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Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

Asthma is a common chronic disease without cure. Our understanding of asthma onset, pathobiology, classification, and management has evolved substantially over the past decade; however, significant asthma-related morbidity and excess healthcare use and costs persist. To address this important clinical condition, the NHLBI convened a group of extramural investigators for an Asthma Research Strategic Planning workshop on September 18-19, 2014, to accelerate discoveries and their translation to patients. The workshop focused on (1) in utero and early-life origins of asthma, (2) the use of phenotypes and endotypes to classify disease, (3) defining disease modification, (4) disease management, and (5) implementation research. This report summarizes the workshop and produces recommendations to guide future research in asthma.

Asthma is remarkably heterogeneous, and there are multiple underlying inflammatory pathways and structural airway abnormalities that lead to symptomatic disease. Consequently, a current challenge in the field is to precisely characterize different types of asthma, with the goal of developing personalized approaches to therapy. In the current issue of the JCI, Dunican et al. developed a noninvasive way to assess airway dysfunction in asthma by measuring mucus accumulation using multidetector computed tomography (MDCT) and found that mucus plugging of small airways was remarkably common in subjects with severe asthma. This work highlights the importance of noninvasive imaging approaches in defining specific asthma subsets and guiding targeted therapies., Mucus score to determine airflow obstruction Asthma is a common disease characterized by intermittent wheezing, chest tightness, and cough and is caused by airway inflammation and airflow obstruction. Overproduction of [...]

Although platelets are the cellular mediators of thrombosis, they are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered bone marrow-resident (BM-resident) cells. However, platelet-producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared with BM Mks. We therefore sought to define the immune functions of lung Mks. Using single-cell RNA sequencing of BM and lung myeloid-enriched cells, we found that lung Mks, which we term [Mk.sub.L], had gene expression patterns that are similar to antigen-presenting cells. This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment, as evidenced by BM Mks having an [Mk.sub.L]-like phenotype under the influence of pathogen receptor challenge and lung-associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that [Mk.sub.L] internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, [Mk.sub.L] induced [CD4.sup.+] T cell activation in an MHC II-dependent manner both in vitro and in vivo. These data indicated that [Mk.sub.L] had key immune regulatory roles dictated in part by the tissue environment., Introduction Platelets are most commonly described as the megakaryocyte-derived (Mk-derived) cellular mediators of thrombosis. Mk differentiation and platelet production have been extensively studied in the bone marrow (BM) environment, but [...]

This document is a correction notice for an article titled "Budesonide promotes airway epithelial barrier integrity following double-stranded RNA challenge" published in the journal PLoS ONE. The correction is related to an incorrectly uploaded Figure 5. The corrected figure shows the results of a study conducted on mice, where therapeutic budesonide treatment was found to promote barrier integrity without affecting neutrophil accumulation. The study assessed various factors such as total protein and albumin levels, FITC-dextran levels, and neutrophil count. The authors of the article are Clara Rimmer, Savas Hetelekides, Sophia I. Eliseeva, Steve N. Georas, and Janelle M. Veazey. [Extracted from the article]

Protein kinase D (PKD) is a serine/threonine kinase family with three isoforms (PKD1–3) that are expressed in most cells and implicated in a wide array of signaling pathways, including cell growth, differentiation, transcription, secretion, polarization and actin turnover. Despite growing interest in PKD, relatively little is known about the role of PKD in immune responses. We recently published that inhibiting PKD limits proinflammatory cytokine secretion and leukocyte accumulation in mouse models of viral infection, and that PKD3 is highly expressed in the murine lung and immune cell populations. Here we focus on the immune‐related phenotypes of PKD3 knockout mice. We report that PKD3 is necessary for maximal neutrophil accumulation in the lung following challenge with inhaled polyinosinic:polycytidylic acid, a double‐stranded RNA, as well as following influenza A virus infection. Using reciprocal bone marrow chimeras, we found that PKD3 is required in the hematopoietic compartment for optimal neutrophil migration to the lung. Ex vivo transwell and chemokinesis assays confirmed that PKD3−/− neutrophils possess an intrinsic motility defect, partly because of reduced surface expression of CD18, which is critical for leukocyte migration. Finally, the peak of neutrophilia was significantly reduced in PKD3−/− mice after lethal influenza A virus infection. Together, these results demonstrate that PKD3 has an essential, and nonredundant, role in promoting neutrophil recruitment to the lung. A better understanding of the isoform‐specific and cell type–specific activities of PKD has the potential to lead to novel therapeutics for respiratory illnesses. [ABSTRACT FROM AUTHOR]

Inflammation-associated lung injury is a major cause of morbidity and mortality for patients in intensive care units. Although the cellular and molecular events that initiate lung inflammation are now well understood, the mechanisms that promote its resolution remain poorly defined. In this issue of the JCI, D'Alessio et al. show in a mouse model that recovery from acute lung injury is not simply a passive process, but involves Tregs in an active resolution program (see the related article beginning on page 2898)., Overview of lung injury Acute lung injury (ALI) is a syndrome defined by bilateral pulmonary infiltrates on chest radiography and arterial hypoxemia in the absence of left atrial hypertension. This [...]