George Ofori-Amanfo, MD, Chief of the Division of Pediatric Critical Care at The Mount Sinai Hospital and Mount Sinai Kravis Children’s Hospital

Nine pediatric patients admitted to The Mount Sinai Hospital during the past two weeks, who either tested positive for COVID-19 or had antibodies, had severe abdominal pain and low blood pressure, which progressed to shock. Some of the patients also had clinical signs of myocarditis. This inflammation affects the heart muscle and the heart’s electrical system, reducing the heart’s ability to pump and causing abnormal rhythms, or arrhythmias. SARS-CoV-2, which causes COVID-19, is the first coronavirus associated with myocarditis.

Prior to their infections, the patients—six boys and three girls—did not have co-morbidities that would have put them at higher risk for disease, according to George Ofori-Amanfo, MD, Chief of the Division of Pediatric Critical Care at The Mount Sinai Hospital and Mount Sinai Kravis Children’s Hospital.

“These patients presented with very unusual symptoms,” says Dr. Ofori-Amanfo. “Until now, the pediatric patients who came to the Emergency Department with COVID-19 all had respiratory problems like the adults—dry coughs, difficulty breathing, and sometimes decreased oxygen saturation. In this recent series of patients, the children presented with abdominal pain, low-grade fever, vomiting, and in some cases diarrhea.” The pain was so severe that one child was sent to Mount Sinai to determine whether the problem was appendicitis, which was not the case. Another child was sent to the hospital for a CT scan to see whether the cause was inflamed abdominal lymph nodes. This was also ruled out upon closer examination.

Two of the nine pediatric patients also had a rash and conjunctivitis, which put their symptoms in a constellation of conditions that are similar to but not the same as Kawasaki disease, which causes blood vessels to become inflamed and also affects the heart. Both of these patients were among those with the least severe symptoms.

Dr. Ofori-Amanfo says that when the children and young adults progressed into a state of shock with low blood pressure, they did not respond to the traditional methods of resuscitation and large amounts of IV fluids, so the clinicians gave them high doses of blood pressure medication, which helped. Three of the patients required mechanical ventilation for shock and two of these patients also required mechanical cardiac support.

“This is a new phenomenon and it is rare. Perhaps these patients had mild symptoms of COVID-19 or were asymptomatic. We think what we’re seeing is a post-infectious process. It is an aggressive immune response to either the virus or some aspect of the viral infection that we don’t know yet. Because when you look at their lab profiles, the patients have very elevated inflammatory markers and this suggests an acute inflammatory response,” says Dr. Ofori-Amanfo. “The exaggerated immune response affects the heart function, which is mildly to moderately depressed, and their low blood pressure is a result of the hyper state of their immune system.”

At Mount Sinai, a team of specialists in areas that include pediatrics, immunology, hematology, infectious diseases, and basic science is treating this syndrome by targeting and modulating the overwhelming immune response and managing anticoagulation therapies for potential strokes. “This is a real entity, but it is rare, and we are hypervigilant and looking out for our patients,” says Dr. Ofori-Amanfo. “We think we have developed some therapies that are working. We have really smart, dedicated specialists working together. It is a great partnership.”

Other hospitals in the New York metropolitan region, around the country, and in Europe have reported smaller clusters of similar pediatric cases.

“We are studying the children to learn what predisposes them to developing this syndrome,” Dr. Ofori-Amanfo says. “These children had siblings. We don’t know why one child gets this but his brother or sister doesn’t.”

Li Li, MD, Sema4’s Vice President of Clinical Information and an Assistant Professor at the Icahn School of Medicine at Mount Sinai

Sema4 scientists released results from an analysis of patients tested for SARS-CoV-2 at five hospitals in the Mount Sinai Health System. Spanning more than 28,000 patients, this is one of the largest and most racially diverse COVID-19 studies performed in the United States to date. The study findings were posted as a preprint on medRxiv.

The team at Sema4 analyzed de-identified electronic medical records from 28,336 patients tested for SARS-CoV-2 at Mount Sinai Health System hospitals in Manhattan, Brooklyn, and Queens between February 24 and April 15. Of those patients, 6,158 tested positive for the coronavirus and 3,273 were admitted to the hospital.

Consistent with other reports, this study confirmed that COVID-19 prevalence in African Americans and Hispanics is disproportionately high in New York City. However, for patients admitted to the hospital, the analysis found no differences in mortality rates based on ethnicity, indicating that inpatient care helps to address this health care disparity.

The team also identified several risk factors linked to increased mortality rates for COVID-19 patients, including age, oxygen levels, body mass index, and elevated creatinine, among others. Asthma was associated with longer hospital stays, but did not appear to be linked to increased mortality rates. The study, which found higher mortality rates at hospitals where patients had more severe cases upon entry, can also be used to guide neighborhood-based testing for SARS-CoV-2.

Li Li, MD, Sema4’s Vice President of Clinical Information and an Assistant Professor at the Icahn School of Medicine at Mount Sinai in the Department of Genetics and Genomic Sciences, who was one of the lead scientists on the project, commented: “In a thorough review of published studies investigating COVID-19 mortality rates, we found unintentional biases, such as small sample size, that limited the broader utility of the data. By including all patients tested at these five member hospitals and performing advanced statistical modeling including multivariate analyses, we have removed that bias and generated findings that should be more useful in improving the understanding of which clinical features track with disease progression and associated outcomes.”

Miriam Merad, MD, PhD

Miriam Merad, MD, PhD, a pioneering immunologist at the Icahn School of Medicine at Mount Sinai, has been elected to the National Academy of Science (NAS), an honor that recognizes her transformational contributions to the fields of myeloid cell biology and innate immunity. Dr. Merad, the Mount Sinai Professor in Cancer Immunology and Director of the Precision Immunology Institute, joins an elite group of international scientists with membership in the NAS.

In a landmark study published in Science in 2010, Dr. Merad showed that macrophages—large white blood cells—arise from embryonic precursors that take residence in tissues prior to life where they play a distinct role in organ physiology and pathophysiology. This study, cited several thousand times, has had important clinical implications. Dr. Merad and her team also established the contribution of this macrophage lineage to cancer progression and response to treatment, and to inflammatory bowel disease, in studies published in prominent journals such as Science, Cell, and Nature.

In addition to her work on macrophages, Dr. Merad is known for her work on dendritic cells, a group of cells that control adaptive immunity. She identified a new subset of dendritic cells, which is now considered a key target of antiviral and antitumor immunity. In a May 2020 study in Nature, she and her team revealed novel therapeutic targets to enhance dendritic cell-mediated antitumor immunity.

“I am thrilled to have been elected to the National Academy of Science and proud to represent Mount Sinai in immunology,” says Dr. Merad, who joined Mount Sinai’s faculty in 2004. She says her parents—both scientific and medical professionals who were educated in France and practiced in Algeria—raised her “to respect the transformational power of science.”

She adds that Mount Sinai helped foster her passion by giving her the freedom to grow and pursue her work. “Mount Sinai has a culture that empowers junior faculty. I tell junior scientists, ‘If you want to be transformative and innovate early in your career, this is the place to be,’” she says.

Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai, and President for Academic Affairs, Mount Sinai Health System, says, “Dr. Merad’s discoveries have helped changed the course of medical treatments and her work continues to shed light on the way the human immune system responds to disease.”

In May, after receiving word of her election to the NAS, Dr. Merad shared the news with all of the former and current postdoctoral fellows in her lab. Many of her original fellows, who continue to collaborate with her on research, are now established investigators in institutions that include Stanford University, the University of Massachusetts-Amherst, the University of Toronto, the University of Zurich, and Charité in Berlin. “I told them that this election recognizes the many hours they spent in my laboratory and I thanked them for everything we have done together,” she says.

A NEW COVID-19 RESEARCH EFFORT

Under Dr. Merad’s leadership, Mount Sinai has become an international hub for the study of the human immune system. She developed Mount Sinai’s Human Immune Monitoring Center (HIMC) as one of the world’s most sophisticated research centers; it uses cutting-edge single-cell technology to understand the contribution of immune cells to major human diseases or treatment responses. HIMC participates in several major consortia funded by the National Institutes of Health.

This center will now play a key role in helping Dr. Merad and her colleagues understand why some patients develop severe forms of COVID-19 and some do not. For the past six weeks, she has led a major effort at Mount Sinai with her colleague Alexander Charney, MD, PhD, Assistant Professor of Psychiatry, Genetics and Genomic Sciences, Neuroscience, and Neurosurgery, to collect blood samples from 500 hospitalized COVID-19 patients. The collection is still ongoing.

She says, “We will use the HIMC to analyze the inflammatory response that is triggered in our patients as a result of COVID-19, as well as the adaptive immune response to the virus.” Her goals for the project include the ability to predict which patients will develop a severe inflammatory response and then find ways to prevent and treat it.

Yet, she adds, even when some patients recover from the disease, they continue to have negative effects. “We do not know if it’s because inflammation persists and does not resolve. There is still a lot to learn. We will be following these patients for a long time because we need to monitor the resolution of inflammation and the quality of the immune response that these patients develop and see whether this response is protective.”

Photo Courtesy: National Institute of Allergy and Infectious Diseases

Did the SARS-CoV-2 virus emerge in the human population spontaneously or was it engineered in a laboratory? Several months into this pandemic, there are still many more questions than answers about this stealthy new coronavirus that has commandeered the world stage. Its ability to enter a human population for the first time and spread quickly and with such unpredictable outcomes has led to many conflicting theories and suspicions about its origins.

“People are hungry for basic information to dispel the rumors that are out there,” says Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology at the Icahn School of Medicine at Mount Sinai.

In March, Jillian Carmichael, PhD, a postdoctoral fellow in Dr. Lee’s lab, created a blog to address the misinformation and confusion about the COVID-19 disease caused by the virus that she was seeing on social media. In addition, “I was getting so many questions about SARS-CoV-2 from friends and family that I couldn’t answer them all. I decided to reach out to my virology colleagues for help.”

Together with Christian Stevens, an MD/PhD student in the Lee lab, Dr. Carmichael launched a science-communications blog. Since then, they have worked with a team of graduate students and postdoctoral fellows to parse through reams of studies to create an ongoing series of posts that educate the public about what is plausible and what is not based on their knowledge of science and virology, in particular. Their posts have received traffic from more than 100 countries.

One persistent rumor they sought to demystify for the public was whether SARS-CoV-2 could have been deliberately engineered.

“While nothing is impossible in science, there are some things we do know, and it is very unlikely that SARS-CoV-2 could have been designed in a lab,” says Mr. Stevens, who helps engineer viruses in Dr. Lee’s lab. “We have a natural hypothesis that fits all the evidence so far.”

There are two ways to engineer something in biology, Mr. Stevens says. You take what you know works and piece it together so that it works in a new way. Or, you simulate the way nature does it and tweak it in order to make improvements.

“When the exact parts of the SARS-CoV-2 virus are plugged into a computer model, they look like they’re going to perform really badly,” he says. “The computer would tell you this is a terrible idea, try something better. A human would have been unlikely to rationally design this.”

In January, when the Chinese government released the virus’ genome, which showed its similarity to a virus from a horseshoe bat, researchers gained a better understanding of its makeup. They found that no prior studies existed to explain the way in which this new virus worked, and two distinct features made the theory supporting its natural evolution more likely.

First, a piece of the virus’ spike protein—called the receptor-binding domain (RBD)—provides the virus with an exceptional ability to attach to the ACE2 protein located on the outer surface of cells in various organs. Second, the backbone of the virus—its overall molecular structure—differed substantially from other coronaviruses and mostly resembled related viruses found in bats. If SARS-CoV-2 had been deliberately engineered in a laboratory it would have been constructed from a virus that was known to cause disease, and these did not.

In addition, the SARS-CoV-2 virus has features that would make it difficult to engineer in a lab. The RBD on the spike protein closely resembles that found in a coronavirus in pangolins—an animal also called a “scaly anteater” that is one of the world’s most trafficked. The theory that a bat virus mixed with, potentially, a pangolin virus, mutated, and then jumped to humans continues to make the most sense.

Then, he says, there is the virus’ biological makeup. It has a polybasic cleavage site, which appears to give it the ability to connect to many different tissue types in the human body. While additional testing is needed, early indications are that SARS-CoV-2 does hit many areas of the body in addition to the lungs. By comparison, previous coronaviruses all had monobasic cleavage sites that connected to fewer tissue types. And last, but not least, the virus has O-linked glycans, which may function to shield the virus from the immune system. This means that in order to develop, the virus probably would have needed a human immune system, something unlikely to have been engineered in cell culture.

On the flip side, says Mr. Stevens, there is plenty of evidence to support the premise that the virus emerged naturally and jumped into humans either already possessing the tools it needed to mutate and begin infecting them quickly, or acquiring these tools soon after landing in the human population.

To learn more about SARS-CoV-2, please go to the Lee lab’s science blog and subscribe for updates.