- Research Letter
- Open Access
Effect of favipiravir and an anti-inflammatory strategy for COVID-19
Critical Care volume 24, Article number: 413 (2020)
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an anti-viral agent that selectively and potently inhibits the ribonucleic acid (RNA)-dependent RNA polymerase of RNA viruses . In Japan, it is approved for use with novel influenza virus and is thought to be an effective drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus disease 2019 (COVID-19) presents a complex pathology including inflammation, endothelial damage, thrombus formation, and acute respiratory failure [2,3,4] This syndrome requires complex treatment to reduce viral genome amounts, anti-inflammatory drugs, and anticoagulation. We attempted the cocktail treatment of favipiravir, steroid, and heparin for COVID-19. This study aimed to evaluate the effect of cocktail therapy for severe COVID-19.
This prospective, single-center study was conducted on all patients admitted to our hospital by transfer from other hospitals who required mechanical ventilation for severe COVID-19 between April 2 and 27, 2020. COVID-19 was diagnosed with real-time reverse transcriptase-polymerase chain reaction in approved laboratories from nasopharyngeal and throat swabs and with lung computed tomography. The treatment protocol was as follows: oral favipiravir (3600 mg on day 1, 1600 mg from day 2 to day 14), methylprednisolone (1000 mg for 3 days), and low molecular weight (2000 IU every 12 h) or unfractionated heparin (10,000–12,000 IU/day). Methylprednisolone administration was begun on the 5th day from initial favipiravir administration. Heparin and dexmedetomidine were administered after intubation and mechanical ventilation was started. Wilcoxon signed-rank tests were used to assess patients’ changes in paired PaO2/FIO2 (P/F) ratio, IL-6, and presepsin. All statistical analyses were performed with JMP, Version 13.0.0 (SAS Institute Inc.).
Thirteen patients with COVID-19 requiring mechanical ventilation were admitted during the study period. The treatment protocol was completed without any clinically important change in 2 patients with bronchial asthma, one with rheumatoid arthritis (early-stage steroid administration) and one with bleeding complication (without heparin). Patient characteristics and initial laboratory data are summarized in Table 1. Mean patient age was 63 (range, 46–80) years, and 69.0% were men. Only one patient required extracorporeal membrane oxygenation. Time from first symptom appearance to favipiravir administration was 8.7 (range, 4–13) days. One patient died due to disseminated intravascular coagulation (DIC) on admission that gradually progressed to multiple organ failure.
The time course of the clinical laboratory data is shown in Fig. 1. Day 1 indicates the first day of favipiravir administration. The P/F ratio changed very little over the first 6 days and then gradually recovered. The interleukin-6 peaked on day 4 and decreased thereafter. Presepsin also peaked on day 3, remained about the same until day 6, and then decreased.
The clinical course of SARS-CoV-2 treatment with the cocktail in mechanically ventilated patients with COVID-19 indicated that favipiravir could partially control inflammatory mediators but could not completely control them or respiratory status. The respiratory distress of SARS-CoV-2 is thought to be due not only to direct viral action but also to chemical mediators induced by SARS-CoV-2. Inflammation and cytokine storm continued after favipiravir administration, and they could be controlled with steroid in our patients. Limitations of this study include its small sample size and performance in a single medical center. The start of favipiravir administration was delayed. Steroid therapy has adverse effects, and we did not assess long-term complications . Nevertheless, the results suggested that favipiravir was of some benefit, and the findings helped inform a treatment strategy for severe COVID-19.
Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available due to institutional policy but are available from the corresponding author on reasonable request.
Coronavirus disease 2019
Severe acute respiratory syndrome coronavirus 2
Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449–63.
Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020. https://doi.org/10.1001/jama.2020.6825.
Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–4.
Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region. Italy JAMA. 2020;323(16):1574–81.
Ethics approval and consent to participate
All studies were approved by the Ethical Committee of Higashiosaka City Medical Center.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Yamamura, H., Matsuura, H., Nakagawa, J. et al. Effect of favipiravir and an anti-inflammatory strategy for COVID-19. Crit Care 24, 413 (2020). https://doi.org/10.1186/s13054-020-03137-5