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The aim of this study was to determine the prevalence, characteristics and outcomes of patients with unclassifiable interstitial lung disease (ILD) and to develop a simple method of predicting disease behaviour. Unclassifiable ILD patients were identified from an ongoing longitudinal cohort. Unclassifiable ILD was diagnosed after a multidisciplinary review did not secure a specific ILD diagnosis. Clinical characteristics and outcomes were compared with idiopathic pulmonary fibrosis (IPF) and non-IPF ILDs. Independent predictors of mortality were determined using Cox proportional-hazards analysis to identify subgroups with distinct disease behaviour. Unclassifiable ILD was diagnosed in 10% of the ILD cohort (132 out of 1370 patients). The most common reason for being unclassifiable was missing histopathological assessment due to a high risk of surgical lung biopsy. Demographic and physiological features of unclassifiable ILD were intermediate between IPF and non-IPF disease controls. Unclassifiable ILD had longer survival rates when compared to IPF on adjusted analysis (hazard ratio 0.62, p = 0.04) and similar survival compared to non-IPF ILDs (hazard ratio 1.54, p = 0.12). Independent predictors of survival in unclassifiable ILD included diffusion capacity of the lung for carbon monoxide (p = 0.001) and a radiological fibrosis score (p = 0.02). Unclassifiable ILD represents approximately 10% of ILD cases and has a heterogeneous clinical course, which can be predicted using clinical and radiological variables.

Background: It is unknown if the radiographic fibrosis score predicts mortality in persistent hypersensitivity pneumonitis (HP) and if survival is similar to that observed in idiopathic pulmonary fibrosis (IPF) when adjusting for the extent of radiographic fibrosis., Methods: We reviewed records from 177 patients with HP and 224 patients with IPF whose diagnoses were established by multidisciplinary consensus. Two thoracic radiologists scored high-resolution CT (HRCT) scan lung images. Independent predictors of transplant-free survival were determined using a Cox proportional hazards analysis. Kaplan-Meier survival curves were constructed, stratified by disease as well as fibrosis score., Results: HRCT scan fibrosis score and radiographic reticulation independently predicted time to death or lung transplantation. Clinical predictors included a history of cigarette smoking, auscultatory crackles on lung examination, baseline FVC, and FEV1/FVC ratio. The majority of HP deaths occurred in patients with both radiographic reticulation and auscultatory crackles on examination, compared with patients with only one of these manifestations (P < .0001). Patients with IPF had worse survival than those with HP at any given degree of radiographic fibrosis (hazard ratio 2.31; P < .01)., Conclusions: Survival in patients with HP was superior to that of those with IPF with similar degrees of radiographic fibrosis. The combination of auscultatory crackles and radiographic reticulation identified patients with HP who had a particularly poor outcome.

Background: Combined pulmonary fibrosis and emphysema (CPFE) is increasingly recognized, but its prevalence and prognosis remain unclear. We sought to determine the prevalence, clinical features, and prognosis of CPFE in idiopathic pulmonary fibrosis (IPF), using a standardized and reproducible definition., Methods: Patients with IPF were identified from two ongoing cohorts. Two radiologists scored emphysema and fibrosis severity on high-resolution CT (HRCT) scans. CPFE was defined as ≥10% emphysema on HRCT scan. Clinical characteristics and outcomes of patients with CPFE and IPF and those with non-CPFE IPF were compared with unadjusted analysis and then analysis after adjustment for HRCT fibrosis score. Mortality was compared using competing risks regression to handle lung transplantation. Sensitivity analyses were performed using Cox proportional hazards, including time to death (transplantation censored) and time to death or transplant., Results: CPFE criteria were met in 29 of 365 patients with IPF (8%), with high agreement between radiologists (κ=0.74). Patients with CPFE had less fibrosis on HRCT scans and higher FVC, but greater oxygen requirements (P≤.01 for all comparisons). Findings were maintained with adjustment for fibrosis severity. Inhaled therapies for COPD were used by 53% of patients with CPFE. There was no significant difference in mortality comparing patients with CPFE and IPF to those with non-CPFE IPF (hazard ratio, 1.14; 95% CI, 0.61-2.13; P=.69)., Conclusions: CPFE was identified in 8% of patients with IPF and is a distinct, clinical phenotype with potential therapies that remain underutilized. Patients with CPFE and IPF and those with non-CPFE IPF have similar mortality.

Background: The clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis is unclear. The objective of this study was to determine the frequency and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis., Methods: We measured an extensive panel of autoantibodies (including rheumatoid factor, anti-cyclic citrullinated peptide, and anti-nuclear antibodies by immunofluorescence) associated with connective tissue disease or vasculitis in a cohort of well-characterized patients with idiopathic pulmonary fibrosis (n = 67). The prevalence of circulating autoantibodies was compared between idiopathic pulmonary fibrosis patients and healthy controls (n = 52). We compared the clinical characteristics of patients with and without circulating autoantibodies, and analyzed the relationship between autoantibody positivity and transplant-free survival time., Results: Positive autoantibodies were found in 22% of patients with IPF and 21% of healthy controls. There were no differences in the types of autoantibodies found between patients with idiopathic pulmonary fibrosis and healthy controls. Among patients with idiopathic pulmonary fibrosis, there were no significant differences in clinical characteristics between those with and without circulating autoantibodies. The presence of circulating autoantibodies was associated with longer transplant-free survival time on adjusted analysis, however the significance varied depending on which statistical model was used (HR 0.22-0.47, p value 0.02-0.17)., Conclusions: The frequency of circulating autoantibodies in patients with idiopathic pulmonary fibrosis is no different compared to healthy controls, but may be associated with longer survival., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Vasospasm after subarachnoid hemorrhage is a common and potentially life-threatening complication. Treatment of vasospasm may include intraarterial (IA) injections of verapamil into the cerebral vasculature. Clinical experience suggests that the average patient experiences an acute reduction in systemic blood pressure after IA verapamil. Our study objective was to (1) identify the effects of IA injection of verapamil on mean arterial blood pressure (MAP) and heart rate (HR) in patients with cerebral vasospasm and (2) determine the effect of verapamil dose on change in MAP and HR. We hypothesized that (1) selective IA injection of verapamil for treatment of cerebral vasospasm is associated with a reduction in MAP and an increase in HR and (2) the change in MAP and HR are linearly related to the dose of verapamil administered., Methods: We prospectively studied subjects with vasospasm scheduled for cerebral angiography with possible IA injection of verapamil. All subjects were given a general anesthetic. Invasive arterial blood pressure and HR were monitored continuously and recorded at 10-second intervals throughout the procedure. We identified the lowest MAP and highest HR before and after verapamil injection. The association between IA verapamil and change in MAP and HR was determined using repeated-measures multivariate regression analysis, adjusting for potential confounding factors (weight, preoperative vasopressor use, and preinjection MAP). Data are reported as adjusted coefficients and 95% confidence intervals (CI)., Results: We included 20 subjects who underwent a total of 46 injections of IA verapamil. On the basis of our multivariate model, on average, each 5 mg of IA verapamil was associated with a 3.5 mm Hg reduction in MAP (95% CI -5.0 to -2.0, P < 0.001). HR was not significantly altered by IA verapamil on both unadjusted and adjusted analyses (nonsignificant increase of 0.4 beats per minute for each 5 mg of IA verapamil, 95% CI -1.6 to 2.4, P = 0.70)., Conclusions: Under general anesthesia, injection of IA verapamil into cerebral arteries reduces MAP but does not change HR in the average patient. Further research is required to determine the clinical significance of these results.

Background and Objective: Little is known about depression in interstitial lung disease (ILD). The aim of this study was to determine the prevalence of depression, characterize the association of depression with clinical variables and describe the natural history of depression in patients with ILD., Methods: In this prospective cohort study, clinical variables were recorded at baseline and 6 months. Depression was measured with the Centre for Epidemiologic Studies Depression scale. Depression prevalence was determined using the established threshold of >15 points. Multivariate linear regression was used to determine the baseline features that independently correlated with baseline depression score and that predicted depression severity at follow-up., Results: Fifty-two subjects were enrolled, and 45 returned for follow-up (three deaths, one lung transplant). Prevalence of depression was 21% at baseline. Independent predictors of depressive symptoms at baseline included dyspnoea severity, pain severity, sleep quality and forced vital capacity (R(2) 0.67). The odds of clinically meaningful depression at follow-up were 34-fold higher for subjects who had clinically meaningful depression at baseline compared with those who were not (95% confidence interval 3.5-422, P < 0.0005). Baseline depression score was the strongest predictor of depression score at follow-up (r 0.59, P < 0.00005)., Conclusions: Depressive symptoms in ILD are common, persistent, and strongly and independently correlated with dyspnoea, pain, sleep quality and forced vital capacity. Clinically meaningful depression at baseline is the most important predictor of depressive symptoms at follow-up. Patients with ILD should routinely be screened for depression., (© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.)

Background and Objective: The clinical associations and prognostic value of cough in IPF have not been adequately described. The objective of this study was to describe the characteristics and prognostic value of cough in IPF., Methods: Subjects with IPF were identified from an ongoing longitudinal database. Cough and other clinical variables were recorded prospectively. Logistic regression was used to determine predictors of cough and predictors of disease progression, defined as 10% decline in FVC, 15% decline in DL(CO) , lung transplantation or death within 6 months of clinic visit. The relationship of cough with time to death or lung transplantation was analysed using Cox proportional hazards analysis., Results: Two hundred and forty-two subjects were included. Cough was reported in 84% of subjects. On multivariate analysis, cough was less likely in previous smokers (OR 0.07, 95% CI: 0.01-0.55, P = 0.01), and more likely in subjects with exertional desaturation (OR 2.56, 95% CI: 1.15-5.72, P = 0.02) and lower FVC (OR 0.76, 95% CI: 0.60-0.96, P = 0.02). Cough predicted disease progression (OR 4.97, 95% CI: 1.25-19.80, P = 0.02) independent of disease severity, and may predict time to death or lung transplantation (HR 1.78, 95% CI: 0.94-3.35, P = 0.08)., Conclusions: Cough in IPF is more prevalent in never-smokers and patients with more advanced disease. Cough is an independent predictor of disease progression and may predict time to death or lung transplantation., (© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.)

The present report describes two patients with long-term survival after being diagnosed with idiopathic pulmonary arterial hypertension more than 20 years earlier. Both patients were treated with calcium channel blockers for several years and are currently maintained on bosentan, an oral endothelin receptor antagonist. Severe dilation of the main pulmonary arteries is present in both patients and may be related to long-term survival with idiopathic pulmonary arterial hypertension.

Background: Little is understood about the characteristics of dyspnea in patients with interstitial lung disease (ILD), and its severity is likely influenced by multiple factors. Depression and functional status are known to influence dyspnea in patients with COPD. The aim of this study was to determine the relationship of dyspnea with clinical parameters, including depression and functional status, in patients with ILD., Methods: Dyspnea was measured with the Baseline Dyspnea Index and the University of California San Diego Shortness of Breath Questionnaire. Clinical parameters were recorded. Regression analysis was performed to determine independent correlates of dyspnea., Results: Fifty-two subjects were enrolled. The two dyspnea scales were strongly correlated (r=-0.79; P<.00005). The mean levels of dyspnea were 6.5 and 41.0, representing a moderate degree of dyspnea. Clinically meaningful depressive symptoms were found in 23% of subjects. Independent correlates of dyspnea severity for each dyspnea scale were depression score (P=.002 and P<.0005), 4-m walk time (P=.001 and P=.06), FVC (P=.07 and P=.004), and diffusing capacity of the lung for carbon monoxide (P=.007). BMI had borderline significant association with the Baseline Dyspnea Index (P=.10)., Conclusions: In patients with ILD, dyspnea is associated with depression score, functional status, and pulmonary function. These results suggest that attention to depression and functional status is important in these patients and that treatment directed at these comorbidities may improve dyspnea and quality of life., Trial Registry: ClinicalTrials.gov; No.: NCT00611182 ; URL: www. clinicaltrials.gov.

Purpose of Review: Dyspnea is the most common symptom in interstitial lung disease, yet little is known about its management. This review summarizes the available evidence for the treatment of dyspnea in interstitial lung disease., Recent Findings: The management of dyspnea in interstitial lung disease remains a challenge, with few effective therapies. Limited evidence suggests that pulmonary rehabilitation is an effective treatment of dyspnea. In patients with interstitial lung disease, dyspnea severity is associated with measures of ventilatory restriction, gas exchange, functional status, mental health, and some comorbid diseases. Treatment directed toward these modifiable correlates of dyspnea might be effective in dyspnea management; however, the outcome of this strategy has not been adequately studied., Summary: Studies support pulmonary rehabilitation as an effective treatment for dyspnea in interstitial lung disease and pulmonary rehabilitation should be considered in all dyspneic patients. Several investigational agents have been developed and evaluated for potential use in fibrotic interstitial lung disease; however, these agents have not been shown to improve dyspnea.

Background: Previous meta-analyses of treatments for pulmonary arterial hypertension (PAH) have not shown mortality benefit from any individual class of medication., Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through November 2009 for randomized trials that evaluated any pharmacotherapy in the treatment of PAH. Reference lists from included articles and recent review articles were also searched. Analysis included randomized placebo controlled trials of at least eight weeks duration and studies comparing intravenous medication to an unblinded control group., Results: 1541 unique studies were identified and twenty-four articles with 3758 patients were included in the meta-analysis. Studies were reviewed and data extracted regarding study characteristics and outcomes. Data was pooled for three classes of medication: prostanoids, endothelin-receptor antagonists (ERAs), and phosphodiesterase type 5 (PDE5) inhibitors. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated for mortality, 6-minute walk distance, dyspnea scores, hemodynamic parameters, and adverse effects. Mortality in the control arms was a combined 4.2% over the mean study length of 14.9 weeks. There was significant mortality benefit with prostanoid treatment (RR 0.49, CI 0.29 to 0.82), particularly comparing intravenous agents to control (RR 0.30, CI 0.14 to 0.63). Mortality benefit was not observed for ERAs (RR 0.58, CI 0.21 to 1.60) or PDE5 inhibitors (RR 0.30, CI 0.08 to 1.08). All three classes of medication improved other clinical and hemodynamic endpoints. Adverse effects that were increased in treatment arms include jaw pain, diarrhea, peripheral edema, headache, and nausea in prostanoids; and visual disturbance, dyspepsia, flushing, headache, and limb pain in PDE5 inhibitors. No adverse events were significantly associated with ERA treatment., Conclusions: Treatment of PAH with prostanoids reduces mortality and improves multiple other clinical and hemodynamic outcomes. ERAs and PDE5 inhibitors improve clinical and hemodynamic outcomes, but have no proven effect on mortality. The long-term effects of all PAH treatment requires further study.