COVID-19 infection often causes a mild or even asymptomatic disease; however, some patients may proceed to severe and critical condition. Various clinical and paraclinical factors have been associated with higher disease severity (13). However, most of the studies are from a restricted geographical region and there is a paucity of evidence regarding the determinant factors of poor prognosis in different ethnicities, as the features of COVID-19 might differ in patients with different characteristics. Thus, we reviewed the clinical, laboratory, and imaging characteristics of COVID-19 patients in a center in Iran and assessed the factors that might possibly associate with disease severity.
We found that critical cases of COVID-19 were significantly older compared to patients with lower severity. Malignant comorbidities were found to be considerably higher in critical and severe cases. Among vital signs, pulse rate, respiratory rate, and oxygen saturation were significantly associated with the severity of disease. Among symptoms, dyspnea, confusion, and nausea/vomiting were associated with higher disease severities. COVID-19-associated complications including shock, sepsis, coagulopathy, acidosis, ARDS, ICU admission, and intubation were significantly more common among the critical cases. Paraclinical factors that were associated with higher disease severity were increased CRP and AST, as well as decreased pH and pO2. Multivariate analyses showed that O2 saturation, nausea/vomiting, and extent of lung involvement in CT were independent predictors of severe COVID-19 in absence of other factors. O2 saturation was the sole independent predictor of critical condition in COVID-19 patients.
In line with the findings of our study, several studies proposed that malignancy is associated with more severe disease and poorer outcomes (14-16). Therefore, it has been proposed that continuing antitumor treatment may further help the outcome of these patients (14). Although we found no significant association between disease severity and diabetes, hypertension, or cardiovascular diseases, a recently published meta-analysis proposed that diabetes, hypertension, and cardiovascular diseases are linked with more severe infection. This inconsistency might be because their study only included Chinese population and proposed a high heterogeneity between studies (14). Moreover, our sample is relatively small, compared with a meta-analysis, and larger samples can yield results that are statistically significant.
As expected, we observed considerably lower O2 saturation and higher values of respiratory and pulse rate in patients with higher severities of the disease. It seems that the pulmonary involvement of COVID-19 and the subsequent respiratory distress, impairs cardiopulmonary functions causing a ventilation-perfusion mismatch (17), which in turn leads to development of tachypnea and tachycardia. On the other hand, tachycardia can be related to fever in these patients (18). However, we found no notable difference in the frequency of fever between patients with different disease severities.
AST was also found to be notably higher in severe COVID-19 infection in our patients. It might be hypothesized that the higher rate of hypoxia in more severe stages of the disease may be the cause of liver injury and subsequent enzyme release as it is evident with AST release. However, the direct invasion of the virus to hepatocytes can also be proposed as an etiologic factor, which was reported by some studies (19). Han et al. reported that AST could be an independent risk factor for COVID-19 infection severity (20), which was not the case in our multivariate assessments.
Another important finding of our study was the markedly higher level of CRP in patients with severe and critical COVID-19 disease. This factor is reported to be independently related to disease severity; CRP levels >37.3 mg/L have been reportedly associated with poorer outcomes (20). In our study, the serum level of CRP showed an incremental increase with the rise in disease severity from mild/moderate to critical. Consistently, Wang et al. reported that higher CRP levels were associated with more lung involvement and more severe diseases (21).
Our results indicate that higher severities of COVID-19 are associated with higher rates of serious complications such as shock, sepsis, ARDS, intubation, coagulopathy, and acidosis, which require ICU admission. It is generally believed that most of the COVID-19 cases develop mild to moderate symptoms and do not need hospitalization or ICU admission. However, some of them may need hospitalization and even intensive care. These patients are more prone to develop sepsis, shock, ARDS, and eventually death (22). Furthermore, despite the usual presence of thrombocytopenia, coagulopathy is predictable in COVID-19 infected patients. Studies have reported elevated levels of D-dimer and thrombotic events in these patients, which might be related to inflammatory processes (23). Acidosis can be present in some of the COVID-19 patients, which heralds a more severe stage of the disease (6). In the present study, we found markedly lower pH levels in the VBG of patients with critical condition, compared to other groups. This implies that acidosis is significantly associated with higher severities of the disease.
We found that low O2 saturation was the only independent predictor of critical condition and poor prognosis in COVID-19 patients. Lower O2 saturation was linked to a one-third lower risk for developing critical disease. In line with our findings, a recent study on 167 patients in Anhui, China, reported that fingertip oxygen saturation and decreased CD4 cell count were the only independent risk factors for severe COVID-19 (24).
We also found that the extent and severity of lung involvement in CT scan, as the number of involved lobes with consolidation or ground-glass opacification, was a significant and independent predictor of severe/critical COVID-19 infection. Similarly, Chaganti et al. developed a score for lung involvement that was composed of the number of lobes with consolidation or ground-glass opacification and found that this score is positively correlated with severe stages of COVID-19 (25).
Among all symptoms, nausea/vomiting proved to be an independent predictive factor for severe disease and poorer prognosis. Several studies have indicated that gastrointestinal manifestations, namely nausea and vomiting, are common among COVID-19 patients. However, nausea and vomiting have not been alluded to as risk factors for severe conditions in these patients (26, 27).
A recent systematic review and meta-analysis on 1813 COVID-19 patients showed that dyspnea, COPD, cardiovascular diseases, and hypertension were predictive factors for severe disease and ICU admission (28). A recent study on 548 patients from Wuhan indicated older age, comorbid hypertension, high LDH, and D-dimer were significantly associated with higher severity in cases with COVID-19 (29). LDH was also identified as a risk factor for severe disease in another retrospective study of 47 patients from Wuhan, which also indicated lymphocyte count, especially CD3, CD4, and CD8 cells, as a predictive factor for higher severity (30). Although age was significantly related to disease severity, inconsistent with the mentioned studies, our multivariate analyses did not find significant associations between disease severity and age, comorbid conditions, LDH, and lymphocyte count.
Our study can provide insights into the factors associated with higher risk for developing severe COVID-19 in the Iranian population. The present study had some limitations. First of all, we had limited access to RT-PCR testing and could not perform it for all patients. Second, further survival and prognosis analyses was not performed, which may be applicable for further studies. However, besides these shortcomings, we enrolled an acceptable sample of patients.
In conclusion, O2 saturation, nausea/vomiting, and extent of lung involvement in chest CT can be potential factors that contribute to early prediction of severe and critical conditions in COVID-19 patients. It is therefore recommended to further evaluate the role of these factors in diagnosis and prognosis of patients with COVID-19 in future studies.