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The Probiotics in Pediatric Asthma Management (PROPAM) Study in the Primary Care Setting: A Randomized, Controlled, Double-Blind Trial with Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706).
Drago, L, Cioffi, L, Giuliano, M, Pane, M, Amoruso, A, Schiavetti, I, Reid, G, Ciprandi, G, Propam Study Group,
Journal of immunology research. 2022;:3837418
Abstract
BACKGROUND Type-2 inflammation commonly marks asthma in childhood. Also, gut and lung dysbiosis is detectable in patients with asthma. Strain-related probiotic supplementation may restore a physiological immune response, dampen airway inflammation, and repair dysbiosis. Therefore, the probiotics in pediatric asthma management (PROPAM) study is aimed at demonstrating that Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706) mixture could reduce asthma exacerbations in children, followed in a primary care setting. METHODS The study was randomized, placebo-controlled, and double-blind. It involved 11 Italian primary care pediatricians. The probiotic mixture (containing Ligilactobacillus salivarius LS01 1 × 109 live cells and Bifidobacterium breve B632 1 × 109 live cells) or placebo was taken twice daily (1 sachet in the morning and 1 in the evening) for eight weeks and subsequently once daily for a further eight weeks. Outcomes included number, severity, and duration of asthma exacerbations, intensity of maintenance and as need treatments, and safety. RESULTS The per-protocol population included 422 children (mean age seven years, 240 males and 182 females). The probiotic mixture significantly reduced the number of asthmatic exacerbations (OR = 3.17). In addition, the number of children with two exacerbations was less than a third in the active group (OR = 3.65). CONCLUSIONS This PROPAM study demonstrated that probiotic strains Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706) were safe and significantly reduced by more than a third the frequency of asthma exacerbations. At present, the first-line treatment of asthma is still drug-based, but specific strains of probiotics may be auxiliary remedies.
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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Jevnikar, Z, Östling, J, Ax, E, Calvén, J, Thörn, K, Israelsson, E, Öberg, L, Singhania, A, Lau, LCK, Wilson, SJ, et al
The Journal of allergy and clinical immunology. 2019;(2):577-590
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Abstract
BACKGROUND Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. OBJECTIVE We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. METHODS An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. RESULTS Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. CONCLUSIONS Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
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Comparison of the Association between Circulating Vitamin D3 Levels and Clinical Outcomes in Patients with Asthma and Chronic Obstructive Pulmonary Disease: A Prospective Observational Study.
Hirai, K, Shirai, T, Suzuki, Y, Shimomura, T, Itoh, K
Biological & pharmaceutical bulletin. 2019;(11):1861-1866
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Abstract
Vitamin D has an immune-modulating effect, related to the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD). However, few studies have focused on the difference between patients with asthma and COPD in the association of circulating vitamin D levels with clinical outcomes. We sought to investigate the associations of circulating vitamin D levels with health-related QOL (HR-QOL), severity, and exacerbations. Subjects included 152 asthma patients and 50 COPD patients. We measured plasma concentrations of 25-hydroxyvitamin D3 [25(OH)D3]. HR-QOL was assessed using the EuroQoL 5-Dimension (EQ-5D) and the 12-item Short Form Health Survey (SF-12) scales. Exacerbations were recorded during a one-year follow-up. Associations between plasma 25 (OH)D3 concentrations and outcome variables were evaluated using linear regression. Plasma concentrations of 25(OH)D3 were positively associated with the EQ-5D index value and the SF-12 physical component score in patients with asthma; however, such associations were not observed in patients with COPD. A significant association between severity and plasma concentrations of 25(OH)D3 was found only in patients with COPD. The hazard ratios (95% confidence interval) of plasma 25(OH)D3 concentrations (per 1 ng/mL decrease) for time to first exacerbation was 1.38 (1.10-1.75; p = 0.006) and 0.95 (0.87-1.03; p = 0.179) in patients with COPD and asthma, respectively. Lower concentrations of plasma 25(OH)D3 contributed to lower HR-QOL in patients with asthma, and were associated with severity and risk of future exacerbations in patients with COPD.
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Maternal and neonatal 25-hydroxyvitamin D concentrations and school-age lung function, asthma and allergy. The Generation R Study.
Mensink-Bout, SM, van Meel, ER, de Jongste, JC, Voortman, T, Reiss, IK, De Jong, NW, Jaddoe, VWV, Duijts, L
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(6):900-910
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BACKGROUND Vitamin D deficiency in early life might affect the developing lung and immune system, and subsequently influence the risk of asthma and allergy in later life. OBJECTIVE We examined the associations of 25-hydroxyvitamin D concentrations in mid-gestation and at birth with lung function, asthma, inhalant allergic sensitization and inhalant allergy at school-age. METHODS This study among 4951 children and their mothers was embedded in a population-based prospective cohort in Rotterdam, the Netherlands. Maternal venous blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D concentrations. At age 10 years, lung function was measured by spirometry, current asthma and physician-diagnosed inhalant allergy by questionnaire, and inhalant allergic sensitization by skin prick tests. We used multivariable regression models to examine associations. RESULTS Higher 25-hydroxyvitamin D concentrations in mid-gestation were associated with a higher forced vital capacity (FVC), but a lower forced expiratory volume in 1 second/FVC (FEV1 /FVC) and a lower forced expiratory flow after exhaling 75% of FVC (FEF75 ) (Z-score differences [95% CI] 0.02 [0.00, 0.03], -0.02 [-0.03, -0.01] and -0.01 [-0.03, -0.00], respectively, per 10 nmol/L 25-hydroxyvitamin D), but not with asthma. Furthermore, higher 25-hydroxyvitamin D concentrations in mid-gestation were associated with an increased risk of inhalant allergy (Odds Ratio [95% CI] 1.07 [1.02, 1.12]), but not with inhalant allergic sensitization. After additional adjustment for child's 25-hydroxyvitamin D concentrations at the age of 6 years, only the associations of 25-hydroxyvitamin D concentrations in mid-gestation with FEV1 /FVC and FEF75 remained. We did not find consistent associations of 25-hydroxyvitamin D concentrations at birth with respiratory or allergy outcomes. CONCLUSION AND CLINICAL RELEVANCE Our results suggest that maternal 25-hydroxyvitamin D concentrations in mid-gestation may influence lung development. The clinical implications of the observed associations remain unclear.
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Efficacy of Lactobacillus Administration in School-Age Children with Asthma: A Randomized, Placebo-Controlled Trial.
Huang, CF, Chie, WC, Wang, IJ
Nutrients. 2018;(11)
Abstract
Probiotics may have immunomodulatory effects. However, these effects in asthma remain unclear and warrant clinical trials. Here, we evaluated the effects of Lactobacillus paracasei (LP), Lactobacillus fermentum (LF), and their combination (LP + LF) on the clinical severity, immune biomarkers, and quality of life in children with asthma. This double-blind, prospective, randomized, placebo-controlled trial included 160 children with asthma aged 6⁻18 years (trial number: NCT01635738), randomized to receive LP, LF, LP + LF, or a placebo for 3 months. Their Global Initiative for Asthma⁻based asthma severity, Childhood Asthma Control Test (C-ACT) scores, Pediatric Asthma Severity Scores, Pediatric Asthma Quality of Life Questionnaire scores, peak expiratory flow rates (PEFRs), medication use, the levels of immune biomarkers (immunoglobulin E (IgE), interferon γ, interleukin 4, and tumor necrosis factor α) at different visits, and the associated changes were evaluated. Compared with the placebo group by generalized estimating equation model, children receiving LP, LF, and LP + LF had lower asthma severity (p = 0.024, 0.038, and 0.007, respectively) but higher C-ACT scores (p = 0.005, < 0.001, and < 0.001, respectively). The LP + LF group demonstrated increased PEFR (p < 0.01) and decreased IgE levels (p < 0.05). LP, LF, or their combination (LP + LF) can aid clinical improvement in children with asthma.
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Asthma status is associated with decreased risk of aggressive urothelial bladder cancer.
Rava, M, Czachorowski, MJ, Silverman, D, Márquez, M, Kishore, S, Tardón, A, Serra, C, García-Closas, M, Garcia-Closas, R, Carrato, A, et al
International journal of cancer. 2018;(3):470-476
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Abstract
Previous studies suggested an association between atopic conditions and specific cancers. The results on the association with urothelial bladder cancer (UBC) are scarce and inconsistent. To evaluate the association between asthma and risk of UBC, we considered 936 cases and 1,022 controls from the Spanish Bladder Cancer/EPICURO Study (86% males, mean age 65.4 years), a multicenter and hospital-based case-control study conducted during 1998-2001. Participants were asked whether they had asthma and detailed information about occupational exposures, smoking habits, dietary factors, medical conditions and history of medication was collected through face-to-face questionnaires performed by trained interviewers. Since asthma and UBC might share risk factors, association between patients' characteristics and asthma was studied in UBC controls. Association between UBC and asthma was assessed using logistic regression unadjusted and adjusted for potential confounders. The complex interrelationships, direct and mediating effect of asthma on UBC, were appraised using counterfactual mediation models. Asthma was associated with a reduced risk of UBC (odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.37, 0.79) after adjusting for a wide range of confounders. No mediating effect was identified. The reduced risk associated with asthma was restricted to patients with high-risk non-muscle invasive (OR = 0.25, 95%CI 0.10, 0.62) and muscle invasive UBC (OR = 0.32, 95%CI 0.15, 0.69). Our results support that asthma is associated with a decreased risk of UBC, especially among aggressive tumors. Further work on the relationship between asthma and other atopic conditions and cancer risk should shed light on the relationship between immune response mechanisms and bladder carcinogenesis.
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Low-grade disease activity in early life precedes childhood asthma and allergy.
Chawes, BL
Danish medical journal. 2016;(8)
Abstract
Asthma and allergies are today the most common chronic diseases in children and the leading causes of school absences, chronic medication usage, emergency department visits and hospitalizations, which affect all members of the family and represent a significant societal and scientific challenge. These highly prevalent disorders are thought to originate from immune distortion in early childhood, but the etiology and heterogeneity of the disease mechanisms are not understood, which hampers preventive initiatives and makes treatment inadequate. The objective of this thesis is to investigate the presence of an early life disease activity prior to clinical symptoms to understand the anteceding pathophysiological steps towards childhood asthma and allergy. The thesis is built on seven studies from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) birth cohort examining biomarkers of disease activity in 411 asymptomatic neonates in cord blood (I-II), urine (III), exhaled breath (IV-V) and infant lung function (VI-VII) in relation to the subsequent development of asthma and allergy during the first seven years of life. In papers I-II, we studied cord blood chemokines and 25(OH)-vitamin D, which represent a proxy of the inborn immature immune system, the intrauterine milieu, and the maternal immune health during pregnancy. High levels of the Th2-related chemokine CCL22 and high CCL22/CXCL11 ratio were positively correlated with total IgE level during preschool age (II). This suggests an inborn Th2 skewing of the immune system in healthy newborns subsequently developing elevated total IgE antibodies, which is considered to increase the risk of asthma and allergies later in life. Additionally, deficient cord blood 25(OH)-vitamin D levels were associated with a 2.7-fold increased risk of recurrent wheeze at age 0-7 years (I). Together, these findings support the concept that early life immune programming in the pre-symptomatic era plays an essential role for promotion of or protection against asthma and allergies. Therefore, preventive initiatives to restore immune health, such as vitamin D supplementation, should be directed to the fetus and the earliest postnatal life. The eosinophil granulocyte has a major role in the allergic inflammatory cascade and eosinophilia is considered a hallmark of many allergic phenotypes. In paper III, we examined neonatal urinary biomarkers including eosinophil protein X (u-EPX), which is contained in the eosinophil granules. Elevated u-EPX in asymptomatic neonates was associated with development of allergic sensitization and nasal eosinophilia, but not with wheezing or asthma (III). These findings suggest the presence of an ongoing low-grade disease process in early life characterized by eosinophil activation prior to appearance of allergy-related conditions. In papers IV-V, we investigated perinatal and genetic predictors of neonatal fractional exhaled nitric oxide (FeNO) and the relationship between neonatal FeNO and wheezing later in child-hood. The a priori selected determinants encompassed asthma genetic risk variants, anthropometrics, demographics, socioeconomics, parental asthma and allergy, maternal smoking, paracetamol and antibiotic usage during pregnancy, and neonatal bacterial airway colonization. Among those, only the DENND1B risk allele and paternal history of asthma and allergy were associated with increased FeNO values (V) suggesting that raised FeNO in neonatal life is primarily an inherited trait. The neonatal FeNO levels were widely dispersed (1-67 ppb) and children with values in the upper quartile were at increased risk of recurrent wheezing in early childhood, but not persistent wheezing, reduced lung function or allergy-related endpoints (IV). This suggests that elevated neonatal FeNO represents an early asymptomatic low-grade disease process other than congenitally small airway calibre contributing to a transient wheezing phenotype. Reduced lung function in neonates is associated with wheezing and asthma proneness, but it is unknown if such host factor also confers a risk of acute bronchiolitis, which is considered an index event of asthma persisting into school age. In paper VI, we investigated neonatal forced flow, volume, and responsiveness to methacholine in relation to occurrence of acute severe bronchiolitis at age 0-2 years. Children developing bronchiolitis had a 2.5-fold increased bronchial responsiveness as neonates (VI) suggesting a preexisting joint propensity of the airways to react adversely to common respiratory viruses and to develop asthma. This finding proposes airway hyperresponsiveness as yet another marker of low-grade disease activity among asymptomatic neonates on a trajectory towards childhood asthma. In paper VII, we examined whether neonates with impaired pulmonary capacity also had signs of systemic inflammation prior to clinical symptoms. Reduced FEV0.5 was significantly associated with elevated serum hs-CRP and other blood inflammatory markers (VII) suggesting presence of systemic low-grade inflammation from the beginning of life. Chronic low-grade inflammation is a common nominator of virtually all the major non-communicable welfare diseases (NCDs) of modernity whereof asthma and allergies are the earliest debuting disorders. The novel finding of systemic low-grade inflammation among neonates at increased risk of asthma and allergy, therefore implies that exploring the origins of asthma and allergy may also unravel disease mechanisms involved in other NCDs. In conclusion, the series of papers presented in this thesis (I-VII) evidence the presence of a pre-symptomatic disease process measurable in several body compartments, which supports the notion of low-grade disease activity in early life as a generic trait among neonates developing asthma and allergy. This hypothesis piggybacking on single biomarker assessments could be enforced and refined by applying novel global omics approaches. In particular, metabolomic analyses of serum, urine, and airway lining fluid from neonates as well as neonatal VOC profiling of exhaled breath may facilitate a broader understanding of the early low-grade disease activity preceding clinical symptoms. Disentangling the introductory pathophysiological mechanisms and underlying endotypes of disease is paramount for generating successful preventive measures to alleviate the major global burden of asthma, allergy, and other NCDs of modern time.
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Childhood allergies and asthma: New insights on environmental exposures and local immunity at the lung barrier.
Smits, HH, van der Vlugt, LE, von Mutius, E, Hiemstra, PS
Current opinion in immunology. 2016;:41-47
Abstract
While certain bacteria and respiratory viruses promote local inflammation and disease onset, a more diverse colonization of the different species in the (gut) microbiome may be linked to more regulatory responses and protection against asthma and allergies. These processes are also influenced in part by food intake, both targeting the composition of the gut microbiome and influencing the immune system via metabolites. Early life environmental microbial exposure also contributes to protection against asthma and allergy and is linked with an early activation of the innate immune system and the development of regulatory immune responses. Although greater mechanistic insight is needed, it is tempting to speculate that part of the environmental effect can be explained by modulation of the microbiome composition at mucosal surfaces, epithelial barrier function and/or local immunity. A review of the latest studies is provided.
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Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases.
Sala-Rabanal, M, Yurtsever, Z, Berry, KN, Brett, TJ
Mediators of inflammation. 2015;:497387
Abstract
Chloride transport proteins play critical roles in inflammatory airway diseases, contributing to the detrimental aspects of mucus overproduction, mucus secretion, and airway constriction. However, they also play crucial roles in contributing to the innate immune properties of mucus and mucociliary clearance. In this review, we focus on the emerging novel roles for a chloride channel regulator (CLCA1), a calcium-activated chloride channel (TMEM16A), and two chloride exchangers (SLC26A4/pendrin and SLC26A9) in chronic inflammatory airway diseases.
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Role of plasmacytoid dendritic cell subsets in allergic asthma.
Maazi, H, Lam, J, Lombardi, V, Akbari, O
Allergy. 2013;(6):695-701
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Plasmacytoid dendritic cells (pDCs) are major type-I interferon-producing cells that play important roles in antiviral immunity and tolerance induction. These cells share a common DC progenitor with conventional DCs, and Fms-like tyrosine kinase-3 ligand is essential for their development. Several subsets of pDCs have been identified to date including CCR9(+) , CD9(+) , and CD2(+) pDCs. Recently, three subsets of pDCs were described, namely CD8α(-) β(-) , CD8α(+) β(-) , and CD8α(+) β(+) subsets. Interestingly, CD8α(+) β(-) and CD8α(+) β(+) but not CD8α(-) β(-) pDCs were shown to have tolerogenic effects in experimentally induced allergic asthma. These tolerogenic effects were shown to be mediated by the generation of FOXP3(+) regulatory T cells through retinoic acid and the induction of retinaldehyde dehydrogenase enzymes. These newly described subsets of pDCs show high potentials for novel therapeutic approaches for the treatment of allergic diseases. In this review, we will address the new progress in our understanding of pDC biology with respect to allergic disease, in particular allergic asthma.