Restrictive lung disease in TNF-transgenic mice: correlation of pulmonary function testing and micro-CT imaging.
ABSTRACT: Purpose: Micro-computed tomography (µCT) is increasingly being used on animal models as a minimally-invasive longitudinal outcome measure of pulmonary disease progression. However, while imaging can elucidate macroscopic structural changes over the whole lung, µCT is unable to describe the mechanical changes and functional impairments imposed by progressive disease, which can only be measured via pulmonary function tests (PFTs). The tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA) develops pulmonary pathology that mimics many aspects of the inflammatory interstitial lung disease (ILD) seen in a subset of patients with RA. Prior studies using µCT imaging of these mice found increased pulmonary density, characteristic of restrictive disease; however, there have been conflicting reports in the literature regarding the obstructive versus restrictive phenotype of this model. Our study looks to 1) define the functional impairments and 2) characterize the restrictive/obstructive nature of the disease found in this model. Materials and Methods: In this study, we performed PFTs at end-stage ILD, and paired these findings with µCT results, correlating radiology to functional parameters. TNF-Tg and WT littermates of both sexes underwent µCT imaging and PFT testing at 5.5?months-old. Spearman's correlation analyses were performed comparing lung tissue volume (LTV) to PFT parameters of gas exchange and tissue stiffness. Results: Compared to WT, TNF-Tg mice had impaired gas exchange capacity, increased respiratory resistance, and reduced lung compliance, elastance, and inspiratory capacity, indicating increased tissue stiffness and compromised pulmonary function. LTV was also consistently higher in TNF-Tg lungs. Conclusions: These findings demonstrate that: 1) TNF-Tg mice display a restrictive pathology, and 2) in vivo µCT is a valid outcome measure to infer changes in pulmonary mechanical and functional parameters.
Project description:Pulmonary fibrosis and pulmonary arteriovenous malformations are known manifestations of dyskeratosis congenita (DC), a telomere biology disorder (TBD) and inherited bone marrow failure syndrome caused by germline mutations in telomere maintenance genes resulting in very short telomeres. Baseline pulmonary function tests (PFTs) and long-term clinical outcomes have not been thoroughly studied in DC/TBDs. In this retrospective study, 43 patients with DC and 67 unaffected relatives underwent baseline PFTs and were followed for a median of 8?years (range 1-14). Logistic regression and competing risk models were used to compare PFT results in relation to clinical and genetic characteristics, and patient outcomes. Restrictive abnormalities on spirometry and moderate-to-severe reduction in diffusing capacity of the lung for carbon monoxide were significantly more frequent in patients with DC than relatives (42% versus 12%; p=0.008). The cumulative incidence of pulmonary disease by age 20?years was 55% in patients with DC with baseline PFT abnormalities compared with 17% in those with normal PFTs (p=0.02). None of the relatives developed pulmonary disease. X-linked recessive, autosomal recessive inheritance or heterozygous TINF2 variants were associated with early-onset pulmonary disease that mainly developed after haematopoietic cell transplantation (HCT). Overall, seven of 14 patients developed pulmonary disease post-HCT at a median of 4.7?years (range 0.7-12). The cumulative incidence of pulmonary fibrosis in patients with heterozygous non-TINF2 pathogenic variants was 70% by age 60?years. Baseline PFT abnormalities are common in patients with DC and associated with progression to significant pulmonary disease. Prospective studies are warranted to facilitate clinical trial development for patients with DC and related TBDs.
Project description:Purpose:Pulmonary dysfunction is a prevalent and potentially debilitating late effect of pediatric cancer treatment. We postulated that age, as a surrogate for respiratory developmental status, might be associated with vulnerability to pulmonary injury. Materials and Methods:Sixty-one children treated with lung radiation at our institution who had undergone a pulmonary function test (PFT) between 1995 and 2016 were analyzed. Data collection included age at diagnosis and treatment, radiation dose and location, spirometry, and plethysmography results. PFTs were normalized according to age, sex, height, and ethnicity, and transformed into standardized z-scores. Obstructive disease was defined as forced expiratory volume in 1 second z score/forced vital capacity z score < -1.645, restrictive as total lung capacity z score < -1.645, and abnormal diffusion as diffusing capacity of the lung for carbon monoxide z score < -1.645. We determined the incidence of PFT abnormalities in our population and estimated the relative risk of developing pulmonary abnormalities using models adjusted for age. Results:At a mean age of 24 years (range, 12-31) and time from radiation of 9 years (range, 1-20), the cumulative incidence of any pulmonary abnormality was 34.4%. Among patients with an abnormal PFT, diffusing and restrictive abnormalities were most common (57.1% and 52.4%). When stratified by age at radiation treatment, 66.7% of patients <5 years had a PFT abnormality, compared with 47.6% for aged 5 to 13 and 20.6% for patients >13. Compared with patients >13 years, those <5 years and 5 to 13 years at radiation treatment had a significantly increased risk of an abnormal PFT with an odds ratio of 7.71 (95% confidence interval, 1.17, 51.06) and 3.51 (95% confidence interval, 1.06, 11.57), respectively (P <. 035). Furthermore, this association remained when examining each type of abnormality (P > .05). Conclusions:PFT abnormalities were common among our cohort of childhood cancer survivors treated with lung radiation. Younger age at treatment is associated with an increased risk of developing pulmonary dysfunction, presumably owing to developmental immaturity.
Project description:Introduction:Severe morning stiffness with painful involvement of the girdles are often referred by patients with Interstitial Lung Disease (ILD), but the association between ILD and Polymyalgia Rheumatica (PMR) is rarely reported. The purpose of the work is to describe a series of patients classified as having PMR with ILD. Material and methods:We retrospectively enrolled patients with a diagnosis of PMR referred to our center during the previous year for respiratory symptoms. Data concerning clinical and serological manifestations suggesting Connective Tissue Disease (CTD), High-Resolution Chest Tomography (HRCT), and Pulmonary Function Tests (PFTs) were systematically collected in order to verify the diagnosis. Results:Fifteen out of seventeen PMR patients had ILD. Ten patients had a confirmed diagnosis of PMR, while in five patients a CTD was discovered. Seven patients showed a severe restrictive pattern at PFTs requiring oxygen supplementation (five with PMR and two with CTD). In thirteen patients pulmonary symptoms started before or together with muscular symptoms. Regarding HRCT patterns, patients showed a Nonspecific Interstitial Pneumonia in nine cases, Usual Interstitial Pneumonia (UIP) and possible UIP in two and three cases, and a single case of Organizing Pneumonia and Combined Pulmonary Fibrosis and Emphysema Syndrome. Conclusions:Lung involvement should be evaluated in PMR patients, especially if asthenia is poorly responsive to low doses of steroids. In these cases, the diagnosis should be re-evaluated in depth, looking for a seronegative Rheumatoid Arthritis, a clinically amyopathic myositis or Interstitial Pneumonia with Autoimmune features.
Project description:A subset of patients with common variable immunodeficiency (CVID) develops granulomatous and lymphocytic interstitial lung disease (GLILD), a restrictive lung disease associated with early mortality. The optimal therapy for GLILD is unknown. This study was undertaken to see if rituximab and azathioprine (combination chemotherapy) would improve pulmonary function and/or radiographic abnormalities in patients with CVID and GLILD.A retrospective chart review of patients with CVID and GLILD who were treated with combination chemotherapy was performed. Complete pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans of the chest were done prior to therapy and >6 months later. HRCT scans of the chest were blinded, randomized, and scored independently (in pairs) by two radiologists. The differences between pre- and post-treatment HRCT scores and PFT parameters were analyzed.Seven patients with CVID and GLILD met inclusion criteria. Post-treatment increases were noted in both FEV1 (p=0.034) and FVC (p=0.043). HRCT scans of the chest demonstrated improvement in total score (p=0.018), pulmonary consolidations (p=0.041), ground-glass opacities (p=0.020) nodular opacities (p=0.024), and both the presence and extent of bronchial wall thickening (p=0.014, 0.026 respectively). No significant chemotherapy-related complications occurred.Combination chemotherapy improved pulmonary function and decreased radiographic abnormalities in patients with CVID and GLILD.
Project description:INTRODUCTION:Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is a debilitating condition with poor survival prognosis. High resolution computed tomography (CT) is a common clinical tool to diagnose RA-ILD, and is increasingly being adopted in pre-clinical studies. However, murine models recapitulating RA-ILD are lacking, and CT outcomes for inflammatory lung disease have yet to be formally validated. To address this, we validate ?CT outcomes for ILD in the tumor necrosis factor transgenic (TNF-Tg) mouse model of RA. METHODS:Cross sectional ?CT was performed on cohorts of male TNF-Tg mice and their WT littermates at 3, 4, 5.5 and 12 months of age (n = 4-6). Lung ?CT outcomes measures were determined by segmentation of the ?CT datasets to generate Aerated and Tissue volumes. After each scan, lungs were obtained for histopathology and 3 sections stained with hematoxylin and eosin. Automated histomorphometry was performed to quantify the tissue area (nuclei, cytoplasm, and extracellular matrix) and aerated area (white space) within the tissue sections. Spearman's correlation coefficients were used to evaluate the extent of association between ?CT imaging and histopathology endpoints. RESULTS:TNF-Tg mice had significantly greater tissue volume, total lung volume and mean intensity at all timepoints compared to age matched WT littermates. Histomorphometry also demonstrated a significant increase in tissue area at 3, 4, and 5.5 months of age in TNF-Tg mice. Lung tissue volume was correlated with lung tissue area (? = 0.81, p<0.0001), and normalize lung aerated volume was correlated with normalized lung air area (? = 0.73, p<0.0001). CONCLUSIONS:We have validated in vivo ?CT as a quantitative biomarker of ILD in mice. Further, development of longitudinal measures is critical for dissecting pathologic progression of ILD, and ?CT is a useful non-invasive method to study lung inflammation in the TNF-Tg mouse model.
Project description:To determine the role of preoperative pulmonary function tests (PFTs) in patients with aortic stenosis (AS) evaluated for aortic valve replacement (AVR), and to evaluate the association between lung disease and mortality in specific subgroups.Between 2008 and 2013, 535 patients with preoperative PFTs underwent AVR (transcatheter AVR [TAVR], n = 246; surgical AVR [SAVR], n = 289). The severity of lung disease determined by the Society of Thoracic Surgeons (STS) definition was evaluated in those with and without a clinical suspicion for lung disease (smoking, inhaled steroids/bronchodilators, or home oxygen). The association between lung disease and 1-year mortality was evaluated.Of the 186 patients (35%) without suspected lung disease, 39 (21%) had moderate/severe lung disease by PFT analysis. Among all patients, 1-year mortality was 12% in those with no lung disease, 17% in those with no mild lung disease, 22% in those with moderate lung disease, and 31% in those with severe lung disease (P < .001, log-rank test). After adjustment, moderate/severe lung disease was associated with increased 1-year mortality (adjusted hazard ratio, 2.07; 95% confidence interval, 1.30-3.29; P = .002); this association was not altered by smoking history, suspicion of lung disease, New York Heart Association class, or AVR type (interaction P value nonsignificant for all).In patients with AS evaluated for AVR, the STS risk score is significantly influenced by the severity of lung disease, which is determined predominantly by PFT results. Even when lung disease is not suspected, PFTs are abnormal in many patients undergoing AVR. Moderate/severe lung disease, diagnosed predominantly by PFTs, is an independent predictor of mortality after SAVR or TAVR. Collectively, these findings suggest that PFTs should be a routine part of the risk stratification of patients considered for AVR.
Project description:BACKGROUND:Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. OBJECTIVE:We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. METHOD:Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. RESULTS:Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). CONCLUSION:Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.
Project description:BACKGROUND:Post-treatment morbidity among subjects with drug-resistant tuberculosis (DR-TB) is unclear. METHODS:This was a cross-sectional study of patients from Tbilisi, Georgia with cavitary DR-TB and an outcome of cure. Participants had a chest X-ray (CXR), St. George Respiratory Quality (SGRQ) survey, and pulmonary function tests (PFTs) performed. Correlations between SGRQ and PFT results and factors associated with pulmonary impairment were examined. RESULTS:Among 58 subjects (median age 31 years), 40% used tobacco, 59% had prior TB, and 47% underwent adjunctive surgical resection. The median follow-up time was 41 months. Follow-up CXR revealed fibrosis in 30 subjects (52%) and bronchiectasis in seven (12%). The median forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio was 0.72, with 24 subjects (41%) having a ratio of ?0.70. Significant correlations existed between PFT measures and overall and component SGRQ scores. In linear regression, age, prior TB, and CXR fibrosis or bronchiectasis were significantly associated with decreased pulmonary function. Adjunctive surgery was significantly associated with a higher percent predicted FEV1 and FVC. CONCLUSIONS:A high proportion of DR-TB subjects had residual pulmonary impairment, particularly with recurrent TB and severe radiological disease. The association of surgical resection with improved lung function deserves further study. PFTs and SGRQ may both be useful to evaluate lung health.
Project description:Abnormal pulmonary function is prevalent in survivors of allogeneic hematopoietic cell transplantation (HCT). Post-transplantation recovery of pulmonary function, and its effect on survival, in children are not known. This retrospective cohort study of 308 children followed for 10 years after HCT at a single institution included 2 groups of patients. Group 1 comprised 188 patients with 3 or more pulmonary function test (PFT) results, of which at least 1 was abnormal, and group 2 comprised 120 patients with 3 or more PFTs, all of which were normal. Pulmonary function normalized post-transplantation in 51 patients (27%) in group 1. Obstructive lung disease, restrictive lung disease, mixed lung disease, and normal pattern were seen in 43%, 25%, 5%, and 27% of patients, respectively, at a median of 5 years (range, 0.5 to 11.9 years) post-transplantation. Lung volumes recovered better than spirometric indices. Pulmonary complications were seen in 80 patients (43%) in group 1. Patients who recovered pulmonary function had better overall survival (P?=?.006), which did not differ significantly from that in patients in group 2 with normal lung function post-transplantation (P?=?.80). After adjusting for duration of follow-up, pulmonary complications (P?=?.01), and lower pretransplantation forced vital capacity z-scores (P?=?.01) were associated with poor recovery. T cell depletion (P?<?.001), lower pretransplantation forced expired volume in 1 second z-scores (P?=?.006), and chronic graft-versus-host disease (P?<?.001) increased the risk for pulmonary complications. Nonrecovery of lung function with pulmonary complications (P?=?.03), acute graft-versus-host disease (P?=?.004), and mechanical ventilation (P?<?.001) were risk factors for nonrelapse mortality. Normalization of pulmonary function is possible in long-term survivors of allogeneic HCT. Strategies to decrease the risk of pulmonary complications may improve outcomes.
Project description:OBJECTIVE: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease. METHODS: Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2-3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein. RESULTS: Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor β (TGFβ)- and interferon (IFN)-regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < -0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins. CONCLUSION: These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGFβ- and IFN-regulated genes Overall design: Gene expression from lung biopsies was measured in 7 patients with SSc-ILD and 4 controls