HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Siwik, J. P. Articles by Zoratti, E. M. Search for Related Content PubMed PubMed Citation Articles by Siwik, J. P. Articles by Zoratti, E. M.

Airway Hyperresponsiveness to Methacholine at Age 6 to 8 Years in Nonasthmatic Patients Is Not Related to Increased Health-Care Utilization for Asthma in the Ensuing 5 Years^*

A Longitudinal Study of a Birth Cohort

^* From the Henry Ford Health System (Drs. Siwik, Johnson, Peterson, and Zoratti, and Ms. Havstad), Detroit, MI; and the Medical College of Georgia (Dr. Ownby), Augusta, GA.

Correspondence to: Jaroslaw P. Siwik, MD, Bronson Internal Medicine Associates, 2600 West Centre St, Portage, MI 49024; e-mail: siwikj{at}bronsonhg.org

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: Children with heightened airway responsiveness have a greater tendency to develop asthma symptoms. Many existing studies describing this relationship have relied on self-reported symptoms that may be prone to recall bias. In addition, few studies have examined the relationship of airway hyperresponsiveness (AHR) to indicators of asthma severity such as health-care utilization.

Objective: To determine whether a positive response to methacholine challenge in children without current or physician-diagnosed asthma at age 6 to 8 years is predictive of the subsequent onset of asthma requiring medical evaluation or treatment in the ensuing 5 years.

Methods: Data were obtained from subjects in a population-based birth cohort (n = 835) enrolled from 1987 to 1989, who were members of a large medical group practice component of a health maintenance organization (HMO). We analyzed a subset of subjects (n = 245) who had completed a methacholine challenge at age 6 to 8 years, had no current or physician-diagnosed asthma, and were still served by the same medical group. These children were followed up from the time of methacholine challenge until HMO disenrollment or through June 2001 (ages 11 to 13 years), whichever came first. Pharmacy claims data and diagnostic codes from physician-patient encounters were evaluated for incident asthma. Incident cases of clinical asthma were defined as any child with two outpatient visits or one hospitalization, one emergency department encounter associated with an asthma diagnostic code (ie, 493.XX), or any child filling prescriptions for two bronchodilators or one antiinflammatory asthma medicine. Methacholine responsiveness was interpreted using American Thoracic Society criteria.

Results: Asthma incidence did not differ based on methacholine challenge results for children with normal, borderline, and mild AHR. No child in the study demonstrated moderate-to-severe AHR.

Conclusion: Our data suggest that AHR with a borderline or weakly positive result in a methacholine challenge in children 6 to 8 years old without current or physician-diagnosed asthma is not related to increased health-care utilization for asthma in the ensuing 5 years.

Key Words: airway hyperresponsiveness • asthma • bronchial reactivity • cohort • methacholine

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Altered lung function is a fundamental characteristic of asthma and may predate clinically recognized disease. Furthermore, it is becoming clear that objective measures of respiratory physiology such as spirometry can be a reliable measure of lung function in early school-age children or even preschool children.¹ Although overt airway obstruction may be present in some children (often prompting a diagnosis of asthma), many children will have normal spirometry findings.

However, some children will exhibit a more subtle form of altered lung function or airway hyperresponsiveness (AHR), which is apparent only by a heightened response to inhaled bronchoconstrictor substances, including but not limited to methacholine, histamine, cold air, and adenosine. AHR is present in almost all patients with asthma, at least when they are experiencing symptoms. Patients with more severe asthma have greater AHR than patients with mild disease. In addition, patients exhibit a further increase in AHR during asthma exacerbation. AHR is also substantially different between healthy and asthmatic patients with most healthy subjects lacking any evidence of AHR by standard testing methods.²

Several cohort studies have indicated that children exhibiting AHR have a greater tendency to develop wheeze and asthma.³⁴⁵ However, many of these studies rely on the distant recall of symptoms and events that may be prone to recall bias. In addition, although airway responsiveness has been linked to an increased risk of asthma, prospective data evaluating indicators of asthma severity, such as asthma-related health-care utilization data among children with heightened airway responsiveness, are limited.

This cohort analysis was designed to determine whether children who exhibited heightened airway responsiveness at age 6 to 8 years but did not have current or physician-diagnosed asthma are at a high risk of developing clinically apparent asthma, as assessed by asthma-related physician visits and the filling of prescriptions for asthma medications in the ensuing 5 years.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study Population
The original birth cohort used in this study has been described previously.⁶ Briefly, all pregnant women living in an area of northern suburban Detroit who were members of the staff model component of Health Alliance Plan, a health maintenance organization (HMO), were eligible for recruitment into the study if their expected delivery dates had been between April 15, 1987, and August 31, 1989. Women meeting the eligibility criteria were invited during prenatal visits to participate in the study. If a woman had agreed to participate, demographic, health, family history, environmental sample, and lifestyle-related data were repeatedly collected during their offspring’s childhood. When the participating mother’s child was between 6 and 8 years of age, a clinical evaluation for asthma was performed including medical history, physical examination, spirometry, and methacholine challenge test. All participating families who could be contacted and who remained within driving distance of the study center were invited to participate in the clinical evaluation.

The current analysis includes the subset of children from the original population-based cohort who underwent methacholine challenges, were enrolled in the HMO at the time of the methacholine challenge, and had negative responses to questions designed to detect asthma. Children were excluded from analysis based on a diagnosis of asthma if their parents answered "yes" to the following questions during the medical examination:

1. Did a doctor ever tell you that your child had asthma?
   
2. Has your child had asthma in the past 12 months?
   

These questions were asked of all subjects in a standardized fashion using a survey instrument by the same board-certified pediatric allergist as part of a clinical examination. Similar questions are used in the validated American Thoracic Society (ATS) Childhood, International Study of Asthma and Allergies in Childhood, and National Health and Nutrition Examination Survey questionnaires.

Those children without a history of current or physician-diagnosed asthma at the time of the methacholine challenge were followed up until disenrollment from the HMO or through June 2001, whichever came first. Any medical visits or prescription drug purchases made during the analysis period would have been covered by the HMO minus the applicable copays. Medical visit copays typically cost the patient $15 to $20, with medication copays being $5 to $10. The HMO databases were analyzed for pharmacy claims and asthma-related diagnostic codes from physician-patient encounters (ie, emergency department, hospital, primary care, or specialist) over that time period.

Patients in incident cases of asthma were defined as any child with two outpatient visits or one hospitalization or one emergency department encounter associated with an asthma diagnostic code (International Classification of Diseases [ICD] codex 493.XX), or any child with two bronchodilator or one antiinflammatory asthma medicine prescription claim (including inhaled steroids, leukotriene antagonists, cromolyn sodium, or nedocromil during the follow-up period). Codes that might be associated with asthma or substituted for ICD code 493.XX were not used. Such ICD codes would include the following: 466.0, bronchitis, acute; 786.07, wheezing; 786.2, cough; and 786.05, shortness of breath. The asthma national drug code list for 2001 in the Health Plan Employer Data and Information Set from the National Committee for Quality Assurance was used to analyze the HMO database for asthma medicine pharmacy claims. The Human Rights Committee at Henry Ford Hospital approved all aspects of the original cohort study and this study.

Spirometry and Methacholine Challenge
Methacholine challenges were performed in children between the ages of 6 and 8 years. Lung function was recorded with a spirometer (KoKo; Pulmonary Data Service; Louisville, CO) connected to a personal computer and was calibrated daily with a 3-L syringe. The children were coached to engage in maximal forced expiratory maneuvers while standing and without the use of nose clips. Spirometry was performed in accordance with ATS standards.⁷ Predicted values were based on the equations of Polgar and Promadhat.⁸ Spirometry findings were considered to be acceptable if the child made a good effort and if two forced exhalation maneuvers showed reproducibility (±5%) for both FVC and FEV₁. If the child’s FEV₁ was 70% predicted and reproducible, the child was challenged with the normal saline solution diluent and then with five sequential doses of methacholine (ie, 0.025, 0.25, 2.5, 10, and 25 mg/mL) administered with a nebulizer (model 646; DeVilbiss Health Care Inc; Somerset, PA) connected to a French-Rosenthal-type dosimeter (Pulmonary Data Service). Spirometry was repeated 3 min after each dose of methacholine was administered. Increasing concentrations of methacholine were administered until the FEV₁ fell to < 80% of the best post saline solution value and remained below this level for at least 2 min or until the maximum concentration of methacholine was reached. Children who could not satisfactorily complete the challenge were excluded from analysis. ATS criteria for AHR were used to categorize the results of the methacholine challenge as follows: normal methacholine responsiveness (provocative concentration of a substance causing a 20% fall in FEV₁ [PC₂₀], > 16 mg/mL); borderline positive result (PC₂₀, 4 to 16 mg/mL); mild AHR (PC₂₀, 1 to < 4 mg/mL); and moderate-to-severe AHR (PC₂₀, < 1 mg/mL).⁹

Statistical Analysis
Odds ratios, 95% confidence intervals (CIs) , and p values were estimated using the Cox regression, with the methacholine group being the independent variable and clinical asthma being the dependent variable. The variables of gender, family history of asthma, parental smoking history, season of challenge, seroatopy (ie, any positive serum test result for allergen-specific IgE), and total IgE levels, all measured at 6 to 7 years of age, were added to the model to assess their impact on the relationship. (The methodology for allergen-specific IgE and total IgE measurements in this cohort has been described elsewhere.¹⁰) Since the total IgE level is highly variable and overlapping in healthy and atopic subjects,¹¹¹² we analyzed this factor as a continuous variable rather than assigning any specific cutoff value as a positive test result. Due to the differing lengths of follow-up and the resulting censored data, survival analysis was performed to evaluate asthma incidence in the baseline AHR borderline/positive groups compared to that in the baseline AHR negative group.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
There were 483 children in the original cohort who were evaluated at 6 to 8 years of age. Forty-five children did not undergo a methacholine challenge because they could not adequately perform spirometry, they had an FEV₁ < 70% predicted, or the parents refused the test. One hundred fifty-eight children were not members of the HMO at the time the methacholine challenges were performed. The remaining 280 children had evaluable methacholine challenges, with 35 of these children reporting a history of current or physician-diagnosed asthma. Thus, 245 children with no history of current asthma at baseline and a mean age of 6.72 years were included in the analysis (Table 1 ).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Our data suggest that AHR with a borderline or weakly positive result to methacholine challenge in children who were 6 to 8 years old without a history of current or physician-diagnosed asthma is not related to increased health-care utilization for asthma in the ensuing 5 years. The measurement of AHR is an objective test to screen for asthma, a relatively common disease with safe and effective available medical intervention. AHR is present in almost all patients with asthma, at least when they are experiencing symptoms.² A negative challenge test result in a patient with asthma-like symptoms can aid a clinician in excluding asthma from the diagnosis. However, a positive test result is limited in the diagnosis of asthma as the test is complicated by several factors including the variability of the challenge testing procedures,¹³ variation in AHR over time,^41415161718 and the association of a positive challenge result with other nonasthmatic disorders. For example, AHR is increased with a variety of environmental stimuli including viral respiratory infections,¹⁹ air pollutants,²⁰²¹ and active and passive cigarette smoke exposure.²²²³²⁴ AHR is also seen in other childhood disease states such as allergic rhinitis,²⁵ cystic fibrosis,²⁶ and bronchopulmonary dysplasia,²⁷ and among healthy subjects with an atopic family history.²⁵ Less clear is the association of AHR with either specific allergic sensitization or total IgE level, with some studies concluding a positive relationship²⁸²⁹ and others failing to show an association.³⁰³¹³² Overall, a single measurement of AHR at an arbitrary point in time may be influenced by the above stimuli or other disease states, impairing its usefulness as a screening tool with which to accurately identify subjects who are at risk of future asthma.

Several investigators have studied asymptomatic subjects with evidence of AHR for future asthma-like symptoms but not incident asthma diagnosis. Peat and colleagues⁴ observed 380 children who had undergone histamine challenges at age 8 to 10 years and had been evaluated on three occasions over a 4-year period. AHR was classified as severe (provocative dose of a substance causing a 20% fall in FEV₁ [PD₂₀], 0.1 µmol), moderate (PD₂₀, 0.11 to 0.8 µmol), mild (PD₂₀, 0.81 to 3.2 µmol), slight (PD₂₀, 3.21 to 7.8 µmol), and normal responsiveness (PD_20, > 7.8 µmol). The researchers found that over a 4-year period children assigned to the severe or moderate AHR group were more likely to have asthma symptoms (eg, wheeze, exercise wheeze, or night cough) when compared to children assigned to the other groups. These authors stressed the importance of the severity of AHR in predicting continuing respiratory morbidity. Since our study did not include a moderate-to-severe AHR group, we could not provide comment confirming or refuting their conclusions.

Hopp and colleagues³³ studied whether increased bronchial reactivity exists prior to the development of asthma. They reported on 13 asthma-free siblings (mean [± SD] age, 10.6 ± 4.2 years) of children with asthma who had participated in the larger ongoing study of the natural history of asthma. Over a 3-year period, these children developed asthma, as determined by the National Heart, Lung, and Blood Institute respiratory questionnaire. Prior to the onset of asthma, 10 of 13 children had positive responses to methacholine (ie, < 208 breath units with asthmatic range airways responsiveness estimated to be a cumulative methacholine dose of < 800 breath units). Compared to age-matched and sex-matched control subjects from nonasthmatic families, these 13 children had higher methacholine responsiveness (p = 0.025). However, there was no difference in AHR between these children and control subjects from asthmatic families. The authors concluded that enhanced AHR usually precedes the development of asthma in genetically susceptible individuals, which contrasted with our study showing no association between AHR and future asthma development. The discrepant results may be due to the fact that all 13 subjects had a positive family history of asthma.

Several cohort studies have supported the ascertainment by Hopp and colleagues³³ of increased AHR prior to the diagnosis of asthma. The East Boston Childhood Respiratory Disease Cohort³ included 121 children who were 5 to 9 years of age who were observed over a 5-year follow-up period for incident wheeze following one or more positive cold-air challenges. This group of children was free of asthma diagnosis and wheeze reports prior to the cold-air challenge. They found an elevated risk (odds ratio, 3.91; 95% CI, 1.21 to 12.66) for incident wheeze when comparing cold-air responders (ie, the 15% of patients with the greatest responsiveness) to nonresponders (ie, the remaining 85% of subjects) after adjustment for passive and personal smoking, any lower respiratory tract infection prior to age 2 years, age, gender, atopy, and family history of atopy. Thus, there was an increased risk for the development of an asthma-like symptoms (wheezing) in those nonasthmatic patients who had a positive cold-air challenge result. It is difficult to equate the cold-air challenge method employed in this study to a specific level of methacholine responsiveness. This may potentially explain the seemingly discrepant conclusion of our investigation.

Burrows and colleagues⁵ addressed the possible need for repeat measurements of AHR to predict future asthma-like symptoms in the Dunedin, New Zealand, cohort. This study involved repeated methacholine challenges in 573 children at ages 9, 11, 13, and 15 years. AHR was categorized as severe (PC₂₀, < 2.5 mg/mL), moderate (PC₂₀, 2.5 to < 8 mg/mL), mild (PC₂₀, 8.0 to < 25 mg/mL), and normal (PC₂₀, > 25 mg/mL). In addition, children who had a low FEV₁ (< 70% predicted) or who were having asthma symptoms were given salbutamol. All of these children who had low FEV₁ values or were symptomatic exhibited a > 10% improvement in FEV₁ and were included in the moderate-to-severe AHR group for the purpose of analysis. They found considerable variability in the degree of AHR over the course of the study in many children and concluded that nonresponsive children at age 15 years had more frequent wheezing and ventilatory abnormalities if they had any previous positive challenge results. However, consistent with our findings, the authors concluded that a single measurement of AHR taken at an arbitrary time may be misleading. An extension of the observations of this cohort to age 26 years has also been published by Rasmussen and colleagues.³⁴ Forty-one subjects with a positive methacholine response (PC₂₀ for methacholine, < 8 mg/mL) at age 9 years who denied ever having wheezing were compared with 506 asymptomatic study members without AHR. Those with AHR at age 9 years were more likely to have reported incident asthma at age 26 years than were subjects in the normal group (odds ratio, 4.0; 95% CI 1.1 to 14.6). Furthermore, the association with self-reported asthma was greatly strengthened (odds ratio, 10.9; 95% CI, 2.6 to 46) if AHR was observed on more than one occasion between the ages of 9 and 15 years. The differing conclusion of our study could be attributed to the differences in the ages at which AHR and asthma were measured.

Finally, observations from the Perth, Australia, birth cohort³⁵ revealed that at age 6 years the majority of asymptomatic children exhibit a fall in FEV₁ exceeding 20% at a level of 7.8 mg/mL. The investigators argued that in children, the test may have to be interpreted with methacholine level cut points that are much lower than those traditionally used for adults. If interpreted by the criteria used in our study, > 60% of asymptomatic children from that cohort would have had mild AHR. Furthermore, although the Perth study did not assess incident asthma after the challenge procedure, the mean PC₂₀ in 440 children without a history of asthma was 2.18 mg/mL, whereas in 80 children with asthma the PC₂₀ averaged 1.37 mg/mL. Thus, the Perth study³⁵ suggests that children with moderate-to-severe AHR are an important group to study.

The above-cited studies suggest that asymptomatic children who have persistent or severe AHR, whether determined via methacholine, histamine, or cold-air challenge, are more likely to develop asthma. Although not all studies used methacholine as the challenge agent, the cited studies that did use methacholine suggested that those subjects with a high degree of AHR were associated with the greatest risk for the development of asthma. In our study, no subject at age 6 years, without a history of asthma, exhibited moderate or severe AHR (methacholine PC₂₀, < 1 mg/mL). Therefore, it is not possible to confirm the association of incident asthma with a high degree of AHR. However, our data suggest that patients with a lesser degree of AHR (PC₂₀, between 1 and 16 mg/mL) are not at increased risk of incident asthma.

This study differs from previous reports in that we analyzed actual asthma-related health-care and pharmacy usage, whereas previous studies relied on patient recall. The use of claims data eliminates recall bias that may have been present in the previous follow-up questionnaire-based studies. We chose to evaluate medication claims and asthma-related diagnostic codes because they would accurately identify children with an overall clinical picture that was consistent with the disease state.³⁶ In addition, asthma-related medication use would identify children whose physicians may have been reluctant to label them as "asthmatic." Although our criteria may miss cases of mild asthma in patients not requiring health-care services or prescription medication, they do identify those patients whose symptoms are sufficient to trigger physician evaluation and may indicate a worse prognosis. The age at which we conducted the methacholine challenge was generally younger than that in many published studies. This may be important in interpreting the results, as children may exhibit a greater degree of AHR to methacholine than adults,³⁷³⁸ although this phenomenon has not been universally accepted.³⁹

Our study had several limitations. The cohort evaluated for this study is predominately a white population in a limited geographic location in the Midwest region of the United States, which may limit the ability to generalize our findings to other ethnic groups and environments. The sample size for this study allowed for the analysis of the relatively large proportion of asymptomatic patients who exhibited normal, borderline, or mild AHR. A major limitation was the lack of asymptomatic patients with moderate-to-severe AHR, which would have helped us to quantify the relationship between the degree of AHR and incident asthma.

Our definition of incident asthma also has some limitations in regard to coding. To apply a 493.XX code, a medical provider would have to possess a high index of suspicion that the clinical presentation was most consistent with asthma in comparison with other diagnostic possibilities. Other codes that attribute symptoms to an alternative diagnosis such as bronchitis, wheezing, cough, or shortness of breath could have been used for children with asthma but also for nonasthmatic children. The additional diagnostic uncertainty that would be introduced by broadening the diagnostic codes would result in misclassification and would reduce the validity of the incidence estimates. The inclusion of these diagnoses would be unlikely to systematically influence our results since the diagnosing and treating medical providers were unaware of the methacholine challenge results. Therefore, we chose to limit our diagnostic definition of asthma to include only asthma diagnostic codes and asthma medication usage.

Analysis of a claims database can also be problematic due to pertinent data that are not captured. For example, health-care utilization data billed to secondary insurance or cash payment for services and medicines would not be captured in our database. In addition, financial burdens may influence the decision to seek medical services. All medical visits (including those for testing and laboratory work) or prescription drug purchases during the analysis period would have been covered by the HMO minus any applicable copays. Medical visit copays were typically $15 to $20, with medication copays of $5 to $10. However, these limitations would be unlikely to introduce bias into the analysis since there would be no reason they would preferentially affect children based on the degree of AHR. Data lost due to children losing or changing medical insurance were not included in the analysis once that change had occurred.

Our study suggests that a methacholine challenge test in nonasthmatic children is unlikely to provide useful clinical information regarding a future diagnosis of asthma. In a group of 245 6-year-old children without current or physician-diagnosed asthma, we did not find any subjects with moderate-to-severe AHR. Although children with a high degree of AHR may have been excluded due to a previous asthma diagnosis, the absence of such patients in our study precludes any analysis of asthma onset in this subset of patients. Previous studies⁴⁵ have suggested that subjects with severe, persistent AHR may have the greatest likelihood of having continued respiratory problems, although our study suggests that nonasthmatic children who are 6 to 8 year old with a high degree of AHR are rare in the general population. In summary, our investigation suggests that nonasthmatic children who are 6 to 8 years old with borderline or weakly positive methacholine AHR do not have increased medical provider visits for asthma or prescription asthma medication use in the ensuing 5 years.

	Footnotes

 
Abbreviations: AHR = airway hyperresponsiveness; ATS = American Thoracic Society; CI = confidence interval; HMO = health maintenance organization; ICD = International Classification of Diseases; PC₂₀ = provocative concentration of a substance causing a 20% fall in FEV₁; PD₂₀ = provocative dose of a substance causing a 20% fall in FEV₁; RR = relative risk

Received for publication November 7, 2004. Accepted for publication May 2, 2005.

	References

TOP Abstract Introduction Materials and Methods Results Discussion References

 

1. Eigen, H, Bieler, H, Grant, D, et al (2001) Spirometric pulmonary function in healthy preschool children. Am J Respir Crit Care Med 163,619-623[Abstract/Free Full Text]
2. Lotvall, J, Inman, M, O’Byrne, P Measurement of airway hyperresponsiveness: new considerations. Thorax 1998;53,419-424[Free Full Text]
3. Carey, VJ, Scott, TW, Tager, IB, et al Airways responsiveness, wheeze onset, and recurrent asthma episodes in young adolescents: the East Boston Childhood Respiratory Disease Cohort. Am J Respir Crit Care Med 1996;153,356-361[Abstract]
4. Peat, JK, Salome, CM, Sedgwick, CS, et al A prospective study of bronchial hyperresponsiveness and respiratory symptoms in a population of Australian school children. Clin Exp Allergy 1989;19,299-306[CrossRef][ISI][Medline]
5. Burrows, B, Sears, MR, Flannery, EM, et al Relation of the course of bronchial responsiveness from age 9 to age 15 to allergy. Am J Respir Crit Care Med 1995;152,1302-1308[Abstract]
6. Ownby, DR, Johnson, CC, Peterson, EL Maternal smoking does not influence cord serum IgE or IgD concentrations. J Allergy Clin Immunol 1991;88,555-560[CrossRef][ISI][Medline]
7. Crapo, RO, Hankinson, JL, Irvin, C, et al Standardization of spirometry: 1994 update. Am J Respir Crit Care Med 1995;152,1107-1136[ISI][Medline]
8. Polgar, G, Promadhat, V Pulmonary function testing in children: techniques and standards. 1971,92-95, WB Saunders. Philadelphia, PA: 109–113, 123–125, 131–135, 153–155, 178–191, 208–212, 254
9. American Thoracic Society. Guidelines for methacholine and exercise testing: 1999. Am J Respir Crit Care Med 2000;161,309-329[Free Full Text]
10. Ownby, DR, Johnson, CC, Peterson, EL Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years. JAMA 2002;288,963-972[Abstract/Free Full Text]
11. Klink, M, Cline, MG, Halonen, M, et al Problems in defining normal limits for serum IgE. J Allergy Clin Immunol 1990;85,440[CrossRef][ISI][Medline]
12. Omenaas, E, Bakke, P, Elsayed, S, et al Total and specific serum IgE levels in adults: relationship to sex, age and environmental factors. Clin Exp Allergy 1994;24,530-539[CrossRef][ISI][Medline]
13. Chinn, S Methodology of bronchial responsiveness. Thorax 1998;53,984-988[Free Full Text]
14. Stanescu, DC, Frans, A Bronchial asthma without increased airway reactivity. Eur J Respir Dis 1982;63,5-12[Medline]
15. Grol, MH, Postma, DS, Vonk, JM, et al Risk factors from childhood to adulthood for bronchial hyperresponsiveness at age 32-42 years. Am J Respir Crit Care Med 1999;160,150-156[Abstract/Free Full Text]
16. Redline, S, Tager, FE, Speizer, B, et al Longitudinal variability in airway responsiveness in a population-based sample of children and young adults. Am Rev Respir Dis 1989;140,172-178[Medline]
17. Josephs, LK, Gregg, I, Mullee, MA, et al Non-specific bronchial reactivity and its relationship to the clinical expression of asthma: a longitudinal study. Am Rev Respir Dis 1989;140,350-357[Medline]
18. Backer, V, Groth, S, Dirksen, A Spontaneous changes in bronchial responsiveness in children and adolescents: an 18 month study. Pediatr Pulmonol 1991;11,22-28[ISI][Medline]
19. Empey, DW, Laitinen, LA, Jacobs, L, et al Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976;113,131-139[ISI][Medline]
20. Holtzman, MJ, Fabbri, LM, O’Byrne, PM, et al Importance of airway inflammation for hyperresponsiveness induced by ozone. Am Rev Respir Dis 1983;123,320-326
21. Orehek, J, Massari, JP, Gayrard, P, et al Effect of short-term, low-level nitrogen dioxide exposure on bronchial sensitivity of asthmatic patients. J Clin Invest 1976;57,301-307[ISI][Medline]
22. Malo, JL, Filiatrault, S, Martin, RR Bronchial responsiveness to inhaled methacholine in young asymptomatic smokers. J Appl Physiol 1982;52,1464-1470[Abstract/Free Full Text]
23. Young, S, Le Souef, PN, Geelhoed, GC, et al The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy. N Engl J Med 1991;324,1168-1173[Abstract]
24. Martinez, FD, Antognoni, G, Macri, F, et al Parental smoking enhances bronchial responsiveness in nine-year-old children. Am Rev Respir Dis 1988;138,518-523[ISI][Medline]
25. Townley, RG, Bewtra, AK, Nair, NM, et al Methacholine inhalation challenge studies. J Allergy Clin Immunol 1979;64,569-574[CrossRef][ISI][Medline]
26. Van Asperen, P, Mellis, CM, South, RT, et al Bronchial reactivity in cystic fibrosis with normal pulmonary function. Am J Dis Child 1981;135135,815-819
27. Northway, WH, Moss, RB, Carlisle, KB, et al Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 1990;323,1793-1799[Abstract]
28. Kono, M, Mochizuki, H, Arakawa, H, et al Age-dependent relationship between bronchial hyperresponsiveness to methacholine and total serum IgE level in asthmatic children. Ann Allergy Asthma Immunol 2001;87,33-38[Medline]
29. Beeh, KM, Ksoll, M, Buhl, R Elevation of total serum immunoglobulin E is associated with asthma in nonallergic individuals. Eur Respir J 2000;16,609-614[Abstract]
30. Takeda, K, Shibasaki, M, Takita, H Relation between bronchial responsiveness to methacholine and levels of IgE antibody against Dermatophagoides farinae and serum IgE in asthmatic children. Clin Exp Allergy 1992;23,450-454
31. Jansen, DF, Rijcken, B, Schouten, JP The relationship of skin test positivity, high serum total IgE levels, and peripheral blood eosinophilia to symptomatic and asymptomatic airway hyperresponsiveness. Am J Respir Crit Care Med 1999;159,924-931[Abstract/Free Full Text]
32. Oettgen, HC, Geha, RS IgE regulation and roles in asthma pathogenesis. J Allergy Clin Immunol 2001;107,429-440[CrossRef][ISI][Medline]
33. Hopp, RJ, Townley, RG, Biven, RE, et al The presence of airway reactivity before the development of asthma. Am Rev Respir Dis 1990;141,2-8[ISI][Medline]
34. Rasmussen, F, Taylor, RD, Flannery, EM, et al Outcome of asymptomatic airway hyperresponsiveness in childhood: a longitudinal population study. Pediatr Pulmonol 2002;34,164-171[CrossRef][ISI][Medline]
35. Joseph-Bowen, J, DeKlerk, NH, Firth, MJ, et al Lung function, bronchial responsiveness, and asthma in a community cohort of 6-year-old children. Am J Respir Crit Care Med 2004;169,850-854[Abstract/Free Full Text]
36. Isken, N, Joseph, CL, Lamerato, L, et al The Chronic Care Performance Measures Project on Childhood Asthma prepared for the National Committee on Quality Assurance: funded by the Robert Wood Johnson Foundation. 1997,8 National Committee on Quality Assurance. Washington, DC:
37. Hopp, RJ, Bewtra, A, Nair, NM, et al The effect of age on methacholine response. J Allergy Clin Immunol 1985;76,609-613[CrossRef][ISI][Medline]
38. Montgomery, GL, Tepper, RS Changes in airway reactivity with age in normal infants and children. Am Rev Respir Dis 1990;142,372-376
39. Peat, JK, Toelle, BG, Mellis, CM Problems and possibilities in understanding the natural history of asthma. J Allergy Clin Immunol 2000;106,S144-S151[CrossRef][Medline]

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Siwik, J. P. Articles by Zoratti, E. M. Search for Related Content PubMed PubMed Citation Articles by Siwik, J. P. Articles by Zoratti, E. M.