Mixed Th2 and non-Th2 inflammatory pattern in the asthma-COPD overlap : a network approach

Altres ajuts: The authors are grateful to all the patients who participated in the study. A number of investigators contributed to the study logistics and they are listed in the Supplementary materials. The project was endorsed by the COPD and Asthma Research Board (PII de EPOC y asma) of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR).The asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms. Determining systemic mediators may help clarify the nature of inflammation in patients with ACO. We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α), Th2-related markers (periostin, IL-5, and IL-13), and IL-17 in asthma, COPD, and ACO. This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity 10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis. In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61-3.57] vs 1.11 [0.12-2.42] pg/mL, respectively; p =0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61-13.12] vs 7.03 [4.69-10.44] pg/mL, respectively; p <0.001). Their values in ACO were intermediate between those in asthma and in COPD. Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD. IL-13 was the most connected node in the network, with different weights among the three conditions. Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern. IL-13 could be central to the regulation of inflammation in these conditions

Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control

Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/β-catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda

Identification of interleukin-27 (IL-27)/IL-27 receptor subunit alpha as a critical immune axis for in vivo hiv control

Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (> 50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/beta-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC. IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach (Peer ReviewedPostprint (published version

Switch of noninvasive ventilation (NIV) to continuous positive airway pressure (CPAP) in patients with obesity hypoventilation syndrome: a pilot study

International audienceObesity is a major worldwide public health issue. The main respiratory complication stemming from obesity is obesity hypoventilation syndrome (OHS). Most of the OHS patients diagnosed during an exacerbation are treated with non invasive ventilation (NIV). Up to date, no prospective study has demonstrated in real life conditions the feasibility of a systematic protocoled switch of NIV to continuous positive airway pressure (CPAP), once stability is achieved

Hospital Epidemics Tracker (HEpiTracker): Description and pilot study of a mobile app to track COVID-19 in hospital workers

Background: Hospital workers have been the most frequently and severely affected professional group during the COVID-19 pandemic, and have a big impact on transmission. In this context, innovative tools are required to measure the symptoms compatible with COVID-19, the spread of infection, and testing capabilities within hospitals in real time. Objective: We aimed to develop and test an effective and user-friendly tool to identify and track symptoms compatible with COVID-19 in hospital workers. Methods: We developed and pilot tested Hospital Epidemics Tracker (HEpiTracker), a newly designed app to track the spread of COVID-19 among hospital workers. Hospital staff in 9 hospital centers across 5 Spanish regions (Andalusia, Balearics, Catalonia, Galicia, and Madrid) were invited to download the app on their phones and to register their daily body temperature, COVID-19-compatible symptoms, and general health score, as well as any polymerase chain reaction and serological test results. Results: A total of 477 hospital staff participated in the study between April 8 and June 2, 2020. Of note, both health-related (n=329) and non-health-related (n=148) professionals participated in the study; over two-thirds of participants (68.8%) were health workers (43.4% physicians and 25.4% nurses), while the proportion of non-health-related workers by center ranged from 40% to 85%. Most participants were female (n=323, 67.5%), with a mean age of 45.4 years (SD 10.6). Regarding smoking habits, 13.0% and 34.2% of participants were current or former smokers, respectively. The daily reporting of symptoms was highly variable across participating hospitals; although we observed a decline in adherence after an initial participation peak in some hospitals, other sites were characterized by low participation rates throughout the study period. Conclusions: HEpiTracker is an already available tool to monitor COVID-19 and other infectious diseases in hospital workers. This tool has already been tested in real conditions. HEpiTracker is available in Spanish, Portuguese, and English. It has the potential to become a customized asset to be used in future COVID-19 pandemic waves and other environments

NIOX VERO: Individualized Asthma Management in Clinical Practice

As we move toward an era of precision medicine, novel biomarkers of disease will enable the identification and personalized treatment of new endotypes. In asthma, fractional exhaled nitric oxide (FeNO) serves as a surrogate marker of airway inflammation that often correlates with the presence of sputum eosinophils. The increase in FeNO is driven by an upregulation of inducible nitric oxide synthase (iNOS) by cytokines, which are released as a result of type-2 airway inflammation. Scientific evidence supports using FeNO in routine clinical practice. In steroid-naive patients and in patients with mild asthma, FeNO levels decrease within days after corticosteroid treatment in a dose-dependent fashion and increase after steroid withdrawal. In difficult asthma, FeNO testing correlates with anti-inflammatory therapy compliance. Assessing adherence by FeNO testing can remove the confrontational aspect of questioning a patient about compliance and change the conversation to one of goal setting and ways to improve disease management. However, the most important aspect of incorporating FeNO in asthma management is the reduction in the risk of exacerbations. In a recent primary care study, reduction of exacerbation rates and improved symptom control without increasing overall inhaled corticosteroid (ICS) use were demonstrated when a FeNO-guided anti-inflammatory treatment algorithm was assessed and compared to the standard care. A truly personalized asthma management approach—showing reduction of exacerbation rates, overall use of ICS and neonatal hospitalizations—was demonstrated when FeNO testing was applied as part of the treatment algorithm that managed asthma during pregnancy. The aim of this article is to describe how FeNO and the NIOX VERO® analyzer can help to optimize diagnosis and treatment choices and to aid in the monitoring and improvement of clinical asthma outcomes in children and adults

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy

BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels