Why COVID-19 May Be More Deadly Than Flu, Other Coronaviruses

Damian McNamara

March 04, 2021

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Although cytokine storms are not unique to COVID-19, they are triggered in an unusual way that makes them potentially more severe and deadly compared with those triggered by influenza or other coronaviruses, new evidence reveals.

Important differences in the host-immune response underline how cytokine storms arise in SARS-CoV-2, SARS-CoV, MERS-CoV, and the influenza viruses H5N1 and H7N9.

Researchers discovered that some beneficial cytokine signals are not elevated in people who experience a SARS-CoV-2 cytokine storm, also known as cytokine release syndrome (CRS). A lack of elevation in type 1 interferon (IFN), for example, could be a leading culprit.

The systematic review was published online March 1 in Frontiers in Immunology.

Some findings were unexpected, lead author Marton Olbei told Medscape Medical News.

Marton Olbei

"Although we suspected certain cytokines such as interferon-alpha and interferon-beta would be dysregulated because others before us have pointed out how the type-I interferon response is altered in COVID-19 patients, some of the other signals we found…were surprising for us," said Olbei, a PhD student at the Earlham Institute in Norwich, United Kingdom.

For example, the investigators found mixed results in the literature for whether or not levels of interleukin-10, interleukin-2, and interferon (IFN)-gamma are elevated in the SARS-CoV-2 cytokine storms. At the same time, in addition to type I IFN, they were surprised to find a lack of increase in interleukin-12 and interleukin-4 reported during these events.

A Loss of Balance

It's not just which cytokines are activated by the host-immune response, it's also a matter of balance. Some of these cytokines, or small proteins, are pro-inflammatory and send important signals when a viral infection first occurs. Others are anti-inflammatory, like type I IFN, and act later to put the brakes on inflammation.

Left unchecked, "a long-lasting pro-inflammatory cytokine production results in high mortality due to the development of severe conditions such as acute respiratory distress syndrome [ARDS] or acute lung injury," the researchers note.

Olbei, senior author Tamas Korcsmaros, PhD, also from Earlham Institute, and their colleagues evaluated more than 5000 studies in the literature. They curated 55 of them to uncover shared and unique characteristics of viral cytokine storms.

They found that SARS-CoV and MERS-CoV infections are characterized by a slow initial innate immune response; when coupled with infection of alveolar macrophages, more severe disease can result. In contrast, the induction of cytokines in SARS-CoV-2 storms occur more rapidly, they note, "possibly explaining why the symptoms of severely ill patients deteriorate rapidly."

Furthermore, compared with SARS-CoV-2, the influenza A viruses studied are better able to boost anti-inflammatory signaling by type I IFN-alpha and type I IFN-beta, thereby preventing the cytokine storm in many cases.

It Takes a Village

Type 1 IFN does not act alone in SARS-CoV-2, either. The researchers discovered that dysregulation of the type I IFN signaling affects a number of downstream cytokines, including IL-4, IL-12, IL-2, IL-10, and type II IFN.

"The findings suggest an inadequate type I interferon response followed up by a lack of anti-inflammatory response during SARS-CoV-2 infection," Jared Radbel, MD, told Medscape Medical News when asked to comment. 

"This supports, but does not directly affirm, the hypothesis that the CRS seen in COVID-19 is due to a lack of an appropriate anti-viral response, followed by overactivation of other compensatory and pro-inflammatory pathways,” added Radbel, a pulmonologist at Rutgers Health and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Limited Treatment Options

Peter Pickkers, MD, PhD, who also was not affiliated with the current study, addressed potential treatment. "The only adjuvant therapies that show a clinical benefit are immune-suppressive treatments — for example, dexamethasone or an IL-6 antibody like tocilizumab," he told Medscape Medical News.

"This indicates that the immune response is indeed deleterious for the patient," he added. "I would argue that the pulmonary immune response is profound and leads to damage to the lungs, and this is why anti-inflammatory effects show a benefit."

Dr Peter Pickkers

Interestingly, Pickkers and colleagues previously compared circulating cytokine levels in COVID-19 to other critical care conditions and found they were no higher. "In fact, they are similar to patients following trauma or cardiac arrest — diseases not known for their cytokine storm — and lower compared to patients with sepsis based on a bacterial infection," said Pickkers, professor, Faculty of Medical Sciences, Radboud University in Nijmegen, the Netherlands.

More Research Warranted

Olbei and colleagues evaluated studies up until summer 2020. "And in a fast-moving field like COVID-19 research, novel data is coming out constantly," Olbei said. He recommended an updated systematic review to gain more insight.

"Following that," he added, "more focused research is required to understand what the absence of these cytokines means for COVID-19 patients."

Some unanswered questions remain: Does dysregulation of the host immune response typically occur early, late or throughout the course of infection? What proportion of patients experience these cytokine storms? What other mechanisms alter the immune system reaction to SARS-CoV-2 and other pulmonary viral infections?

Olbei, Pickkers, and Radbel have disclosed no relevant financial relationships. Olbei received support for this study from the UKRI Biotechnological and Biosciences Research Council and Norwich Research Park Biosciences Doctoral Training Partnership.

Front Immunol. Published online March 1, 2021. Full text

Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and critical care. Follow Damian on Twitter:  @MedReporter.

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