Jogh 13 06015
Jogh 13 06015
© 2023 The Author(s) Cite as: Cazé AB, Cerqueira-Silva T, Bomfim AP, de Souza GL, Azevedo ACA, Brasil MQA,
Santos NR, Cunha RK, Dan J, Bandeira AC, de Goes Cavalcanti LP, Barral-Netto M, Barral AMP,
Barbosa CG, Boaventura VS. Prevalence and risk factors for long COVID after mild disease: A
cohort study with a symptomatic control group. J Glob Health 2023;13:06015.
evaluated in 102 out of 122 cases of long COVID, with 57 (55.9%) reporting an impact in at least one
dimension of the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) questionnaire.
Conclusions In this prospective study consisting predominantly of individuals with mild disease, the
persistence of symptoms after an acute respiratory illness was associated with a diagnosis of COVID-19.
Polysymptomatic acute disease and older age were risk factors for long COVID.
Long COVID has received less attention from the scientific community than acute COVID-19, representing
less than 2% of COVID-19 publications in PubMed Clinical Queries (as of August 31, 2022). Consequent-
ly, several important aspects remain undefined, such as its prevalence. Long COVID has been reported to
affect between 7.5% to 89% of patients [1-4]. However, most of these studies do not include well-matched
controls, which is essential because long COVID symptoms are non-specific and may be attributed to other
factors such as the physical and mental impact of having COVID-19 infection or hospitalization [5,6]. Pro-
spective studies enrolling symptomatic individuals with and without confirmed COVID-19 are necessary
to better estimate the prevalence of long COVID and its associated risk factors.
Identifying risk factors for developing long COVID is key to mitigating its anticipated impact on the health-
care systems [7]. Some large cohorts using previously hospitalized patients reported risk factors for devel-
oping long COVID [1,8,9]. However, few studies evaluated risk factors in individuals after mild disease [10].
We examined the clinical characteristics and diagnosis of all patients presenting with acute respiratory ill-
ness at three healthcare units in Bahia-Brazil and the prevalence of long COVID in the SARS-CoV-2 posi-
tive group. Additionally, we explored the risk factors associated with this condition and its impact on the
participants’ quality of life.
METHODS
Study population
We recruited individuals aged ≥15 years who were suspected of having a SARS-CoV-2 infection from
healthcare units in three municipalities of Bahia State, Brazil (Irecê, Campo Formoso, and Lauro de Fre-
itas). We excluded individuals who had difficulty reporting symptoms, who were at >20 days post-symp-
tom onset at the time of recruitment, or who previously reported a SARS-CoV-2 infection. The recruitment
period lasted from September 2020 to April 2021. The ancestral strain or gamma variant of SARS-CoV-2
was dominant in Brazil from November 2020 to August 2021 (Figure S1 in the Online Supplementary
Document) [11].
Exposure measurement
We collected nasopharyngeal swab samples from all patients to test for SARS-COV-2 using reverse tran-
scriptase polymerase chain reaction (RT-PCR). We excluded patients who had an RT-PCR ten days follow-
ing symptom onset. We collected the samples using either the BIOMOL OneStep/COVID-19 or the Allplex
SARS-CoV-2 Assay testing kit, with a sensitivity above 90% and specificity above 97% [12,13]. We reported
the results following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)
(Online Supplementary Document) [14].
Outcomes of interest
We defined long COVID according to the Centers for Disease Control and Prevention classification [15] and
persistence of symptoms as the presence of at least one residual symptom >1 month post-disease onset. The
list of evaluated residual symptoms (Questionnaire 3) was based on previous studies [16,17].
We applied the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) questionnaire via telephone to
assess health dimensions: mobility, self-care, daily activities, pain/discomfort, and anxiety/depression. We
also used the European Quality visual analogue scale (EQ-VAS), with 0 rated as the worst and 100 as the
best imaginable health state [18]. We applied the Portuguese-validated version of the EQ-5D-3L question-
naire [19].
Statistical analysis
We described categorical data using counts and percentages and continuous data (determined using the
Shapiro-Wilk test) using medians and interquartile ranges (IQRs). We constructed the correlation matrix
based on the frequency of reported residual symptoms. We performed multivariable logistic regression to
explore risk factors previously associated with long COVID in the literature: age, sex, and number of symp-
toms in the acute phase [10,20-22]. We also performed a sensitivity analysis, including on the comorbidi-
ties. The estimated 95% Wald confidence interval
(95% CI) was employed for measures of associa-
tion to interpret the findings. We used the R statis-
tical software (version 4.2.0) for all analyses [23].
Ethics
We obtained informed consent from all partici-
pants. The Ethics in Research Committee of the
Gonçalo Moniz Research Center approved this
study (approval No. 4.315.319/202).
RESULTS
We recruited 1268 patients with suspected SARS-
CoV-2 infection up to five days post-disease onset,
all of whom answered the first questionnaire. We
excluded 39 (3.0%) individuals who were tested
outside RT-PCR recommended period or reported
a second SARS-CoV-2 infection and 415 (32.8%)
who were lost to follow-up. A total of 814 (64.2%)
patients were considered eligible for the analysis
Figure 1. Flowchart of the study population. RT-PCR – reverse transcription of residual symptoms (Figure 1 and Figure S5 in
polymerase chain reaction. the Online Supplementary Document). Ques-
Table 1. Clinical, sociodemographic characteristics and frequency of residual symptoms for COVID-19 and non-
COVID-19 cases
COVID-19 cases Non-COVID-19 cases
Characteristics P-value*
(n = 412), n (%) (n = 402), n (%)
Age in years, median (IQR) 36 (28-48) 34 (25-43) <0.001
Age group in years <0.001
15-30 126 (30.6) 167 (41.5)
31-40 123 (29.9) 106 (26.4)
41-50 75 (18.2) 82 (20.4)
>50 88 (21.4) 47 (11.7)
Female sex 228 (55.3) 259 (64.4) 0.01
Number of acute symptoms, median (IQR) 11 (8-14) 10 (7-13) 0.01
Any comorbidities 148 (35.9) 131 (32.5) 0.3
Number of comorbidities 0.6
0 264 (64.1) 271 (67.4)
1 101 (24.5) 90 (22.4)
>1 47 (11.4) 41 (10.2)
BMI in kg/m2, median (IQR) 27 (23.5-29.8) 26.1 (23.5-29.1) 0.05
Obesity 102 (24.8) 86 (21.4) 0.7
Normal 310 (75.2) 316 (78.6)
Obese (BMI = 30-34) 21 (5.1) 17 (4.2)
Overweight (BMI = 35-39) 79 (19.2) 67 (16.7)
Extremely obese (BMI>40) 2 (0.5) 2 (0.5)
Type of hospitalization <0.001
Outpatient (mild) 346 (84.2) 395 (98.5)
Hospitalization, non-ICU (moderate) 59 (14.4) 6 (1.5)
Hospitalization, ICU (severe) 6 (1.5) 0 (0)
At least one residual symptom >1 month after disease onset 122 (29.6) 24 (5.8) <0.001
Number of residual symptoms <0.001
0 292 (70.9) 378 (94.0)
1 57 (13.8) 9 (2.2)
>1 63 (15.3) 15 (3.7)
Length of follow-up in months, median (IQR) 3.35 (2.1-5.2) 3.65 (2.1-4.9) 0.5
BMI – body-mass index, IQR – interquartile range
*Pearson χ2 test or Wilcoxon rank sum test.
After one-month post-disease onset, 122/412 (29.6%) individuals from the COVID group reported at least
one residual symptom, meeting the CDC’s definition of long COVID [15]. Residual symptoms were report-
ed only by 24 (6%) individuals (Table 1) from the non-COVID group. Among 122 long COVID cases, 57
(46.7%) presented with more than two residual symptoms.
Within the COVID group, fatigue (n = 56, 13.7%), olfactory disorder (n = 42, 9.9%), myalgia (n = 36, 8.7%), gus-
tatory disorder (n = 27, 6.6%), and headache (n = 26, 6.1%) were the most frequently reported residual symp-
toms (Figure 2), starting during the acute phase. Other symptoms not reported during the acute phase, such
as memory loss and hair loss, were reported by patients with long COVID (Table S3 in the Online Supple-
mentary Document). Compared to patients who recovered, the long COVID group had more women (63.1%
vs 52.1%) and older individuals (40 (IQR = 32-51) vs 35 (IQR = 28-47) years; (Table 2)). Hospitalisation for
disease was comparable between long COVID (n = 21/122, 17.2%) and recovered patients (n = 44/290, 15.2%).
Table 2. Clinical and sociodemographic characteristics for COVID cases with or without long COVID
No long COVID (n = 290), Long COVID (n = 122),
Characteristics P-value*
n (%) n (%)
Age in years, median (IQR) 35 (28-47) 40 (32-51) 0.01
Age group in years 0.07
15-30 99 (34.1) 27 (22.1)
31-40 85 (29.3) 38 (31.1)
41-50 51 (17.9) 24 (19.7)
>50 55 (19.0) 33 (27.0)
Female sex 151 (52.1) 77 (63.1) 0.04
BMI in kg/m2, median (IQR) 26.9 (23.5-29.7) 27.2 (23.8-30.1) 0.8
Number of acute symptoms, median (IQR) 11 (7-14) 12 (9-15) 0.01
Obesity 70 (24.1) 32 (26.2) 0.4
Obese (BMI = 30-34) 12 (4.1) 9 (7.4)
Overweight (BMI = 35-39) 57 (19.7) 22 (18.0)
Extremely obese (BMI >40) 1 (0.3) 1 (0.3)
Number of comorbidities 0.05
0 189 (65.0) 75 (61.0)
1 75 (25.9) 26 (21.3)
>1 26 (9.0) 21 (17.2)
Length of follow-up – months, median (IQR) 3.30 (2.00-5.10) 3.75 (2.12-5.55) 0.07
Required hospitalization or ICU 44 (15.2) 21 (17.2) 0.27
BMI – body mass index, ICU – intensive care unit, IQR – interquartile range
*Pearson χ2 test or Wilcoxon rank sum test.
The risk of long COVID increased with age and was higher among individuals aged >50 years (odds ra-
tio (OR) = 2.44; 95% CI = 1.29-4.66) compared to individuals aged 15-30. Individuals with more than five
symptoms in the acute phase (OR = 3.15; 95% CI = 1.37-8.55) and females (OR = 1.55; 95% CI = 0.99-2.44)
were more likely to develop long COVID (Table 3). After adjusting for the number of comorbidities, body
mass index (BMI), respiratory allergy, and smoking in the sensitivity analysis, the results for the primary
variables did not change significantly (Table S4 in the Online Supplementary Document).
We also observed a co-occurrence of long COVID symptoms. At least 50% of individuals who reported fa-
tigue also complained of gustatory dysfunction, anorexia, dysphonia, chest pain, headache, breathlessness,
or myalgia, while 80% of participants with gustatory dysfunction also reported olfactory dysfunction (Fig-
ure S7 in the Online Supplementary Document).
CONCLUSIONS
We detected long COVID in 29.6% of patients with mild COVID-19 disease, with older age, female sex, and
polysymptomatic acute disease as the main risk factors for persistent symptoms. Estimating the prevalence
of long COVID is important for preparing healthcare systems to assist and guide these patients. Further
studies should evaluate the effect of different variants of SARS-CoV-2 on long COVID and the potential im-
pact of vaccines in reducing residual symptoms.
Acknowledgements: We wish to thank all patients who were willing to participate in the study. In addition, we would
like to thank Hospital Aeroporto and Municipal Health Secretariats of Irecê and Campo Formoso for logistical support
and to Roberta de Carvalho Freitas for patient-related support.
Funding: This study was supported by MCTI/CNPq/FNDCT/MS/SCTIE/Decit (nº 07/2020). This study was partial-
ly supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code
001 - and by CNPq 409004/2022-7. M.B.N., A.B. and V.S.B. are research fellows from CNPq, the Brazilian National
Research Council.
Authorship contributions: ABC, TCS and VB structured the original draft. VB and CB were responsible for concep-
tualization and methodology. APB, GLS, ACAA, MQAB, NRS, and ABC collected patient data. TCS made the formal
analysis statistics. AMPB and VB participated in the project administration and the funding acquisition. ABC, TCS, JD,
ACB, LPGC, MBN, ABN, CGB substantively revised the manuscript. All authors read and approved the final manuscript.
Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the
corresponding author) and disclose no relevant interests.
Additional material
Online Supplementary Document
1 Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global Prevalence of Post- Coronavirus Disease
(COVID-19) Condition or Long COVID: A Meta-Analysis and Systematic Review. J Infect Dis. 2022;226:1593-607. Med-
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