Mast Cell Disease and COVID 19

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Spike proteins of coronaviruses activate mast cells for degranulation via stimulating Src/PI3K/AKT/Ca2+ intracellular signaling cascade

COVID-19 and Mast Cell Diseases
General Thoughts on MCAS and Covid by Dr. Afrin
Dr Afrin suggests here that the more severe and even deadly cases of COVID 19 may be partially (or fully) the result of a disproportionate response to the virus from undiagnosed abnormal mast cells that were already present in the patient's body before the COVID infection.  In particular, they may be over-reacting to the virus in an extreme way and driving the hyperinflammatory response that is largely responsible for patients being admitted to the ICU.  He also speculates that COVID "long haul" syndrome may also be largely (or entirely) driven by abnormal mast cell function which could have been present before they were infected with COVID, but in a milder way that was not recognized.  He notes that anecdotally, patients with MCAS whose disease was well-controlled before being infected with COVID 19 seem to have an overall relatively mild case, and none have died.  As far as vaccine safety is concerned he says that he is only aware of a few MCAS patients who have had serious adverse events, interestingly not all against the same vaccine.  He points out there is no scientific evidence to support vaccine safety in people with MCAS but that in his opinion it is relatively safe, especially when compared to the risk of catching the disease.  There is no actual scientific evidence on way or the other though.

Potential association of mast cells with coronavirus disease 2019
"The pulmonary pathological findings associated with COVID-19 seems to result from the release of multiple proinflammatory cytokines, especially interleukin (IL)-6, that can damage the lungs. A key source of such cytokines and chemokines is the mast cells, which are ubiquitous in the body, especially the lungs, and are critical for allergic and pulmonary diseases. In fact, activated mast cells were recently detected in the lungs of deceased patients with COVID-19 and were linked to pulmonary edema, inflammation, and thromboses."

Histamine receptors and COVID-19
"Clinical research into the potential benefits of H₂ receptor antagonists in managing COVID-19 inflammation began from a simple observation and now is being tested in multi-centre clinical trials. The positive effects of famotidine may be due to H₂ receptor-mediated immunomodulatory actions on mast cell histamine-cytokine cross-talk, rather than a direct action on SARS-CoV-2."

NOT THE VACCINE, BUT ANAPHYLAXIS TO THE COVID-19 VIRUS ITSELF
A patient developed systemic allergic symptoms including fatigue, rash, rhinitis, and lip swelling after exposure to the COVID 19 virus (most likely omicron variant).  She had a history of chronic idiopathic urticaria and dermatographism, so her mast cells may have already been disordered.  Her symptoms lasted for 4 days, during which time she required a continuous IV benadryl infusion as well as remdesivir, Solu-Medrol, loratadine, and famotidine.  Testing showed that she had an elevated level of IL10.  

Acute urticaria with angioedema in the setting of coronavirus disease 2019
"We report a new case of acute urticaria (AU) in the setting of COVID-19, including both wheals and angioedema and provide, for the first time, clinical images of skin manifestations of COVID-19."

Anaphylactic shock following the diagnosis of coronavirus disease 2019
"This case indicates how anaphylaxis may mimic symptoms caused by SARS-CoV-2. Cytokine release syndrome has been described in patients with COVID-19, which present with sudden-onset dyspnea, hypoxemia, and increased D-dimer levels; a variety of skin lesions have also been reported, including urticaria. However, these signs and symptoms may also be present in patients with anaphylaxis, including elevated D-dimer levels. Therefore, the differential diagnosis between these 2 conditions can be challenging. In this patient, the presence of typical anaphylaxis symptoms (itching of palms and soles) and its acute development after exposure to a likely allergen, and also an elevated serum tryptase were key in the diagnosis of anaphylaxis. Curiously, she had much higher D-dimer levels during anaphylaxis than when she suffered more severe signs from COVID-19. Although there has been no experience with COVID-19, other viral infections are known to act as cofactors, increasing the severity of anaphylaxis"

Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome
"The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19's hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors' treated MCAS patients with Covid-19 suffered severe infection, let alone mortality.

Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications."

Cytokine Storm Syndrome in SARS-CoV-2 Infections: A Functional Role of Mast Cells
"Cytokine storm syndrome is a cascade of escalated immune responses disposing the immune system to exhaustion, which might ultimately result in organ failure and fatal respiratory distress. Infection with severe acute respiratory syndrome-coronavirus-2 can result in uncontrolled production of cytokines and eventually the development of cytokine storm syndrome. Mast cells may react to viruses in collaboration with other cells and lung autopsy findings from patients that died from the coronavirus disease that emerged in 2019 (COVID-19) showed accumulation of mast cells in the lungs that was thought to be the cause of pulmonary edema, inflammation, and thrombosis. In this review, we present evidence that a cytokine response by mast cells may initiate inappropriate antiviral immune responses and cause the development of cytokine storm syndrome. We also explore the potential of mast cell activators as adjuvants for COVID-19 vaccines and discuss the medications that target the functions of mast cells and could be of value in the treatment of COVID-19. Recognition of the cytokine storm is crucial for proper treatment of patients and preventing the release of mast cell mediators, as impeding the impacts imposed by these mediators could reduce the severity of COVID-19." 

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

Impact of Famotidine Use on Clinical Outcomes of Hospitalized Patients With COVID-19
"Famotidine use in hospitalized patients with COVID-19 is associated with a lower risk of mortality, lower risk of combined outcome of mortality and intubation, and lower levels of serum markers for severe disease in hospitalized patients with COVID-19.(Equation is included in full-text article.)."

Famotidine Repurposing for Novel Corona Virus Disease of 2019: A Systematic Review
"Molecular computational studies showed that famotidine selectively acts on viral replication proteases papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro). Additionally, it acts via inverse-agonism on the H2 receptors present in neutrophils and eosinophils which leads to inhibition of cytokine release. Clinical study findings have pointed toward significant improvements in COVID-19 patient-reported symptoms in non-hospitalized patients and reduction in intubation or death in critically ill patients associated with the usage of famotidine.  Famotidine has the potential to answer the ongoing global challenge owing to its selective action on viral replication. Additionally, clinical findings in COVID-19 patients support its efficacy to reduce clinical symptoms of COVID-19."

The in-vitro effect of famotidine on sars-cov-2 proteases and virus replication
"A recent, large-scale, retrospective clinical study showed that famotidine, when administered at a high dose to hospitalized COVID-19 patients, reduced the rates of intubation and mortality. A separate, patient-reported study associated famotidine use with improvements in mild to moderate symptoms such as cough and shortness of breath."

Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection
"In a case series, nonhospitalized patients with COVID-19 experienced rapid symptom resolution after taking famotidine, but the molecular basis of these observations remains elusive. Here we show using biochemical, cellular, and functional assays that famotidine has no effect on viral replication or viral protease activity. However, famotidine can affect histamine-induced signaling processes in infected Caco2 cells. Specifically, famotidine treatment inhibits histamine-induced expression of Toll-like receptor 3 (TLR3) in SARS-CoV-2 infected cells and can reduce TLR3-dependent signaling processes that culminate in activation of IRF3 and the NF-κB pathway, subsequently controlling antiviral and inflammatory responses. SARS-CoV-2-infected cells treated with famotidine demonstrate reduced expression levels of the inflammatory mediators CCL-2 and IL6, drivers of the cytokine release syndrome that precipitates poor outcome for patients with COVID-19. Given that pharmacokinetic studies indicate that famotidine can reach concentrations in blood that suffice to antagonize histamine H2 receptors expressed in mast cells, neutrophils, and eosinophils, these observations explain how famotidine may contribute to the reduced histamine-induced inflammation and cytokine release, thereby improving the outcome for patients with COVID-19."

Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy
"Coronavirus infection (regardless of the various types of coronavirus) is primarily attacked by immune cells including mast cells (MCs), which are located in the submucosa of the respiratory tract and in the nasal cavity and represent a barrier of protection against microorganisms. Viral activate MCs release early inflammatory chemical compounds including histamine and protease; while late activation provoke the generation of pro-inflammatory IL-1 family members including IL-1, IL-6 and IL-33. Here, we propose for the first time that inflammation by coronavirus maybe inhibited by anti-inflammatory cytokines belonging to the IL-1 family members.

Coronavirus is classified as an RNA virus, with a genome that can often escape the innate immune system, especially if it is malfunctioning. Regardless of the various types of coronavirus,  the entry of the virus into the organism activates innate immunity, which intervene in the first instance to engulf the invader. The severity of the disease lies in the ability of innate immunity cells to stem viral infection. Stronger is the innate immune system, less is the ability of the virus to replicate itself, suppress the immunity and therefore to induce the pathological state. In the case of innate immune suppression by the virus, adaptive immunity is also inhibited, as the coronavirus is capable of producing viral enzymes and proteases that damage the immunity and inhibit the signaling pathways of type I interferon (IFN), along with the nuclear factor-κB, facilitating the innate immune evasion.  Experiments in the laboratory on rodents show that inoculating various different types of coronavirus, all induce an innate and adaptive immune response, but also an acute encephalomyelitis with invasion of the virus throughout the brain. Therefore, the virus mainly settles in the white matter causing chronic neuroinflammation and demyelination. 

Connecting the Dots in Emerging Mast Cell Research: Do Factors Affecting Mast Cell Activation Provide a Missing Link between Adverse COVID-19 Outcomes and the Social Determinants of Health?
"Here, we synthesize emerging literature on mast cell disease, and the role of mast cells in chronic illness, alongside emerging research on mechanisms of COVID illness and vaccines. We propose that a focus on aberrant and/or hyperactive mast cell behavior associated with chronic underlying health conditions can elucidate adverse COVID-related outcomes and contribute to the pandemic recovery. Standards of care for mast cell activation syndrome (MCAS), as well as clinical reviews, experimental research, and case reports, suggest that effective and cost-efficient remedies are available, including antihistamines, vitamin C, and quercetin, among others. Primary care physicians, specialists, and public health workers should consider new and emerging evidence from the biomedical literature in tackling COVID-19. Specialists and researchers note that MCAS is likely grossly under-diagnosed; therefore, public health agencies and policy makers should urgently attend to community-based experiences of adverse COVID outcomes." 

COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome?
"These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C). Now the US Center for Disease Control (CDC) announced the recognition of a similar condition in adults, named Multisystem Inflammatory Syndrome (MIS-A). The symptoms characterizing these conditions are very similar to those associated with Mast Cell Activation Syndrome (MCAS, US ICD-110 code D89.42-idiopathic mast cell activation syndrome). Hence, the possibility of MCAS should be evaluated in any patient with MIS and/or multisystem inflammatory symptoms. In either case, these syndromes should be addressed with liposomal formulation (in olive pomace oil) of the flavone luteolin (e.g. PureLut® or FibroProtek®) together with the antihistamine rupatadine, which also has anti-platelet activating factor (PAF) activity and inhibits mast cells that have been implicated in the pathogenesis of cytokine storms in COVID-19."

Mast cell disease in the age of COVID-19: Part 1