Advancing precision medicine for acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV): Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics.

Working in an unprecedented time frame, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership developed and launched 9 master protocols between 14 April 2020 and 31 May 2021 to allow for the coordinated and efficient evaluation of multiple investigational therapeutic agents for COVID-19. The ACTIV master protocols were designed with a portfolio approach to serve the following patient populations with COVID-19: mild to moderately ill outpatients, moderately ill inpatients, and critically ill inpatients. To facilitate the execution of these studies and minimize start-up time, ACTIV selected several existing networks to launch the master protocols. The master protocols were also designed to test several agent classes prioritized by ACTIV that covered the spectrum of the disease pathophysiology. Each protocol, either adaptive or pragmatic, was designed to efficiently select those treatments that provide benefit to patients while rapidly eliminating those that were either ineffective or unsafe. The ACTIV Therapeutics-Clinical Working Group members describe the process by which these master protocols were designed, developed, and launched. Lessons learned that may be useful in meeting the challenges of a future pandemic are also described.

Rationale and Design of ORCHID: A Randomized Placebo-controlled Clinical Trial of Hydroxychloroquine for Adults Hospitalized with COVID-19.

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including 1) widespread, off-label use of the study drug before the availability of safety and efficacy data; 2) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; 3) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; 4) obtaining indistinguishable drug and placebo without delaying enrollment; and 5) rapidly obtaining administrative and regulatory approvals. Our goals in describing how the ORCHID trial progressed from study conception to enrollment of the first patient in 15 days are to inform the development of other high-quality, multicenter trials targeting COVID-19. We describe lessons learned to improve the efficiency of future clinical trials, particularly in the setting of pandemics. The ORCHID trial will provide high-quality, clinically relevant data on the safety and efficacy of hydroxychloroquine for the treatment of COVID-19 among hospitalized adults.Clinical trial registered with www.clinicaltrials.gov (NCT04332991).

Identifying Clinical Research Priorities in Adult Pulmonary and Critical Care. NHLBI Working Group Report.

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the NHLBI. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising preclinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data," causal inference using observational data, novel clinical trial designs, preclinical disease modeling, and understanding of recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state of, research priorities for, and future directions in adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including 1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment response with the goal of developing targeted, personalized interventions; 2) optimizing preclinical models by incorporating comorbidities, cointerventions, and organ support; 3) developing and applying novel clinical trial designs; and 4) advancing mechanistic understanding of injury and recovery to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial.

Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg [4 to 6 L in an 80-kg adult] during the first 6 hours) and later use of vasopressors, versus a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg [≤2 to 3 L]), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Early fluid therapy may enhance or maintain tissue perfusion by increasing venous return and cardiac output. However, fluid administration may also have deleterious effects by causing edema within vital organs, leading to organ dysfunction and impairment of oxygen delivery. Conversely, a restrictive fluids approach primarily relies on vasopressors to reverse hypotension and maintain perfusion while limiting the administration of fluid. Both strategies have some evidence to support their use but lack robust data to confirm the benefit of one strategy over the other, creating clinical and scientific equipoise. As part of the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network, we designed a randomized clinical trial to compare the liberal and restrictive fluids strategies, the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis trial. The purpose of this article is to review the current literature on approaches to early fluid resuscitation in adults with septic shock and outline the rationale for the upcoming trial.

Effect of public reporting on intensive care unit discharge destination and outcomes.

RATIONALE: Public reporting of hospital performance is designed to improve healthcare outcomes by promoting quality improvement and informing consumer choice, but these programs may carry unintended consequences. OBJECTIVE: To determine whether publicly reporting in-hospital mortality rates for intensive care unit (ICU) patients influenced discharge patterns or mortality. METHODS: We performed a retrospective cohort study taking advantage of a natural experiment in which California, but not other states, publicly reported hospital-specific severity-adjusted ICU mortality rates between 2007 and 2012. We used multivariable logistic regression adjusted for patient, hospital, and regional characteristics to compare mortality rates and discharge patterns between California and states without public reporting for Medicare fee-for-service ICU admissions from 2005 through 2009 using a difference-in-differences approach. MEASUREMENTS AND MAIN RESULTS: We assessed discharge patterns using post-acute care use and acute care hospital transfer rates and mortality using in-hospital and 30-day mortality rates. The study cohort included 936,063 patients admitted to 646 hospitals. Compared with control subjects, admission to a California ICU after the introduction of public reporting was associated with a reduced odds of post-acute care use in post-reform year 2 (ratio of odds ratios [ORs], 0.94; 95% confidence interval [CI], 0.91-0.96) and increased odds of transfer to another acute care hospital in both post-reform years (year 1: ratio of ORs, 1.08; 95% CI, 1.01-1.16; year 2: ratio of ORs, 1.43; 95% CI, 1.33-1.53). There were no significant differences in in-hospital or 30-day mortality. CONCLUSIONS: Public reporting of ICU in-hospital mortality rates was associated with changes in discharge patterns but no change in risk-adjusted mortality.

Hospital factors associated with discharge bias in ICU performance measurement.

OBJECTIVE: Performance assessments based on in-hospital mortality for ICU patients can be affected by discharge practices such that differences in mortality may reflect variation in discharge patterns rather than quality of care. Time-specific mortality rates, such as 30-day mortality, are preferred but are harder to measure. The degree to which the difference between 30-day and in-hospital ICU mortality rates-or "discharge bias"-varies by hospital type is unknown. The aim of this study was to quantify variation in discharge bias across hospitals and determine the hospital characteristics associated with greater discharge bias. DESIGN: Retrospective cohort study. SETTING: Nonfederal Pennsylvania hospital discharges in 2008. PATIENTS: Eligible patients were 18 years old or older and admitted to an ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used logistic regression with hospital-level random effects to calculate hospital-specific risk-adjusted 30-day and in-hospital mortality rates. We then calculated discharge bias, defined as the difference between 30-day and in-hospital mortality rates, and used multivariable linear regression to compare discharge bias across hospital types. A total of 43,830 patients and 134 hospitals were included in the analysis. Mean (SD) risk-adjusted hospital-specific in-hospital and 30-day ICU mortality rates were 9.6% (1.3) and 12.7% (1.5), respectively. Hospital-specific discharge biases ranged from -1.3% to 6.6%. Discharge bias was smaller in large hospitals compared with small hospitals, making large hospitals appear comparatively worse from a benchmarking standpoint when using in-hospital mortality instead of 30-day mortality. CONCLUSIONS: Discharge practices bias in-hospital ICU mortality measures in a way that disadvantages large hospitals. Accounting for discharge bias will prevent these hospitals from being unfairly disadvantaged in public reporting and pay-for-performance.

Nighttime intensivist staffing and the timing of death among ICU decedents: a retrospective cohort study.

INTRODUCTION: Intensive care units (ICUs) are increasingly adopting 24-hour intensivist physician staffing. Although nighttime intensivist staffing does not consistently reduce mortality, it may affect other outcomes such as the quality of end-of-life care. METHODS: We conducted a retrospective cohort study of ICU decedents using the 2009-2010 Acute Physiology and Chronic Health Evaluation clinical information system linked to a survey of ICU staffing practices. We restricted the analysis to ICUs with high-intensity daytime staffing, in which the addition of nighttime staffing does not influence mortality. We used multivariable regression to assess the relationship between nighttime intensivist staffing and two separate outcomes potentially related to the quality of end-of-life care: time from ICU admission to death and death at night. RESULTS: Of 30,456 patients admitted to 27 high-intensity daytime staffed ICUs, 3,553 died in the hospital within 30 days. After adjustment for potential confounders, admission to an ICU with nighttime intensivist staffing was associated with a shorter duration between ICU admission and death (adjusted difference: -2.5 days, 95% CI -3.5 to -1.5, p-value < 0.001) and a decreased odds of nighttime death (adjusted odds ratio: 0.75, 95% CI 0.60 to 0.94, p-value 0.011) compared to admission to an ICU without nighttime intensivist staffing. CONCLUSIONS: Among ICU decedents, nighttime intensivist staffing is associated with reduced time between ICU admission and death and reduced odds of nighttime death.

Viral infections of the central nervous system: a case-based review.

Three patients with viral infections of the central nervous system (CNS) were evaluated on an inpatient infectious diseases consultation service within a two-week period. These cases, caused by herpes simplex virus, varicella zoster virus and enterovirus, highlight the importance of viral pathogens in causing debilitating infections of the CNS and provide examples of the utility of molecular diagnostics in evaluating patients with encephalitis and meningitis. The importance of antiviral therapy is particularly underscored by these cases, as is the variability in response of patients to such agents.

"Diffusion-clinical mismatch" is associated with potential for early recovery of aphasia.

BACKGROUND: Diffusion-perfusion mismatch (perfusion-weighted imaging [PWI] abnormality minus diffusion-weighted imaging [DWI] abnormality) can identify candidates for acute stroke intervention, but PWI is often not obtainable. The authors hypothesized that language tests can predict volume of hypoperfusion, and thus mismatch, in acute left hemisphere stroke, and that the estimated mismatch can predict potential for early recovery of language. METHODS: A consecutive series of 81 patients with acute left hemisphere ischemic stroke underwent language testing within 1 day of MRI scans. Volumes of abnormality on PWI and DWI were measured without knowledge of language scores. Using tests that correlated well with PWI abnormality (oral naming and repetition), the authors computed an estimated PWI abnormality (ePWI) for each patient from a linear regression model and derived a diffusion-clinical percent mismatch ([ePWI-DWI/ePWI] x 100). The authors then tested the hypothesis that patients with > or =20% diffusion-clinical mismatch have a greater chance of short-term improvement in language by examining scores of the 23 patients with repeat testing within 1 week. RESULTS: Within-group comparisons: patients with > or =20% diffusion-clinical mismatch showed improvement in total language score within 1 week (Wilcoxon signed rank: p < 0.02), whereas patients without mismatch did not. Across-group comparison: patients with > or =20% mismatch showed more short-term improvement in language scores than those without mismatch (Mann-Whitney U: p < 0.05). CONCLUSIONS: Tests of oral naming or repetition can be used in patients with acute left hemisphere stroke to estimate perfusion-weighted imaging abnormality and compute a diffusion-clinical mismatch that may predict potential for short-term language improvement.

Crystal structure of the Ly49I natural killer cell receptor reveals variability in dimerization mode within the Ly49 family.

Natural killer (NK) cells play a crucial role in the detection and destruction of virally infected and tumor cells during innate immune responses. The cytolytic activity of NK cells is regulated through a balance of inhibitory and stimulatory signals delivered by NK receptors that recognize classical major histocompatabilty complex class I (MHC-I) molecules, or MHC-I homologs such as MICA, on target cells. The Ly49 family of NK receptors (Ly49A through W), which includes both inhibitory and activating receptors, are homodimeric type II transmembrane glycoproteins, with each subunit composed of a C-type lectin-like domain tethered to the membrane by a stalk region. We have determined the crystal structure, at 3.0 A resolution, of the murine inhibitory NK receptor Ly49I. The Ly49I monomer adopts a fold similar to that of other C-type lectin-like NK receptors, including Ly49A, NKG2D and CD69. However, the Ly49I monomers associate in a manner distinct from that of these other NK receptors, forming a more open dimer. As a result, the putative MHC-binding surfaces of the Ly49I dimer are spatially more distant than the corresponding surfaces of Ly49A or NKG2D. These structural differences probably reflect the fundamentally different ways in which Ly49 and NKG2D receptors recognize their respective ligands: whereas the single MICA binding site of NKG2D is formed by the precise juxtaposition of two monomers, each Ly49 monomer contains an independent binding site for MHC-I. Hence, the structural constraints on dimerization geometry may be relatively relaxed within the Ly49 family. Such variability may enable certain Ly49 receptors, like Ly49I, to bind MHC-I molecules bivalently, thereby stabilizing receptor-ligand interactions and enhancing signal transmission to the NK cell.