[Use of forced oscillation technique to detect airflow limitations in adult Japanese asthmatics].

BACKGROUND: The forced oscillation technique (FOT) is a noninvasive method that is used to measure respiratory mechanics, including respiratory resistance and reactance at multiple frequencies. The advantage of FOT over spirometry is that FOT does not require forced expiratory maneuvers. Moreover, a new FOT machine called MostGraph (Chest Co. Ltd., Tokyo, Japan), has been developed in Japan, and can be used clinically to diagnose and monitor asthma. The purpose of this study is to show the standard of FOT measured with MostGraph in adult Japanese asthmatics. METHODS: From our outpatient clinic, we recruited 151 stable asthmatics who were being treated with inhaled corticosteroids at the time of the study. For each subject, we measured the fraction of exhaled nitric oxide (FeNO) by using a chemiluminescent nitric oxide analyzer (Sievers280, GE, Boulder, Co); we determined the levels of forced expiratory volume in 1s (%FEV1) and maximum mid-expiratory flow rate (%MMF) by using spirometory; and we measured resistance at 5 Hz(R5), resistance at 20 Hz(R20), R5-R20, reactance at 5 Hz(X5), frequency of resonance (Fres), and low-frequency reactance area (ALX), by using a MostGraph FOT machine. RESULTS: Each of the FOT parameters measured by using the MostGraph machine was significantly correlated with %FEV1 and %MMF (p<0.001), with Fres showing the strongest association. Three of the FOT parameters, X5, Fres, and ALX, were significantly associated with the subject's age (p=0.01, p<0.001, p<0.001, respectively), and all FOT parameters were significantly associated with the subject's body mass index (BMI) (p<0.001 to p=0.018). The results of multiple regression analyses between FOT parameters and FEV1, age, BMI, and FeNO, showed that Fres was significantly associated with FEV1(p<0.001) and BMI (p<0.001). From the results of the simple linear regression between Fres and FEV1, we estimated that Fres values of 17.5 Hz corresponded to %FEV1 values of 60%; Fres values of 11.3 Hz corresponded to %FEV1 values of 80%; and Fres values of 4.94 Hz corresponded to %FEV1 values of 100%. CONCLUSION: FOT parameters measured by using a MostGraph machine can be used successfully to assess the level of airflow limitation in adult stable asthmatics.

[Differences in fraction of exhaled nitric oxide values measured by two offline methods or NIOXmino in adult Japanese asthmatics].

BACKGROUND: The fraction of exhaled nitric oxide (FeNO) is a useful marker of asthma control. The FeNO measurement with two offline methods and NIOXmino may be more affordable, no studies have examined the differences in FeNO values measured with various methods in adult asthmatics. METHODS: The study population comprised 39 stable asthmatics treated with inhaled steroids at our outpatient clinic. FeNO values were measured by two offline methods (Sievers and CEIS), NIOXmino. RESULTS: FeNO(NIOXmino) values were significantly correlated with those of FeNO(Sievers) (r=0.935, P< 0.001) and FeNOCEIS (r=0.908, P< 0.001). However, FeNO(NIOXmino) values were low compared with FeNO(Sievers) (FeNO(NIOXmino)=0.848 x FeNO(Sievers)) and FeNO(CEIS) (FeNO(NIOXmino)=0.672 x FeNO(CEIS)). CONCLUSION: Differences exist in the values of FeNO measured by various methods: conversion equations are needed to compare the FeNO values among these three methods.

Changes in exhaled nitric oxide measured by two offline methods predict improvements in bronchial hyperresponsiveness after inhaled steroid therapy in Japanese adults with asthma.

BACKGROUND: The fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. No studies have examined the relationship between the change in FeNO levels measured offline and changes in bronchial hyperresponsiveness (BHR) in asthmatic patients treated with inhaled corticosteroids (ICS). The objective of this study was to investigate the relationship between the change in FeNO levels measured offline and the change in BHR to acetylcholine in asthmatic patients taking ICS. METHODS: The study population comprised 41 ICS-treated asthmatics from our outpatient clinic. We measured FeNO levels by two methods -with a Sievers kit ("FeNOs") and with a kit from the Center for Environmental Information Science, Japan ("FeNOc") at baseline and after 1 year of regular treatment. We also used spirometry to test BHR to acetylcholine (PC(20Ach)). RESULTS: The mean of duration of observation was 406 days. There were significant relationships between DeltalogPC(20Ach) and logPC(20Ach) (r = -0.877, P < 0.001), FeNOs (r = 0.465, P = 0.002), and FeNOc (r = 0.524, P = 0.004) at baseline, but not with age, the dose of ICS, FEV(1), or %FEV(1). Moreover, there was a significant relationship between DeltalogPC(20Ach) and DeltaFeNOs (r = -0.386, P = 0.013) and DeltaFeNOc (r = -0.473, P = 0.004), but not with DeltaFEV(1). CONCLUSIONS: Changes in FeNOs and FeNOc correlated with improvements in BHR to acetylcholine in adult asthmatics after ICS therapy. Our findings suggest that offline monitoring of FeNO will facilitate the management of bronchial asthma in patients treated with ICS.

[The methodological aspects of nasal and exhaled nitric oxide levels in adult Japanese asthmatics].

BACKGROUND: Because both allergic rhinitis and asthma are caused by eosinophilic airway inflammation, using the same method to measure the eosinophilic inflammation of both the upper and lower airway would be advantageous. The levels of nitric oxide in exhaled air (FeNO) and nasal air (nNO) are useful as noninvasive markers of eosinophilic airway inflammation. Although the off-line method of measuring these parameters is easier and more useful than the on-line method, studies using the off-line method are rare in Japan. METHODS: In Study 1, we measured the levels of nNO and FeNO in 9 healthy controls and 9 subjects with allergic rhinitis, to validate the methodology for using the off-line method to measure nNO. In Study 2, we measured the nNO and FeNO levels of and performed spirometry on 69 stable asthmatics treated with inhaled corticosteroid. RESULTS: In Study 1, nNO levels were significantly increased in patients with allergic rhinitis compared with healthy subjects (31.0 [20.8 to 41.2] versus 7.4 [0.0 to 14.8] ppb {median [95% confidence interval]}, p=0.018). The 69 patients with asthma that comprised the study population in Study 2 were classified as asthmatics with rhinitis (treatment-naïve, n=14; treated with antiallergic drugs, n=11; treated with intranasal corticosteroid, n=19) and asthmatics without rhinitis (n=15). Although FeNO did not differ among groups, nNO was significantly increased in treatment-naïve asthmatics with rhinitis compared with patients with asthma only (26.5 [17.1 to 35.9] versus 8.0 [-1.1 to 17.1] ppb, p=0.033). CONCLUSION: nNO levels measured by the off-line method are useful markers of allergic rhinitis.

[Cutoff point of the fraction of exhaled nitric oxide (FeNO) with the off-line method for diagnosing asthma and the effect of smoking on FeNO].

Evidences have shown that the fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. There is no study to show the FeNO cutoff point for detecting asthma and the influence of smoking, measured by the Sievers Bag collection kit. The study population comprised 60 steroid-naive asthmatic patients (BA) (32 non-smokers, 28 smokers) and 59 patients with chronic cough (CC) without asthma (42 non-smokers, 17 smokers) in our outpatient clinic. We measured FeNO levels, spirometory, bronchial hyperresponsiveness against acetylcholine, and other parameters. The levels of FeNO were significantly increased in asthmatics compared with subjects with chronic cough. According to the ROC curve, the cutoff point of FeNO was 30 ppb (AUC = 0.83, sensitivity 78.1%, specificity 73.5%, p < 0.001) in non-smokers. The levels of FeNO in smokers were not significantly different from those in non-smokers, both bronchial asthma and chronic cough subjects. But the cutoff point of FeNO was 40 ppb (AUC = 0.65, sensitivity 67.8%, specificity 70.6%, p = 0.012). In conclusion, the cutoff point of FeNO was 30 ppb in non-smokers and 40 ppb in smokers. In smokers, FeNO measurement was less useful.

Relationship between exhaled nitric oxide measured by two offline methods and bronchial hyperresponsiveness in Japanese adults with asthma.

BACKGROUND: Exhaled nitric oxide (eNO) is a useful marker of eosinophilic airway inflammation in asthmatics. There have been no studies to show the relationship between eNO measured by offline methods and the degree of bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids. METHODS: The study population comprised asthmatics at our outpatient clinic. We measured eNO levels by two methods ("eNOs" was measured with a Sievers kit; and "eNOc" was measured with a kit from the Center for Environmental Information Science, Japan). We also used spirometry to test bronchial hyperresponsiveness to acetylcholine (PC(20Ach)). RESULTS: We recruited 192 stable asthmatics. There was a significant relationship between eNOs and eNOc (r = 0.919, p < 0.001). LogPC(20Ach) levels were negatively correlated with eNOs or eNOc levels (eNOs, r = -0.31, p < 0.001; eNOc, r = -0.23, p = 0.0013). We classified the subjects into two groups based on eNOs levels ((A) the subjects with high eNOs levels (n = 92) and (B) the subjects with normal eNOs levels (n = 100)) ; logPC(20Ach) was significantly correlated with eNOs (r = -0.34, p = 0.001) or eNOc (r = -0.28, p = 0.0075) but not correlated with %FEV(1) in (A), whereas logPC(20Ach) was not significantly correlated with eNO but significantly correlated with %FEV(1) (r = 0.33, p = 0.002) in (B). CONCLUSIONS: Levels of eNOs and eNOc were correlated with the degree of bronchial hyperresponsiveness to acetylcholine in adult asthmatics treated with inhaled corticosteroids. Our findings suggest that offline monitoring of eNO will facilitate the management of bronchial asthma in patients treated with these drugs.

[Relationship between cysteinyl leukotriene in exhaled breath condensate and the severity of asthma in adult asthmatics in Japan].

BACKGROUND: The measurement of several mediators in exhaled breath condensate (EBC) can be useful as the biomarker for asthma. But there are a few reports about EBC of asthmatics in Japan. AIM: We examined the safety of the collection of EBC and the utility of cysteinyl leukotriene (cysLTs) in EBC as the biomarker of asthma. METHODS: Fifty-three asthmatics and eleven subjects without asthma were recruited. After the measuring of exhaled nitric oxide (eNO) and spirometory, EBC were collected. The levels of cysLTs in EBC were measurement by ELISA within 2 months. RESULTS: The collection of EBC did not induce any other symptoms in all subjects. In 48 subjects, the collection significantly increased their FEV1 and MMF level (DeltaFEV1: 2.27+/-0.77%, DeltaMMF 14.6+/-3.92% (mean+/-SEM). The level of cysLTs in EBC on asthmatics treated with high-dose ICS was significantly high compared with control group (p=0.0034), steroid-naïve asthmatics or asthmatics treated with low-dose ICS (steroid naive vs. high dose ICS, p=0.041, low dose ICS vs. high dose ICS, p=0.021). The relationship between cysLTs in EBC and the levels of LTE4 in urine was significantly correlated (n=34, r=0.32, p=0.0435). The relationship between cysLTs in EBC and the levels of eNO was significantly correlated only in steroid-naïve asthmatics (r=-0.57, p=0.0369). There was no relationship between cysLTs in EBC and FEV1, or log PC20Ach. CONCLUSION: The collection of EBC was perfectly non-invasive. The level of cysLTs can be useful as a biomarker of asthma.

[The effect of inhaled corticosteroid on the fraction of exhaled nitric oxide (FeNO) with off-line method in adult Japanese asthmatics].

BACKGROUND: The fraction of exhaled nitric oxide (FeNO) is a useful marker of asthma control. The FeNO measurement with our offline method using SIEVERS bag collection kit may be more affordable, but there have been no studies to show the effect of anti-asthmatic therapy on FeNO with our offline method. METHODS: The study population comprised 36 steroid-naïve asthmatics at our outpatient clinic. We treated them according to asthma prevention and management guideline 2006, Japan. We also measured eNO levels by our offline method and spirometory on baseline, 4weeks, and 12 weeks of treatment. RESULTS: All asthmatics were symptom-free on 12 weeks of treatment. The levels of FeNO FEV1/FVC were significantly decreased on 4 weeks and 12 weeks of treatment, compared with that on first visit. We classified the subjects into two groups; (A) FEV1/FVC <70% (n=11) or (B) FEV1/FVC > or =70% (n=25) on baseline. In (A) group, the level of FeNO and FEV1/FVC were significantly improved on 4 and 12 weeks of treatment. In (B) group, on 4 weeks of treatment, the level of FEV1/FVC was significantly increased but the level of FeNO was not significantly changed. On 12 weeks of treatment, the levels of FeNO was significantly decreased, but the level of FEV1/FVC was not significantly changed. CONCLUSION: The levels of FeNO were decreased by antiasthmatic therapy, so that offline monitoring of eNO will facilitate the management of bronchial asthma in patients treated with these drugs.

[The change of exhaled nitric oxide levels in early response after inhaled antigen in antigen-specific provocation test].

BACKGROUND: Inhaled antigen increases exhaled nitric oxide (eNO) in atopic asthmatics. Recent study showed that the increase of eNO levels was observed in late response (8-10 hours after inhaled antigen) but not in early response (1.5 hour after inhaled antigen). But we recognized that in some asthmatics eNO levels were increased during early response induced by antigen. METHODS: Atopic stable subjects with asthma induced by specific antigen (mite 11, housedust 3) were recruited in this study. Through bronchial provocation test with Mite or Housedust antigen, eNO levels were examined. As the control group, 7 atopic asthmatics who were not induced by specific antigen were recruited. RESULTS: In 7 subjects, the levels of eNO were increased during early response after inhaled antigen, and in other 7 subjects the levels of eNO were decreased. There were significant difference in the falling of FEV1 at threshold between the two groups (eNO increased group vs eNO decreased group, 22.1+/-0.87 (%) vs. 44.2+/-6.57 (%), p=0.016). In 6 subjects in control group, the levels of eNO were decreased. CONCLUSION: Inhaled antigen increased the levels of eNO in some asthmatics during early response in bronchial provocation test. The level of eNO has possibility of predicting the sudden decrease of FEV1 in bronchial provocation test.

[The methodological aspects of off-line sampling of exhaled air for nitric oxide measurement in Japanese].

The measurement of exhaled nitric oxide (eNO) is a non-invasive biomarker of bronchial inflammation. Despite the usefulness of eNO measurement, NO analyzers are too expensive for widespread use by general practitioners. In comparison, the off-line (bag collection) method of eNO measurement may be more useful. In Japan, however, there have been few studies about eNO in asthmatics using the off-line method. This study shows methodological aspects of the off-line method. Briefly, with a SIEVERS bag collection kit, we recommend that the flow rate and pressure level of exhaled air should be 70 ml/sec and 10 cm H2O, respectively and that the sampled air should be measured within 12 hours.

The relationship between exhaled nitric oxide measured with an off-line method and airway reversible obstruction in Japanese adults with asthma.

BACKGROUND: Exhaled nitric oxide (eNO) is a useful marker of eosinophilic airway inflammation in asthma patients. There is no study to show the relationship between the eNO measured by using an off-line method and the degree of reversibility of airflow limitation in Japanese asthma patients. We sought to investigate the relationship between the eNO level measured by using an off-line method and the degree of reversibility of bronchial constriction in Japanese asthma patients. METHODS: The study population comprised 97 asthma patients in our outpatient clinic with some patients in both groups who received inhaled corticosteroid treatment. We measured eNO levels, forced expiratory volume in one second (FEV1) before and after treatment, reversible airway obstruction (DeltaFEV1) after inhalation of bronchodilator, and other parameters. RESULTS: eNO was significantly correlated with peripheral blood eosinophil counts in asthma patients (in steroid-naïve asthma patients, r=0.544, p<0.0001; in asthma patients treated with inhaled corticosteroid, r=0.463, p=0.026), and subjects with severe eosinophilia in sputum showed high levels of eNO (mild eosinophilia versus severe, p=0.0152). Among patients with obstructive impairment, eNO levels were correlated with DeltaFEV1 regardless of whether patients received (r=0.527, p=0.0435) or did not receive (r=0.64, p = 0.0056) inhaled corticosteroid. In subjects with normal pulmonary function, there was no significant relationship between eNO and DeltaFEV1 with or without inhaled corticosteroid. CONCLUSIONS: In patients with obstructive impairment, eNO reflects the degree of reversible airflow limitation. In subjects with normal pulmonary function, eNO may facilitate the diagnosis and management of asthma, rather than indicate reversible bronchial obstruction. eNO measurement by off-line methods is applicable as a potential tool for the diagnosis of asthma and management of asthma patients.

[A case of lung infection due to Mycobacterium abscessus].

We report a case of lung infection due to Mycobacterium abscessus (M. abscessus). A 60 year-old woman was admitted to our hospital because of an abnormal shadow found on chest radiography and a bloody sputum. Chest radiography revealed infiltrative and linear shadows in the middle and lower fields of both lungs. The sputum smears were negative for acid-fast bacilli, but sputum culture was positive. Rapidly growing mycobacteria were detected. The patient was treated with clarithromycin. Since M. abscessus was identified from repeated cultures of the sputa, the patient was treated with Imipenem/Cilastatin and Amikacin for four weeks, during which the chest radiography improved. After discharge, the treatment with clarithromycin and minocycline was continued for ten months, and the chest radiography improved further. Our treatment for M. abscessus may be a useful choice for drug treatment of such cases.

[Hypogammaglobulinemia associated with thymoma (Good syndrome) similar to diffuse panbronchiolitis].

A 65-year-old woman complained of dyspnea and a productive cough after surgical treatment and irradiation therapy for thymoma. Chest radiography and high-resolution computed tomography showed small nodules in centrilobular lesions in all of both lung fields, but predominantly in the lower fields. In addition, blood tests showed hypogammaglobulinemia. Chronic sinusitis, mild hypoxemia, severe obstructive impairment and the pathological findings of bronchiolitis led to a diagnosis of sinobronchial syndrome caused by Good syndrome. Treatment with oral erythromycin 600 mg/day was started. After 6 months, the patient improved both clinically and radiologically. Low-dose, long-term treatment with erythromycin was effective against sinobronchial syndrome caused by Good syndrome.

[Acute lung injury caused by inhalation of waterproofing spray].

A 55-year-old man was admitted to our hospital because of severe dyspnea 30 minutes after inhalation of waterproofing spray. He had used the spray outdoors and had then smoked a cigarette with spray-contaminated fingers. Chest radiography and computed tomography (CT) revealed diffuse ground glass opacities in both lungs. In pulmonary function tests, the lungs showed a moderately decreased diffusing capacity and there was slight hypoxemia. Transbronchial lung biopsy specimens demonstrated extensive alveolitis and marked eosinophil migration. Without any specific treatment, the patient recovered clinically in 4 days. We speculated that acute lung injury in this patient may have been induced by not only direct inhalation of the waterproofing spray itself, but also by inhalation of spray by-products resulting from decomposition due to heat. When waterproofing spray is used, precautions should be taken to avoid both inhalation and heating of the fumes.

Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin-induced pulmonary fibrosis via a Fas-Fas ligand-independent pathway.

Heme oxygenase 1 (HO-1) is an inducible enzyme that catalyzes heme to generate bilirubin, ferritin, and carbon monoxide. Because enhanced expression of HO-1 confers protection against many types of cell and tissue damage by modulating apoptotic cell death or cytokine expression profiles, we hypothesized that adenovirus-mediated transfer of HO-1 cDNA and subsequent overexpression of the protein in lung would provide therapeutic benefit in a murine model of bleomycin-induced pulmonary fibrosis. In C57BL/6 mice, HO-1 overexpression clearly suppressed the development of fibrotic changes and was associated with enhanced interferon gamma production in lung and reduced numbers of respiratory epithelial cells with damaged DNA. However, HO-1 overexpression did not prevent pulmonary fibrosis induced by agonistic anti-Fas antibody inhalation in C57BL/6 or ICR mice, a strain known to develop pulmonary fibrosis via the Fas-Fas ligand (FasL) pathway. Consistent with the concept that HO-1 overexpression prevents fibrosis via a pathway independent of Fas-FasL interaction, Ad.HO-1 administration prevented bleomycin-induced pulmonary fibrosis in gld/gld mice, which express nonfunctional FasL. These observations suggest that using HO-1 overexpression strategies to treat idiopathic pulmonary fibrosis, or fibrotic disorders of other target organs, by attenuating apoptotic cell death likely would be effective in clinical situations.