key: cord-0703688-kbnonq8y
authors: Hogan, Reed B.; Hogan, Reed B.; Cannon, Tim; Rappai, Maria; Studdard, John; Paul, Doug; Dooley, Thomas P.
title: Dual-Histamine Receptor Blockade with Cetirizine - Famotidine Reduces Pulmonary Symptoms in COVID-19 Patients
date: 2020-08-29
journal: Pulm Pharmacol Ther
DOI: 10.1016/j.pupt.2020.101942
sha: 68ba00c1931ef0a9bdf3b7cb0859ea306ce43a23
doc_id: 703688
cord_uid: kbnonq8y

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.

Histamine and mast cells play a fundamental role in modulating inflammation through increased capillary blood flow and vascular permeability, as well as cytokine release.

Histamine-1 (H1) receptor antagonists (e.g., cetirizine) are administered for allergies.

Histamine-2 (H2) receptor antagonists (e.g., famotidine) are used to control acid in the stomach and heart burn. Prescription branded, generic, and over-the-counter (OTC) drugs of both classes are safe and commercially available worldwide.

Humans have been treated using dual-histamine receptor blockade. Urticaria (hives) has been successfully treated with dual-histamine receptor blockade since the 1970's [1] [2] [3] , and remains a common practice in dermatology. And, a few reports have begun to demonstrate that diarrhea can be treated similarly [4, 5] . At present no H1-H2 receptor combination drug has been US FDA-approved.

COVID-19 (SARS-CoV-2) emerged in late 2019 in China, and nucleic acid sequence results indicate that it was very likely from a bat vector. The disease can manifest as a hyper-immune response with pulmonary cytokine release resembling that of other respiratory infections, such as Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza. Studies from China have defined the COVID-19 cytokine profile [6] and identified risk factors that increase mortality [7] . These retrospective studies suggest mortality may be linked to inflammatory processes caused by a "cytokine storm", which was very common in patients with severe to critical symptoms [8] . Pulmonary pathology in early-phase COVID-19 pneumonia has shown acute lung injury [9] . In the later stage of disease, patients can develop Acute Respiratory Distress Syndrome (ARDS) or ARDS-like conditions and multi-organ failure [10] .

According to the Centers for Disease Control (CDC), the disease severity from China is 14% severe and 5% critical, and the critical patients displayed a fatality rate of 49%.

(www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html).

Furthermore the CDC reports, "Among U.S. COVID- 19 Because of the sudden emergence of COVID-19, rapid research efforts are being conducted to repurpose existing approved drugs or biologic immunotherapies in this new indication, as these options are more likely to have near-term benefit during the pandemic. A major goal of many of these initiatives is to prevent or reduce the cytokine storm in pulmonary tissue [11] [12] [13] .

Animal model studies are informative at this juncture. Sars-CoV-infected mice have shown that T-cell responses are required for protection from disease and for virus clearance [14] . The immunomodulation by histamine depends mostly on its influence of T-cells [15] . Histamine stimulates inflammation, cytokine release, and can lead to tissue damage, including lung [16] . A porcine study evaluating H1N1 influenza demonstrated the accumulation of histamine in severe pneumonia [17] . Furthermore, the H1 receptor antagonist, ketotifen, decreased inflammatory cytokines and severe pneumonia [17] .

Dual-histamine receptor blockade has been effective in animal models of bacterial ARDS and allergy. A porcine animal model study has shown successful treatment of Pseudomonas-J o u r n a l P r e -p r o o f induced ARDS with diphenhydramine and cimetidine [18] . In this model for the treatment of hypoxemia, pulmonary hypertension, and pulmonary microvascular injury, the combination of diphenhydramine and cimetidine was essential, and was augmented somewhat by ibuprofen. In a guinea pig model, treatment with clemastine and cimetidine protected against allergen-induced bronchial obstruction [19] .

Therefore, based upon prior efficacious dual-histamine receptor blocker studies in humans and animal models in a variety of diseases, we believe it is reasonable to bridge into humans infected by COVID-19 using dual-histamine receptor blockade, in order to prevent or diminish the cytokine storm. Furthermore, the safety and efficacy of dual-histamine receptor blockade previously evidenced in human urticaria (and diarrhea) makes this an appealing approach.

Therefore, the major goals of the present proof-of-principle study include to decrease the progression of adverse outcomes in a cohort of severe and critical (high-acuity) hospitalized patients, most notably from ventilation independence to dependence, from life to death, and by reducing the duration of stay until discharge.

This physician-sponsored and -initiated cohort study was led by a team of board certified pulmonologists from a single practice group in Jackson, MS. All patients were treated in a single hospital operated by Baptist Health Systems, with IRB approval (IRB # 20-49 exemption) for retrospective access to patient data. The first dual drug-treated patient date was 3 April 2020 and the study period for this cohort concluded on 13 June 2020. The study was motivated by the The study endpoints were compared to SOC patient outcomes from Atlanta, GA [20] , Louisiana [21] , New York City, NY [22] , United Kingdom [23] , and Wuhan, China [24, 25] .

This comparison to external sources is informative, as the number of available SOC-only patients was limited in this medical center during the rapidly-evolving SOC in the COVID-19 pandemic.

This new dual drug treatment paradigm was rapidly adopted as SOC in this hospital. Table II) . The investigators anticipated DNR patients would be a confounding factor, and there were 13 DNR patients. The endpoints were: (a) discharge rate; (b) intubation rate; (c) intubation rate after a minimum of 48 hours of dual drug treatment; (d) inpatient mortality rate;

and (e) average number of days to discharge. The rate of discharge during the study period (10 weeks plus 1 day) was 84.5% (and 91.8% excluding DNR). The intubation rate was 16.4% (and 16.5% excluding DNR). The intubation rate after a minimum of 48 hours of drug treatment was J o u r n a l P r e -p r o o f 7.3% (and 6.2% excluding DNR). The inpatient mortality rate was 15.5% (and 8.2% excluding DNR). The average number of days to discharge was 11.0 (and 10.9 days excluding DNR). (Table III) . For instance, the vast majority (84.5%) of the patients were administered hydroxychloroquine (HCQ). Based upon recent publications [26] [27] [28] [29] , one may assert that HCQ very likely provided no therapeutic benefit, and HCQ might have had an adverse effect on the outcomes in this cohort of 110 patients, as it correlated with worse outcomes (i.e., higher rates of intubation and death).

In some of the patients, and especially those who progressed to ventilation dependence, a biologic (tocilizumab in 50.9% of patients), a glucocorticoid (methylprednisolone in 30.9% of patients), and/or convalescent plasma (in 30.0% of patients) were used at the discretion of the pulmonologist-led critical care team as concomitant treatments (Table III) 

Here we describe an initial study of dual-histamine receptor blockade to retard the histaminecytokine network and with the intention of blunting the cytokine storm. The safety profile of dual-histamine receptor blockade makes this an appealing consideration for COVID-19-positive patients. If dual-histamine receptor blockade is able to blunt the cytokine system, the risk of progressing to severe and/or critical disease should lessen.

The results of this initial physician-sponsored study provide a proof-of-principle that it can reduce disease severity and the need for ventilators, and save lives. The results of patients who received at least 48 hours of the combination drug treatment demonstrated reduced rates of intubation (16.4%), of intubation after 48 hours of dual drug treatment (7.3%), of inpatient mortality (15.5%), and of duration of hospitalization (11.0 days). If DNR patients were excluded, then the inpatient mortality rate was only 8.2%. These clinical outcomes represent reductions in the anticipated symptom severity expressed as ventilator dependence and lethality relative to SOC reported in Atlanta, Georgia [20] , Louisiana [21] , New York City, New York [22] , the United Kingdom [23] , and Wuhan, China [24, 25] [21] , 21% in New York City, NY [22] , 25.7% in the large RECOVERY trial in the United Kingdom [23] , and 21.9 and 28.3% in Whuan, China [24, 25] .

In other words, we experienced a reduction in inpatient fatalities of approximately one fourth to one third relative to these reference locations ranging from 21% to 28.3% in inpatient fatality rates, some of which were obtained from very large clinical trials.

The reports of inpatient mortality rate can be dependent on multiple variables, such as inclusion/exclusion criteria (e.g., DNR patients), diagnosis (e.g., presumptive COVID-19 vs. in the USA at the time of our study. The risk-benefit reward analysis of HCQ rapidly evolved to a highly unfavorable impression, based upon controlled clinical trials. The efficacy of HCQ in COVID-19 is now seriously doubted, and at least one cardio-toxic side effect has been noted [26] . This study consisted of 75 patients per arm, comparing SOC vs SOC + HCQ. The authors concluded that HCQ was not beneficial and resulted in more adverse events.

In another study HCQ was also ineffective in inpatients who required oxygen; 84 patients were treated with HCQ within 48 hours of admission vs 97 patients receiving SOC without HCQ [28] . There were no benefits to HCQ when assessing: Two prospective well controlled clinical trials are high level evidence of a lack of efficacy of HCQ in early disease prevention or treatment in COVID-19 outpatients. A randomized, double-blind, placebo-controlled treatment trial with 423 outpatients concluded, "Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19." Side effects were greater with HCQ than placebo [29] . Another randomized, J o u r n a l P r e -p r o o f double-blind, placebo-controlled prevention trial with 719 individuals with high-risk exposure to a confirmed COVID-19 contact did not prevent illness when used as post-exposure prophylaxis within 4 days after exposure [27] . Side effects were greater with HCQ than placebo [27] .

However, in spite of these solid clinical trial results, at this juncture many anecdotes about HCQ are being widely reported in the media, while lacking published scientific validation. Whether nuanced dosing, scheduling, and/or coincident medical treatments with HCQ might be efficacious in COVID-19 outpatients is an open question at this juncture.

Regardless, in aggregate these studies indicate that HCQ was not effective in preventing or treating disease progression in COVID-19 patients. Therefore, it should be noted that HCQ was administered to most of the patients in our study, and it is reasonable to speculate that it impaired patients in our cohort, in view of the demonstrated correlation with worse outcomes. 4.7 Remdesivir: Second, remdesivir was developed prior to the COVID-19 pandemic as a retroviral replication inhibitor. A well-designed placebo-controlled trial suggested a reduction in the time to clinical improvement [30] . However, the study was not sufficiently powered statistically [31] . Thus, there was no improvement with regard to patient deaths or viral load. This trial did not provide convincing evidence of a substantial therapeutic benefit of remdesivir.

Regardless, the US FDA granted EUA for this prescription medication, which is expected to be expensive in the USA. 4.8 Famotidine: Third, famotidine has been evaluated in a retrospective association study of COVID-19 patients in New York City [32] . A cohort of 84 hospitalized patients out of 1,620 total received famotidine within 24 hours of hospitalization, and a subset of the patients (15%) were already treated with famotidine at home prior to admission. Patients intubated within 48 hours of admission were excluded. The doses ranged from 10-40 mg. Famotidine use was associated with a reduced risk of death and intubation. By comparison proton pump inhibitors (that reduce gastric acid independent of a histamine mechanism) were not associated with reduced risk of death or intubation. The results suggest a histamine-mediated effect in the COVID-19 patients. This report lacks information on concomitant medications or treatments (either SOC or experimental), with the exception of proton pump inhibitors [32] .

Comparing our cetirizine + famotidine results with high comorbidity patients to the famotidine-only study [32] , note the following comorbidity and other factors might account for the magnitude of treatment effect in our 110 cetirizine + famotidine patients vs. 84 famotidine patients in New York City: obesity 58.2% vs. 26%; hypertension 78.2% vs. 35%; diabetes 42.7% vs. 29%. In addition, the representation of Black patients was 59.1% vs. 21%. These comorbidity and racial factors are known to be causal in adverse COVID-19 inpatient outcomes.

In addition, the overall intubation rate in all patients in New York City was only 8.8% and excluded patients intubated within 48 hours of admission. Once again this indicates a lower relative acuity level in the famotidine-only cohort of 84 patients. Our cohort's intubation rate was 16.4% overall, whereas after a minimum of 48 hours of cetirizine + famotidine treatment it was only 7.3%. In addition, the inpatient mortality rate in all 1620 patients was 15% in the New York City study, which was essentially a lower baseline than expected for our Mississippi cohort.

These acuity, comorbidity, and outcome differences underscore a very likely comorbid burden in our patient cohort in Mississippi, relative to the famotidine-only study in New York City. Furthermore, concomitant medications (or other treatments) were not reported in the New J o u r n a l P r e -p r o o f York City study, whereas concomitant medicines were reported herein in Table III Taken together three studies with moderately sized treatment cohorts (range of 83 to 110 patients) that were administered cetirizine plus famotidine (this work) or famotidine-alone [32] (and Mather et al, in press) have shown efficacy in COVID-19 inpatients. Controlled prospective trials that are randomized with equivalent levels of acuity, comorbidity, concomitant medications, and other determinants (e.g., race) would be welcome to assess the relative contributions of famotidine and/or cetirizine in the presumptive blocking of the cytokine storm in COVID-19.

Although less informative than the two moderately sized cohort studies in New York City and Hartford, a case series of only 10 outpatients administered very high dose famotidine (most of them received 80 mg t.i.d. = 240 mg daily) perhaps suggested the possibility of a benefit [33] .

For comparison to the three famotidine-only studies, our inpatient study used 20 mg twice daily (40 mg daily) of famotidine, which is within the FDA-approved OTC dosage level.

However, the cetirizine amount was 10 mg twice daily in this inpatient context, which is double the daily FDA-approved dosage as an OTC medication. 

In aggregate these controlled trials and cohort studies reveal at this juncture that COVID-19 inpatients in general are likely to benefit from: (a) cetirizine -famotidine combination or famotidine alone; (b) remdesivir; and/or (c) dexamethasone; but, not from hydroxychloroquine.

What is the current context and unmet medical need for repurposing old active ingredients, especially OTC medications, during the COVID-19 Pandemic? Given (a) the recent emergence of COVID-19, (b) the rapid need for safe and effective treatments deployable immediately, and (c) the rapid evolution in the SOC treatments for inpatients, recent innovations might not permit sufficient time for the statistically robust clinical trials that are customary for an FDA regulatory approval process. In this time-is-of-the-essence pandemic context, the results of this dualhistamine receptor blockade treatment compares favorably to current SOC protocols. We have demonstrated reductions in ventilator dependence and inpatient fatality rates relative to other published studies using two safe OTC medications. This dual drug approach is consistent with the historic axiom in medicine -"first do no harm", by utilizing historically well tolerated OTC medications.

Although this study provides initial evidence in support of a safe and effective treatment, many questions remain to be addressed. Randomized and controlled trials are warranted with outpatients "early" and inpatients "late". We have initiated a separate randomized placebocontrolled outpatient trial of cetirizine -famotidine to begin to address this question in PCRconfirmed asymptomatic or mild-to-moderate severity outpatients, thus early in disease progression. Furthermore, is the beneficial effect dependent on this particular combination of J o u r n a l P r e -p r o o f active pharmaceutical ingredients, or would alternative H1 and/or H2 receptor antagonists also be effective? Given the historic safety profiles for the two selected ingredients within approved OTC monotherapies, it follows that one is likely to prefer these two over other active ingredients that have not been granted OTC status. And, would some patients benefit (more) from alternative doses or dosage schedules?

Given that famotidine alone has been reported to be beneficial in COVID-19 inpatients, it would be desirable to conduct a factorial-design randomized trial with cohorts having equivalent (a) acuities, (b) comorbidities, (c) concomitant medications, and (d) appropriate dosing to address the relative contributions of cetirizine and famotidine. It would also be beneficial to exclude hydroxychloroquine as a confounding factor in prospective clinical trials, as it appears to have been ineffective and/or detrimental in other retrospective inpatient trials, as well as in our cohort of high acuity patients.

The present clinical investigation provides a new method of treatment for this unmet medical need. The favorable circumstances of having commercially-available branded, generic, and OTC drugs targeting both H1 and H2 receptor types provide another distinct advantage relative to other experimental drug and biologic research programs in COVID-19, some of which may take numerous years to develop and commercialize. This approach with OTC cetirizine (e.g., Zyrtec ® ) and OTC famotidine (e.g., Pepcid ® ) could be rapidly deployed worldwide and should be affordable, even for economically under-served populations, not just for the economically advantaged.

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The authors gratefully acknowledge the assistance of the clinical staff and