In this study, we investigated the impact of comorbidity burden on mortality in patients with COVID-19 from a nationwide claims database. The main finding of our study was that comorbid hypertension, diabetes, congestive heart failure, chronic pulmonary disease, liver disease, renal disease, dementia, and cancer were identified as significant risk factors for mortality in patients with COVID-19 after age and sex adjustment. The predictive performance of the ACCI was superior to that of the CCI. ACCI ≥ 4 was found to be the optimal cut-off value for the prediction of death in patients with COVID-19. Our results could provide useful prognostic information to health care professionals, allowing the selection of patients in most need of medical attention and resources.
The mortality rate reported in our study was lower than that reported in studies conducted in other countries.5,11 According to the most recent reports from the WHO and the KCDC (last updated June 2, 2020), mortality rates in Europe, Americas and South-East Asia were 8.4, 5.7, and 2.8%, respectively. These differences may be explained by several factors. One possible explanation for the difference in mortality rates between different countries is the different clinical characteristics of the populations. The risk of COVID-19 mortality has been consistently reported to increase in patients with male sex, advanced age, and the presence of comorbidities, similar to the observations in our study. The patients in our study were relatively younger and had fewer comorbidities than those reported in studies from other countries.5,11 These characteristics might be associated with the COVID-19 outbreak in a relatively large number of young people in South Korea.12,13 Second, striking differences between Asian and European mortality might indicate the effect of ethnicity on disease outcome.14 However, because ethnicity is a complex entity composed of social constructs, cultural identity, genetic make-up, and behavioral patterns,15 it might be difficult to conclude the association between ethnicity and disease outcome. In addition, differences in the organization of health care systems and strategies to contain COVID-19 among different countries may have affected the result. Korea’s rapid and extensive diagnostic testing (more than 10,000 tests daily), and intensive anti-contagion policies may have contributed to the disease outcome.16
In this study, we adjusted both sex and age that could affect the prevalence of comorbidities to investigate its effects on the severity of COVID-19. Further, some studies have suggested that male sex is a risk factor for the severity of COVID-19.17,18 It has been suggested that the sex-based difference between the circulating angiotensin-converting enzyme (ACE)-2 levels, the receptor of which was associated with intracellular penetration of SARS-CoV-2,19 or the smoking rate difference according to sex may have affected the sex difference on the severity of COVID-19.18,20 In addition, the potential association between androgen level and COVID-19 severity was suggested.21 Our results also revealed the tendency toward sex difference in the mortality of COVID-19. Further research is needed to assess the effect of sex on the severity of COVID-19. Age has consistently been reported to affect the severity of COVID-19 in several studies.22,23 In addition to the increased prevalence of comorbidities in older age,24 physiological changes caused by aging itself may affect the severity of COVID-19. Aging leads to impaired function of various organs including immune system, resulting it greater susceptibility to inflammation or death.25,26 Therefore, we adjusted age and sex in each analysis to investigate the effects of various comorbidities on patient mortality due to COVID-19.
The results from our study revealed multiple risk factors that were associated with mortality in patients with COVID-19 after age- and sex-adjustment. SARS-CoV-2 binds to the target cells through the angiotensin-converting enzyme (ACE) 2 receptor expressed in epithelial cells of several organs.19 Because the expression of ACE2 is increased in patients with hypertension, diabetes, and chronic obstructive pulmonary disease (COPD), these comorbidities can increase both the risk and the severity of COVID-19 infection.17,18 In addition, evidence of myocardial or liver damage has been observed in patients with COVID-19, and pre-existing cardiovascular and liver diseases could be associated with the severity of COVID-19 infection.29,30 Recent meta-analyses have identified that cardiovascular diseases and COPD can greatly affect the severity of COVID-19.31,32 Renal disease, dementia and cancer could be also important risk factors for severe COVID-19.33-35 The effects of each comorbidity on the COVID-19 mortality have been observed in our results as well, and if they are combined, the effect will be stronger on the severity of COVID-19.
Our study showed that the ACCI could be useful for predicting mortality in COVID-19 patients. A study of 52 critically ill patients with COVID-19 revealed that the median duration between the onset of symptoms and intensive care unit admission was 9–10 days, suggesting a gradual progression of the disease.36 Therefore, the early detection of risk factors that can predict the severity of disease can improve the patient's prognosis and enable an efficient allocation of medical resources. To this end, we have created a simple but powerful prediction model for the mortality of COVID-19, combining age and comorbidities, known to be important risk factors for the severity of COVID-19. In addition, the high predictive power of the ACCI for mortality in our results could support the importance of old age and comorbidities in the severity of COVID-19. To date, several prognostic models for the severity of COVID-19 have been suggested.37,38 However, because most previous models require laboratory tests, they may be difficult to apply in areas where medical resources are restrictive. Further, the predictive value of ACCI in our study showed similarity to that of the recently reported clinical risk score that predicts the occurrence of critical illness in hospitalized patients with COVID-19 (development cohort: AUC 0.88 [95% CI 0.85–0.91], validation cohort: AUC 0.88 [95% CI 0.84–0.93]).37 The COVID-19 pandemic has created a shortage of medical resources,39,40 and assessments that rely on laboratory tests may be limited in the COVID-19 crisis situation. On the other hand, we expect our results to be more widely used, as they can easily be applied by medical practitioners, health professionals, or policy-makers.
The results of our study should be interpreted cautiously for several reasons. Firstly, the data from insurance claims did not contain detailed clinical information such as vital signs or laboratory values. Secondly, the CCI does not consider the use of drugs and relies on diagnosis codes only; thus, over- or underestimation of the risk is likely to have happened. Thirdly, due to the different medical situations and resources for the COVID-19 crisis in each country, the generalizability of the results may be limited. However, the contribution of this study is that it uses nationwide data to provide predictions on the risk of mortality, which is the most serious outcome of COVID-19 infection. Lastly, the original ACCI did not include hypertension, which is the most common comorbidity in patients with COVID-19. The development of a COVID-19-specific comorbidity scoring system will be necessary.
In conclusion, our study identified that the ACCI, combined with age and various comorbidities, was associated with mortality in patients with COVID-19 in South Korea. If an increasing number of patients with COVID-19 develop severe illness, plans should be made at the national level to better manage the surge and ensure the need for critical care resources. Furthermore, because the availability of medical resources for critical care is likely to be restrictive, resource allocation policies based on risk factors should be implemented by medical professionals and policy makers. We hope our study findings will provide important information to guide health care professionals facing the global health threat of COVID-19 in decision-making.