Mechanical ventilation promotes lung tumour spread by modulation of cholesterol cell content.

BACKGROUND: Mechanical stretch of cancer cells can alter their invasiveness. During mechanical ventilation, lungs may be exposed to an increased amount of stretch, but the consequences on lung tumours have not been explored. METHODS: To characterise the influence of mechanical ventilation on the behaviour of lung tumours, invasiveness assays and transcriptomic analyses were performed in cancer cell lines cultured in static conditions or under cyclic stretch. Mice harbouring lung melanoma implants were submitted to mechanical ventilation and metastatic spread was assessed. Additional in vivo experiments were performed to determine the mechanodependent specificity of the response. Incidence of metastases was studied in a cohort of lung cancer patients that received mechanical ventilation compared with a matched group of nonventilated patients. RESULTS: Stretch increases invasiveness in melanoma B16F10luc2 and lung adenocarcinoma A549 cells. We identified a mechanosensitive upregulation of pathways involved in cholesterol processing in vitro, leading to an increase in pro-protein convertase subtilisin/kexin type 9 (PCSK9) and LDLR expression, a decrease in intracellular cholesterol and preservation of cell stiffness. A course of mechanical ventilation in mice harbouring melanoma implants increased brain and kidney metastases 2 weeks later. Blockade of PCSK9 using a monoclonal antibody increased cell cholesterol and stiffness and decreased cell invasiveness in vitro and metastasis in vivo. In patients, mechanical ventilation increased PCSK9 abundance in lung tumours and the incidence of metastasis, thus decreasing survival. CONCLUSIONS: Our results suggest that mechanical stretch promote invasiveness of cancer cells, which may have clinically relevant consequences. Pharmacological manipulation of cholesterol endocytosis could be a novel therapeutic target in this setting.

Assessment of risk scores in Covid-19.

OBJECTIVE: To analyse the accuracy of commonly used risk scores (PSI and CURB-65) in predicting mortality and need for ICU admission in Covid-19. MATERIAL AND METHODS: Prospective study of patients diagnosed with Covid-19 pneumonia. Patients were followed until home discharge or death. PSI, CURB-65, SMART-COP and MuLBSTA severity scores were assessed on admission. Risk scores were related to mortality and ICU admission. RESULTS: About 249 patients, 143 males (57.4%) were included. The mean age was 65.6 + 16.1 years. Factors associates with mortality in the multivariate analysis were age > 80 years (OR: 13.9; 95% CI 3.8-51.1) (P = .000), lymphocytes < 800 (OR: 2.9; CI 95% 1.1-7-9) (P = .040), confusion (OR: 6.3; 95% CI 1.6-24.7) (P = .008) and NT-proBNP > 500 pg/mL (OR: 10.1; 95% CI 1.1-63.1) (P = .039). In predicting mortality, the PSI score: AUC 0.874 (95% CI 0.808-0.939) and the CURB-65 score: AUC 0.852 (95% CI 0.794-0.909) were the ones that obtained the best results. In the need for ICU admission, the SMART-COP score: AUC 0.749 (95% CI 0.695-0.820) and the MuLBSTA score: AUC 0.777 (95% CI 0.713-0.840) were the ones that obtained better results, with significant differences with PSI and CURB-65. The scores with the lowest value for ICU admission prediction were PSI with AUC of 0.620 (95% CI 0.549-0.690) and CURB-65 with AUC of 0.604 (95% CI 0.528-0.680). CONCLUSIONS: Prognosis scores routinely used for CAP (PSI and CURB-65) were good predictors for mortality in patients with Covid-19 CAP but not for need of hospitalisation or ICU admission. In the evaluation of Covid-19 pneumonia, we need scores that allow to decide the appropriate level of care.

Severe asthma and bronchiectasis.

Objective: The aim of our study was to determine the tomographic findings and prevalence of bronchiectasis in our population of patients with severe asthma, and to identify factors associated with the presence of bronchiectasis in these patients. Materials and methods: We retrospectively collected data from the medical histories of patients referred to the asthma unit of our hospital, with a diagnosis of severe asthma between 2015 and 2017. Patients with ABPA, cystic fibrosis, immunodeficiency or systemic disease were excluded. High-resolution thorax-computed tomodensitography (HRCT) was performed in all patients. A standardized protocol was applied in data collection. Results: A total of 108 patients comprising 50 men (46%) and 58 women (54%) were included in the study. Of the 108 patients, 59 (55%) had at least one abnormality detected by HRCT, the most commonly reported abnormalities being bronchiectasis (35%), bronchial wall thickening (33%), emphysema (7%), atelectasis area (6%), mosaic attenuation due to air trapping (4%), and "tree in bud" image (2%). Subjects with bronchiectasis were older (p = 0.001), had a longer asthma history (p = 0.048), had poorer pulmonary function tests with lower FVC (p = 0.031), had more severe bronchial obstruction with lower FEV1 (p = 0.008) and had lower FEV1/FVC (p = 0.003). They also experienced more frequent hospitalizations in the previous year (p = 0.019) and received treatment with omalizumab more frequently (p = 0.049). Plasma eosinophil count and IgE levels were comparable in both groups. In the multivariate analysis, the presence of bronchiectasis was associated with ages older than 40 (OR: 8.3; 95% CI: 1.7-41.2) and chronic airflow obstruction (OR: 5.4; 95% CI: 1.9-15.3). Conclusions: We found that in patients with severe asthma, the prevalence of bronchiectasis is high and that bronchiectasis is associated with a longer asthma history, greater severity and, more importantly, chronic airflow obstruction. These findings are still insufficient evidence to considere features of asthma-bronchiectasis overlap syndrome, a distinct phenotype of severe asthma, but bronchiectasis is a frequent phenomenon leading to a more severe disease with frequent exacerbations. The performance of thorax HRCT on patients with severe asthma can help to evaluate management strategies for the disease in order to improve treatment and prognosis.

Risk factors for tuberculosis in inflammatory bowel disease: anti-tumor necrosis factor and hospitalization.

AIMS: To determine risk factors for active tuberculosis in patients with inflammatory bowel diseases. METHODS: Retrospective, case-control study at 4 referral hospitals in Spain. Cases developed tuberculosis after a diagnosis of inflammatory bowel disease. Controls were inflammatory bowel disease patients who did not develop tuberculosis. For each case, we randomly selected 3 controls matched for sex, age (within 5 years) and time of inflammatory bowel disease diagnosis (within 3 years). Inflammatory bowel disease characteristics, candidate risk factors for tuberculosis and information about the tuberculosis episode were recorded. Multivariate analysis and a Chi-squared automatic interaction detector were used. RESULTS: Thirty-four cases and 102 controls were included. Nine of the 34 cases developed active tuberculosis between 1989 and 1999, and 25 became ill between 2000 and 2012. Multivariate regression showed an association between active tuberculosis and anti-TNF (tumor necrosis factor) therapy in the previous 12 months (OR 7.45; 95% CI, 2.39-23.12; p = .001); hospitalization in the previous 6 months (OR 4.38; 95% CI, 1.18-16.20; p = .027); and albumin levels (OR 0.88; 95% CI, 0.81-0.95; p = .001). The median time between the start of biologic therapy and the onset of active tuberculosis was 13 (interquartile range, 1-58) months. Tuberculosis developed after a year of anti-TNF therapy in 53%, and late reactivation occurred in at least 3 of 8 patients. CONCLUSIONS: The main risks factors for developing tuberculosis were anti-TNF therapy and hospitalization. Over half the cases related to anti-TNF treatment occurred after a year.

Clinical and Epidemiological Correlates of Low IFN-Gamma Responses in Mitogen Tube of QuantiFERON Assay in Tuberculosis Infection Screening During the COVID-19 Pandemic: A Population-Based Marker of COVID-19 Mortality?

Background: The clinical and epidemiological implications of abnormal immune responses in COVID-19 for latent tuberculosis infection (LTBI) screening are unclear. Methods: We reviewed QuantiFERON TB Gold Plus (QFT-Plus) results (36,709 patients) from July 2016 until October 2021 in Asturias (Spain). We also studied a cohort of ninety hospitalized patients with suspected/confirmed COVID-19 pneumonia and a group of elderly hospitalized patients with COVID-19 who underwent serial QFT-Plus and immune profiling testing. Results: The indeterminate QFT-Plus results rate went from 1.4% (July 2016 to November 2019) to 4.2% during the COVID-19 pandemic. The evolution of the number of cases with low/very low interferon-gamma (IFN-gamma) response in the mitogen tube paralleled the disease activity and number of deaths during the pandemic waves in our region (from March 2020 to October 2021). The percentages of positive QFT-plus patients did not significantly change before and during the pandemic (13.9% vs. 12.2%). Forty-nine patients from the suspected/confirmed COVID-19 pneumonia cohort (54.4%) had low/very low IFN-gamma response to mitogen, 22 of them (24.4%) had severe and critical pneumonia. None received immunosuppressants prior to testing. Abnormal radiological findings (P = 0.01) but not COVID-19 severity was associated with low mitogen response. Immune profiling showed a reduction of CD8 + T cells and a direct correlation between the number of EMRA CD8 + T-cells and IFN-gamma response to mitogen (P = 0.03). Conclusion: Low IFN-gamma responses in mitogen tube of QFT-Plus often occur in COVID-19 pneumonia, which is associated with a low number of an effector CD8 + T-cell subset and does not seem to affect LTBI screening; however, this abnormality seems to parallel the dynamics of COVID-19 at the population level and its mortality.

Acquisition of New Migratory Properties by Highly Differentiated CD4+CD28null T Lymphocytes in Rheumatoid Arthritis Disease.

Expanded CD4+CD28null T lymphocytes are found in the tissues and peripheral blood of patients with many autoimmune diseases, such as rheumatoid arthritis (RA). These highly differentiated cells present potent inflammatory activity and capability to induce tissue destruction, which has been suggested to predispose to the development of more aggressive disease. In fact, preferential migration to inflammatory sites has been proposed to be a contributing factor in the progression of autoimmune and cardiovascular diseases frequently found in these patients. The functional activity of CD4+CD28null T lymphocytes is largely dependent on interleukin 15 (IL-15), and this cytokine may also act as a selective attractor of these cells to local inflammatory infiltrates in damaged tissues. We have analysed, in RA patients, the migratory properties and transcriptional motility profile of CD4+CD28null T lymphocytes compared to their counterparts CD28+ T lymphocytes and the enhancing role of IL-15. Identification of the pathways involved in this process will allow us to design strategies directed to block effector functions that CD4+CD28null T lymphocytes have in the target tissue, which may represent therapeutic approaches in this immune disorder.

Biotrauma during ultra-low tidal volume ventilation and venoarterial extracorporeal membrane oxygenation in cardiogenic shock: a randomized crossover clinical trial.

BACKGROUND: Cardiogenic pulmonary oedema (CPE) may contribute to ventilator-associated lung injury (VALI) in patients with cardiogenic shock. The appropriate ventilatory strategy remains unclear. We aimed to evaluate the impact of ultra-low tidal volume ventilation with tidal volume of 3 ml/kg predicted body weight (PBW) in patients with CPE and veno-arterial extracorporeal membrane oxygenation (V-A ECMO) on lung inflammation compared to conventional ventilation. METHODS: A single-centre randomized crossover trial was performed in the Cardiac Intensive Care Unit (ICU) at a tertiary university hospital. Seventeen adults requiring V-A ECMO and mechanical ventilation due to cardiogenic shock were included from February 2017 to December 2018. Patients were ventilated for two consecutive periods of 24 h with tidal volumes of 6 and 3 ml/kg of PBW, respectively, applied in random order. Primary outcome was the change in proinflammatory mediators in bronchoalveolar lavage fluid (BALF) between both ventilatory strategies. RESULTS: Ventilation with 3 ml/kg PBW yielded lower driving pressures and end-expiratory lung volumes. Overall, there were no differences in BALF cytokines. Post hoc analyses revealed that patients with high baseline levels of IL-6 showed statistically significant lower levels of IL-6 and IL-8 during ultra-low tidal volume ventilation. This reduction was significantly proportional to the decrease in driving pressure. In contrast, those with lower IL-6 baseline levels showed a significant increase in these biomarkers. CONCLUSIONS: Ultra-low tidal volume ventilation in patients with CPE and V-A ECMO may attenuate inflammation in selected cases. VALI may be driven by an interaction between the individual proinflammatory profile and the mechanical load overimposed by the ventilator. Trial registration The trial was registered in ClinicalTrials.gov (identifier NCT03041428, Registration date: 2nd February 2017).

Clinical Impact of a Pleural Unit in a Tertiary Level Hospital. / Impacto clínico de una unidad de patología pleural en un hospital de tercer nivel.

INTRODUCTION: Pleural disease involves a large number of admissions and long hospital stays. In order to improve this situation, a Pleural Unit (PU) was created in our hospital. Our aim was to analyze the clinical impact of this unit. MATERIAL AND METHODS: In this prospective study, we included patients admitted to the PU of the Hospital Universitario Central de Asturias for primary spontaneous pneumothorax (PSP), secondary spontaneous pneumothorax (SSP), complicated parapneumonic pleural effusion (CPPE), and malignant pleural effusion (MPE) between January 2015 and December 2018. We analyzed descriptive parameters, mean length of stay, readmissions at 1 month, need for surgery, and in the CPPE group, in-hospital mortality. The data were compared with those of patients admitted to the respiratory medicine department for the same diseases during the previous two years (2013-2014). We also describe all procedures performed in the PU, in both inpatients and outpatients. RESULTS: A total of 741 patients were included, We observed a progressive decrease in total admissions for pleural diseases and mean length of stay (days) (with the exception of MPE), as follows: PSP: from 6.2 to 4.2 (P=.004); SSP: 13.2 to 8.6 (P=.005), MPE: 10.3 to 12.3 (P=.05); and CPPE: 18.3 to 11.3 (P=.001) There was a reduction in hospital readmissions at 1 month and in in-hospital mortality due to CPPE in the PU period (14.9% to 5.5%) (P=.021). CONCLUSIONS: The creation of a PU could decrease the number of unnecessary admissions, and reduce mean lengths of stay and, in the case of CPPE, in-hospital mortality.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study.

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries. The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs. Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile. A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.

High rates of tuberculin skin test positivity due to methotrexate therapy: False positive results?

RATIONALE: The tuberculin skin test (TST) and interferon ? release assays (IGRAs) are commonly used for latent tuberculosis infection (LTBI) screening. Unexpectedly high TST positivity rates have been reported in patients with rheumatic diseases, and methotrexate is frequently used in this population. We hypothesized that methotrexate use could be associated with false-positive TST results. OBJECTIVES: To investigate whether treatment with methotrexate and other factors are associated with false-positive TST results in patients with rheumatic diseases. METHODS: Prospective single-center study conducted between April 2013 and March 2016. Adult patients with rheumatic diseases were evaluated with a TST and two IGRAs for LTBI screening. We compared TST and IGRA results in patients treated and not treated with methotrexate and analyzed for factors associated with positive TST results. CONCLUSIONS: Our data suggest false-positive TST results associated with methotrexate therapy. Thus, we recommend against using the TST for LTBI screening in patients receiving methotrexate and the preferential use of IGRAs in such patients. MEASUREMENTS AND MAIN RESULTS: We studied 393 patients with rheumatic diseases, including ankylosing spondylitis (ASP, n = 90), rheumatoid arthritis (RA; n = 120), psoriatic arthritis (PA, n = 126), and other disorders (n = 57). The rate of TST positivity varied across the groups: ASP 22.2%, RA 25%, PA 35.7%, and other disorders (22.8%). Positivity rates were lower with IGRAs. Methotrexate use was associated with a statistically significant two-fold increase in the risk of a positive TST and a dose\x96 response relationship was observed. We found no statistically significant associations between methotrexate use and IGRA test positivity.

Consensus Document on Prevention and Treatment of Tuberculosis in Patients for Biological Treatment.

Tuberculosis risk is increased in patients with chronic inflammatory diseases receiving any immunosuppressive treatment, notably tumor necrosis factor (TNF) antagonists therapy. Screening for the presence of latent infection with Mycobacterium tuberculosis and targeted preventive treatment to reduce the risk of progression to TB is mandatory in these patients. This Consensus Document summarizes the current knowledge and expert opinion of biologic therapies including TNF-blocking treatments. It provides recommendations for the use of interferon-gamma release assays (IGRA) and tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection in these patients, and for the type and duration of preventive therapy.

T-cell profiling and the immunodiagnosis of latent tuberculosis infection in patients with inflammatory bowel disease.

BACKGROUND: Factors associated with performance of interferon-γ release assays (IGRA) and the tuberculin skin test (TST) in screening for latent tuberculosis infection in patients with inflammatory bowel diseases (IBD) are still poorly understood. The influence of peripheral T-cell subset counts on the results also remain unclear. METHODS: Prospective single-center study in 205 patients with IBD. Latent tuberculosis infection screening included a chest radiograph, TST (retest if negative), and 2 IGRAs: QuantiFERON-TB Gold In-Tube (QFT-GIT) and TSPOT-TB (TSPOT). T-cell subpopulations were determined by flow cytometry. RESULTS: Twenty-one (10.2%) patients had an abnormal chest radiograph, 55 (26.8%) had a positive TST, 16 (7.8%) had a positive QFT-GIT, and 25 (12.6%) had a positive TSPOT. TST positivity was lower in patients on ≥2 immunosuppressants compared with the controls (5-aminosalicylic acid treatment) (10.4% versus 38.2%, respectively) (P = 0.0057). No other drugs influenced TST or IGRA positivity. In patients on corticosteroid treatment, anti-TNF treatment, or ≥2 immunosuppressants, IGRAs detected 10 cases of latent tuberculosis infection not identified by TST. TSPOT and QFT-GIT increased yield by 56% and 22%, respectively. No significant differences in T-cell subpopulations were found between patients with positive or negative TST or TSPOT results. However, patients with positive QFT-GIT findings had more CD8 T cells (mean, 883 ± 576 versus 484 ± 385 cells per microliter in patients with negative results) (P = 0.022). CONCLUSIONS: IGRAs can improve TST-based screening in patients with IBD on immunosuppressive therapy. A low CD8 count can affect QFT-GIT results. We suggest combining TSPOT and TST screening in patients with IBD on immunosuppressants.

Advances in the diagnosis of tuberculosis infection.

One-third of the world-wide population currently presents latent tuberculosis infection (LTI). In Spain, TB is situated as the third disease of mandatory notification. The standard technique for the diagnosis of ITL is the tuberculin test (PPD), although its most important drawback is its specificity since the proteins used are not specific for Mycobacterium tuberculosis. In recent years, research has been done and new diagnostic methods have been approved based on the in vitro quantification of the immune cell response, the so-called interferon gamma release assays (IGRA). Compared with PPD, the main difference is that IGRAs detect the release of interferon-gamma in response to specific tuberculous antigens. In the absence of a true reference test for the diagnosis of tuberculosis infection, it is difficult to establish the sensitivity and specificity of these new diagnostic techniques. IGRAs have been used in the detection of ITL in subjects with immune system alterations (HIV, EEI, IRC, rheumatologic diseases) with good results. They are also being extensively used in the study of contacts. In recent studies involving serial controls of said tests, they were observed to present conversions and reversions that occur after exposure to M. tuberculosis. Today and with the current knowledge, it seems that IGRAs can complement PPD, but not substitute them.