Written informed consent for the off-label use of drugs and publication of this report was obtained from the patient and his family. The patient was an 82-year-old man who was a passenger on the Diamond Princess cruise ship, which experienced an outbreak of novel coronavirus (SARS-CoV-2). Prior to the off-label use of the antiviral drugs (lopinavir/ritonavir, chloroquine, and favipiravir) and use of remdesivir, which is an unapproved drug in Japan, all the drugs were reviewed and approved by the ethics committee of our hospital. Remdesivir was obtained from the drug manufacturer (Gilead Science, Inc., Foster City, CA, USA) through a Compassionate Use Program.
The patient tested positive for SARS-CoV-2 by real-time reverse transcription-polymerase chain reaction (rRT-PCR) assay while on board the ship. Two days later, he was transferred to the infectious disease ward at our hospital. He had a history of bronchial asthma, hypertension, and dyslipidemia and showed no respiratory symptoms including cough, sputum, and dyspnea at the time of admission. His vital signs, except blood pressure (165/94 mmHg), were within their normal ranges at admission. Computed tomography (CT) scan and chest radiographs showed bilateral, subpleural ground-glass opacities in both lungs (Figure 1). Blood tests showed almost normal results on admission (Table S1). Both urinary pneumococcal antigen and urinary legionella antigen were negative. Simple inspection kit results were negative for both influenza virus types A and B. Oral administration of lopinavir/ritonavir, an anti-human immunodeficiency virus (HIV) drug, and ceftriaxone were commenced.  Figure 2 illustrates the course of use of therapeutic drugs and medical devices.
On day 2, he had no noticeable symptoms other than dry cough. On day 3, however, he developed appetite loss and a fever of 38 C. SpO2 decreased to 90% on room air. Oxygen administration via a nasal cannula was started that night. However, his respiratory condition further deteriorated on day 4, and he was unable to maintain an SpO2 of 90% even with administration of 2 L/min oxygen. CT scan clearly showed exacerbation of the pulmonary pathology compared to the previous scan, with infiltration and reticular shadows appearing in wide areas of both lung fields (Figure 1). He was transferred to the intensive care unit (ICU), where a blood test showed worsening of inflammatory findings (Table S1).
Poor oxygenation continued after ICU admission, with an SpO2 of 90-95% even with oxygen administration of 10 L/min using a reservoir mask. Tracheal intubation was performed due to further worsening of oxygenation at midnight on day 5. We initiated mechanical ventilation in the pressure-controlled mode. Sedation with propofol and fentanyl and administration of dopamine and noradrenaline were commenced after intubation. The antibiotic was changed to meropenem, and oral administration of lopinavir/ritonavir was discontinued. In the afternoon of day 6, we decided to introduce veno-venous extracorporeal membrane oxygenation (VV-ECMO) because his oxygenation could not be maintained with the assistance of mechanical ventilation alone. On day 7, administration of chloroquine, which has been reported to have an inhibitory effect on coronavirus, was commenced and was continued for two days until favipiravir became available. On day 9, the administration of favipiravir, which was developed for treating RNA viruses including influenza virus, was started. On the first day, 1600 mg was administered twice, and thereafter, 600 mg was administered through a gastric tube twice per day for 5 days, as instructed in the package insert. However, even after five days of favipiravir treatment in this case, PCR assay using sputum collected from the lower respiratory tract continued to show a positive result (Figure 2, Table S2).
Administration of remdesivir was started on day 14, with an initial IV loading dose of 200 mg, followed by 100 mg IV once daily for 9 days. ECMO was terminated on day 24 with improvement in his symptoms. The administration of chloroquine was also resumed on day 24. On day 32, tracheostomy was performed. Through this period, we repeatedly performed sputum testing using PCR assay, which was established broadly in Japan. Briefly, RNA was extracted using the QIAamp Viral RNA Mini kit (QIAGEN, Valencia, VA) and the primer set that targeted the specific gene of SARS-CoV-2 coding N protein (N2). The results were validated by comparing the results to the synthesized RNA of an internal control, following which cycle threshold (Ct) values were determined. Details of the sets are shown in the supplemental methods. Ultimately, we confirmed a negative PCR result 41 and 43 days after the first positive result (Figure 2; Table S2) and weaned the patient off mechanical ventilation. Currently, although he has recovered from the life-threatening condition, he requires continued treatment for several complications, namely, bacterial infection and liver dysfunction, which is suspected as being induced by one of the therapeutic drugs.