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Review article

Supported by an unrestricted grant from Zeneca Pharmaceuticals

Pathophysiology of nocturnal asthma

Philip E Silkoff, MD and Richard J Martin, MD

Learning Objectives: This article will focus on the pathophysiologic changes underlying the nocturnal worsening of asthma and the therapeutic approach to this disorder. Data Sources: Selected articles appearing since 1985 dealing specifically with the underlying pathologic features and therapy of nocturnal asthma. Study Selection: Studies that aimed to elucidate the pathologic features, mech- anisms, and therapeutic strategies for the treatment of nocturnal asthma are sum- marized. Results: Nocturnal asthma is associated with significant decline in pulmonary function and increase of airway inflammation at night. The administration of medications must be designed to achieve the maximal effect during the night in nocturnal asthma. Conclusions: The further elucidation of the reasons underlying nocturnal asthma should lead to more specific therapeutic interventions with maximal effect at night.

Ann Allergy Asthma Immunol 1998;81:378–387.

INTRODUCTION Asthma, in common with many other disease processes, shows a pronounced circadian variation in the majority of patients who demonstrate a striking de- cline in lung function overnight termed nocturnal asthma (NA). Nocturnal asthma is a marker for more severe disease and carries significant morbid- ity 1 and mortality. 2 The nocturnal worsening of asthma is well recog- nized by patients, but not always ap- preciated by practitioners. A classic survey conducted by Turner-Warwick 3 included more than 7,600 asthma pa- tients and revealed that 74% of those surveyed awakened from sleep at least once per week with symptoms of wheezing, chest tightness, or cough re- quiring inhaled 2 agonist use. Almost 40% awakened nightly due to asthma

From the Department of Medicine, The Na-

tional Jewish Medical and Research Center, Denver Colorado. Received for publication September 14,

1998.

Accepted for publication September 29,

and 64% reported awakening at least three times per week. Asthma incidence, with resultant in- creased morbidity and mortality, is ris- ing in western societies despite modern therapy. Airway inflammation is re- garded as the primary abnormality un- derlying the manifestations of asthma such as airway obstruction and this has been the focus of recent research and therapy. 4 A recent document “Guide- lines for the Diagnosis and Manage- ment of Asthma” by the National Asthma Education and Prevention Pro- gram of the National Institutes of Health 5 recommended anti-inflamma- tory medication, eg, inhaled corticoste- roids in all severities of asthma except the mildest category termed “the mild intermittent” group.

BACKGROUND Biologic Rhythms Chronobiology is the study of the bio- logic rhythms of physiologic and pathologic processes. Circadian cycles have approximately a 24-hour period. The terms diurnal and nocturnal

strictly refer to the day and night peri- ods, respectively, and are part of the circadian cycle as a whole. A mamma- lian circadian pacemaker located in the suprachiasmal nucleus of the brain controls many physiologic functions such as core temperature which itself is used to monitor the phase of the circa- dian rhythm. In man, the circadian cy- cle is about 24.1 hours in length and continues to cycle in the absence of external stimuli such as ambient light. The sleep-wake cycle, controlled by

a sleep homeostat, also influences physiologic and pathologic processes and subserves a homeostatic function. Normally, the circadian rhythm en- trains the sleep-wake cycle to facilitate daytime activity for humans and night- time activity for nocturnal species. The circadian and sleep-wake cycles, how- ever, can become desynchronized, eg, in international travel, a condition pop- ularly known as “jet lag.” Similar to circadian rhythms, the sleep-wake cy-

cle continues in the absence of external

stimuli. The intentional desynchroni-

zation of the circadian and sleep cycles can allow study of their separate phys- iologic effects (forced desynchrony). Both circadian and the sleep-wake rhythms control the propensity to sleep and wakefulness on a continuous basis. The balance between these two cycles determines the sleep-wake pattern and also quality of sleep. The investigation of circadian phys- iologic and pathologic changes are rel- evant to the elucidation of the patho- genesis of asthma and may help design more effective therapy. The variation

in asthmatic lung function may be un-

der the control of both circadian and sleep-wake cycles. In addition, the state of sleep itself has additional phys-

1998.

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iologic effects such as change in pos- ture, fluid distribution, and muscle tone. The relative contribution of the circadian and sleep-wake cycle and sleep itself to nocturnal asthma are not completely understood.

CIRCADIAN CHANGES IN PULMONARY FUNCTION IN HEALTH AND DISEASE

Airflows and Bronchial Reactivity Normal and asthmatic subjects show circadian variation in pulmonary func- tion as assessed by spirometric param- eters such as FEV 1 and peak expiratory flow rate (PEFR) which are maximal around 4 PM and lowest around 4 AM. 6 The magnitude of change in non-asth- matic subjects and non-nocturnal asth- matic subjects (NNA) is about 8% while in NA the changes are much larger. The change in airway caliber is associated with a change in non-spe- cific airway reactivity. In one study, bronchial reactivity assessed by metha- choline challenge worsened overnight by factor of 8 in NA compared with a factor of 2 in NNA. 7

Airway Resistance There are dynamic changes in airway resistance overnight. In one study, lower airway resistance to airflow rose progressively from 12 midnight to 6

AM in asleep asthmatic subjects (Fig 1). This pattern of change was also seen, albeit to a milder degree, during a sub- sequent night when sleep was with- held. 8 In an ongoing study here, pe- ripheral airway resistance measured with a bronchoscope according to the method of Wagner et al 9 increased at 4 AM in NA compared to 4 PM. 10

Lung volumes Functional residual capacity (FRC) is increased in asthmatics as compared with normal subjects, a condition termed hyperinflation. An increased FRC is associated with a greater air- way caliber and thus is beneficial. Bal- lard et al, 11 using a horizontal body plethysmograph, measured FRC in non-asthmatic and asthmatic subjects during sleep. Functional residual ca- pacity which was higher in the asth- matics before the onset of sleep, fell in both groups and equalized in the two groups especially during rapid eye movement phase sleep. The observed fall in FRC could account in part for the increase in airway resistance which occurs in NA. In a subsequent study, however, application of a negative pressure device around the chest to reduce this decline in FRC did not alter the overnight changes in FEV 1 or bron- chial reactivity. 12 Thus, the change in

1 or bron- chial reactivity. 1 2 Thus, the change in Figure 1. Airway resistance (Ria,

Figure 1. Airway resistance (Ria, cm H 2 O/L/s) in 6 asthmatic subjects progressively increases from midnight to 6 AM (0600 h) independent of sleep (- -) but sleep itself has a profound effect on the increase in airway resistance (--). Reprinted with permission from reference 7.

airway caliber is not solely due to the reduction in FRC.

Intrathoracic blood volume In contrast to the FRC decline, Desjar- din et al 13 reported that intrathoracic blood volume increased in NA subjects (but not in NNA or normal subjects) due to a shift of blood from peripheral venous to central compartments. The increased lung blood volume could cause engorgement of airways with re- duction in airway caliber, and also dis- place gas from the thoracic cavity lead- ing to an decrease in lung compliance and increased work of breathing.

Autonomic tone Stimulation of the vagus nerve results in bronchoconstriction in normal and asthmatic subjects. Vagal tone is in- creased at night and this may worsen airway function. Morrison and col- leagues 14 demonstrated that atropine, a muscarinic antagonist, resulted in an improvement in the 4 AM PEFR in NA as compared with placebo.

Section Summary The net effects of the changes in pulmonary function in NA will be to narrow airway caliber (de- creased FRC, increased vagal tone and increased lung blood content) and to increase reactivity to non- specific and specific stimuli, eg, nocturnal environmental allergens.

CIRCADIAN HORMONAL CHANGES IN HEALTH AND DISEASE Circulating hormones vary in a circadian fashion in everyone and may contribute to overnight fall in lung function.

Adrenal Cortical Hormones Peak levels of circulating cortisol oc- cur upon awakening with trough levels noted between 10 PM and midnight. 15 The circadian change in cortisol is sim- ilar in both asthmatic and non-asth- matic individuals. 16 The occurrence of trough cortisol levels in the late evening could set the scene for NA as cortisol exerts an anti-inflammatory ef- fect upon the chronically inflamed air-

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ways of asthmatics. Additionally, the absence of higher cortisol levels in the NA group could represent a deficiency in cortisol production inappropriate to the stress of bronchoconstriction. Cer- tainly, the administration of corticoste- roids attenuates nocturnal asthma 17 as does the infusion of corticotrophin re- leasing factor (CRF). 18 Finally, there may be defects in the binding affinity of cortisol to glucocorticoid receptors in asthma 19 with decreased steroid-re- sponsiveness. Recently, a nocturnal re- duction in glucocorticoid binding and steroid responsiveness has been dem- onstrated in peripheral blood mono- cytes in NA. 20

Adrenal Medullary Hormones The adrenal hormone epinephrine is a bronchodilator due to stimulation of airway 2 receptors and inhibits leak- age of histamine and other mediators from sensitized mast cells. Epineph- rine reaches peak levels during the af- ternoon hours with trough levels dur- ing the early morning hours. 15 This circadian pattern could promote NA by reducing bronchodilatation and by al- lowing the release of spasmogenic me- diators from mast cells. In one study, however, infusion of physiologic doses of epinephrine lessened but did not abolish the overnight decline in airway caliber. 15 This suggests that the circa- dian change in epinephrine is just one component of many factors that influ- ence airway caliber at night. Similar to the changes in glucocor- ticoid binding described above, noctur- nal bronchoconstriction could be due in part to a reduction in the number of and/or physiologic response of 2 re- ceptors located in the smooth muscle and inflammatory cells in the airways. Indeed a reduced density of -adren- ergic receptors has been noted on cir- culating leukocytes of asthmatic sub- jects with NA as compared with those with NNA and normal controls. 21 While this reduction in receptors may be a down regulation mechanism as a result of previous 2 agonist therapy, a reduced density of receptors has also been reported on untreated asthmatics. This phenotypic down regulation may

be related to a genetic abnormality of the 2 receptor 22 and thus lead to a genetic predisposition to NA.

Other Hormones Other circulating hormones may also have a pathogenic role in asthma. An example is melatonin, 2325 the cyclic variation of which has been used to characterize the periodicity of the cir- cadian rhythm. Treatment with mela- tonin has been used by some to coun- teract jet lag.

Section Summary Circulating hormone levels appear to be unaltered in asthma. There is, however, evidence for altered hor- mone binding with possible reduc- tion of tissue responsiveness.

CIRCADIAN CHANGES IN AIRWAY INFLAMMATION IN NOCTURNAL ASTHMA The current concept of airway inflam- mation as the primary process in asth- ma 4 has led to studies that examine airway cells and mediators at different time points in the circadian cycle. The

reason for airway inflammation in asthma and the exacerbation of this inflammation at night are not yet clear.

IgE/Mast Cell Interaction IgE-mediated allergy is one important mechanism underlying asthma with binding of relevant allergens to IgE on airway mast cells resulting in degran- ulation and release of mediators, eg, histamine which causes broncho- spasm. Serum IgE is fivefold greater in asthma compared with nonallergic controls. In asthmatics, IgE levels peak around midday and fall at night. 26 This

pattern is opposite to that seen in in- flammatory parameters and may re- flect temporal differences in the bind- ing of IgE to tissue or cells rather than

a fall in production. Serum histamine,

a mast cell product, also varies in a

circadian fashion with the peak levels coinciding in time with the greatest bronchoconstriction, ie, 4 AM. 15 This suggests that mast cell activation is enhanced at night in NA.

Bronchoscopic Assessment of Airway Inflammation Direct sampling of lung cells and me- diators have generally shown that in-

of lung cells and me- diators have generally shown that in- Figure 2. The number per

Figure 2. The number per volume (Nv) of eosinophils in the nocturnal asthma (NA) and non-nocturnal asthma (NNA) groups are shown in the endobronchial (airway tissue-EBBX) and transbronchial (alveolar tissue TBBX) biopsies at 4:00 AM and 4:00 PM. More eosinophils are present in TBBX at both time points in both NNA and NA. At 4:00 PM, there is no significant difference between the NA and NNA groups. At 4 AM however, the number of eosinophils in TBBX has dramatically increased in the NA group alone. Reprinted with permission from reference 28.

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dices of inflammation increase from 4 PM to 4 AM in asthmatics with NA. In one recent study at our institution, (Fig 2), bronchoalveolar lavage (BAL) fluid contained significantly more in- flammatory cells, eg, eosinophils and neutrophils in NA at 4 AM compared with NNA, whereas at 4 PM there was no difference between the groups. 27 In a recent study, bronchial and trans- bronchial biopsies (sampling of alveo- lar tissue) were taken in subjects with and without NA. 28 First, alveolar tissue in the NA group contained signifi- cantly increased inflammatory cells such as eosinophils and macrophages when compared with the NNA group. Second, the degree of alveolar inflam- mation was worse at 4 AM compared with 4 PM in the NA group only. In the same subjects, bronchial biopsies, which sample proximal large and me- dium sized airways, did not show the same differences between the NA and NNA groups. The degree of eosino- philic alveolar infiltration correlated with the overnight decline in airway caliber. This study demonstrated the importance of inflammation in the gas exchange area of the lung in the NA group associated with or even preced- ing nocturnal bronchospasm.

Section Summary Bronchoscopic studies have shown that airway inflammation increases at night in NA in BAL and even extends into the gas exchange re- gions of the lung.

THE SLEEP STATE AND ASTHMA The relationship between sleep itself and asthma is not clear. The state of sleep involves postural and neurophys- iologic changes. Bronchoconstriction and the increase in airway resistance still occur in NA during the night when patients are kept awake but the changes observed are greater when the subjects sleep. 29 The state of sleep it- self does not seem essential for the development of NA. Finally, NA does not seem to be related to postural change from an upright to supine po- sition. Patients who are confined to

bed throughout an entire 24-hour pe- riod still display day-night variation in airway tone. 30

Section Summary The sleep state itself may play a role in the pathogenesis of NA. The cir- cadian pattern in lung function per- sists in nocturnal asthmatics kept awake and in subjects who maintain the supine posture throughout a 24- hour period.

OTHER FACTORS INVOLVED IN THE PATHOGENESIS OF NOCTURNAL ASTHMA

Gastroesophageal Reflux Although gastroesophageal reflux dis- ease (GERD) is often discussed as a possible trigger for nocturnal broncho- spasm, Tan and colleagues 31 studied subjects with NA and GERD using pH probes in the esophagus to detect re- flux and found no correlation between increased overnight acid secretion and nocturnal bronchospasm. During a trial of an H 2 antagonist that reduces stom- ach acidity, inpatients with both symp- tomatic reflux and nocturnal broncho- spasm showed a small but significant improvement in asthma symptoms but with no change in morning PEFR. Asthmatics with GERD should cer- tainly be treated for their symptoms, but GERD does not appear to be a significant trigger of nocturnal bron- chospasm.

Sleep Apnea Chan et al 32 reported that asthmatics with sleep apnea had a significant im- provement in asthma control and a re- duction in the severity of NA follow- ing the application of nasal CPAP. Nasal CPAP in non-apneic asthmatics, however, did not appear to convey any benefit. 33 The association between sleep apnea and asthma may involve stimulation of pharyngeal afferents causing reflex bronchoconstriction, or other mechanisms such as hypoxia-in- duced bronchospasm or negative in- trathoracic pressure increasing lung blood volume.

THE TREATMENT OF NOCTURNAL ASTHMA

Chronopharmacology Chronopharmacology or chronotherapy is a branch of pharmacology that aims to optimize therapy by taking into account cyclical variation in a disease process and cyclical pharmacokinetics (drug ab- sorption and delivery) and pharmacody- namics (drug effects). The pharmacoki- netics and pharmacodynamics of certain drugs may vary on a circadian basis and this requires investigation so as to opti- mize therapy. The previous discussion has outlined some of the pathogenic fea- tures that may underlie nocturnal asthma. There are, however, several well-established approaches to the treat- ment of NA which take into account chronopharmacologic findings. The noc- turnal augmentation of inflammation in NA has led to the design of therapy aimed at preventing airway inflamma- tion and bronchospasm to maximize drug effects overnight.

Corticosteroids Corticosteroids are the cornerstone of antiinflammatory therapy in asthma and physicians attempt to maximize the therapeutic effect while minimiz- ing systemic toxicity. On the toxicity side, one popular approach to therapy in Europe takes into account the circa- dian rhythm-dependent susceptibility and tolerance of the body to the ad- verse effects of synthetic corticoste- roids. Inhibition of the brain hypotha- lamic-pituitary axis may result in a lack of endogenous steroid hormone if the therapy is stopped abruptly with symptoms such as weakness, apathy, and decreased circulatory volume. The susceptibility of the hypothalamic-pi- tuitary axis to suppression varies on a circadian basis being more susceptible at night. In the European approach, two-thirds of the total daily dose is taken in the morning upon awakening, and the remaining one third is taken about 8 hours later (approximately 3 PM for most patients). On the therapeu- tic side, the therapeutic effect of corti- costeroids also demonstrates a circa- dian fluctuation.

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In a placebo-controlled study, Beam et al 17 examined nocturnal FEV 1 fall, blood eosinophils and 4 AM BAL cy- tology after 50 mg predisone given at 8 AM, 3 PM, and 8 PM (six visits) in 7 subjects. The study showed that the 3-PM dose of oral prednisone alone re- sulted in a significant attenuation of the overnight fall in mean FEV 1 from 28.2% (placebo) to 10.4% accom- panied by a significant FEV 1 response to bronchodilator. The mean FEV 1 at 4 AM was almost a liter better than that seen on placebo. The 3 PM dose re- sulted in a significant pancellular re- duction in BAL cytology not seen with the 8 AM or 8 PM dosing; thus, 3 PM may prove to be an effective and safe time to administer oral corticosteroids for treatment of reactive airway disease with nocturnal exacerbation. Inhaled steroids, a first-line therapy for asthma, have also been evaluated chronothera- peutically. Pincus et al 34 showed that 3 PM dosing of inhaled steroid was equally efficacious for improvement of AM and PM PEFR and FEV 1 as taking the medication four times a day. Nei- ther regime was associated with evi- dence of pituitary axis suppression which reflects systemic absorption of the medication.

Theophylline Theophylline is a bronchodilator used in COPD and asthma but may also possess anti-inflammatory effects. Many different preparations exist with distinct pharmacokinetic properties. Twice-daily theophylline preparations designed to produce consistent serum theophylline concentrations give rise to varying serum levels over 24 hours. Other preparations produce higher nighttime levels to meet increased noc- turnal demands without compromising daytime asthma control. Chronothera- peutic dosing of theophylline, once- daily in the evening around 6 to 7 PM, attenuates nocturnal symptoms and early morning bronchoconstriction without deterioration in asthma control at other times of the day. This regimen has been found to be clinically superior to conventional twice daily dosing. 3537 Lung function is improved by higher

serum theophylline levels during sleep with preservation of sleep quality and architecture and less nocturnal oxygen desaturation.

Long-Acting Bronchodilators Slow release -agonist tablets, which are used to maintain a longer period of bronchodilation (10 to 12 hours), can significantly moderate the morning dip in airways patency in asthmatic pa- tients. Recently, the long-acting in- haled 2 -agonist salmeterol has shown promise in improving the overnight decrement in lung function, but further evaluation is needed. 38

Section Summary Asthma varies in a circadian fash- ion, making it ideally suited for chronotherapy. The three classes of medications most efficacious for the chronotherapy of reactive airway disease are corticosteroids, slow-re- lease theophylline and slow-release 2 agonists. The benefits are most pronounced in the asthma popula- tion, but these medications also ben- efit the COPD population, especially the long-acting theophylline prepa- rations.

THE OVERALL APPROACH TO NOCTURNAL ASTHMA It is important to specifically inquire about nocturnal asthma and to monitor the frequency and severity as this may be life-threatening. The home monitor- ing of asthma should record nocturnal awakenings and rescue medication use and include objective measures of pul- monary function such as PEFR. Patient education should include specific in- structions about the course of action to be taken if nocturnal asthma occurs including early telephone consultation with medical personnel in the event of a change in the frequency and severity of the nocturnal events. Relatives should also be instructed about the course of action to be taken. Nocturnal asthma is a sign of more severe disease reflecting more airway inflammation. Correspondingly, effective therapy with antiinflammatory medications is recommended and at present this

usually entails inhaled or even oral corticosteroids. The role of newer medications such as salmeterol and leukotriene inhibitors in asthma in gen- eral and nocturnal asthma in particular remains to be defined. Chronopharma- cologic considerations may help de- sign therapeutic regimens that may include nocturnal theophylline or long- acting oral or inhaled 2 agonists. The afternoon administration of oral corti- costeroids may also be indicated as discussed previously. General mea- sures that may require attention in- clude the identification and treatment of nocturnal gastroesophageal reflux, reduction of allergen load in the home and particularly in the bedroom, the exclusion of other non-asthmatic condi- tions such as sleep apnea, and heart fail- ure that may be concurrent with asthma.

Section Summary Nocturnal asthma is a marker of more severe disease. The physi- cian-patient partnership is impor- tant in educating the patient and his family how to manage nocturnal epi- sodes of asthma. Home monitoring with recording nocturnal symptoms will allow an objective assessment of NA and the response to management. The chronotherapeutic approach will usually include inhaled or even oral corticosteroids with the addition of theophylline, long-acting oral or in- haled 2 agonists with timing of ther- apy to give adequate effect during the night as discussed above.

CONCLUSION Nocturnal asthma results in consider- able morbidity and mortality. 2 This re- quires a concerted effort to elucidate the mechanisms of the nocturnal asthma exacerbations and to design therapy towards a maximal effect dur- ing the critical hours of the night. The further elucidation of the relative con- tributions of the circadian and sleep- wake cycles to the pathogenesis of NA may allow more specific therapeutic measures to be taken.

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Request for reprints should be addressed to:

Philip E Silkoff, MD National Jewish Medical and Research Center 1400 Jackson St Denver, CO 80206

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CME Examination Identification No 008-004 Questions 1–20, PE Silkoff and RJ Martin. 1998;81:378–387.

CME Test Questions

1. In the classical survey by Turner-Warwick, nocturnal

asthma was reported at least once a week by:

a. Less than 20% of subjects

b. At least 30% of subjects

c. At least 40% of subjects

d. At least 50% of subjects

e. At least 70% of subjects

2. Nocturnal asthma

a. is present in a minority of asthmatics

b. is a significant cause of morbidity and mortality

c. is well appreciated by prac- titioners

d. is not a significant health problem

e. while causing morbidity is rarely life-threatening

3. Asthma

a. has shown dramatic in- creases in recent years in the North American Conti- nent alone

b. has shown increases in many different geographi- cal locations

c. while increasing has not re- sulted in a rising mortality

d. is less common since the use of corticosteroids

e. is still primarily regarded as a disorder of smooth

muscle function

4. The recent NIH publication “Guidelines for the diagnosis and management of asthma” recommended antiinflamma- tory therapy for:

a. All severities of asthma

b. All severities except the mild persistent and mild in- termittent groups.

c. All severities except the mild intermittent group

d. The severe persistent group alone

e. The severe and moderate persistent groups alone.

5. Circadian rhythms:

a. Are entrained by the sleep wake cycle

b. Are controlled by a frontal lobe “pacemaker”

c. Are abolished if external stimuli such as light are re- moved

d. Continue to cycle in the ab- sence of external cues

e. Have a cycle of approxi- mately 22 hours in man.

6. The sleep-wake cycle

a. Is entrained by the circa- dian pacemaker

b. Is primarily under the con- trol of the circadian “pace- maker”

c. Is always synchronized with the circadian pace- maker

d. Alone controls the propen- sity to sleep

e. Is abolished in the absence of external cues

7. Circadian changes in spirome- try:

a. Are found in asthmatics only

b. Show the maximal values at 10 AM

c. Show minimal values in the early morning (2 to 4

AM)

d. Are only found in noctur- nal asthma

e. Are not associated with changes in nonspecific

bronchial reactivity in noc- turnal asthma

8. Airway resistance in asthma:

a. increases between 12 PM to

6 AM

b. falls at night in contrast to spirometric parameters

c. starts to increase at 4 PM

d. remains constant overnight if the subjects are kept awake.

e. increases as a result of changes in central airway caliber alone

9. In nocturnal asthma:

a. FRC increases greatly overnight reflecting dy- namic hyperinflation

b. FRC which is initially high falls during the night.

c. maintenance of FRC using external thoracic cage neg- ative pressure attenuates nocturnal bronchoconstric- tion

d. intrathoracic blood volume falls

e. vagal tone is decreased

10. Circulating cortisol levels

a. are maximal at 4 AM in noc- turnal asthma

b. show different circadian patterns in nocturnal as compared to non-nocturnal asthma

c. show trough levels in the late evening in asthmatics alone

d. show trough levels in the late evening in asthmatics and normal subjects

e. show trough levels at 4 PM in asthmatics

11. Steroid responsiveness

a. may be reduced in noctur- nal asthma as evidenced by glucocorticoid binding studies

b. can be assumed to be nor- mal as circulating hormone levels are unaltered in noc- turnal asthma

c. can be assumed to be nor- mal as patients respond to inhaled or oral steroids

d. is irrelevant to nocturnal asthma as glucocorticoid binding is unchanged in asthma

e. is impaired as shown by a lack of a therapeutic re- sponse to corticotrophin re- leasing factor in nocturnal asthma

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ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

12. Circulating catecholamines:

a. show an abnormal circa- dian pattern in nocturnal asthma

b. show maximal levels at the time of nocturnal broncho- constriction due to stress

c. show trough levels in the early morning in asthmat- ics alone

d. show trough levels in the early morning in asthmat- ics and non-asthmatics

e. show trough levels at 4 PM in nocturnal asthmatics as

this is the time of best lung function

13. IgE levels

a. are normal in asthma

b. are maximal during the night in nocturnal asthma

c. paradoxically fall at night in nocturnal asthma possi- ble due to increased tissue binding

d. show maximal levels at the same time as circulating histamine

e. peak at 8 PM in asthmatic subjects

14. Airway inflammation

a. increases from 4 PM to 4 AM in subjects with nocturnal bronchoconstriction

b. is present even in non-asth- matics at 4 AM compared to

4 PM

c. is increased at 4 PM com- pared to 4 AM as it takes 12 hours for this inflammation to result in bronchospasm

d. is present in central air- ways only in nocturnal asthma

e. has resolved by the time nocturnal bronchoconstric- tion develops

15. Concerning the sleep state:

a. sleep is essential for noc- turnal bronchoconstriction to occur

b. sleep results in a decrease in intrathoracic blood vol- ume

c. sleep if associated with sleep apnea can worsen nocturnal asthma

d. nasal CPAP improves sleep apnea but not nocturnal asthma

e. nasal CPAP helps subjects with nocturnal asthma even without sleep apnea

16. Gastroesophageal reflux

a. shows a clear relationship to nocturnal asthma

b. occurs in all subjects with nocturnal asthma due to mechanical effects on the lower esophageal sphincter

c. may play a role in the indi- vidual patient as evidenced by a lessening of nocturnal symptoms after anti-reflux measures

d. should be investigated in all subjects with nocturnal asthma

e. could cause asthma by stimulating esophageal 2 receptors

17. Chronopharmacology studies

a. are concerned with the side effects of chronic adminis- tration of drugs

b. suggest that the timing of oral steroid administration at 3 PM is optimal in noc- turnal asthma

c. suggest that the timing of inhaled corticosteroid ad- ministration at 8 AM is op- timal in nocturnal asthma

d. suggest that pituitary axis

suppression after steroids is not affected by time of ad- ministration

e. have shown that theophyl- line given only at night alone has a reduced clinical effect as compared to bid administration

18. Long-acting bronchodilators

a. are well-established first- line therapies in nocturnal asthma

b. should not be used in noc- turnal asthma for fear of worsening asthma

c. are important therapeutic options in nocturnal asthma

d. given at bedtime do not at- tenuate nocturnal broncho- spasm due to hyporespon- sive 2 receptors

e. can be safely substituted

for anti-inflammatory drugs

19. The overall approach to noc- turnal asthma requires

a. patient and family educa- tion

b. home monitoring of PEFR and symptoms

c. recognition that nocturnal asthma is a sign of disease severity

d. treatment with antiinflam- matory therapy, e.g. inhaled

corticosteroids in the major- ity of cases

e. all of the above

20. Nocturnal asthma

a. is a significant health prob- lem

b. is a good example of a cir- cadian disease

c. is associated with circadian changes in the severity of airway inflammation

d. is best managed with a chronopharmacological ap- proach

e. all of the above

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