Clinical characteristics and long-term consequences of COVID-19 patients in a dedicated COVID unit of a tertiary care hospital: an 8-month follow-up study

Introduction

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), has continued to pose a fatal threat causing substantial mortality and morbidity worldwide, resulting in more than 188 million confirmed cases and more than 4 million deaths worldwide.¹ Since the first detection of COVID-19 on 8^th March, 2020 in Bangladesh, a total of 1,071,774 cases were identified with 17,278 deaths till the writing of this article.¹ The clinical spectrum of COVID-19 ranges from asymptomatic infection to critical illness.² In most of the patients, the presentation is mild but hospitalization is needed in around 20% of patients, and around 5% require critical care with non-invasive or mechanical ventilation.³ A significant percentage of patients who recovered from the acute COVID-19, develop new or continue to have previous symptoms lasting weeks to months. Additionally, delayed resolution of symptoms has been seen even in patients with mild symptoms who did not require any hospitalization.^4,5 This emerging condition has been given a variety of terms such as long COVID, post-acute COVID-19, chronic COVID-19, post-COVID syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC).⁶ This new condition is posing a significant effect on people’s quality of life.

To understand the “Long COVID”, long-term follow-up studies are necessary. Few studies have looked into the persistent symptoms, functional limitations and lung functions of discharged patients with the longest follow-up duration being 6 months.^7–11 Huang et al. found fatigue or muscle weakness, sleep difficulties and anxiety or depression as the most common symptoms 6 months following COVID-19 infection.⁸

As there is inadequacy of data on this new emerging condition in Bangladesh, we aimed to follow-up the COVID-19 patients for a longer period to describe the long-term consequences after hospital discharge and describe the functional limitation and potential risk factors.

Methods

Results

A total of 58 patients were included in the study. About 57 (98.3%) patients were discharged from the hospital. Among them, 10 (17.2%) patients recovered without residual damage and 47 (81.0%) recovered with residual damage. There was one case of death during hospital stay and one case of death after 6 months of discharge. Four patients were lost to follow-up.

The demographic and clinical characteristics of the study population are shown in Table 1. Twenty eight (48.3%) patients had non-severe disease and 30 (51.7%) patients suffered from severe COVID-19. The mean age of the study population was 47.79 ± 15.99 years and 53.4% were male. Around 38 (65.5%) patients had co-morbidities, which were diabetes mellitus (41.4%), hypertension (36.2%), ischaemic heart disease (20.7%), obesity (13.8%) and bronchial asthma (13.8%). The mean duration from symptom onset to hospital admission was 4.78 ± 2.73 days and mean duration of hospital stay was 15.37 ± 8.57 days. The common symptoms at admission were fever (87.9%), cough (72.4%), dyspnea (69.0%), fatigue (69.0%), anosmia (46.6%) and headache (36.2%). Severe COVID-19 patients received more oxygen, intravenous fluids, anticoagulant therapy, antiviral therapy and corticosteroid therapy than non-severe COVID-19 patients. Higher age, male gender, smoking, co-morbidities, diabetes mellitus, obesity, fever, cough, dyspnea at admission and increased duration of hospital stay were significantly associated with severe COVID-19 disease. Headache at admission was found more in non-severe COVID-19 patients.

About 43 (82.7%) patients had at least one symptom at 6-month follow-up which was significantly reduced (p = 0.001) to 29 (55.8%) patients at 8-month follow-up (Figure 1A). The common post COVID-19 symptoms were fatigue, poor memory, dyspnea, insomnia, chest pain, alopecia, depression, anxiety, joint pain and among them, the former 7 symptoms were significantly reduced from 6-month to 8-month follow-up (57.5% to 40.4% for fatigue, 40.4% to 15.4% for poor memory, 28.8% to 13.5% for dyspnea, 26.9% to 13.5% for insomnia, 21.2% to 9.69% for chest pain, 19.2% to 3.8% for alopecia, 17.3% to 3.8% for depression, all p < 0.05). There was a statistically significant increase in PCFS Grade 0 (17.3% to 44.2%, p < 0.05) and decrease in PCFS Grade 1 (50.0% to 34.6%, p = 0.039) from 6-month to 8-month follow-up (Figure 1B). The 4 patients that were lost to follow-up and the 2 patients that died during hospital stay and 6 months following discharge were excluded from the statistical analysis.

Figure 1. Follow-up of COVID-19 patients at 6-month and 8-month.

(A) Post COVID-19 symptoms; (B) Post COVID-19 Functional Status Scale (PCFS).

When the follow-up symptoms were further subdivided according to the severity of COVID-19, cough (23.1%) and visual blurriness (11.5%) were significantly associated with severe COVID-19 at 6 months while fatigue (56.0%) and insomnia (24.0%) were significantly associated with severe COVID-19 at 8 months (Table 2).

Table 3 shows the association of post COVID-19 functional status scale (PCFS) at 8-month follow-up with demographic and clinical characteristics of the study population. There were 23 (44.2%) patients with no post COVID-19 symptoms (PCFS grade 0), 18 (34.6%) patients having post COVID-19 symptoms with negligible functional impairment (PCFS grade 1) and 11 (21.2%) patients had some form of functional limitation (PCFS grade 2-4) even at 8 months. Patients with PCFS grades 2-4 showed significant association with severe COVID-19 diagnosis at admission, higher age, dyspnea, ageusia, diarrhea at admission and post COVID-19 fatigue, dyspnea, joint pain, insomnia, poor memory at 8-month follow-up when compared to patients with PCFS grade 0 and with higher age, increased duration of hospital stay, dyspnea and diarrhea at admission when compared to patients with PCFS grade 1. Post COVID-19 fatigue and poor memory were significantly associated with PCFS grade 1 when compared to PCFS grade 0.

Univariate analysis showed age (OR: 1.13; 95% CI: 1.07-1.21), male gender (OR: 5.81; 95% CI: 1.87-18.03), smoking (OR: 7.53; 95% CI: 1.49-37.99) and co-morbidities (OR: 13.91; 95% CI: 3.38-57.17) as predictors for severe COVID-19 but multivariate analysis showed only age (OR: 1.08; 95% CI: 1.02-1.16) as the significant factor for severe COVID-19. Age (OR: 1.04; 95% CI: 1.01-1.08) and smoking (OR: 9.38; 95% CI: 2.33-37.69) were predictors associated with PCFS grade 2-4 on univariate analysis but on multivariate analysis increased age (OR: 1.05; 95% CI: 1.00-1.11), female sex (OR: 10.83; 95% CI: 2.08-56.35) and smoking (OR: 27.48; 95% CI: 4.30-175.61) were at increased odds for developing post COVID-19 functional impairment (Table 4).

Discussion

In this prospective cohort study, the demographic and clinical characteristics of COVID-19 patients at admission, at 6-month and 8-month follow-up was assessed and their association was seen according to severity of COVID-19 and PCFS.

The mean age of the current study population was 47.79 ± 15.99 years with higher male preponderance. The common symptoms at admission were fever, cough, dyspnea and fatigue. These findings are similar to other previous studies.^16–19 The increased male predilection to COVID-19 maybe explained by increased expression of angiotensin converting enzyme receptor-2 (ACE-2) in male, increased resistance to infection by females due to sex hormones and irresponsible attitude of men towards preventive measures.²⁰ Much like in this study, diabetes mellitus and hypertension were the common co-morbidities also in studies in Pakistan, China and France.^17,18,21 About 98.3% patients were discharged from the hospital while 1.7% patient(s) died during hospital stay in the current study. Initial study from China reported 1.4% deaths¹⁷ but other studies have shown larger number of deaths, 25.1% in a Netherlands study,²² 14% in a British study²³ and 10.9% in a United States study.²⁴ Lower proportion of deaths may be attributed to smaller sample size in the current study and lower co-morbidities in the Chinese study.

This study found severe COVID-19 patients had higher mean age, male majority, more smokers, more co-morbidities, greater presentations of fever, cough, dyspnea at admission and increased duration of hospital stay than non-severe COVID-19 patients. Patients with severe illness were older, predominantly male and likely to have co-morbidities in other studies as well.^{17,22,25–30} Elderly people had reduced immune response due to immunosenescence, inflammaging, alteration of T-cell diversity, epigenetic changes and dysregulation of renin-angiotensin system (RAS) and also are prone to cytokine storm, specially due to age-related decline of oxidized nicotinamide dinucleotide, resulting in increased risk of severe infection.³¹ An Ethiopian study revealed cough, dyspnea, myalgia, headache, fever, chest pain and anosmia as common symptoms of severe COVID-19²⁵ while a Chinese study reported increased expectoration, dyspnea, anorexia and confusion in the severe COVID-19.²⁸ A study of 101 patients in Wuhan found no association of smoking with severity of COVID-19²⁶ but a meta-analysis showed smoking to be significantly associated with severe disease.³² Smoking may result in upregulation of ACE-2 gene regulation, which may be the cause of increased severity of COVID-19 infection.³³ The current study found age as the only significant independent predictor for severe COVID-19. Other studies reported older age, co-morbidities, increased white blood cell count, increased C-reactive protein and higher D-dimer at increased risk of developing severe disease.^{21,25–27,29,30}

The persistent post COVID-19 symptoms at follow-up of this study were fatigue, poor memory, dyspnea, insomnia, chest pain, alopecia, depression, anxiety and joint pain with 82.7% and 55.8% patients having at least one symptom at 6 and 8 months respectively. A large cohort study in Wuhan, China found 76% of patients had at least one post COVID-19 symptom at 6 months with females getting more affected than males. The common symptoms were fatigue or muscle weakness and sleep difficulties.⁸ Another Nigerian study found most common post COVID-19 symptoms to be fatigue, headache, chest pain and insomnia.⁹ The pathophysiology behind persistence of symptoms is still unknown but probable mechanisms maybe vascular inflammation, massive inflammatory response from cytokine storm and endothelial dysfunction by the coronavirus.⁹ Our study also revealed that over time, the post COVID-19 symptoms significantly reduced in frequency. Furthermore, patients with PCFS grade 0 increased and those with PCFS grade 1 decreased in frequency from 6 to 8-month follow-up. Hence, it can be postulated that the post-COVID 19 symptoms may improve with time. An article by O’Sullivan O, demonstrated that previous coronavirus outbreak, severe acute respiratory syndrome (SARS) and Middle-Eastern respiratory syndrome (MERS) coronavirus, also lead to long-term sequelae after recovery from disease and problems like fatigue, shortness of breath, reduced quality of life and mental health issues reduced with time and rehabilitation but still persisted even after 1 year from disease onset.³⁴

Patients with functional impairment (PCFS grade 2-4) at 8 months were found to have higher age, increased symptoms of dyspnea, ageusia and diarrhea at admission, severe COVID-19 infection at admission and more post COVID-19 symptoms of fatigue, dyspnea, joint pain, insomnia and poor memory when compared to patient with no post COVID-19 sequelae (PCFS grade 0). PCFS grade 2-4 were found to be associated with female sex, age, duration of hospital stay, mechanical ventilation and admission to ICU by Taboada M et al.¹⁰ and de Graaf M et al. reported that patients with functional limitation were more likely to have longer period of hospital stay, needed mechanical ventilation, depression and cognitive impairments.⁷ After adjusting for confounding variables, our study found increasing age, female sex and smoking at higher odds of developing post COVID-19 functional limitation. A Spanish study demonstrated that age and duration of hospital stay were linked to higher functional impairment¹⁰ while another study reported that increased age, male gender, duration and need for mechanical ventilation during admission, length of hospital and ICU stay were associated with PCFS grade 2-4 at 6 months in patients who recovered from COVID-19 associated ARDS.¹¹

There were, however, some limitations to the study. The study population was small, which led to smaller sample size of sub-groups, limiting the power of statistical analysis. The single center study may not be representative of the whole population. Four patients who were lost to follow-up, resulting in missing data and preventing detailed analysis of factors associated with the risk of severe COVID-19 and functional status of patients. Most of the patients belonged to a low- income group so few investigations were done; as a result, adequate data regarding investigation could not be taken. Due to the nature of telephone call follow-up, some information may be less accurate and subjected to memory bias. Our data was also lacking in baseline functional status scale scores, which could have provided a better picture of functional outcomes.

Conclusion

Despite the limitations, this paper provided some important information about the demographic, clinical characteristics and long-term follow up of Bangladeshi COVID-19 patients. To our knowledge, this is the first study to use PCFS as a tool to follow-up patients at two points of time after recovering from COVID-19, namely at 6 and 8 months. The demographic and clinical characteristics of the Bangladesh population were similar to those of other countries. Age was a significant independent predictor for severe COVID-19 disease. Majority of the patients recovered with persistent symptoms up to 6 months; symptoms improved with time but were still present even at 8 months. Patients with higher age, female gender and smoking history were more prone to develop functional impairment after recovery. Therefore, strategies should be aimed at rehabilitation of these patients to improve their outcome. A multi-centered prospective study of larger sample size and longer follow-up period with demographic, clinical, investigational and treatment data, including assessment of physical, functional, psychiatric and cognitive domain of recovered COVID-19 patients would provide a much more comprehensive health spectrum of the COVID-19 infection that can be representative of the whole population.