Comparative outcomes in patients receiving pirfenidone or nintedanib for idiopathic pulmonary fibrosis.

BACKGROUND: Real-world data regarding outcomes of idiopathic pulmonary fibrosis (IPF) are scarce, outside of registries. In France, pirfenidone and nintedanib are only reimbursed for documented IPF, with similar reimbursement criteria with respect to disease characteristics, prescription through a dedicated form, and IPF diagnosis established in multidisciplinary discussion. RESEARCH QUESTION: The data of the comprehensive French National Health System were used to evaluate outcomes in patients newly treated with pirfenidone or nintedanib in 2015-2016. STUDY DESIGN AND METHODS: Patients aged < 50 years or who had pulmonary fibrosis secondary to an identified cause were excluded. All-cause mortality, acute respiratory-related hospitalisations and treatment discontinuations up to 31 December 2017 were compared using a Cox proportional hazards model adjusted for age, sex, year of treatment initiation, time to treatment initiation and proxies of disease severity identified during a pre-treatment period. RESULTS: During the study period, a treatment with pirfenidone or nintedanib was newly initiated in 804 and 509 patients, respectively. No difference was found between groups for age, sex, time to treatment initiation, Charlson comorbidity score, and number of hospitalisations or medical contacts prior to treatment initiation. As compared to pirfenidone, nintedanib was associated with a greater risk of all-cause mortality (hazard ratio [HR], 1.8; 95% confidence interval [CI] 1.3-2.6), a greater risk of acute respiratory-related hospitalisations (HR 1.3; 95% CI 1.0-1.7) and a lower risk of treatment discontinuation at 12 months (HR 0.7; 95% CI 0.6-0.9). INTERPRETATION: This observational study identified potential differences in outcome under newly prescribed antifibrotic drugs, deserving further explorations.

A delayed diagnosis of atypical immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A case report.

INTRODUCTION: Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is a rare monogenic autoimmune disease, which is caused by mutations in the forkhead box protein 3 gene, can affect various systems. The typical clinical manifestations of IPEX are enteropathy, type 1 diabetes mellitus, and skin diseases. However, some atypical phenotypes can easily be misdiagnosed clinically. PATIENT CONCERNS: A 9-year-and-7-month old patient suffered from recurrent wheezing, hematochezia, and eczematous dermatitis at the age of six months, but did not have any manifestations of autoimmune endocrinopathy. The patient was treated with glucocorticoids for more than six years, and he developed bronchiectasis. DIAGNOSIS: Whole exome sequencing revealed a hemizygous pathogenic mutation c.1010G>A, p. (Arg337Gln) in Forkhead box protein 3 gene (NM_014009.3). INTERVENTIONS: The patient was treated with oral mycophenolate mofetil combined with inhaled budesonide formoterol for six months after diagnosis. OUTCOMES: The respiratory symptoms of the patient seemed to be controlled but eczematous dermatitis progressed, which led the patient to give up the treatment. CONCLUSION: Early diagnosis and treatment of IPEX are crucial. Lung injury may be a major problem in the later stages of atypical IPEX, and mycophenolate mofetil seems to control the respiratory symptoms, but could induce significant skin side effects.

Metabolism-based Drug-drug Interactions in Patients with Chronic Respiratory Diseases: A Review Focusing on Drugs Affecting the Respiratory System.

BACKGROUND: Chronic respiratory diseases (CRDs) are increasing in prevalence, as reported by the World Health Organization (WHO). Patients with CRDs usually require co-administration of multiple drugs due to the complex pathogenic mechanisms of CRDs and the existence of concomitant diseases. Polypharmacy (co-administration of more than four medications) is the main risk factor of the occurrence of drug-drug interactions (DDIs) that may lead to reducing treatment efficacy and/or increasing adverse effects. METHODS: This literature-based review focuses on metabolism-based DDIs, the most prevalent DDIs responsible for difficulties in therapeutic management in patients with CRDs. RESULTS: Clinically relevant metabolism-based DDIs occur between drugs used for the treatment of respiratory diseases (corticosteroids, orally inhaled bronchodilators, methylxanthines, anti-leukotrienes, antimicrobials, endothelin receptor antagonists, phosphodiesterase inhibitors, antitussives, and antineoplastic agents) and drugs affecting cytochrome P450 (CYP) (inducers and inhibitors). Considering alternative therapies, adjusting medication doses, or monitoring patients during treatment are recommended to prevent the harmful consequences of these interactions. CONCLUSION: Providing information on clinically relevant interactions of drugs more likely prescribed in daily practices of physicians is essential to improve patient safety. A list of known metabolism-based interactions of drugs affecting the respiratory systems should be available for physicians engaged in the treatment of CRDs.

Real-life experiences in a single center: efficacy of pirfenidone in idiopathic pulmonary fibrosis and fibrotic idiopathic non-specific interstitial pneumonia patients.

BACKGROUND: Pirfenidone is the first antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis (IPF) and it is used in the treatment of other interstitial pneumonias, such as unclassifiable interstitial lung disease (ILD) and connective tissue-related ILD. This study examined the efficacy of pirfenidone in patients with IPF and fibrotic idiopathic non-specific interstitial pneumonia (f-iNSIP). METHODS: In a retrospective real-life study, 67 IPF and 24 f-iNSIP patients were enrolled and classified into a pirfenidone group and a non-antifibrotic group. The level of forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLco) at baseline, 6, 12 and 24 months were recorded. The level of KL-6 in serum was detected by chemiluminescence enzyme immunoassay (CLEIA). The prognosis and safety outcomes were collected from patients. RESULTS: In IPF patients, pirfenidone decreased the mean change of FVC and DLco, and decreased the proportion of patients with a ⩾10% decline in FVC or a ⩾15% decline in DLco compared with the non-antifibrotic group. There was no difference in the mean change of FVC and DLco between smokers and non-smokers who received pirfenidone treatment. There was an improvement in progression-free survival, defined as the time to the first occurrence of acute exacerbation or death related to pulmonary fibrosis. Moreover, the ratio of patients who experienced acute exacerbation and death related to pulmonary fibrosis was lower in the pirfenidone group. There was no change in lung function and prognosis between the pirfenidone and non-antifibrotic groups in f-iNSIP patients. The KL-6 level slightly decreased after 1 year of pirfenidone treatment but not significantly. Gastrointestinal and skin-related adverse events were most common, and four patients ceased treatment due to the side effects. CONCLUSIONS: Pirfenidone safely reduced disease progression by improving the lung function and progression-free survival in IPF patients, with acceptable side effects. The efficacy of pirfenidone on f-iNSIP was not significant, suggesting the need for further studies.The reviews of this paper are available via the supplemental material section.

Prognostic significance of forced vital capacity decline prior to and following antifibrotic therapy in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD). Currently, two antifibrotic drugs are available for reducing forced vital capacity (FVC) decline in IPF. However, many pulmonologists wait before initiating treatment, especially when IPF patients have stable disease. This study aimed to investigate the impact on survival outcome of FVC decline and a slow rate of FVC decline prior to and following treatment with these two antifibrotic drugs. METHODS: Out of the 235 IPF patients treated with antifibrotic therapy that were screened, 105 cases were eligible, who then underwent physiological evaluation at 6 months prior to and following antifibrotic therapy. Clinical characteristics and prognostic outcomes were compared among groups, and prognostic factors were evaluated using a Cox proportional hazards analysis. RESULTS: In terms of %FVC decline prior to the therapy and a slow rate of FVC decline, there was no significant difference between stable and worsened groups and responder and non-responder groups, respectively. On the other hand, in terms of %FVC decline (decline >5%) following antifibrotic therapy, the stable/improved group had significantly better prognosis than the worsened group. Prognostic analysis revealed that a stable/improved status following antifibrotic therapy [HR: 0.35 (0.15-0.87)] was significantly associated with a better prognosis. CONCLUSIONS: Concerning the FVC decline prior to and following antifibrotic therapy and a slow rate of FVC decline, only the FVC decline following the therapy is associated with a greater survival outcome. An early treatment decision may thus be beneficial for IPF.The reviews of this paper are available via the supplemental material section.

Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease.

Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug-drug interactions, are discussed.

Statin Use and the Risk of Subsequent Hospitalized Exacerbations in COPD Patients with Frequent Exacerbations.

Rationale: The potential benefits of statins for the prevention of exacerbations in patients with COPD remains controversial. No previous studies have investigated the impact of statins on clinical outcomes in COPD patients with frequent exacerbations. Objective: This study aimed to evaluate the association between the use of statins and the risk of subsequent hospitalized exacerbations in COPD frequent exacerbators. Materials and Methods: We conducted a population-based cohort study using the Taiwan National Health Insurance Research Database. 139,223 COPD patients with a first hospitalized exacerbation between 2004 and 2012 were analyzed. Among them, 35,482 had a second hospitalized exacerbation within a year after the first exacerbation, and were defined as frequent exacerbators. 1:4 propensity score matching was used to create matched samples of statin users and non-users. The competing risk regression analysis model was used to evaluate the association between statin use and exacerbation risk. Results: The use of statins was associated with a significantly reduced risk in subsequent hospitalized exacerbations in COPD patients after their first hospitalized exacerbation (adjusted subdistribution hazard ration [SHR], 0.89; 95% CI, 0.85-0.93, P<0.001). In frequent exacerbators, the SHR for subsequent hospitalized exacerbations in statins users was 0.88 (95% CI, 0.81-0.94, P=0.001). Subgroup analysis among frequent exacerbators demonstrated that the use of statins only provided a protective effect against subsequent hospitalized exacerbations in male patients aged 75 years and older, with coexisting diabetes mellitus, hypertension or cardiovascular disease, and no protective effect was observed in those with lung cancer or depression. Current use of statins was associated with a greater protective effect for reducing subsequent hospitalized exacerbation. Conclusion: The use of statins was associated with a significant reduction in the risk of hospitalized exacerbations in COPD patients after a first hospitalized exacerbation and in specified COPD frequent exacerbators.

The therapy of idiopathic pulmonary fibrosis: what is next?

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease, characterised by progressive scarring of the lung and associated with a high burden of disease and early death. The pathophysiological understanding, clinical diagnostics and therapy of IPF have significantly evolved in recent years. While the recent introduction of the two antifibrotic drugs pirfenidone and nintedanib led to a significant reduction in lung function decline, there is still no cure for IPF; thus, new therapeutic approaches are needed. Currently, several clinical phase I-III trials are focusing on novel therapeutic targets. Furthermore, new approaches in nonpharmacological treatments in palliative care, pulmonary rehabilitation, lung transplantation, management of comorbidities and acute exacerbations aim to improve symptom control and quality of life. Here we summarise new therapeutic attempts and potential future approaches to treat this devastating disease.

A systematic review of pharmacotherapeutic clinical trial end-points for bronchiectasis in adults.

Bronchiectasis is an increasing clinical problem, but multiple recent clinical trials have failed to reach their primary end-point. Difficulties in achieving "positive" bronchiectasis trials is reflected in a lack of agreement from trialists and regulators on what are the optimal end-points.To evaluate the use of end-points in bronchiectasis trials, we conducted a systematic review of published bronchiectasis trials from 2008 to 2018 and extracted end-points used, definitions, methods of analysis and responsiveness.Our analysis shows that quality of life and exacerbation end-points are most frequently used. Trials using exacerbation end-points have been characterised by varying definitions, multiple methods of analysis and durations of follow-up. There are multiple quality of life tools for bronchiectasis (Quality of Life - Bronchiectasis questionnaire, St George's Respiratory Questionnaire, etc.). The majority of studies measure lung function (e.g. forced expiratory volume in 1 s), but this is shown to be nonresponsive to the majority of interventions. Microbiology end-points frequently show statistically significant differences in phase 2 antibiotic studies but their correlation with clinical end-points is unknown.This systematic review demonstrates a need for guidance to standardise definitions and design features to improve reproducibility and increase the likelihood of demonstrating statistically significant benefits with new therapies.

Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial of BMS-986020, a Lysophosphatidic Acid Receptor Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. The lysophosphatidic acid receptor 1 (LPA1) pathway is implicated in IPF etiology. Safety and efficacy of BMS-986020, a high-affinity LPA1 antagonist, was assessed vs placebo in a phase 2 study in patients with IPF. METHODS: IM136003 was a phase 2, parallel-arm, multicenter, randomized, double-blind, placebo-controlled trial. Adults with IPF (FVC, 45%-90%; diffusing capacity for carbon monoxide, 30%-80%) were randomized to receive placebo or 600 mg BMS-986020 (once daily [qd] or bid) for 26 weeks. The primary end point was rate of change in FVC from baseline to week 26. RESULTS: Of 143 randomized patients, 108 completed the 26-week dosing phase. Thirty-five patients discontinued prematurely. Patient baseline characteristics were similar between treatment groups (placebo: n = 47; 600 mg qd: n = 48; 600 mg bid: n = 48). Patients treated with BMS-986020 bid experienced a significantly slower rate of decline in FVC vs placebo (-0.042 L; 95% CI, -0.106 to -0.022 vs -0.134 L; 95% CI, -0.201 to -0.068, respectively; P = .049). Dose-related elevations in hepatic enzymes were observed in both BMS-986020 treatment groups. The study was terminated early because of three cases of cholecystitis that were determined to be related to BMS-986020 after unblinding. CONCLUSIONS: BMS-986020 600 mg bid treatment for 26 weeks vs placebo significantly slowed the rate of FVC decline. Both regimens of BMS-986020 were associated with elevations in hepatic enzymes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01766817; URL: www.clinicaltrials.gov.

Preventing Clinically Important Deterioration of COPD with Addition of Umeclidinium to Inhaled Corticosteroid/Long-Acting ß2-Agonist Therapy: An Integrated Post Hoc Analysis.

INTRODUCTION: Assessing clinically important measures of disease progression is essential for evaluating therapeutic effects on disease stability in chronic obstructive pulmonary disease (COPD). This analysis assessed whether providing additional bronchodilation with the long-acting muscarinic antagonist umeclidinium (UMEC) to patients treated with inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) therapy would improve disease stability compared with ICS/LABA therapy alone. METHODS: This integrated post hoc analysis of four 12-week, randomized, double-blind trials (NCT01772134, NCT01772147, NCT01957163, NCT02119286) compared UMEC 62.5 µg with placebo added to open-label ICS/LABA in symptomatic patients with COPD (modified Medical Research Council dyspnea scale score ≥ 2). A clinically important deterioration (CID) was defined as: a decrease from baseline of ≥ 100 mL in trough forced expiratory volume in 1 s (FEV1), an increase from baseline of ≥ 4 units in St George's Respiratory Questionnaire (SGRQ) total score, or a moderate/severe exacerbation. Risk of a first CID was evaluated in the intent-to-treat (ITT) population and in patients stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) classification, exacerbation history and type of ICS/LABA therapy. Adverse events (AEs) were also assessed. RESULTS: Overall, 1637 patients included in the ITT population received UMEC + ICS/LABA (n = 819) or placebo + ICS/LABA (n = 818). Additional bronchodilation with UMEC reduced the risk of a first CID by 45-58% in the ITT population and all subgroups analyzed compared with placebo (all p < 0.001). Improvements were observed in reducing FEV1 (69% risk reduction; p < 0.001) and exacerbation (47% risk reduction; p = 0.004) events in the ITT population. No significant reduction in risk of a SGRQ CID was observed. AE incidence was similar between treatment groups. CONCLUSION: Symptomatic patients with COPD receiving ICS/LABA experience frequent deteriorations. Additional bronchodilation with UMEC significantly reduced the risk of CID and provided greater short-term stability versus continued ICS/LABA therapy in these patients. FUNDING: GlaxoSmithKline (study number: 202067). Plain language summary available for this article.

The utility of drug reaction assessment trials for inhaled therapies in patients with chronic lung diseases.

BACKGROUND: Current guidelines recommend a Drug Reaction Assessment (DRA) before beginning inhaled therapies to assess for bronchoconstriction and tolerability. There is limited evidence to support this recommendation. METHODS: In this study we aimed to establish the predictors of successful DRAs in different patient groups using a cohort of all DRAs performed in adults between 2011 and 2016 at the Royal Brompton Hospital. Spirometry, age, gender, height, and underlying lung disease were recorded. A multivariable logistic regression model was constructed to ascertain variables associated with successful DRAs. RESULTS: There were 1492 DRA trials using hypertonic saline (32%), antimicrobials (63%), or rhDNase (5%). The majority of patients (94%, n = 1408) passed the DRA. Mean FEV1% predicted was 58.03 (SD 23.36). Female sex, type of inhaled product, and FEV1% predicted were established as significant predictors for DRA success. An FEV1% predicted > 55% was associated with greater probability of DRA success (Odds Ratio [OR]: 2.96 (1.80,4.86) p < 0.0001). Those receiving dry powder, inhaled antibiotics were more likely to pass the DRA compared to nebulised antibiotics (OR: 3.99 (1.38,11.51) p = 0.01)). CONCLUSION: This study classifies distinct patient groups with varying baseline risks which can be used to predict tolerability when adding an inhaled product to their management plan. Some "low risk" patients may in future be able to self-assess their tolerability for inhaled therapies at home to avoid unneeded hospital monitoring.

Idiopathic Pulmonary Fibrosis Among Young Patients: Challenges in Diagnosis and Management.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is considered a disease of older patients, being rare in patients ≤ 50 years. Still, IPF can occur in younger patients, but this particular patient group is not well characterised so far. The aim of this study was to compare the diagnostic certainty, clinical features, comorbidities and survival in young versus older IPF patients. METHODS: We reviewed our medical records from February 2011 until February 2015, to identify IPF patients, who were then classified as young (≤ 50 years) or older IPF (> 50 years). Radiographic and histological findings, lung function parameters, comorbidities, disease progression and survival were analysed and compared between the two groups. RESULTS: Of 440 patients with interstitial lung disease, 129 patients with IPF were identified, including 30 (23.3%) ≤50 years and 99 (76.7%) > 50 years. There were no differences between age groups in baseline demographics; younger patients were less likely to have a confirmed diagnosis by high-resolution computed tomography (p = 0.014), more likely to require a biopsy (p = 0.08) and less likely to have received antifibrotic therapy (p = 0.006). Despite an overall limited prognosis, younger patients had a significantly better median survival after diagnosis (p = 0.0375), with a significantly higher proportion of older patients dying due to respiratory failure (p = 0.0383). CONCLUSION: IPF patients under the age of 50 years have similar features and clinical course compared to older IPF patients. These patients should be diagnosed by adopting a multidisciplinary team approach, potentially benefitting from earlier intervention with effective antifibrotic therapy.

A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators.

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

Ototoxicity monitoring through the eyes of the treating physician: Perspectives from pulmonology and medical oncology.

OBJECTIVES: Integrating audiological management into the care pathways of clinical specialties that prescribe ototoxic medications for essential, often life-preserving medical care that is critical for early hearing loss identification and remediation. Research shows that successful implementation of a new health service or intervention requires alignment of goals among provider groups, institutional leadership and patients. Thoughtful consideration of the physician's viewpoints about ototoxicity and its implications for treatment planning is, therefore, important for the implementation and enduring success of an ototoxicity monitoring programme (OMP). DESIGN: This discussion paper uses qualitative methods to explore the perspectives of four physicians on OMP provision in their patient populations. STUDY SAMPLE: Three pulmonologists and one oncologist completed the written survey or survey-based interview described in this report. RESULTS: Each physician indicated that (i) ototoxicity is a potential problem for their patients; (ii) monitoring hearing is important to ensure good quality of life among their patients and (iii) treatment modification would be considered if an alternative treatment option were available. The physicians differed in their approaches to ototoxicity monitoring, from routine referrals to audiology, to relying on patient self-referral. CONCLUSION: Physician provider input is needed to optimise monitoring schedules and OMP care coordination with audiology.

Targeting oxidant-dependent mechanisms for the treatment of respiratory diseases and their comorbidities.

Oxidative stress is implicated in the pathogenesis of respiratory diseases, such as COPD and its comorbidities, asthma, idiopathic pulmonary fibrosis and radiation pneumonitis. Antioxidants drugs, such as small molecule thiols, nuclear erythroid-2 related factor 2 activators and catalytic enzyme mimetics have been developed to target oxidant-dependent mechanisms. The therapeutic effects of antioxidants have been generally disappointing. A small number of antioxidants are approved for clinical use, such as the small molecule thiol N-acetyl-l-cysteine for chronic obstructive pulmonary disease, and in the United States, the superoxide dismutase mimetic AEOL 10150 for severe radiation pneumonitis. The future use of antioxidants for the treatment of chronic respiratory diseases may require a precision medicine approach to identify responsive patients.

Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important cause of mortality and morbidity in preterm infants and inflammation plays a significant role in its pathogenesis. The use of inhaled corticosteroids may modulate the inflammatory process without concomitant high systemic steroid concentrations and less risk of adverse effects. This is an update of a review published in 2012 (Shah 2012). We recently updated the related review on "Inhaled versus systemic corticosteroids for treating bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates". OBJECTIVES: To determine the effect of inhaled versus systemic corticosteroids started within the first 7 days of life on preventing death or BPD in ventilated very low birth weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 23 February 2017), Embase (1980 to 23 February 2017), and CINAHL (1982 to 23 February 2017). We searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting in the first seven days of life in very low birth weight preterm infants receiving assisted ventilation. DATA COLLECTION AND ANALYSIS: Clinical outcomes data were extracted and analysed using Review Manager. When appropriate, meta-analysis was performed using typical relative risk (RR), typical risk difference (RD) and weighted mean difference (WMD). Meta-analyses were performed using typical relative risk, typical risk difference (RD), and weighted mean difference with their 95% confidence intervals (CI). If RD was statistically significant, the number needed to benefit or the number needed to harm was calculated. We assessed the quality of evidence was evaluated using GRADE principles. MAIN RESULTS: We included two trials that involved 294 infants. No new studies were included for the 2017 update. The incidence of death or BPD at 36 weeks' postmenstrual age was not statistically significantly different between infants who received inhaled or systemic steroids (RR 1.09, 95% CI 0.88 to 1.35; RD 0.05, 95% CI -0.07 to 0.16; 1 trial, N = 278). The incidence of BPD at 36 weeks' postmenstrual age among survivors was not statistically significant between groups (RR 1.34, 95% CI 0.94 to 1.90; RD 0.11, 95% CI -0.02 to 0.24; 1 trial, N = 206). There was no statistically significant difference in the outcomes of BPD at 28 days, death at 28 days or 36 weeks' postmenstrual age and the combined outcome of death or BPD by 28 days between groups (2 trials, N = 294). The duration of mechanical ventilation was significantly longer in the inhaled steroid group compared with the systemic steroid group (typical MD 4 days, 95% CI 0.2 to 8; 2 trials, N = 294; I² = 0%) as was the duration of supplemental oxygen (typical MD 11 days, 95% CI 2 to 20; 2 trials, N = 294; I² = 33%).The incidence of hyperglycaemia was significantly lower with inhaled steroids (RR 0.52, 95% CI 0.39 to 0.71; RD -0.25, 95% CI -0.37 to -0.14; 1 trial, N = 278; NNTB 4, 95% CI 3 to 7 to avoid 1 infant experiencing hyperglycaemia). The rate of patent ductus arteriosus increased in the group receiving inhaled steroids (RR 1.64, 95% CI 1.23 to 2.17; RD 0.21, 95% CI 0.10 to 0.33; 1 trial, N = 278; NNTH 5, 95% CI 3 to 10). In a subset of surviving infants in the United Kingdom and Ireland there were no significant differences in developmental outcomes at 7 years of age. However, there was a reduced risk of having ever been diagnosed as asthmatic by 7 years of age in the inhaled steroid group compared with the systemic steroid group (N = 48) (RR 0.42, 95% CI 0.19 to 0.94; RD -0.31, 95% CI -0.58 to -0.05; NNTB 3, 95% CI 2 to 20).According to GRADE the quality of the evidence was moderate to low. Evidence was downgraded on the basis of design (risk of bias), consistency (heterogeneity) and precision of the estimates.Both studies received grant support and the industry provided aero chambers and metered dose inhalers of budesonide and placebo for the larger study. No conflict of interest was identified. AUTHORS' CONCLUSIONS: We found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator-dependent preterm infants. Based on this review inhaled steroids cannot be recommended over systemic steroids as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects, with particular attention to neurodevelopmental outcome.

Treatment burden, clinical outcomes, and comorbidities in COPD: an examination of the utility of medication regimen complexity index in COPD.

BACKGROUND: COPD patients are often prescribed multiple medications for their respiratory disease and comorbidities. This can lead to complex medication regimens resulting in poor adherence, medication errors, and drug-drug interactions. The relationship between clinical outcomes and medication burden beyond medication count in COPD is largely unknown. OBJECTIVES: The aim of this study was to explore the relationships of medication burden in COPD with clinical outcomes, comorbidities, and multidimensional indices. METHODS: In a cross-sectional study, COPD patients (n=222) were assessed for demographic information, comorbidities, medication use, and clinical outcomes. Complexity of medication regimens was quantified using the validated medication regimen complexity index (MRCI). RESULTS: Participants (58.6% males) had a mean (SD) age of 69.1 (8.3) years with a postbronchodilator forced expiratory volume in 1 second % predicted of 56.5 (20.4) and a median of five comorbidities. The median (q1, q3) total MRCI score was 24 (18.5, 31). COPD-specific medication regimens were more complex than those of non-COPD medications (median MRCI: 14.5 versus 9, respectively; P<0.0001). Complex dosage formulations contributed the most to higher MRCI scores of COPD-specific medications while dosing frequency primarily drove the complexity associated with non-COPD medications. Participants in Global Initiative for Chronic Obstructive Lung Disease quadrant D had the highest median MRCI score for COPD medications (15.5) compared to those in quadrants A (13.5; P=0.0001) and B (12.5; P<0.0001). Increased complexity of COPD-specific treatments showed significant but weak correlations with lower lung function and 6-minute walk distance, higher St George's Respiratory Questionnaire and COPD assessment test scores, and higher number of prior year COPD exacerbations and hospitalizations. Comorbid cardiovascular, gastrointestinal, or metabolic diseases individually contributed to higher total MRCI scores and/or medication counts for all medications. Charlson Comorbidity Index and COPD-specific comorbidity test showed the highest degree of correlation with total MRCI score (ρ=0.289 and ρ=0.326; P<0.0001, respectively). CONCLUSION: In COPD patients, complex medication regimens are associated with disease severity and specific class of comorbidities.

When to start and when to stop antifibrotic therapies.

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive changes of the lung architecture causing cough and dyspnoea and ultimately leading to lung failure and death. Today, for the first time, two drugs that may reduce the inexorable progression of the disease are available, suggesting that treatment with specific drugs for IPF should be started as soon as diagnosis is made. This applies to any disease and particularly to IPF, which is marked by a 5-year survival comparable or even worse than many cancers. However, despite common sense and even worse, in spite of scientific data coming from clinical trials, post hoc analysis, long-term safety studies and real-life experiences, the question of when to start and when to stop treatment with antifibrotics is still debated. In IPF, particularly when the disease is diagnosed at an early stage, "wait and watch" behaviour is not rare to observe. This is largely due to the lack of awareness of both patients and clinicians regarding the progression of the disease and its prognosis. Another important issue is when treatment should be stopped. In general, there are two main reasons to stop a therapy: unbearable side-effects and/or lack of efficacy. According to current (although preliminary) evidence, antifibrotic drugs should not be discontinued except for safety issues.

Fast monitoring of tooth erosion caused by medicaments used in the treatment of respiratory diseases by ATR-FTIR and µ-EDXRF analysis.

The present study aimed to evaluate the erosive potential of four most commonly prescribed syrup medicaments for respiratory diseases. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy combined with multivariate statistical analysis and micro-energy-dispersive X-ray fluorescence spectrometry (µ-EDXRF) mapping was performed. Fifty-five root dentin fragments obtained from the buccal surface of 30 bovine teeth were prepared and divided into five experimental groups (n = 10): control-artificial saliva (S), acebrofilin hydrochloride (AC), ambroxol hydrochloride (AM), bromhexine hydrochloride (BR), and salbutamol sulfate (SS). The S group was stored only in artificial saliva and the other groups were treated with the medicaments (immersed for 1 min in 3 mL of the medication, three times daily, with 1-h intervals between the immersion cycles, during 5 days, 15 immersion cycles). There were a significant decrease in the Ca and P weight percentages (wt%) for dentin after medication treatments, except for AC (p > 0.05). Mineral content of dentin showed a clear gradation with increasing Ca and P wt% reduction in the order S < AC < AM < BR < SS. SS resulted in a significant increase in Ca/P ratio when compared to the control (p < 0.001). ATR-FTIR combined with multivariate, statistical analysis can quickly and reliably indicate extent of dentin erosion. Considering syrups with high-erosive potential should always follow with proper oral hygiene practices or search for an alternative medications void of such detrimental effects. Regular and prolonged use of these medicaments might bear the risk of causing erosion.