Allergology International (1997) 46: 17-24

Review Article

Nocturnal asthma: Understanding chronobiology and

chronotherapy

Richard J Martin
Pulmonary Division, National Jewish Center for Immunology and Respiratory Medicine and Universityof
Colorado Health Sciences Center, Denver, Colorado, USA

ABSTRACT Figure 1 schematically shows the circadian rhythm

change in lung function in both normal subjects and asth-
The field of chronobiology and chronotherapy in
matic patients.3 Even in normal subjects there is a day-
medicine is in its relative infancy. However, important
to-day change in lung function. The best lung function
knowledge has been gained so as to better understand
occurs around 4pm and the worst lung function approx-
both the pathophysiology of diseases and the corre-
imately 4am with about an 8% change in the normal
sponding therapeutic interventions. Asthma is one of
the disease entities that has been studied in detail in population. The asthmatic patients, however, start with a
lower lung function level, but independent of medications
regard to both time related alterations in pathophysiol-
still have the highest peak flow rates at approximately
ogy and treatment. This article reviews the nocturnal
4pm and the lowest at approximately 4am. The asth-
worsening of asthma.
matic population, however, can have much more dra-
matic overnight decrements in lung function than the
Key words: chronobiology, chronotherapy, nocturnal
normal population.
asthma, pathophysiology.
Bronchial hyperresponsiveness has been evaluated
between 4pm and 4am in two asthmatic groups.4 One
INTRODUCTION
group was an asthmatic control population, and the
Asthma is a disease particularly suited to a discussion of other had nocturnal asthma. As can be seen in Fig. 2,
chronobiology and chronotherapy because the pattern of
the disease often changes from the waking to the sleep-
ing state. Dr John Floyer describing his own asthma in
1698 wrote, 'I have observed the fit always to happen
after sleep in the night, when the nerves are filled with
windy spirits and the heat of the bed has rarefied the spir-
its and humours.'1 Dr Floyer is giving us an insight into
what our asthma patients experience at night. DrTurner-
Warwick demonstrated in a very large population study of
almost 8000 asthmatic outpatients that 39% had symp-
toms of asthma every night, 64% at least three nights per
week and 74% at least one night per week.2 Thus, the
asthmatic patient who appears stable during the daytime
hours may in fact have marked worsening of asthma at
night.
Fig. 1 Peak expiratory flow rate (PEFR)and forced expiratory
Correspondence: Dr Richard J Martin, National Jewish Center volume in 1 second (FEV1)are schematically shown for normal
for Immunology and Respiratory Medicine, 1400 Jackson subjects and asthmatic patients. For both groups, the peak lung
Street, Room J116, Denver, Colorado 80206, USA. E-mail: function occurs at approximately 4pm (1600h) and nadir lung
〈martinr@njc.org〉 function at 4am (0400h). (Reprinted with permission from
Received 25 November 1996. Ref. 49.)
18 RJ MARTIN

Fig. 2 Bronchial hyperresponsiveness increases by approxi- Fig. 3 Airway resistance (Rla) in six asthmatic patients progres-
mately two-fold from 4pm (1600h) to 4am (0400h) in a sively increases from midnight (0000h) to 6am (0600h) inde-
group of asthmatic subjects who have small alterations in their penden†ot sleep (□), but sleep itselt has a profound effect on

FEV1(control group) and by eight-fold in the nocturnal asthma increased airway resistonce (●). (Reprinted With permission

group. (Drawn from data from Ref. 50.) from Ref. 4.)

Fig. 4 The complex interactions between various factors leading to the nocturnal worsening of asthma. Epi, epinephrine; SaO
2'
oxygen saturation. (Reprinted with permission from Ref. 49.)

even the asthma control population from 4pm to 4am Does sleep itself alter the asthma rate? As shown in
had a worsening of bronchial reactivity. However, the Fig. 3 there was a progressive increase in airway resis-
nocturnal asthma group had a much greater increase in tance from midnight until 6am, independent of sleep.
bronchial reactivity during the night. Sleep itself produces a further worsening of lung function
 NOCTURNAL ASTHMA 19

(increasing in airway resistance).5 This worsening of air- of lung function at night or in normal individuals this cir-
way function overnight is not caused by a single process. radian alteration in β-2 receptors does not occur. These

Although we do not know all the interactions involved, differences appear to be related to a genetic polymor-
what is becoming evident is that there is a complex inter- phism. Those individuals with nocturnal asthma have a
action of many factors (Fig. 4). significantly higher genetic make-up for the Gly-16 poly-
morphism of the β-2 adrenergic receptor, which is asso-

dated with down-regulation of the receptor.11

MECHANISMS OF NOCTURNAL CHANGES IN
AIRWAYFUNCTION
Cholinergic tone
Neurohormonal changes
There is evidence to suggest that cholinergic or vagal
Several neurohormones vary in a circadian fashion and
tone is increased at night, thus contributing to the circa-
are thought to contribute to the overnight fall in lung
dian change in airway function. Morrison et al. adminis-
function. Cortisol is known to vary in a circadian fashion,
tered atropine intravenously to subjects with nocturnal
with peak levels occurring upon awakening and trough
asthma and found improvement in the 4am PEFR as
levels around midnight.6 These changes are seen in both
compared with a placebo.12 Kallenbach et al. studied the
asthmatic and non-asthmatic individuals and thus alone
heart rate variations induced by deep breathing, Valsalva
are not felt to be responsible for the exaaaerated over-
maneuver and standing from the recumbent position in
night fall in peak expiratory flow rate (PEFR)seen in asth-
asthmatic and non-asthmatic subjects.13 The asthmatic
matics. However, the decreased levels at night certainly
subjects had evidence of enhanced parasympathetic
contribute to the nocturnal asthma process as cortisol is
neural drive to the sinoatrial node consistent with
thought to exert an anti-inflammatory effect upon the
increased parasympathetic activity, both during the day
chronically inflamed airways of asthmatics.
and night.
Epinephrine also varies in a circadian fashion, with
peak levels during the afternoon hours and trough levels
during the early morning hours.6 Patients with nocturnal Plasma cyclic adenosine monophosphate
asthma who were infused with physiologic doses of epi- Plasma cyclic adenosine monophosphate (CAMP)exhibits
nephrine lessened but did not abolish their overnight a prominent high amplitude circadian rhythm with the
decline in PEFR.6Although epinephrine varies in a circa- highest levels at 4pm and the lowest at 4am, correlating
dian fashion in both asthmatic and non-asthmatic sub- to the time of the lowest airway patency.6 The pattern is
jects, asthmatics may experience bronchoconstriction due similar in both asthmatics and non-asthmatics, although
to decreased responsiveness to epinephrine. For example, the 24-hour mean tends to be somewhat greater in non-
a reduced density of β-adrenergic receptors has been
asthmatics. Changes in plasma CAMP over the day and
noted on circulating leukocytes of asthmatic subjects.'-8
night probably reflect epinephrine-mediated activation of
This down-regulation of receptors may represent previous tissue adenyl cyclase.
β-2 agonist therapy, but a reduced density of receptors
has also been reported on untreated asthmatics.9 Epi-
Inflammatory cells and mediators
nephrine also relaxes airway smooth muscle and inhibits
leakage of histamine and other mediators from sensitized Asthma appears to be a disease at least partially asso-
mast cells. Thus, circadian changes in circulating epi- ciated with and modulated by inflammation. The inflam-
nephrine may promote asthma at night both by reducing matory cell most characteristic of asthma remains the
bronchodilatation and by contributing to a 'permissive' eosinophil,14 but contributions by macrophages, lympho-
release of spasmogenic mediators from mast cells. cytes and possibly neutrophils remain the focus of many
current investigations.
From a chronobiologic perspective, Martin et al. have
Beta-2 adrenergic receptors
implicated eosinophils in the pathogenesis of nocturnal
Both the receptor density (number) and the physiologic worsening of asthma by showing that asthmatics who are
response to isoproterenol decrease at 4am in patients prone to nocturnal worsening have increased recruitment
with nocturnal asthma.10 In asthmatics without worsening of eosinophils into their 4am bronchoalveolar lavage
20 RJ MARTIN

(BAL)fluid.15This phenomenon is not seen in asthmatics erbation of nocturnal bronchospasm.22 However, during
without nocturnal worsening. a trial of an H2 antagonist in patients with both sympto-
Circadian variation in blood eosinophil numbers has matic GERD and nocturnal bronchospasm, a small sig-
been demonstrated in asthmatics with a nadir at 10am nificant improvement in asthma symptoms was seen.23
and a maximum concentration near midnight.16 In that There was no change in morning PEFR. Thus, asthmatics
study, the 4pm and 4am counts were similar. This raises with GERD should certainly be treated for their symptoms,
the possibility that peak blood eosinophil levels precede but at present GERD does not appear to be a significant
the increase of eosinophils seen in the airway. Conse- trigger of nocturnal bronchospasm.
quently, nocturnal worsening of asthma and circadian
eosinophil trafficking into the lung appear to be related
CHRoNoTHEPEuTIc
RAINTERVENTIONS IN
events.
ASTHMA
In addition to eosinophils, T lymphocytes are com-
monly found in the inflammatory milieu associated with With understanding of the chronobiology of asthma, we
severe asthma.17-19 The observations that blood T lym- now see the importance of assessing the disease manifes-
phocytes expressing the interleukin-2 receptor are ele- tations, as they differ in the day and in the night. For those
vated in patients with acute, severe asthma, that T patients with marked nocturnal worsening of disease,
lymphocytes appear to emigrate from the circulatory pool pharmacotherapy must be altered to specifically tailor
into the lung following allergen challenge, and that mod- treatment for sleep hours. Even in the treatment of
els of eosinophilic inflammation are T-lymphocyte-medi- asthma that does not worsen at night, there may be opti-
ated suggests a role for lymphocytes in asthmatic mal timing of medication use to provide maximal efficacy
inflammation.20 In asthmatics prone to nocturnal worsen- and minimal toxicity.These issues will be addressed in the
ing, elevated BAL lymphocyte numbers have been following discussion of the many pharmacologic agents
demonstrated at 4am, the typical nadir of overnight lung now available for the treatment of asthma.
function.15 These observations support a role for lympho-
cytes in the pathogenesis of nocturnal asthma and sug-
Corticosteroids
gest a situation in which biologic rhythms may influence
inflammatory events by altering an available pool of cir- Although numerous investigators have demonstrated that
culating cells. Many mediators of bronchoconstriction corticosteroid side-effects, such as adrenal suppression,
have been shown to be elevated at night. are influenced by the dosing schedule as well as the
dosage, the alternative approach of evaluating differ-
ences in corticosteroid efficacy by varying dose schedules
Exogenous factors
has received less attention. Recognition that cortico-
Exogenous environmental factors can be important trig- steroid administration should be adjusted to achieve the
gering factors in the overnight decrement in lung function. most favorable balance between time-dependent varia-
Exposure to specific agents during the daytime is not only tions in both efficacy and adversity is central to therapeu-
capable of provoking acute asthma, but also in producing tic success.
a late asthmatic response that may result in nocturnal Reinberg et al. have a sustained interest in the time-
symptoms. In addition, the late asthmatic response has dependent pharmacology of corticosteroids with respect
been found to be more profound and more prolonged in to efficacy in managing asthma.24-27 Their studies have
subjects challenged with antigen later in the day.21 shown repeatedly the importance of time-related dosing
with afternoon superiority in efficacy and no increase in
side effects.
Gastroesophageal reflux
To better clarify the contribution of the timing of
Although gastroesophageal reflux disease (GERD) is corticosteroids to their ability to block circadian recruit-
often discussed as a possible trigger for nocturnal bron- ment of inflammatory cells into the lung and attenuate the
chospasm, Tan et al. studied subjects with nocturnal nocturnal worsening of asthma, Beam et al. evaluated
asthma and GERD using pH probes and found no corre- the response of blood eosinophil counts, BAL cytology,
lation with increased overnight acid secretion and exac- and overnight pulmonary function to a single, variably
 NOCTURNAL ASTHMA 21

timed dose of prednisone.28 Seven asthmatic males with ration, which produced relatively constant therapeutic
stable, well-controlled daytime asthma but persistent noc- serum theophylline concentrations in the 11-14μg/mL

turnal worsening of spirometry were treated in a double- range, was not as effective in treating patients as a single-
blind placebo controlled design with a single 50mg dose daily preparation giving peaks of approximately 15-16
of prednisone at dose times of 8am or 3pm or 8pm. mg/mL during the sleep-related hours and falling to as
Compared with the placebo, a single prednisone dose at low as 7-8μg/mL during the daytime hours.36 Com-

3pm resulted in a reduction in the overnight percent fall paring the FEV, measured every 2h during the daytime
in FEV1 and improvement in the inflammatory environ- showed no difference. Again, this is due to the fact that
ment of the airways. In contrast, neither the 8 am nor the during the daytime lung function, independent of medi-
8pm prednisone dose when compared to placebo cation, is at its best. Thus, to produce a given amount of
resulted in overnight spirometric improvement. bronchodilatation during the daytime, it does not take
In a study by Pincus et al. using inhaled steroids in a as high a drug level. Conversely, the improvement in
general asthma population, the 3pm dose timing effect the overnight decrement in lung function indeed
was again evaluated.29 In that study, a single dose of depended upon a higher serum theophylline concentra-
800μg of triamcinolone acetonide at 3pm was com- tion. Although the traditional way of giving theophylline
pared tothe sametotal dose divided into 200μg given at produced a therapeutic nocturnal theophylline level,
7am, noon, 7pm and 10pm. The group receivingthe there still was approximately a 28% fall in the FEV1
3pm inhaled steroidhad improvementequivalentto that overnight. With the higher serum theophylline con-
seen in the four timesa day dosing group as measured by centration, the overnight decrement in FEV1 was only

FEY1,morningand evening peak flow rates, and the use approximately 9%.
of β-agonists. Previous studies examining dosage sched- D'Alonzo et al. also demonstrated that time-related
ule effect had already demonstrated that four-times-a- drug levels resulted in improvements of lung function.39
day scheduling was the most consistently effective These investigators looked at the effects over a 4-hour
treatment schedule for inhaled steroids in asthmatic block of time from 2 to 6pm compared with 2 to 6am. In
patients.30,31 Therefore, the finding that 3pm dosing for the afternoon they did not find a significant correlation of
inhaled steroids was as effective as four times daily dos- increasing serum theophylline concentrations with
ing again provided evidence for the value of the 3pm improvement in FEV1. This is similar to many other day-
dosage time in asthma therapy for corticosteroids. In time studies.36,38 However, looking at the 4-hour time
addition, the group receiving 3pm treatment had no block from 2 to 6am these investigators did find a pro-
greater evidence of adrenal suppression or drug toxicity gressive and significant increase in the FEV1as the serum
than the four-times-a-day treatment group. theophylline concentration was increasing.
With evidence pointing to the importance of mid-after- Do theophyllines grossly disturb sleep? In the study by
noon steroid dosing in asthma, the question of possible Martin et al. no significant difference was found between
time-dependent adverse effects must be addressed. Well- the higher and lower serum theophylline concentrations
controlled studies have shown between 8am and 4pm, in regard to polysomnographic evaluation.36 The sleep
adrenal suppression with oral steroids is equivalent.32,33 latency (how long it takes an individual to go to sleep),
After 6pm and approaching 11pm is where adrenal the sleep efficiency (how well the patient sleeps), and the
suppression is the highest.32,34 different sleep stages were not different between the two
levels of theophylline. Of interest, with the higher serum
theophylline concentration there was a marked reduction
Theophylline
in the amount of oxygen desaturation that occurred over-
Many studies have now shown that dosing theophylline night. Other studies of normal subjects have shown mini-
on a time-related basis is superior to the standard home- mal to no adverse effects of theophylline on sleep
ostatic dosing.35-38 That is, a relatively constant serum characteristics or daytime function,40,41
theophylline concentration over a 24-hour period is not Thus, if theophylline is selected to be used as therapy in
as beneficial to the asthmatic individual as having peaks an asthmatic individual, higher levels should be obtained
and troughs at the appropriate times of day. Martin et al. during sleep (15μg/mL) and then the level can fall dur-

have shown that giving a twice-daily theophylline prepa- ing the daytime (7-9μg/mL).
22 RJ MARTIN

Slow-release β-adrenergic agonist therapy worsening of asthma. Further studies on optimal dosing
and the risk of tolerance to the beneficial effects of these
Slow-release (SR) β-agonist tablets can significantly mod-
medications are still needed.
erate the morning dip in airway patency in asthmatic
patients. In this regard, Postma et al. showed the advan-
Anticholinergics
tage of an unequal morning-evening treatment schedule
(one-third daily dose at 8am and two-thirds at 8pm) for Because vagal tone increases in all of us at night, this is
terbutaline.42 Despite the potential of this class of med- one possible mechanism of circadian alteration in lung
ication, only a limited number of published investigations function. Many studies have not demonstrated a benefit
have addressed the utilityof these drugs as an evening of vagalytics, such as atropine or ipratropium bromide,
chronotherapy for alleviating nocturnal asthma. Moore- but these studies have all been done during the daytime
Gillon evaluated the efficacy of an 8mg dose of albu- (unpubl. data). Morrison et al. have shown that one can
terol in patients with nocturnal symptoms.43 Evening SR indeed see marked bronchodilatation depending on the
albuterol resulted in a significant increase in morning time of day the anticholinergic medication is given.12,49
PEFR and a decrease in wheezing and shortness of breath That is, during the daytime hours they found only slight
as compared with placebo.43 Furthermore, evening SR bronchodilatory effects from atropine. However, at 4am
albuterol dosing was associated with significantly there was a marked improvement in PEFR to approxi-
reduced daytime symptom scores of wheeze, shortness of mately the daytime levels. This strongly supports the need
breath and sputum production.43,44 Finally, the recently for us to understand when and how to use certain med-
released long-acting inhaled B-2 agonist salmeterol has ications. The problem with any vagalytic medication is
shown promise in improving the overnight decrement in that the duration of effect is not particularly long. Thus,
lung function. In a 12 month study of moderate asth- even if given only at bedtime, within 2-3 h the potency of
matics comparing short-acting inhaled salbutamol with the medication will have been eliminated.
long-acting salmeterol, the patient group receiving the It is still important to keep in mind that vagalytics can
long-acting salmeterol showed greater improvement in play a role in asthma. That is, if the patient is having diffi-
lung function, symptom scores, nocturnal awakening, culty during the sleep-related hours and commonly
and use of additional bronchodilator.45 There was no evi- awakens without experiencing benefit from other inter-
dence for deterioration of asthma control during the ventions then one may strongly consider the use of an
long-term administration of this medication. This was of agent such as ipratropium bromide at the time of these
particular importance in view of the concern that long- awakenings during the middle of the night.
term use of regular β-agonists might decrease asthma

control.46 Another study carried out over 3 months con-

CONCLUSION
firmed the greater efficacy of long-acting salmeterol over
salbutamol, especially for nocturnal worsening of There is no doubt that many pathophysiologic conditions
asthma.47 In addition, no increased adverse effects or change over a 24-hour period and thus therapy needs to
decreased asthma control were seen with the salmeterol be directed at these changes. In particular, asthma has
group. been one of the better studied disease processes in
Fitzpatrick et al. evaluated a dose comparison of 50 regard to circadian changes in pathophysiology.50As we
and 100μg of salmeterol inhaled twice daily.48 Both continue to learn more about circadian changes, better
doses were found to produce similar improvement in approaches to treating the disease with the same med-
nocturnal asthma lung function but only the 50μg dose ications will emerge. It should be remembered that many
objectivity improved sleep quality; the patients spent less asthmatics do not perceive the degree of bronchocon-
time awake or in light sleep and more time in stage 4 striction that they have. This was brought forth in
slow wave sleep compared with the placebo. It appears Margaret Turner-Warwick's epidemiological study in that
that the higher dose of salmeterol may have had a stimu- less than one-half of the asthmatic individuals who had
latory effect on the central nervous system. problems with their asthma every night describe their
Therefore, it appears that the longer acting inhaled β- asthma as being severe.2 The majority stated they either
agonists are suited for use in patients with nocturnal had mild or moderate asthma. Therefore, it is important
 NOCTURNAL ASTHMA 23

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determining an individual patient's day-to-night changes eosinophil leukocytes in normal controls and asthmatics.
Acta Allergol. 1977; 32: 301-3.
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