There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled “a randomized embedded multifactorial adaptive platform.” The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas. Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

A complex network of biological mediators underlies the clinical syndrome of sepsis. The nonspecific physiologic criteria of sepsis syndrome or the systemic inflammatory response syndrome do not adequately identify patients who might benefit from either conventional anti-infective therapies or from novel therapies that target specific mediators of sepsis. Validated biomarkers of sepsis may improve diagnosis and therapeutic decision making for these high-risk patients. To develop a methodologic framework for the identification and validation of biomarkers of sepsis. A small group meeting of experts in clinical epidemiology, biomarker development, and sepsis clinical trials; selective narrative review of the biomarker literature. The utility of a biomarker is a function of the degree to which it adds value to the available clinical information in the domains of screening, diagnosis, risk stratification, and monitoring of the response to therapy. We identified needs for greater standardization of biomarker methodologies, greater methodologic rigor in biomarker studies, wider integration of biomarkers into clinical studies (in particular, early phase studies), and increased collaboration among investigators, pharmaceutical industry, biomarker industry, and regulatory agencies. Biomarkers promise to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders. This transformation could aid therapeutic decision making, and hence improve the prognosis for patients with sepsis, but will require an unprecedented degree of systematic investigation and collaboration.

PD-L1 is a ligand for PD-1, and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. In this study, PD-L1 expression correlated negatively with rates of apoptosis in human neutrophils harvested from patients with sepsis. Coimmunoprecipitation assays on control neutrophils challenged with interferon-γ and LPS showed that PD-L1 complexes with the p85 subunit of phosphatidyl 3-kinase (PI3K) to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared with wild-type animals, PD-L1–deficient animals presented lower levels of plasma tumor necrosis factor-α and interleukin-6 (IL-6) and higher levels of IL-10 after CLP, and reduced 7-day mortality in CLP PD-L1–knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI3K–dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.