Core B:  Clinical Phenotyping and Technology Core

PROJECT SUMMARY CORE B Lower respiratory tract infections cause 79% of deaths from infectious diseases in the United States. The international burden of pneumonia is even greater; pneumonia is the leading cause of death in resource- challenged countries and in the top 10 causes of death in the entire world. Viruses were increasingly recognized as a cause of community-acquired pneumonia (CAP), including in patients requiring mechanical ventilation or vasopressor therapy, even before the SARS-CoV-2 pandemic. The Core B will support testing the overall hypothesis of our PPG that the mortality and persistent organ failure in CAP, including influenza-, SARS-CoV-2, and other virus-induced CAP, represent a failure of resolution and lung repair. Mechanisms that underlie persistence of lung injury and progression of multiple organ dysfunction in the absence of pathogen persistence are incompletely understood, and all four projects in this proposal address this knowledge deficit with sophisticated animal models. The overarching goal of Core B is to validate findings from these murine models of influenza pneumonia in patients with severe CAP caused by viral pathogens and to provide support to all projects with statistical and bioinformatics analysis. Most CAP patients requiring mechanical ventilation (severe CAP) meet the definition of sepsis and the acute respiratory distress syndrome (ARDS). Recent data suggest that endotypes vary in sepsis and ARDS, with at least hypo- and hyper-inflammatory patterns, if not more. Unfortunately, most of these studies performed limited phenotyping of patients. In particular, discrimination between persistent infection versus persistent inflammation is not clear. For severe viral pneumonia, this includes not only viral clearance but assessment of the presence and clearance of bacterial superinfection. The major hypothesis of Core B is that human correlation of findings from murine influenza models requires careful and extensive clinical phenotyping. Core B will directly support the Specific Aims of each PPG Project with the following aims: Specific Aim 1. Provide bronchoalveolar lavage (BAL) fluid from mechanically ventilated patients with severe viral pneumonia due to influenza A virus or SARS-CoV-2. Specific Aim 2. Define the microbiologic milieu at each BAL sampling time point. Specific Aim 3. Apply robust clinical phenotypes and relevant clinical endpoints. Specific Aim 4. Provide statistical and bioinformatics support. Ultimately, the goal of this PPG is to define immune system pathways and mechanisms of failed resolution and repair following viral pneumonia that are amenable to therapeutic interventions. Core B is integral to supporting this goal by demonstrating strong clinical correlations to findings from the proposed murine models.