Whole-Blood Gene Expression in Pulmonary Nontuberculous Mycobacterial Infection.

The factors predisposing toward the development of pulmonary nontuberculous mycobacterial (pNTM) disease and influencing disease progression remain unclear. Impaired immune responses have been reported in individuals with pNTM disease, but data are limited and inconsistent. In this study, we sought to use gene expression profiling to examine the host response to pNTM disease. Microarray analysis of whole-blood gene expression was performed on 25 subjects with pNTM disease and 27 uninfected control subjects with respiratory disease. Gene expression results were compared with phenotypic variables and survival data. Compared with uninfected control subjects, pNTM disease was associated with downregulation of 213 transcripts enriched for terms related to T cell signaling, including IFNG. Reduced IFNG expression was associated with more severe computed tomography changes and impaired lung function. Mortality was associated with the expression of transcripts related to the innate immune response and inflammation, whereas transcripts related to T and B cell function were associated with improved survival. These findings suggest that pNTM disease is associated with an aberrant immune response, which may reflect an underlying propensity to infection or result from NTM infection itself. There were important differences in the immune response associated with survival and mortality in pNTM disease.

The impact of trained radiographers as concurrent readers on performance and reading time of experienced radiologists in the UK Lung Cancer Screening (UKLS) trial.

OBJECTIVES: To compare radiologists' performance reading CTs independently with their performance using radiographers as concurrent readers in lung cancer screening. METHODS: 369 consecutive baseline CTs performed for the UK Lung Cancer Screening (UKLS) trial were double-read by radiologists reading either independently or concurrently with a radiographer. In concurrent reading, the radiologist reviewed radiographer-identified nodules and then detected any additional nodules. Radiologists recorded their independent and concurrent reading times. For each radiologist, sensitivity, average false-positive detections (FPs) per case and mean reading times for each method were calculated. RESULTS: 694 nodules in 246/369 (66.7%) studies comprised the reference standard. Radiologists' mean sensitivity and average FPs per case both increased with concurrent reading compared to independent reading (90.8 ± 5.6% vs. 77.5 ± 11.2%, and 0.60 ± 0.53 vs. 0.33 ± 0.20, respectively; p < 0.05 for 3/4 and 2/4 radiologists, respectively). The mean reading times per case decreased from 9.1 ± 2.3 min with independent reading to 7.2 ± 1.0 min with concurrent reading, decreasing significantly for 3/4 radiologists (p < 0.05). CONCLUSIONS: The majority of radiologists demonstrated improved sensitivity, a small increase in FP detections and a statistically significantly reduced reading time using radiographers as concurrent readers. KEY POINTS: • Radiographers as concurrent readers could improve radiologists' sensitivity in lung nodule detection. • An increase in false-positive detections with radiographer-assisted concurrent reading occurred. • The false-positive detection rate was still lower than reported for computer-aided detection. • Concurrent reading with radiographers was also faster than single reading. • The time saved per case using concurrently reading radiographers was relatively modest.

Pulmonary hypertension in interstitial lung disease: Limitations of echocardiography compared to cardiac catheterization.

BACKGROUND AND OBJECTIVE: In interstitial lung disease (ILD), pulmonary hypertension (PH) is a major adverse prognostic determinant. Transthoracic echocardiography (TTE) is the most widely used tool when screening for PH, although discordance between TTE and right heart catheter (RHC) measured pulmonary haemodynamics is increasingly recognized. We evaluated the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE screening recommendations against RHC testing in a large, well-characterized ILD cohort. METHODS: Two hundred and sixty-five consecutive patients with ILD and suspected PH underwent comprehensive assessment, including RHC, between 2006 and 2012. ESC/ERS recommended tricuspid regurgitation (TR) velocity thresholds for assigning high (>3.4 m/s), intermediate (2.9-3.4 m/s) and low (<2.8 m/s) probabilities of PH were evaluated against RHC testing. RESULTS: RHC testing confirmed PH in 86% of subjects with a peak TR velocity >3.4 m/s, and excluded PH in 60% of ILD subjects with a TR velocity <2.8 m/s. Thus, the ESC/ERS guidelines misclassified 40% of subjects as 'low probability' of PH, when PH was confirmed on subsequent RHC. Evaluating alternative TR velocity thresholds for assigning a low probability of PH did not significantly improve the ability of TR velocity to exclude a diagnosis of PH. CONCLUSION: In patients with ILD and suspected PH, currently recommended ESC/ERS TR velocity screening thresholds were associated with a high positive predictive value (86%) for confirming PH, but were of limited value in excluding PH, with 40% of patients misclassified as low probability when PH was confirmed at subsequent RHC.

Effect of Nintedanib in Subgroups of Idiopathic Pulmonary Fibrosis by Diagnostic Criteria.

RATIONALE: In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus, the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP. OBJECTIVES: To investigate the potential impact of diagnostic subgroups on the progression of IPF and the effect of nintedanib. METHODS: We conducted a post hoc subgroup analysis of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy versus patients without either, using pooled data from the INPULSIS trials. MEASUREMENTS AND MAIN RESULTS: Seven hundred twenty-three (68.1%) patients had honeycombing and/or biopsy, and 338 (31.9%) patients had no honeycombing or biopsy. In these subgroups, respectively, the adjusted annual rate of decline in FVC in patients treated with placebo was -225.7 and -221.0 ml/yr, and the nintedanib versus placebo difference in the adjusted annual rate of decline in FVC was 117.0 ml/yr (95% confidence interval, 76.3-157.8) and 98.9 ml/yr (95% confidence interval, 36.4-161.5). There was no significant treatment-by-subgroup interaction (P = 0.8139). Adverse events were similar between the subgroups. CONCLUSIONS: Patients with IPF diagnosed in clinical practice who had possible UIP with traction bronchiectasis on HRCT and had not undergone surgical lung biopsy had disease that progressed in a similar way, and responded similarly to nintedanib, to that of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy.

Effect of Emphysema Extent on Serial Lung Function in Patients with Idiopathic Pulmonary Fibrosis.

RATIONALE: Patients with idiopathic pulmonary fibrosis and emphysema may have artificially preserved lung volumes. OBJECTIVES: In this post hoc analysis, we investigated the relationship between baseline emphysema and fibrosis extents, as well as pulmonary function changes, over 48 weeks. METHODS: Data were pooled from two phase III, randomized, double-blind, placebo-controlled trials of IFN-γ-1b in idiopathic pulmonary fibrosis (GIPF-001 [NCT00047645] and GIPF-007 [NCT00075998]). Patients with Week 48 data, baseline high-resolution computed tomographic images, and FEV1/FVC ratios less than 0.8 or greater than 0.9 (<0.7 or >0.9 in GIPF-007), as well as randomly selected patients with ratios of 0.8-0.9 and 0.7-0.8, were included. Changes from baseline in pulmonary function at Week 48 were analyzed by emphysema extent. The relationship between emphysema and fibrosis extents and change in pulmonary function was assessed using multivariate linear regression. MEASUREMENTS AND MAIN RESULTS: Emphysema was identified in 38% of patients. A negative correlation was observed between fibrosis and emphysema extents (r = -0.232; P < 0.001). In quartile analysis, patients with the greatest emphysema extent (28 to 65%) showed the smallest FVC decline, with a difference of 3.32% at Week 48 versus patients with no emphysema (P = 0.047). In multivariate analyses, emphysema extent greater than or equal to 15% was associated with significantly reduced FVC decline over 48 weeks versus no emphysema or emphysema less than 15%. No such association was observed for diffusing capacity of the lung for carbon monoxide or composite physiologic index. CONCLUSIONS: FVC measurements may not be appropriate for monitoring disease progression in patients with idiopathic pulmonary fibrosis and emphysema extent greater than or equal to 15%.

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

Diffuse Pulmonary Ossification in Fibrosing Interstitial Lung Diseases: Prevalence and Associations.

Purpose To investigate the prevalence of diffuse pulmonary ossification (DPO) in patients with fibrosing interstitial lung disease (ILD) and determine whether there are differences among the types of ILDs. Materials and Methods Institutional review board approval was given and patient consent was not required for this study. The study population comprised 892 consecutive patients with fibrosing ILD, including 456 patients with idiopathic pulmonary fibrosis (IPF) (men, 366; women, 90; median age, 72 years [range, 38-93 years]), 244 with nonspecific interstitial pneumonia (men, 79; women, 165; median age, 60.5 years [range, 23-86 years]), and 192 with chronic hypersensitivity pneumonitis (men, 76; women, 116; median age, 66 years [range, 35-88 years]). Pulmonary ossifications were recorded when nodules (<4 mm diameter) were identified on bone window images (width, 2500 HU; level, 500 HU). DPO was defined as 10 or more bilateral nodular ossifications (definition 1) or as one or more lobes with five or more bilateral nodular ossifications (definition 2). Relationships among pulmonary ossification and parenchymal patterns, clinical parameters, and multidisciplinary team diagnoses were examined. The prevalence of DPO was compared with the χ2 statistic or Fisher exact test, and multivariate analysis was performed with logistic regression. Results In the whole population, the prevalence of DPO was 166 (18.6%) and 106 (11.9%) of 892 patients according to definitions 1 and 2, respectively. The prevalence of DPO (definition 1) was significantly higher in patients with IPF (28.5%) than in those without IPF (8.3%, P < .001). Nine of 192 (4.7%) had chronic hypersensitivity pneumonitis (P < .001), and 27 of 244 (11.1%) had nonspecific interstitial pneumonia (P < .001). At multivariate analysis, DPO according to definition 1 was an independent predictor of IPF diagnosis (P < .001) and male sex (P = .003). Coarseness of fibrosing ILD (P = .011) and IPF diagnosis (P = .016) were independently associated with pulmonary ossification profusion. Conclusion DPO is common in patients with fibrosing ILD and is significantly more prevalent in patients with IPF than in those with other fibrosing ILDs, and thus, computed tomographic signs of DPO may be helpful for diagnosis of IPF. © RSNA, 2017 Online supplemental material is available for this article.

Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis.

This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis.Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide (DLCO), transfer coefficient of the lung for carbon monoxide (KCO), composite physiologic index (CPI)) and mortality.The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using DLCO, and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p<0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p<0.0001) reduced gas transfer (DLCO).There is no prognostic impact of emphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema.

Mortality prediction in idiopathic pulmonary fibrosis: evaluation of computer-based CT analysis with conventional severity measures.

Computer-based computed tomography (CT) analysis can provide objective quantitation of disease in idiopathic pulmonary fibrosis (IPF). A computer algorithm, CALIPER, was compared with conventional CT and pulmonary function measures of disease severity for mortality prediction.CT and pulmonary function variables (forced expiratory volume in 1 s, forced vital capacity, diffusion capacity of the lung for carbon monoxide, transfer coefficient of the lung for carbon monoxide and composite physiologic index (CPI)) of 283 consecutive patients with a multidisciplinary diagnosis of IPF were evaluated against mortality. Visual and CALIPER CT features included total extent of interstitial lung disease, honeycombing, reticular pattern, ground glass opacities and emphysema. In addition, CALIPER scored pulmonary vessel volume (PVV) while traction bronchiectasis and consolidation were only scored visually. A combination of mortality predictors was compared with the Gender, Age, Physiology model.On univariate analyses, all visual and CALIPER-derived interstitial features and functional indices were predictive of mortality to a 0.01 level of significance. On multivariate analysis, visual CT parameters were discarded. Independent predictors of mortality were CPI (hazard ratio (95% CI) 1.05 (1.02-1.07), p<0.001) and two CALIPER parameters: PVV (1.23 (1.08-1.40), p=0.001) and honeycombing (1.18 (1.06-1.32), p=0.002). A three-group staging system derived from this model was powerfully predictive of mortality (2.23 (1.85-2.69), p<0.0001).CALIPER-derived parameters, in particular PVV, are more accurate prognostically than traditional visual CT scores. Quantitative tools such as CALIPER have the potential to improve staging systems in IPF.

Bronchiectasis in yellow nail syndrome.

BACKGROUND AND OBJECTIVE: Yellow nail syndrome (YNS) is a rare and poorly described disease process. In this case-control study, clinical features and findings on HRCT were compared with idiopathic bronchiectasis (IBx). METHODS: A review of all patients attending an adult bronchiectasis clinic between 2007 and 2013 identified 25 YNS patients. IBx patients were matched in a 2:1 ratio for age, duration of symptoms and gender. RESULTS: Median age of onset was 53 years. There were 12 male and 23 Caucasian YNS patients. Respiratory manifestations included chronic productive cough (100%), chronic rhinosinusitis (88%), pleural effusions (20%) and lymphoedema (12%). Chest symptoms preceded yellow nails in the majority (68%). Abnormal nails persisted at follow-up in 23 of 25 patients but improved in 14. In both disorders, there was symmetrical, predominantly lower lobe bronchiectasis on HRCT. Extent (P = 0.04), severity (P = 0.03) and bronchial wall thickness (P = 0.05) scores were lower in YNS, with less upper and middle lobe disease. Multivariate analysis showed an independent association with increased mucus plugging in YNS. There was a similar prevalence of Pseudomonas aeruginosa infection and mild lung function abnormalities. CONCLUSION: Bronchiectasis in YNS is less severe than IBx but is associated with increased mucus plugging, onset is in middle age and there is no female predominance. Treatment targeted at improved secretion clearance may improve both chest and nail symptoms, with consideration of long-term macrolide antibiotics.

Evaluation of visual and computer-based CT analysis for the identification of functional patterns of obstruction and restriction in hypersensitivity pneumonitis.

BACKGROUND AND OBJECTIVE: To determine whether computer-based quantification (CALIPER software) is superior to visual computed tomography (CT) scoring in the identification of CT patterns indicative of restrictive and obstructive functional indices in hypersensitivity pneumonitis (HP). METHODS: A total of 135 consecutive HP patients had CT parenchymal patterns evaluated quantitatively by both visual scoring and CALIPER. Results were evaluated against: forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO ) and a composite physiological index (CPI) to identify which CT scoring method better correlated with functional indices. RESULTS: CALIPER-derived scores of total interstitial lung disease extent correlated more strongly than visual scores: FVC (CALIPER R = 0.73, visual R = 0.51); DLCO (CALIPER R = 0.61, visual R = 0.48); and CPI (CALIPER R = 0·70, visual R = 0·55). The CT variable that correlated most strongly with restrictive functional indices was CALIPER pulmonary vessel volume (PVV): FVC R = 0.75, DLCO R = 0.68 and CPI R = 0.76. Ground-glass opacity quantified by CALIPER alone demonstrated strong associations with restrictive functional indices: CALIPER FVC R = 0.65; DLCO R = 0.59; CPI R = 0.64; and visual = not significant. Decreased attenuation lung quantified by CALIPER was a better morphological measure of obstructive lung disease than equivalent visual scores as judged by relationships with TLC (CALIPER R = 0.63 and visual R = 0.12). All results were maintained on multivariate analysis. CONCLUSION: CALIPER improved on visual scoring in HP as judged by restrictive and obstructive functional correlations. Decreased attenuation regions of the lung quantified by CALIPER demonstrated better linkages to obstructive lung physiology than visually quantified CT scores. A novel CALIPER variable, the PVV, demonstrated the strongest linkages with restrictive functional indices and could represent a new automated index of disease severity in HP.

Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report.

Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.

Chronic hypersensitivity pneumonitis: identification of key prognostic determinants using automated CT analysis.

BACKGROUND: Chronic hypersensitivity pneumonitis (CHP) has a variable disease course. Computer analysis of CT features was used to identify a subset of CHP patients with an outcome similar to patients with idiopathic pulmonary fibrosis (IPF). METHODS: Consecutive patients with a multi-disciplinary team diagnosis of CHP (n = 116) had pulmonary function tests (FEV1, FVC, DLco, Kco, and a composite physiologic index [CPI]) and CT variables predictive of mortality evaluated by analysing visual and computer-based (CALIPER) parenchymal features: total interstitial lung disease (ILD) extent, honeycombing, reticular pattern, ground glass opacities, pulmonary vessel volume (PVV), emphysema, and traction bronchiectasis. Mean survival was compared between both CHP and IPF patients (n = 185). RESULTS: In CHP, visual/CALIPER measures of reticular pattern, honeycombing, visual traction bronchiectasis, and CALIPER ILD extent were predictive of mortality (p < 0 · 05) on univariate analysis. PVV was strongly predictive of mortality on univariate (p < 0 · 0001) and multivariate analysis independent of age, gender and disease severity (represented by the CPI [p < 0 · 01]). CHP patients with a PVV threshold >6 · 5% of the lung had a mean survival (35 · 3 ± 6 · 1 months; n = 20/116 [17%]) and rate of disease progression that closely matched IPF patients (38 · 4 ± 2 · 2 months; n = 185). CONCLUSIONS: Pulmonary vessel volume can identify CHP patients at risk of aggressive disease and a poor IPF-like prognosis.

Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial.

BACKGROUND: Lung volume reduction surgery improves survival in selected patients with emphysema, and has generated interest in bronchoscopic approaches that might achieve the same effect with less morbidity and mortality. Previous trials with endobronchial valves have yielded modest group benefits because when collateral ventilation is present it prevents lobar atelectasis. METHODS: We did a single-centre, double-blind sham-controlled trial in patients with both heterogeneous emphysema and a target lobe with intact interlobar fissures on CT of the thorax. We enrolled stable outpatients with chronic obstructive pulmonary disease who had a forced expiratory volume in 1 s (FEV1) of less than 50% predicted, significant hyperinflation (total lung capacity >100% and residual volume >150%), a restricted exercise capacity (6 min walking distance <450 m), and substantial breathlessness (MRC dyspnoea score ≥3). Participants were randomised (1:1) by computer-generated sequence to receive either valves placed to achieve unilateral lobar occlusion (bronchoscopic lung volume reduction) or a bronchoscopy with sham valve placement (control). Patients and researchers were masked to treatment allocation. The study was powered to detect a 15% improvement in the primary endpoint, the FEV1 3 months after the procedure. Analysis was on an intention-to-treat basis. The trial is registered at controlled-trials.com, ISRCTN04761234. FINDINGS: 50 patients (62% male, FEV1 [% predicted] mean 31·7% [SD 10·2]) were enrolled to receive valves (n=25) or sham valve placement (control, n=25) between March 1, 2012, and Sept 30, 2013. In the bronchoscopic lung volume reduction group, FEV1 increased by a median 8·77% (IQR 2·27-35·85) versus 2·88% (0-8·51) in the control group (Mann-Whitney p=0·0326). There were two deaths in the bronchoscopic lung volume reduction group and one control patient was unable to attend for follow-up assessment because of a prolonged pneumothorax. INTERPRETATION: Unilateral lobar occlusion with endobronchial valves in patients with heterogeneous emphysema and intact interlobar fissures produces significant improvements in lung function. There is a risk of significant complications and further trials are needed that compare valve placement with lung volume reduction surgery. FUNDING: Efficacy and Mechanism Evaluation Programme, funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

Interobserver agreement for the ATS/ERS/JRS/ALAT criteria for a UIP pattern on CT.

OBJECTIVES: To establish the level of observer variation for the current ATS/ERS/JRS/ALAT criteria for a diagnosis of usual interstitial pneumonia (UIP) on CT among a large group of thoracic radiologists of varying levels of experience. MATERIALS AND METHODS: 112 observers (96 of whom were thoracic radiologists) categorised CTs of 150 consecutive patients with fibrotic lung disease using the ATS/ERS/JRS/ALAT CT criteria for a UIP pattern (3 categories--UIP, possibly UIP and inconsistent with UIP). The presence of honeycombing, traction bronchiectasis and emphysema was also scored using a 3-point scale (definitely present, possibly present, absent). Observer agreement for the UIP categorisation and for the 3 CT patterns in the entire observer group and in subgroups stratified by observer experience, were evaluated. RESULTS: Interobserver agreement across the diagnosis category scores among the 112 observers was moderate, ranging from 0.48 (IQR 0.18) for general radiologists to 0.52 (IQR 0.20) for thoracic radiologists of 10-20 years' experience. A binary score for UIP versus possible or inconsistent with UIP was examined. Observer agreement for this binary score was only moderate. No significant differences in agreement levels were identified when the CTs were stratified according to multidisciplinary team (MDT) diagnosis or patient age or when observers were categorised according to experience. Observer agreement for each of honeycombing, traction bronchiectasis and emphysema were 0.59±0.12, 0.42±0.15 and 0.43±0.18, respectively. CONCLUSIONS: Interobserver agreement for the current ATS/ERS/JRS/ALAT CT criteria for UIP is only moderate among thoracic radiologists, irrespective of their experience, and did not vary with patient age or the MDT diagnosis.

Long-term psychosocial outcomes of low-dose CT screening: results of the UK Lung Cancer Screening randomised controlled trial.

BACKGROUND: The UK Lung Cancer Screening (UKLS) trial is a randomised pilot trial of low-dose CT (LDCT) screening for individuals at high risk of lung cancer. We assessed the long-term psychosocial impact on individuals participating in the UKLS trial. METHODS: A random sample of individuals aged 50-75 years was contacted via primary care. High-risk individuals who completed T0 questionnaires (baseline) were randomised to LDCT screening (intervention) or usual care (no screening control). T1 questionnaires were sent 2 weeks after baseline scan results or control assignment. T2 questionnaires were sent up to 2 years after recruitment. Measures included cancer distress, anxiety, depression and decision satisfaction. RESULTS: A total of 4037 high-risk individuals were randomised and they completed T0 questionnaires (n=2018 intervention, n=2019 control). Cancer distress was higher at T1 in intervention arm participants who received positive screening results (p≤0.001), but not at T2 (p=0.04). T2 anxiety (p≤0.001) and depression (p≤0.01) were higher in the control arm, but the absolute differences were small and not clinically relevant. At both time points, fewer control than screened participants were satisfied with their decision to participate in UKLS (p≤0.001). Regardless of trial allocation, cancer distress was higher in women (p≤0.01), participants aged ≤65 years (p≤0.001), current smokers (p≤0.001), those with lung cancer experience (p≤0.001) and those recruited from the Liverpool area (p≤0.001). CONCLUSION: Lung cancer screening using LDCT appears to have no clinically significant long-term psychosocial impact on high-risk participants. Strategies for engaging and supporting underserved groups are the key to implement routine lung cancer screening in the UK. TRIAL REGISTRATION NUMBER: ISRCTN 78513845; results.

A longitudinal study characterising a large adult primary ciliary dyskinesia population.

Primary ciliary dyskinesia (PCD) in adults has not been well described. In this retrospective observational study we aimed to characterise a large adult population and identify features associated with disease progression.We retrospectively analysed 151 adult patients at a single tertiary centre at baseline and longitudinally for a median of 7 years.We found significant variation in age at diagnosis (median 23.5 years; range <1-72 years). Older age at diagnosis was associated with impaired baseline forced expiratory volume in 1 s (FEV1) (r= -0.30, p=0.01) and increased Pseudomonas aeruginosa colonisation (difference in medians 17 years (95% CI 4.5-20 years); p=0.002). Lung function decline was estimated at FEV1 decline of 0.49% predicted per year. Lung function decline was associated with ciliary ultrastructure, with microtubular defect patients having the greatest decline (p=0.04). High-resolution computed tomography (HRCT) scores of severity of bronchial wall dilatation (p<0.001) and extent of bronchiectasis (p=0.03) additionally showed evidence of modifying FEV1 decline with age.Our study reveals that a large proportion of adult PCD patients are diagnosed late, with impaired FEV1 and increased P. aeruginosa colonisation. Increased disease burden on HRCT and ciliary ultrastructure may predict progressive lung function decline. This study characterises a large adult PCD population, identifies features associated with disease progression and highlights the need for prospective trials to determine whether early diagnosis of high-risk subgroups alongside optimal management can modify disease progression.

Evaluation of computer-based computer tomography stratification against outcome models in connective tissue disease-related interstitial lung disease: a patient outcome study.

BACKGROUND: To evaluate computer-based computer tomography (CT) analysis (CALIPER) against visual CT scoring and pulmonary function tests (PFTs) when predicting mortality in patients with connective tissue disease-related interstitial lung disease (CTD-ILD). To identify outcome differences between distinct CTD-ILD groups derived following automated stratification of CALIPER variables. METHODS: A total of 203 consecutive patients with assorted CTD-ILDs had CT parenchymal patterns evaluated by CALIPER and visual CT scoring: honeycombing, reticular pattern, ground glass opacities, pulmonary vessel volume, emphysema, and traction bronchiectasis. CT scores were evaluated against pulmonary function tests: forced vital capacity, diffusing capacity for carbon monoxide, carbon monoxide transfer coefficient, and composite physiologic index for mortality analysis. Automated stratification of CALIPER-CT variables was evaluated in place of and alongside forced vital capacity and diffusing capacity for carbon monoxide in the ILD gender, age physiology (ILD-GAP) model using receiver operating characteristic curve analysis. RESULTS: Cox regression analyses identified four independent predictors of mortality: patient age (P < 0.0001), smoking history (P = 0.0003), carbon monoxide transfer coefficient (P = 0.003), and pulmonary vessel volume (P < 0.0001). Automated stratification of CALIPER variables identified three morphologically distinct groups which were stronger predictors of mortality than all CT and functional indices. The Stratified-CT model substituted automated stratified groups for functional indices in the ILD-GAP model and maintained model strength (area under curve (AUC) = 0.74, P < 0.0001), ILD-GAP (AUC = 0.72, P < 0.0001). Combining automated stratified groups with the ILD-GAP model (stratified CT-GAP model) strengthened predictions of 1- and 2-year mortality: ILD-GAP (AUC = 0.87 and 0.86, respectively); stratified CT-GAP (AUC = 0.89 and 0.88, respectively). CONCLUSIONS: CALIPER-derived pulmonary vessel volume is an independent predictor of mortality across all CTD-ILD patients. Furthermore, automated stratification of CALIPER CT variables represents a novel method of prognostication at least as robust as PFTs in CTD-ILD patients.

Rare idiopathic interstitial pneumonias: LIP and PPFE and rare histologic patterns of interstitial pneumonias: AFOP and BPIP.

In the 2013 reclassification of the idiopathic interstitial pneumonias (IIPs), two rare IIPs (idiopathic lymphoid interstitial pneumonia (LIP), idiopathic pleuroparenchymal fibroelastosis (IPPFE)) and two rare histologic patterns (acute fibrinous and organizing pneumonia (AFOP), bronchiolocentric pattern of interstitial pneumonia (BPIP)) are described. All these entities are rare with small series published to date, mostly containing primary and secondary forms of disease. LIP is histologically characterized by diffuse polyclonal lymphoid cell infiltrate surrounding the airways and expanding the interstitium. Thin-walled cysts and diffuse ground glass are considered the typical radiologic features. The clinical course is highly variable with corticosteroid responsiveness evident in approximately half of cases. IPPFE is defined histologically by coexisting upper lobe pleural and intra-alveolar fibrosis with elastosis. Dense subpleural irregular fibrosis and consolidation are the cardinal radiologic features. A history of recurrent lower respiratory tract infection is frequent. Responses to immunomodulation have not been reported and the rate of progression appears to be highly variable. AFOP is a rare histologic pattern lying within the spectrum of acute/subacute lung injury, characterized by organizing pneumonia and intra-alveolar fibrin deposition without hyaline membranes. BPIP is characterized histologically by fibrosis and/or inflammation confined to the alveolar interstitium around bronchovascular bundles, overlapping with peribronchial metaplasia and fibrosis in some series. Currently, AFOP and BPIP are both best viewed as histological entities rather than true clinical disorders, in the absence of characteristic associated imaging patterns and clinical features.

The reproducibility and responsiveness of the lung clearance index in bronchiectasis.

Lung clearance index (LCI) is a potential clinical outcome marker in bronchiectasis. Its responsiveness to therapeutic intervention has not been determined. This study evaluates its responsiveness to a session of physiotherapy and intravenous antibiotic treatment of an exacerbation.32 stable and 32 exacerbating bronchiectasis patients and 26 healthy controls were recruited. Patients had LCI and lung function performed before and after physiotherapy on two separate occasions in the stable patients and at the beginning and end of an intravenous antibiotic course in the exacerbating patients.LCI was reproducible between visits in 25 stable patients, with an intraclass correlation of 0.978 (0.948, 0.991; p<0.001). There was no significant difference in LCI (mean±sd) between stable 11.91±3.39 and exacerbating patients 12.76±3.47, but LCI was significantly higher in both bronchiectasis groups compared with healthy controls (7.36±0.99) (p<0.001). Forced expiratory volume in 1 s improved after physiotherapy, as did alveolar volume after intravenous antibiotics, but LCI did not change significantly.LCI is reproducible in stable bronchiectasis but unlike conventional lung function tests, is unresponsive to two short-term interventions and hence is unlikely to be a useful clinical tool for short-term acute assessment in these patients. Further evaluation is required to establish its role in milder disease and in the evaluation of long-term interventions.