Maria Padilla

Case report: Lung disease in World Trade Center responders exposed to dust and smoke: carbon nanotubes found in the lungs of World Trade Center patients and dust samples.

Context After the collapse of the World Trade Center (WTC) on 11 September 2001, a dense cloud of dust containing high levels of airborne pollutants covered Manhattan and parts of Brooklyn, New York. Between 60,000 and 70,000 responders were exposed. Many reported adverse health effects. Case presentation In this report we describe clinical, pathologic, and mineralogic findings in seven previously healthy responders who were exposed to WTC dust on either 11 September or 12 September 2001, who developed severe respiratory impairment or unexplained radiologic findings and underwent video-assisted thoracoscopic surgical lung biopsy procedures at Mount Sinai Medical Center. WTC dust samples were also examined. We found that three of the seven responders had severe or moderate restrictive disease clinically. Histopathology showed interstitial lung disease consistent with small airways disease, bronchiolocentric parenchymal disease, and nonnecrotizing granulomatous condition. Tissue mineralogic analyses showed variable amounts of sheets of aluminum and magnesium silicates, chrysotile asbestos, calcium phosphate, and calcium sulfate. Small shards of glass containing mostly silica and magnesium were also found. Carbon nanotubes (CNT) of various sizes and lengths were noted. CNT were also identified in four of seven WTC dust samples. Discussion These findings confirm the previously reported association between WTC dust exposure and bronchiolar and interstitial lung disease. Long-term monitoring of responders will be needed to elucidate the full extent of this problem. The finding of CNT in both WTC dust and lung tissues is unexpected and requires further study.

Idiopathic pleuroparenchymal fibroelastosis: an unrecognized or misdiagnosed entity?

Idiopathic pleuroparenchymal fibroelastosis is a rare recently described entity likely to be under- and misdiagnosed, as awareness of this entity is not yet widespread. We report two cases that show the need to include this disease in the differential diagnosis of patients with predominantly pleural and subpleural fibrotic processes. The condition is a fibrotic thickening of the pleura and subpleural parenchyma due to elastic fiber proliferation predominantly in the upper lobes. Performing elastic fiber stains routinely in patients with fibrosis of this distribution may, therefore, aid in establishing the diagnosis and differentiating it from usual interstitial pneumonia/idiopathic pulmonary fibrosis. These patients may be prone to the development of secondary spontaneous pneumothoraces and persistent postoperative bronchopleural fistulae. Continued study of newly diagnosed cases may uncover shared characteristics or features helpful in generating an etiologic hypothesis. Only with better understanding of this disease can we hope in the future to be able to offer treatments other than supportive care and ultimately lung transplantation, which are the only therapeutic options available today.

Bosentan for Sarcoidosis-Associated Pulmonary Hypertension: A Double-Blind Placebo Controlled Randomized Trial

BACKGROUND Sarcoidosis-associated pulmonary hypertension (SAPH) is a common problem in patients with persistent dyspneic sarcoidosis. The objective of this study was to determine the effect of bosentan therapy on pulmonary arterial hemodynamics in patients with SAPH. METHODS This 16-week study was a double-blind, placebo-controlled trial of either bosentan or placebo in patients with SAPH confirmed by right-sided heart catheterization. Patients were enrolled from multiple academic centers specializing in sarcoidosis care. They were stable on sarcoidosis therapy and were receiving no therapy for pulmonary hypertension. The cohort was randomized two to one to receive bosentan at a maximal dose of 125 mg or placebo bid for 16 weeks. Pulmonary function studies, 6-min walk test, and right-sided heart hemodynamics, including pulmonary artery mean pressure and pulmonary vascular resistance (PVR), were performed before and after 16 weeks of therapy. RESULTS Thirty-five patients completed 16 weeks of therapy (23 treated with bosentan, 12 with placebo). For those treated with bosentan, repeat hemodynamic studies at 16 weeks demonstrated a significant mean±SD fall in PA mean pressure (-4±6.6 mm Hg, P=.0105) and PVR (-1.7±2.75 Wood units, P=.0104). For the patients treated with placebo, there was no significant change in either PA mean pressure (1±3.7 mm Hg, P>.05) or PVR (0.1±1.42 Wood units, P>.05). There was no significant change in 6-min walk distance for either group. Two patients treated with bosentan required an increase of supplemental oxygen by >2 L after 16 weeks of therapy. CONCLUSIONS This study demonstrated that bosentan significantly improved pulmonary hemodynamics in patients with SAPH. TRIAL REGISTRY ClinicalTrials.gov; No: NCT00581607; URL: www.clinicaltrials.gov.

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.

Original Research: Pulmonary Vascular DiseaseBosentan for Sarcoidosis-Associated Pulmonary Hypertension: A Double-Blind Placebo Controlled Randomized Trial

BACKGROUND Sarcoidosis-associated pulmonary hypertension (SAPH) is a common problem in patients with persistent dyspneic sarcoidosis. The objective of this study was to determine the effect of bosentan therapy on pulmonary arterial hemodynamics in patients with SAPH. METHODS This 16-week study was a double-blind, placebo-controlled trial of either bosentan or placebo in patients with SAPH confirmed by right-sided heart catheterization. Patients were enrolled from multiple academic centers specializing in sarcoidosis care. They were stable on sarcoidosis therapy and were receiving no therapy for pulmonary hypertension. The cohort was randomized two to one to receive bosentan at a maximal dose of 125 mg or placebo bid for 16 weeks. Pulmonary function studies, 6-min walk test, and right-sided heart hemodynamics, including pulmonary artery mean pressure and pulmonary vascular resistance (PVR), were performed before and after 16 weeks of therapy. RESULTS Thirty-five patients completed 16 weeks of therapy (23 treated with bosentan, 12 with placebo). For those treated with bosentan, repeat hemodynamic studies at 16 weeks demonstrated a significant mean±SD fall in PA mean pressure (-4±6.6 mm Hg, P=.0105) and PVR (-1.7±2.75 Wood units, P=.0104). For the patients treated with placebo, there was no significant change in either PA mean pressure (1±3.7 mm Hg, P>.05) or PVR (0.1±1.42 Wood units, P>.05). There was no significant change in 6-min walk distance for either group. Two patients treated with bosentan required an increase of supplemental oxygen by >2 L after 16 weeks of therapy. CONCLUSIONS This study demonstrated that bosentan significantly improved pulmonary hemodynamics in patients with SAPH. TRIAL REGISTRY ClinicalTrials.gov; No: NCT00581607; URL: www.clinicaltrials.gov.

Localized lymphoid nodules of lung. A reappraisal of the lymphoma versus pseudolymphoma dilemma

Eleven patients with localized lymphoid nodules of the lung (LLN) were seen at the Mount Sinai Hospital from 1962–1981. The diagnosis of pseudolymphoma was made in six instances based on the following criteria: (1) solitary or multiple nodules discovered on chest roentgenograms composed of cytologically benign lymphoid cells (small lymphocytes); (2) polymorphic character of the infiltrate, including plasma cells, histiocytes and monocytes; and (3) presence of germinal centers in the lesion. Five lesions were classified as lymphomas and exhibited: (2) solitary or multiple nodules composed of atypical lymphoid cells; (2) absence of germinal centers; (3) lack of mediastinal lymph node involvement. Bronchial and/or pleural infiltration by lymphoid cells was present in lymphomas as well as in pseudolymphomas. Five lesions were studied with immunofluorescent techniques for the presence of intracytoplasmic immunoglobulins and in one pseudolymphoma, lymphocyte marker studies were performed. The procedures were not useful in separating benign from malignant lesions. All patients underwent surgery; three with lymphoma and one with pseudolymphoma received adjuvant chemotherapy. Patients were followed post surgically for up to 13 years. None of the six patients with pseudolymphoma died as a result of their lesions but two had either recurrences or developed extra‐pulmonary lymphoid lesions. All five lymphoma patients did well. Only one died while on chemotherapy with invasive pulmonary aspergillosis but no tumor. One‐hundred and sixty‐seven reported cases from the literature are analyzed. Pulmonary pseudolymphomas do not necessarily follow a benign course and malignant lymphomas limited to the lungs do not usually undergo progressive disease. Present pathologic criteria do not allow prediction of recurrence or progression of disease and are not acceptable for determining the advocacy of chemotherapy in patients with LLN.

Liver and combined lung and liver transplantation for cystic fibrosis: analysis of the UNOS database.

Arnon R, Annunziato RA, Miloh T, Padilla M, Sogawa H, Batemarco L, Willis A, Suchy F, Kerkar N. Liver and combined lung and liver transplantation for cystic fibrosis: Analysis of the UNOS database.
Pediatr Transplantation 2011: 15: 254–264.

Spectrum of Fibrosing Diffuse Parenchymal Lung Disease

The interstitial lung diseases are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the pulmonary interstitium. In 2002, the American Thoracic Society and the European Respiratory Society revised the classification of interstitial lung diseases and introduced the term diffuse parenchymal lung disease. The idiopathic interstitial pneumonias are a subtype of diffuse parenchymal lung disease. The idiopathic interstitial pneumonias are subdivided into usual interstitial pneumonia (with its clinical counterpart idiopathic interstitial pneumonia), nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, and lymphocytic pneumonia. Sarcoidosis and hypersensitivity pneumonitis are the 2 most common granulomatous diffuse parenchymal lung diseases. Rheumatoid arthritis, systemic sclerosis, and dermatomyositis/polymyositis (causing antisynthetase syndrome) are diffuse parenchymal lung diseases of known association because these conditions are associated with connective tissue disease. Hermansky-Pudlak syndrome is a rare genetic diffuse parenchymal lung disease characterized by the clinical triad of pulmonary disease, oculocutaneous albinism, and bleeding diathesis. This review provides an overview of the chronic fibrosing diffuse parenchymal lung diseases. Its primary objective is to illuminate the clinical challenges encountered by clinicians who manage the diffuse parenchymal lung diseases regularly and to offer potential solutions to those challenges. Treatment for the diffuse parenchymal lung diseases is limited, and for many patients with end-stage disease, lung transplantation remains the best option. Although much has been learned about the diffuse parenchymal lung diseases during the past decade, research in these diseases is urgently needed.

Clinical Utility of Combined FDG-PET/MR to Assess Myocardial Disease

The assessment of both the pattern and activity of myocardial injury has important implications for the clinical management of patients with cardiovascular disease. Comprehensive evaluation of these has previously been challenging using a single imaging modality. Cardiac magnetic resonance (CMR)

Potential for diffuse parenchymal lung disease after exposures at World Trade Center Disaster site

OBJECTIVE The diffuse parenchymal lung diseases (DPLDs) are a heterogeneous group of disorders that result from damage to the lung parenchyma. While the cause of most DPLDs remains unknown, extensive epidemiological and experimental evidence has linked exposure to environmental toxins to the pathogenesis of some of those diseases. The purpose of this review is to examine the potential relation between exposure to toxins released from the World Trade Center (WTC) collapse on September 11th, 2001 and the development of DPLD based on published evidence up to date. METHODS We examine such evidence from two points of view, (1) exposure, and (2) histopathogenesis. EXPOSURE Analyses of WTC-dust and particle size demonstrate that some portion of the dust was composed of particles small enough to penetrate deep into the lungs, reaching distal airways and alveoli. The presence of such particles has been confirmed in studies of induced sputum and bronchoalveolar lavage in WTC-exposed firefighters. Histopathogenesis: In vitro and animal experiments and patient evidence suggest that WTC dust is capable of inducing a pulmonary interstitial inflammatory response. RESULTS To date, there have been limited clinical reports documenting the development of diffuse parenchymal responses following exposure to WTC dust. No single common pathologic response has been described. The one common denominator in the reports is that the individuals who developed disease were heavily exposed either during the disaster or during the initial 2-to-3 days following the disaster. CONCLUSION DLPDs are probably associated with heavy or extended exposure to the toxins released at the WTC disaster site. Coupled with the historical experience with exposures to occupational toxins this mandates continued long-term clinical observation of this cohort.