This single-center case series describes 20 consecutive patients admitted to ICU during the first wave of the SARS-CoV-2 infection in Japan who required invasive mechanical ventilation. Our hospital is located in Osaka, Japan, with a population of 8.8 million. In Osaka, we expected to have 300 intubated patients during the peak period, and our hospital had prepared 20 beds for severe COVID-19 in the ICU. In actuality, the maximum number of intubated patients treated at the same time was 10, and we were able to provide sufficient intensive care in all cases without the collapse of medical services. A treatment protocol was prepared for critically ill patients after referring to the papers based on experiences with Wuhan patients and those from the cruise ship Diamond Princess. We used favipiravir, nafamostat mesilate, ciclesonide, and azithromycin in combination as antiviral drugs. If oxygenation could not be maintained by usual invasive mechanical ventilation and antiviral therapy, we administered methylprednisolone according to ARDS treatment and daily proning therapy. If oxygenation worsened despite methylprednisolone and proning, we would initiate ECMO.
The mortality rate of patients with COVID-19 who require invasive mechanical ventilation is not clear. In an early report from Wuhan, all 25 patients who required invasive mechanical ventilation died . The mortality rates of patients requiring treatment in an ICU were reported from Washington State in the US , Wuhan in China , and the Lombardy region of Italy ;, however, these reports did not mention the exact mortality rate of patients received invasive mechanical ventilation. A large multicenter study reported on 5700 patients requiring hospitalization for COVID-19 in New York . Among 2634 patients who were discharged or died at the study endpoint, 88.1% of 320 patients who received invasive mechanical ventilation died. However, 831 intubated patients remained in hospital, and the prognosis of the intubated patients cannot be determined. In our small series, the mortality rate of the patients receiving invasive mechanical ventilation was 30%. The reason for the lower mortality rate than those in the past reports is that medical services did not collapse in Japan, and the combination of antiviral, methylprednisolone, and proning therapies was effective. Especially, methylprednisolone and proning therapies effectively improved the patients’ respiratory condition.
Our most anticipated antiviral drug is favipiravir, which is an RNA polymerase inhibitor developed as an anti-influenza drug and has been reported to have growth inhibitory activity against SARS-CoV-2 . In a non-randomized study conducted in China, patients receiving favipiravir and interferon α had a faster negative PCR result for SARS-CoV-2 and faster improvement of CT findings than those receiving lopinavir/ritonavir and interferon α . We administered favipiravir from the first day in all patients at a dose of 1800 mg on the first day and 800 mg on the second and subsequent days. We used favipiravir for 2 weeks or until the patients received a negative PCR result for SARS-CoV-2 or serious side effects occurred. In Japan, an observational study on COVID-19 patients treated with favipiravir was started in February 2020, and the results are anticipated.
Nafamostat mesylate is one of the serine protease inhibitors and has been used in Japan as an anticoagulant during hemodialysis and as an agent for disseminated intravascular coagulation. It inhibits the process of membrane fusion of SARS-CoV-2 and cells in vitro and is expected to have an antiviral effect on SARS-CoV-2 . In addition, COVID-19 is reported to be associated with thrombosis, and prophylactic administration of anticoagulants is recommended in all hospitalized patients . In anticipation of its antiviral and anticoagulant effects, we administered nafamostat mesylate for 1 week in all patients.
Ciclesonide is a safe drug widely used as an inhaled steroid for bronchial asthma and is expected to have local anti-inflammatory and viral replication inhibitory effects on COVID-19 . We administered ciclesonide 800 µg daily from a reservoir connected to the ventilator circuit for 2 weeks in all patients.
Some patients struck severely by SARS-CoV-2 might suffer cytokine storm syndrome that can lead to multi-organ failure including ARDS . Conquering the cytokine storm is one of the essential strategies to save severely ill patients with ARDS from SARS-CoV-2 infection, and corticosteroid is a candidate drug to control cytokine storm syndrome after SARS-CoV-2 infection. However, there is insufficient evidence to recommend corticosteroid treatment according to the current interim guidance from WHO . They concluded that administration of corticosteroid for acute severe lung injury from SARS-CoV and MARS-CoV inhibits immune response and virus clearance, making the patient vulnerable to side effects such as psychosis, viremia, diabetes, avascular necrosis and secondary bacterial or fungal infection. Meanwhile, Shang et al. offered a negative perspective on use of corticosteroids for lung injury caused by SARS-CoV-2 because the evidence supporting the effectiveness of corticosteroids came mostly from observational studies and was insufficient to conclude its usefulness . Chen et al. supportively reported that proper use of corticosteroids reduced mortality and shortened the length of the hospital stay in critically ill patients without secondary infection and other complications . Wu et al. reported that administration of methylprednisolone to patients with severe COVID-19 was effective and reduced the risk of death from ARDS . In reference to the standard therapy of methylprednisolone for interstitial pneumonia , we used a new protocol of methylprednisolone therapy as described above. With the use of this protocol, all patients under the age of 70 survived from ARDS. Unfortunately, our protocol had a limited effect on elderly patients. More than half of the patients over age 70 died from complications due to long-term use of methylprednisolone including brain infarction, upper GI bleeding and secondary bacterial and fungal infections. Although the administration of methylprednisolone for severe pneumonia caused by SARS-CoV-2 is controversial, our protocol exhibited a certain effect for limited cases.
Tocilizumab, an anti-IL-6 receptor antibody, has been approved for the cytokine release syndrome associated with CAR-T (chimeric antigen receptor-modified T cell) therapy . Tocilizumab, along with steroids, is expected to control cytokine storm syndrome in COVID-19 . In our case series, tocilizumab was administered to two patients prior to intubation, but it failed to improve oxygenation, and these patients required additional methylprednisolone administration. Thus, it was difficult to assess the effect of tocilizumab in the present study.
In intubated patients with severe ARDS, early and prolonged proning improves oxygenation and decreases mortality [24, 25]. In adult patients with severe ARDS, prone ventilation for 12–16 hours per day is recommended also in COVID-19 . Among the treatment methods introduced for the management of ARDS patients, proning can be used as an adjuvant therapy for improving respiratory function in these patients. Proning should not be a desperate final attempt but should be considered in the early stages of respiratory therapy  as the available evidence suggests that the early application of prolonged ventilation in the prone position decreases 28- and 90-day mortality in patients with severe ARDS . In our case series, 19 of the 20 patients were placed in a completely prone position with mechanical ventilation for 16 consecutive hours every day, which continued until improvement of respiratory condition or a life-threatening reason caused its cessation. The time from intubation to the first proning procedure was a median 1.8 (range 1–9) days, and the median number of procedures per person was 8.9 (range 0–24). Patients ventilated in the prone position face risks such as accidental removal of the tracheal tube, bending or pulling of catheters, pressure sores, facial edema, gastroesophageal reflux, and hypersalivation . Several of our patients developed facial pressure sores, but no life-threatening complications occurred. We did not initiate ECMO in any of our patients because oxygenation was improved by proning.