Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial.

INTRODUCTION: Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression. METHODS: This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks. RESULTS: We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group. DISCUSSION: Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted. TRIAL REGISTRATION NUMBER: ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.

Cardiorespiratory responses to muscle metaboreflex activation in fibrosing interstitial lung disease.

NEW FINDINGS: What is the central question of this study? We determined whether sensory feedback from metabolically sensitive skeletal muscle afferents (metaboreflex) causes a greater ventilatory response and higher dyspnoea ratings in fibrosing interstitial lung disease (FILD). What is the main finding and its importance? Ventilatory responses and dyspnoea ratings during handgrip exercise and metaboreflex isolation were not different in FILD and control groups. Blood pressure and heart rate responses to handgrip were attenuated in FILD but not different to controls during metaboreflex isolation. These findings suggest that the muscle metaboreflex contribution to the respiratory response to exercise is not altered in FILD. ABSTRACT: Exercise limitation and dyspnoea are hallmarks of fibrosing interstitial lung disease (FILD); however, the physiological mechanisms are poorly understood. In other respiratory diseases, there is evidence that an augmented muscle metaboreflex may be implicated. We hypothesized that metaboreflex activation in FILD would result in elevated ventilation and dyspnoea ratings compared to healthy controls, due to augmented muscle metaboreflex. Sixteen FILD patients (three women, 69±14 years; mean±SD) and 16 age-matched controls (four women, 67±7 years) were recruited. In a randomized cross-over design, participants completed two min of rhythmic handgrip followed by either (i) two min of post-exercise circulatory occlusion (PECO trial) to isolate muscle metaboreflex activation, or (ii) rested for four min (Control trial). Minute ventilation ( V̇E$\dot{V}_E$ ; pneumotachometer), dyspnoea ratings (0-10 Borg scale), mean arterial pressure (MAP; finger photoplethysmography) and heart rate (HR; electrocardiogram) were measured. V̇E$\dot{V}_E$ was higher in the FILD group at baseline and exercise increased V̇E$\dot{V}_E$ similarly in both groups. V̇E$\dot{V}_E$ remained elevated during PECO, but there was no between-group difference in the magnitude of this response (Δ V̇E$\dot{V}_E$ FILD 4.2 ± 2.5 L·min-1  vs. controls 3.6 ± 2.4 L·min-1 , P = 0.596). At the end of PECO, dyspnoea ratings in FILD were similar to controls (1.0 ± 1.3 units vs. 0.5 ± 1.1 units). Exercise increased MAP and HR (P < 0.05) in both groups; however, responses were lower in FILD. Collectively, these findings suggest that there is not an augmented effect of the muscle metaboreflex on breathing and dyspnoea in FILD, but haemodynamic responses to handgrip are reduced relative to controls.

Diagnosis and management of connective tissue disease-associated interstitial lung disease in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand.

Pulmonary complications in CTD are common and can involve the interstitium, airways, pleura and pulmonary vasculature. ILD can occur in all CTD (CTD-ILD), and may vary from limited, non-progressive lung involvement, to fulminant, life-threatening disease. Given the potential for major adverse outcomes in CTD-ILD, accurate diagnosis, assessment and careful consideration of therapeutic intervention are a priority. Limited data are available to guide management decisions in CTD-ILD. Autoimmune-mediated pulmonary inflammation is considered a key pathobiological pathway in these disorders, and immunosuppressive therapy is generally regarded the cornerstone of treatment for severe and/or progressive CTD-ILD. However, the natural history of CTD-ILD in individual patients can be difficult to predict, and deciding who to treat, when and with what agent can be challenging. Establishing realistic therapeutic goals from both the patient and clinician perspective requires considerable expertise. The document aims to provide a framework for clinicians to aid in the assessment and management of ILD in the major CTD. A suggested approach to diagnosis and monitoring of CTD-ILD and, where available, evidence-based, disease-specific approaches to treatment have been provided.

Diagnostic Likelihood Thresholds That Define a Working Diagnosis of Idiopathic Pulmonary Fibrosis.

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown.Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB.Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues.Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04).Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood ≥ 70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.

Ethnicity, socioeconomic status and the severity and course of non-cystic fibrosis bronchiectasis.

BACKGROUND AND AIMS: This study evaluated whether there are ethnic factors which affect the severity and progression of bronchiectasis in our adult multi-ethnic population in Auckland, New Zealand. METHODS: Clinical records were reviewed from patients attending the outpatient facilities of our institution between 2007 and 2010. Data collected included demographics, clinical features, smoking status, self-reported ethnicity, socioeconomic status (NZDep), pulmonary function and sputum microbiology. RESULTS: A total of 437 patients was identified: median age 65 years, 66% female, mean forced expiratory volume in the first second (FEV1 ) 62.4% predicted, and 10.5% of patients had recurrent growth of Pseudomonas aeruginosa. Patients of Maori and Pacific ethnicity were overrepresented compared to the institution population catchment and had more severe impairment of lung function: mean % predicted FEV1 for Pacific 52.0, Maori 58.6, European 68.6, Asian 64.2 (P < 0.0001). This was independent of socioeconomic status. However, no overall decline was seen in serial lung function measurements, either across the whole cohort or in any particular ethnic group. CONCLUSIONS: Patients of Maori and Pacific ethnicity are both overrepresented and have more severe bronchiectasis in this cohort, independent of socioeconomic status. Ethnicity did not predict decline in pulmonary function. Further studies into genetic predisposition to bronchiectasis in Maori or Pacific people may be warranted.

Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: an international case-cohort study.

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts.A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (κw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index.A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53-0.72, p<0.0001) than academic physicians (κw=0.56, IQR 0.45-0.65, p<0.0001) or physicians with access to multidisciplinary team (MDT) meetings (κw=0.54, IQR 0.45-0.64, p<0.0001). The prognostic accuracy of academic physicians with >20 years of experience (C-index=0.72, IQR 0.0-0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70-0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72-0.75).Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts.

Characteristics of sarcoidosis in Maori and Pacific Islanders.

BACKGROUND AND OBJECTIVE: Ethnicity is strongly associated with variable clinical presentation in sarcoidosis but the association between ethnicity and clinical characteristics has not previously been described in patients of Polynesian ancestry, Maori and Pacific Islander (PI). The objective of this study was to describe the clinical characteristics of sarcoidosis in Maori and PI patients and determine if those were different to European patients. METHODS: A retrospective review of the medical records of 406 patients (69 Maori/PI) attending a specialist interstitial lung disease (ILD) clinic. RESULTS: The population (207 females, mean age at presentation: 36) reflected the current New Zealand census data (2013) with only people of Indian ethnicity over-represented. Parenchymal lung involvement was uncommon in Maori and PI patients (21% Scadding stage 2, 2% stage 3), and no patient had extensive pulmonary fibrosis (stage 4). Computed tomography (CT) patterns of sarcoid parenchymal lung involvement were less commonly reported for Maori/PI. There were no differences in respect of baseline lung function or requirement for treatment. Ocular and skin involvement occurred more frequently in Maori and PI (P = 0.0045, P = 0.03), and erythema nodosum was more common in Caucasians (P = 0.0008). CONCLUSION: People of Polynesian ancestry appear to have less pulmonary and more extra-pulmonary manifestations of sarcoidosis. This adds to our knowledge that sarcoidosis heterogeneity is influenced by ethnicity.

Current Australasian practice for diagnosis and management of idiopathic pulmonary fibrosis: Where are we now?

BACKGROUND AND OBJECTIVE: Recent international consensus statements have refined evidence-based guidelines for the diagnosis and management of idiopathic pulmonary fibrosis (IPF). This study sought to investigate how closely these guidelines are adhered to and to compare current practices with those of a similar cohort 15 years ago. METHODS: A questionnaire on IPF diagnosis and management was distributed to respiratory physicians practising in Australia and New Zealand, in 2012-2013, and results were compared with a similar survey conducted in 1999. RESULTS: A total of 172 and 144 questionnaires were completed in 1999 and 2012-2013, respectively. The most important investigations in both survey populations were high-resolution computed tomography scans, spirometry, diffusing capacity for carbon monoxide, chest X-ray, static lung volumes and autoimmune serology. In 1999, physicians were more likely to perform arterial blood gases, bronchoalveolar lavage and transbronchial lung biopsy. In the 2012-2013 cohort, 6-min walk tests and pulse oximetry were more widely utilized. Treatment choices differed considerably between the two survey populations. In 1999, the majority would offer a steroid-based regimen, whereas most would not use any specific treatment or would refer for trial participation in 2012-2013. CONCLUSIONS: Approach to IPF diagnosis and management is not uniform and has changed over 15 years. Surveyed respiratory physicians were generally practising in accordance with clinical guidelines, although significant variation in practice was identified in both cohorts. This study identifies the need to standardize care of IPF patients across Australia and New Zealand.

The relationships among dyspnoea, health-related quality of life and psychological factors in sarcoidosis.

BACKGROUND AND OBJECTIVES: Dyspnoea is a common symptom in sarcoidosis and is not predictably related to pulmonary function or radiology. A subjective symptom of dyspnoea is likely to be influenced by patient perception and experience. The aim of this study was to determine the prevalence and nature of dyspnoea in sarcoidosis and describe the relationship of dyspnoea to psychological factors and health-related quality of life (HRQL). METHODS: Fifty-six subjects (31 men, mean age 51 years) with sarcoidosis completed an HRQL measure, St George's Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Scale (HADS) and Nijmegen questionnaire. The presence of symptoms of dyspnoea was noted and qualitative descriptors for dyspnoea were chosen at peak exercise. Resting pulmonary function was performed. RESULTS: Sixty-four per cent of the subjects reported dyspnoea. Those with symptoms were older, had a longer duration of disease and with lower forced expiratory volume in 1 s (FEV1 ) and FEV1 /forced vital capacity (FVC) (all P < 0.05). Symptoms of dyspnoea were associated with worse HRQL (P < 0.005) and higher scores on the Nijmegen questionnaire (P < 0.05). Anxiety was not associated with dyspnoea and only a trend to greater depression was observed (P = 0.066). In multivariate analysis, SGRQ and Nijmegen scores predicted dyspnoea independent of demographic factors and resting pulmonary function. CONCLUSION: Dyspnoea is common in sarcoidosis and is associated with worse HRQL irrespective of baseline pulmonary function. Hyperventilation appears to be a factor contributing to dyspnoea and the Nijmegen questionnaire may be helpful in assessing dyspnoea and hyperventilation in sarcoidosis patients.

Comparison of the modified shuttle walk test and cardiopulmonary exercise test in sarcoidosis.

BACKGROUND AND OBJECTIVE: Dyspnoea and exercise intolerance are common in sarcoidosis and are often poorly correlated with resting lung function. Measurement of peak exercise capacity is likely to be helpful in assessing and monitoring disease. The aim of this study was to compare the modified shuttle walk test (MSWT) to cardiopulmonary exercise test (CPET) as a measure of peak exercise capacity in sarcoidosis. METHODS: Thirty-three (17 male, mean age 48 years) patients with sarcoidosis completed a standardized exponential exercise protocol cycle ergometer CPET and a single corridor MSWT in random order. RESULTS: Subjects has a mean forced expiratory volume in 1 s (FEV1) 2.4 L (75.7%predicted), forced vital capacity (FVC) 3.43 L (88.7%predicted) and diffusing capacity for carbon monoxide (DLCO) 20.3 mL/min/mm Hg (71.4%predicted). There was a strong correlation between MSWT distance and peak oxygen uptake (VO2) during CPET (r = 0.87; P < 0.0001), and between maximum heart rate during MSWT and CPET (r = 0.82; P < 0.0001). There was a moderate correlation between FEV1 , FVC and DLCO with MSWT distance (r = 0.55, r = 0.61, r = 0.61, respectively; all P < 0.001) and with peak VO2 (r = 0.62, r = 0.63, r = 0.62, respectively; all P < 0.0001). CONCLUSIONS: Peak VO2 achieved during CPET strongly correlated with MSWT distance. MSWT is a measure of peak exercise capacity in sarcoidosis that does not require equipment and can be readily available in the clinic.

Evaluating Tissue Heterogeneity in the Radiologically Normal-Appearing Tissue in IPF Compared to Healthy Controls.

RATIONALE AND OBJECTIVES: Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease characterised by heterogeneously distributed fibrotic lesions. The inter- and intra-patient heterogeneity of the disease has meant that useful biomarkers of severity and progression have been elusive. Previous quantitative computed tomography (CT) based studies have focussed on characterising the pathological tissue. However, we hypothesised that the remaining lung tissue, which appears radiologically normal, may show important differences from controls in tissue characteristics. MATERIALS AND METHODS: Quantitative metrics were derived from CT scans in IPF patients (N = 20) and healthy controls with a similar age (N = 59). An automated quantitative software (CALIPER, Computer-Aided Lung Informatics for Pathology Evaluation and Rating) was used to classify tissue as normal-appearing, fibrosis, or low attenuation area. Densitometry metrics were calculated for all lung tissue and for only the normal-appearing tissue. Heterogeneity of lung tissue density was quantified as coefficient of variation and by quadtree. Associations between measured lung function and quantitative metrics were assessed and compared between the two cohorts. RESULTS: All metrics were significantly different between controls and IPF (p < 0.05), including when only the normal tissue was evaluated (p < 0.04). Density in the normal tissue was 14% higher in the IPF participants than controls (p < 0.001). The normal-appearing tissue in IPF had heterogeneity metrics that exhibited significant positive relationships with the percent predicted diffusion capacity for carbon monoxide. CONCLUSION: We provide quantitative assessment of IPF lung tissue characteristics compared to a healthy control group of similar age. Tissue that appears visually normal in IPF exhibits subtle but quantifiable differences that are associated with lung function and gas exchange.

Quantitative Analysis of Lung Shape in Idiopathic Pulmonary Fibrosis: Insights Into Disease- and Age-Associated Patterns.

RATIONALE AND OBJECTIVES: Fibrotic scarring in idiopathic pulmonary fibrosis (IPF) typically develops first in the posterior-basal lung tissue before advancing to involve more of the lung. The complexity of lung shape in the costo-diaphragmatic region has been proposed as a potential factor in this regional development. Intrinsic and disease-related shape could therefore be important for understanding IPF risk and its staging. We hypothesized that lung and lobe shape in IPF would have important differences from controls. MATERIALS AND METHODS: A principal component (PC) analysis was used to derive a statistical shape model (SSM) of the lung for a control cohort aged > 50 years (N = 39), using segmented lung and fissure surface data from CT imaging. Individual patient shape models derived for baseline (N = 18) and follow-up (N = 16) CT scans in patients with IPF were projected to the SSM to describe shape as the sum of the SSM average and weighted PC modes. Associations between the first four PC shape modes, lung function, percentage of fibrosis (fibrosis%) and pulmonary vessel-related structures (PVRS%), and other tissue metrics were assessed and compared between the two cohorts. RESULTS: Shape was different between IPF and controls (P < 0.05 for all shape modes), with IPF shape forming a distinct shape cluster. Shape had a negative relationship with age in controls (P = 0.013), but a positive relationship with age in IPF (P = 0.026). Some features of shape changed on follow-up. Shape in IPF was associated with fibrosis% (P < 0.05) and PVRS% (P < 0.05). CONCLUSION: Quantitative comparison of lung and lobe shape in IPF with controls of a similar age reveals shape differences that are strongly associated with age and percent fibrosis. The clustering of IPF cohort shape suggests that it could be an important feature to describe disease.

Pulmonary vessel volume in idiopathic pulmonary fibrosis compared with healthy controls aged > 50 years.

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive fibrosing interstitial pneumonia with an associated irreversible decline in lung function and quality of life. IPF prevalence increases with age, appearing most frequently in patients aged > 50 years. Pulmonary vessel-like volume (PVV) has been found to be an independent predictor of mortality in IPF and other interstitial lung diseases, however its estimation can be impacted by artefacts associated with image segmentation methods and can be confounded by adjacent fibrosis. This study compares PVV in IPF patients (N = 21) with PVV from a healthy cohort aged > 50 years (N = 59). The analysis includes a connected graph-based approach that aims to minimise artefacts contributing to calculation of PVV. We show that despite a relatively low extent of fibrosis in the IPF cohort (20% of the lung volume), PVV is 2-3 times higher than in controls. This suggests that a standardised method to calculate PVV that accounts for tree connectivity could provide a promising tool to provide early diagnostic or prognostic information in IPF patients and other interstitial lung disease.

Psychological stress in sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a chronic illness associated with emotional and physical consequences which impact on quality of life. Although the impact of fatigue is well understood, emotional impacts of sarcoidosis are less commonly recognized and addressed in routine clinical practice. The purpose of this review is to highlight that sarcoidosis can result in considerable psychological distress. RECENT FINDINGS: Not only is there a high prevalence of depressive symptoms in sarcoidosis, but clinical depressive and anxiety disorders are more common than seen in the general population. Patients with sarcoidosis have perceptions and beliefs about their disease that may impact on their willingness to engage in recommended therapies. They may also exhibit a disordered perception of their disease and a personality profile of neuroticism. Understanding the minimally important clinical difference in the Fatigue Assessment Scale (FAS) and validation of the Sarcoidosis Health Questionnaire (SHQ) across different populations supports the use of these tools in routine clinical practice and clinical trials. SUMMARY: Understanding the global impact of sarcoidosis is important for patients and clinicians, and use of validated instruments, such as the SHQ and FAS, allows for more comprehensive assessment of the disease and the impact of any interventions.

Validation of the Sarcoidosis Health Questionnaire in a non-US population.

BACKGROUND AND OBJECTIVE: Sarcoidosis is a multi-system disease with an unpredictable course and variable clinical manifestations that are often associated with impaired quality of life. The Sarcoidosis Health Questionnaire (SHQ), which was developed for an 80% African American population, assesses health-related quality of life in sarcoidosis patients. The aim of this study was to validate the SHQ in a predominantly European population of sarcoidosis patients. METHODS: Consecutive outpatients (n = 92) with sarcoidosis, who were attending a teaching hospital clinic, completed three questionnaires (SHQ, Short Form (SF) 36, Fatigue Assessment Scale (FAS)) and pulmonary function tests were performed. RESULTS: The mean age of the patients was 51 years, 52% were males and 74% were of European ethnicity. The mean number of organs involved was 1.3, with pulmonary involvement in 95% of patients (mean forced expiratory volume in 1 s 74.4%, forced vital capacity 84.6%). Seventy percent of patients had current symptoms and 26.5% were receiving immunosuppressant therapy. The SHQ total score (mean 5.13) was significantly correlated with the SF 36 physical component score (46.7, r = 0.78) and the FAS (20.8, r = -0.7) but only weakly correlated with pulmonary function. There were significant differences in SHQ scores when patients were stratified according to symptoms, oral therapy, health status (P < 0.0001 for all), forced expiratory volume in 1 s ≥70% (P = 0.008) and forced vital capacity ≥70% (P = 0.01). CONCLUSIONS: The SHQ correlated well with health-related quality of life and fatigue measures in a predominantly European population of sarcoidosis patients, despite differences in organ involvement and disease burden, when compared with the development study.

The prevalence and predictors of airway hyperresponsiveness in sarcoidosis.

BACKGROUND AND OBJECTIVE: Obstructive airflow limitation is the most common physiological impairment in sarcoidosis. This study determined the prevalence of airway hyperresponsiveness (AHR) in sarcoidosis, the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge, and the clinical, physiological and radiological predictors of AHR. METHODS: Subjects with sarcoidosis and a baseline forced expiratory volume in 1 s (FEV(1)) >35% predicted underwent hypertonic and histamine challenge, lung function testing and high resolution computed tomography (HRCT) of the chest. AHR was defined as a 15% fall in FEV(1) to hypertonic saline and a 20% fall in FEV(1) to histamine. RESULTS: The 52 subjects had well-preserved lung function (FEV(1) = 2.8 ± 0.7 L, 87% predicted). AHR was detected in 5/47 (11%) to hypertonic saline and 19/43 (44%) to histamine challenge. On univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (P = 0.02) and reticular pattern (P = 0.03) on HRCT. The baseline % predicted forced expiratory volume in 1 s was significantly inversely associated with AHR on univariate (P = 0.004) and multivariate analysis (P = 0.01) when adjusted by HRCT patterns. CONCLUSIONS: The higher prevalence of AHR using histamine challenge than hypertonic saline challenge and the association with baseline % predicted FEV(1) suggest that the AHR in sarcoidosis may reflect the consequences of airway remodelling following inflammation.

A computational model of contributors to pulmonary hypertensive disease: impacts of whole lung and focal disease distributions.

Pulmonary hypertension has multiple etiologies and so can be difficult to diagnose, prognose, and treat. Diagnosis is typically made via invasive hemodynamic measurements in the main pulmonary artery and is based on observed elevation of mean pulmonary artery pressure. This static mean pressure enables diagnosis, but does not easily allow assessment of the severity of pulmonary hypertension, nor the etiology of the disease, which may impact treatment. Assessment of the dynamic properties of pressure and flow data obtained from catheterization potentially allows more meaningful assessment of the strain on the right heart and may help to distinguish between disease phenotypes. However, mechanistic understanding of how the distribution of disease in the lung leading to pulmonary hypertension impacts the dynamics of blood flow in the main pulmonary artery and/or the pulmonary capillaries is lacking. We present a computational model of the pulmonary vasculature, parameterized to characteristic features of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension to help understand how the two conditions differ in terms of pulmonary vascular response to disease. Our model incorporates key features known to contribute to pulmonary vascular function in health and disease, including anatomical structure and multiple contributions from gravity. The model suggests that dynamic measurements obtained from catheterization potentially distinguish between distal and proximal vasculopathy typical of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. However, the model suggests a non-linear relationship between these data and vascular structural changes typical of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension which may impede analysis of these metrics to distinguish between cohorts.

Systemic Associations of Sarcoid Uveitis: Correlation With Uveitis Phenotype and Ethnicity.

PURPOSE: To examine systemic associations of sarcoid uveitis and association with uveitis clinical phenotype and ethnicity. DESIGN: Retrospective cross-sectional study. SUBJECTS: A total of 362 subjects with definite or presumed sarcoid uveitis from Moorfields Eye Hospital, Royal Victorian Eye and Ear, and Auckland District Health Board. METHODS: Data were collected from the review of clinical notes, imaging, and investigations. Sarcoidosis was diagnosed in accordance with the International Workshop on Ocular Sarcoidosis guidelines. MAIN OUTCOME MEASURE: Diagnosis of associated systemic disease secondary to sarcoidosis. RESULTS: A total of 362 subjects with sarcoid uveitis were identified. Median age was 46 years, and 226 (62.4%) were female. Granulomatous anterior uveitis (47.8%), intermediate uveitis with snowballs (46.4%), and multifocal choroiditis (43.1%) were the most frequent clinical presentations, and disease was bilateral in 313 (86.5%). Periphlebitis was observed in 21.0%, and solitary optic nerve or choroidal granuloma in 11.3%. Lung parenchymal disease was diagnosed in 200 subjects (55.2%), cutaneous sarcoid in 98 (27.1%), sarcoid arthritis in 57 (15.7%), liver involvement in 21 (5.8%), neurosarcoid in 49 (13.5%), and cardiac sarcoid in 16 subjects (4.4%). Subjects with cardiac sarcoid were less likely to have granulomatous anterior uveitis (P = .017). Caucasian subjects were older at presentation (48 vs 41 years; P = .009), had less granulomatous anterior uveitis (26.4% vs 51.7%; P < .001), and were less likely to present with cutaneous involvement (23.1% vs 35.4%; P = .040). CONCLUSIONS: Ophthalmologists need to be aware of the systemic associations of sarcoid uveitis, in particular potentially life-threatening complications such as cardiac sarcoidosis. Differences observed in uveitis phenotype and between ethnicities require further investigation.