Utility of a Molecular Classifier as a Complement to High-Resolution Computed Tomography to Identify Usual Interstitial Pneumonia.

Rationale: Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A "molecular diagnosis of UIP" in transbronchial lung biopsy, the Envisia Genomic Classifier, accurately predicted histopathologic UIP.Objectives: We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern.Methods: Ninety-six patients who had diagnostic lung pathology as well as a transbronchial lung biopsy for molecular testing with Envisia Genomic Classifier were included in this analysis. The classifier results were scored against reference pathology. UIP identified on high-resolution computed tomography (HRCT) as documented by features in local radiologists' reports was compared with histopathology.Measurements and Main Results: In 96 patients, the Envisia Classifier achieved a specificity of 92.1% (confidence interval [CI],78.6-98.3%) and a sensitivity of 60.3% (CI, 46.6-73.0%) for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology, with a sensitivity of 34.0% (CI, 21.5-48.3%) and a specificity of 96.9% (CI, 83.8-100%). In conjunction with HRCT patterns of UIP, the Envisia Classifier results identified 24 additional patients with UIP (sensitivity 79.2%; specificity 90.6%).Conclusions: In 96 patients with suspected interstitial lung disease, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an interstitial lung disease (especially IPF) diagnosis without the need for a surgical lung biopsy.

Risk of progression of interstitial pneumonia with autoimmune features to a systemic autoimmune rheumatic disease.

OBJECTIVE: The aim of this study was to determine the risk of developing a systemic autoimmune rheumatic disease (ARD) after an initial diagnosis of interstitial pneumonia with autoimmune features (IPAF). METHODS: We performed a retrospective cohort study of patients with interstitial lung disease (ILD) who were evaluated at Columbia University Irving Medical Center from 2009 to 2017. We divided patients with idiopathic ILD into two groups: those who met IPAF criteria and those who did not meet IPAF criteria at initial ILD diagnosis. We examined the association between IPAF and diagnosis of ARD during the follow-up period using a multivariable-adjusted logistic regression model. RESULTS: Of the 697 patients with ILD who were screened, 174 met inclusion criteria (50 met IPAF criteria and 124 did not). During a median follow-up period of 5.2 years, 16% (8/50) of subjects with IPAF were diagnosed with an ARD compared with 1.6% (2/124) of subjects without IPAF (P = 0.001). Adjusting for age, sex, smoking status and use of immunosuppressive therapy, the odds of progressing to an ARD were 14 times higher in subjects with IPAF than in those without IPAF (odds ratio 14.18, 95% CI 1.44-138.95, P = 0.02). CONCLUSION: The presence of IPAF confers an increased risk of developing an ARD. Patients with IPAF should therefore be followed closely for the development of an ARD.

Favorable response to asthma-dosed subcutaneous mepolizumab in eosinophilic pneumonia.

Introduction: Mepolizumab targets eosinophils in the treatment of asthma. The dose used for asthma is considerably lower than that used for treating eosinophilic granulomatosis with polyangiitis, a recently approved indication. While intravenous mepolizumab use has reported utility in non-asthma eosinophilic disorders, the efficacy of the subcutaneous asthma dosing of the drug for eosinophilic pneumonia is not known. Case study: A middle-aged female was diagnosed with eosinophilic pneumonia. The patient's clinical/radiologic/laboratory findings, response to treatment, and respiratory function studies are described. Results: A woman, born in 1962, had repeated pneumonia hospitalizations from 2007 through 2010. In October 2010, a lung biopsy showed findings consistent with chronic eosinophilic pneumonia and chronic asthma. The patient also had chronic sinusitis. Long term systemic corticosteroids were prescribed but the patient became oxygen dependent by 2014. Omalizumab was administered for 1 year starting in 2015 without improvement in symptoms. In 2016, mepolizumab 100 mg subcutaneously every 4 weeks was initiated. Symptomatic improvement with decreased oxygen and systemic corticosteroid requirements were noted. A chest CT performed in February 2018 showed marked improvement compared to a study in 2016. Interval spirometric improvements were noted. Peripheral blood eosinophils/mm3 prior to mepolizumab were 237, and while on mepolizumab were 10. Conclusion: Parenchymal eosinophilic lung disease may respond to asthma-dosed mepolizumab. Mepolizumab treatment in asthma where concomitant interstitial disease is suspected, may offer an advantage over omalizumab in the ability to reduce eosinophils not only in airways, but also in lung parenchyma.

Pulmonary arteriole gene expression signature in idiopathic pulmonary fibrosis.

A third of patients with idiopathic pulmonary fibrosis (IPF) develop pulmonary hypertension (PH-IPF), which is associated with increased mortality. Whether an altered gene expression profile in the pulmonary vasculature precedes the clinical onset of PH-IPF is unknown. We compared gene expression in the pulmonary vasculature of IPF patients with and without PH with controls. Pulmonary arterioles were isolated using laser capture microdissection from 16 IPF patients: eight with PH (PH-IPF) and eight with no PH (NPH-IPF), and seven controls. Probe was prepared from extracted RNA, and hybridised to Affymetrix Hu133 2.0 Plus genechips. Biometric Research Branch array tools and Ingenuity Pathway Analysis software were used for analysis of the microarray data. Univariate analysis revealed 255 genes that distinguished IPF arterioles from controls (p<0.001). Mediators of vascular smooth muscle and endothelial cell proliferation, Wnt signalling and apoptosis were differentially expressed in IPF arterioles. Unsupervised and supervised clustering analyses revealed similar gene expression in PH-IPF and NPH-IPF arterioles. The pulmonary arteriolar gene expression profile is similar in IPF patients with and without coexistent PH. Pathways involved in vascular proliferation and aberrant apoptosis, which may contribute to pulmonary vascular remodelling, are activated in IPF patients.

Clinical characteristics associated with small airways disease in systemic sclerosis.

Objective: Pulmonary manifestations of systemic sclerosis are a major cause of morbidity and mortality. Small airways disease can cause dyspnea and pulmonary function test abnormalities. We aimed to determine the prevalence of small airways disease and describe the characteristics associated with small airways disease in a cohort of systemic sclerosis patients. Methods: We performed a retrospective cohort study of adults with systemic sclerosis who met American College of Rheumatology/European League Against Rheumatism 2013 classification criteria and were evaluated at our institution between November 2000 and November 2015. Patients with prior lung transplantation were excluded. Small airways disease was defined as the presence of one or more of the following: airway-centered fibrosis on surgical lung biopsy, forced expiratory volume at 25-75% ⩽ 50% on pulmonary function tests, and/or high-resolution computed tomography scan of the chest with bronchiolitis, mosaic attenuation, or air trapping on expiratory views. The primary outcome was small airways disease diagnosis. We performed multivariable logistic regression to determine the association of clinical variables with small airways disease. Results: One-hundred thirty-six systemic sclerosis patients were included; 55 (40%) had small airways disease. Compared to those without small airways disease, a significantly greater proportion of those with small airways disease had interstitial lung disease, chronic obstructive pulmonary disease, pulmonary hypertension, and gastroesophageal reflux disease. On multivariable analysis, pulmonary hypertension (odds ratio = 2.91, 95% confidence interval = 1.11-7.65, p-value = 0.03), gastroesophageal reflux disease (odds ratio = 2.70, 95% confidence interval = 1.08-6.79, p-value = 0.034), and anti-topoisomerase I (anti-Scl-70) antibody positivity (odds ratio = 0.42, 95% confidence interval = 0.19-0.93, p-value = 0.033) were associated with diagnosis of small airways disease. Conclusion: Small airways disease is prevalent among systemic sclerosis patients; those with pulmonary hypertension or gastroesophageal reflux disease may have a higher risk of small airways disease.

Cough-Specific Quality of Life Predicts Disease Progression Among Patients With Interstitial Lung Disease: Data From the Pulmonary Fibrosis Foundation Patient Registry.

BACKGROUND: Cough is a common symptom of interstitial lung disease (ILD) and negatively impacts health-related quality of life (QOL). Previous studies have shown that among patients with idiopathic pulmonary fibrosis, cough may predict progression of lung disease and perhaps even respiratory hospitalizations and mortality. RESEARCH QUESTION: Does cough-specific QOL predict disease progression, respiratory hospitalization, lung transplantation, and death among patients with ILD? STUDY DESIGN AND METHODS: We analyzed data from the Pulmonary Fibrosis Foundation Registry, which comprises a multicenter population of well-characterized patients with ILD. We first examined associations between patient factors and baseline scores on the Leicester Cough Questionnaire (LCQ), a cough-specific QOL tool, using a proportional odds model. Next, we examined associations between baseline LCQ scores and patient-centered clinical outcomes, as well as pulmonary function parameters, using a univariable and multivariable proportional hazards model that was adjusted for clinically relevant variables, including measures of disease severity. RESULTS: One thousand four hundred forty-seven patients with ILD were included in our study. In the multivariable proportional odds model, we found that the following patient factors were associated with worse cough-specific QOL: younger age, diagnosis of "other ILD," gastroesophageal reflux disease, and lower FVC % predicted. Multivariable Cox regression models, adjusting for several variables including baseline disease severity, showed that a 1-point decrease in LCQ score (indicating lower cough-specific QOL) was associated with a 6.5% higher risk of respiratory-related hospitalization (hazard ratio [HR], 1.065; 95% CI, 1.025-1.107), a 7.4% higher risk of death (HR, 1.074; 95% CI, 1.020-1.130), and an 8.7% higher risk of lung transplantation (HR, 1.087; 95% CI, 1.022-1.156). INTERPRETATION: Among a large population of well-characterized patients with ILD, cough-specific QOL was associated independently with respiratory hospitalization, death, and lung transplantation.

Nuclear import of serum response factor in airway smooth muscle.

We have previously shown that the transcription-promoting activity of serum response factor (SRF) is partially regulated by its extranuclear redistribution. In this study, we examined the cellular mechanisms that facilitate SRF nuclear entry in canine tracheal smooth muscle cells. We used in vitro pull-down assays to determine which karyopherin proteins bound SRF and found that SRF binds KPNA1 and KPNB1 through its nuclear localization sequence. Immunoprecipitation studies also demonstrated direct SRF-KPNA1 interaction in HEK293 cells. Import assays demonstrated that KPNA1 and KPNB1 together were sufficient to mediate rapid nuclear import of SRF-GFP. Our studies also suggest that SRF is able to gain nuclear entry through an auxiliary, nuclear localization sequence-independent mechanism.

Management and support of patients with fibrosing interstitial lung diseases.

ABSTRACT: Fibrosing interstitial lung diseases have a variable clinical course. Regular monitoring is important to assess disease progression and inform patient care and counseling. NPs play a key role in helping patients understand their disease and its treatment and manage the adverse reactions of pharmacologic therapies.

Forty Postmortem Examinations in COVID-19 Patients.

OBJECTIVES: Although diffuse alveolar damage, a subtype of acute lung injury (ALI), is the most common microscopic pattern in coronavirus disease 2019 (COVID-19), other pathologic patterns have been described. The aim of the study was to review autopsies from COVID-19 decedents to evaluate the spectrum of pathology and correlate the results with clinical, laboratory, and radiologic findings. METHODS: A comprehensive and quantitative review from 40 postmortem examinations was performed. The microscopic patterns were categorized as follows: "major" when present in more than 50% of cases and "novel" if rarely or not previously described and unexpected clinically. RESULTS: Three major pulmonary patterns were identified: ALI in 29 (73%) of 40, intravascular fibrin or platelet-rich aggregates (IFPAs) in 36 (90%) of 40, and vascular congestion and hemangiomatosis-like change (VCHL) in 20 (50%) of 40. The absence of ALI (non-ALI) was novel and seen in 11 (27%) of 40. Compared with ALI decedents, those with non-ALI had a shorter hospitalization course (P = .02), chest radiographs with no or minimal consolidation (P = .01), and no pathologically confirmed cause of death (9/11). All non-ALI had VCHL and IFPAs, and clinically most had cardiac arrest. CONCLUSIONS: Two distinct pulmonary phenotypic patterns-ALI and non-ALI-were noted. Non-ALI represents a rarely described phenotype. The cause of death in non-ALI is most likely COVID-19 related but requires additional corroboration.

Interstitial Lung Disease in Systemic Sclerosis: Focus on Early Detection and Intervention.

Systemic sclerosis (SSc) is a progressive and often devastating disease characterized by autoimmune dysfunction, vasculopathy, and fibrosis. Interstitial lung disease (ILD) is identified in the majority of patients with SSc and is the leading cause of SSc-related mortality. Although clinical manifestations and ILD severity vary among patients, lung function typically declines to the greatest extent during the first 3-4 years after disease onset. We aim to provide an overview of SSc-associated ILD (SSc-ILD) with a focus on current and emerging tools for early diagnosis of ILD and current and novel treatments under investigation. Early detection of ILD provides the opportunity for early therapeutic intervention, which could improve patient outcomes. Thoracic high-resolution computed tomography is the most effective method of identifying ILD in patients with SSc; it enables detection of mild lung abnormalities and plays an important role in monitoring disease progression. Cyclophosphamide and mycophenolate mofetil are the most commonly prescribed treatments for SSc-ILD. Recently, nintedanib (an antifibrotic) was approved by the Food and Drug Administration for patients with SSc-ILD; it is indicated for slowing the rate of decline in pulmonary function. However, there is a need for additional effective and well-tolerated disease-modifying therapy. Ongoing studies are evaluating other antifibrotics and novel agents. We envision that early detection of lung involvement, combined with the emergence and integration of novel therapies, will lead to improved outcomes in patients with SSc-ILD.

Outcomes and Mortality Prediction Model of Critically Ill Adults With Acute Respiratory Failure and Interstitial Lung Disease.

BACKGROUND: We aimed to examine short- and long-term mortality in a mixed population of patients with interstitial lung disease (ILD) with acute respiratory failure, and to identify those at lower vs higher risk of in-hospital death. METHODS: We conducted a single-center retrospective cohort study of 126 consecutive adults with ILD admitted to an ICU for respiratory failure at a tertiary care hospital between 2010 and 2014 and who did not undergo lung transplantation during their hospitalization. We examined associations of ICU-day 1 characteristics with in-hospital and 1-year mortality, using Poisson regression, and examined survival using Kaplan-Meier curves. We created a risk score for in-hospital mortality, using a model developed with penalized regression. RESULTS: In-hospital mortality was 66%, and 1-year mortality was 80%. Those with connective tissue disease-related ILD had better short-term and long-term mortality compared with unclassifiable ILD (adjusted relative risk, 0.6; 95% CI, 0.3-0.9; and relative risk, 0.6; 95% CI, 0.4-0.9, respectively). Our prediction model includes male sex, interstitial pulmonary fibrosis diagnosis, use of invasive mechanical ventilation and/or extracorporeal life support, no ambulation within 24 h of ICU admission, BMI, and Simplified Acute Physiology Score-II. The optimism-corrected C-statistic was 0.73, and model calibration was excellent (P = .99). In-hospital mortality rates for the low-, moderate-, and high-risk groups were 33%, 65%, and 96%, respectively. CONCLUSIONS: We created a risk score that classifies patients with ILD with acute respiratory failure from low to high risk for in-hospital mortality. The score could aid providers in counseling these patients and their families.

Pulmonary hypertension in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an untreatable diffuse parenchymal lung disease with a median survival of < 3 years. Pulmonary hypertension (PH) is frequently seen in patients with IPF and is commonly attributed to hypoxic vasoconstriction and capillary destruction. Pathology findings include endothelial proliferation and medial hypertrophy that exceed those expected in the setting of hypoxia. Noninvasive evaluation has limited sensitivity and specificity for the diagnosis of PH in IPF; therefore, right-heart catheterization remains the "gold standard" diagnostic test. PH in patients with IPF is associated with decreased exercise capacity and worse survival. Given the grave consequences of this condition, treatment of PH could improve functional outcomes and survival. However, possible treatments such as long-term supplemental oxygen and targeted vascular therapy are either unstudied or remain unproven.

Conventional transbronchial needle aspiration decreases the rate of surgical sampling of intrathoracic lymphadenopathy.

BACKGROUND: Previous studies have suggested a decreased need for the surgical biopsy of intrathoracic lymph nodes (LNs) due to improved diagnostic rates utilizing transbronchial needle aspiration (TBNA) with endobronchial ultrasound and endoscopic ultrasound. The goal of this study was to determine whether conventional TBNA using combined cytologic and histologic analysis of tissue specimens impacted the rates of surgical diagnostic biopsies of patients with intrathoracic lymphadenopathy. METHODS: Retrospective review at a single academic center. All mediastinal and hilar tissue samples submitted for pathologic analysis over an 8.4-year period were analyzed. Patients were categorized into a "before" group and an "after" group based on two different time periods. The before group underwent only cytologic analysis of Wang needle (19-gauge or 21-gauge) aspirates. The after group had cytologic analysis of aspirates as well as histologic analysis of needle "core" (19 gauge) biopsy specimens. The groups were compared for the rate of intrathoracic LNs sampled by surgical means vs TBNA and the number of times that TBNA averted the need for a surgical diagnostic procedure. RESULTS: The success of TBNA increased significantly in the after group compared to that in the before group. The yield for the successful sampling of mediastinal and hilar LNs increased from 53 to 91% (p < 0.001) in the before group vs the after group. TBNA averted a surgical biopsy in 35% of the before cases compared to 66% of the after cases (p < 0.001). CONCLUSIONS: Conventional TBNA using large-bore needles with both cytology and surgical pathology evaluation decreases the need for surgical sampling of the mediastinum to diagnose thoracic lymphadenopathy.

Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21.

Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.