Miriam Merad, MD, PhD, left, Director of the Precision Immunology Institute, with Adeeb Rahman, PhD, Director of the Human Immune Monitoring Center at the Icahn School of Medicine at Mount Sinai.

Immunologists at the Icahn School of Medicine at Mount Sinai are playing a major role in managing the care of severely ill patients with COVID-19, who often experience an excessive inflammatory response to the disease that can ultimately overwhelm them.

Under the leadership of Miriam Merad, MD, PhD, the Mount Sinai Professor in Cancer Immunology and Director of the Precision Immunology Institute, Mount Sinai has created a quick test that monitors a patient’s inflammatory response to COVID-19 and helped launch a clinical trial that uses the drug sarilumab to manage these responses. The drug, manufactured by Regeneron Pharmaceuticals Inc., is typically used to treat rheumatoid arthritis. Dr. Merad says she may also roll out clinical trials that would test drugs used after CAR T cell adaptive therapies.

“Immunologists understand inflammation and know how to control it,” says Dr. Merad. “We developed a test with a three-hour turnaround time that we will repeat many times a day to see what type of inflammation the patient is developing and potentially guide treatment.” By identifying the features of severe immunological reactions in patients quickly, “we can speed the implementation of a cytokine blockade and significantly improve patient outcome.”

Cytokines are small proteins that modulate immunity. In trying to fight the COVID-19 virus the immune system may mount a major response, which can lead to excess inflammation that is also called a ‘cytokine storm.’ This overdrive reaction is happening in a range of COVID-19 patients, from the elderly to some young people with no apparent underlying health conditions.

“You need a strong immune response to fight the virus and this is why some people do well,” says Dr. Merad. “But others develop this storm of cytokines and this is what leads to fatalities. People are not dying from a virus that is running rampant in their bodies and killing tissue. We believe people are dying because of excessive inflammation. If we learn how to prevent this damaging immune response without compromising the fight against the virus we will be able to save many lives while waiting for curative treatment such as an antiviral drug or a vaccine.”

Benjamin K. Chen, MD, PhD

Dr. Merad adds, “There is urgency in learning how to best block the fatal inflammatory response.” To that end, she and other researchers are using the leading technology platform that she helped build in Mount Sinai’s Human Immune Monitoring Center, which allows them to “map with unprecedented depth the immune response to the virus in our patients.”

Benjamin K. Chen, MD, PhD, the Irene and Dr. Arthur M. Fishberg Professor of Medicine, and Vice Chair for Research in the Department of Medicine (Infectious Diseases), has been supporting the evolution of many proposed clinical trials with the help of leaders throughout the Mount Sinai Health System. Dr. Chen says there is limited but encouraging data to support cytokine blockers. Dr. Merad’s lab and the Human Immune Monitoring Center are uniquely capable of mapping out the “cytokine release profile,” he says. “With these trials we have the opportunity to measure those changes very carefully and decide what other trials or studies might be best to use for coronavirus. We are doing everything we can to support promising developments against COVID-19.”

Dr. Chen is working with Linda Rogers, MD, Associate Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine), and Michele Cohen, Clinical Research Program Director in the Department of Medicine, who have been coordinating several major COVID-19 clinical trials at the Mount Sinai Health System. Judith A. Aberg, MD, the Dr. George Baehr Professor of Clinical Medicine and Chief of the Division of Infectious Diseases, Department of Medicine, is leading key clinical trials, including one for the antiviral drug remdesivir, made by Gilead Sciences. Remdesivir has shown promise in treating patients with COVID-19 and was developed in response to the Ebola crisis.

Physicians need to consider that gastrointestinal (GI) symptoms, such as nausea, vomiting, and diarrhea could be early signs of COVID-19 infection, especially in those GI patients who also present with upper respiratory complaints. Meanwhile, patients with digestive diseases should closely monitor the news and stay in touch with their doctors if they experience new or unusual GI symptoms.

These were among the insights summarized recently by clinical researchers at the Icahn School of Medicine at Mount in New York City. They also provided renewed guidance to physicians for those patients who have inflammatory bowel disease (IBD) and are being treated with immunosuppressive agents. Research suggests, they said, these patients may be considered at high risk for COVID-19, which is caused by the SARS-CoV-2 virus.

“This is a rapidly evolving area with new information emerging on a daily basis,” said Ryan Ungaro, MD, MS, Assistant Professor of Medicine (Gastroenterology). “We strongly urge our patients to closely monitor the news and to stay in touch with their doctors if they experience new or unusual GI symptoms.”

For physicians seeing a patient with predominant GI symptoms, and some respiratory symptoms, “COVID-19 should be part of a differential diagnosis,” he added.

Dr. Ungaro and world-renowned physician-scientist Jean-Frederic Colombel, MD, published an overview of COVID-19 research findings for the gastroenterology community to help them address their patients’ questions and concerns. It was published on March 17, 2020, in Clinical Gastroenterology and Hepatology, a journal of the American Gastroenterological Association. Dr. Colombel is Director of the Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center at Mount Sinai, and Professor of Medicine (Gastroenterology). Also contributing were Mount Sinai’s Timothy Sullivan, MD, Assistant Professor of Medicine (Infectious Diseases), and Gopi Patel, MD, Associate Professor of Medicine (Infectious Diseases).

In their overview, the researchers recounted what has been learned to date:

— The SARS-CoV-2 virus shares 79.5 percent of the genetic sequence of SARS, a respiratory illness caused by a coronavirus that appeared in 2002.

— In that outbreak, diarrhea was reported in up to 25 percent of SARS patients.

— The reported frequency of diarrhea among COVID-19 patients has varied from 2 percent to 33 percent, however, it was one of the prominent symptoms reported in the first U.S. COVID-19 case.

— SARS-CoV-2 has been detected in the stool of COVID-19 patients.

— Common laboratory findings described in COVID-19 patients also include liver function test abnormalities.

“While COVID-19 appears to primarily spread through respiratory droplets and secretions,” the authors wrote, “the gastrointestinal tract may be another potential route of infection.” With this possibility, they reinforced the importance that gastroenterologists use personal protective equipment during endoscopy.

They acknowledged that there are no data currently about the impact of immunosuppressive agents. “At the current time, we should not advise IBD patients, or others on immunosuppressive agents, such as those with autoimmune hepatitis, for example, to hold or stop medications,” they wrote, as the risk of disease flare is still a larger concern at this time. They further suggested that physicians advise their patients on immunosuppression to follow the Centers for Disease Control and Prevention (CDC) guidelines for at-risk populations.

They additionally highlighted new evidence on the cell entry receptor ACE2. “Interestingly,” they wrote, “the cell entry receptor ACE2 appears to mediate entry of SARS-CoV-2,” a similar phenomenon observed with SARS, “and has been demonstrated to be highly expressed in small intestinal enterocytes,” the intestinal absorptive cells that line the inner surface of the small and large intestines. ACE2 is important in regulating nutrient absorption, in particular basic amino acids such as tryptophan, and its disruption may lead to diarrhea.

Mount Sinai is actively studying ACE2 expression in intestinal tissue, said Dr. Ungaro, referring to the work of Saurabh Mehandru, MD, Associate Professor of Medicine (Gastroenterology). “We are particularly interested in determining if the ACE2 inhibitor is differentially expressed in patients with inflammatory conditions of the GI tract to better understand this patient population’s susceptibility to SARS-CoV-2.”

Additionally, Mount Sinai, with collaborators from the University of North Carolina, has started a web-based registry for physicians to report any IBD patients who have a confirmed case of COVID-19. The goal is to better understand the impact of immunosuppressive medications and other risk factors to best guide clinical decisions, he said. Regular updates on reported cases are available at https://covidibd.org/.

Dr. Ungaro reports he served as an advisory board member or consultant for Eli Lilly, Janssen, Pfizer, and Takeda and has research grants from AbbVie, Boehringer Ingelheim, and Pfizer.

Image from Florian Krammer lab. The main target on the surface of most coronaviruses is the spike protein or S. This is a model of the virus and a visualization of a crystal structure of the spike of SARS-CoV-2.

The Mount Sinai Health System this week plans to initiate a procedure known as plasmapheresis, where the antibodies from patients who have recovered from COVID-19 will be transferred into critically ill patients with the disease, with the expectation that the antibodies will neutralize it.

The process of using antibody-rich plasma from COVID-19 patients to help others was used successfully in China, according to a state-owned organization, which reported that some patients improved within 24 hours, with reduced inflammation and viral loads, and better oxygen levels in the blood.

Mount Sinai is collaborating with the New York Blood Center and the New York State Department of Health’s Wadsworth Center laboratory in Albany, with guidance from the U.S. Food and Drug Administration, and expects to begin implementing the treatment later this week.

“We are hoping to identify patients who can provide the antibodies,” says Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai, and President for Academic Affairs, Mount Sinai Health System. “We are at the front lines in fighting this pandemic and making discoveries that will help our patients.”

Late last week, researchers at the Icahn School of Medicine, in collaboration with scientists in Australia and Finland, were among the first to create an antibody test that detects the disease’s antibodies in a person’s blood. Development of the enzyme-linked immunosorbent assay (ELISA) was led by Florian Krammer, PhD, Professor of Microbiology, in collaboration with Viviana A. Simon, MD, PhD, Professor of Microbiology and Medicine (Infectious Diseases). Dr. Krammer, a renowned influenza researcher, recently made this so-called recipe available to other laboratories around the world so they can replicate it during the pandemic. In January, his lab was quickly retooled to begin studying COVID-19.

In addition to its widespread use in plasmapheresis, the antibody test will provide experts with an accurate infection rate so they can track the trajectory of the disease. The test will help identify health care workers who are already immune to the disease, who can work directly with infectious patients, and it can also help scientists understand how the human immune system reacts to the virus.

The new assay uses recombinant or manufactured antigens from the spike protein on the surface of the SARS-CoV-2 virus. That protein helps the virus enter cells, and it is a key target in the immune reaction against the virus, as the body creates antibodies that recognize the protein and seek to destroy the virus. The researchers also isolated the short piece of the spike protein called the receptor-binding domain (RBD), which the virus uses to attach to cells it tries to invade. The scientists then used cell lines to produce large quantities of the altered spike proteins and RBDs.

According to Dr. Krammer and his co-authors, the assay is “sensitive and specific,” and allows for the screening and identification of COVID-19 in human plasma/serum as soon as three days after the onset of symptoms. The antibodies were derived from three patients who had the disease. The study’s control participants—who did not have COVID-19 but had other viruses, including the common cold—ranged in age from 20 to 70.

Dr. Krammer says his preliminary findings also show that humans have no natural immunity to the SARS-CoV-2 virus, which would help explain why it spreads so quickly. But once the antibody sets in humans do become protected. He also says that at this early stage in the research, there is no evidence that people can lose their immunity and become re-infected.