Az LTRA-k helye a terápiában

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1 Az LTRA-k helye a terápiában
Az asztma és az allergiás rinitisz terápiájának globális irányelvei és ajánlásai PRACTALL EAACI-AAAI, ARIA és GINA Az LTRA-k helye a terápiában Dr. Mezei Mónika Bajai Kórház Gyermek pulmonológia Provided as a service to the medical profession by MERCK & CO., INC./ MSD. The views expressed reflect the experience and opinions of the author(s) and does not necessarily reflect the opinions and recommendations of MERCK & CO., INC./ MSD. For detailed information on any drugs discussed herein, please consult the full prescribing information issued by the manufacturer.

2 A gyermekkori asztma diagnózisa és terápiája
The European Academy of Allergy and Clinical Immunology (EAACI) and the American Academy of Allergy, Asthma, and Immunology (AAAAI) recently published a consensus report on the diagnosis and treatment of asthma in childhood.1 This report is a component of the Practicing Allergology (PRACTALL) initiative.1 PRACTALL EAACI-AAAAI konszenzus jelentés PRACTALL=Practicing Allergology; EAACI=European Academy of Allergy and Clinical Immunology; AAAAI=American Academy of Allergy, Asthma, and Immunology. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

3 PRACTALL EAACI-AAAAI konszenzus jelentés
Elméleti alapok Az asztma a leggyakoribb krónikus gyermekbetegség az iparosodott országokban A gyermekkori asztma sajátosságaival kapcsolatban kevés tudományos adat áll rendelkezésre A természetes kórlefolyás egyénenként eltér A kiváltó okok időben változnak Korspecifikus patofiziológia és fenotípusok Az utóbbi időben nem volt olyan nemzetközi irányelv, melyet kizárólag a gyermekkori asztmának szenteltek The rationale for a Consensus Report on childhood asthma was founded on facts such as the following: Asthma continues to be the most common chronic disease in children in nearly all industrialized countries.1 The evidence base for specific aspects of pediatric asthma is limited.1 No recent international guidelines have focused exclusively on pediatric asthma.1 Defining the disease itself can be a challenge, given the variable natural history of asthma in children in general and infants and preschool children in particular.1 Asthma triggers, particularly allergens, can also be variable with respect to seasonality, geographic regions, and indoor versus outdoor exposure. As a child grows, his or her triggers may also shift among various inhaled allergens.1 Childhood asthma reflects a heterogeneity of age-related phenotypes, with distinct features among infants 0 to 2 years of age, preschool children 3 to 5 years of age, school children 6 to 12 years of age, and adolescents. The responsiveness of children with asthma to pharmacotherapy must be monitored carefully with adjustments made, as appropriate.1 The choice among pharmacotherapeutic options needs to be carefully considered because individual children of various ages respond differently to pharmacotherapy.1 A PRACTALL EAACI-AAAAI konszezus jelentés a diagnózisra és terápiára vonatkozó első széles körű ajánlás, melyet gyermekgyógyász szakértők fejlesztettek ki a gyermekeket ellátó gyakorló orvosoknak Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

4 A gyermekkori asztma 44 szakértője
PRACTALL EAACI-AAAAI konszezus jelentés A PRACTALL csoport A gyermekkori asztma 44 szakértője 20 országból The PRACTALL Pediatric Consensus Report presents clinical information on asthma, the disease and its management, from the medical literature as of June 2007 and current best clinical practice from Europe and North America.1 The 44 participants in the report represented 20 countries on those 2 continents.1 Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

5 Az asztma-fenotípusok azonosítása döntő jelentőségű
PRACTALL EAACI-AAAAI konszezus jelentés Az asztma-fenotípusok azonosítása döntő jelentőségű Asztma-fenotípusok 2 év feletti gyermekekben A szimptomatikus időszakok között teljesen jól van-e a gyermek? Igen Nem Various asthma phenotypes can be defined on the basis of the child’s age and asthma triggers. Recognition of these different phenotypes and disease severity can help provide better direction for prognosis and therapeutic strategies.1 This slide summarizes an approach to determining asthma phenotypes in children older than 2 years of age. In this approach, the initial question is based on whether the child is completely well between symptomatic periods.1 If the child is well beween such periods, possible phenotypes are virus-induced asthma and exercise-induced asthma, depending on the precipitating factors. For either of these phenotypes, the possibility that the child may also be atopic must be explored.1 The child who is not completely well between symptomatic periods and does not meet the criteria for virus- or exercise-induced asthma may have clinically relevant allergic sensitization. In this case, the child may have allergen-induced asthma or unresolved asthma. In the latter case, different etiologies, including irritant exposure and as-yet not evident allergies, may need to be considered.1 Among preschool children 3 to 5 years of age, persistence of asthma symptoms during the year can be a key differentiator of asthma phenotype. Since viruses are the most common trigger in these children, viral-induced asthma is an appropriate diagnosis among these patients whose symptoms disappear completely between episodes and usually recur following a cold. The phenotype of exercise-induced asthma can also be observed in this age group.1 Tests for the presence of specific immunoglobin E (IgE) antibodies, such as skin prick or in vitro tests, should be performed to obtain information that may supplement clinical information regarding a relationship between exposure to a potential allergen and the occurrence of asthma symptoms. Findings of such antibodies are consistent with the phenotype of allergen-induced asthma. The Pediatric Consensus Report emphasized that atopy is a risk factor for the persistence of asthma, regardless of any observation that allergens are or are not obvious triggers of disease activity in an individual child. The absence of a specific allergic trigger may indicate a phenotype of nonallergic asthma. The clinician should consider this phenotype with caution, however, since the failure to identify an allergic trigger may reflect the fact that a specific allergic trigger was not detected.1 Among school-age children 6 to 12 years of age, the differentiators of asthma phenotypes are identical to those in younger children; however, the clinician should consider that cases of allergen-induced asthma are more common and visible in the older children, and seasonality may be a more evident factor. Finally, virus-induced asthma should also be considered in these children since it is still common.1 Nem Leggyakrabban vagy kizárólag testmozgás váltja ki? Nem Van-e a gyermeknek klinikailag releváns allergiás érzékenysége? Leggyakrabban a megfázások váltják ki? Igen Igen Van Nincs Vírus indukálta asztmaa Terhelés indukálta asztmaa Allergén indukálta asztma Tisztázatlan eredetű asztmaa,b a A gyermek atópiás is lehet. b Különféle etiológiájú – pl. irritáló ágens vagy még nem tisztázott allergiák okozta – asztmák tartozhatnak ide. Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

6 Diagnózis Kórtörténet Fizikális vizsgálat IgE-mediált allergia
PRACTALL EAACI-AAAAI konszezus jelentés Diagnózis Kórtörténet Fizikális vizsgálat IgE-mediált allergia Egyéb vizsgálatok Mellkasröntgen, eNO, kilélegzett levegő kondenzátuma stb. Légzésfunkciók vizsgálata Bronchodilatátorra adott reakció Differenciáldiagnózis és társbetegségek The diagnosis of asthma continues to pose challenges in pediatric patients, particularly in infants and preschool children. Recurrent wheezing and episodes of coughing should raise suspicion for the diagnosis in any infant. The clinician will also need to consider and ask about the potential role of triggers, such as passive smoke, pets, altered sleep patterns that may involve awakening, night cough, or sleep apnea, or exacerbations within the past year. The presence of nasal symptoms, such as running, itching, sneezing in all children, with particular attention to nasal structures and listening for forced expiration, should also be evaluated.1 Evaluation of IgE-mediated allergy should involve in vivo and in vitro testing for allergies, as well as other tests, such as chest x-ray, exhaled nitric oxide, or exhaled breath condensates, that may indicate the presence of allergic inflammation.1 Assessment of lung function in terms of peak expiratory flow or forced expiratory flow is recommended, with evaluation of bronchodilator responsiveness as a measure of the reversibility of airflow limitations with a β2-agonist.1 Finally, differential diagnosis of asthma must exclude other potential etiologies for asthma symptoms in children, particularly in the presence of comorbidities that might aggravate the situation.1 IgE=immunglobin E; eNO=kilélegzett nitrogén-monoxid. Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

7 Allergének/triggerek elkerülése
PRACTALL EAACI-AAAAI konszezus jelentés Allergének/triggerek elkerülése Ajánlott, ha szenzitizáció áll fenn, vagy ha egyértelmű összefüggés van az allergénexpozíció és a tünetek között Allergénteszt (minden életkorban) Cigarettafüst-belégzés kerülése Kiegyensúlyozott étrend; az elhízás kerülése A testmozgás NEM kerülendő Management of asthma in children generally involves avoidance measures against airborne allergens and irritant triggers, whenever possible.1 Such measures are recommended in the Pediatric Consensus Report when the patient has become sensitized to an allergen and there is clear evidence of an association between allergen exposure and the emergence of asthma symptoms.1 It should be noted, however, that clinically relevant results may require thorough allergen avoidance, which may be difficult to achieve and sustain in daily life.1 Allergen testing is recommended at all ages for children who have asthma.1 These patients should also avoid exposure to asthma triggers, such as cigarette smoke, which should be eliminated from the environment of children with a history of wheezing and, ideally, of all children, according to the consensus report.1 To avoid comorbid obesity, children with asthma should be encouraged to consume balanced diets.1 Finally, children with asthma should not avoid exercise and should be encouraged to participate in sports while controlling asthma inflammation and symptoms.1 Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

8 Gyógyszeres kezelés (2 év feletti gyermekek)
PRACTALL EAACI-AAAAI konszezus jelentés Gyógyszeres kezelés (2 év feletti gyermekek) ICS (200 µg BDP-nek megfelelő dózis) VAGY LTRAa (Kortól függő dózis) Megfelelő esetekben visszalépés ELÉGTELEN KONTROLLb ICS-dózis emelése (400 µg BDP-ekvivalens) VAGY ICS hozzáadása az LTRA-hoz Terápiás előrelépés a kontroll elérése érdekében ELÉGTELEN KONTROLLc Megfelelő esetekben visszalépés The approach to pharmacologic treatment of asthma recommended for children older than 2 years of age in the Pediatric Consensus Report is summarized in this slide. The approach is based on first-line therapies followed by a series of step-ups to more-intensive therapy to overcome insufficient control and step-downs to less-intensive therapy, if appropriate.1 First-line controller therapy may involve either an inhaled corticosteroid (ICS), at a dose of 200 µg of beclomethasone dipropionate equivalent, or a leukotriene receptor antagonist (LTRA) at an age-dependent dose in pediatric patients with persistent asthma. An LTRA may be an especially appropriate choice in patients with concomitant asthma and rhinitis.1 Evidence of insufficient control with first-line therapy should prompt the treating physician to ask the patient, parent, and/or caregivers about compliance with prescribed therapy and allergen avoidance, and to reevaluate the patient’s diagnosis of asthma.1 For pediatric patients confirmed to have uncontrolled asthma, the ICS dose could be doubled or an ICS could be added to LTRA therapy. Continued failure to achieve asthma control should prompt the physician to ask again about compliance issues and consider referring the patient to a specialist. Therapeutic options at this point include doubling the ICS dose again, adding an LTRA to ICS therapy, or adding a long-acting 2-agonist (LABA).1 Safety concerns with LABAs have been raised recently, suggesting that their use should be restricted to add-on therapy to ICS when indicated.1 Subsequent failure to achieve asthma control in pediatric patients may necessitate the use of theophylline or oral corticosteroids.1 ICS-dózis emelése (800 µg BDP-ekvivalens) VAGY LTRA hozzáadása az ICS-hez LABA hozzáadása ELÉGTELEN KONTROLLc Egyéb lehetőségek mérlegelése Teofillin Per os kortikoszteroidok a Az LTRA különösen hasznos lehet, ha egyidejűleg rinitisz is fennáll; b Ellenőrizni kell a compliance-t, az allergének elkerülését, és felül kell vizsgálni a diagnózist; c Ellenőrizni kell a compliance-t, és fontolóra kell venni a beutalást egy asztmaspecialistához. ICS=inhalációs kortikoszteroid; LTRA=leukotriénreceptor-antagonista; BDP=beklometazon-dipropionát; LABA=hosszú hatású β2-agonista. Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

9 Ajánlás a 0-2 éves gyerekek gyógyszeres kezelésére
PRACTALL EAACI-AAAAI konszezus jelentés Ajánlás a 0-2 éves gyerekek gyógyszeres kezelésére Az asztma diagnózisa: 6 hónapon belül legalább 4 alkalommal reverzibilis bronchiális obstrukció fordult elő Periodikus β2-agonista Első választás – az ellentmondó adatok ellenére LTRA Napi fenntartó kezelés vírusos eredetű sípoló légzés esetén (hosszú vagy rövid távú kezelés) Porlasztott vagy inhalációs kortikoszteroid Napi fenntartó kezelés perzisztáló asztma eseténa Első vonalbeli kezelés atópiára/allergiára utaló bizonyíték esetén Orális kortikoszteroidb Akut és gyakran rekurráló obstruktív epizódok esetén The Pediatric Consensus Report notes that the diagnosis and treatment of asthma in patients 0 to 2 years of age pose the greatest challenges due to the limited availability of clinical evidence.1 For example, there is no clear basis for determining how frequent a child’s obstructive episodes should be before the decision is made to initiate continuous therapy with an ICS or LTRA.1 The consensus report recommends that a diagnosis of asthma be considered in a child 2 years of age or younger who has had more than 3 documented episodes of reversible bronchial obstruction within a period of 6 months.1 For these children, intermittent therapy with a β2-agonist is recommended as first-line therapy despite conflicting evidence. In Europe, this therapy would be administered orally, whereas in the United States, therapy would be administered as inhalation therapy via jet nebulizers.1 An LTRA can be used as daily controller therapy on either a long- or short-term basis for children 2 years of age or younger who have viral wheezing.1 Nebulized corticosteroids or ICS therapy delivered via metered-dose inhalers with spacers are recommended as daily controller therapy in these young patients who have persistent asthma. This is particularly relevant in cases of severe disease or those that require frequent use of oral corticosteroids. Evidence of atopy and allergy in these cases should lower the decision threshold for the use of ICS, which may be considered for first-line therapy.1 Oral corticosteroids, such as prednisone 1 to 2 mg/kg/day for 3 to 5 days, may be appropriate in children 2 years of age or younger who experience acute and frequently recurrent obstructive episodes.1 a Főként, ha súlyos, vagy ha gyarkan igényel orális kortikoszteroid-kezelést; b Pl. 1-2 mg/kg/nap prednizon 3-5 napig az akut vagy gyakran rekurráló obstruktív epizódok idején. Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

10 (200 µg BDP-nek megfelelő dózis)
PRACTALL EAACI-AAAAI konszezus jelentés A PRACTALL ICS-t vagy LTRA-t ajánl a perzisztáló asztma kezdeti fenntartó kezelésére ICS (200 µg BDP-nek megfelelő dózis) VAGY LTRA (Kortól függő dózis) A perzisztáló asztma első vonalbeli kezelésére Elégtelen asztmakontroll esetén kezdeti fenntartó kezelésként adandó A kedvező hatás atópia és rossz légzésfunkciók esetén valószínűbb Ha kis dózissal elégtelen a kontroll, annak okait ki kell deríteni. Ha indikált, akkor nagyobb ICS-dózis, ill. LTRA vagy LABA hozzáadása mérlegelendő Idősebb gyermekeknél a hatás a kezelés abbahagyása után azonnal csökkenni kezd Az újabb adatok nem támasztják alá, hogy 6 év alatti gyermekeknél a kezelés abbahagyása után bármilyen hatással lenne a betegség lefolyására A perzisztáló asztma alternatív első vonalbeli kezelésére A bizonyítékok alátámasztják az LTRA kezdeti fenntartó kezelésként történő adását enyhe asztmás gyermekeknek A kedvező hatás fiatalabb (<10 éves) korban és magas vizelet-leukotriénszint esetén valószínűbb Azoknak a betegeknek is megfelelő terápia, akik nem tudnak vagy nem hajlandók ICS-t használni ICS mellett kiegészítő terápiaként is hasznos: hatásmechanizmusa eltérő és komplementer Javasolható fiatal gyermekek vírus indukálta sípoló légzése estén Nagyon fiatal, már 6 hónapos gyermekeknél is igazolódott kedvező hatása Az LTRA különösen hasznos lehet, ha egyidejűleg rinitisz is fennáll The goals of pharmacotherapy in pediatric patients with asthma are to control symptoms and prevent exacerbations with minimal adverse effects. The specific goal of regular controller therapy should be to reduce bronchial inflammation in these patients, because appropriate treatment of airway inflammation is known to lead to optimal asthma control. Two controller medications featured in the algorithm for preventive treatment in the Pediatric Consensus Report are ICS and LTRAs.1 ICS reduce the frequency and severity of asthma exacerbations. Therapy with an ICS should be initiated at a dose equivalent to 200 µg of beclomethasone dipropionate in patients who experience inadequate asthma control with reliever medications alone. If, after 1 to 2 months of initial low-dose ICS therapy, asthma control remains inadequate, the reason for poor control should be identified and the clinician should consider either increasing the ICS dose or adding an LTRA or LABA. The Pediatric Consensus Report notes that it is well known that the benefit of ICS therapy begins to disappear as soon as treatment is discontinued in older children. Additionally, newly available evidence does not support a disease-modifying role for ICS therapy after cessation of treatment in preschool children. Predictors of favorable response to ICS therapy include atopy and poor lung function prior to initiation of therapy.1 The Pediatric Consensus Report states that LTRAs are an alternative first-line treatment for persistent asthma in pediatric patients. Clinical evidence supports the use of oral montelukast for initial controller therapy in children with mild asthma: it provides bronchoprotection and reduces airway inflammation, as measured by nitric oxide levels, in some preschool children with allergic asthma.1 Two factors may be considered as predictors of a favorable response to LTRA therapy. These factors are a younger age (<10 years) and a high level of urinary leukotrienes.1 LTRAs may be particularly appropriate choices in several clinical situations, including the following: patients who cannot or will not use an ICS; patients who could benefit from add-on therapy to ICS, due to the different and complementary mechanisms of action of these agents; patients with concomitant rhinitis; patients with viral-induced wheeze; and, in children 2 to 5 years of age, to reduce the frequency of asthma exacerbations. It should be noted that the benefit of LTRA therapy has been demonstrated in children as young as 6 months of age.1 Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

11 A legfőbb ajánlások összefoglalása
PRACTALL EAACI-AAAAI konszezus jelentés A legfőbb ajánlások összefoglalása Az asztma-fenotípusok azonosítása döntő jelentőségű Az asztma átfogó ellátásába bele kell tartozzon az allergének/triggerek elkerülése, valamint az oktatás is A légúti gyulladás kezelése optimális asztmakontrollt eredményez Az ICS-k és az LTRA-k ajánlottak a perzisztáló asztma kezdeti fenntartó kezelésére A LABA-k nem használhatók megfelelően dozírozott ICS nélkül, amíg hatásosságukról és hosszú távú biztonságosságukról további adatok nem lesznek elérhetők Az immunterápia megfelelő környezeti kontroll és gyógyszeres kezelés mellett alkalmazható In summary, the Pediatric Consensus Report provides specific recommendations for management of asthma in childhood. Fundamentally, comprehensive asthma management in children must feature avoidance measures, pharmacotherapy, and education. Identification of asthma phenotype should be attempted, including evaluation of atopic status.1 Because asthma symptoms most often occur in the setting of inflammation, the guidelines recommend that the main goal of controller therapy should be to reduce bronchial inflammation. In fact, treatment of airway inflammation is needed to achieve optimal asthma control. ICS and LTRAs are recommended first-line treatments for persistent asthma. LTRAs are also recommended first-line treatment in mild asthma. LABAs should not be used without an appropriate dose of ICS until further evidence of effectiveness and long-term safety becomes available.1 Immunotherapy may be appropriate for selected patients.1 Átvéve: Bacharier LB, et al. Allergy. 2008;63(1):5–34. Reference Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34.

12 Köszönöm a megtisztelő figyelmüket!
Bibliography ARIA Workshop. ARIA At-A-Glance Pocket Reference Accessed 24 October 2007. Bacharier LB, Boner A, Carlsen K-H, et al; the European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63(1):5–34. Bousquet J, van Cauwenberge P, Khaled NA, et al. Pharmacologic and anti-IgE treatment of allergic rhinitis ARIA update (in collaboration with GA2LEN). Allergy. 2006;61(9):1086–1096. Global Initiative for Asthma. GINA At-A-Glance Asthma Management Reference. Staten Island, NY: Medical Communications Resources, Inc; 2006. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Revised Accessed 9 January 2008. Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention. A pocket guide for physicians and nurses. Revised Accessed 24 October 2007. Köszönöm a megtisztelő figyelmüket!