This study evaluated the mortality rate and clinical outcomes in 24 critically ill Japanese patients with COVID-19 who were admitted to the ICU between late March and mid-April 2020. The majority of patients were male, most were normal weight, and two-thirds were former or current smokers. Mortality rates in the current study were 8% for overall ICU admissions and 6% for mechanically ventilated patients.
The highlight of this study was its focus on a population in East Asia besides China, which was the initial epicenter of COVID-19. East Asia is reported to have a lower COVID-19 mortality than that in the American or the European countries.[13] As of July 1, 2020 we were unable to find published reports of critically ill patients in East Asia, and the reasons underpinning these regional differences are unclear. The mortality rate was low in our study, including survivors who underwent prolonged mechanical ventilation for more than 3 weeks. The clinical course of patients who were intubated was described based on days of illness in this study. Furthermore, we reported the trends of laboratory findings such as NLR, CRP, and D-dimer throughout the disease course. The use of the antiviral agents of favipiravir and lopinavir/ritonavir and the high frequency of systemic steroid administration may have been practices that are unique to Japan and requires further assessment and documentation.
In this study, 17 of the 24 patients received mechanical ventilation for less than 2 weeks, with the exception of 4 patients that required tracheostomy and prolonged ventilation. The intubation rate of 71% in the ICU setting was lower than the 88% reported in a multicenter study in Italy[4] and 93% reported in a large single institutional study in New York,[14] but was similar to the rates of 71 to 79% reported in multiple multicenter studies in the United States[15–17] and was higher than the rates of 30 to 47% reported during the early phase of the endemic in Wuhan, China.[18–20] The median PaO2/FIO2 ratio of the intubated patients was 169, which was close to the value of 160 in the Italian study[4] although higher than that reported in most American studies.[15, 17] The median duration of mechanical ventilation was 7 days, and the extubation rate was 77%. The 8% mortality rate in the current study was significantly lower than the rates of 26 to 78% reported in other affected cities or regions[4, 14–17, 19, 21, 22].
An early intubation strategy was enforced, and the decision to adopt invasive mechanical ventilation was made promptly. Thresholds for intubation were lowered to avoid the use of high-flow nasal-cannula or non-invasive positive pressure ventilation therapy, which carry the risk of aerosol contamination that may increase the SARS-CoV-2 transmission risk for health care providers.[12] Patients who were at risk were closely monitored and transferred to the ICU without delay. This practice may explain the relatively low SOFA, APACHE-Ⅱ, and SAPS-Ⅱ scores on ICU admission. Unlike in the Lombardy Region or New York,[4, 15] Tokyo did not experience a severe outbreak of COVID-19. Therefore, the ICU capacity and the need for ventilators were not overwhelmed. These factors may have permitted early intervention before the point-of-no-return deterioration or death.
The median BMI of 24.7 kg/m2 in our study was significantly lower than the mean of 30 kg/m2 reported in New York[14, 15] although it was similar to that of Chinese patients[23]. According to previous studies, obesity has been associated with worse outcomes.[24, 25] The lower BMI of our study subjects may have been protective. Further investigations are required to understand the influence of body weight on outcomes in Japanese patients.
Elucidating the underlying inflammatory mechanism of COVID-19 may aid clinicians’ comprehension of the disease and clarify the deterioration in clinical course on Day 10 of illness as well as trends of laboratory findings.[7, 26] In our study, the median day of illness on ICU admission and intubation was Day 11. Laboratory findings such as WBC, NLR, and CRP consistently peaked at this phase. NLR and CRP are well-known indicators of inflammatory damage and have been associated with worse outcomes.[19, 27, 28] However, changes in laboratory findings throughout the clinical course of the disease have not been delineated. Combined assessment of the clinical timeframe and laboratory trends may be beneficial for predicting patients’ course of COVID-19. Furthermore, coagulation abnormalities are predominant features of COVID-19, and high D-dimer levels are reported on initial laboratory testing.[29] In this study, D-dimer peaked on Day 20 of illness. Recognition of these changes guided the institutional clinical practice for active surveillance for the detection of thromboembolism and early administration of prophylaxis.[30]
Corticosteroid administration in critically ill patients with COVID-19 remains controversial.[31, 32] In previous studies, the use of systemic steroids in ICU patients varied from 26–50%.[14, 15, 19, 21] Low dose steroid treatment in the range of 1 to 2 mg/kg were frequently administered.[31, 33] In this study, 88% of patients used systemic steroids, including 16 survivors that received high dosage (500 to 1,000 mg) of methylprednisolone. Given the underlying inflammatory mechanisms of COVID-19[34, 35] and the trend of inflammatory laboratory findings, systemic steroids may play a role in the suppression of inflammatory responses when used judiciously.[36] Further studies are necessary to evaluate the efficacy of systemic steroid therapy in COVID-19.
Favipiravir, a flu drug developed in Japan[37] was the main antiviral agent predominantly used during the observation period, after April 1, 2020. Moreover, 9 of 10 patients were survivors, and no adverse events were observed with use in this study population. Notably, patients in the wards were not frequently transferred to the ICU in April 2020 despite the surge of infections in Tokyo.[1] The association between favipiravir use and reduction in inpatient deteriorations remains speculative, and the results of clinical trials are anticipated.[38]
Limitations
Several limitations of this study need to be addressed. First, given that this was a single-center retrospective cohort study, there was potential selection bias. Moreover, uncontrolled confounding factors may have been present. Second, the number of patients included in this study was low. Third, statistical analyses were not conducted due to the small sample size.