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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. 4 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. Lato 2003 ALERGIA 5 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. 6 ALERGIA Lato 2003 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. References: 1. Boulet LP, Laviolette M, Boucher S, Knight A, Hebert J, Chapman KR A twelve-week comparison of salmeterol and salbutamol in the treatment of mild-to-moderate asthma: a Canadian multicenter study.J Allergy Clin Immunol 1997 Jan;99(1 Pt 1):13-21, 2. Chisholm SL, Dekker FW, Knuistingh 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 using inhaled corticosteroids. Am J Respir Crit Care Med 1999 Mar;159(3):824-8, 4. Cumming RG, Mitchell P, Leeder SR Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med 1997 Jul 3;337(1):8-14, 5. Drazen JM, Arm JP, Austen KF Sorting out the cytokines of asthma. J Exp Med 1996 Jan 1;183(1):1-5, 6. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, Nikander K, Persson T, Selroos O, Sovijarvi A, et al Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994 Sep 15;331(11):700-5, 7. Osterman K, Carlholm M, Ekelund J, Kiviloog J, Nikander K, Nilholm L, Salomonsson P, Strand V, Venge P, Zetterstrom O Effect of 1 year daily treatment with 400 microg budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics. Eur Respir J 1997 Oct;10(10):2210-5, 8. Palmqvist M, Persson G, Lazer L, Rosenborg J, Larsson P, Lotvall J Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 1997 Nov;10(11):2484-9, 9. Palmqvist M, Ibsen T, Mellen A, Lotvall J Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Am J Respir Crit Care Med 1999 Jul;160(1):244-9, 10. Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, Ullman A Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997 Nov 13;337(20):1405-11, 11. Pauwels RA, Yernault JC, Demedts MG, Geusens P Safety and efficacy of fluticasone and beclomethasone in moderate to severe asthma. Belgian Multicenter Study Group. Am J Respir Crit Care Med 1998 Mar;157(3 Pt 1):827-32, 12. Petersen W, Karup-Pedersen F, Friis B, Howitz P, Nielsen F, Stromquist LH Sodium cromoglycate as a replacement for inhaled corticosteroids in mild-to-moderate childhood asthma. Allergy 1996 Dec;51(12):870-5, 13. Platts-Mills TA, Sporik RB, Wheatley LM, Heymann PW Is there a dose-response relationship between exposure to indoor allergens and symptoms of asthma? J Allergy Clin Immunol 1995 Oct;96(4):435-40, 14. Saha MT, Laippala P, Lenko HL Growth of asthmatic children is slower during than before treatment with inhaled glucocorticoids. Acta Paediatr 1997 Feb;86(2):138-42, 15. Taylor DR, Town GI, Herbison GP, Boothman-Burrell D, Flannery EM, Hancox B, Harre E, Laubscher K, Linscott V, Ramsay CM, Richards G Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998 Sep;53(9):744-52, 16. Wasserfallen JB, Baraniuk JN Clinical use of inhaled corticosteroids in asthma. J Allergy Clin Immunol 1996 Jan;97(1 Pt 2):177-82 Lato 2003 ALERGIA 7