key: cord-293942-n5ypkftc
authors: Takoi, Hiroyuki; Togashi, Yuki; Fujimori, Daiki; Kaizuka, Haruki; Otsuki, Shunsuke; Wada, Takuya; Takeuchi, Yoshikazu; Abe, Shinji
title: Favipiravir-induced fever in coronavirus disease 2019: A report of two cases
date: 2020-09-28
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.09.1450
sha: 
doc_id: 293942
cord_uid: n5ypkftc

Favipiravir, an antiviral agent, is undergoing clinical trials for treating novel coronavirus disease 2019 (COVID-19). We report two cases of COVID-19 with favipiravir-induced fever. In both cases, pyrexia was observed following administration of favipiravir despite symptoms of COVID-19 improving. No other cause for the fever was evident after careful physical examination and laboratory investigation. Once favipiravir was discontinued, the fever subsided in both patients. To our knowledge, this is the first report of favipiravir-induced fever.

Hiroyuki Takoi, PhD Department of Respiratory Medicine, Tokyo Medical University Hospital 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Tokyo, Japan taco155485@hotmail.com

The coronavirus disease 2019 pandemic is one of the most significant public health crisis in recent history. A randomized clinical trial showed that treatment with remdesivir accelerated recovery in patients with severe COVID-19 (Wang et al., 2020) . Therefore, this antiviral agent has become one of the standard therapies for COVID-19. Favipiravir, a promising antiviral agent, is undergoing clinical trials as an alternative drug for treating COVID-19 (Arab-Zozani et al., 2020) in several countries, including China (Chen et al., 2020) , Iran, Germany, and Japan.

Drug-induced fever is difficult to diagnose in patients with febrile illnesses, especially if the J o u r n a l P r e -p r o o f drug is a novel drug for an emerging infectious disease such as COVID-19. Reporting such cases might contribute to the accurate diagnosis of future cases. We experienced two cases of favipiravir-induced fever in patients hospitalized with COVID-19. Here we report the cases.

In April 2020, a 42-year-old man was admitted to hospital with COVID-19, 13 days after the onset of symptoms. He was taking febuxostat for hyperuricemia. On admission, he was asymptomatic and did not require supplemental oxygen. Chest computed tomography (CT) showed ground-glass opacity in both lungs. Favipiravir was started on the day of admission.

He received two doses of 1,800 mg on Day 1 and 800 mg twice daily thereafter. His uric acid level became elevated, possibly as a side effect of favipiravir; therefore, benzbromarone was added to his treatment regimen. On Day 12 of favipiravir treatment, his temperature rose to 38°C with blood eosinophilia (630 cells/μL), despite an improvement in his chest X-ray findings.

His general condition was good except for the fever and relative bradycardia. Favipiravir treatment was discontinued on Day 14, and his temperature returned to normal the following day ( Fig. 1) . His blood eosinophil count also returned to normal. Benzbromarone was initially considered to be the causative agent of the fever; however, clinical improvement occurred before benzbromarone was discontinued. Thus, he was diagnosed with favipiravir-induced J o u r n a l P r e -p r o o f fever.

In August 2020, a 28-year-old woman with an unremarkable medical history was admitted 5 days after the onset of COVID-19 symptoms. She had a fever of 39°C, and her chest CT revealed mild ground-glass opacity at the base of each lung. She did not require supplemental oxygen. Favipiravir treatment was started on the day of admission. She received two doses of 1,800 mg on Day 1 and 800 mg twice daily thereafter. Her temperature returned to normal the following day; however, on the following day, her temperature rose to 39°C. Physical examination, laboratory investigation, and bacteriological and radiological findings did not determine the cause of the fever. Her respiratory symptoms improved but she experienced relative bradycardia. Drug-induced fever was suspected and favipiravir was discontinued on Day 10. She became afebrile the following day and was discharged on Day 15 (Fig. 2) . In contrast to Case 1, she did not develop blood eosinophilia.

To our knowledge, this is the first report of favipiravir-induced fever. Favipiravir is used to treat influenza A subtype H1N1. It exhibits antiviral activity against other RNA viruses and is thought to have an antiviral effect on severe acute respiratory syndrome coronavirus-2 (Shiraki and Daikoku, 2020) . It has been approved in Japan for treating novel influenza virus diseases.

In a case series of 11 patients, favipiravir in combination with nafamostat mesylate was found to have an antiviral effect in critically ill COVID-19 patients (Doi et al., 2020) .

In both of our cases, a discrepancy was observed between the patients' clinical course and their fever, and no possible cause of pyrexia other than favipiravir was identified.

A definition of drug fever is "a disorder characterized by fever coinciding with the administration of a drug and disappearing after the discontinuation of the drug, when no other cause for the fever is evident after a careful physical examination and laboratory investigation," with a period of 1.3 ± 1.1 days from discontinuation of the causative drug to pyretolysis (Makowiak and LeMaistre, 1987) . Drug fever can be ruled out if pyretolysis is not confirmed within 72 h after the discontinuation of the drug (Mourad et al., 2003) .

A wide variety of drugs have been implicated in drug fever (Patel and Gallagher, 2010 ).

Favipiravir has not been previously reported to cause drug fever. This preliminary report may help differentiate paradoxical fever in patients receiving favipiravir therapy for COVID-19. Early accurate diagnosis may reduce not only inappropriate, potentially harmful, and expensive diagnostic and therapeutic interventions, but may also lead to unnecessary patient isolation, bed occupation, and effort of healthcare workers.

J o u r n a l P r e -p r o o f The patient's fever subsided after discontinuation of favipiravir. The patient's fever subsided after discontinuation of favipiravir.

Favipiravir for treating patients with novel coronavirus (COVID-19): protocol for a systematic review and meta-analysis of randomised clinical trials

Favipiravir versus arbidol for COVID-19: A randomized clinical trial

Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: A case series

Drug fever: a critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature

A comprehensive evidence-based approach to fever of unknown origin

Drug fever

Favipiravir, an anti-influenza drug against life-threatening RNA virus infections

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Both patients have provided written informed consent for the publication of this report.

The authors did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors for writing this report.

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