日本呼吸器学会 咳嗽・喀痰の診療ガイドライン 2019作成委員会：咳嗽・喀痰の診療ガイドライン2019、2019年．.
Akio Niimi, Alfonso Torrego, Andrew G Nicholson, Borja G Cosio, Tim B Oates, Kian Fan Chung
Nature of airway inflammation and remodeling in chronic cough.
J Allergy Clin Immunol. 2005 Sep;116(3):565-70. doi: 10.1016/j.jaci.2005.07.010.
Abstract/Text
BACKGROUND: Chronic cough may be a result of asthma and non-asthma causes, but it is unclear whether there are specific inflammatory or remodeling changes.
OBJECTIVE: We determined airway mucosal changes in patients presenting with asthmatic cough and cough associated with non-asthmatic causes.
METHODS: Patients with chronic cough of non-asthmatic (n=33; postnasal drip/rhinitis in 6, gastroesophageal reflux in 5, bronchiectasis in 3, and idiopathic in 19) and asthmatic (n=14) causes and 15 healthy controls underwent fiberoptic bronchoscopy. Morphometry of bronchial biopsies and capsaicin cough sensitivity were assessed.
RESULTS: Compared with controls, submucosal eosinophils and neutrophils were increased in patients with asthmatic cough (P<.005) and submucosal mast cells in patients with non-asthmatic cough (P=.01). Sub-basement membrane thickness, goblet cell area, vascularity, and vessel size were also increased in both groups. Smooth muscle area was higher only in patients with non-asthmatic cough (P=.0007 vs control and P=.019 vs asthmatic cough). None of the pathologic changes were related to the duration of coughing. Cough sensitivity was heightened in patients with non-asthmatic cough compared with controls and patients with asthmatic cough. The degree of goblet cell hyperplasia and epithelial shedding positively correlated with cough sensitivity in patients with non-asthmatic cough (r=0.43; P=.01; and r=0.40; P=.02, respectively).
CONCLUSION: Features of airway wall remodeling are prominent in the airways with non-asthmatic as well as asthmatic cough. These are linked to chronic cough rather than to asthma. Mast cell hyperplasia rather than eosinophilia is distinctive for non-asthmatic cough.
Hisako Matsumoto, Akio Niimi, Rollin P Tabuena, Masaya Takemura, Tetsuya Ueda, Masafumi Yamaguchi, Hirofumi Matsuoka, Makiko Jinnai, Kazuo Chin, Michiaki Mishima
Airway wall thickening in patients with cough variant asthma and nonasthmatic chronic cough.
Chest. 2007 Apr;131(4):1042-9. doi: 10.1378/chest.06-1025.
Abstract/Text
BACKGROUND: Chronic cough, which may be of asthmatic or nonasthmatic origin, is an important clinical issue. Airway inflammation, and remodeling demonstrated by subbasement membrane thickening has been associated with cough variant asthma (CVA) as well as with nonasthmatic chronic cough (NAC). CT studies have shown airway wall thickening in patients with asthma who wheeze. We examined airway wall thickness by CT in adult patients with chronic cough and examined its pathophysiologic implication.
METHODS: Nonsmoking, steroid-naïve patients with CVA (n = 27), NAC (n = 26), and healthy control subjects (n = 15) were studied. Airway dimensions were assessed by a validated CT technique, in which we measured airway wall area (WA) corrected by body surface area (BSA), the ratio of WA to outer wall area (percentage of wall area [WA%]), absolute wall thickness (T)/ square root BSA, and airway luminal area/BSA of a segmental bronchus. Correlations between CT parameters and clinical indexes such as disease duration and cough sensitivity were examined.
RESULTS: In patients with CVA, WA/BSA, WA%, and T/ square root BSA were all significantly greater than those in control subjects. In patients with NAC, WA/BSA and T/ square root BSA were significantly greater than in control subjects. The increase of WA/BSA and T/ square root BSA of NAC patients was less than that of CVA patients. In a subset of patients with NAC, WA% correlated with capsaicin cough sensitivity (n = 9, r = 0.75, p = 0.034).
CONCLUSIONS: Walls of central airways are thickened in patients with CVA, and also to a lesser degree in patients with NAC. Airway wall thickening in NAC may be associated with cough hypersensitivity.
Akio Niimi, Hiroyuki Ohbayashi, Hironori Sagara, Kohei Yamauchi, Kazuo Akiyama, Kiyoshi Takahashi, Hideki Inoue, Tomoshige Wakayama, Hitoshi Kobayashi, Maki Hasegawa, Goro Kimura, Takuya Yokoe, Mitsuru Adachi
Cough variant and cough-predominant asthma are major causes of persistent cough: a multicenter study in Japan.
J Asthma. 2013 Nov;50(9):932-7. doi: 10.3109/02770903.2013.823444. Epub 2013 Aug 20.
Abstract/Text
OBJECTIVE: Persistent cough is a frequent cause of doctor and hospital visits, and its incidence may be increasing. However, diagnosis of the cause of cough remains difficult. Because different causes of cough have different treatments, accurate diagnosis of the cause of cough is critical. To gain a better understanding of the causes of cough in Japan, we performed a multicenter epidemiological study of Japanese patients.
METHODS: The study involved seven institutions in five different areas of Japan, and was conducted over 1 year from March 2009. Patients aged ≥16 years attending the participating centers for the first time complaining of cough persisting for ≥3 weeks were eligible. Patients with chest X-ray abnormalities responsible for cough, fever or blood-stained sputum were excluded, while those with wheeze or shortness of breath were included. Frequency and severity of cough were assessed using questionnaires, and laboratory tests were performed to enable differential diagnoses.
RESULTS: Among the 313 patients evaluated, mean duration of cough symptoms was 192.1 ± 558.4 days. Cough variant asthma (CVA) was the most common cause of prolonged/chronic cough (42.2%), followed by cough-predominant asthma (CPA) (28.4%), atopic cough (7.3%) and chronic obstructive pulmonary disease (6.7%). Patients with an unclear diagnosis were treated with tulobuterol, a transdermal β2-agonist preparation, for 1-2 weeks. Transdermal tulobuterol improved assessments of cough in patients with CVA or CPA, enabling rapid diagnosis of these diseases.
CONCLUSIONS: These findings show that CVA and CPA are the main causes of cough persisting for ≥3 weeks.
R S Irwin, C T French, N A Smyrnios, F J Curley
Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma.
Arch Intern Med. 1997 Sep 22;157(17):1981-7.
Abstract/Text
BACKGROUND: In diagnosing cough due to asthma, methacholine chloride inhalation challenge (MIC) interpreted in a traditional fashion has been shown to have positive predictive values from 60% to 82%.
OBJECTIVE: To determine whether any features of positive results of an MIC or the results of a 1-week trial of inhaled beta-agonist therapy were helpful in predicting when the cough was due to asthma.
METHODS: The study design was a prospective, randomized, double-blind, placebo-controlled, crossover format performed in adult, nonsmoking subjects, who were referred for diagnosis and treatment of chronic cough. The subjects had no other respiratory complaints or medical conditions for which they were taking medications, the results of baseline spirometry and chest roentgenograms were normal, and the results of MIC were positive. After obtaining baseline data, including MICs on 2 separate days, objective cough counting, and self-assessment of cough severity using a visual analog scale, subjects were randomized to receive 2 inhalations (1.3 mg) of metaproterenol sulfate or placebo by metered dose inhaler attached to a spacer device every 4 hours while awake. At 1 week, data identical to baseline were collected, and subjects received the other metered dose inhaler for 7 days. At 1 week, data identical to baseline were collected. After completion of the protocol, subjects were followed up in the clinic to observe the final response of the cough to specific therapy.
RESULTS: Based on the disappearance of the cough with specific therapy, the cough was due to asthma in 9 of 15 subjects and nonasthma in 6 of 15 subjects. Baseline data were similar between groups. With respect to MICs, there were no significant differences between groups in the cumulative dose of methacholine that provoked a 20% decrease in forced expiratory volume in 1 second from the postsaline baseline value (PD20 values), slopes of dose-response curves, and maximal-response plateaus. Cough severity significantly improved after 1 week of metaproterenol use compared with the severity of the cough at baseline (P = .03) and with placebo (P = .02) only in subjects with asthma.
CONCLUSIONS: No matter how the results are analyzed, positive MIC results, without observing response to therapy, are only consistent with asthma as the cause of the cough. The results are only diagnostic of asthma when they are followed by a favorable response to asthma therapy. After 1 week of inhaled beta-agonist, only the cough due to cough-variant asthma is significantly better.
M Fujimura, N Songür, Y Kamio, T Matsuda
Detection of eosinophils in hypertonic saline-induced sputum in patients with chronic nonproductive cough.
J Asthma. 1997;34(2):119-26. doi: 10.3109/02770909709075656.
Abstract/Text
This study was conducted to examine (1) whether an appropriate sputum can be obtained by inducing with inhalation of hypertonic saline in patients with chronic nonproductive cough and (2) whether eosinophils can be detected in the induced sputum. Appropriate samples were obtained by the induction in 25 of 31 patients with bronchial asthma (BA), 12 of 17 patients with cough-variant asthma (CVA), 17 of 20 patients with bronchodilator-resistant cough associated with atopy (atopic cough, AC), and 23 of 25 healthy subjects. Eosinophils were detected in the successfully induced sputum in 100%, 66.6%, and 88.2% of the patients with BA, CVA, and AC, respectively. Detection of eosinophils in induced sputum may be the initial diagnostic procedure for nonproductive cough of allergic nature.
Suguru Sato, Junpei Saito, Yasuko Sato, Taeko Ishii, Wang Xintao, Yoshinori Tanino, Takashi Ishida, Mitsuru Munakata
Clinical usefulness of fractional exhaled nitric oxide for diagnosing prolonged cough.
Respir Med. 2008 Oct;102(10):1452-9. doi: 10.1016/j.rmed.2008.04.018. Epub 2008 Jul 9.
Abstract/Text
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.
Yoshihiro Kanemitsu, Hisako Matsumoto, Nuriamina Osman, Tsuyoshi Oguma, Tadao Nagasaki, Yumi Izuhara, Isao Ito, Tomoko Tajiri, Toshiyuki Iwata, Akio Niimi, Michiaki Mishima
"Cold air" and/or "talking" as cough triggers, a sign for the diagnosis of cough variant asthma.
Respir Investig. 2016 Nov;54(6):413-418. doi: 10.1016/j.resinv.2016.07.002. Epub 2016 Aug 24.
Abstract/Text
BACKGROUND: Fractional exhaled nitric oxide (FeNO) is considered an alternative marker of eosinophilic airway inflammation and is sometimes incorporated in the diagnosis of asthma. However, many patients with cough variant asthma (CVA) demonstrate an FeNO in the normal range. Therefore, additional information is needed to confirm the diagnosis of CVA, particularly in patients with low FeNO levels. We aimed to investigate the feasibility of using cough triggers to help diagnose CVA.
METHODS: We studied 163 patients presenting with prolonged/chronic cough alone (including 104 CVA patients) who underwent FeNO measurements and an airway responsiveness test, and answered a questionnaire listing 18 cough triggers. The sensitivity and specificity of FeNO levels and cough triggers for the diagnosis of CVA were determined.
RESULTS: CVA patients showed higher FeNO levels than non-CVA patients. When the cut-off value of FeNO levels for the diagnosis of CVA was set at 22ppb, its sensitivity was 57%. CVA patients more frequently responded to "cold air" and "talking" as cough triggers than non-CVA patients. When the analysis was confined to those with a low FeNO (<22ppb) group, the sensitivity and positive predictive values of "cold air" and "talking" for the diagnosis of CVA were 36% and 70% for "cold air", and 44% and 74% for "talking", respectively. Their specificity was 81%. "Cold air" was associated with airway hyperresponsiveness in all patients with an emphasis on those with low FeNO levels.
CONCLUSION: "Cold air" and/or "talking" as cough triggers could be signs for the diagnosis of CVA, particularly when FeNO levels are low.
Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Sheldon L Spector, Ricardo A Tan
Effectiveness of montelukast in the treatment of cough variant asthma.
Ann Allergy Asthma Immunol. 2004 Sep;93(3):232-6. doi: 10.1016/S1081-1206(10)61493-7.
Abstract/Text
BACKGROUND: Antileukotriene agents have been shown to be beneficial in chronic asthma. Although patients with cough variant asthma have cough with minimal wheezing and dyspnea, airway hyperresponsiveness from chronic inflammation is believed to be the underlying mechanism.
OBJECTIVE: To evaluate the effectiveness of montelukast, a leukotriene receptor antagonist, in the treatment of cough variant asthma.
METHODS: Fourteen patients with cough variant asthma participated in a randomized, double-blind, placebo-controlled trial with a 7- to 10-day baseline period and a 4-week treatment period with montelukast, 10 mg, or placebo daily. Inclusion criteria were (1) chronic cough with a duration of at least 4 weeks with minimal or no wheezing or dyspnea and (2) forced expiratory volume in 1 second of 50% to 85% of predicted and reversibility of 12% with use of an inhaled beta-agonist or forced expiratory volume in 1 second greater than 85% and positive methacholine challenge results. Patients fulfilled the minimum criteria for cough frequency and symptom scores for randomization.
RESULTS: Eight patients received montelukast and 6 received placebo. The primary efficacy variable, mean percentage change from baseline in cough frequency, was significantly improved by the second week, and by the fourth week the mean percentage change from baseline was 75.7% for the treatment group and 20.7% for the placebo group.
CONCLUSIONS: The leukotriene receptor antagonist montelukast seems to be effective in the treatment of cough variant asthma. Larger studies are recommended to confirm this effect.
M Fujimura, H Ogawa, Y Nishizawa, K Nishi
Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?
Thorax. 2003 Jan;58(1):14-8.
Abstract/Text
BACKGROUND: We have described a group of patients who present with isolated chronic bronchodilator resistant non-productive cough with an atopic constitution, eosinophilic tracheobronchitis, and airway cough receptor hypersensitivity without bronchial hyperresponsiveness, which we have termed "atopic cough". Although cough variant asthma (in which the cough responds to bronchodilators) is recognised as a precursor of typical asthma, it is not known whether atopic cough is also a precursor of asthma.
METHODS: Eighty two patients with atopic cough were retrospectively examined for onset of typical asthma and compared with 55 patients with cough variant asthma (20 untreated patients and 35 treated with long term inhaled beclomethasone dipropionate (BDP), 218-467 micro g/day). The median follow up period for patients with atopic cough and cough variant asthma was 4.8 (1-11.5) years and 3.7 (1-12.4) years, respectively.
RESULTS: Onset of typical asthma occurred in only one of the patients with atopic cough. In patients with cough variant asthma, typical asthma developed in two of 35 patients taking BDP and six of 20 untreated patients (difference 24.3%, 95% CI 2.8 to 45.8, p<0.02).
CONCLUSIONS: These findings suggest that cough variant asthma is a precursor of typical asthma but that atopic cough is not. Treatment with inhaled steroids may prevent the transformation of cough variant asthma into typical asthma.
