Publications
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Antoniou KM, Margaritopoulos GA, Goh NS, et al., 2016, Combined Pulmonary Fibrosis and Emphysema in Scleroderma-Related Lung Disease Has a Major Confounding Effect on Lung Physiology and Screening for Pulmonary Hypertension, Arthritis & Rheumatology, Vol: 68, Pages: 1004-1012, ISSN: 2326-5191
ObjectiveTo assess the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) and the effect of CPFE on the pulmonary function tests used to evaluate the severity of SSc-related ILD and the likelihood of pulmonary hypertension (PH).MethodsHigh-resolution computed tomography (HRCT) scans were obtained in 333 patients with SSc-related ILD and were evaluated for the presence of emphysema and the extent of ILD. The effects of emphysema on the associations between pulmonary function variables and the extent of SSc-related ILD as visualized on HRCT and echocardiographic evidence of PH were quantified.ResultsEmphysema was present in 41 (12.3%) of the 333 patients with SSc-related ILD, in 26 (19.7%) of 132 smokers, and in 15 (7.5%) of 201 lifelong nonsmokers. When the extent of fibrosis was taken into account, emphysema was associated with significant additional differences from the expected values for diffusing capacity for carbon monoxide (DLco) (average reduction of 24.1%; P < 0.0005), and the forced vital capacity (FVC)/DLco ratio (average increase of 34.8%; P < 0.0005) but not FVC. These effects were identical in smokers and nonsmokers. Multivariate analysis showed that the presence of emphysema had a greater effect than echocardiographically determined PH on the FVC/DLco ratio, regardless of whether it was analyzed as a continuous variable or using a threshold value of 1.6 or 2.0.ConclusionAmong patients with SSc-related ILD, emphysema is sporadically present in nonsmokers and is associated with a low pack-year history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in patients with SSc-related ILD.
Goh N, Raghu G, Wells A, et al., 2016, CONSISTENT EFFECT OF NINTEDANIB ON DECLINE IN FVC IN PATIENTS ACROSS SUBGROUPS BASED ON HIGH-RESOLUTION COMPUTED TOMOGRAPHY DIAGNOSTIC CRITERIA: RESULTS FROM THE INPULSIS (R) TRIALS IN IDIOPATHIC PULMONARY FIBROSIS, RESPIROLOGY, Vol: 21, Pages: 148-148, ISSN: 1323-7799
Evans IC, Barnes JL, Garner IM, et al., 2016, Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis, Clinical Science, Vol: 130, Pages: 575-586, ISSN: 1470-8736
Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E2, due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE2 production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4.
Ravaglia C, Bonifazi M, Wells AU, et al., 2016, Safety and Diagnostic Yield of Transbronchial Lung Cryobiopsy in Diffuse Parenchymal Lung Diseases: A Comparative Study versus Video-Assisted Thoracoscopic Lung Biopsy and a Systematic Review of the Literature, Respiration, Vol: 91, Pages: 215-227, ISSN: 1423-0356
Background: A diagnosis of interstitial lung diseases (ILDs) may include surgical lung biopsy (SLB), which is associated with significant morbidity and mortality and also appreciable costs. Transbronchial lung cryobiopsy (TBLC) is adopting an important role. Objectives: The aim of this study was to compare the diagnostic yield (DY) and safety of TBLC and SLB in a large cohort of patients and to perform a systematic review of the literature as well as a meta-analysis. Methods: We performed a retrospective analysis of 447 cases with ILD undergoing TBLC and/or SLB and a systematic review of the literature (MEDLINE and Embase for all original articles on the DY and safety of TBLC in ILDs up to July 2015). Results: A total of 150 patients underwent SLB and 297 underwent TBLC. The median time of hospitalization was 6.1 days (SLB) and 2.6 days (TBLC; p < 0.0001). Mortality due to adverse events was observed for 2.7% (SLB) and 0.3% (TBLC) of the patients. Pneumothorax was the most common complication after TBLC (20.2%). No severe bleeding was observed. TBLC was diagnostic for 246 patients (82.8%), SLB for 148 patients (98.7%, p = 0.013). A meta-analysis of 15 investigations including 781 patients revealed an overall DY of 0.81 (0.75-0.87); the overall pooled probability of developing a pneumothorax, as retrieved from 15 studies including 994 patients, was 0.06 (95% CI 0.02-0.11). Conclusion: Cryobiopsy is safe and has lower complication and mortality rates compared to SLB. TBLC might, therefore, be considered the first diagnostic approach for obtaining tissue in ILDs, reserving the surgical approach for cases in which TBLC is not diagnostic.
Conti C, Montero-Fernandez A, Borg E, et al., 2016, Mucins MUC5B and MUC5AC in Distal Airways and Honeycomb Spaces: Comparison among Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia, Fibrotic Nonspecific Interstitial Pneumonitis, and Control Lungs, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 462-464, ISSN: 1535-4970
Wells AU, 2016, "Any fool can make a rule and any fool will mind it", BMC MEDICINE, Vol: 14, ISSN: 1741-7015
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- Citations: 31
Dubrey S, Sharma R, Underwood R, et al., 2016, Sarcoidosis of the cardio-pulmonary systems, Clinical Medicine, Vol: 16, Pages: 34-41, ISSN: 1470-2118
Sarcoidosis is a multi-system disease with a wide range ofphenotypes. Pulmonary involvement is the most frequentlyidentified target for sarcoidosis and is responsible forthe majority of deaths. Cardiac sarcoid is less commonlyidentified, may be occult, is significantly influenced by race,and can portend an unpredictable and sometimes fataloutcome. Sarcoidosis remains an enigmatic disease spectrumof unknown aetiology, frequently difficult to diagnose andwith a variable disease course. This article summarises currentviews on the diagnosis and management of cardiopulmonaryinvolvement.
Khanna D, Berrocal VJ, Giannini EH, et al., 2016, The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis, ARTHRITIS CARE & RESEARCH, Vol: 68, Pages: 167-178, ISSN: 2151-464X
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- Citations: 11
Khanna D, Berrocal VJ, Giannini EH, et al., 2016, The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis, ARTHRITIS & RHEUMATOLOGY, Vol: 68, Pages: 299-311, ISSN: 2326-5191
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- Citations: 103
Paschalaki KE, Jacob J, Wells AU, 2016, Monitoring of lung involvement in rheumatologic disease, Respiration, Vol: 91, Pages: 89-98, ISSN: 1423-0356
The monitoring of lung involvement in patients with connective tissue diseases is central to optimal long-term management and is directed towards: (a) the detection of supervening lung involvement not present at presentation and (b) the identification of disease progression in established lung disease. For both goals, accurate surveillance requires multi-disciplinary evaluation with the integration of symptomatic change, serial pulmonary function trends and imaging data. Evaluated in isolation, each of these monitoring domains has significant limitations. Symptomatic change may be confounded by a wide variety of systemic factors. Pulmonary function tests provide the most reliable data, but are limited by measurement variability, the heterogeneity of functional patterns and the confounding effects of non-pulmonary factors. Chest radiography is insensitive to change but may provide rapid confirmation of major disease progression or alert the clinician to respiratory co-morbidities. Although high-resolution computed tomography has a central role in assessing disease severity, it should be used very selectively as a monitoring tool due to the associated radiation burden. Ancillary tests include echocardiography and exercise testing to proactively identify cases of pulmonary hypertension and worsening of oxygenation. In summary, a multi-disciplinary approach is essential for the identification of disease progression and prompt treatment of comorbidities that severely impact on the morbidity and mortality of disease.
Salisbury ML, Xia M, Zhou Y, et al., 2016, Idiopathic Pulmonary Fibrosis Gender-Age-Physiology Index Stage for Predicting Future Lung Function Decline, CHEST, Vol: 149, Pages: 491-498, ISSN: 0012-3692
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- Citations: 62
Wells AU, Rosas IO, 2016, Broad Therapeutic Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 193, Pages: 112-113, ISSN: 1073-449X
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- Citations: 7
Currow DC, Abernethy AP, Allcroft P, et al., 2016, The need to research refractory breathlessness, EUROPEAN RESPIRATORY JOURNAL, Vol: 47, Pages: 342-+, ISSN: 0903-1936
Khanna D, Nagaraja V, Tseng C-H, et al., 2015, Predictors of lung function decline in scleroderma-related interstitial lung disease based on high-resolution computed tomography: implications for cohort enrichment in systemic sclerosis-associated interstitial lung disease trials, ARTHRITIS RESEARCH & THERAPY, Vol: 17, ISSN: 1478-6354
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- Citations: 72
Kokosi MA, Nicholson AG, Hansell DM, et al., 2015, Rare idiopathic interstitial pneumonias: LIP and PPFE and rare histologic patterns of interstitial pneumonias: AFOP and BPIP., Respirology, Vol: 21, Pages: 600-614, ISSN: 1440-1843
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.
George PM, Richardson L, Renzoni EA, et al., 2015, EFFECT OF PIRFENIDONE ON GAS TRANSFER IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A79-A79, ISSN: 0040-6376
Kouranos V, Jacob J, Wells AU, 2015, Severe Sarcoidosis, CLINICS IN CHEST MEDICINE, Vol: 36, Pages: 715-+, ISSN: 0272-5231
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- Citations: 20
Raghu G, Wells A, Nicholson AG, et al., 2015, CONSISTENT EFFECT OF NINTEDANIB ON DECLINE IN FVC IN PATIENTS ACROSS SUBGROUPS BASED ON HRCT DIAGNOSTIC CRITERIA: RESULTS FROM THE INPULSIS (R) TRIALS IN IPF, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A60-A61, ISSN: 0040-6376
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- Citations: 1
Saunders P, Stock CJ, Molyneaux PL, et al., 2015, MUC5B GENOTYPE DOES NOT INFLUENCE COUGH SEVERITY IN IPF, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A29-A29, ISSN: 0040-6376
Cove J, Russell AM, Wright J, et al., 2015, PILOT STUDY TO TEST THE FEASIBILITY OF A PSYCHOLOGICAL SUPPORT WORKSHOP FOR PATIENTS NEWLY DIAGNOSED WITH IDIOPATHIC PULMONARY FIBROSIS (IPF) AND THEIR FAMILIES, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A75-A76, ISSN: 0040-6376
Raghu G, Martinez FJ, Brown KK, et al., 2015, CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 1740-1750, ISSN: 0903-1936
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- Citations: 78
De Lauretis A, Ward S, Murray C, et al., 2015, ROLE OF NON ACID AND PROXIMAL REFLUX IN SCLERODERMA-ASSOCIATED INTERSTITIAL LUNG DISEASE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A92-A92, ISSN: 0040-6376
Kokosi M, Saunders P, Karagiannis K, et al., 2015, RITUXIMAB AS RESCUE THERAPY IN ADVANCED PROGRESSIVE SYSTEMIC SCLEROSIS ASSOCIATED INTERSTITIAL LUNG DISEASE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A92-A92, ISSN: 0040-6376
Walsh SLF, Calandriello L, Sverzellati N, et al., 2015, Interobserver agreement for the ATS/ERS/JRS/ALAT criteria for a UIP pattern on CT, Thorax, Vol: 71, Pages: 45-51, ISSN: 1468-3296
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.
Khanna D, Mittoo S, Aggarwal R, et al., 2015, Connective Tissue Disease-associated Interstitial Lung Diseases (CTD-ILD) - Report from OMERACT CTD-ILD Working Group, JOURNAL OF RHEUMATOLOGY, Vol: 42, Pages: 2168-2171, ISSN: 0315-162X
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- Citations: 119
Raghu G, Nathan SD, Behr J, et al., 2015, Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 1370-1377, ISSN: 0903-1936
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- Citations: 91
Fischer A, Antoniou KM, Brown KK, et al., 2015, An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 976-987, ISSN: 0903-1936
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- Citations: 636
Kumar N, Price LC, Montero MA, et al., 2015, Pulmonary tumour thrombotic microangiopathy: unclassifiable pulmonary hypertension?, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 1214-1217, ISSN: 0903-1936
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- Citations: 30
Walsh SLF, Wells AU, Sverzellati N, et al., 2015, Relationship between fibroblastic foci profusion and high resolution CT morphology in fibrotic lung disease, BMC Medicine, Vol: 13, ISSN: 1741-7015
BackgroundFibroblastic foci profusion on histopathology and severity of traction bronchiectasis on highresolution computed tomography (HRCT) have been shown to be predictors of mortality in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the relationship between fibroblastic foci (FF) profusion and HRCT patterns in patients with a histopathologic diagnosis of usual interstitial pneumonia (UIP), fibrotic non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (CHP).MethodsThe HRCT scans of 162 patients with a histopathologic diagnosis of UIP or fibrotic NSIP (n = 162) were scored on extent of groundglass opacification, reticulation, honeycombing, emphysema and severity of traction bronchiectasis. For each patient, a fibroblastic foci profusion score based on histopathologic appearances was assigned. Relationships between extent of fibroblastic foci and individual HRCT patterns were investigated using univariate correlation analysis and multivariate linear regression.ResultsIncreasing extent of reticulation (P < 0.0001) and increasing severity of traction bronchiectasis (P < 0.0001) were independently associated with increasing FF score within the entire cohort. Within individual multidisciplinary team diagnosis subgroups, the only significant independent association with FF score was severity of traction bronchiectasis in patients with idiopathic pulmonary fibrosis (IPF)/UIP (n = 66, r2 = 0.19, P < 0.0001) and patients with chronic hypersensitivity pneumonitis (CHP) (n = 49, r2 = 0.45, P < 0.0001). Furthermore, FF score had the strongest association with severity of traction bronchiectasis in patients with IPF (r2 = 0.34, P < 0.0001) and CHP (r2 = 0.35, P < 0.0001). There was no correlation between F
Margaritopoulos GA, Vasarmidi E, Jacob J, et al., 2015, Smoking and interstitial lung diseases, EUROPEAN RESPIRATORY REVIEW, Vol: 24, Pages: 428-435, ISSN: 0905-9180
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- Citations: 45
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