Download Bronchial Asthma: Use of Inhalant Glucocorticoids and

D Z I A Ł
Prof. Dr.
Volker Wahn
Brandenburg Allergy
and Asthma Center
for Children
and Adolescents,
Klinikum Uckermark,
Schwedt/Oder
Z A G R A N I C Z N Y
Bronchial Asthma:
Use of Inhalant
Glucocorticoids and
Long-acting ß2-agonists
Asthma is the most frequent chronic disease in children and adolescents.
In the group up to 18 years of age prevalences between 5-10% have been
reported. Some studies indicate an increase of prevalences over the last decades.
Several reasons may be responsible for this increase: Air pollution, increased
allergen exposure, changing living habits, changes in nutrition, changes in exposure
to microorganisms causing minor infections, or changes in vaccination programs.
Two forms of obstructive airway diseases in children
and adolescents must be distinguished from each other:
1.) Wheezy bronchitis (bronchiolitis), sometimes recurrent wheezy bronchitis. Inherited factors do not play
a predisposing role. Mainly infants and toddlers up to 2
years of age are affected. The etiology is mostly infectious, allergens play a minor role only. About 1/3 of
affected children are likely to develop asthma later on.
2.) Bronchial asthma. In the pediatric population children with atopic parents or siblings are at special risk.
Usually, inherited risk factors lead to increased manifestations of atopic disease in children from 3 years
on. Besides atopic disease in 1st degree relatives early
manifestation of atopic eczema, either transient or perProf. Dr. med. Volker Wahn
Klinik für Kinder und Jugendliche
Klinikum Uckermarck Schwedt
Profesor Volker Wahn jest kierownikiem Kliniki Pediatrii
w Schwedt i wybitnym znawcą zagadnienia wrodzonych
i nabytych niedoborów odpornościowych u dzieci. Jest
konsultantem Kliniki Pediatrii i Immunologii Uniwersytetu im.
Humboldta w Berlinie w tym zakresie. Przedmiotem jego
zainteresowań naukowych są także zagadnienia związane
z genetycznymi aspektami atopii. W wykazie MEDLINE odnaleźć można 153 publikacje,
których jest autorem lub współautorem. Jest współautorem monografii “Pädiatrische
Allergologie und Immunologie”, której kolejne wydanie ukazywały się w Niemczech w latach 1988, 1994 i 1999. Chętnie odwiedza Polskę uczestnicząc między innymi w kolejnych
Pomorskich Warsztatach Alergologicznych, w latach 2000 i 2001 oraz w II Pomorskim
Sympozjum Alergologicznym, które odbyło się Szczecinie w roku ubiegłym.
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ALERGIA Lato 2003
sistent, increases the probability for bronchial asthma
in later years. Besides infections and exercise allergens
are the major trigger for obstructive airway disease in
this age group. Its a chronic disease with persistence of
bronchial hyperreactivity into adulthood in the majority
of patients.
In this review I will only focus on bronchial asthma.
This may be defined as follows: A chronic inflammatory
airway disease with episodes of wheezing, dyspnea and
cough accompanied by a variable degree of airway
obstruction and bronchial hyperreactivity.
This definition includes major clinical symptoms:
Episodes of cough and/or wheezing and/or dyspnea.
Occasionally, precipitants of such episodes can be
identified: Infections, exercise (especially long distance
running), massive allergen exposure. In some children
decreased physical fitness maybe the only presenting
symptom. The severe asthma attack which can easily be
diagnosed even without lung function testing is relatively
rare. Much more frequent are chronic or recurrent
problems stimulation a visit at a pediatric allergists office.
In allergic asthma the acute asthma attack induced
by massive exposure to allergens may occur in some
cases. However, in most cases pathogenetic events are
insufficiently understood on this basis. It is much more
common that patients inhale amounts of allergens
that do not cause severe obstruction. However, these
low amounts of allergens are capable of inducing
chronic airway inflammation in atopic individuals. Allergic
airway inflammation, in turn, is the basis for bronchial
hyperreactivity, and the latter one for clinical symptoms.
Platts-Mills (1995) has depicted these pathogenetic
events (fig. 1).
D Z I A Ł
Events on the molecular level are depicted in fig. 2.
Bronchial hyperreactivity is a prerequisite for clinical
asthma (fig. 3)
Recognition of the fact that clinical asthma develops
on the basis of bronchial inflammation has significantly
contributed to the improvement of therapy. Wherever
possible allergen avoidance measures are the first step
to reduce this inflammation. Pets clearly responsible for
disease must be eliminated from households. The same
is necessary for moulds. Against house dust mites at
least encasings should be used, possible in conjunction
with other measures. In general, avoidance measures
are the first step in asthma therapy, a step without any
risk of side effects.
For pharmacologic treatment several guidelines and
recommendations exist which basically are very similar.
In Schwedt we try to use antiasthmatic drugs as follows
(fig. 4).
The majority of allergists involved in treatment of
children with asthma replaces cromones by steroids if
the cromone effect is not satisfactory. However, at least
one study demonstrated that DNCG may have a steroid
sparing effect (Petersen et al., 1997). Whenever someone introduces steroids as add-on therapy together with
a comone it maybe uncommon but cannot be regarded
as a mistake.
Pharmacologic aspects of inhalant steroids can be
summarized as in fig. 5:
Z A G R A N I C Z N Y
Adverse effects
Adverse effects are clearly dose related and result from
minor adrenal suppression. Thus, in children 250 µg of
fluticasone and 400 µg for budesonide should not be
exceded wherever possible. Even lower doses maybe
appropriate if a patient is treated with powder inhalation
because lung deposition seems to be more effective
with powder. We try to find out the lowest dose of steroids in every patients which is effective to control inflammation.
In children adrenal suppression is of major interest
with regard to growth. Saha et al. (1997) studied standard
deviation scores (SDS) of length under inhalant steroids
Mode of action
Glucocorticoids exert their pharmacologic effects after
interaction with specific receptors. Several intracellular
mechanisms on the molecular level utilized by steroids
for their antiinflammatory action have been described
involving arachidonic acid metabolism, cytokine synthesis and many others. Regarding steroid affinity to their
receptors significant differences have been reported:
The highest affinities were described for fluticasone and
budesonide. Receptor affinity and the extent of first-pass
metabolism in the liver may represent major criteria to
judge about the quality of inhalant steroids because
high values may be associated with a positive efficacy/
toxicity ratio.
Inhalant steroids help to reduce oral steroid doses.
Their clinical efficacy has been well documented in
many studies in both adults and children. There is a
clear dose-response relationship with respect to lung
function. The most important effect of steroids, however, maybe reduction of bronchial hyperreactivity as
a consequence of reduction of bronchial inflammation.
Osterman et al. (1997) in adult asthmatics showed that
under treatment with 400 µg budesonide the PD20 for
metacholine continuously increased 4-fold to reach a
maximum after 6 months of therapy. After discontinuation of therapy it took a few weeks only before initial
hyperreactivity returned. This clearly shows that in cases
with persisting bronchial hyperreactivity continuous treatment is required while in cases with seasonal problems
seasonal treatment maybe sufficient.
Upon allergen exposure the genetically predisposed individual develops allergen-specific sensitization. Three
groups maybe present: In highly allergic patients even extremely low doses of allergen are able to induce
bronchial inflammation. Avoidance measures are not sufficient to revert this process. In the second group
of patients moderate allergen doses are required for bronchial inflammation. Avoidance measures may contribute to clinical improvement. Finally, a group of sensitized patients exists in whom even high doses of
allergen are unable to cause bronchial inflammation.
An allergen is primarily taken up by allergen-presenting cells, i.e. macrophages, monocytes, dendritic cells
etc., and digested to peptides intracellularly. These peptides associate with HLA class II molecules and in this
combination reach the cell surface for peptide presentation. Appropriately presented peptides can be recognized
by T helper cells using their T cell receptor. In allergy, mostly TH2 cells are activated and, in turn, secrete
regulatory cytokines: IL-4 is essential for IgE synthesis, IL-5 for development and maturation of eosinophils.
IgE sensitizes mast cells following contact with the high-affinity receptor for IgE-Fc. Upon repeated exposure
polyvalent allergens crosslink cell-bound IgE and subsequently trigger release of mediators of inflammation.
Such mediators, possibly in connection with certain cytokines induce bronchial hyperreactivity.
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D Z I A Ł
Z A G R A N I C Z N Y
and found an increase of SDS over time. Several other
investigators used knemometry in short term clinical studies. They all unanimously demonstrate that inhalant steroids at doses exceding those mentioned above impair
short term lower leg growth. On the other hand we have
clear evidence that chronically impaired lung function in
asthmatic children per se reduces growth. The art of asthma therapy in children is to control bronchial inflammation
as far as possible without taking significant risks.
In adults side effects can no longer be monitored
by growth. In this group of patients adrenal suppression
can be detected by measuring plasma cortisol, bone
density and or plasma osteocalcin (Pauwels et al., 1998).
Besides effects on bone metabolism an increased risk
for developing cataracts has been reported for beclomethasone: If cumulative doses exceded 2000 mg the
risk of developing cataracts increased by a factor of 5,5
(Cumming et al., 1997).
Mediators from mast cells (M), neutrophil granulocytes (PMNL), and eosinophils (Eos) all contribute to
elements of bronchial obstruction, although at different stages of the inflammatory process. Histamin causes
muscular brochospasm, leukotrienes, prostaglandins, and thromboxanes mucosal edema, ECP and certain
cytokines (i.e. IL-9 and others) abnormal mucus secretion.
In children with mild asthma short acting ß2-mimetic drugs are given on demand. If asthma is persistent, or if
ß2-mimetics are required >1x/month we try to control inflammation with one of the cromones, either DNCG
or nedocromil. After a few weeks of treatment efficacy must be analyzed. If no sufficient control of asthma has
been achievd (symptoms, use of ß2-mimetics, peak flow, lung function) inhalant steroids should be given.
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So in both adults and children it is highly desirable to
find the minimal effective steroid dose for every individual patient by down titration. Haahtela et al. (1994) have
shown in adults that in the majority of cases the steroid
dose can be reduced without loss of asthma control.
Administration of steroids once daily is another way to
decrease the doses (Chisholm et al.,1998).
Longacting ß2 mimetics
Because high doses of inhalant steroids maybe associated with the risk of side effects all possibilities should
be used not to exceed doses mentioned above especially in growing children. If asthma is insufficiently controlled by low dose inhalant steroids combination regimens should be selected before steroid doses are
increased. A good combination partner for steroids are
long acting ß2 agonists.
Pharmacology
Long acting ß2 agonists (salmeterol, formoterol, bambuterol) use the same receptor as short acting drugs like
salbutamol or terbutalin. However, due to their chemical modification by introduction of a long side chain
binding to the receptor is much longer compared
to short acting drugs. Prolonged action was convincingly shown, for instance, by the work of Taylor et al.
(1997) and Boulet et al. (1998). In the first paper the
authors showed that placebo influences neither morning nor evening reak flow (PEF). Salbutamol significantly improved daytime PEF but not values obtained at
night. In comparison, salmeterol improves values at
day and night. Taylor et al. compared the duration of
the effects of salbutamol and salmeterol. They clearly
showed that sufficient asthma control can be achieved
by twice daily inhalation. Upon a close look at the data
one may recognize one of the problems with salmeterol:
The improvement of lung function is most pronounced
after introduction of the drug but slightly decreases over
time. The reasons for this phenomenon are not clear.
Downregulation of the receptor or other events causing
tachyphylaxis maybe responsible.
While all lang acting ß2 agonsts improve lung function they have little effects on bronchial hyperreactivity.
Thus, these drugs should not be given as monotherapy
but only in combination with antiinflammatory drugs,
preferentially inhaled steroids.
Besides salmeterol formoterol is available for inhalation. Palmqvist et al. (1997) compared the effects of
different doses of formoterol with the effects of 50 µg
salmeterol and placebo. The onset of formoterol effects
could be recognized earlier than that of salmeterol, and
even 12 µg of the drug showed a slightly stronger bronchodilating effect than salmeterol.
Bambuterol is the first long acting ß2 agonist for oral
administration. In a study by Crompton et al. (1999) it
was equally efficaceous compared to inhaled salmeterol. It remains to be shown whether or not oral administration of the drug may improve patient compliance in a
subgroup of patients.
D Z I A Ł
Combinations
In many patients the therapeutic efficacy of low dose
inhaled steroids is not sufficient. Pauwels et al. (1997)
could convincingly show that in those patients a combination with a long acting ß2 mimetic drug (formoterol)
is significantly better than doubling the dose of inhaled
steroids. The latter option resulted in a slight (additional)
stabilization of lung function only.
Palmqvist et al. (1999) confirmed the additive effects
of long acting ß2 agonists in patients on inhaled steroids. They compared the effects of salmeterol and formoterol. Both drugs had comparable effects on lung
function but formoterol also seemed to improve bronchial hyperreactivity.
In an analogous study it could be shown that also
oral bambuterol is an appropriate combination partner
for inhalant steroids (Crompton et al., 1999). The effects
were similar compared to inhaled salmeterol.
Further measures
Z A G R A N I C Z N Y
long acting ß2 agonists, theophyllin, and leukotrien receptor antagonists have steroid sparing effects. However, to
date we do not know whether or nor for instance in steroid
treated patients a combination of long acting ß2 agonists
and theophyllin exerts more effects than either drug alone.
For several other drugs clinical efficacy was reported
in a small number of patients. Larger studies for promising drugs are required in order to be able to come to
valid conclusions regarding efficacy and toxicity.
Interesting perspectives may also come from immunological therapies already studied in patients (antiIgE, anti-IL5, sIL-4 receptor etc.). These biologicals may
enable us to treat asthma more effectively than today
without increasing therapeutic risks. This maybe a big
advantage over drugs like cyclosporin A or methotrexate that both have considerable side effects. Clinical
results might finally not only be just proof of a principle
but also, hopefully, a step towards improvement of clinical practice.
n
Especially in children with mild to moderate allergic asthma caused by one relevant allergen specific immunotherapy may further contribute to clinical improvement. It is
currently recommended for children older than 6 years.
Especially in children drug therapy can only be effective if drugs are used appropriately under special supervision. This is the reason why we recommend intensive
training programs in all children on any sort of long
term treatment. So a qualified team of asthma trainers is
needed in order to make education programs as effective as possible. Certain concepts have been critically
evaluated and were proven to be effective. Institutions
that train the trainers are still rare and their number must
be increased over time in order to make training programs available to everyone who needs them.
Future perspectives
Not all open questions regarding steroid sparing combinations have been answered so far. We know that cromones,
The drug is partly deposited in the lung, the rest will be swallowed and reaches the GI tract. Following enteral
absorption of parts of this drug a high percentage will be inactivated by the liver by the so-called first-pass
effect. Only very small amounts pass the liver and these, in connection with steroids absorbed from the lungs
(via vascular leaks?) reach the circulation and are thus able to contribute to adrenal suppression.
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Neven A, Petri H Once-daily budesonide in mild asthma. Respir Med 1998 Mar;92(3):421-5, 3. Crompton GK, Ayres JG, Basran G, Schiraldi G,
Brusasco V, Eivindson A, Jamieson AH, Olsson H Comparison of oral bambuterol and inhaled salmeterol in patients with symptomatic asthma and
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