Elizabeth A. Belloli

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

Longitudinal forced vital capacity monitoring as a prognostic adjunct after lung transplantation

RATIONALE After lung transplantation, spirometric values are routinely followed to assess graft function. FEV1 is used to characterize chronic allograft dysfunction, whereas the course of FVC change has been less acknowledged and rarely used. OBJECTIVES To better understand the temporal relationship and prognostic ability of FEV1 and FVC decline after lung transplantation. METHODS Serial FEV1 and FVC values were studied among 205 bilateral lung transplant recipients. Different decline patterns were characterized and evaluated for prognostic value via restricted mean modeling of mortality and times to other pertinent events. MEASUREMENTS AND MAIN RESULTS Baseline FEV1 was achieved earlier than baseline FVC (median, 296 vs. 378 d; P < 0.0001). Decline in FEV1 or FVC from their respective post-transplant baselines occurred in 85 patients (41%). Fifty-nine of 85 (69%) had an isolated FEV1 decline, with 80% later meeting the FVC decline criterion. This subsequent FVC decline was associated with worsening FEV1 and lower median survival. Twenty-five of 85 patients (29%) demonstrated concurrent FEV1 and FVC decline. Patients with concurrent decline had higher 1- and 5-year mortality rates (1-yr, 53% vs. 18%, P < 0.0001; 5-yr, 61% vs. 48%, P = 0.001). These patients were more likely to have rapid-onset of spirometry decline (P = 0.05) and lower FEV1% predicted (P = 0.04) at presentation. CONCLUSIONS FVC decline from its post-transplant baseline provides valuable prognostic information. Concurrent FEV1 and FVC decline identifies patients with fulminant, rapid deterioration and is the strongest clinical predictor of poor survival. Subsequent FVC decline in patients with an initial isolated FEV1 decline identifies disease progression and portends poor prognosis.

Parametric Response Mapping as an Imaging Biomarker in Lung Transplant Recipients

Rationale: The predominant cause of chronic lung allograft failure is small airway obstruction arising from bronchiolitis obliterans. However, clinical methodologies for evaluating presence and degree of small airway disease are lacking. Objectives: To determine if parametric response mapping (PRM), a novel computed tomography voxel‐wise methodology, can offer insight into chronic allograft failure phenotypes and provide prognostic information following spirometric decline. Methods: PRM‐based computed tomography metrics quantifying functional small airways disease (PRMfSAD) and parenchymal disease (PRMPD) were compared between bilateral lung transplant recipients with irreversible spirometric decline and control subjects matched by time post‐transplant (n = 22). PRMfSAD at spirometric decline was evaluated as a prognostic marker for mortality in a cohort study via multivariable restricted mean models (n = 52). Measurements and Main Results: Patients presenting with an isolated decline in FEV1 (FEV1 First) had significantly higher PRMfSAD than control subjects (28% vs. 15%; P = 0.005), whereas patients with concurrent decline in FEV1 and FVC had significantly higher PRMPD than control subjects (39% vs. 20%; P = 0.02). Over 8.3 years of follow‐up, FEV1 First patients with PRMfSAD greater than or equal to 30% at spirometric decline lived on average 2.6 years less than those with PRMfSAD less than 30% (P = 0.004). In this group, PRMfSAD greater than or equal to 30% was the strongest predictor of survival in a multivariable model including bronchiolitis obliterans syndrome grade and baseline FEV1% predicted (P = 0.04). Conclusions: PRM is a novel imaging tool for lung transplant recipients presenting with spirometric decline. Quantifying underlying small airway obstruction via PRMfSAD helps further stratify the risk of death in patients with diverse spirometric decline patterns.

Mechanistic Target of Rapamycin Complex 1 (mTORC1) and mTORC2 as Key Signaling Intermediates in Mesenchymal Cell Activation

Fibrotic diseases display mesenchymal cell (MC) activation with pathologic deposition of matrix proteins such as collagen. Here we investigate the role of mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived from fibrotic human lung allografts (Fib-MCs) demonstrated increased phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2, as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates) and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited 4E-BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs, increased mTORC1 signaling was shown to augment collagen I expression. mTORC1/4E-BP1 pathway was identified as an important driver of collagen I expression in Fib-MCs in experiments utilizing raptor gene silencing and overexpression of dominant-inhibitory 4E-BP1. Furthermore, siRNA-mediated knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together these studies suggest a novel paradigm where fibrotic activation in MCs increases PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I expression via the mTORC1-dependent 4E-BP1/eIF4E pathway. These data provide rationale for targeting specific components of mTORC pathways in fibrotic states and underscore the need to further delineate mTORC2 signaling in activated cell states.

Idiopathic non‐specific interstitial pneumonia

Non‐specific interstitial pneumonia (NSIP) is an interstitial lung disease that may be idiopathic or secondary to connective tissue disease, toxins or numerous other causes. Idiopathic NSIP is a rare diagnosis and requires exclusion of these other possible causes. Patients typically present in mid‐adulthood with dyspnoea, cough and often constitutional symptoms including fever and fatigue. The disease has a female predominance, and more than 50% of patients have never smoked. Physical exam features mild hypoxaemia and inspiratory rales. Pulmonary function tests demonstrate restriction and a low diffusing capacity for carbon monoxide. High‐resolution computed tomography abnormalities include predominantly lower lobe subpleural reticular changes, traction bronchiectasis and ground‐glass opacities; honeycombing is rarely seen. An evaluation of the underlying pathology is necessary for a firm diagnosis. Histologically, alveolar and interstitial mononuclear cell inflammation and fibrosis are seen in a temporally uniform pattern with preserved underlying alveolar architecture. NSIP must be differentiated from other parenchymal lung diseases including idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. A thorough exposure history and assessment for underlying connective tissue diseases are highly important, as positive findings in these categories would likely denote a case of secondary NSIP. A multi‐disciplinary discussion that includes pulmonologist(s), radiologist(s) and pathologist(s) assists in reaching a consensus diagnosis and improves diagnostic accuracy. Treatment of idiopathic NSIP, although not well proven, is generally instituted in the form of immunosuppression. Prognosis is favourable compared with idiopathic pulmonary fibrosis, although the diagnosis still carries an attributable mortality. Herein we will summarize the clinical characteristics and management of idiopathic NSIP.

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

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.