COVID-19 untested: a good model suggests optimal treatment strategies

BOSTON – COVID-19 can be controlled over a wide range of vaccines; it also requires a better understanding of why the disease does not cause obvious symptoms in some people but leads to rapid multi-organ failure and death in others, as well as a better insight into what treatments that work best and who the patients are.

To meet the unprecedented challenge, researchers at Massachusetts General Hospital (MGH), in collaboration with researchers from Brigham and Women’s Hospital and the University of Cyprus, have created a mathematical model based on knowledge that includes information on the known infectious mechanism of SARS-CoV -2, the virus that causes COVID-19, and the possible mechanisms of action of several therapies that have been tested in patients with COVID-19.

Its model and its important clinical applications are described in the journal Proceedings of the National Academy of Sciences (PNAS).

“Our model predicts that antiviral and anti-inflammatory drugs initially employed to treat COVID-19 may have limited efficacy, depending on the stage of disease progression,” he said. Corresponding author Rakesh K. Jain, PhD, from Edwin L. Steele Laboratories in the Department of Radiation Oncology at MGH and Harvard Medical School (HMS).

Jain and his colleagues found that, in all patients, the viral load (the level of SARS-CoV-2 granules in the bloodstream) increases during early lung disease, but then may they go in different directions starting after Day 5, depending on levels of key immune cells, called T cells. T cells are the first responders of the immune system that co -effectively prescribe other aspects of immunity. T cell response is called adaptive immunity because it is flexible and responds to immediate threats.

In patients younger than 35 who have healthy immune systems, sustained recruitment of T cells occurs, accompanied by a decrease in viral load and inflammation and a decrease in nonspecific immune cells (so-called “tissue” immunity). . All of these processes lead to a lower risk of blood clot formation and the restoration of oxygen levels in lung tissue, and these patients are more likely to recover.

In contrast, people who have higher levels of inflammation at the time of the disease – such as those with diabetes, obesity or high blood pressure – or whose immune systems are switched to ‘attacks more active textural responses but less effective adaptive immune responses. there are bad consequences.

The researchers also tried to answer the question of why COVID-19 is more potent in men compared to women, and found that although the variable immune response is not as strong in women as it is in men, women have lower levels of a protein called TMPRSS2 that allows SARS-CoV-2 to enter and enter normal cells.

Based on their findings, Jain and colleagues suggest the best treatment for older patients – who are already prone to inflammation and weak immune responses compared to younger patients. – the ingestion of clot-inhibiting drugs heparin and / or the use of a drug-altering response inhibitor (checkpoint inhibitor) at early stages of the disease, and the anti-inflammatory drug dexamethasone at later stages onwards.

In patients with pre-existing illnesses such as obesity, diabetes and high blood pressure or immune system dysfunction, treatment may include targeted drugs especially on substances that stimulate inflammation (cytokines, such as interleukin-6) in the body, as well as drugs that can block the renin-angiotensin system (the body’s main blood pressure control device) , thus preventing excessive blood pressure and counteracting blood flow that may occur in response to viral infections.

This work demonstrates how tools originally developed for cancer research may be useful for understanding COVID-19: The model was first created to study the involvement of the reni angiotensin system in the development of fibrous necrosis in tumors, but was modified to include SARS-CoV-2 infection and COVID-19 specific mechanisms. The team is further developing the model and plans to use it to study the dynamics of the immune system in response to different types of COVID-19 vaccines as well as specific cancer comorbidities that may require special consideration for treatment.

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Corresponding authors are Lance L. Munn, MGH, and Triantafyllos Stylianopoulos, University of Cyprus. Other authors are Chrysovalantis Voutouri, U. Cyprus; Mohammad Reza Nikmaneshi, Sharif University of Technology, Iran; C. Corey Hardin, Melin J. Khandekar and Sayon Dutta, all from MGH; and Ankit B. Patel and Ashish Verma from Brigham and Women ‘s Hospital.

Jain research is supported by a Researcher Award and grants from the National Foundation for Cancer Research, the Jane Trust Trust, the American Medical Research Foundation and the Harvard Ludwig Cancer Center. Munn’s research is supported by a grant from the National Institutes of Health. Stylianopoulos’ research is supported by the European Research Council and the Cyprus Research and Innovation Foundation. Patel is supported by the Joseph A. Carlucci Nephrology Society of America Research Association.

About Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital in Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the country, with an annual research activity of more than $ 1 billion and includes more than 9,500 researchers working over more than 30 institution, center and department. In August 2020, Mass General was named # 6 on the U.S. News and World Report list of “America’s best hospitals.”