Margaret L. Salisbury

Idiopathic Pulmonary Fibrosis: Gender-Age-Physiology Index Stage for Predicting Future Lung Function Decline

BACKGROUND Idiopathic pulmonary fibrosis is a progressive lung disease with variable course. The Gender-Age-Physiology (GAP) Index and staging system uses clinical variables to stage mortality risk. It is unknown whether clinical staging predicts future decline in pulmonary function. We assessed whether the GAP stage predicts future pulmonary function decline and whether interval pulmonary function change predicts mortality after accounting for stage. METHODS Patients with idiopathic pulmonary fibrosis (N = 657) were identified retrospectively at three tertiary referral centers, and baseline GAP stages were assessed. Mixed models were used to describe average trajectories of FVC and diffusing capacity of the lung for carbon monoxide (Dlco). Multivariable Cox proportional hazards models were used to assess whether declines in pulmonary function ≥ 10% in 6 months predict mortality after accounting for GAP stage. RESULTS Over a 2-year period, GAP stage was not associated with differences in yearly lung function decline. After accounting for stage, a 10% decrease in FVC or Dlco over 6 months independently predicted death or transplantation (FVC hazard ratio, 1.37; Dlco hazard ratio, 1.30; both, P ≤ .03). Patients with GAP stage 2 with declining pulmonary function experienced a survival profile similar to patients with GAP stage 3, with 1-year event-free survival of 59.3% (95% CI, 49.4-67.8) vs 56.9% (95% CI, 42.2-69.1). CONCLUSIONS Baseline GAP stage predicted death or lung transplantation but not the rate of future pulmonary function decline. After accounting for GAP stage, a decline of ≥ 10% over 6 months independently predicted death or lung transplantation.

Diagnosis and Treatment of Fibrotic Hypersensitivity Pneumonia. Where We Stand and Where We Need to Go

Diagnosis and Treatment of Fibrotic Hypersensitivity Pneumonia Where We Stand and Where We Need to Go Margaret L. Salisbury, Jeffrey L. Myers, Elizabeth A. Belloli, Ella A. Kazerooni, Fernando J. Martinez, and Kevin R. Flaherty Division of Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pathology, and Department of Radiology, University of Michigan, Ann Arbor, Michigan; and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cornell Medical College, New York, New York

Idiopathic Pulmonary Fibrosis: The Association between the Adaptive Multiple Features Method and Fibrosis Outcomes

Rationale: Adaptive multiple features method (AMFM) lung texture analysis software recognizes high‐resolution computed tomography (HRCT) patterns. Objectives: To evaluate AMFM and visual quantification of HRCT patterns and their relationship with disease progression in idiopathic pulmonary fibrosis. Methods: Patients with idiopathic pulmonary fibrosis in a clinical trial of prednisone, azathioprine, and N‐acetylcysteine underwent HRCT at study start and finish. Proportion of lung occupied by ground glass, ground glass‐reticular (GGR), honeycombing, emphysema, and normal lung densities were measured by AMFM and three radiologists, documenting baseline disease extent and postbaseline change. Disease progression includes composite mortality, hospitalization, and 10% FVC decline. Measurements and Main Results: Agreement between visual and AMFM measurements was moderate for GGR (Pearsons correlation r = 0.60, P < 0.0001; mean difference = −0.03 with 95% limits of agreement of −0.19 to 0.14). Baseline extent of GGR was independently associated with disease progression when adjusting for baseline Gender‐Age‐Physiology stage and smoking status (hazard ratio per 10% visual GGR increase = 1.98, 95% confidence interval [CI] = 1.20‐3.28, P = 0.008; and hazard ratio per 10% AMFM GGR increase = 1.36, 95% CI = 1.01‐1.84, P = 0.04). Postbaseline visual and AMFM GGR trajectories were correlated with postbaseline FVC trajectory (r = −0.30, 95% CI = −0.46 to −0.11, P = 0.002; and r = −0.25, 95% CI = −0.42 to −0.06, P = 0.01, respectively). Conclusions: More extensive baseline visual and AMFM fibrosis (as measured by GGR densities) is independently associated with elevated hazard for disease progression. Postbaseline change in AMFM‐measured and visually measured GGR densities are modestly correlated with change in FVC. AMFM‐measured fibrosis is an automated adjunct to existing prognostic markers and may allow for study enrichment with subjects at increased disease progression risk.

Microbiome in interstitial lung disease: From pathogenesis to treatment target

Purpose of review This review summarizes current knowledge of the role of the lung microbiome in interstitial lung disease and poses considerations of the microbiome as a therapeutic target. Recent findings Although historically considered sterile, bacterial communities have now been well documented in lungs in health and disease. Studies in idiopathic pulmonary fibrosis (IPF) suggest that increased bacterial burden and/or abundance of potentially pathogenic bacteria may drive disease progression, acute exacerbations, and mortality. More recent work has highlighted the interaction between the lung microbiome and the innate immune system in IPF, strengthening the argument for the role of both host and environment interaction in disease pathogenesis. In support of this, studies of interstitial lung diseases other than IPF suggest that it may be the host immune response, which shapes the microbiome in these diseases. Some clinical and mouse model data also suggest that the lung microbiome may represent a therapeutic target, via antibiotic administration, immunization against pathogenic organisms, or treatment directed at gastroesophageal reflux. Summary Evidence suggests that the lung microbiome may serve as a prognostic biomarker, a therapeutic target, or provide an explanation for disease pathogenesis in IPF.

Development and validation of a radiological diagnosis model for hypersensitivity pneumonitis.

High-resolution computed tomography (HRCT) may be useful for diagnosing hypersensitivity pneumonitis. Here, we develop and validate a radiological diagnosis model and model-based points score. Patients with interstitial lung disease seen at the University of Michigan Health System (derivation cohort) or enrolling in the Lung Tissue Research Consortium (validation cohort) were included. A thin-section, inspiratory HRCT scan was required. Thoracic radiologists documented radiological features. The derivation cohort comprised 356 subjects (33.9% hypersensitivity pneumonitis) and the validation cohort comprised 424 subjects (15.5% hypersensitivity pneumonitis). An age-, sex- and smoking status-adjusted logistic regression model identified extent of mosaic attenuation or air trapping greater than that of reticulation (“MA-AT>Reticulation”; OR 6.20, 95% CI 3.53–10.90; p<0.0001) and diffuse axial disease distribution (OR 2.33, 95% CI 1.31–4.16; p=0.004) as hypersensitivity pneumonitis predictors (area under the receiver operating characteristic curve 0.814). A model-based score >2 (1 point for axial distribution, 2 points for “MA-AT>Reticulation”) has specificity 90% and positive predictive value (PPV) 74% in the derivation cohort and specificity 96% and PPV 44% in the validation cohort. Similar model performance is seen with population restriction to those reporting no exposure (score >2: specificity 91%). When radiological mosaic attenuation or air trapping are more extensive than reticulation and disease has diffuse axial distribution, hypersensitivity pneumonitis specificity is high and false diagnosis risk low (<10%), but PPV is diminished in a low-prevalence setting. When HRCT shows more mosaic attenuation than reticulation and diffuse axial ILD, false hypersensitivity pneumonitis diagnosis risk is <10% http://ow.ly/tthG30k3Vj2

Computed Tomographic Biomarkers in Idiopathic Pulmonary Fibrosis: The Future of Quantitative Analysis

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with great variability in disease severity and rate of progression. The need for a reliable, sensitive, and objective biomarker to track disease progression and response to therapy remains a great challenge in IPF clinical trials. Over the past decade, quantitative computed tomography (QCT) has emerged as an area of intensive research to address this need. We have gathered a group of pulmonologists, radiologists and scientists with expertise in this area to define the current status and future promise of this imaging technique in the evaluation and management of IPF. In this Pulmonary Perspective, we review the development and validation of six computer-based QCT methods and offer insight into the optimal use of an imaging-based biomarker as a tool for prognostication, prediction of response to therapy, and potential surrogate endpoint in future therapeutic trials.

Hypersensitivity Pneumonitis: Radiologic Phenotypes are Associated with Distinct Survival Time and Pulmonary Function Trajectory

Background Hypersensitivity pneumonitis (HP) is an interstitial lung disease with a better prognosis, on average, than idiopathic pulmonary fibrosis (IPF). We compare survival time and pulmonary function trajectory in patients with HP and IPF by radiologic phenotype. Methods HP (n = 117) was diagnosed if surgical/transbronchial lung biopsy, BAL, and exposure history results suggested this diagnosis. IPF (n = 152) was clinically and histopathologically diagnosed. All participants had a baseline high‐resolution CT (HRCT) scan and FVC % predicted. Three thoracic radiologists documented radiologic features. Survival time is from HRCT scan to death or lung transplant. Cox proportional hazards models identify variables associated with survival time. Linear mixed models compare post‐HRCT scan FVC % predicted trajectories. Results Subjects were grouped by clinical diagnosis and three mutually exclusive radiologic phenotypes: honeycomb present, non‐honeycomb fibrosis (traction bronchiectasis and reticulation) present, and nonfibrotic. Nonfibrotic HP had the longest event‐free median survival (> 14.73 years) and improving FVC % predicted (1.92%; 95% CI, 0.49‐3.35; P = .009). HP with non‐honeycomb fibrosis had longer survival than IPF (> 7.95 vs 5.20 years), and both groups experienced a significant decline in FVC % predicted. Subjects with HP and IPF with honeycombing had poor survival (2.76 and 2.81 years, respectively) and significant decline in FVC % predicted. Conclusions Three prognostically distinct, radiologically defined phenotypes are identified among patients with HP. The importance of pursuing a specific diagnosis (eg, HP vs IPF) among patients with non‐honeycomb fibrosis is highlighted. When radiologic honeycombing is present, invasive diagnostic testing directed at determining the diagnosis may be of limited value given a uniformly poor prognosis.