Introduction

COVID-19 pandemic has caused over 2.4 million deaths and over 111 million cases worldwide by 24^th February 2021 [1]. Due to widespread transmission, several countries were burdened with high case load and deaths. Critical care resources have been stretched across some countries [2, 3]. The fatalities reported by countries and regions also varied widely.

While the available data on absolute number of deaths is fairly reliable, the calculation of mortality rates and comparing them across countries is difficult because countries widely differ in their screening and testing criteria. The analysis of 72,314 cases using data from the Chinese Centre for Disease Control and Prevention [4], indicated most cases to be mild (81%; i.e., non-pneumonia and mild pneumonia), whereas 14% were severe (i.e., dyspnea, respiratory frequency ≥30/min, blood oxygen saturation ≤93%, the partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300, and/or lung infiltrates >50% within 24 to 48 hours), and 5% were critical (i.e., respiratory failure, septic shock, and/or multiple organ dysfunction or failure). India rapidly scaled up hospital and critical care resources and a proactive public health response targeting surveillance, wearing masks, limiting movement in the early phase of the epidemic along with an intensive information dissemination campaign. The mortality attributed to COVID-19 in India was relatively low compared to the rest of the world. India had reported 1,19,71,624 cases and 1,61,552 deaths till 28 March 2021 with lowest case fatality ratio of 1.5% globally [5].

The determinants of severity can guide clinical management; proactively screening for their presence could prioritize COVID-19 patients for intensive care treatment and thereby allocate scarce medical resources appropriately. Risk factors for the development of severe disease and death have been widely reported across several studies [6], and vulnerable groups include older adults, cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer. Obesity and smoking were also associated with increased risks in some studies [6]. Lymphopenia is a predictor of disease progression [7]. Cytokine storm is also associated with disease severity [8].

Knowledge of characteristics of people at high risk of experiencing a poor outcome from the infection could help in care provision [9]. We conducted this study to identify the determinants of severe COVID-19 disease in India using a case-control study design.

Methods

Results

We included 244 patients with severe COVID-19 disease (Cases) and 245 with mild to moderate COVID-19 disease (Controls). Compared to the controls, a significantly higher proportion of cases were more than 60 years old, had lower monthly household income, less educated, and possessed a below poverty line (BPL) card. (Table 1).

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Table 1. Background characteristics of cases and controls with COVID-19 in India, 2020.

https://doi.org/10.1371/journal.pone.0261529.t001

The most common symptoms at admission were fever, shortness of breath, cough and myalgia. A significantly higher proportion of cases reported cough and presented with hypertension, diabetes mellitus and chronic kidney disease. Cases also had a significantly higher proportion of multiple comorbidities compared to the controls. (Table 2).

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Table 2. Clinical characteristics of cases and controls at the time of admission in India, 2020.

https://doi.org/10.1371/journal.pone.0261529.t002

A significantly higher proportion of cases compared to controls had abnormal laboratory parameters at the time of admission, except for blood group, creatinine kinase and vitamin D. (Table 3).

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Table 3. Laboratory parameters of cases and controls with COVID-19 at the time of admission in India, 2020.

https://doi.org/10.1371/journal.pone.0261529.t003

On univariate analysis, age of 60 years and above, duration before admission more than five days, diabetes mellitus, hypertension, chronic kidney disease, leucocytosis, elevated levels of erythrocyte sedimentation rate, prothrombin time, serum ferritin, d-dimer, pro-calcitonin, fibrin degradation products, c-reactive protein, lactate dehydrogenase, interleukin-6, neutrophil lymphocyte ratio (NLR) and deranged liver function tests, renal function tests and serum electrolytes were associated with severe COVID-19 disease. After adjusting for known confounders, factors associated with severe COVID-19 were age above 60 years, duration before admission >5 days, pre-existing diabetes, chronic kidney disease, leucocytosis, prothrombin time > 14 sec, serum ferritin >250 ng/mL, d-dimer >0.5 ng/mL, pro-calcitonin >0.15 μg/L, fibrin degradation products >5 μg/mL, C-reactive protein >5 mg/L, lactate dehydrogenase >150 U/L, interleukin-6 >25 pg/mL, NLR ≥3, and deranged liver function, renal function and serum electrolytes. (Table 4).

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Table 4. Factors associated with severity among hospitalised COVID-19 patients, India, 2020.

https://doi.org/10.1371/journal.pone.0261529.t004

Discussion

We identified older age, co-morbidities (diabetes, chronic kidney disease) and laboratory parameters (leucocyte count, prothrombin time, serum ferritin, d-dimer, pro-calcitonin, fibrin degradation products, lactate dehydrogenase, neutrophil lymphocyte ratio, C-reactive protein, interleukin-6, liver function, renal function and serum electrolytes) as determinants of severe disease at the time of admission among COVID-19 patients.

Diabetes has been recognized as important in the prediction of severe disease of COVID-19. Diabetes in patients with COVID-19 was associated with a two-fold increase in mortality and severity of COVID-19, compared to non-diabetics in a meta-analysis [13]. Jain et al., studied the predictive symptoms and comorbidities for severe COVID-19 and intensive care unit admission. They concluded that elderly patients with comorbidities are more vulnerable to severe disease [14]. A systematic review by Del Sole et al included 12 studies with 2794 patients where 596 patients with severe disease. They reported patients with severe disease were older in age and had diabetes than patients with non-severe disease [15].

Del Sole identified that increased procalcitonin (OR: 8.21, 95% CI 4.48–15.07), increased D-Dimer (OR: 5.67, 95% CI 1.45–22.16) and thrombocytopenia (OR: 3.61, 95% CI 2.62–4.97) predicted severe infection [15]. A meta-analysis by Coomes and Haghbayan [16] reported that IL-6 levels are significantly elevated and associated with adverse clinical outcomes.

A study in a north Indian tertiary care centre used retrospective data to conclude that more than half of patients admitted to the hospital with SARS-CoV-2 infection had an abnormal liver function which was found to be associated with raised levels of inflammatory markers [17]. These patients had significantly higher proportions of patients with abnormal liver function were elderly and males and were at higher risk of progressing to severe disease. Organ specific manifestations, which include the liver and the kidney along with their possible mechanism of injury have been available in literature [18]. A systematic review and meta-analysis of the published studies indicate that COVID-19 incidence was higher in people receiving maintenance dialysis than in those with CKD not requiring kidney replacement therapy or those who were kidney or pancreas/kidney transplant recipients [19]. In patients with COVID-19, acute Kidney Injury (AKI) may have an inflammatory etiology mediated by a cytokine storm [20]. CKD and COVID-19 may have a higher incidence of death than people with CKD without COVID-19. [19]

Elevated levels of lactate dehydrogenase were suggested to be associated right from the early studies on COVID-19 severity. Work by Wang and Wang reported that compared to survival cases, patients who died during hospitalization had higher plasma levels of D-dimer, creatinine, creatine kinase, lactate dehydrogenase, lactate, and lower percentage of lymphocytes (LYM [%]), platelet count and albumin levels [21]. Similarly, a multicentre retrospective cohort study from Wuhan to develop and validate a prognostic nomogram for predicting in-hospital mortality of COVID-19 included age (Hazard Ratio for per year increment: 1.05), severity at admission (Hazard Ratio for per rank increment: 2.91), dyspnea (Hazard Ratio: 2.18), cardiovascular disease (Hazard Ratio: 3.25), and levels of lactate dehydrogenase (Hazard Ratio: 4.53), total bilirubin (Hazard Ratio: 2.56), blood glucose (Hazard Ratio: 2.56), and urea (Hazard Ratio: 2.14) [22].

Other parameters that we found to be associated with severe Covid-19 at admission such as leucocytosis, prothrombin time, serum ferritin, fibrin degradation products, C-reactive protein, interleukin-6, and serum electrolytes operate through a clinical pathway or indicate pathology similar to others described above.

Our study had certain limitations. There is potential for selection bias in this hospital-based study. The cases were poorer and less educated than the controls, which indicates a difference in the source population to which cases and controls belonged to. The location and type of participating hospitals could have influenced the selection of study participants. Misclassification of case-control status is unlikely as we used the standardized criteria for classification of severe cases across the study sites. There is a likelihood of misclassification of laboratory parameters, albeit minimal, on account of testing by different laboratories across the study sites. However, all laboratories were assured to have quality control mechanisms in place.

Conclusions

We have identified a set of parameters characterizing severe Covid-19 that are part of routinely available investigations within Indian hospital settings, both public and private. Knowledge of these risk factors has the potential to triage COVID-19 patients at the time of admission in terms of severity of disease and adequate management of the same.

Supporting information

Acknowledgments

We acknowledge the role of the Epidemiology and Surveillance Working Group of the ICMR, constituted by the COVID-19 National Task Force of Government of India, for its review of the protocol and project implementation.