Serum from patients with asthma potentiates macrophage phagocytosis and human mesenchymal stromal cell therapy in experimental allergic asthma.

BACKGROUND/AIMS: Although several studies have demonstrated that mesenchymal stromal cells (MSCs) exhibit beneficial immunomodulatory properties in preclinical models of allergic asthma, effects on airway remodeling have been controversial. Recent evidence has shown that MSCs modify their in vivo immunomodulatory actions depending on the specific inflammatory environment encountered. Accordingly, we assessed whether the therapeutic properties of human mesenchymal stromal cells (hMSCs) could be potentiated by conditioning these cells with serum (hMSC-serum) obtained from patients with asthma and then transplanted in an experimental model of house dust mite (HDM)-induced allergic asthma. METHODS: hMSC and hMSC-serum were administered intratracheally 24 h after the final HDM challenge. hMSC viability and inflammatory mediator production, lung mechanics and histology, bronchoalveolar lavage fluid (BALF) cellularity and biomarker levels, mitochondrial structure and function as well as macrophage polarization and phagocytic capacity were assessed. RESULTS: Serum preconditioning led to: (i) increased hMSC apoptosis and expression of transforming growth factor-ß, interleukin (IL)-10, tumor necrosis factor-α-stimulated gene 6 protein and indoleamine 2,3-dioxygenase-1; (ii) fission and reduction of the intrinsic respiratory capacity of mitochondria; and (iii) polarization of macrophages to M2 phenotype, which may be associated with a greater percentage of hMSCs phagocytosed by macrophages. Compared with mice receiving hMSCs, administration of hMSC-serum led to further reduction of collagen fiber content, eotaxin levels, total and differential cellularity and increased IL-10 levels in BALF, improving lung mechanics. hMSC-serum promoted greater M2 macrophage polarization as well as macrophage phagocytosis, mainly of apoptotic hMSCs. CONCLUSIONS: Serum from patients with asthma led to a greater percentage of hMSCs phagocytosed by macrophages and triggered immunomodulatory responses, resulting in further reductions in both inflammation and remodeling compared with non-preconditioned hMSCs.

Recurrent WWTR1 S89W mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix.

Clear cell carcinoma (CCC) of the cervix (cCCC) is a rare and aggressive type of human papillomavirus (HPV)-negative cervical cancer with limited effective treatment options for recurrent or metastatic disease. Historically, CCCs of the lower genital tract were associated with in utero diethylstilbestrol exposure; however, the genetic landscape of sporadic cCCCs remains unknown. Here we sought to define the molecular underpinning of cCCCs. Using a combination of whole-exome, targeted capture, and RNA-sequencing, we identified pathogenic genetic alterations in the Hippo signaling pathway in 50% (10/20) of cCCCs, including recurrent WWTR1 S89W somatic mutations in 40% (4/10) of the cases harboring mutations in the Hippo pathway. Irrespective of the presence or absence of Hippo pathway genetic alterations, however, all primary cCCCs analyzed in this study (n = 20) harbored features of Hippo pathway deregulation at the transcriptomic and protein levels. In vitro functional analysis revealed that expression of the WWTR1 S89W mutation leads to reduced binding of TAZ to 14-3-3, promoting constitutive nuclear translocation of TAZ and Hippo pathway repression. WWTR1 S89W expression was found to lead to acquisition of oncogenic behavior, including increased proliferation, migration, and colony formation in vitro as well as increased tumorigenesis in vivo, which could be reversed by targeted inhibition of the TAZ/YAP1 complex with verteporfin. Finally, xenografts expressing WWTR1 S89W displayed a shift in tumor phenotype, becoming more infiltrative as well as less differentiated, and were found to be composed of cells with conspicuous cytoplasmic clearing as compared to controls. Our results demonstrate that Hippo pathway alterations are likely drivers of cCCCs and likely contribute to the clear cell phenotype. Therapies targeting this pathway may constitute a new class of treatment for these rare, aggressive tumors. © 2022 The Pathological Society of Great Britain and Ireland.

Rapid On-Site Evaluation by Endosonographer of Endoscopic Ultrasound Fine-Needle Aspiration of Solid Pancreatic Lesions: A Randomized Controlled Trial.

OBJECTIVES: Rapid on-site evaluation (ROSE) by cytopathologists during endoscopic ultrasound-fine-needle aspiration (EUS-FNA) of solid pancreatic lesions (SPLs) improves adequacy and diagnostic accuracy while reducing the number of needle passes. We evaluated the usefulness of ROSE performed by the endosonographer. METHODS: Patients with an SPL were randomly assigned to EUS-FNA with ROSE or non-ROSE. Procedure duration, number of needle passes, specimen adequacy, and adverse event rates were compared. RESULTS: Sixty-five patients were enrolled (33 in the ROSE vs 32 in the non-ROSE group). Both groups were similar in terms of age, sex, size, and location of the lesion. Specimen adequacy rates were high and similar between groups. Mean (standard deviation) procedure duration was shorter in the ROSE versus non-ROSE group (30.0 [11.3] vs 37.0 [7.2] minutes, P < 0.005), as well as the mean (standard deviation) number of needle passes (2.6 [0.8] vs 3.5 [0.8], P < 0.005). Accuracy parameters as sensitivity and accuracy of ROSE by the endosonographer for malignancy were 93% and 88%, respectively. CONCLUSIONS: After specific training, the endosonographer can accurately evaluate samples during EUS-FNA of SPL, allowing for a shorter procedure duration and a lower number of needle passes.

Safety and effectiveness of bronchial thermoplasty after 10 years in patients with persistent asthma (BT10+): a follow-up of three randomised controlled trials.

BACKGROUND: Bronchial thermoplasty is an endoscopic treatment for uncontrolled asthma. Previous randomised clinical trials have shown that bronchial thermoplasty reduces severe exacerbations in people with asthma. However, the long-term efficacy and safety of bronchial thermoplasty beyond 5 years is unknown. The BT10+ study aimed to investigate the efficacy and safety of bronchial thermoplasty after 10 or more years of follow-up. METHODS: BT10+ was an international, multicentre, follow-up study of participants who were previously enrolled in the AIR, RISA, and AIR2 trials and who had 10 or more years of follow-up since bronchial thermoplasty treatment. Data on patient demographics, quality of life, lung function, CT scans (AIR2 participants only), severe exacerbations, and health-care use during the previous year were collected at the BT10+ 10-year outcomes study visit. The primary effectiveness endpoint was durability of the thermoplasty treatment effect, determined by comparing the proportion of participants who had severe exacerbations during the first and fifth years after bronchial thermoplasty treatment with the proportion of participants who had severe exacerbations during the 12-month period before the BT10+ visit. The primary safety endpoint was the absence of clinically significant post-treatment respiratory image changes after bronchial thermoplasty, defined as bronchiectasis or bronchial stenosis as confirmed by pulmonary volumetric high-resolution CT scan at the BT10+ visit (AIR2 participants only). All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03243292. The last patient was enrolled on Dec 11, 2018. The last patient completed follow-up on Jan 10, 2019. FINDINGS: The BT10+ study enrolled 192 (45%) of the 429 participants who were enrolled in the AIR, RISA, and AIR2 trials. The BT10+ participants comprised 136 who received bronchial thermoplasty (52% of the 260 participants who received bronchial thermoplasty in the original trials), and 56 sham or control participants (33% of 169 from the original trials). 18 (32%) sham or control participants received bronchial thermoplasty after the previous trials concluded. The participants included in BT10+ were followed for 10·8-15·6 years (median 12·1 years) post-treatment. Baseline characteristics were similar between participants enrolled in BT10+ and those not enrolled. Participants treated with bronchial thermoplasty had similar proportions of severe exacerbations at the BT10+ visit (34 [25%] of 136 participants) compared with 1 year (33 [24%] of 135 participants; difference 0·6%, 95% CI -9·7 to 10·8) and 5 years (28 [22%] of 130 participants; difference 3·5%, -6·7% to 13·6) after treatment. Quality of life measurements and spirometry were similar between year 1, year 5, and the BT10+ visit. At the BT10+ study visit, pulmonary high-resolution CT scans from AIR2 participants treated with bronchial thermoplasty showed that 13 (13%) of 97 participants had bronchiectasis. When compared with baseline high-resolution CT scans, six (7%) of 89 participants treated with bronchial thermoplasty who did not have bronchiectasis at baseline had developed bronchiectasis after treatment (5 classified as mild, 1 classified as moderate). Participants treated with bronchial thermoplasty after the original study and participants in the sham or control group also had reductions in severe exacerbations at the BT10+ visit compared with baseline. INTERPRETATION: Our findings suggest that efficacy of bronchial thermoplasty is sustained for 10 years or more, with an acceptable safety profile. Therefore, bronchial thermoplasty is a long-acting therapeutic option for patients with asthma that remains uncontrolled despite optimised medical treatment. FUNDING: Boston Scientific.

An Uncommon Lung Neoplasm in a Young Patient: Diagnostic Challenges.

BACKGROUND Adenosquamous carcinoma of the lung (ASC) is a rare subtype of non-small-cell lung carcinoma (NSCLC), histologically defined by the presence of both squamous cell carcinoma and adenocarcinoma components. This aggressive malignancy has been rarely described in young female patients. Due to its low incidence and difficult-to-establish preoperative diagnosis, little is known about the complete clinical course for young patients with this specific NSCLC subtype. Moreover, a history of smoking is positively associated with ASC, but evidence for an association with exposure to secondhand smoke is sparse. CASE REPORT We present the case of a previously healthy 29-year-old woman with a long-standing history of secondhand smoke exposure, who was ultimately diagnosed with advanced ASC via fiberoptic bronchoscopy with transbronchial biopsy after a number of different investigations and treatments performed outside our service. She had visited many clinicians in 4 months of symptoms, initially presented as thoracic pain and cough thought to be due to a complicated pneumonia. Symptoms progressed despite empiric treatment and eventually included low back pain, weight loss, and night sweats. The hypothesis of tuberculosis was then investigated and discarded, at which point, 3 months after the onset of symptoms, she had a CT scan of the chest, revealing a pulmonary mass. She was referred to our hospital to further investigate this finding via fiberoptic bronchoscopy with transbronchial biopsy. During the procedure, she experienced an acute exacerbation of the low back pain, which prompted her admission in the Emergency Department, and she was later admitted to our pneumology ward. An extensive treatment plan including chemotherapy and radiotherapy was initially started, but could not be completed due to rapid disease progression, defined by pulmonary and spine metastatic implants, which limited treatment to palliative care. The patient died 6 months after the initial onset of symptoms. CONCLUSIONS This case report shows the clinical course of a difficult and rare diagnosis, and demonstrates the high level of suspicion required for the early diagnosis of lung neoplasms in young patients.

Endobronchial ultrasound-guided transbronchial needle aspiration versus mediastinoscopy for mediastinal staging of lung cancer: A systematic review of economic evaluation studies.

INTRODUCTION: The emergence of endobronchial ultrasound (EBUS) changed the approach to staging lung cancer. As a new method being incorporated, the use of EBUS may lead to a shift in clinical and costs outcomes. OBJECTIVE: The aim of this systematic review is to gather information to better understand the economic impact of implementing EBUS. METHODS: This review is reported according to the PRISMA statement and registered on PROSPERO (CRD42019107901). Search keywords were elaborated considering descriptors of terms related to the disease (lung cancer / mediastinal staging of lung cancer) and the technologies of interest (EBUS and mediastinoscopy) combined with a specific economic filter. The literature search was performed in MEDLINE, EMBASE, LILACS, Cochrane Library of Trials, Web of Science, Scopus and National Health System Economic Evaluation Database (NHS EED) of the Center for Reviews and Dissemination (CRD). Screening, selection of articles, data extraction and quality assessment were carried out by two reviewers. RESULTS: Seven hundred and seventy publications were identified through the database searches. Eight articles were included in this review. All publications are full economic evaluation studies, one cost-effectiveness, three cost-utility, and four cost-minimization analyses. The costs of strategies using EBUS-TBNA were lower than the ones using mediastinoscopy in all studies analyzed. Two of the best quality scored studies demonstrate that the mediastinoscopy strategy is dominated by the EBUS-TBNA strategy. CONCLUSION: Information gathered in the eight studies of this systematic review suggest that EBUS is cost-effective compared to mediastinoscopy for mediastinal staging of lung cancer.

Oncogenic properties and signaling basis of the PAX8-GLIS3 fusion gene.

Hyalinizing trabecular tumors of the thyroid are rare and mostly benign epithelial neoplasms of follicular cell origin, which have recently been shown to be underpinned by the PAX8-GLIS3 fusion gene. In our study, we sought to investigate the potential oncogenic mechanisms of the PAX8-GLIS3 fusion gene. Forced expression of PAX8-GLIS3 was found to increase proliferation, clonogenic potential and migration of human nonmalignant thyroid (Nthy-ori 3-1) and embryonic kidney (HEK-293) cells. Moreover, in xenografts, Nthy-ori 3-1 PAX8-GLIS3 expressing cells generated significantly larger and more proliferative tumors compared to controls. These oncogenic effects were found to be mediated through activation of the Sonic Hedgehog (SHH) pathway. Targeting of smoothened (SMO), a key protein in the SHH pathway, using the small molecule inhibitor Cyclopamine partially reversed the increased proliferation, colony formation and migration in PAX8-GLIS3 expressing cells. Our data demonstrate that the oncogenic effects of the PAX8-GLIS3 fusion gene are, at least in part, due to an increased activation of the SHH pathway.

Increased Frequency of Memory CD4+ T-Cell Responses in Individuals With Previously Treated Extrapulmonary Tuberculosis.

Extrapulmonary TB (EPTB) occurs with increased frequency in persons with underlying immunodeficiency. Even after recovery from acute illness, differences in immune phenotype and activation persist. Studies defining characteristics of immune responses after recovery from extrapulmonary TB may provide insights into factors that increase TB risk. We performed two case-control studies (in the United States and Brazil) among HIV-seronegative adults with previous EPTB (n = 9; 25), previous pulmonary TB (n = 7; 25), latent M. tuberculosis (Mtb) infection (n = 11; 25), and uninfected TB contacts (n = 10; 25). We assessed the frequency of dual CD4+ interferon-γ and tumor necrosis factor-α responses after stimulation with overlapping Mtb peptides from ESAT-6 or CFP-10, or gamma-irradiated Mtb H37Rv, proliferative responses to Mtb antigens, T-regulatory cell (Treg) frequency and phenotype. In both study populations, individuals with prior EPTB had the highest frequency of intracellular cytokine-producing cells in response to Mtb antigens (p < 0.05; p <.0001). Persons with prior EPTB in Brazil had the highest levels of CD4 proliferation to Mtb antigens (p < 0.0001), and the highest expression of CD39 on Tregs (p < 0.0001). Individuals with treated EPTB maintained high frequencies of Mtb-specific memory responses and active Treg cells, suggesting that susceptibility to EPTB occurs despite the ability to develop and maintain enhanced adaptive immune responses.

Endobronchial ultrasound-guided transbronchial needle aspiration versus mediastinoscopy for mediastinal staging of lung cancer: A protocol for a systematic review of economic evaluation studies.

BACKGROUND: Lung cancer is a major health problem, with estimates of 1.6 million tumor-related deaths annually worldwide. The emergence of endobronchial ultrasound (EBUS), a minimally invasive procedure capable of providing valuable information for primary tumor diagnosis and mediastinal staging, significantly changed the approach of pulmonary cancer, becoming part of the routine mediastinal evaluation of lung cancer in developed countries. Some economic evaluation studies published in the last 10 years have already analyzed the incorporation of the EBUS technique in different health systems. The aim of this systematic review is to synthesize the relevant information brought by these studies to better understand the economic effect of the implementation of this staging tool. METHODS: The systematic review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. Eletronic databases (Medline, Lilacs, Embase, Cochrane Library of Trials, Web of Science, Scopus, National Health System Economic Evaluation Database) will be searched for full economic analyses regarding the use of EBUS-guided transbronchial needle aspiration (EBUS-TBNA) compared to the surgical technique of mediastinoscopy for the mediastinal staging of lung cancer. Two authors will perform the selection of studies, data extraction, and the assessment of risk of bias. Occasionally, a senior reviewer will participate, if necessary, on study selection or data extraction. RESULTS: Results will be published in a peer-reviewed journal. CONCLUSION: This review may influence a more cost-effective mediastinal staging approach for patients with lung cancer around the world and help health decision makers decide whether the EBUS-TBNA technique should be incorporated into their health systems and how to do it efficiently. PROTOCOL REGISTRY: PROSPERO 42019107901.

Mesenchymal stromal cell therapy in COPD: from bench to bedside.

COPD is the most frequent chronic respiratory disease and a leading cause of morbidity and mortality. The major risk factor for COPD development is cigarette smoke, and the most efficient treatment for COPD is smoking cessation. However, even after smoking cessation, inflammation, apoptosis, and oxidative stress may persist and continue contributing to disease progression. Although current therapies for COPD (primarily based on anti-inflammatory agents) contribute to the reduction of airway obstruction and minimize COPD exacerbations, none can avoid disease progression or reduce mortality. Within this context, recent advances in mesenchymal stromal cell (MSC) therapy have made this approach a strong candidate for clinical use in the treatment of several pulmonary diseases. MSCs can be readily harvested from diverse tissues and expanded with high efficiency, and have strong immunosuppressive properties. Preclinical studies have demonstrated encouraging outcomes of MSCs therapy for lung disorders, including emphysema. These findings instigated research groups to assess the impact of MSCs in human COPD/emphysema, but clinical results have fallen short of expectations. However, MSCs have demonstrated a good adjuvant role in the clinical scenario. Trials that used MSCs combined with another, primary treatment (eg, endobronchial valves) found that patients derived greater benefit in pulmonary function tests and/or quality of life reports, as well as reductions in systemic markers of inflammation. The present review summarizes and describes the more recent preclinical studies that have been published about MSC therapy for COPD/emphysema and discusses what has already been applied about MSCs treatment in COPD patients in the clinical setting.

Combined Bone Marrow-Derived Mesenchymal Stromal Cell Therapy and One-Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial.

One-way endobronchial valves (EBV) insertion to reduce pulmonary air trapping has been used as therapy for chronic obstructive pulmonary disease (COPD) patients. However, local inflammation may result and can contribute to worsening of clinical status in these patients. We hypothesized that combined EBV insertion and intrabronchial administration of mesenchymal stromal cells (MSCs) would decrease the inflammatory process, thus mitigating EBV complications in severe COPD patients. This initial study sought to investigate the safety of this approach. For this purpose, a phase I, prospective, patient-blinded, randomized, placebo-controlled design was used. Heterogeneous advanced emphysema (Global Initiative for Chronic Lung Disease [GOLD] III or IV) patients randomly received either allogeneic bone marrow-derived MSCs (108 cells, EBV+MSC) or 0.9% saline solution (EBV) (n = 5 per group), bronchoscopically, just before insertion of one-way EBVs. Patients were evaluated 1, 7, 30, and 90 days after therapy. All patients completed the study protocol and 90-day follow-up. MSC delivery did not result in acute administration-related toxicity, serious adverse events, or death. No significant between-group differences were observed in overall number of adverse events, frequency of COPD exacerbations, or worsening of disease. Additionally, there were no significant differences in blood tests, lung function, or radiological outcomes. However, quality-of-life indicators were higher in EBV + MSC compared with EBV. EBV + MSC patients presented decreased levels of circulating C-reactive protein at 30 and 90 days, as well as BODE (Body mass index, airway Obstruction, Dyspnea, and Exercise index) and MMRC (Modified Medical Research Council) scores. Thus, combined use of EBV and MSCs appears to be safe in patients with severe COPD, providing a basis for subsequent investigations using MSCs as concomitant therapy. Stem Cells Translational Medicine 2017;6:962-969.

Endobronchial ultrasound in real life: primary diagnosis and mediastinal staging of lung cancer in patients submitted to thoracic surgery.

BACKGROUND: Since the first articles published for over 10 years ago, endobronchial ultrasound (EBUS) has gained a strong scientific backing and has been incorporated into routine medical practice in pulmonology and thoracic surgery centers. How is EBUS performing outside the scientific environment, as a diagnostic and mediastinal staging tool in a subset of patients that undergo thoracic surgery, is an interesting question. METHODS: This study evaluated consecutive patients who, during the period from January 2010 to August 2012, were submitted to EBUS and later to thoracic surgery. The samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) were compared to surgical samples. The primary endpoint was the proportion of patients with a final diagnosis of non-small cell lung cancer (NSCLC) by EBUS-TBNA correctly subtyped. The secondary endpoint was the negative predictive value (NPV) of EBUS-TBNA for mediastinal staging of lung cancer. RESULTS: Two hundred eighty seven patients were studied. Considering 84 patients with a final diagnosis of NSCLC by EBUS-TBNA, 79 % (CI 95 % 70.1-87.3) were correctly subclassified. The NPV of EBUS-TBNA for mediastinal staging was 89 % (IC 95 % 84.9-92.7). From a total of 21 false negative cases of mediastinal staging, 16 (76 %) did not undergo positron emission tomography-computed tomography (PET-CT) before the EBUS and in 15 (71 %) the affected lymph node chain was not punctured by EBUS-TBNA. Ten (47 %) patients had only lymph node metastases not directly accessible by the EBUS. CONCLUSIONS: Performed in hospital routine and in patients submitted to thoracic surgery, EBUS-TBNA proved to be a good tool for proper pathological diagnosis of lung cancer. The negative predictive value of 89 % for mediastinal staging of lung cancer is comparable to that reported in previous studies, but the relatively high number of 21 false negative cases points to the need for standardization of routine strategies before, during and after EBUS.

Difficulties in access and estimates of public beds in intensive care units in the state of Rio de Janeiro.

OBJECTIVE: To estimate the required number of public beds for adults in intensive care units in the state of Rio de Janeiro to meet the existing demand and compare results with recommendations by the Brazilian Ministry of Health. METHODS: The study uses a hybrid model combining time series and queuing theory to predict the demand and estimate the number of required beds. Four patient flow scenarios were considered according to bed requests, percentage of abandonments and average length of stay in intensive care unit beds. The results were plotted against Ministry of Health parameters. Data were obtained from the State Regulation Center from 2010 to 2011. RESULTS: There were 33,101 medical requests for 268 regulated intensive care unit beds in Rio de Janeiro. With an average length of stay in regulated ICUs of 11.3 days, there would be a need for 595 active beds to ensure system stability and 628 beds to ensure a maximum waiting time of six hours. Deducting current abandonment rates due to clinical improvement (25.8%), these figures fall to 441 and 417. With an average length of stay of 6.5 days, the number of required beds would be 342 and 366, respectively; deducting abandonment rates, 254 and 275. The Brazilian Ministry of Health establishes a parameter of 118 to 353 beds. Although the number of regulated beds is within the recommended range, an increase in beds of 122.0% is required to guarantee system stability and of 134.0% for a maximum waiting time of six hours. CONCLUSIONS: Adequate bed estimation must consider reasons for limited timely access and patient flow management in a scenario that associates prioritization of requests with the lowest average length of stay.

Impact of Pre-Analytical Variables on Cancer Targeted Gene Sequencing Efficiency.

Tumor specimens are often preserved as formalin-fixed paraffin-embedded (FFPE) tissue blocks, the most common clinical source for DNA sequencing. Herein, we evaluated the effect of pre-sequencing parameters to guide proper sample selection for targeted gene sequencing. Data from 113 FFPE lung tumor specimens were collected, and targeted gene sequencing was performed. Libraries were constructed using custom probes and were paired-end sequenced on a next generation sequencing platform. A PCR-based quality control (QC) assay was utilized to determine DNA quality, and a ratio was generated in comparison to control DNA. We observed that FFPE storage time, PCR/QC ratio, and DNA input in the library preparation were significantly correlated to most parameters of sequencing efficiency including depth of coverage, alignment rate, insert size, and read quality. A combined score using the three parameters was generated and proved highly accurate to predict sequencing metrics. We also showed wide read count variability within the genome, with worse coverage in regions of low GC content like in KRAS. Sample quality and GC content had independent effects on sequencing depth, and the worst results were observed in regions of low GC content in samples with poor quality. Our data confirm that FFPE samples are a reliable source for targeted gene sequencing in cancer, provided adequate sample quality controls are exercised. Tissue quality should be routinely assessed for pre-analytical factors, and sequencing depth may be limited in genomic regions of low GC content if suboptimal samples are utilized.

Feasibility study of a smoking cessation intervention in Directly Observed Therapy Short-Course tuberculosis treatment clinics in Rio de Janeiro, Brazil.

A pilot feasibility study was conducted to determine whether Directly Observed Therapy Short-Course (DOTS) workers could be trained to deliver smoking cessation counseling and referral interventions, identify potential barriers to a full-scale randomized controlled trial on the effectiveness of integrated smoking cessation in DOTS, and determine whether tuberculosis (TB) patients who smoke would agree to participate in such a program. DOTS providers in two Rio de Janeiro primary health clinics received 1-day training in cessation counseling. They completed pre- and post-training surveys and participated in post-program focus groups. Patients were surveyed 3 months after program completion, and semiquantitative urine assays for cotinine were used to confirm cessation. Providers' mean self-efficacy scores for cessation counseling improved significantly (advise to quit, assess readiness, assist with quitting, and arrange follow-up) from scores (on a scale of 1-5) of 2-3 pre-training to 3-4 post-training (P < 0.05), with only ability to change motivation not significant. Providers' knowledge about cessation (withdrawal, nicotine replacement therapy, precontemplation) was low before training and did not improve after training (P > 0.1 for all comparisons). Implementation of a smoking cessation intervention by DOTS providers in TB clinics in Brazil is feasible. Randomized controlled trials to test intervention effectiveness in reducing TB-related morbidity must include cross-training for tobacco control and TB providers. Smoking cessation in DOTS programs may be important in reducing the global burden of TB, improving the health of TB patients, and reducing TB transmission in households.

[Inflammatory cells and their mediators in COPD pathogenesis]. / Células inflamatórias e seus mediadores na patogênese da DPOC.

Chronic Obstructive Pulmonary Disease (COPD) is considered to be a progressive disease characterized by chronic inflammation and irreversible airflow obstruction, mainly caused by tobacco smoking. Based on World Health Organization data, COPD will be the fourth cause of mortality in 2020, after vascular, cardiac and cerebral diseases and cancer. To date no therapy retards or suppresses progression of COPD. The chronic inflammatory process caused by tobacco smoking promotes structural changes predominantly in the small airways (less than 2mm). Macrophages, neutrophils and T cells are thought to be important key players, as well as structural cells like fibroblasts, epithelial and smooth muscle cells. The interaction between macrophages and lymphocytes, especially CD8+, has been implicated in the pathogenesis of COPD. Chemokines such as CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC and CCL5/ RANTES have been described as possibly responsible for recruitment of T cells and blood monocytes increasing the number of macrophages and CD8+ T cells in the lung of COPD patients. The study of the influx of mononuclear cells to the lung is very important not only to promote a better understanding of the COPD physiopathology but also to help identify new targets for treatment. Based on this new evidence, the study of several mediator antagonists that can block the recruitment of inflammatory cells to the lung have been tested in COPD.

Bronchoalveolar lavage analysis in victims of severe facial burns.

OBJECTIVE: To analyze bronchoalveolar lavage (BAL) specimens of burn victims who inhaled smoke, in order to identify alterations associated with mortality or survival. METHODS: Eighteen victims of facial burns were submitted to BAL up to 24 h after the event. We investigated cell and protein content, including TNF-alpha, HLA-DR, CD14, CD68 and iNOS. RESULTS: Of the 18 patients submitted to bronchoscopy, 8 (44.4%) died during the follow-up period. The mean age of patients who died was significantly higher (44.7 vs. 31.5 years). On average, the patients who died had burns covering 60.1% of the total body surface area, compared with 26.1% in the survivors (p < 0.0001). Of the 18 patients submitted to bronchoscopy, 11 (61.1%) showed endoscopic signs of smoke inhalation injury, and 4 (36.4%) of those 11 died. Of the 7 patients with no signs of smoke inhalation injury, 4 (57.1%) died. The mean number of ciliated epithelial cells in the BAL fluid was significantly higher in the patients who died than in the survivors (6.6% vs. 1.4%; p = 0.03). There were no significant differences between the groups in terms of any of the other parameters evaluated. CONCLUSIONS: The total body surface area burned was a predictive factor for mortality. Increased numbers of ciliated epithelial cells in the BAL fluid, denoting bronchial epithelial desquamation, were associated with higher mortality in patients with facial burns.

BCG como modulador do processo inflamatório na asma / BCG as an inflammatory modulator in asthma

A aplicação da vacina do bacilo de Calmette-Guérin (BCG) tem sido bastante estudada, no que concerne ao tratamento/prevenção do processo alérgico da asma. Nesse artigo, será realizada uma revisão crítica dos efeitos do BCG na asma, abordando as conseqüências respiratórias relacionadas a diferentes doses, momentos de aplicação e vias de administração da BCG. O BCG parece aumentar a resposta Th1, contra balançando a resposta alérgica Th2, de modo a reduzir a eosinofilia nos pulmões e a hiperreatividade brônquica, bem como promover maiores níveis de IL-12 e menores níveis de IL-4, com conseqüente melhora da função pulmonar. Entretanto, o papel do BCG na asma ainda é pouco entendido e controverso, estando diversas questões acerca de dose e momento de aplicação do BCG ainda sem respostas. Portanto, mais estudos precisam ser realizados nesta área, para que a terapia com BCG possa vir a ser utilizada de maneira segura e eficaz em humanos.

The application of the vaccine of the bacillus Calmette-Guérin (BCG) has been studied regarding the treatment/prevention of the allergic asthma process. In this article, a review will be conducted on the effects of BCG in asthma addressing the respiratoryconsequences related to different doses, time of application and BCG administration routes. The BCG appears to increase the Th1 response, balancing the allergic Th2 response in order to reduce lung eosinophilia and bronchial hyperreactivity, and promote higher levels of IL-2 and lower levels of IL-4, with consequent improvement in lung function. However, the role of BCG in asthma is still poorly understood and controversial, with several questions related to its dosage and time of application. Therefore, more studies need to be performed in this area, enabling a safe and effective therapy in humans.

Células inflamatórias e seus mediadores na patogênese da DPOC / Inflammatory cells and their mediators in COPD pathogenesis

A doença pulmonar obstrutiva crônica (DPOC) é causada por processo inflamatório crônico que limita o fluxo aéreo, sendo sua principal causa o tabagismo. Conforme dados da Organização Mundial de Saúde (OMS), a DPOC será a quarta causa de mortalidade em 2020, atrás apenas das doenças vasculares, cardíacas e cerebral, além das neoplasias. Apesar do enorme crescimento da prevalência e da mortalidade da DPOC, não existe nenhuma terapêutica que consiga controlar a evolução da doença estabelecida. O processo inflamatório crônico causado pelos gases da fumaça de tabaco desencadeia alterações estruturais que predominam nas pequenas vias aéreas (menores que 2 mm). Essa agressão provoca um processo inflamatório que conta com a participação não apenas de macrófagos, linfócitos e neutrófilos, mas células estruturais como epiteliais, musculares e fibroblastos. Atualmente, a interação entre macrófagos e linfócitos, especialmente CD8+, tem sido implicada na patogênese da DPOC. Quimiocinas como CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC e CCL5/RANTES têm sido descritas como possíveis responsáveis pelo recrutamento de linfócitos T e monócitos sanguíneos, facilitando o aumento de macrófagos alveolares e linfócitos T CD8+ no parênquima dos pacientes com DPOC. Conhecer melhor como ocorre o tráfego de células mononuclerares em direção ao pulmão é fundamental não só para um maior entendimento da patogênese da DPOC, mas para o desenvolvimento de terapêuticas adequadas. Com base nessas evidências tem sido proposto o estudo de moléculas capazes de bloquear de forma específica o recrutamento de células inflamatórias para o pulmão por meio de ação direta nos seus receptores.

Chronic Obstructive Pulmonary Disease (COPD) is considered to be a progressive disease characterized by chronic inflammation and irreversible airflow obstruction, mainly caused by tobacco smoking. Based on World Health Organization data, COPD will be the fourth cause of mortality in 2020, after vascular, cardiac and cerebral diseases and cancer. To date no therapy retards or suppresses progression of COPD. The chronic inflammatory process caused by tobacco smoking promotes structural changes predominantly in the small airways (less than 2mm). Macrophages, neutrophils and T cells are thought to be important key players, as well as structural cells like fibroblasts, epithelial and smooth muscle cells. The interaction between macrophages and lymphocytes, especially CD8+, has been implicated in the pathogenesis of COPD. Chemokines such as CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC and CCL5/ RANTES have been described as possibly responsible for recruitment of T cells and blood monocytes increasing the number of macrophages and CD8+ T cells in the lung of COPD patients. The study of the influx of mononuclear cells to the lung is very important not only to promote a better understanding of the COPD physiopathology but also to help identify new targets for treatment. Based on this new evidence, the study of several mediator antagonists that can block the recruitment of inflammatory cells to the lung have been tested in COPD.

Immune function in young children with previous pulmonary or miliary/meningeal tuberculosis and impact of BCG vaccination.

OBJECTIVE: Children <5 years old are at increased risk of miliary/meningeal tuberculosis, but the immunologic factors that place them at risk are unknown. BCG vaccine protects against miliary/meningeal tuberculosis, but the mechanism of protection is unknown. We assessed for abnormalities in immune response associated with miliary/meningeal or pulmonary tuberculosis in young children. PATIENTS AND METHODS: We conducted a case-control study among HIV-seronegative Brazilian children who were <5 years old. Case subjects had previous culture-confirmed or clinical miliary/meningeal tuberculosis. There were 2 sets of control subjects: those with culture-confirmed pulmonary tuberculosis and purified protein derivative-positive household contacts. All of the children had completed treatment. Peripheral blood mononuclear cells were stimulated (phytohemagglutinin, phytohemagglutinin + interleukin 12, lipopolysaccharide, lipopolysaccharide + interferon-gamma, and purified protein derivative), and cytokine responses (interleukin 1beta, interleukin-4, interleukin-6, interleukin-8, interleukin 10, interleukin 12, interferon-gamma, tumor necrosis factor-alpha, and monocyte chemoattractant protein 1) were quantified by bead-based assay. Median cytokine responses were compared by the Kruskal-Wallis test. Multivariate analysis of variance accounted for multiple comparisons. RESULTS: There were 18 case subjects with miliary/meningeal tuberculosis, 28 pulmonary control subjects, and 29 purified protein derivative-positive control subjects. The median age was 4.2 years. There was no difference in case and control subjects by age, gender, race, BMI, or median CD4 count. Twelve (67%) of 18 case subjects, 26 (93%) of 28 pulmonary control subjects, and 28 (97%) of 29 purified protein derivative-positive subjects had received BCG vaccine. No cytokine defects were identified in case subjects with miliary/meningeal tuberculosis compared with either set of control subjects. Pulmonary control subjects had uniformly higher monocyte chemoattractant protein 1 levels than case subjects with miliary/meningeal tuberculosis and purified protein derivative-positive control subjects, both at rest and with lipopolysaccharide, lipopolysaccharide + interferon-gamma, and purified protein derivative stimulation. Pulmonary control subjects did not have a higher frequency of allele G in the -2518 monocyte chemoattractant protein 1 promoter polymorphism. Case subjects with miliary/meningeal tuberculosis who had received BCG vaccine (n = 12) had lower stimulated interleukin 8 production than children who did not receive BCG vaccine (n = 6). CONCLUSIONS: Children with previous miliary/meningeal tuberculosis did not have a major defect in the cytokine pathways studied. Increased monocyte chemoattractant protein 1 levels were associated with pulmonary disease, occurred despite BCG vaccination, and were not associated with a polymorphism in the monocyte chemoattractant protein 1 promoter.