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Biomedical subjects

Kevin K Brown

Publications and source records attributed to Kevin K Brown.

At least 37 records · Page 2Linked to original sources
PubMed2005

Clinical and pathologic features of familial interstitial pneumonia.

RATIONALE: Several lines of evidence suggest that genetic factors and environmental exposures play a role in the development of pulmonary fibrosis. OBJECTIVES: We evaluated families with 2 or more cases of idiopathic interstitial pneumonia among first-degree family members (familial interstitial pneumonia, or FIP), and identified 111 families with FIP having 309 affected and 360 unaffected individuals. METHODS: The presence of probable or definite FIP was based on medical record review in 28 cases (9.1%); clinical history, diffusing capacity of carbon monoxide (DL(CO)), and chest X-ray in 16 cases (5.2%); clinical history, DL(CO), and high-resolution computed tomography chest scan in 191 cases (61.8%); clinical history and surgical lung biopsy in 56 cases (18.1%); and clinical history and autopsy in 18 cases (5.8%). RESULTS: Older age (68.3 vs. 53.1; p < 0.0001), male sex (55.7 vs. 37.2%; p < 0.0001), and having ever smoked cigarettes (67.3 vs. 34.1%; p < 0.0001) were associated with the development of FIP. After controlling for age and sex, having ever smoked cigarettes remained strongly associated with the development of FIP (odds ratio(adj), 3.6; 95% confidence interval, 1.3-9.8). Evidence of aggregation of disease was highly significant (p < 0.001) among sibling pairs, and 20 pedigrees demonstrated vertical transmission, consistent with autosomal dominant inheritance. Forty-five percent of pedigrees demonstrated phenotypic heterogeneity, with some pedigrees demonstrating several subtypes of idiopathic interstitial pneumonia occurring within the same families. CONCLUSIONS: These findings suggest that FIP may be caused by an interaction between a specific environmental exposure and a gene (or genes) that predisposes to the development of several subtypes of idiopathic interstitial pneumonia.

Adult↗
PubMed2005

Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency.

Patients who have common variable immunodeficiency (CVID) and granulomatous/lymphocytic interstitial lung disease (GLILD) are at high risk for early mortality and B cell lymphomas. Infection with human herpes virus type 8 (HHV8), a B cell lymphotrophic virus, is linked to lymphoproliferative disorders in people who have secondary immunodeficiencies. Therefore, we determined the prevalence of HHV8 infection in CVID patients with GLILD. Genomic DNA isolated from peripheral blood mononuclear cells was screened by nested- and real time-quantitative PCR (QRT-PCR) for the presence of HHV8 genome. It was positive in 6/9 CVID patients with GLILD (CVID-GLILD), 1/21 CVID patients without GLILD (CVID-control), and no patients receiving intravenous gamma globulin (n = 13) or normal blood donors (n = 20). Immunohistochemistry (IHC) demonstrated expression of the latency-associated nuclear antigen-1 (LANA-1) in the biopsies of the lung, liver, and bone marrow of four patients with CVID-GLILD. One CVID-GLILD patient developed a B cell lymphoma during the course of the study. QRT-PCR demonstrated high copy number of HHV8 genome and IHC showed diffuse staining for LANA-1 in the malignant lymph node. HHV8 infection may be an important factor in the pathogenesis of the interstitial lung disease and lymphoproliferative disorders in patients with CVID.

Adult↗
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

Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema.

RATIONALE: Within the lungs of patients with severe emphysema, inflammation continues despite smoking cessation. Foci of T lymphocytes in the small airways of patients with emphysema have been associated with disease severity. Whether these T cells play an important role in this continued inflammatory response is unknown. OBJECTIVE: The aim of this study was to determine if T cells recruited to the lungs of subjects with severe emphysema contain oligoclonal T-cell populations, suggesting their accumulation in response to antigenic stimuli. METHODS: Lung T-cell receptor (TCR) Vbeta repertoire from eight patients with severe emphysema and six control subjects was evaluated at the time of tissue procurement (ex vivo) and after 2 weeks of culture with interleukin 2 (in vitro). Junctional region nucleotide sequencing of expanded TCR-Vbeta subsets was performed. RESULTS: No significantly expanded TCR-Vbeta subsets were identified in ex vivo samples. However, T cells grew from all emphysema (n = 8) but from only one of the control lung samples (n = 6) when exposed to interleukin 2 (p = 0.0013). Within the cultured cells, seven major CD4-expressing TCR-Vbeta subset expansions were identified from five of the patients with emphysema. These expansions were composed of oligoclonal populations of T cells that had already been expanded in vivo. CONCLUSION: Severe emphysema is associated with inflammation involving T lymphocytes that are composed of oligoclonal CD4+ T cells. These T cells are accumulating in the lung secondary to conventional antigenic stimulation and are likely involved in the persistent pulmonary inflammation characteristic of severe emphysema.

Adult↗
PubMed2005

High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis.

RATIONALE: High-resolution computed tomography (HRCT) is an integral aspect of the evaluation of patients with suspected idiopathic pulmonary fibrosis (IPF). However, few studies have evaluated its use in a large cohort. OBJECTIVES: To describe HRCT features in patients with mild to moderate IPF, compare diagnostic evaluations by a radiology core (three thoracic radiologists) with those by study-site radiologists, correlate baseline clinical and physiologic variables with HRCT findings, and evaluate their association with mortality. METHODS: We assessed HRCT scans from patients with IPF (n = 315) enrolled in a randomized controlled study evaluating IFN-gamma1b. MEASUREMENTS AND MAIN RESULTS: There was concordance between study-site and core radiologists regarding the diagnosis of IPF in 86% of cases. Diffusing capacity of carbon monoxide (DLCO) was the physiologic characteristic most highly correlated with HRCT findings. Multivariate analysis identified three independent predictors of mortality: a higher extent of fibrosis score increased the risk of death (p < 0.0001), whereas a higher percent-predicted DLCO (p = 0.004) and treatment assignment to IFN-gamma1b rather than placebo (p = 0.04) reduced the risk of death. CONCLUSIONS: A study-site diagnosis of IPF on HRCT was regularly confirmed by core radiologists. Extent of reticulation and honeycombing on HRCT is an important independent predictor of mortality in patients with IPF.

Female↗
PubMed2005

Analyses of efficacy end points in a controlled trial of interferon-gamma1b for idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease, yet validated, reliable criteria for evaluating patient response to therapies in clinical trials are lacking. METHODS: To optimize selection of end point criteria for the study of interferon (IFN)-gamma1b in patients with IPF, we retrospectively analyzed the components of the primary efficacy end point used in a large, controlled study of 330 patients for reliability, validity, and sensitivity to treatment effect. The primary end point components were death, disease progression defined as a > or = 5 mm Hg increase in resting alveolar-arterial oxygen pressure gradient (P[A-a]O2), and disease progression defined as a > or = 10% decrease in percentage of predicted FVC. RESULTS: We found that the P(A-a)O2 criterion was not reliable and was not associated with mortality. In contrast, the FVC criterion was reliable and was associated with a 2.4-fold increase in the risk of death. Of the three measures, only mortality was sensitive to a treatment effect of IFN-gamma1b. Additionally, the tendency for mortality benefit was observed in nearly all patient subgroups defined by baseline physiology. The effect of IFN-gamma1b on mortality was strongest in patients with baseline percentage of predicted FVC > or = 55% (p = 0.004) or percentage of predicted diffusing capacity of the lung for carbon monoxide > or = 30% (p = 0.008). CONCLUSION: We conclude that mortality is the most inclusive end point for future trials of IFN- gamma1b in patients with IPF, and that a > 10% decrement in the percentage of predicted FVC represents a valid measure of disease progression.

Adult↗
PubMed2005

Radiologic and pathologic features of bronchiolitis.

OBJECTIVE: The purpose of this article is to describe and illustrate the clinical, pathologic, and imaging features of the inflammatory and fibrotic forms of bronchiolitis. The CT features presented in this article represent the typical features associated with each entity. CONCLUSION: Direct signs of bronchiolitis include centrilobular nodules and tree-in-bud pattern. Indirect signs include mosaic attenuation and air trapping. Although classic examples of each entity exist, there can be substantial overlap in the appearances, and distinguishing among these entities is not always possible. When high-resolution CT features overlap, clinical details will usually help to narrow the differential diagnosis.

Bronchiolitis↗
PubMed2004

Rheumatoid arthritis-related lung diseases: CT findings.

PURPOSE: To evaluate computed tomographic (CT) findings of rheumatoid arthritis-related lung disease and categorize findings according to pathologic features. MATERIALS AND METHODS: CT scans obtained in 63 patients (27 men, 36 women; mean age, 61.7 years +/- 11.2 [SD]; range, 28-81 years) with rheumatoid arthritis were assessed. Mean duration of disease was 7.6 years +/- 9.2. Lung parenchymal abnormalities that included airspace consolidation, ground-glass opacity (GGO), reticulation, honeycombing, nodules, bronchiectasis, and air trapping were assessed retrospectively by two chest radiologists. Final decision was reached with consensus of these radiologists and a third radiologist. Patients were classified according to the predominant CT pattern. One of the chest radiologists and a pulmonary pathologist compared CT findings with pathologic findings in 17 patients. Interobserver agreement between the first two radiologists was assessed. Correlation between CT finding extent score and pulmonary function test results was estimated with Spearman rank correlation coefficient. RESULTS: GGO (57 [90%] patients) and reticulation (62 [98%] patients) were the most common CT features. Four major CT patterns were identified: usual interstitial pneumonia (n = 26), nonspecific interstitial pneumonia (n = 19), bronchiolitis (n = 11), and organizing pneumonia (n = 5). Usual interstitial pneumonia and nonspecific interstitial pneumonia CT patterns overlapped; GGO was more extensive in patients with nonspecific interstitial pneumonia CT pattern (P =.028). In 17 patients who underwent biopsy, CT findings reflected pathologic findings. Exceptions were two patients classified with usual interstitial pneumonia at CT but with nonspecific interstitial pneumonia at pathologic analysis; one patient, with nonspecific interstitial pneumonia at CT but desquamative interstitial pneumonia at pathologic analysis; and one patient, with lymphoid interstitial pneumonia at CT but nonspecific interstitial pneumonia at pathologic analysis. CONCLUSION: Rheumatoid arthritis is associated with four CT patterns: usual interstitial pneumonia, nonspecific interstitial pneumonia, bronchiolitis, and organizing pneumonia. The most common CT features of rheumatoid arthritis-related lung disease were GGO and reticulation.

Adult↗
PubMed2004

The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis.

PURPOSE: To determine the effect of pulmonary fibrosis on survival in an unselected group of patients with hypersensitivity pneumonitis. METHODS: We identified 72 patients with hypersensitivity pneumonitis confirmed by surgical lung biopsy in the database of the Clinical Interstitial Lung Disease Program at the National Jewish Medical and Research Center. All biopsy specimens were scored according to the presence or absence of fibrosis. Comparisons were made between patients with (fibrotic group) and without (nonfibrotic group) pathologic fibrosis. Vital status was ascertained and Kaplan-Meier curves were plotted. Cox regression analysis was used to determine predictors of survival. RESULTS: Forty-six patients were classified as fibrotic and 26 as nonfibrotic. Twenty-nine percent had exposure to a bird antigen, 33% had exposure to a microbial antigen, and 38% had unknown exposure. Patients with fibrosis were significantly older, showed greater restrictive lung physiology, and had greater all-cause and respiratory mortality. Median survival in fibrotic patients was 7.1 years, which was significantly less than survival in those without fibrosis. In an age-adjusted regression analysis, antigen class, symptom duration, and lung function had no effect on survival. Only the presence of pathologic fibrosis was predictive of increased mortality (hazard ratio = 6.01; 95% confidence interval: 1.68 to 21.45; P = 0.006). CONCLUSION: Pulmonary fibrosis is associated with diminished survival in patients with hypersensitivity pneumonitis.

Alveolitis, Extrinsic Allergic↗
PubMed2004

Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis.

Pigment epithelium-derived factor (PEDF) is a 50-kD protein with angiostatic and neurotrophic activities that regulates vascular development within the eye. PEDF expression was increased in the lungs of patients with idiopathic pulmonary fibrosis (IPF) based on microarray analyses. Angiogenesis has been implicated in the pathogenesis of fibrotic lung diseases, we therefore hypothesized that regional abnormalities in vascularization occur in IPF as a result of an imbalance between PEDF and vascular endothelial growth factor. We demonstrated that vascular density is regionally decreased in IPF within the fibroblastic foci, and that within these areas PEDF was increased, whereas vascular endothelial growth factor was decreased. PEDF colocalized with the fibrogenic cytokine, transforming growth factor (TGF)-beta 1, particularly within the fibrotic interstitium and the fibroblastic focus, and prominently within the epithelium directly overlying the fibroblastic focus. This suggested that TGF-beta 1 might regulate PEDF expression. Using 3T3-L1 fibroblasts and human lung fibroblasts, we showed that PEDF was indeed a TGF-beta 1 target gene. Collectively, our findings implicate PEDF as a regulator of pulmonary angiogenesis and an important mediator in IPF.

Biopsy↗
PubMed2004

A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive, fatal disease with no known efficacious therapy. METHODS: In a double-blind, multinational trial, we randomly assigned 330 patients with idiopathic pulmonary fibrosis that was unresponsive to corticosteroid therapy to receive subcutaneous interferon gamma-1b or placebo. RESULTS: Over a median of 58 weeks, interferon gamma-1b therapy did not significantly affect the primary end point of progression-free survival, defined as the time to disease progression or death, and no significant treatment effect was observed on measures of lung function, gas exchange, or the quality of life. Ten percent of patients in the interferon gamma-1b group died, as compared with 17 percent of patients in the placebo group (P=0.08). Treatment with interferon gamma-1b was associated with more frequent constitutional symptoms. However, the rates of treatment adherence and premature discontinuation of treatment were similar in the two groups. More pneumonias were reported among patients in the interferon gamma-1b group, but the incidence of severe or life-threatening respiratory tract infections was similar in the two groups. CONCLUSIONS: In a well-defined population of patients with idiopathic pulmonary fibrosis, interferon gamma-1b did not affect progression-free survival, pulmonary function, or the quality of life. Owing to the size and duration of the trial, a clinically significant survival benefit could not be ruled out.

Disease Progression↗
PubMed2004

Medical treatment for pulmonary fibrosis: current trends, concepts, and prospects.

A diagnosis of idiopathic pulmonary fibrosis (IPF) carries a poor prognosis, with our currently available therapies offering little clinical benefit. Unfortunately, recent major advances in our understanding of the clinical and biologic features of this disease have not been matched by similar advances in treatment. This is likely because of the complex cascade of biologic and pathobiologic events that occurs in IPF. The necessary, and desperately needed, next generation of therapies, focused on specific molecular targets thought to play pivotal roles in the development and progression of fibrosis, are under active investigation.

Antioxidants↗
PubMed2004

Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum immunoglobulins and an inability to make specific antibodies. OBJECTIVE: We sought to determine the prevalence, clinical characteristics, and effect on survival of noninfectious pulmonary disease in patients with CVID. METHODS: A retrospective analysis of 69 patients with CVID was performed. Patients were divided into 3 groups on the basis of the type of pulmonary disease present: group 1 (n=29), no pulmonary disease; group 2 (n=23), chronic respiratory symptoms without diffuse radiographic abnormalities; and group 3 (n=18), chronic respiratory symptoms and diffuse radiographic abnormalities. Group 3 patients were divided into 2 subgroups on the basis of the histopathologic pattern seen on biopsy. Group 3A (n=13) included patients with granulomatous lung disease, lymphocytic interstitial pneumonia, follicular bronchiolitis, and lymphoid hyperplasia, a group of syndromes referred to as granulomatous-lymphocytic interstitial lung disease (GLILD). Group 3B (n=5) consisted of patients with all other types of interstitial lung disease (ILD). RESULTS: Fifty-eight percent of patients with CVID had noninfectious pulmonary complications. Group 3A (GLILD) patients had worse prognosis than the other groups, with a median survival of 13.7 versus 28.8 years (P<.001). Lymphoproliferative disease occurred in 31% of patients with GLILD. GLILD was associated with the presence of dyspnea (P<.05); splenomegaly (P<.05); restrictive pulmonary physiology; consolidation, ground-glass, and reticular radiographic abnormalities; and low CD3+ (P<.05) and CD8+ cell populations (P<.01). CONCLUSION: ILD is common in patients with CVID. The presence of GLILD was associated with a worse prognosis and increased prevalence of lymphoproliferative disorders.

Adult↗
PubMed2004

Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient with acromegaly.

Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHPNC) is a rare disorder that most often presents clinically as obliterative bronchiolitis, but has also been associated with ectopic corticotropin syndrome. We describe a 49-year-old lifetime non-smoking female with longstanding cough, progressive exertional dyspnoea, and fixed airflow limitation, who presented with acromegaly. Head magnetic resonance imaging revealed a pituitary microadenoma and open lung biopsy revealed a multifocal proliferation of neuroendocrine cells which were immunopositive for both corticotropin and growth hormone-releasing hormone. To our knowledge, this is the first report of acromegaly associated with IDHPNC, and supports the possibility that IDHPNC may fall at one extreme of the spectrum of disorders encountered in multiple endocrine neoplasia type 1.

Acromegaly↗
PubMed2004

Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis.

STUDY OBJECTIVES: Treatment of patients with idiopathic pulmonary fibrosis (IPF) conventionally includes corticosteroids and cytotoxic agents. No study to date has adequately evaluated the benefits of this approach. This study retrospectively compared combination corticosteroid and cyclophosphamide therapy in a large population of patients who meet the current consensus definition of IPF. DESIGN: Patients were identified retrospectively and treatment addressed on an intention-to-treat basis. Treated and untreated patients were matched by age and percentage of predicted FVC (FVC%) at the time of the initial visit. SETTING: Two academic tertiary referral centers. PATIENTS OR PARTICIPANTS: The diagnosis of IPF was based on current consensus criteria. A total of 164 patients (82 treated and 82 untreated) were included. INTERVENTIONS: Treatment consisted of combined corticosteroid and cyclophosphamide therapy using a standardized protocol. MEASUREMENTS AND RESULTS: There was no difference in age, FVC%, gender, or smoking status between groups. No survival difference was found between patients who were treated (median survival, 1,431 days) or untreated (median survival, 1,665 days) [p = 0.58]. The lack of treatment effect persisted when only those patients with a diagnosis by surgical biopsy (n = 24) or FVC% >/= 60 (n = 107) were analyzed. CONCLUSIONS: Our data suggest that combined corticosteroid and cyclophosphamide therapy has no impact on survival in patients with IPF. This finding supports the evolving concept that chronic inflammation plays a minimal role in the progression of IPF and reinforces the importance of careful consideration of the risks and benefits of such therapies prior to their institution.

Adrenal Cortex Hormones↗
PubMed2004

Idiopathic pleuroparenchymal fibroelastosis: description of a novel clinicopathologic entity.

Between 1996 and 2001, we identified five cases of a unique idiopathic pleuroparenchymal lung disease characterized by a clinical presentation suggestive of a chronic idiopathic interstitial pneumonia, marked pleural and parenchymal radiographic involvement with an upper lobe predominance, and surgical lung biopsy findings that did not fit with any of the currently defined interstitial pneumonias. The pathologic findings included the following: (1) intense fibrosis of the visceral pleura; (2) prominent, homogenous, subpleural fibroelastosis; (3) sparing of the parenchyma distant from the pleura; (4) mild, patchy lymphoplasmacytic infiltrates; and (5) small numbers of fibroblastic foci present at the leading edge of the fibrosis. In this report, we characterize the clinical, radiographic, physiologic, and pathologic findings of this entity, which we term idiopathic pleuroparenchymal fibroelastosis.

Adult↗