Altered pituitary-adrenal interaction in nocturnal asthma

BACKGROUND: Increased airway inflammation at night contributes to the nocturnal worsening of asthma, but the mechanisms regulating circadian variations in airway inflammation are unknown. OBJECTIVE: We hypothesized that altered hypothalamic-pituitary-adrenal axis function serves as an endogenous controller of inflammation in nocturnal asthma. METHODS: Patients with nocturnal asthma (n = 7), patients with nonnocturnal asthma (n = 13), and healthy control subjects (n = 11) adhered to a regular sleep-wake cycle for 1 week. Corticotropin and cortisol levels were assayed every 2 hours for 24 hours. Low-dose corticotropin stimulation was performed. Circadian hormonal flux was analyzed by means of cosinor modeling and calculation of the area under the 24-hour curve. RESULTS: Corticotropin peak levels and areas under the 24-hour curve were significantly increased in patients with nocturnal asthma versus values in patients with nonnocturnal asthma and control subjects. Patients with nonnocturnal asthma demonstrated significantly increased areas under the 24-hour cortisol curve when compared with control subjects, but peak cortisol levels did not differ between groups. Cortisol levels after low-dose corticotropin stimulation did not differ between groups. Corticotropin and cortisol levels were not correlated with the degree of physiologic impairment. CONCLUSION: Nocturnal asthma is marked by increased corticotropin levels that are not accompanied by commensurate increases in cortisol levels. This observation might indicate blunted adrenal responsiveness in the nocturnal asthma phenotype. Conversely, adrenal response to corticotropin might be enhanced in nonnocturnal asthma, attenuating nocturnal worsening of airway inflammation.     

Environmental tobacco smoke exposure and nocturnal symptoms among inner-city children with asthma

BACKGROUND: Environmental tobacco smoke (ETS) is a frequent exposure and is linked to asthma among inner-city children. OBJECTIVE: We sought to examine the relationship among ETS exposure, select asthma symptoms, and consequences among inner-city children with asthma. METHODS: Data from interviews with primary caregivers of inner-city elementary school children with asthma were evaluated (n = 590). Caregiver reports of child asthma symptoms, exercise limitations, asthma management, health care use, and ETS exposure were examined. RESULTS: Smoking in the home was reported by 29.4% of primary caregivers. ETS exposure (yes/no) was not related to frequency of child nocturnal symptoms or other select asthma morbidity markers. However, among children exposed to ETS, the frequency and severity of child nocturnal symptoms were highest among children exposed to moderate-to-heavy levels of ETS. After controlling for child age, anti-inflammatory medication use, asthma primary care, and caregiver's education, exposure to higher levels of ETS was associated with nearly a 3-fold increase in nocturnal symptoms in children (odds ratio, 2.83; 95% CI, 1.22-6.55). CONCLUSION: Among elementary school inner-city children with asthma, exposure to higher levels of ETS was associated with increased frequency of nocturnal symptoms. Reducing the exposure of children with asthma to ETS should be a clear priority in developing effective asthma management plans for inner-city families.     

Recurrent nocturnal asthma due to tolylene di-isocyanate: a case report

In a carpenter with a history of nocturnal dyspnoea, a bronchial provocation test with a tolylene diisocyanate (TDI) activator elicited a non-immediate asthmatic reaction, followed by recurrent nocturnal asthma for five subsequent nights. Subsequently, the study of the circadian rhythm of airflow, registered during work, confirmed the presence of recurrent nocturnal asthma of occupational origin.     

Nocturnal asthma: a study in general practice.

Symptoms of nocturnal asthma were studied using questionnaires returned by 1199 general practitioners throughout the United Kingdom. Of 7729 asthmatic patients seen consecutively and prescribed a bronchodilator aerosol, 73% woke with asthma at least once a week and 39% woke nightly. The percentage of asthmatics waking at night at least once a week in this population, where 48% were prescribed corticosteroid aerosols, was very similar to the 74% found to have asthma attacks at night in an earlier study of new hospital referrals at a time when such medication was not available. While sampling bias cannot be excluded, the clinical characteristics and profile of medications found in this study are similar to other reports and the evidence suggests that the general practitioners were managing these patients carefully. There was an overall association between the patients' perception of the severity of their asthma and frequency of waking at night (P less than 0.001). However, 26% of 2928 patients waking every night regarded their asthma as mild. These patients were taking significantly less medication than those also waking nightly but assessing their asthma as severe (P less than 0.001). The seriousness of nocturnal symptoms may be underestimated by asthmatics and they should be asked specifically about the frequency of nocturnal waking. Those with nocturnal asthma had a generally higher frequency of allergic and non-allergic provoking factors, but no single factor distinguished these patients from those without nocturnal symptoms. There was a strong correlation between the frequency of nightly waking and the number of medications used (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase-response curve to 1-hour light pulses for the marsupial, Dasyuroides byrnei

Most Australian marsupials are nocturnal and consequently it might be expected that the circadian system of this group may be similar to the circadian system of nocturnal rodents. Ten male kowaris (Dasyuroides byrnei) were allowed to free-run in constant darkness and were subsequently administered 1-hour light pulses (1000 lux) at known circadian times in their cycles at intervals of greater than 2 weeks. Changes in the phase of the kowari's circadian rhythm of wheel-running were measured when their rhythms reached a new steady-state after each light pulse and these data were used to construct a phase-response curve to light for the species. The kowari PRC exhibited essentially the same characteristics as those reported for the nocturnal rodents and the marsupial species Sminthopsis macroura. It appears that the kowari entrains its circadian rhythms to light/dark cycles via the discrete phase shifting mechanism as described in nocturnal rodents.     

Altered circadian rhythms in rheumatoid arthritis patients play a role in the disease's symptoms

The circadian changes in the metabolism or nocturnal secretion of endogenous corticosteroids (reduction) observed in rheumatoid arthritis (RA) patients are responsible, in part, for the time-dependent changes that are observed in the inflammatory response and related early morning clinical symptoms of the disease. Melatonin (MLT), another circadian nocturnal hormone that is the secretory product of the pineal gland, has been implicated in the time-dependent RA inflammatory reaction with effects that are opposite to those of corticosteroids. As a consequence, altered functioning of the HPA axis (early morning reduced corticosteroid production) and of the pineal gland (night increased MLT production) found in RA patients, seem to be important factors in the appearance and perpetuation of the clinical circadian symptoms of the disease. Consistently, human proinflammatory Th1-type cytokine production (related to MLT stimulation) exhibits a diurnal rhythmicity with peak levels during the night and early morning, at a time when plasma cortisol (inducing the Th2-type cytokine production) is lowest and MLT is highest. Reduced daily light exposure as observed in northern Europe (Estonia), at least during the winter, might explain the higher and more prolonged serum MLT concentrations that were observed in northern RA patients, as well as some epidemiological features versus southern Europe patients.     

Nocturnal awakening caused by asthma in children with mild-to-moderate asthma in the childhood asthma management program

BACKGROUND: Nocturnal symptoms of asthma are a cause of significant morbidity and are included as a central feature in the categorization of asthma severity. OBJECTIVES: Data from the Childhood Asthma Management Program were used to estimate the prevalence of nocturnal awakenings in 1041 children with mild-to-moderate asthma and to investigate the relationships between awakenings and peak flows, severity of asthma, and allergen sensitivity and exposure. METHODS: Daily diary care data were recorded during a 28-day interval in the Childhood Asthma Management Program screening process. The data on morning and evening peak flows, overall symptom codes, albuterol use for symptoms, and nocturnal awakenings for asthma symptoms were analyzed and compared with measures of personal characteristics, pulmonary function, and environmental characteristics of the patients. RESULTS: Three hundred fifty-one (33.7%) children experienced 1 or more night awakenings caused by asthma during the 28-day screening period while not taking any maintenance medications. Greater risk of night awakening was associated with more severe asthma (greater responsiveness to bronchodilator, airway reactivity to methacholine, peak flow variability, and use of albuterol for symptoms, all P <.0001) and atopy (increased IgE and allergy skin test reactivity, both P =.0002). Those with a positive skin test response to dog and a high level of dog allergen in the home had a greater risk of night awakening caused by asthma (P =.01), as did those with a positive skin test response to cat and a high level of cat allergen in the home (P =.04). Mean daily symptom code and use of albuterol for asthma symptoms increased in the 3 days immediately before a single awakening compared with in the 4 to 6 days before the awakening (P =.02 and P =.01, respectively); however, both morning and evening peak flows as a percentage of personal best were similar in both intervals. Mean daily symptom code and daily use of albuterol were greater in the 3 days after an awakening than in the 3 days before (P <.0001 and P =.0002, respectively). Mean evening peak flow percentage of personal best the day after an episode of awakening was lower when a second consecutive awakening occurred than when there was only a single awakening (P =.01). CONCLUSIONS: Nocturnal awakening occurred in one third of the children with mild-to-moderate asthma during a month of relative stability and appears to be an indicator of asthma that is becoming increasingly severe.     

Blood eosinophil numbers and activity during 24 hours: effects of treatment with budesonide and bambuterol.

The effects of the inhaled corticosteroid budesonide and the oral long-acting beta-agonist bambuterol on circadian variation of blood eosinophil numbers, serum levels of eosinophil cationic protein (ECP), serum eosinophil chemotactic activity (ECA), and serum neutrophil chemotactic activity (NCA) were studied in two groups of patients with allergic asthma. Group 1 (n = 8) had a circadian variation of peak expiratory flow (PEF) 15% or greater, and group 2 (n = 9) had a circadian PEF variation less than 15%. Both groups were randomized and crossover treated for 4 weeks with (A) 0.4 mg budesonide at 8 AM and 8 PM, (B) 20 mg bambuterol at 8 PM, and (C) placebo. At the end of each period blood eosinophil numbers, ECP, ECA, and NCA were measured during 24 hours at 4-hour intervals. No significant differences in the inflammatory parameters could be observed between the groups, although eosinophil numbers tended to be higher in group 1 than in group 2. Highest eosinophil numbers were observed at night. Budesonide reduced both eosinophil numbers and ECP levels, especially at night; bambuterol had no effect on both variables. No circadian variation or treatment effects were observed for ECA and NCA. This study suggests a role for the eosinophil in the nocturnal worsening of asthma, and it demonstrates that budesonide produces, in contrast to bambuterol, a reduction of (nocturnal) eosinophil numbers and activity.     

Severe mood dysregulation: in the "light" of circadian functioning

Severe affective and behavioral dysregulation, labeled as severe mood dysregulation (SMD), is a widely spread phenomenon among adolescent psychiatric patients. This phenotype constitutes severe impairment across multiple settings, including various symptoms, such as non-episodic anger, mood instability, and hyperarousal. Moreover, SMD patients often show depression and reduced need for sleep. Despite a lifetime prevalence of 3.3%, systematic research is still scarce, and treatments that have been established do not account for the range of symptoms present in SMD. Considering the circadian dysfunctions, two hormones, melatonin and cortisol, are essential. When these hormones are dysregulated, the circadian rhythm gets out of synchrony. Since evidence is emerging showing that the worse the sleep-wake cycle is entrained, the worse the psychiatric symptoms are depicted, the importance of proper circadian functioning becomes clear.Chronotherapy as the controlled exposure to environmental stimuli (e.g. light) acting on biological rhythms has shown therapeutic effects. In both seasonal and major depression chronotherapy has been implemented, decreasing depressive symptoms and stabilizing circadian rhythms. Preliminary evidence from SMD related disorders, namely attention-deficit/hyperactivity disorder and pediatric bipolar depression, indicates that morning light therapy elicits positive influences on other symptoms as well. Hence, light therapy might not only be effective for depressive symptoms and circadian rhythms, but might also be beneficial for symptoms including inattention and irritability.We hypothesize that light therapy might be a helpful adjunctive treatment enhancing affective and circadian functioning, and eliciting positive influences on behavior. Physiologically, changes of both cortisol levels and melatonin production are expected.     

Elevated serum melatonin is associated with the nocturnal worsening of asthma

BACKGROUND: Increased airway inflammation at night contributes to the nocturnal worsening of asthma. In vitro studies have shown exogenous melatonin to be pro-inflammatory in asthma, but it is unknown whether endogenous melatonin levels are a controller of airway inflammation in nocturnal asthma. OBJECTIVE: Our aim was to determine 24-hour patterns of serum melatonin and their relationship to overnight decline in physiology in subjects with nocturnal asthma, non-nocturnal asthma, and in healthy controls. METHODS: Observational study of pulmonary physiology and melatonin levels in patients with nocturnal asthma (n = 7), non-nocturnal asthma (n = 13), and healthy controls (n = 11). Subjects maintained a constant sleep-wake regimen for 7 days. On day 8, serum melatonin was measured every 2 hours by radioimmunoassay and analyzed by cosinor modeling. The correlation between serum melatonin levels and overnight change in spirometry was evaluated by Spearman's rank correlation analysis. RESULTS: In subjects with nocturnal asthma, peak melatonin levels were significantly elevated compared with healthy controls (67.6 +/- 5.0 pg/mL versus 53.5 +/- 4.0 pg/mL, P =.03). Melatonin acrophase was delayed in nocturnal asthma (02:54 versus 01:58 in healthy controls, P =.003, and 02:15 in non-nocturnal asthma, P =.01). In subjects with nocturnal asthma, increasing melatonin levels were significantly and inversely correlated with overnight change in FEV(1) (r = -.79, P =.04), a relationship that was not observed in non-nocturnal asthma or healthy controls. CONCLUSIONS: Nocturnal asthma is associated with elevation and phase delay of peak serum melatonin levels. Elevated melatonin levels might contribute to the pathogenesis of nocturnal asthma.     

Severe upper airway obstruction during sleep

Few disorders may manifest with predominantly sleep-related obstructive breathing. Obstructive sleep apnea (OSA) is a common disorder, varies in severity and is associated with significant cardiovascular and neurocognitive morbidity. It is estimated that between 8 and 18 million people in the United States have at least mild OSA. Although the exact mechanism of OSA is not well-delineated, multiple factors contribute to the development of upper airway obstruction and include anatomic, mechanical, neurologic, and inflammatory changes in the pharynx. OSA may occur concomitantly with asthma. Approximately 74% of asthmatics experience nocturnal symptoms of airflow obstruction secondary to reactive airways disease. Similar cytokine, chemokine, and histologic changes are seen in both disorders. Sleep deprivation, chronic upper airway edema, and inflammation associated with OSA may further exacerbate nocturnal asthma symptoms. Allergic rhinitis may contribute to both OSA and asthma. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA. Treatment with CPAP therapy has also been shown to improve both daytime and nighttime peak expiratory flow rates in patients with concomitant OSA and asthma. It is important for allergists to be aware of how OSA may complicate diagnosis and treatment of asthma and allergic rhinitis. A thorough sleep history and high clinical suspicion for OSA is indicated, particularly in asthma patients who are refractory to standard medication treatments.     

BMAL1 links the circadian clock to viral airway pathology and asthma phenotypes

Patients with asthma experience circadian variations in their symptoms. However it remains unclear how specific aspects of this common airway disease relate to clock genes, which are critical to the generation of circadian rhythms in mammals. Here, we used a viral model of acute and chronic airway disease to examine how circadian clock disruption affects asthmatic lung phenotypes. Deletion of the core clock gene bmal1 or environmental disruption of circadian function by jet lag exacerbated acute viral bronchiolitis caused by Sendai virus (SeV) and influenza A virus in mice. Post-natal deletion of bmal1 was sufficient to trigger increased SeV susceptibility and correlated with impaired control of viral replication. Importantly, bmal1^−/− mice developed much more extensive asthma-like airway changes post infection, including mucus production and increased airway resistance. In human airway samples from two asthma cohorts, we observed altered expression patterns of multiple clock genes. Our results suggest a role for bmal1 in the development of asthmatic airway disease via the regulation of lung antiviral responses to common viral triggers of asthma.     

Asthma treatment and asthma prevention: a tale of 2 parallel pathways

Three recent clinical trials used different study designs to test the hypothesis that early introduction of inhaled corticosteroids in infants and young children at high risk for the development of asthma could change the natural course of the disease. All 3 trials reached the same conclusion: treatment requirement, symptom frequency while off treatment, and lung function did not differ between children receiving active drug or placebo, with outcomes measured 2 to 4 years after randomization. These findings challenge the concept that the inflammatory processes that cause asthma symptoms and are responsive to inhaled corticosteroids are also responsible for the chronic changes in airway structure and function that are believed to predispose to the development of persistent asthma. This conclusion is supported by studies showing that bronchial hyperresponsiveness, independent of current asthma symptoms, is associated with subsequent deficits in airway function growth during childhood. Successful strategies for the prevention of asthma will require a better understanding of the genetic, environmental, and developmental factors that predispose toward inappropriate responses to airway injury. Abnormal airway remodeling and persistent dysregulation of airway tone might be the final common pathway for different disease mechanisms, and this might explain the heterogeneity of clinical phenotypic syndromes that go under the common label of "asthma."     

Salmeterol compared with slow-release terbutaline in nocturnal asthma A multicenter, randomized, double-blind, double-dummy, sequential clinical trial

Brambilla C, Chastang C, Georges D, Bertin L. Salmeterol compared with slow-release terbutaline in nocturnal asthma. A multicenter, randomized, double-blind, double-dummy, sequential clinical trial.
The aim of the multicenter, randomized, double-blind, double-dummy, parallel-group clinical trial with a 2-week treatment period was to compare the efficacy and safety of salmeterol (50 ug twice daily) with slow-release (SR) terbutaline (5 μg orally, twice daily) in nocturnal asthma. A total of 159 asthmatic adults (FEV, 50-90% of predicted value; sex ratio: 0.87) with at least two nocturnal awakenings during a 7-d run-in period was included in the study. Patients were centrally randomized with a national computer network (Minitel®). The main variable (number of awakening-free nights during the last week of treatment) was analyzed according to a sequential method with the one-sided triangular test. The number of awakening-free nights (± SD) was significantly higher in the salmeterol group: 5.3 ± 2.4 vs 4.6 ± 2.3 (P = 0.006). Salmeterol was significantly more effective than SR-terbutaline in the following factors: number of patients without any awakening during the last week of treatment (50% vs 27%, P = 0.003), mean morning PEF (351 ± 1091/min^-1 vs 332 + 105 I/min^-1, P = 0.04), PEF diurnal variation 6 ± 10% vs 11 ± 12%, P = 0.01), overall assessment of efficacy by the patient and the investigator (P = 0.001 and 0.005, respectively), and daily rescue salbutamol intakes ( P =0.004). In the salmeterol group, significantly fewer patients reported adverse events (16% vs 29%, P = 0.04). This study confirms that salmeterol, 50 μg twice daily, is particularly useful in controlling nocturnal symptoms of asthma: as compared with the control group, twice as many salmeterol-treated patients were totally free of nocturnal symptoms after 2 weeks of treatment.     

Nocturnal symptoms and sleep disturbances in clinically stable asthmatic children

Presence of nocturnal symptoms is related to asthma severity. Clinically stable asthmatic children, too, report frequent nocturnal symptoms and sleep disturbances. The study determined these parameters in stable, asthmatic children, in their home environment. This case-control, questionnaire-based study in 70 school-going children comprised 40 asthmatics (Group 1) and 30, age/gender matched, healthy children (Group 2). Parents maintained peak expiratory flow (PEF) and sleep diaries for one week. Group 1 had significantly lower mean morning (250.3 vs. 289.1 I/minute) and mean evening PEF values (261.7 vs. 291.3 I/minute). Group 1 (38.95%), reported frequent nocturnal symptoms like cough (36.90%), breathlessness (32.80%), wheeze (27.68%) and chest tightness (14.35%). Sleep disturbances, significant in Group 1 (38, 95% vs. 14.35%), included daytime sleepiness (24.60%), daytime tiredness (20.50%), difficulty in maintaining sleep (15.38%), early morning awakening (14.35%), struggle against sleep during daytime (12.30%), and involuntarily falling asleep (17.43%). On a scale of 1-6, Group 1 scored significant sleep disturbances/patient (3 vs. 0.8); lethargy/tiredness in morning (2.9 vs. 2.2), poorer sleep quality (4.7 vs. 5.4), less parents' satisfaction with child's sleep (4.5 vs. 5.5) and daytime fitness (4.1 vs. 5.3). Group 1, when exposed to environmental tobacco smoke (22, 55%), reported significant nocturnal symptoms (18/22, 81%) and reduced mean morning and evening PEF values (17/22, 77%). It is concluded that clinically stable, asthmatic children reported increased nocturnal symptoms, sleep disturbances and poorer sleep quality. Lack of awareness of asthma-sleep association and its clinical implications could lead to poor asthma control and impaired daytime activity.     

Methacholine reactivity and asthma

Methacholine tests were used in an epidemiologic study of the prevalence of asthma and chronic bronchitis in northern Sweden. Of 6610 subjects in three age groups from eight representative geographic areas in the northernmost province of Sweden, 5698 (86%) completed a postal questionnaire on respiratory symptoms, and 1506 underwent a structured interview and a lung function test. A total of 292 (5%) were diagnosed as having asthma. A subsample of 284 subjects (of 320 invited) classified at the interview as having asthma ( n = 98) or as having respiratory symptoms that might be due to asthma but not fulfilling the interview criteria for the diagnosis of asthma ( n = 186) underwent a methacholine test. Subjects who, before the interview study, already had a well-defined asthma diagnosis were not invited to the methacholine testing. Of those 98 subjects classified as having asthma, 61 % reacted to methacholine doses ≤ 4 mg/ml and 79% to doses ≤ 8 mg/ml, while the corresponding figures in the symptomatic but nonasthma group were 20% and 34%, respectively. The results show that a carefully performed structured interview accurately diagnoses asthma in epidemiologic studies. The methacholine tests provide important diagnostic information primarily in subjects in whom the medical history is equivocal.     

Recurrent nocturnal asthma after bronchoprovocation with Western Red Cedar sawdust: association with acute increase in non-allergic bronchial responsiveness

Recurrent nocturnal asthma following a single exposure to Western Red Cedar sawdust was documented by measurements of peak flow rates in two sensitized subjects. The nocturnal asthma followed a dual asthmatic response in the first subject and a late (non-immediate) asthmatic response in the second. Both subjects developed a 10-fold reduction in the dose of histamine required to decrease the FEV₁ by 20%. This cedar-induced increase in non-specific bronchial reactivity was maximal at the time of the recurrent nocturnal asthma, and persisted after nocturnal asthma had ceased and after FEV₁ had returned to normal. We hypothesize that the enhanced non-specific bronchial reactivity which occurs following late asthmatic responses to bronchial challenge is the cause of recurrent nocturnal asthma following single exposure to a sensitizing agent.     

Geographical variations of asthma and asthma symptoms among schoolchildren aged 5 to 8 years and 12 to 15 years in Palestine: the International Study of Asthma and Allergies in Childhood (ISAAC).

BACKGROUND: Many studies demonstrated the existence of geographic differences, within and between countries, in the prevalence of asthma, rhinitis, and eczema. However, in Palestine, there are no comprehensive Palestinian data to compare with those from other regional and international centers. OBJECTIVE: To describe the prevalence of asthma and asthma symptoms in schoolchildren in two districts (Ramallah and North Gaza) in Palestine. METHODS: After a two-stage stratified systematic sampling, approximately 14,500 schoolchildren, from the first and second grades of elementary school (ages 5 to 8 years) and eighth and ninth school grades (ages 12 to 15 years), were invited to participate in a survey using International Study of Asthma and Allergies in Childhood phase III questionnaires and protocols. RESULTS: In general, younger children were reported to have a higher 12-month wheezing prevalence rate than older children (9.6 and 7.2%, respectively), and more physician-diagnosed asthma (8.4 and 5.9%, respectively). However, nocturnal cough and exercise-related wheezing were higher in the older age group compared with younger children. Younger children living in North Gaza district showed slightly higher prevalence rates for asthma and asthma symptoms, but older children had higher rates in Ramallah district. After adjustment using logistic regression analysis, male sex, living in inland areas, and younger age were shown to predict 12-month wheezing and physician-diagnosed asthma. CONCLUSIONS: Palestinian children have asthma symptoms rates that are similar to several countries in the Mediterranean region such as Spain and Turkey, but still lower than other Middle East countries such as Saudi Arabia and Israel.     

Stability of the circadian alteration in lung function in asthma.

Although studies on pharmacologic interventions for nocturnal asthma are increasing, information about the long-term stability of circadian spirometric changes or bronchial responsiveness is not known. This study was undertaken to evaluate these variables in 10 patients with asthma measured quarterly during a 1-year period. We have found that the overnight decrease in peak expiratory flow rate measurements is stable (mean range, 13.8% to 16.4%) during the year, as are the quarterly 4 PM (1600-hour) and 4 AM (0400-hour) FEV1 values. The 4 PM provocative concentration of methacholine that produced a 20% fall in FEV1 (PC20) (range of geometric mean, 0.213 to 0.359 mg/ml) and the 4 AM PC20 (range, 0.057 to 0.152 mg/ml) for the group were also relatively stable. Individual variation was higher for the PC20 values than for the FEV1. We concluded that during a 1-year period, without acute respiratory events, (1) the overnight decrement in peak expiratory flow rate and the 4 AM and 4 PM FEV1 values were constant and (2) bronchial responsiveness demonstrated some individual variability, but for the group, it remained stable.