Association between Hydroxyzine Use and Reduced Mortality in Patients Hospitalized for Coronavirus Disease 2019: Results from a multicenter observational study

Abstract

Objective: To examine the association between hydroxyzine use and mortality in patients hospitalized for COVID-19, based on its anti-inflammatory and antiviral properties. Design: Multicenter observational retrospective cohort study. Setting: Greater Paris University hospitals, France. Participants: 7,345 adults hospitalized for COVID-19 between 24 January and 1 April 2020, including 138 patients (1.9%) who received hydroxyzine during the visit at a mean dose of 49.8 mg (SD=51.5) for an average of 22.4 days (SD=25.9). Data source: Assistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measures: The study endpoint was death. We compared this endpoint between patients who received hydroxyzine and those who did not in time-to-event analyses adjusting for patient characteristics (such as age, sex, and comorbidities), clinical and biological markers of disease severity, and use of other medications. The primary analysis was a multivariable Cox model with inverse probability weighting. Sensitivity analyses included a multivariable Cox model and a univariate Cox regression model in a 1:1 ratio matched analytic sample. Results: Over a mean follow-up of 20.3 days (SD=27.5), 994 patients (13.5%) had a primary end-point event. The primary multivariable analysis with inverse probability weighting showed a significant association between hydroxyzine use and reduced mortality (HR, 0.42; 95% CI, 0.25 to 0.71; p=0.001) with a significant dose-effect relationship (HR, 0.10; 95% CI, 0.02 to 0.45; p=0.003). This association was similar in sensitivity analyses. In secondary analyses conducted among subsamples of patients, we found a significant association between hydroxyzine use and a faster decrease in biological inflammatory markers associated with COVID-19-related mortality, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCRP), and circulating interleukin 6 levels (IL-6) (all p<0.016), with a significant dose-effect relationship for NLR and LCRP (both p<0.037). Conclusions: In this retrospective observational study, hydroxyzine use was associated with reduced mortality in patients hospitalized for COVID-19. This association may be partially mediated by specific anti-inflammatory properties of H1 antihistamines. Double-blind controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results.

Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities

“…2 In fact, very recent and interesting clinical observations suggest that Hydroxyzine could reduce mortality in patients hospitalized for COVID-19 most likely in part due to anti-inflammatory properties. 41 These data suggest that additional investigations are needed for this compound to fully understand the molecular mechanisms at play and fully assess its activity on the virus and on the host. Along the same line and with the idea of drug combination, it seems possible that the use of two anti-histamine molecules, Cetirizine and Famotidine (not predicted to be CAD), both found to be inactive in the analyzed CPE assays, might be a safe and effective approach to reduce the severity of COVID-19, presumably via a modulation of the histamine-mediated cytokine storm.…”

Hydroxyzine inhibits SARS-CoV-2 Spike protein binding to ACE2 in a qualitativein vitroassay

“…These findings are in agreement with the reported in vitro antiviral activity of hydroxyzine (6). Hydroxyzine and other antihistaminic drugs have already been shown to have some beneficial effects in treating 7).…”

“…These findings are in agreement with the reported in vitro antiviral activity of hydroxyzine (6). Hydroxyzine and other antihistaminic drugs have already been shown to have some beneficial effects in treating COVID-19 (6,7). Thus, hydroxyzine has been reported to reduce the incidence of SARS-CoV-2 infection in older people and the mortality in hospitalized patients (6,7).…”

“…Hydroxyzine and other antihistaminic drugs have already been shown to have some beneficial effects in treating COVID-19 (6,7). Thus, hydroxyzine has been reported to reduce the incidence of SARS-CoV-2 infection in older people and the mortality in hospitalized patients (6,7). Although these effects may be explained in part by its antihistaminic properties (7), our findings suggest an additional potential effect by blocking the binding of Spike to ACE2.…”

“…We hypothesized that the binding of hydroxyzine to ACE2 might also interfere with SARS-CoV-2 binding to ACE2. This idea may help to understand the reported beneficial effect of hydroxyzine in this disease (6,7). To investigate it, we analyzed the effect of hydroxyzine on an in vitro assay that qualitatively determines the binding of recombinant Spike to ACE2.…”