Carlos Cordon-Cardo, MD, PhD

The more SARS-CoV-2 virus, or viral load, individuals have in their bodies, the greater their chances of dying of COVID-19. This association was borne out in a new study at the Icahn School of Medicine at Mount Sinai that was led by Carlos Cordon-Cardo, MD, PhD, the Irene Heinz Given and John LaPorte Given Professor and Chair of the Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Molecular and Cell-Based Medicine.

Dr. Cordon-Cardo and his team measured the viral load of 1,145 patients with COVID-19 who were admitted to the Mount Sinai Health System between March 13 and May 5, during the height of the pandemic in New York. These patients had an overall mortality rate of 29.5 percent. When the researchers adjusted for age, sex, and race, and comorbidities such as asthma, heart disease, hypertension, and chronic obstructive pulmonary disease, they found that a higher viral load was still associated with a significantly higher mortality rate.

Based on such a strong correlation, Dr. Cordon-Cardo and his team would like to see quantitative reporting for viral load added to the polymerase chain reaction (PCR) tests that are used to determine if someone has COVID-19. Right now, PCR tests provide a yes or no answer: either someone has or doesn’t have COVID-19. Determining an individual’s viral load would add another layer of knowledge and could be easily implemented by most testing facilities. PCR tests differ from antibody tests that establish whether someone has recovered and may now have some level of immunity.

The chart demonstrates a significant mortality difference between hospitalized patients with high and low SARS-CoV-2 viral load.

“At the beginning of the disease this is the first test you’re going to get, and more viral presence means a more aggressive disease,” says Dr. Cordon-Cardo. “Chances are you are going to get a lot sicker. Taking Tylenol and staying home is probably not going to be enough to help you.” If doctors are aware of a patient’s viral load, they would be prepared to help the patient remotely or admit them to the hospital for observation and, perhaps, early antiviral treatment. Clinicians would have the opportunity to treat the disease at its earliest stage, the best opportunity to prevent it from becoming more destructive.

The amount of virus individuals have in their body could also determine how much they are able to spread the disease to others. Early quarantining of these “superspreaders” would help protect others. Quantitative testing for viral load is relatively quick and inexpensive, according to Dr. Cordon-Cardo. Results can be obtained in a few hours and easily added to current PCR tests.

Understanding this key differentiator in disease progression is the first step in applying personalized medicine to the standard of care for COVID-19. The study’s first author, Elisabet Pujadas, MD, PhD, a Mount Sinai pathology resident and postdoctoral fellow, says, “Obtaining quantitative results that help guide management for the individual patient is one of the bigger goals here. COVID-19 is unique in that the disease offers many new challenges. People get sick and deteriorate so quickly that it surprises clinicians who are treating them. So it’s hard to know up front who is going to do worse than others.”

Knowing which patient is likely to become sicker would also help hospitals better manage their resources, she says. “This illness is not the same for everyone, and this information has great implications for what the best treatment for each patient may be and how we manage limited resources when there is a big surge of people who need to be cared for.”

Elisabet Pujadas, MD,PhD

Mount Sinai’s Department of Pathology is working closely with the Mount Sinai COVID Informatics Center, which was created in the spring to analyze large amounts of health data among patients with the disease. Together, the groups are developing algorithms based on viral loads, comorbidities, and other clinical values that would help doctors evaluate patients based on individualized data.

“All of this up-front clinical information would help guide us in knowing how infected the patient is, how concerned we should be, and which therapies could help or not so we could do a better job of caring for each patient,” says Dr. Pujadas.

Stratifying patients with COVID-19 would follow the same paradigm of care that has already been established for patients with HIV or cancer who receive personalized medicine.

“The more virus you have, the more virus is going to travel in your blood vessels, like cancer cells. And it happens that certain vessels have receptors to the virus that are hospitable,” says Dr. Cordon-Cardo. “In individuals who already have vascular damage you are now adding another condition and the patient is at much higher risk of getting worse. COVID-19 is different diseases at different moments. We should be able to apply the right treatments and the right management for the patient with the knowledge we are obtaining.”

In this plaque assay, the cell culture has been stained purple so that the infectious SARS-CoV-2 particles, or virions, can be seen clearly. The circles represent single infectious virions that have poked holes in the cell culture.

The race to identify U.S. Food and Drug Administration (FDA)-approved drugs that can be repurposed to prevent or treat COVID-19 is advancing toward the finish line, under a $6.3 million federal grant that was recently awarded to Benjamin tenOever, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine, Icahn Professor of Microbiology, and Director of the Virus Engineering Center for Therapeutics and Research (VECToR) at the Icahn School of Medicine at Mount Sinai.

Dr. tenOever’s lab is currently testing a group of 20 promising drugs that were narrowed down from thousands over the course of several months by teams led by Donald Ingber, MD, PhD, at the Wyss Institute for Biologically Inspired Engineering at Harvard University, and Matthew Frieman, PhD, at the University of Maryland School of Medicine. All three institutions are working together under a one-year $16 million umbrella grant from the U.S. Defense Advanced Research Projects Agency (DARPA).They have created a full drug-testing pipeline with the goal of finding effective treatments for COVID-19 or prophylactics that prevent the SARS-CoV-2 virus from entering human cells. None exist at this time.

The institutional collaboration loosely resembles a relay race, with a baton that has now been passed from Harvard and the University of Maryland to Dr. tenOever’s lab.

“Both groups have provided me with a small list of drugs from their respective screens, with quite a bit of overlap, and we will decide together and with DARPA to prioritize the ones that are the most promising,” says Dr. tenOever. “We are running the last set of tests here.” The drugs have all been FDA-approved for a range of different treatments.

Members of Benjamin tenOever’s lab, postdoctoral fellow Ben Nilsson-Payant, PhD, left, and PhD candidate Skyler Uhl, enter Mount Sinai’s Biosafety level 3 laboratory to begin testing the SARS-CoV-2 virus in a batch of drugs that may protect against viral replication.

Each participant in the DARPA grant has contributed to a specific leg of the drug-discovery process. The Wyss Institute provided the human organ chip technology. The University of Maryland provided high-throughput screening. And Mount Sinai is testing the drugs in animal models using the actual virus.

Currently, Dr. tenOever’s lab is testing the drugs in lung organoids—tiny replicas of the human lung that are composed of multiple cell types. In July, his lab will begin to test the drugs in a more sophisticated human organ chip technology, which was developed by a Wyss Institute spinoff, Emulate, Inc. After that, Dr. tenOever’s lab will test the finalists in animal models.

He says his timeline is flexible. Largely, it depends on how quickly his lab finds something that appears to be really promising. “If we find a drug that looks fantastic, then we will probably focus on that one and learn everything we can about it and start a human trial because it’s already FDA-approved. But if none of the first batch of drugs work, we move onto the next batch,” Dr. tenOever says. “In cell culture, some drugs look like miracles. But when you move them into more complex systems like human organ chips, things really fall apart. Just because a drug works in cells doesn’t mean it works in animals. That’s exactly the kind of situation we want to avoid and exactly what my lab is trying to parse out.”

The goal of the DARPA project is to find drugs that can be used in the very early stages of the disease cycle to either prevent the virus from entering cells or dismantle the virus before it has a chance to replicate in the lungs. The drugs being tested in Dr. tenOever’s lab would focus on the early aspects of the disease prior to the respiratory complications of COVID-19. Once that occurs the disease is more about inflammation than viral infection and, for that reason drugs such as dexamethasone would be used to diminish inflammation.

Individuals with Down syndrome, the nation’s most common genetic disorder, represent a small, vulnerable segment of the U.S. population whose comorbid conditions may make them particularly susceptible to severe forms of COVID-19.

In fact, people with Down syndrome who are over the age of 30 appear to be about nine times as likely as the general population to be hospitalized for COVID-19, and their hospital stays tend to be more than twice as long, with a median of 17 days, according to a recent study from the Icahn School of Medicine at Mount Sinai that was uploaded onto the pre-print server medRxiv. Approximately 250,000 people in the United States have Down syndrome.

“When you don’t have a critical mass of people who are able to advocate for themselves, which is the case with Down syndrome, then people start falling through the cracks,” says the study’s senior author, Dusan Bogunovic, PhD, Associate Professor of Microbiology, and Pediatrics, and Director of the Center for Inborn Errors of Immunity, which is part of the Mindich Child Health and Development Institute. “We did not want that to happen. We felt that particular attention should be paid to the prevention and treatment of COVID-19 in individuals with Down syndrome.”

From left: Dusan Bogunovic, PhD, and Louise Malle, MD/PhD candidate

Dr. Bogunovic and MD/PhD candidate Louise Malle led a research team that examined the electronic medical records of 4,615 patients with COVID-19 who were hospitalized within the Mount Sinai Health System. They expected to find one or perhaps even two patients with Down syndrome based on the syndrome’s low prevalence within the population. Instead, they identified six adults, all of whom were in their 50s except for one, who was in her 30s. Two of the six patients, both in their 50s, succumbed to the disease. By comparison, Dr. Bogunovic says, 2 out of 30 cases were fatal in an age, sex, and race-matched control group of people who did not have Down syndrome.

Four of the six Down syndrome patients with COVID-19 were also diagnosed with sepsis, which is a marker of extreme inflammation, according to Ms. Malle. The individuals with Down syndrome were more likely to be hospitalized in an intensive care unit and to have been placed on a ventilator. In addition, she says, a constellation of other health issues associated with Down syndrome, such as autoimmune disease, epilepsy, and dementia, may have played a role in the severity of COVID-19. Further studies will be needed to determine whether these patients were more likely to produce higher levels of inflammatory markers.

Over the past 20 years, improved health care for individuals with Down syndrome has led to increased longevity, with many now living into their early 60s. That however, is still roughly 20 years shorter than individuals without the disorder. The median age of the hospitalized patients with Down syndrome was 54, roughly 12 years younger than the rest of the population that was hospitalized as a result of the disease.

Dr. Bogunovic says one positive finding was that “none of the patients we looked at were pediatric patients, so it does follow the trend of the general population that the older you are the more likely you are to be hospitalized with COVID-19.” He adds that the current study points to the need for “additional research into the medical conditions of marginalized patients with rare genetic conditions,” particularly during a pandemic.

Members of the Pathology Department’s autopsy study, from left: Elisabet Pujadas, MD, PhD; Zachary Grimes, DO; Kenneth Haines, MD; Clare Bryce, MBChB; Mary Fowkes, MD, PhD; and Carlos Cordon-Cardo, MD, PhD.

Since March 8, when Mount Sinai West hospitalized its first patient with COVID-19, more than 8,000 individuals with the disease have been admitted to the Mount Sinai Health System. During that time, the medical community’s knowledge of COVID-19 has evolved from seeing it as a respiratory illness to understanding its effect on the blood vessels and multiple organs.

“Mount Sinai has been the epicenter of the epicenter,” 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. “We’ve been attacking COVID-19 from many different perspectives and we’ve made a lot of progress in a short amount of time.”

Indeed, as Mount Sinai’s front-line doctors, nurses, and others faced a tsunami of sick patients entering their hospitals, they were able to improve patient outcomes by working closely with their colleagues in other specialties and in laboratories at the Icahn School of Medicine at Mount Sinai. Through careful observations and investigations they have come to define COVID-19 as a new disease that attacks the endothelial cells that line the body’s blood vessels. How the disease plays out in each individual depends largely on the state of their immune system and whether they have co-morbidities, such as obesity, hypertension, or heart disease, which affect blood flow within the body. Approximately 80 percent of people with COVID-19 are able to recover without hospitalization.

“This is a disease we had not seen before,” says Carlos Cordon-Cardo, MD, PhD, the Irene Heinz Given and John LaPorte Given Professor and Chair of the Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Molecular and Cell-Based Medicine, who developed accurate, widespread testing throughout the Health System to help diagnose and manage COVID-19. “Initially, it was conceptualized as a viral respiratory illness. But now we know it causes endothelial damage.” This damage leads to excessive blood clots throughout the body, which can also lead to multi-organ failure. There is a strong immune component to the disease, as well, which is led by macrophages or scavenger blood cells that eat viruses and dead cells and can be very difficult to control, even with targeted immunotherapy.

A clearer understanding of the biology of the disease and the range of organ damage inflicted by COVID-19 was provided by the Department of Pathology, which “uncompromisingly performed as many autopsies as possible, and conducted over 90 in COVID-19-positive patients,” says Mary E. Fowkes, MD, PhD, Professor of Pathology, Molecular and Cell Based Medicine, and Director of Mount Sinai’s Neuropathology and Autopsy Service.

Pulmonary embolism in 3D.

Recently, Drs. Cordon-Cardo and Fowkes published a study of 67 individuals with the disease who were treated at Mount Sinai between March 20 and April 29, 2020. “We expected severe changes in the lungs, which we were able to confirm,” says Dr. Fowkes. “But one of our surprising findings in the lungs was that in addition to the viral infection, there was a secondary bacterial infection that made it worse.” Another surprising finding, she says, was that in a number of cases, the patients had experienced large pulmonary embolisms that traveled directly to the lungs and caused sudden death.

The pathologists also found blood clots in the small blood vessels of many major organs, as well as the central nervous system, and identified a syndrome similar to hemophagocytic lymphohistiocytosis (HLH), a rare condition in which the body makes too many activated immune cells, specifically macrophages and lymphocytes, produced in the bone marrow. HLH can overlap with Kawasaki syndrome, which has been compared to a rare reaction seen in children who seem to recover from COVID-19 but go on to experience severe symptoms that include heart inflammation, low blood pressure, and trouble breathing.

Initially, doctors were concerned that people with asthma would be at greater risk for severe symptoms due to the disease’s respiratory component. But that did not turn out to be the case, even though the disease spreads from one person to another through respiratory droplets. Another surprising finding was that in comparison with the heart, brain, lungs, and liver, the kidneys were less affected by blood clots. Researchers think that may be because the ACE2 receptor—to which the SARS-CoV-2 virus attaches in order to enter the cell—is less prevalent in the kidney’s network of blood vessels.

“In reality, it’s the patients who have heart disease who seem to be at greater risk,” for severe outcomes, says Dr. Fowkes. “Diabetes accelerates vascular disease with plaque located in blood vessels throughout the body. So that if you have pre-existing damage to blood vessels you would be at greater risk. Heart disease is similar. If you have hypertension you see damage to tissues that surround the blood vessels and to the blood vessels themselves.”

Adam Bernheim, MD, Assistant Professor of Diagnostic, Molecular and Interventional Radiology at the Icahn School of Medicine at Mount Sinai, was one of the first U.S. radiologists to review the lung CT scans of COVID-19 patients from China. Since early March, he says, doctors have begun to understand the breadth of injuries that COVID-19 inflicts on the body and its relentlessness in doing so.

“The patterns of injury to the body run the spectrum from blood clots and pulmonary embolisms to pneumonia and abdominal issues,” he says. Some patients, including those in their 20s and 30s, take months to heal and others develop permanent scarring in their lungs. With many diseases he says, the body takes a big hit and then is able to repair itself. But COVID-19 can “cause continuous injury to the lungs over weeks. It just keeps hitting and hitting.”

David L. Reich, MD, President of The Mount Sinai Hospital and Mount Sinai Queens says the last three months illustrated how well the Mount Sinai Health System functioned in ensuring that patients in each of the seven Health System hospitals treating COVID-19 patients received the life-saving care they needed. In addition, he says, “The Icahn School of Medicine, with its top scientists, was completely in lockstep with the largest health system in New York City. We were able to do things together that we never would have been able to do separately. And because of that, we were able to change the course of therapeutics for this disease, as well.”

The Mount Sinai Health System has had the largest worldwide experience with convalescent plasma therapy and was the first to demonstrate its benefit in this disease, he says.  Additionally, Mount Sinai instituted a policy to administer anticoagulant treatment, which has also been beneficial. Through its clinical trials infrastructure, Mount Sinai had early access to the antiviral drug remdesivir, the anti-inflammatory drug sarilumab, and allogeneic stem cell therapy.

During the height of the pandemic, as other health systems “were doing their best to provide some level of care while not being overwhelmed, Mount Sinai was innovating,” says Dr. Reich. “Mount Sinai was applying science and showing improved outcomes with therapeutic innovations in a way that demonstrated we are one of the best institutions in the world, especially with regard to COVID-19 care.”

The Jonas Brothers. From left, Joe, Nick, and Kevin Jonas.

Kevin and Danielle Jonas, Joe Jonas and his wife, Sophie Turner, and Nick Jonas and his wife, Priyanka Chopra Jonas, have donated $500,000 to the Mindich Child Health and Development Institute at the Icahn School of Medicine at Mount Sinai, to support pediatric research into COVID-19 at a time when a rare syndrome is affecting children who become severely ill about four weeks after they seemed to have recovered from the disease.

Since early May, The Mount Sinai Hospital has admitted almost 20 patients between the ages of five and twenty, with multi-system inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). It is defined as a syndrome in patients under the age of 21, with onset of fever for at least one day, laboratory evidence of inflammation, and severe illness with multi-system involvement.

George Ofori-Amanfo, MD, Chief of the Division of Pediatric Critical Care at The Mount Sinai Hospital and Mount Sinai Kravis Children’s Hospital, says Mount Sinai has developed a “strong and standardized process” for caring for these pediatric patients. This streamlined approach includes every phase of care, from the initial presentation in the pediatrician’s office or the emergency department through the entire hospitalization, discharge, and follow-up. It includes specific therapies and procedures, handoffs between the different levels of care within the hospital, and video phone calls with patients after they have been discharged and returned home.

The gift from the Jonas family will be used to support research into this inflammatory syndrome that is being conducted at the Icahn School of Medicine in areas that include genetics, bioinformatics, precision immunology, microbiology, and pediatrics.

Dusan Bogunovic, PhD, and Conor Gruber, MD/PhD candidate, Icahn School of Medicine at Mount Sinai

The effort is being spearheaded by Dusan Bogunovic, PhD, Associate Professor of Microbiology, and Pediatrics, and Director of the Center for Inborn Errors of Immunity, which is part of the Mindich Child Health and Development Institute. “We are studying two main questions,” says Dr. Bogunovic. “What causes this severe immune response that leads to MIS-C associated with COVID-19 in some children? And why do most other children seem to handle the SARS-CoV-2 virus so easily?”

This second question continues to puzzle physicians and scientists. Most children with COVID-19 appear to be asymptomatic and do not display the dry cough or trouble breathing that adults do.

Mount Sinai’s scientists will be characterizing the immune response of children at the RNA and DNA level to understand the disease pathology in cells by studying patients with the syndrome, in addition to healthy children. They will explore whether genetics plays a role in determining which children may be more susceptible to MIS-C; whether the types of antibodies these children produce influence MIS-C; and what in the immune system is driving the children’s clinical presentation. Is it the hyper-activation of their immune systems that triggers a cytokine storm or the specific cell subtype that drives pathogenesis?

“Through this work, we are striving to keep all of our children as safe as possible. The lessons we learn are sure to inform care for infections in children that go beyond COVID-19,” says Dr. Bogunovic.

Dr. Ofori-Amanfo says, “It is paramount that as we take care of our patients, we partner with our research teams and bring in their perspective in order to understand the underlying disease progression and treatment options.”

He adds that even though MIS-C is rare, if parents see their children developing abdominal pain in association with a fever or rash they should call their pediatrician immediately and not be fearful about coming to the hospital, if they need to. “The hospital is a safe place,” he says. “We are taking all of the infection prevention measures to ensure that our patients and staff are safe. We are committed to providing patients with the best care.”