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Background: The extent to which biomarkers of asthma activity persist in spontaneous asthma remission and whether such markers are associated with future respiratory outcomes remained unclear. We investigated the association between sub‐clinical inflammation in adults with spontaneous asthma remission and future asthma relapse and lung function decline. Methods: The Tasmanian Longitudinal Health Study is a population‐based cohort (n = 8583). Biomarkers of systemic inflammation were measured on participants at age 45, and latent profile analysis was used to identify cytokine profiles. Bronchial hyperresponsiveness (BHR) and nitric oxide products in exhaled breath condensate (EBC NOx) were measured at age 50. Participants with spontaneous asthma remission at ages 45 (n = 466) and 50 (n = 318) were re‐evaluated at age 53, and associations between baseline inflammatory biomarkers and subsequent asthma relapse and lung function decline were assessed. Results: We identified three cytokine profiles in adults with spontaneous asthma remission: average (34%), Th2‐high (42%) and Th2‐low (24%). Compared to the average profile, a Th2‐high profile was associated with accelerated decline in post‐BD FEV1/FVC (MD −0.18% predicted per‐year; 95% CI −0.33, −0.02), while a Th2‐low profile was associated with accelerated decline in both post‐BD FEV1 (−0.41%; −0.75, −0.06) and post‐BD FVC (−0.31%; −0.62, 0.01). BHR and high TNF‐α during spontaneous remission were associated with an increased risk of asthma relapse. In contrast, we found no evidence of association between EBC NOx and either asthma relapse or lung function decline. Conclusion: BHR and serum inflammatory cytokines have prognostic value in adults with spontaneous asthma remission. At‐risk individuals with BHR, Th2‐high or Th2‐low cytokine profiles may benefit from closer monitoring and on‐going follow‐up. [ABSTRACT FROM AUTHOR]

PKC interacts with Cav1.3 calcium channels to promote the Cav1.2/Cav1.3 duo tuning Th2 functions In conclusion, the interaction of PKC with Ca SB v sb 1.3 upon TCR engagement is a new mechanism setting off calcium influx through Ca SB v sb 1 channels in non-excitable cells. Antisense oligonucleotides (ODN) targeting PKC mRNA (AS-PKC ) significantly decreased PKC but not PKC protein levels in Th2 cells (Figure 2A). [Extracted from the article]

The stronger mould-rhinitis association observed in participants without asthma as compared to those with ever asthma could be related to the avoidance of mould exposure among ever-asthmatics, or to the hypothesis that rhinitis and rhinitis asthma multimorbidity represent distinct diseases with different risk factors. As we focused on current rhinitis, we considered all participants who had had rhinitis symptoms in the past 12 months regardless of the duration of the symptoms, and participants who reported non-current rhinitis were excluded from the analyses. Although rhinitis is among the most common diseases worldwide,[1] few studies have investigated among adults the association between past and current exposure to indoor mould, a modifiable environmental factor and current rhinitis.[[2]] Furthermore, even if rhinitis and asthma often coexist, the potential modifying impact of asthma on this association has never been studied. [Extracted from the article]

To the Editor: Although bronchial hyperreactivity was first reported in 1859, it was only in the 1960s that nasal hyperreactivity (NHR) emerged as a field of interest in medicine. Given that CRS and NHR may give rise to similar nasal symptoms, the presence of NHR in CRS has not yet been documented. Over half of patients with NHR (52.0%) were classified as uncontrolled based on their VAS-TNSS score, while 18.1% of patients, whose sinonasal disease was under control, reported symptoms consistent with NHR (Table). Additionally, 52% of patients with NHR were classified as uncontrolled, which is in line with the hypothesis that hyperreactivity is a possible feature of uncontrolled disease. [Extracted from the article]

Background: Asthma is a complicated chronic inflammatory disorder characterized by airway inflammation and bronchial hyperresponsiveness. Group 2 innate lymphoid cells (ILC2) are tissue‐resident innate effector cells that can mediate airway inflammation and hyperresponsiveness through production of IL‐5, IL‐13 and VEGFA. ILC2 in asthma patients exhibit an activated phenotype. However, molecular pathways that control ILC2 activation are not well understood. Methods: MYC expression was examined in ILC2 sorted from peripheral blood of healthy controls and asthma patients or cultured with or without activating cytokines. CRISPR knockout technique was used to delete c‐Myc in primary murine lung ILC2 or an ILC2 cell line. Cell proliferation was examined, gene expression pattern was profiled by genome‐wide microarray analysis, and direct gene targets were identified by Chromatin immunoprecipitation (ChIP). ILC2 responses, airway inflammation and airway hyperresponsiveness were examined in Balb/c mice challenged with Alternaria extracts, with or without treatment with JQ1. Results: ILC2 from asthma patients expressed increased amounts of MYC. Deletion of c‐Myc in ILC2 results in reduced proliferation, decreased cytokine production, and reduced expression of many lymphocyte activation genes. ChIP identified Stat6 as a direct gene target of c‐Myc in ILC2. In vivo inhibition of c‐Myc by JQ1 treatment repressed ILC2 activity and suppressed Alternaria‐induced airway inflammation and AHR. Conclusion: c‐Myc expression is upregulated during ILC2 activation. c‐Myc is essential for ILC2 activation and their in vivo pathogenic effects. These findings suggest that targeting c‐Myc may unlock novel strategies to combat asthma or asthma exacerbation. [ABSTRACT FROM AUTHOR]

Background: Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of TH1‐directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in TH2‐regulated allergic bronchial asthma. Methods: To determine the role of Asm under baseline conditions, wild‐type (WT) and Asm−/− mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro TH2 differentiations with cells from WT and Asm−/− mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin‐induced model of asthma in WT‐ and Asm−/− mice. Results: At baseline, Asm−/− mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm−/− T cells in bronchoalveolar lavage fluid released lower levels of IL‐4 and IL‐5, and these results were paralleled by decreased production of typical TH2 cytokines in Asm−/− T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbumin asthma model, Asm−/− animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and TH2 cytokines. Conclusion: Asm deficiency could induce higher numbers of TH2 cells in the lung, but those cells release decreased TH2 cytokine levels. Hereby, Asm−/− animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade. [ABSTRACT FROM AUTHOR]

Asthma in combination with rhinitis and eczema is associated with a higher degree of type-2 inflammation and symptom burden than asthma alone In conclusion, asthmatics with allergic multimorbidity had a higher degree of type-2 inflammation and a higher burden of asthma and allergy symptoms. The comparison between asthma and rhinitis, and asthma, rhinitis and eczema was significant only for total IgE ( I p i <0.001). [Extracted from the article]

The article discusses a study of patients suffering from allergic rhinitis (AR) which aimed to identify subgroups of AR patients with possible distinct phenotypes. Topics include Cluster analysis, comparison by the chi‐square or the Fisher's exact test, Ascending hierarchical clustering analysis which produced clusters of patients; and concluded that clustering analysis could be a useful tool in the management of AR patients as it allow to identify specific clusters of patients at risk.

Background The severity of bronchial hyperresponsiveness ( BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study ( GWAS) on the slope of BHR in adult asthmatics. Methods We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort ( n = 650), adjusting for smoking and inhaled corticosteroid use, and verified results in three other cohorts. Furthermore, we performed e QTL and co-expression analyses in lung tissue. Results In the discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, c AMP-specif ( PDE4D) and 26 SNPs with P-values < 1*10−5 were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumour-transforming 1 interacting protein ( PTTG1 IP) and rs345983 in Mastermind-like 3 ( MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1 IP showed significant co-expression with pituitary tumour-transforming 1, the binding factor of PTTG1lP, and with vimentin and E-cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 ( MAML2), both involved in Notch signalling. Conclusions PTTG1 IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the e QTL analyses and co-expression of PTTG1lP with vimentin and E-cadherin1, and MAML3 with MAML2. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a heterogeneous disease with various biological origins and clinical appearances. Having decreased NMF did not show an association with early-onset AD, allergic rhinitis, BHR, asthma and combined asthma, and/or BHR. The results show a strong association between AD disease severity based on prior therapy, and NMF value. This study supports the hypothesis that patients with a decreased NMF value might benefit from different treatment regimens than patients with normal NMF value. [Extracted from the article]

Allergic rhinitis (AR) is the most common chronic allergic respiratory disease that become symptomatic after allergen exposure and commonly associated with asthma and/or sometimes with bronchial hyperresponsiveness (BHR).[[1]] Bronchial challenges with methacholine or histamine are the most commonly used and better-standardized tests for quantifying BHR.[2] Most of the studies on relation of AR and BHR were done in adults.[[3]] However, there is a need of further studies in childhood to uncover the actual prevalence of BHR in children with both coseasonal AR and preseasonal AR and the risk factors underneath. Patients with AR developed BHR at 1.6%, 11%, and 23.2% of the children within 12, 36, and 60 months after the onset of AR symptoms, respectively. GLO:1X5/01aug19:all13755-fig-0001.jpg PHOTO (COLOR): The percentage of bronchial hyperresponsiveness (BHR) in children with allergic rhinitis (AR) patients after the onset of symptoms in months in (A) Whole AR group (B) intermittent allergic rhinitis and persistent allergic rhinitis groups, (C) Boys and girls, (D) Blood eosinophil percentage in AR patients and BHR presence (ROC curve analysis) and sensitivity, specificity, positive, and negative predictive values for different cutoff values [Colour figure can be viewed at wileyonlinelibrary.com] gl. [Extracted from the article]

Background Genomewide association studies ( GWASs) of asthma have identified single-nucleotide polymorphisms ( SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness ( BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis- eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR. Methods A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis- eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data. Results A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3 BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature. Conclusions Combining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma. [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical research studies which include the effect of early life travelling on the development of asthmatic allergies, risk factors of allergic multimorbidity, and bronchial hyperreactivity.

Background: House dust mites (HDMs) are the most important source of indoor aeroallergens that contribute to the rising incidence of allergic diseases such as allergic asthma. The major HDM, Der f 2, induces inflammatory cytokine expression. Little is known about the signaling pathway involved. Objective: We wanted to define the Der f 2 signaling pathway from its receptor to the transcription factor responsible for IL-13 expression and production. Methods: Human bronchial epithelial cells were stimulated with Der f 2. The release and gene expression of IL-13 were measured by means of ELISA and RTPCR, respectively. In the airway inflammation mouse model, airway responses were assessed using ELISA, histology, BAL fluid, and methacholine responsiveness. Results: Here, we show that Der f 2 binds to TLR4 and induces IL-13 expression and production. In the airway inflammation mouse model, Der f 2-induced IL-13 production significantly decreased with treatment of TAK-242, a novel TLR4 inhibitor. Activation of TLR4 by Der f 2 requires the recruitment and activation of Syk, which leads to phosphorylation of PLCγ and membrane translocation of PKCα. p38 MAPK is then activated by PKCα and stimulates PLD1 activity by phosphorylating the Thr147 residue of PLD1. PLD1 activation enhanced binding of ROCK1 to ATF-2 and leads to increased expression of IL-13. Conclusion: Our data extend the knowledge for a variety of possible roles of PLD1 in allergic disorders including asthma pathogenesis and suggest possible candidacy of PLD1 as a molecular target for novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Asthma is an inflammatory disease that involves airway hyper-responsiveness and mucus hypersecretion. The LIM-only protein FHL2 is a crucial modulator of multiple signal transduction pathways and functions as a scaffold in specific protein-protein interactions. Objective: We sought to investigate the role of FHL2 in airway inflammation. Methods: Allergic airway inflammation was induced in WT and FHL2-knock out (FHL2-KO) mice with ovalbumin (OVA). Lung tissue, bronchoalveolar lavage fluid (BALF) and draining lymph node cells were analysed for inflammation. FHL2 loss and gain of function studies were performed in lung epithelial cells. Results: FHL2-deficient mice challenged with OVA show significantly reduced airway inflammation as evidenced by reduced infiltration of inflammatory cells including eosinophils, dendritic cells, B cells and T cells. Furthermore, mucus production was decreased in FHL2-KO mice. In BALF, the levels of IL-5, IL-13, eotaxin-1 and eotaxin-2 were significantly lower in FHL2-KO mice. In addition, draining lymph node cells from FHL2-KO mice show reduced levels of IL-5 and IL-13. Consistent with this, OVA-specific serum IgG and IgE levels were reduced in FHL2-KO mice. We also found that phosphorylation of ERK1/2 is markedly attenuated in FHL2-KO lung. Knock-down of FHL2 in human lung epithelial cells resulted in a striking decrease in ERK1/2 phosphorylation and mRNA levels of inflammatory cytokines and MUC5AC, whereas FHL2 overexpression exhibited opposite effects. Finally, the SNP rs4851765 shows an association with the severity of bronchial hyper-responsiveness. Conclusion: These results highlight functional involvement of FHL2 in airway inflammation and identify FHL2 as a novel gene associated with asthma severity in human. [ABSTRACT FROM AUTHOR]

In the general population, a history of asthma (HA) is associated with a higher risk of mortality of anaphylactic shock (AS), but it is unknown whether this association remains valid for intra-operative AS. The goal of this retrospective study was to investigate whether a HA was associated with a higher risk of broncho-spasm during intra-operative AS. We analyzed 106 patients (January 2009-December 2012) with intra-operative AS: 57% of them had a confirmed IgE-mediated reaction and 27% had a HA. On logistic regression, the only factor statistically associated with bronchospasm was a neuromuscular blocking drug, with both IgE- or non-IgE-mediated reactions. These results suggest that the mechanisms of bronchospasm in AS may be different from those of asthma and that, in the presence of bronchospasm during anesthesia, AS should be considered to be the most likely cause. [ABSTRACT FROM AUTHOR]

Background: The small airways are an important site of inflammation in asthma. However, the relation between small airway dysfunction and clinical expression of asthma has hardly been studied. Aim: To investigate the association of small and large airway dysfunction with asthma symptoms and bronchial hyper-responsiveness (BHR). Methods: Fifty-eight patients with asthma were characterized with spirometry, body plethysmography, impulse oscillometry, alveolar and bronchial exhaled nitric oxide, and a methacholine provocation. Symptoms of nocturnal asthma, exercise-related symptoms, BHR symptoms, and respiratory symptoms were assessed with the Asthma Control Questionnaire and Bronchial Hyper-responsiveness Questionnaire. Perception of dyspnea was rated with the Borg score during the provocation test. Results: Small and large airway dysfunction did not associate with higher scores for nocturnal, exercise-related, or BHR symptoms. Only higher scores on wheezing were significantly associated with higher values of difference between R5 and R20 (R5-R20) (r = 0.367, P < 0.01) and AX (r = 0.354, /><0.0l). Lower FEF25-75% (P = 0.024) and higher R5-R20 (P = 0.003) values were independently associated with more severe BHR to methacholine, but not FEV! or R20 values. The increase in dyspnea during the methacholine provocation was strongly and independently correlated with the decrease in FEVj and reactance of the respiratory system at 5 Hertz. Conclusion: Small and large airway dysfunction poorly associate with asthma symptoms in our patients. However, deteriorations in small airway dysfunction are strongly related to an increase in dyspnea during bronchial provocation with methacholine. Small airway dysfunction contributes also independently to the clinical expression of asthma, as reflected by the severity of BHR. [ABSTRACT FROM AUTHOR]

Anti-doping Policy, therapeutic use exemption and medication use in athletes with asthma: a narrative review and critical appraisal of current regulations. In our meta-analysis, only the study by Koch et al3 favoured 2-agonists (salbutamol) over placebo, when comparing VO2max, but this study included only female athletes. In addition, most athletes with asthma will need daily inhaled corticosteroid maintenance therapy or other drugs to avoid potential side effects or reduced tolerance and efficacy of short-acting 2-agonists. [Extracted from the article]

Background Bronchial hyperresponsiveness ( BHR) can be present in subjects without any respiratory symptoms. Little is known about the role of the small airways in asymptomatic subjects with BHR. Methods We investigated small airway function assessed by spirometry and impulse oscillometry, as well as Borg dyspnea scores at baseline and during a methacholine provocation test in 15 subjects with asymptomatic BHR, 15 asthma patients, and 15 healthy controls. Results At baseline, small airway function ( R5- R20 and X5) was comparable between subjects with asymptomatic BHR and healthy controls, whereas asthma patients showed small airway dysfunction as reflected by higher R5- R20 and lower X5 values. During methacholine provocation, small airway dysfunction was more severe in asthma patients than in subjects with asymptomatic BHR. Interestingly, a higher increase in small airway dysfunction during methacholine provocation was associated with a higher increase in Borg dyspnea scores in subjects with asymptomatic BHR, but not in asthma patients. Conclusion Subjects with asymptomatic BHR may experience fewer symptoms in daily life because they have less small airway dysfunction. [ABSTRACT FROM AUTHOR]

Asthma is a chronic respiratory disease, characterized by airway obstruction and inflammation. Increasing evidence shows that the small airways contribute significantly to the clinical expression and severity of asthma. Traditionally, high levels of disease activity are thought to be necessary before symptoms occur in the small airways because of their large reserve capacity. However, this concept is being challenged and increasing evidence shows small airway disease to be associated with symptoms, disease severity, and bronchial hyper-responsiveness. Particle size and distribution are of key importance when developing inhaled treatments for small airway disease. The availability of small-particle aerosols such as HFA-ciclesonide and HFA-beclomethasone dipropionate ( HFA- BDP) enables a higher drug deposition into the peripheral lung and potentially provides additional clinical benefits compared with large-particle treatment. However, improved methods are needed to monitor and assess small airway disease and its response to treatment because conventional spirometry mainly reflects large airway function. This remains a challenging area requiring further research. The aim of the current manuscript is to review the clinical relevance of small airway disease and the implications for the treatment of asthma. [ABSTRACT FROM AUTHOR]

To cite this article: Antó JM, Sunyer J, Basagaña X, Garcia-Esteban R, Cerveri I, de Marco R, Heinrich J, Janson C, Jarvis D, Kogevinas M, Kuenzli N, Leynaert B, Svanes C, Wjst M, Gislason T, Burney P. Risk factors of new-onset asthma in adults: a population-based international cohort study. Allergy 2010; 65: 1021–1030 Background: The occurrence of new-onset asthma during adulthood is common, but there is insufficient understanding of its determinants including the role of atopy. Objective: To assess the risk factors for the development of new-onset asthma in middle-aged adults and to compare them according to atopy. Methods: A longitudinal analysis of 9175 young adults who participated in two surveys of the European Community Respiratory Health Survey (ECRHS) conducted 9 years apart. Findings: We observed 179 cases of new-onset asthma among 4588 participants who were free of asthma and reported at the beginning of the follow-up that they had never had asthma (4.5 per 1000 person-years). In a logistic regression, the following risk factors were found to increase the risk of new-onset asthma: female gender (OR: 1.97; 95% confidence interval (CI): 1.38,2.81), bronchial hyperresponsiveness (3.25; 2.19,4.83), atopy (1.55;1.08,2.21), FEV1 < 100 % predicted (1.87;1.34,2.62), nasal allergy (1.98;1.39,2.84) and maternal asthma (1.91;1.13;3.21). Obesity, respiratory infections in early life and high-risk occupations increased the risk of new-onset asthma although we had limited power to confirm their role. Among the atopics, total IgE and sensitization to cat were independently related to the risk of new-onset asthma. The proportion of new-onset asthma attributable to atopy varied from 12% to 21%. Conclusion: Adults reporting that they had never had asthma were at a substantial risk of new-onset asthma as a result of multiple independent risk factors including lung function. Atopy explains a small proportion of new-onset adult asthma. [ABSTRACT FROM AUTHOR]

Background: Remarkable relationship exists between upper and lower airways. Bronchial hyperreactivity (BHR) is a paramount feature of asthma and may be considered a strong risk factor for the onset of asthma in patients with allergic rhinitis. Objective: This study is aimed at evaluating the presence of BHR in a large group of patients with moderate-severe persistent allergic rhinitis alone, and at investigating possible risk factors related to severe BHR. Methods: Three hundred and forty-two patients with moderate-severe persistent allergic rhinitis were prospectively and consecutively evaluated. Clinical examination, skin prick test, spirometry and bronchial methacholine (MCH) test were performed in all patients. Results: Twenty-two (6.4%) patients had severe BHR, 74 (21.6%) patients had mild BHR and 192 (56.2%) had borderline BHR; 54 (15.8%) patients had a negative MCH test. The logistic regression analysis evidenced that trees and house dust mites sensitization (ORAdj: 8.1), rhinitis duration > 5 years (ORAdj: 5.4) and FEV1 ≤ 86% of predicted (ORAdj: 4.0) were significantly associated with severe BHR. The discriminative ability of this model is appreciably satisfactory, being the AUC = 0.90. Conclusion: This study highlights the close link between upper and lower airways and the role of some risk factors, such as tree and mite sensitization, > 5-year duration, and ≤ 86% FEV1 values, as risk factors for severe BHR in patients with moderate-severe persistent allergic rhinitis alone. Therefore, BHR is frequently present in patients with chronic rhinitis and should be suspected in the presence of defined risk factors. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis with nasal polyposis (CRSNP) and asthma are inflammatory lesions of the respiratory epithelium. This study was conducted to evaluate predictive factors of bronchial hyperresponsiveness (BHR) in patients with CRSNP. Methods: BHR was evaluated using a methacholine bronchoprovocation test (MBPT) in 122 consecutive patients newly diagnosed with CRSNP at Seoul National University Hospital from January 2004 to June 2006. The following parameters were analyzed and compared between the BHR and non-BHR groups: symptoms, atopic status, current smoking, disease severity of CRSNP based on the Lund–Mackay scoring system of sinus CT, and counts of eosinophils in the serum and nasal tissues. Results: Thirty-five percent of the patients were found to have BHR, and BHR was found to occur more frequently in patients that were currently suffering from sneezing ( P = 0.007). In addition, the mean eosinophil counts of the serum and nasal tissues were higher in the BHR group than in the non-BHR group ( P = 0.001 for the serum, P = 0.045 for the nasal tissues), and the eosinophil counts of the serum correlated to those of the nasal tissues ( r = 0.334, P = 0.013). The disease severity, as determined by the Lund–Mackay scoring system, was not different between the two groups ( P > 0.05). The best cutoff serum eosinophil count for predicting BHR in CRSNP patients was determined to be 300 cells/μl (sensitivity 70%, specificity 70%). Conclusion: Taken together, these results indicate that moderate to severe sneezing and a serum eosinophil count ≥ 300 cells/μl may be predictive factors for BHR in patients with CRSNP. [ABSTRACT FROM AUTHOR]

Background: Patients with allergic rhinitis (AR) feature both allergic airway inflammation and a hyperresponsiveness to nonspecific stimuli which is partly neuronally controlled. Still, it is unclear whether or not neurotrophins are involved in airway pathophysiology of AR and in nasobronchial interaction. Methods: Nine AR patients with mono-allergy to grass pollen and nine healthy controls underwent nasal allergen provocation (NP). Serum samples, nasal and bronchial biopsies were taken before (T0) and 24 h after (T24) NP. Pan-neurotrophin receptor p75NTR, tyrosine kinase A (trkA), trkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) were assessed with immunohistochemistry, and NGF and BDNF levels with ELISA. Results: At T24, BDNF and NGF were upregulated in nasal mucosa ( P < 0.05) and increased in the peripheral blood of AR compared with T0. The increase in nasal BDNF expression correlated positively with the maximum increase in total nasal symptom score in AR ( P = 0.02). p75NTR was expressed on peripheral nerves and epithelial layer, trkA on endothelial cells, and trkB on mast cells. trkB + mast cells significantly decreased after NP in AR ( P < 0.01). NP did not modulate p75NTR and trkA expression in nasal mucosa and had no effect on the expression of neurotrophins and receptors in bronchial mucosa. Conclusion: This study shows that neurotrophins and their receptors are expressed in human airways. Allergic rhinitis was characterized by a modulation of BDNF, NGF, and trkB in nasal mucosa after NP and a correlation of nasal BDNF with the maximal increase of total nasal symptom score. Therefore, our data suggest that neurotrophins participate in upper-airway pathophysiology in AR, whereas their role in nasobronchial interaction remains unclear. [ABSTRACT FROM AUTHOR]

Background: Subjects with allergic rhinitis but no clinical evidence of asthma have greater bronchial hyperresponsiveness (BHR), and several factors have been implicated as its determinants. However, studies in young children are lacking. The aims of this study were to evaluate the prevalence of BHR in young children with allergic rhinitis and to investigate its risk factors. Methods: Methacholine bronchial challenges were performed in 4- to 6-year-old nonasthmatic children with allergic rhinitis ( n = 83) and in healthy nonatopic controls ( n = 32), using a modified auscultation method. The end-point was defined as the appearance of wheezing and/or oxygen desaturation. Subjects were considered to have BHR when they had end-point concentrations of methacholine ≤8 mg/mL. Clinical and laboratory data in allergic rhinitis patients and a history of allergic diseases in their parents were collected. Results: BHR was observed in 27 subjects with allergic rhinitis (32.5%) and three controls (9.4%). Among subjects with allergic rhinitis, serum total IgE, the number and pattern of skin-prick test responses, blood eosinophil markers, and parental history of allergic rhinitis and atopic dermatitis were not different between the BHR(+) and BHR(−) groups, whereas the persistent type of rhinitis and parental history of asthma were more frequent in the BHR(+) group than in the BHR(−) group. These associations remained significant in a multivariable logistic regression. Conclusions: Young children with allergic rhinitis alone showed an increased prevalence of BHR. Both persistent type of rhinitis and parental history of asthma were significant and independent risk factors for BHR in these children. [ABSTRACT FROM AUTHOR]

Background: In asthmatic patients, both symptoms and hyperresponsiveness are related to immunoglobulin E (IgE) concentration in serum. The anti-IgE monoclonal antibody omalizumab improved the control of asthma, but its effect on airway hyperresponsiveness is controversial. Passive sensitization reproduced in vitro a bronchial hyperresponsiveness, an increase in IgE bearing cells, and a mast cell degranulation. This study was designed to examine the effect of omalizumab on passive sensitization-induced hyperresponsiveness, alterations in IgE positive inflammatory cells and mast cell degranulation within the bronchial wall. Methods: Proximal (3–5 mm diameter) and distal (0.5–1.5 mm diameter) human bronchi dissected out from 10 lung specimens were incubated in normal or asthmatic serum containing various concentrations of omalizumab. Contractile responses to histamine or Dermatophagoides pteronyssinus ( D. pter) were recorded using an organ bath system and expressed as percentage of maximal contractile response to acetylcholine (ACh). Immunohistochemistry was performed using monoclonal antibodies directed against IgE or tryptase. Mast cells were classified as fully granulated (type I), partly (type II) or largely degranulated (type III). Results: The specific bronchial hyperresponsiveness to D. pter and the nonspecific bronchial hyperresponsiveness to histamine following passive sensitization were significantly inhibited by omalizumab in both distal and proximal airways. Passive sensitization-induced increase in IgE positive cells was also abolished by omalizumab in a concentration dependent manner. Mast cell degranulation which was inhibited by omalizumab was positively correlated with the contractile response to D. pter. Conclusions: Omalizumab blocks specific and nonspecific bronchial hyperresponsiveness. Anti-IgE also decreases IgE bearing cell number and mast cell degranulation. [ABSTRACT FROM AUTHOR]

At an early age, Philip S. Norman developed a keen interest in science - first with astronomy and mathematics, then with meteorology during his military training, and subsequently with a medical career that took him from the coalfields of Kansas to his eventual tenure at Johns Hopkins. In 1968, Dr AM Harvey, Chairman of Medicine at Johns Hopkins at that time, made an offer to Phil & Larry to establish a formal Division of Clinical Immunology. Studies with Creticos defined the target maintenance dose for SIT with ragweed, an approach that served as a model for other allergens used in immunotherapy. [Extracted from the article]

Background: Quantitative relationships between immunological reactivity, non-specific bronchial responsiveness and bronchial responsiveness to allergens have scarcely been investigated in occupational asthma. Methods: We assessed the above relationships in 24 subjects with baker's asthma. The skin endpoint titration to bakery allergens as a measure of immunological reactivity, together with the methacholine PC20 and allergen PC20 during early asthmatic reaction were determined. Results: All patients had positive skin tests to some bakery allergens (wheat and rye flour, soybean flour, fungal enzymes and egg white proteins) and bronchial hyperresponsiveness to methacholine. Specific inhalation challenge (SIC) tests were performed with aqueous allergen extracts of cereal flour ( n = 14), soybean ( n = 8), baking enzymes ( n = 12), and egg white proteins ( n = 8) in sensitized workers. A positive asthmatic reaction was observed in 84% of the inhalation challenges. SIC elicited isolated early asthmatic reactions in 62%, dual reactions in 32% and isolated late reactions in 5%. Multiple linear regression analysis showed allergen PC20 as a function of skin sensitivity to allergen and methacholine PC20, yielding the following highly significant regression formula: log-allergen PC20 = 0.18 + 0.99 log(skin sensitivity) + 0.343 log(methacholine PC20) ( r = 0.89, P < 0.001). This formula predicted allergen PC20 to within one double concentration in 67%, to within two double concentrations in 85% and within three double concentrations in 97%. Conclusion: The main determinant of bronchial responsiveness to allergen in patients with baker's asthma is the degree of sensitization to occupational allergens as determined by skin reactivity, modulated to a lesser extent by non-specific bronchial hyperresponsiveness. [ABSTRACT FROM AUTHOR]

Background: Numerous factors affect the evolution of respiratory allergy, in children, but little is known in adults. We assessed in a prospective study the influence of the type of allergen on the progression of disease. Methods: Outpatients, with respiratory allergy underwent skin tests and pulmonary function/methacholine challenge at baseline and after 3 years. Patients were subdivided in pure rhinitis or rhinitis + bronchial hyperreactivity (BHR). In polysensitized subjects a single relevant allergen (mites, grasses, birch, Parietaria) was identified based on symptom distribution and when needed on nasal challenge. Results: 6750 patients (age range 12–46) were studied. Of them, 17.8% were monosensitized but this percentage decreased to 10.4% after 3 years ( P < 0.05). Subjects with pure rhinitis were 81% at the beginning and 48% at the end. After 3 years, the patients with bronchial responsiveness increased from 18% to 58% for mites, 22% to 49% for birch, 18% to 44% for grasses, 17% to 32% for Parietaria, with a significant difference among allergens ( P < 0.05). Almost the same was seen in monosensitized subjects, being mites most likely to cause a worsening. All patients with BHR at baseline received immunotherapy. In these patients the onset of new sensitizations was significantly lower than in the group (pure rhinitis) receiving drugs only and lower airways symptoms disappeared more frequently. Conclusion: The different type of allergen influences the course of the disease, as well as the use of immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The β2-adrenoceptor exhibits genetic polymorphism which may be clinically relevant in terms of treatment response or bronchial hyper-responsiveness (BHR). The combined effect of these genotypes, or the haplotype, has not been fully characterized in terms of BHR. Methods: We performed a retrospective analysis of the effects of haplotypes of amino acid substitution at position 16 (Gly/Arg) and position 27 (Gln/Glu) on spirometry and BHR to methacholine and adenosine monophosphate (AMP) in 594 asthmatic patients. Results: There was a significant ( P < 0.05) overall effect for forced expiratory volume (FEV1) but not after correction for steroid dose and atopic status. There were no significant differences for BHR to methacholine or AMP between the different haplotypes and no difference between the numbers of patients with or without clinically relevant BHR. Methacholine PD20 geometric mean-fold difference was 1.63 (95% CI: 0.95–2.80) between Arg–Arg/Gln–Gln and Gly–Gly/Gln–Gln and 1.26 (95% CI: 0.75–2.11) between Gly–Gly/Gln–Gln and Gly–Gly/Glu–Glu. Conclusions: The degree of BHR to indirect and direct stimuli does not differ between β2-adrenoceptor haplotypes, and haplotypes cannot be used to predict BHR in patients presenting with asthma. Although β2-adrenoceptor haplotypes do not predict BHR they may be important in predicting response to bronchodilator therapy. [ABSTRACT FROM AUTHOR]

Background: Lifestyle changes over the last 30 years are the most likely explanation for the increase in allergic disease over this period. Aim: This study tests the hypothesis that the consumption of fast food is related to the prevalence of asthma and allergy. Methods: As part of the International Study of Asthma and Allergies in Childhood (ISAAC) a cross-sectional prevalence study of 1321 children (mean age = 11.4 years, range: 10.1–12.5) was conducted in Hastings, New Zealand. Using standard questions we collected data on the prevalence of asthma and asthma symptoms, as well as food frequency data. Skin prick tests were performed to common environmental allergens and exercise-induced bronchial hyperresponsiveness (BHR) was assessed according to a standard protocol. Body mass index (BMI) was calculated as weight/height2 (kg/m2) and classified into overweight and obese according to a standard international definition. Results: After adjusting for lifestyle factors, including other diet and BMI variables, compared with children who never ate hamburgers, we found an independent risk of hamburger consumption on having a history of wheeze [consumption less than once a week (OR = 1.44, 95% CI: 1.06–1.96) and 1+ times a week (OR = 1.65, 95% CI: 1.07–2.52)] and on current wheeze [consumption less than once a week (OR = 1.17, 95% CI: 0.80–1.70) and 1+ times a week (OR = 1.81, 95% CI: 1.10–2.98)]. Takeaway consumption 1+ times a week was marginally significantly related to BHR (OR = 2.41, 95% CI: 0.99–5.91). There was no effect on atopy. Conclusions: Frequent consumption of hamburgers showed a dose-dependent association with asthma symptoms, and frequent takeaway consumption showed a similar association with BHR. [ABSTRACT FROM AUTHOR]

Allergic rhinitis is traditionally subdivided into seasonal (SAR) and perennial (PAR), although the new definitions of persistent and intermittent were recently proposed. We assessed the validity of the traditional classification in a large group of subjects suffering from allergic rhinitis alone.Young males referred to a Navy Military Hospital for routine fitness visit, and reporting symptoms of rhinitis alone were selected. According to the sensitization they were subdivided into (i) sensitized to pollens only (seasonal, SAR), (ii) to perennial allergens only (perennial, PAR) and (iii) to both (mixed, MAR). Spirometry, methacholine challenge, severity and characteristics of symptoms were assessed in all participants.Of 19 325 subjects, 2347 had allergic rhinitis. Seventy-two percent of the subjects had MAR, 17% SAR and 11% PAR. Ocular involvement and irritative symptoms were more frequent in SAR (P < 0.03), whereas obstruction was predominant in PAR (P < 0.01). Nasal symptoms varied according to the period of the year in SAR (P < 0.01) and PAR (P < 0.03). An overt bronchial obstruction was detected in 12% of PAR patients, in 7.8% of MAR, and in 4.2% of SAR. forced expiratory volume/1 s was significantly lower during season in SAR patients only (P < 0.05). The FEF25–75 was impaired in 22.5% MAR patients, 21% PAR, and 14% SAR, with a seasonal change in SAR (P < 0.05) and PAR (P < 0.001). Bronchial hyperreactivity was present in 82.2% of PAR, 73.6% of MAR, and 53.5% of SAR, with a seasonal change in SAR (P < 0.001) and MAR (P < 0.05).This study provides evidence that up to 80% of allergic rhinitics have a mixed form, and SAR and PAR definitions are poorly adherent to real life. Lung involvement is frequent in patients reporting nose symptoms alone. [ABSTRACT FROM AUTHOR]

Montelukast has been shown to be effective in controlling the increase in exhaled NO in asthmatic children re-exposed to house dust mite (HDM). This study compared the effect of low dose inhaled budesonide and oral montelukast in preventing the expected relapse of airway inflammation and reactivity in a group of 24 mild asthmatic children allergic to HDM after a brief period of exposure to relevant allergens.Lung function, bronchial hyperresponsiveness (BHR) to methacholine (PC20), fractional exhaled nitric oxide (FeNO) levels and sputum eosinophilia were evaluated.Pulmonary function remained stable. The BHR was unchanged after exposure in the group treated with budesonide, whereas a significant increase (P = 0.028) was observed in the patients receiving montelukast. No significant difference was observed in FeNO levels after exposure to mite antigen in the two groups. In both the groups of asthmatic children we observed a significant increase in sputum eosinophil % after the exposure to mite antigen.The significant increase in BHR level observed in the group of children receiving montelukast suggests a more comprehensive effect as disease controller by inhaled steroids than by leukotriene antagonist in allergic asthmatic children re-exposed to relevant allergens. [ABSTRACT FROM AUTHOR]

The inflammatory mechanisms of hypertonic saline-induced bronchoconstriction are not well understood.Seventeen asthmatics with (n = 11) and without bronchial hyperresponsiveness (BHR) (n = 6) and 18 randomly selected nonatopic nonasthmatic controls without BHR were evaluated by urine samples collected before and 1 h after hypertonic saline provocation test. Histamine, 11β-PGF2α, and LTE4 were analysed by enzyme immunoassay (EIA) and eosinophil protein X (EPX) by radioimmunoassay (RIA).The levels of leukotriene E4 (LTE4) increased significantly after the challenge tests, both in the asthmatics (median: 354 pg/mg pre-challengevs.628 pg/mg post-challenge;P = 0.05) and in the controls (median: 294 pg/mg pre-challengevs.460 pg/mg post-challenge;P < 0.01). The levels of histamine also increased significantly in the latter (median: 299 μmol/mg pre-challengevs.569 μmol/mg post-challenge;P = 0.03). However, the levels of 11β-PGF2α and EPX did not change significantly after the challenge tests either in the asthmatics or in the controls.The inhalation of hypertonic saline increased urinary excretion of LTE4 both in the asthmatics and in the controls. The slight increase of leukotrienes was enough to induce airway obstruction in some of the asthmatics, because of the hyperresponsiveness in their airways. [ABSTRACT FROM AUTHOR]

Severe acute asthma can be induced by different triggers, allergens, irritants, viruses, etc., which induce inflammation and provoke acute bronchoconstriction. Inflammatory cells, such as activated eosinophils and neutrophils identified in sputum and bronchial lavages (BL) in severe acute asthma from children and adults are associated with increased levels of IL-5, IL-8, and of proinflammatory mediators. Viruses, but also endotoxin or allergen exposure, are able to recruit neutrophils, via an IL-8 production by activated macrophages or epithelial cells. Together, these inflammatory mediators are responsible for the diffuse bronchial inflammation, which involve large and small airways. Activated T cells may also be related to the pathogenesis of severe asthma. An aberrant CD8+ T lymphocyte response in bronchi, with a cytotoxic activity has been associated with fatal asthma. Moreover, the persistence of inflammatory cells in bronchi, particularly neutrophils, which respond poorly to corticosteroids, could be in part responsible for the epithelial damage, the extensive mucus plugging, and the abnormalities of epithelial and endothelial permeability which are associated with severe acute asthma. Further studies are necessary to better identify the implication of this increased bronchial permeability in the persistence of high levels of airway resistance, particularly in patients with status asthmaticus. [ABSTRACT FROM AUTHOR]

Early asthmatic responses (EAR) and late asthmatic responses (LAR) to allergen are induced by the local release of a series of bronchoconstrictor mediators, including leukotrienes and histamine. Both anti-leukotrienes and other anti-asthma drugs, such as inhaled glucocorticoids, have been shown to reduce both EAR and LAR. The aim of the present study was to directly compare the effects of regular treatment with an oral anti-leukotriene, montelukast (Mont; 10 mg once daily, for 8 days), and an inhaled glucocorticoid [fluticasone propionate (FP) 250 μg twice daily for 8 days] on the EAR and LAR to an inhaled allergen challenge. Patients with a documented EAR and LAR at a screening visit were randomized to these treatments, or placebo, in a double-blind, double-dummy, crossover fashion. Allergen challenge at a dose causing both an EAR and LAR was given on the eighth day of treatment. The maximum fall in FEV1 during the EAR was 17.8% during placebo treatment, 8.3% during Mont and 16.3% during FP (P < 0.05 for Montvsplacebo). The maximum fall during the EAR was 13.8% during placebo treatment, 11.8% during Mont and 2% during FP treatment (P < 0.05 for FPvsplacebo and FPvsMont). PC20 methacholine was significantly higher 24 h after allergen challenge during FP-treatment compared with Mont (P < 0.05). Both montelukast and fluticasone reduced the relative amount of sputum eosinophils after allergen compared with placebo treatment. This study shows that anti-leukotrienes are effective to attenuate the EAR, whereas inhaled glucocorticoids are more effective than anti-leukotrienes in attenuating the EARs and improves bronchial hyperresponsiveness to a greater extent. In conclusion, inhaled glucocorticoids have overall greater efficacy than oral anti-leukotrienes to attenuate allergen-induced airway responses in mild asthmatic patients. [ABSTRACT FROM AUTHOR]

Some aspects of sublingual immunotherapy (SLIT)still need to be addressed: magnitude of the clinical efficacy, effect on the bronchial hyperreactivity adherence to treatment, preventive effect. We attempted to clarify these points in a randomized open, controlled, two parallel group study in a real-life setting.Five hundred and eleven patients with allergic rhinitis with or without intermittent asthma were randomized to drugs only or drugs + SLIT (rate 2 : 3) for 3 years. The clinical score (symptoms + drug intake) was measured each year during the allergen exposure. Pulmonary function test, methacholine challenge and skin tests were performed at the beginning and at the end of the study. Adherence to treatment was assessed by measuring the consumed extract.Three hundred and nineteen patients received SLIT and 192 drugs only. Dropouts were 15% in the SLIT group and 12% in the controls. There was a significant improvement of clinical scores in the SLIT group: baseline 147 ± 3.3, first year 72.9 ± 1.3, second year 68.3 ± 1.8, third year 54.7 ± 2.8 (P < 0.0001vsbaseline). Control group: baseline 138 ± 2.3, first year 124.1 ± 3.7, second year 111 ± 3.3, third year 121 ± 3.8 (P = NS). Only four patients reported systemic itching. Adherence was>80% in 72% and>60% in 18% of patients. The number of patients with a positive MCh challenge decreased significantly after 3 years only in the SLIT group. New skin sensitizations appeared in 38% of the controls and in 5.9% of the SLIT patients (P = 0.01).Sublingual immunotherapy approximately halved the clinical scores and significantly reduced the bronchial hyperreactivity. Similarly to subcutaneous immunotherapy, SLIT displayed a preventive effect on the onset of new skin sensitizations. The adherence rate was quantitatively satisfactory. [ABSTRACT FROM AUTHOR]

Bronchial hyperresponsiveness (BHR) and airway inflammation are frequently associated with allergic rhinitis, and may be important risk factors for the development of asthma. Specific immunotherapy (SIT) reduces symptom in subjects with allergic rhinitis, but the mechanisms are not clear.To assess the effect ofParietaria-SIT on asthma progression, rhinitic symptoms, BHR, and eosinophilic inflammation.Nonasthmatic subjects with seasonal rhinitis were randomly assigned to receiveParietariapollen vaccine (n = 15) or matched placebo (n = 15). Data on symptoms and medication score, BHR to methacholine, eosinophilia in sputum were collected throughout the 3-year study.By the end of the study, in the placebo group, symptoms and medication scores significantly increased by a median (interquartile range) of 121% (15–280) and 263% (0–4400) respectively (P < 0.01), whereas no significant difference was observed in the SIT group. We found no significant changes in sputum eosinophils and BHR to methacholine in both groups throughout the study. Nine of 29 participants developed asthma symptoms during the study; of these, only two subjects (14%) in the SIT-treated group (P = 0.056).Parietaria-SIT reduces symptom and rescue medication scores, but no changes in BHR to methacholine or sputum eosinophilia were observed. Moreover,Parietaria-SIT appears to prevent the natural progression of allergic rhinitis to asthma, suggesting that SIT should be considered earlier in the management of subjects with allergic rhinitis. [ABSTRACT FROM AUTHOR]

Our aims were to compare the doses of wheat and rye flour that induce early bronchial responses in occupationally exposed asthmatic subjects and to assess the effects of the dose of inhaled flour, the duration of exposure and the dose rate. Ten patients underwent tests with lactose, wheat flour and rye flour. We compared the decrease in forced expiratory volume in 1 s ( FEV1) observed during the challenge with flour and with lactose. We also calculated the amount of flour that was instantaneously active. Seven subjects had significantly decreased FEV1 values following exposure to wheat and rye flour and two subjects only did so for rye flour. The provocative dose (PD, dose required to reduce FEV1 by 15%) of rye was lower than that of wheat flour (geometric mean; PD15 rye: 95 μg; wheat: 368 μg). The calculated doses of rye and wheat flour were better correlated with the change in FEV1 than were the cumulative doses. The bronchial response was greater with rye than with wheat flour. The response was related to the dose of allergen inhaled and to the dose rate. [ABSTRACT FROM AUTHOR]

The use of immunotherapy in asthmatic children is still controversial. Sublingual immunotherapy (SLIT) may represent an advance, due to the good safety profile, but little is known about its effects on lung function and nonspecific bronchial responsiveness. The aim of this study was to assess the effects of SLIT on these parameters, in children with Parietaria pollen-induced asthma. Thirty children with asthma solely due to Parietaria who participated in a previous randomized, placebo-controlled trial with SLIT were studied: pulmonary function test and methacholine challenge were carried out at baseline in winter 1999 (out season), during the 1999 season (before randomization), and during the 2001 season. Before randomization, there was a significant fall in methacholine provocation concentration during the pollen season vs baseline in both groups (SLIT group 9.78 ± 5.95 mg/ml vs 3.37 ± 2.99 mg/ml; placebo 8.70 ± 6.25 mg/ml vs 2.44 ± 2.25 mg/ml; P = .005). In the second pollen season, the response to methacholine returned to baseline values in the active group (9.10 ± 7.7 mg/ml; P = NS vs baseline), whereas in the placebo group a significant increase in reactivity was still present (2.46 ± 2.26; P = 0.008 vs baseline). No significant difference in FEV1 and FEF25−75 between the two groups was observed at all times. Our data show that SLIT abrogates the seasonal bronchial hyperreactivity in children with asthma due to Parietaria. This may be regarded as an indirect evidence of the effect on bronchial inflammation. [ABSTRACT FROM AUTHOR]

The association between nasal and bronchial symptoms, and the course of bronchial responsiveness and airway inflammation in house dust mite sensitive persistent rhinitis over a prolonged time period has not been thoroughly explored. To determine if nasal symptoms were associated with bronchial symptoms in persistent rhinitic subjects, and to assess their bronchial responsiveness and airway inflammation in comparison to nonrhinitic, nonatopic controls. The additional impact of pollen sensitivity on the lower airways in rhinitic subjects was also addressed. Rhinitics and controls answered telephone symptom questionnaires once every 2 weeks for 1 year. Every 3 months, exhaled nitric oxide (eNO) and bronchial responsiveness to histamine were measured. Thirty-seven rhinitics and 19 controls completed the study. High nasal symptom scores in rhinitic subjects were associated with bronchial symptoms (OR = 1.7, 95% CI 1.2–2.5). Bronchial hyper-responsiveness was present in 32.4% of rhinitic subjects on at least one clinical visit during the year. Pollen allergy caused seasonal variation in eNO ( P = 0.03). In persistent rhinitic subjects, high nasal symptom scores were associated with bronchial symptoms, and many subjects experienced bronchial hyper-responsiveness during the year. Persistent rhinitic subjects were more at risk than healthy adults of bronchial symptoms and airway inflammation, which are likely risk factors for asthma. [ABSTRACT FROM AUTHOR]

Controlled clinical trials on the effects of leukotriene antagonists on asthma-like symptoms, bronchial hyperresponsiveness and airway inflammation have not been performed in elite athletes. In 2001, we examined 88 of 102 (86%) players from three junior, national league ice hockey teams in Helsinki. Athletes were included in the intervention if they reported at least two exercise-induced bronchial symptoms (wheeze, cough, shortness of breath) weekly during the previous month on a previously validated respiratory-symptom questionnaire. Sixteen male ice hockey players fulfilled the study criteria. A double-blind, randomized, cross-over, placebo-controlled study included 4-week active treatment (10 mg oral montelukast, bedtime), 1-week washout period, and 4-week placebo treatment. Before entering the study, all patients were clinically examined, skin prick tested, filled in a respiratory symptom questionnaire, performed a spirometry and a histamine challenge test, and gave induced sputum samples. Exhaled NO was measured. These measures were repeated after both treatment periods. During the treatment the athletes kept daily diary on lower respiratory tract symptoms on a scale from 0 (no symptoms) to 10 (most severe symptoms), morning peak expiratory flow (PEF), training amount, and use of study medication. Primary end-point was daily lower respiratory tract symptom score. Montelukast had no effect on daily lower respiratory symptom scores, spirometry parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, PEF], bronchial hyperresponsiveness, sputum eosinophil or neutrophil cell counts, exhaled NO measurements, or morning PEF. Nine subjects were atopic in skin prick test, but their results did not differ from the nonatopic subjects. A leukotriene antagonist, montelukast, was of no benefit in the treatment of asthma-like symptoms, increased bronchial hyperresponsiveness or a mixed type of eosinophilic and neutrophilic airway inflammation in highly-trained ice hockey players. [ABSTRACT FROM AUTHOR]

The prevalence of asthma and bronchial hyperreactivity has been reported to be higher in athletes than in the general population. This has also been related to reported asthma in order to obtain permitted use of β2-agonists, whose assumption in athletes is ruled by anti-doping regulations. The paper addresses the issue whether the recently established and evaluated rules of the International Olympic Committee on tests and procedures for diagnosis of asthma in athletes and permitted use of β2-agonists are consistent with an adequate diagnosis and management of asthma according to international guidelines. [ABSTRACT FROM AUTHOR]

Most previous epidemiological studies on the relationship between allergy and bronchial hyperresponsiveness (BHR) have made no distinction between sensitization to indoor and outdoor allergens. We studied the relationship between specific sensitization to allergen and BHR and further assessed whether this was different in young adults and older subjects. Specific IgE to indoor allergens (house dust mite and cat) and outdoor allergens (timothy grass and birch) were measured using the CAP System. BHR was defined as PD20 ≤ 2 mg methacholine. Multiple logistic regression analysis was performed to study independent relationships between BHR and specific IgE to indoor and outdoor allergens in 1018 young adults (20–44 years) and 909 older subjects (45–70 years). In the older age group specific IgE to indoor allergens was associated with BHR at a lower level (class 2) than in young adults (class ≥ 3). Young adults with multiple sensitization had the highest risk of BHR. Subjects who were exclusively sensitized to pollen did not show increased BHR in both age groups. Total IgE had, independently of sensitization, only a significant dose–response relationship with BHR in the oldest age group. The association between sensitization and BHR is dependent on the nature of the allergen and the level of specific IgE. Furthermore, this study shows for the first time that total IgE is associated with BHR at older ages, independently of sensitization. [ABSTRACT FROM AUTHOR]

Background: About 70% of childhood asthmatics become free of asthma-related symptoms during adolescence. Little is known about bronchial hyperresponsiveness (BHR) and airway inflammation in young adults with “outgrown” childhood asthma. Methods: We studied 61 nonsmoking medical students (18 intermittent mild asthmatics, 23 students with outgrown childhood asthma but free of asthma-related symptoms for 10 years (asymptomatic asthmatics) and 20 healthy students). BHR and lung function were measured, and induced sputum samples analyzed for eosinophil count, eosinophilic cationic protein (ECP), granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF-α). Results: BHR was still present in most asymptomatic asthmatics, but it was milder compared with healthy students. Only three subjects with previous asthma had no BHR and no signs of airway inflammation. Percentages of eosinophil, and ECP, TNF-α and GM-CSF concentrations in induced sputum of mild asthmatics and asymptomatic asthma groups were higher than in the healthy group. In asymptomatic asthmatics group, the duration of asthma, sputum eosinophil percentage, and the level of TNF-α in sputum correlated significantly with BHR. Conclusions: Only a few subjects with longstanding asymptomatic asthma could be considered as cured; most asymptomatic asthmatics continued to exhibit BHR and signs of airway inflammation. The outcome of childhood asthma and BHR was associated with the degree of airway inflammation and the duration of childhood asthma. [ABSTRACT FROM AUTHOR]

Background: Clarification of the relationship between atopy and bronchial hyperresponsiveness (BHR), both key features of asthma, is critical to our understanding of the disease. We therefore investigated the putative relationship between skin-prick reactivity to aeroallergens and BHR to direct and indirect stimuli. Methods: We performed a retrospective analysis of data from 332 patients presenting with a diagnosis of asthma. Patients were characterized by skin prick tests (SPT), spirometry and bronchial challenge with methacholine and adenosine monophosphate (AMP). Results: For patients who had BHR to methacholine but not AMP, the presence of atopy was associated with a lower PD20 (the provocative dose of methacholine producing a fall in FEV1 of 20%), amounting to a geometric mean (95% confidence interval (CI)) of 2.3-fold (1.4–4.0) difference. Furthermore, the number of skin-prick positive (SPP) responses was related to methacholine reactivity: 0–1 SPP, PD20 = 69.9 µg; 2–4 SPP, PD20 = 47.8 µg; 5–8 SPP, PD20 = 35.6 µg. There was a 2.0- fold (1.1–3.6) difference between the groups with a low (0–1 SPP) and high (5–8 SPP) degree of skin-prick reactivity. A similar pattern was seen when data were analyzed including only perennial allergens. Spirometry was unrelated to the degree of skin-prick reactivity. Discussion: These results suggest that skin-prick reactivity to aeroallergens is associated with BHR to methacholine. [ABSTRACT FROM AUTHOR]

Background: Although airway eosinophilia is seen as a cardinal feature of asthma, data eosinophilia are still lacking on the proportion of the asthma group exhibiting raised airway eosinophilia. This study aimed to assess the distribution of sputum eosinophil count and its relationship with methacholine bronchial hyperresponsiveness in mild to moderate steroid-naive asthmatic people. Methods: Sputum was induced by inhalation of hypertonic saline (NaCl 4.5%) in 118 mild to moderate steroid-naive asthmatic people consecutively recruited from our outpatient clinic, and in 44 healthy people. The asthma group was selected on the basis of an forced expiratory volume in 1 s (FEV1 ) of ≥ 70% predicted, and a provocative methacholine concentration causing a fall of 20% in FEV1 (PC20 methacholine; PC20 M) ≤ 16 mg/ml. Results: In the asthma group, the median (range) of the percentage and the absolute values of sputum eosinophils were 4.8% (0–75) and 38 103 /g (0–14 191), respectively, vs 0% (0–2.3) (P < 0.001) and 0 103 /g (0–53) (P < 0.001) in healthy participants. Based on the 95% percentile for normal values calculated from our healthy group, 69% of the asthma group had significantly raised sputum eosinophil count (that is > 2%). In the asthma group, multiple regression analysis followed by a stepwise procedure revealed that sputum eosinophil count was significantly and inversely associated with PC20 M accounting for 16% of its total variance (P < 0.001) while neutrophil counts positively related to PC20 M accounting for 4% of total variance (P < 0.05). By contrast, no significant relationship was found between either eosinophil or neutrophil counts and the slope of forced vital capacity (FVC) vs FEV1 from the methacholine challenge. Conclusions: We conclude that two-thirds of people in the mild to moderate asthma group had... [ABSTRACT FROM AUTHOR]

Background: Patients with food allergy (FA) have been recently shown to develop bronchial hyperresponsiveness (BHR), despite the absence of any concomitant asthmatic manifestation. In order to explain this observation, we sought to examine the presence of a bronchial inflammation in induced sputum of nonasthmatic patients with FA. Methods: Twelve nonasthmatic patients with FA (urticaria, digestive symptoms, anaphylaxis) were included in the study. Results were compared to these obtained from eight asthmatic patients without food allergy and eight healthy controls. Diagnosis of FA was based on double-blind placebo-controlled challenge. Sputum cells and fluid-phase eosinophil cationic protein (ECP), myeloperoxidase (MPO) and interleukin-8 (IL-8) were measured in induced sputum. BHR was evaluated using methacholine inhalation. Results: Sputum from asthmatics, in comparison with the sputum of healthy subjects and patients with FA contained a higher proportion of eosinophils and higher levels of ECP (< 0.001). In marked contrast, patients with FA exhibited an increased proportion of neutrophils and IL-8 in comparison with asthmatics and controls (P < 0.05 for neutrophils and P < 0.001 for IL-8). There was a significant correlation between sputum neutrophils and IL-8 (r = 0.68, P < 0.001). MPO levels were not different between the groups. There was a trend toward higher levels of IL-8 and ECP in food allergic patients with BHR in comparison with patients with FA without BHR. Conclusion: Our results demonstrate that a subclinical neutrophil airway inflammation is present in patients with food allergy free of clinical respiratory symptoms and that IL-8 may be an important mediator of this neutrophilia. [ABSTRACT FROM AUTHOR]

Describes the metacholine challenge as a useful tool in the diagnosis of allergic respiratory disorders. Mechanisms of airway narrowing; Relationship between the presence of inflammatory cells and airway hyperresponsiveness; Effect of smooth-muscle linear shortening on airway caliber; External modulation of airway narrowing.