New Study Finds Likely Driver of COVID-19 Deaths – Dispels Previous Theories

A buildup of coronavirus in the lungs is likely to blame for the high death rates seen during the pandemic, a new study finds. The results contrast with previous suspicions that concomitant infections, such as bacterial pneumonia or overreaction of the body’s immune system, played an important role in an increased risk of death, the researchers say.

Led by researchers at the NYU Grossman School of Medicine, the new study showed that people who died from COVID-19 had an average of 10 times as much virus or viral load in their lower respiratory tract as critically ill patients who survived their illness. Meanwhile, the researchers found no evidence that a secondary bacterial infection was the cause of the deaths, although they cautioned that it could be due to the frequent course of antibiotics given to critically ill patients.

“Our findings suggest that the body’s inability to cope with the large numbers of viruses that infect the lungs is largely responsible for the deaths from COVID-19 during the pandemic,” said lead author Imran Sulaiman, MD, PhD, a researcher. adjunct professor in the Department of Medicine at NYU Langone Health.

Current guidelines from the Centers for Disease Control and Prevention, he notes, do not encourage the use of antivirals such as remdesivir for critically ill patients with mechanical ventilation. But Sulaiman says NYU Langone’s research findings suggest these drugs could still remain a valuable tool in treating these patients.

Despite previous concerns that the virus could prompt the immune system to attack the body’s own lung tissue and lead to dangerous levels of inflammation, the researchers found no evidence that this was a major contributor to COVID-19 deaths in the group studied. In fact, Sulaiman notes that the strength of the immune response seemed proportional to the amount of virus in the lungs.

The coronavirus has so far killed more than 4 million people worldwide, researchers say. Those placed on mechanical ventilators to breathe are doing particularly poorly, with 70 percent across the country succumbing to the disease. In particular, experts attribute the high mortality in other viral pandemics such as the Spanish flu in 1918 and the swine flu in 2009 to a secondary bacterial infection. However, it remained unclear whether a similar problem affected people with COVID-19.

The new study, published online today (Aug. 31, 2021) in the journal Nature Microbiology, was designed to clarify the role of secondary infections, viral load and immune cell populations in COVID-19 death, Sulaiman said. He says the study provides the most detailed overview of the lower respiratory tract environment in coronavirus patients.

For the study, the researchers collected bacterial and fungal samples from the lungs of 589 men and women admitted to NYU Langone facilities in Manhattan and Long Island. All required mechanical ventilation. For a subset of 142 patients who also had a bronchoscopy procedure to clear their airways, the researchers analyzed the amount of virus in their lower airways and identified the microbes present by studying tiny bits of the germs’ genetic code. The study authors also examined the type of immune cells and connections in the lower respiratory tract.

Among the findings, the study found that those who died had an average of 50 percent less production of a type of immune chemical that targets the coronavirus compared to the COVID-19 patients who survived the disease. These custom proteins are part of the body’s adaptive immune system, a subset of cells and chemicals that “remember” that new microbes have entered, better preparing the body for future exposure.

“These results suggest that a problem with the adaptive immune system prevents it from effectively fighting the coronavirus,” said study lead author Leopoldo Segal, MD. “If we can identify the root of this problem, we may be able to find an effective treatment that works by boosting the body’s own defenses,” said Segal, an associate professor in the Department of Medicine at NYU Langone.

He warns that the researchers only studied coronavirus patients who survived their first two weeks of hospitalization. It’s possible, he says, that bacterial infections or autoimmune responses may play a greater role in earlier-onset COVID-19 death.

Segal says the research team next plans to observe how the microbial community and immune response in the lungs of coronavirus patients changes over time.

Reference: “Microbial Signatures in the Lower Airways of Mechanically Ventilated COVID-19 Patients Associated with Poor Clinical Outcome” by Imran Sulaiman, Matthew Chung, Luis Angel, Jun-Chieh J. Tsay, Benjamin G. Wu, Stephen T. Yeung Kelsey Krolikowski, Yonghua Li, Ralf Duerr, Rosemary Schluger, Sara A. Thannickal, Akiko Koide, Samaan Rafeq, Clea Barnett, Radu Postelnicu, Chang Wang, Stephanie Banakis, Lizzette Pérez-Pérez, Guomiao Shen, George Jour, Peter Meyn, Joseph Carpenito , Xiuxiu Liu, Kun Ji, Destiny Collazo, Anthony Labarbiera, Nancy Amoroso, Shari Brosnahan, Vikramjit Mukherjee, David Kaufman, Jan Bakker, Anthony Lubinsky, Deepak Pradhan, Daniel H. Sterman, Michael Weiden, Adriana Heguy, Laura Evans, Timothy M Uyeki, Jose C. Clemente, Emmie de Wit, Ann Marie Schmidt, Bo Shopsin, Ludovic Desvignes, Chan Wang, Huilin Li, Bin Zhang, Christian V. Forst, Shohei Koide, Kenneth A. Stapleford, Kamal M. Khanna, Elodie Ghedin and Leopoldo N. Segal, August 31 2021, Nature Microbiology j.
DOI: 10.1038/s41564-021-00961-5

Funding for the study was provided by National Institutes of Health grants R37 CA244775, R01 HL125816, R21 AI158997, R01 AI143861, R01 AI143861-02S, R01 DK110014, P20 CA252728, and P30 CA016087; and CDC Foundation grant UWSC1085.1. Further financing was provided by Ingelheim Pharma GmbH & Co. Bristol-Myers Squibb, Celgene Corporation, Genentech Inc., Gilead, GlaxoSmithKline plc, Janssen Pharmaceutical Companies of Johnson & Johnson, Novartis Institutes for Biomedical Research, Pfizer Inc. and Sanofi.

In addition to Sulaiman and Segal, other NYU Langone researchers were Luis Angel, MD; Jun-Chieh Tsay, MD; Benjamin Wu, MD; Kelsey Krolikowski, BA; Yonghua Li, MD, PhD; Rosemary Schluger, RN; Stephen Yeung, PhD; Ralf Duerr, MD, PhD; Sara Thannickal; Chang Wang, MS; George Jour, MD; Guomiao Shen, PhD; Joseph Carpenito, B.S.; Xiuxiu Liu, MD; Kun Ji, MD; Destiny Collazo, BA; Anthony Labarbiera, BA; Nancy Amoroso, MD; Shari Brosnahan, MD; Vikramjit Mukherjee, MD; David Kaufman, MD; Jan Bakker, MD, PhD; Anthony Lubinsky, MD; Deepak Pradhan, MD; Daniel Sterman, MD; Michael Weiden, MD; Adriana Heguy; doctorate; Ludovic Desvignes, PhD; Shohei Koide, PhD; Kenneth Stapleford, PhD; Kamal Khanna, PhD; Ann Marie Schmidt, MD; Bo Shopsin, MD, PhD; Peter Meyn; Chan Wang, PhD; and Huilin Li, PhD. Other study co-investigators were Matthew Chung, PhD; Stephanie Banakis, MS; and Elodie Ghedin, PhD, at the National Institute of Allergy and Infectious Diseases in Bethesda, Md.; Lizzette Perez-Perez, MSc; and Emmie De Wit, PhD, at the National Institute of Allergy and Infectious Diseases in Hamilton, Mont.; Laura Evans, MD, MSc, at the University of Washington in Seattle; Timothy Uyeki, MD, at the Centers for Disease Control and Prevention in Atlanta, Georgia; and Jose Clememte, PhD; Bin Zhang, PhD; and Christian Forst, PhD, at the Icahn School of Medicine at Mount Sinai in New York City.