J. Mark Madison

Chronic obstructive pulmonary disease

Summary Acute exacerbations of underlying COPD are a common cause of respiratory deterioration. Developments have been made in preventive measures, but admission to hospital for acute exacerbations can be expected to remain common. Several expert consensus guidelines have been published to define the appropriate management of COPD patients. These consensus guidelines generally agree, but all acknowledge a lack of large well-controlled clinical studies, especially studies focusing on the management of acute exacerbations. Consequently, many potential controversies exist about the details of managing patients with acute exacerbations. Although studies of many fundamental aspects of management are still needed, the results of controlled clinical trials are sufficient to emphasise the importance of a careful clinical assessment, supplemental oxygen, inhaled bronchodilators to partially improve airway obstruction, corticosteroids to decrease the likelihood of treatment failures and to speed recovery, antibiotics, especially in severe patients, and non-invasive positive-pressure ventilation for treatment of acute ventilatory failure in selected patients.

The cough reflex and its relation to gastroesophageal reflux

Each cough involves a complex reflex arc beginning with the stimulation of sensory nerves that function as cough receptors. There is evidence, primarily clinical, that the sensory limb of the reflex exists in and outside of the lower respiratory tract. Although myelinated, rapidly adapting pulmonary stretch receptors (RARs), also known as irritant receptors, are the most likely type of sensory nerve that stimulates the cough center in the brain, afferent C-fibers and slowly adapting pulmonary stretch receptors (SARs) also may modulate cough. RARS, C-fibers, and SARs have been identified in the distal esophageal mucosa; however, studies have not been performed to determine whether they can participate in the cough reflex. Although gastroesophageal reflux disease can potentially stimulate the afferent limb of the cough reflex by irritating the upper respiratory tract without aspiration and by irritating the lower respiratory tract by micro- or macroaspiration, there is evidence that strongly suggests that reflux commonly provokes cough by stimulating an esophageal-bronchial reflex. Theoretically, the pathways of this reflex may be modeled in a variety of ways, and these are speculated upon in this article. The predominant role of acid in triggering cough by means of this reflex is unclear because of conflicting results from provocative challenge studies. It is interesting to speculate that a distal esophageal-bronchial reflex evolved as an early warning defense so that coughing could be started, just in case the refluxate were to reach the inlet of the lower respiratory tract. That is, thinking teleologically, it is possible that an esophageal-bronchial reflex evolved as one of several mechanisms designed to protect the lungs from aspiration of gastric contents.

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 in adults with interstitial lung disease

Purpose of review Although dyspnea is the most common and distressing symptom in patients with chronic interstitial lung disease, chronic cough, a potentially debilitating symptom that impairs health-related quality of life, has been described as another common symptom in these patients. Recent findings Many patients with interstitial lung disease have their chronic cough mistakenly attributed to that condition when, in fact, the cough is due to more common disorders such as asthma, upper airway cough syndrome (previously referred to as postnasal drip syndrome), or gastroesophageal reflux disease. This article presents new data on a select group of patients and shows that more than 50% of patients with interstitial lung disease who are referred to a cough clinic for evaluation can have cough caused by these other more common causes of chronic cough. It is also clear, however, that chronic interstitial lung disease, by itself, can cause chronic cough, perhaps related to an increased cough reflex sensitivity. Summary Clinicians should be cautious when ascribing chronic cough to interstitial lung disease without first completely evaluating for other possible causes of cough. When cough is attributed to interstitial lung disease, therapy, when available, should be directed at the specific underlying diagnosis. Corticosteroids may be helpful in alleviating chronic cough in some cases of interstitial lung disease, but, because of the potential side effects of corticosteroids and lack of proven efficacy for some types of interstitial lung disease (e.g. idiopathic pulmonary fibrosis), treatment should weigh the risks and benefits for each patient individually. Nonspecific antitussive therapies shown to be clinically effective for chronic cough in general are codeine and dextromethorphan, but these have not been studied specifically in interstitial lung disease.

Loss of chemokine SDF-1alpha-mediated CXCR4 signalling and receptor internalization in human hepatoma cell line HepG2.

Expression of the chemokine stromal cell-derived factor-1alpha (SDF-1alpha) is absent from many carcinomas, including hepatomas. We note an early signalling defect in the hepatocellular carcinoma (HCC) cell line HepG2 that expresses the CXCR4 receptor and binds biotin-labelled SDF, but fails to stimulate downstream signalling events after engagement with SDF. In HepG2, the SDF/CXCR4 interaction did not result in calcium influx, phosphorylation and internalization of CXCR4, nor in a rapid phosphorylation of p44/42 MAP kinase. There were no CXCR4 mutations in the second chemokine binding loop or C terminal phosphorylation and internalization domains. The downstream signalling machinery in HepG2 appears to be intact since transfection of wild-type CXCR4 restored functional responsiveness. We conclude that HepG2 is unresponsive to SDF stimulation because of a defect located after receptor binding but before the activation of the signalling cascade. A hypothetical blocking molecule could hinder receptor internalization or CXCR4 signalling.

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.

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 authors 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.

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.

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

Large‐conductance, calcium‐activated potassium (BKCa) 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 BKCa 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 μm) was added to the bath during the recordings. Immunofluorescence studies with selective antibodies against the α and β1 subunits of BKCa 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 BKCa 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 BKCa 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 BKCa channel activity, but inhibited the effect of IL‐4. Thus, HBSMC contain functional BKCa 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 BKCa 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