Managing Chronic Cough Associated with Idiopathic Pulmonary Fibrosis - Will Nalbuphine Fill an Unmet Need?

In this issue of NEJM Evidence, Maher et al.1 report the results of a randomized, controlled, 22-day treatment crossover trial comparing the antitussive effect of extended-release nalbuphine, an opioid agonist-antagonist, with placebo in a cohort of patients with definite or probable idiopathic pulmonary fibrosis (IPF). In this small, short-term trial of 38 evaluable patients, the active drug was associated with a 75.1% reduction in daytime objective cough frequency (the primary outcome) compared with a 22.6% reduction in placebo-treated patients, yielding a substantial and statistically significant 52.5 percentage point placebo-adjusted change from baseline.

Effect of mindfulness training on asthma quality of life and lung function: a randomised controlled trial.

BACKGROUND: This study evaluated the efficacy of a mindfulness training programme (mindfulness-based stress reduction (MBSR)) in improving asthma-related quality of life and lung function in patients with asthma. METHODS: A randomised controlled trial compared an 8-week MBSR group-based programme (n=42) with an educational control programme (n=41) in adults with mild, moderate or severe persistent asthma recruited at a university hospital outpatient primary care and pulmonary care clinic. Primary outcomes were quality of life (Asthma Quality of Life Questionnaire) and lung function (change from baseline in 2-week average morning peak expiratory flow (PEF)). Secondary outcomes were asthma control assessed by 2007 National Institutes of Health/National Heart Lung and Blood Institute guidelines, and stress (Perceived Stress Scale (PSS)). Follow-up assessments were conducted at 10 weeks, 6 and 12 months. RESULTS: At 12 months MBSR resulted in clinically significant improvements from baseline in quality of life (differential change in Asthma Quality of Life Questionnaire score for MBSR vs control: 0.66 (95% CI 0.30 to 1.03; p<0.001)) but not in lung function (morning PEF, PEF variability and forced expiratory volume in 1 s). MBSR also resulted in clinically significant improvements in perceived stress (differential change in PSS score for MBSR vs control: -4.5 (95% CI -7.1 to -1.9; p=0.001)). There was no significant difference (p=0.301) in percentage of patients in MBSR with well controlled asthma (7.3% at baseline to 19.4%) compared with the control condition (7.5% at baseline to 7.9%). CONCLUSIONS: MBSR produced lasting and clinically significant improvements in asthma-related quality of life and stress in patients with persistent asthma, without improvements in lung function. CLINICAL TRIAL REGISTRATION NUMBER: Asthma and Mindfulness-Based Reduction (MBSR) Identifier: NCT00682669. clinicaltrials.gov.

Chronic Cough Due to Stable Chronic Bronchitis: CHEST Expert Panel Report.

BACKGROUND: Chronic cough due to chronic bronchitis (CB) causes significant impairment in quality of life, and effective treatment strategies are needed. We conducted a systematic review on the management of chronic cough due to CB to update the recommendations and suggestions of the American College of Chest Physicians (CHEST) 2006 guideline on this topic. METHODS: This systematic review asked three questions: (1) What are the clinical features of the history that suggest a patient's cough-phlegm syndrome is due to CB? (2) Can treatment of stable CB improve or eliminate chronic cough? (3) Can therapy that targets chronic cough due to CB prevent or reduce the occurrence of acute CB exacerbations? Studies of adult patients with CB were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using the CHEST organization methodology. RESULTS: The search strategy used an assortment of descriptors and assessments to identify studies of chronic cough due to CB. CONCLUSIONS: The evidence supporting the management of chronic cough due to CB is limited overall and of low quality. This article provides guidance on treatment by presenting suggestions based on the best currently available evidence and identifies gaps in our knowledge and areas for future research.

Vibration response imaging technology in healthy subjects.

OBJECTIVE: The vibration response imaging device that we studied (VRIxp) records the intensity and location of lung sounds during a cycle of breathing. The goals of this study were to describe the characteristic features and quantitative lung data recorded by the VRIxp device from healthy asymptomatic subjects. SUBJECTS AND METHODS: Breath sounds (frequency range, 150-250 Hz) recorded from the backs of 151 healthy asymptomatic subjects (96 nonsmokers and 55 smokers) by the VRIxp device were mapped to create a sequence of 2D images. Three raters interpreted and scored the images for predefined static and dynamic features. In addition, quantitative lung data were analyzed for characteristic regional distributions. RESULTS: The readers of the images had good inter- and intrarater agreement. Image development in 93% of the evaluations showed an inspiratory and expiratory phase with a progressive and regressive stage that developed bilaterally in a vertical and synchronized manner. Characteristic image features of the maximum energy frame included a smooth, rounded, uninterrupted contour and a planar distribution, area size, and intensity that had right-left symmetry. Quantitative lung data expressed as percentages of the total (100%) vibration energy were normally distributed with mean values (+/- SD) of 55% +/- 6% for the left lung and 45% +/- 6% for the right lung. Most of the subjects with images, quantitative lung data, or both lacking these typical features were cigarette smokers or had a history of smoking (p < 0.05). CONCLUSION: Breath sounds in healthy asymptomatic subjects can be recorded and displayed in a dynamic series of images that have predictable and characteristic features recognizable and complemented by quantitative lung data. Identification and description of these characteristic image features in this study will facilitate future studies of vibration imaging in specific pulmonary diseases.

Leadership Primer for Current and Aspiring Pulmonary, Critical Care, and Sleep Medicine Academic Division Chiefs.

An academic medical career traditionally revolves around patient care, teaching, and scholarly projects. Thus, when an opportunity for a leadership role arises, such as division chief, the new leader is often unprepared with little or no formal leadership training. In this focused review, academic leaders of the Association of Pulmonary, Critical Care, and Sleep Division Directors describe several leadership concepts adapted from the business sector and apply their years of experience to aid new division chiefs with their first day on the job. The first 90 days are highlighted to include achieving early wins; performing a division-wide Strengths, Weaknesses, Opportunities, Threats analysis; establishing division rapport; redefining the division infrastructure; avoiding conflicts; and managing the relationship with the department chair. The five levels of leadership applicable to academic medicine are discussed: position, permission, production, people, and pinnacle. Finally, emotional intelligence and behavior styles crucial to leadership success are reviewed.

IL-4 inhibits calcium transients in bovine trachealis cells by a ryanodine receptor-dependent mechanism.

IL-4 and IL-13 have important roles in the pathogenesis of asthma. A novel finding was that brief exposure of airway smooth muscle cells to IL-4 inhibited carbachol-stimulated calcium transients. We hypothesized that IL-4 inhibits transients by decreasing calcium store content and tested this by measuring the effects of IL-4 on transients induced by a nonspecific ionophore. Bovine trachealis cells were loaded with fura 2-AM, and cytosolic calcium concentrations ([Ca2+]i) were measured in single cells by digital microscopy. Stimulation (S1) with carbachol (10 microM) caused rapid, transient increases in [Ca2+]i to 1299 +/- 355 nM (n=5). After recovery of calcium stores, stimulation (S2) of the same cells with ionomycin (10 microM), in the absence of extracellular calcium, also increased [Ca2+]i to give S2/S1 ratio of 1.03 +/- 0.29. However, after 20 min of IL-4 (50 ng/ml), but not IL-13, ionomycin transients were decreased to 0.50 +/- 0.16 (S2/S1, P=0.02, n=6). IL-4 did not inhibit transients with ryanodine receptor calcium release channels (RyR) blocked by ryanodine (200 microM) (S2/S1=1.01+/-0.11) but still did in the presence of 8-bromo cyclic ADP-ribose, an antagonist of cyclic ADP-ribose (cADPR) signaling at RyR (S2/S1=0.48+/-0.13). Together, findings suggest that IL-4 decreases intracellular calcium stores by mechanisms dependent on RyR, but not on cADPR signaling.

Pharmacotherapy of chronic cough in adults.

Chronic cough is a debilitating symptom for which patients commonly seek medical attention. Among adult non-smokers who are not taking an angiotensin-converting enzyme inhibitor and have a normal or near normal chest radiograph, postnasal drip syndrome caused by a variety of rhinosinus conditions, asthma and non-asthmatic eosinophilic bronchitis and gastro-oesophageal reflux disease singly or in combination, are the most common diagnoses underlying chronic cough. Pharmacotherapy for chronic cough can be either specific or non-specific. Specific therapy is preferable and the most effective as it is directed at the aetiologies and pathophysiological mechanisms responsible for cough. In contrast, non-specific therapy is used only in limited clinical settings, as it is directed at the symptom rather than underlying aetiologies and aims only to control, rather than eliminate cough.

Integrating advanced practice providers into medical critical care teams.

Because there is increasing demand for critical care providers in the United States, many medical ICUs for adults have begun to integrate nurse practitioners and physician assistants into their medical teams. Studies suggest that such advanced practice providers (APPs), when appropriately trained in acute care, can be highly effective in helping to deliver high-quality medical critical care and can be important elements of teams with multiple providers, including those with medical house staff. One aspect of building an integrated team is a practice model that features appropriate coding and billing of services by all providers. Therefore, it is important to understand an APP's scope of practice, when they are qualified for reimbursement, and how they may appropriately coordinate coding and billing with other team providers. In particular, understanding when and how to appropriately code for critical care services (Current Procedural Terminology [CPT] code 99291, critical care, evaluation and management of the critically ill or critically injured patient, first 30-74 min; CPT code 99292, critical care, each additional 30 min) and procedures is vital for creating a sustainable program. Because APPs will likely play a growing role in medical critical care units in the future, more studies are needed to compare different practice models and to determine the best way to deploy this talent in specific ICU settings.

Cough: a worldwide problem.

Cough is a common and important respiratory symptom that can produce significant complications for patients and be a diagnostic challenge for physicians. An organized approach to evaluating cough begins with classifying it as acute, subacute, or chronic in duration. Acute cough lasting less than 3 weeks may indicate an acute underlying cardiorespiratory disorder but is most commonly caused by a self-limited viral upper respiratory tract infection (eg, common cold). Subacute cough lasting 3 to 8 weeks commonly has a postinfectious origin; among the causes, Bordetella pertussis infection should be included in the differential diagnosis. Chronic cough lasts longer than 8 weeks. When a patient is a nonsmoker, is not taking an angiotensin-converting enzyme inhibitor, and has a normal or near-normal chest radiograph, chronic cough is most commonly caused by upper airway cough syndrome, asthma, nonasthmatic eosinophilic bronchitis, or gastroesophageal reflux disease alone or in combination.

Accuracy of gray-scale coding in lung sound mapping.

Stethoscope evaluation of the lungs is widely accepted and practiced; however, there are some widely recognized, major limitations with its use. A safe device that helped solve these limitations by translating sound into objective, quantifiable images would have clinical utility. Translating lung sounds into quantifiable images in which regional differences or asymmetry in intensities of breath sounds are presented as gradients in gray-scale is not a trivial process. Healthy lungs and lung pathology are characterized by different patterns of regional breath sound distribution and, therefore, the accuracy of mapping gray-scale images must be ensured in a controlled systematic fashion prior to clinical use of such a technique. Vibration response imaging (VRI) maps lung sounds from 40 sensors to a two-dimensional gray-scale image. To assess mapping accuracy, a simulated lung sound map with uniform signals was compared to modified maps where sound signals were reduced (1-3db) at one sensor. Also, 8 readers evaluated the gray-scale images. The computer algorithm accurately displayed gray-scale coding changes in correct locations in 97% of images. There was 95+/-4% accuracy rate by readers to correctly identify gray-scale changes. In addition, quantitative data at different stages of signal processing were investigated in a LSM of a subject with asthma. Signal processing was 97% accurate overall in that the gray-scale values from which the image was derived corresponded with intensity values from recorded signals. These results suggest VRI accurately maps acoustic signals to a gray-scale image and that trained readers can detect small changes.

Hypersensitivity pneumonitis: clinical perspectives.

CONTEXT: The clinical course of hypersensitivity pneumonitis (HSP) is highly variable and its diagnosis clinically challenging. OBJECTIVE: To provide a concise review of major clinical, radiographic, and laboratory findings that permits diagnosis of HSP from the standpoint of a clinician/pulmonologist. DATA SOURCES: Review of major contemporary and historical literature in combination with the author's experience and viewpoints. CONCLUSIONS: The approach to the diagnosis of HSP is multidisciplinary. For patients being evaluated for unexplained dyspnea and cough and an unknown interstitial disease process, the initial evaluation should include detailed environmental and occupational histories with ancillary testing such as serology, chest imaging, inhalation challenges, and bronchoalveolar lavage, as indicated. In uncertain cases, lung biopsy is recommended.

Interleukin-4 activates large-conductance, calcium-activated potassium (BKCa) channels in human airway smooth muscle cells.

Large-conductance, calcium-activated potassium (BK(Ca)) channels are regulated by voltage and near-membrane calcium concentrations and are determinants of membrane potential and excitability in airway smooth muscle cells. Since the T helper-2 (Th2) cytokine, interleukin (IL)-4, is an important mediator of airway inflammation, we investigated whether IL-4 rapidly regulated BK(Ca) activity in normal airway smooth muscle cells. On-cell voltage clamp recordings were made on subconfluent, cultured human bronchial smooth muscle cells (HBSMC). Interleukin-4 (50 ng ml(-1)), IL-13 (50 ng ml(-1)) or histamine (10 microm) was added to the bath during the recordings. Immunofluorescence studies with selective antibodies against the alpha and beta1 subunits of BK(Ca) were also performed. Both approaches demonstrated that HBSMC membranes contained large-conductance channels (>200 pS) with both calcium and voltage sensitivity, all of which is characteristic of the BK(Ca) channel. Histamine caused a rapid increase in channel activity, as expected. A new finding was that perfusion with IL-4 stimulated rapid, large increases in BK(Ca) channel activity (77.2 +/- 63.3-fold increase, P < 0.05, n = 18). This large potentiation depended on the presence of external calcium. In contrast, IL-13 (50 ng ml(-1)) had little effect on BK(Ca) channel activity, but inhibited the effect of IL-4. Thus, HBSMC contain functional BK(Ca) channels whose activity is rapidly potentiated by the cytokine, IL-4, but not by IL-13. These findings are consistent with a model in which IL-4 rapidly increases near-membrane calcium concentrations to regulate BK(Ca) activity.

Laryngeal candidiasis mimicking malignancy.

Isolated laryngeal candidiasis in immunocompetent individuals is a rare entity with fewer than 40 cases reported in the literature. Laryngeal candidiasis secondary to inhaled steroid therapy is usually mild and has been reported in 10% to 15% of patients complaining of dysphonia during treatment. We present a case of laryngeal candidiasis mimicking laryngeal carcinoma in an immunocompetent patient being treated with inhaled fluticasone for chronic obstructive pulmonary disease. Biopsy of the lesion failed to show any signs of malignancy, and patient responded well to oral fluconazole therapy.

Adenosine A1 receptors mediate mobilization of calcium in human bronchial smooth muscle cells.

Adenosine stimulates contraction of airway smooth muscle, but the mechanism is widely considered indirect, depending on release of contractile agonists from mast cells and nerves. The goal was to determine whether adenosine, by itself, directly regulates calcium signaling in human bronchial smooth muscle cells (HBSMC). Primary cultures of HBSMC from normal subjects were loaded with fura 2-AM, and cytosolic calcium concentrations ([Ca(2+)](i)) were determined ratiometrically by imaging single cells. The nonselective adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), and the adenosine A(1) receptor agonist, N(6)-cyclopentyladenosine (CPA), both stimulated rapid, transient increases in [Ca(2+)](i). In contrast, there were no calcium responses to 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adenosine (100 nM) or N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (100 nM), selective agonists at adenosine A(2A) receptors and adenosine A(3) receptors, respectively. Calcium responses to NECA and CPA were inhibited by 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A(1) receptor antagonist, and by pertussis toxin (PTX). In other experiments, NECA stimulated calcium transients in the absence of extracellular calcium, but not when cells were preincubated in cyclopiazonic acid or thapsigargin to empty intracellular calcium stores. Calcium responses were attenuated by xestospongin C and 2-aminoethoxydiphenylborane, inhibitors of inositol trisphosphate (IP(3)) receptors, and by U73122, an inhibitor of phospholipase C. It was concluded that stimulation of adenosine A(1) receptors on HBSMC rapidly mobilizes intracellular calcium stores by a mechanism dependent on PTX-sensitive G proteins, and IP(3) signaling. These findings suggest that, in addition to its well-established indirect effects on HBSMC, adenosine also has direct effects on contractile signaling pathways.