Regenerative Metaplastic Clones in COPD Lung Drive Inflammation and Fibrosis.

Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema that represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers.

Five-Year Outcomes among U.S. Bronchiectasis and NTM Research Registry Patients.

Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM (P < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.

Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.

BACKGROUND: Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. METHODS: In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed. RESULTS: Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo. CONCLUSIONS: In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).

A Comparative Analysis of Catheter Directed Thrombolysis with Anticoagulation Alone or Systemic tPA in Acute Pulmonary Embolism with Cor Pulmonale.

BACKGROUND: Pulmonary embolism (PE) with cor pulmonale causes considerable mortality and morbidity. Randomized trials have failed to show a mortality difference between treatment modalities including anticoagulation (AC), Catheter directed thrombolysis (CDT) and systemic tPA (tissue plasminogen activator). METHODS: This is a cross-sectional retrospective case-control study utilizing the 2017 National Inpatient Sample (NIS). Patients admitted with acute PE with cor pulmonale were divided into groups based on whether they received anticoagulation, CDT or systemic tPA based on appropriate ICD-10 PCS codes. The AC group and CDT group were compared using univariate and multivariate analyses after adjusting for age, gender, race, comorbidities, insurance status and Charlson comorbidity index (CCI). Secondary outcomes included factors influencing length of stay (LOS) and total charges incurred. Similar analyses were done to compare the CDT group with the tPA group. RESULTS: In 2017, 13240 patients were admitted with acute PE and cor pulmonale, of whom 18% underwent CDT, 10% underwent systemic tPA and 72% underwent AC alone. Patients who received CDT over AC alone were significantly younger (61.5 vs. 65.5, p = 0.00). Mortality rate overall was 4.8% with tPA group, CDT group and AC alone group having a 11.2%, 3.0% and 4.4% mortality rate respectively. On multivariate analyses, there was no significant mortality difference between the CDT and AC groups (aOR 0.61, 0.34-1.1 95%CI, p = 0.103). Patients with liver disease had significantly higher mortality while obese patients had a significantly lower mortality after adjusting for treatment strategy and confounders. Length of stay (LOS) was not significantly different between the groups however, compared to AC alone, patients who underwent CDT or tPA incurred significantly higher total hospital charges. CONCLUSIONS: CDT offers an attractive alternative to tPA therapy; however, our study does not show an in-hospital mortality benefit. More studies are required to guide patient selection prior to establishing treatment protocols.

Nucleic Acid-based Testing for Noninfluenza Viral Pathogens in Adults with Suspected Community-acquired Pneumonia. An Official American Thoracic Society Clinical Practice Guideline.

Background: This document provides evidence-based clinical practice guidelines on the diagnostic utility of nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in adults with suspected community-acquired pneumonia (CAP).Methods: A multidisciplinary panel developed a Population-Intervention-Comparison-Outcome question, conducted a pragmatic systematic review, and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.Results: The panel evaluated the literature to develop recommendations regarding whether routine diagnostics should include nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in suspected CAP. The evidence addressing this topic was generally adjudicated to be of very low quality because of risk of bias and imprecision. Furthermore, there was little direct evidence supporting a role for routine nucleic acid-based testing of respiratory samples in improving critical outcomes such as overall survival or antibiotic use patterns. However, on the basis of direct and indirect evidence, recommendations were made for both outpatient and hospitalized patients with suspected CAP. Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was not addressed in the literature at the time of the evidence review.Conclusions: The panel formulated and provided their rationale for recommendations on nucleic acid-based diagnostics for viral pathogens other than influenza for patients with suspected CAP.

Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America.

Background: This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia.Methods: A multidisciplinary panel conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.Results: The panel addressed 16 specific areas for recommendations spanning questions of diagnostic testing, determination of site of care, selection of initial empiric antibiotic therapy, and subsequent management decisions. Although some recommendations remain unchanged from the 2007 guideline, the availability of results from new therapeutic trials and epidemiological investigations led to revised recommendations for empiric treatment strategies and additional management decisions.Conclusions: The panel formulated and provided the rationale for recommendations on selected diagnostic and treatment strategies for adult patients with community-acquired pneumonia.

Future Research Directions in Pneumonia. NHLBI Working Group Report.

Pneumonia is a complex pulmonary disease in need of new clinical approaches. Although triggered by a pathogen, pneumonia often results from dysregulations of host defense that likely precede infection. The coordinated activities of immune resistance and tissue resilience then dictate whether and how pneumonia progresses or resolves. Inadequate or inappropriate host responses lead to more severe outcomes such as acute respiratory distress syndrome and to organ dysfunction beyond the lungs and over extended time frames after pathogen clearance, some of which increase the risk for subsequent pneumonia. Improved understanding of such host responses will guide the development of novel approaches for preventing and curing pneumonia and for mitigating the subsequent pulmonary and extrapulmonary complications of pneumonia. The NHLBI assembled a working group of extramural investigators to prioritize avenues of host-directed pneumonia research that should yield novel approaches for interrupting the cycle of unhealthy decline caused by pneumonia. This report summarizes the working group's specific recommendations in the areas of pneumonia susceptibility, host response, and consequences. Overarching goals include the development of more host-focused clinical approaches for preventing and treating pneumonia, the generation of predictive tools (for pneumonia occurrence, severity, and outcome), and the elucidation of mechanisms mediating immune resistance and tissue resilience in the lung. Specific areas of research are highlighted as especially promising for making advances against pneumonia.

National trends in patient safety for four common conditions, 2005-2011.

BACKGROUND: Changes in adverse-event rates among Medicare patients with common medical conditions and conditions requiring surgery remain largely unknown. METHODS: We used Medicare Patient Safety Monitoring System data abstracted from medical records on 21 adverse events in patients hospitalized in the United States between 2005 and 2011 for acute myocardial infarction, congestive heart failure, pneumonia, or conditions requiring surgery. We estimated trends in the rate of occurrence of adverse events for which patients were at risk, the proportion of patients with one or more adverse events, and the number of adverse events per 1000 hospitalizations. RESULTS: The study included 61,523 patients hospitalized for acute myocardial infarction (19%), congestive heart failure (25%), pneumonia (30%), and conditions requiring surgery (27%). From 2005 through 2011, among patients with acute myocardial infarction, the rate of occurrence of adverse events declined from 5.0% to 3.7% (difference, 1.3 percentage points; 95% confidence interval [CI], 0.7 to 1.9), the proportion of patients with one or more adverse events declined from 26.0% to 19.4% (difference, 6.6 percentage points; 95% CI, 3.3 to 10.2), and the number of adverse events per 1000 hospitalizations declined from 401.9 to 262.2 (difference, 139.7; 95% CI, 90.6 to 189.0). Among patients with congestive heart failure, the rate of occurrence of adverse events declined from 3.7% to 2.7% (difference, 1.0 percentage points; 95% CI, 0.5 to 1.4), the proportion of patients with one or more adverse events declined from 17.5% to 14.2% (difference, 3.3 percentage points; 95% CI, 1.0 to 5.5), and the number of adverse events per 1000 hospitalizations declined from 235.2 to 166.9 (difference, 68.3; 95% CI, 39.9 to 96.7). Patients with pneumonia and those with conditions requiring surgery had no significant declines in adverse-event rates. CONCLUSIONS: From 2005 through 2011, adverse-event rates declined substantially among patients hospitalized for acute myocardial infarction or congestive heart failure but not among those hospitalized for pneumonia or conditions requiring surgery. (Funded by the Agency for Healthcare Research and Quality and others.).

New guidelines for nosocomial pneumonia.

PURPOSE OF REVIEW: Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain important causes of morbidity and mortality in hospitalized patients. New evidence-based guidelines for the diagnosis and treatment of these entities were released by the Infectious Diseases Society of America and the American Thoracic Society in 2016. This review summarizes the recommendations contained within these guidelines and their supporting rationale. RECENT FINDINGS: With respect to diagnosis of HAP and VAP, the guidelines suggest using semiquantitative cultures of noninvasively obtained respiratory samples instead of quantitative cultures of invasively obtained samples. With respect to antibiotic treatment, the guidelines separate the treatment approach for VAP and HAP (non-VAP), and stress the importance of devising an appropriate empiric regimen based on an appropriate hospital or unit-specific antibiogram. For VAP, coverage of methicillin-resistant Staphylococcus aureus is recommended only when patients have specific risk factors for multidrug-resistant (MDR) pathogens or in units where greater than 10-20% of Staphylococcus aureus isolates are methicillin resistant. Single coverage for MDR gram-negative pathogens can be used in many HAP and VAP patients without risk factors for MDR pathogens when the antibiogram demonstrates that at least 90% of gram negatives are sensitive to the agent being considered for monotherapy. A 7-day course of antibiotics was recommended for most patients, including those with glucose nonfermenting gram-negative organisms. SUMMARY: New guidelines for the diagnosis and treatment of HAP and VAP contain several novel recommendations regarding the diagnosis and treatment of these entities.

How to translate the new hospital-acquired and ventilator-associated pneumonia guideline to the bedside.

PURPOSE OF REVIEW: Hospital-acquired pneumonia and ventilator-associated pneumonia remain significant causes of morbidity, mortality, and financial burden in the United States and around the globe. Although guidelines for the management of patients with these conditions have been available for several years, implementation remains challenging. Here, we review the most common barriers faced by clinicians in implementing the current guidelines and offer suggestions for improved adherence. RECENT FINDINGS: Recent studies have identified barriers to the implementation of the guidelines regarding management of hospital-acquired and ventilator-associated pneumonia. The most common difficulties encountered are lack of awareness of the guidelines, practice variation among providers delivering care to affected patients, lack of antibiogram information, and lack of antibiotic stewardship programs. SUMMARY: Translating the current hospital-acquired and ventilator-associated pneumonia guidelines to the bedside requires understanding of the current barriers affecting care of patients with these conditions. Adopting clinical guidelines facilitates the management of these patients and improves outcomes. Dissemination of the guidelines, provider education, antibiotic stewardship programs, access to local antibiogram information, audit and feedback, electronic tools and leadership commitment are likely to play important roles in guideline implementation. More studies on hospital-acquired and ventilator-associated pneumonia guideline implementation are necessary to identify the most effective interventions.

Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

Executive Summary: Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

Predictors of Pseudomonas and methicillin-resistant Staphylococcus aureus in hospitalized patients with healthcare-associated pneumonia.

BACKGROUND AND OBJECTIVE: Patients with healthcare-associated pneumonia (HCAP) are at high risk of infection with multidrug-resistant (MDR) pathogens. Factors discriminating infection with MDR Gram-negative (MDR-GN) organism from infection with methicillin-resistant Staphylococcus aureus (MRSA) are not well understood and patients are often treated for both organisms. This study was performed to determine risk factors predicting pneumonia due to Pseudomonas versus MRSA. METHODS: Veterans age ≥65 hospitalized with HCAP between 2002 and 2012 were identified from the Veterans Affairs administrative databases. Patients were identified with Pseudomonas pneumonia, MRSA pneumonia or neither according to the International Classification of Diseases, 9th Revision, Clinical Modification codes. We assessed unadjusted and adjusted associations of patient characteristics and HCAP due to Pseudomonas or MRSA. RESULTS: Of the 61,651 patients with HCAP, 1156 (1.9%) were diagnosed with Pseudomonas pneumonia, 641 (1.0%) with MRSA pneumonia and 59,854 (97.1%) with neither. MRSA pneumonia was positively associated with male gender, age >74, diabetes, chronic obstructive pulmonary disease (COPD), recent nursing home or hospital stay, recent exposure to fluoroquinolone or antibiotics treating Gram-positive organisms, and severe pneumonia. MRSA pneumonia was negatively associated with complicated diabetes. Pseudomonas pneumonia was positively associated with recent hospital stay, immunocompromise, COPD, hemiplegia, recent exposure to inhaled corticosteroids, ß-lactam/cephalosporin/carbapenem antibiotics, antibiotics against Gram-positive organisms, 'other antibiotics' and severe pneumonia. Pseudomonas pneumonia was negatively associated with age >84, higher socioeconomic status, drug abuse and diabetes. CONCLUSIONS: Patient characteristics may assist in identifying patients at risk for HCAP due to Pseudomonas or MRSA.

Community Level Association between Home Health and Nursing Home Performance on Quality and Hospital 30-day Readmissions for Medicare Patients.

We evaluated whether community-level home health agencies and nursing home performance is associated with community-level hospital 30-day all-cause risk-standardized readmission rates for Medicare patients used data from the Centers for Medicare & Medicaid Service from 2010 to 2012. Our final sample included 2,855 communities that covered 4,140 hospitals with 6,751,713 patients, 13,060 nursing homes with 1,250,648 residents, and 7,613 home health agencies providing services to 35,660 zipcodes. Based on a mixed effect model, we found that increasing nursing home performance by one star for all of its 4 measures and home health performance by 10 points for all of its 6 measures is associated with decreases of 0.25% (95% CI 0.17-0.34) and 0.60% (95% CI 0.33-0.83), respectively, in community-level risk-standardized readmission rates.

New therapeutic options for noncystic fibrosis bronchiectasis.

PURPOSE OF REVIEW: Patients with noncystic fibrosis bronchiectasis (NCFB) share many of the respiratory symptoms of cystic fibrosis and often are provided therapies effective in cystic fibrosis, often without clear evidence of benefit. There are currently no approved therapies for NCFB, but in recent years, there has been increased interest in developing new therapies due to the increasing prevalence and perceived unmet needs. This review is meant to provide the most recent information to clinicians about currently available and pipeline therapies for NCFB. RECENT FINDINGS: Inhaled antibiotics may provide effective bacterial suppressive therapy with an acceptable safety profile in adults with NCFB, although evidence of improved outcomes is limited. Inhaled hyperosmolar agents such as hypertonic saline and mannitol are promising but study results have been mixed. Macrolide antibiotics have anti-inflammatory properties and, in several randomized controlled trials, demonstrated the benefit of chronic low-dose treatment. Other anti-inflammatory agents that have shown promising preliminary results include statins and neutrophil elastase inhibitors. SUMMARY: There is high-quality evidence supporting chronic low-dose macrolide therapy in patients with NCFB. There is limited evidence of benefit of other therapies, including inhaled antibiotics and pharmacologic agents to enhance mucus clearance.