ABSTRACT
We seek to rapidly identify, test and develop combinations of repurposed drugs to enable cost-effective treatments that reduce the risk of disease or death from SARS-CoV-2 infection. We hypothesize that the morbidity and mortality of COVID-19 reflects overactive host inflammatory responses to infection and is not principally due to the primary direct cellular, organ and tissue damage attributable to viral infection. Stepwise clinical development has identified the combination of High Dose (HD) famotidine and celecoxib (famcox) as a promising adjuvant anti-inflammatory protocol. We now report results from a retrospective observational comparative cohort study designed to provide an estimate of the potential benefits, risks, prognosis and diagnostic laboratory findings associated with administration of dexamethasone in addition to famcox for treatment of newly hospitalized COVID-19 disease in a community hospital setting. Study enrollment was restricted to patients at WHO 4–5. In the group receiving adjuvant treatment with famcox without dexamethasone (active control) there were no deaths during hospitalization (0/18 = 0% mortality). A total of six deaths occurred in the group receiving famcox + dexamethasone (6/21 = 29% mortality). There was a significant difference in mortality between the two groups, Χ2 (1, N = 43) = 7.305, p < 0.007. Median time to event for reaching WHO score of < 4 was 3.5 days in the control group (famcox (–) dex) versus 10 days for the experimental group (famcox (+) dex) P < 0.001. We conclude that use of the potent non-specific anti-inflammatory corticosteroid dexamethasone in addition to the specific anti-inflammatory famcox protocol should only be considered in late stage COVID-19 disease in patients less than 70 years of age. The effects of added dexamethasone on laboratory biomarkers, and particularly on neutrophil count, lymphocyte count, and neutrophil to lymphocyte ratio raise concerns about the long-term effects of dexamethasone treatment with or without famcox during acute COVID-19 on the incidence and severity of chronic COVID (“long COVID” or PASC).
Subject(s)
COVID-19ABSTRACT
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.
Subject(s)
COVID-19ABSTRACT
Background: In 80% of patients, COVID-19 presents as mild disease1,2. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome, but include a T-predominant lymphopenia3, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation including immunosuppression4. Methods: All major SARS-CoV-2 proteins were characterized using an amino acid residue variation analysis method. Results predict that most SARS-CoV-2 proteins are evolutionary constrained, with the exception of the spike (S) protein extended outer surface. Results were interpreted based on known SARS-like coronavirus virology and pathophysiology, with a focus on medical countermeasure development implications. Findings: Non-neutralizing antibodies to variable S domains may enable an alternative infection pathway via Fc receptor-mediated uptake. This may be a gating event for the immune response dysregulation observed in more severe COVID-19 disease. Prior studies involving vaccine candidates for FCoV5,6 SARS-CoV-17-10 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) 11 demonstrate vaccination-induced antibody-dependent enhancement of disease (ADE), including infection of phagocytic antigen presenting cells (APC). T effector cells are believed to play an important role in controlling coronavirus infection; pan-T depletion is present in severe COVID-19 disease3 and may be accelerated by APC infection. Sequence and structural conservation of S motifs suggests that SARS and MERS vaccine ADE risks may foreshadow SARS-CoV-2 S-based vaccine risks. Autophagy inhibitors may reduce APC infection and T-cell depletion12 13. Amino acid residue variation analysis identifies multiple constrained domains suitable as T cell vaccine targets. Evolutionary constraints on proven antiviral drug targets present in SARS-CoV-1 and SARS-CoV-2 may reduce risk of developing antiviral drug escape mutants. Interpretation: Safety testing of COVID-19 S protein-based B cell vaccines in animal models is strongly encouraged prior to clinical trials to reduce risk of ADE upon virus exposure.