Post-COVID-19 syndrome among symptomatic COVID-19 patients: A prospective cohort study in a tertiary care center of 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.

Introduction

Since the first report of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), which causes coronavirus disease (COVID-19) on December 31 [1], the virus has dominated the life of every person worldwide. The clinical presentation of COVID-19 ranges from asymptomatic, mild symptomatic to fulminant and fatal cases. Severe cases of infection can lead to serious complications including, pneumonia, acute respiratory distress syndrome (ARDS), sepsis, multiple organ failure, blood clotting, myocarditis, acute myocardial infarction, acute kidney injury, and other viral and bacterial infections that are not unique to coronavirus [2, 3]. COVID-19-associated death is possibly a result of pneumonia and hyperinflammation associated with cytokine storm syndrome [4].

The COVID-19 symptoms last for an average of 11.5±5.7 days [5]. However, a significant proportion of patients have been found to remain unwell at post-discharge follow-ups [6]. In the United Kingdom, a smartphone application-based study revealed the persistence of COVID-19 symptoms in approximately 10% patients after 3 weeks of disease onset; in some patients, the symptoms persisted for months [7]. The mechanism of this post-disease syndrome is unclear.

To address this issue, we need to define this condition first. There is no clear consensus on the definition of post-COVID-19 syndrome. In this article, we have defined post-COVID-19 syndrome as (1) persistence of illness signs and symptoms (except fever, respiratory distress, and hypoxia) after viral clearance (negative real time-polymerase chain reaction [RT-PCR] results for COVID-19 at day 14 after initial positivity) or meeting the World Health Organization (WHO) clinical criteria of improvement [8], including no fever for >3 days, improved respiratory symptoms, pulmonary imaging showing obvious absorption of inflammation, and no hospital care needed for any pathology or clinician assessment; (2) fresh development of symptoms within a month after initial clinical and virological cure, the etiology of which is postulated to be a viral infection (occurring after recovery); (3) exaggeration of previously experienced chronic disease, such as migraine, mental disorder, bronchial asthma, and rheumatologic disorders, within a month after initial recovery from COVID-19.

Past experience with another coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), revealed post-viral fatigue syndrome/myalgic encephalomyelitis as the most common symptom of the disease. As previously reported, the virus reaches the hypothalamus via the olfactory pathway and disturbs its lymphatic drainage. This leads to the formation of pro-inflammatory cytokines, interleukins, and interferon gamma [9, 10] within the hypothalamus, which leads to the development of post-viral fatigability. Similarly, in COVID-19, the most common symptoms after acute COVID-19 are fatigue and dyspnea [11]. Diagnosis of post-viral fatigue [12] requires certain specific symptoms. It is most commonly accompanied by a substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persist for >6 months. In many cases, there is new or definite onset (not lifelong) of profound fatigue, which is not the result of ongoing excessive exertion and is not substantially alleviated by rest. Further, post-exertional malaise and unrefreshing sleep are some of the common features. For further exploration of post-COVID-19 syndrome, it is necessary to have knowledge regarding the incidence, types, and risk factors of this syndrome. Therefore, this study aimed to determine the incidence, types of association, and risk factors for the development of post-COVID-19 syndrome in a cohort of patients with COVID-19.

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 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.

Results

Of the 486 patients who were screened and assessed for eligibility, 400 patients were enrolled in the study. In total, 42 patients were lost to follow-up and 3 patients died during follow-up. Hence, 355 patients completed the study (Fig 1).

Fig 1

Patient selection for this prospective cohort study.

The mean (SD) age of the study patients in was 39.8 (13.4) years. Most patients (60%) were younger than 40 years of age. The ratio of male and female patients was 1.4:1. Most patients presented fever (75%) and cough (62%), and a few (36%) patients showed signs of respiratory distress. Other important clinical features included anosmia (39%), hypoxia (30%), headache (20%), and lethargy (23%). Among the recruited patients, 62% patients had mild disease, 26% patients exhibited moderate disease, and 11% patients had severe disease. Some (27%) patients also had associated comorbidities (Table 1).

Table 1

Baseline characteristics of COVID-19 patients with or without post-COVID-19 syndrome.

Variables	Total populationn = 355	Group 1an = 162	Group 2bn = 193	p value	RR (95% CI)
Age (years), mean (SD)	39.8 (13.4)	40 (12.3)	39.6 (14.3)	0.81c
Age <40 years, mean (SD)	219 (61.7)	100 (61.7)	119 (61.7)	0.65
Age = 40–60 years, mean (SD)	107 (30.1)	51 (31.5)	56 (29)
Age >60 years, mean (SD)	29 (8.2)	11 (6.8)	18 (9.3)
Sex (male), n (%)	207 (58.3)	84 (51.9)	123 (63.7)	0.03	1.2(1.02–1.48)
Total duration of illness (days) median (IQR)	12 (8–16)	15 (10–20)	10 (7–13)	<0.001d
Fever, n (%)	267 (75.2)	131 (80.9)	136 (70.5)	0.03	1.5(1.05–2.27)
Cough, n (%)	224 (68.1)	112 (69.1)	112 (58)	0.04	1.36(1.02–1.81)
Respiratory distresse, n (%)	129(36.3)	75(45.7)	55(28.5)	0.001	1.3(1.14–1.56)
Running Nose, n (%)	29 (8.2)	11 (6.8)	18 (9.3)	0.44	0.97(0.91–1.03)
Chest pain	17(4.8)	6(3.7)	11(5.7)	0.45	0.97(0.94–1.03)
Sore throat, n (%)	80 (22.5)	28 (17.3)	56 (26.9)	0.03	0.88(0.79–0.98)
Diarrhea, n (%)	23 (6.5)	11 (6.8)	12 (6.2)	0.83	1.01(0.95–1.06)
Vomiting, n (%)	17 (4.8)	9 (5.6)	8 (4.1)	0.62	1.02(0.97–1.06)
Anorexia, n (%)	107 (30.1)	56 (34.6)	51 (26.4)	0.12	1.12(0.98–1.39)
Anosmia, n (%)	138 (38.9)	63 (38.9)	75 (38.9)	1	1(0.85–1.18)
Headache, n (%)	73 (20.6)	37 (22.8)	36 (11.7)	0.36	1.05(0.95–1.170
Lethargy, n (%)	81 (22.8)	49 (30.2)	32 (16.6)	0.003	1.20(1.06–1.35)
Body ache, n (%)	66 (18.8)	34 (21)	32 (16.6)	0.34	1.06(0.95–1.17)
Persistent positivityf	49 (13.8)	29 (17.9)	20 (10.4)	0.04	1.09(1.00–1.19)
Severity conversiong	56 (15.8)	28 (17.3)	28 (14.5)	0.56	1.03(0.94–1.13)
Comorbidity	97 (27.3)	47 (29)	50 (25.9)	0.55	1.04(0.96–1.19)
Hypertension, n (%)	54 (15.2)	21 (13)	33 (17.1)	0.30	0.95(0.87–1.04)
Diabetes, n (%)	49 (13.8)	25 (15.4)	24 (12.4)	0.44	1.04(0.95–1.13)
Severity gradeh
Mild, n (%)	221 (62.3)	90 (55.6)	131 (67.3)	0.02
Moderate, n (%)	93 (26.2)	54 (33.3)	39 (20.2)
Severe n (%)	41 (11.5)	18 (11.1)	23 (11.3)

RR, relative risk; CI, confidence interval; SD, standard deviation; IQR, interquartile range.

a Group 1 patients who developed post-COVID-19 syndrome.

b Group 2 patients who did not develop post-COVID-19 syndrome.

c Independent sample t-test.

d Non-parametric test, Mann–Whitney U test.

e Shortness of breath, respiratory rate >25/min, or oxygen saturation <93%.

f Persistent positivity: patient who remained positive on the 14-day RT-PCR test after initial positivity.

g Patient experienced disease progression to the next level of severity during the follow-up from the initial presenting severity.

h Disease severity at presentation: mild symptoms of upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, anosmia, or malaise; moderate respiratory symptoms such as cough and shortness of breath are present without signs of severe pneumonia (tachypnea >30 breaths/min and hypoxia: oxygen saturation <90% on room air).

The incidence of post-COVID-19 syndrome was 46%. The median (IQR) interval between the recovery and development of post-COVID-19 symptoms was 7 (5–10.5) days. COVID-19 symptoms persisted beyond recovery in approximately 17% cases, whereas they developed after 7 days of recovery in 43% cases. In total, 105 (30%) patients shows at least one post-COVID-19 symptom, while 57 (16%) patients showed multiple symptoms. Post-viral fatigue was the most prevalent feature (117 [33%]). Other features included persistent cough (8.5%), post-exertional dyspnea (7%), headache (3.4%), vertigo (2.3%), and sleep-related disorders (5.9%) (Table 2).

Table 2

Spectrum of post-COVID-19 symptoms.

Trait	Total patientsn = 355, n (%)	Symptomatic patientsn = 162, (%)
Post viral fatiguea	117 (33)	70.7
Persistent coughb	30 (8.5)	18.3
Insomniac	8 (2.3)	4.9
Circadian rhythm sleep disordersd	14 (3.9)	8.5
Headache	12 (3.4)	7.3
Vertigo	8 (2.3)	4.9
Post-exertional dyspneae	25 (7)	15.2
Rash	2 (0.6)	1.2
Pneumoniaf	2 (0.6)	1.2
Restless leg syndromeg	2 (0.6)	1.2
Bradycardia	2 (0.6)	1.2
Palpitation	4 (1.4)	2.4
Anosmia	7 (2)	1.2
Tinnitus	1 (0.3)	0.6
Nasal blockade	2 (0.3)	1.2
Chest pain	3 (0.8)	1.8
Adjustment disorderh	5 (1.4)	3
Arthralgia	4 (1.4)	4.8
New-onset diabetes	1 (0.3)	0.6
New-onset hypertension	2 (0.6)	1.2
Non-ulcer Dyspepsia	4 (1.4)	4.8
Excessive sweating	4 (1.4)	4.8
Myalgia	2 (0.6)	1.2
Burning feet	1 (0.6)	0.6
Disturbance of memoryi	2 (0.6)	1.2
Precipitation of gout	1 (0.3)	0.6
Frequency of symptoms
Single	105 (29.6)	65.2
Multiple	57 (16.1)	34.8
Interval of symptom development from recovery
From beginning	27 (7.6)	16.7
<7 days	64 (18.0)	39.5
>7 days	71 (20)	43.8

aA substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities accompanied by profound fatigue.

bCoughing for >1 h or ≥3 coughing episodes in 24 h.

cPersistent difficulty with sleep initiation, duration, consolidation, or quality.

dAbnormalities in length, timing, and/or rigidity of the sleep–wake cycle relative to the day–night cycle.

ePerception of respiratory discomfort that occurs for an activity level that does not normally lead to breathing discomfort.

fNew-onset bacterial pneumonia.

gUnpleasant sensation in the legs, causing overwhelming irresistible urge to move the legs, especially at bedtime.

hEmotional or behavioral symptoms occurring within 3 months of a stressor and lasting ≤6 months after the stressor or its consequences end.

iPathological partial or complete loss of the ability to recall past experiences (retrograde amnesia) or to form new memories (anterograde amnesia).

Post-COVID-19 features were significantly higher among women (RR: 1.2, 95% CI: 1.02–1.48, p = 0.03), those who required a long time to achieve clinical improvement (p<0.001), and those showing COVID-19 positivity on RT-PCR after day 14 of initial positivity (RR: 1.09, 95% CI: 1.00–1.19, p<0.001). Additionally, patients with severe forms of the disease at presentation had a higher tendency to develop post-COVID-19 symptoms (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 more susceptible to develop post-COVID-19 syndrome compared to other presenting features. However, sore throat (RR: 10.88, 95% CI: 0.79–0.98, p = 0.03) was negatively associated with the development of post-COVID-19 syndrome (Table 1).

The logistic regression model explained 26% variation with 79% specificity. The variables made a unique statistically significant contribution to the model, as determined by forward conditional methods—female sex (odds ratio [OR]: 1.7, 95% CI: 1.1–2.8, p = 0.02), respiratory distress (OR: 0.21; 95% CI: 0.08–0.55, p = 0.001), lethargy (OR: 0.40, 95% CI: 0.22–0.70, p = 0.002), duration of illness (OR: 1.2, 95% CI: 1.1–1.2, p<0.001), and severity of illness (OR: 0.43, 95% CI: 0.20–0.93, p = 0.03) (Table 3). Some of the initial COVID-19 features overlap with the post-COVID-19 symptoms. However, the post-COVID symptoms have diverse presentations (Fig 2).

Table 3

Risk factors for post-COVID-19 syndrome (binary logistic regression analysis).

Variables	Reference category	Bd	SEe	Waldf	p value	Odd Ratio	95% CI
Gender	Female	0.56	0.24	5.0	0.02	1.7	1.1–2.8
Respiratory distressb	Absence	−1.5	0.49	10.1	0.001	0.21	0.08–0.55
Lethargy	Absence	−0.92	0.29	9.9	0.002	0.40	0.22–0.70
Total duration of illness		0.15	0.03	33	<0.001	1.2	1.1–1.2
Severityc	Mild	−0.85	0.39	4.6	0.03	0.43	0.20–0.93
Constant		−0.005	1.1	0.00	0.99	0.99

aIndependent variables: sex, age, all COVID-19 symptoms, severity of COVID-19, severity conversion, persistent positivity, total duration of illness, patient suffering for <7 days and >14 days; Omnibus test of model coefficient, 0.00; Nagelkerke R square, 0.26; Hosmer–Lemeshow test, 0.83; Step 7, sensitivity 60%, specificity 79%.

bShortness of breath, respiratory rate >25 breath/min, or oxygen saturation <93%.

cDisease severity at presentation: mild symptoms of upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, anosmia, or malaise; moderate respiratory symptoms such as cough and shortness of breath without signs of severe pneumonia (tachypnea >30 breaths/min and hypoxia: SpO2 <90% on room air).

This is the coefficient for the constant (also called the “intercept”) in the null model.

This is the standard error around the coefficient for the constant.

fThe Wald chi-square value.

Fig 2

Comparison of COVID-19 and post-COVID-19 symptoms.

Discussion

In this study involving 355 patients, the incidence of the post-COVID-19 syndrome was 46%, and most patients developed the symptoms after 7 days of initial recovery from the disease. The presentations varied widely; some patients had overlapping symptoms between COVID-19 and post-COVID-19 syndrome. Post-viral fatigue was the most common symptom, followed by persistent cough, exertional dyspnea, sleep disorders, adjustment disorders, and headache. Female sex, presenting features of respiratory distress, long recovery period, and disease severity were found to be risk factors for post-COVID-19 syndrome. Thus, this study revealed that the patients did not completely recover, even after apparent clinical recovery. The COVID-19 also caused long-term sequelae and distress in nearly half of the patients.

The demographics of patients with COVID-19 in this study varied from that of patients from Western countries. The most notable feature was patient age. In this study, 60% patients were aged <40 years and only 8% patients were aged >60 years. In a study from the USA, 31% patients were aged >65 years [14]. This is probably due to the sociocultural background of Bangladesh, where the proportion of the elderly population (5%) is lower than that in Western world (North America, 16%; Europe, 21%) [15]. In the present study, the proportion of men with COVID-19 was higher than that of women. Most patients presented fever, cough, anosmia, hypoxia, and lethargy at initial presentation of the disease. Previous studies have reported such a pattern [16, 17]. The median (IQR) for the duration of illness was 12 (8–16) days, which is consistent with that reported in a previous study [18].

There is no consensus regarding the persistence or fresh development of symptoms in the post-COVID-19 state, and the condition is not defined. Greenhalgh et al. [19] tried to define the conditions as “post-acute COVID-19” and “chronic COVID-19,” which can extend beyond 3 weeks and 12 weeks, respectively, of the onset of first symptoms. This study was conducted among hospitalized patients, and approximately 10% patients showed post-COVID-19 symptoms. These patients required a long time to recover to meet the WHO criteria for recovery. Patients developing new symptoms or follow-up of mild COVID-19 symptoms were not considered in the study. Therefore, this study excluded a significant proportion of patients who had mild severity, did not need hospitalization, or developed new symptoms. Another study from Italy by Carfì et al. [6] followed-up the patients who met the WHO criteria for discontinuation of quarantine (no fever for consecutive 3 days, improvement in other symptoms, and two negative test results for SARS-CoV-2, 24 h apart. In approximately 87% cases, they found persistence of at least one symptom. However, the study sample was small, and a substantial number of patients received intensive care. Thus, the abovementioned studies are inadequate for explaining the post-COVID scenario as a whole. Moreover, a significant number of patients described in the studies were admitted to the intensive care unit. Patients admitted to the intensive care unit may develop symptoms such as executive dysfunction, anxiety, depression, and post-traumatic stress disorder due to post-intensive care syndrome [20]. If these symptoms are present in the post-COVID state among patients admitted to the intensive care unit, it is very difficult to differentiate whether these symptoms are purely post-COVID-19 related or are outcomes of post-intensive care syndrome. To avoid such bias, we excluded critical patients requiring intensive care unit admission.

Thus, we attempted to define the condition by including patients with mild, moderate, and severe disease, and excluding critical patients admitted to the intensive care unit who have risk of developing post-intensive care syndrome. We found that about half of the patients developed new symptoms, had persistent mild COVID symptoms, or had exacerbated chronic diseases. Approximately 15% patients continued to have mild COVID-19 symptoms (excluding fever, cough, and respiratory distress) and 85% patients developed new symptoms. A study from the USA revealed that 35% patients did not return to their usual health status even after 3 weeks of COVID-19 positivity [21].

In this study, approximately 46% patients developed the post-COVID-19 syndrome. In another study, nearly 90% hospitalized patients who recovered from COVID-19 reported persistence of at least one symptom even after 2 months of discharge; 12.6% patients had no related symptoms, 32% patients had one or two symptoms, and 55% patients exhibited three or more symptoms [6]. In our study, 65% patients had at least one persistent symptom and 34% had multiple persistent symptoms.

Various post-COVID-19 symptoms have been reported in different studies. Post-COVID-19 symptoms can develop even in mild cases [6]. Most studies have reported fatigue, cough, respiratory distress, and headache as the dominant features [6, 7, 11, 19]. In our study, fatigue, persistent cough, exertional dyspnea, sleep disorders, and headache or vertigo were observed in 70%, 18%, 15%, 13%, and 12% cases, respectively. The reason for the dominance of fatigue was mostly unexplained. Viral infection-related immune system alterations may be the cause of fatigue [9, 10]. Cough and respiratory distress can be explained by persistent squeal lung damage. A recent study from China [22] reported decreased diffusion capacity for carbon monoxide in 25% patients 3 months after hospital discharge. In our study, a significant proportion of patients had sleep disturbances, including insomnia and circadian rhythm sleep disturbances. Previous experience with other SARS-CoV infections has revealed that involvement of the hypothalamus might be the reason for such symptoms [10]. We also found a large number of patients with adjustment disorders. Mental stress due to COVID-19 might have a role in developing adjustment disorders.

Risk factors related to post-COVID-19 syndrome were not identified in most previous studies [6, 7, 19, 21]. In this study, there was a significant association between post-COVID-19 syndrome and female sex, prolonged recovery, persistent positivity on RT-PCR after day 14 of the initial test, and moderate or severe illness at presentation. Fever, cough, respiratory distress, and lethargy were positively associated with the development of post-COVID-19 syndrome, but sore throat was negatively associated with the development of post-COVID-19 syndrome. The reason for this could not be explained. The following risk factors were identified in our study: female sex, respiratory distress, lethargy, long duration of illness, and moderate severity of the disease. All age groups had a similar susceptibility to develop post-COVID symptoms. In a study by Carfì A et al. [6], most COVID-19 symptoms persisted during the post-COVID-19 follow-up. However, in this study, we found an overlap of fatigue, cough, dyspnea, chest pain, headache, anosmia, and body ache (Fig 2). Diverse new symptoms including sleep disorder, adjustment disorder, memory disturbances, and restless leg syndrome that developed in the post-COVID-19 state also require attention.

This study included patients aged >18 years as it was difficult to comment about post-COVID-19 syndrome in younger patients. The demographics of the study patients were different from those of patients from Western countries. We did not find any association between age and the post-COVID-19 state; however, the findings might be different in other parts of the world.

This study has some limitations. It was a single-center study. Patients were followed up via a telephonic interview. Therefore, proper assessment of the patient’s quality of life was not possible. Moreover, the follow-up period for patients was limited (1 month after disease onset), and asymptomatic or critical cases were excluded from the study. More representative findings could be obtained if all cases could be followed up for a longer period. Moreover, the effect size of most associated variables was small. A larger sample size is required to determine a strong association.

Conclusions

Patients with COVID-19 require long-term follow-up even after recovery for observation and management of their post-COVID ailments. A comprehensive rehabilitation program is essential for such patients during hospitalization and discharge. During the ongoing COVID-19 pandemic, most health facilities are overloaded. Hence, arranging follow-up for patients can be a challenge. However, a significant population in the post-COVID state needs continuous monitoring. Female patients, patients presenting with respiratory distress, patients with lethargy, and patients with a disease for a prolonged duration require special attention in the post-COVID-19 state.

Post COVID syndrome.

(DOCX)

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Telephonic interview guide.

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COVID 19 study post COVID.

(XLS)

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2 Mar 2021

PONE-D-21-02914

Post COVID Syndrome among Symptomatic COVID-19 Patients: A Prospective Study in a Tertiary Care Center in Bangladesh

PLOS ONE

Dear Dr. Mahmud,

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Jakaria Been Sayeed.

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: No

Reviewer #2: No

**********

5. Review Comments to the Author

Reviewer #1: Post COVID Syndrome among Symptomatic COVID-19 Patients: A Prospective Study

in a Tertiary Care Center in Bangladesh. This study presents a detailed description of incidence and risk factors of Post Covid sequelae. This is an interesting study, providing useful information for clinical practice.

Some points need to be clarified:

General:

The manuscript should go through a linguistic editing, as well as revision in accordance with academic writing guidelines

Abstract:

- Post COVID features are significantly higher among the female [RR, 95% CI, p 1.2, (1.02-1.48), 0.03], those who suffered for longer period (p= 0.00) and those who had prolonged positivity [RR, 95% CI, p; 1.09, (1.00-1.19), 0.00] for Covid 19. Please explain, it is not clear. The definitions seem to overlap, which is why p = 0.00

- Severity of the COVID had also positive association (p value=0.02). Please explain, it is not clear.

Main text:

- “the virus is dominating the life of every people of this universe.” please refer to our World only or add a reference about Covid people infection in other worlds.

- “To address this health problem and plan for future action.” This is very interesting but, this health problem has been already considered: in literature there are reviews about the Covid sequelae and rehabilitation of patients post-covid-19 infection. Please address this aspect in your article describing the status of art in this field. What do you mean for future action?

- Post COVID features are significantly higher among the female [RR, 95% CI, phi, p 1.2, (1.02-1.48), 0.12, 0.03], those who suffered for longer period (partial eta squared p value 0.18, 0.00), and those who had prolonged positivity [RR, 95% CI, phi, p; 1.09, (1.00-1.19), 0.11, 0.0] for COVID 19. The same as above. The definitions seem to overlap, which is why p = 0.00

- “It seems that they were the patient who required log time to recover to meet WHO criteria for recovery.” Not clear.

- “a new symptoms”. Correct this.

- “So the suffering of the COVID patients does not end with apparent clinical recovery. It also leaves long term sequels and sufferings for nearly half of the patients which also need to be addressed with proper attention.” Add a reference.

- “Mental agony related to having COVID infection might have a role.” What do you mean with mental agony?

- “More over intensive care unit patient may develop symptoms unrelated to COVID, due to post intensive care syndrome.” Which are these symptoms and how can you differentiate them from COVID symptoms, considering that covid is the cause of intensive care admission?

- “Those two study failed to identify the scenario as a whole.” Please don’t use the verb fail to.

- “COVID- 19 affected patients require long-term follow up even after recovery for observation and managing their ailments.” COVID-19 affected patients need a rehabilitation program during hospitalization and most of all at discharge. Please consider this aspect.

Reviewer #2: PONE-D-21-02914

Mahmud et al. report the prevalence of post-COVID-19 syndrome among relatively young patients in Bangladesh. Although this study was limited by single-centered design, fairly early time for evaluation, and more than 10% of loss-to-follow, it is still surprising to see a high prevalence of post-COVID-19 syndrome among young patients and its potential social impact in post-COVID-19 era. I would like to point out the following concerns:

Major comments:

1. While this study appears to be sound, the manuscript requires extensive elaboration on language to achieve clarity. In addition to the grammatical editing, the use of subheadings in the Methods and Results section will help to organize and improve the flow and readability of the manuscript.

2. For new symptom onset after the COVID-19, the data were not stratified further to determine if the symptoms were persistent following initial COVID-19, worsened after COVID-19 recovery, or occurred post-recovery. It would be valuable if the authors could delineate the prevalence more concisely.

3. The overall values of coefficient are low; thus, their interpretation is not clear. In contrast, Table 3 provides clear data, and this alone may be sufficient to report.

Minor comments:

1. In Table 3, if the purpose of the authors were to emphasize the independent risk factors for post-COVID-19 syndrome, it is more intuitive to use the mild group as a reference group fir severity.

2. What is the X axis of Figure 2? Is it the percentage of each symptoms among patients who developed the post-COVID-19 syndrome all COVID-19 patients?

3. I have trouble finding figure legends. Please include them in the revision.

4. Please edit Figure 1 as appropriate because eligible patients seem to increase from 352 to 355.

5. Please make sure to mention all the statistical methods used in the Methods section. For example, Mann-Whitney test is used in the results but does not appear in the Methods.

6. Please spell out RBS, SGPT considering the broad spectrum of the readers of this journal.

7. Please define “respiratory distress” in the Methods.

**********

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Reviewer #1: No

Reviewer #2: No

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19 Mar 2021

Response to Academic editor

1. PLOS ONE style-I have revised the manuscript according to PLOS ONE style.

2. Captions for Supporting Information files-Added at the end of the manuscript

3. The manuscript was edited by Editage. A copy was uploaded as supporting information. A clean copy of edited manuscript was uploaded as manuscript file.

4. Inclusion of S.K. Jakaria Been Sayeed- Included in the author list

5. About informed consent: Informed written consent was obtained. Mentioned in the manuscript( page 5 line 97-98)

6. Telephonic interview guide-added as supporting information.

7. The manuscript was edited by Editage. The certificate is added as supporting file

Thanks for reviewing the manuscript and giving the important comments about the manuscript.

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Response: I have tried to correct the issues you raised in the subsequent section.

Reviewer #2: Yes

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Response: Thanks for your positive response.

3. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Response: Thanks for your positive response. I have also submitted the Data in the Dryad data repository to be published after acceptance of the manuscript. https://doi.org/10.5061/dryad.m0cfxpp3g

4. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: No

Response: Thanks for your critique. The manuscript is now edited by editage for its language and grammar. I think now you will find it standard. Certificate attached as supporting information

5. Review Comments to the Author

Reviewer #1: Post COVID Syndrome among Symptomatic COVID-19 Patients: A Prospective Study in a Tertiary Care Center in Bangladesh. This study presents a detailed description of incidence and risk factors of Post Covid sequelae. This is an interesting study, providing useful information for clinical practice.

Response: Thanks for your appraisal

Some points need to be clarified:

General:

The manuscript should go through a linguistic editing, as well as revision in accordance with academic writing guidelines

Response: Revised by Editage during resubmission.

Abstract:

- Post COVID features are significantly higher among the female [RR, 95% CI, p 1.2, (1.02-1.48), 0.03], those who suffered for longer period (p= 0.00) and those who had prolonged positivity [RR, 95% CI, p; 1.09, (1.00-1.19), 0.00] for Covid 19. Please explain, it is not clear. The definitions seem to overlap, which is why p = 0.00

- Severity of the COVID had also positive association (p value=0.02). Please explain, it is not clear.

Response: It is now written in the following way to clarify-

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). (Page 2, line 30-34)

Main text:

- “the virus is dominating the life of every people of this universe.” please refer to our World only or add a reference about Covid people infection in other worlds.

Response: sorry for the mistake. The word universe is now replaced with world.

Since the first report of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), which causes coronavirus disease (COVID-19) on December 31 [1], the virus has dominated the life of every person worldwide. (Page 3, line 44-46)

- “To address this health problem and plan for future action.” This is very interesting but, this health problem has been already considered: in literature there are reviews about the Covid sequelae and rehabilitation of patients post-covid-19 infection. Please address this aspect in your article describing the status of art in this field. What do you mean for future action?

Response: I have replaced the line with “For further exploration of post-COVID-19 syndrome, it is necessary to have knowledge regarding the incidence, types, and risk factors of this syndrome”.( Page-4, line 81-82)

- Post COVID features are significantly higher among the female [RR, 95% CI, phi, p 1.2, (1.02-1.48), 0.12, 0.03], those who suffered for longer period (partial eta squared p value 0.18, 0.00), and those who had prolonged positivity [RR, 95% CI, phi, p; 1.09, (1.00-1.19), 0.11, 0.0] for COVID 19. The same as above. The definitions seem to overlap, which is why p = 0.00

- “It seems that they were the patient who required log time to recover to meet WHO criteria for recovery.” Not clear.

Response: thank you for pointing this. I have corrected this as following

Post-COVID-19 features were significantly higher among women (RR: 1.2, 95% CI: 1.02–1.48, p=0.03), those who required a long time to achieve clinical improvement (p<0.001), and those showing COVID-19 positivity on RT-PCR after day 14 of initial positivity (RR: 1.09, 95% CI: 1.00–1.19, p<0.001). Additionally, patients with severe forms of the disease at presentation had a higher tendency to develop post-COVID-19 symptoms (p=0.02). (Page 14 line 225-229)

- “a new symptoms”. Correct this.

Response: Corrected

- “So the suffering of the COVID patients does not end with apparent clinical recovery. It also leaves long term sequels and sufferings for nearly half of the patients which also need to be addressed with proper attention.” Add a reference.

Response: this statement I have made according to my study findings. As the statement is creating confusion I have replaced it with following –

Thus, this study revealed that the patients did not completely recover, even after apparent clinical recovery. The COVID-19 also caused long-term sequelae and distress in nearly half of the patients. (Page 16, line 268-270)

- “Mental agony related to having COVID infection might have a role.” What do you mean with mental agony?

Response: As the term agony is creating confusion it have been replaced with mental stress.

Mental stress due to COVID-19 might have a role in developing adjustment disorders.(page 18, line 328-329)

- “More over intensive care unit patient may develop symptoms unrelated to COVID, due to post intensive care syndrome.” Which are these symptoms and how can you differentiate them from COVID symptoms, considering that covid is the cause of intensive care admission?

Impression: we had excluded the ICU patient from our study. As this line is creating confusion we rewrite it as

Thus, the abovementioned studies are inadequate for explaining the post-COVID scenario as a whole. Moreover, a significant number of patients described in the studies were admitted to the intensive care unit. Patients admitted to the intensive care unit may develop symptoms such as executive dysfunction, anxiety, depression, and post-traumatic stress disorder due to post-intensive care syndrome [20]. If these symptoms are present in the post-COVID state among patients admitted to the intensive care unit, it is very difficult to differentiate whether these symptoms are purely post-COVID-19 related or are outcomes of post-intensive care syndrome. To avoid such bias, we excluded critical patients requiring intensive care unit admission. (Page 17, line 294-301)

- “Those two study failed to identify the scenario as a whole.” Please don’t use the verb fail to.

Response: thanks for addressing this. I have replace the word.

Thus, the abovementioned studies are inadequate for explaining the post-COVID scenario as a whole. (page17, line 294)

- “COVID- 19 affected patients require long-term follow up even after recovery for observation and managing their ailments.” COVID-19 affected patients need a rehabilitation program during hospitalization and most of all at discharge. Please consider this aspect.

Response: Thank you for addressing this aspect. I have added this aspect in the text.

A comprehensive rehabilitation program is essential for such patients during hospitalization and discharge (page 20, line 357-358)

Reviewer #2: PONE-D-21-02914

Mahmud et al. report the prevalence of post-COVID-19 syndrome among relatively young patients in Bangladesh. Although this study was limited by single-centered design, fairly early time for evaluation, and more than 10% of loss-to-follow, it is still surprising to see a high prevalence of post-COVID-19 syndrome among young patients and its potential social impact in post-COVID-19 era. I would like to point out the following concerns:

Major comments:

1. While this study appears to be sound, the manuscript requires extensive elaboration on language to achieve clarity. In addition to the grammatical editing, the use of subheadings in the Methods and Results section will help to organize and improve the flow and readability of the manuscript.

Response: thank you for your concern and advice. I am very grateful that you reviewed the article with utmost importance.

The article was edited by Eitage during resubmission for linguistic and grammatical error. In some context I have also made elaboration.

Subheadings added in the Methods and result section as per APA guideline. Some section were rewritten.

2. For new symptom onset after the COVID-19, the data were not stratified further to determine if the symptoms were persistent following initial COVID-19, worsened after COVID-19 recovery, or occurred post-recovery. It would be valuable if the authors could delineate the prevalence more concisely.

Response: It occurred post-recovery, to avoid confusion I have rewritten the line as

fresh development of symptoms (Page-2 line 18)

3. The overall values of coefficient are low; thus, their interpretation is not clear. In contrast, Table 3 provides clear data, and this alone may be sufficient to report.

Response: In revised manuscript it was omitted

Minor comments:

1. In Table 3, if the purpose of the authors were to emphasize the independent risk factors for post-COVID-19 syndrome, it is more intuitive to use the mild group as a reference group fir severity.

Response: I have corrected the table 3 according to your instruction

2. What is the X axis of Figure 2? Is it the percentage of each symptoms among patients who developed the post-COVID-19 syndrome all COVID-19 patients?

Response: added. It is the percentage of each symptoms among all COVID -19 patients on right side and among the patients with post-COVID syndrome on left side.

3. I have trouble finding figure legends. Please include them in the revision.

Responses: added

4. Please edit Figure 1 as appropriate because eligible patients seem to increase from 352 to 355.

Response: Edited, error was in calculation

5. Please make sure to mention all the statistical methods used in the Methods section. For example, Mann-Whitney test is used in the results but does not appear in the Methods.

Response: Added in the revised manuscript

The Mann–Whitney U test was used to compare skewed continuous variables. (Page 8, line 162)

6. Please spell out RBS, SGPT considering the broad spectrum of the readers of this journal.

Response: Done in the revised manuscript.

7. Please define “respiratory distress” in the Methods.

Response: Definition added to the methods section

Respiratory distress was defined as shortness of breath, respiratory rate >25breath /min, or SpO2 <93 %,( page 6, line 119-120)

Thanks

Dr. Reaz Mahmud

Principal investigator

23 Mar 2021

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

PONE-D-21-02914R1

Dear Dr. Mahmud,

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Kind regards,

Aleksandar R. Zivkovic

Academic Editor

PLOS ONE

30 Mar 2021

PONE-D-21-02914R1

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

Dear Dr. Mahmud:

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on behalf of

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PLOS ONE