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Respiratory Research Feb 2024Intra-breath oscillometry has been proposed as a sensitive means of detecting airway obstruction in young children. We aimed to assess the impact of early life wheezing...
BACKGROUND
Intra-breath oscillometry has been proposed as a sensitive means of detecting airway obstruction in young children. We aimed to assess the impact of early life wheezing and lower respiratory tract illness on lung function, using both standard and intra-breath oscillometry in 3 year old children.
METHODS
History of doctor-diagnosed asthma, wheezing, bronchiolitis and bronchitis and hospitalisation for respiratory problems were assessed by questionnaires in 384 population-based children. Association of respiratory history with standard and intra-breath oscillometry parameters, including resistance at 7 Hz (R), frequency-dependence of resistance (R), reactance at 7 Hz (X), area of the reactance curve (AX), end-inspiratory and end-expiratory R (R, R) and X (X, X), and volume-dependence of resistance (ΔR = R-R) was estimated by linear regression adjusted on confounders.
RESULTS
Among the 320 children who accepted the oscillometry test, 281 (88%) performed 3 technically acceptable and reproducible standard oscillometry measurements and 251 children also performed one intra-breath oscillometry measurement. Asthma was associated with higher R, R, ΔR and R and wheezing was associated with higher ΔR. Bronchiolitis was associated with higher R and AX and lower X and bronchitis with higher R. No statistically significant association was observed for hospitalisation.
CONCLUSIONS
Our findings confirm the good success rate of oscillometry in 3-year-old children and indicate an association between a history of early-life wheezing and lower respiratory tract illness and lower lung function as assessed by both standard and intra-breath oscillometry. Our study supports the relevance of using intra-breath oscillometry parameters as sensitive outcome measures in preschool children in epidemiological cohorts.
Topics: Humans; Child, Preschool; Respiratory Sounds; Spirometry; Respiratory System; Asthma; Respiratory Mechanics; Bronchiolitis; Bronchitis
PubMed: 38402379
DOI: 10.1186/s12931-024-02701-9 -
Biomedicines Feb 2024Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other... (Review)
Review
Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.
PubMed: 38398039
DOI: 10.3390/biomedicines12020437 -
PloS One 2024People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory...
People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory infections that are difficult to treat due in part to the accumulation of hyperconcentrated mucus within the airway. Mucus accumulation and obstruction promote chronic inflammation and infection and reduce therapeutic efficacy. Bacterial aggregates in the form of biofilms exhibit increased resistance to mechanical stressors from the immune response (e.g., phagocytosis) and chemical treatments including antibiotics. Herein, combination treatments designed to disrupt the mechanical properties of biofilms and potentiate antibiotic efficacy are investigated against mucus-grown Pseudomonas aeruginosa biofilms and optimized to 1) alter biofilm viscoelastic properties, 2) increase mucociliary transport rates, and 3) reduce bacterial viability. A disulfide bond reducing agent (tris(2-carboxyethyl)phosphine, TCEP), a surfactant (NP40), a biopolymer (hyaluronic acid, HA), a DNA degradation enzyme (DNase), and an antibiotic (tobramycin) are tested in various combinations to maximize biofilm disruption. The viscoelastic properties of biofilms are quantified with particle tracking microrheology and transport rates are quantified in a mucociliary transport device comprised of fully differentiated primary human bronchial epithelial cells. The combination of the NP40 with hyaluronic acid and tobramycin was the most effective at increasing mucociliary transport rates, decreasing the viscoelastic properties of mucus, and reducing bacterial viability. Multimechanistic targeting of biofilm infections may ultimately result in improved clinical outcomes, and the results of this study may be translated into future in vivo infection models.
Topics: Humans; Mucociliary Clearance; Pseudomonas aeruginosa; Hyaluronic Acid; Anti-Bacterial Agents; Tobramycin; Pseudomonas Infections; Biofilms
PubMed: 38394229
DOI: 10.1371/journal.pone.0294120 -
Pathogens (Basel, Switzerland) Feb 2024It has been noted by the World Health Organisation that cases of tuberculosis in 2022 globally numbered 10.6 million, resulting in 1.3 million deaths, such that TB is... (Review)
Review
It has been noted by the World Health Organisation that cases of tuberculosis in 2022 globally numbered 10.6 million, resulting in 1.3 million deaths, such that TB is one of the infectious diseases causing the greatest morbidity and mortality worldwide. Since as early as 1918, there has been an ongoing debate as to the relationship between cigarette smoking and TB. However, numerous epidemiological studies, as well as meta-analyses, have indicated that both active and passive smoking are independent risk factors for TB infection, development of reactivation TB, progression of primary TB, increased severity of cavitary disease, and death from TB, among several other considerations. With this considerable body of evidence confirming the association between smoking and TB, it is not surprising that TB control programmes represent a key potential preventative intervention. In addition to coverage of the epidemiology of TB and its compelling causative link with smoking, the current review is also focused on evidence derived from clinical- and laboratory-based studies of disease pathogenesis, most prominently the protective anti-mycobacterial mechanisms of the alveolar macrophage, the primary intracellular refuge of . This section of the review is followed by an overview of the major strategies utilised by the pathogen to subvert these antimicrobial mechanisms in the airway, which are intensified by the suppressive effects of smoke inhalation on alveolar macrophage function. Finally, consideration is given to a somewhat under-explored, pro-infective activity of cigarette smoking, namely augmentation of antibiotic resistance due to direct effects of smoke per se on the pathogen. These include biofilm formation, induction of cellular efflux pumps, which eliminate both smoke-derived toxicants and antibiotics, as well as gene modifications that underpin antibiotic resistance.
PubMed: 38392889
DOI: 10.3390/pathogens13020151 -
Antibiotics (Basel, Switzerland) Feb 2024Sepsis stands as a formidable global health challenge, with persistently elevated mortality rates in recent decades. Each year, sepsis not only contributes to heightened... (Review)
Review
Sepsis stands as a formidable global health challenge, with persistently elevated mortality rates in recent decades. Each year, sepsis not only contributes to heightened morbidity but also imposes substantial healthcare costs on survivors. This narrative review aims to highlight the targeted measures that can be instituted to alleviate the incidence and impact of sepsis in intensive care. Here we discuss measures to reduce nosocomial infections and the prevention of equipment and patient colonisation by resilient pathogens. The overarching global crisis of bacterial resistance to newly developed antimicrobial agents intensifies the imperative for antimicrobial stewardship and de-escalation. This urgency has been accentuated in recent years, notably during the COVID-19 pandemic, as high-dose steroids and opportunistic infections presented escalating challenges. Ongoing research into airway colonisation's role in influencing disease outcomes among critically ill patients underscores the importance of tailoring treatments to disease endotypes within heterogeneous populations, which are important lessons for intensivists in training. Looking ahead, the significance of novel antimicrobial delivery systems and drug monitoring is poised to increase. This narrative review delves into the multifaceted barriers and facilitators inherent in effectively treating critically ill patients vulnerable to nosocomial infections. The future trajectory of intensive care medicine hinges on the meticulous implementation of vigilant stewardship programs, robust infection control measures, and the continued exploration of innovative and efficient technological solutions within this demanding healthcare landscape.
PubMed: 38391547
DOI: 10.3390/antibiotics13020162 -
Theranostics 2024Bitter taste receptors (TAS2Rs) are abundantly expressed in airway smooth muscle cells (ASMCs), which have been recognized as promising targets for bitter agonists to...
BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation.
Bitter taste receptors (TAS2Rs) are abundantly expressed in airway smooth muscle cells (ASMCs), which have been recognized as promising targets for bitter agonists to initiate relaxation and thereby prevent excessive airway constriction as the main characteristic of asthma. However, due to the current lack of tested safe and potent agonists functioning at low effective concentrations, there has been no clinically approved TAS2R-based drug for bronchodilation in asthma therapy. This study thus aimed at exploring TAS2R agonists with bronchodilator potential by BitterDB database analysis and cell stiffness screening. Bitter compounds in the BitterDB database were retrieved and analyzed for their working subtype of TAS2R and effective concentration. Compounds activating TAS2R5, 10, and 14 at < 100 μM effective concentration were identified and subsequently screened by cell stiffness assay using optical magnetic twisting cytometry (OMTC) to identify the most potent to relax ASMCs. Then the compound identified was further characterized for efficacy on various aspects related to relaxation of ASMCs, incl. but not limited to traction force by Fourier transform traction force microscopy (FTTFM), [Ca] signaling by Fluo-4/AM intensity, cell migration by scratch wound healing, mRNA expression by qPCR, and protein expressing by ELISA. The compound identified was also compared to conventional β-agonist (isoproterenol and salbutamol) for efficacy in reducing cell stiffness of cultured ASMCs and airway resistance of ovalbumin-treated mice. BitterDB analysis found 18 compounds activating TAS2R5, 10, and 14 at < 100 μM effective concentration. Cell stiffness screening of these compounds eventually identified flufenamic acid (FFA) as the most potent compound to rapidly reduce cell stiffness at 1 μM. The efficacy of FFA to relax ASMCs and abrogate airway resistance was equivalent to that of conventional β-agonists. The FFA-induced effect on ASMCs was mediated by TAS2R14 activation, endoplasmic reticulum Ca release, and large-conductance Ca-activated K (BK) channel opening. FFA also attenuated lipopolysaccharide-induced inflammatory response in cultured ASMCs. FFA as a potent TAS2R14 agonist to relax ASMCs while suppressing cytokine release might be a favorite drug agent for further development of TAS2R-based novel dual functional medication for bronchodilation and anti-inflammation in asthma therapy.
Topics: Mice; Animals; Flufenamic Acid; Receptors, G-Protein-Coupled; Lung; Myocytes, Smooth Muscle; Asthma
PubMed: 38389834
DOI: 10.7150/thno.92492 -
Clinical Interventions in Aging 2024The concomitant rise in the prevalence of obstructive sleep apnea (OSA) and frailty among the elderly population has been linked to an increase in mortality rates....
BACKGROUND
The concomitant rise in the prevalence of obstructive sleep apnea (OSA) and frailty among the elderly population has been linked to an increase in mortality rates. Despite continuous positive airway pressure (CPAP) being the gold standard treatment for OSA, its impact on incident frailty remains inadequately explored.
METHODS
In this cohort study, we analyzed data from 1290 patients diagnosed with OSA, aged 60 years and older. A subset of 71 patients who demonstrated high adherence to CPAP therapy were categorized as the CPAP group. Propensity score matching (PSM) was employed at a 1:4 ratio, matching for variables such as age, gender, body mass index (BMI), and sleep apnea-hypopnea index (AHI), to establish a non-CPAP group for comparison. The FRAIL scale was utilized to evaluate the frailty status of participants. Logistic regression analysis examined the relationship between CPAP therapy and incident frailty, as well as its individual components, in elderly patients with OSA.
RESULTS
During a median follow-up period of 52 months, incident frailty was observed in 70 patients (19.7%). Patients with OSA receiving CPAP therapy exhibited a lower incidence of frailty compared to those not receiving CPAP (11.26% vs 21.83%, =0.045). In the multivariate model, CPAP therapy was significantly correlated with a reduced risk of incident frailty (OR = 0.36, 95% CI, 0.15-0.88; = 0.025). Subcomponent analyses revealed that CPAP was associated with a lower risk of fatigue (OR=0.35, 95% CI, 0.19-0.63; < 0.001), resistance (OR = 0.32, 95% CI, 0.14-0.74; =0.008), and weight loss (OR = 0.38, 95% CI, 0.19-0.75; = 0.007).
CONCLUSION
CPAP therapy was associated with a reduced risk of incident frailty among elderly patients with OSA.
Topics: Humans; Aged; Middle Aged; Cohort Studies; Continuous Positive Airway Pressure; Frailty; Propensity Score; Sleep Apnea, Obstructive
PubMed: 38380228
DOI: 10.2147/CIA.S446129 -
PloS One 2024The objectives of the present study were to evaluate the discriminating power of spirometric and plethysmographic lung function parameters to differenciate the diagnosis...
The objectives of the present study were to evaluate the discriminating power of spirometric and plethysmographic lung function parameters to differenciate the diagnosis of asthma, ACO, COPD, and to define functional characteristics for more precise classification of obstructive lung diseases. From the databases of 4 centers, a total of 756 lung function tests (194 healthy subjects, 175 with asthma, 71 with ACO, 78 with COPD and 238 with CF) were collected, and gradients among combinations of target parameters from spirometry (forced expiratory volume one second: FEV1; FEV1/forced vital capacity: FEV1/FVC; forced expiratory flow between 25-75% FVC: FEF25-75), and plethysmography (effective, resistive airway resistance: sReff; aerodynamic work of breathing at rest: sWOB), separately for in- and expiration (sReffIN, sReffEX, sWOBin, sWOBex) as well as static lung volumes (total lung capacity: TLC; functional residual capacity: FRCpleth; residual volume: RV), the control of breathing (mouth occlusion pressure: P0.1; mean inspiratory flow: VT/TI; the inspiratory to total time ratio: TI/Ttot) and the inspiratory impedance (Zinpleth = P0.1/VT/TI) were explored. Linear discriminant analyses (LDA) were applied to identify discriminant functions and classification rules using recursive partitioning decision trees. LDA showed a high classification accuracy (sensitivity and specificity > 90%) for healthy subjects, COPD and CF. The accuracy dropped for asthma (~70%) and even more for ACO (~60%). The decision tree revealed that P0.1, sRtot, and VT/TI differentiate most between healthy and asthma (68.9%), COPD (82.1%), and CF (60.6%). Moreover, using sWOBex and Zinpleth ACO can be discriminated from asthma and COPD (60%). Thus, the functional complexity of obstructive lung diseases can be understood, if specific spirometric and plethysmographic parameters are used. Moreover, the newly described parameters of airway dynamics and the central control of breathing including Zinpleth may well serve as promising functional marker in the field of precision medicine.
Topics: Humans; Cystic Fibrosis; Asthma; Lung; Vital Capacity; Forced Expiratory Volume; Spirometry; Pulmonary Disease, Chronic Obstructive
PubMed: 38377145
DOI: 10.1371/journal.pone.0292270 -
Cureus Jan 2024Add-on biological monoclonal antibodies such as benralizumab (anti-IL-5Ra) are recommended by international guidelines to reduce exacerbations in severe eosinophilic...
INTRODUCTION
Add-on biological monoclonal antibodies such as benralizumab (anti-IL-5Ra) are recommended by international guidelines to reduce exacerbations in severe eosinophilic asthma (SEA). However, few studies have assessed the impact of these therapies on lung function-related outcomes. Our goal was to evaluate the effectiveness of benralizumab on lung function, including lung volumes and airway resistance, in SEA patients in Portugal.
METHODS
This was a real-world, observational, prospective, multicentric study including adult patients diagnosed with SEA (January-June 2023). Spirometry and plethysmography were performed at baseline (T0) and after six months of treatment (T6) with benralizumab to assess: total lung capacity (TLC), residual volume (RV), forced expiratory volume in one second (FEV), forced vital capacity (FVC), mean forced expiratory flow between 25% and 75% of FVC (mFEF-25/75), intrathoracic gas volume (ITGV), and respiratory airway resistance (Raw). Descriptive statistics (with categorical variables described as frequencies and continuous values as mean and standard deviation (SD)) and paired t-test and Cohen's d effect size were calculated (analyses performed in StataCorp v.15.1; StataCorp LLC, TX, USA).
RESULTS
Overall, 30 SEA patients were evaluated, mostly women (n=18, 60.0%), with atopy (n=22, 73.3%), a mean age of 58.4 years (SD 11.7), and assisted by pulmonology (n=19, 63.3%) or immunology-allergology (n=11, 36.7%) services. Mean eosinophilia at baseline was 1103.57 cells/mcL (SD 604.88; minimum-maximum 460-2400); after the use of benralizumab, the count dropped to zero. After six months of treatment, a significant increase (p<0.0001) in FVC (15.3%), FEV (22.6%), and mFEF-25/75 (17.7%) were observed from baseline (Cohen's d between 0.78 and 1.11). ITGV, RV, RV/TLC, and Raw significantly decreased (p<0.0001) during the study period (-17.3%, -29.7%, -8.9%, and -100.6%, respectively) (Cohen's d between -0.79 and -1.06). No differences in TLC were obtained (p=0.173). No differences between sexes were observed for any measure. Patients with more significant eosinophilia (>900 cells/mcL count; n=15) presented better responses in FEV (p=0.001) and mFEF-25/75 (p=0.007).
CONCLUSIONS
A notable eosinophil depletion with add-on benralizumab led to significant improvements in SEA patients' respiratory function (static lung volumes and airway resistance) in real-world settings after six months. The significant deflating effect of benralizumab on patients' hyperinflated lungs led to enhanced expiratory flow (increased FEV and mFEF-25/75) and air trapping (decreased RV/TLC), suggesting this antibody improves bronchial obstruction, lung hyperinflation, and airway resistance. Further studies in a larger population are required to confirm these findings.
PubMed: 38371150
DOI: 10.7759/cureus.52452 -
BioRxiv : the Preprint Server For... Jan 2024Infections caused by multi-drug resistant (MDR) pathogenic bacteria are a global health threat. Phage therapy, which uses phage to kill bacterial pathogens, is...
Infections caused by multi-drug resistant (MDR) pathogenic bacteria are a global health threat. Phage therapy, which uses phage to kill bacterial pathogens, is increasingly used to treat patients infected by MDR bacteria. However, the therapeutic outcome of phage therapy may be limited by the emergence of phage resistance during treatment and/or by physical constraints that impede phage-bacteria interactions . In this work, we evaluate the role of lung spatial structure on the efficacy of phage therapy for infection. To do so, we developed a spatially structured metapopulation network model based on the geometry of the bronchial tree, and included the emergence of phage-resistant bacterial mutants and host innate immune responses. We model the ecological interactions between bacteria, phage, and the host innate immune system at the airway (node) level. The model predicts the synergistic elimination of a infection due to the combined effects of phage and neutrophils given sufficiently active immune states and suitable phage life history traits. Moreover, the metapopulation model simulations predict that local MDR pathogens are cleared faster at distal nodes of the bronchial tree. Notably, image analysis of lung tissue time series from wild-type and lymphocyte-depleted mice (n=13) revealed a concordant, statistically significant pattern: infection intensity cleared in the bottom before the top of the lungs. Overall, the combined use of simulations and image analysis of experiments further supports the use of phage therapy for treating acute lung infections caused by while highlighting potential limits to therapy given a spatially structured environment, such as impaired innate immune responses and low phage efficacy.
PubMed: 38352502
DOI: 10.1101/2024.01.31.578251