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A Review of the Risk Factors Associated With Poor Outcomes in Patients With Coronavirus Disease 2019

The global pandemic of coronavirus disease 2019 (COVID-19) and its rapid spread throughout the globe is of much concern. With little known about the peculiar virus and the changing mortality and morbidity, we attempt to review the risk factors associated with significant outcome. We conducted a review of the information available in medical journals published on COVID-19 risk factors associated with poor outcomes using PubMed®, Google Scholar, and material published online. The risk factors associated with poor outcome were kept in particular consideration. A total of 96 articles were thoroughly reviewed and analyzed so as to highlight the risk factors and the subsequent disease presentation that were present in patients with COVID-19. With little data available in this regard, emphasis and consideration of risk factors might help health care workers preclude the worst outcome. From the aforementioned search we can conclude that the most prevalent risk factors were reported to be hypertension followed by diabetes. In terms of mortality, age greater than 65 was the most significant risk factor. Among non-survivors, coagulation profile including d-dimers, prothrombin time, and inflammatory markers like erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum ferritin levels were very deranged. Much emphasis and consideration in relation to risk factors must be deliberated by health care workers so as to prevent severe outcomes and mitigate appropriate treatment modalities.


Age
It is well documented that advanced age is a predictor of mortality in patients with COVID-19, especially in those over 65 years of age. Yang et al. [3] reported that non-survivors were older than survivors (mean age=64·6 vs. 51·9, respectively) and were more likely to have chronic medical conditions, compared to survivors. Mehra et al. [4] found that age greater than 65 years was independently associated with an increased risk of in-hospital death (mortality of 10 [6]. A cohort study by Wang et al. [7] found that the mean age of the non-survivor group was remarkably higher than that of the survivor group. Wang et al. [8], using a multivariate Cox proportional hazards regression model, showed that higher hazard ratios (HRs) for 15-day in-hospital death were associated with age >65 years. Nikpouraghdam et al. [9], in Iran, also demonstrated that for each one-year increase in age, the odds of death increased by 5% (OR=1.05; 95% CI=1.04−1.06). Similarly, Leung et al. [10] found a significant high mortality ratio in COVID-19 patients aged ≥80 years. A quantitative evidence synthesis of clinical and laboratory factors in 852 patients, from Martins-Filho et al. [11], showed an increased risk of in-hospital death in older patients.

Hematological biomarkers
Ruan et al. [12] found that there were significant differences in total white blood cell (WBC) counts, absolute values of lymphocytes, and platelets between the non-survivor and survivor groups, from a retrospective multicenter study in Wuhan, China. In comparison to nonsurvivors, there was significant higher lymphocyte count in survivors. In addition, Zhou et al. [13] found that the lymphocyte count was lowest on day seven after onset of illness and improved during hospitalization. Severe lymphopenia was also observed in non-survivors. The most influential marker of risk, according to Wang et al. [7], was severe lymphopenia (<0.5 × 109/L), which was associated with higher mortality (HR=4.410) compared to patients with a lymphocyte count >0.5 × 109/L. Recently, a retrospective review of 323 hospitalized patients with COVID-19 in Wuhan, conducted by Hu et al. [5], indicated that leukocytosis (>10 x109/L, p<0.001) and neutrophilia (>75 × 109/L, p<0.001) predicted unfavorable clinical outcomes. Similarly, in comparison to the survivor group, the non-survivor group was found to have high higher total WBC and neutrophil counts and lower lymphocyte counts as reported by Wang, et al. [8]. Liuet et al. [14] reported that there was an 8% higher risk of in-hospital mortality in patients with increased neutrophil-to-lymphocyte ratio (NLR), and patients in the highest NLR had a 15.04-fold higher risk of death. A meta-analysis from Henry et al. [15] also concluded that compared to survivors, non-survivors had significantly increased WBC counts and decreased lymphocyte and platelet counts. Quantitative evidence of clinical and laboratory factors in 852 patients, from Martins-Filho et al. [11], also showed that survivors had lower levels of white blood cells and neutrophils. Therefore, increased total WBC counts, as well as increased NLR, decreased lymphocytes, and decreased platelet counts are independent risk factors of inhospital mortality in COVID-19 patients.

Biochemical markers
Ruan et al. [12] reported that total serum bilirubin, blood urea nitrogen (BUN), serum creatinine (Cr), myoglobin, and cardiac troponin were higher in non-survivors than survivors. In comparison to non-survivors, survivors were found to have low levels of cardiac troponin I, Cr, alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) as reported by Zhou et al. [13]. Serum albumin was lower in non-survivors than in survivors. High-sensitivity cardiac troponin I (>0.04 pg/mL, p=0.02) was reported to predict unfavorable clinical outcomes. Wang et al. [8] also demonstrated that Cr, BUN, ALT, aspartate aminotransferase (AST), LDH, and blood ammonia were significantly higher, whereas GFR and serum albumin were significantly lower in the non-survivor group. A meta-analysis by Henry et al. [15] also found that non-survivors had significantly elevated levels of cardiac troponin, liver enzymes (ALT and AST), and renal biomarkers (BUN, Cr) at presentation. Martins-Filho et al. [11] also found that non-survivor patients had increased levels of Cr, creatine kinase, high-sensitivity cardiac troponin I, LDH, and decreased levels of albumin. A meta-analysis of 2389 patients from Santoso et al. [16] demonstrated that cardiac injury was associated with higher mortality, which was defined as high-sensitivity cardiac troponin I>99thpercentile.

Inflammatory biomarkers
Inflammation is the body's innate immune response to various kinds of injury or insult and during this process a number of proteins are released into the bloodstream. Based on current clinical evidence, inflammatory biomarkers such as C-reactive protein (CRP), serum ferritin, procalcitonin, interleukins, and the erythrocyte sedimentation rate (ESR), play key roles as predictors in evaluating severity and mortality in COVID-19 patients [17].
In another study, Wang et al. evaluated the clinical course of 69 patients with COVID-19 and established that peripheral capillary oxygen saturation (SpO2) <90% was associated with a higher rate of erythrocyte sedimentation and CRP in comparison with patients with SpO2 ≥90% (p<0.001) [19].
In light of the above-mentioned studies, it is evident that high levels of CRP, ESR, IL-6, procalcitonin, and serum ferritin are associated with worse outcomes and increased mortality of patients with COVID-19.
Coagulation abnormalities, ranging from a small decrease in platelet count to disseminated intravascular coagulation, are associated with septicemia, as well as multisystem organ dysfunction syndrome (MODS) [21]. Many coagulative abnormalities have also been observed with SARS-CoV-2 infection, and have been proposed to be associated with increased mortality in COVID-19 patients.
Tang et al. concluded, from a retrospective study involving patients with COVID-19, that nonsurvivors had higher levels of D-dimers and fibrin degradation products (FDPs), and a raised prothrombin time, compared to survivors (p<0.001) [22]. In another retrospective study, Zhang et al. established that high levels of D-dimers are associated with increased mortality in patients with COVID-19 (p<0.001) [23].

Cerebrovascular co-morbidities
It has been reported that pre-existing cerebrovascular disease, and stroke after diagnosis of COVID-19, are both predictors of mortality, which might be related to hypercoagulable state from clotting variables and platelet count [24,25,26]. Neurological manifestations including acute cerebrovascular diseases (5.7%), were found more in patients with severe condition with COVID-19 as reported Mao et al. [27]. A meta-analysis of observational studies from Tralhao et al. [28] reported that the incidence of acute stroke was 0.71% in pooled inpatients. Avula et al. [29] reported a series of four COVID-19 patients with acute stroke as a presenting symptom. Lodigiani et al. [30] found that 2.5% of patients admitted to the hospital with laboratory-proven COVID-19 were diagnosed with ischemic stroke. In a single-centered, retrospective, study conducted by Yang et al. [3], the mortality rate was 61.5% by four weeks in 52 critically ill patients with COVID-19. From the review of Madjid et al. [31], cerebrovascular diseases were found to be one of the most important factors associated with mortality in patients with COVID-19. A pooled analysis of published literature from Aggarwal et al. [32], with a sample of 1829 confirmed COVID-19 patients, showed a ∼2.5-fold increase in odds of severe COVID-19 illness with a history of cerebrovascular disease. While a trend was observed, there was no statistically significant association between stroke and mortality in patients with COVID-19 infection.

Hypertension
Hypertension is the single most prevalent comorbid condition in COVID-19 patients, as shown in a study from China where 15% of the patients had hypertension [33]. Similarly, a nationwide survey, a meta-analysis, and a cross-sectional study from China showed that 16.9% [34], 15.6% [35], and 12.6% [36] of the COVID-19 patients had hypertension. However, two other studies showed that 30% [13] and 30.7% [37] had hypertension. These results are not surprising, as this proportion is quite similar to the general incidence of hypertension observed in the general Chinese population, which is 23.2% [38].

Diabetes mellitus
Diabetes mellitus, characterized by hyperglycemia and insulin resistance, is a chronic inflammatory condition that leads to increased end products of glycosylation, inflammatory cytokine production, and oxidative stress, resulting in tissue damage and increased risk of infections, and leading to morbidity and mortality [41,42,43]. People with diabetes are prone to respiratory tract infections such as influenza and pneumonia [44], and possibly COVID-19. Chronic inflammation, immune response impairment, increased coagulation activity, and (possibly) direct pancreatic damage caused by SARS-CoV-2 are potential underlying mechanisms [45].  [47]. Similarly, a significantly higher mortality (31% versus 14%; p=0.0051) was seen in patients with diabetes with COVID-19 than in those without diabetes in a retrospective cohort study conducted in Wuhan [13].
In conclusion, the existing literature is clearly showing increased mortality in diabetic patients compared to non-diabetic, especially in patients of advanced age. There is a need to develop novel ways to deliver healthcare to patients with DM using tele-health and for remote patient monitoring for tight glycemic control, without exposing them to unnecessary hazards.

Conclusions
From the aforementioned literature as summarized in Table 2, we can conclude that the most prevalent risk factor is hypertension followed by diabetes. In terms of mortality, age greater than 65 was the most significant. Amongst non-survivors coagulation profile including ddimers, prothrombin time, and inflammatory markers like ESR, CRP, and serum ferritin levels were much deranged. Patients with diabetes mellitus, hypertension, cerebrovascular accidents, and age greater than 65 must be in particular managed at home in order to decrease unnecessary exposure at the hospital. From the above data we recommend that the patients with COVID-19 should initially be stratified and segregated on the basis of the above risk factors. Much emphasis and consideration in relation to risk factors must be deliberated by health care providers so as to prevent severe outcomes and mitigate appropriate treatment modalities.