Both the late asthmatic response (LAR) and nocturnal bronchial obstruction are based on airway inflammation; however, definite airway inflammation following antigen inhalation does not necessarily cause LAR in anesthetized animals with acquired sensitization, and airway inflammation alone cannot explain the mechanism of LAR. In asthmatic patients who have LAR following bronchial provocation, a further increase in bronchial responsiveness is associated with LAR, and it already starts to increase around 2 h after the provocation, obviously preceding actual bronchial obstruction of the LAR. The increase in bronchial responsiveness also affects circadian variation of bronchial caliber. Generally, an upward arm of circadian variation of bronchial caliber in asthmatic patients continues until early afternoon. Its downward arm starts from late afternoon and terminates between late night and early morning. The magnitude of this circadian variation increases further as bronchial responsiveness increases. Even a single exposure to antigen increases the maximum bronchocon-strictive response, as well as bronchial responsiveness, and amplifies the circadian variation of bronchial caliber with nocturnal exacerbation. Furthermore, the Denver group demonstrated that the LAR following morning bronchial provocation occurs later than the one following evening provocation. Taken together, these raise the possibility that further transiently amplified circadian variation of bronchial caliber following bronchial provocation may have a relationship to the LAR, and the downward arm of such variation may participate in causing the LAR in asthmatic patients.
If that is true, maximum bronchial obstruction (maximum LAR) may range between late night and early morning, when bronchial obstruction based on the circadian variation usually becomes most severe, regardless of when the bronchial provocation is made and also regardless of when the bronchial obstruction starts. To confirm the possibility, antigen inhalation was made at 10 am and 6 pm on separate days in 6 children with stable asthma. The hour of maximum bronchial obstruction (maximum LAR) was assessed through measurements of FEV, at 4-h intervals from 24 h before to 24 h after the inhalation to see its consistency with the trough of nocturnal bronchial obstruction.
The group studied consisted of 6 children with stable asthma (4 boys and 2 girls) aged 8 to 13 years (Table 1). They all met the criteria of the American Thoracic Society for the diagnosis of asthma and had an intradermal reaction of 10 mm or more of wheal to 0.02 ml of either a 1:100,000 or 1:10,000 (weight/volume) house-dust solution (Torii Co, Tokyo, Japan). The children were staying in a residential treatment center because of uncontrollable asthma at their home. They performed spirometry almost every morning except for Sunday morning. The coefficient of variation (CV) of the 5 consecutive morning FEV, values before the beginning of each challenge study was less than 5 percent in all patients. No child was steroid-dependent, and none had had a respiratory tract infection for at least 6 weeks before the study. The patients stayed indoors quietly except for a walk around the center throughout the study. Although they went to bed at 8:30 pm and got up at 6 am, they could lie down for a rest at any time they wanted.
Six other patients were studied; however, they were excluded from the study because three had an immediate asthmatic response (1AR) following the antigen inhalation, and three did not have a LAR after the morning challenge.
Written consent was given by each parent. The protocol was approved by the Clinical Research Committee, Childrens Asthmatic Center, Kawasaki City Ida Hospital.
Table 1—Characteristics of Patients
|Patient, Sex, Age (yr)||Height,cm||Dose of Inhaled House-dust Solution, ml||MaintenanceMedication|
|1, M, 11||139||0.3||Ketotifen|
|2, M, 12||147||0.5||Cromolyn sodium|
|4, M, 12||140||0.3||Ketotifen|
|5, F, 11||150||0.5||Cromolyn sodium|
|6, M, 13||145||0.3||Ketotifen|