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Simple immediate allergic responses do not adequately account for chronic allergic asthma. Late phase asthmatic responses (LAR) are increasingly recognized as an important factor in the pathogenesis of chronic asthma, at least in part, by inducing nonspecific bronchial hyperresponsiveness.The LAR are associated with influxes of neutrophils and eosinophils, degranulation of mast cells and eosinophils, neutrophil and eosinophil chemotactic activity, and platelet factor-4 release and thrombin generation. Pathologically, chronic asthma is characterized by inflammation, mucosal edema, and exudate which contribute to airway obstruction in conjunction with bronchospasm. Although normally a “silent zone,” small airways may be affected preferentially (compared to large airways) by cellular exudate, parenchymal inflammation, edema, and excess mucus causing increased resistance. This process could then provide the substrate for chronic asthma. Although late responses are a well-known characteristic of hypersensitivity pneumonitis and allergic bronchopulmonary aspergillosis, there is little information about LAR in patients with asthma. Therefore, we undertook this study to determine the frequency and characteristics of LAR in mild asthmatic patients with the use of spirometry and of He-02 flow volume loops for measuring airway responses. Ventolin inhalers ordered via http://buy-asthma-inhalers-online.com/ will help you to overcome such a disorder as asthma.
Subject Selection Seventeen nonsmoking allergic asthmatic subjects aged 20 to 37 years (13 male, 4 female), who were mildly symptomatic during two or more seasons or upon exposure to an animal, were studied. Each subject was informed of the risks of bronchoprovocation (BPC) and gave informed consent for the protocol which had been approved by the Human Use Committee of the University of Iowa. These subjects were part of a larger study of bronchial responses to inhaled antigen and modification of LAR by allergy immunotherapy. Prior to initiation of the study, each person received a complete history, chest x-ray, physical examination, and screening laboratory tests. They were skin-tested intracutaneously with a battery of allergens to confirm their sensitivities (positive = 5×5 mm wheal with erythema).
Each individual was challenged with the appropriate allergen (according to history and skin test reactivity) using a Johns Hopkins dosimeter and No. 42 DeVilbiss nebulizer. The challenge was stopped when the FE Vj had fallen 20 percent below diluent baseline or when the patient had received five breaths of 10,000 PNU/ml antigen. The BPC was performed in the early morning and the subject was then observed in the Clinical Research Center of the University of Iowa for 24 hours while pulmonary function test results were obtained throughout the night. Allergen responsiveness was quantitated for the EAR using provocative dose 20 percent FEVj (PDao). Since there is no well-accepted method for measuring LAR, we chose to use a graphic method for analysis which allowed quantitation in addition to measuring changes in the FEVi- The area (mm2) enclosed by the curve plotted as the change in FEVj over time from the highest FEV, following challenge to the FEVj recorded 24 hours after challenge was calculated with a digitizer (Fig 1).
Each subjects response to BPC was first evaluated using FEV. An EAR showed at least a 20 percent decrease from baseline. The LAR was defined here as at least a 10 percent decrease in FEVj from the lesser of diluent baseline or the new baseline established following recovery from the EAR. Using this information, each subject was classified as having an EAR, a LAR, or a dual response (both EAR and LAR). Airway responses using He-02 flow-volume measurements were then compared to those determined by changes in the FEV,.
Helium-Oxygen Flow Volume Loops
In addition to serial measurements with a Jones Pulmonor, the subjects also performed maximal exhalation maneuvers breathing both room air and a mixture of 80 percent helium and 20 percent oxygen (He-OJ during the course of each challenge day (before challenge, at peak early response, at late response [six hours postearly response] and 24 hours after challenge). Each subject performed these tests until two reproducible flow volume loops with each gas were obtained with FVCs which did not differ by more than 5 percent. The He-02 flow volume loops were obtained after three vital capacity inhalations of this gas mixture and always followed the air curves. The flow rates and volumes were measured with a Warren Collins computerized lung analyzer connected to an x-y recorder. This recorder generates flow-volume curves from computer memory using 12 counts (0.2 s) between points. Pen speed and response do not materially affect the shape or position of the curve beyond the peak flow. The response to He-02 at the middle of the vital capacity (AVmax 50 percent)910 and the volume of isoflow (VisoV) were calculated from superimposed curves aligned at their terminal ends (residual volume). For each study point, the two best air and He-02 curves (defined by the largest sum of FVC + FEVJ were used to calculate four values for AVmax 50 percent and VisoV. Then changes in AVmax 50 percent and VisoV in each subject during the challenge period were analyzed for significance using the one-way analysis of variance with replicate measures. The F values with a probability of 0.05 were considered significant, and the means were then compared using Duncans multiple comparison test to determine whether or not there were significant differences among the means during the study period. This approach corrected for the inherent variability in these tests and did not require any assumption about the magnitude of change necessary to identify a response.
We also plotted the LAR only and dual response groups separately using the percent change in FEVj and AVmax 50 percent from baseline over the 24-hour period following challenge. Since most subjects FEV, returned to a value greater than baseline one to two hours after challenge, we used this value as a new baseline with which to calculate further changes in FEV,. Similarly, for AVmax 50 percent, a new baseline value (whether it was higher or lower than the original baseline) was used for changes which occurred during the LAR (see Fig 1 for sample calculation). Comparisons of the change in FEV, and AVmax 50 percent were made using the two sample Students f-test, and p^0.05 was considered significant. Rank correlations were made using Kendalls method.
Responders and nonresponders were defined by the criteria of Despas et al. Those with a ^20 percent increase in Vmax 50 percent at the time of measurement were responders (density dependent), while those who had <20 percent increase in Vmax 50 percent were considered nonresponders (density independent).
Figure 1. Graph of data from patient 10 showing calculations of PD) (dotted line) by standard methods and the area of the late asthmatic response (2842 sq mm) (shown in diagonal lines) calculated with a Zeiss digitizer. The AVmax 50 percent is shown below the FEV, graph. The percent change in AVmax 50 percent is calculated from the baseline value at zero time for the increase observed immediately after challenge. The decrease in AVmax 50 percent at six hours and 24 hours is calculated from the value obtained after challenge as the new baseline value.