key: cord-0836087-kh2uyhrx
authors: Takahashi, Hidenori; Iwasaki, Yoshinobu; Watanabe, Takayasu; Ichinose, Naoki; Okada, Yasusei; Oiwa, Akito; Kobayashi, Takehiro; Moriya, Mariko; Oda, Toshimi
title: Case studies of SARS-CoV-2 treated with favipiravir among patients in critical or severe condition
date: 2020-08-21
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.08.047
sha: 236646a6b327d3d8d1be89c5a7c5a5f309d46643
doc_id: 836087
cord_uid: kh2uyhrx

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is rising globally. However, clinically effective antiviral treatments are not established. Favipiravir may prevent pneumonia and acute respiratory distress syndrome aggravation. We describe SARS-CoV-2-positive patients, two of whom were in a critical condition and one of whom was in a severe condition, who were administered favipiravir for their deteriorating conditions and cured.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly became a worldwide health emergency. The resulting coronavirus disease can rapidly progress to dyspnea and hypoxemia, develop into acute respiratory distress syndrome (ARDS), and be fatal.

As of May 11, 2020, the World Health Organization reported over 4,500,000 confirmed cases and over 300,000 deaths; incidence and mortality continue to rise globally (World Health Organization 2020).

Effective antiviral treatments for COVID-19 are not sufficiently established, and knowledge regarding antiviral treatment for SARS-CoV-2 is limited. Favipiravir, developed to treat influenza by inhibiting the RNA polymerase of RNA viruses, may be effective against SARS-CoV-2 (Furuta et al. 2013, Shiraki and Daikoku 2020) . For example, a clinical trial of favipiravir reported reduced pyrexia and cough in all patients and an improved recovery rate in patients with moderate severity; however, the recovery rate among patients in severe or critical condition remained unchanged (Chen et al. 2020a ).

In these case reports, we present our experience with three COVID-19 patients; two in a critical condition and one in a severe condition. These patients needed high dose oxygen therapy or extracorporeal membrane oxygenation (ECMO). After treatment with favipiravir, they recovered from SARS-CoV-2 pneumonia and we could taper oxygenation. This study was approved by the Ethics Review Committee of our hospital (protocol REC-222), and all patients provided their written informed consent for the publication of de-identified medical histories.

A 64-year-old man with a smoking history of 42-pack years and a mild fever and fatigue since J o u r n a l P r e -p r o o f late March 2020 (day 1: the first day symptoms begin) was brought to our hospital in early April (day 10) because of worsening dyspnea. He had no significant travel history or contact with COVID-19 patients. Physical examination revealed a fever of 37.8℃ with an oxygen saturation of 93% under an 8 L/min reservoir mask. Computed tomography (CT) detected emphysema and showed bilateral diffuse multiple ground glass opacities (Figure 1a ).

We performed a nasopharyngeal swab test for SARS-CoV-2 using a reverse transcriptasepolymerase chain reaction (RT-PCR) assay and promptly admitted the patient to an isolated negative pressure room. The RT-PCR test returned positive the next day. Thereafter, the patient was started on favipiravir orally (1800 mg twice daily [day 1], followed by 800 mg twice daily [days 2-14]).

Within 12 hours after admission, his respiratory condition worsened, and his oxygen saturation decreased to 90% under a 14 L/min reservoir mask. Approximately 24 hours after admission, the patient's oxygen saturation declined to 88% (oxygen concentration 100%, 50 L/min via nasal high flow) and mechanical ventilation was performed by orotracheal intubation.

The patient underwent intensive care unit (ICU) monitoring. Favipiravir was continued for 14 days via a nasogastric tube (Table 1) .

After intubation, the patient's blood oxygen saturation was maintained at an oxygenation index of approximately 100 mmHg (ventilator conditions: Pressure Support 10 cmH2O, Positive End Expiratory Pressure 15 cmH2O, FiO2 70%). Veno-venous ECMO (VV-ECMO) J o u r n a l P r e -p r o o f rescue therapy was performed from day 13-20, applying a rest lung strategy and treatment with steroids, azithromycin, sivelestat, and nafamostat. After evacuation from ECMO, tapering ventilation continued until day 23.

His RT-PCR test returned negative on day 27. A chest radiograph showed consolidation with reticular shadows in both outermost lung fields that had progressed and thickened until day 35, then starting to regress. Oxygen administration was tapered, and he was free of oxygen administration on day 51. He is continuing rehabilitation.

A 60-year-old man with no history of smoking, recent travel, or contact with COVID-19 patients, complaining of a 38℃ fever since early March (day 1), who had been tested positive for COVID-19 via RT-PCR on day 8, was admitted to our hospital in mid-March 2020 (day 11).

On admission, physical examination revealed a fever of 37.6℃ with an oxygen saturation of 97% under a 6 L/min reservoir mask.

CT showed bilateral diffuse ground glass opacities with bronchiectasis, suggesting ARDS ( Figure 1b) . Although he promptly began favipiravir, his respiratory condition worsened, and he needed a maximum oxygen intake of 8 L/min via reservoir mask for over 36 hours. However, within 5 days, his symptoms were alleviated, his respiratory condition improved, and oxygen J o u r n a l P r e -p r o o f administration was tapered (Table 1) . A chest radiograph showed consolidation with a reticular shadow that had progressed for a week and then started to regress.

He did not need treatments such as steroids or antiviral drugs, and he was free of oxygen administration on day 24. His RT-PCR test returned negative on day 34, and he was discharged on day 38.

A 51-year-old man with no history of smoking, recent travel, or contact with COVID-19 patients, who had persistent fever and dyspnea since early April 2020 (day 1) presented to our hospital in mid-April (day 11).

On admission, physical examination revealed fever of 37.2℃ with an oxygen saturation of 97% under a 6 L/min reservoir mask. CT showed bilateral multiple patchy ground glass opacities with bronchiectasis, suggesting ARDS (Figure 1c ).

We tested for COVID-19 via RT-PCR, and the patient was promptly admitted to an isolated negative pressure room. Within 6 hours, his respiratory condition worsened, and he needed a maximum oxygen intake of 100% via 40 L/min nasal high flow. He underwent ICU monitoring and favipiravir was initiated; treatments with steroids (7 days) and nafamostat (14 days) were started on day 12.

Within 3 days, his symptoms were alleviated, his respiratory condition improved, and J o u r n a l P r e -p r o o f oxygen administration was tapered (Table 1) . A chest radiograph showed consolidation with reticular shadows in the left mid and right lower lung fields that had progressed until day 14, then started to regress, though remained unchanged since day 31. His RT-PCR test returned negative on day 23. He did not require oxygen administration from day 33 and was discharged on day 36.

In these reports, we present our experience treating COVID-19 patients with favipiravir. Two patients in a critical condition needed 100% oxygen via nasal high flow or ECMO rescue therapy, and one patient in a severe condition needed a maximum oxygen of 8 L/min. All began favipiravir administration on day 11 after symptom onset for deteriorating conditions. SARS-CoV-2 proliferates over 10 days after symptom onset (Zou et al. 2020) , and cytokine storms or ARDS typically begin 8-14 days after symptom onset ).

SARS-CoV-2 viremia may induce these conditions (Chen et al. 2020b) . ARDS leads to a higher mortality risk, with a mortality rate of approximately 74% (Yang et al. 2020) . Favipiravir potentially inhibits SARS-CoV-2 proliferation (Furuta et al. 2013, Shiraki and Daikoku 2020) , which may lead to reduced cytokine production and protect the lung from fibrosis in subsequent hypoxemia (Yamamura et al. 2020) . A recent study of favipiravir among non-severe patients showed an earlier time of viral clearance (medians of 4 vs. 11 days) (Cai et al. 2020) ; however, J o u r n a l P r e -p r o o f our patients had viral clearance at 18, 27, and 13 days, respectively, possibly reflecting higher viral replication amidst worsening symptoms (Liu et al. 2020) . Additionally, the study showed chest imaging improvement in patients on favipiravir, which was also observed among our patients. Favipiravir can effectively work even in severe cases with high viral load (Takahashi et al. 2003) . The predominant mechanisms by which favipiravir inhibits SARS-CoV-2 virus replication are its considerable inhibitory activity against RNA synthesis and lethal mutagenesis (Shannon et al. 2020 ).

Our report of three COVID-19 cases suggests that favipiravir may slow/stop pneumonia progression and cytokine increase, improve respiratory function, and produce immediate effects even in severe or critical condition patients. Favipiravir clinical trials generally exclude patients in critical or severe condition (Cai et al. 2020 , Chen et al. 2020a , NIPH Clinical Trials 2020 , Russian Direct Investment Fund 2020 . However, our observations suggest that favipiravir be considered for treating severe or critical patients.

Funding: This research did not receive any specific grants from public or governmental funding agencies, nor from commercial or not-for-profit sectors.

None to declare.

Ethical approval: All study participants provided informed consent, and the study design was approved by the appropriate ethics review board. This case study was ethically approved by the Human Research Ethics Committee of our hospital (Approval number: REC-222.)

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

J o u r n a l P r e -p r o o f NIPH Clinical Trials. Multicenter, adaptive, randomized, placebo-controlled, comparative study to evaluate the efficacy and safety of favipiravir in patients with COVID-19 non-severe pneumonia [JapicCTI-205238] 

Experimental treatment with favipiravir for COVID-19: An Open-Label Control Study

Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiV

Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients

T-705), a novel viral RNA polymerase inhibitor

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Viral dynamics in mild and severe cases of COVID-19

In vitro and in vivo activities of T-705 and oseltamivir against influenza virus

Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study

SARS-CoV2 viral load in upper respiratory specimens of infected patients