Hospitalized COVID-19 Patients Treated With Celecoxib and High Dose Famotidine Adjuvant Therapy Show Significant Clinical Responses

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.