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Biomedical subjects

Kevin R Flaherty

Publications and source records attributed to Kevin R Flaherty.

At least 19 recordsLinked to original sources
PubMed2006

Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test.

RATIONALE AND HYPOTHESIS: Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide. METHODS: One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation < or = 88% during a baseline 6MWT. For patients with a baseline saturation < or = 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation > 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients. CONCLUSION: These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables.

Aged↗
PubMed2006

Nonspecific interstitial pneumonia.

Nonspecific interstitial pneumonia (NSIP) describes a histopathologic pattern that can be seen in patients with immunodeficiency, drug or environmental exposures, and connective tissue diseases. The clinical diagnosis of NSIP, however, should be reserved for idiopathic cases in which no causative factor is identified. Patients typically present with cough, dyspnea, restrictive pulmonary physiology with decreased gas transfer, and ground-glass infiltrates on high-resolution computed tomography (HRCT). Response to immunosuppressive therapy is often successful; however, patients with progressive disease are at increased risk of subsequent mortality and should be considered for alternative treatment strategies such as lung transplantation.

Humans↗
PubMed2006

Thoracic lymph node enlargement in usual interstitial pneumonitis and nonspecific-interstitial pneumonitis: prevalence, correlation with disease activity and temporal evolution.

PURPOSE: To evaluate the prevalence of thoracic lymph node enlargement (LNE) in usual (UIP) and nonspecific (NSIP) interstitial pneumonitis, change in LNE over time, and if LNE is related to disease activity. METHODS AND MATERIALS: High-resolution CT scans (HRCT) in 20 patients each with UIP and NSIP were retrospectively reviewed. Two HRCT scans were reviewed for each patient, at diagnosis and a mean of 1 +/- 0.7 years later. Two thoracic radiologists independently recorded the location and size of thoracic lymph nodes (LNs) > 10-mm in short-axis diameter, using the American Thoracic Society lymph node mapping scheme. HRCT disease severity was scored for ground glass opacity and fibrosis. The number and size of enlarged LN stations were compared with HRCT scores. RESULTS: LNE was found on 44 HRCT examinations (21 baseline prevalence 52.5%, 23 follow-up, prevalence 57.5%), most common in the low right paratracheal (38%) and subcarinal (36%) regions. There was no significant difference in LN size or number of enlarged LN stations between baseline and follow-up CT. LNE prevalence was not different on baseline CT (P = 0.34) follow-up CT (P = 0.11) between UIP and NSIP patients. The mean size of the largest enlarged LN was 1.36 cm (1 to 2.1 cm) at baseline and 1.43 cm (1 to 1.9 cm) on follow-up CT. Mean CT ground glass and fibrosis scores were 1.98 and 1.6 when LNE was present, and 1.34 and 1.03 when absent (P = 0.008 and 0.003, respectively). The number and maximum size of enlarged LNs did not correlate with CT ground glass or fibrosis scores. Five patients who developed LNE between baseline and follow-up CT examinations had a greater increase in CT fibrosis scores than patients whose LNE status did not change (P = 0.004); CT ground glass scores were not significantly different. There was a trend for UIP patients to progress from absence of LNE to presence of LNE (4/20 patients or 20%). CONCLUSIONS: Intrathoracic LNE is common in both UIP and NSIP, and becomes increasingly prevalent in UIP patients over time. LNE is more prevalent with more severe lung disease. An increase in LNE over time is associated with the progression of fibrosis, and should not raise concern for co-existing infection or malignancy, in the absence of other clinical findings that would suggest this.

Adult↗
PubMed2005

Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10).

RATIONALE: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (IPF). Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents. OBJECTIVE: To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity in vivo, and to identify a potential mechanism by which this occurs. METHODS: We used tissue sections of surgical lung biopsies from patients with IPF to localize expression of PTEN and alpha-smooth muscle actin (alpha-SMA). We used cell culture of pten(-/-) and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which PTEN inhibits alpha-SMA, fibroblast proliferation, and collagen production. RESULTS: In human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished PTEN expression. Furthermore, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten(-/-) fibroblasts, and in normal fibroblasts in which PTEN was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not pten(-/-) cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten(-/-) cells, reconstitution of PTEN decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of PTEN were capable of modulating the myofibroblast phenotype. CONCLUSIONS: The results indicate that in IPF, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro.

Actins↗
PubMed2005

The clinical course of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Prospective data defining the clinical course in idiopathic pulmonary fibrosis (IPF) are sparse. OBJECTIVE: To analyze the clinical course of patients with mild to moderate IPF. DESIGN: Analysis of data from the placebo group of a randomized, controlled trial evaluating interferon-gamma1b. SETTING: Academic and community medical centers. PATIENTS: 168 patients in the placebo group of a trial evaluating interferon-gamma1b. MEASUREMENTS: Measures of physiology and dyspnea assessed at 12-week intervals; hospitalizations; and the pace of deterioration and cause of death over a median period of 76 weeks. RESULTS: Physiologic variables changed minimally during the study. However, 23% of patients required hospitalization for a respiratory disorder and 21% died. Idiopathic pulmonary fibrosis was the primary cause of death in 89% of patients who died, and an apparent acute clinical deterioration preceded death in 47% of these patients. LIMITATIONS: The instrument used to define the pace of deterioration and cause of death was applied retrospectively. CONCLUSIONS: Recognition of the common occurrence of acute fatal deterioration in patients with mild to moderate IPF has important implications for monitoring patients and supports early referral for lung transplantation.

Aged↗
PubMed2005

Prognostic value of bronchiolitis obliterans syndrome stage 0-p in single-lung transplant recipients.

RATIONALE: Early diagnosis of bronchiolitis obliterans syndrome (BOS) is critical in understanding pathogenesis and devising therapeutic trials. Although potential-BOS stage (BOS 0-p), encompassing early changes in FEV(1) and forced expiratory flow, midexpiratory phase (FEF(25-75%)), has been proposed, there is a paucity of data validating its utility in single-lung transplantation. OBJECTIVE: The aim of this study was to define the predictive ability of BOS 0-p in single-lung transplantation. METHODS: We retrospectively analyzed spirometric data for 197 single-lung recipients. Sensitivity, specificity, and positive predictive value of BOS 0-p were examined over time using Kaplan-Meier methodology. RESULTS: BOS 0-p FEV(1) was associated with higher sensitivity, specificity, and positive predictive value than the FEF(25-75%) criterion over different time periods investigated. The probability of testing positive for BOS 0-p FEV(1) in patients with BOS (sensitivity) was 71% at 2 years before the onset of BOS. The probability of being free from development of BOS 0-p FEV(1) in patients free of BOS at follow-up (specificity) was 93% within the last year. Of patients who met the BOS 0-p FEV(1) criterion, 81% developed BOS or died within 3 years. The specificity and positive predictive value curves for the BOS 0-p FEV(1) were significantly different between patients with underlying restrictive versus obstructive physiology (p = 0.05 and 0.01, respectively). CONCLUSION: The FEV(1) criterion for BOS 0-p provides useful predictive information regarding the risk of development of BOS or death in single-lung recipients. The predictive value of this criterion is higher in patients with underlying restriction and is superior to the FEF(25-75%) criterion.

Bronchiolitis Obliterans↗
PubMed2005

Peribronchiolar metaplasia: a common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases.

Peribronchiolar metaplasia (PBM) is a histologic lesion consisting of peribronchiolar metaplasia (PBM) of bronchiolar-type epithelium. Although widely recognized, PBM has received little attention in the pathologic literature and is not known to have clinical significance. We identified 15 cases in which PBM was the only major histologic finding in surgical lung biopsies from patients with interstitial lung disease (PBM-ILD), and we reviewed the clinical, imaging, and pathologic findings. The mean age was 57 years (range, 44-74 years) with 13 females and 2 males. One patient had been a welder with fume and asbestos exposure; another had pigeon exposure. Smoking history was available for 13 patients: three current smokers, one cocaine user, two former smokers, and seven never smokers. Three patients had collagen vascular disease. One had elevated serum antinuclear antibody titers. Pulmonary function data were available for 10 patients: one obstructive, five restrictive, two mixed obstructive and restrictive, and two normal. Computerized tomography in 7 patients showed mosaic attenuation in 3 patients and air trapping in 1 patient; no bronchiectasis, septal lines, or honeycombing were seen in any cases. All 11 patients with available follow-up are alive; 4 of them have experienced symptomatic improvement (follow-up, 0.6-6.9 years; mean, 2.4 years). PBM was found focally in other interstitial lung diseases, which were assessed for this lesion: 59% of usual interstitial pneumonia (17 of 29), 50% of nonspecific interstitial pneumonia (10 of 20), desquamative interstitial pneumonia (3 of 6), hypersensitivity pneumonitis (9 of 18), and 11% of respiratory bronchiolitis (2 of 18). In summary, PBM is a common histologic finding in various interstitial lung disorders. It is rarely the sole major lung biopsy finding in patients presenting with interstitial lung disease (PBM-ILD). Patients are mostly older women, with mild symptoms and CT findings. Survival appears to be favorable.

Adult↗
PubMed2005

Emerging drugs for idiopathic pulmonary fibrosis.

Pulmonary fibrosis is often the end stage of chronic, persistent, low-level lung injury, either of known or unknown cause. The most severe form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF), a disease process of unknown aetiology and one that often leads to respiratory failure and death. At present there are no proven or effective drug therapies for IPF. Recent advances in understanding of disease pathogenesis have focused attention on drug targeting of fibrogenic pathways, as opposed to traditional anti-inflammatory approaches. In this report, the present status of drug development of a number of emerging antifibrotic strategies and agents that may prove more effective in the therapy of this progressive, debilitating and fatal disease are reviewed.

Animals↗
PubMed2004

Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?

Current guidelines recommend that the clinician, radiologist, and pathologist work together to establish a diagnosis of idiopathic interstitial pneumonia. Three clinicians, two radiologists, and two pathologists reviewed 58 consecutive cases of suspected idiopathic interstitial pneumonia. Each participant was provided information in a sequential manner and was asked to record their diagnostic impression and level of confidence at each step. Interobserver agreement improved from the beginning to the end of the review. After the presentation of histopathologic information, radiologists changed their diagnostic impression more often than did clinicians. In general, as more information was provided the confidence level for a given diagnosis improved, and the diagnoses rendered with a high level of confidence were more likely congruent with the final pathologic consensus diagnosis. The final consensus pathologist diagnosis was idiopathic pulmonary fibrosis in 30 cases. Clinicians identified 75% and radiologists identified 48% of these cases before presentation of the histopathologic information. Histopathologic information has the greatest impact on the final diagnosis, especially when the initial clinical/radiographic diagnosis is not idiopathic pulmonary fibrosis. We conclude that dynamic interactions between clinicians, radiologists, and pathologists improve interobserver agreement and diagnostic confidence.

Diagnosis, Differential↗
PubMed2004

Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual interstitial pneumonia.

Chemokines are increased and may exert effects on both inflammatory and remodeling events in idiopathic pulmonary pneumonia (IIP). Accordingly, we examined the concomitant expression of inflammatory CC chemotactic cytokines or chemokines and their corresponding receptors in surgical lung biopsies obtained at the time of disease diagnosis and pulmonary fibroblasts grown from these biopsies. By gene array analysis, upper and lower lobe biopsies and primary fibroblast lines from patients with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, and respiratory bronchiolitis-interstitial lung disease, but not patients without IIP, exhibited CCL7 gene expression. TAQMAN, immunohistochemical, and ELISA analyses confirmed that CCL7 was expressed at significantly higher levels in UIP lung biopsies compared with biopsies from patients with nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, and from patients without IIP. Higher levels of CCL7 were present in cultures of IIP fibroblasts compared with non-IIP fibroblasts, and CCL5, a CCR5 agonist, significantly increased the synthesis of CCL7 by UIP fibroblasts. Together, these data suggest that CCL7 is highly expressed in biopsies and pulmonary fibroblast lines obtained from patients with UIP relative to patients with other IIP and patients without IIP, and that this CC chemokine may have a major role in the progression of fibrosis in this IIP patient group.

Adult↗
PubMed2004

Cigarette smoking in interstitial lung disease: concepts for the internist.

Cigarette smoking is a common cause of lung disease. It is clearly implicated in the development of chronic obstructive pulmonary disease and lung cancer. Importantly, cigarette smoking has also been implicated in the development of interstitial lung diseases such as respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonia, pulmonary Langerhans' cell histiocytosis,and idiopathic pulmonary fibrosis. The exact role of cigarette smoking in the development of interstitial lung diseases is still being defined; the relatively low prevalence of interstitial lung disease makes epidemiologic studies difficult.

Humans↗
PubMed2004

Human pulmonary fibroblasts exhibit altered interleukin-4 and interleukin-13 receptor subunit expression in idiopathic interstitial pneumonia.

Abnormal proliferation of pulmonary fibroblasts is a prominent feature of chronic pulmonary fibrotic diseases such as idiopathic interstitial pneumonia (IIP), but it is not presently clear how this proliferative response by lung fibroblasts can be therapeutically modulated. In the present study, we examined whether it was possible to selectively target primary human pulmonary fibroblasts grown out of surgical lung biopsies (SLBs) from IIP patients based on their expression of interleukin-4 receptor (IL-4R) and IL-13R subunits. Pulmonary fibroblast lines cultured from patients with the severest form of IIP, namely usual interstitial pneumonia, exhibited the greatest gene and protein expression of IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2 compared with primary pulmonary fibroblast lines grown from other IIP SLBs and normal SLBs. When exposed to increasing concentrations of a chimeric protein comprised of human IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), the proliferation of primary usual interstitial pneumonia fibroblasts was inhibited to a much greater extent compared with fibroblast lines from nonspecific interstitial pneumonia and respiratory bronchiolitis/interstitial lung disease patient groups. Fibroblasts from normal patients exhibited minimal susceptibility to the cytotoxic effect of IL13-PE. IL13-PE-mediated targeting of IIP fibroblasts was dependent on their expression of IL-4Ralpha and IL-13Ralpha2. Thus, these data suggest that the abnormal proliferative properties of human lung fibroblasts from certain IIP patient groups can be modulated in a manner that is dependent on the IL-4 and IL-13 receptor subunit expression by these cells.

Base Sequence↗
PubMed2004

Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing disease of the distal air spaces of the lung of unknown aetiology. IPF is usually fatal with a median survival of < 3 years. There are currently no effective pharmacotherapeutic agents for the treatment of IPF. In this review, unifying concepts on the pathogenesis of IPF based on understanding of host responses to tissue injury are presented. These host responses involve tightly regulated and contextually orchestrated inflammatory and repair processes. Dysregulation of either of these processes can lead to pathological outcomes. Fibrosis results from an exaggerated or dysregulated repair process that proceeds 'uncontrolled' even after inflammatory responses have subsided. Disease heterogeneity may arise when inflammation and repair are in different (dys)regulatory phases, thus accounting for regional disparity. Usual interstitial pneumonia (UIP), the histopathological correlate of clinical IPF, represents a more fibrotic tissue reaction pattern and for which anti-inflammatory agents are ineffective. Emerging 'antifibrotic' drugs and strategies for UIP/IPF are discussed. The importance of accurately phenotyping a highly heterogeneous disease process that may require individualised and 'combined' therapies is emphasised.

Acetylcysteine↗
PubMed2003

Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia.

Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation. We conclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.

Cohort Studies↗
PubMed2003

Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia.

Idiopathic interstitial pneumonias are a diverse group of lung diseases with varied prognoses. We hypothesized that changes in physiologic and radiographic parameters would predict survival. We retrospectively examined 80 patients with usual interstitial pneumonia and 29 patients with nonspecific interstitial pneumonia. Baseline characteristics were examined together with 6-month change in forced vital capacity, diffusing capacity for carbon monoxide, and ground glass infiltrate and fibrosis on high resolution computed tomography. Patients with usual interstitial pneumonia were more likely to have a statistically significant or marginally significant decline in lung volume, diffusing capacity for carbon monoxide, and an increase in ground glass infiltrates (p < or = 0.08) compared with patients with nonspecific interstitial pneumonia. For patients with usual interstitial pneumonia, change in forced vital capacity was the best physiologic predictor of mortality (p = 0.05). In a multivariate Cox proportional hazards model controlling for histopathologic diagnosis, gender, smoking history, baseline forced vital capacity, and 6-month change in forced vital capacity, a decrease in forced vital capacity remained an independent risk factor for mortality (decrease > 10%; hazard ratio 2.47; 95% confidence interval 1.29, 4.73; p = 0.006). We conclude that a 6-month change in forced vital capacity gives additional prognostic information to baseline features for patients with idiopathic interstitial pneumonia.

Adult↗
PubMed2003

Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease.

A histologic feature of usual interstitial pneumonia is the presence of fibroblastic foci. As some patients with usual interstitial pneumonia and an underlying collagen vascular disease have a better prognosis, we hypothesized that they would have fewer fibroblastic foci. Pathologists reviewed surgical lung biopsies from 108 patients with usual interstitial pneumonia (nine with collagen vascular disease) and assigned a score (absent 0, mild 1, moderate 2, and marked 3) for fibroblastic foci. Patients with idiopathic usual interstitial pneumonia had a higher median profusion of fibroblastic foci (1.75 vs. 1.0, p = 0.003). Baseline characteristics were similar, although patients with a collagen vascular disease were younger, had a shorter duration of symptoms, and had a higher percentage of predicted total lung capacity. Profusion of fibroblastic foci was the most discriminative feature for separating idiopathic from collagen vascular disease-associated usual interstitial pneumonia (odds ratio 8.31; 95% confidence interval, 1.98, 59.42; p = 0.002 for a one-unit increase in fibroblastic foci score). No deaths were noted in the collagen vascular disease-associated usual interstitial pneumonia group; 52 deaths occurred in the idiopathic usual interstitial pneumonia group (log rank; p = 0.005). We conclude that patients with collagen vascular disease-associated usual interstitial pneumonia have fewer fibroblastic foci and improved survival.

Analysis of Variance↗
PubMed2003

Patient selection for lung volume reduction surgery.

LVRS represents a valid surgical option for a limited number of patients who have symptomatic emphysema. The results of recent controlled studies have provided a realistic view of LVRS outcomes and yielded a validated algorithm for selection of optimal candidates for surgery. Furthermore, the NETT has provided simultaneously collected cost data that have provided a unique view of the costs and benefits of LVRS in patients who have advanced emphysema. Additional data collection will better define the long-term benefits of such surgical intervention in patients who have COPD.

Algorithms↗