Use of 6-minute walk distance to predict lung transplant-free survival in fibrosing non-IPF interstitial lung diseases.

BACKGROUND AND OBJECTIVE: The identification of progression in patients with fibrosing non-idiopathic pulmonary fibrosis (IPF) interstitial lung diseases (ILDs) represents an ongoing clinical challenge. Lung function decline alone may have significant limitations in the detection of clinically significant progression. We hypothesized that longitudinal changes of 6-min walk distance (6MWD) from baseline, simultaneously considered with measures of lung function, may independently predict survival and identifying clinically significant progression of disease. METHODS: Forced vital capacity (FVC), diffusing lung capacity (DLCO) and 6MWD were considered both at baseline and at 1 year in a discovery cohort (n = 105) and in a validation cohort (n = 138) from different centres. The primary endpoint was lung transplant (LTx)-free survival. RESULTS: Average follow-up was 3 years in both cohorts. Combined incidence of deaths and LTx was 29% and 21%, respectively. No collinearity and no strong correlations were observed among FVC, DLCO and 6MWD longitudinal changes. While age, gender and BMI were not significant, 6MWD decline ≥24 m predicted LTx-free-survival significantly and independently from FVC and DLCO declines, with high sensitivity and specificity, in both the discovery and the validation cohorts. Although FVC and DLCO declines remained significant predictors of LTx-free survival, 6MWD decline was more accurate than the proposed ATS/ERS/JRS/ALAT functional criteria. Results were confirmed after stratifying patients by baseline FVC. CONCLUSION: Longitudinal declines of 6MWD are associated with poor survival in fibrosing ILDs across a wide range of baseline severity, with high accuracy. 6MWD longitudinal decline is largely independent from lung function decline and may be integrated into the routine assessment of progression.

Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis.

BACKGROUND: Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes. METHODS: We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases). FINDINGS: We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10-5). INTERPRETATION: We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with increased expression of cyclin-dependent kinase inhibitors such as p16 and p21, and subsequent induction of cell cycle arrest, cellular senescence, and pro-fibrotic gene expression. We sought to link p16-expression with a diagnosis of IPF or other fibrotic interstitial lung diseases (ILDs), radiographic pattern, senescent foci-specific gene expression, antifibrotic therapy response, and lung transplant (LTx)-free survival. METHODS: Eighty-six cases of fibrosing ILD were identified with surgical lung biopsy. Immunohistochemistry for p16 was performed on sections with the most active fibrosis. p16-positive foci (loose collection of p16-positive fibroblasts with overlying p16-positive epithelium) were identified on digital slides and quantified. Cases were scored as p16-low (≤ 2.1 foci per 100 mm2) or p16-high (> 2.1 foci per 100 mm2). Twenty-four areas including senescent foci, fibrotic and normal areas were characterized using in situ RNA expression analysis with digital spatial profiling (DSP) in selected cases. RESULTS: The presence of p16-positive foci was specific for the diagnosis of IPF, where 50% of cases expressed any level of p16 and 26% were p16-high. There was no relationship between radiographic pattern and p16 expression. However, there was increased expression of cyclin-dependent kinase inhibitors, collagens and matrix remodeling genes within p16-positive foci, and cases with high p16 expression had shorter LTx-free survival. On the other hand, antifibrotic therapy was significantly protective. DSP demonstrated that fibroblastic foci exhibit transcriptional features clearly distinct from that of normal-looking and even fibrotic areas. CONCLUSIONS: We demonstrated the potential clinical applicability of a standardized quantification of p16-positive fibroblastic foci. This method identifies an IPF phenotype associated with foci-specific upregulation of senescence-associated and matrix remodeling gene expression. While these patients have reduced LTx-free survival, good response to antifibrotic therapies was observed in those who were treated.

Use of nintedanib in interstitial lung disease other than idiopathic pulmonary fibrosis: much caution is warranted.

Interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) is currently treated with immunosuppressive therapy, with a dynamic algorithm based on continued clinical surveillance. Published results on mycophenolate mofetil, cyclophosphamide and azathioprine showed either stabilization or improvement of lung function with these therapies. However, despite treatment optimization, progression of disease in ILD other than IPF is often observed, and a role for antifibrotic drug nintedanib has been hypothesized. The present article first reviews relevant aspects when considering anti-fibrotic therapy in progressing ILD other than IPF, including accuracy of the diagnosis, optimization of disease-modifying, immunosuppressive therapy and optimal timing. Next, a critical appraisal of published results on nintedanib in ILD other than IPF considers the design of the studies, inclusion criteria, used definition of "progression" of disease, frequency and severity of side effects observed and cost of the therapy. There currently is a strong and legitimate interest in additional therapies that can help controlling progressing ILD other than IPF. When the studies on the use of nintedanib are carefully considered, however, caution should be exercised before prematurely endorsing and applying this therapy. The conduction of studies that will clarify and justify its potential role as switch vs. add-on therapy and, at the same time, a more rigorous definition of disease progression are both strongly encouraged.

TPMT and HLA-DQA1-HLA-DRB genetic profiling to guide the use of azathioprine in the treatment of interstitial lung disease: First experience.

BACKGROUND: The choice of immunosuppressive therapy in interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) is based on safety profile and expected efficacy. Azathioprine is one of the most commonly used agents to treat ILD. The immunosuppressive effect and pancreatitis risk of azathioprine are influenced by the activity of the enzyme thiopurine methyltransferase (TPMT) and by the genetic mutations in HLA-DQA1-HLA-DRB locus, respectively. We hypothesized that systematic genotyping prior to starting azathioprine improves the rate of discontinuation of immunosuppressive therapy and the total incidence of adverse drug reactions (ADRs). METHODS: Eighty-two patients with ILD other than IPF were included in the study. The rate of immunosuppressive therapy discontinuation due to major ADRs and the total incidence of ADRs were compared between a cohort of genotyped patients (n = 49) and an untested cohort of patients (n = 33). RESULTS: Thirty-seven out of 49 patients in the genotyped cohort and 27 out of 33 patients in the untested cohort were started on azathioprine. The rate of immunosuppressive therapy discontinuation due to major ADRs was significantly lower (6/49) in the genotyped cohort compared to the untested cohort (11/33; p = 0.0276). All but one discontinuation due to severe ADRs occurred within a month of therapy. However, the total incidence rate of ADRs was very similar in the 2 cohorts (0.025 in the genotyped cohort vs. 0.023 in the untested cohort). CONCLUSION: In patients with ILD other than IPF, genotyping for azathioprine metabolism prior to starting therapy is associated with a significantly reduced rate of immunosuppressive therapy discontinuation due to major ADRs, with prevention of bone marrow suppression and pancreatitis, but without a reduction of the total incidence of ADRs. While these data support the use of genetic profiling prior to starting azathioprine to treat ILD, its cost effectiveness remains to be established.

Fat-Free Mass Index Controlled for Age and Sex and Malnutrition Are Predictors of Survival in Interstitial Lung Disease.

BACKGROUND: Literature focusing on nutritional variables and survival in interstitial lung disease (ILD) is limited by its focus on weight and BMI and has not considered body composition. OBJECTIVES: The primary objective of this study was to examine whether body composition measures, specifically fat-free mass index z-score (z-FFMI) and body fat mass index z-score (z-BFMI), were predictors of survival in fibrotic ILD patients. The second objective was to examine if nutrition status was a predictor of survival. METHOD: Seventy-eight outpatients diagnosed with fibrotic ILD were recruited in this cross-sectional study. Body composition data using dual frequency bioelectrical impedance analysis (BodyStat 1500MD; UK) and nutrition status using the subjective global assessment (SGA) were determined. To control for age and sex, z-FFMI and z-BFMI were calculated using population means. Participant charts were reviewed for diagnosis, age, disease severity, and exercise capacity. RESULTS: Age (HR 1.08, 95% CI [1.03-1.13], p < 0.01), BMI (HR 0.90, 95% CI [0.84-0.97], p < 0.01]), z-FFMI (HR 0.70, 95% CI [0.56-0.87], p = 0.02), z-BFMI (HR 0.74, 95% CI [0.57-0.96], p < 0.01), 6-min walk distance (6MWD) (HR 0.99, 95% CI [0.99-1.00], p < 0.01), percent predicted diffusing capacity for carbon monoxide (%DLco) (HR 0.93, 95% CI [0.89-0.97], p < 0.01), and severe malnutrition (SGA-C) (HR 6.98, 95% CI [2.00-24.27], p < 0.01) were significant predictors of survival. When controlled for exercise capacity and disease severity, z-FFMI and severe malnutrition were significant predictors of survival independent of %DLco. CONCLUSION: z-FFMI and severe malnutrition were significant predictors of survival in fibrotic ILD patients independent of disease severity.

Tobacco Worker's Lung: A Neglected Subtype of Hypersensitivity Pneumonitis.

Tobacco worker's lung (TWL) is a type of hypersensitivity pneumonitis (HP) affecting workers exposed to tobacco leaves and molds in the humidified environment of the tobacco production industry. Limited epidemiological data point to a prevalence of TWL that is not negligible and probably underestimated. As in other types of HP, an acute vs. chronic presentation depends on the pattern of the exposure. Therefore, the clinical presentation can vary from an acute influenza-like syndrome, mostly self-limiting with the removal of the exposure, to an insidious onset of cough, exertional dyspnea, fatigue and weight loss in chronic presentations, where fibrotic changes may be observed. The main treatment strategy is the removal of the exposure to tobacco dust and molds, while the main aim of corticosteroid therapy is to reduce morbidity and prevent complications, namely the development of pulmonary fibrosis and permanent lung dysfunction. Despite the fact that TWL is quite well described, preventive measures are not usually adopted in the tobacco production industry. We present here a state of the art review of this neglected, preventable, but still prevalent and occupational-related subtype of HP.

Validation of the risk stratification score in idiopathic pulmonary fibrosis: study protocol of a prospective, multi-centre, observational, 3-year clinical trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by a poor prognosis, with a progressive decline in lung function and considerable variability in the disease's natural history. Besides lung transplantation (LTx), the only available treatments are anti-fibrosing drugs, which have shown to slow down the disease course. Therefore, predicting the prognosis is of pivotal importance to avoid treatment delays, which may be fatal for patients with a high risk of progression. Previous studies showed that a multi-dimensional approach is practical and effective in the development of a reliable prognostic score for IPF. In the RIsk Stratification scorE (RISE), physiological parameters, an objective measure of patient-reported dyspnea and exercise capacity are combined to capture different domains of the complex pathophysiology of IPF. METHODS: This is an observational, multi-centre, prospective cohort study, designed to reflect common clinical practice in IPF. A development cohort and a validation cohort will be included. Patients newly diagnosed with IPF based on the ATS/ERS criteria and multi-disciplinary discussion will be included in the study. A panel of chest radiologists and lung pathologists will further assess eligibility. At the first visit (time of diagnosis), and every 4-months, MRC dyspnea score, pulmonary function tests (FEV1, FVC and DLCO), and 6-min walking distance will be recorded. Patients will be prospectively followed for 3 years. Comorbidities will be considered. The radiographic extent of fibrosis on HRCT will be recalculated at a 2-year interval. RISE, Gender-Age-Physiology, CPI and Mortality Risk Scoring System will be calculated at 4-month intervals. Longitudinal changes of each variable considered will be assessed. The primary endpoint is 3-year LTx-free survival from the time of diagnosis. Secondary endpoints include several, clinically-relevant information to ensure reproducibility of results across a wide range of disease severity and in concomitance of associated pulmonary hypertension or emphysema. DISCUSSION: The objective of this study is to validate RISE as a simple, straightforward, inexpensive and reproducible tool to guide clinical decision making in IPF, and potentially as an endpoint for future clinical trials. TRIAL REGISTRATION: U.S National Library of Medicine Clinicaltrials.gov, trial n. NCT02632123 "Validation of the risk stratification score in idiopathic pulmonary fibrosis". Date of registration: December 16th, 2015.

Persistent subretinal fluid following diabetic tractional retinal detachment repair: risk factors, natural history, and management outcomes.

PURPOSE: To study the natural history, anatomical and functional outcomes of persistent subretinal fluid (SRF) after pars plana vitrectomy (PPV) for diabetic tractional retinal detachment (TRD) and combined traction-rhegmatogenous retinal detachment (TRRD). METHODS: Retrospective interventional case series of 43 patients (46 eyes) with persistent SRF following PPV for diabetic TRD or combined TRRD from January 2010 to December 2017 at single tertiary institution. Primary outcomes included best corrected visual acuity (BCVA) and central foveal thickness (CFT). RESULTS: Thirty-one eyes (67.4%) had macula-off TRD, 5 (10.9%) had fovea-threatening TRD and 10 (21.7%) had combined TRRD. The mean (± SD) duration of decreased vision was 48.0 ± 58.2 weeks. The mean follow-up duration was 21 ± 13.2 months. Residual macular SRF was detected by optical coherence tomography in all eyes at 3 months and in 10 eyes (23.8%) at 12 months after surgery. Only 3 eyes (6.5%) had persistent SRF at final follow up. The mean time to resolution was 10.6 ± 4.1 months [range 6.0-23.0]. Thirteen eyes received additional intervention to address SRF. The mean CFT gradually improved until final follow-up (P-value < 0.001). The mean BCVA improved from 1.62 ± 0.88 LogMAR at presentation to 1.05 ± 0.76 LogMAR at final follow up. No statistically significant difference in final BCVA was found between eyes that had intervention and eyes that were observed (P value = 0.762). CONCLUSION: Persistent SRF after diabetic vitrectomy resolves slowly over time with gradual improvement in visual acuity. Additional drainage of persistent SRF may not be necessary.

Longitudinal functional changes with clinically significant radiographic progression in idiopathic pulmonary fibrosis: are we following the right parameters?

BACKGROUND: Progression of the disease in idiopathic pulmonary fibrosis (IPF) is difficult to predict, due to its variable and heterogenous course. The relationship between radiographic progression and functional decline in IPF is unclear. We sought to confirm that a simple HRCT fibrosis visual score is a reliable predictor of mortality in IPF, when longitudinally followed; and to ascertain which pulmonary functional variables best reflect clinically significant radiographic progression. METHODS: One-hundred-twenty-three consecutive patients with IPF from 2 centers were followed for an average of 3 years. Longitudinal changes of HRCT fibrosis scores, forced vital capacity (FVC), total lung capacity and diffusing lung capacity for carbon monoxide were considered. HRCTs were scored by 2 chest radiologists. The primary outcome was lung transplant (LTx)-free survival after the follow-up HRCT. RESULTS: During the follow-up period, 43 deaths and 11 LTx occurred. On average, the HRCT fibrosis score increased significantly, and a longitudinal increase > 7% predicted LTx-free survival significantly, with good specificity, but limited sensitivity. The correlation between radiographic and functional progression was moderately significant. HRCT progression and FVC decline predicted LTx-free survival independently and significantly, with better sensitivity, but worse specificity for a ≥ 5% decline of FVC. However, the area under the curve towards LTx-survival were only 0.61 and 0.62, respectively. CONCLUSIONS: The HRCT fibrosis visual score is a reliable and responsive tool to detect clinically meaningful disease progression. Although no individual pulmonary function test closely reflects radiographic progression, a longitudinal FVC decline improves sensitivity in the detection of clinically significant disease progression. However, the accuracy of these methods remains limited, and better prognostication models need to be found.

The CALIPER-Revised Version of the Composite Physiologic Index is a Better Predictor of Survival in IPF than the Original Version.

CALIPER is a computer-based quantitative algorithm to accurately characterize and quantify pulmonary fibrosis, and a revised version of composite physiologic index (CPI) has been developed against this new algorithm. The prognostic capabilities of the original and CALIPER-revised versions of CPI were compared in a cohort of 185 patients with IPF prospectively followed in 2 centers. CALIPER-revised CPI was a significant risk factor towards lung transplant (LTx)-free survival, with enhanced hazard ratio (5.68) compared to the original CPI (5.36). Accuracy of LTx-free survival was substantially improved with CALIPER-revised CPI (area under the curve [AUC] 0.75 vs. 0.66), with much better specificity (83% vs. 55%). Six-month changes of CALIPER-revised CPI predicted survival significantly (AUC 0.65). CALIPER-revised CPI is a better predictor of LTx-free survival in patients with IPF. Since CALIPER technology is not available to all centers, this simple and easy to obtain tool may be used to guide management decisions in IPF.

Implementing an interstitial lung disease clinic improves survival without increasing health care resource utilization.

BACKGROUND: Multidisciplinary collaboration is the cornerstone of interstitial lung disease (ILD) care. Delayed access to specialized care is associated with worse outcome. At the same time, the economic burden of ILD is high. We hypothesized that the establishment of a regional, dedicated ILD clinic would improve survival, but without necessarily causing an increase of health care resource utilization (HRU). METHODS: A historic cohort (January 2000-June 2013, n = 127) and a specialized care cohort followed by a dedicated ILD clinic (July 2013-June 2016, n = 144) were compared. Patients with idiopathic pulmonary fibrosis were excluded, due to the impact of new anti-fibrotic agents. Patients' data were linked to multiple provincial health administrative datasets. HRU included hospitalizations, doctor and emergency visits, pulmonary (including chest x-ray, chest CT scans, pulmonary function tests, bronchoscopies), cardio-vascular investigations, and specific ILD therapies. HRU was calculated as annual rate by domain. Three-year survival from initial assessment was the secondary outcome. RESULTS: The 2 cohorts were closely comparable in terms of specific ILD diagnosis, baseline lung function, comorbidities, neighbourhood income. There were overall no significant differences in terms of HRU. In the specialized care cohort, the use of non-steroid immunosuppressive therapies increased and survival significantly improved, despite significantly older age of patients at the time of initial assessment. Specialized ILD care was independently protective towards survival. CONCLUSIONS: Specialized, multi-disciplinary ILD care in a dedicated regional clinic is associated with improved survival and does not cause an increase of HRU, supporting the institution of potentially more cost-effective care with specialized ILD clinics.

Osteopontin lung gene expression is a marker of disease severity in pulmonary arterial hypertension.

BACKGROUND AND OBJECTIVE: Osteopontin (OPN) is a pleiotropic cytokine involved in the proliferation of pulmonary artery smooth muscle cells (PA-SMC). OPN is upregulated in the lungs of patients with pulmonary hypertension (PH) associated with pulmonary fibrosis, suggesting that the lung is a source of OPN. We hypothesized that OPN lung expression is elevated in Group I pulmonary arterial hypertension (PAH) and is correlated to haemodynamics. METHODS: Microarray analysis (Affymetrix) was performed after RNA was extracted from explanted lungs in 15 patients with Group I PAH who underwent lung transplantation (LTx) and 11 normal controls. PA pressure levels were recorded intraoperatively, immediately before starting LTx. Serum OPN levels were measured in subjects with PAH, Group II PH and normal controls on the day of right heart catheterization. RESULTS: OPN was among the top five upregulated genes in PAH compared to normal controls, which was confirmed by reverse transcription polymerase chain reaction (RT-PCR). OPN expression was similar and equally elevated in different subtypes of PAH. A strong significant correlation was observed between mean pulmonary arterial pressure and OPN gene expression. Ingenuity pathway analysis showed the involvement of OPN in functions and networks relevant to angiogenesis, cell death and proliferation of PA-SMC. OPN serum levels did not differ in subjects with Group I PAH and Group II PH. CONCLUSION: In the lungs of patients with severe PAH, OPN is highly expressed and the level of expression is significantly correlated to disease severity. OPN may play an important role in the vascular remodelling process of PAH.

Sickle cell retinopathy. A focused review.

PURPOSE: To provide a focused review of sickle cell retinopathy in the light of recent advances in the pathogenesis, multimodal retinal imaging, management of the condition, and migration trends, which may lead to increased prevalence of the condition in the Western world. METHODS: Non-systematic focused literature review. RESULTS: Sickle retinopathy results from aggregation of abnormal hemoglobin in the red blood cells in the retinal microcirculation, leading to reduced deformability of the red blood cells, stagnant blood flow in the retinal precapillary arterioles, thrombosis, and ischemia. This may be precipitated by hypoxia, acidosis, and hyperosmolarity. Sickle retinopathy may result in sight threatening complications, such as paracentral middle maculopathy or sequelae of proliferative retinopathy, such as vitreous hemorrhage and retinal detachment. New imaging modalities, such as wide-field imaging and optical coherence tomography angiography, have revealed the microstructural features of sickle retinopathy, enabling earlier diagnosis. The vascular growth factor ANGPTL-4 has recently been identified as a potential mediator of progression to proliferative retinopathy and may represent a possible therapeutic target. Laser therapy should be considered for proliferative retinopathy in order to prevent visual loss; however, the evidence is not very strong. With recent development of wide-field imaging, targeted laser to ischemic retina may prove to be beneficial. Exact control of intraoperative intraocular pressure, including valved trocar vitrectomy systems, may improve the outcomes of vitreoretinal surgery for complications, such as vitreous hemorrhage and retinal detachment. Stem cell transplantation and gene therapy are potentially curative treatments, which may prevent retinopathy. CONCLUSIONS: There is lack of evidence regarding the optimal management of sickle retinopathy. Further study is needed to determine if recent progress in the understanding of the pathophysiology and diagnosis of sickle retinopathy may translate into improved management and outcome.

Comprehensive gene expression profiling identifies distinct and overlapping transcriptional profiles in non-specific interstitial pneumonia and idiopathic pulmonary fibrosis.

BACKGROUND: The clinical-radiographic distinction between idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) is challenging. We sought to investigate the gene expression profiles of IPF and NSIP vs. normal controls. METHODS: Gene expression from explanted lungs of patients with IPF (n = 22), NSIP (n = 10) and from normal controls (n = 11) was assessed. Microarray analysis included Significance Analysis of Microarray (SAM), Ingenuity Pathway, Gene-Set Enrichment and unsupervised hierarchical clustering analyses. Immunohistochemistry and serology of proteins of interest were conducted. RESULTS: NSIP cases were significantly enriched for genes related to mechanisms of immune reaction, such as T-cell response and recruitment of leukocytes into the lung compartment. In IPF, in contrast, these involved senescence, epithelial-to-mesenchymal transition, myofibroblast differentiation and collagen deposition. Unlike the IPF group, NSIP cases exhibited a strikingly homogenous gene signature. Clustering analysis identified a subgroup of IPF patients with intermediate and ambiguous expression of SAM-selected genes, with the interesting upregulation of both NSIP-specific and senescence-related genes. Immunohistochemistry for p16, a senescence marker, on fibroblasts differentiated most IPF cases from NSIP. Serial serum levels of periostin, a senescence effector, predicted clinical progression in a cohort of patients with IPF. CONCLUSIONS: Comprehensive gene expression profiling in explanted lungs identifies distinct transcriptional profiles and differentially expressed genes in IPF and NSIP, supporting the notion of NSIP as a standalone condition. Potential gene and protein markers to discriminate IPF from NSIP were identified, with a prominent role of senescence in IPF. The finding of a subgroup of IPF patients with transcriptional features of both NSIP and senescence raises the hypothesis that "senescent" NSIP may represent a risk factor to develop superimposed IPF.

Robotic-assisted surgery in ophthalmology.

PURPOSE OF REVIEW: Provide an overview of the current landscape of robotics in ophthalmology, including the pros and cons of system designs, the clinical development path, and the likely future direction of the field. RECENT FINDINGS: Robots designed for eye surgery should meet certain basic requirements. Three designs are currently being developed: smart surgical tools such as the steady hand, comanipulation devices and telemanipulators using either a fixed or virtual remote center of motion. Successful human intraocular surgery is being performed using the Preceyes surgical system. Another telemanipulation robot, the da Vinci Surgical System, has been used to perform a pterygium repair in humans and was successful in ex-vivo corneal surgery despite its nonophthalmic design. Apart from Preceyes' BV research platform, none of the currently eye-specific systems has reached a commercial stage. Systems are likely to evolve from robotic assistance during specific procedural steps to semiautonomous surgery, as smart sensors are introduced to enhance the basic functionalities of robotic systems. SUMMARY: Robotics is still in its infancy in ophthalmology but is rapidly reaching a stage wherein it will be introduced into everyday ophthalmic practice. It will most likely be introduced first for demanding vitreo-retinal procedures, followed by anterior segment applications.

Associated Pulmonary Hypertension Is an Independent Contributor to Exercise Intolerance in Chronic Fibrosing Interstitial Pneumonias.

BACKGROUND: Associated pulmonary hypertension (APH) is frequently observed in fibrosing interstitial pneumonias (FIP), such as idiopathic pulmonary fibrosis (IPF). APH is associated with worse prognosis, but it remains unclear whether it is associated with greater functional impairment. Six-minute walk distance (6MWD) is widely used to assess functional capacity in pulmonary hypertension and FIP. OBJECTIVES: To investigate if APH independently contributes to exercise intolerance in FIP, irrespective of the extent of underlying fibrosis. METHODS: Patients diagnosed with FIP (September 2009 to June 2017) were included in the study if they underwent right heart catheterization, high-resolution chest computed tomography (HRCT), and 6MWD within 3 months. Recruitment was not limited only to patients undergoing lung transplant assessment. APH was defined as mean pulmonary artery pressure (mPAP) ≥25 mm Hg. The extent of fibrosis was quantified on HRCT using a visual fibrosis score by 2 separate observers. RESULTS: Seventy-two patients (60 with IPF) were identified. Fifty-five patients had APH. mPAP was not significantly different in subgroups stratified according to the extent of fibrosis on HRCT. Pulmonary vascular resistance (PVR) was the strongest predictor of 6MWD on both univariate and stepwise regression analyses, and remained so considering only patients with normal wedge pressure (< 15 mm Hg) (n = 61). HRCT fibrosis score and pulmonary function tests did not significantly correlate with 6MWD. CONCLUSIONS: In patients with FIP, PVR is a significant contributor of 6MWD, independently from the extent of fibrosis on HRCT. These results strengthen both the rationale to use 6MWD as endpoint in FIP and to target APH with specific therapies.

Multi-dimensional Assessment of IPF Across a Wide Range of Disease Severity.

PURPOSE: The pathophysiology of idiopathic pulmonary fibrosis (IPF) is complex, and its clinical course is difficult to predict. Perceived dyspnea, exercise capacity, and lung physiology have all been associated with mortality outcomes in IPF, but the significance of these relationships is unclear. We sought to investigate the correlation among these variables and their independent predictive capability in determining mortality outcomes. METHODS: Four-hundred-thirty-seven patients diagnosed with IPF from three independent centers were included in the study. Medical Research Council Dyspnea Score (MRCDS), 6-min walk distance (6MWD), and pulmonary function tests were determined at baseline. The end-point was 18-month transplant-free survival. RESULTS: Correlations between MRCDS, 6MWD, forced vital capacity (FVC), and diffusing lung capacity for carbon monoxide were either very weak or weak. Calculation of variance inflation factors demonstrated absence of collinearity among these variables. Univariate regression analysis and c-statistics identified MRCDS, 6MWD, and FVC as significant predictors of 18-month transplant-free survival. Multivariate regression analysis retained MRCDS, 6MWD, and FVC as independent predictors of mortality. To ensure generalizability, we confirmed the results in subgroups of patients stratified according to baseline FVC, and further by considering lung transplant as a competing event to death. CONCLUSIONS: In a cohort of patients with IPF encompassing a wide range of disease severity, baseline perceived exertional dyspnea, exercise capacity, and lung function are weakly correlated to each other, translating in the absence of collinearity. MRCDS, 6MWD, and FVC are significant and independent predictors of outcome, suggesting that a multi-dimensional assessment of IPF is prognostically appropriate and advantageous.

A simple dyspnoea scale as part of the assessment to predict outcome across chronic interstitial lung disease.

BACKGROUND AND OBJECTIVE: The Medical Research Council dyspnoea score (MRCDS) is a simple, objective scale to assess dyspnoea, the main complaint in patients with chronic interstitial lung disease (ILD). We sought to investigate whether MRCDS is a predictor of outcome in patients with chronic ILD. METHODS: One hundred and fifteen patients (50 idiopathic pulmonary fibrosis (IPF) and 65 non-IPF ILD) were retrospectively studied. Baseline (time of diagnosis) MRCDS and 3-6-month changes were considered. Endpoints were (i) 18-month clinical progression, defined as either: ≥10% absolute reduction in forced vital capacity (FVC) percent predicted; ≥50-m decline in 6-min walk distance; hospitalization for respiratory causes; lung transplantation (LTx) assessment or death and (ii) 18-month survival. RESULTS: At the end of the observation period, 54 subjects (47%) experienced clinical progression (including 22 deaths and 3 LTx). In patients with IPF, a longitudinal increase in MRCDS predicted clinical progression significantly (area under the curve (AUC) = 0.76, sensitivity = 62%, specificity = 91%); baseline MRCDS was a strong predictor of mortality (AUC = 0.80, sensitivity = 87%, specificity = 57%). In patients with non-IPF ILD, longitudinal increases in MRCDS, but not baseline values, were predictive of both clinical progression (AUC = 0.81, sensitivity = 85%, specificity = 77%) and mortality (AUC = 0.76, sensitivity = 91%, specificity = 61%). Considering the whole population, MRCDS increase and FVC decline were independent predictors of mortality. CONCLUSION: Longitudinal increases of MRCDS predict poor outcome in chronic ILD, with good accuracy. Baseline MRCDS remains a strong predictor of mortality in IPF. MRCDS should be included in the global assessment of the clinical course of chronic ILD.

INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE FOR MACULAR HOLE SURGERY WITHOUT EXTRA MANIPULATION OF THE FLAP.

PURPOSE: To determine whether surgical manipulation steps of the internal limiting membrane (ILM) flap, such as ILM trimmed, ILM tuck inside the hole, ILM massage, are mandatory to obtain satisfactory outcomes for the repair of large stage IV idiopathic macular hole using the inverted ILM flap technique. METHODS: In this interventional comparative prospective single-masked study, 81 eyes were randomized into 2 treatments groups. In Group 1 (41 eyes), the classic inverted ILM flap technique was performed. In Group 2 (40 eyes), a modified procedure was used: after ILM peeling, no extra flap manipulation was performed. The macular hole was covered by the inverted ILM flap because of the air pressure at the time of the fluid-air exchange. RESULTS: At 12 months, macular hole closure was observed in 40 eyes (97.6%) in Group 1 and in 39 eyes in Group 2 (97.5%). U-shape closure rate, ellipsoid zone defects, and external limiting membrane defects were similar in both groups. The results indicate no statistical difference in anatomical and functional success between both groups. CONCLUSION: The macular hole closure rate, improved visual acuity, and no extra complications indicate noninferiority of the modified inverted ILM technique. Internal limiting membrane finishing, tucking, and massage may not be required to obtain surgical success.