Junpei Saito

Clinical usefulness of fractional exhaled nitric oxide for diagnosing prolonged cough

BACKGROUND Prolonged cough is one of the troublesome symptoms commonly seen in daily practice. Especially, detection of allergic cough such as bronchial asthma (BA), cough variant asthma (CVA) and eosinophilic bronchitis without asthma (EB) is important because the prevalence of these disorders are high. We previously reported fractional exhaled nitric oxide (FeNO) can be a non-invasive marker of allergic airway inflammation. We examined whether FeNO could be applicable for the proper diagnosis of prolonged cough. METHOD About 71 consecutive subjects complaining prolonged cough who gave informed consent for the study were enrolled. FeNO, pulmonary function tests, bronchial hyperresponsiveness (BHR), IgE, and eosinophils in induced sputum and peripheral blood were measured. Final diagnosis of the subjects was 30 with BA, 18 with CVA, 8 with EB, and 15 with other respiratory disorders (Others). RESULT FeNO had significant correlations with non-specific IgE, mite-specific IgE, FEV/FVC, BHR, and eosinophils. The level of cedar-specific IgE was significantly higher in subjects with EB than CVA. FeNO levels in BA and CVA were significantly higher than those in EB and Others. The optimal cutoff level of FeNO was 38.8 ppb with sensitivity of 79.2% and specificity of 91.3% for distinguishing BA and CVA from EB and Others. CONCLUSION FeNO could be used as a diagnostic marker of prolonged cough, especially for the differential diagnosis BA and CVA from EB and others.

Sputum hydrogen sulfide as a novel biomarker of obstructive neutrophilic asthma

clinical risk management of food allergy, false-positive results are probably preferable to false-negative results. We must note some limitations to the present study: the small sample size used for analysis and the infrequency (n 5 1) of positive challenges with egg. Although it could be suggested that the tool might not be suitable for patients without prior reactions to the food (ie, high specific IgE levels/skin prick test responses and no known prior ingestion of the specific food), this sample type is currently under investigation in an ongoing study. We have also shown its applicability with data generated a priori from a different clinic setting and patient groups and that it can accommodate different preparations of the index foods (raw or baked egg as with pasteurized egg). We intend to further validate the calculator in real time in diverse partner clinics worldwide and to explore its applicability in secondary and possibly primary care settings. This calculator is intended as a further aide to clinical decision making. The aim of the model is to support decision making by clinicians and not to replace it. Audrey DunnGalvin, PhD L. M. Segal, MD Ann Clarke, MD, MSc, FRCP Reza Alizadehfar, MD Jonathan O’B. Hourihane, PhD Med, MB, MRCPI, FRCPCH

Molecular-Based Haplotype Analysis of the β 2-Adrenergic Receptor Gene (ADRB2) in Japanese Asthmatic and Non-Asthmatic Subjects

BACKGROUND The β2-adrenergic receptor gene (ADRB2) is a target molecule of β2-agonists. Single nucleotide polymorphisms (SNPs) in the ADRB2 are related to the effectiveness of β2-agonists. However, there are some discrepancies in the results of pharmacogenetic studies of ADRB2 among different ethnic groups. The aims of this study were to determine the ADRB2 haplotypes and diplotypes in Japanese asthmatic and non-asthmatic subjects and to examine their relation to asthma and to compare these results with previous studies done in other ethnic groups. METHODS Complete sequences for 3 kb promoter and 1.2 kb structural regions of ADRB2 were analyzed in 48 Japanese asthmatics and 100 controls, and haplotypes and diplotypes of SNPs were analyzed. RESULTS Fifteen SNPs including a novel one in -839 were observed. Allele frequencies for all SNPs were similar between asthmatics and controls. We also identified 42 haplotypes and 54 diplotypes of ADRB2 in a Japanese population. The frequencies were similar between the two groups. They were classified into 17 and 23 types, respectively, according to Drysdales haplotype-organization system, and a significant ethnic difference was observed between the Japanese and Caucasian populations. CONCLUSIONS The frequencies of SNPs and ADBR2 haplotypes in Japanese are different from those in Caucasians and African Americans. These divergences might imply the need for independent pharmacogenetic studies for ADBR2 in each ethnic group.

Pulmonary fibrosis in dyskeratosis congenita with TINF2 gene mutation

To the Editor: Dyskeratosis congenita is a rare inherited disorder of ectodermal dysplasia characterised by the classical mucocutaneous triad of abnormal skin pigmentation, nail dystrophy and leukoplakia [1–3], at least one of which is present in around 80–90% of dyskeratosis congenita cases. Bone marrow failure is another common feature, and a variety of other abnormalities ( e.g. dental, gastrointestinal, neurological, ophthalmic, pulmonary and skeletal) have been also described [1–3]. The main causes of mortality in dyskeratosis congenita are bone marrow failure, pulmonary disease and malignancy [1]. Three modes of inheritance have been recognised: X-linked recessive, autosomal dominant and autosomal recessive [1, 3]. Eight dyskeratosis congenita genes ( DKC1 (dyskeratosis congenita 1), TERC (telomerase RNA component), TERT (telomerase reverse transcriptase), NOP10 (nucleolar protein 10), NHP2 , TINF2 (TERF1-interacting nuclear factor 2), TCAB1 and RTEL1 (regulation of telomere elongation helicase 1)) have already been identified, and their mutations account for ∼60% of all dyskeratosis congenita cases [1]. Among the dyskeratosis congenita genes, mutations in TERC , TERT and DKC1 have recently been reported to be associated with familial pulmonary fibrosis and idiopathic pulmonary fibrosis, and pulmonary fibrosis is recognised as one of the features of dyskeratosis congenita. However, the relationship between mutations in the other dyskeratosis congenita genes and pulmonary fibrosis has not yet been clarified. To the best of our knowledge, this is the first case report describing a dyskeratosis congenita patient with pulmonary fibrosis who had a TINF2 mutation. A 43-year-old female visited our hospital with cough and progressive dyspnoea. She had never smoked, and had a …

The relationship between 25-hydroxyvitamin D levels and treatment course of pulmonary tuberculosis

BACKGROUND Low serum vitamin D level is associated with a high risk of developing active tuberculosis (TB). We investigated the relationships between serum vitamin D levels and clinical course of TB after standard chemotherapy in hospitalized non-HIV patients with TB. METHODS Hospitalized patients with TB were recruited between February 2008 and July 2010. Confirmatory tests were performed using sputum smear and culture positivity tests for Mycobacterium tuberculosis. Drug sensitivity testing was performed for all the subjects and those not showing drug resistances for the first-line anti-TB drugs were included in the study. These patients were treated with the standard first-line anti-TB drugs. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured on admission, and the relationships between 25(OH)D and clinical characteristics (laboratory data on admission and treatment outcomes) were examined. We defined vitamin D deficiency as a condition where serum level of 25(OH)D was lower than 20 ng/ml. RESULTS A total of 38 patients were included in the study. Mean (± SD) 25(OH)D levels were 13.7 ± 5.9 ng/ml. The prevalence of vitamin D deficiency was 87%. In 23 patients treated with the standard first-line 4-drug regimen (Age < 80 years) serum 25(OH)D levels showed significant negative correlation with time taken to obtain 3 consecutive negative sputum smears or TB bacteria cultures. This relationship suggests that low serum vitamin D level may not only increase the risk of developing active TB but may also be related to the poor treatment outcomes in these patients. CONCLUSIONS Low serum vitamin D level is a good predictor of prolonged clinical course in patients with active pulmonary TB.

Polymorphism of egfr Intron1 is associated with susceptibility and severity of asthma.

To clarify the associations of the egfr CA repeat polymorphism with asthma and its severity, we examined 579 Japanese asthmatics and 232 control subjects. The number of CA repeat ranges from 9 to 24. Asthmatic patients had a significantly higher incidence of having shorter alleles (≦16 CA repeats) compared with control subjects (p < 0.05). The most severe asthmatic patients have the highest frequency of short alleles (p < 0.05). In addition, subjects treated with leukotriene modifiers had higher incidence of having shorter allele compared to those without it (p < 0.01). Thus, the egfr CA repeat polymorphism is associated with the susceptibility and the severity of asthma.

Mannose binding lectin gene polymorphisms and asthma

Background Bronchial asthma is a chronic inflammatory disorder of the airways. Recently, it has been suggested that complement plays significant roles in asthma. Mannose‐binding lectin (MBL) is one of the key molecules in complement activation pathways that are associated with several infectious and immune disorders.

Analysis of the Comorbidity of Bronchial Asthma and Allergic Rhinitis by Questionnaire in 10,009 Patients

BACKGROUND Bronchial asthma (BA) and allergic rhinitis (AR) are thought to share a common pathogenesis. However, reports concerning the comorbidity of the two diseases in a large-scaled population are rare in Japan. In the present study, we performed an analysis on the two diseases using questionnaires that addressed the diagnosis, symptoms and period of occurrence in more than 10,000 patients with BA or AR. METHODS Patients with BA (adult: n = 2,781, childhood: n = 3,283) and AR (n = 3,945) were enrolled in the present study during the 3 months from August 1, 2006 to October 31, 2006. RESULTS Sixty one percent of the patients with adult BA showed symptoms of AR. Among them, 68% of the patients were diagnosed with AR. Among the patients with childhood BA, 68% showed AR symptoms and 60% were diagnosed with AR. On the other hand, 49% of AR patients showed BA symptoms and 35% of them were diagnosed with BA. The symptoms of both BA and AR in the BA and AR patients were frequent in two seasons, March and April, and September and October. In addition, BA and AR symptoms often co-occurred in the patients with BA and AR. CONCLUSIONS Comorbidity of BA and AR was high in both populations of BA and AR. The symptoms of both BA and AR co-occurred on both a daily and seasonal basis. These results suggested that BA and AR share a common immuno-pathogenesis in the airway and need to be treated as a single airway disease.

Genetic linkage analysis of pulmonary fibrotic response to silica in mice

Inter-individual variations in the development of silicosis, even within the same environments, have been reported, which suggest the contribution of genetic factors in silicosis aetiology. The aim of the present study was to determine whether there is any significant genetic influence on the development of silicosis. Furthermore, which genetic loci are responsible for the pulmonary response to silica exposure? Eight strains of inbred mice were used to examine the genetic influence on the lung fibrotic response to silica exposure. After intercross-breeding between the most susceptible and most resistant strains, a genome-wide linkage analysis of quantitative trait loci (QTL) was performed. Hydroxyproline was applied as an index, and genotypes of 167 marker genes were analysed by fragment analysis using a capillary-type sequencer. There was significant inter-strain difference in the mean concentration of hydroxyproline contents among the eight strains of mice. Breeding studies were conducted between the most susceptible, C57BL/6J, and the most resistant strain, CBA/J. A genome-wide linkage analysis of silica-exposed intercrossed cohorts identified significant QTL on chromosome 4 and suggestive QTL on chromosomes 3 and 18. The present study demonstrates that genetic factors may play a significant role in fibrotic-lung responses to silica; one significant and two suggestive quantitative trait loci were identified.

Domiciliary diurnal variation of exhaled nitric oxide fraction for asthma control

A major goal of asthma management is maintaining optimal control. Current assessment is based on symptoms and lung function. We evaluated whether domiciliary daily home exhaled nitric oxide fraction (FeNO) monitoring could be useful as an index of asthma control. 50 asthmatic subjects and 15 healthy volunteers with a range of asthma severity underwent asthma control questionnaire (ACQ), spirometry before and after salbutamol and sputum induction. FeNO and peak expiratory flow (PEF) were measured twice daily for 2 weeks. A record of exacerbations was obtained 3 months later. Diurnal FeNO variation in uncontrolled asthmatics was significantly greater than in controlled asthmatics (p<0.01). PEF variation was not different. The daily variation of FeNO levels was also greater in uncontrolled asthmatics compared with controlled asthmatic and healthy subjects (p<0.01). 80% of uncontrolled asthmatics experienced at least one or more exacerbations over the 3 months after the enrolment. The combination of diurnal FeNO variation ≥16.6% and ACQ scores ≥1.8 was best at predicting uncontrolled asthma (area under curve 0.91, 95% CI 0.86–0.97; p<0.001). Diurnal variation in FeNO can be used as a biomarker of asthma control and as a predictor of the risk of future exacerbation. Prospective studies are warranted. Diurnal variation in FeNO can be used as a biomarker of asthma control and a predictor of the risk of future exacerbation http://ow.ly/r2MCY