Elisabeth Bendstrup

Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease

BACKGROUND The prevalence, prognostic importance, and factors that predict the presence and degree of pulmonary hypertension (PH) diagnosed with right heart catheterization (RHC) in patients with end-stage chronic obstructive pulmonary disease (COPD) remain unclear. METHODS This retrospective study included 409 patients (61% women) with COPD/emphysema or α-1-antitrypsin deficiency who underwent lung transplant evaluation during 1991 to 2010. We analyzed the occurrence and degree of PH and compared demographics, oxygenation, lung function, hemodynamics, functional capacity, and survival in patients with and without PH. Prediction of PH was assessed using univariate and multivariate regression analysis. RESULTS The mean age at evaluation was 54 ± 7 years. All patients were in New York Heart Association functional class III-IV, with forced expiratory volume in 1 second of 23% ± 7% and total lung capacity of 126% ± 21% of predicted. PH was present in 146 (36%). The analysis excluded 53 (13%) with pulmonary venous hypertension (PVH). The distribution of the mean pulmonary artery pressure (mPAP) in patients with or without PH showed a unimodal normally distributed population, with a mean of 23.8 ± 6.0 mm Hg. Predictors of PH were partial pressures of oxygen and carbon dioxide. The 5-year survival rate was 37% in COPD patients with PH vs 63% in patients without PH (p = 0.016). Survival after lung transplantation did not differ (p = 0.37). CONCLUSIONS RHC verified PH in 36% of COPD patients. Hypoxemia and hypercapnia were associated with mPAP. PH is associated with worse survival in COPD, but PH does not influence the prognosis after lung transplantation.

Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study

BACKGROUND Diffuse parenchymal lung disease represents a diverse and challenging group of pulmonary disorders. A consistent diagnostic approach to diffuse parenchymal lung disease is crucial if clinical trial data are to be applied to individual patients. We aimed to evaluate inter-multidisciplinary team agreement for the diagnosis of diffuse parenchymal lung disease. METHODS We did a multicentre evaluation of clinical data of patients who presented to the interstitial lung disease unit of the Royal Brompton and Harefield NHS Foundation Trust (London, UK; host institution) and required multidisciplinary team meeting (MDTM) characterisation between March 1, 2010, and Aug 31, 2010. Only patients whose baseline clinical, radiological, and, if biopsy was taken, pathological data were undertaken at the host institution were included. Seven MDTMs, consisting of at least one clinician, radiologist, and pathologist, from seven countries (Denmark, France, Italy, Japan, Netherlands, Portugal, and the UK) evaluated cases of diffuse parenchymal lung disease in a two-stage process between Jan 1, and Oct 15, 2015. First, the clinician, radiologist, and pathologist (if lung biopsy was completed) independently evaluated each case, selected up to five differential diagnoses from a choice of diffuse lung diseases, and chose likelihoods (censored at 5% and summing to 100% in each case) for each of their differential diagnoses, without inter-disciplinary consultation. Second, these specialists convened at an MDTM and reviewed all data, selected up to five differential diagnoses, and chose diagnosis likelihoods. We compared inter-observer and inter-MDTM agreements on patient first-choice diagnoses using Cohens kappa coefficient (κ). We then estimated inter-observer and inter-MDTM agreement on the probability of diagnosis using weighted kappa coefficient (κw). We compared inter-observer and inter-MDTM confidence of patient first-choice diagnosis. Finally, we evaluated the prognostic significance of a first-choice diagnosis of idiopathic pulmonary fibrosis (IPF) versus not IPF for MDTMs, clinicians, and radiologists, using univariate Cox regression analysis. FINDINGS 70 patients were included in the final study cohort. Clinicians, radiologists, pathologists, and the MDTMs assigned their patient diagnoses between Jan 1, and Oct 15, 2015. IPF made up 88 (18%) of all 490 MDTM first-choice diagnoses. Inter-MDTM agreement for first-choice diagnoses overall was moderate (κ=0·50). Inter-MDTM agreement on diagnostic likelihoods was good for IPF (κw=0·71 [IQR 0·64-0·77]) and connective tissue disease-related interstitial lung disease (κw=0·73 [0·68-0·78]); moderate for non-specific interstitial pneumonia (NSIP; κw=0·42 [0·37-0·49]); and fair for hypersensitivity pneumonitis (κw=0·29 [0·24-0·40]). High-confidence diagnoses (>65% likelihood) of IPF were given in 68 (77%) of 88 cases by MDTMs, 62 (65%) of 96 cases by clinicians, and in 57 (66%) of 86 cases by radiologists. Greater prognostic separation was shown for an MDTM diagnosis of IPF than compared with individual clinicians diagnosis of this disease in five of seven MDTMs, and radiologists diagnosis of IPF in four of seven MDTMs. INTERPRETATION Agreement between MDTMs for diagnosis in diffuse lung disease is acceptable and good for a diagnosis of IPF, as validated by the non-significant greater prognostic separation of an IPF diagnosis made by MDTMs than the separation of a diagnosis made by individual clinicians or radiologists. Furthermore, MDTMs made the diagnosis of IPF with higher confidence and more frequently than did clinicians or radiologists. This difference is of particular importance, because accurate and consistent diagnoses of IPF are needed if clinical outcomes are to be optimised. Inter-multidisciplinary team agreement for a diagnosis of hypersensitivity pneumonitis is low, highlighting an urgent need for standardised diagnostic guidelines for this disease. FUNDING National Institute of Health Research, Imperial College London.

Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events.

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

How does comorbidity influence survival in idiopathic pulmonary fibrosis

INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It is a serious and progressive lung disease with a median survival of three years. The role of comorbidities in the prognosis of IPF is not clear. OBJECTIVES To describe comorbidity and co-medication in a Danish IPF cohort and the association between clinically important comorbidities and survival. METHODS The study cohort included all patients diagnosed with IPF at Aarhus University Hospital, Denmark between April 2003 and April 2009. Details on diagnostic examinations, pulmonary function, medication and comorbidities were registered based on medical records. RESULTS A total of 121 patients were included. The most frequently observed comorbidities were cardiovascular disease (20%), arterial hypertension (15%) and diabetes mellitus (11%). Cardiovascular disease diagnosed during follow-up significantly increased mortality (HR 4.7, 95% CI 2.0-11.1). No difference was found based on cardiovascular disease already present at the time of IPF diagnosis. Diabetes (HR 2.5, 95% CI 1.04-5.9) and anticoagulant treatment (HR 3.3, 95% CI 1.5-7.2) were also factors associated with a significantly higher mortality in this population-based cohort. CONCLUSION These findings emphasize the need of careful diagnosis and treatment of comorbidities and their risk factors in patients with IPF. In the absence of efficient treatment options for the majority of patients diagnosed with IPF, this may play a role in the effort to optimize the survival of IPF patients. Further studies are needed to fully clarify the impact of comorbidities on prognosis in patients diagnosed with IPF.

Autoimmune pulmonary alveolar proteinosis: Treatment options in year 2013

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of a periodic acid Schiff (PAS)‐positive eosinophilic material in the distal airways. For decades, the standard treatment of PAP has been whole lung lavage (WLL), where large quantities of saline are instilled into the lungs to remove the proteinaceous material. However, not all patients respond to this treatment. Thus, new treatment modalities, such as subcutaneous or inhaled granulocyte macrophage colony‐stimulating factor (GM‐CSF), and the CD20 antibody rituximab and plasmapheresis, have been investigated. Based on the current literature, a stepwise treatment plan is suggested starting with WLL, continuing to inhaled GM‐CSF, and then to rituximab if the former treatment regimes are unsuccessful.

Pulmonary hypertension in interstitial lung disease: prevalence, prognosis and 6 min walk test.

BACKGROUND Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the prevalence and impact of PH on prognosis and exercise capacity in ILD patients. METHODS 212 ILD patients were screened for PH by echocardiography. Criteria for PH were either a tricuspid pressure regurgitation gradient >40 mmHg, a tricuspid annular plane systolic excursion <1.8 cm or right ventricular dilatation. If possible, PH was confirmed by right heart catheterisation. Pulmonary function tests and 6 min walk tests (6MWT) were performed. RESULTS 29 patients (14%) had PH, 16 (8%) had mild and 13 (6%) had severe PH (mean pulmonary artery pressure ≥ 35 mmHg). Compared to patients without PH, lung function parameters were lower in PH patients, a larger proportion had idiopathic pulmonary fibrosis (IPF) (41 vs 21%, p = 0.006), and the hazard ratio for death was 8.5 (95% CI: 4-17). After correction for lung function parameters and the presence of IPF, 6MWT was significantly lower in patients with PH compared to non-PH patients (difference ± SEM: 58 ± 22 m, p = 0.01). CONCLUSIONS PH occurred in 14% of a cohort of patients with ILD and was associated to IPF and lower lung function parameters. Mortality was markedly higher in PH patients, and the presence of PH reduced 6MWT independently of lung function and the presence of IPF. The present results emphasize the need for intensified treatment of patients with ILD and PH.

Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND Oral acetylcysteine (also known as N-acetylcysteine) is used with pirfenidone to treat idiopathic pulmonary fibrosis (IPF) in Europe. However, no randomised studies have investigated the safety and tolerability of this combination. The PANORAMA study assessed the safety and tolerability of acetylcysteine combined with pirfenidone in patients with IPF. Exploratory efficacy endpoints were also assessed. METHODS We did a double-blind randomised trial at 48 sites in eight countries. Patients with IPF aged 40-80 years and established on pirfenidone (at least 1602 mg/day for 8 weeks or longer) were randomly assigned in a 1:1 ratio by interactive voice response system to receive concomitant oral acetylcysteine (600 mg, three times daily) or placebo for 24 weeks. A stratified blocked randomisation scheme was used with a block size of 4. Randomisation was stratified by dose of pirfenidone (2403 mg/day [the maximum dose] or <2403 mg/day). Patients, physicians, study staff and the sponsor were masked to treatment group allocation. The primary endpoint was assessment of adverse events, which were collected at each visit and for 28 days after the last dose of study drug. Exploratory efficacy measurements included forced vital capacity (FVC), carbon monoxide diffusing capacity, and 6 min walk distance. Analyses were done in the modified intention-to-treat population, which included all patients who were randomised and received at least one dose of study medication. This study is registered with the European Clinical Trials Database (EudraCT number 2012-000564-14) and has been completed. FINDINGS 123 patients participated in the study between June 28, 2013, and Feb 24, 2015. 61 were assigned to the acetylcysteine group (60 received study medication and included in analysis) and 62 were assigned to the placebo group (all included in analysis). The occurrence of at least one adverse event (46 [77%] patients receiving acetylcysteine vs 50 [81%] receiving placebo), adverse events related to study treatment (17 [28%] vs 16 [26%]), and the number of patients experiencing severe adverse events (three [5%] vs two [3%]), life-threatening adverse events (one [2%] vs one [2%]), or death (one [2%] vs three [5%]) was similar between treatment groups. One case of diarrhoea in the acetylcysteine group was considered severe and related to study treatment. Nine serious adverse events were reported by seven patients: dyspnoea, headache, hypertension, intervertebral disc protrusion, and malignant lung neoplasm in the acetylcysteine group, and aortic aneurysm, contusion, forearm fracture, and worsening IPF in the placebo group. The most common adverse events were cough, nasopharyngitis, and diarrhoea. Photosensitivity occurred more frequently with acetylcysteine (eight [13%] patients) than placebo (one [2%] patient; difference 11·7%; 95% CI 2·6-20·9; p=0·016]), and was not attributable to differences in location, season, or concomitant medication. Four (7%) patients receiving acetylcysteine and three (5%) receiving placebo discontinued study treatment due to adverse events. In the exploratory analysis, change in FVC indicated that clinical benefit from addition of acetylcysteine to pirfenidone is unlikely, with the possibility of a harmful effect in patients with IPF (adjusted rate of decline 125·6 mL/6 months for acetylcysteine vs 34·3 mL/6 months for placebo; difference -91·3 mL; 95% CI -174·4 to -8·3; p=0·031). INTERPRETATION Findings from the PANORAMA study suggest that addition of acetylcysteine to pirfenidone does not substantially alter the tolerability profile of pirfenidone, and is unlikely to be beneficial in IPF. FUNDING InterMune International AG (Roche).

Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis

Pirfenidone has been shown in three recently published trials to slow down the progression of the devastating interstitial lung disease, idiopathic pulmonary fibrosis (IPF). The precise mechanisms that initiate and perpetuate the histopathological process leading to lung fibrosis in IPF are still uncertain, but increased concentrations of reactive oxidative species and fibrogenetic factors have been observed in the pulmonary tissue of patients. Although the exact mechanisms of its action are unknown, pirfenidone is a small molecule with antifibrotic and some hydroxyl scavenger properties that has recently been approved in Europe and elsewhere for the treatment of IPF. Along with the new ATS/ERS/JRS/ALAT 2011 statement for ‘Evidence Based Guidelines for Diagnosis and Management’, there is now a more profound basis for offering IPF patients an evidence‐based evaluation and treatment. This review summarizes the background to the recommended use of pirfenidone for the treatment of IPF.

Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?

Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF.

Opioids: an unexplored option for treatment of dyspnea in IPF

Background Idiopathic pulmonary fibrosis (IPF) is the most common among the idiopathic interstitial pneumonias and has the worst prognosis, with a median survival of 3–5 years. The most common symptom in IPF is dyspnea, impacting on the patients quality of life and life expectancy. Morphine in the treatment of dyspnea has been investigated but with conflicting results. This review aims to clarify the role of opioids in the treatment of dyspnea in patients with IPF. Methods A literature search was performed using the MeSH and PubMed databases. As only very few studies included patients with IPF, studies conducted primarily with patients with chronic obstructive pulmonary disease were also included. In total, 14 articles were found. Results Seven studies reported use of systemic morphine and seven studies of inhaled morphine. Five of the seven studies investigating systemic administration detected an improvement in either dyspnea or exercise capacity, whereas no beneficial effect on dyspnea was detected in any study using inhaled morphine. No severe adverse effects such as respiratory depression were reported in any study, although constipation was reported as a notable adverse effect. Conclusions Results were inconsistent, but in some studies systemic morphine administration showed a significant improvement in the dyspnea score on a visual analog scale without observation of severe side effects. Nebulized morphine had no effect on dyspnea.