Carlyne Cool - Academia.edu (original) (raw)
Papers by Carlyne Cool
BMC genomics, 2015
Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable di... more Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs. Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted DLCO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, ...
Journal of Computer Assisted Tomography
Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual inters... more Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, lymphoid interstitial pneumonia, bronchiectasis, constrictive bronchiolitis, follicular bronchiolitis, alveolar hemorrhage, pulmonary hypertension, and drug-induced lung disease. The frequency of each lung disease is different among underlying CVDs. Although high-resolution computed tomography (HRCT) findings of lung disease are often nonspecific, there are some characteristic HRCT findings for some lung diseases based on pathologic findings.
Previous investigation demonstrated predominantly lymphocytic inflammation in sinus mucosa of you... more Previous investigation demonstrated predominantly lymphocytic inflammation in sinus mucosa of young children with chronic rhinosinusitis (CRS) rather than eosinophilic inflammation typical of adult CRS. Immunohistopathological study was undertaken to define further the cellular response in pediatric CRS. Maxillary mucosal biopsies from children and adults with CRS were stained for CD3 (T lymphocytes), CD4 (helper T lymphocytes), CD8 (cytotoxic T lymphocytes), CD20 (B lymphocytes), CD68 (monocytes/macrophages), CD56 (natural killer cells), kappa and lambda (plasma cells), and myeloperoxidase (MPO; neutrophils). Nineteen children with CRS (median age, 3.0 years; range, 1.4-8.2 years) had more CD8+, MPO+, and CD68+ cells (P < or = .03) and a trend toward more CD3+ and CD4+ cells (P = .06) in their epithelium and more CD20+, kappa+ and lambda+, MPO+, and CD68+ cells (P < or = .05) and a trend toward more CD4+ cells (P = .06) in their submucosa compared with adult control subjects. Immunostains from children with positive sinus cultures were similar to those with negative cultures except for more MPO+ cells in the submucosa (P = .04). The inflammatory response of young children with CRS is characterized by a mixed lymphocyte population, macrophages, and neutrophils. Differences between pediatric and adult CRS suggest differing pathogenic mechanisms or progression in the inflammatory response with protracted disease.
Medicine, 2000
Acute interstitial pneumonitis (AIP) is an acute, idiopathic interstitial lung disease characteri... more Acute interstitial pneumonitis (AIP) is an acute, idiopathic interstitial lung disease characterized by rapidly progressive diffuse pulmonary infiltrates and hypoxemia requiring hospitalization. The case-fatality ratio is high. Previous reports suggested that survivors of the acute event have a favorable outcome. We undertook this study to examine the natural history of survivors. We had observed several patients who experienced recurrent episodes of AIP and chronic progressive interstitial lung disease. We sought to determine longitudinal survival in these patients and to compare our experience with that in the medical literature. Overall, we identified 13 biopsy-proven cases of AIP. The mean patient age was 54 years in our review, which is identical to previous reports. Twelve patients were hospitalized and all 12 required mechanical ventilation. Overall hospital survival was 67%. All patients demonstrated abnormalities in gas exchange at presentation. Radiographs typically demonstrated bilateral patchy densities that progressed to a diffuse alveolar filling pattern in nearly all cases. All biopsy specimens showed organizing diffuse alveolar damage. Longitudinal data were available for 7 patients. Two died of AIP recurrences. A third died of complications of heart failure shortly after hospital discharge. One patient progressed to end-stage lung disease and required lung transplantation. Two patients experienced persistent pulmonary symptoms, accompanied in 1 by progressive lung fibrosis. One patient had nearly complete recovery of lung function 2 years following AIP. (Follow-up information was unavailable for 2 survivors.) In our literature review, 5 of 7 patients reported experienced some recovery of lung function. One case of progressive interstitial lung disease requiring lung transplantation was reported. The reported mortality was much higher than in our experience (74% versus 33%). The mean time from symptom onset to death was 26 days, compared with 34 days in our experience. The use of corticosteroids did not appear to influence survival, although this has not been tested in a rigorous manner. The better survival in our series may be related in part to a survivor selection bias. In contrast to previous reports, we found that survivors of AIP may experience recurrences and chronic, progressive interstitial lung disease. We did not identify any clinical or pathologic features that predict mortality in these patients. Likewise, there were no features that predicted the longitudinal course in survivors. Further study to identify causal factors is required in the hope of preventing morbidity and mortality related to this disease.
Many of the body's tissues once thought to be only locally regenerative may, in fact, be actively... more Many of the body's tissues once thought to be only locally regenerative may, in fact, be actively replaced by circulating stem cells following hematopoietic stem cell transplantation.
Seminars in Respiratory and Critical Care Medicine, 2008
Practicing pulmonologists are often faced with the question of whether a lung disease is related ... more Practicing pulmonologists are often faced with the question of whether a lung disease is related to something in the patient's workplace, home, or recreational environment. Recognizing a lung disease as exposure related creates both opportunities and obligations for clinicians. In addition to managing the patient, the obligation to consider risks to others and to prevent ongoing exposure is a challenge that requires diagnostic clarity and collaboration between multiple specialists. We present five illustrative case studies of patients with diffuse lung diseases from environmental and occupational exposures in which communication between the pulmonologist, radiologist, and pathologist was essential for both medical and public health management. Diagnostic and treatment strategies as well as social and preventive interventions are reviewed, with key points for the practicing pulmonologist.
Respirology, 2004
Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHPNC) is a rare disorder that... more 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.
Radiology, 2004
To evaluate computed tomographic (CT) findings of rheumatoid arthritis-related lung disease and c... more To evaluate computed tomographic (CT) findings of rheumatoid arthritis-related lung disease and categorize findings according to pathologic features. 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. 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. 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.
Radiology, 2007
To retrospectively compare in patients with chronic hypersensitivity pneumonitis (HP) the compute... more To retrospectively compare in patients with chronic hypersensitivity pneumonitis (HP) the computed tomographic (CT) imaging features suggestive of fibrosis with pathologic evidence of fibrosis at surgical lung biopsy and to compare a usual interstitial pneumonia (UIP) pattern at CT with survival. Institutional review board approval and informed consent were obtained for this study, which was HIPAA compliant. Twenty-six patients (15 women, 11 men; age range, 37-76 years) with chronic HP had their surgical lung biopsy results reviewed by two pathologists for the presence of fibrosis. Two radiologists systematically reviewed the CT scans. The two radiologists were blinded to all clinical information, including pathologic diagnosis, patient information, and outcomes. The combination of a subpleural reticular pattern and lower zone predominance was considered a UIP pattern. CT findings were compared with the histopathologic presence of fibrosis, physiologic parameters, symptoms, and survival. The chi(2) or Fisher exact test (each two-tailed) was used to compare nominal and ordinal variables. A t test (with unequal variances) was used to compare continuous variables. The log-rank procedure was used to compare Kaplan-Meier survival curves. Fifteen patients had fibrotic HP at biopsy, and 11 had nonfibrotic HP. Patients with fibrotic HP had more extensive reticular pattern and were more likely to have traction bronchiectasis, honeycombing, and a UIP pattern than those with nonfibrotic HP (P = .015, P = .007, P = .007, respectively). Although the presence of histologic fibrosis was associated with decreased survival (P = .003), the CT features were not associated with decreased survival. CT findings of extensive reticular pattern, traction bronchiectasis, and honeycombing are closely related to the presence of histologic fibrosis in chronic HP.
Pharmacological Research, 2007
The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes ... more The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.
Pediatric and Developmental Pathology, 2006
This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in ... more This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in Pediatric Pathology over the coming months. The series will include practical issues, such as this protocol for handling lung biopsies and another on bronchoalveolar lavage in childhood, as well as reviews of advances in various areas in pediatric pulmonary pathology. It has been 11 years since the last Perspectives on pulmonary disease. Much has happened since then in this area, and this collection will highlight some emerging and rapidly advancing areas in pediatric lung disease. These will include a review of molecular mechanisms of lung development, and another of mechanisms of pulmonary vascular development. The surfactant system and its disorders, as well as recent advances in the biology of the pulmonary neuroendocrine system and mechanisms of respiratory viral disease, will be addressed. Articles on pulmonary hypertension, pulmonary neoplasia, and pediatric lung transplantation, with their implications for the pediatric pathologist, are also planned. The contributors to this series are a diverse group with special interests and expertise in these areas. As Dr. William Thurlbeck noted in his foreword to the previous volume, Pulmonary Disease, volume 18 of Perspectives in Pediatric Pathology, pediatric pathology had been largely concerned with phenomenology, rather than with mechanisms, model systems, and experimental investigation. I think he would have been pleased to see the changes that have occurred over the past 10 years in pediatric lung biology and pathology in particular, because these were particularly favored interests of his later years.
Pediatric and Developmental Pathology, 2006
This review of pediatric pulmonary arterial hypertension provides a framework within which to vie... more This review of pediatric pulmonary arterial hypertension provides a framework within which to view pulmonary hypertension in children. Classification schemes, including the latest recommendations from the World Health Organization, are discussed, and the histopathology of severe pulmonary hypertension is reviewed. New information is provided regarding idiopathic and familial forms of the disease. Specific childhood etiologies, including persistent pulmonary hypertension of the newborn and congenital heart disease, are reviewed. Additionally, we examine the role of collagen vascular diseases, portal hypertension, and viruses in the pathogenesis of severe pulmonary arterial hypertension.
Oncogene, 2002
Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely... more Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of beta-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that beta-catenin was highly and uniformly expressed in a panel of NSCLC cell lines and primary lung tumors. By contrast, gamma-catenin was weakly expressed or absent in several NSCLC cell lines and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak gamma-catenin staining in approximately 30% of the specimens. Treatment of NSCLC cells expressing reduced gamma-catenin protein with 5-aza-2'-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A (TSA), a histone deacetylase inhibitor, increased gamma-catenin protein content in NSCLC cells with low gamma-catenin expression. Significantly, the activity of a beta-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed gamma-catenin relative to those lines that highly expressed gamma-catenin. Moreover, transfection of these cells with a gamma-catenin expression plasmid reduced the elevated TCF activity by 85% and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that gamma-catenin can function as an inhibitor of beta-catenin/TCF-dependent gene transcription and highlights gamma-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.
The Journal of Heart and Lung Transplantation, 2004
The clinical outcomes of lung transplant recipients presenting with post-transplant pulmonary cap... more The clinical outcomes of lung transplant recipients presenting with post-transplant pulmonary capillaritis have not been well described. We retrospectively reviewed 40 cases of biopsy-proven pulmonary capillaritis in lung transplant recipients. Patients presented with a clinical ...
Journal of Experimental Medicine, 2005
. Immunohistochemistry (IHC) demonstrated expression of the latency-associated nuclear antigen-1 ... more . 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.
Journal of Computer Assisted Tomography, 2004
Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual inters... more Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, lymphoid interstitial pneumonia, bronchiectasis, constrictive bronchiolitis, follicular bronchiolitis, alveolar hemorrhage, pulmonary hypertension, and drug-induced lung disease. The frequency of each lung disease is different among underlying CVDs. Although high-resolution computed tomography (HRCT) findings of lung disease are often nonspecific, there are some characteristic HRCT findings for some lung diseases based on pathologic findings.
Journal of Computer Assisted Tomography, 2006
To evaluate chest radiographic and computed tomographic (CT) findings of lung disease related to ... more To evaluate chest radiographic and computed tomographic (CT) findings of lung disease related to common variable immunodeficiency. Thirty-five chest radiographs and 30 CT scans of 46 patients were assessed. Lung parenchymal abnormalities that were evaluated included airspace consolidation, ground-glass attenuation, nodules, bronchiectasis, and air trapping. On CT, ground-glass attenuation and nodules were the most frequent findings, observed in 60% (n = 18/30) and 83% (n = 25/30), respectively. Three major CT patterns were identified: airway disease (n = 13), nodules (n = 8), and parenchymal opacification (n = 6). All 13 patients with airway disease showed centrilobular opacities. One patient with peribronchial nodules showed lymphoid interstitial pneumonia, and 1 with randomly distributed nodules showed noncaseating granulomas. Patients with a CT pattern of parenchymal opacification showed lower lung predominance; surgical biopsies showed organizing pneumonia in 1 patient and lymphoid interstitial pneumonia with nonnecrotizing granulomas in another. Common variable immunodeficiency is associated with 3 major CT patterns: airway disease, nodules, and parenchymal opacification.
Journal of Computer Assisted Tomography, 2005
To assess the accuracy of high-resolution computed tomography (HRCT) in the diagnosis of nonspeci... more To assess the accuracy of high-resolution computed tomography (HRCT) in the diagnosis of nonspecific interstitial pneumonia (NSIP). We hypothesized that the computed tomography (CT) features of NSIP could be distinguished from those of usual interstitial pneumonia (UIP). The HRCT images of 47 patients with surgical lung biopsy-proven NSIP (n = 25) and UIP (n = 22) were independently reviewed by 2 thoracic radiologists. Predominant imaging patterns, most likely diagnosis, and diagnostic level of confidence were recorded. A confident HRCT diagnosis of NSIP was based on the presence of spatially uniform, bilateral, basal-predominant ground-glass and/or reticular opacities with little if any honeycombing, whereas UIP was confidently diagnosed if a spatially inhomogeneous, bilateral, peripheral, basal-predominant pattern of reticular opacities and honeycombing with little if any ground-glass attenuation was identified. A predominant pattern of ground-glass and/or reticular opacity with minimal to no honeycombing was demonstrated in 48 (96%) of 50 readings in patients with NSIP. Conversely, the presence of honeycombing as a predominant feature had a predictive value of 90% for UIP (P < 0.001). Usual interstitial pneumonia was more likely than NSIP to be subpleural and patchy (P < 0.001). A confident CT diagnosis of NSIP and UIP was correct in 73% and 88% of cases, respectively. The correctness of a CT diagnosis made at intermediate or high confidence was 68% and 88%, respectively. The kappa value for distinction of NSIP from UIP was 0.72. In contrast to previous reports, NSIP can be separated from UIP in most cases. The presence of honeycombing as a predominant imaging finding is highly specific for UIP and can be used to differentiate it from NSIP, particularly when the distribution is patchy and subpleural predominant. The presence of predominant ground-glass and reticular opacity is highly characteristic of NSIP, but there is a subset of patients with UIP who have this pattern and may require biopsy for differentiation from NSIP.
Journal of Allergy and Clinical Immunology, 2004
RationalePatients with Common Variable Immunodeficiency (CVID) coupled with granulomatous lymphop... more RationalePatients with Common Variable Immunodeficiency (CVID) coupled with granulomatous lymphoproliferative interstitial lung disease (GLILD) have higher rates of mortality and morbidity than those without GLILD. GLILD-CVID patients are at high risk for developing Non-Hodgkin's Lymphoma and have reduced survival compared to patients lacking GLILD (10.2 years vs. 30 years, p
Journal of Allergy and Clinical Immunology, 2004
Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels... more Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum immunoglobulins and an inability to make specific antibodies. We sought to determine the prevalence, clinical characteristics, and effect on survival of noninfectious pulmonary disease in patients with CVID. 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). 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). ILD is common in patients with CVID. The presence of GLILD was associated with a worse prognosis and increased prevalence of lymphoproliferative disorders.
BMC genomics, 2015
Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable di... more Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs. Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted DLCO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, ...
Journal of Computer Assisted Tomography
Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual inters... more Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, lymphoid interstitial pneumonia, bronchiectasis, constrictive bronchiolitis, follicular bronchiolitis, alveolar hemorrhage, pulmonary hypertension, and drug-induced lung disease. The frequency of each lung disease is different among underlying CVDs. Although high-resolution computed tomography (HRCT) findings of lung disease are often nonspecific, there are some characteristic HRCT findings for some lung diseases based on pathologic findings.
Previous investigation demonstrated predominantly lymphocytic inflammation in sinus mucosa of you... more Previous investigation demonstrated predominantly lymphocytic inflammation in sinus mucosa of young children with chronic rhinosinusitis (CRS) rather than eosinophilic inflammation typical of adult CRS. Immunohistopathological study was undertaken to define further the cellular response in pediatric CRS. Maxillary mucosal biopsies from children and adults with CRS were stained for CD3 (T lymphocytes), CD4 (helper T lymphocytes), CD8 (cytotoxic T lymphocytes), CD20 (B lymphocytes), CD68 (monocytes/macrophages), CD56 (natural killer cells), kappa and lambda (plasma cells), and myeloperoxidase (MPO; neutrophils). Nineteen children with CRS (median age, 3.0 years; range, 1.4-8.2 years) had more CD8+, MPO+, and CD68+ cells (P < or = .03) and a trend toward more CD3+ and CD4+ cells (P = .06) in their epithelium and more CD20+, kappa+ and lambda+, MPO+, and CD68+ cells (P < or = .05) and a trend toward more CD4+ cells (P = .06) in their submucosa compared with adult control subjects. Immunostains from children with positive sinus cultures were similar to those with negative cultures except for more MPO+ cells in the submucosa (P = .04). The inflammatory response of young children with CRS is characterized by a mixed lymphocyte population, macrophages, and neutrophils. Differences between pediatric and adult CRS suggest differing pathogenic mechanisms or progression in the inflammatory response with protracted disease.
Medicine, 2000
Acute interstitial pneumonitis (AIP) is an acute, idiopathic interstitial lung disease characteri... more Acute interstitial pneumonitis (AIP) is an acute, idiopathic interstitial lung disease characterized by rapidly progressive diffuse pulmonary infiltrates and hypoxemia requiring hospitalization. The case-fatality ratio is high. Previous reports suggested that survivors of the acute event have a favorable outcome. We undertook this study to examine the natural history of survivors. We had observed several patients who experienced recurrent episodes of AIP and chronic progressive interstitial lung disease. We sought to determine longitudinal survival in these patients and to compare our experience with that in the medical literature. Overall, we identified 13 biopsy-proven cases of AIP. The mean patient age was 54 years in our review, which is identical to previous reports. Twelve patients were hospitalized and all 12 required mechanical ventilation. Overall hospital survival was 67%. All patients demonstrated abnormalities in gas exchange at presentation. Radiographs typically demonstrated bilateral patchy densities that progressed to a diffuse alveolar filling pattern in nearly all cases. All biopsy specimens showed organizing diffuse alveolar damage. Longitudinal data were available for 7 patients. Two died of AIP recurrences. A third died of complications of heart failure shortly after hospital discharge. One patient progressed to end-stage lung disease and required lung transplantation. Two patients experienced persistent pulmonary symptoms, accompanied in 1 by progressive lung fibrosis. One patient had nearly complete recovery of lung function 2 years following AIP. (Follow-up information was unavailable for 2 survivors.) In our literature review, 5 of 7 patients reported experienced some recovery of lung function. One case of progressive interstitial lung disease requiring lung transplantation was reported. The reported mortality was much higher than in our experience (74% versus 33%). The mean time from symptom onset to death was 26 days, compared with 34 days in our experience. The use of corticosteroids did not appear to influence survival, although this has not been tested in a rigorous manner. The better survival in our series may be related in part to a survivor selection bias. In contrast to previous reports, we found that survivors of AIP may experience recurrences and chronic, progressive interstitial lung disease. We did not identify any clinical or pathologic features that predict mortality in these patients. Likewise, there were no features that predicted the longitudinal course in survivors. Further study to identify causal factors is required in the hope of preventing morbidity and mortality related to this disease.
Many of the body's tissues once thought to be only locally regenerative may, in fact, be actively... more Many of the body's tissues once thought to be only locally regenerative may, in fact, be actively replaced by circulating stem cells following hematopoietic stem cell transplantation.
Seminars in Respiratory and Critical Care Medicine, 2008
Practicing pulmonologists are often faced with the question of whether a lung disease is related ... more Practicing pulmonologists are often faced with the question of whether a lung disease is related to something in the patient's workplace, home, or recreational environment. Recognizing a lung disease as exposure related creates both opportunities and obligations for clinicians. In addition to managing the patient, the obligation to consider risks to others and to prevent ongoing exposure is a challenge that requires diagnostic clarity and collaboration between multiple specialists. We present five illustrative case studies of patients with diffuse lung diseases from environmental and occupational exposures in which communication between the pulmonologist, radiologist, and pathologist was essential for both medical and public health management. Diagnostic and treatment strategies as well as social and preventive interventions are reviewed, with key points for the practicing pulmonologist.
Respirology, 2004
Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHPNC) is a rare disorder that... more 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.
Radiology, 2004
To evaluate computed tomographic (CT) findings of rheumatoid arthritis-related lung disease and c... more To evaluate computed tomographic (CT) findings of rheumatoid arthritis-related lung disease and categorize findings according to pathologic features. 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. 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. 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.
Radiology, 2007
To retrospectively compare in patients with chronic hypersensitivity pneumonitis (HP) the compute... more To retrospectively compare in patients with chronic hypersensitivity pneumonitis (HP) the computed tomographic (CT) imaging features suggestive of fibrosis with pathologic evidence of fibrosis at surgical lung biopsy and to compare a usual interstitial pneumonia (UIP) pattern at CT with survival. Institutional review board approval and informed consent were obtained for this study, which was HIPAA compliant. Twenty-six patients (15 women, 11 men; age range, 37-76 years) with chronic HP had their surgical lung biopsy results reviewed by two pathologists for the presence of fibrosis. Two radiologists systematically reviewed the CT scans. The two radiologists were blinded to all clinical information, including pathologic diagnosis, patient information, and outcomes. The combination of a subpleural reticular pattern and lower zone predominance was considered a UIP pattern. CT findings were compared with the histopathologic presence of fibrosis, physiologic parameters, symptoms, and survival. The chi(2) or Fisher exact test (each two-tailed) was used to compare nominal and ordinal variables. A t test (with unequal variances) was used to compare continuous variables. The log-rank procedure was used to compare Kaplan-Meier survival curves. Fifteen patients had fibrotic HP at biopsy, and 11 had nonfibrotic HP. Patients with fibrotic HP had more extensive reticular pattern and were more likely to have traction bronchiectasis, honeycombing, and a UIP pattern than those with nonfibrotic HP (P = .015, P = .007, P = .007, respectively). Although the presence of histologic fibrosis was associated with decreased survival (P = .003), the CT features were not associated with decreased survival. CT findings of extensive reticular pattern, traction bronchiectasis, and honeycombing are closely related to the presence of histologic fibrosis in chronic HP.
Pharmacological Research, 2007
The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes ... more The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.
Pediatric and Developmental Pathology, 2006
This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in ... more This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in Pediatric Pathology over the coming months. The series will include practical issues, such as this protocol for handling lung biopsies and another on bronchoalveolar lavage in childhood, as well as reviews of advances in various areas in pediatric pulmonary pathology. It has been 11 years since the last Perspectives on pulmonary disease. Much has happened since then in this area, and this collection will highlight some emerging and rapidly advancing areas in pediatric lung disease. These will include a review of molecular mechanisms of lung development, and another of mechanisms of pulmonary vascular development. The surfactant system and its disorders, as well as recent advances in the biology of the pulmonary neuroendocrine system and mechanisms of respiratory viral disease, will be addressed. Articles on pulmonary hypertension, pulmonary neoplasia, and pediatric lung transplantation, with their implications for the pediatric pathologist, are also planned. The contributors to this series are a diverse group with special interests and expertise in these areas. As Dr. William Thurlbeck noted in his foreword to the previous volume, Pulmonary Disease, volume 18 of Perspectives in Pediatric Pathology, pediatric pathology had been largely concerned with phenomenology, rather than with mechanisms, model systems, and experimental investigation. I think he would have been pleased to see the changes that have occurred over the past 10 years in pediatric lung biology and pathology in particular, because these were particularly favored interests of his later years.
Pediatric and Developmental Pathology, 2006
This review of pediatric pulmonary arterial hypertension provides a framework within which to vie... more This review of pediatric pulmonary arterial hypertension provides a framework within which to view pulmonary hypertension in children. Classification schemes, including the latest recommendations from the World Health Organization, are discussed, and the histopathology of severe pulmonary hypertension is reviewed. New information is provided regarding idiopathic and familial forms of the disease. Specific childhood etiologies, including persistent pulmonary hypertension of the newborn and congenital heart disease, are reviewed. Additionally, we examine the role of collagen vascular diseases, portal hypertension, and viruses in the pathogenesis of severe pulmonary arterial hypertension.
Oncogene, 2002
Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely... more Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of beta-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that beta-catenin was highly and uniformly expressed in a panel of NSCLC cell lines and primary lung tumors. By contrast, gamma-catenin was weakly expressed or absent in several NSCLC cell lines and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak gamma-catenin staining in approximately 30% of the specimens. Treatment of NSCLC cells expressing reduced gamma-catenin protein with 5-aza-2'-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A (TSA), a histone deacetylase inhibitor, increased gamma-catenin protein content in NSCLC cells with low gamma-catenin expression. Significantly, the activity of a beta-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed gamma-catenin relative to those lines that highly expressed gamma-catenin. Moreover, transfection of these cells with a gamma-catenin expression plasmid reduced the elevated TCF activity by 85% and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that gamma-catenin can function as an inhibitor of beta-catenin/TCF-dependent gene transcription and highlights gamma-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.
The Journal of Heart and Lung Transplantation, 2004
The clinical outcomes of lung transplant recipients presenting with post-transplant pulmonary cap... more The clinical outcomes of lung transplant recipients presenting with post-transplant pulmonary capillaritis have not been well described. We retrospectively reviewed 40 cases of biopsy-proven pulmonary capillaritis in lung transplant recipients. Patients presented with a clinical ...
Journal of Experimental Medicine, 2005
. Immunohistochemistry (IHC) demonstrated expression of the latency-associated nuclear antigen-1 ... more . 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.
Journal of Computer Assisted Tomography, 2004
Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual inters... more Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, lymphoid interstitial pneumonia, bronchiectasis, constrictive bronchiolitis, follicular bronchiolitis, alveolar hemorrhage, pulmonary hypertension, and drug-induced lung disease. The frequency of each lung disease is different among underlying CVDs. Although high-resolution computed tomography (HRCT) findings of lung disease are often nonspecific, there are some characteristic HRCT findings for some lung diseases based on pathologic findings.
Journal of Computer Assisted Tomography, 2006
To evaluate chest radiographic and computed tomographic (CT) findings of lung disease related to ... more To evaluate chest radiographic and computed tomographic (CT) findings of lung disease related to common variable immunodeficiency. Thirty-five chest radiographs and 30 CT scans of 46 patients were assessed. Lung parenchymal abnormalities that were evaluated included airspace consolidation, ground-glass attenuation, nodules, bronchiectasis, and air trapping. On CT, ground-glass attenuation and nodules were the most frequent findings, observed in 60% (n = 18/30) and 83% (n = 25/30), respectively. Three major CT patterns were identified: airway disease (n = 13), nodules (n = 8), and parenchymal opacification (n = 6). All 13 patients with airway disease showed centrilobular opacities. One patient with peribronchial nodules showed lymphoid interstitial pneumonia, and 1 with randomly distributed nodules showed noncaseating granulomas. Patients with a CT pattern of parenchymal opacification showed lower lung predominance; surgical biopsies showed organizing pneumonia in 1 patient and lymphoid interstitial pneumonia with nonnecrotizing granulomas in another. Common variable immunodeficiency is associated with 3 major CT patterns: airway disease, nodules, and parenchymal opacification.
Journal of Computer Assisted Tomography, 2005
To assess the accuracy of high-resolution computed tomography (HRCT) in the diagnosis of nonspeci... more To assess the accuracy of high-resolution computed tomography (HRCT) in the diagnosis of nonspecific interstitial pneumonia (NSIP). We hypothesized that the computed tomography (CT) features of NSIP could be distinguished from those of usual interstitial pneumonia (UIP). The HRCT images of 47 patients with surgical lung biopsy-proven NSIP (n = 25) and UIP (n = 22) were independently reviewed by 2 thoracic radiologists. Predominant imaging patterns, most likely diagnosis, and diagnostic level of confidence were recorded. A confident HRCT diagnosis of NSIP was based on the presence of spatially uniform, bilateral, basal-predominant ground-glass and/or reticular opacities with little if any honeycombing, whereas UIP was confidently diagnosed if a spatially inhomogeneous, bilateral, peripheral, basal-predominant pattern of reticular opacities and honeycombing with little if any ground-glass attenuation was identified. A predominant pattern of ground-glass and/or reticular opacity with minimal to no honeycombing was demonstrated in 48 (96%) of 50 readings in patients with NSIP. Conversely, the presence of honeycombing as a predominant feature had a predictive value of 90% for UIP (P < 0.001). Usual interstitial pneumonia was more likely than NSIP to be subpleural and patchy (P < 0.001). A confident CT diagnosis of NSIP and UIP was correct in 73% and 88% of cases, respectively. The correctness of a CT diagnosis made at intermediate or high confidence was 68% and 88%, respectively. The kappa value for distinction of NSIP from UIP was 0.72. In contrast to previous reports, NSIP can be separated from UIP in most cases. The presence of honeycombing as a predominant imaging finding is highly specific for UIP and can be used to differentiate it from NSIP, particularly when the distribution is patchy and subpleural predominant. The presence of predominant ground-glass and reticular opacity is highly characteristic of NSIP, but there is a subset of patients with UIP who have this pattern and may require biopsy for differentiation from NSIP.
Journal of Allergy and Clinical Immunology, 2004
RationalePatients with Common Variable Immunodeficiency (CVID) coupled with granulomatous lymphop... more RationalePatients with Common Variable Immunodeficiency (CVID) coupled with granulomatous lymphoproliferative interstitial lung disease (GLILD) have higher rates of mortality and morbidity than those without GLILD. GLILD-CVID patients are at high risk for developing Non-Hodgkin's Lymphoma and have reduced survival compared to patients lacking GLILD (10.2 years vs. 30 years, p
Journal of Allergy and Clinical Immunology, 2004
Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels... more Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum immunoglobulins and an inability to make specific antibodies. We sought to determine the prevalence, clinical characteristics, and effect on survival of noninfectious pulmonary disease in patients with CVID. 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). 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). ILD is common in patients with CVID. The presence of GLILD was associated with a worse prognosis and increased prevalence of lymphoproliferative disorders.