William Sexauer

Design of A Case Control Etiologic Study of Sarcoidosis (ACCESS)

Sarcoidosis is a chronic granulomatous disorder of unknown cause, characterized by activation of T-lymphocytes and macrophages. A Case Control Etiologic Study of Sarcoidosis (ACCESS) is a multicenter study designed to determine the etiology of sarcoidosis. The study organization includes 10 Clinical Centers, a Clinical Coordinating Center, specialized Core Laboratories, a Central Specimen Repository, and a Project Office at the National Heart, Lung, and Blood Institute. In addition to etiology, ACCESS will examine the socioeconomic status and clinical course of patients with sarcoidosis. We propose to enroll 720 newly diagnosed cases of sarcoidosis and compare them to 720 age, sex, and race matched controls and follow the first 240 cases for two years. Leads to the etiology of sarcoidosis have come from diverse sources: in clinical laboratory investigations, alveolitis has been found to precede granulomatous inflammation; in case control studies, familial aggregation has been identified; and in case reports, recurrence of granulomatous inflammation has been observed after lung transplantation. We describe the rationale for the study design based on genetic, environmental, infectious, and immune dysregulation hypotheses and the methods used for selecting controls. The cause may not prove to be a single, known exposure. Interactions of exposures with genetic predispositions would have important implications for our understanding of immune responses as well as the pathogenesis of sarcoidosis.

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.

Vitamin D deficiency is associated with pulmonary dysfunction in cystic fibrosis

BACKGROUND Vitamin D deficiency is common in CF. Whether vitamin D affects pulmonary function in CF is unknown. METHODS Data were abstracted from clinically stable CF patients who had pulmonary function studies and serum 25-hydroxyvitamin D [25(OH)D, ng/ml] levels drawn within 2 months of each other. Findings were adjusted for multiple variables known to affect pulmonary function in CF. RESULTS Enrollees totaled 597. Overall mean 25(OH)D level was 29.6±12.8 ng/ml (SD). Serum 25(OH)D levels showed a significant correlation with forced expiratory volume in 1s (FEV1) % predicted (r=0.20, p<0.0001) and forced vital capacity % predicted (r=0.13, p=0.0019). Multivariate analysis revealed that serum 25(OH)D remained an independent predictor of FEV1 % predicted even after controlling for multiple other factors known to affect CF lung function. CONCLUSIONS Serum 25(OH)D levels are significantly associated with pulmonary function in CF. Further study is required to determine whether this association is causal.

Readmissions After Hospital Discharge With Acute Exacerbation of COPD: Are We Missing Something?

Abstract Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an important part of the diseases morbidity, mortality, and progression, and is associated with increasing utilization of health care resources. The concept of integrated care based on a chronic care model is relatively new to chronic obstructive pulmonary disease, but has proved successful in improving clinical outcomes and probably in decreasing health care utilization in other chronic conditions. A comprehensive approach is needed to target a change in behavioral patterns in patients, increase physicians awareness and adherence to evidence-based recommendations, and address system related issues. This article discusses the evidence for various facets of nonpharmacological management of AECOPD and proposes a model of care that might be the missing link for reducing hospital readmissions for AECOPD. This model may decrease the morbidity, slow disease progression, and curb the increasing health care resource utilization without compromising patient care.

New treatment modalities for cystic fibrosis.

Refinements in standard therapy for cystic fibrosis have led to dramatic increases in survival and quality of life over the past three decades. Standard therapy has consisted of oral and intravenous antibiotics, chest percussion with postural drainage, and aerosol bronchodilator therapy. The discovery of the cystic fibrosis gene and elucidation of the underlying biochemical defect have broadened our understanding of the pathophysiology of cystic fibrosis and provided a rationale for many new and innovative therapies. Modulation of airway epithelial ion transport may improve mucociliary clearance and delay colonization by infective organisms. Anti-inflammatory therapy may decrease lung injury that results from the hosts attempt to limit airway infection. Supplementation of airway antiproteases may limit the destructive effects of unopposed proteases on pulmonary architecture. Genetic biotechnology has already produced agents that preserve pulmonary function and decrease infectious exacerbations by altering the viscoelastic properties of sputum from patients with cystic fibrosis. Both active and passive immunotherapy are currently being investigated as a measure to delay or combat endobronchial infection with Pseudomonas spp. Aerosolized aminoglycoside antibiotics are being increasingly employed to control pulmonary infection while minimizing systemic toxicity. These treatment modalities, combined with the prospects for gene therapy, provide a brighter outlook for the patient with cystic fibrosis than ever before.