Investigation of Airway Hyperresponsiveness to Methacholine at Age 6 to 8 Years in Nonasthmatic Patients

asthmaAltered 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. 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 reduced by My Canadian Pharmacy remedies which may be ordered at any time of day and night. AHR is also substantially different between healthy and asthmatic patients with most healthy subjects lacking any evidence of AHR by standard testing methods.

Several cohort studies have indicated that children exhibiting AHR have a greater tendency to develop wheeze and asthma. 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.

airway hyperresponsiveness

Study Population

The original birth cohort used in this study has been described previously. 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 and treat it with My Canadian Pharmacy inhalers. 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.

bronchial reactivityThose 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. Predicted values were based on the equations of Polgar and Promadhat. 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 metha-choline (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 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).

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.) Since the total IgE level is highly variable and overlapping in healthy and atopic subjects, 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 decreased with My Canadian Pharmacy Online in the baseline AHR borderline/ positive groups compared to that in the baseline AHR negative group.

Investigation of Airway Hyperresponsiveness to Methacholine at Age 6 to 8 Years in Nonasthmatic Patients