The risk factors for COVID-19 mortality have been extensively reported worldwide. Although reports on such risk factors in Japanese patients are limited, a nationwide COVID-19 inpatient registry, COVID-19 Registry Japan (COVIREGI-JP), was created in March 2020. Matsunaga et al. identified the clinical epidemiological characteristics of hospitalized patients with COVID-19 registered in COVIREGI-JP and reported that the mortality rate of these patients was 7.5%, which was lower than that in other countries (~ 15–25%) [4, 11, 12]. However, some Japanese patients with COVID-19 developed respiratory failure and required oxygen administration or mechanical ventilation despite having no or mild symptoms on admission. Hence, this study investigated the clinical characteristics of patients with COVID-19 with no or mild symptoms on admission. The results revealed that old age, overweight, DM, and high serum ferritin level were risk factors for developing a severe form of COVID-19 after hospitalization. Although these risk factors are mentioned in a previous COVIREGI-JP cohort study, our study was novel in that it was limited to patients without any symptoms or those having mild symptoms on admission and demonstrated that these are statistically significant risk factors for disease progression. Asymptomatic patients with COVID-19 or those with mild symptoms are often monitored at home or in a hotel rather than being hospitalized. Therefore, the clinical implication of our study is that whether these patients have the risk factors for disease progression identified in this study will help determine their monitoring facility (hospital, hotel, or home) at the time of diagnosis. Thereby, physicians can carefully follow-up on patients with risk factors for disease progression and provide immediate treatment on worsening of symptoms.
The OR for disease progression in patients who were overweight was 3.260, which was the highest among statistically significant risk factors in this study. Obesity affects the respiratory function through different mechanisms, such as respiratory compromise, chronic inflammation, and complications. Obesity is also associated with pulmonary restriction, ventilation–perfusion mismatch, respiratory muscle fatigue, and sleep apnea syndrome; thus, patients with obesity have a background of hypoxemia and are more prone to respiratory failure . These patients also have higher expression levels of tumor necrosis factor α, IL-1, and IL-6. These proinflammatory cytokines increase the inflammatory response and abnormal T cell response, causing drastic lung injury and severe pneumonia . When chronic hypoxia stimulates the hypoxia-inducible factor, detrimental effects occur on the immune system, as well as cytokine storm, which is associated with the poor outcomes of COVID-19 . Overweight and obesity are risk factors of severe illness in patients with COVID-19 [16,17,18]. Therefore, one factor that can explain the low COVID-19 mortality rate in Japan is that this country has a small obese population compared with Western countries. Our study also revealed that DM was a statistically significant risk factor for disease progression. Hyperglycemia causes immune dysfunction, including impaired neutrophil function, antioxidant system function, and humoral immunity; thus, patients with DM with COVID-19 have a high risk of disease progression [19, 20]. Furthermore, high serum ferritin levels at admission were significantly associated with the disease progression of COVID-19. Because serum ferritin is an iron-storage protein that regulates cellular oxygen metabolism, it is used as a marker for iron overload disorders, including hemochromatosis and hemosiderosis, which were not identified in patients enrolled in this study. It is also an immunomodulatory molecule with both immunosuppressive and proinflammatory functions that cause cytokine storms . Elevated ferritin serum levels reportedly correlate with disease severity in patients with COVID-19 [22,23,24]. Therefore, patients with elevated serum ferritin levels are more likely to develop cytokine storms and subsequently, severe respiratory failure.
Recent studies have shown that high levels of D-dimer and NLR are risk factors for mortality in patients with COVID-19 [5, 10]. However, these factors were not significantly different in our study. Considering that these studies included patients who already had severe COVID-19 on admission, it is possible that high levels of D-dimer and NLR are the result of disease severity and are not risk factors for disease progression in patients without any symptoms or those with mild symptoms.
This study has some limitations. First, it is retrospective in nature and has a relatively small sample size. There were several cases with missing values, particularly in the early stage of the pandemic, and we excluded those cases and adopted complete case analysis. In multivariate analysis, we included all factors and applied backward elimination to maximize the statistical power. As the number of patients who experienced the defined outcomes was small and statistically underpowered, we cannot conclude that they are critical risk factors for disease progression. However, our findings are consistent with those of previous studies from other countries, and we believe that the factors found in this study are likely to be risk factors for disease progression in Japanese patients with COVID-19. A larger-scale study is required to confirm our results. Second, the effects of treatment given after admission were not considered. Owing to the lack of information about effective treatment in the early stages of the COVID-19 pandemic, various drugs, including inhaled ciclesonide, intravenous dexamethasone, remdesivir, and unapproved investigational drugs, have been tried. Thus, a prospective controlled trial is needed to assess the effectiveness of a particular treatment.