Spectrum of Asthma in Children—III,Psychological and Social Components

Behavioural disturbances in the child, the mother-child and family relationships, and the family social structure were studied in a representative sample of the whole range of asthmatic children and compared with a control group of normal children. Behavioural disturbances occurred more often and at a statistically significant level only in the small group of children with severe and continuing asthma. These children were those with severe chronic airways obstruction as assessed physiologically and also with the most severe allergic manifestations.Predominant in the mother-child relations was an over-concern to protect the child''s health in those children with continuing asthma at 14 years of age. The families of the very severely affected group of children showed evidence of more stress than other families. Socioeconomic conditions were not significantly different in any group of asthmatic children compared with the control group.     

Respiratory syncytial virus predisposes mice to augmented allergic airway responses via IL-13-mediated mechanisms.

The development of severe childhood asthma may be influenced by several factors including environmental and infectious stimuli. The causal relationship between infectious viral responses, such as respiratory syncytial virus (RSV), and severe asthma during early childhood is unclear. In these studies, the ability for an initial RSV infection to exacerbate and promote a more severe asthmatic-type response was investigated by combining established murine models of disease. We examined the ability of RSV to induce exacerbation of allergic disease over a relatively long period, leading to development of severe airway responses including airway inflammation and hyperreactivity. The preferential production of IL-13 during a primary RSV infection appears to play a critical role for the exacerbation of cockroach allergen-induced disease. The depletion of IL-13 during RSV infections inhibited the exacerbation and acceleration of severe allergen-induced airway hyperreactivity. This was indicated by decreases in airway hyperreactivity and changes in lung chemokine production. These data suggest that the airway responses during asthma can be greatly affected by a previous RSV infection, even when infection occurs before allergen sensitization. Overall, infection of the airways with RSV can induce an IL-13-dependent change in airway function and promotes an environment that contributes to the development of severe allergic asthmatic responses.     

Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation.

Five to ten percent of asthma cases are poorly controlled chronically and refractory to treatment, and these severe cases account for disproportionate asthma-associated morbidity, mortality, and health care utilization. While persons with severe asthma tend to have more airway obstruction, it is not known whether they represent the severe tail of a unimodal asthma population, or a severe asthma phenotype. We hypothesized that severe asthma has a characteristic physiology of airway obstruction, and we evaluated spirometry, lung volumes, and reversibility during a stable interval in 287 severe and 382 nonsevere asthma subjects from the National Heart, Lung, and Blood Institute Severe Asthma Research Program. We partitioned airway obstruction into components of air trapping [indicated by forced vital capacity (FVC)] and airflow limitation [indicated by forced expiratory volume in 1 s (FEV(1))/FVC]. Severe asthma had prominent air trapping, evident as reduced FVC over the entire range of FEV(1)/FVC. This pattern was confirmed with measures of residual lung volume/total lung capacity (TLC) in a subgroup. In contrast, nonsevere asthma did not exhibit prominent air trapping, even at FEV(1)/FVC <75% predicted. Air trapping also was associated with increases in TLC and functional reserve capacity. After maximal bronchodilation, FEV(1) reversed similarly from baseline in severe and nonsevere asthma, but the severe asthma classification was an independent predictor of residual reduction in FEV(1) after maximal bronchodilation. An increase in FVC accounted for most of the reversal of FEV(1) when baseline FEV(1) was <60% predicted. We conclude that air trapping is a characteristic feature of the severe asthma population, suggesting that there is a pathological process associated with severe asthma that makes airways more vulnerable to this component.     

Bacteria in sputum of stable severe asthma and increased airway wall thickness

Background

Patients with chronic asthma have thicker intrapulmonary airways measured on high resolution computed tomography (HRCT). We determined whether the presence of lower airway bacteria was associated with increased airway wall thickness.

Methods

In 56 patients with stable severe asthma, sputum specimens obtained either spontaneously or after induction with hypertonic saline were cultured for bacteria and thoracic HRCT scans obtained. Wall thickness (W_T) and area (W_A) expressed as a ratio of airway diameter (D) and total area, respectively, were measured at five levels.

Results

Positive bacterial cultures were obtained in 29 patients, with H. influenzae, P. aeruginosa and S. aureus being the commonest strains. Logistic regression analysis showed that this was associated with the duration of asthma and the exacerbations during the past year. In airways > 2 mm, there was no significant difference in W_A (67.5 ± 5.4 vs 66.4 ± 5.4) and W_T/D (21.6 ± 2.7 vs 21.3 ± 2.4) between the culture negative versus positive groups. Similarly, in airways (≤ 2 mm), there were no significant differences in these parameters. The ratio of √wall area to P_i was negatively correlated with FEV₁% predicted (p < 0.05).

Conclusions

Bacterial colonization of the lower airways is common in patients with chronic severe asthma and is linked to the duration of asthma and having had exacerbations in the past year, but not with an increase in airway wall thickness.     

Plasminogen activator inhibitor-1 in the pathogenesis of asthma

Plasminogen activator inhibitor (PAI)-1 is the main inhibitor of the fibrinolytic system and is known to play an essential role in tissue remodeling. Recent evidence indicates that chronic asthma may lead to tissue remodeling such as subepithelial fibrosis and extracellular matrix (ECM) deposition in the airways. However, the role of PAI-1 in asthma is unknown. Recently the mast cell (MC), which plays a major role in asthma, was found as a novel source of PAI-1, and a large number of MCs expressing PAI-1 are infiltrated in the airways of patients with severe asthma. Furthermore, PAI-1-deficient mice show reduced ECM deposition in the airways of a murine model of chronic asthma by inhibiting MMP-9 activity and fibrinolysis. In a human study, the 4G allele frequency was significantly higher in the asthmatic patients than in the control group. In view of the findings that the 4G allele is associated with elevated plasma PAI-1 level, elevated PAI-1 level in the lung may contribute to the development of asthma. In summary, PAI-1 may play an important role in the pathogenesis of asthma and further studies evaluating the mechanisms of PAI-1 action may lead to the development of a novel therapeutic target for the treatment and prevention of asthma.     

A major outbreak of asthma associated with a thunderstorm: experience of accident and emergency departments and patients' characteristics. Thames Regions Accident and Emergency Trainees Association.

OBJECTIVE--To investigate the time course of an epidemic of asthma after a thunderstorm, characteristics of patients affected, and the demand on emergency medical resources. DESIGN--Study of registers and records in accident and emergency departments and questionnaire to staff. SETTING--London area. SUBJECTS--All patients presenting at 12 accident and emergency departments with asthma or other airway disease. MAIN OUTCOME MEASURES--Numbers of patients, clinical features, information on shortage of resources--equipment, drugs and staff. RESULTS--The epidemic had a sudden onset on 24 June 1994; 640 patients with asthma or other airways disease attended during 30 hours from 1800 on 24 June, nearly 10 times the expected number. Over half (365) the patients were aged 21 to 40 years. A history of hay fever was recorded in 403 patients; for 283 patients this was the first known attack of asthma; a history of chronic obstructive airways disease was recorded in 12 patients. In all, 104 patients were admitted (including five to an intensive care unit). Several departments ran out of equipment or drugs, called in additional doctors, or both. CONCLUSIONS--This study supports the view that this epidemic was larger than previously reported epidemics and the hypothesis that "thunderstorm associated asthma'' is related to aeroallergens. Demands on resources were considerable; a larger proportion of patients needing intensive care would have caused greater problems.     

Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia

Abstract

Potential bacterial pathogens are found in the airways in several diseases that are associated with neutrophilic inflammation. The aim of this study was to characterize subjects with stable asthma, with no symptoms of respiratory infection, to assess whether key potentially pathogenic bacteria were present in significant quantities in the airways and to correlate this with the pattern of airway inflammation and oxidative stress. Subjects with stable asthma (n = 115) and healthy controls (n = 8) underwent clinical assessment, including hypertonic saline challenge combined with sputum induction. A significant load of potentially pathogenic bacteria (> 10⁶ cfu/mL) was cultured from the sputum of 17 (15%) subjects with stable asthma and was associated with higher total cell counts, proportion and number of neutrophils, sputum IL-8 and 8-isoprostane concentrations. The role of bacteria in potentiating neutrophilic asthma warrants further investigation. Therapies such as antibiotic and antioxidant treatment may be most effective in this sub-group of patients.     

Airway Microbiota in Severe Asthma and Relationship to Asthma Severity and Phenotypes

BackgroundThe lower airways harbor a community of bacterial species which is altered in asthma.ObjectivesWe examined whether the lower airway microbiota were related to measures of asthma severity.MethodsWe prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed.ResultsWe obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P = 2.8x10^-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR = 2.26; 95% CI = 1.94–2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR = 2.15; 95%CI = 1.89–2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia.ConclusionsSputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.     

Bronchial Thermoplasty: A Novel Therapeutic Approach to Severe Asthma

Bronchial thermoplasty is a non-drug procedure for severe persistent asthma that delivers thermal energy to the airway wall in a precisely controlled manner to reduce excessive airway smooth muscle. Reducing airway smooth muscle decreases the ability of the airways to constrict, thereby reducing the frequency of asthma attacks. Bronchial thermoplasty is delivered by the Alair System and is performed in three outpatient procedure visits, each scheduled approximately three weeks apart. The first procedure treats the airways of the right lower lobe, the second treats the airways of the left lower lobe and the third and final procedure treats the airways in both upper lobes. After all three procedures are performed the bronchial thermoplasty treatment is complete.Bronchial thermoplasty is performed during bronchoscopy with the patient under moderate sedation. All accessible airways distal to the mainstem bronchi between 3 and 10 mm in diameter, with the exception of the right middle lobe, are treated under bronchoscopic visualization. Contiguous and non-overlapping activations of the device are used, moving from distal to proximal along the length of the airway, and systematically from airway to airway as described previously. Although conceptually straightforward, the actual execution of bronchial thermoplasty is quite intricate and procedural duration for the treatment of a single lobe is often substantially longer than encountered during routine bronchoscopy. As such, bronchial thermoplasty should be considered a complex interventional bronchoscopy and is intended for the experienced bronchoscopist. Optimal patient management is critical in any such complex and longer duration bronchoscopic procedure. This article discusses the importance of careful patient selection, patient preparation, patient management, procedure duration, postoperative care and follow-up to ensure that bronchial thermoplasty is performed safely.Bronchial thermoplasty is expected to complement asthma maintenance medications by providing long-lasting asthma control and improving asthma-related quality of life of patients with severe asthma. In addition, bronchial thermoplasty has been demonstrated to reduce severe exacerbations (asthma attacks) emergency rooms visits for respiratory symptoms, and time lost from work, school and other daily activities due to asthma.Download video file.^{(90M, mov)}     

Spectrum of Asthma in Children—I,Clinical and Physiological Components

A sample of 315 asthmatic children, representative of the whole range of asthma in childhood, and a control group of 82 children were studied clinically and physiologically from 7 to 14 years of age. The asthmatic children were arbitrarily classified into four grades according to the relative frequency and persistence of their asthma to 14 years of age. Each of these grades could be more clearly defined on analysis of other clinical and physiological characteristics.The characteristics of severe persistent asthma were: onset usually in the first three years of life, a high frequency of attacks in the initial year, clinical and physiological evidence of persisting airways obstruction and pulmonary hyperinflation, chest deformity, and impairment of growth. By contrast, mild asthma usually began later in childhood, was episodic, and there was little or no evidence of airways obstruction between attacks. The attacks generally stopped before 10 years of age. In between these two extremes were two intermediate grades.The clinical and physiological characteristics of each grade of asthma at 14 years of age were usually evident by 10 years, and in the most severe grade by 7 years of age. These characteristics provide a sound basis for assessment, management, and prognosis.     

Decreased expression of uteroglobin-related protein 1 in inflamed mouse airways is mediated by IL-9

Uteroglobin-related protein 1 (UGRP1) is a secretory protein, highly expressed in epithelial cells of airways. Although an involvement of UGRP1 in the pathogenesis of asthma has been suggested, its function in airways remains unclear. In the present study, a relationship between airway inflammation, UGRP1 expression, and interleukin-9 (IL-9), an asthma candidate gene, was evaluated by using a murine model of allergic bronchial asthma. A severe airway inflammation accompanied by airway eosinophilia and elevation of IL-9 in bronchoalveolar lavage (BAL) fluids was observed after ovalbumin (OVA) challenge to OVA-sensitized mice. In this animal model of airway inflammation, lung Ugrp1 mRNA expression was greatly decreased compared with control mice. A significant inverse correlation between lung Ugrp1 mRNA levels and IL-9 levels in BAL fluid was demonstrated by regression analysis (r = 0.616, P = 0.023). Immunohistochemical analysis revealed a distinct localization of UGRP1 in airway epithelial cells of control mice, whereas UGRP1 staining was patchy and faint in inflamed airways. Intranasal administration of IL-9 to naive mice decreased the level of Ugrp1 expression in lungs. These findings suggest that UGRP1 is downregulated in inflamed airways, such as allergic asthmatics, and IL-9 might be an important mediator for modulating UGRP1 expression.     

Small airway inflammation in asthma

Asthma was originally described as an inflammatory disease that predominantly involves the central airways. Pathological and physiological evidence reported during the past few years suggests that the inflammatory process extends beyond the central airways to the peripheral airways and the lung parenchyma. The small airways are capable of producing T-helper-2 cytokines, as well as chemokines, and they have recently been recognized as a predominant site of airflow obstruction in asthmatic persons. The inflammation at this distal site has been described as more severe than large airway inflammation. These findings are of great clinical significance, and highlight the need to consider the peripheral airways as a target in any therapeutic strategy for treatment of asthma.     

Comparison of whole-blood eosinophil counts in extrinsic asthmatics with acute and chronic asthma.

Venous whole-blood eosinophil counts were performed on 50 occasions in 42 patients with varying patterns of asthma. None of the patients studied had received systemic corticosteroids during the previous year. Patients with acute severe asthma, as defined by symptomatic airways obstruction with a tachycardia of at least 120 beats/min, showed eosinopenia (21 x 10(9)/l +/- SD 57 x 10(9)/l). Patients with chronic asthma, as defined by symptomatic airways obstruction with a heart rate of less than 100 beats/min, showed appreciable eosinophilia (1048 x 10(9)/l +/- SD 708 x 10(9)/l). Finally, asymptomatic patients had a variable total eosinophil count but with values lower than those of patients with chronic asthma (345 x 10(9)/l +/- SD 431 x 10(9)/l). Eosinophilia may contain chronic asthma, thereby mediating bronchial damage, whereas absence of eosinophils in acute asthma enables vasoactive mediators to enter the systemic circulation, possibly causing circulatory disturbances.     

Assessment of Upper Airways Obstruction

An indication of obstruction to the upper airways (trachea and larynx) may be obtained by calculating the ratio of the forced expired volume in one second to the peak expiratory flow rate (FEV₁/PEFR). This index was found to be usually less than 10 in normal subjects (mean 7·3), and in patients with asthma (mean 6·9), chronic bronchitis (mean 7·7), or interstitial lung disease (mean 6·3). A study of simulated upper airways obstruction showed that this index rises as the obstruction becomes more severe. All of 18 patients with proved upper airways obstruction had FEV₁/PEFR indices greater than 10 (mean 14·0). This test can be carried out with forced expiratory manoeuvres only, and it does not require the use of complicated equipment. An FEV₁/PEFR ratio greater than 10, when upper airways obstruction is suspected, indicates that significant obstruction may be present. High values suggest that the obstruction may be severe, and that further investigations are indicated.     

Death from asthma in two regions of England

The British Thoracic Association has conducted a confidential inquiry into death from asthma of adults aged 15 to 64 years resident in the West Midland and Mersey regions in 1979. Information concerning the patients, their asthma, and death was obtained by questionnaire, interview with the general medical practitioner and a relative, and from patient records. A panel of three physicians, helped by a pathologist, identified 90 patients as dying of asthma and assessed management and treatment in the last year, last month of life, and the fatal attack. They were generally chronic asthmatics, but unstable, most having suffered severe attacks previously. Corticosteroids and bronchodilator drugs were in general underprescribed or not given in sufficiently large doses. Inhaled corticosteroids and cromoglycate had frequently not been tried. The patient''s co-operation with the management of the asthma was satisfactory for only 42 of the 90 patients. For 71 of the patients the fatal attack lasted under 24 hours; of the 77 who died at home or at work, 50 did not receive any medical attention in the fatal attack. Failure to recognise the severity of the asthma by patients, relatives, and doctor often caused delay in starting appropriate treatment. The interaction of several of these adverse factors often contributed to the patient''s death. The panel considered that there were potentially preventable factors contributory to the death of 77 (86%) of the 90 patients. Within the limits of retrospective judgment the panel considered that the routine management of the asthma was often unsatisfactory as patients known to suffer severe acute attacks were often not adequately supervised or instructed in the management and treatment of their asthma. From this retrospective inquiry we concluded that closer overall supervision, including careful attention to patient education, earlier and more intensive treatment, and pre-arranged immediate admission to hospital for asthma emergencies is desirable.     

Famine in the Young and Risk of Later Hospitalization for COPD and Asthma

Background

Undernutrition during critical periods of growth and development may permanently affect lung physiology and function.

Objectives

To investigate whether acute undernutrition in childhood or young adulthood increases the risk of later hospitalization for obstructive airways disease, chronic obstructive pulmonary disease (COPD), or asthma.

Methods

We studied 7,841 women from Prospect-EPIC who experienced the 1944–45 Dutch famine between ages 0 and 21. Pulmonary outcomes were measured by registered hospital admissions and exposure-blinded computed tomography (CT) in a subgroup of 295 women. With Cox proportional hazard regression we explored effects of famine exposure on risk of hospitalization for obstructive airways disease, COPD, and asthma. With logistic regression we explored effects of famine on risk of CT evidence of pulmonary disease.

Results

Risks of hospitalization for obstructive airways disease, COPD, and asthma were increased after moderate famine exposure, and significantly increased after severe famine exposure: hazard ratios for obstructive airways disease were 1.31 (95% CI: 0.97 to 1.77) and 1.57 (95% CI: 1.10 to 2.23) respectively. Associations between famine exposure and hospitalization for COPD were stronger in ever-smokers than in never-smokers.

Conclusions

Acute undernutrition in childhood or young adulthood is associated with an increased risk of later COPD and asthma hospitalization, possibly through increased sensitivity for tobacco smoke.     

Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions

Objective

Whether distal inflammation in asthmatics also leads to structural changes in the alveolar parenchyma remains poorly examined, especially in patients with uncontrolled asthma. We hypothesized that patients who do not respond to conventional inhaled corticosteroid therapy have a distinct tissue composition, not only in central, but also in distal lung.

Methods

Bronchial and transbronchial biopsies from healthy controls, patients with controlled atopic and patients with uncontrolled atopic asthma were processed for immunohistochemical analysis of fibroblasts and extracellular matrix molecules: collagen, versican, biglycan, decorin, fibronectin, EDA-fibronectin, matrix metalloproteinase (MMP)-9 and tissue-inhibitor of matrix metalloproteinase (TIMP)-3.

Results

In central airways we found increased percentage areas of versican and decorin in patients with uncontrolled asthma compared to both healthy controls and patients with controlled asthma. Percentage area of biglycan was significantly higher in both central airways and alveolar parenchyma of patients with uncontrolled compared to controlled asthma. Ratios of MMP-9/TIMP-3 were decreased in both uncontrolled and controlled asthma compared to healthy controls. In the alveolar parenchyma, patients with uncontrolled asthma had increased percentage areas of collagen, versican and decorin compared to patients with controlled asthma. Patients with uncontrolled asthma had significantly higher numbers of myofibroblasts in both central airways and alveolar parenchyma compared to patients with controlled asthma.

Conclusions

Tissue composition differs, in both central and distal airways, between patients with uncontrolled and controlled asthma on equivalent doses of ICS. This altered structure and possible change in tissue elasticity may lead to abnormal mechanical properties, which could be a factor in the persistent symptoms for patients with uncontrolled asthma.     

Neonatal Streptococcus pneumoniae Infection May Aggravate Adulthood Allergic Airways Disease in Association with IL-17A

Epidemiologic studies have demonstrated that some bacteria colonization or infections in early-life increased the risk for subsequent asthma development. However, little is known about the mechanisms by which early-life bacterial infection increases this risk. The aim of this study was to investigate the effect of neonatal Streptococcus pneumoniae infection on the development of adulthood asthma, and to explore the possible mechanism. A non-lethal S. pneumoniae lung infection was established by intranasal inoculation of neonatal (1-week-old) female mice with D39. Mice were sensitized and challenged with ovalbumin in adulthood to induce allergic airways disease (AAD). Twenty-four hours later, the lungs and bronchoalveolar lavage fluid (BALF) were collected to assess AAD. Neonatal S. pneumoniae infection exacerbated adulthood hallmark features of AAD, with enhanced airway hyperresponsiveness and increased neutrophil recruitment into the airways, increased Th17 cells and interleukin (IL)-17A productions. Depletion of IL-17A by i.p. injection of a neutralizing monoclonal antibody reduced neutrophil recruitment into the airways, alleviated airway inflammation and decreased airway hyperresponsiveness. Furthermore, IL-17A depletion partially restored levels of inteferon-γ, but had no effect on the release of IL-5 or IL-13. Our data suggest that neonatal S. pneumoniae infection may promote the development of adulthood asthma in association with increased IL-17A production.     

Hyaluronan and Its Heavy Chain Modification in Asthma Severity and Experimental Asthma Exacerbation

Hyaluronan (HA) is a large (>1500 kDa) polysaccharide of the extracellular matrix that has been linked to severity and inflammation in asthma. During inflammation, HA becomes covalently modified with heavy chains (HC-HA) from inter-α-inhibitor (IαI), which functions to increase its avidity for leukocytes. Our murine model of allergic pulmonary inflammation suggested that HC-HA may contribute to inflammation, adversely effecting lower airway remodeling and asthma severity. Our objective was to characterize the levels of HA and HC-HA in asthmatic subjects and to correlate these levels with asthma severity. We determined the levels and distribution of HA and HC-HA (i) from asthmatic and control lung tissue, (ii) in bronchoalveolar lavage fluid obtained from non-severe and severe asthmatics and controls, and (iii) in serum and urine from atopic asthmatics after an experimental asthma exacerbation. HC-HA distribution was observed (i) in the thickened basement membrane of asthmatic lower airways, (ii) around smooth muscle cells of the asthmatic submucosa, and (iii) around reserve cells of the asthmatic epithelium. Patients with severe asthma had increased HA levels in bronchoalveolar lavage fluid that correlated with pulmonary function and nitric oxide levels, whereas HC-HA was only observed in a patient with non-severe asthma. After an experimental asthma exacerbation, serum HA was increased within 4 h after challenge and remained elevated through 5 days after challenge. Urine HA and HC-HA were not significantly different. These data implicate HA and HC-HA in the pathogenesis of asthma severity that may occur in part due to repetitive asthma exacerbations over the course of the disease.     

Administration-time-dependency of the pharmacokinetic behavior and therapeutic effect of a once-a-day theophylline in asthmatic children

Using a double-blind, placebo-control, crossover study design, 8 asthmatic children (8-15 years) were evaluated for temporal patterns in airways function throughout separate study periods when treatment was placebo or Theo-24 once-daily on separate occasions at 0600, 1500 or 2100 hr. During 39-hr in-hospital observations, pulmonary function and serum theophylline concentrations (STC) were assessed every 3 hr under all treatments. The pharmacokinetics of Theo-24 varied greatly depending on the dosing time. For the afternoon and evening dosings, the Cmax, Tmax, AUC, % swing, % fluctuation, % AUC fluctuation, % nocturnal excess and Cav(2-6 hr) were all statistically significantly greater than for the morning dosing. Compared with the placebo regimen, dosing patients with Theo-24 at 1500 hr disrupted circadian patterns of airways function, especially airways patency, while dosing at 2100 hr, reduced the amplitude and shifted the acrophase of several spirometric measures to a slightly earlier time. Theo-24 treatment irrespective of dosing time resulted in comparable enhancement of the group 24-hr mean, minimum and maximum values of airways patency with reference to placebo baselines. Theo-24 dosing at 1500 or 2100 hr, however, resulted in the best effect on the airways as assessed by the 24-hr mean FEV 1.0 level in 7 of the 8 asthmatic children. When the drug was given at 1500 hr, the time of lowest FEV 1.0 was shifted from the nighttime hours in 5 of 8 patients. These findings suggest that clinicians need to individualize the theophylline dosing schedule of patients to best control the symptoms of asthma.