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Critically ill patients on mechanical ventilatory support for acute respiratory failure are vulnerable to numerous complications and high mortality risk. Care is mostly supportive, and efficacious pharmacologic treatments have been difficult to develop because of the underlying complexity of acute respiratory failure and its heterogeneous presentation in patients. In recent years, adverse outcomes in patients with the most severe form of acute respiratory failure, acute respiratory distress syndrome (ARDS), have been associated with an exacerbated immuno-inflammatory response. However, the mechanisms that drive a deleterious immune response are unclear, and there may be interplay with genetic or environmental factors.
A research study led by Georgios D. Kitsios, MD, PhD, from the Division of Pulmonary, Allergy and Critical Care Medicine at UPMC, reinforces the critical role of the microbiome in the upper and lower respiratory tract in critically ill patients needing mechanical ventilator support for acute respiratory failure. Dr. Kitsios and colleagues' study shows that respiratory tract dysbiosis, i.e., disruption of microbial communities, is correlated with both an exacerbated inflammatory response as well as worse patient outcomes, including lower 30-day survival.
The study1 was published in the American Journal of Respiratory and Critical Care Medicine in December 2020. An editorial2 authored by Drs. Farhana Ali and Daniel A. Sweeney from the University of California, San Diego, accompanied the paper and discussed the study's clinical implications and importance.
Dr. Kitsios and colleagues’ study examined oral swab and endotracheal aspirate samples using microbial DNA sequencing techniques (16S rRNA gene sequencing) from a cohort of 301 patients on mechanical ventilatory support for acute respiratory failure, including patients with ARDS or sepsis.
The study sought to characterize the microbiome profiles of the upper and lower respiratory tracts, as well as the systemic inflammatory response in blood samples, and examined whether a relationship existed between the composition of the microbiome, the nature of the inflammatory response, and ultimately how these patients progressed in outcomes.
“ARDS and sepsis present across such a broad spectrum, with similarly diverse outcomes. The underlying biological heterogeneity of these syndromes, and the various presentations of patients admitted to the ICU in need of mechanical ventilatory support mirror our lack of broadly efficacious pharmacologic therapies,” says Dr. Kitsios. “The underlying mechanisms of this complexity, and the potentially modifiable factors that can influence it form the basis for our research.”
Dr. Kitsios and colleagues’ study showed that they could agnostically define three clusters of microbial profiles in the lower respiratory tract of mechanically-ventilated patients. Patients belonging to a microbial cluster of low biodiversity (low alpha diversity) and high abundance of typical pathogenic bacteria had intensified inflammatory responses, and worse clinical outcomes, including overall survival and the amount of time spent on mechanical ventilatory support, even after adjustment for common clinical predictors and confounders.
“Our research builds upon prior work by our group and others, moving us toward a more concrete understanding of the role of the lung microbiome in critical illness,” says Dr. Kitsios. "Our research demonstrates that respiratory tract dysbiosis predicts poor outcomes in mechanically-ventilated patients, and may represent a modifiable target for therapy. Perhaps if we can in some way restore normalcy to the microbial communities within our patients' airways, we might be able to dampen adverse inflammatory responses and ultimately improve our patients’ outcomes."
1. Kitsios GD, Yang H, Yang L, Qin S, Fitch A, Wang X-H, Fair K, Evankovich J, Bain W, Shah F, Li K, Methe B, Benos PV, Morris A, McVerry BJ. Respiratory Tract Dysbiosis Is Associated With Worse Outcomes in Mechanically Ventilated Patients. Am J Resp Crit Care Med. 2021; 202(12): 1666-1667.
2. Farhana A, Sweeney DA. In Pursuit of Microbiome-Based Therapies for Acute Respiratory Failure. Am J Resp Crit Care Med. 2021; 202(12): 1616-1617. Editorial.
Georgios D. Kitsios, MD, PhD, is an Assistant Professor of Medicine in the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh School of Medicine. He also serves as the director of the American Board of Internal Medicine (ABIM) Research Pathway in the Internal Medicine Residency Program, and is a co-leader alongside Bryan McVerry, MD, of the ICU Microbiome Program at the Center for Medicine & The Microbiome. Dr. Kitsios’s translational research focuses on the development of microbial DNA sequencing-based diagnostics for pneumonia and sepsis in the ICU to improve upon major deficiencies in sensitivity and timeliness of the current culture-dependent diagnostic paradigm. His work further examines the ability to define ARDS subphenotypes from lung microbiome profiles and host innate immune response to explain the clinical heterogeneity of the syndrome and allow for better targeting of interventions.
Dr. Kitsios also is interested in the impact of the gut microbiome on critical illness outcomes and the use of microbial replacement therapies with fecal transplant for the eradication of multidrug-resistant organisms in chronically critically ill patients.