This was a single-center, hospital-based prospective observational study conducted at a 1300-bed academic tertiary-care referral center in South India from February to July 2021. The hospital had a dedicated isolation facility comprising ICU and non-ICU locations for treating patients admitted with COVID-19. Eligible patients included those aged ≥18 years and were hospitalized in a COVID-19 isolation unit for COVID-19 based on a positive SARS-CoV-2 reverse transcription-polymerase chain reaction or antigen test at the time of admission.

All patients who were admitted to the COVID-19 isolation unit during the specified period were screened for eligibility and those meeting eligibility criteria were recruited after providing informed written consent. Patients younger than 18 years of age, those with a life condition triggering palliative intent, those with COVID-19 and a surgical indication (intended or actual), or those transferred outside specific COVID-19 wards for continued care for conditions not directly triggered by the COVID-19 infection were excluded. Patients who did not consent to long-term follow-up postdischarge were also excluded from the study (Figure 1).

The data collection included demographic characteristics such as age, sex, social history, and comorbidities. We also recorded COVID-19–specific parameters, including the severity of COVID-19 infection, level of clinical care received (ICU or non-ICU locations), length of hospital stay (LOS), vaccination status, disease symptoms, and treatment details (eg, antiviral, anticoagulation, and steroid administration), in COVID-19 patients.

A questionnaire was prepared to assess the post-COVID-19 symptoms in patients after their discharge from the hospital. The follow-up was conducted at 2 weeks (first follow-up) and 6 weeks (second follow-up) after discharge. The post-COVID-19 symptoms were grouped into “acute COVID-19” and “ongoing symptomatic COVID-19” categories based on the 2-week and 6-week timeline postdischarge, respectively [7]. Information regarding the current symptoms and working status of each patient was obtained. Face-to-face interviews and questionnaire completion were performed during the patients’ hospital visit for follow-up. Patients who were not able to come to the hospital were followed up by telephone. The collected data were entered in a predesigned data collection form and populated in a Microsoft Excel sheet for further analysis.

Statistical analysis was performed using IBM SPSS version 20.0 software. Categorical variables are summarized using frequency and percentage. Numerical variables are presented using mean (SD). To test the statistical significance of the comparison of categorical variables between two subject groups, a χ² test with continuity correction was applied. To test the statistical significance of the difference in the mean values of numerical variables between two subject groups, the Student t-test was used. Logistic regression was employed to identify the predictors of presence of symptoms lingering at 6 weeks. P<.05 was considered to indicate a statistically significant difference.

The study participants were informed that participation was anonymous and voluntary, that all responses would be kept confidential, and that the collected data would be used for academic research only. The study was approved by the Institutional Review Board of Amrita Institute of Medical Sciences and Research Centre (approval number IEC-AIMS-2021-PHARM-095), and all participants provided written informed consent.

Our study revealed a 61% incidence of post-COVID-19 syndrome at 6 weeks and the predominant symptoms included fatigue (55.8%), dyspnea (20%), and weight loss (16.7%). Importantly, the prevalence of these symptoms was not significantly different between those requiring critical care and those who were hospitalized but did not require intensive care. In addition, our study identified female sex and use of steroids during the hospital stay as significant predictors of persistent symptoms at 6 weeks.

As the media and public attention related to COVID-19 was primarily focused on mortality, the political machinery in the LMIC setting has been in a state of hubris to claim a low death rate; consequently, the morbidity due to post-COVID-19 syndrome, which is by large a societal health issue, remained overshadowed and unaddressed. There has been no systematic approach to capture the incidence and formulate treatment protocols for those who continue to suffer postinfective symptoms. Our study shows that a large proportion (61%) of survivors report persistent symptoms. As pointed out by others, this result suggests that the number reported here could be a significant underestimation on account of ascertainment bias, and the chance that others not requiring hospitalization or not able to access appropriate care during a peak wave could also suffer such consequences [8].

The predominant post-COVID-19 symptoms identified in our study included fatigue (55.8%), dyspnea (20%), and weight loss (16.7%), and 10% of the cohort reported other symptoms such as loss of appetite and cough. A UK-based study reported fatigue in 72% of ICU patients and in 60.3% of patients in other wards, and dyspnea in 65% of ICU patients and 42.6% of patients in other wards at 4-8 weeks after discharge [19]. Another prospective cohort study from the United States found fatigue and dyspnea reported among 55% and 45.3% of COVID-19 survivors at 35 days postdischarge, respectively [20]. Our study observations at 6 weeks postdischarge were overall in accordance with these previous publications regarding the prevalence of post-COVID-19 symptoms. However, our cohort had a lower prevalence of respiratory symptoms such as dyspnea and cough at 20% and 10%, respectively. The appearance of new post-COVID-19 symptoms at 2 weeks among the patients in our cohort included anxiety/depression, weight loss, sleep disturbance, blurred vision, skin rashes, and infections. Despite the possibility of postintensive care syndrome interfering with the post-COVID-19 syndrome assessment, the lack of a significant difference in the prevalence of post-COVID-19 symptoms at 6 weeks among ICU- and non-ICU–requiring patients in our study suggests that patients discharged from non-ICU locations with relatively lower COVID-19 severity could also develop post-COVID-19 symptoms similar to patients discharged from the ICU.

Despite the existing publications portraying the major role of comorbidities, advancing age, and LOS in the development of postdischarge COVID-19 symptoms, our data failed to show any significant association with these covariates [21]. In our study, female sex and steroid administration during the hospital stay were found to be significant risk factors for the persistence of post-COVID-19 symptoms at 6 weeks. Similar observations regarding female sex as a risk factor for developing post-COVID-19 symptoms was found in a prospective cohort study conducted by Mahmud et al [22] and in a retrospective multicenter study conducted by Zhang et al [23]. In addition, our study identified that patients who received steroids during their hospital stay (12/70, 17%) and at discharge (5/70, 7%) had post-COVID-19 symptoms at 6 weeks of follow-up irrespective of whether they had an ICU stay during hospitalization. Steroid-associated myopathy could have contributed to the fatigue-like state that persisted in some patients, since steroid use itself was associated with a higher chance of reporting this symptom [24]. This indicates a potential role for steroid stewardship programs that optimize the use of steroids in COVID-19 patients with special reference to mild cases not requiring intensive care, given the increased risk of lingering post-COVID-19 symptoms after discharge [25]. Therefore, patients receiving steroids discordantly should be under heightened surveillance for post-COVID-19 syndrome, particularly if they belong to the mild to moderate severity category.

The rate of hospitalization of patients after discharge from the hospital was 5.8% and 3.3% at the second and sixth week of follow-up, respectively. These rehospitalizations were due to the presence of post-COVID-19 symptoms; thus, any service targeting these subjects will have to distinguish among complaints as having a distinct pathophysiologic correlate to the acute infection, such as sequelae like lung fibrosis and ongoing inflammation related to lung damage, which would also have therapeutic implications. A retrospective study of hospitalized patients for post-COVID-19 sequelae demonstrated a higher risk of poor clinical outcomes, including mortality, as compared to that of the general population [26]. Richard Horton famously labeled the COVID-19 pandemic a “syndemic” [6]. Most notably, compared to other respiratory illnesses such as influenza, COVID-19 survivors were determined to suffer higher rates of rehospitalization and all-cause mortality in addition to mental health and cognitive impairment, posing a substantial burden on the health care system [27,28] owing to the syndemic nature of COVID-19 [6,29]. The concept of COVID-19 being a syndemic implies that it cannot be considered as simply an acute viral infectious syndrome but rather as a disease with long-lasting health effects, which requires the adoption of an interdisciplinary approach as a way forward for comprehensive management of this underrecognized health condition.

Our study also highlights higher risks faced by women in developing persistent post-COVID-19 symptoms. Unfortunately, women are known to be at the bottom heap in terms of health care availability and delivery in India [30], with poor accessibility to health-related services, particularly for symptoms such as fatigue, which is recognized to be widespread across many other postinfectious states and needs a comprehensive approach to its management [8].

In LMIC settings, where health expenditure is largely out of pocket [27,31], the majority of patients who suffer from post-COVID-19 syndrome—as an ill-defined clinical entity—are likely to ignore the health effects by not seeking the appropriate medical care. In this context, defining the illness and identifying its magnitude is of paramount importance, along with determining the predictive risk factors that would predispose an individual for this adverse health condition [32]. Our study identified women as having a higher risk of post-COVID-19 syndrome, which is a significant finding considering that in LMICs, neglected populations, including women and older adults, are also on the fringes of the health care delivery apparatus [33]. This study highlights the significant impact of COVID-19 on its survivors, pointing toward the need for holistic care for those who are identified as high risk and the unmet need for surveillance for post-COVID-19 issues.

Our study represents data from an unvaccinated population; thus, the realm of post-COVID-19 symptoms in the postvaccination era is worth capturing to elicit the possible difference brought about by vaccination. The reduced post-COVID-19 symptom burden among the vaccinated who suffer from breakthrough infections, as evidenced by the ZOE COVID Study, although promising, is in turn a call to address the existing global vaccine inequity [34] and to address the prevailing vaccine hesitancy.

In our plea for the recognition of the syndemic is a hope that we also recognize the need for a country-specific strategy to address the health needs of the majority population in the postpandemic era via harnessing the potential of technology. For example, this could be achieved by adopting and validating rapidly deployable strategies such as telemedicine to support post-COVID-19 symptoms such as fatigue, along with addressing the mental health issues, especially in the context of the persistent and looming threat of potential outbreaks from the newer and emerging variants. While these interventions have shown mixed results [35-37], the effects in post-COVID-19 syndrome recognition and management are still unexplored. Our study seeks to draw attention to the large group of hospitalized COVID-19 survivors who developed post-COVID-19 syndrome during the initial phase of the pandemic, especially women and patients treated with steroids who have an enhanced risk, irrespective of the COVID-19 severity. Future research is required to estimate the prevalence of persistent, recurrent, and new post-COVID-19 symptoms associated with COVID-19 infection and the changes in trends with vaccination and variants.

This study has many limitations. Our conclusion is based on data from a single tertiary-care center, which largely catered to morbidly ill patients. This study was limited to COVID-19 survivors who were hospitalized. Since the period of the follow-up was limited to 6 weeks, the duration of the persistence of the symptoms of long COVID beyond this period could not be determined. The prevalent SARS-CoV-2 variant during the study period was Delta; however, variant-specific influences on the incidence and severity of post-COVID-19 syndrome have not been investigated, which would require future prospective studies. Similarly, our study observations cannot be extrapolated to a vaccinated population as the study cohort was unvaccinated. However, this adds strength to the study as in the current context we are unlikely to obtain an unvaccinated cohort for studying the effects of long COVID. We did not use structured questionnaires to quantitatively measure the mood or fatigue given the lack of validation of most global instruments in our population.

Our study revealed a high prevalence of post-COVID-19 symptoms at a minimum of 6 weeks postdischarge among inpatients who recovered from COVID-19. All severity categories of COVID-19 had an equal risk of contracting post-COVID-19 syndrome after hospitalization irrespective of their status of ICU or non-ICU stay. Female sex and steroid administration during the hospital stay were identified as predictors of the persistence of post-COVID-19 symptoms at 6 weeks. Health care systems across the globe have to account for the tail end crisis of the COVID-19 pandemic (ie, post-COVID-19 syndrome). Understanding the syndemic nature of the disease will help in formulating strategies for the management of COVID-19 by duly emphasizing the rehabilitation process of those who are suffering from an extended illness.