Is there a uniform approach to the management of diffuse parenchymal lung disease (DPLD) in the UK? A national benchmarking exercise

BACKGROUND: Benchmarking is the comparison of a process to the work or results of others. We conducted a national benchmarking exercise to determine how UK pulmonologists manage common clinical scenarios in diffuse parenchymal lung disease (DPLD), and to determine current use and availability of investigative resources. We compared management decisions to existing international guidelines. METHODS: Consultant members of the British Thoracic Society were mailed a questionnaire seeking their views on the management of three common scenarios in DPLD. They were asked to choose from various management options for each case. Information was also obtained from the respondents on time served as a consultant, type of institution in which they worked and the availability of a local radiologist and histopathologist with an interest/expertise in thoracic medicine. RESULTS: 370 out of 689 consultants replied (54% response rate). There were many differences in the approach to the management of all three cases. Given a scenario of relapsing pulmonary sarcoidosis in a lady with multiple co-morbidities, half of respondents would institute treatment with a variety of immunosuppressants while a half would simply observe. 42% would refer a 57-year old lady with new onset DPLD for a surgical lung biopsy, while a similar number would not. 80% would have referred her for transplantation, but a fifth would not. 50% of consultants from district general hospitals would have opted for a surgical biopsy compared to 24% from cardiothoracic centres: this may reflect greater availability of a radiologist with special interest in thoracic imaging in cardiothoracic centres, obviating the need for tissue diagnosis. Faced with an elderly male with high resolution CT thorax (HRCT) evidence of usual interstitial pneumonia (UIP), three quarters would observe, while a quarter would start immunosuppressants. 11% would refer for a surgical biopsy. 14% of UK pulmonologists responding to the survey revealed they had no access to a radiologist with an interest in thoracic radiology. CONCLUSION: From our survey, it appears there is a lack of consensus in the management of DPLD. This may reflect lack of evidence, lack of resources or a failure to implement current guidelines

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy

Small fibre neuropathy (SFN) has been demonstrated in sarcoidosis. However, a systematic analysis of neuropathic pain and autonomic symptoms, key features of SFN, has not been performed. Clinimetric evaluation of pain and autonomic symptoms using the neuropathic pain scale (NPS) and the modified Composite Autonomic Symptoms Scale (mCOMPASS) was used in sarcoidosis patients for this study. A total of 91 sarcoidosis patients (n = 23 without SFN symptoms, n = 43 with SFN symptoms but normal intraepidermal nerve fibre density (IENFD), n = 25 with SFN symptoms and reduced IENFD) were examined. NPS and mCOMPASS were assessed twice (reliability studies). Severity of pain was compared between the subgroups. Correlation between NPS and a visual analogue pain scale (VAS) was assessed (validity studies). Healthy controls (n = 105) completed the mCOMPASS for comparison with patients’ scores. Patients with sarcoidosis, SFN complaints, and reduced IENFD demonstrated more severe pain scores on the NPS. The mCOMPASS differentiated between subjects with and without SFN symptoms. A significant correlation was obtained between the NPS and VAS, indicating good construct validity. Good reliability values were obtained for all scales. The use of the NPS to evaluate SFN symptoms is suggested, as it shows differences between patients with SFN symptoms with normal or reduced IENFD values. The mCOMPASS might be used to select patients for further testing

The role of measuring exhaled breath biomarkers in sarcoidosis: A systematic review

Introduction: Sarcoidosis is a chronic granulomatous disease of unknown aetiology with a variable clinical course and prognosis. There is a growing need to identify non-invasive biomarkers to differentiate between clinical phenotypes, identify those at risk of disease progression and monitor response to treatment. Objectives: We undertook a systematic review and meta-analysis, to evaluate the utility of breath-based biomarkers in discriminating sarcoidosis from healthy controls, alongside correlation with existing non-breath based biomarkers used in clinical practice, radiological stage, markers of disease activity and response to treatment. Methods: Electronic searches were undertaken during November 2017 using PubMed, Ebsco, Embase and Web of Science to capture relevant studies evaluating breath-based biomarkers in adult patients with sarcoidosis. Results: 353 papers were screened; 21 met the inclusion criteria and assessed 25 different biomarkers alongside VOCs in exhaled breath gas or condensate. Considerable heterogeneity existed amongst the studies in terms of participant characteristics, sampling and analytical methods. Elevated biomarkers in sarcoidosis included 8-isoprostane, carbon monoxide, neopterin, TGF-β1, TNFα, CysLT and several metallic elements including chromium, silicon and nickel. Three studies exploring VOCs were able to distinguish sarcoidosis from controls. Meta-analysis of four studies assessing alveolar nitric oxide showed no significant difference between sarcoidosis and healthy controls (2.22ppb; 95% CI -0.83, 5.27) however, a high degree of heterogeneity was observed with an I2 of 93.4% (p<0.001). Inconsistent or statistically insignificant results were observed for correlations between several biomarkers and radiological stage, markers of disease activity or treatment. Conclusions: The evidence for using breath biomarkers to diagnose and monitor sarcoidosis remains inconclusive with many studies limited by small sample sizes and lack of standardisation. VOCs have shown promising potential but further research is required to evaluate their prognostic role

Who wants to join preventive trials? – Experience from the Estonian Postmenopausal Hormone Therapy Trial [ISRCTN35338757]

BACKGROUND: The interest of patients in participating in randomized clinical trials involving treatments has been widely studied, but there has been much less research on interest in preventive trials. The objective of this study was to find out how many women would be interested in a trial involving postmenopausal hormone therapy (PHT) and how the women's background characteristics and opinions correlated to their interest. METHODS: The data come from recruitment questionnaires (n = 2000) sent to women in Estonia in 1998. A random sample of women aged 45 to 64 was drawn from the Population Registry. The trial is a two-group randomized trial comparing estrogen-progestogen therapy with placebo or no drugs. A brief description of the study was attached to the questionnaires. Women were not told at this stage of the recruitment which group they would be assigned to, however, they were told of the chance to receive either hormone, placebo or no treatment. RESULTS: After two reminders, 1312 women (66%) responded. Eleven percent of the women approached (17% of the respondents) were interested in joining the trial, and 8% wanted more information before deciding. When the 225 women who stated clearly that they were interested in joining and the 553 women who said they were not interested were compared, it was found that interested women were younger and, adjusting for age, that more had given birth; in other respects, the sociodemographic characteristics and health habits of the interested women were similar to those of the non-interested women. The interested women had made more use of more health services, calcium preparations and PHT, they were more often overweight, and more had chronic diseases and reported symptoms. Interested women's opinions on the menopause were more negative, and they favoured PHT more than the non-interested women. CONCLUSION: Unlike the situation described in previous reports on preventive trials, in this case Estonian women interested in participating in a PHT trial were not healthier than other women. This suggests that trials involving PHT are more similar to treatment trials than to preventive trials. In a randomized controlled trial, more information should be obtained from those women who decline to participate

The effects of ginger supplementation on markers of inflammatory and oxidative stress: a systematic review and meta-analysis of clinical trials

The present systematic review and meta-analysis was conducted to investigate the effects of ginger supplementation on markers of inflammatory and oxidative stress. PubMed, Embase, Scopus and Web of Science were systematically searched to identify relevant clinical trials evaluating the effects of ginger on serum CRP (C-reactive protein), TNF-α (tumor necrosis factor‐alpha), IL-6 (interleukin-6), PGE2 (Prostaglandin E2), TAC (Total antioxidant capacity) and MDA (Malondialdehyde) from inception up to September 2019. Mean difference (MD) and its 95 % confidence interval (CI) was determined using a random effects model. Potential publication bias was assessed using visual inspection of funnel plot and Egger's weighted regression tests. After excluding irrelevant records, 20 full-text articles that included 25 separate studies were included to the meta-analysis. Pooled results of the present study indicated a statistically significant effect of ginger on serum CRP, TNF-α, IL-6, TAC and MDA levels following ginger supplementation. Also, the effects of ginger on serum PGE2 was marginally significant. Moreover, the significant heterogeneity disappeared in subgroup analysis performed by age, duration, dosage, and quality. This current analysis indicates that ginger supplementation has significant effects on serum inflammatory markers

Migratory marker expression in fibroblast foci of idiopathic pulmonary fibrosis

BACKGROUND: Fibroblast foci (FF) are considered a relevant morphologic marker of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), and are recognised as sites where fibrotic responses are initiated and/or perpetuated in this severe disease. Despite their relevance, the cellular and molecular mechanisms responsible for the formation of FF and their role in tissue remodelling are poorly defined. In previous studies we have provided evidence of abnormal activation of the wnt-signaling-pathway in IPF/UIP that is centred on FF and the overlying epithelium. This important morphogenetic pathway is able to trigger epithelial-mesenchymal-transition (EMT), a mechanism involved in developmental and metastatic processes, which is also potentially involved in pulmonary fibrosis. METHODS: Since EMT is characterised by enhancement of migratory potential of cells, we investigated the molecular profile of FF in 30 biopsies of IPF/UIP and a variety of control samples, focussing on the immunohistochemical expression of three molecules involved in cell motility and invasiveness, namely laminin-5-γ2-chain, fascin, and heat-shock-protein-27. RESULTS: We provide evidence that in UIP these three molecules are abnormally expressed in discrete clusters of bronchiolar basal cells precisely localised in FF. These cellular clusters expressed laminin-5-γ2-chain and heat-shock-protein-27 at very high levels, forming characteristic three-layered lesions defined as "sandwich-foci" (SW-FF). Upon quantitative analysis SW-FF were present in 28/30 UIP samples, representing more than 50% of recognisable FF in 21/30, but were exceedingly rare in a wide variety of lung pathologies examined as controls. In UIP, SW-FF were often observed in areas of microscopic honeycombing, and were also found at the interface between normal lung tissue and areas of dense scarring. CONCLUSION: These molecular abnormalities strongly suggest that SW-FF represent the leading edge of pulmonary remodelling, where abnormal migration and re-epithelialisation take place, and that abnormal proliferation and migration of bronchiolar basal cells have a major role in the remodelling process characterising IPF/UIP. Further investigations will assess their possible use as reliable markers for better defining the UIP-pattern in difficult cases

Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells

Abstract Background Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease. Methods We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. controls. To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles. Results Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis. Conclusions BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness