review - pathophysiology of nocturnal asthma

Review articleSupported by an unrestricted grant from Zeneca Pharmaceuticals

Pathophysiology of nocturnal asthmaPhilip E Silkoff, MD and Richard J Martin, MD

Learning Objectives: This article will focus on the pathophysiologic changesunderlying the nocturnal worsening of asthma and the therapeutic approach to thisdisorder.

Data Sources:Selected articles appearing since 1985 dealing specifically withthe 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 pulmonaryfunction and increase of airway inflammation at night. The administration ofmedications must be designed to achieve the maximal effect during the night innocturnal asthma.

Conclusions:The further elucidation of the reasons underlying nocturnal asthmashould lead to more specific therapeutic interventions with maximal effect at night.

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

INTRODUCTIONAsthma, in common with many otherdisease processes, shows a pronouncedcircadian variation in the majority ofpatients who demonstrate a striking de-cline in lung function overnight termednocturnal asthma (NA). Nocturnalasthma is a marker for more severedisease and carries significant morbid-ity1 and mortality.2 The nocturnalworsening of asthma is well recog-nized by patients, but not always ap-preciated by practitioners. A classicsurvey conducted by Turner-Warwick3

included more than 7,600 asthma pa-tients and revealed that 74% of thosesurveyed awakened from sleep at leastonce per week with symptoms ofwheezing, chest tightness, or cough re-quiring inhaledb2 agonist use. Almost40% awakened nightly due to asthma

and 64% reported awakening at leastthree times per week.

Asthma incidence, with resultant in-creased morbidity and mortality, is ris-ing in western societies despite moderntherapy. Airway inflammation is re-garded as the primary abnormality un-derlying the manifestations of asthmasuch as airway obstruction and this hasbeen the focus of recent research andtherapy.4 A recent document “Guide-lines for the Diagnosis and Manage-ment of Asthma” by the NationalAsthma Education and Prevention Pro-gram of the National Institutes ofHealth5 recommended anti-inflamma-tory medication, eg, inhaled corticoste-roids in all severities of asthma exceptthe mildest category termed “the mildintermittent” group.

BACKGROUND

Biologic RhythmsChronobiology is the study of the bio-logic rhythms of physiologic andpathologic processes. Circadian cycleshave approximately a 24-hour period.The terms diurnal and nocturnal

strictly refer to the day and night peri-ods, respectively, and are part of thecircadian cycle as a whole. A mamma-lian circadian pacemaker located in thesuprachiasmal nucleus of the braincontrols many physiologic functionssuch as core temperature which itself isused to monitor the phase of the circa-dian rhythm. In man, the circadian cy-cle is about 24.1 hours in length andcontinues to cycle in the absence ofexternal stimuli such as ambient light.

The sleep-wake cycle, controlled bya sleep homeostat, also influencesphysiologic and pathologic processesand subserves a homeostatic function.Normally, the circadian rhythm en-trains the sleep-wake cycle to facilitatedaytime activity for humans and night-time activity for nocturnal species. Thecircadian and sleep-wake cycles, how-ever, can become desynchronized, eg,in international travel, a condition pop-ularly known as “jet lag.” Similar tocircadian rhythms, the sleep-wake cy-cle continues in the absence of externalstimuli. The intentional desynchroni-zation of the circadian and sleep cyclescan allow study of their separate phys-iologic effects (forced desynchrony).Both circadian and the sleep-wakerhythms control the propensity to sleepand wakefulness on a continuous basis.The balance between these two cyclesdetermines the sleep-wake pattern andalso 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 designmore effective therapy. The variationin asthmatic lung function may be un-der the control of both circadian andsleep-wake cycles. In addition, thestate of sleep itself has additional phys-

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 29,1998.

378 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

iologic effects such as change in pos-ture, fluid distribution, and muscletone. The relative contribution of thecircadian and sleep-wake cycle andsleep itself to nocturnal asthma are notcompletely understood.

CIRCADIAN CHANGES INPULMONARY FUNCTION INHEALTH AND DISEASE

Airflows and Bronchial ReactivityNormal and asthmatic subjects showcircadian variation in pulmonary func-tion as assessed by spirometric param-eters such as FEV1 and peak expiratoryflow rate (PEFR) which are maximalaround 4PM and lowest around 4AM.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 muchlarger. The change in airway caliber isassociated with a change in non-spe-cific airway reactivity. In one study,bronchial reactivity assessed by metha-choline challenge worsened overnightby factor of 8 in NA compared with afactor of 2 in NNA.7

Airway ResistanceThere are dynamic changes in airwayresistance overnight. In one study,lower airway resistance to airflow roseprogressively 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 measuredwith a bronchoscope according to themethod of Wagner et al9 increased at 4AM in NA compared to 4PM.10

Lung volumesFunctional residual capacity (FRC) isincreased in asthmatics as comparedwith normal subjects, a conditiontermed hyperinflation. An increasedFRC is associated with a greater air-way caliber and thus is beneficial. Bal-lard et al,11 using a horizontal bodyplethysmograph, measured FRC innon-asthmatic and asthmatic subjectsduring sleep. Functional residual ca-pacity which was higher in the asth-matics before the onset of sleep, fell inboth groups and equalized in the twogroups especially during rapid eyemovement phase sleep. The observedfall in FRC could account in part forthe increase in airway resistance whichoccurs in NA. In a subsequent study,however, application of a negativepressure device around the chest toreduce this decline in FRC did not alterthe overnight changes in FEV1 or bron-chial reactivity.12 Thus, the change in

airway caliber is not solely due to thereduction in FRC.

Intrathoracic blood volumeIn contrast to the FRC decline, Desjar-din et al13 reported that intrathoracicblood volume increased in NA subjects(but not in NNA or normal subjects)due to a shift of blood from peripheralvenous to central compartments. Theincreased lung blood volume couldcause 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 complianceand increased work of breathing.

Autonomic toneStimulation of the vagus nerve resultsin bronchoconstriction in normal andasthmatic subjects. Vagal tone is in-creased at night and this may worsenairway function. Morrison and col-leagues14 demonstrated that atropine, amuscarinic antagonist, resulted in animprovement in the 4AM PEFR in NAas compared with placebo.

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

CIRCADIAN HORMONALCHANGES IN HEALTHAND DISEASECirculating hormones vary in a circadianfashion in everyone and may contributeto overnight fall in lung function.

Adrenal Cortical HormonesPeak levels of circulating cortisol oc-cur upon awakening with trough levelsnoted between 10PM and midnight.15

The circadian change in cortisol is sim-ilar in both asthmatic and non-asth-matic individuals.16 The occurrence oftrough cortisol levels in the lateevening could set the scene for NA ascortisol exerts an anti-inflammatory ef-fect upon the chronically inflamed air-

Figure 1. Airway resistance (Ria, cm H2O/L/s) in 6 asthmatic subjects progressively increases frommidnight to 6AM (0600 h) independent of sleep (- -) but sleep itself has a profound effect on the increasein airway resistance (-●-). Reprinted with permission from reference 7.

VOLUME 81, NOVEMBER, 1998 379

ways of asthmatics. Additionally, theabsence of higher cortisol levels in theNA group could represent a deficiencyin cortisol production inappropriate tothe stress of bronchoconstriction. Cer-tainly, the administration of corticoste-roids attenuates nocturnal asthma17 asdoes the infusion of corticotrophin re-leasing factor (CRF).18 Finally, theremay be defects in the binding affinityof cortisol to glucocorticoid receptorsin asthma19 with decreased steroid-re-sponsiveness. Recently, a nocturnal re-duction in glucocorticoid binding andsteroid responsiveness has been dem-onstrated in peripheral blood mono-cytes in NA.20

Adrenal Medullary HormonesThe adrenal hormone epinephrine is abronchodilator due to stimulation ofairway b2 receptors and inhibits leak-age of histamine and other mediatorsfrom sensitized mast cells. Epineph-rine reaches peak levels during the af-ternoon hours with trough levels dur-ing the early morning hours.15 Thiscircadian pattern could promote NA byreducing bronchodilatation and by al-lowing the release of spasmogenic me-diators from mast cells. In one study,however, infusion of physiologic dosesof epinephrine lessened but did notabolish the overnight decline in airwaycaliber.15 This suggests that the circa-dian change in epinephrine is just onecomponent 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 duein part to a reduction in the number ofand/or physiologic response ofb2 re-ceptors located in the smooth muscleand inflammatory cells in the airways.Indeed a reduced density ofb-adren-ergic receptors has been noted on cir-culating leukocytes of asthmatic sub-jects with NA as compared with thosewith NNA and normal controls.21

While this reduction in receptors maybe a down regulation mechanism as aresult of previousb2 agonist therapy, areduced density of receptors has alsobeen reported on untreated asthmatics.This phenotypic down regulation may

be related to a genetic abnormality ofthe b2 receptor22 and thus lead to agenetic predisposition to NA.

Other HormonesOther circulating hormones may alsohave a pathogenic role in asthma. Anexample is melatonin,23–25 the cyclicvariation of which has been used tocharacterize the periodicity of the cir-cadian rhythm. Treatment with mela-tonin has been used by some to coun-teract jet lag.

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

CIRCADIAN CHANGES INAIRWAY INFLAMMATION INNOCTURNAL ASTHMAThe current concept of airway inflam-mation as the primary process in asth-ma4 has led to studies that examineairway cells and mediators at differenttime points in the circadian cycle. The

reason for airway inflammation inasthma and the exacerbation of thisinflammation at night are not yet clear.

IgE/Mast Cell InteractionIgE-mediated allergy is one importantmechanism underlying asthma withbinding of relevant allergens to IgE onairway mast cells resulting in degran-ulation and release of mediators, eg,histamine which causes broncho-spasm. Serum IgE is fivefold greater inasthma compared with nonallergiccontrols. In asthmatics, IgE levels peakaround midday and fall at night.26 Thispattern 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 thana fall in production. Serum histamine,a mast cell product, also varies in acircadian fashion with the peak levelscoinciding in time with the greatestbronchoconstriction, ie, 4AM.15 Thissuggests that mast cell activation isenhanced at night in NA.

Bronchoscopic Assessment ofAirway InflammationDirect sampling of lung cells and me-diators have generally shown that in-

Figure 2. The number per volume (Nv) of eosinophils in the nocturnal asthma (NA) and non-nocturnalasthma (NNA) groups are shown in the endobronchial (airway tissue-EBBX) and transbronchial (alveolartissue TBBX) biopsies at 4:00AM and 4:00PM. More eosinophils are present in TBBX at both time pointsin both NNA and NA. At 4:00PM, 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.


dices of inflammation increase from 4PM to 4 AM in asthmatics with NA. Inone recent study at our institution, (Fig2), bronchoalveolar lavage (BAL)fluid contained significantly more in-flammatory cells, eg, eosinophils andneutrophils in NA at 4AM comparedwith NNA, whereas at 4PM there wasno difference between the groups.27 Ina recent study, bronchial and trans-bronchial biopsies (sampling of alveo-lar tissue) were taken in subjects withand without NA.28 First, alveolar tissuein the NA group contained signifi-cantly increased inflammatory cellssuch as eosinophils and macrophageswhen compared with the NNA group.Second, the degree of alveolar inflam-mation was worse at 4AM comparedwith 4 PM in the NA group only. In thesame subjects, bronchial biopsies,which sample proximal large and me-dium sized airways, did not show thesame differences between the NA andNNA groups. The degree of eosino-philic alveolar infiltration correlatedwith the overnight decline in airwaycaliber. This study demonstrated theimportance of inflammation in the gasexchange area of the lung in the NAgroup associated with or even preced-ing nocturnal bronchospasm.

Section SummaryBronchoscopic studies have shownthat airway inflammation increasesat night in NA in BAL and evenextends into the gas exchange re-gions of the lung.

THE SLEEP STATE ANDASTHMAThe relationship between sleep itselfand asthma is not clear. The state ofsleep involves postural and neurophys-iologic changes. Bronchoconstrictionand the increase in airway resistancestill occur in NA during the night whenpatients are kept awake but thechanges observed are greater when thesubjects sleep.29 The state of sleep it-self does not seem essential for thedevelopment of NA. Finally, NA doesnot seem to be related to posturalchange 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 inairway tone.30

Section SummaryThe sleep state itself may play a rolein the pathogenesis of NA. The cir-cadian pattern in lung function per-sists in nocturnal asthmatics keptawake and in subjects who maintainthe supine posture throughout a 24-hour period.

OTHER FACTORS INVOLVEDIN THE PATHOGENESIS OFNOCTURNAL ASTHMA

Gastroesophageal RefluxAlthough gastroesophageal reflux dis-ease (GERD) is often discussed as apossible trigger for nocturnal broncho-spasm, Tan and colleagues31 studiedsubjects with NA and GERD using pHprobes in the esophagus to detect re-flux and found no correlation betweenincreased overnight acid secretion andnocturnal bronchospasm. During a trialof an H2 antagonist that reduces stom-ach acidity, inpatients with both symp-tomatic reflux and nocturnal broncho-spasm showed a small but significantimprovement in asthma symptoms butwith no change in morning PEFR.Asthmatics with GERD should cer-tainly be treated for their symptoms,but GERD does not appear to be asignificant trigger of nocturnal bron-chospasm.

Sleep ApneaChan et al32 reported that asthmaticswith 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 anybenefit.33 The association betweensleep apnea and asthma may involvestimulation of pharyngeal afferentscausing reflex bronchoconstriction, orother mechanisms such as hypoxia-in-duced bronchospasm or negative in-trathoracic pressure increasing lungblood volume.

THE TREATMENT OFNOCTURNAL ASTHMA

ChronopharmacologyChronopharmacology or chronotherapyis a branch of pharmacology that aims tooptimize therapy by taking into accountcyclical variation in a disease processand cyclical pharmacokinetics (drug ab-sorption and delivery) and pharmacody-namics (drug effects). The pharmacoki-netics and pharmacodynamics of certaindrugs may vary on a circadian basis andthis requires investigation so as to opti-mize therapy. The previous discussionhas outlined some of the pathogenic fea-tures that may underlie nocturnalasthma. There are, however, severalwell-established approaches to the treat-ment of NA which take into accountchronopharmacologic findings. The noc-turnal augmentation of inflammation inNA has led to the design of therapyaimed at preventing airway inflamma-tion and bronchospasm to maximizedrug effects overnight.

CorticosteroidsCorticosteroids are the cornerstone ofantiinflammatory therapy in asthmaand physicians attempt to maximizethe therapeutic effect while minimiz-ing systemic toxicity. On the toxicityside, one popular approach to therapyin Europe takes into account the circa-dian rhythm-dependent susceptibilityand tolerance of the body to the ad-verse effects of synthetic corticoste-roids. Inhibition of the brain hypotha-lamic-pituitary axis may result in alack of endogenous steroid hormone ifthe therapy is stopped abruptly withsymptoms such as weakness, apathy,and decreased circulatory volume. Thesusceptibility of the hypothalamic-pi-tuitary axis to suppression varies on acircadian basis being more susceptibleat night. In the European approach,two-thirds of the total daily dose istaken in the morning upon awakening,and the remaining one third is takenabout 8 hours later (approximately 3PM for most patients). On the therapeu-tic side, the therapeutic effect of corti-costeroids also demonstrates a circa-dian fluctuation.


In a placebo-controlled study, Beamet al17 examined nocturnal FEV1 fall,blood eosinophils and 4AM BAL cy-tology after 50 mg predisone given at 8AM, 3 PM, and 8 PM (six visits) in 7subjects. The study showed that the3-PM dose of oral prednisonealonere-sulted in a significant attenuation ofthe overnight fall in mean FEV1 from228.2% (placebo) to210.4% accom-panied by a significant FEV1 responseto bronchodilator. The mean FEV1 at 4AM was almost a liter better than thatseen on placebo. The 3PM dose re-sulted in a significant pancellular re-duction in BAL cytology not seen withthe 8AM or 8 PM dosing; thus, 3PM mayprove to be an effective and safe timeto administer oral corticosteroids fortreatment of reactive airway diseasewith nocturnal exacerbation. Inhaledsteroids, a first-line therapy for asthma,have also been evaluated chronothera-peutically. Pincus et al34 showed that 3PM dosing of inhaled steroid wasequally efficacious for improvement ofAM and PM PEFR and FEV1 as takingthe medication four times a day. Nei-ther regime was associated with evi-dence of pituitary axis suppressionwhich reflects systemic absorption ofthe medication.

TheophyllineTheophylline is a bronchodilator usedin COPD and asthma but may alsopossess anti-inflammatory effects.Many different preparations exist withdistinct pharmacokinetic properties.Twice-daily theophylline preparationsdesigned to produce consistent serumtheophylline concentrations give riseto varying serum levels over 24 hours.Other preparations produce highernighttime levels to meet increased noc-turnal demands without compromisingdaytime asthma control. Chronothera-peutic dosing of theophylline, once-daily in the evening around 6 to 7PM,attenuates nocturnal symptoms andearly morning bronchoconstrictionwithout deterioration in asthma controlat other times of the day. This regimenhas been found to be clinically superiorto conventional twice daily dosing.35–37

Lung function is improved by higher

serum theophylline levels during sleepwith preservation of sleep quality andarchitecture and less nocturnal oxygendesaturation.

Long-Acting BronchodilatorsSlow releaseb-agonist tablets, whichare used to maintain a longer period ofbronchodilation (10 to 12 hours), cansignificantly moderate the morning dipin airways patency in asthmatic pa-tients. Recently, the long-acting in-haledb2-agonist salmeterol has shownpromise in improving the overnightdecrement in lung function, but furtherevaluation is needed.38

Section SummaryAsthma varies in a circadian fash-ion, making it ideally suited forchronotherapy. The three classes ofmedications most efficacious for thechronotherapy of reactive airwaydisease are corticosteroids, slow-re-lease theophylline and slow-releaseb2 agonists. The benefits are mostpronounced in the asthma popula-tion, but these medications also ben-efit the COPD population, especiallythe long-acting theophylline prepa-rations.

THE OVERALL APPROACH TONOCTURNAL ASTHMAIt is important to specifically inquireabout nocturnal asthma and to monitorthe frequency and severity as this maybe life-threatening. The home monitor-ing of asthma should record nocturnalawakenings and rescue medication useand include objective measures of pul-monary function such as PEFR. Patienteducation should include specific in-structions about the course of action tobe taken if nocturnal asthma occursincluding early telephone consultationwith medical personnel in the event ofa change in the frequency and severityof the nocturnal events. Relativesshould also be instructed about thecourse of action to be taken. Nocturnalasthma is a sign of more severe diseasereflecting more airway inflammation.Correspondingly, effective therapywith antiinflammatory medications isrecommended and at present this

usually entails inhaled or even oralcorticosteroids. The role of newermedications such as salmeterol andleukotriene inhibitors in asthma in gen-eral and nocturnal asthma in particularremains to be defined. Chronopharma-cologic considerations may help de-sign therapeutic regimens that mayinclude nocturnal theophylline or long-acting oral or inhaledb2 agonists. Theafternoon administration of oral corti-costeroids may also be indicated asdiscussed previously. General mea-sures that may require attention in-clude the identification and treatmentof nocturnal gastroesophageal reflux,reduction of allergen load in the homeand particularly in the bedroom, theexclusion of other non-asthmatic condi-tions such as sleep apnea, and heart fail-ure that may be concurrent with asthma.

Section SummaryNocturnal asthma is a marker ofmore severe disease. The physi-cian-patient partnership is impor-tant in educating the patient and hisfamily how to manage nocturnal epi-sodes of asthma. Home monitoringwith recording nocturnal symptomswill allow an objective assessment ofNA and the response to management.The chronotherapeutic approach willusually include inhaled or even oralcorticosteroids with the addition oftheophylline, long-acting oral or in-haledb2 agonists with timing of ther-apy to give adequate effect during thenight as discussed above.

CONCLUSIONNocturnal asthma results in consider-able morbidity and mortality.2 This re-quires a concerted effort to elucidatethe mechanisms of the nocturnalasthma exacerbations and to designtherapy towards a maximal effect dur-ing the critical hours of the night. Thefurther elucidation of the relative con-tributions of the circadian and sleep-wake cycles to the pathogenesis of NAmay allow more specific therapeuticmeasures to be taken.


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KF, et al. Morbidity in nocturnal asthma:sleep quality and daytime cognitive per-formance. Thorax 1991;46:569–573.

2. Hetzel MR, Clark TJ, BranthwaiteMA. Asthma: analysis of suddendeaths and ventilatory arrests in hospi-tal. Br Med J 1977;1:808–811.

3. Turner-Warwick M. Epidemiology ofnocturnal asthma. Am J Med 1988;85:6–8.

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7. Martin RJ, Cicutto LC, Ballard RD.Factors related to the nocturnal wors-ening of asthma. Am Rev Respir Dis1990;141:33–38.

8. Ballard RD, Saathoff MC, Patel DK, etal. Effect of sleep on nocturnal bron-choconstriction and ventilatory pat-terns in asthmatics. J Appl Physiol1989;67(1):243–249.

9. Wagner EM, Liu MC, Weinmann GG,et al. Peripheral lung resistance in nor-mal and asthmatic subjects. Am RevRespir Dis 1990;141:584–588.

10. Kraft M, Pak J, Martin RJ, Irvin CJ.Peripheral airways resistance increasesat night in nocturnal asthma [Abstract].Am J Respir Crit Care Med 1997;155:A679.

11. Ballard RD, Irvin CG, Martin RJ, et al.Influence of sleep on lung volume inasthmatic patients and normal subjects.J Appl Physiol 1990;68:2034–2041.

12. Martin RJ, Pak J, Irvin CG. Effect oflung volume maintenance during sleepin nocturnal asthma. J Appl Physiol1993;75:1467–1470.

13. Desjardin JA, Sutarik JM, Suh BY,Ballard RD. Influence of sleep on pul-monary capillary volume in normaland asthmatic subjects. Am J RespirCrit Care Med 1995;152:193–198.

14. Morrison JF, Pearson SB. The effect ofthe circadian rhythm of vagal activityon bronchomotor tone in asthma. Br JClin Pharmacol 1989;28:545–549.

15. Barnes P, FitzGerald G, Brown M,Dollery C. Nocturnal asthma andchanges in circulating epinephrine,

histamine, and cortisol. N Engl J Med1980;303:263–267.

16. Kraft M, Pak J, Martin RJ. Serum cor-tisol in asthma: marker of nocturnalworsening of symptoms and lung func-tion? Chronobiol Int 1998;15:85–92.

17. Beam WR, Weiner DE, Martin RJ.Timing of prednisone and alterationsof airways inflammation in nocturnalasthma. Am Rev Respir Dis 1992;146:1524–1530.

18. Georges G, Kraft M, Vianna EO, Mar-tin RJ. Human corticotrophin-releasinghormone improves overnight FEV1 innocturnal asthma. J Asthma 1998;35(3):261–265.

19. Spahn JD, Leung DY, Surs W, et al.Reduced glucocorticoid binding affin-ity in asthma is related to ongoing al-lergic inflammation. Am J Respir CritCare Med 1995;151:1709–1714.

20. Kraft M, Vianna E, Martin RJ, LeungDYM. Nocturnal asthma is associatedwith reduced glucocorticoid receptorbinding affinity and decreased steroidresponsiveness at night. J Allergy ClinImmunol 1998; (In Press)

21. Szefler SJ, Ando R, Cicutto LC, et al.Plasma histamine, epinephrine, corti-sol, and leukocyte beta-adrenergic re-ceptors in nocturnal asthma. Clin Phar-macol Ther 1991;49:59–68.

22. Turki J, Pak J, Green SA, et al. Geneticpolymorphisms of the beta 2-adrenergicreceptor in nocturnal and nonnocturnalasthma. Evidence that Gly16 correlateswith the nocturnal phenotype. J Clin In-vest 1995;95:1635–1641.

23. Weekley LB. Influence of melatoninon bovine pulmonary vascular andbronchial airway smooth muscle tone.Clin Auton Res 1995;5:53–56.

24. Weekley LB. Effects of melatonin onpulmonary and coronary vessels areexerted through perivascular nerves.Clin Auton Res 1993;3:45–47.

25. Lopes C, deLyra JL, Markus RP, Mari-ano M. Circadian rhythm in experi-mental granulomatous inflammation ismodulated by melatonin. J Pineal Res1997;23:72–78.

26. Gaultier C, De Montis G, Reinberg A,Motohashi Y. Circadian rhythm of se-rum total immunoglobin E (IgE) inasthmatic children. Biomed Pharmaco-ther 1987;41:186–188.

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28. Kraft M, Djukanovic R, Wilson S, et

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29. Ballard RD, Saathoff MC, Patel DK, etal. Effect of sleep on nocturnal bron-choconstriction and ventilatory pat-terns in asthmatics. J Appl Physiol1989;67:243–249.

30. Ballard RD, Pak J, White DP. Influ-ence of posture and sustained loss oflung volume on pulmonary function inawake asthmatic subjects. Am Rev Re-spir Dis 1991;144:499–503.

31. Tan WC, Martin RJ, Pandey R, BallardRD. Effects of spontaneous and simu-lated gastroesophageal reflux on sleep-ing asthmatics [see comments]. AmRev Respir Dis 1990;141:1394–1399.

32. Chan CS, Woolcock AJ, Sullivan CE.Nocturnal asthma: role of snoring andobstructive sleep apnea. Am Rev Re-spir Dis 1988;137:1502–1504.

33. Martin RJ, Pak J. Nasal CPAP in non-apneic nocturnal asthma. Chest 1991;100:1024–1027.

34. Pincus DJ, Humeston TR, Martin RJ.Further studies on the chronotherapyof asthma with inhaled steroids: theeffect of dosage timing on drug effi-cacy. J Allergy Clin Immunol 1997;100:771–774.

35. Martin RJ, Cicutto LC, Ballard RD, etal. Circadian variations in theophyllineconcentrations and the treatment ofnocturnal asthma [published erratumappears in Am Rev Respir Dis 1989Apr;139(4):1065]. Am Rev Respir Dis1989;139:475–478.

36. Grossman J. Multicenter comparisonof once-daily Uniphyl tablets adminis-tered in the morning or evening withbaseline twice-daily theophylline ther-apy in patients with nocturnal asthma.Am J Med 1988;85:11–13.

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Request for reprints should be addressed to:Philip E Silkoff, MDNational Jewish Medical and Research Center1400 Jackson StDenver, CO 80206


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

CME Test Questions1. In the classical survey by

Turner-Warwick, nocturnalasthma was reported at leastonce a week by:a. Less than 20% of subjectsb. At least 30% of subjectsc. At least 40% of subjectsd. At least 50% of subjectse. At least 70% of subjects

2. Nocturnal asthmaa. is present in a minority of

asthmaticsb. is a significant cause of

morbidity and mortalityc. is well appreciated by prac-

titionersd. is not a significant health

probleme. while causing morbidity is

rarely life-threatening3. Asthma

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

b. has shown increases inmany different geographi-cal locations

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

d. is less common since theuse of corticosteroids

e. is still primarily regardedas a disorder of smoothmuscle function

4. The recent NIH publication“Guidelines for the diagnosisand management of asthma”recommended antiinflamma-tory therapy for:a. All severities of asthmab. All severities except the

mild persistent and mild in-termittent groups.

c. All severities except themild intermittent group

d. The severe persistent groupalone

e. The severe and moderatepersistent groups alone.

5. Circadian rhythms:a. Are entrained by the sleep

wake cycleb. 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 cyclea. Is entrained by the circa-

dian pacemakerb. Is primarily under the con-

trol of the circadian “pace-maker”

c. Is always synchronizedwith the circadian pace-maker

d. Alone controls the propen-sity to sleep

e. Is abolished in the absenceof external cues

7. Circadian changes in spirome-try:a. Are found in asthmatics

onlyb. Show the maximal values

at 10AM

c. Show minimal values inthe early morning (2 to 4AM)

d. Are only found in noctur-nal asthma

e. Are not associated withchanges in nonspecificbronchial reactivity in noc-turnal asthma

8. Airway resistance in asthma:a. increases between 12PM to

6 AM

b. falls at night in contrast tospirometric parameters

c. starts to increase at 4PM

d. remains constant overnight ifthe subjects are kept awake.

e. increases as a result ofchanges in central airwaycaliber alone

9. In nocturnal asthma:a. FRC increases greatly

overnight reflecting dy-namic hyperinflation

b. FRC which is initially highfalls during the night.

c. maintenance of FRC usingexternal thoracic cage neg-ative pressure attenuatesnocturnal bronchoconstric-tion

d. intrathoracic blood volumefalls

e. vagal tone is decreased10. Circulating cortisol levels

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

b. show different circadianpatterns in nocturnal ascompared to non-nocturnalasthma

c. show trough levels in thelate evening in asthmaticsalone

d. show trough levels in thelate evening in asthmaticsand normal subjects

e. show trough levels at 4PM

in asthmatics11. Steroid responsiveness

a. may be reduced in noctur-nal asthma as evidencedby glucocorticoid bindingstudies

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

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

d. is irrelevant to nocturnalasthma as glucocorticoidbinding is unchanged inasthma

e. is impaired as shown by alack of a therapeutic re-sponse to corticotrophin re-leasing factor in nocturnalasthma


12. Circulating catecholamines:a. show an abnormal circa-

dian pattern in nocturnalasthma

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

c. show trough levels in theearly morning in asthmat-ics alone

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

e. show trough levels at 4PM

in nocturnal asthmatics asthis is the time of best lungfunction

13. IgE levelsa. are normal in asthmab. are maximal during the

night in nocturnal asthmac. paradoxically fall at night

in nocturnal asthma possi-ble due to increased tissuebinding

d. show maximal levels at thesame time as circulatinghistamine

e. peak at 8PM in asthmaticsubjects

14. Airway inflammationa. increases from 4PM to 4 AM

in subjects with nocturnalbronchoconstriction

b. is present even in non-asth-matics at 4AM compared to4 PM

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

d. is present in central air-ways only in nocturnalasthma

e. has resolved by the timenocturnal bronchoconstric-tion develops

15. Concerning the sleep state:a. sleep is essential for noc-

turnal bronchoconstrictionto occur

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

c. sleep if associated withsleep apnea can worsennocturnal asthma

d. nasal CPAP improves sleepapnea but not nocturnalasthma

e. nasal CPAP helps subjectswith nocturnal asthma evenwithout sleep apnea

16. Gastroesophageal refluxa. shows a clear relationship

to nocturnal asthmab. occurs in all subjects with

nocturnal asthma due tomechanical effects on thelower esophageal sphincter

c. may play a role in the indi-vidual patient as evidencedby a lessening of nocturnalsymptoms after anti-refluxmeasures

d. should be investigated inall subjects with nocturnalasthma

e. could cause asthma bystimulating esophagealb2

receptors17. Chronopharmacology studies

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

b. suggest that the timing oforal steroid administrationat 3 PM is optimal in noc-turnal asthma

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

d. suggest that pituitary axissuppression after steroids isnot affected by time of ad-ministration

e. have shown that theophyl-line given only at nightalone has a reduced clinicaleffect as compared to bidadministration

18. Long-acting bronchodilatorsa. are well-established first-

line therapies in nocturnalasthma

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

c. are important therapeuticoptions in nocturnal asthma

d. given at bedtime do not at-tenuate nocturnal broncho-spasm due to hyporespon-sive b2 receptors

e. can be safely substitutedfor anti-inflammatory drugs

19. The overall approach to noc-turnal asthma requiresa. patient and family educa-

tionb. home monitoring of PEFR

and symptomsc. recognition that nocturnal

asthma is a sign of diseaseseverity

d. treatment with antiinflam-matory therapy, e.g. inhaledcorticosteroids in the major-ity of cases

e. all of the above20. Nocturnal asthma

a. is a significant health prob-lem

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

c. is associated with circadianchanges in the severity ofairway inflammation

d. is best managed with achronopharmacological ap-proach

e. all of the above


review - pathophysiology of nocturnal asthma

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