Cough variant asthma and atopic cough

Chronic cough has been reported to be the fifth most common complaint seen by primary care physicians in the world, the third in Italy. Chronic cough in non-smoking, non-treated with ACE-inhibitor adults with normal chest radiogram could be a symptom of asthma and can be sub-classified into: cough-variant asthma, atopic cough, and eosinophilic bronchitis. This review discusses the differential diagnosis of these three disorders.     

Functional gastrointestinal disorders are associated with capsaicin cough sensitivity in severe asthma

BackgroundAlthough sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs.MethodsFifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 μM was defined as heightened C-CS.ResultsSeventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 μM vs. 8.91 ± 5.5 μM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD.ConclusionsComorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma.     

Bronchial sensitivity and bronchial reactivity in children with cough variant asthma

BACKGROUND: Cough variant asthma (CVA) is diagnosed in some children with chronic cough who do not have wheezing. However, the precise mechanism of CVA in children is unclear. OBJECTIVE: To evaluate the physiologic differences in the airways of children with classic asthma and CVA, the methacholine dose-response curves of respiratory resistance (Rrs) were studied. PATIENTS AND METHODS: CVA was diagnosed in 31 children with chronic cough (age range, 5 to 14 years; 19 boys and 12 girls; mean age, 8.5 years) on the basis of methacholine inhalation challenge using an oscillation method. For comparison, the study included 86 age-matched children with classic asthma (age range, 5 to 15 years; 42 boys and 44 girls; mean age, 9.5 years), 25 age-matched children with cough (age range, 5 to 15 years; 17 boys and 8 girls; mean age, 8.8 years), and 23 age-matched control subjects (8 boys and 15 girls; mean age, 9.2 years). Consecutive doses of methacholine were doubled until a 200% increase in Rrs from baseline was reached. The cumulative dose of methacholine at the inflection point of Rrs was considered to represent the bronchial sensitivity to inhaled methacholine (minimum dose of methacholine [Dmin]). The slope of the methacholine dose-response curve (SRrs), which was considered to represent bronchial reactivity, was measured from the increasing Rrs curve. RESULTS: The values of Dmin in classic asthma patients and in CVA patients were significantly lower than those for cough patients and control subjects. There was no significant difference in the values of Dmin between the classic asthma and CVA patients. The value of SRrs in CVA patients was significantly lower than that in classic asthma patients, cough patients, and control subjects (p < 0.05, p < 0.01, and p < 0.01, respectively). There was no significant difference in the value of SRrs between classic asthma patients, cough patients, and control subjects. CONCLUSIONS: These data show that bronchial reactivity in the children with CVA was significantly lower than that in the children with classic asthma, and this specificity has an effect on prolonged cough without wheezing in children with CVA.     

布地奈德吸入治疗儿童咳嗽变异性哮喘的疗效研究

目的探讨布地奈德吸入治疗儿童咳嗽变异性哮喘的临床疗效和安全性。方法将60例咳嗽变异性哮喘患儿随机分为观察组30例和对照组30例,观察组采用布地奈德气雾剂,一日200～600μg,分2～4次使用;对照组采用丙酸氟替卡松气雾剂,一日100～500μg,分2次使用。两组疗程均为6d,然后比较两组患儿的治疗效果及安全性。结果观察组和对照的有效率分别为97.67%和76.67%,两组间差异存在显著性（P〈0.05）。两组患者治疗期间均未发生明显不良反应。结论布地奈德吸入治疗儿童咳嗽变异性哮喘安全有效,值得临床推广应用。     

沙美特罗替卡松粉剂吸入治疗儿童咳嗽变异性哮喘的临床观察

目的观察沙美特罗替卡松粉剂吸入治疗咳嗽变异性哮喘(CVA)的临床疗效及安全性。方法将92例CVA患者随机分为两组各46例,治疗组予舒利迭(每吸内含50μg沙美特罗和100μg丙酸氟替卡松),1吸/次,早晚各1次;对照组予普米克气雾剂(每喷内含布地奈德200μg),1喷/次,早晚各1次。咳嗽明显缓解后改为1吸/d,疗程维持3个月。结果治疗组显效率为86.96%,总有效率为95.65%,对照组显效率为63.04%,总有效率为78.26%,两组疗效比较差异均有统计学意义(P<0.05);治疗组在咳嗽缓解和咳嗽消失时间上明显优于对照组(P<0.01);治疗组在临床改善咳嗽、夜间呼吸症状及日常活动与运动行为不受限方面均优于对照组(P<0.05);两组均未发生明显药物不良反应及肝肾损害。结论沙美特罗替卡松吸入治疗CVA临床疗效确切,能迅速缓解和减轻症状、恢复正常呼吸功能,使用安全,具有协同增效作用。     

咳嗽变异性哮喘与白三烯关系的研究进展

咳嗽变异性哮喘（CVA）是以咳嗽为唯一或主要临床表现的特殊类型的哮喘,其发病机制及病理生理与典型哮喘相似,两者均以持续气道炎症、气道高反应性和气道重构为特点,平均约有30％的CVA患儿最终发展为典型哮喘。白三烯（LTs）是体内重要的炎症介质,LTs及其拮抗剂在CVA的发病和治疗中起重要作用。在CVA的治疗对策中,早期干预具有重要临床意义,在众多合理、有效的指导与治疗选项中,LTs拮抗剂不失为一项有效、安全的选择。该文就CVA与LTs关系的研究进展作一综述。     

Cough, cough receptors, and asthma in children.

This review discusses current general concepts on cough and the relationship between cough, cough receptor sensitivity, and asthma in children. It presents models of the relationship between cough and bronchoconstriction, and proposes a new model outlining the relationship between cough receptor sensitivity, airway hyperresponsiveness, and the clinical issues of cough, wheeze, and dyspnea in children with and without asthma. Cough is very common in children, with a prevalence of 15-20%. Those with non-specific cough (dry cough in the absence of identifiable respiratory illness) are often treated with a variety of drugs, in particular, medications for asthma and gastroesophageal reflux. However, there is little evidence to use these medications for the sole symptom of cough in children. Clinical studies on cough need to be interpreted in light of inherent methodological problems in studying cough. These methodological problems include the nonrepeatable nature of questions on cough, the unreliability of subjective measurements of cough, the lack of objective measurements to quantify cough severity, and the period effect (spontaneous resolution of cough). Although cough can be troublesome, cough serves as an important function for maintaining normal health of the respiratory system. The importance of cough in maintaining respiratory health is reflected in the development of lung atelactasis/collapse from retained secretions and recurrent pneumonia in clinical situations where the cough reflex is ineffective. The cough reflex is complex and still poorly understood. In this article the simplified cough pathway is presented and involves cough receptors, mediators of sensory nerves and the afferent pathway, the vagus nerve, the cough centre, efferent pathway, and cough effectors.     

布地耐德与福美特罗吸入治疗咳嗽变异性哮喘临床疗效分析

目的探讨布地耐德与福美特罗吸入治疗咳嗽变异性哮喘的临床疗效。方法40例确诊咳嗽变异性哮喘患者给予布地耐德与福美特罗吸入,观察咳嗽缓解情况。结果咳嗽症状3d后消失21例,1周后消失10例,6例1个月后消失,仅3例持续用药2个月后咳嗽症状消失。结论咳嗽变异性哮喘患者早期给予支气管扩张剂和激素吸入可明显缓解咳嗽症状。     

Predictors for typical asthma onset from cough variant asthma.

Cough variant asthma is recognized to be a precursor of asthma or preasthmatic state because nearly 30% patients with cough variant asthma develop typical asthma within several years. However, predictors for risk of typical asthma onset from cough variant asthma are unknown. Forty-one patients with cough variant asthma (median age 50 years, 13 men and 28 women), who had undertaken spirometry, bronchial reversibility test, methacholine provocation test, measurements of peripheral blood eosinophil count, serum total IgE, and specific IgE to common allergens, and induced sputum eosinophil count at presentation, were followed up with special emphasis on typical asthma onset during 1 year or more (median 4 years, range 1-12.4). Long-term inhaled corticosteroids (ICS) were taken in 27 patients. Univariate and multivariate logistic analyses were performed to determine the predictors for typical asthma onset. Asthma onset was recognized in 7 patients. Bronchial hyperresponsiveness, peripheral blood eosinophil count, and no use of ICS were significant predictors for the typical asthma onset by univariate analysis. However, only bronchial hyperresponsiveness was the significant predictor when multivariate analysis was used (adjusted OR 0.028, 95% CI 0.001-0.783, p = 0.0355). Bronchial hyperresponsiveness may be the most important predictor for risk of typical asthma onset from cough variant asthma.     

Heightened cough response to bronchoconstriction in cough variant asthma

Background and objective: The pathophysiology of cough variant asthma (CVA) is poorly understood. We compared bronchoconstriction‐triggered cough between CVA patients and normal control (NC) subjects. Methods: There were two protocols in the study. We measured bronchial responsiveness to methacholine (MCh) and counted the number of coughs in nine CVA patients and seven NC subjects (Study A). Using partial and full flow–volume curves, expiratory flow of the partial flow–volume curve at 40% above residual volume level (PEF40) and FEV₁ were used to measure bronchoconstriction. Mild bronchoconstriction was defined as a 35% fall in PEF40 (PC₃₅‐PEF40), and more severe bronchoconstriction as a 20% fall in FEV₁ (PC₂₀‐FEV₁). In study B, the same measurements were obtained in six CVA patients before and after therapy. Results: In study A, more coughs were provoked at PC₃₅‐PEF40 in CVA patients (median, 60 coughs/32 min post challenge; range, 12–135) than in NC subjects (median, 0/32 min; range, 0–13; P < 0.05). At PC₂₀‐FEV₁, more coughs were provoked in CVA patients (median, 60/32 min; range, 12–150) than in NC subjects (median, 20/32 min; range, 0–54; P < 0.05). In study B, the six CVA patients who underwent re‐examination after treatment had less coughs at PC₃₅‐PEF40 (median, 3/32 min; range, 0–14) and PC₂₀‐FEV1 (median, 13/32 min; range, 3–26) after therapy than before therapy (median, 54/32 min; range, 33–125 and 52/32 min, 45–96, respectively; P < 0.05). Conclusions: We identified heightened cough response to bronchoconstriction as a feature of CVA.     

白三烯与咳嗽变异性哮喘

1972年由Glauser提出咳嗽变异性哮喘(cough variantasthma,CVA),这是一种特殊类型的支气管哮喘(简称哮喘),其发病机制和病理生理学表现与典型哮喘相似,但以咳嗽为唯一或主要临床表现,无明显喘息、气促等症状或体征,有呼吸道高反应性。CVA被认为是由嗜酸粒细胞(Eos)、肥大细胞和T细胞等多种炎症细胞参与的慢性、非特异性、变     

咳嗽变异性哮喘与气道重塑

咳嗽变异性哮喘（coughvariantasthma,CVA）是指以慢性咳嗽为主要或唯一症状的一种特殊类型哮喘,其病理生理改变与典型哮喘相同,若未及时诊治,约30％～40％可发展成为典型哮喘。气道炎细胞浸润和气道重塑是CVA的病理基础。CVA可称之为一种隐匿性哮喘,常被临床医师所忽略,患者失去正确的诊断与治疗。正确认识CVA的病理生理特征,对临床诊断和治疗具有重要的指导意义,可降低典型哮喘的发病率。本文就CVA与气道炎性反应和气道重塑的关系作一综述。     

Cough reflex testing with inhaled capsaicin in the study of chronic cough

OBJECTIVES: To assess the utility of capsaicin test in the differential diagnosis of non-productive causes of chronic cough and to examine the effects of treatment on this reflex. PARTICIPANTS: 86 healthy volunteers and 101 patients with chronic cough: asthma (n: 54) gastroesophageal reflux (n: 35) and post-nasal drip syndrome (n: 12). DESIGN: Prospective intervention trial. Spirometry, bronchoprovocation test with histamine (PC20), and cough challenge with ascending concentrations of capsaicin (0.49-500 microM) were initially performed in all subjects. Patients were treated for 3 months according to the origin of the cough. Concentrations that elicited two (C2) and five or more coughs (C5) were determined before and after treatment. RESULTS: In healthy subjects, cough sensitivity to capsaicin was not influenced by gender or smoking status; however, women with chronic cough were more sensitive to cough challenge than men. C2 and C5 were significantly lower in patients with asthma or gastroesophageal reflux than in post-nasal drip syndrome. No significant correlation was observed between the capsaicin cough threshold and PC20. Cough sensitivity did not improve significantly in most patients with asthma or gastroesophageal reflux despite adequate medical treatment during 3 months. Discriminative value of capsaicin test to differentiate healthy subjects from patients with asthma or reflux was poor. CONCLUSIONS: Cough sensitivity to inhaled capsaicin is a safe and reproducible tool in the study of chronic cough. However, its usefulness for the management and differential diagnosis is limited.     

吸入糖皮质激素佐治咳嗽变异性哮喘的疗效评估

目的探讨吸入布地奈德干粉吸入剂佐治咳嗽变异性哮喘的临床价值。方法将2011年03月-2012年03月本院诊治的90例咳嗽变异性哮喘患者随机分成两组：实验组45例,对照组45例。对照组采用异丙托溴铵气雾剂＋常规基础治疗;实验组则再给予布地奈德干粉吸入剂辅助治疗。观察比较两组的临床疗效、住院时间、哮喘症状评分、症状改善时间、肺功能。结果实验组的总有效率明显高于对照组（P〈0．05）;实验组患者的住院时间明显短于对照组（P〈0．05）;实验组患者的哮喘症状评分明显低于对照组（P〈0．05）;实验组患者气喘缓解、咳嗽消失、哮鸣音消退等症状改善时间均明显短于对照组（P〈0．05）;实验组患者治疗后的FEV1、FVC、FEV1／FVC、PEF、FEF25等肺功能指标水平明显优于对照组（P〈0．05）。结论吸入布地奈德干粉吸入剂佐治咳嗽变异性哮喘的临床疗效显著。     

Cough variant and cough-predominant asthma are major causes of persistent cough: a multicenter study in Japan

Abstract

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.     

Cough frequency, cough sensitivity and health status in patients with chronic cough

BACKGROUND: Little is known about the frequency of cough in health and in patients with chronic cough. METHODS: We measured cough frequency and its relationship with other markers of cough severity in 20 patients with chronic cough and 9 healthy subjects using the Leicester Cough Monitor (LCM), which is an automated ambulatory digital cough monitor that records sound only. All subjects had a 6-h recording and recordings were manually counted. A subgroup of 6 normals and 6 patients with a stable chronic cough had repeat measurements up to 6 months apart. RESULTS: Mean (sem) cough counts/hour were 43(8) in patients with chronic cough and 2(1) in normals (mean difference 41; 95% confidence interval 24-59; P<0.001). The cough counts were repeatable (within subject standard deviation: 23 coughs/hour; intraclass correlation coefficient 0.8). Cough counts correlated significantly with physical (r=-0.6, P=0.03), social (r=-0.7, P=0.01) and total Leicester Cough Questionnaire (LCQ) health status scores (r=-0.6, P=0.03) and cough sensitivity (concentration of capsaicin causing 5 coughs: r=0.9, P=0.008). CONCLUSION: We have shown that there are marked differences in cough frequency between patients with chronic cough and healthy subjects, that these measurements are repeatable, and that they correlate with cough-specific health status.     

神经生长因子与咳嗽变异性哮喘

咳嗽变异性哮喘是指以慢性咳嗽为主要或惟一临床表现的一种特殊类型的哮喘.目前发病机制尚不十分清楚.神经生长因子(nerve growth factor,NGF)是神经营养家族中成员之一.随着NGF在慢性咳嗽患者诱导痰中的发现,对NGF在咳嗽变异性哮喘发病机制中的作用引起人们的重视.研究发现,NGF是一种多功能的细胞生长和调节因子,对免疫细胞的生长、分化、激活可产生重要影响,从而参与咳嗽变异性哮喘的免疫失衡.因此,NGF是联系免疫细胞与神经细胞之间的双向信号分子.因而对NGF的研究,有助于探讨咳嗽变异性哮喘发病机制.