A systematic review and meta-analysis of regional risk factors for critical outcomes of COVID-19 during early phase of the pandemic

The mortality rates of COVID-19 vary across the globe. While some risk factors for poor prognosis of the disease are known, regional differences are suspected. We reviewed the risk factors for critical outcomes of COVID-19 according to the location of the infected patients, from various literature databases from January 1 through June 8, 2020. Candidate variables to predict the outcome included patient demographics, underlying medical conditions, symptoms, and laboratory findings. The risk factors in the overall population included sex, age, and all inspected underlying medical conditions. Symptoms of dyspnea, anorexia, dizziness, fatigue, and certain laboratory findings were also indicators of the critical outcome. Underlying respiratory disease was associated higher risk of the critical outcome in studies from Asia and Europe, but not North America. Underlying hepatic disease was associated with a higher risk of the critical outcome from Europe, but not from Asia and North America. Symptoms of vomiting, anorexia, dizziness, and fatigue were significantly associated with the critical outcome in studies from Asia, but not from Europe and North America. Hemoglobin and platelet count affected patients differently in Asia compared to those in Europe and North America. Such regional discrepancies should be considered when treating patients with COVID-19.


Assessment of study quality and publication bias.
While most studies at least partly met the quality standards of each area, several studies did not. The two studies did not represent the population of interest (study participation), two studies did not adequately measure the prognostic factor of interest (prognostic factor measurement), and nine studies did not account for important potential confounders (confounding measurement and account). (Supplementary Table S2).

Sensitivity analysis. A sensitivity analysis was performed in 17 studies without any restriction in patient
selection, outcome confined to death, and at least partly achieving every standard of the six areas of potential study biases. The results were largely consistent with the main analyses. Male sex (pooled RR 1. 17   www.nature.com/scientificreports/ 0.14], I 2 = 63.0%, 7 studies). The results of the sensitivity analysis are summarized in Supplementary Fig. S5, and the details are described in Supplementary Table S4.

Discussion
This is the first study to summarize the risk factors for the critical outcomes (death, admission to the ICU, or critical type of COVID-19) of COVID-19 according to the location of infected patients. It is also the largest updated systematic review regarding risk factors for the poor prognosis of patients with COVID-19. While most risk factors were largely similar across the three continents, several differences were noted. The presence of respiratory disease was associated with a higher risk of the critical outcome in Asia and Europe, but not North America. The presence of hepatic disease was associated with a higher risk of the critical outcome in Europe, but not in Asia and North America. Symptoms of vomiting, anorexia, dizziness, and fatigue were significantly associated with the critical outcome in Asia, but not Europe and North America. While platelet count was inversely associated www.nature.com/scientificreports/ with the critical outcome in Asia, it was not in Europe and North America. In contrast, lower hemoglobin levels were associated with the poor outcome in Europe but not in Asia and North America. Our findings of the overall population are consistent with those of previous reviews. Male sex, older age, underlying comorbidities, and several laboratory parameters have been repeatedly emphasized as risk factors for poor outcomes in patients with COVID-19 9,10,[99][100][101][102][103] . This disease is well-known for male-sex predominant deterioration. A nationwide study from Denmark reported that male sex was an independent risk factor for death even after adjusting for age and comorbidities 104 . The underlying mechanism for this observation has not yet been elucidated but may be explained by the immune regulatory genes encoded by the X chromosome, which makes men more susceptible to viral infections as compared to women 105 . In addition, sex hormones may act directly in innate immune cells to regulate their function, and indirectly via non-immune cells resulting in immune cell actions 106 . Older age was also a risk factor for grave prognosis among COVID-19 patients in previous systematic reviews 9,10 . This is easily understandable as old age is also a well-known risk factor for death among patients with community-acquired pneumonia and influenza [107][108][109] . Among many symptoms, dyspnea was the only symptom that was consistently associated with a higher risk of the critical outcome in all three continents, a finding concordant with those in previous reviews 9,102 . Dyspnea is relatively uncommon among COVID-19 patients despite typical lung involvement 2,110 . Therefore, the presence of dyspnea could imply extensive involvement of the lung and lead to poor outcomes.
The results of our study not only confirm previous knowledge regarding the risk factors for the deterioration of COVID-19 patients but also reveal some novel findings. First, some risk factors revealed inter-continental differences. Recognizing such differences can aid the development of proper guidelines for the management of patients according to their region and ethnicity. As noted, underlying respiratory disease was associated with the critical outcomes in Asia and Europe, but not in North America. Although the exact reason for this disparity is beyond the scope of our review, it may be partly explained by the differences in therapies for the treatment of these chronic respiratory diseases 111 . In China, only about 56% of patients with chronic obstructive pulmonary disease receive treatments that are standard in Western countries, while 23% receive Chinese traditional treatments 111 . Considering the protective effect of corticosteroids in the treatment of COVID-19 112 , such a gap in the treatment of chronic respiratory disease may have led to different outcomes among continents. Underlying hepatic disease also showed different impacts on critical outcomes across the three continents. This may be partly due to differences in per capita alcohol consumption, which is higher in Europe compared to North America and Asia 113 . Alcohol consumption is also associated with mortality rates among patients with liver cirrhosis 114 and also increases the severity of respiratory viral infection and pneumonia 115,116 . Thus, patients from Europe with hepatic disease may have had worse prognoses compared to those in patients from North America and Asia. Among the symptoms of COVID-19, vomiting, anorexia, dizziness, and fatigue were risk factors in Asia, but not in Europe and North America. These symptoms can be associated with weight loss and poor nutritional status during the course of the disease, while BMI is mostly higher for individuals living in Europe and North America, compared to those in Eastern Asian countries 117 . Although our meta-analysis suggested that Hispanic patients may have better prognosis compared to non-Hispanic white, the impact of ethnicity on the prognosis of COVID-19 is yet to be explained. While a regional study from the United States reported that ethnicity may be a factor for diverse outcomes 118 , other studies denied these findings after adjusting for risk factors 119,120 . A recent meta-analysis of has suggested that, after adjusting patient characteristics, ethnicity may not be an independent prognostic factor 121 .
Second, with enough pooled analysis, various comorbidities are proven to be risk factors. Because viral infections can cause a systemic inflammatory response which can induce myocardial injury and vascular inflammation 122,123 , studies have focused on diseases associated with cardiovascular outcomes as risk factors. In previous systematic reviews including 13,16,25, and 36 studies 9,99,101,124 , underlying cardiovascular disease, hypertension, diabetes, congestive heart failure, cerebrovascular disease, chronic kidney disease, respiratory disease, and cancer were identified as risk factors for poor patient outcome. The reviews did not find or mention any significant impact of underlying liver disease. However, several studies have inferred the impact of liver disease on the prognosis of COVID-19. For example, laboratory abnormalities associated with hepatic dysfunction were frequently observed in patients with COVID-19, and were more common in severe forms of COVID-19 125 . Furthermore, a pooled analysis showed a higher incidence of acute hepatic injury in severe COVID-19 compared to that in non-severe disease 126 .
To correctly acknowledge our study findings, several limitations should be noted. First, most of the included studies had retrospective design. This was inevitable because COVID-19 is a novel disease that caused a sudden pandemic. Second, residual heterogeneity was observed in the analyses of continuous variables. The residual extent of heterogeneity may be partially explained by differences in the reported forms of the variables (i.e., mean and SD, median and range, median, and interquartile range), age distribution, level of care, medication details, and nutritional status among studies. Third, some key factors, such as pregnancy, could not be evaluated because they were not commonly reported 127 .
Our extensive systematic review summarized the risk factors associated with the critical outcome (death, admission to the ICU, and critical type of COVID-19) of COVID-19 patients according to location of infected patients (Asia, Europe, and North America). Although the risk factors were mostly consistent across the three continents, underlying diseases, patient symptoms, and laboratory findings posed different impact on patient prognosis in each location. Future studies are required to understand the reasons for such discrepancy.

Data availability
The data used in this systematic review is available from the corresponding author with a reasonable request.