key: cord-0049518-nrwzco6c
authors: Eldanasory, Omar Abdelhay; Eljaaly, Khalid; Memish, Ziad A.; Al-Tawfiq, Jaffar A.
title: Histamine release theory and roles of antihistamine in the treatment of cytokines storm of COVID-19
date: 2020-09-03
journal: Travel Med Infect Dis
DOI: 10.1016/j.tmaid.2020.101874
sha: 82704b2684e7413be083debc24c3cbe25ddffd7e
doc_id: 49518
cord_uid: nrwzco6c

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In a recent study, authors described therapeutic options for Coronavirus Disease-19 (COVID-19) [1] . Histamine is an endogenous biogenic amine distributed ubiquitously in the body and is present in high concentrations in the lungs, skin, and gastrointestinal tract. It acts as a local mediator in the immune system. Histamine brings about complex physiologic changes, including chemotaxis, cytokine production, and gastric acid secretion. These biologic changes occur via four G protein-coupled receptor (GPCR) subtypes: H 1 receptor (H1R), H 2 receptor, H 3 receptor, and H 4 receptor ( Table 1 ). H1R is expressed in various cell types, such as neurons, endothelial cells, adrenal medulla, muscle cells, hepatocytes, chondrocytes, monocytes, neutrophils, eosinophils, dendritic cells (DCs), T cells, and B cells. H1R activation leads to activation of Th1 lymphocytes, and decreased humoral immunity. H2R is expressed by parietal cells of the gastric mucosa, muscle, epithelial, endothelial, neuronal, hepatocyte, and immune cells. H2R antagonizes some of the effects mediated by H1R and leads to the relaxation of smooth muscle cells, causing vasodilation. In a murine lung inflammation model, H2R loss has an effect on invariant natural killer T (iNKT) cells, aggravating local inflammation [2] .

H3R functions were identified in the central nervous system and peripheral and presynaptic receptors to control the release of histamine and other neurotransmitters. H4R is preferentially expressed in the intestine, spleen, thymus, bone marrow, peripheral haematopoietic cells, and cells of the innate and adaptive immune systems. Expression of H4R is regulated by stimulation with TNF-α, IL-6, IL-10, and IL-13, leading to inhibition of cAMP accumulation and activation of mitogen-activated protein kinases (MAPK) by H4R. To date a few studies looking into the use of antihistamine products in patients with COVID-19.

In self-administered high dose oral famotidine therapy, all 10 patients had marked improvements of COVID-19 symptoms [3] . Interestingly, analysis of pharmacokinetic parameters of famotidine might indicate that it needs to be given intravenously to be effective in COVID-19 treatment given its low gastrointestinal absorption and volume of distribution [4] . In propensity-score matched retrospective cohort study comparing famotidine cohort (84 patients) to non-famotidine cohort (1536 patients), a crude analysis showed that famotidine use was significantly associated with reduced risk for death and was independently associated with risk for death or intubation (adjusted hazard ratio (aHR) 0.42, 95% CI 0.21-0.85) [5] . The famotidine group received between 10-40 mg/day for a median of 5.8 days, and 72% received it orally [5] . One limitation to recognize is the risk of unmeasured confounders, particularly that sicker patients might be more likely to receive proton-pump inhibitors than H2R blockers. Although famotidine is an H2R antagonist and used mainly for peptic ulcer and gastroesophageal reflux, its potential benefit was attributed to binding and inhibiting the 3-chymotrypsin-like protease [4] . There is currently one J o u r n a l P r e -p r o o f ongoing double-blind randomized controlled trial in New York evaluating the efficacy of high dose intravenous famotidine (360 mg/day) with standard of care for a maximum of 14 days in hospitalized COVID-19 patients [6] . The H2R antagonists class also includes ranitidine cimetidine, and nizatidine. In allergic reactions, the preferred antihistamines target H1R [4] .

Currently, we could not find studies evaluating the efficacy of H1R blockers in COVID-19.

Histamine is a main mediator that is being released 

A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.

All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated.

Signature (a scanned signature is acceptable, Print name but each author must sign) ______________ ____________ Khalid Eljaaly __ Manuscript number (if applicable): TMAID_ Article Title: Histamine release theory and roles of antihistamine in the treatment of cytokines storm of COVID-19

Author name: Khalid Eljaaly

Comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with COVID-19: A systematic review and meta-analysis

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Acute At Home Management of Anaphylaxis During the Covid-19 Pandemic

Class a G protein-coupled receptor antagonist famotidine as a therapeutic alternative against SARS-CoV2: An in silico analysis

Famotidine Use is Associated with Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study

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