Dynamic duo

Father-daughter DO team at Cleveland Clinic research COVID-19 inflammation and immunology

Since the pandemic started, Leonard Calabrese, DO, and Cassandra Calabrese, DO, have been working together to research the inflammatory phases of and immune responses to the virus.


Cleveland Clinic rheumatologist-immunologists Leonard Calabrese, DO, and Cassandra Calabrese, DO, often say their COVID-19 research tends to feel Sisyphean. Right as they begin to develop an understanding for an aspect of the virus, new conflicting research emerges and the proverbial rock rolls back down the hill.

“I like to say, ‘you can’t put your foot into the same COVID river twice,” Dr. Leonard Calabrese said. “Everything changes by the hour. From the beginning of February to the beginning of October, over 70,000 research publications about this virus have been released, and that’s rising exponentially. Nobody has a grand bird’s-eye-view of this just yet.”

Despite these challenges, this father-daughter team has still made great strides in advancing the medical community’s understanding of COVID-19 through their research. Most recently, the two DOs were recognized by the CDC as contributors to the agency’s efforts to categorize the symptoms of a new inflammatory syndrome in infected adults in order to name it. The syndrome is now called multisystem inflammatory syndrome in adults (MIS-A).

Since COVID-19 started, The DO has been speaking with osteopathic physicians about their experiences during the pandemic. If you are a physician and would like to be featured in an interview as we continue our COVID-19 coverage, please email abrown@osteopathic.org.

In this edited Q&A, the Drs. Calabrese discuss their COVID-19 research, how they’ve helped support a global rheumatology alliance, and what they hope to learn about the virus moving forward.

What research areas have you focused on during COVID-19?

Dr. Leonard Calabrese: “We’re particularly interested in the inflammatory phases of COVID-19, where a variety of immune-based therapies are being investigated, as well as immunologic therapies against the virus, like antivirals, the monoclonal antibody cocktail, and beyond. We have far-reaching interests because this pandemic is an infection that kills people through immune-mediated mechanisms.”

Dr. Cassandra Calabrese: “We’re looking at humoral immune responses (via secreted antibodies) in patients who receive B-cell depletion and get COVID. We’re also looking into what immunologically is going on in people who recover from COVID and still have these persistent symptoms that are now referred to as ‘long COVID.'”

What have you learned about severe immune reactions like cytokine storms in COVID-19 patients?

Dr. Leonard Calabrese: “Cytokine storms are the biggest pull from our research. I’ve been in cytokine research education and publication for two decades. COVID, for most people, ends before an inflammatory phase. Maybe 90% of people get over this. But in a vulnerable population, typically those who are older, obese, diabetic, or have heart disease, a highly inflammatory phase can follow and can be fatal.

“But now that we’re six months into this, we’re recognizing that there isn’t just one inflammatory syndrome, there are probably many. Some patients have acute respiratory distress, ARDS, and they can have tons of inflammation. But that could be a totally different mechanism from the cytokine storms, and may overlap with other diseases. So it’s not simple, but the longer we go, we can get fingerprints on the way people are headed. All the candidate therapies for this phase of the disease come from the IMIDs experience, which is why we have so much to do with it.”

Are rheumatic patients at an increased risk for severe COVID-19 symptoms?

Dr. Leonard Calabrese: “We’ve been trying to track if they’re disproportionately affected in our own patient population, and working collaboratively with investigators around the world. At the moment, we don’t think they are particularly predisposed. Most of them do pretty well. How being on certain medications, like glucocorticoids or immune-based therapies, impacts them is still a work in progress.

“But it’s not just rheumatic patients we’re concerned about. We call them IMIDs patients (immune-mediated inflammatory diseases). So that’s not just rheumatoid arthritis and lupus and things like that, but also psoriasis and inflammatory bowel disease and other diseases of the immune system. We’re looking into if those patients are more vulnerable to COVID-19, and if the therapies they’re on make them have worse outcomes or better outcomes. There are many deep questions to answer in this area.”

What is the COVID-19 Global Rheumatology Alliance, and how has it contributed to your work?

Dr. Cassandra Calabrese: “The global alliance is a registry of rheumatology patients who have developed COVID. That was created from an idea that my dad tweeted in March. Within two days, there was a global database where anyone can enter patient data about patients with rheumatic diseases to learn more about COVID and learn more about the natural history and the risks associated with medications they might be on, and comorbidities. That now has thousands of patients in it, including ours at the Cleveland Clinic. It’s pretty cool.”

What types of patients and conditions do you typically see and treat?

Dr. Cassandra Calabrese: “My areas of interest are the intersection of infection and rheumatology, and then rheumatic manifestations of infectious diseases, infection prevention, immunizations and HIV. I also have a separate specialty in something called immune-related adverse events from checkpoint inhibitor therapy, which is a newer class of anti-cancer drugs that actually can cause autoimmune diseases as side effects.”

Dr. Leonard Calabrese: “I am the director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic. We deal with diseases in the immune system, immunodeficiencies, autoimmune diseases, and we’re particularly interested in the overlap of infections and immunologic disease. We also have the only combined training program in rheumatology and infectious diseases in the country. So we’ve been pretty busy during COVID.”

What do you hope to understand better as this pandemic goes on?

Dr. Cassandra Calabrese: “One big goal is to better understand the humoral immune response and immunopathogenesis so we that we can have an effective vaccine. And then also a better understanding of risk factors. There’s a lot left to learn, but one silver lining of COVID-19 has been that we get to work together every day and are having lots of fun.”

Dr. Leonard Calabrese: “There will be more advances in biomedical research as a result of COVID-19 than any other time in human history. I’m confident of that. I was around at the beginning of HIV. It took us a decade to figure out the root of that disease. We’re talking weeks to months here of actually being able to look at possible vaccines. Technology and our understanding of the immune system have evolved greatly.

“We’re interested to know about the nature of that disease and the relation between the infection and the immune system and the brain. That’s where we’re going.”

Related reading:

What we know about COVID-19 immunity

How a DO is helping a Native American reservation navigate a COVID-19 outbreak

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