Hospitalized COVID-19 Patients Treated With Celecoxib and High Dose Famotidine Adjuvant Therapy Show Significant Clinical Responses
42 Pages Posted: 24 Jul 2020 Last revised: 1 Oct 2020
Date Written: July 8, 2020
BACKGROUND: Up to 80% of SARS-CoV-2 positive patients are asymptomatic and do not appear to progress to COVID-19. SARS-CoV-2 infection is not sufficient for development of COVID-19 disease; this may reflect differences in host inflammatory responses to infection. COX-2 expression is transcriptionally upregulated by SARS nucleocapsid N protein, and COVID-19 is associated with markedly elevated levels of prostaglandin E2 (PGE2). PGE2 modulates a wide variety of innate and adaptive inflammatory responses including mast cell activation. SARS-CoV-2 infection-associated mast cell degranulation may play a role in development of COVID-19. A randomized trial of hospitalized COVID-19 cases has demonstrated that COX-2 protein antagonist celecoxib dampened systemic PGE2 levels, prevented clinical deterioration, and was associated with rapid pulmonary CT-chest improvement. High doses of famotidine, a histamine H2 receptor antagonist/inverse agonist reduces severity of COVID-19 symptoms. We hypothesize that adjuvant therapy with a combination of celecoxib and high dose (HD) famotidine may improve COVID-19 outcomes.
METHODS: We report a single institution, consecutive case series of 25 COVID-19 hospitalized patients treated with celecoxib and HD famotidine as adjuvant therapy. Outcome measurements include time to discharge, changes in supplemental oxygen requirements, pulmonary CT-chest findings, and laboratory changes in peripheral blood lactate dehydrogenase (LDH), C-reactive protein (CRP), ferritin, neutrophil counts, lymphocyte levels, neutrophil/lymphocyte ratio, creatinine, glomerular filtration rate, Interleukin 6 (IL6) and D-dimer concentrations. Nucleocapsid N protein sequence analysis was performed to compare COX-2 promoter activation domains of SARS, SARS-CoV-2, and related Sarbecovirus betacoronaviruses.
RESULTS: All 25 patients in the series survived hospitalized COVID-19 without mechanical ventilation or renal replacement therapy (RRT) and were discharged on room air within a median of 3 days (range 1-16 days). Statistically significant improvements from admission to discharge were observed for all aggregated outcome measures. In general, progressive improvement was noted in supplemental oxygen requirements and ground-glass CT findings. Amino acid sequence analysis demonstrated high levels of conservation of N2 protein COX-2 promoter transactivation domains and nuclear localization sequences between SARS, SARS-CoV-2, and closely related Pangolin, Civet cat, and Horseshoe bat coronaviruses, but not MERS or other human or animal Betacoronaviruses.
DISCUSSION: In this series, combined treatment with oral celecoxib and HD famotidine in an adjuvant setting was associated with 100% survival and improved radiographic outcomes, as well as statistically significant improvements in clinical, biomarker, and renal function measurements. The 9 patients with extremely high LDH (>365, Wuhan model prediction of 98% mortality) survived and were discharged on room air. Conservation of SARS and SARS-CoV-2 nucleocapsid N protein N2 sequences support that celecoxib treatment may mitigate the effects of direct viral transactivation of COX-2 expression in infected cells. HD famotidine acts to reduce cellular effects of local histamine via H2 receptor antagonism. Acute kidney injury was either prevented or mitigated by treatment; HD famotidine contributes to this effect. In contrast to these findings, previously published COVID-19 clinical intervention studies have not shown consistent laboratory or radiographic improvement. The data support performing randomized placebo-controlled trials to further examine the hypothesis that celecoxib with HD famotidine as adjuvant therapy to standard of care may reverse and prevent clinical deterioration in adult hospitalized COVID-19 patients.
Note: Funding: Support was provided by the Department of Defense (DoD),
Defense Threat Reduction Agency (DTRA), and the Joint Science and
Technology Office (JSTO) of the Chemical and Biological Defense
Program (CBDP) under the Discovery of Medical countermeasures Against
Novel Entities (DOMANE) initiative. This support has been provided
under Air Force Contract No. FA8702-15-D-0001. Any opinions, findings,
conclusions or recommendations expressed in this material are those of
the author(s) and do not necessarily reflect the views of the U.S. Air
Conflict of interest: none
Ethical statement: This study was approved by the institutional review board of Beloit Memorial Hospital.
Keywords: coronavirus 2019; SARS-CoV-2; famotidine; histamine-2 receptor antagonists, celecoxib, Cox-2 receptor antagonist, COVID-19, immunomodulators
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