Without long COVID syndrome (n=322) . | |||
---|---|---|---|---|---|---|
. | n . | % . | n . | % . | N . | % . |
Age, y | ||||||
<20 | 13 | 2.0 | 4 | 1.2 | 9 | 2.8 |
21–40 | 180 | 27.9 | 102 | 31.5 | 78 | 24.2 |
41–60 | 274 | 42.4 | 138 | 42.6 | 136 | 42.2 |
61–80 | 160 | 24.8 | 69 | 21.3 | 91 | 28.3 |
>81 | 19 | 2.9 | 11 | 3.4 | 8 | 2.5 |
Gender | ||||||
Female | 348 | 53.9 | 205 | 63.3 | 143 | 44.4 |
Male | 298 | 46.1 | 119 | 36.7 | 179 | 55.6 |
Comorbidities | ||||||
Chronic arterial hypertension | 223 | 34.5 | 97 | 29.9 | 126 | 39.1 |
Previous stroke | 15 | 2.3 | 8 | 2.5 | 7 | 2.2 |
Heart disease | 44 | 6.8 | 22 | 6.8 | 22 | 6.8 |
Asthma | 37 | 5.7 | 20 | 6.2 | 17 | 5.3 |
Chronic obstructive pulmonary disease | 31 | 4.8 | 19 | 5.9 | 12 | 3.7 |
Chronic kidney disease | 92 | 14.2 | 45 | 13.9 | 47 | 14.6 |
Diabetes | 114 | 17.6 | 51 | 15.7 | 63 | 19.6 |
Cancer | 83 | 12.8 | 37 | 11.4 | 46 | 14.3 |
Obesity | 64 | 9.9 | 33 | 10.2 | 31 | 9.6 |
Dyslipidemia | 19 | 2.9 | 8 | 2.5 | 11 | 3.4 |
Alzheimer's disease | 2 | 0.3 | 2 | 0.6 | 0 | 0.0 |
Depression | 11 | 1.7 | 9 | 2.8 | 2 | 0.6 |
Smoker or alcoholic | 77 | 11.9 | 29 | 9.0 | 48 | 14.9 |
Hypothyroidism | 11 | 1.7 | 1 | 0.3 | 10 | 3.1 |
Thromboembolic disorders | 4 | 0.6 | 1 | 0.3 | 3 | 0.9 |
Hypothyroidism | 13 | 2.0 | 2 | 0.6 | 11 | 3.4 |
HIV | 2 | 0.3 | 1 | 0.3 | 1 | 0.3 |
Clinical course of COVID-19 | ||||||
Mild | 329 | 50.9 | 195 | 60.2 | 134 | 41.6 |
Moderate | 57 | 8.8 | 43 | 13.3 | 14 | 4.3 |
Severe | 260 | 40.2 | 86 | 26.5 | 174 | 54.0 |
. | Total (n=646) . | With long COVID syndrome (n=324) . | Without long COVID syndrome (n=322) . | |||
---|---|---|---|---|---|---|
. | n . | % . | n . | % . | N . | % . |
Age, y | ||||||
<20 | 13 | 2.0 | 4 | 1.2 | 9 | 2.8 |
21–40 | 180 | 27.9 | 102 | 31.5 | 78 | 24.2 |
41–60 | 274 | 42.4 | 138 | 42.6 | 136 | 42.2 |
61–80 | 160 | 24.8 | 69 | 21.3 | 91 | 28.3 |
>81 | 19 | 2.9 | 11 | 3.4 | 8 | 2.5 |
Gender | ||||||
Female | 348 | 53.9 | 205 | 63.3 | 143 | 44.4 |
Male | 298 | 46.1 | 119 | 36.7 | 179 | 55.6 |
Comorbidities | ||||||
Chronic arterial hypertension | 223 | 34.5 | 97 | 29.9 | 126 | 39.1 |
Previous stroke | 15 | 2.3 | 8 | 2.5 | 7 | 2.2 |
Heart disease | 44 | 6.8 | 22 | 6.8 | 22 | 6.8 |
Asthma | 37 | 5.7 | 20 | 6.2 | 17 | 5.3 |
Chronic obstructive pulmonary disease | 31 | 4.8 | 19 | 5.9 | 12 | 3.7 |
Chronic kidney disease | 92 | 14.2 | 45 | 13.9 | 47 | 14.6 |
Diabetes | 114 | 17.6 | 51 | 15.7 | 63 | 19.6 |
Cancer | 83 | 12.8 | 37 | 11.4 | 46 | 14.3 |
Obesity | 64 | 9.9 | 33 | 10.2 | 31 | 9.6 |
Dyslipidemia | 19 | 2.9 | 8 | 2.5 | 11 | 3.4 |
Alzheimer's disease | 2 | 0.3 | 2 | 0.6 | 0 | 0.0 |
Depression | 11 | 1.7 | 9 | 2.8 | 2 | 0.6 |
Smoker or alcoholic | 77 | 11.9 | 29 | 9.0 | 48 | 14.9 |
Hypothyroidism | 11 | 1.7 | 1 | 0.3 | 10 | 3.1 |
Thromboembolic disorders | 4 | 0.6 | 1 | 0.3 | 3 | 0.9 |
Hypothyroidism | 13 | 2.0 | 2 | 0.6 | 11 | 3.4 |
HIV | 2 | 0.3 | 1 | 0.3 | 1 | 0.3 |
Clinical course of COVID-19 | ||||||
Mild | 329 | 50.9 | 195 | 60.2 | 134 | 41.6 |
Moderate | 57 | 8.8 | 43 | 13.3 | 14 | 4.3 |
Severe | 260 | 40.2 | 86 | 26.5 | 174 | 54.0 |
. | Total (n=646) . | With long COVID syndrome (n=324) . | Without long COVID syndrome (n=322) . | |||
---|---|---|---|---|---|---|
. | n . | % . | n . | % . | N . | % . |
Age, y | ||||||
<20 | 13 | 2.0 | 4 | 1.2 | 9 | 2.8 |
21–40 | 180 | 27.9 | 102 | 31.5 | 78 | 24.2 |
41–60 | 274 | 42.4 | 138 | 42.6 | 136 | 42.2 |
61–80 | 160 | 24.8 | 69 | 21.3 | 91 | 28.3 |
>81 | 19 | 2.9 | 11 | 3.4 | 8 | 2.5 |
Gender | ||||||
Female | 348 | 53.9 | 205 | 63.3 | 143 | 44.4 |
Male | 298 | 46.1 | 119 | 36.7 | 179 | 55.6 |
Comorbidities | ||||||
Chronic arterial hypertension | 223 | 34.5 | 97 | 29.9 | 126 | 39.1 |
Previous stroke | 15 | 2.3 | 8 | 2.5 | 7 | 2.2 |
Heart disease | 44 | 6.8 | 22 | 6.8 | 22 | 6.8 |
Asthma | 37 | 5.7 | 20 | 6.2 | 17 | 5.3 |
Chronic obstructive pulmonary disease | 31 | 4.8 | 19 | 5.9 | 12 | 3.7 |
Chronic kidney disease | 92 | 14.2 | 45 | 13.9 | 47 | 14.6 |
Diabetes | 114 | 17.6 | 51 | 15.7 | 63 | 19.6 |
Cancer | 83 | 12.8 | 37 | 11.4 | 46 | 14.3 |
Obesity | 64 | 9.9 | 33 | 10.2 | 31 | 9.6 |
Dyslipidemia | 19 | 2.9 | 8 | 2.5 | 11 | 3.4 |
Alzheimer's disease | 2 | 0.3 | 2 | 0.6 | 0 | 0.0 |
Depression | 11 | 1.7 | 9 | 2.8 | 2 | 0.6 |
Smoker or alcoholic | 77 | 11.9 | 29 | 9.0 | 48 | 14.9 |
Hypothyroidism | 11 | 1.7 | 1 | 0.3 | 10 | 3.1 |
Thromboembolic disorders | 4 | 0.6 | 1 | 0.3 | 3 | 0.9 |
Hypothyroidism | 13 | 2.0 | 2 | 0.6 | 11 | 3.4 |
HIV | 2 | 0.3 | 1 | 0.3 | 1 | 0.3 |
Clinical course of COVID-19 | ||||||
Mild | 329 | 50.9 | 195 | 60.2 | 134 | 41.6 |
Moderate | 57 | 8.8 | 43 | 13.3 | 14 | 4.3 |
Severe | 260 | 40.2 | 86 | 26.5 | 174 | 54.0 |
Taken together, long COVID symptoms were reported by 324 (50.2%) of the whole study population. Among those, 42.6% were aged 41–60 y (138), 31.5% 21–40 y (102) and 21.3% 61–80 y (69). Gender classification revealed a majority of females presenting with persistent symptoms (205; 63.3%) compared with males (119; 36.7%) (Table 1). Figure 2 shows that long COVID varied in a total of 23 manifestations, although most patients complained of fatigue (115; 35.6%), persistent cough (110; 34.0%), dyspnea (86; 26.5%), loss of smell or taste (65; 20.1%) and frequent headaches (56; 17.3%). Volunteers also described myalgia (35; 10.8%), body ache (29; 9.0%), red eyes (26; 8.0%) and change in blood pressure (24; 7.4%) as frequent manifestations. Mental difficulties such as insomnia, anxiety and vertigo or dizziness were reported by 26 (8.0%), 23 (7.1%) and 18 (5.6%), respectively, and in these cases symptoms’ duration was up to 11 mo after acute infection. Thrombosis was diagnosed in 20 patients (6.2%) of the study population with a duration of 5 mo, when all these patients had been treated and had recovered. Diarrhea (22; 6.8%), chest pain (19; 5.9%), low mobility (17; 5.2%), tachycardia (13; 4.0%) and other manifestations were also reported. The duration of each symptom was defined with a follow-up of 14 mo and the data are presented in Figure 2 (illustrated by color). All reported symptoms started after acute infection and some of them persisted for the whole follow-up period of 14 mo, with some exceptions, such as thrombosis, which was properly treated in all cases ending after 5 mo, as well as red eyes, insomnia, anxiety and red spots on the skin, which were no longer reported after 11 mo. Four patients (1.2%) were still experiencing symptoms at the time of study completion, reporting fatigue, dyspnea, joint pain, myalgia, tachycardia, change in blood pressure, cough, loss of smell or taste, runny nose and loss of appetite. Symptoms occurred early in the illness, reaching a high point in the first 2–5 mo, with most of them decreasing over time. Nearly half of patients (138; 42.6%) were diagnosed with only one persistent symptom postacute infection, while 142 (43.8%) presented 2–3 symptoms at once, 26 (8.0%) presented 4–5, 10 (3.1%) 6–10 symptoms, 5 (1.5%) 11–20 and 3 (0.9%) >21 symptoms concurrently.
Among the 260 patients who experienced severe symptoms during SARS-CoV-2 acute infection, 86 (33.1%) presented long COVID syndrome, among whom 38 (44.2%) were >60 y old and 48 (55.8%) were ⩽60 y old (Figure 3). On the other hand, most (75.4%) of the 57 patients with moderate symptoms developed long COVID syndrome (in all ages). Together, most (59.3%) of the 329 patients with mild symptoms during infection developed persistent symptoms, especially when aged <60 y (83.1%). The duration of symptoms was correlated with patients’ age (rho=0.269, p<0.001) (Figure 4B). The association is driven by COVID-19 severity because older patients tended to have more severe symptoms, leading to a longer post-COVID-19 period (Figure 4A). The duration of persistent symptoms in long COVID is longer in patients with severe COVID-19 compared with patients with moderate and mild disease, although in the patients with mild disease group, it ranged from 1 to 420 d (Figure 4C).
Although comorbidities were noticed in patients with and without long COVID syndrome, the mean duration of symptoms was higher in the presence of seven comorbidities (p<0.05): chronic arterial hypertension, diabetes, heart disease, cancer, chronic obstructive pulmonary disease, chronic kidney disease and smoker or alcoholic (Supplementary Figure 1). For most of these comorbidities, the relationship of the symptom's duration is associated with the prevalence of patients with severe disease in the comorbidity group compared with those without comorbidity (Supplementary Figure 1).
Discussion
Although the COVID-19 pandemic has not yet been controlled, long COVID syndrome is already a challenging topic when considering the occurrence of long-term multiorgan sequelae9 and, as presented here, it appears after severe, moderate and even mild infections. As broadly described, the new human pathogen, SARS-CoV-2, is a respiratory coronavirus, and injury to the lungs is expected. However, there is often damage to numerous other vital structures in the body, leading to an array of symptoms.13,14 Reports about long COVID syndrome are recent and describe a number of neurological and psychiatric symptoms including fatigue, cognitive impairment, insomnia, myalgia, headaches, vertigo, anxiety and depression.15–18 Beyond symptoms, people with long COVID are reporting an impaired quality of life, employment issues, impacts on physical and cognitive functions, health-related quality of life and participation in society, and may require multidisciplinary care, including social services support.19,20
In this work, 50.2% of the 646 COVID-19 positive patients presented with long COVID syndrome, with 23 different manifestations reported. Most predominant and lasting symptoms were related to respiratory and neurological functions including fatigue, cough, dyspnea, pain and, in some cases, insomnia, anxiety, vertigo and dizziness, lasting for up to 14 mo. Similar to our findings, the most frequently reported manifestations in other studies are of a neurological, psychiatric and respiratory nature and led to continuous functional impairment in work, social and home life.7,8,21–23 Vascular disorders were also reported here with patients presenting changes in blood pressure and thrombosis. The systemic inflammation developed in cases of SARS-CoV-2 infection is the major reason why several organs can be affected. Vital organ dysfunction results from pathophysiological self-amplifying loops of innate immunological hyperactivation, cytokine release, complement deposition, endothelial damage and macrovascular and microvascular thromboembolism.24 The clotting pathway is disturbed causing an excessive synthesis of thrombin, which regulates the coagulation process and generates hypercoagulability,25 thus may explain persistent vascular symptoms.
Although the precise pathophysiology of long COVID syndrome needs further clarification, COVID-19 has a complex pathology involving severe acute respiratory infection, hyperimmune response and coagulopathy,26 which is supposedly related to such diverse and prolonged manifestations, leading to the involvement of multiple organ systems. Following any severe infection or trauma, the human body reacts with an overwhelming immune response called systemic inflammatory response syndrome, followed by a prolonged compensatory, counterbalancing anti-inflammatory cascade called compensatory anti-inflammatory response syndrome.27 This concept may lead us to consider that severe infections are associated with longer post-COVID-19 manifestations, which was in fact noticed here when separating patients by age groups. The duration of symptoms was longer in older patients with severe COVID-19 when compared with patients with mild or moderate disease, although 60% of long COVID syndrome identified in this work came from mild and 13% from moderate disease, with symptoms persisting for 1–14 mo in all severity groups.
SARS and Middle East respiratory syndrome (MERS) both cause persistent postinfection symptoms and psychological sequelae. The long-term effects of SARS include chronic fatigue, myalgia, anorexia and pulmonary damage.28–30 MERS has been linked to long-term insomnia and impaired pulmonary function. Both viruses have been shown to result in long-term depression and anxiety persisting for many years postinfection.31 As SARS-CoV-2 is closely related to SARS and MERS, it should not be surprising to see similar manifestations in COVID-19 survivors.32
Comorbidities are known to increase the severity of SARS-CoV-2 acute infection.33–35 The presence of chronic arterial hypertension, diabetes, heart disease, cancer, chronic obstructive pulmonary disease, chronic kidney disease and being a smoker or alcoholic was significantly correlated with the severity of disease in the current study, and the severity of acute infection was the main factor that determined the duration of symptoms in long COVID cases. Although this perspective of correlating pre-existing comorbidities with long COVID syndrome duration is recent, it is well known that the severity-mortality of COVID-19 is directly correlated with the presence of comorbidities, such as hypertension, cardiovascular disease, acute cardiac injury and diabetes, among others.33,36,37 SARS-CoV-2 infection in patients with underlying comorbidities may lead to excessive cytokine release, which results in acute respiratory distress syndrome, hypercoagulable state, maladaptation of the angiotensin-converting enzyme 2 (ACE2) pathway and hypoperfusion to end-organs.38,39
From the entire cohort studied in this work, only five patients (0.8%) were identified as positive for COVID-19 after being fully vaccinated. Three of thosepresented with long COVID syndrome after mild or moderate infections with persistent symptoms lasting for up to 3 mo. It was not possible to statistically correlate unvaccinated and fully vaccinated patients due to the low number of infections in the vaccinated group, which reinforces the importance of vaccination as the most important measure of virus control. Vaccination leads to a significant reduction in the number of infections, reinfections and severe cases.40 Consequently, a reduction in long COVID syndrome is expected. This work showed that even infections with milder symptoms lead to the development of long COVID syndrome and its sequelae. The duration of these manifestations and the prolonged distortion of the senses can be devastating and can lead to loss of work capacity and quality of life. Thus continuous evaluation is imperative.
Conclusions
This work highlights the wide range of symptoms experienced by patients with long COVID syndrome after mild, moderate and severe SARS-CoV-2 infection. Little is known about the pathogenesis of these manifestations that start after acute infection and can remain for at least 14 mo, even after a mild course of infection, as presented here. Viral infections causing persistent symptoms are not a new concept, as SARS and MERS both cause persistent postinfection symptoms that remain many years postinfection. What remains to be determined with COVID-19 is the severity and duration of long COVID manifestations. Continuous evaluation of the long-term effects and its impact on the quality of life of recovering patients is required, as we need to be prepared for the increase in pulmonary, cardiac, vascular, renal and other organ events after SARS-CoV-2 infection.
Authors’ contributions
DM collected the data, performed the analysis, monitored patients and wrote the paper. SG collected the data, performed the analysis and monitored patients. PF collected the data, performed the analysis and monitored patients. CC collected the data, performed the analysis and monitored patients. NA collected the data, performed the analysis and monitored patients. RS collected the data and monitored patients in hospitals. MM collected the data and monitored patients in hospitals. RV monitored patients in hospitals. GF designed and performed the analysis and wrote the paper. RG coordinated the study, designed, performed the analysis and wrote the paper.
Acknowledgements
We thank Hospital da Baleia and Hospital Metropolitano Dr Celio de Castro care team members for the partnership and for providing an excellent service on the frontline during COVID-19.
Funding
Oswaldo Cruz Foundation (Fiocruz) (to RFQG and scholarship to CC), The Brazilian National Council for Scientific and Technological Development (CNPq) (scholarships to DM and SG), Coordination for the Improvement of Higher Education Personnel (CAPES) (scholarship to NA) and The Minas Gerais Research Funding Foundation (FAPEMIG) (scholarship to PF).
Competing interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Ethical approval
Written informed consent was obtained from each enrolled patient. This study was approved by the Ethical in Human Research Committee of Oswaldo Cruz Foundation and the National Brazilian Ethical Board (CONEP N. 30428720.3.0000.5091 and N. 42898621.9.0000.5091).
Data availability
Data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices), will be available for researchers who provide a methodologically sound proposal to the corresponding author. To gain access, data requestors will need to sign a data access agreement.
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