key: cord-0923386-cj1i9l41
authors: Sakr, Yasser; Bensasi, Hatim; Taha, Ahmed; Bauer, Michael; Ismail, Khaled
title: Camostat mesylate therapy in critically ill patients with COVID-19 pneumonia
date: 2021-04-12
journal: Intensive Care Med
DOI: 10.1007/s00134-021-06395-1
sha: f26577f1c81496b9ec5ffa8fa722b77861fc4486
doc_id: 923386
cord_uid: cj1i9l41

nan

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 Chi 2 = 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. Table 1 Characteristics of the study groups on admission to the ICU APACHE II acute physiologic and chronic health evaluation score, BMI body mass index, ICU intensive care unit, IQR 25-75% interquartile range, LOS length of stay, SD standard deviation Missing values (whole cohort: camostat/no camostat: weight: 3 (2/1), BMI: 3 (2/1), APACHE II: 10 (9/1) a 30 patients were referred from the hospital ward to the ICU after a range of 3-9 days; 11 have received camostat mesylate (prehospital stay; range 3-7 days) and 19 patients did not (prehospital stay; range 3-9 days)

The whole cohort (n = 371) Propensity score-matched cohort (n = 122) 

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

Middle east respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2

Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Camostat mesylate may reduce severity of Coronavirus disease 2019 sepsis: a first observation

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The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s00134-021-06395-1. 1 

The datasets analyzed in the current manuscript are available from the corresponding author on reasonable request.

The software codes are available from the corresponding author on reasonable request.

The authors declare that they do not have conflict of interests in relation to this manuscript.

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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