Factors associated with risk of death
Logistic regression analysis was performed to determine factors associated with mortality in patients with COVID-19. In the univariate analysis, mortality was significantly associated with older age, male sex, co-morbid conditions, and presence of complications such as septic shock, multi-organ dysfunction, acute kidney injury, myocardial infarction, and nosocomial infection (Table 3). However, presence of septic shock (AOR= 13.2; 95%CI: 3.78-46.65), Multi-organ dysfunction (AOR= 8.6 (95%CI: 2.08- 35.64), presence of acute kidney injury (AOR= 5.52; 95%CI: 1.78-17.06), admission to the intensive care unit ICU) (AOR= 3.99; 95%CI: 1.22- 13), age of greater than or equal to 60 years (AOR= 3.25; 95%CI: 1.07 – 9.89) and among laboratory investigations; serum Ferritin of greater than or equal to 1500ng/ml (AOR= 3.78; 95%CI: 1.21 -11.8) and NLR of greater than or equal to 5 (AOR= 4.04; 95%CI:1.14-14.35 )were independently associated with mortality in the multivariable logistic regression analysis after adjusting for confounding and interactions.
Discussion
Our study reports several notable findings. First, while our cohort had a comorbid prevalence comparable to, or higher than that reported by other centers, no comorbid was found to have a statistically significant association with disease severity on multivariate analysis. This is in contrast to global reports of the association between several comorbid and COVID-19, including Ischemic Heart Disease, Diabetes Mellitus, Hypertension, cancer, Chronic Lung Disease, and Cerebrovascular Disease (7, 8). Limited studies in the literature report a similar absence of statistically significant association (9) (10). It is possible that baseline control of comorbid conditions may influence COVID-19 outcomes. For instance, uncontrolled inpatient hyperglycemia, with or without known diabetes, is an independent predictor of worse outcomes (11) (12) (13). Data on baseline and inpatient comorbid control was not collected in our study. Future analyses of the association of outcomes with comorbid conditions should be stratified according to comorbid control to better describe the possible relationship.
Second, on multivariate analysis of laboratory parameters at presentation, only the NLR was found to have a statistically significant association with both disease severity and mortality. C-Reactive protein, Lactate Dehydrogenase, and Creatinine were found to be associated with disease severity alone, whereas ferritin was associated with mortality alone. A trend of higher levels of biochemical and hematological markers of inflammation and organ dysfunction with increasing disease severity and mortality was also observed, consistent with literature from other centers (14). However, our study supports the early use of NLR as a single marker for risk stratification for both disease progression and mortality, making this cost-effective and readily available tool especially valuable in resource-limited settings.
The case fatality rate from Pakistan has remained around 2-3 % which is considerably lower than Italy and Iran but similar to CFR reported from China and India (1). In this study, in-hospital mortality was 13.88%, and the mean length of hospitalization was 7.37 days. In-hospital mortality has been reported to be 28% from tertiary care centers in China (15), 21.7% from centers in New York (16), 20% from Iran (17), and 53.4% in-hospital mortality from ICUs in Lombardy, Italy (18). To better characterize differences in mortality, we determined the risk factors for death among hospitalized patients. Our study showed that multi-organ dysfunction, septic shock, and admission to intensive care unit on presentation were associated with mortality. These are similar to risk factors reported from various regions across the globe, though individual risk factors have varied (16) (19). Acute kidney injury was also one of the independent predictors of mortality and has been reported from various countries as well (19). Most studies found an independent association with comorbid conditions such as diabetes, chronic kidney disease, and malignancy (16) (20, 21). However, although these were significant on univariable analysis, these were not found to be independent predictors of death on multivariable analysis. This is quite interesting considering the greater proportion of diabetics in our cohort (36%) compared to (7.5 to 19%) from hospitalized COVID-19 patients in China and 13 % from Italy. This is similar if we consider lower CFR from South Asia despite the greater prevalence of Diabetes in this region and possible reasons could be multifactorial including epigenetic and lifestyle differences (22) (23).
Fourth, compared to studies that have shown increased age and male sex to be risk factors for an adverse outcome (24), our study found an association of mortality with advanced age of greater than or equal to 60 years, but we did not find an association of mortality with male sex on multivariable analysis. To understand this further, we looked at mortality sex ratios across all age groups and found that while it was 7.6 for the age interval 50-70 years, it was 2.3 for the age interval of 70-90 years. This highlights the need for disaggregated data to better understand the interaction between biological sex and age and its association with mortality (25). Among laboratory investigations we found the association of increased NLR and high serum ferritin level to be independent predictors of mortality which is consistent with literature reported from other studies and hence can be used to identify patients at risk early in course of disease (9) (26, 27).
Also noteworthy is the lack of mortality benefit from any of the treatment modalities used. This includes the use of steroids in a large proportion of patients with moderate to severe disease, although a recently published clinical trial has shown benefit (28) in this population. Moreover, we found a greater incidence of nosocomial infections compared to other studies (29-31). Nosocomial infections were also associated with mortality in univariable analysis, which may be related to immunosuppression with tocilizumab and steroids. This may be an important observation in the context of low-middle income countries where the incidence of nosocomial infections is higher and can contribute to poor outcomes in COVID-19 (32).
Our study has several limitations including retrospective data collection and single-center experience that may limit generalizability. However, our study highlights important differences in factors associated with severity and mortality particularly relevant to a low-middle income country whereby despite a high prevalence of diabetes and increased incidence of nosocomial infections there was comparatively lower in-hospital mortality. It also emphasizes the key epidemiological differences in the nature of the outbreak experienced in our country for which we recommend validation by population-based studies.