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Over the past few years, researchers at �ٺ���Ƶ Health have developed culture-independent techniques to study microbe–host interactions in the lung mucosa that may affect lung cancer, bronchiectasis, chronic obstructive pulmonary disease, and other conditions. The team has routinely collected samples from the lungs of patients receiving clinically indicated bronchoscopies or lung surgeries.

When the SARS-CoV-2 pandemic hit New York, Leopoldo N. Segal, MD, associate professor in the and the lead investigator in �ٺ���Ƶ’s Lung Microbiome Program, realized that the same research infrastructure might be useful to study factors that can predict coronavirus disease (COVID-19) patient outcomes. His laboratory has since channeled its unique capabilities toward collecting lower-airway samples from hospitalized patients receiving a bronchoscopy to clear lung secretions or a tracheostomy to aid mechanical ventilation. So far, the lab’s effort, funded by the National Institutes of Health (NIH), has yielded lower-airway samples from more than 150 patients with severe acute respiratory syndrome due to COVID-19.

“The unique opportunity and main focus of our research has been to start understanding what factors are associated with poorer outcomes in patients with SARS-CoV-2,” Dr. Segal says. “Why are patients having such a heterogeneous clinical evolution of this disease?” Answering that question, in turn, may allow clinicians to tailor their therapeutic interventions to counter the underlying contributors to worse outcomes.

For the most severe clinical courses, Dr. Segal is focusing on three potential explanations: Patients may have uncontrollable viral replication that leads to cytotoxicity and lung damage, they may be co-infected with a second pathogen, or their immune system’s exaggerated response may result in self-inflicted inflammatory damage. To distinguish among these possibilities, Dr. Segal is characterizing the microbe–host biosignatures associated with different outcomes.

Among its complementary approaches, his lab is quantifying each study participant’s viral load via targeted RT-PCR and conducting extensive RNA and DNA sequencing to profile the composition of the upper- and lower-airway microbiomes. Because it’s a culture-independent technique, Dr. Segal says, the unbiased sequencing approach can capture the entire viral and bacterial community. In addition, the lab is measuring levels of proinflammatory cytokines and chemokines and of messenger RNA transcription in the lower-airway lung cells to gauge the reaction of each patient’s immune system. Such measurements may point toward contributing host factors such as a larger inflammatory response or higher abundance of lung cell ACE2 receptors, a major portal for viral infection. “We know that some patients have different viral loads, and we’re looking to see how the host immune phenotype and host transcriptome are different among patients with different viral loads,” Dr. Segal says.

Biomarkers Identifying Patient Subgroups Could Yield More Personalized Therapeutics

To extend its observations, the lab is collaborating with , associate professor in the , to study the effects of SARS-CoV-2 infection in a mouse model with a humanized ACE2 receptor. “We’re looking at the transcriptome of those mice and comparing it with the transcriptome of the human patients infected with this coronavirus,” Dr. Segal says. “The next step would be to add some of the microbial dysbiotic signatures that we can identify from the human cohort and see how that modulates the severity of the infection in the mice.”

A dysbiotic signature may reflect a change in bacterial or viral diversity, a shift toward or away from particular populations, or the selective enrichment or depletion of key taxa. “The question is whether the outcome is related only to this virus or whether it’s also related to some of the other microbial or host factors that might be present in the lung,” Dr. Segal says. If the lab can identify a reliable signature, the research could yield an effective biomarker for patients at higher risk for poorer outcomes.

More important, he says, the effort could identify biosignatures to help define different patient subgroups. One of such signatures, for example, might suggest the need for therapeutics that decrease viral replication. Another might point toward countering co-infection with a second pathogen. A third might suggest the need to modulate the patient’s immune response. Hospitals are already employing separate strategies for patients with COVID-19, such as treating some with steroids and others with type 1 interferon. “We don’t know which patients will benefit from any of this,” Dr. Segal says. “We are treating them as a whole, rather than personalized to each individual’s status. So I think this type of investigation can allow us to dissect the heterogeneity among different patients.”

Monitoring COVID-19’s Chronic Symptoms and Potential Effects on Lung Cancer

Aided by its strong infrastructure, the Segal Lab has extended its reach to investigate several related COVID-19 questions. For one extension, Dr. Segal is collaborating with Rany Condos, MD, clinical professor of medicine, who has led �ٺ���Ƶ’s effort to establish a post–COVID-19 pulmonary clinic and patient registry. Together they are conducting a longitudinal study of the COVID-19 patient subgroup with “long-haulers syndrome,” who are experiencing chronic fatigue, ongoing shortness of breath, or other lingering symptoms.

The program is delving into both the underlying mechanism and the clinical evolution, Dr. Segal says. One possibility is that the microbial dysbiosis or exaggerated immune response seen during an acute COVID-19 infection may not fully resolve in such patients. “It could be that you have a different response and have some persistence of this very inflammatory state,” he says.

The high rate of prior COVID-19 infection in the New York metropolitan region has led to another intriguing line of research as well. As part of a supplemental NIH grant, the Segal Lab is investigating whether prior COVID-19 infection alters the presentation or evolution of the lower-airway immune profile or microbial profile in patients with newly diagnosed early-stage or advanced lung cancer. One big question is whether prior infection with the coronavirus might spur a more aggressive presentation of lung cancer. Another is whether the infection—known to boost the immune system—could increase the risk of autoimmune complications in patients with cancer receiving immunotherapy. If so, the research could alert clinicians to the need for careful monitoring of side effects and cancer progression.