Exploring the Impact of Hydroxyzine on COVID-19 Mortality: A Groundbreaking Study
Abstract
The COVID-19 pandemic has prompted an urgent search for effective treatments, and recent research highlights the potential of hydroxyzine, a widely used antihistamine, in reducing COVID-19 mortality. A multicenter observational study conducted across 36 hospitals in Greater Paris involving 15,103 hospitalized adults found that hydroxyzine administration within the first 48 hours of hospitalization significantly lowered mortality rates (AOR, 0.51; 95% CI, 0.29–0.88, p = 0.016). Hydroxyzine’s mechanisms include functional inhibition of acid sphingomyelinase (FIASMA) and anti-inflammatory properties, which may mitigate severe inflammatory responses in COVID-19 patients. The study underscores the importance of further investigation through randomized clinical trials to confirm these findings and explore the therapeutic potential of hydroxyzine and its deuterated form, hydroxyzine-d8. The promising results advocate for the repurposing of existing medications to accelerate the availability of effective treatments during public health crises.
Keywords: COVID-19 treatment, Hydroxyzine, Mortality reduction, Antihistamine, FIASMA
Introduction
The COVID-19 pandemic has relentlessly swept across the globe, leaving a trail of devastation in its wake. As scientists and medical professionals race against time to find effective treatments, a recent multicenter observational study has shed light on a promising candidate: hydroxyzine. This widely used antihistamine, known for its antiviral and anti-inflammatory properties, has shown a significant association with reduced mortality in COVID-19 patients. Conducted across 36 hospitals in Greater Paris, the study involved 15,103 adults hospitalized due to COVID-19. Out of these, 164 patients received hydroxyzine within the first 48 hours of their hospital stay. The findings revealed a remarkable outcome: patients who were administered hydroxyzine had a notably lower mortality rate compared to those who did not receive the drug. Specifically, the analysis demonstrated a significant association between hydroxyzine use and reduced mortality, with an adjusted odds ratio (AOR) of 0.51 (95% CI, 0.29–0.88, p = 0.016). Hydroxyzine's potential mechanisms of action in combating COVID-19 are multifaceted. It functions as a functional inhibitor of acid sphingomyelinase (FIASMA), which may contribute to its antiviral effects. Additionally, its anti-inflammatory properties, achieved through both receptor-dependent and receptor-independent mechanisms, could play a crucial role in mitigating the severe inflammatory response seen in COVID-19 patients. Despite the study’s observational nature, which inherently carries the risk of biases, the results are compelling and warrant further investigation through randomized clinical trials. The findings suggest that hydroxyzine could be a valuable addition to the arsenal of treatments against COVID-19, potentially saving numerous lives. As we continue to navigate through the challenges posed by the pandemic, studies like this offer a glimmer of hope and underscore the importance of exploring existing medications for new therapeutic purposes.Background Information
The COVID-19 pandemic has necessitated the rapid development and identification of effective treatments to mitigate its impact. COVID-19, caused by the SARS-CoV-2 virus, has resulted in significant morbidity and mortality worldwide, prompting an urgent need for therapeutic interventions. While vaccines have proven to be a critical tool in combating the virus, the search for effective treatments remains a priority, particularly for severe cases. Hydroxyzine, a first-generation H1 antihistamine, is commonly used to treat conditions such as urticaria, allergic rhinitis, hay fever, conjunctivitis, and pruritus. Beyond its primary antihistaminic activity, hydroxyzine is also recognized for its tranquilizer and sedative properties. The drug exerts its effects by competitively binding to H1 receptors, thereby inhibiting the action of histamine—a key mediator in allergic inflammatory responses. Recent studies have highlighted additional anti-inflammatory properties of hydroxyzine, including both receptor-dependent and receptor-independent mechanisms. The receptor-dependent mechanisms involve the inhibition of NF-kB-dependent cytokines such as IL-1, IL-2, IL-6, IL-8, IL-12, and TNF-α, as well as adhesion proteins like ICAM-1 and VCAM-1. These mechanisms are crucial in controlling the excessive inflammatory responses seen in severe COVID-19 cases. Moreover, hydroxyzine belongs to a group of drugs known as functional inhibitors of acid sphingomyelinase (FIASMA). This group includes various medications such as antidepressants, calcium channel blockers, and mucolytics. These drugs inhibit the acid sphingomyelinase enzyme, which is implicated in the SARS-CoV-2 infection process by facilitating viral entry into host cells. This inhibition potentially reduces the severity of the infection and the associated inflammatory response. Given these properties, hydroxyzine emerged as a candidate for repurposing in the treatment of COVID-19. The multicenter observational study conducted across 36 hospitals in Greater Paris aimed to explore this potential, revealing a significant association between hydroxyzine use and reduced mortality in hospitalized COVID-19 patients.Analysis and Implications
The findings from the multicenter observational study on hydroxyzine use in COVID-19 patients provide significant insights into potential therapeutic avenues. The study revealed that hydroxyzine, when administered within the first 48 hours of hospitalization, was associated with a substantial reduction in mortality. This association held even after adjusting for various confounding factors, indicating a strong potential for hydroxyzine to play a beneficial role in the treatment of COVID-19. One of the key mechanisms through which hydroxyzine may exert its effects is its action as a functional inhibitor of acid sphingomyelinase (FIASMA). By inhibiting this enzyme, hydroxyzine could potentially disrupt the SARS-CoV-2 infection process, thereby reducing viral entry and subsequent cellular damage. This mechanism is supported by previous research demonstrating the antiviral effects of FIASMA medications against other viruses, including hepatitis C and MERS. Additionally, hydroxyzine's anti-inflammatory properties are noteworthy. The drug’s ability to inhibit NF-kB-dependent cytokines and adhesion proteins suggests it could mitigate the severe inflammatory response often observed in COVID-19 patients. This anti-inflammatory action could be crucial in preventing the progression of mild to severe disease, particularly by controlling the cytokine storm associated with severe COVID-19 cases.
However, the observational nature of the study inherently includes potential biases and confounding factors, despite the multivariable adjustments made. These limitations underscore the need for randomized controlled trials to definitively ascertain the efficacy and safety of hydroxyzine in COVID-19 treatment. Such trials would help to eliminate biases and provide more robust evidence of hydroxyzine's therapeutic potential.
The study’s implications extend beyond immediate clinical applications. It highlights the importance of drug repurposing in the rapid response to emerging infectious diseases. The findings encourage further exploration of existing medications with known safety profiles, potentially accelerating the availability of effective treatments during public health crises.
