Many of the elderly patients who survived the virus were poor: not exactly the demographic you would expect to fare well in a health crisis.
A review of the survivors’ medical records revealed that a significant number suffered from chronic heartburn and were taking an inexpensive drug called famotidine, the key ingredient in Pepcid. (Wealthier patients tended to take the more costly drug omeprazole, found in Prilosec.)
This is how many medical studies begin, said biomedical engineering professor Phil Bourne, who serves as founding dean for the School of Data Science.
“There’s often a phenomenon that doctors report anecdotally, or that’s mentioned in passing in a particular research paper, and that provides a clue—a hook,” he said.
Typically, to find out whether a drug is effective in treating a particular medical condition, scientists develop prospective clinical trials. But this method is expensive and can take years, Bourne pointed out. When faced with a global pandemic, it’s helpful to explore other options.
That’s where data scientists come in. Bourne and UVA senior scientist Cameron Mura worked with an international team of researchers to analyze information from a database that holds the medical records of millions of COVID-19 patients living in 30 different countries.
The team winnowed that number down to around 22,000 people, the largest sample size for a study on famotidine and the disease to date.
“The power of the electronic health record, which is really yet to be fully realized as a research tool, is that you’ve suddenly got all this data you can mine to see whether what you determined in passing or anecdotally has any basis,” Bourne said.
The team’s analysis, which appeared in the journal Signal Transduction & Targeted Therapy (from the Nature publishing group), showed that the data supported findings from other smaller-scale studies. When delivered at high doses (the equivalent of about 10 Pepcid tablets), famotidine appears to improve the odds of survival for COVID-19 patients, especially when it is combined with aspirin.
It also seems to hinder the severity of disease progression, making patients less likely to reach the point where they require intubation or a ventilator.
The next challenge was to figure out why. Data scientists like Mura and Bourne perform extensive detective work for medical analyses like this one, looking at existing information and drawing upon biochemical and molecular principles to propose a cohesive theory that helps elucidate the population-scale patterns they identify.
Mura calls this “weaving a story” based on the data. He needed to work backwards from massive groups of people and draw some possible conclusions about what was happening at a totally different scale—the scale of proteins that are “one millionth the size of an ant,” he said.
One of the most dangerous phenomena COVID-19 can trigger in your body is something called a cytokine storm, which is a potentially fatal amplification of an immune response. When you become sick, your immune system releases inflammatory proteins called cytokines that tell your immune cells how to fight the infection.
But in more severe illnesses, cytokine production can spiral out of control, becoming dysregulated.
“Basically, your immune system goes haywire and starts attacking things like your otherwise healthy lung tissue because it’s so desperate to kill off the invading virus,” Mura said. “Your own physiology essentially uses a sledgehammer against the pathogen when a fly swatter would suffice.”
The team’s theory is that famotidine suppresses that reaction. Although it was developed with a specific purpose in mind—blocking the histamine receptors that help produce acid in your stomach – famotidine, like all other medications, can cause side effects. Mura and his colleagues believe that interfering with cytokine storms might be one of them.
“It may well be a case of famotidine having a beneficial off-target effect,” Mura said. We generally think of side effects as a bad thing, but in some cases, they can be harnessed to treat other conditions. In the future, it’s possible that famotidine could be re-purposed in this way.
But the team’s findings are far from conclusive. Other studies have offered conflicting pictures of what famotidine can do for COVID-19 patients: Some have found that it has a neutral effect and one has even suggested that it might be detrimental. Mura, Bourne and their colleagues recently published a review of existing research on the subject, along with suggestions for a framework that could help reconcile the contradictory reports.
Still, with its unique focus on combining famotidine with aspirin and its impressively large sample size, the team’s study has shed further light on an inexpensive and safe potential treatment that would be easy for doctors to prescribe. In the midst of an international health crisis, the study has also laid important groundwork for further research.
“Scientific studies are sometimes viewed as the end-all, be-all, but they’re really just a starting point or a springboard,” Mura said. “Any good study raises more questions than it answers, and data science is often what kick-starts that process.”
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.
As of early June 2020, there have been nearly 7 million cases of diagnosed COVID-19 and over 400,000 deaths reported worldwide. While approximately 80% of patient report mild or moderate symptoms, the remaining 20% develop severe or critical disease and require hospitalization.
In-hospital mortality has been reported to range from 10% to 26%, but rises much higher in those who require admission to an intensive care unit and those who require mechanical ventilation. Despite multiple trials that are currently underway to investigate the safety and efficacy of a large number of possible therapeutic agents, no drug to date has been shown to reduce COVID-19 mortality.
The main finding of our single-center, retrospective study of hospitalized patients with COVID-19 is that use of famotidine is associated with improved clinical outcomes including lower in-hospital mortality and a lower composite end point of death and/or intubation.
The impact of the drug on mortality appears to be most pronounced in patients with the highest level of acuity as measured by the mean NEWS. In addition, famotidine patients were shown to have lower levels of markers for serious disease including serum ferritin levels, CRP, and procalcitonin.
The observed benefit of famotidine was unrelated to concurrent use of experimental treatments including hydroxychloroquine, azithromycin, remdesivir, and corticosteroids.
Apart from the impact of famotidine, our analyses demonstrating the increased risk of death in patients with COVID-19 who are older, having comorbidities of obesity and CKD, or having higher NEWS and higher neutrophil-lymphocyte ratios are in agreement with the literature.
Our results on mortality and combined mortality/intubation corroborate the findings from the recent report by Freedberg et al. (2) that examined the effect of famotidine use on clinical outcomes in 1,620 consecutive hospitalized patients with COVID-19 infection from February 25, 2020, to April 13, 2020, at a single medical center.
The authors reported that famotidine, received within 24 hours of hospital admission in 84 patients with COVID-19, was associated with reduced risk for death or intubation (adjusted HR 0.42, 95% CI 0.21–0.85) and also with reduced risk for death alone (HR 0.30, 95% CI 0.11–0.80). After baseline patient characteristics were balanced using propensity score matching, these relationships were unchanged (HR for famotidine and death or intubation: 0.43, 95% CI 0.21–0.88).
The mechanism by which famotidine might improve COVID-19 outcomes is currently unknown. One theory, based on earlier reports on the efficacy of famotidine in inhibiting human immunodeficiency virus replication (4), is that famotidine may directly inhibit the SARS-CoV-2 virus.
Recent studies using a Vero E6 cell-based assay, however, have failed to demonstrate any direct inhibitory effect of famotidine on SARS-CoV-2 infection (5). A second theory, based on computational methods that identified famotidine as a potential agent capable of binding and inhibiting key SARS-CoV-2 proteases critical to viral replication (6,7), has likewise been discounted (5).
A more recent mechanism that has been postulated is that famotidine’s effect is achieved via its antagonism or inverse agonism of the histamine-2 receptor, inferring that the SARS-CoV-2 infection that results in COVID-19 is at least partially mediated by pathological histamine release and perhaps dysfunctional mast cell activation (5,8).
Preventing the deleterious sequelae of this histamine release has been suggested as fundamental to preventing the cytokine storm that may cause acute respiratory distress syndrome, leading to hypoxia, sepsis, organ failure, and ultimately death in the patient with COVID-19 (8). Lower levels of ferritin, CRP, and procalcitonin in famotidine-treated patients in this study are compatible with the hypothesis that the drug may limit the abnormal excessive cytokine release from an uncontrolled immune activation.
In addition, it is notable that certain unusual clinical aspects of COVID-19 could be explained by excessive histamine release and stimulation of the histamine-2 receptor. First, along with early typical nonspecific viral symptoms of fever, sore throat, cough, headache, diarrhea, and myalgia, some patients with COVID-19 may experience anosmia, ageusia, and skin rashes including pruritis and urticarial symptoms (9,10).
All of these symptoms could be explained by histamine signaling. Second, seriously ill patients with COVID-19 with hypoxia and abnormal pulmonary computed tomography findings who require intubation have been found to have near-normal compliance (i.e., >50 mLcmH2O) with little response to positive end-expiratory pressure ventilation (5).
In part, this observation could be related to a loss of pulmonary restriction mediated by the histamine-2 receptor on smooth muscle cells and/or pericytes. Third, it is notable that limited lung autopsy specimens have demonstrated a paucity of neutrophils and eosinophils in postmortem photomicrographs (11).
The histamine-2 receptor has been documented to inhibit neutrophil effector functions including O2 release (12), platelet-activating factor–induced chemotaxis (13) and leukotriene biosynthesis (14), as well as inhibition of eosinophil peroxidase release (15) and eosinophil chemotaxis (16).
In humans, histamine is found in nearly all tissues of the body stored in the granules of tissue mast cells and serum basophils. Mast cells located in the submucosa of the respiratory tract and in the nasal cavity represent a barrier of protection against microorganisms (17). Their functions include mastocytosis by secreting histamine, leukotrienes, and proteases (18).
They also play a role in inflammation development via release of multiple proinflammatory cytokines and chemokines (19). Mast cells are known to be triggered by viruses (20), and it has been documented that they have the angiotensin-converting enzyme 2 receptor used by SARS-CoV-2 to gain entry to cells and replicate (21).
The findings in this report should be interpreted with caution in light of the single-center, retrospective, and observational nature of the study. Assessment of the possible effects of additional H2 receptor antagonists (such as cimetidine, nizatidine, or ranitidine) was not possible due to limited cases. Additional studies are needed to ascertain the potential efficacy of famotidine in the patient with COVID-19, including the impact of drug dose, route of administration, and timing of therapy.
In light of the need for additional trials, famotidine is currently being tested under an Investigational New Drug application waiver for treating COVID-19 in a double-blind randomized clinical trial in combination with either hydroxychloroquine or remdesivir (ClinicalTrials.gov Identifier: NCT04370262).
In summary, we found that famotidine is associated with improved clinical outcomes in hospitalized patients with COVID-19, including lower in-hospital mortality, a lower composite of death and/or intubation, and lower levels of serum markers for serious disease. Additional studies are warranted to fully evaluate the impact of famotidine in the COVID-19 population.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473796/
More information: Cameron Mura et al, Real-world evidence for improved outcomes with histamine antagonists and aspirin in 22,560 COVID-19 patients, Signal Transduction and Targeted Therapy (2021). DOI: 10.1038/s41392-021-00689-y