The complement pathway, particularly the alternative complement (AP) pathway, is an ancient immune surveillance system developed as a mechanism to eliminate pathogen or cellular debris before the development of specific immune responses. This pathway has ?built-in? regulators of its own activation that prevent collateral tissue damage, and the imbalance of the positive and negative arms of the pathway may result in collateral tissue damage during profound illness. The goal of this application is to utilize the existing biospecimen collection that are stored in the NHLBI Biologic Specimen Repository and test whether alternative complement pathway (AP) activity and key components of the alternative pathway predict overall survival in patients with ARDS. We propose to use serum samples available from subjects enrolled in the Lisofylline for ALI/ARDS trial (LARMA) study to determine AP activity and explore the balance of complement factor B (CFB) an essential proximal mediator of AP activation, and CFH, a negative regulator of AP activation, levels. We also propose to use plasma samples from subjects enrolled in the Statins for Acutely Injured Lungs from Sepsis trial (SAILS) to assess the balance of CFB and CFH levels and association with inflammation and mortality. Our preliminary data from a single center cohort of critically ill mechanically ventilated patients with acute respiratory failure show that higher AP activity, but not classical complement pathway activity, is associated with reduced all-cause mortality. Enhanced AP function is associated with reduced risk of bloodstream infection, and serum from individuals with enhanced AP function show ability to substantially inhibit extensively-drug resistant carbepenemase-producing Klebsiella pneumoniae growth in vitro. Moreover, increased AP function is associated with higher CFB and CFH levels and both higher CFB and CFH levels predict enhanced survival. The major hypothesis is that alternative pathway activity (AH50) and key components of AP predict overall survival in patients with ARDS from two multi-center, randomized, prospective trials available through BioLINCC.
Aim 1 will test the association between AP activity, CFB and CFH levels, and risk of 28-day mortality in patients enrolled in LARMA. As secondary endpoints, we will test the relationship between AP activity and ventilator-free days, organ failure-free days for the five non-pulmonary organs examined in the original LARMA study.
Aim 2 will identify whether CFB and CFH levels predict mortality in a cohort with sepsis-associated acute lung injury. As secondary endpoints, we will examine the relationship between CFB, CFH levels and ventilator-free days, organ-failure free days, and systemic inflammation as measured by C-reactive protein in the original SAILS cohort. Understanding the balance of immune activation and regulatory factors is an important step toward design of future clinical trials and successful completion of the work proposed may provide new opportunities for targeting therapy to those with acquired AP complement deficiency in the critical care setting.
Acute Respiratory Distress Syndrome (ARDS) is the final common pathway for a variety of direct and indirect insults to the lungs and is clinically defined as acute respiratory failure characterized by diffuse lung leak. Although biomarkers that identify sub-phenotypes ARDS and predict outcome are important in strategizing about clinical trial design, none thus far provides a functional ?readout? of robust immune capacity and resilience in ARDS patients. The goal of this application is to utilize the existing biospecimen collection that are stored in the NHLBI Biologic Specimen Repository to determine whether the ability to boost alternative complement pathway function during critical illness is protective and improves survival in ARDS patients.
