Michael G. Crooks

Gastroesophageal Reflux and Idiopathic Pulmonary Fibrosis: A Review

The histological counterpart of idiopathic pulmonary fibrosis is usual interstitial pneumonia, in which areas of fibrosis of various ages are interspersed with normal lung. This pattern could be explained by repeated episodes of lung injury followed by abnormal wound healing responses. The cause of the initiating alveolar epithelial injury is unknown, but postulated mechanisms include immunological, microbial, or chemical injury, including aspirated gastric refluxate. Reflux is promoted by low basal pressure in the lower oesophageal sphincter and frequent relaxations, potentiated by hiatus hernia or oesophageal dysmotility. In susceptible individuals, repeated microaspiration of gastric refluxate may contribute to the pathogenesis of IPF. Microaspiration of nonacid or gaseous refluxate is poorly detected by current tests for gastroesophageal reflux which were developed for investigating oesophageal symptoms. Further studies using pharyngeal pH probes, high-resolution impedance manometry, and measurement of pepsin in the lung should clarify the impact of reflux and microaspiration in the pathogenesis of IPF.

Coagulation and anticoagulation in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an incurable, progressive interstitial lung disease with a prognosis that is worse than that of many cancers. Epidemiological studies have demonstrated a link between IPF and thrombotic vascular events. Coagulation and fibrinolytic systems play central roles in wound healing and repair, processes hypothesised to be abnormal within the IPF lung. Animal models of pulmonary fibrosis have demonstrated an imbalance between thrombosis and fibrinolysis within the alveolar compartment, a finding that is also observed in IPF patients. A systemic prothrombotic state also occurs in IPF and is associated with increased mortality, but trials of anticoagulation in IPF have provided conflicting results. Differences in methodology, intervention and study populations may contribute to the inconsistent trial outcomes. The new oral anticoagulants have properties that may prove advantageous in targeting both thrombotic risk and progression of lung fibrosis. A review of the coagulation system in IPF exploring scientific and clinical studies in this area http://ow.ly/OdXwX

Serum carcinoembryonic antigen correlates with severity of idiopathic pulmonary fibrosis

Background and objective:  Idiopathic pulmonary fibrosis (IPF) is the commonest idiopathic interstitial pneumonia and carries a poor prognosis. Epidemiological evidence suggests that patients with IPF have an increased risk of developing lung cancer. Carcinoembryonic antigen (CEA) has a close association with epithelial malignancy. The aim of this study was to evaluate serum CEA concentrations in patients with IPF and to perform correlation with pulmonary function.

Increased Platelet Reactivity in Idiopathic Pulmonary Fibrosis Is Mediated by a Plasma Factor

Introduction Idiopathic Pulmonary Fibrosis (IPF) is a progressive, incurable fibrotic interstitial lung disease with a prognosis worse than many cancers. Its pathogenesis is poorly understood. Activated platelets can release pro-fibrotic mediators that have the potential to contribute to lung fibrosis. We determine platelet reactivity in subjects with IPF compared to age-matched controls. Methods Whole blood flow cytometry was used to measure platelet-monocyte aggregate formation, platelet P-selectin expression and platelet fibrinogen binding at basal levels and following stimulation with platelet agonists. A plasma swap approach was used to assess the effect of IPF plasma on control platelets. Results Subjects with IPF showed greater platelet reactivity than controls. Platelet P-selectin expression was significantly greater in IPF patients than controls following stimulation with 0.1 µM ADP (1.9% positive ±0.5 (mean ± SEM) versus 0.7%±0.1; p = 0.03), 1 µM ADP (9.8%±1.3 versus 3.3%±0.8; p<0.01) and 10 µM ADP (41.3%±4.2 versus 22.5%±2.6; p<0.01). Platelet fibrinogen binding was also increased, and platelet activation resulted in increased platelet-monocyte aggregate formation in IPF patients. Re-suspension of control platelets in plasma taken from subjects with IPF resulted in increased platelet activation compared to control plasma. Conclusions IPF patients exhibit increased platelet reactivity compared with controls. This hyperactivity may result from the plasma environment since control platelets exhibit increased activation when exposed to IPF plasma.

Azithromycin for prevention of exacerbations of COPD.

To the Editor: Albert et al. (Aug. 25 issue)1 report that the use of daily azithromycin reduced the frequency of exacerbations in patients with chronic obstructive pulmonary disease (COPD). However, they did not mention the possible role of the immunomodulatory effects of macrolides in the discussion of their results.2,3 Macrolides decrease the production of a range of inflammatory cytokines, leukotriene B4, and matrix metalloproteases, as well as the expression of adhesion molecules such as Mac-1 and intracellular adhesion molecule 1.2 The result is a decreased influx of neutrophils and blunted neutrophil activity in inflamed lungs and airways.3 These effects are thought to be largely responsible for the benefit associated with the long-term use of low-dose macrolide therapy in patients with other chronic lung conditions such as diffuse panbronchiolitis4 and cystic fibrosis.5 If the observed benefit of azithromycin in the study by Albert et al. were related exclusively to the antibacterial properties of this antibiotic, the far less costly doxycycline could be used instead. Nearly all haemophilus and moraxella are susceptible to doxycycline, just as they are to azithromycin, and the rates of resistance of pneumococci to these two drugs are comparable. Daniel M. Musher, M.D.

Eosinophils in COPD: how many swallows make a summer?

There is considerable controversy over the place of the blood eosinophil as a biomarker in chronic obstructive pulmonary disease (COPD). Recent literature suggests its use in assessing responsiveness to inhaled corticosteroids (ICS) [1, 2] and in predicting exacerbations [3, 4]. Other studies either wholly or partially refute these associations [5–7]. We suggest that what underlies this confusion is the failure to understand the temporal variation in the biomarker, and the inherent imprecision in the collection of associated end-point data. Repeated measures of eosinophil counts increased the proportion of eosinophilic patients http://ow.ly/LhnV30hlR5j

Objective Measurement of Cough Frequency During COPD Exacerbation Convalescence.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Cough and sputum production are associated with adverse outcomes in COPD and are common during COPD exacerbation (AE-COPD). This study of objective cough monitoring using the Hull Automated Cough Counter and Leicester Cough Monitor software confirms that this system has the ability to detect a significant decrease in cough frequency during AE-COPD convalescence. The ability to detect clinically meaningful change indicates a potential role in home monitoring of COPD patients.

Continuous Cough Monitoring Using Ambient Sound Recording During Convalescence from a COPD Exacerbation

PurposeCough is common in chronic obstructive pulmonary disease (COPD) and is associated with frequent exacerbations and increased mortality. Cough increases during acute exacerbations (AE-COPD), representing a possible metric of clinical deterioration. Conventional cough monitors accurately report cough counts over short time periods. We describe a novel monitoring system which we used to record cough continuously for up to 45 days during AE-COPD convalescence.MethodsThis is a longitudinal, observational study of cough monitoring in AE-COPD patients discharged from a single teaching hospital. Ambient sound was recorded from two sites in the domestic environment and analysed using novel cough classifier software. For comparison, the validated hybrid HACC/LCM cough monitoring system was used on days 1, 5, 20 and 45. Patients were asked to record symptoms daily using diaries.ResultsCough monitoring data were available for 16 subjects with a total of 568 monitored days. Daily cough count fell significantly from mean ± SEM 272.7 ± 54.5 on day 1 to 110.9 ± 26.3 on day 9 (p < 0.01) before plateauing. The absolute cough count detected by the continuous monitoring system was significantly lower than detected by the hybrid HACC/LCM system but normalised counts strongly correlated (r = 0.88, p < 0.01) demonstrating an ability to detect trends. Objective cough count and subjective cough scores modestly correlated (r = 0.46).ConclusionsCough frequency declines significantly following AE-COPD and the reducing trend can be detected using continuous ambient sound recording and novel cough classifier software. Objective measurement of cough frequency has the potential to enhance our ability to monitor the clinical state in patients with COPD.

Is cough important in acute exacerbations of COPD

Chronic obstructive pulmonary disease is predicted to become the 4th leading cause of death worldwide by 2030. The natural history of the disease includes progressive symptoms punctuated by acute exacerbations during which symptoms rapidly deteriorate. The resulting disability places significant burden on health and social care systems. Cough is the second most common symptom reported by COPD patients, is a source of significant distress and is associated with adverse outcomes. We discuss the importance of cough in COPD, its mechanism and the relationship between cough and COPD exacerbations. We review the literature and present original data relating to the investigation of cough during COPD exacerbation, its associations and potential benefits of cough monitoring.

A new era of drug therapy for idiopathic pulmonary fibrosis

964 www.thelancet.com/respiratory Vol 2 December 2014 Substantial eff ort by the cystic fi brosis research community has been directed at development of therapies to correct CFTR function in homozygous Phe508del patients. In-vitro studies have shown that combination therapy is necessary, including a corrector (lumacaftor) to increase traffi cking of the Phe508 protein to the cell surface and a potentiator to enhance chloride transport. The report from a phase 2 dose-escalation study by Boyle and colleagues of lumacaftor (a corrector) and ivacaftor (a potentiator) is the fi rst to show that this drug combination might be eff ective in homozygous Phe508del patients. This trial tested sequential cohorts of participants receiving increasing doses of lumacaftor monotherapy followed by addition of ivacaftor. Although lumacaftor monotherapy resulted in a dose dependent decrease in the forced expiratory volume in 1 sec (FEV1), the addition of ivacaftor resulted in a signifi cant increase in FEV1 (treatment diff erence vs placebo for absolute change in percent predicted FEV1 of 7·7 [95% Cl 2·7– 12·6]) at the highest dose, lumacaftor 400 mg with ivacaftor 250 mg, both taken every 12 h. The encouraging results in the homozygous Phe508del population led to the undertaking of two large phase 3 trials. These phase 3 trials of lumacaftor and ivacaftor combination therapy—TRAFFIC (NCT01807923) and TRANSPORT (NCT01807949)—were completed in 2014 and the results presented at the North American Cystic Fibrosis Conference in Atlanta, GA, USA, in October 2014. In both dose groups tested (lumacaftor 600 mg once daily and lumacaftor 400 mg every 12 h, both combined with ivacaftor 250 mg every 12 h) a treatment diff erence compared with placebo in absolute change in percent predicted FEV1 ranging from 2·6 to 4·0 percentage points was recorded. From animal models to clinical trials, the abundance of publications about cystic fi brosis in 2014 provides additional optimism. Indeed, an analysis of a cystic fi brosis registry reported in August, 2014, that median survival increased by 1·8% per year from 2000 to 2010. Patients born in 2010 are now projected to survive to 39 years; these patients could survive to 56 years if the rate of mortality continues to decrease at the rate observed from 2000 to 2010.