Dual-Histamine Receptor Blockade with Cetirizine - Famotidine Reduces Pulmonary Symptoms in COVID-19 Patients

  1. Reed B. Hogan
  2. Reed B. Hogan
  3. Tim Cannon
  4. Maria Rappai
  5. John Studdard
  6. Doug Paul
  7. Thomas P. Dooley

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Abstract

Background

The COVID-19 pandemic due to SARS-CoV-2 infection can produce Acute Respiratory Distress Syndrome as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria, and might reduce the histamine-mediated pulmonary cytokine storm in COVID-19. Can a combination of Histamine-1 and Histamine-2 receptor blockers improve COVID-19 inpatient outcomes?

Methods

A physician-sponsored cohort study of cetirizine and famotidine was performed in hospitalized patients with severe to critical pulmonary symptoms. Pulmonologists led the inpatient care in a single medical center of 110 high-acuity patients that were treated with cetirizine 10 mg b.i.d . and famotidine 20 mg b.i.d . plus standard-of-care.

Results

Of all patients, including those with Do Not Resuscitate directives, receiving the dual-histamine receptor blockade for at least 48 hours, the combination drug treatment resulted in a 16.4% rate of intubation, a 7.3% rate of intubation after a minimum of 48 hours of treatment, a 15.5% rate of inpatient mortality, and 11.0 days duration of hospitalization. The drug combination exhibited beneficial reductions in inpatient mortality and symptom progression when compared to published reports of COVID-19 inpatients. Concomitant medications were assessed and hydroxychloroquine was correlated with worse outcomes.

Conclusions

This physician-sponsored cohort study of cetirizine and famotidine provides proof-of-concept of a safe and effective method to reduce the progression in symptom severity, presumably by minimizing the histamine-mediated cytokine storm. Further clinical studies in COVID-19 are warranted of the repurposed off-label combination of two historically-safe histamine receptor blockers.

Article activity feed

  1. Version published to 10.1101/2020.06.30.20137752v2 on medRxiv
  2. Version published to 10.1016/j.pupt.2020.101942
  3. ScreenIT

    SciScore for 10.1101/2020.06.30.20137752: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableIn lieu of a placebo control group, for comparison the control(s) consisted of published SOC patient results that were not administered the dual-histamine receptor blockade from the USA, United Kingdom, and China. 2.1 Inclusion and Exclusion Criteria: The inclusion criteria were: (a) Males or females of minimum age of 17; (b) Admission to the hospital with suspected or confirmed pulmonary symptoms of COVID-19.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    4.4 Limitations: There are multiple limitations to any physician-sponsored cohort (or case series) study. Within this initial study the limitations were most notably: (a) This proof-of-principle study was not a placebo-controlled, randomized, and blinded study that is customary for a regulatory registration trial; and (b) The study lacked a sufficiently high number of untreated SOC patients for use as a retrospective control cohort. However, the investigators have provided comparisons to the published SOC cohorts from other regions in the USA, UK, and China. However, offsetting these limitations it should be noted that this work was performed in April through June 2020 during an intense season within the COVID-19 pandemic crisis, at a time-is-of-the-essence season when pulmonologists, emergency room physicians, critical care specialists, and hospitalists were eager to attempt rational repurposing of previously FDA-approved medications. Thus, the physicians desired near-term improved outcomes, compassionate care, and to identify new proof-of-concept off-label therapies for COVID-19 ARDS or ARDS-like patients. Cetirizine and famotidine were intentionally incorporated into treatment of this severe and critical patient cohort in view of exceptional historic safety of each medication, as evidenced by their approved OTC status, and in view of prior efficacy of dual-histamine receptor blockade in diseases in humans and animal models. This resulted in the vast majority of all COVID-1...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  4. Version published to 10.1101/2020.06.30.20137752v1 on medRxiv