Summary
Background
A comprehensive study of the post-COVID syndrome (PCS) remains scarce in low-and middle-income countries. We assessed the prevalence, incidence rate, evolution over time, and risk factors of PCS among hospitalized (HS) and non-hospitalized (NHS) COVID-19 survivors.
Methods
We undertook a prospective longitudinal study of COVID-19 survivors at months 1, 3, and 5 post-discharge or post-isolation period. The study was conducted at two COVID-19-designated hospitals in Dhaka, Bangladesh, between December 2020 and October 2021.
Findings
362 participants were enrolled in the study; the median time from the onset of COVID-19 to enrolment was 57 days (IQR 41, 82). At enrolment, after adjusting for potential confounders, the HS more often had one or more symptoms, peripheral neuropathy (PN), depression and anxiety disorder, poor quality of life, dyspnea, tachycardia, restrictive lung disease on spirometry, anemia, proteinuria, and need for insulin therapy than the non-hospitalized group (95% CI > 1 for all). Although most of these findings decreased significantly over time in HS, PN increased in both groups. The incidence of diabetes was 9.8/1000 person-month, and the new requirement of insulin therapy was higher (aOR, 6.71; 95% CI, 2.87, 15.67) among HS than the NHS. Older age, being female, comorbidity, cigarette smoking, hospitalization, and contact with COVID-19 cases were independently associated with PCS.
Interpretation
We observed a high burden of PCS in hospitalized and non-hospitalized survivors despite most findings' decreasing trend over time. Our results underscore the importance of continuing long-term follow-up and subsequent management.
Funding
The United States Agency for International Development (USAID).
Keywords: Post-COVID syndrome, PCS, Long COVID, COVID-19, Bangladesh, South asia, Longitudinal study
Research in context.
Evidence before this study
We searched PubMed and Web of Science for studies on sequelae of COVID-19 published in English up to April 2022. We used the following terms "(COVID-19 OR Coronavirus disease-19 OR SARS-CoV2) AND (Post COVID-19 syndrome OR Post-acute COVID-19 syndrome OR Post-acute COVID symptoms OR Long COVID OR Long haul COVID OR COVID sequalae OR follow up OR long-term sequelae)".
We found several studies reporting different symptoms after recovery from COVID-19 in hospitalized and non-hospitalized patients. The proportion of patients with respiratory findings, including dyspnea, abnormal chest X-rays, exercise desaturation, and activity impairment was more among hospitalized than in non-hospitalized cases. No association was found between hospitalization and post COVID-19 fatigue. To our knowledge, those studies are not longitudinal and thus unable to provide complete insight into the evolution of post-COVID syndrome. Several studies are retrospective in nature. Many studies used virtual or telephonic data collection tools. It is important to note that longitudinal studies are required to understand the prevalence and evolution of clinical findings over time, incidence rate, and risk factors of post-COVID syndrome specifically among hospitalized and non-hospitalized COVID-19 survivors.
Added value of this study
We revealed that hospitalized participants are at increased risk of the post COVID syndrome (PCS) compared to the non-hospitalized group. The hospitalized survivors more often had one or more symptoms, peripheral neuropathy, depression and anxiety disorder, poor quality of life, dyspnea, tachycardia, restrictive lung disease on spirometry, anemia, proteinuria, and need for insulin therapy than the non-hospitalized group at one month after clinical recovery from acute COVID-19. We also showed that the manifestations of PCS decreased significantly over time in the hospitalized participants, while some findings, such as the prevalence of dyspnea, tachycardia, depression and anxiety disorder, and post-traumatic stress disorder remained unchanged among the non-hospitalized group. Peripheral neuropathy increased significantly over time in both groups. We estimated the incidence rate of clinical findings of PCS among COVID-19 survivors. We found a high incidence rate of diabetes and the new requirement for insulin therapy among hospitalized survivors than in their non-hospitalized counterparts. We found that older COVID-19 survivors, females, cigarette smokers, any co-existing illness, and participants who required hospitalization more often developed PCS than younger survivors, males, non-smokers, and participants who did not require hospitalization.
Implications of all the available evidence
The burden of PCS is high among COVID-19 survivors. The hospitalized participants showed an increased risk of PCS shortly after discharge than the non-hospitalized participants. In this study, we portrayed clinical manifestations of PCS and evolution over time; thus, our findings could aid in building a bundle of care for COVID-19 survivors. The results underscore the need for continuing follow-up of COVID-19 survivors for PCS and multidisciplinary care for older and female patients who require hospitalization or have a comorbidity, or history of cigarette smoking, particularly in low- and middle-income countries.
Introduction
The COVID-19 pandemic has affected more than 627 million people globally and 60 million in South Asia as of October 30, 2022 (WHO).1 Although many individuals have straightforward recoveries, some have prolonged illness even after recovering from acute infection.2, 3, 4, 5 The timeframe of sequelae after COVID-19 or ‘long COVID’ or ‘post-COVID syndrome (PCS)’ is yet to be elucidated.6 Instead, the sequelae of COVID-19 has been defined as ‘acute PCS’ indicating symptoms between 4 and 12 weeks; and ‘chronic PCS’ indicating symptoms continuing beyond 12 weeks after the start of acute symptoms.7,8 Although many studies have depicted an overview of the PCS, how the clinical consequences evolve is uncertain, particularly in hospitalized (HS) and non-hospitalized survivors (NHS).9, 10, 11, 12 Frequently reported PCS includes dyspnea, fatigue, headache, anosmia, ageusia, chest pain, joint pain, and palpitations.13 Though individuals from low-and middle-income countries (LMICs) have also been harshly affected by the pandemic,14, 15, 16 very few studies exist on PCS from LMICs.
Thus, there is a dire need for longitudinal studies to provide a broad overview of the PCS in LMICs and better understand the long-lasting impact of the disease. This comprehensive longitudinal study aimed to assess the prevalence of symptoms and clinical and laboratory findings among (HS) and NHS after discharge from the hospital or post-isolation at 1, 3-month, and 5-month follow-ups to capture the evolution of clinical characteristics over time. We reported the incidence of new findings after study entry and examined the association of sociodemographic and clinical manifestations, including the impact of hospitalization on these after-effects of COVID-19.
Methods
Study design and patients
This prospective longitudinal study was conducted at two COVID-19 designated hospitals [Dhaka hospital of icddr,b and the Bangabandhu Sheikh Mujib Medical University Hospital (BSMMU)] in Dhaka, Bangladesh, between 15 December 2020 and 30 October 2021. Participants were eligible for enrollment if they met the following criteria: 1) older than 18 years with RT-PCR-confirmed COVID-19 and sought care from the study hospitals with or without the requirement for hospitalization, 2) showed significant improvement of symptoms for three consecutive days with concomitant hospital discharge. NHS were enrolled if they showed significant improvement of symptoms for three consecutive days and at least ten days had elapsed from the onset of COVID-19 infection as indicated by WHO guideline (end of isolation period),17 3) residing within Dhaka city and willing to come for follow up visits. We excluded participants with pre-existing mental illness or who resided outside Dhaka. All consecutive consenting participants were enrolled within 4–6 weeks of discharge from the hospital or end of the isolation period. The overall design was to conduct a comprehensive in-person follow up of COVID-19 survivors at 1 month (baseline), 3- and 5-months after clinical recovery. The study protocol was approved by the institutional review board of icddr,b and BSMMU. Participants provided written informed consent that was translated into the local language.
Procedure
Follow-up visits and procedures are detailed in the appendix. A symptom checklist was used to record newly developed or persistent symptoms. Trained clinicians performed physical examinations, including a 6-min walk test (6MWT) at each visit to identify respiratory, cardiovascular, and neurological findings using standard clinical procedures. Tools used to identify peripheral neuropathy, dyspnea, fatigue, functional limitations of daily activities, and psychiatric sequelae are described in the appendix. A structured clinical interview by a psychiatrist further evaluated participants with psychiatric findings. Mental health counselling and treatment were integral components of the follow-up evaluation. We followed the American Diabetes Association diagnostic criteria to identify new-onset diabetes and the new requirement of insulin therapy as a measure of worsening glycemic control.
Laboratory assessment
We performed the lung function test using spirometry (Spirolab, Italy) following the American Thoracic Society guidelines,18 and in case of moderate or severe disease, we did a chest X-ray at the first and fifth-month points. ECG and echocardiograms (only for HS) evaluated the cardiovascular sequelae. Blood and urine samples were collected during follow-up visits for complete blood count (CBC), serum alanine transaminase (ALT), serum creatinine, urine routine microscopy test, and random blood glucose (RBG) using a glucometer. 20% of NHS and 30% of HS underwent thyroid function tests such as FT4, FT3, and TSH and C peptide levels only at the 5-month visit.
Outcome measures
The outcomes were the prevalence of one or more PCS developed during or following acute COVID-19 and continuing at 1-month (acute PCS), 3 (intermediate PCS), and 5-month (chronic PCS) after clinical recovery of COVID-19. We defined PCS as follows: (1) the onset or persistence of at least one self-reported symptom of COVID-19, (2) neurological findings (anosmia, absent or altered taste, peripheral neuropathy as evident by the United Kingdom Screening Test score >2, tremor) (3) psychiatric sequelae as evident by having Post-traumatic stress disorder (PTSD), depression or anxiety disorder or cognitive impairment, (4) respiratory function abnormalities (mMRC ≥2 scores, tachypnea, abnormal breath sound), (5) cardiovascular findings (hypertension, tachycardia, edema), (6) muscle weakness, (7) poor quality of life, and (8) worsening glycemic control as evidenced by the new requirement of insulin therapy. Outcome measures are listed in detail in the appendix. Secondary outcomes were incidence, prevalence, and the association between socio-demographic characteristics, underlying comorbidities, hospitalization status, and the PCS. The outcomes are shown in HS and NHS.
Definition
We categorized the participants as HS if they needed hospitalization for moderate and severe/critical COVID-19 according to the classification of WHO guidelines on COVID-19 case management.17 NHS were those who visited the hospital for COVID-19 but did not require hospitalization and were advised for home isolation.17 We described reinfection with COVID-19 if the participants had RT PCR-positive SARS CoV-2 infection during the follow-up period.
Statistical analysis
We presented the sociodemographic characteristics, sequelae-symptoms and findings at 1, 3- and 5-month follow-up visits as count (%) for categorical variables and median (IQR) for continuous variables. We employed a doubly robust propensity score (PS) matching-based approach to standardize the baseline characteristics between HS and NHS. We employed a 1:1 PS with a greedy nearest neighbor matching approach with a caliper width of 0.2. After estimating PS, weights were calculated for each participant as the inverse of the propensity score for HS and as the inverse of (1- propensity score) for NHS. Thus, all baseline characteristics were equally distributed between the cohorts.19 Any covariates with a standardized mean difference of less than 10% were considered well-matched between the cohorts. We applied multivariable logistic regression models to determine the relative difference in the prevalence of outcome variables (appendix p 4), including sequelae-symptoms and clinical findings between the cohorts at all follow-up visits. Each model adjusted for all covariates [age, sex (biological factor), BMI, group, site, and comorbidity] in the PS-matched cohort. The proportion of missing explanatory variables in the data-set was unremarkable (1–2%). The statistical analysis is detailed in the appendix (p 5–6). To determine the temporal trend of PCS among survivors from 1 to 5-month follow-up visit, we applied similarly adjusted generalized estimating equation (GEE) models (logit link and binomial family). We used an interaction term between group and time to determine if the relative difference between HS and NHS in outcome measures are increasing or decreasing over time. The incidence (the number of survivors who developed new sequelae-symptoms or findings during follow-up visits and the rate per 1000 person-month) among HS and NHS was also reported with odds ratio and 95% confidence intervals after adjustment with age, sex (biological factor), BMI, site, and comorbidity. We excluded the reinfection cases from the analysis.
We applied GEE models to determine the risk factors associated with sequelae-symptoms, respiratory, cardiovascular, neurologic findings, and psychiatric sequelae. In the GEE models, we adjusted age, sex, group, comorbidity, cigarette smoking, site, occupation, and history of contact with COVID-19 patients to determine the predictors of sequelae among COVID-19 survivors. Selection of variables was based on biological plausibility and bivariate association in our data. All hypothesis tests were 2-sided. A p-value of <0.05 was considered statistically significant. We performed all statistical analysis using the Stata software, version 15.0 for Windows (Stata Corp LLC, College Station, TX, USA). For analysis and reporting, we followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline (Appendix p 17–18).
Role of the funding source
The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
We screened a total of 1981 confirmed COVID-19 cases for eligibility who were in the registry of the Dhaka Hospital of icddr,b and BSMMU (Fig. S1 in appendix). 622 survivors were invited to participate, of whom 362 consented and enrolled in the study. 351 (97%) and 346 (95%) of survivors completed follow-up visits at 3 and 5 months, respectively. 1.1% of participants (3/242 of HS and 1/104 of NHS) developed reinfection with COVID-19 after the 3-month visit; thus, 342 participants formed the analyzable dataset at the 5-month visit. Table S1 in the supplementary appendix (p 8) displays the estimates for the logit models from which the propensity scores are derived. Adequate PS matching with standardized mean difference of <10% was attained for all baseline characteristics (appendix p 9). Table 1 (Table S3 in appendix p 10) shows the sociodemographic characteristics of enrolled participants, and Table S4 in the supplementary appendix shows the clinical characteristics during acute COVID-19. The COVID survivors reported a wide array of sequelae-symptoms, the complete list of reported symptoms is shown in Table S5 in the appendix. At the 1-month visit, after adjusting for potential confounders, the HS more often reported one or more sequelae-symptoms, fatigue, sleeping difficulty, muscle weakness, loss of appetite, and skin rash than NHS. The prevalence of most of the sequelae-symptoms decreased significantly over time from 1-month visit among survivors except for joint pain and rash, which remained stable over time in HS; and headache, joint pain, loss of appetite, smell and taste, burning sensation in the mouth and skin rash in NHS (Table 2 and S5). However, the prevalence of any sequelae symptoms declined significantly over time in both groups (p < 0.001).
Table 1.
Baseline characteristics among non-hospitalized and hospitalized COVID-19 survivors.
| Total (n = 362) | Non-hospitalized (n = 107) | Hospitalized (n = 255) | p value | |
|---|---|---|---|---|
| Age in years | 50 (38, 60) | 39 (31, 51) | 54 (43, 62) | <0.001 |
| Male | 226 (62) | 63 (59) | 163 (64) | 0.366 |
| Cigarette smoking | 54 (15) | 20 (19) | 34 (13) | 0.192 |
| Occupation | ||||
| Employed | 222 (61) | 69 (64) | 153 (60) | 0.424 |
| Unemployed | 95 (26) | 31 (29) | 64 (25) | 0.445 |
| Retired | 45 (12) | 7 (7) | 38 (15) | 0.028 |
| Lost a family member due to COVID-19 | 68 (19) | 18 (17) | 50 (20) | 0.536 |
| Comorbidity | 245 (68) | 53 (50) | 192 (75) | <0.001 |
| Hypertension | 180 (50) | 30 (28) | 150 (59) | <0.001 |
| Ischemic heart disease | 54 (15) | 13 (12) | 41 (16) | 0.338 |
| Chronic liver disease | 9 (2) | 1 (1) | 8 (3) | 0.200 |
| Diabetes | 137 (38) | 22 (21) | 115 (45) | <0.001 |
| Hypothyroidism | 35 (10) | 10 (9) | 25 (10) | 0.893 |
| Chronic kidney disease | 19 (5) | 3 (3) | 16 (6) | 0.177 |
| Immunocompromised conditions | 13 (4) | 3 (3) | 10 (4) | 0.432 |
| Stroke | 18 (5) | 2 (2) | 16 (6) | 0.078 |
| Duration between symptoms onset to enrollment in days | 57 (41,82) | 67 (44, 83) | 53 (40, 82) | 0.052 |
| Duration between clinical recovery to enrollment in days | 38 (21, 64) | 49 (25, 66) | 33 (21, 63) | 0.030 |
| Diagnosis during acute COVID-19 | ||||
| Mild | 89 (25) | 89 (83) | 0 (0) | <0.001 |
| Moderate | 101 (28) | 18 (17) | 83 (33) | 0.002 |
| Severe | 77 (21) | 0 (0) | 77 (30) | <0.001 |
| Critical | 95 (26) | 0 (0) | 95 (37) | <0.001 |
| BSMMU site | 137 (38) | 25 (23) | 112 (44) | <0.001 |
Data are n (%) or median (IQR). BSMMU: Bangabandhu Sheikh Mujib Medical University; icddr,b: International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh. Baseline characteristic stratified by the study hospital is presented in Table S3 in appendix. Additional baseline characteristic during acute COVID-19 are presented in Table S4 in the appendix.
Table 2.
Sequelae-symptoms and findings on physical examination among non-hospitalized and hospitalized COVID-19 survivors over time.
| Sequelae-symptom or Findings | 1-month follow-up visit |
3-month follow-up visit |
5-month follow-up visit |
Pb |
Pb |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Outpatient (n = 107) | Inpatient (n = 255) | Odds ratioa (95% CI) | Outpatient (n = 104) | Inpatient (n = 247) | Odds ratioa (95% CI) | Outpatient (n = 103) | Inpatient (n = 239) | Odds ratioa (95% CI) | Outpatient (n = 107) | Inpatient (n = 255) | |
| Duration from symptom onset to follow-up (days) | 67 (44, 83) | 53 (40, 82) | NA | 121 (111, 136) | 113 (105, 129) | NA | 172 (168, 177) | 170 (164, 178) | NA | NA | NA |
| Any Sequelae-symptomc | 100 (93) | 252 (99) | 5.9 (1.2, 28.6) | 90 (87) | 219 (87) | 0.5 (0.2, 1.2) | 78 (76) | 200 (84) | 1.3 (0.6, 3.0) | <0.001 | <0.001 |
| Fatigue | 79 (74) | 214 (84) | 1.8 (1.2, 2.9) | 58 (56) | 154 (62) | 1.0 (0.5, 1.9) | 46 (45) | 126 (53) | 1.3 (0.7, 2.5) | <0.001 | <0.001 |
| Sleeping difficulty | 40 (37) | 141 (55) | 1.9 (1.1, 3.3) | 34 (33) | 108 (44) | 1.5 (0.8, 3.0) | 27 (26) | 87 (36) | 1.7 (0.8, 3.8) | 0.033 | <0.001 |
| Muscle weakness | 22 (21) | 89 (35) | 2.8 (1.3, 5.7) | 12 (12) | 45 (18) | 1.2 (0.7, 2.1) | 14 (14) | 46 (19) | 1.1 (0.5, 2.5) | 0.085 | <0.001 |
| Loss of appetite | 22 (21) | 81 (32) | 2.1 (1.0, 4.2) | 13 (13) | 43 (17) | 1.1 (0.3, 3.3) | 15 (15) | 46 (19) | 1.1 (0.5, 2.3) | 0.209 | <0.001 |
| Skin rash | 6 (6) | 36 (14) | 2.9 (1.1, 8.0) | 5 (5) | 18 (7) | 1.8 (0.5, 7.3) | 7 (7) | 23 (10) | 2.3 (0.9, 6.1) | 0.656 | 0.131 |
| Neurologic findings | 14 (13) | 87/246 (35) | 2.8 (1.4, 5.8) | 30/101 (30) | 99/234 (42) | 1.4 (0.9, 2.2) | 22/102 (22) | 96/232 (41) | 1.6 (1.1, 2.4) | 0.072 | 0.157 |
| Peripheral neuropathy | 7 (7) | 39 (15) | 2.9 (1.5, 5.5) | 22 (21) | 81 (33) | 1.7 (0.7, 3.9) | 19 (18) | 84 (35) | 1.6 (0.8, 3.1) | 0.005 | <0.001 |
| Anosmia | 3/69 (4) | 27/222 (12) | 3.6 (0.8, 17.0) | 7/102 (7) | 24/246 (10) | 1.1 (0.3, 3.9) | 3 (3) | 7 (3) | 1.3 (0.4, 4.5) | 0.649 | <0.001 |
| Absent/impaired taste | 2/50 (4) | 26/217 (12) | 0.4 (0.1, 1.8) | 2/102 (2) | 12/244 (5) | 0.3 (0.1, 1.3 | 2/102 (2) | 4 (2) | 0.5 (0.1, 6.4) | 0.623 | <0.001 |
| Tremor | 2 (2) | 26 (10) | 3.3 (0.7, 15.9) | 4 (4) | 19 (8) | 2.2 (0.7, 7.1) | 1 (1) | 9 (4) | 1.9 (0.2, 16.7) | 0.629 | 0.003 |
| Psychiatric sequelae | 58 (54) | 177 (69) | 2.2 (1.1, 4.4) | 53 (51) | 130 (53) | 0.9 (0.5, 1.6) | 47 (46) | 111 (46) | 0.7 (0.4, 1.2) | 0.091 | <0.001 |
| Depression/anxiety disorder | 55 (51) | 167 (65) | 2.1 (1.1, 4.0) | 51 (49) | 125 (51) | 0.9 (0.5, 1.6) | 43 (42) | 104 (44) | 0.7 (0.4, 1.3) | 0.056 | <0.001 |
| Post-traumatic stress disorder | 16 (15) | 51 (20) | 1.6 (1.0, 2.6) | 15 (14) | 29 (12) | 0.6 (0.3, 1.4) | 15 (15) | 16 (7) | 0.2 (0.1, 0.6) | 0.898 | <0.001 |
| Cognitive impairment | 2 (2) | 24 ( 9) | 2.5 (0.5, 12.3) | 0 (0) | 17 (7) | NA | 1 (1) | 16 (7) | 2.6 (0.4, 17.6) | 0.397 | 0.125 |
| Respiratory findings | 39 (36) | 156 (61) | 2.1 (1.1, 4.0) | 26 (25) | 118 (48) | 2.4 (1.2, 5.0) | 32 (31) | 107 (45) | 1.4 (0.7, 2.9) | 0.335 | <0.001 |
| mMRC grade 2 or more | 35 (33) | 137 (54) | 2.8 (1.9, 4.0) | 21 (20) | 104 (42) | 2.7 (1.2, 5.7) | 29 (28) | 86 (36) | 1.4 (0.6, 3.1) | 0.305 | <0.001 |
| Bronchial/diminished breath sound | 1 (1) | 42 (16) | 14.9 (2.5, 89.8) | 3 (3) | 28 (11) | 2.3 (0.3, 18.9) | 2 (2) | 16 (7) | 2.7 (0.6, 12.8) | 0.567 | <0.001 |
| Tachypnea | 5 (5) | 35 (14) | 1.6 (0.3, 8.1) | 5 (5) | 21 (9) | 1.7 (0.5, 5.7) | 6 (6) | 21 (9) | 1.6 (0.4, 6.8) | 0.719 | 0.041 |
| Cardiovascular findings | 34 (32) | 126 (49) | 1.9 (0.9, 3.8) | 24 (23) | 98 (40) | 1.5 (0.8, 2.8) | 34 (33) | 91 (38) | 0.9 (0.5, 1.8) | 0.047 | 0.001 |
| Hypertension | 23 (22) | 79 (31) | 1.8 (0.8, 4.1) | 17 (16) | 61 (25) | 1.1 (0.5, 2.2) | 22 (21) | 50 (21) | 0.7 (0.3, 1.7) | 0.931 | 0.001 |
| Tachycardia | 8 (7) | 48 (19) | 3.5 (1.4, 9.1) | 10 (10) | 26 (11) | 1.8 (0.9, 3.6) | 12 (12) | 29 (12) | 1.8 (0.7, 4.8) | 0.270 | 0.011 |
| Edema | 8 (7) | 44 (17) | 1.7 (0.7, 4.3) | 4 (4) | 28 (11) | 1.6 (0.5, 5.6) | 5 (5) | 31 (13) | 3.2 (1.2, 8.4) | 0.319 | 0.085 |
| Muscle weaknessd | 7 (7) | 29 (11) | 1.5 (0.3, 7.2) | 3 (3) | 32 (13) | 2.4 (0.4, 13.8) | 1 (1) | 25 (10) | 5.1 (0.9, 27.2) | 0.018 | 0.621 |
| Poor quality of lifee | 61 (57) | 196 (77) | 2.6 (1.7, 3.8) | 45 (44) | 134 (54) | 1.5 (0.8, 2.9) | 42 (40) | 103 (43) | 1.4 (0.8, 2.9) | 0.004 | <0.001 |
| Others | |||||||||||
| Required insulinf | 6/22 (27) | 80/115 (70) | 8.6 (3.9, 18.9) | 0/19 (0) | 25/108 (23) | NA | 2/20 (2) | 58/105 (55) | 10.6 (4.3, 25.9) | 0.045 | 0.002 |
| Required hospitalization | 0 (0) | 12 (5) | NA | 1 (1) | 5 (2) | 0.8 (0.2, 2.9) | 1 (1) | 5 (2) | 1.2 (0.3, 4.6) | 0.398 | 0.076 |
| Distance walked in 6 min (m), Median (IQR) | 332 (293,380) | 320 (265,370) | NA | 342 (286,390) | 340 (286,390) | NA | 359 (317,386) | 354 (300,405) | NA | <0.001 | <0.001 |
Data are n (%) or median (IQR).
All estimates are adjusted for age, sex, body mass index, any comorbidity and group (outpatient or non-hospitalized/inpatient or hospitalized), and site (icddr,b/BSMMU). CI: confidence interval.
P value is for the interaction between the follow-up visit and the groups. P value is derived from the generalized estimating equation (GEE) models, indicating the trend of changing characteristics over time. The pooled odds ratios from GEE models are not shown.
Sequelae symptoms with a significant difference between the groups are displayed. Additional characteristics are presented in Table S3 in the appendix.
The Medical Research Council (MRC) scale for muscle strength was applied to determine muscle weakness.
Poor quality of life include fatigue assessed by the modified Borg scale1 and the functional limitations of daily activities by the Post-COVID-19 Functional Status.
Among subsamples with diagnosed diabetes. The complete list of reported symptoms is shown in Table S5 in the supplementary appendix.
The prevalence of any neurological findings (aOR, 2.8, 95% CI, 1.4, 5.8) particularly peripheral neuropathy (aOR, 2.9, 95% CI, 1.5, 5.5), was higher among HS than NHS at the 1-month visit. Peripheral neuropathy significantly increased from 13% at baseline visit to 29% and 30% at follow-up visits; the change over time was significant in both groups (p < 0.05). Although the prevalence of absent or altered smell and taste sensation and tremor significantly decreased over time in HS, the prevalence remained the same in the NHS (Table 2). At the 1-month visit, the depression and anxiety disorder (aOR 2.1, 95% CI, 1.1, 4.0) were more prevalent among HS than NHS. However, the odds of depression and anxiety disorder (HS vs NHS) did not differ significantly at 3 and 5-month visits. Regarding evolution, we observed that both depression and anxiety, and PTSD declined significantly over time in the HS (p < 0.001), but the time course remained unchanged in the NHS (Table 2). Based on the initial findings, 40% (145/362) of participants underwent a structured interview and management by a psychiatrist. Among 145 participants, the prevalence of depression and anxiety disorder, PTSD, insomnia disorder, neurocognitive disorder, and male hypoactive sexual desire disorder were 42%, 10%, 14%, 5%, and 3.5%, respectively, at enrolment in our cohort (Table S6 in appendix).
HS more often had respiratory findings at 1-month (aOR 2.1, 95% CI, 1.1, 4.0) and 3-month visits (aOR 2.4, 95% CI, 1.2, 5.0) than NHS. The prevalence of dyspnea (mMRC ≥2) significantly decreased over time among the HS (54%, 42% and 36%, respectively) but remained stable among the NHS (33%, 20%, 28%, respectively) (Table 2). 44% (160/362), 35% (122/351) and 36% (125/342) survivors had one or more abnormal CVS findings at 1-month and subsequent visits. Overall, the prevalence of CVS findings were comparable between the groups except for tachycardia (aOR 3.5, 95% CI, 1.4, 9.1), which was more evident in the HS. The prevalence of hypertension and tachycardia significantly declined over time from the 1-month visit (p = 0.001 and 0.011) among the HS; however, the prevalence remained stable among the NHS (Table 2).
63% (86/137) of survivors with preexisting diabetes required insulin therapy after discharge from the hospital or post-isolation. Insulin therapy was more often required among HS compared to NHS at 1-month (aOR, 8.6; 95% CI, 3.9, 18.9) and 5-month visit (aOR, 10.6; 95% CI, 4.3, 25.9). Although the insulin requirement reduced significantly over time among survivors (p < 0.05 for all). Quality of life was more often compromised among the HS than their counterpart at the 1-month visit, although the prevalence decreased significantly over time among participants of both groups. We noted a significant increase in the median of 6MWD among survivors of both groups from the 1 to 5-month visit (p < 0.001). One participant (0.4%) in the HS died after the initial visit. During the 3-month visit, 1/104 (0.96%) of NHS (appendicitis) and 2/247 (0.8%) of HS [coronary artery bypass graft (CABG) and heart failure with atrial fibrillation] developed other significant illnesses. During the 5-month visit, 3/239 (1.25%) of HS developed another disease (CABG 1/239 and dengue fever 2/239).
The prevalence of anemia decreased significantly among HS (p < 0.05) than in the NHS. The multivariable logistic regression analysis revealed that HS more often had anemia (aOR 2.10, 95% CI, 1.43, 3.09) at 1-month, high creatinine at 3 (aOR 3.18, 95% CI, 1.08, 9.31) and 5-month (aOR 3.15, 95% CI, 1.07, 9.25), proteinuria at 1 (aOR 2.41, 95% CI, 1.26, 4.60) and 3-month (aOR 4.18, 95% CI, 1.88, 9.28); and restrictive patterns on spirometry at the 1-month (aOR 3.14, 95% CI, 2.02, 4.87) and 5-month (aOR 1.66, 95% CI, 1.10, 2.50) visit than the NHS. The characteristics did not evolve significantly among survivors over five months (Tables 3 and S7 in the appendix). The median (IQR) of FT3, FT4, thyroid stimulating hormone, and C-peptide levels at 5-months follow-up visit was within the normal limit in both the groups. Even though the prevalence of abnormal ECG findings significantly decreased over time in the HS but remained stable in NHS; we noted that 36% (85/234) of HS and 28% (28/101) of NHS had one or more abnormal ECG findings at the 5-month visit. 172 and 131 HS underwent echocardiogram at 1 and 5-month visits. The proportion of participants with pulmonary hypertension increased from 6% (11/172) at the 1-month visit to 24% (31/131) at the 5-month visit (p < 0.001).
Table 3.
Laboratory findings among non-hospitalized and hospitalized survivors over time.
| 1-month follow-up visit |
3-month follow-up visit |
5-month follow-up visit |
∗∗p value outpatient | ∗∗p value Inpatient | ||||
|---|---|---|---|---|---|---|---|---|
| Outpatient (n = 107) | Inpatient (n = 255) | Outpatient (n = 104) | Inpatient (n = 247) | Outpatient (n = 103) | Inpatient (n = 239) | |||
| Anemiac,f | 38 (36) | 125/254 (49)a | 34/85 (40) | 97/224 (43) | 41/94 (44) | 101/232 (44) | 0.286 | 0.007 |
| NL ratio | 1.8 (1.5, 2.3) | 2.1 (1.5, 2.7) | 1.9 (1.4, 2.2) | 1.8 (1.3, 2.6) | 1.9 (1.4, 2.3) | 1.8 (1.4, 2.4) | 0.669 | <0.001 |
| High creatinined,g | 2 (2) | 22 (9) | 4/103 (4) | 28/246 (11)a | 4 (4) | 27 (11)a | 0.324 | 0.226 |
| Random blood glucose (mmol/L) | 5.6 (5.2, 7.0) | 6.7 (5.4, 9.0) | 5.6 (5.3, 6.5) | 7.0 (5.8, 9.4) | 6.7 (5.5, 10.9) | 7.8 (6.2, 10.1) | 0.283 | 0.947 |
| Fasting blood glucose (mmol/L) | 5.7 (5.3, 6.7) | 9.8 (6.4, 14.0) | 6.6 (5.5, 8.1) | 10.3 (6.4, 13.8) | 6.7 (5.5, 10.9) | 7.8 (6.2, 10.1) | 0.711 | 0.004 |
| Proteinuriae,h | 6 (6) | 33/253 (13)a | 4/103 (4) | 31/245 (13)a | 6 (6) | 30 (13) | 0.958 | 0.951 |
| FT3 (pmol/L) | NA | NA | NA | NA | 4.8 (4.4, 5.3) | 4.8 (4.5, 5.2) | NA | NA |
| FT4 (pmol/L) | NA | NA | NA | NA | 12.3 (11.4, 12.8) | 11.9 (11.1, 12.6) | NA | NA |
| Thyroid stimulating hormone (μIU/mL) | NA | NA | NA | NA | 1.5 (0.9, 1.9) | 1.5 (1.0, 2.2) | NA | NA |
| C-peptide (ng/mL) | NA | NA | NA | NA | 4.9 (2.6, 8.5) | 4.1 (2.9, 7.2) | NA | NA |
| Pneumonitis in X-Ray | 3/42 (7) | 38/189 (20) | NA | NA | 3/13 (23) | 19/115 (17) | 0.284 | 0.068 |
| Spirometry findings | ||||||||
| Restrictive changesi | 15 (15) | 89 (37)a | 22 (25) | 87 (40)a | 22 (22) | 84 (36)a | 0.143 | 0.978 |
| Obstructive | 4 (4) | 9 (4) | 6 (7) | 12 (6) | 10 (10) | 24 (10) | 0.047 | 0.004 |
| Mixed | 2 (2) | 10 (4) | 4 (5) | 13 (6) | 2 (2) | 5 (2) | 0.938 | 0.145 |
| ECG findings | ||||||||
| Any abnormality in ECG | 38/100 (38) | 107/247 (43) | 26/93 (28) | 82/224 (37) | 28/101 (28) | 85/234 (36) | 0.092 | 0.043 |
| Sinus tachycardia | 4 (28) | 26 (11) | 3 (3) | 11 (5) | 2 (2) | 11 (5) | 0.294 | 0.002 |
| Sinus bradycardia | 5 (5) | 4 (2) | 4 (4) | 11 (5) | 6 (6) | 7 (3) | 0.467 | 0.317 |
| Ischemic changesj | 10 (10) | 46 (19)a | 6 (6) | 44 (20)a | 15 (15) | 43 (18) | 0.171 | 0.868 |
| Prolonged PR interval | 2 (2) | 4 (2) | 3 (3) | 4 (2) | 3 (3) | 10 (4) | 0.545 | 0.020 |
| Short PR interval | 6 (6) | 7 (3) | 1 (1) | 3 (1) | 1 (1) | 2 (1) | 0.044 | 0.119 |
| Prolonged QTc | 19 (19) | 48 (19) | 12 (13) | 30 (13) | 7 (7) | 28 (12) | 0.002 | 0.002 |
| Any echocardiogram findingsb | NA | 96/172 (56) | NA | NA | NA | 109/131 (83) | NA | <0.001 |
| Pulmonary hypertension | NA | 11 (6) | NA | NA | NA | 31 (24) | NA | <0.001 |
| Diastolic relaxation abnormality | NA | 47 (27) | NA | NA | NA | 46 (35) | NA | 0.120 |
| Ischemic heart disease | NA | 8 (5) | NA | NA | NA | 7 (5) | NA | NA |
| Cardiomyopathy | NA | 2 (1) | NA | NA | NA | 0 | NA | NA |
| Pericardial effusion | NA | 1 (0.6) | NA | NA | NA | 1 (1) | NA | NA |
| Global hypokinesia | NA | 3 (2) | NA | NA | NA | 2 (2) | NA | NA |
| Ejection fraction | NA | 65 (62, 70) | NA | NA | NA | 64 (60, 66) | NA | <0.001 |
| Fractional shortening | NA | 35 (33, 39) | NA | NA | NA | 34 (32, 36) | NA | 0.001 |
| Pulmonary arterial systolic pressure | NA | 30 (16, 34) | NA | NA | NA | 32 (30, 37) | NA | 0.003 |
Data are n (%) or median (IQR). Findings showing a significant difference (p < 0.05) between outpatient/non-hospitalized and inpatient/hospitalized survivors at baseline visit are displayed. Additional characteristics are presented in Table S7 in appendix. NL ratio: neutrophil to lymphocyte ratio; NA: not applicable.
∗∗p value is for the interaction between follow-up visit and group, indicating the trend of changing characteristics over time, p-value from the generalized estimating equation models adjusted for age, sex, body mass index, any comorbidity, site, and group (outpatient/inpatient).
Adjusted odds ratio (aOR) and (95% CI) > 1; adjusted for age, sex, body mass index, any comorbidity, site, and group (outpatient or non-hospitalized/inpatient or hospitalized). Only significant estimates are shown in the foot note.
Echocardiogram was done only in Inpatient cohort.
Hemoglobin (g/dl) < 13 for male, and <12 for female.
High creatinine >106 mmol/L.
One plus or more protein in urine.
aOR (95% CI) anemia: 1-month 2.10 (1.43, 3.09).
aOR (95% CI) high creatinine: 3-month 3.18 (1.08, 9.31) and 5-month 3.15 (1.07, 9.25).
aOR (95% CI) proteinuria: 1-month 2.41 (1.26, 4.60), 3-month 4.18 (1.88, 9.28).
aOR (95% CI) restrictive changes: 1-month 3.14 (2.02, 4.87), 5-month 1.66 (1.10, 2.50).
aOR (95% CI) ischemic changes: 1-month 2.06 (1.00, 4.26), 3-month 3.72 (1.18, 11.74).
Table 4 lists the incidence (cases per 1000 person-month) of sequelae-symptom and physical and laboratory findings among COVID-19 survivors over time. HS were significantly less likely to develop new depression, anxiety disorders, and PTSD than NHS. The incidence rate of new DM among HS was 9.8/1000 person-month, however none among NHS. As evident by the new requirement of insulin therapy, the incidence rate of worsening glycemic control was higher (aOR, 6.71; 95% CI, 2.87, 15.67) among HS than in the NHS. Overall the incidence of hospitalization due to COVID-19-related complications was 5.7/1000 person-month among survivors.
Table 4.
Incidence of new Sequelae-symptom and findings among COVID-19 survivors.
| Total COVID survivors |
Non-hospitalized cohort |
Hospitalized cohort |
Adjusted Odds ratioa |
|||||
|---|---|---|---|---|---|---|---|---|
| Number | Cases/1000 person-month | Number | Cases/1000 person-month | Number | Cases/1000 person-month | Estimate | p value | |
| Any Sequelae-symptom | 25 | 14.3 | 11 | 21.1 | 14 | 11.4 | 0.64 (0.22, 1.83) | 0.402 |
| Joint pain | 89 | 50.9 | 19 | 36.5 | 70 | 57.0 | 1.70 (0.84, 3.43) | 0.141 |
| Headache | 80 | 45.8 | 26 | 49.9 | 54 | 44.0 | 0.78 (0.41, 1.50) | 0.460 |
| Body ache | 65 | 37.2 | 18 | 34.5 | 47 | 38.3 | 1.27 (0.62, 2.62) | 0.514 |
| Sleeping difficulty | 63 | 36.0 | 20 | 38.4 | 43 | 35.0 | 0.93 (0.45, 1.92) | 0.835 |
| Dizziness | 57 | 32.6 | 12 | 23.0 | 45 | 36.7 | 1.45 (0.89, 2.39) | 0.138 |
| Muscle weakness | 55 | 31.5 | 13 | 24.9 | 42 | 34.2 | 1.48 (0.64, 3.44) | 0.363 |
| Foggy thinking | 45 | 25.7 | 9 | 17.3 | 36 | 29.3 | 2.05 (0.77, 5.46) | 0.151 |
| Loss of appetite | 45 | 25.7 | 12 | 23.0 | 33 | 26.9 | 0.86 (0.39, 1.91) | 0.708 |
| Palpitation | 41 | 23.5 | 11 | 21.1 | 30 | 24.4 | 0.91 (0.38, 2.14) | 0.821 |
| Cough | 41 | 23.5 | 7 | 13.4 | 34 | 27.7 | 1.76 (0.68, 4.57) | 0.245 |
| Chest pain | 39 | 22.3 | 8 | 15.4 | 31 | 25.3 | 1.53 (0.60, 3.93) | 0.373 |
| Fatigue | 36 | 20.6 | 12 | 23.0 | 24 | 19.6 | 1.76 (0.88, 3.53) | 0.112 |
| Skin rash | 37 | 21.2 | 9 | 17.3 | 28 | 22.8 | 1.90 (0.72, 5.00) | 0.192 |
| Clinical findings | ||||||||
| Neurologic findings | 116 | 66.4 | 36 | 69.1 | 80 | 65.2 | 0.68 (0.37, 1.22) | 0.192 |
| Peripheral neuropathy | 110 | 62.9 | 28 | 53.7 | 82 | 66.8 | 0.79 (0.42, 1.46) | 0.450 |
| Depression/anxiety disorder | 48 | 27.5 | 22 | 42.2 | 26 | 21.2 | 0.27 (0.12, 0.60) | 0.001 |
| Post-traumatic stress disorder | 38 | 21.7 | 17 | 32.6 | 21 | 17.1 | 0.36 (0.15, 0.84) | 0.019 |
| Cognitive impairment | 11 | 6.3 | 1 | 1.9 | 10 | 8.1 | 1.19 (0.16, 8.67) | 0.864 |
| Respiratory findings | 80 | 45.8 | 24 | 46.1 | 56 | 45.6 | 1.00 (0.52, 1.92) | 0.994 |
| Cardiovascular findings | 93 | 53.2 | 33 | 63.3 | 60 | 48.9 | 0.61 (0.33, 1.15) | 0.126 |
| Muscle weakness | 24 | 13.7 | 2 | 3.8 | 22 | 17.9 | 2.49 (0.63, 9.82) | 0.194 |
| Diabetes Mellitus | 12 | 6.9 | 0 | 0 | 12 | 9.8 | NA | NA |
| Poor quality of life | 69 | 39.5 | 24 | 46.1 | 45 | 36.7 | 0.70 (0.36, 1.34) | 0.278 |
| Overweight/obese | 40 | 22.9 | 15 | 28.8 | 25 | 20.4 | 1.08 (0.44, 2.66) | 0.861 |
| Laboratory findings | ||||||||
| Restrictive pattern on spirometry | 82 | 46.9 | 24 | 46.1 | 58 | 47.3 | 1.25 (0.64, 2.42) | 0.514 |
| Pneumonitis in chest X-ray | 8 | 4.6 | 1 | 1.9 | 7 | 5.7 | 1.47 (0.10, 22.18) | 0.782 |
| Any abnormality in ECG | 78 | 44.6 | 20 | 38.4 | 58 | 47.3 | 1.44 (0.93, 2.25) | 0.105 |
| Anemiab | 44 | 25.2 | 18 | 34.5 | 26 | 21.2 | 0.50 (0.22, 1.12) | 0.093 |
| High creatininec | 17 | 9.7 | 3 | 5.8 | 14 | 11.4 | 1.11 (0.29, 4.25) | 0.877 |
| High ALTd | 49 | 28.0 | 15 | 28.8 | 34 | 27.7 | 1.40 (0.80, 2.45) | 0.242 |
| Protinuriae | 27 | 15.4 | 7 | 13.4 | 20 | 16.3 | 0.78 (0.29, 2.08) | 0.616 |
| Required insulin | 39 | 22.5 | 2 | 3.9 | 37 | 30.4 | 6.71 (2.87, 15.67) | <0.001 |
| Hospitalization | 10 | 5.7 | 2 | 3.8 | 8 | 6.5 | 0.83 (0.16, 4.39) | 0.826 |
All estimates are adjusted for age, sex, body mass index, any comorbidity, group (non-hospitalized or outpatient/hospitalized or inpatient), and site (icddr,b/BSMMU).
Hemoglobin (g/dl) < 13 for male, and <12 for female.
High creatinine >106 mmol/L.
ALT (alanine transaminase) > 40 U/L.
One plus or more protein in urine; NA: not applicable.
After adjustment, the multivariable GEE models revealed that older age (>60 years) was independently associated with cardiovascular findings than participants aged less than 40 years (Table 5). However, neurological findings were more prevalent among older participants (>60 years) and participants aged 40–60 years than those younger than 40 years. Being a woman was an independent risk factor for sequelae-symptom, psychiatric sequelae, respiratory, cardiovascular, and neurological findings than a man. Similarly, hospitalization was significantly associated with respiratory, cardiovascular, neurological, and psychiatric sequelae than those who did not require hospitalization. Comorbidity and cigarette smoking were independent risk factors for cardiovascular and neurological findings, respectively. History of contact with acute COVID-19 patient was associated with the psychiatric sequelae.
Table 5.
Results of generalized estimating equation models showing risk factors associated with symptom-sequelae and findings among Covid-19 survivors.
| Sequelae-symptomb |
Respiratory findingsc |
Cardiovascular findingsd |
Neurologic findingse |
Psychiatric sequelaef |
|
|---|---|---|---|---|---|
| OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95%CI) | |
| Age Groupa | |||||
| 40–60 years | 1.44 (0.82, 2.51) | 1.24 (0.80, 1.93) | 1.24 (0.79, 1.95) | 2.03 (1.29, 3.19) | 1.18 (0.64, 2.18) |
| >60 years | 1.46 (0.61, 3.50) | 1.53 (0.83, 2.83) | 2.01 (1.09, 3.70) | 2.27 (1.24, 4.15) | 1.60 (0.65, 3.95) |
| Femalea | 4.12 (2.16, 7.88) | 1.62 (1.05, 2.50) | 1.60 (1.04, 2.47) | 2.73 (1.78, 4.17) | 2.32 (1.26, 4.25) |
| Hospitalized survivorsa | 2.49 (0.68, 9.10) | 3.14 (1.56, 6.32) | 2.46 (1.21, 4.99) | 2.73 (1.19, 6.25) | 2.19 (1.27, 3.75) |
| Comorbidity | 1.71 (1.00, 2.91) | 1.28 (0.85, 1.93) | 1.63 (1.07, 2.48) | 1.22 (0.81, 1.84) | 0.93 (0.52, 1.67) |
| Cigarette smoking | 1.76 (0.93, 3.34) | 1.49 (0.92, 2.44) | 1.29 (0.79, 2.11) | 1.69 (1.05, 2.73) | 1.35 (0.70, 2.60) |
| BSMMU site | 1.21 (0.73, 1.99) | 1.41 (0.98, 2.01) | 0.96 (0.67, 1.37) | 1.37 (0.97, 1.92) | 0.73 (0.44, 1.22) |
| Contact with COVID patient | 1.56 (0.96, 2.55) | 0.61 (0.41, 0.89) | 0.86 (0.59, 1.26) | 0.90 (0.62, 1.32) | 1.82 (1.07, 3.08) |
| Occupation | |||||
| Unemployed | 0.78 (0.40, 1.50) | 1.62 (1.02, 2.57) | 0.84 (0.52, 1.34) | 0.93 (0.59, 1.46) | 1.47 (0.74, 2.91) |
| Retired | 2.14 (0.80, 5.72) | 2.05 (1.10, 3.80) | 1.09 (0.60, 1.98) | 1.32 (0.97, 1.80) | 0.58 (0.25, 1.34) |
OR = Odds ratio, CI = confidence interval.
Reference group: age <40 years; male; non-hospitalized survivors; employed.
Respiratory findings = mMRC (modified Medical Research Council) dyspnea grade ≥2, bronchial or diminished breath sound, tachypnea, hypoxemia.
Cardiovascular findings = hypertension, tachycardia, edema.
Neurologic findings = peripheral neuropathy, anosmia, absent/impaired taste, tremor.
Psychiatric sequelae = Depression/anxiety disorder, Post-traumatic stress disorder, cognitive impairment.
Discussion
This longitudinal study of COVID-19 survivors provides vital insight into PCS, especially in low-resource settings. This study determined the prevalence, the changing characteristics over time, incidence, and risk factors of clinical and laboratory findings among COVID-19 survivors up to five months following recovery from the initial acute illness. Our results suggest that HS and NHS exhibited myriad clinical manifestations and laboratory findings. We found a higher prevalence of sequelae-symptoms and physical findings among HS than those of the NHS except for cardiovascular findings and muscle weakness at the 1-month visit. We observed a declining trend of most of these clinical manifestations over time in both the groups reflecting the gradual resolution of organ and tissue damage sustained throughout acute COVID-19.5 The pattern of sequelae-symptoms that survivors reported was similar to that described in previous studies.3,5
The prevalence and incidence of cardiovascular findings were similar between the groups indicating that even NHS are at increased risk of cardiovascular events.20 This result provides insight into long-term cardiovascular monitoring for all COVID-19 survivors irrespective of hospitalization, a proxy of disease severity. Among the echocardiogram findings, the signs of pulmonary hypertension (PH) merit distinct insinuation; as such, the prevalence of PH increased over time. In contrast, a previous observational study found the prevalence of PH remained stable with a prevalence of 10% between 60 days and 100 days after diagnosis of COVID-19.21 Many previous studies reported dyspnea as the most common respiratory finding among COVID-19 survivors.5,22, 23, 24 We also found a high prevalence of respiratory findings and restrictive patterns in spirometry among survivors. This finding suggests that partial recovery or ongoing tissue remodeling with fibrosis may persist for a prolonged duration in some COVID-19 survivors. Dysregulated respiratory T cell (CD8+) responses might be responsible for persistent tissue injury and impaired lung function among survivors.25
We found a high burden of neurological findings among COVID-19 survivors. However, the reassuring fact is that the manifestations were most often milder such as mild peripheral neuropathy (PN), tremor, anosmia, ageusia, as reported in previous studies.26 The increasing trend of PN in our cohort is concerning, and future research, including nerve conduction studies, should be conducted to detect the severity and subsequent course of the illness. The high burden of depression/anxiety disorder and PTSD in our cohort is consistent with previous studies.4 The incidence of new-onset diabetes and worsening glycemic control, as evidenced by the increased requirement of insulin therapy, was significantly higher among our HS than NHS. Previous studies have shown an association between acute COVID-19 and new-onset hyperglycemia as well as worsening glycemic control.27 Several previous studies of SARS-Cov 1 have also shown a greater incidence of acute-onset diabetes and metabolic derangement among participants with SARS-Cov1 infection than those with non-SARS-Cov1 infection.28 Our findings provide some support for the proposition of a probable long term diabetogenic consequence of Covid-19.29
As shown in a previous study, we found an association between older adults (>60 years) and hospitalization with some sequelae of COVID-19.5,22 Being a woman is an independent predictor of PCS. Huang et al. reported that women were prone to develop anxiety or depression, and lung diffusion impairment.5 We found that cigarette smoking and contact with acute COVID-19 cases were significantly associated with some after-effects of COVID-19.
We provided a comprehensive overview and evolution of sequelae among COVID-19 survivors at 1, 3, and 5 months after clinical recovery. Our findings could aid in building a bundle of care for survivors as the sequelae of COVID-19 could evolve over the long term. A strength of the study is the inclusion of many symptoms and clinical findings in the analysis, based on a literature review5 and a multidisciplinary approach with a comprehensive consultation with clinical experts. Our participants received specialized management from clinical experts for significant complaints and findings, and despite that, we found a relatively high prevalence of PCS among survivors. Thus, our results highlight the importance of regular follow-up of NHS like that of HS. The study had several limitations. First, we did not include age and sex-matched control groups to compare the symptoms and findings with COVID-19 survivors. Second, the study did not cover rural areas, thus only including survivors from urban areas. Therefore, the study findings should be used with caution in survivors of rural or underprivileged zones. Third, we included a diverse population with various manifestations of PCS; thus, we observed heterogenicity in the data. Fourth, we could not eliminate the chance of self-reporting bias leading to overreporting or under-reporting the symptoms. Fifth, we simultaneously tested many hypotheses, raising the multiple comparison issues and increasing the potential risk of type 1 error. Therefore, a limitation of the analysis is that multiple comparisons were not considered. Finally, the lack of laboratory and imaging studies among NHS during acute COVID-19 hinders us from identifying the impact of inflammatory markers of acute COVID-19 with the subsequent development of PCS.
In conclusion, the findings of hospitalized and non-hospitalized survivors provided imperative insight into the clinical manifestations of PCS. We observed a high burden of clinical findings among COVID-19 survivors despite the decreasing trend of most of the findings over time. Our results emphasize the importance of continuing a comprehensive longitudinal evaluation of COVID-19 patients, even survivors of mild COVID-19 who do not need hospitalization. Additional research is imperative to comprehend PCS's health and social impacts, assist patients living with PCS, and develop structured and targeted management.
Contributors
TA, SMA, MJC and FA had conceived and designed the study. TA, SMA, MJC, SA and CMA supervised the project administration, MJI, FA, MMA and IP did data analysis. FA, TA, SMA, and MJC drafted the manuscript. CMA, BA, SB, MM, IS, FI, MS, ANC, MFUR, AHK and MNH critically revised and edited the paper. FA, MZI, TA, MMA, and IP had full access to all study data. FI, MS, ANC, MMA and IP collected and verified the data. All authors agree to be responsible for the accuracy and integrity of the data and accept accountability for publication.
Data sharing statement
After getting institutional approval, the corresponding author will share the data upon reasonable request.
Declaration of interests
We declare no competing interests.
Acknowledgments
This publication was produced with the support of the United States Agency for International Development (USAID) under the terms of USAID’s Alliance for Combating TB in Bangladesh activity cooperative agreement no. CA # 72038820CA00002. Views expressed herein do not necessarily reflect the views of the U.S. Government or USAID. icddr,b is also grateful to the Governments of Bangladesh, Canada, Sweden and the UK for providing unrestricted/institutional support.
Footnotes
Supplementary data related to this article can be found at https://doi.org/10.1016/j.lansea.2022.100134.
Appendix A. Supplementary data
References
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