In this retrospective study, we focused on identifying and quantifying the relationship between fatality and laboratory indicators for 192 critical patients with COVID-19 pneumonia, using robust statistical methods. Using quantile regression, we found that, after controlling demographic and baseline diseases variates, non-survivors demonstrated significantly higher indicator values (under FDR correcting) of CRP (𝜏 = 0.3, 0.5, 0.7, 0.9; QS = 0.835, p <0.001), WBC (𝜏 = 0.9; QS = 0.743, p <0.001), AST (𝜏 = 0.5; QS = 0.735, p <0.001), BG (𝜏 = 0.9; QS = 0.608, p = 0.059), FDP (𝜏 = 0.9; QS = 0.730, p = 0.080), PCO2 (𝜏 = 0.9), and lower indicator values of SO2 (𝜏 = 0.3; QS = 0.312, p <0.001), Ca2+ (𝜏 = 0.5; QS = 0.306, p = 0.073) and PH (𝜏 = 0.1). Most of these discrepant indicators had a big and significant QS effect size, which indicates that the null hypothesis of equal distribution of indicators between non-survivors and survivors should be rejected. Post hoc logistic regression was conducted to calculate the probability ratio and predictive power of risk factors, which implied that CRP was a prominent marker for severe COVID-19 pneumonia.
Critically ill patients who are older have a higher fatality rate, as confirmed by our data.[4, 15] The mean duration of non-survivors (~21 days) from onset to admission was 13 days much longer than survivors (~8 days) and each additional day was associated with a 33% increase in odds of death, indicating that early detection and early treatment are vital to reduce the case fatality rate of critically ill patients. Although there was no significant sex difference in fatality among critical patients, recent literature has pointed out that there may be sex differences in the susceptibility and disease progression of patients with COVID-19.[16] Therefore, we included sex as a covariate to consider more general situations. From the perspective of clinical symptoms, fever, cough, and chest pain were the most common symptoms in patients with COVID-19 pneumonia, consistent with the general symptoms of viral infection and pneumonia. Dyspnea was more prevalent in non-surviving patients, which might reflect impaired respiratory function and the severity of lung lesions caused by infection or inflammation.[7] Moreover, the presence of underlying diseases can be seen among many critical patients, especially, digestive, cardiovascular, cerebrovascular and COPD diseases were more prevalent in the dead patients, which might greatly increase the vulnerability of critical patients when faced with COVID-19 pneumonia.
In addition to performing Wilcoxon tests for comparing laboratory variables, which discovered 14 (/30) significantly different indexes (Puncorrected < 0.001) using comparative statistics between the dead and survivors (Table 2), we conducted quantile regressions with 𝜏 = 0.1, 0.3, 0.5, 0.7, 0.9 to more comprehensively capture data information and generate general conclusions. CRP, an important inflammation marker, was a prominent feature in our findings. CRP had consistently and significantly higher values in non-survivors than survivors among 0.3, 0.5, 0.7, 0.9 quantiles, with a considerable QS effect size of 0.835, and were significantly associated with a higher mortality risk (OR: ~206). Previous studies showed normal or slightly elevated CRP levels in the mildly ill patients[17, 18] but, in our findings, most of critically ill patients (71.9%) had higher CRP levels with a median value of 25 mg/L, especially in the non-survival group with an abnormal of 98% and median values of 68.75 mg/L, which informs the severity of illness and thus prognosis. Similarly, CRP was also deemed a crucial factor contributing to the pulmonary pathology severity triggered by viral infection[19], such as H1N1 [8], H7N9 [20] and SARS [21]. Moreover, CRP was found to be the largest contributory factor among all lab-examination indexes in another analysis that used machine learning and distinguished between the two groups (non-survivor and survivors) (unpublished). Taken together, the substantial and consistent difference in CRP between the two groups, plus the high OR values associated with death indicates that it might be a reliable biomarker of disease severity.
Increased WBC counts, AST, and reduced blood gas observations (PH, SO2,) were also noteworthy features. While normal or decreased WBC count was observed in mildly ill patients [22] or most survivors of critical illness (5.81 [4.42, 7.80]), increased WBC count was found in non-survivors with critical illness (10.82 [7.12, 15.46]) and correlated with higher odds of death (OR: 7.82), suggesting that comorbid bacterial or fungal infection might have occurred in these deceased patients. This was consistent with our clinical observations and some reports of other viral diseases. In critically ill patients with Middle East respiratory syndrome (MERS), 18% had bacterial coinfections.[23] Viral-bacterial coinfections in the respiratory tract increase mortality and morbidity in children and adults.[24–26] As mentioned in a previous study, nearly 100% of COVID patients who died in the ICU had sepsis [4] The death of the non-survivors who tended to suffer from severe coinfection may be due to the need for invasive treatments such as tracheal intubation, tracheotomy or urinary tract intubation-assisted treatment. In addition, many critically ill patients had to receive a high dose of glucocorticoid treatment to suppress cytokine storm and so were then at a high risk of glucocorticoid-related secondary infections, some even developed sepsis. Previous literature has indicated acute liver damage was more frequent in COVID-19 patients than in other pneumonia patients[27] and patients with severe COVID-19 pneumonia seem to have higher rates of liver dysfunction.[28, 29] Huang et al. (2020) suggested that elevation of AST was observed in eight (62%) of 13 patients in the intensive care unit (ICU) compared with seven (25%) of 28 patients who did not require care in the ICU [30], Wang et al. (2020) found that the median AST of ICU patients was 52 (30-70) U/L more than non-ICU patients with 29 (21-38) U/L [3]. These findings together with our results, suggests that liver health can be a reliable indicator of disease severity, and close monitoring and evaluation of liver function in critically ill patients should be considered. Reduced PH and SO2 often suggest poor prognosis in pulmonary diseases, and are associated with the possibility of rapid progression to acute respiratory distress syndrome, septic shock, uncorrectable metabolic acidosis, coagulation dysfunction and even death.
This study has several limitations. First, this was a retrospective study. While our results identified and quantified risk factors for COVID-19 pneumonia using robust methods, further cohort study is still needed to confirm our findings. Second, although the sample size of the analysis was close to 200, there is an unbalanced sample size only with 50 non-survivors, which limited the number of covariables used in logistic regression.[31] Third, since currently there is no clear method for evaluating multivariate effect size for quantile regressions, we only calculated univariate estimates of QS to quantify the difference [13].
In conclusion, while there have been some studies on the risk factors of COVID-19, there are few studies that have comprehensively quantified the association of case fatality and laboratory indexes while adjusting false discovery and controlling for numerous confounders. We found that abnormal values of CRP, WBC, AST, PH, SO2, etc. associated with a higher risk of fatality, and suggest that, for those with abnormal values at these indexes, especially for CRP, close monitoring and early intervention might be very important and could help to reduce mortality.