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.