Nontuberculous Mycobacterial Infections in a French Hospital: A 12-Year Retrospective Study.

BACKGROUND: Nontuberculous mycobacteria (NTM) are environmental organisms associated with a range of infections. Reports of NTM epidemiology are mainly focused on pulmonary infections and isolations, and extrapulmonary infections are less frequently described. METHODS: We conducted a retrospective study of NTM infections at the Bordeaux University Hospital, France, between January 2002 and December 2013. We used the microbiologic component of the American Thoracic Society/Infectious Diseases Society of America's pulmonary NTM disease criteria to define cases of pulmonary NTM, and patients with isolates from a normally sterile site were classified as having extrapulmonary disease. RESULTS: In our setting, 170 patients were included. Pulmonary cases predominated (54.1%), followed by skin and soft tissue infections (22.9%), disseminated cases (10.6%), lymphadenitis (7.7%), bone and joint infections (2.9%) and the remaining 1.8% catheter-related infections. Overall, 16 NTM species were isolated. Mycobacterium avium (31.8%) and M. intracellulare (20%) were the most common species identified, followed by M. marinum (13.5%), M. kansasii (10.6%), M. xenopi (9.4%), rapidly growing mycobacteria (9.4%) and other slowly growing mycobacteria (5.3%). In general, NTM isolates were largely prevalent in people older than 50 (62.4%); patients aged 1-10 year-old exclusively yielded M. avium from lymph nodes, almost cases having being diagnosed after 2007. Among the 121 patients with complete follow-up, 78 (64.5%), 24 (19.8%), and 19 (15.7%) were cured, experienced relapse, or died, respectively. CONCLUSION: In our study, extrapulmonary NTM infections represented almost half of cases, consisting mainly in skin and soft tissue infections. The increase lymphadenitis cases in children after 2007 could be linked to the cessation of mandatory BCG vaccination in France. We observed similar cure rates (64%) between pulmonary and extrapulmonary infections.

Role of YKL-40 in bronchial smooth muscle remodeling in asthma.

RATIONALE: Bronchial remodeling, including increased bronchial smooth muscle (BSM) mass, contributes to bronchial obstruction in asthma. However, its mechanisms are complex and remain controversial. Recently, a role of the chitinase 3-like 1 protein (YKL-40) has been evoked in asthma. Indeed, YKL-40 concentration was increased in asthmatic serum, and correlated with asthma severity and subepithelial membrane thickness. Nevertheless, the role of YKL-40 on BSM cells remains to be investigated. OBJECTIVES: To evaluate whether YKL-40 altered the physiologic properties of BSM cells in asthma in vitro and ex vivo. METHODS: We enrolled 40 subjects with asthma, 13 nonsmokers, and 16 smokers. BSM cells were derived from bronchial specimens obtained by either fiberoptic bronchoscopy or lobectomy. We assessed cell proliferation using BrdU, flow cytometry, and cell count; signaling intermediates using Western blot; cell migration using inserts, wound healing, and phalloidin staining; and cell synthesis using ELISA and Western blot. The involvement of protease activated receptor (PAR)-2 was evaluated using blocking antibody and dedicated lentiviral small hairpin RNA. We also determined the BSM area and the YKL-40 staining ex vivo using immunohistochemistry on biopsies from subjects with asthma and control subjects. MEASUREMENTS AND MAIN RESULTS: We demonstrated that YKL-40 increased BSM cell proliferation and migration through PAR-2-, AKT-, ERK-, and p38-dependent mechanisms. The increased cell migration was higher in BSM cells of subjects with asthma than that of control subjects. Furthermore, YKL-40 epithelial expression was positively correlated with BSM mass in asthma. CONCLUSIONS: This study indicates that YKL-40 promotes BSM cell proliferation and migration through a PAR-2-dependent mechanism.

Control maintenance can be predicted by exhaled NO monitoring in asthmatic patients.

BACKGROUND: Fractional exhaled nitric oxide (F(E)NO) is a marker of airway inflammation in asthma. Monitoring of such inflammation is currently not included in asthma guidelines and remains controversial. The hypothesis underlying the present study was that, F(E)NO could help assessing asthma control and, therefore, improve its management, by predicting loss of control in asthmatics. METHODS: A total of 90 adult asthmatics were included in the study. Asthma control was evaluated according to ACQ. All patients underwent F(E)NO by chemiluminescent (EndoNO) and hand-held (MINO) devices, followed by lung function testing. RESULTS: MINO was accurate as compared to EndoNO. F(E)NO was significantly increased in uncontrolled as compared to controlled asthmatics using both devices. F(E)NO measurement was able to predict control maintenance in controlled asthmatics in the absence of any change in their treatment. Indeed, using cut-off values of 31 and 40 ppb, the negative predictive values were 95 and 97% for EndoNO and MINO, respectively. EndoNO and MINO were also able to assess asthma control, although to a lesser extent. CONCLUSIONS: These findings suggest that F(E)NO can predict the persistence of asthma control in controlled patients and may now be used in asthma management since it can accurately be measured by means of hand-held devices.

Airway remodeling in asthma: new mechanisms and potential for pharmacological intervention.

The chronic inflammatory response within the airways of asthmatics is associated with structural changes termed airway remodeling. This remodeling process is a key feature of severe asthma. The 5-10% of patients with a severe form of the disease account for the higher morbidity and health costs related to asthma. Among the histopathological characteristics of airway remodeling, recent reports indicate that the increased mass of airway smooth muscle (ASM) plays a critical role. ASM cell proliferation in severe asthma implicates a gallopamil-sensitive calcium influx and the activation of calcium-calmodulin kinase IV leading to enhanced mitochondrial biogenesis through the activation of various transcription factors (PGC-1α, NRF-1 and mt-TFA). The altered expression and function of sarco/endoplasmic reticulum Ca(2+) pump could play a role in ASM remodeling in moderate to severe asthma. Additionally, aberrant communication between an injured airway epithelium and ASM could also contribute to disease severity. Airway remodeling is insensitive to corticosteroids and anti-leukotrienes whereas the effect of monoclonal antibodies (the anti-IgE omalizumab, the anti-interleukin-5 mepolizumab or anti-tumor necrosis factor-alpha) remains to be investigated. This review focuses on potential new therapeutic strategies targeting ASM cells, especially Ca(2+) and mitochondria-dependent pathways.

Bronchial measurements in patients with asthma: comparison of quantitative thin-section CT findings with those in healthy subjects and correlation with pathologic findings.

PURPOSE: To analyze and compare computed tomographic (CT) bronchial measurements in patients with asthma and healthy subjects and to correlate bronchial morphometric parameters with functional data and immunohistologic markers of airway remodeling and inflammation. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board; patient informed consent was not required. CT and pulmonary function tests were performed in 27 patients separated into two groups: 15 patients with asthma (three men; mean age, 43.1 years +/- 5.3 [standard error of mean]) and 12 healthy subjects (10 men; mean age, 45.0 years +/- 5.4). Endobronchial biopsies were performed in 11 subjects. Bronchial cross-sectional wall area (WA) and lumen area (LA) were measured by using validated software, and wall thickness (WT), total area (TA), WA/LA ratio, and WA/TA ratio were computed. Slope and maximal local slope of each parameter along bronchial generations were calculated. RESULTS: Patients with asthma demonstrated significantly lower LA, TA, and WA and higher WA/LA and WA/TA ratios than healthy subjects downward from the fourth bronchial generation. Correlations existed between slope and maximal local slope of WA/LA and/or WA/TA ratios and functional data reflecting bronchial obstruction (r = 0.46-0.58, P = .001-.025), subepithelial membrane thickness (r = 0.67-0.69, P = .019-.023), smooth muscle layer area (r = 0.75, P = .007), subepithelial layer area (r = 0.81, P = .002), and infiltration of the bronchial wall by inflammatory cells (r = 0.67-0.86, P = .049-.003). CONCLUSION: Axial reconstructions with orthogonal measurements along the airways enabled by three-dimensional segmentation methods are able to demonstrate significant changes in bronchial morphometry, predicting airflow limitation in asthma, and may have a role in the noninvasive measurement of airway remodeling.

Bronchial morphometry in smokers: comparison with healthy subjects by using 3D CT.

The assessment of airway dimensions in patients with airway disease by using computed tomography (CT) has been limited by the obliquity of bronchi, the ability to identify the bronchial generation, and the limited number of bronchial measurements. The aims of the present study were (i) to analyze cross-sectional bronchial dimensions after automatic orthogonal reconstruction of all visible bronchi on CT images, and (ii) to compare bronchial morphometry between smokers and nonsmokers. CT and pulmonary function tests were performed in 18 males separated into two groups: 9 nonsmokers and 9 smokers. Bronchial wall area (WA) and lumen area (LA) were assessed using dedicated 3D software able to provide accurate cross-sectional measurements of all visible bronchi on CT. WA/LA and WA/(WA+LA) ratios were computed and all parameters were compared between both groups. Smokers demonstrated greater WA, smaller LA, and consequently greater LA/WA and LA/(WA+LA) ratios than nonsmokers. These differences occurred downward starting at the fourth bronchial generation. 3D quantitative CT method is able to demonstrate significant changes in bronchial morphometry related to tobacco consumption.

[Allergy and refractory asthma: new etiological and treatment pathways]. / Allergie et asthme réfractaire: nouvelles pistes étiologiques et thérapeutiques.

Severe asthma is often refractory to standard treatments and presents real problems of management. It necessitates rigorous clinical procedures to identify the aggravating factors. Allergic factors probably play an important role but are often ignored; atopy is more often associated with mild or moderate asthma. The prevalence of severe refractory asthma is not known with any precision, in view of the lack of a consensus definition. Few studies have examined the role of allergic factors. From a pathophysiologic perspective, genetic factors are probably responsible for greater severity, and allergic response plays an important role in some severe asthma phenotypes. From an environmental perspective, some airborne allergens are associated with the refractory character of the disease. Molds such as Alternaria are, for example, implicated in the onset of asthma attacks, as are some occupational exposure. Better knowledge of the pathophysiology of refractory asthma and its allergic dimensions have made it possible to use new treatment agents, such as omalizumab. New treatment targets are being discovered and evaluated in this domain.

Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma.

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by different patterns of airway remodeling, which all include an increased mass of bronchial smooth muscle (BSM). A remaining major question concerns the mechanisms underlying such a remodeling of BSM. Because mitochondria play a major role in both cell proliferation and apoptosis, we hypothesized that mitochondrial activation in BSM could play a role in this remodeling. We describe that both the mitochondrial mass and oxygen consumption were higher in the BSM from asthmatic subjects than in that from both COPD and controls. This feature, which is specific to asthma, was related to an enhanced mitochondrial biogenesis through up-regulation of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A. The priming event of such activation was an alteration in BSM calcium homeostasis. BSM cell apoptosis was not different in the three groups of subjects. Asthmatic BSM was, however, characterized by increased cell growth and proliferation. Both characteristics were completely abrogated in mitochondria-deficient asthmatic BSM cells. Conversely, in both COPD and control BSM cells, induction of mitochondrial biogenesis reproduced these characteristics. Thus, BSM in asthmatic patients is characterized by an altered calcium homeostasis that increases mitochondrial biogenesis, which, in turn, enhances cell proliferation, leading to airway remodeling.

Air trapping in mild and moderate asthma: effect of inhaled corticosteroids.

BACKGROUND: Air trapping reflects small airway obstruction in asthma and can be assessed quantitatively by high-resolution computed tomography (HRCT). Hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) is deposited across all sizes of airways, including the small ones. However, its long-term effect on air trapping remains unknown in uncontrolled asthma. OBJECTIVES: To compare the effect of inhaled corticosteroids of different particle size - HFA-BDP and fluticasone propionate (FP) - on lung attenuation in mild-to-moderate uncontrolled asthma. METHODS: A randomized study was performed to analyze the effect of HFA-BDP (400 microg/d) or FP (500 microg/d) given over a period of 3 months to patients with uncontrolled mild-to-moderate asthma. HRCT was performed with spirometric gating, and lung attenuation was measured at residual volume and at pulmonary total capacity. The difference between inspiratory and expiratory attenuation was calculated as an air trapping index. RESULTS: Twenty-five out of 58 patients had abnormal air trapping and could be included in the study. Lung attenuation significantly diminished in the posterior zones of the lung after a 3-month treatment with HFA-BDP or FP, but the difference between the groups was not significant. Adjusted mean variations of the air trapping index from baseline to treatment completion were 34.3 (11.2, 57.3) and 27.3 (6.4, 48.2) for the HFA-BDP and FP groups, respectively. However, the reduction of air trapping area was more pronounced in the group treated with HFA-BDP. CONCLUSION: Inhaled corticosteroids decrease air trapping in uncontrolled asthma regardless of their particle size. CLINICAL IMPLICATIONS: In mild-to-moderate asthma, air trapping assessed by HRCT may be a new outcome related to the control of the disease.

Assessment of airways with three-dimensional quantitative thin-section CT: in vitro and in vivo validation.

PURPOSE: To prospectively validate the ability of customized three-dimensional (3D) software to enable bronchial tree skeletonization, orthogonal reconstruction of the main bronchial axis, and measurement of cross-sectional wall area (WA) and lumen area (LA) of any visible bronchus on thin-section computed tomographic (CT) images. MATERIALS AND METHODS: Institutional review board approval and patient agreement and informed consent were obtained. Software was validated in a phantom that consisted of seven tubes and an excised human lung obtained and used according to institutional guidelines. In vivo validation was performed with multi-detector row CT in six healthy subjects (mean age, 47 years; range, 20-55 years). Intra- and interobserver agreement and reproducibility over time for bronchial tree skeletonization were evaluated with Bland-Altman analysis. Concordance in identifying bronchial generation was assessed with the kappa statistic. WA and LA obtained with the manual method were compared with WA and LA obtained with validated software by means of the Wilcoxon test and Bland-Altman analysis. RESULTS: WA and LA measurements in the phantom were reproducible over multiple sessions (P > .90) and were not significantly different from WA and LA assessed with the manual method (P > .62). WA and LA measurements in the excised lung and the subjects were not different from measurements obtained with the manual method (intraclass correlation coefficient > 0.99). All lobar bronchi and 80.8% of third generation bronchi, 72.5% of fourth generation bronchi, and 37.7% of fifth generation bronchi were identified in vivo. Intra- and interobserver agreement and reproducibility over time for airway skeletonization and concordance in identifying bronchial generation were good to excellent (intraclass correlation coefficient > 0.98, kappa > 0.54, respectively). CONCLUSION: This method enables accurate and reproducible measurement of WA and LA on reformatted CT sections perpendicular to the main axis of bronchi visible on thin-section CT scans.

Bronchial measurement with three-dimensional quantitative thin-section CT in patients with cystic fibrosis.

PURPOSE: To prospectively compare bronchial measurements obtained with three-dimensional quantitative thin-section computed tomography (CT) with those obtained with thin-section CT scores in the assessment of the severity of pulmonary cystic fibrosis (CF). MATERIALS AND METHODS: Ethics committee approval was obtained. Sixteen patients with CF (mean age, 26.6 years; range, 18-42 years) and five healthy volunteers (mean age, 27.4 years; range, 21-44 years) gave written informed consent, underwent multi-detector row CT and a pulmonary function test (PFT), and were divided into three groups: group A, healthy volunteers; group B, patients with mild CF (forced expiratory volume in 1 second [FEV(1)] > 80%); and group C, patients with severe CF (FEV(1) < 80%). Two observers obtained thin-section CT scores with eight scoring systems. Bronchial cross-sectional wall area (WA), lumen area (LA), airway area, and wall thickness (WT) were measured with customized software and were normalized on the basis of subject body surface. Morphologic characteristics, PFT results, thin-section CT scores, and quantitative measurements were compared among the three groups with analysis of variance. Correlations among bronchial measurements, PFT results, and CT scores were calculated with the Spearman correlation coefficient. RESULTS: Thin-section CT scores were different between group C and either group A or group B (P < .05). WA and WT were significantly different among all groups (P < .05). Interscore correlations and correlations between bronchial parameters and scores were high (r > 0.89, P < .0001). Scores, WA, and WT were significantly correlated with PFT obstructive indexes (P < .047). CONCLUSION: WA and WT assessed with dedicated software on multi-detector row CT images allow evaluation of the severity of pulmonary CF.

Airway wall thickness in cigarette smokers: quantitative thin-section CT assessment.

PURPOSE: To design and validate a dedicated software tool to measure airway dimensions on thin-section computed tomographic (CT) images and to use the tool to prospectively compare airway wall thickness in nonsmokers with normal lung function with that in smokers with and without chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: All subjects gave written informed consent. The study was approved by local ethics committee. With Laplacian of Gaussian algorithm, software was tested in phantom and excised sheep lung fixed in inflation and validated with Bland-Altman analysis. Study prospectively included nine nonsmokers (six women, three men; mean age, 53 years +/- 5.6 [standard error of the mean]) with normal lung function (group 1), seven smokers (three women, four men; mean age, 56 years +/- 5.6) with normal lung function (group 2), and eight smokers (zero women, eight men; mean age, 65 years +/- 4.0) with COPD. Calculations were determined with spirometrically gated CT: For each selected bronchus, the wall area (WA), internal area (IA), airway caliber (sum of IA and WA), and WA/IA ratio were calculated. For each patient, summation of WA to summation of IA (SigmaWA/SigmaIA) ratio, which reflected normalized airway wall thickness, was calculated. Groups were compared by using analysis of variance with generalized linear model and unpaired t test. Pearson correlation coefficient was used to assess correlation between software measurements and pulmonary function test results. RESULTS: Comparison of measurements in phantom and excised sheep lung with algorithm measurements revealed that the latter were reliable and repeatable. In clinical study, SigmaWA/SigmaIA ratio was significantly different among three groups (P < .001). Normalized airway wall thickness and IA were significantly related to lung function test data, including forced expiratory volume in 1 second (r = -0.54, P = .006), specific airway conductance (r = -0.45, P = .03), and forced expiratory flow between 25% and 75% of vital capacity (r = -0.65, P < .001). CONCLUSION: This software provides accurate and reproducible measurements of IA and WA of bronchi on thin-section CT images and demonstrates that in vivo normalized airway wall thickness was larger in smokers with COPD than it was in smokers or nonsmokers without COPD.