Airway hyperresponsiveness correlates with airway TSLP in asthma independent of eosinophilic inflammation.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is released from the airway epithelium in response to various environmental triggers, inducing a type-2 inflammatory response, and is associated with airway inflammation, airway hyperresponsiveness (AHR), and exacerbations. TSLP may also induce AHR via a direct effect on airway smooth muscle and mast cells, independently of type-2 inflammation, although association between airway TSLP and AHR across asthma phenotypes has been described sparsely. OBJECTIVES: This study sought to investigate the association between AHR and levels of TSLP in serum, sputum, and bronchoalveolar lavage in patients with asthma with and without type-2 inflammation. METHODS: A novel ultrasensitive assay was used to measure levels of TSLP in patients with asthma (serum, n = 182; sputum, n = 81; bronchoalveolar lavage, n = 85) and healthy controls (serum, n = 47). The distribution and association among airway and systemic TSLP, measures of AHR, type-2 inflammation, and severity of disease were assessed. RESULTS: TSLP in sputum was associated with AHR independently of levels of eosinophils and fractional exhaled nitric oxide (ρ = 0.49, P = .005). Serum TSLP was higher in both eosinophil-high and eosinophil-low asthma compared to healthy controls: geometric mean: 1600 fg/mL (95% CI: 1468-1744 fg/mL) and 1294 fg/mL (95% CI: 1167-1435 fg/mL) versus 846 fg/mL (95% CI: 661-1082 fg/mL), but did not correlate with the level of AHR. Increasing age, male sex, and eosinophils in blood were associated with higher levels of TSLP in serum, whereas lung function, inhaled corticosteroid dose, and symptom score were not. CONCLUSIONS: The association between TSLP in sputum and AHR to mannitol irrespective of markers of type-2 inflammation further supports a role of TSLP in AHR that is partially independent of eosinophilic inflammation.

Allergen Immunotherapy Enhances Airway Epithelial Antiviral Immunity in Patients with Allergic Asthma (VITAL Study): A Double-Blind Randomized Controlled Trial.

Rationale: Allergic asthma is linked to impaired bronchial epithelial secretion of IFNs, which may be causally linked to the increased risk of viral exacerbations. We have previously shown that allergen immunotherapy (AIT) effectively reduces asthma exacerbations and prevents respiratory infections requiring antibiotics; however, whether AIT alters antiviral immunity is still unknown. Objectives: To investigate the effect of house dust mite sublingual AIT (HDM-SLIT) on bronchial epithelial antiviral and inflammatory responses in patients with allergic asthma. Methods: In this double-blind, randomized controlled trial (VITAL [The Effect of Allergen Immunotherapy on Anti-viral Immunity in Patients with Allergic Asthma]), adult patients with HDM allergic asthma received HDM-SLIT 12-SQ or placebo for 24 weeks. Bronchoscopy was performed at baseline and at Week 24, which included sampling for human bronchial epithelial cells. Human bronchial epithelial cells were cultured at baseline and at Week 24 and stimulated with the viral mimic polyinosinic:polycytidylic acid (poly(I:C)). mRNA expression was quantified using qRT-PCR, and protein concentrations were measured using multiplex ELISA. Measurements and Main Results: Thirty-nine patients were randomized to HDM-SLIT (n = 20) or placebo (n = 19). HDM-SLIT resulted in increased polyinosinic:polycytidylic acid-induced expression of IFN-ß at both the gene (P = 0.009) and protein (P = 0.02) levels. IFN-λ gene expression was also increased (P = 0.03), whereas IL-33 tended to be decreased (P = 0.09). On the other hand, proinflammatory cytokines IL-6 (P = 0.009) and TNF-α (tumor necrosis factor-α) (P = 0.08) increased compared with baseline in the HDM-SLIT group. There were no significant changes in TSLP (thymic stromal lymphopoietin), IL-4, IL-13, and IL-10. Conclusions: HDM-SLIT improves bronchial epithelial antiviral resistance to viral infection. These results potentially explain the efficacy of HDM-SLIT in reducing exacerbations in allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT04100902).

Urinary creatinine based equations for estimation of fat free mass in patients with intestinal insufficiency or intestinal failure.

BACKGROUND & AIMS: Assessment of body composition is an important aspect of disease management in patients with intestinal insufficiency (INS) or intestinal failure (IF). However, in daily clinical settings most body composition methods are too expensive or impractical, leaving body composition to be assessed by less reliable methods such as skin fold thickness. The aim of this study was to investigate and validate the use of an equation for the estimation of fat-free mass (FFM) with bioelectrical impedance analysis (BIA) as reference method. METHODS: A literature search for identification of urinary creatinine-based FFM-prediction equations was carried out a long side the creation of an equation by multiple linear regression. The correlation of each equation with FFM (measured by BIA in 277 patients with either INS or IF) was done by Pearson's correlation. Further investigation and validation of performance was done for the equations with the strongest correlation by Bland-Altman analysis, determination of root mean square error (RMSE), and intraclass correlation (ICC). The validation was carried out in a new group of 37 patients with either INS or IF. RESULTS: A total of 11 prediction equations were correlated with FFM measured by BIA. The equation called FFMmultiple and FFM-5 had the strongest correlation (r = 0.969, p < 0.01 and r = 0.950, p < 0.01, respectively). FFMmultiple was superior to FFM-5 regarding Bland-Altman analysis, RMSE, and ICC in the study group (Mean bias ± Standard Deviation = 0.042 ± 2.352 versus 0.309 ± 3.196; 95% limits of agreement = [-4.568; 4.651] versus [-5.955; 6.578]; RMSE = 0.158 versus 0.236; ICC = 0.969 versus 0.948). Cross-validation resulted in a Bland-Altman analysis with a statistically significant difference between FFMmultiple and FFM by BIA. FFM-5 showed wide 95% limits of agreement ([-6.977; 6.421]). CONCLUSIONS: Two urinary creatinine-based equations (FFMmultiple and FFM-5) showed promising results as possible substitutes to BIA, however further investigation and cross validation revealed inauspicious results. Thus, the present study cannot recommend the use of a prediction equation instead of BIA for the assessment of FFM in patients with INS and IF.

Treating severe asthma: Targeting the IL-5 pathway.

Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)-4, IL-5 and IL-13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL-5R and IL-5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late-onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non-response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL-5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non-response.

Presence and characteristics of senile pruritus among Danish elderly living in nursing homes.

AIM: To explore the pattern of occurrence and characteristics of senile pruritus among elderly living in nursing homes in the Northern region of Denmark. MATERIALS & METHODS: A Danish questionnaire was developed and distributed to six nursing homes from which 46 residents participated. RESULTS: The prevalence of chronic itch was 28.9%. Evening-night and autumn-winter with an average daily itch of 30 min were reported. Itch interfered with night sleep and daily activities. Scratching was common with 61.5% accompanying scratch marks. Half of participants reported Xerosis. Cream, cold compress and cold shower were found to be the most effective remedies for itch relief. CONCLUSION: The present study revealed a high prevalence of chronic pruritus including cases of senile pruritus that needs further exploration for treatment or preventive strategies.