Prevalence and Impact of Preexisting Comorbidities on Overall Clinical Outcomes of Hospitalized COVID-19 Patients

COVID-19 risk increases with comorbidities, and the effect is magnified due to the contribution of individual and combined comorbidities to the overall clinical outcomes. We aimed to explore the influence of demographic factors, clinical manifestations, and underlying comorbidities on mortality, severity, and hospital stay in COVID-19 patients. Therefore, retrospective chart reviews were performed to identify all laboratory-confirmed cases of SARS-CoV-2 infection in Apollo Hospitals, Hyderabad, between March 2020 and August 2020.A total of 369 confirmed SARS-CoV-2 cases were identified: 272 (73.7%) patients were male, and 97 (26.2%) were female. Of the confirmed cases, 218 (59.1%) had comorbidities, and 151 (40.9%) were devoid of comorbidities. This study showed that old age and underlying comorbidities significantly increase mortality, hospital stay, and severity due to COVID-19 infection. The presence of all four comorbidities, diabetes mellitus (DM) + Hypertension (HTN) + coronary artery disease (CAD) + chronic kidney disease (CKD), conferred the most severity (81%). The highest mortality (OR: 44.03, 95% CI: 8.64-224.27) was observed during the hospital stay (12.73 ± 11.38; 95% CI: 5.08-20.38) in the above group. Multivariate analysis revealed that nonsurvivors are highest (81%) in (DM + HTN + CAD + CKD) category with an odds ratio (95% CI) of 44.03 (8.64-224.27). Age, gender, and comorbidities adjusted odds ratio decreased to 20.25 (3.77-108.77). Median survival of 7 days was observed in the (DM + HTN + CAD + CKD) category. In summary, the presence of underlying comorbidities has contributed to a higher mortality rate, greater risk of severe disease, and extended hospitalization periods, hence, resulting in overall poorer clinical outcomes in hospitalized COVID-19 patients.


Introduction
Novel coronavirus disease (COVID- 19), a global disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was initially reported in December 2019 in Wuhan city of China. It had rapidly spread across over 180 countries and was declared a pandemic by WHO in March 2020 [1]. This pandemic had an enormous adverse impact on socioeconomic conditions, traditional human lifestyle, and healthcare resources worldwide. As of August 2021, 213,752,662 confirmed cases of COVID-19 and 4,459,381 deaths were recorded globally [2]. As the virus continues to evolve, more infections and mortality are expected worldwide. On the other hand, recurrence of COVID-19 infection has also been reported despite the ongoing global vaccination drives [3]. Therefore, it is essential to understand the clinical and epidemiological characteristics of COVID-19 infected patients to develop effective preventative strategies to stall the spread of infection.
Although evidence from recent studies suggests that individuals with preexisting comorbidities are at a greater risk of mortality due to COVID-19 [4], the available data regarding the association between COVID-19 and underlying comorbidities is still limited. The most prevalent comorbidities in COVID-19 patients include diabetes, hypertension, cardiovascular disease, renal complications, and cancer. Although all comorbidities do not confer the same risk, many of these are strongly associated with each other, resulting in multiple comorbid conditions in many patients, putting them at a greater risk of severity and mortality associated with COVID-19 [5]. It was also reported that poorer prognosis and clinical outcomes were observed in patients with any comorbidity or a combination of comorbidities than those without [6].
In COVID-19 patients, hypertension was reported to be the highest preexisting comorbidity with an increased risk for severe infection and death [7][8][9][10]. An increased mortality rate has also been highly reported in patients with underlying cardiovascular disease [6,9,11]. At the same time, diabetes stands as the third most prevalent comorbidity [12,13] and is responsible for developing severe illness in COVID-19 patients [14]. Chronic kidney disease is associated with disease severity and increased mortality in COVID-19 patients [15]. However, the prevalence of comorbidities was highly variable in COIVD-19 patients, as reported in many studies [14].
In our study, we have presented the baseline demographics, clinical parameters, prevalence, and impact of the four          Table 4 and depicted in Figure 1(b). The severity of the disease is higher in CKD (100%) and DM + HTN + CAD + CKD (81.8%) groups. Disease severity was significantly high in the presence of all four comorbidities, with p≤0.001, as shown in Table 5 and Figure 1(c), except in HTN, CAD, and HTN + CAD groups (severity of disease was not compared between the comorbidity groups).

Number of Comorbidities and Their Impact on Overall
Clinical Outcomes. With an increase in the number of comorbidities, mortality also increased significantly. The  Notes: p ≤ 0:001 suggests significant association between comorbidity groups and severity of the disease. t-test was viewed for comparison of proportions between no comorbidity and other comorbidity groups. Variations in superscripts (a, b) indicate significance (p < 0:05) of disease severity across these groups.           Figure 3. Furthermore, a significant negative association of survival with comorbidities was observed with p < 0:05, as shown in Table 9.

Discussion
In this study, we report the impact of four selected comorbidities, DM, HTN, CAD, and CKD, at the individual level and their combinations, on mortality, severity of the disease, and length of hospital stay of COVID-19 patients.
In the baseline clinical characteristics, we observed significantly high systolic blood pressure, respiratory rate, mean age of patients, and low SPO2 in patients having one or more comorbidities than those without. In addition, a considerably longer length of hospital stay was observed in patients with any comorbidity, suggesting that patients with underlying comorbidities were required to spend more treatment days in the hospital when compared to patients without any comorbidity. There were fewer survivors among those with comorbidities. As reported elsewhere, patients with two or more comorbidities had poorer outcomes [16]. Mortality was significantly high in patients with HTN, CAD, CKD, and all combinations analyzed except DM and DM + CAD groups compared to patients without comorbid-ities. In our study, DM was not independently associated with mortality. However, the risk of progression to severe disease was observed in patients with DM, as has been highlighted in previous studies [17,18].
The presence of comorbidities is significantly associated with the severity of the disease in patients having DM, CKD, DM + HTN, DM + CAD, DM + HTN + CAD, DM + HTN + CKD, DM + HTN + CAD + CKD, which is evident through Table 5. Furthermore, our results show an association between the length of hospital stay and the presence of underlying comorbidities as the duration of hospital stay was significantly longer in patients with DM, HTN, DM + HTN, DM + HTN + CAD, DM + HTN + CKD, and DM + HTN + CAD + CKD compared to patients without any comorbidities. The Kaplan-Meier plots showed that for individual comorbidities, the relative probability of mortality was CAD > CKD > DM > HTN > no comorbidity, p < 0:0001. With comorbidities, the least survival was observed in the (DM + HTN + CKD + CAD) group. The mean time from the onset of symptoms to death differs from the published information inferring differences in arrival time, stage of patients arrival to the hospital, ABO blood groups, probably ethnicity, etc.
Our analysis indicates that an increasing number of comorbidities has significantly affected clinical outcomes in   [16,19]. Likewise, a prolonged hospitalization period and a higher risk of severe disease were observed in patients with an increasing number of comorbidities compared to those with none. However, no significance was observed in the length of the hospital stay in patients having one or two or three or four comorbidities. In addition, disease severity was not significantly different in patients with one or two and three comorbidities as indicated by variation in superscripts, as shown in Table 6.
Studies have reported comparative differences in clinical outcomes in COVID-19 patients during 1 st and 2 nd waves of infection in India and worldwide [21]. Several variations in clinical characteristics in both waves in India were reported, including a low death rate and patients less affected by comorbidities in the second wave than the first [22]. Another study reported a sharp decline in the case of fatality rate in the second wave from the first wave in India, which could be due to the younger demographic profile [23].
We observed variations in outcomes over time in our study setting by comparing present data with data collected from hospitalized COVID-19 patients admitted to our hospital during the postsecond wave of infection in India, i.e., from August 2021 to December 2021. In this new cohort, comorbidities did not show a significant association with mortality and severity of the disease, unlike that of present data. However, patients with comorbidities required longer hospitalization than those without in both the data sets. This variation in outcomes over time could be attributed to the emergence of new variants/mutants of the virus, improvement in overall understanding of the disease management such as evolving therapeutic regimes, preparedness in healthcare settings, and most importantly, the implementation of mass vaccination drives. Our observations are consistent with other studies that reported both similarities [24] and variations [21] in their data over a period of time. All the above observations are presented in Supplementary  Tables 1-4.
Although several studies have reported the impact of comorbidities on the clinical outcomes in COVID-19 patients, our study highlights the prevalence and impact of all possible combinations of the four most prevalent comorbidities, DM, HTN, CAD, and CKD, on the overall outcomes in hospitalized COVID-19 patients which were not reported earlier.
Limitations of our work, the study population included patients from a single centre within Hyderabad city, India.
The presence of comorbidities was confirmed with patient medical records only. However, the degree of control and timespan of comorbidities and interaction were not considered, which might affect the outcomes. Relatively low sample numbers in groups such as CAD, CKD, DM + CAD, and HTN + CAD could also affect the results. Furthermore, the study is limited to the initial four months of India's first wave of infection, from March 2020 to August 2020.

Conclusions
We consider this study to be an essential contribution to the worldwide effort to understand the role of comorbidities (single and multiple) in the outcome of COVID-19 patients; we have presented significant aspects of COVID-19 prognosis, including the epidemiological profile, length of hospital stay, survival, mortality, and baseline comorbidities. The critical findings of our study are that a combination of DM + HTN, DM + HTN + CAD, DM + HTN + CAD, and DM + HTN + CAD + CKD are essential risk factors to be considered while managing COVID-19 patients' hospital stay, independent of age and gender. Our results imply that both the category and the number of comorbidities should be regarded as the prognosis in COVID-19 patients. With evolving strains, knowledge of the effects of these comorbidities, independent of age and gender, is instrumental primarily to protect individuals with conditions that increase adverse outcomes from COVID-19.

Data Availability
Request should be placed to the corresponding author.

Conflicts of Interest
All authors have declared no conflict of interest.