Cryobiopsy for Identification of Usual Interstitial Pneumonia and Other Interstitial Lung Disease Features. Further Lessons from COLDICE, a Prospective Multicenter Clinical Trial.

Rationale: Transbronchial lung cryobiopsy (TBLC) is an emerging technique for interstitial lung disease diagnosis. Good histopathologic agreement between TBLC and surgical lung biopsy (SLB) was demonstrated in the COLDICE (Cryobiopsy versus Open Lung Biopsy in the Diagnosis of Interstitial Lung Disease Alliance) study; however, diagnostic confidence was frequently lower for TBLC than SLB. Objectives: To characterize specific features of TBLC predictive of usual interstitial pneumonia (UIP) in corresponding SLB and to identify clinical indices predictive of biopsy concordance. Methods: The COLDICE study was a prospective, multicenter study investigating diagnostic agreement between TBLC and SLB. The participants underwent both procedures with blinded pathologist analysis of specimens, applying international guideline criteria. The TBLC features predictive of UIP in the paired SLB and predictive features of overall concordance were analyzed. Measurements and Main Results: A total of 65 patients (66.1 ± 9.3 yr; FVC, 84.7 ± 14.2%; DlCO, 63.4 ± 13.8%) participated in the COLDICE study. UIP was identified in 33/65 (50.8%) SLB, and 81.5% were concordant with corresponding TBLC (κ, 0.61; 95% confidence interval [CI], 0.38-0.77). The UIP guideline criteria of "predominantly subpleural or paraseptal fibrosis" was infrequently reported in TBLC (8/33, 24.2%), whereas "patchy fibrosis," "fibroblast foci," and the "absence of alternative diagnostic features" were frequently observed in TBLC. The combination of these three features strongly predicted UIP in paired SLB (odds ratio [OR], 23.4; 95% CI, 6.36-86.1; P < 0.0001). Increased numbers of TBLC samples predicted histopathologic concordance with SLB (OR, 1.8; 95% CI, 1.08-3.01; P = 0.03). The predictors of discordance included older age, family history, and radiologic asymmetry. Conclusions: Subpleural and/or paraseptal fibrosis were not essential for diagnosing UIP in TBLC, provided that other guideline criteria features were present. The diagnostic accuracy of TBLC was strengthened when increased numbers of samples were taken. Clinical trial registered with www.anzctr.org.au (ACTRN12615000718549).

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation.

BACKGROUND: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population. METHODS: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. RESULTS: 55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up. CONCLUSIONS: Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH.

Inspiratory Muscle Training Improves Inspiratory Muscle Strength and Functional Exercise Capacity in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: A Pilot Randomised Controlled Study.

BACKGROUND: Exercise intolerance is present even in the early stages of pulmonary arterial hypertension (PAH) and is associated with poorer prognosis. Respiratory muscle dysfunction is common and may contribute to exercise limitation. We sought to investigate the effects of inspiratory muscle training (IMT) to improve exercise capacity in PAH. METHODS: Adults with PAH were prospectively recruited and randomly assigned to either IMT or a control group. At baseline and after 8 weeks, assessment of respiratory muscle function, pulmonary function, neurohormonal activation, 6-minute walk distance and cardiopulmonary exercise testing variables were conducted. Inspiratory muscle strength was assessed by maximal static inspiratory pressure (PImax). The IMT group performed two cycles of 30 breaths at 30-40% of their PImax 5 days a week for 8 weeks. RESULTS: Twelve (12) PAH patients (60±14 years, 10 females) were recruited and randomised (six in the IMT group and six in the control group). After 8 weeks, the IMT group improved PImax by 31 cmH2O compared with 10 cmH2O in controls, p=0.02. Following IMT, 6-minute walk distance improved by 24.5 m in the IMT group and declined by 12 m in the controls (mean difference 36.5 m, 95% CI 3.5-69.5, p=0.03). There was no difference in peak oxygen uptake between-groups (mean difference 0.4 mL/kg/min, 95% CI -2.6 to 3.4, p=0.77). There was no difference in the mean change between-groups in neurohormonal activation or pulmonary function. CONCLUSION: In this pilot randomised controlled study, IMT improved PImax and 6-minute walk distance in PAH patients.

Nocturnal hypoxaemia is associated with adverse outcomes in interstitial lung disease.

BACKGROUND AND OBJECTIVE: Sleep-disordered breathing (SDB) has been reported as highly prevalent in idiopathic pulmonary fibrosis (IPF) and other interstitial lung disease (ILD) populations. Nocturnal oxygen desaturation (NOD), or the total sleep time spent with SpoO2 < 90% (TST < 90), can occur both with and without associated apnoeas, and is common in ILD. This study aimed to characterize abnormal SDB and extent of TST < 90 in ILD patients and evaluate relationships between TST < 90 and markers of disease severity, development of pulmonary hypertension (PH) and mortality. METHODS: Consecutive, newly referred ILD patients attending a specialist clinic underwent polysomnography (PSG). Serial lung function tests, echocardiography and other clinical variables were recorded. Predictors of PH and mortality were evaluated using logistic regression and Cox proportional hazards regression analyses. RESULTS: A total of 92 ILD patients (including 44 with IPF) underwent PSG. At least mild obstructive sleep apnoea (OSA) was observed in 65.2%, with rapid eye movement (REM)-related events occurring frequently. At least 10% TST < 90 (designated 'significant NOD') was present in 35.9% of patients, and was associated with PH at baseline echocardiography. Multiple indices of hypoxaemia during sleep, including significant NOD, predicted the development of new or worsening PH. TST < 90 predicted overall and progression-free survival. CONCLUSION: Nocturnal oxygen saturation is associated with poorer prognosis in ILD patients and may contribute towards the pathogenesis of pulmonary vascular disease.

Pathophysiology of exercise intolerance in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a chronic disease with poor prognosis and important exercise limitation despite the proliferation of treatment options in the last decade. Chronically increased right ventricular (RV) afterload results in right heart failure and without treatment, rapid clinical deterioration is common. Exercise intolerance is the cardinal feature of the disease impacting upon quality of life and clinical outcome. The pathophysiological mechanisms that lead to reduced exercise capacity in this population are complex with ventriculoarterial uncoupling likely to be the predominant feature. The relative contributions of additional factors that contribute to exercise limitation beyond ventriculoarterial uncoupling have not been characterized. This review addresses these factors with a focus on recent developments and uncertainties. RV maladaptation and the intricate interplay between the heart, abnormal pulmonary vascular bed and peripheral factors such as dysfunction of the respiratory and peripheral muscles are discussed in detail.

Resting pulmonary artery pressure of 21-24†mmHg predicts abnormal exercise haemodynamics.

A resting mean pulmonary artery pressure (mPAP) of 21-24 mmHg is above the upper limit of normal but does not reach criteria for the diagnosis of pulmonary hypertension (PH). We sought to determine whether an mPAP of 21-24 mmHg is associated with an increased risk of developing an abnormal pulmonary vascular response during exercise.Consecutive patients (n=290) with resting mPAP <25 mmHg who underwent invasive exercise haemodynamics were analysed. Risk factors for pulmonary vascular disease or left heart disease were present in 63.4% and 43.8% of subjects. An abnormal pulmonary vascular response (or exercise PH) was defined by mPAP >30 mmHg and total pulmonary vascular resistance >3 WU at maximal exercise.Exercise PH occurred in 74 (86.0%) out of 86 versus 96 (47.1%) out of 204 in the mPAP of 21-24 mmHg and mPAP <21 mmHg groups, respectively (OR 6.9, 95% CI: 3.6-13.6; p<0.0001). Patients with mPAP of 21-24 mmHg had lower 6-min walk distance (p=0.002) and higher New York Heart Association functional class status (p=0.03). Decreasing levels of mPAP were associated with a lower prevalence of exercise PH, which occurred in 60.3%, 38.7% and 7.7% of patients with mPAP of 17-20, 13-16 and <13 mmHg, respectively.In an at-risk population, a resting mPAP between 21-24 mmHg is closely associated with exercise PH together with worse functional capacity.

Exercise pathophysiology and the role of oxygen therapy in idiopathic interstitial pneumonia.

Exercise limitation is a common feature in idiopathic interstitial pneumonia (IIP). There are multiple contributing pathophysiological mechanisms, including ventilatory mechanical limitation, impaired gas exchange, pulmonary vascular insufficiency and peripheral muscle dysfunction. Progressive exertional dyspnoea and functional incapacity impact significantly on quality of life. Exercise-induced desaturation is frequently observed and is predictive of poorer outcomes. Tests to assess the cardiorespiratory system under stress (e.g. cardiopulmonary exercise testing and the 6-min walk test) can provide important physiologic and prognostic information as adjuncts to resting measurements of lung function. Despite many advances in understanding disease mechanisms, therapies to improve exercise capacity, symptom burden and quality of life are lacking. Exercise training and supplemental oxygen are two potential interventions that require closer evaluation in patients with IIP.

Pulmonary vascular resistance and compliance relationship in pulmonary hypertension.

Right ventricular adaptation to the increased pulmonary arterial load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance (PVR) and total arterial compliance (C) quantify resistive and elastic properties of pulmonary arteries that modulate the steady and pulsatile components of pulmonary arterial load, respectively. PVR is commonly calculated as transpulmonary pressure gradient over pulmonary flow and total arterial compliance as stroke volume over pulmonary arterial pulse pressure (SV/PApp). Assuming that there is an inverse, hyperbolic relationship between PVR and C, recent studies have popularised the concept that their product (RC-time of the pulmonary circulation, in seconds) is "constant" in health and diseases. However, emerging evidence suggests that this concept should be challenged, with shortened RC-times documented in post-capillary PH and normotensive subjects. Furthermore, reported RC-times in the literature have consistently demonstrated significant scatter around the mean. In precapillary PH, the true PVR can be overestimated if one uses the standard PVR equation because the zero-flow pressure may be significantly higher than pulmonary arterial wedge pressure. Furthermore, SV/PApp may also overestimate true C. Further studies are needed to clarify some of the inconsistencies of pulmonary RC-time, as this has major implications for our understanding of the arterial load in diseases of the pulmonary circulation.

Dobutamine stress for evaluation of right ventricular reserve in pulmonary arterial hypertension.

Right ventricular contractile response to pharmacological stress in pulmonary arterial hypertension (PAH) has not been characterised. We evaluated right ventricular contractile reserve in adults with PAH using dobutamine stress echocardiography. 16 PAH patients and 18 age-matched controls underwent low-dose dobutamine stress echocardiography. Contractile reserve was assessed by the change (Δ; peak stress minus rest value) in tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular systolic velocity (S'). A subgroup of 13 PAH patients underwent treadmill cardiopulmonary exercise testing for peak oxygen uptake (V'O2peak). At rest, TAPSE and S' were reduced in the PAH group compared with controls (1.7 ± 0.4 versus 2.4 ± 0.2 cm and 9.7 ± 2.6 versus 12.5 ± 1.2 cm · s(-1), respectively; p<0.05). Contractile reserve was markedly attenuated in PAH compared to controls (ΔTAPSE 0.1 ± 0.2 versus 0.6 ± 0.3 cm and ΔS' 4.6 ± 2.8 versus 11.2 ± 3.6 cm · s(-1); p<0.0001). In the sub-group of PAH patients with preserved right ventricular systolic function at rest, contractile reserve remained depressed compared to controls. V'O2peak was significantly correlated with ΔS' (r=0.87, p=0.0003) and change in stroke volume (r=0.59, p=0.03). Dobutamine stress can reveal sub-clinical reduction in right ventricular contractile reserve in patients with PAH. A correlation with exercise capacity suggests potential clinical value beyond resting measurements.

Exercise Hemodynamics Predict Pulmonary Arterial Hypertension in BMPR2 Mutation Carriers.

BACKGROUND: Exercise hemodynamics are recommended for early detection of pulmonary arterial hypertension (PAH) and have been suggested to be predictive of future development of PAH in high-risk populations such as BMPR2 mutation carriers. However, the optimal exercise hemodynamic screening parameter remains to be determined. Recent data suggest that pulmonary vascular distensibility coefficient (α) may serve as a useful parameter for early detection of PAH. RESEARCH QUESTION: What is the value of exercise hemodynamics, including α, for predicting the occurrence of PAH during long-term follow-up in BMPR2 mutation carriers? STUDY DESIGN AND METHODS: Fifty-two asymptomatic BMPR2 mutation carriers who underwent symptom-limited exercise hemodynamic assessment were followed up for a median of 10 years. The impact of hemodynamics at rest and exercise, presence of exercise pulmonary hypertension, and α on occurrence of PAH during long-term follow-up were assessed. RESULTS: During long-term follow-up, five patients demonstrated PAH. Patients who demonstrated PAH showed a significantly lower α (0.8 ± 0.4%/mm Hg) than patients without PAH (1.8 ± 0.8%/mm Hg; P = .008). The only hemodynamic parameter that predicted the occurrence of PAH during long-term follow-up at regression analysis was α. Receiver operating characteristic analysis showed that α ≤ 1.5%/mm Hg predicted PAH occurrence with a specificity of 75% and sensitivity of 100%. INTERPRETATION: Before development of PAH in BMPR2 mutation carriers, α is reduced markedly and may serve as a useful parameter in the setting of early disease detection. Given the low event rate, caution is warranted in interpreting these results, highlighting the need for validation studies.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

Early detection of pulmonary vascular disease in pulmonary arterial hypertension: time to move forward.

Pulmonary arterial hypertension (PAH) can be a rapidly progressive disorder and is associated with high rate of mortality, despite medical intervention. With the availability of effective therapy, early disease detection is an important strategic objective to improve treatment outcomes. Resting echocardiography is currently the recommended screening modality for high-risk population groups. However, it is clear that derangements in resting haemodynamics (and symptoms) are late sequelae of the pathobiological processes that begin in the distal pulmonary arteries. Exercise stress may unmask early pulmonary vascular dysfunction but the definition, clinical significance, and natural history of 'exercise PAH' remain undefined. We will review the currently available and potential future strategies aimed at early disease detection, and propose that ultimately the way forward is to detect disease at a stage prior to the rise in resting pulmonary artery pressure.

Pregnancy outcomes in the current era of cystic fibrosis care: a 15-year experience.

BACKGROUND: With improvement in clinical care and longer survival of patients with cystic fibrosis (CF), pregnancy has become commonplace. However, the impact of pregnancy on maternal health and fetal outcomes requires ongoing review. METHODS: A retrospective study of 20 pregnancies from 18 women with CF during the period 1995-2009 was performed. Changes in lung function, body mass index (BMI) and development of gestational diabetes were recorded. Fetal outcomes and maternal survival were examined, and the influence of pre-pregnancy parameters on outcomes was evaluated. RESULTS: Mean maternal age at pregnancy was 29±5 years with a mean pre-pregnancy forced expiratory volume in 1 s (FEV1) of 65.6±20.8% predicted. Eleven of 20 pregnancies had a pre-pregnancy FEV1 <60% predicted. During pregnancy, FEV1% predicted fell by 4.8% (CI 1.6-7.9), but recovered to baseline within 6 months post-partum. Mothers gained a mean weight of 7.6±3.2 kg, and gestational diabetes developed in 43% of women. All women delivered live births apart from one therapeutic abortion. Five infants were preterm, and two mature infants had low birth weight. Three mothers either died or required lung transplantation after pregnancy (range 2.5-8.0 years). FEV1 <60% predicted and BMI <20 kg/m(2) were significant predictors of fetal complications. CONCLUSION: Most women tolerated pregnancy well without major complications despite many having at least moderate lung function impairment. Pre-pregnancy FEV1 and BMI were important predictors of outcomes.

Pulmonary Vascular Disease as a Systemic and Multisystem Disease.

Pulmonary arterial hypertension (PAH) is a disease of progressive pulmonary vascular remodeling due to abnormal proliferation of pulmonary vascular endothelial and smooth muscle cells and endothelial dysfunction. PAH is a multisystem disease with systemic manifestations and complications. This article covers the chronic heart failure syndrome, including the systemic consequences of right ventricle-pulmonary artery uncoupling and neurohormonal activation, skeletal and respiratory muscle effects, systemic endothelial dysfunction and coronary artery disease, systemic inflammation and infection, endocrine and metabolic changes, the liver and gut axis, sleep, neurologic complications, and skin and iron metabolic changes.

The isobaric pulmonary arterial compliance in pulmonary hypertension.

Pulmonary hypertension is associated with stiffening of pulmonary arteries which increases right ventricular pulsatile loading. High pulmonary artery wedge pressure (PAWP) in postcapillary pulmonary hypertension (Pc-PH) further decreases pulmonary arterial compliance (PAC) at a given pulmonary vascular resistance (PVR) compared with precapillary pulmonary hypertension, thus responsible for a higher total arterial load. In all other vascular beds, arterial compliance is considered as mainly determined by the distending pressure, due to non-linear stress-strain behaviour of arteries. We tested the applicability, advantages and drawbacks of two comparison methods of PAC depending on the level of mean pulmonary arterial pressure (mPAP; isobaric PAC) or PVR. Right heart catheterisation data including PAC (stroke volume/pulse pressure) were obtained in 112 Pc-PH (of whom 61 had combined postcapillary and precapillary pulmonary hypertension) and 719 idiopathic pulmonary arterial hypertension (iPAH). PAC could be compared over the same mPAP range (25-66 mmHg) in 792 (95.3%) out of 831 patients and over the same PVR range (3-10.7 WU) in only 520 (62.6%) out of 831 patients. The main assumption underlying comparisons at a given PVR was not verified as the PVR×PAC product (RC-time) was not constant but on the contrary more variable than mPAP. In the 788/831 (94.8%) patients studied over the same PAC range (0.62-6.5 mL·mmHg-1), PVR and thus total arterial load tended to be higher in iPAH. Our study favours comparing PAC at fixed mPAP level (isobaric PAC) rather than at fixed PVR. A reappraisal of the effects of PAWP on the pulsatile and total arterial load put on the right heart is needed, and this point deserves further studies.