Background: Post-coronavirus disease (COVID-19) syndrome includes persistence of symptoms beyond viral clearance and fresh development of symptoms or exaggeration of chronic diseases within a month after initial clinical and virological cure of the disease with a viral etiology. We aimed to determine the incidence, association, and risk factors associated with development of the post-COVID-19 syndrome.

Methods: We conducted a prospective cohort study at Dhaka Medical College Hospital between June 01, 2020 and August 10, 2020. All the enrolled patients were followed up for a month after clinical improvement, which was defined according the World Health Organization and Bangladesh guidelines as normal body temperature for successive 3 days, significant improvement in respiratory symptoms (respiratory rate <25/breath/minute with no dyspnea), and oxygen saturation >93% without assisted oxygen inhalation.

Findings: Among the 400 recruited patients, 355 patients were analyzed. In total, 46% patients developed post-COVID-19 symptoms, with post-viral fatigue being the most prevalent symptom in 70% cases. The post-COVID-19 syndrome was associated with female gender (relative risk [RR]: 1.2, 95% confidence interval [CI]: 1.02–1.48, p=0.03), those who required a prolonged time for clinical improvement (p<0.001), and those showing COVID-19 positivity after 14 days (RR: 1.09, 95% CI: 1.00–1.19, p<0.001) of initial positivity. Patients with severe COVID-19 at presentation developed post-COVID-19 syndrome (p=0.02). Patients with fever (RR: 1.5, 95% CI: 1.05–2.27, p=0.03), cough (RR: 1.36, 95% CI: 1.02–1.81, p=0.04), respiratory distress (RR: 1.3, 95% CI: 1.4–1.56, p=0.001), and lethargy (RR: 1.2, 95% CI: 1.06–1.35, p=0.003) as the presenting features were associated with the development of the more susceptible to develop post COVID-19 syndrome than the others. Logistic regression analysis revealed female sex, respiratory distress, lethargy, and long duration of the disease as risk factors.

Conclusion: Female sex, respiratory distress, lethargy, and long disease duration are critical risk factors for the development of post-COVID-19 syndrome.      

Materials and methods

This single-center prospective cohort study was performed to determine the extent of post-COVID-19 symptoms along with its risk factors in patients with COVID-19. The study was conducted in the COVID-19 unit of Dhaka Medical College Hospital from June 01, 2020 to August 10, 2020. Ethical approval was obtained from the Institutional Ethical Committee (ERC-DMC/ECC/2020/559).   

Participants

Patients with COVID-19 presented to the triage and inpatient department of Dhaka Medical College were screened for the study. The recruitment was limited to patients aged >18 years with confirmed SARS-CoV-2 positivity on RT-PCR. Asymptomatic or critical COVID-19 cases and patients unwilling to participate were excluded from the study. Informed written consent was obtained from all patients. The recruited patients were followed up for at least a month after clinical recovery and/or viral clearance. Consecutive patients were enrolled in the study. The sample size for this study was determined using the formula:

z²pqd²       

where z=1.96 (at 95% confidence level); p=50%, as the prevalence of post-COVID-19 syndrome is not known in Bangladesh; and q=(100-p)=50. Here, d represents absolute error and was set at 5%. Therefore, the sample size, calculated as n= (1.96)²×50×50/5², was 384 patients. A total of 400 patients were enrolled in the study.

Study design

A case record form was constructed to collect baseline information of patients, such as demographics, clinical signs and symptoms, comorbidities, and oxygen saturation. Routine tests, including those for complete blood count, C-reactive protein, creatinine, random blood sugar, alanine aminotransferase, and D-dimer and chest X-ray, were advised on enrollment. RT-PCR testing for COVID-19 was performed 14 days after the initial positive test result for all the patients. A telephonic interview guide for the follow-up of patients after discharge was also developed. Patients were followed up via telecon for at least a month after recovery or hospital discharge. Clinical improvement was defined according to the WHO and Bangladesh guidelines [8, 13] as follows: normal body temperature for at least 3 days, significant improvement in respiratory symptoms (respiratory rate <25breath/ minute and no dyspnea), oxygen saturation (SpO₂) >93% with no assistance for oxygen inhalation, and no hospital care needed for any pathology or clinician assessment. Respiratory distress was defined as shortness of breath, respiratory rate >25breath /min, or SpO₂ <93%, and mild disease was defined as symptoms of an upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, anosmia, or malaise. Moderate disease was defined as respiratory symptoms such as cough and shortness of breath without signs of severe pneumonia. Severe disease was defined as severe dyspnea, tachypnea (>30 breaths/min), and hypoxia (SpO2 <90% in room air). Critical cases involved patients who developed ARDS or sepsis. These classifications were made according to the WHO and national guidelines of Bangladesh [8, 13]. The WHO has defined viral clearance as laboratory evidence of SARS-CoV-2 clearance in respiratory samples, i.e., two negative RT-PCR results using respiratory tract samples (nasopharynx and throat swabs), with a sampling interval of ≥24 h, after 14 days of initial positivity. However, due to limited testing facilities, we could perform RT-PCR only on day 14 after initial positivity for each patient. The criteria for post-COVID-19 syndrome considered in this research are described in the introduction of this manuscript. In our study, we have considered post-viral fatigue as symptoms reported in the literature and listed in the previous section along with any of the following: cognitive impairment and orthostatic intolerance. However, unlike previous reports, the criteria of its duration for 6 months was not considered in the present study.

Procedure                         

Patients who met the inclusion criteria were enrolled in this study. Patients who required immediate hospital care were admitted. Routine and special investigations were performed according to the attending physician’s advice. All patients received standard care of treatment as advised by the accompanying physicians. Patients were followed up every day and their conditions were recorded. RT-PCR for COVID-19 was performed on day 14 after initial positivity. After discharge, patients were followed up for at least a month via telecon using the telephone interview guide.

Patients who did not require admission were sent home with appropriate treatment as recommended by the attending physician. They were advised to undergo routine investigations for their next visit. They were also followed up via telecon for at least a month after clinical recovery. Patients whose conditions deteriorated during the follow-up period were immediately advised for admission and were followed up similarly as those who received hospital care.

Statistical analysis

A sample size of 400 patients would provide a power of at least 90% in the two-tailed test using a p-value of <0.05 to detect a 50% incidence of post-COVID-19 syndrome. Statistical Package for Social Sciences version 20 was used to analyze the data. Categorical variables are presented as n (%), normally distributed continuously are presented as mean (standard deviation [SD]), and skewed continuous variables are presented as median (interquartile range [IQR]). Statistical significance was set at p <0.05. For the comparison of variables, two groups were considered. Group 1 included patients who developed post-COVID-19 syndrome, and Group 2 included patients who did not develop post-COVID-19 syndrome. Categorical variables were compared using the chi-square test, and continuous variables were compared using an independent sample Student’s t-test. Relative risk (RR) with a 95% confidence interval (CI) was calculated using crosstab analysis. The Mann–Whitney U test was used to compare skewed continuous variables. A binary logistic regression model was developed to assess the impact of different variables on the likelihood of developing post-COVID-19 syndrome with the forward conditional method. Independent variables included in the model were age, sex, presenting features of COVID-19, duration of recovery, conversion to next level of severity, persistent positivity for the virus, comorbidities, and severity of illness.

A funding statement: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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