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Camostat mesylate inhibits several serine proteases implicated in SARSCoV and SARS-CoV-2 virus-to-host cell membrane fusion, such as transmembrane serine protease (TMPRSS) 2, − 13, and − 11D/E/F [1,2,3]. In particular, inhibition of the SARS-CoV-2-activating host cell TMPRSS2 have been shown to block SARS-CoV-2 entry into the lung cells and represents, therefore, a possible therapeutic option in patients with coronavirus disease 2019 (COVID-19) [4]. A preliminary observation suggested that camostat mesylate may be also effective to treat the most advanced cases of COVID-19 with organ dysfunction [5]; however, randomized clinical trials are ongoing.
In a retrospective analysis of 371 adult patients (> 18 years) admitted to the intensive care unit (ICU) of Al Ain Hospital, Abu Dhabi, United Arabs Emirates between March 16 and July 19, 2020 with COVID-19 pneumonia, we assessed whether treatment with camostat mesylate is associated with an improved outcome (Figure S1–2, Supplementary material). Details of data collection, patients’ management, and statistical methods are presented in appendix S1 of the supplementary material. Off-label camostat mesylate (Foipan®, Osaka, Japan) was given to 141 (38%) patients on admission to the ICU (200 mg po TID) for 7 days (Table 1 and table S1–2 of the Supplementary material). The overall ICU and hospital lengths of stay were 9 (25–75% interquartile range 5–17) and 18 (25–75% interquartile range 13–29) days, respectively, and ICU and hospital mortality rates were both 20.2% (n = 75). ICU/hospital mortality rate were lower (9.9 vs. 26.5, p < 0.001); whereas, the hospital length of stay was longer in patients who received camostat mesylate than who did not (Table 1).
In a propensity score-adjusted multivariable Cox proportional hazard analysis in the whole cohort, camostat mesylate therapy was independently associated with a lower risk of in-hospital death, right censored at 60 days (relative hazard 0.31, 95% confidence interval 0.15–0.60, p = 0.001; table S3 and figure S3 of the supplementary material). Moreover, after inversed propensity treatment weight (IPTW)-adjustment and robust estimation using generalized estimating equations, camostat mesylate therapy was found to be independently associated with a lower risk of in-hospital death (odds ratio 0.254; 95% confidence interval 0.108–0.595, p < 0.001). In 122 propensity score-matched patients (61 pairs), ICU/hospital mortality rates (9.8 vs. 29.5, p = 0.006), the need for vasopressor therapy (45.9 vs. 67.2%, p = 0.018) or invasive mechanical ventilation (47.5 vs. 67.2%, p = 0.045) during the ICU stay were lower; whereas, 60-day survival was higher (log rank Chi2 = 18.6, p < 0.001) in patients treated with camostat mesylate than those who were not (Table 1, tables S1–3 and figure S4 of the supplementary material). Nonetheless, despite of the observed therapeutic benefit of camostat mesylate in these patients, our analysis may be limited by the specific case-mix, the residual confounding effect due to unmeasured variables, and the influence of concomitant therapies.
In summary: in this cohort, a therapeutic benefit of camostat mesylate therapy was observed in critically ill patients with COVID-19 pneumonia using several propensity score-based statistical techniques. Randomized control trials should identify target populations for this promising therapy throughout COVID-19 disease trajectory.
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The datasets analyzed in the current manuscript are available from the corresponding author on reasonable request.
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The software codes are available from the corresponding author on reasonable request.
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Acknowledgements
We would like to thank Ghanem Al Hassani and all ICU nurses, doctors, respiratory therapist, Infectious disease team, Pharmacist and laboratory staff of Al Ain Hospital, Abu Dhabi for their hard work over the period of the pandemic to achieve these results.
The UAE-Jena Research group consists of the authors mentioned in the byline in addition to: Ghazala Belhaj (Department of Anesthesiology and Critical Care Medicine, Al Ain Hospital, SEHA, Abu Dhabi, UAE), Khaled M Afet Department of Anesthesiology and Critical Care Medicine, Al Ain Hospital, SEHA, Abu Dhabi, UAE), Dnyanwshwar Munde (Department of Anesthesiology and Critical Care Medicine, Al Ain Hospital, SEHA, Abu Dhabi, UAE). David Monk (Institute of surgery, Al Ain Hospital, SEHA, Abu Dhabi, UAE), and Samuel Buschbeck (Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany).
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KI, YS, AT, MB, and HB designed the scientific work. YS, HB, GB, AT, D Munde, D Monk, SB, and KMA contributed to data collection and handling. YS, SB, HB performed the statistical analysis. AT, KI, KMA, D Munde, and SB reviewed the literature. YS, KI, AT, GB, MB, and SB wrote the first draft of the manuscript. All the authors reviewed, revised, and approved the submitted manuscript. KI and HB have complete access to the clinical data of the reported cases and hold responsibility for integrity and correctness of data.
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The off-label use of camostat mesylate was recommended by the Department of Health, Abu Dhabi (PO box 5674, Abu Dhabi, UAE). Informed consents for the off-label use of camostat mesylate were obtained on admission to the hospital according to the guidelines of UAE-Ministry of health. The analysis provided in the current manuscript was done retrospectively after obtaining the approval of the responsible institutional review board (Institutional review board of Department of Health, Abu Dhabi, PO box 5674, Abu Dhabi, UAE, application number: DOH/CVDC/2020/1669, August 8th 2020), which waived informed consent for data collection and analysis due to the retrospective nature of data collection.
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Sakr, Y., Bensasi, H., Taha, A. et al. Camostat mesylate therapy in critically ill patients with COVID-19 pneumonia. Intensive Care Med 47, 707–709 (2021). https://doi.org/10.1007/s00134-021-06395-1
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DOI: https://doi.org/10.1007/s00134-021-06395-1