James T. Good

Adult Respiratory Distress Syndrome: Risk with Common Predispositions

A 1-year survey of patients in three hospitals identified 936 patients who had one predisposition and 57 who had several predispositions to the adult respiratory distress syndrome. From the total predisposed population of 993 patients, 68 subsequently developed the syndrome. An additional 20 patients developed the syndrome from causes other than eight identified predispositions, to bring the total of patients studied to 88. A highly significant difference (p less than 0.0001) was found in the incidence rates of the syndrome between patients with one and several predispositions (5.8 versus 24.6 per 100 patients). Within 72 hours of onset of predisposition, 89.5% of patients who developed the syndrome had been intubated and placed on mechanical ventilation. Fifty-seven of the 88 patients (64.8%) with the syndrome died. By the 14th day 90% of deaths had occurred. There were no age- or sex-specific differences in either incidence or mortality rates. Case fatality rates of the syndrome were high in all predisposed groups.

Pleural Fluid pH in Malignant Effusions: Diagnostic, Prognostic, and Therapeutic Implications

STUDY OBJECTIVE To determine whether the measurement of pleural fluid pH in malignant effusions has diagnostic use, predicts survival, and has therapeutic implications. DESIGN A prospective comparison of cytologic examinations and pleural biopsy results, survival, and response to chemical pleurodesis with tetracycline in patients with normal-pH (7.30 or greater) and low-pH (less than 7.30) malignant pleural effusions. SETTING Academic medical center, university referral hospital, city hospital, and Veterans Administration hospital. PATIENTS Sixty patients with malignant pleural effusions, proven at either initial thoracentesis by cytologic examination or within 4 months of initial thoracentesis by repeat thoracentesis, thoracotomy, or autopsy, were followed until death. INTERVENTION Twenty-one patients, 12 with normal pleural fluid pH and 9 with low pleural fluid pH, were treated with tube thoracostomy and intrapleural tetracycline for symptomatic, recurrent pleural effusions. MAIN RESULTS The 20 patients with low-pH malignant effusions had a significantly greater positivity on initial pleural fluid cytologic evaluation, a shorter mean survival, and a poorer response to tetracycline pleurodesis compared with 40 patients with normal-pH malignant effusions. CONCLUSIONS Determination of pleural fluid pH in malignant effusions provides a rational approach to further diagnostic testing, prognostic information, and a rationale for palliative treatment.

The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma

RATIONALE The role of airway microbiome in corticosteroid response in asthma is unknown. OBJECTIVES To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids. METHODS 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation. MEASUREMENTS AND MAIN RESULTS Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids. CONCLUSIONS A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.

Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33

BACKGROUND Asthma in a mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model in which asthma features persisted for 6 months after cessation of allergen exposure. OBJECTIVE We sought to elucidate factors contributing to the persistence of asthma. METHODS We used a combination of immunologic, genetic, microarray, and pharmacologic approaches to dissect the mechanism of asthma persistence. RESULTS Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of recombination-activating gene (Rag1)(-/-) bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and type 2 innate lymphoid cells (ILC2s) through lethal irradiation and transplantation of Rag2(-/-)γc(-/-) bone marrow or blockade of IL-33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed-forward circuits between ILC2s and epithelial cells. Epithelial IL-33 induced ILC2s, a rich source of IL-13. The latter directly induced epithelial IL-33, establishing a positive feedback circuit. IL-33 autoinduced, generating another feedback circuit. IL-13 upregulated IL-33 receptors and facilitated IL-33 autoinduction, thus establishing a feed-forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL-33 and ILC2 levels were increased in the airways of asthmatic patients. IL-33 levels correlated with disease severity. CONCLUSIONS We present a critical network of feedback and feed-forward interactions between epithelial cells and ILC2s involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma, they were redundant in maintaining airway hyperreactivity and remodeling.

Macrolides in the treatment of asthma.

Purpose of review This review summarizes the importance of macrolide therapy in the treatment of asthma, discusses macrolide mechanisms of action, and outlines new clinical data supporting their use. The effects of macrolides on both the innate and adaptive immune responses are discussed. Recent findings Subacute bacterial infection with both typical and atypical organisms contributes to poor asthma control. Identification of pathogens using polymerase chain reaction (PCR) and cultures from bronchoscopic samples directs antibiotic therapy and improves asthma control. PCR identification of Mycoplasma pneumoniae and Chlamydophila pneumoniae in asthmatics best identifies the macrolide responsive phenotype. Summary Because of their effect on protein synthesis, macrolides have both antimicrobial and anti-inflammatory properties. Both mechanisms appear to be important in their clinical efficacy in treating a wide variety of pulmonary disorders, including asthma.

Naloxone, Beta Endorphins, and High-Altitude Pulmonary Edema

Excerpt To the editor: High-altitude pulmonary edema develops in certain unacclimatized and susceptible persons acutely exposed to extreme elevation. Since its original report the clinical manifest...

Airway and serum biochemical correlates of refractory neutrophilic asthma

Background: Despite progress in the diagnosis and management of asthma, many patients have poorly controlled or refractory asthma (RA). The mechanism of this RA is not well understood. Objective: We sought to explore the relationship between neutrophils and other biomarkers of RA. Method: Sixty patients with RA, 30 patients with nonrefractory asthma (NRA), and 20 healthy subjects were enrolled. We performed a comprehensive characterization of these study subjects, which included laboratory and pulmonary function studies, chest computed tomography, and bronchoscopy with bronchoalveolar lavage (BAL). We analyzed BAL fluid and serum for a total of 244 biomolecules using a multiplex assay and correlated them with clinical and other laboratory parameters. Results: RA was significantly different from NRA with regard to pulmonary function indices, bronchial basement membrane thickness, and BAL fluid neutrophil and lymphocyte counts but not eosinophil counts. BAL fluid neutrophil counts negatively and positively correlated with forced vital capacity and age, respectively. Of the 244 biomolecules studied, 52 and 14 biomolecules from BAL fluid and serum, respectively, were significantly different among the study groups. Thirteen of these 52 molecules correlated with BAL fluid neutrophil counts. BAL fluid from 40% of patients with RA was positive for a pathogenic microbe. Infection‐negative neutrophilic RA was associated with an increase in levels of select biomarkers of inflammation in the serum, suggesting the presence of systemic inflammation. Conclusions: RA was associated with increased numbers of neutrophils and proneutrophilic biomolecules in the airways. Subclinical infection was present in 40% of patients with RA, which likely contributed to neutrophilic inflammation. A subgroup of patients with noninfected neutrophilic RA was associated with systemic inflammation. Graphical abstract Figure. No Caption available.

Glutathione Depletion Accelerates Cigarette Smoke-Induced Inflammation and Airspace Enlargement

The study objective was to assess age-related changes in glutathione (GSH) adaptive response to cigarette smoke (CS) exposure. Older cigarette smokers show a decline (67%) in lung epithelial lining fluid (ELF) GSH and a 1.8-fold decreased GSH adaptive response to cigarette smoking with a concomitant elevation (47%) of exhaled nitric oxide compared with younger smokers. In order to isolate the changes in tissue GSH from other age-related effects, pharmacological inhibition of the rate limiting step in GSH synthesis was employed to examine the lungs response to CS exposure in young mice. The γ-glutamylcysteine ligase inhibitor L-buthionine-sulfoximine (BSO) was administered in the drinking water (20 mM) to decrease by half the in vivo GSH levels to those found in aged mice and humans. Mice were then exposed to CS (3 h/day) for 5 or 15 days. Biochemical analysis of the ELF and lung tissue revealed an inhibition of the CS-induced GSH adaptive response by BSO with a concurrent increase in mixed protein-GSH disulfides indicating increased cysteine oxidation. The prevention of the GSH adaptive response led to an increase in pro-inflammatory cytokines present in the lung. Airspace enlargement is a hallmark of lung emphysema and was observed in mice treated with BSO and exposed to CS for as little as 15 days, whereas these types of changes normally take up to 6 months in this model. BSO treatment potentiated both lung elastase and matrix metalloproteinase activity in the CS group. These data suggest that age-related decline in the GSH adaptive response can markedly accelerate many of the factors thought to drive CS-induced emphysema.

An Index to Objectively Score Supraglottic Abnormalities in Refractory Asthma

BACKGROUND Patients with refractory asthma frequently have elements of laryngopharyngeal reflux (LPR) with potential aspiration contributing to their poor control. We previously reported on a supraglottic index (SGI) scoring system that helps in the evaluation of LPR with potential aspiration. However, to further the usefulness of this SGI scoring system for bronchoscopists, a teaching system was developed that included both interobserver and intraobserver reproducibility. METHODS Five pulmonologists with expertise in fiber-optic bronchoscopy but novice to the SGI participated. A training system was developed that could be used via Internet interaction to make this learning technique widely available. RESULTS By the final testing, there was excellent interreader agreement (κ of at least 0.81), thus documenting reproducibility in scoring the SGI. For the measure of intrareader consistency, one reader was arbitrarily selected to rescore the final test 4 weeks later and had a κ value of 0.93, with a 95% CI of 0.79 to 1.00. CONCLUSIONS In this study, we demonstrate that with an organized educational approach, bronchoscopists can develop skills to have highly reproducible assessment and scoring of supraglottic abnormalities. The SGI can be used to determine which patients need additional intervention to determine causes of LPR and gastroesophageal reflux. Identification of this problem in patients with refractory asthma allows for personal, individual directed therapy to improve asthma control.BACKGROUND Patients with refractory asthma frequently have elements of laryngopharyngeal reflux (LPR) with potential aspiration contributing to their poor control. We previously reported on a supraglottic index (SGI) scoring system that helps in the evaluation of LPR with potential aspiration. However, to further the usefulness of this SGI scoring system for bronchoscopists, a teaching system was developed that included both interobserver and intraobserver reproducibility. METHODS Five pulmonologists with expertise in fiber-optic bronchoscopy but novice to the SGI participated. A training system was developed that could be used via Internet interaction to make this learning technique widely available. RESULTS By the final testing, there was excellent interreader agreement (κ of at least 0.81), thus documenting reproducibility in scoring the SGI. For the measure of intrareader consistency, one reader was arbitrarily selected to rescore the final test 4 weeks later and had a κ value of 0.93, with a 95% CI of 0.79 to 1.00. CONCLUSIONS In this study, we demonstrate that with an organized educational approach, bronchoscopists can develop skills to have highly reproducible assessment and scoring of supraglottic abnormalities. The SGI can be used to determine which patients need additional intervention to determine causes of LPR and gastroesophageal reflux. Identification of this problem in patients with refractory asthma allows for personal, individual directed therapy to improve asthma control.

Naloxone: Effects on hypoxic pulmonary vasoconstriction

To determine the effect of naloxone on the hypoxic pulmonary vasoconstrictive response, six mongrel dogs were rendered hypoxic with 10% oxygen and were given either saline or naloxone. Following hypoxia all dogs had significant increases in mean pulmonary artery pressure (PAP) and pulmonary arterial resistance index (PARI) without changes in cardiac output or systemic blood pressure. Beta endorphins did not change at any time following hypoxia. Dogs receiving naloxone had significant lowering of PAP and PARI without changes in plasma beta endorphin levels. We conclude that naloxone attenuates hypoxic pulmonary vasoconstriction without measurable alterations of plasma beta endorphin levels.