**4. Discussion**

As the COVID-19 pandemic continues unabated, a vast majority of survivors have presented to healthcare providers with a multitude of signs and symptoms representing possible long-term effects following acute COVID-19 infection [6]. With the persistence of debilitating complaints by the survivors of previous coronavirus infections like Severe Acute Respiratory Syndrome (SARS) in 2003 and Middle East Respiratory Syndrome (MERS) in 2012, the current concern regarding long haulers of COVID-19 seems justified [7]. In a systematic review on the long-term effects of COVID-19 by Leon et al., 80% post-COVID-19 patients (95% confidence interval 65–92%) continue to have one or more symptoms following two weeks of acute COVID-19 infection [5]. Another study by Morin et al. reported that 51% patients had at least one symptom after four months of diagnosis of COVID-19 in a cohort of 478 hospitalized patients [8]. Similarly, in a review by Pavli et al., the incidence of post-COVID syndrome was estimated to be 10 to 35% among patients who were treated on an outpatient basis, and reached 85% among patients who were hospitalized [9]. In our study, around 82.2% patients, with a recent history of confirmed COVID-19 infection, continue to have at least one persistent/new symptom beyond two weeks of diagnosis.

Shortness of breath was the commonest complaint reported by 40.7% patients at mean follow-up duration of 28 days in our study. In a study done in Italy by Carfi et al., fatigue (53.1%) and dyspnea (43.4%) were the commonest complaints of post-COVID-19 patients at mean follow-up duration of 60 days [10]. Persistent dyspnea could result due to the underlying pathology of impaired diffusion capacity, impaired respiratory muscle strength, and fibrotic abnormalities in post-COVID lungs, which were more frequently encountered in severe forms of COVID-19 following convalescence [11]. Another study from China reported fatigue (63%) and sleep disturbances (26%) to be persistent among post-COVID-19 patients at the median duration of six months from the disease onset [12]. Our study reported fatigue in 33.1% patients, whereas insomnia and anxiety were persistent in 16.1% and 13.6% patients during their first follow-up visit following COVID-19. Post viral fatigue has been postulated to result from immune dysregulation and autonomic alterations following COVID-19 infection [13]. Psychological effects following recovery from acute COVID-19 illness could result due to direct viral effects on cognition or may result from the social circumstances related to disease like loss of loved ones, spanning fears about future, job loss, anticipation anxiety, lockdown, and intensive care strategies following which the patient survived [14].

Neurological symptoms like anosmia/hyposmia and ageusia/dysgeusia were found to be persistent in 9.3% and 6.8% patients at their first follow-up visit. One patient reported perception of foul smell and altered smell pattern suggestive of parosmia even after three months of mild COVID-19 infection. Post-infectious olfactory dysfunction in form of misperception of existing odors has been previously reported as a delayed complication following COVID-19 [15]. Similarly, another patient reported a new onset of burning sensation and lancating pain at the left perinostrillar and maxillary area eight weeks following recovery from mild COVID-19 infection, suggestive of left-sided trigeminal neuralgia. The existence of trigeminal neuralgia in relation to SARS-CoV-2 has been recently described in the literature as one of the uncommon manifestations of COVID-19 [16]. Two (1.7%) patients complained of impaired concentration following COVID-19, of which one was below 30 years of age who did not require hospital admission and the other was above 75 years of age, treated in an intensive care unit. 'Brain fog' is a colloquial term being used to describe the cognitive difficulties faced by a large group of patients following COVID-19. Neuroinflammation, resulting from the pathogenic and stress stimuli, is the proposed mechanism for this condition, though concrete evidence is ye<sup>t</sup> to be seen [17].

Around two-third (65.3%) of total patients said that they did not feel as normal as before the diagnosis at mean duration of 28 days following COVID-19 infection. Eighteen percent of the total patients reported more than four persistent symptoms during their follow-up visit at STIDH. An important finding in our study was that the presence of at least one persistent/new symptom in post-COVID-19 patients did not correlate with age groups, gender, comorbidities, or severity of COVID-19. Similar findings were also mentioned by Rio et al., who stated that long COVID symptoms did not correlate with chronic comorbidities or severity of acute COVID-19 illness. [18]. Likewise, Terfonde et al. stressed on the persistence of symptoms in younger group of patients without any comorbid conditions, such that could result in a prolonged road to recovery to usual state of health, leading to absenteeism from work and poor quality of life [19]. Significant association was demonstrated between the presence of at least one persistent/new symptom in post-COVID-19 patients to mode of isolation (Table 6), whereby patients who were treated in an intensive care unit had higher chances of getting at least one prolonged symptom beyond two weeks from diagnosis of COVID-19. Post intensive care syndrome is a well-defined morbid entity, which has been described in patients after discharge from an intensive care unit following severe illnesses. However, post-COVID syndrome has been described not only in patients who were discharged from intensive care but also in those that did not seek medical help and recovered at home [18]. Thus, our finding regarding the association of mode of isolation to persistence of post-COVID symptoms needs further evaluation.

The emergence of multiple variants of SARS-CoV-2 in recent times is a matter of grave concern that raises the question of a possible escape from vaccine-induced immunity and could be a major driving force for perpetuality of the current pandemic. Healthcare workers need to be aware of the persistence of multitude of symptoms in COVID-19 patients post discharge, and ways to mitigate it. The physical and psychological burden on survivors of this novel disease is ye<sup>t</sup> to be addressed in a holistic way. Despite the fact that the scientific community is still in search for a breakthrough to save lives during the acute phase of the disease, the post-COVID morbidity of millions cannot be ignored. This study addresses the post-COVID symptomatology in one of the tertiary care centers in Nepal and represents data from low- and middle-income countries in South Asia. With a third wave of COVID-19 looming round the corner in South Asia, more studies need to be planned to investigate the long-term consequences of COVID-19.

This was a single-centered study and had a small sample size. Larger studies need to be conducted to know the actual burden of persistent symptoms in post-COVID-19 patients. An important point of consideration is that this was a hospital-based study; thus, the actual prevalence of post-COVID-19 symptoms might have been overestimated. A single follow-up visit was only considered in this study. Longer duration of follow-up is warranted to study the evolution of persistent symptoms in post-COVID-19 patients.
