RESUMO
COVID-19 has spurred much interest in the therapeutic potential of repurposed drugs. A family of acid-reducing drugs, known as histamine H2 receptor antagonists (H2RA), competitively bind the H2R and block its stimulation by histamine; examples of such drugs are famotidine (e.g., Pepcid) and ranitidine (e.g., Zantac). A dense web of functionalities between histamine and H2RAs, on the one hand, and downstream cellular pathways, on the other hand, links disparate physiological pathways in gastrointestinal contexts (e.g., acid reduction) to the dysregulated inflammatory cas-cades (cytokine storm) underlying the pathophysiology of COVID-19. Is famotidine beneficial in treating COVID-19? This question remains unresolved, though not for lack of effort: over 10 studies have examined the potential therapeutic value of famotidine in COVID-19, but have found conflicting results (pro-famotidine, anti-famotidine, and neutral). Given the contradictory reports, we have undertaken the new analysis reported herein. Notably, studies published thus far rest upon substantially smaller datasets than drawn upon in the present work. We analyzed a cohort of 22,560 COVID-19 patients taking H1/H2 receptor antagonists, focusing on 1,379 severe cases requiring respiratory support. We analyzed outcomes for treatment with the H1RAs loratadine (e.g., Claritin) and cetirizine (e.g., Zyrtec), the H2RA famotidine, aspirin, and a famotidine & aspirin combination. For cases that reached the point of respiratory support, we found a significantly reduced fatality risk for famotidine treatment. We did not detect a benefit from dual-histamine receptor blockade (concurrently targeting H1 and H2 receptors). Notably, famotidine combined with aspirin did exhibit a significant synergistic survival benefit (odds ratio of 0.55). The relative risk for death decreased by 32.5%--an immense benefit, given the more than 2.6 million COVID-19-related deaths thus far. We found lower levels of serum markers for severe disease (e.g., C-reactive protein) in famotidine users, consistent with prior findings by others and with a role for famotidine in attenuating cytokine release. The large, international, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases, hopefully helps clarify the possible value of clinically-approved histamine antagonists such as famotidine. Given these findings, alongside the cost-effectiveness and mild side-effects of popular drugs like famotidine and aspirin, we suggest that further prospective clinical trials, perhaps utilizing the aspirin combination reported here, are advisable.
RESUMO
BackgroundGiven that an individuals age and gender are strongly predictive of COVID-19 outcomes, do such factors imply anything about preferable therapeutic options? MethodsAn analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in five-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds Ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and post-menopausal (>50 years). ResultsThe incidence of SARS-CoV-2 infection is higher in women than men (about +15%) and, in contrast, the fatality rate is higher in men (about +50%). Interestingly, the relationships between these quantities are also linked to age. Pre-adolescent girls had the same risk of infection and fatality rate as boys. Adult premenopausal women had a significantly higher risk of infection than men in the same five-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17{beta}-estradiol has a positive effect on expression of the human ACE2 protein--which plays an essential role for SARS-CoV-2 cellular entry--propensity score matching was performed for the womens sub-cohort, comparing users versus non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women >50 yrs receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95 % CI [0.18, 0.62] and the Hazard Ratio was 0.29, 95% CI[0.11,0.76]. For younger, pre-menopausal women (15-49 yrs), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels. ConclusionsAs of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.
RESUMO
Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases. SummaryL-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronans receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.
