Association of musculoskeletal involvement with lung function and mortality in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with high mortality. Low muscle mass, frailty and sarcopenia lead to functional impairment that negatively impact quality of life and survival but are not used in clinical practice. We aimed to determine the association of Fat-free mass index (FFMI) and frailty with lung function, exercise tolerance and survival in patients with IPF. In this study, 70 patients with IPF underwent assessment of body composition, lung function, 6-min walk distance (6MWD) testing, hand grip strength, quality of life (QoL) assessment by St. George's Respiratory questionnaire (SGRQ) and frailty assessment using the SHARE-FI tool. FFMI was calculated using pectoralis muscle cross-sectional area (PM-CSA) on CT chest images and the lowest quartile defined reduced muscle mass. Sarcopenia was defined as low FFMI and handgrip strength. Regression analyses were conducted to determine predictive value of frailty, low FFMI and sarcopenia on clinical outcomes. The Cox proportional hazards model was used to analyze the impact of FFMI and frailty score on survival. The mean age was 70 years with moderate impairment in lung function (mean ppFVC 68.5%, ppDLCO 45.6%). Baseline forced vital capacity (p < 0.001), diffusion capacity of lung for carbon monoxide (p = < 0.01), 6WMD (p < 0.05) were significantly lower in frail patients compared to non-frail patients. BMI was found to closely correlate with FFMI (r = 0.79, p < 0.001), but not with frailty score (r = - 0.2, p = 0.07). Frailty was a significant predictor of FVC, DLCO, 6MWD, SGRQ scores when adjusted for age and gender. Muscle mass and sarcopenia were significant predictors of FVC, DLCO, but not 6MWD or QoL scores. Multivariate cox-proportional hazards ratio model adjusting for age and gender showed that frailty was significantly associated with increased mortality (HR = 2.6, 95% CI 1.1-6.1). Low FFMI (HR = 1.3, 95% CI 0.6-2.8), and sarcopenia (HR = 2.1, 95% CI 0.8-5.3), though associated with a trend to increased mortality, were not statistically significant. Frailty is associated with lower lung function and higher mortality in patients with IPF. Longitudinal evaluations are necessary to further determine the associations between low FFMI, sarcopenia and frailty with outcomes in IPF.

Optic Disc and Retinal Architecture Changes in Patients with Spinocerebellar Ataxia Type 2.

BACKGROUND: ATXN2 is the causative gene of spinocerebellar ataxia type 2 (SCA2) and has been implicated in glaucoma pathogenesis. Therefore, studying ocular changes in SCA2 could uncover clinically relevant changes. OBJECTIVE: The aim was to investigate optic disc and retinal architecture in SCA2. METHODS: We evaluated 14 patients with SCA2 and 26 controls who underwent intraocular pressure measurement, fundoscopy, and macular and peripapillary spectral domain optical coherence tomography (SD-OCT). We compared SD-OCT measurements in SCA2 and controls, and the frequency of glaucomatous changes among SCA2, controls, and 76 patients with other SCAs (types 1, 3, 6, and 7). RESULTS: The macula, peripapillary retinal nerve fiber and inner plexiform layers were thinner in SCA2 than in controls. Increased cup-to-disc ratio was more frequent in SCA2 than in controls and other SCAs. CONCLUSIONS: Ocular changes are part of SCA2 phenotype. Future studies should further investigate retinal and optic nerve architecture in this disorder.

An algorithm for the National Institute of Health Stroke Scale assessment: A multicenter, two-arm and cluster randomized study.

BACKGROUND: The NIH Stroke Scale (NIHSS) is a validated tool for assessing stroke severity, increasingly used by general practitioners in telemedicine services. Mobile apps may enhance its reliability. We aim to validate a digital platform (SPOKES) for NIHSS assessment in telemedicine and healthcare settings. METHODS: Hospitals using a telemedicine service were randomly allocated to control or SPOKES-user groups. The discrepancy between the NIHSS scores reported and those confirmed by experts was evaluated. Healthcare providers from comprehensive stroke centers were invited for interrater validation. Participants were randomized to assess the NIHSS using videos of real patients. Weighted Kappa (wk) statistics analyzed the agreement, and logistic regression determined the correlation with the congruency. RESULTS: A total of 299 telemedicine consultations from 12 hospitals were included. The difference between the NIHSS scores reported and double-checked was lower in the SPOKES group (p = 0.03), with a significantly higher level of complete agreement (72.5 % vs. 50.4 %, p = 0.005). Adoption of SPOKES was associated with complete congruency (OR 4.01, 95 %CI 1.42-11.35, p = 0.009). For interrater validation, 20 participants were considered. In the SPOKES group, almost-perfect and strong agreement occurred in 13.3 %(n = 6/45) and 84.4 %(n = 38/45) of ratings, respectively; in the control group, 6.7 %(n = 3/45) were almost-perfect, 28.9 %(n = 13/45) strong and 51 %(n = 23/45) were minimal. CONCLUSION: A free and reliable mobile application for NIHSS assessment can significantly improve interrater agreement between healthcare professionals, and between NIHSS-certified neurologists and general practitioners. Our results underscore the importance of ongoing training and education in enhancing the consistency and reliability of NIHSS scores.

Associations between resources and practices of ILD centers and outcomes in patients with idiopathic pulmonary fibrosis: data from the IPF-PRO Registry.

BACKGROUND: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes. METHODS: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient case mix by adjusting for known predictors of each outcome. We assessed whether site-level heterogeneity existed for each patient-level outcome, and if so, we investigated potential drivers of the heterogeneity. RESULTS: All 27 sites that enrolled ≥ 10 patients returned the questionnaire. Most sites were actively following > 100 patients with IPF (70.4%), had a lung transplant program (66.7%), and had a dedicated ILD nurse leader (77.8%). Substantial heterogeneity was observed in the event rates of clinically relevant outcomes across the sites. After controlling for patient case mix, there were no outcomes for which the site variance component was significantly different from 0, but the p-value for hospitalization was 0.052. Starting/completing an ILD-related quality improvement project in the previous 2 years was associated with a lower risk of hospitalization (HR 0.60 [95% CI 0.44, 0.82]; p = 0.001). CONCLUSIONS: Analyses of data from patients with IPF managed at sites across the US found no site-specific characteristics or practices that were significantly associated with clinically relevant outcomes after adjusting for patient case mix. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511.

Characterization of Retinal Architecture in Spinocerebellar Ataxia Type 3 and Correlation with Disease Severity.

BACKGROUND: Neurodegeneration affects the brain and peripheral nervous system in spinocerebellar ataxia type 3 (SCA3). As the retina is also involved, studying the retinal architecture in a cohort of patients could reveal clinically relevant biomarkers. OBJECTIVE: The aim is to investigate retinal architecture in SCA3 to identify potential biomarkers. METHODS: We evaluated 38 patients with SCA3 and 25 healthy age-matched controls, who underwent visual acuity assessment, intraocular pressure measurement, and fundoscopy and macular and peripapillary spectral domain optical coherence tomography (SD-OCT). We measured the peripapillary retinal nerve fiber layer (pRNFL) thickness in each quadrant of the temporal-superior-nasal-inferior-temporal chart and the macular layer thicknesses in each sector of the inner circle of the Early Treatment Diabetic Retinopathy Study (IC-ETDRS) grid. Linear regression analysis was employed to test the associations between retinal parameters and age, disease duration, CAG repeats, and SARA (Scale of the Assessment and Rating of Ataxia) and ICARS (International Cooperative Ataxia Rating Scale) scores in SCA3. RESULTS: In all sectors, except for the temporal quadrant, pRNFL was significantly thinner in SCA3 patients than in controls. Average total macular, ganglion cell layer (GCL), and inner plexiform layer (IPL) thicknesses were significantly decreased in SCA3 patients in comparison to controls. The average total macular thickness and the average thicknesses of RNFL, GCL, and IPL negatively correlated with ICARS scores, whereas average GCL and IPL thicknesses negatively correlated with SARA scores. CONCLUSIONS: The retinal ganglion cells, their dendrites, and axons are selectively affected in SCA3 patients. The RNFL, GCL, and IPL thicknesses in SD-OCT correlate with the clinical phenotype and represent potential biomarkers for future clinical trials and natural history studies. © 2021 International Parkinson and Movement Disorder Society.

Association of Circulating Proteins with Death or Lung Transplant in Patients with Idiopathic Pulmonary Fibrosis in the IPF-PRO Registry Cohort.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, corrected p ≤ 0.05). In multivariable analyses, a set of 4 clinical measures and 47 unique proteins predicted the probability of respiratory death or lung transplant with an optimism-corrected C-index of 0.76. Our results suggest that select circulating proteins strongly associate with the risk of mortality in patients with IPF and confer information independent of clinical measures.

Waveform Morphology as a Surrogate for ICP Monitoring: A Comparison Between an Invasive and a Noninvasive Method.

BACKGROUND: Although the placement of an intraventricular catheter remains the gold standard technique for measuring intracranial pressure (ICP), the method has several limitations. Therefore, noninvasive alternatives to ICP (ICPni) measurement are of great interest. The main objective of this study was to compare the correlation and agreement of wave morphology between ICP (standard intraventricular ICP monitoring) and a new ICPni monitor in patients admitted with stroke. The second objective was to estimate the discrimination of the noninvasive method to detect intracranial hypertension. METHODS: We prospectively collected data of adults admitted to an intensive care unit with subarachnoid hemorrhage, intracerebral hemorrhage, or ischemic stroke in whom an invasive ICP monitor was placed. Measurements were simultaneously collected from two parameters [time-to-peak (TTP) and the ratio regarding the second and first peak of the ICP wave (P2/P1 ratio)] of ICP and ICPni wave morphology monitors (Brain4care). Intracranial hypertension was defined as an invasively measured sustained ICP > 20 mm Hg for at least 5 min. RESULTS: We studied 18 patients (subarachnoid hemorrhage = 14; intracerebral hemorrhage = 3; ischemic stroke = 1) on 60 occasions with a median age of 52 ± 14.3 years. A total of 197,400 waves (2495 min) from both ICP (standard ICP monitoring) and the ICPni monitor were sliced into 1-min-long segments, and we determined TTP and the P2/P1 ratio from the mean pulse. The median invasively measured ICP was 13 (9.8-16.2) mm Hg, and intracranial hypertension was present on 18 occasions (30%). The correlation and agreement between invasive and noninvasive methods for wave morphology were strong for the P2/P1 ratio and moderate for TTP using categoric (κ agreement 88.1% and 71.3%, respectively) and continuous (intraclass correlation coefficient 0.831 and 0.584, respectively) measures. There was a moderate but significant correlation with the mean ICP value (P2/P1 ratio r = 0.427; TTP r = 0.353; p < 0.001 for all) between noninvasive and invasive techniques. The areas under the curve to estimate intracranial hypertension were 0.786 [95% confidence interval (CI) 0.72-0.93] for the P2/P1 ratio and 0.694 (95% CI 0.60-0.74) for TTP. CONCLUSIONS: The new ICPni wave morphology monitor showed a good agreement with the standard invasive method and an acceptable discriminatory power to detect intracranial hypertension. Clinical trial registration Trial registration: NCT05121155.

Retinal Architecture in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Insights into Disease Pathogenesis and Biomarkers.

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) causes unique retinal abnormalities, which have not been systematically investigated. OBJECTIVE: To deeply phenotype the retina in ARSACS in order to better understand its pathogenesis and identify potential biomarkers. METHODS: We evaluated 29 patients with ARSACS, 66 with spinocerebellar ataxia (SCA), 38 with autosomal recessive cerebellar ataxia (ATX), 22 with hereditary spastic paraplegia (SPG), 21 cases of papilledema, and 20 healthy controls (total n = 196 subjects). Participants underwent visual acuity assessment, intraocular pressure measurement, fundoscopy, and macular and peripapillary optical coherence tomography (OCT). Macular layers thicknesses in ARSACS were compared with those of age-matched healthy controls. Ophthalmologists analyzed the scans for abnormal signs in the different patient groups. Linear regression analysis was conducted to look for associations between retinal changes and age, age at onset, disease duration, and Scale for the Assessment and Rating of Ataxia (SARA) scores in ARSACS. RESULTS: Only patients with ARSACS exhibited peripapillary retinal striations (82%) on fundoscopy, and their OCT scans revealed foveal hypoplasia (100%), sawtooth appearance (89%), papillomacular fold (86%), and macular microcysts (18%). Average peripapillary retinal nerve fiber layer (pRNFL) was thicker in ARSACS than in SCA, ATX, SPG, and controls; a cut-off of 121 µm was 100% accurate in diagnosing ARSACS. All macular layers were thicker in ARSACS when compared to healthy controls. RNFL thickness in the inferior sector of the macula positively correlated with SARA scores. CONCLUSIONS: Retinal abnormalities are highly specific for ARSACS, and suggest retinal hyperplasia due to abnormal retinal development. OCT may provide potential biomarkers for future clinical trials. © 2021 International Parkinson and Movement Disorder Society.

A Proposal for Classification of Retinal Degeneration in Spinocerebellar Ataxia Type 7.

The aim of this study is to propose a classification system for the spinocerebellar ataxia type 7 retinal degeneration (SCA7-RD). Twenty patients with molecularly confirmed SCA7 underwent slit lamp examination, fundus photography, and optical coherence tomography (Spectralis®). Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale (ICARS) were applied, and age, sex, age at symptom onset, and number of CAG expansions were recorded. After analyzing the ophthalmological findings in each participant, a panel of retinal disease experts created a qualitative classification system for SCA7-RD comprising four stages. We assessed the correlations of retinal degeneration severity with SARA and ICARS scores, number of CAG repeats in ATXN7 allele, and age at symptom onset. We graded retinal degeneration as stage 1 in nine participants, as stage 2 in five, and as stage 3 in six. No differences in age and visual symptoms duration were found between groups. SARA and ICARS scores correlated with the severity of SCA7-RD on the classification system (p = 0.024 and p = 0.014, respectively). After adjusting for disease duration, retinal disease stage association with SARA and ICARS scores remained significant (ANCOVA, p < 0.05). The classification system for SCA7-RD was able to characterize different disease stages representing the landmarks in the cone-rod dystrophy natural history. Neurodegeneration appears to occur in parallel in the cerebellum and in the visual pathway. We conclude that retinal degeneration in SCA7 is a potential biomarker of the neurological phenotype severity.

Cerebral Microembolism in Intracerebral Hemorrhage: A Prospective Case-Control Study.

BACKGROUND: Small and remote acute ischemic lesions may occur in up to one-third of patients with spontaneous intracerebral hemorrhage (ICH). Possible mechanisms include cerebral embolism, small vessel disease, blood pressure variability and others. The embolic mechanism has not been adequately studied. Using transcranial Doppler (TCD), we assessed the incidence of spontaneous microembolic signals (MESs) in patients with acute ICH. METHODS: Twenty acute ICH patients were prospectively evaluated within 48 h of hospital admission. Clinical and imaging data were collected. Continuous TCD monitoring was performed in both middle cerebral arteries for a one-hour period on days 1, 3 and 7 of hospital admission. Monitoring was performed in the emergency room, ICU or ward, according to patient location. We compared the frequency and risk factors for MES in patients with ICH and in 20 age- and gender-matched controls without history of ischemic or hemorrhagic stroke. RESULTS: The mean age was 57.5 ± 14.1 years, and 60% were male. MESs were detected in 7 patients with ICH and in one control patient without ICH (35% vs 5%, p = 0.048). The frequency of MES on day 1 was 15% (3 of 20 patients), on day 3, 26% (5 of 19 patients) and on day 7, 37.5% (3 of 8 patients). Among patients with ICH, those with MES had a tendency to higher frequencies of dyslipidemia (83% vs 33%, p = 0.13) and lobar location of hemorrhages (71% vs 30%, p = 0.15). Two out of 6 patients with ICH who also underwent MRI had remote DWI lesions, of whom one showed MES on TCD. CONCLUSION: Micro-embolic signals occur in over one-third of patients with ICH. Further research is needed to identify the sources of cerebral microembolism and their relationship with small acute infarcts in ICH.

Patient Registries in Idiopathic Pulmonary Fibrosis.

Over the past decade, several large registries of patients with idiopathic pulmonary fibrosis (IPF) have been established. These registries are collecting a wealth of longitudinal data on thousands of patients with this rare disease. The data collected in these registries will be complementary to data collected in clinical trials because the patient populations studied in registries have a broader spectrum of disease severity and comorbidities and can be followed for a longer period of time. Maintaining the quality and completeness of registry databases presents administrative and resourcing challenges, but it is important to ensuring the robustness of the analyses. Data from patient registries have already helped improve understanding of the clinical characteristics of patients with IPF, the impact that the disease has on their quality of life and survival, and current practices in diagnosis and management. In the future, analyses of biospecimens linked to detailed patient profiles will provide the opportunity to identify biomarkers linked to disease progression, facilitating the development of precision medicine approaches for prognosis and therapy in patients with IPF.

Assessment of viral RNA in idiopathic pulmonary fibrosis using RNA-seq.

BACKGROUND: Numerous publications suggest an association between herpes virus infection and idiopathic pulmonary fibrosis (IPF). These reports have employed immunohistochemistry, in situ hybridization and/or PCR, which are susceptible to specificity artifacts. METHODS: We investigated the possible association between IPF and viral RNA expression using next-generation sequencing, which has the potential to provide a high degree of both sensitivity and specificity. We quantified viral RNA expression for 740 viruses in 28 IPF patient lung biopsy samples and 20 controls. Key RNA-seq results were confirmed using Real-time RT-PCR for select viruses (EBV, HCV, herpesvirus saimiri and HERV-K). RESULTS: We identified sporadic low-level evidence of viral infections in our lung tissue specimens, but did not find a statistical difference for expression of any virus, including EBV, herpesvirus saimiri and HERV-K, between IPF and control lungs. CONCLUSIONS: To the best of our knowledge, this is the first publication that employs RNA-seq to assess whether viral infections are linked to the pathogenesis of IPF. Our results do not address the role of viral infection in acute exacerbations of IPF, however, this analysis patently did not support an association between herpes virus detection and IPF.

Expert consensus on the management of adverse events and prescribing practices associated with the treatment of patients taking pirfenidone for idiopathic pulmonary fibrosis: a Delphi consensus study.

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) treated with pirfenidone (Esbriet®, Genentech USA, Inc. South San Francisco, CA.), effectively managing treatment-related adverse events (AEs) may improve adherence. Due to a lack of clinical evidence and expertise, managing these AEs can be challenging for patients and physicians alike. In the absence of evidence, consensus recommendations from physicians experienced in using pirfenidone to treat IPF are beneficial. METHODS: Using a modified Delphi process, expert recommendations were developed by a panel of physicians experienced with using pirfenidone for IPF. Over three iterations, panelists developed and refined a series of statements on the use of pirfenidone in IPF. Their agreement on each statement was ranked using a Likert scale. RESULTS: A panel of 12 physicians participated and developed a total of 286 statements on dosing and administration, special populations, drug-drug interactions, laboratory analysis, warnings and precautions, and AE management. Expert recommendations were achieved with regard to slower initial titrations and slower titrations for AEs, dosing with meal(s) or substantial meals, and adding other prescribed pharmacological agents for AEs. CONCLUSION: Until there is further clinical evidence, the resulting consensus recommendations are intended to provide direction on the practical management of IPF with pirfenidone, by encompassing a broad experience from the real world to complement data gleaned from clinical trials.

Predicting hemorrhagic transformation in patients not submitted to reperfusion therapies.

BACKGROUND: Well studied in patients with ischemic stroke after reperfusion therapies (RT), hemorrhagic transformation (HT) is also common in patients not treated with RT and can lead to disability even in initially asymptomatic cases. The best predictors of HT in patients not treated with RT are not well established. Therefore, we aimed to identify predictors of HT in patients not submitted to RT and create a user-friendly predictive score (PROpHET). MATERIAL AND METHODS: Patients admitted to a Comprehensive Stroke Center from 2015 to 2017 were prospectively evaluated and randomly selected to the derivation cohort. A multivariable logistic regression modeling was built to produce a predictive grading score for HT. The external validation was assessed using datasets from 7 Comprehensive Stroke Centers using the area under the receiver operating characteristic curve (AUROC). RESULTS: In the derivation group, 448 patients were included in the final analysis. The validation group included 2,683 patients. The score derived from significant predictors of HT in the multivariate logistic regression analysis was male sex (1 point), ASPECTS ≤ 7 (2 points), presence of leukoaraiosis (1 point), hyperdense cerebral middle artery sign (1 point), glycemia at admission ≥180 mg/dL (1 point), cardioembolism (1 point) and lacunar syndrome (-3 points) as a protective factor. The grading score ranges from -3 to 7. A Score ≥3 had 78.2% sensitivity and 75% specificity, and AUROC of 0.82 for all cases of HT. In the validation cohort, our score had an AUROC of 0.83. CONCLUSIONS: The PROpHET is a simple, quick, cost-free, and easy-to-perform tool that allows risk stratification of HT in patients not submitted to RT. A cost-free computerized version of our score is available online with a user-friendly interface.

Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an "age-suppressing" hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-ß (TGF-ß)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-ß signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.

Predictors of death or lung transplant after a diagnosis of idiopathic pulmonary fibrosis: insights from the IPF-PRO Registry.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a variable clinical course and high mortality. We used data from a large national US registry of patients with IPF to investigate relationships between patient characteristics, including markers of disease severity, and mortality. METHODS: The analysis cohort comprised patients enrolled in the IPF-PRO Registry from its inception on 5 June 2014 to 26 October 2017. The primary criterion for inclusion in this registry is that patients must be diagnosed or confirmed with IPF at the enrolling centre within 6 months. Associations between patient characteristics and markers of disease severity at enrolment and mortality outcomes were investigated using univariable, multivariable and adjustment models. RESULTS: Among 662 patients enrolled, 111 patients died or had a lung transplant over a follow-up period of 30 months. The probability of being free of both events at month 30 was 50.6% (95% CI: 40.0, 60.2). When patient characteristics and markers of disease severity were jointly examined in a multivariable analysis, oxygen use at rest (hazard ratio [HR] 2.44 [95% CI: 1.45, 4.10]), lower forced vital capacity (FVC) % predicted (HR 1.28 [95% CI: 1.10, 1.49] per 10% decrease) and diffusion capacity for carbon monoxide (DLco) % predicted (HR 1.25 [95% CI: 1.04, 1.51] per 10% decrease) were significantly associated with increased risk of death or lung transplant. The risk of death or lung transplant increased with increasing age in patients ≥62 years old (HR 1.18 [95% CI: 0.99, 1.40] per 5-year increase), and decreased with increasing age in patients <62 years old (HR 0.60 [95% CI: 0.39, 0.92] per 5-year increase). CONCLUSIONS: In an observational US registry of patients with IPF, oxygen use at rest, lower FVC % predicted, and lower DLco % predicted were associated with risk of death or lung transplant. An audio podcast of the lead author discussing these data can be downloaded from: http://www.usscicomms.com/respiratory/snyder/IPF-PROsurvival1/ . TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01915511 .

Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis.

Autoimmunity has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the repertoire of autoantigens involved in this disease and the clinical relevance of these autoimmune responses are still being explored. Our initial discovery assays demonstrated that circulating and intrapulmonary vimentin levels are increased in IPF patients. Subsequent studies showed native vimentin induced HLA-DR-dependent in vitro proliferation of CD4 T cells from IPF patients and enhanced the production of IL-4, IL-17, and TGF-ß1 by these lymphocytes in contrast to normal control specimens. Vimentin supplementation of IPF PBMC cultures also resulted in HLA-DR-dependent production of IgG with anti-vimentin specificities. Circulating anti-vimentin IgG autoantibody levels were much greater in IPF subjects from the University of Alabama at Birmingham (n = 102) and the University of Pittsburgh (U. Pitt., n = 70) than in normal controls. Anti-vimentin autoantibody levels in IPF patients were HLA biased and inversely correlated with physiological measurements of lung function (i.e., forced expiratory volumes and diffusing capacities). Despite considerable intergroup differences in transplant-free survival between these two independent IPF cohorts, serious adverse outcomes were most frequent among the patients within each population that had the highest anti-vimentin autoantibody levels (University of Alabama at Birmingham: hazard ratio 2.5, 95% confidence interval 1.2-5.3, p = 0.012; University of Pittsburgh: hazard ratio 2.7, 95% confidence interval 1.3-5.5, p = 0.006). These data show that anti-vimentin autoreactivity is prevalent in IPF patients and is strongly associated with disease manifestations. These findings have implications with regard to the pathogenesis of this enigmatic disease and raise the possibility that therapies specifically directed at these autoimmune processes could have therapeutic efficacy.

Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis.

BACKGROUND: Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking. METHODS: In our initial double-blind, placebo-controlled trial, we randomly assigned patients who had idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo. The study was interrupted owing to safety concerns associated with the three-drug regimen. The trial continued as a two-group study (acetylcysteine vs. placebo) without other changes; 133 and 131 patients were enrolled in the acetylcysteine and placebo groups, respectively. The primary outcome was the change in forced vital capacity (FVC) over a 60-week period. RESULTS: At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (-0.18 liters and -0.19 liters, respectively; P=0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P=0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P>0.99). CONCLUSIONS: As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00650091.).