“This is the revenge of the viruses,” said Dr. Peter Piot, the director of the London School of Hygiene and Tropical Medicine. “I’ve made their lives difficult. Now they’re trying to get me.”

A key mystery about the COVID-19 pandemic is why the disease presents as mild or asymptomatic in the majority of the population, while presenting as severe or even life-threatening in approximately 15% of the population.  An additional mystery is why COVID-19 generally presents more severely in adults than in children.  A common underlying disease, Mast Cell Activation Syndrome (MCAS), may provide vital clues to solving these mysteries.  MCAS is thought to be present in approximately 17% of the population, but most individuals who have MCAS remain undiagnosed.  Our hypothesis is that many – perhaps even most – severe cases of COVID-19 can be attributed to pre-existing Mast Cell Activation Disease in those patients. Severe cases of COVID-19 are characterized by multi-system inflammation, caused by the body’s overreaction to the virus.  Many times, it is this overreaction, not the virus itself, which becomes life-threatening.  Mast cells which catastrophically over-activate in response to the virus could very well explain this phenomenon. Mast cells are tissue-resident immune system cells which act as the “sentries” of the immune system.  They maintain numerous receptors on their surface, including histamine receptors as well as receptors to detect invading pathogens (PAMPS).  When an invading pathogen (such as a virus) is detected, the mast cells release a variety of chemical mediators in a process called degranulation.  These mediators both facilitate and coordinate the immune response, as well as provide signals to potentially every system in the body.  In a normal individual, this degranulation process is well regulated and proportional to the detected threat.  In an individual with MCAS, defective mast cells activate out of proportion with the need to defend the body from the perceived danger.  This hyperreactivity can result in inappropriate continued activation even after the infection has passed.  In our model, this underlying hyperreactivity is the “gun”, and the virus which causes COVID-19 merely “pulls the trigger”.  In MCAS patients, some of the mast cell’s surface receptors (which typically function like an on/off switch) can become stuck in the “on” position.  When this happens, MCAS patients can severely react to trace amounts of triggers which would be undetectable to normal individuals.  When stuck in this “on” position, the mast cells will continue to release their proinflammatory mediators. This inappropriate activation in turn leads to the presentation of a multi-system inflammatory disease, affecting multiple, diverse systems in the body. Mast cells are central to the body’s immune response – as long as mast cells are activating in response to a perceived viral threat, they will both signal for more white blood cells to migrate to the infection site, and also cause the nearby tissue to expand in order to allow sufficient room for this migration to occur.  Furthermore, the histamine released by mast cells activates the receptors on neighboring mast cells, causing them to degranulate, which then activates their neighboring mast cells in turn.  In this manner, a cascading activation effect can sweep through all nearby mast cells, causing them to continually degranulate and release their mediators into the body.  These inflammatory “cytokine storms”, which are characteristic in severe COVID-19, can affect such disparate systems as the lungs, the skin, and the blood.  As a result, some of the unusual symptoms of the disease, such as blood clotting, skin rashes, and lung failure can all be explained by an underlying case of MCAS which becomes triggered by COVID-19. Further evidence for our hypothesis is seen in the correlation of the risk factors for severe COVID-19 with the most common symptoms of MCAS.  High blood pressure is the primary comorbidity for COVID-19 patients who go on to develop Acute Respiratory Distress Syndrome.  High blood pressure is also the second most common comorbidity seen in MCAS.  Heartburn, the most common comorbidity seen in MCAS, has also been found to be highly prevalent in hospitalized COVID-19 patients.  Severe COVID-19 is also correlated with a number of other inflammatory diseases, which are also comorbid with MCAS.  The symptoms of the recently described Multisystem Inflammatory Syndrome in Children also fit an underlying diagnosis of MCAS extremely well. MCAS is frequently a lifelong, progressive disease, which tends to “step up” in severity over the patient’s lifetime.  In the event our hypothesis is correct, this feature also describes why it is far more common to see severe COVID-19 in adults than in children.  In our model, adults are far more likely to have severe MCAS, so they are far more likely to have severe COVID-19. Some of the treatments which are showing promise for severe COVID-19 – such as the drugs tocilizumab, famotidine, and vitamin D – are exactly the drugs one would expect to be effective if an underlying case of MCAS is present.  The early evidence which shows famotidine (an H2 antihistamine sold under the brand name Pepcid) as a potentially effective treatment for severe COVID-19 is particularly striking.  Two separate studies have found that famotidine use is associated with a 50% reduction in severe COVID-19 outcomes.  Famotidine is a common over the counter medication which has no known anti-viral properties.  However, it is commonly used to treat MCAS by suppressing overly active mast cells.  If additional famotidine studies continue to substantiate the 50% reduction in severe COVID-19 outcomes, then it becomes imperative to determine the drug’s mechanism of action.  In our model, famotidine is doing in COVID-19 patients what it is known to do in MCAS patients – block the histamine cascades, stabilize the patients mast cells and prevent the patient’s immune system from inappropriately overreacting. If an underlying case of MCAS is indeed the “gun” and the virus that causes COVID-19 merely “pulls the trigger”, then awareness of this connection is vital to proper treatment.  This awareness can then lead to the necessary actions for better outcomes and a lower mortality rate during the COVID-19 pandemic. Mast Cell Activation Syndrome affects a large minority of the population, but it is a disease that most people have never heard of.  If MCAS is indeed the key to the COVID-19 mystery, there may be no better time than this moment to raise the profile of this important disease.

"One thing seems clear: there are many reasons why one population is more protected than another. Theoretical epidemiologist Sunetra Gupta of the University of Oxford thinks that a key one is immunity that was built up prior to this pandemic. “It’s been my hunch for a very long time that there is a lot of cross-protection from severe disease and death conferred by other circulating, related bugs,” she says. Though that cross-protection may not protect a person from infection in the first place, it could ensure they only experience relatively mild symptoms."

“I understand that sharing the story, it’s going to be frightening to some people,” he said. “I hope that it doesn’t fuel any sort of general antagonism towards vaccines in general or towards even this vaccine.”

“As we rush to get a vaccine developed as quickly as possible, the reality of vaccine development is that it can only be rushed so much and the trial still needs to take place,” Haydon said. “They have to move at the speed they move at. And stories like what happened to me, they matter because they shape the approval process.”