Elevated Histamine Etiology Model for Most Major Vaccine Associated Adverse Events including SARS-CoV-2 Spike Vaccines.

Vaccinees experience no adverse events, mild adverse events, multiple adverse events, or serious adverse events post vaccination. Many of these vaccine adverse events occur with different vaccines with different occurrence frequencies. Many of these adverse events are generally considered as associated with immune responses to the active vaccine components (antigens) and/or to possibly one or more of the vaccine excipients. Most of these vaccine adverse events are self-limiting and resolve within days. Many of these adverse events symptoms overlap symptoms associated with elevated histamine levels. Based on these observations, the hypothesis that the majority of vaccine associated reactogenicity adverse events are caused by temporal histamine intolerance in vaccinees is proposed. This hypothesis is based on a model of innate immune responses releasing a surge of inflammatory molecules including histamine; this surge is hypothesized to exceed the normal histamine tolerance level for vaccinees with reactogenicity adverse events. Further, these symptoms resolve as histamine levels fall below the vaccinee's tolerance threshold. This model can be evaluated by the detection of elevated histamine levels in vaccinees corresponding to timing of symptoms onset. If confirmed, a direct consequence of this model predicts that some antihistamine treatments, mast cell stabilizers, and possibly diamine oxidase enzyme may reduce the incidence or severity of adverse events experienced by vaccinees post vaccinations for most or all high reactogenicity vaccines including coronavirus disease 2019 (COVID-19) Spike vaccines.

Models for SARS-CoV-2 associated thrombocytopenia associated with hemophagocytic histiocytes.

A subset of COVID-19 patients is experiencing secondary immune thrombocytopenia, also called immune thrombocytopenic purpura (ITP) or secondary hemophagocytic lymphohistiocytosis (HLH). The pathogenesis of SARS-CoV-2 associated thrombocytopenia is unknown. Very rare cases of vaccine induced prothrombotic immune thrombocytopenia (VIPIT) are occurring associated with COVID-19 vaccines. COVID-19 VIPIT is associated with autoantibodies targeting platelet factor 4 (PF4) for COVID-19 adenovirus vaccines. Herein, four models for hemophagocytic histocytes contributions to the etiology of thrombocytopenia associated with SARS-CoV-2 are proposed. One of the models proposes potential involvement of hemophagocytic histocytes targeting platelets bound by autoantibodies consistent with observed PF4 autoantibodies in COVID-19 VIPIT.

Models for COVID-19 Early Cardiac Pathology Following SARS-CoV-2 Infection.

OBJECTIVES: The clinical manifestations of COVID-19 associated cardiac complications are heterogeneous, ranging from asymptomatic to severe symptoms, including arrhythmias and cardiogenic shock. For COVID-19 patients with cardiac sequela, only a small subset of patients have myocarditis; the pathogenesis of cardiac sequela caused by SARS-CoV-2 other than microthrombi associated sequela remains to be determined. METHODS: Retrospective analysis of 71 heart autopsy specimens from COVID-19 and putative COVID-19 in the NIH COVID Digital Pathology Repository. RESULTS: The most consistent observation was localized myocardial cell death not associated with either myocarditis or microthrombi. Red blood cells were typically absent from capillaries but, when observed, were predominately in linear clusters (stacks) of adjacent cells. CONCLUSIONS: Based on our retrospective analysis, we propose that localized ischemia and subsequent cell death by anoxia contributes to the cardiac pathogenesis in some COVID-19 patients. We propose two new models predicting vasoconstriction of cardiac pericyte cells induced by elevated histamine from hyper-activated mast cells or direct infection. We propose that impeded blood flow and cell death by anoxia are initial steps in the development of SARS-CoV-2 induced cardiac injury in COVID-19 patients independent of microthrombi or myocarditis.

COVID-19 Disease, Women's Predominant Non-Heparin Vaccine-Induced Thrombotic Thrombocytopenia and Kounis Syndrome: A Passepartout Cytokine Storm Interplay.

Coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitute one of the deadliest pandemics in modern history demonstrating cardiovascular, gastrointestinal, hematologic, mucocutaneous, respiratory, neurological, renal and testicular manifestations and further complications. COVID-19-induced excessive immune response accompanied with uncontrolled release of cytokines culminating in cytokine storm seem to be the common pathogenetic mechanism of these complications. The aim of this narrative review is to elucidate the relation between anaphylaxis associated with profound hypotension or hypoxemia with pro-inflammatory cytokine release. COVID-19 relation with Kounis syndrome and post-COVID-19 vaccination correlation with heparin-induced thrombocytopenia with thrombosis (HITT), especially serious cerebral venous sinus thrombosis, were also reviewed. METHODS: A current literature search in PubMed, Embase and Google databases was performed to reveal the pathophysiology, prevalence, clinical manifestation, correlation and treatment of COVID-19, anaphylaxis with profuse hypotension, Kounis acute coronary syndrome and thrombotic events post vaccination. RESULTS: The same key immunological pathophysiology mechanisms and cells seem to underlie COVID-19 cardiovascular complications and the anaphylaxis-associated Kounis syndrome. The myocardial injury in patients with COVID-19 has been attributed to coronary spasm, plaque rupture and microthrombi formation, hypoxic injury or cytokine storm disposing the same pathophysiology with the three clinical variants of Kounis syndrome. COVID-19-interrelated vaccine excipients as polysorbate, polyethelene glycol (PEG) and trometamol constitute potential allergenic substances. CONCLUSION: Better acknowledgement of the pathophysiological mechanisms, clinical similarities, multiorgan complications of COVID-19 or other viral infections as dengue and human immunodeficiency viruses along with the action of inflammatory cells inducing the Kounis syndrome could identify better immunological approaches for prevention, treatment of the COVID-19 pandemic as well as post-COVID-19 vaccine adverse reactions.

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved 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 have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.

Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies.

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

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 H 2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.