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(Chest. 2005;128:2427-2434.)
© 2005 American College of Chest Physicians

Bronchial Sensitivity and Bronchial Reactivity in Children With Cough Variant Asthma*

Hiroyuki Mochizuki, MD; Hirokazu Arakawa, MD; Kenichi Tokuyama, MD and Akihiro Morikawa, MD

* From the Department of Pediatrics and Developmental Medicine, Gunma University, Graduate School of Medicine, Gunma, Japan.

Correspondence to: Hiroyuki Mochizuki, MD, Department of Pediatrics and Developmental Medicine, Gunma University, Graduate School of Medicine, Showa-Machi 3–39-15, Maebashi, Japan


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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.

Key Words: allergy • pediatrics, allergy • pediatrics, pulmonary


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cough is a common symptom in children with respiratory tract infections and bronchial asthma. Persistent dry cough lasting > 8 weeks, termed chronic cough, has varied etiologies.12 The presence of chronic cough without causative factors and bronchial hyperresponsiveness is termed cough variant asthma (CVA).34

Previously, the hyperresponsiveness of cough receptors has been evaluated using chemical irritant inhalation challenges,56 and the relationship between the hyperresponsiveness of cough receptors and chronic cough has been reported.7 Although little has been written regarding the mechanisms of chronic cough, studies89 suggest that recurrent cough without wheeze differs in some respects from asthma. However, the precise mechanism of CVA in infants and children is still unclear.

The association between asthma and bronchial hyperresponsiveness (BHR) has been demonstrated,10 and some reports1112 have suggested that the degree of BHR, especially bronchial sensitivity, shows a correlation with the severity of the asthmatic symptoms Previously, a technique to evaluate BHR using continuous-monitoring respiratory resistance (Rrs), which can be used over a wide age range in children13 and allows examination of both bronchial sensitivity and bronchial reactivity,14 was described.1516 We have also reported that the degree of bronchial sensitivity shows a correlation with the severity of the asthmatic symptoms,14 whereas the degree of bronchial reactivity indicated by the slope of methacholine dose-response curve (SRrs) does not reflect the severity of asthma, and the SRrs in children with nonatopic asthma is markedly higher than that in children with atopic asthma.17

It is very interesting that patients with CVA demonstrate BHR or bronchoconstriction without wheezing. In this report, to evaluate the physiologic differences in airways of CVA, we performed a methacholine inhalation challenge using the oscillation technique in children with CVA and children classic asthma, and compared the results of bronchial sensitivity and bronchial reactivity among them.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
We began measuring childhood bronchial sensitivity and bronchial reactivity in 1982, and have performed methacholine inhalation challenge using the same oscillation technique. The subjects of this study were children who visited Gunma University Hospital from 1982 to 2004 with asthma, bronchiolitis, pneumonia, sinusitis, and other respiratory and nonrespiratory diseases.

Diagnosis of CVA and Classic Asthma
The clinical diagnosis of chronic cough was based on previous reports, a characteristic history of persistent dry cough lasting > 8 weeks with neither dyspnea nor perceptible wheezing, with no identifiable cause of the cough after chest radiography and clinical assessment, and in the absence of chronic sinusitis, bronchiectasis, whooping cough, immunodeficiency, cardiac or neonatal pulmonary problems,1819 infantile chronic respiratory infections, and obvious gastroesophageal reflux.20 Furthermore, in this report, CVA was diagnosed in chronic cough patients who demonstrate BHR21 and showed an apparent improvement of cough with ß2-agonist therapy.22 Conventionally, obvious BHR is judged as being the minimum dose of methacholine (Dmin) causing bronchoconstriction of < 7.0 U, that is, the threshold point of methacholine concentration is < 3.13 mg/mL.23 We believe that postviral cough and eosinophilic bronchitis do not react to ß2-agonist, and do not show obvious BHR.

Clinical diagnosis of classic asthma was based on a characteristic history of recurrent attacks of dyspnea with perceptible wheezing, and without acute or chronic bronchitis, pulmonary emphysema, or cardiovascular diseases1024 Clinical diagnosis of atopy was based on a positive reaction to common environmental allergens administered to the skin, and to radioallergosorbent tests, that is, development of a wheal ≥ 5 mm in width in a skin-prick test and > 0.70 Phadebas radioallergosorbent units in the radioallergosorbent tests.17 In this report, all of the asthmatics were of the atopic type.

Criteria of Cough Group and Control Subjects
The cough group was selected from the age-matched children who had cough induced by airway infections for > 4 weeks, and did not show wheezing or dyspnea and had no remarkable improvement with ß2-stimulant treatment. Their cough disappeared as a result of the treatment of the relevant causative disease, or by observation without medication.

Furthermore, we added the data of 23 children as age-matched control subjects who were free of chronic respiratory and atopic diseases and in whom classic asthma did not develop in > 3 years of follow-up observation (Table 1 ). This study includes previously published data of disease control subjects.13 No child in the age-matched control group was receiving medication.


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  		Table 1.. Profiles of Each Group*

 
Inclusion Criteria
All subjects were free of upper respiratory tract infections for > 4 weeks prior to the start of study, and none had received inhaled or oral steroid therapy or any medication for at least 12 h prior to the testing. We asked CVA patients aged > 16 years for information concerning the development of their asthma. Informed parental consent was obtained before the study.

Methacholine Inhalation Challenge
Methacholine inhalation challenges were performed according to the procedure described by Takishima et al.15 An Astograph aerosol generator (TCK 6100H; Chest Company; Tokyo, Japan) delivered increasing doses of methacholine from 12 serially arranged nebulizers. The nebulizers were activated by a constant airflow of 5 L/min generated by an air compressor. The airflow was switched from one nebulizer to the next at predetermined intervals. Each nebulizer delivered approximately 0.15 mL of solution per minute of increasing concentrations of methacholine and bronchodilator.

Bronchial responsiveness was displayed in the form of a continuous record of Rrs, measured by the oscillation technique. A constant-amplitude pressure generator was connected to a mouthpiece that produced a constant-amplitude sinusoidal pressure wave of 2 cm H2O of 7 Hz at the mouth. Recordings showing excessive fluctuations, caused especially by coughing, were excluded after two independent examiners agreed that such records were not suitable for use in the evaluation of BHR.

Methacholine (Daiichi Kagaku Yakuhin; Tokyo, Japan), prepared on the day of the test, was serially diluted twofold with saline solution (10 dose steps starting from a concentration of 25 mg/mL down to approximately 49 µg/mL). The first nebulizer contained 2 mL of saline solution, the second nebulizer contained 2 mL of the highest dilution of methacholine, and the third to eleventh nebulizers contained increasing concentrations of methacholine. Each concentration of the methacholine solution was inhaled for 1 min. The twelfth nebulizer contained salbutamol hemisulfate (1.7 mg/mL in saline solution) and was inhaled for 2 min.

Subjects were examined during quiet breathing in a sitting position with a nose clip attached and two air-filled balloons pressing against both cheeks; doses of inhaled methacholine were doubled every minute. When Rrs reached double the baseline value, methacholine administration was stopped and salbutamol solution was administered. The total amount of nebulized salbutamol was approximately 0.5 mg. Rrs was continuously measured until it reached a stable state.

We calculated the following parameters in the Rrs dose-response curve (Fig 1 ): (1) the linear SRrs increase, which indicates the speed of bronchoconstriction to methacholine, representing bronchial reactivity; and (2) the Dmin causing bronchoconstriction, that is, the cumulative dose of methacholine at the inflection point of the Rrs tracing, representing bronchial sensitivity.1617 One Dmin unit was considered to be equal to 1 min of inhaling an aerosolized methacholine solution of 1.0 mg/mL during tidal breathing. An increase in Rrs at 5.5 min from the start of methacholine inhalation meant that the subjects had inhaled the cumulative dose of methacholine from the first solution to the fifth solution (total, 1.514 U) and 30 s of inhalation from the sixth solution (0.782 U), a total inhalation of 2.296 U.



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  		Figure 1.. The dose-response curve of Rrs in methacholine inhalation challenge using the oscillation method. Rrs increased with inhalation of incremental amounts of methacholine. When Rrs reached approximately twice the baseline value, administration of methacholine was stopped and a ß2-agonist was administered. Two parameters, Dmin and SRrs, were calculated. BD = bronchodilator inhalation.

 
Data Analysis
A parametric analysis of variance was made to determine the significant variance between groups. Data are expressed as means ± SEM; p values < 0.05 were considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The participants in this study were 31 children with CVA aged 5 to 14 years (19 boys and 12 girls; mean age, 8.5 years), 86 age-matched children with classic asthma aged 5 to 15 years (42 boys and 44 girls; mean age, 9.5 years), 25 age-matched children with cough aged from 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) [Table 1]. All participants underwent the methacholine inhalation challenge safely. There was no difference in baseline Rrs values among the four groups (analysis of variance, p = 0.224; Table 1).

The values of Dmin in the CVA group (2.48 ± 0.4 U) and in the classic asthma group (1.95 ± 0.2 U) were significantly lower than in the cough group (9.83 ± 2.1 U) and the control subjects (6.60 ± 1.2 U). There was no statistical difference between Dmin in the CVA group and the classic asthma group (Fig 2 ).



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  		Figure 2.. Comparison of Dmin among four groups: CVA, classic asthma, cough, and control. ***p < 0.01.

 
SRrs in the CVA group (1.59 ± 0.2 cm H2O/L/s/min) was lower than in the classic asthma group (2.03 ± 0.2 cm H2O/L/s/min), the cough group (2.20 ± 0.3 cm H2O/L/s/min), and the control subjects (2.47 ± 0.3 cm H2O/L/s/min). There was no statistical difference in SRrs among the classic asthma group, the cough group, and the control subjects (Fig 3 ).



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  		Figure 3.. Comparison of SRrs among four groups: CVA, classic asthma, cough, and control. *p < 0.05, **p < 0.02.

 
In girls, SRrs in the CVA group (1.35 ± 0.3 cm H2O/L/s/min, n = 12) was lower than in both the classic asthma group (2.09 ± 0.2 cm H2O/L/s/min, n = 44) and the control subjects (2.63 ± 0.4 cm H2O/L/s/min, n = 15, p < 0.02 and p < 0.01, respectively) [Fig 4 ]. There was no difference in the value of SRrs in the cough group (2.20 ± 0.6 cm H2O/L/s/min, n = 8) and the CVA group. There was no difference in SRrs among boys in the CVA group (1.75 ± 0.2 cm H2O/L/s/min, n = 19), the classic asthma group (1.96 ± 0.2 cm H2O/L/s/min, n = 42), the cough group (2.31 ± 0.4 cm H2O/L/s/min, n = 17), and the control subjects (2.18 ± 0.4 cm H2O/L/s/min, n = 8), but the same tendency was seen. There was no significant difference in SRrs between boys and girls in the CVA group, the classic asthma group, and the control subjects. Also, there was no difference in the value of SRrs among the CVA group (2.10 ± 0.3 cm H2O/L/s/min, n = 10), the classic asthma group (2.57 ± 0.3 cm H2O/L/s/min, n = 21), the cough group (3.20 ± 0.7 cm H2O/L/s/min, n = 3), and the control subjects (2.58 ± 0.5 cm H2O/L/s/min, n = 5) in younger children (aged < 6 years). In the older children, however, SRrs in the CVA group (1.35 ± 0.2 cm H2O/L/s/min, n = 21) was lower than in both the classic asthma group (1.85 ± 0.1 cm H2O/L/s/min, n = 65) and cough group (2.08 ± 0.3 cm H2O/L/s/min, n = 22), and the control subjects (2.44 ± 0.3 cm H2O/L/s/min, n = 18, p < 0.02 and p < 0.01, respectively) [Fig 5 ]. There was no significant difference in SRrs between the younger children and the older children in the CVA group, the classic asthma group, and the control subjects.



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  		Figure 4.. Comparison of SRrs between girls and boys in the four groups. **p < 0.02, ***p < 0.01.

 


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  		Figure 5.. Comparison of SRrs between younger children and older children in the four groups. *p < 0.05, **p < 0.02, ***p < 0.01.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
CVA is one of the causes of chronic cough and is associated with several different etiologic factors; it is not so common in children.21 Reports indicate that an increase in BHR has a pathogenetic role in the development of wheezing during the course of CVA.25 Considering previous results, BHR-related persistent cough with latent bronchoconstriction and without wheezing may be present in children with CVA, which then develops into classic asthma as a natural course of events. Other reports have proposed differences in the mechanisms between the hypersensitivity of cough receptors and BHR or the independence of these two states.

The Tuscon prospective longitudinal study26 suggested that recurrent cough without wheezing differs in important respects from classic asthma. Clifford and coworkers27 similarly found that the risk factors for wheezing were not risk factors for cough after controlling for wheezing. In children with chronic cough who do not demonstrate BHR, cough-receptor sensitivity is heightened during the coughing phase and declines during the cough-free phase.18 Also, in adults with or without asthma, no correlation has been found between cough-receptor sensitivity and BHR.2829 These results suggest that the mechanism of BHR, bronchial sensitivity, is essentially different from that of hypersensitivity of cough receptors.

We examined two BHR parameters, bronchial sensitivity (Dmin) and bronchial reactivity (SRrs), which were measured by continuously monitoring Rrs.16 In this study, we found that bronchial reactivity significantly decreases in children with CVA compared with the control subjects and children with classic asthma. That is, the children with CVA demonstrate slower bronchoconstriction against nonspecific airway stimuli than the children with classic asthma, whereas both the children with CVA and the children with classic asthma demonstrate a significant increase in bronchial sensitivity: the so-called BHR. Koh and coworkers30 suggested that it is the level of maximal airway response, rather than the degree of bronchial sensitivity, that is an important risk factor for the future development of classic asthma in patients with CVA. This is compatible with our results, namely, that CVA with lower bronchial reactivity does not become classic asthma. Their results suggest that the outstanding feature of CVA is the lower SRrs.

Concerning a major puzzle in the clinical feature of CVA—the absence of wheezing—our results indicate one possible mechanism that airways in CVA children are not easily constricted and are limited in their extent of constriction and deformation, resulting in persist cough without wheezing because of the small degree of bronchoconstriction. It has been suggested that there is an individual variation in the level of airway obstruction that produces wheezing,31 and that production of wheezing may need more severely constricted airways in patients with CVA. Previously, to characterize the pathophysiologic abnormalities in CVA, a bronchial provocation test with methacholine was performed and the severity of airway obstruction at the first sign of wheezing was measured.32 It was demonstrated that patients with CVA have a higher wheezing threshold than those with classic asthma, and that this is not due to greater BHR. This report is also compatible with our results.

Considering the reason why CVA patients do not show rapid bronchoconstriction, Niimi et al16 suggested that airway remodeling does not protect against bronchial sensitivity but against bronchial reactivity. Thus, we speculate that there is airway remodeling or mechanisms that introduce the rigidity of airway walls in CVA patients. Previous reports2125 have demonstrated the high frequency of asthma development in CVA, which suggests the presence of a common mechanism between CVA and BHR. One of the most common mechanisms, which exacerbates both BHR and hypersensitivity of cough receptors, is airway inflammation. CVA and classic asthma may appear to share a common pattern of inflammation in terms of both cellular infiltration and inflammatory cytokine gene expression. Airway inflammation has been detected in BAL fluid33 and bronchial biopsies.34 Also, CVA patients are responsive to inhaled corticosteroid35 and leukotoriene antagonist.36

Niimi and coworkers37 demonstrated that airway wall thickness was significantly greater in patients with asthma than in the control subjects and in patients with classic asthma than in those with CVA. Although it is not easy to make comparisons between adults with CVA and children with CVA, airway remodeling, which induces a decrease in SRrs16 and which may also exist in children with CVA, induces a lower value of SRrs in patients with CVA than in control subjects. However, we cannot clearly explain the mechanism that induces the difference in the value of SRrs between classic asthma and CVA. Airway inflammation can induce persistent cough in children with CVA without outstanding wheezing and/or bronchoconstriction. The difference between CVA and classic asthma may depend on variations in cytokine production or cytokine sensitivity, which induce airway remodeling. Further investigation is needed to clarify this matter.

There was no difference in SRrs level between boys and girls or between younger children and older children. Some reports1338 have shown that gender has no significant effect on BHR; others39 have shown that gender is not a determinant of bronchial responsiveness to methacholine in the overall population except in girls aged 11 to 15 years, who have a statistically higher mean methacholine area than their male counterparts. However, our data show that SRrs in the girls with CVA is significantly lower than in the girls with asthma. In the boys, this difference was not so clear. Also, SRrs in the older children with CVA is significantly lower than in the older children with asthma; this difference was not so significant in the younger children.

Although there is no statistical difference in the value of SRrs in the children with CVA between boys and girls, or between younger children and older children, we speculate that there may be a mechanism that induces low bronchial reactivity in older girls with CVA. Previous reports4041 have suggested that girls show an increased frequency of BHR compared to boys, and the specificity of adolescent girls, such as the effects of hormones and body size, has been discussed. Forastiere et al42 reported a longitudinal study conducted to evaluate the determinants of the FEV1-indicated bronchial responsiveness to methacholine in children and adolescents, and demonstrated that girls had greater bronchial responsiveness than boys during the adolescent period. Considering these results, adolescent girls with asthma and control subjects may have a raised SRrs, so the lower SRrs in the girls with CVA may stand out. However, we cannot explain why only older girls with CVA have lower SRrs in this report.

Previously, Hills and Chen43 proposed the unmasking of receptor sites secondary to disruption of the phospholipid barrier as a mechanism for the sensitization of reflexes. They suggested that various agents, especially infectious inflammation, can strip away subepithelial cough receptors, thereby increasing cough receptor sensitivity. Generally, airway infection is more common in infants, and the occurrence of respiratory tract infections declines with increasing age. These findings suggest that persistent cough occurs more frequently in infants than in older children. In this study, however, this pathologic weakness in infants does not explain the decrease of bronchial reactivity in childhood CVA.

Consequently, we have demonstrated that, rather than bronchial sensitivity, it is bronchial reactivity that significantly decreased in the children with CVA compared with the control subjects and the children with classic asthma, and that the decrease of bronchial reactivity induces either slower or less bronchoconstriction, resulting in the clinical feature of CVA: persistent cough without wheezing. Considering the factors that influence the degree of the slope of the response, not only airway remodeling but also smooth-muscle activity may have a potent effect on the slope of the response. However, in this report, we cannot define the mechanisms by which airway remodeling increases or airway smooth-muscle reactivity decreases; further investigation is needed.


   Footnotes
 
Abbreviations: BHR = bronchial hyperresponsiveness; CVA = cough variant asthma; Dmin = minimum dose of methacholine; Rrs = respiratory resistance; SRrs = slope of the methacholine dose-response curve

Received for publication February 16, 2005. Accepted for publication April 26, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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