Post COVID syndrome among symptomatic COVID-19 patients: a prospective study in a tertiary care center in Bangladesh

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.      

Methods
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.

背景：新冠病毒病（coronavirus disease 2019, COVID-19）后综合征指在初始临床与病毒学治愈后1个月内，病毒清除后仍持续存在症状、新发症状或慢性疾病加重的情况。本研究旨在明确新冠后综合征的发生率、相关性及相关危险因素。

方法：本研究于2020年6月1日至2020年8月10日在达卡医学院附属医院开展一项前瞻性队列研究。所有入组患者在临床症状改善后接受为期1个月的随访。临床症状改善的判定标准参照世界卫生组织（World Health Organization, WHO）及孟加拉国指南，定义为连续3天体温正常、呼吸道症状显著改善（呼吸频率<25次/分且无呼吸困难）、未接受辅助氧疗时血氧饱和度>93%。

结果：本研究共纳入400例患者，最终对355例患者进行数据分析。总体而言，46%的患者出现新冠后症状，其中病毒感染后疲劳是最常见的症状，占比达70%。新冠后综合征与女性性别（相对危险度[RR]=1.2，95%置信区间[CI]：1.02~1.48，p=0.03）、临床症状改善所需时间延长（p<0.001）以及初始病毒检测阳性14天后仍呈阳性的患者（RR=1.09，95%CI：1.00~1.19，p<0.001）显著相关。就诊时即为重症新冠的患者更易发生新冠后综合征（p=0.02）。以发热（RR=1.5，95%CI：1.05~2.27，p=0.03）、咳嗽（RR=1.36，95%CI：1.02~1.81，p=0.04）、呼吸窘迫（RR=1.3，95%CI：1.4~1.56，p=0.001）、嗜睡（RR=1.2，95%CI：1.06~1.35，p=0.003）为首发表现的患者，相较于其他患者更易发生新冠后综合征。Logistic回归分析显示，女性性别、呼吸窘迫、嗜睡及病程延长是新冠后综合征发生的危险因素。

结论：女性性别、呼吸窘迫、嗜睡及病程延长是新冠后综合征发生的关键危险因素。

材料与方法：本研究为单中心前瞻性队列研究，旨在明确新冠患者的新冠后症状发生情况及其危险因素。研究于2020年6月1日至2020年8月10日在达卡医学院附属医院新冠病房开展。本研究已获得机构伦理委员会批准（编号：ERC-DMC/ECC/2020/559）。

研究对象：本研究筛选就诊于达卡医学院分诊及住院部的新冠患者。入组标准为年龄>18岁且经逆转录聚合酶链反应（reverse transcription-polymerase chain reaction, RT-PCR）确诊为严重急性呼吸综合征冠状病毒2型（severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）阳性的患者。排除无症状或重症新冠患者以及不愿参与本研究的受试者。所有患者均签署书面知情同意书。入组患者在临床康复及/或病毒清除后接受至少1个月的随访。本研究纳入连续性就诊的患者。本研究样本量通过以下公式计算：$n=frac{z^2pq}{d^2}$，其中z=1.96（对应95%置信水平）；因孟加拉国尚无新冠后综合征患病率数据，故设定p=50%，q=1-p=50%；d为绝对误差，设定为5%。经计算，样本量$n=frac{(1.96)^2×50×50}{5^2}=384$例，最终共纳入400例患者。

研究设计：本研究自制病例记录表以收集患者基线资料，包括人口学特征、临床体征与症状、合并症及血氧饱和度。入组时为患者开具常规检查项目，包括全血细胞计数、C反应蛋白、肌酐、随机血糖、丙氨酸氨基转移酶、D-二聚体及胸部X线检查。所有患者在初始新冠病毒检测阳性后第14天接受RT-PCR复查。本研究同时制定了出院患者随访电话访谈指南。患者在临床康复或出院后通过电话随访至少1个月。临床症状改善参照WHO及孟加拉国指南[8,13]定义为：连续至少3天体温正常、呼吸道症状显著改善（呼吸频率<25次/分且无呼吸困难）、未接受氧疗时脉搏血氧饱和度（SpO2）>93%，且无需因任何疾病或临床评估再次住院。呼吸窘迫定义为呼吸困难、呼吸频率>25次/分或SpO2<93%；轻症新冠定义为上呼吸道病毒感染相关症状，包括轻度发热、（干性）咳嗽、咽痛、鼻塞、乏力、头痛、肌肉酸痛、嗅觉减退或丧失。中症新冠定义为存在咳嗽、呼吸困难等呼吸道症状，但无重症肺炎征象。重症新冠定义为严重呼吸困难、呼吸急促（>30次/分）及低氧血症（室内空气下SpO2<90%）。危重症患者指出现急性呼吸窘迫综合征（acute respiratory distress syndrome, ARDS）或脓毒症的患者。上述病情分类均参照WHO及孟加拉国国家指南[8,13]制定。WHO将病毒清除定义为呼吸道样本实验室检测证实SARS-CoV-2已清除，即初始阳性后14天内，采集呼吸道样本（鼻咽拭子及咽拭子）行RT-PCR检测结果连续2次阴性，且两次采样间隔≥24小时。但由于检测设施有限，本研究仅在每位患者初始病毒检测阳性后第14天进行1次RT-PCR检测。本研究采用的新冠后综合征判定标准已在本文引言部分阐述。本研究将病毒感染后疲劳视为文献报道的典型症状，并纳入前文所列的相关表现，同时结合以下任一症状：认知功能障碍及体位不耐受。与既往研究不同，本研究未将症状持续6个月作为新冠后综合征的判定标准。

研究流程：符合入组标准的患者纳入本研究。需紧急住院治疗的患者直接收治入院。常规及特殊检查项目均按照主治医师的建议开展。所有患者均接受主管医师推荐的标准化治疗方案。研究人员每日对患者进行随访并记录病情变化。所有患者在初始病毒检测阳性后第14天接受RT-PCR检测。患者出院后，通过电话随访指南进行至少1个月的远程随访。无需住院的患者按照主管医师的建议接受相应治疗后出院，并被告知下次就诊时需完成常规检查。这些患者在临床康复后同样接受至少1个月的远程随访。随访期间病情恶化的患者将被建议立即住院，并按照住院患者的流程进行随访。

统计学分析：本研究纳入400例患者，在双侧检验、p<0.05的检验水准下，可获得至少90%的检验效能以检测50%的新冠后综合征发生率。本研究采用社会科学统计软件包（Statistical Package for the Social Sciences, SPSS）20.0版本进行数据分析。分类变量以例数（百分比）[n (%)]表示；正态分布的连续变量以均数±标准差（$ar{x}±SD$）表示；偏态分布的连续变量以中位数（四分位数间距，IQR）表示。本研究设定统计学显著性检验水准为p<0.05。本研究将患者分为两组：组1为发生新冠后综合征的患者，组2为未发生新冠后综合征的患者。分类变量比较采用卡方检验，正态分布的连续变量比较采用独立样本t检验，通过交叉表分析计算相对危险度（RR）及95%置信区间（CI）。偏态分布的连续变量比较采用Mann-Whitney U检验。本研究采用前进法构建二元logistic回归模型，以评估各变量对新冠后综合征发生风险的影响。模型纳入的自变量包括年龄、性别、新冠首发表现、康复时长、病情进展至更严重分级的情况、病毒持续阳性情况、合并症及病情严重程度。

资助声明：本研究未获得公共、商业或非营利性部门任何资助机构的专项资助。