This retrospective cohort study showed that hypertension, increased levels of D-dimer, and higher N/L were associated with increased mortality in patients with COVID-19; high APACHE II score was also correlated with death in critically ill patients. Hypertension was the most prominent of the abovementioned risk factors in both cohorts. This study is the first to report risk factors for mortality in COVID-19 patients using PSM analysis. The results of PSM were the same as those we had already obtained before PSM analysis. Via PSM analysis, we provided robust evidence to support the association between hypertension and increased mortality.
In a study involving 191 patients with COVID-19, logistic-regression analysis showed that odds of in-hospital death were higher in patients with hypertension4. In another study conducted in January 2020, 11 of 99 patients with COVID-19 died, and 3 of the 11 had hypertension7. Yang et al. performed a systematic review and meta-analysis including 46,248 COVID-19 patients5. The results showed that the pooled odds ratio (OR) of hypertension in severe patients was 2.36 (95% CI [1.46–3.83]) compared with non-severe patients, indicating that hypertension might be a risk factor for severely ill patients. In addition, previous studies have shown that hypertension was also a factor in the prognoses of patients infected with other viruses. Hypertension was one predictor of ARDS in patients with severe acute respiratory syndrome, per the results of a study on clinical features and outcomes of severe acute respiratory syndrome8. Based on the six indices of Multilobular infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history, hyper-Tension, and Age, Guo et al. created the MuLBSTA score system based on a multivariate logistic-regression model to predict mortality in patients with viral pneumonia within 90 days9. The OR of hypertension is 2.39, and its MuLBSTA score is 2. A study on influenza suggested that patients with hypertension suffered a significantly higher risk of death (OR 1.49; 95% CI [ 1.10–2.10]) than patients who had no comorbidities10. Researchers reported the deaths of three people infected with avian-influenza H7N9 virus in Shanghai in 2013; two of them had hypertension11 .
The role of hypertension in COVID-19 progression remains unclear. Our results showed that L count in the hypertensive group was significantly lower than in the non-hypertensive group, and the same was true in critically ill patients. We speculated that the poor outcome of the hypertension group might be associated with impairment of immune function caused by the decrease in lymphocytes. Consistent with our hypothesis, a recent study involving 61 patients with hypertension showed a significant decrease in peripheral blood CD3, CD4 and CD8 T-cell in hypertensive patients versus healthy controls12. Additionally, it has been found that some angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker drugs could significantly increase the expression of angiotensin-converting enzyme 2 (ACE2) messenger ribonucleic acid in rat hearts13. As ACE2 is the receptor of SARS-CoV-2 in humans, the increase in ACE2 messenger ribonucleic acid expression could aggravate the illness. Further study is needed to determine whether certain antihypertensive drugs contribute to poor clinical outcomes in patients with COVID-19. Finally, hypertension and other chronic diseases share some common characteristics, such as a proinflammatory state and attenuation of the innate immune response. Therefore, the body cannot effectively control the virus in the early stage, which leads to aggravation of illness in COVID-19 patients5,14. Further study is needed on the role of hypertension in this disease.
In addition to hypertension, we found that high D-dimer levels and high N/L were associated with increased in-hospital mortality of COVID-19 patients in general and of critically ill ones in particular, which was consistent with previous studies. N/L might reflect levels of both inflammation and immune response of the human body during viral infection. Some studies have shown that coronaviruses consume many immune cells, leading to a great reduction in lymphocytes, which inhibits cellular immune function. Damage to T cells might be an important factor leading to deterioration of patients7,15. Neutropenia represents the aggravation of inflammatory response and cytokine storm, while lymphocytes are the main immune-active cells in the body, and L count is an early marker of physiological stress and systemic inflammation3,16,17. Wang et al. have reported that in 33 patients with COVID-19, survivors had higher N counts and lower L counts than non-survivors16. Neutrophils are proven to be related to the development of ARDS and progression from ARDS to death in patients with COVID-20193. In a study by Zhou et al., univariate analysis showed that decreased L count was associated with in-hospital death in such patients1 .
Consistent with our results, a recent study of 191 patients with COVID-19 showed that D-dimer > 1 µg/ml was associated with fatal outcomes1. In the other two studies including 33 and 183 patients with COVID-19, D-dimer levels were significantly higher in non-survivors versus survivors16,18. Recently, a bivariate Cox regression analysis also suggested that higher D-dimer levels were related to the development of ARDS and progression from ARDS to death in patients with COVID-19 (HR 1.03; 95% CI [1.01–1.04] and HR 1.02; 95% CI [1.01–1.04], respectively)3. The mechanism of fatal outcome in patients with higher D-dimer could be that systemic pro-inflammatory cytokine responses induce the production of procoagulant factors and hemodynamic changes1,19 .
In addition, our study showed that a high score on the APACHE II, a tool for estimating disease severity and mortality in-hospital in critically ill patients, was associated with increased mortality in patients with severe COVID-19. Patients with high APACHE II scores have also been found to have higher risk of death in other studies. These studies suggest that clinicians should pay more attention to patients with high APACHE II scores.
The following shortcomings existed in our research. First, this was a single-center study with a limited number of cases included. At this writing, the epidemic has spread throughout the world. A multi-center study should be carried out that includes other hospitals in Wuhan, other cities in China, and other countries worldwide, as it will yield a more comprehensive understanding of the factors affecting the outcomes of COVID-19 patients. Second, as this study was retrospective, the indicators included in our study were finite. The findings of chest CT, viral load in the respiratory tract or circulation, angiotensin II, and lymphocyte subsets could be potential indicators of outcomes of patients, which should be further confirmed by more studies. Finally, due to failure to record the classification, stratification, and use of antihypertensive drugs in patients with hypertension, it is necessary to further explore whether these factors could influence patient outcomes.