nuevas perspectivas en el tratamiento del asma · • los pacientes con rinitis alérgica...

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Dr José Mª Negro AlvarezH.U. “Virgen de la Arrixaca”.Profesor Asociado de Alergología. Universidad de Murcia (España)

NUEVAS PERSPECTIVAS EN ELTRATAMIENTO DEL ASMA

Dr Negro AlvarezAbril 2004

www.alergomurcia.com 2

POSITION PAPER POSITION PAPER BousquetBousquet & ARIA Workshop Group & ARIA Workshop Group JACI Nov. 2001JACI Nov. 2001

www.alergomurcia.com

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• Actualizar el conocimiento de los médicos en relación con la rinitis alérgica.

• Poner de manifiesto el impacto de la rinitis alérgica en el asma.

• Proporcionar una aproximación basada en la evidenciapara el diagnóstico y el tratamiento.

• Describir el manejo de la rinitis alérgica.

Objetivos de la iniciativa ARIA (Allergic Rhinitis and its Impact on Asthma)



Resumen bibliografía (epidemiología)

• El asma y la rinitis alérgica tienen una prevalencia similar en todo el mundo.

• Los pacientes con rinitis alérgica tienen un riesgo 3 veces mayor de desarrollar asma.

• Aproximadamente el 80% de los pacientes asmáticostienen rinitis alérgica.

• Los pacientes con rinitis alérgica y asma presentan un deterioro en su calidad de vida.

• El tratamiento de la rinitis alérgica en pacientesasmáticos se ha asociado con una disminución en la utilización de recursos sanitarios.



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Directrices de la ARIA.

• Los pacientes con rinitis alérgica persistente deberán ser evaluados por la posible coexistencia de asma.

• En los pacientes con asma se valorará la existencia de rinitis alérgica.

• La estrategia terapéutica deberá combinar el tratamientode las vías respiratorias superiores e inferiores en términos de eficacia y seguridad.

AproximaciAproximacióónn combinadacombinada parapara el el manejomanejo de de laslaspatologpatologííasas de de laslas vvííasas respiratoriasrespiratorias superioressuperiores e e inferioresinferiores..



Rinitis alérgica y asma. InmunopatologíaComún.

Casale TB, Amin BV. Clin Rev Allergy Immunol 2001; 21 : 1: 27-49

Kay AB. N Engl J Med 2001; 344: 30-37.

Reacción alérgicaaguda (incluyendorespuesta precoz).

Reacción alérgicacrónica (incluyendorespuesta tardia).

Mastocito

Linf. T

Alergeno

Citocinas

Mediadorespreformados

HistaminaSintesis nuevos

mediadoresCysLTs, PGs, PAF

Eosin ófilos



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Asma y rinitis alérgica: Inflamación eosinófila característica.

Adaptado de Bousquet J et al J Allergy Clin Immunol 2001; 108: 5: S148-S149.

Infiltraci ón eosinófila

Rinitis alérgica Asma



RINITIS: Fisiopatología.

• En la rinitis alérgica estacional y perenne se liberan mediadores inflamatorios tras la exposición alergénica:– Histamina.

– Cisteinil leucotrienos.

– Prostaglandinas.

• Histamina: prurito nasal y estornudos.

• Cisteinil leucotrienos: congestión y rinorrea.

• Objetivo de los tratamientos actuales: bloquear el efecto de losmediadores de la inflamación.



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Settipane RJ, Hagy GW, Settipane GA. Long-term risk factors for developingasthma and allergic rhinitis: a 23-year follow-up study of college students. AllergyProc 1994;15(1):21-5.

In the initial study of 23 years ago, 1836 college freshmen wereprospectively evaluated by questionnaires, interviews, and physicalexaminations for medical conditions which included the presence ofasthma, allergic rhinitis, and positive allergy skin tests to a battery ofpollens, animal extracts, and mold. In a 23-year follow-up study, 1021 (64%) returned their completed questionnaires. Of these, 738 (72%) had been skin tested as freshmen. The results of this follow- up studyrevealed that the frequency of asthma and allergic rhinitis continue toincrease as the individuals become older. Allergic rhinitis and positiveallergy skin tests are significant risk factors for developing newasthma. Individuals with either of these diagnoses are about three times more likely to develop asthma than negative controls. Positive allergy skintested students have more than twice (2.3x) the risk of developing new hay fever than do negative skin tested students over a 23- year period.



12

10

8

6

4

2

0

% de pacientesquedesarrollanasma

10.5

Con rinitisalérgica(n=162)

3.6

Sin rinitisalérgica(n=528)

p<0.002

ASMA Y RINITIS ALÉRGICA:La rinitis alérgica como factor de riesgo.



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Crystal-Peters J, Neslusan C, Crown WH, Torres A. Treating allergic rhinitis in patients with comorbid asthma: the risk of asthma-related hospitalizationsand emergency department visits. J Allergy Clin Immunol. 2002;109(1):57-62.

Although asthma and allergic rhinitis commonly occur together, the nature of the associationhas yet to be determined. Treatments for one condition could potentially alleviate thecoexisting condition. OBJECTIVE: Patients with both allergic rhinitis and asthma werestudied to test the hypothesis that treating allergic rhinitis reduces health care utilization forco- morbid asthma. METHODS: A retrospective cohort study was carried out with 1994-1995 MarketScan claims data. The cohort was limited to patients with both allergic rhinitisand asthma, aged 12 to 60 years, who were continuously enrolled and had no evidence ofchronic obstructive pulmonary disease. Allergic rhinitis treatment and asthma- related events(hospitalizations and emergency department visits) were identified. An incidence density ratio (IDR) associated with exposure to allergic rhinitis treatment was calculated. A multivariatePoisson regression was estimated, and the parameter estimates were transformed into IDRsfor each explanatory variable. An allergic rhinitis treatment indicator was included in allregressions. RESULTS: The study sample population consisted of 4.944 patients withallergic asthma, approximately 73% of whom were treated for their allergic rhinitis.Asthma- related events occurred more often for the untreated group compared with thetreated group, 6.6% compared with 1.3%. An IDR of 0.49 for the treatment group (P =.001) indicates that the risk of an asthma- related event for the treated group was about half that forthe untreated group. CONCLUSION: In summary, those who were treated for allergic rhinitishave a significantly lower risk of subsequent asthma- related events (emergency departmentvisits or hospitalizations) than those who were not treated.



0.9

El tratamiento de la rinitis alérgica disminuye la utilización de recursos sanitarios.

2.5

2.0

1.5

1.0

0.5

0

% depacientes

Pacientes no tratados derinitis alérgica (n=1357)

Pacientes tratados derinitis alérgica (n=3587)

2.3

p<0.01

61% menos hospitalizaciones en pacientes tratados.



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Resumen

• El asma y la rinitis alérgica son patologíasinflamatorias que han sido relacionadasepidemiológicamente, patofisiológicamente, y terapéuticamente como una enfermedad de la “víaaérea única”.

• ARIA recomienda una estrategia combinada para el manejo de la comorbilidad asma y rinitis alérgica.



• Rinitis alérgica y asma.

• Rinitis alérgica perenne.

• Montelukast HI.V. en el tratamiento del asma agudo.

• Intervención precoz: papel de montelukast en la modificación temprana de la enfermedad en pacientes pediátricos.

• Bronquiolitis.

• Montelukast en la prevención de las exacerbaciones asmáticas inducidas por virus: estudio PREVIA.

Nuevas perspectivasde los ALTs



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Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment ofchronic asthma: a multicenter, randomized, double-blind trial. MontelukastClinical Research Study Group. Arch Intern Med 1998;158: 11:1213-20.

OBJECTIVES: To determine the clinical effect of oral montelukast sodium, a leukotriene receptor antagonist, in asthmatic patients aged 15 years or more. DESIGN: Randomized, multicenter, double-blind, placebo-controlled, parallel-group study. A 2-week, single-blind, placebo run-in period wasfollowed by a 12-week, double-blind treatment period (montelukast sodium, 10 mg, or matchingplacebo, once daily at bedtime) and a 3-week, double-blind, washout period. SETTING/PATIENTS: Fifty clinical centers randomly allocated 681 patients with chronic, stable asthma to receive placebo ormontelukast after demonstrating a forced expiratory volume in 1 second 50% to 85% of the predicted value, at least a 15% improvement in forced expiratory volume in 1 second (absolute value) after inhaled beta-agonist administration, a minimal predefined level of daytime asthma symptoms, and inhaled beta-agonistuse. Twenty-three percent of the patients used concomitant inhaled corticosteroids. PRIMARY END POINTS: Forced expiratory volume in 1 second and daytime asthma symptoms. RESULTS: Montelukastimproved airway obstruction (forced expiratory volume in 1 second, morning and evening peak expiratoryflow rate) and patient-reported end points (daytime asthma symptoms, "as-needed" beta-agonist use, nocturnal awakenings) (P<.001 compared with placebo). Montelukast provided near-maximal effect in theseend points within the first day of treatment. Tolerance and rebound worsening of asthma did not occur. Montelukast improved outcome end points, including asthma exacerbations, asthma control days (P<.001 compared with placebo), and decreased peripheral blood eosinophil counts (P<.001 compared withplacebo). The incidence of adverse events and discontinuations from therapy were similar in themontelukast and placebo groups. CONCLUSIONS: Montelukast, compared with placebo, significantlyimproved asthma control during a 12-week treatment period. Montelukast was generally well tolerated, withan adverse event profile comparable with that of placebo.



El tratamiento con antileucotrienos en asma

3

15

10

5

0

0 6 9 12 15

Placebo(n=273)

Asma

Media ± DS FEV1*

Placebo(n=352)

Montelukast10 mg una vez/d ía(n=408)

FEV1matutino% cambio

mediodesdebasal.

Semanas

Estudio multicéntrico, 12 semanas, aleatorizado, doble ciego, de montelukast vs. placebo en pacientes > 15 años con asma.*p<0.001 montelukast vs. placebo



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Philip G, Malmstrom K, Hampel FC, Weinstein SF, LaForce CF, Ratner PH, Malice MP, ReissTF; Montelukast Spring Rhinitis Study Group. Montelukast for treating seasonal allergicrhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring. ClinExp Allergy. 2002; 32: 7:1020-8.

Cysteinyl leukotrienes are important proinflammatory mediators believed to have a role in allergic rhinitis. OBJECTIVE: This multicentre, randomized, double-blind, placebo- andactive- controlled trial evaluated the effectiveness and tolerability of montelukast, a cysteinylleukotriene receptor antagonist, for treating patients with seasonal allergic rhinitis. METHODS: After a 3- to 5- day, single- blind placebo run- in period, 1302 male and femalepatients (aged 15- 81 years) with active allergic rhinitis symptoms were randomly assigned toreceive montelukast 10 mg (n = 348), loratadine 10 mg (n = 602), or placebo (n = 352)administered once daily at bedtime for 2 weeks during the spring allergy season. RESULTS: Mean patient characteristics and symptom scores at baseline were similar for the threetreatment groups. The primary end- point, daytime nasal symptoms score (mean of nasal congestion, rhinorrhea, nasal pruritus, and sneezing scores; 0- 3 scale), improved from baselineduring treatment by (least squares mean, 95% confidence interval) - 0.37 (- 0.43, - 0.31), - 0.47 (- 0.52, - 0.43), and- 0.24 (- 0.29, - 0.18) in the montelukast, loratadine, and placebo groups, respectively (P < or = 0.001 comparing each active treatment with placebo). Mean changesfrom baseline in all other diary- based scores, including night- time and eye symptom scores, were significantly greater for each active treatment than for placebo. The rhinoconjunctivitisquality of life overall score improved significantly with montelukast and with loratadine as compared with placebo. Montelukast and loratadine showed a safety profile comparable to thatof placebo. CONCLUSION: Montelukast is well tolerated and provides improvements in daytime and night- time symptoms, as well as quality of life parameters, for patients withseasonal allergic rhinitis.



El tratamiento con antileucotrienos en rinitisalérgica.

3

15

10

5

0

0 6 9 12 15

Placebo(n=273)

Asma

Media ± DS FEV1*

0

–0.1

–0.2

–0.3

–0.4

–0.5Montelukast

10 mg una vez/d íapor la noche (n=348)

Rinitis alérgica

Puntuación síntomasnasales diurnos*

Placebo(n=352)

Montelukast10 mg una vez/d ía(n=408)

Cambiodesde

puntuaciónbasal

( media)

Semanas



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• El tratamiento óptimo de la rinitis alérgica mejora el control del asma coexistente.

• Debe considerarse la utilización de tratamientos que aborden eficazmente ambas patologías.

• Los corticoides y los antileucotrienos son eficaces en el tratamiento del asma y la rinitis alérgica.

• Los agonistas beta adrenérgicos son sólo eficaces en el tratamiento del asma; los antagonistas alfa adrenérgicos sólo tienen eficacia en el tratamiento de la rinitis alérgica.

• Es importante valorar la vía de administración. Los fármacos orales pueden actuar frente a los síntomas nasales y bronquiales.

• Considerar los efectos secundarios aditivos de los corticoides cuando se administran por vía inhalada e intranasal.

Conclusiones



2000

1975

1980

1985

19901995

Broncoespasmo Inflamación Remodelado

Uso de 2-agonistas

de cortaduración

Introduccióndel tratamiento

conGCS1972

Introducciónde ß2-agonistasde larga duración

Combinaciónde productosintroducidos

Introducciónde salbutamol

1968

Progresióndel tratamientoantiasmáticoProgresióndel tratamientoantiasmático



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RINITIS PERENNE. Nuevas perspectivas.

• Montelukast es eficaz en el tratamiento de los síntomas de la rinitis alérgica estacional.

• Actualmente en desarrollo un estudio multicéntrico, aleatorizado, doble ciego, controlado con placebo, de grupos paralelos para investigar el efecto clínico de montelukast en pacientes con rinitis alérgica perenne.



• El asma agudo es una causa frecuentes de consulta en urgencias.

• Objetivos del tratamiento:– Corregir la hipoxemia.

– Revertir rápidamente la obstrucción al flujo aéreo.

– Reducir la probabilidad de recurrencia de la obstrucción severa al flujo aéreo.

• Actualmente aceptadas como terapias iniciales: – Oxígeno.

– Hidroterapia.

– Beta agonistas de rápida acción como salbutamol (corta acción) o formoterol (rápidfa y larga acción).

• Adicionalmente corticoides sistémicos en formas severas de la enfermedad o fallo terapéutico con las medidas iniciales.

ASMA AGUDOIntroducción



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Green SA, Malice MP, Tanaka W, Tozzi CA, Reiss TF. Increase in urinaryleukotriene LTE4 levels in acute asthma: correlation with airflow limitation. Thorax. 2004 Feb;59(2):100-4.

Leukotrienes play a key role in the pathophysiology of chronic asthma. Activation ofleukotriene pathways is accompanied by rises in detectable urinary levels of leukotriene E4 (LTE4). The relationship between urinary LTE4 levels and factors associated with acuteasthma has not been determined. METHODS: Adults aged 15- 54 years presenting withmoderate to severe acute asthma were evaluated at emergency departments in 16 US sites. Forced expiratory volume in 1 second (FEV1) was measured during the first 60 minutes after arrival and at specified times until discharge or admission. Urine samples formeasurement of LTE4 levels were obtained either on arrival at the study site and/or beforedischarge. Patients were seen 2 weeks later for follow up, at which time repeat FEV1 measurements and urine samples for LTE4 were obtained. RESULTS: One hundred andeighty four patients were evaluated; LTE4 results from both the acute and follow up periodswere available for analysis in 146. Urinary LTE4 levels were increased during asthmaexacerbations compared with levels obtained 2 weeks later (geometric means 111.7 and75.6 pg/mg creatinine, respectively, mean percentage change- 32.3; 95% confidenceinterval (CI) for the mean percentage change- 39.6 to- 24.3, p<0.001). The correlationbetween improvement in FEV1 and decline in LTE4 over the 2 week interval was significant(p<0.001, r=0.43). CONCLUSIONS: Activation of leukotriene pathways in acute asthmais correlated with the degree of airflow obstruction, and resolution of the asthmaexacerbation is associated with a reduction in leukotriene levels.



• Elevación significativa de LTE4 en orina durante el episodio de exacerbación asmática comparado con los niveles obtenidos 2 semanas después.

• El grado de limitación al flujo aéreo se correlacionó con los niveles de LTE4 en orina durante la fase aguda y en el período de seguimiento:– Durante la fase aguda los niveles de LTE4 fueron

significativamente más elevados en pacientes con FEV1 basal < 49%.

– A las dos semanas los niveles de LTE4 continuaban siendo significativamente más altos en los pacientes con mayor limitación al flujo aéreo.

• La vía de los leucotrienos se activa durante la exacerbación asmática y tienen un papel clave en la fisiopatología del asma agudo.

Asma agudo.Correlación leucotrienos – función pulmonar.



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Camargo CA Jr, Smithline HA, Malice MP, Green SA, Reiss TF. A randomizedcontrolled trial of intravenous montelukast in acute asthma. Am J Respir CritCare Med 2003;167: 4: 528-33

Many patients with acute asthma do not respond adequately to currently acceptedtherapy, including oxygen, beta- agonists, and corticosteroids. Leukotriene receptor antagonists such as montelukast have demonstrated efficacy in chronic asthma, but their efficacy in acute asthma is unknown. In this randomized, double- blind, parallel- group pilot study, adults with moderate to severe acute asthma receivedstandard therapy plus either intravenous montelukast (7 or 14 mg) or matchingplacebo. A total of 201 patients were randomized, and 194 had complete dataavailable for analysis. There was no difference in FEV1 response between the 7-and 14- mgmontelukast groups. Montelukast improved FEV1 over the first 20 minutes after intravenous administration (mean percentage change fromprerandomization baseline, 14.8% versus 3.6% for the pooled montelukast andplacebo treatment groups, respectively; p = 0.007). This benefit was observed at10 minutes and over 2 hours after intravenous therapy. Patients treated withmontelukast tended to receive less beta- agonists and have fewer treatmentfailures than patients receiving placebo. The tolerability profile for montelukast wassimilar to that observed for placebo, and no unexpected adverse experiences wereobserved. We conclude that intravenous montelukast in addition to standardtherapy causes rapid benefit and is well tolerated in adults with acute asthma.



Montelukast iv en asma agudo.



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Asma agudo.Conclusiones: Montelukast intravenoso.

• Hasta un 30% de los pacientes con asma agudo no responden al tratamiento con beta agonistas y el efecto beneficioso de los corticoides sistémicos no se observa hasta las 4 ó 6 horas.

• Montelukast iv combinado con el tratamiento estándar produce un incremento significativo en el FEV1 medido a los 20 minutos de su administración.

• Además:

– recibieron menos corticoides,

– necesitaron menor número de inhalaciones de beta agonistas y

– tuvieron menos fracasos terapéuticos.

• Perfil de tolerancia similar a placebo.



A study was conducted to assess the effects of montelukast on the development of peribronchialand interstitial inflammation in a chronic asthma rat model. Asthma was induced in 30 inbred, four- week- old Brown Norway rats; 10 additional rats were left untreated (naïve controls).Allergen challenges were repeated every other day from day 14 to day 30. Every other day from days 13 to day 29 and one hour before the allergen challenge, the 30 rats assigned to active treatment received intraperitoneal montelukast 0.01 mg (n=10), subcutaneous dexamethasone 300 mg (n=10), or subcutaneous 0.9% normal saline (n=10; control group). Following this period of repeated allergen challenge and treatment, lung tissues were obtained for histology analysis and assigned a pathology score according to severity (1 = no inflammation, 2 = mild peribronchial or interstitial inflammation, 3 = mild peribronchial and interstitial inflammation, 4 = moderate peribronchial and/or interstitial inflammation, and 5 = severe peribronchial and/or interstitial inflammation). The significance of the inhibitory effect of montelukast was calculated by a nonparametric analysis for multiple treatment groups by Kruskal- Wallis one- way analysis of variance (ANOVA). In the control group of rats with induced asthma, repeated allergen challenges without treatment resulted in the histologic characteristics of severe chronic asthma: severe peribronchial infiltrate with inflammatory cells, alveolar interstitial infiltrate, and peribronchialsmooth- muscle thickening. None of these changes were seen in the naïve or treated rats: mean pathology scores were significantly lower in both naïve and treated animals (p<0.0001 vs. control). These results in an animal model of chronic asthma demonstrate that montelukast prevented the development of peribronchial and interstitial inflammation as well as airway remodeling changes2 that can lead to permanent bronchial destruction.

Shoseyov D, Bibi H, Ofer S et al. Montelukast prevents airway remodeling in rats with chronic asthma. Poster presentation at the 96th International Conference of the American Thoracic Society, Toronto, Canada,May 2000.



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Efecto de montelukast sobre la inflamación y el remodelado de la vía aérea en un modelo animal.

PuntuaciónMedia AP*

0

1

2

3

4

5

No tratado Montelukast Dexametasona No sensibilizados

4.3

1.3 1.41.3

Montelukast previene el remodelado de las vías respiratorias.

INTERVENCIÓN PRECOZ.

*Puntuación de 1 (no inflamación) a 5 (inflamación severa peribroquial y/ointersticial)p<0.0001 animales no tratados vs. el resto de grupos.



Intervención precoz.

• Cambios histológicos característicos de la inflamación en el asma crónico:– Infiltración celular por macrófagos y linfocitos.

– Proliferación de fibroblastos.

– Angiogénesis.

– Aumento del tejido conectivo (fibrosis).

– Destrucción tisular.

• A largo plazo: daño tisular progresivo y deterioro funcional.

• En muchos pacientes con asma estas alteraciones en la estructurabronquial (remodelado) daño bronquial permanente.

PAPEL DE MONTELUKAST EN LA MODIFICACIÓN TEMPRANA DE LA ENFERMEDAD EN PACIENTES PEDIÁTRICOS.



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BRONQUIOLITIS.

• Infección del tracto respiratorio inferior más frecuente en el primer año de vida.

• Inflamación aguda de las vías respiratorias. Obstrucción del bronquiolo debido a edema con acumulación de moco y restos celulares.

• Caracteriza por sibilancias, junto con tos y dificultad respiratoria.

• Síntomas respiratorios motivo fundamental de atención médica.

• Puede predisponer a episodios recurrentes de síntomas respiratorios y contribuir al desarrollo y/o severidad del asma.

• No terapias eficaces para el tratamiento de los síntomas respiratorios de la bronquiolitis.

Hall CB, McCarthy CA. In: Principles and Practice of Infectious Diseases 2000: 1782-1801Panitch HB et al. Clin Chest Med 1993;14:715-731



Carballal G, Videla CM, Espinosa MA, Savy V, Uez O, Sequeira MD, Knez V, Requeijo PV, Posse CR, Miceli I. Multicentered study of viral acute lowerrespiratory infections in children from four cities of Argentina, 1993-1994.J Med Virol 2001; 64: 2: 167-74.

This study describes the first multicentered study of acute lower respiratory infectionviral etiology in young children from four different geographical areas of Argentina. A total of 1,278 children under 5 years of age, hospitalized in primary care centersfrom Buenos Aires, Cordoba, Santa Fe and Mar del Plata cities during a 2- yearperiod were studied (1993-1994). Nasopharyngeal aspirates were investigated forrespiratory syncytial virus (RSV), adenovirus, parainfluenza, and influenza A and B viruses by indirect immunofluorescence. Out of the patients studied, 946 (74%) wereunder 1 year of age. Viruses were detected in 399 patients (32%). RSV wasobserved in 25.3% of the samples, representing 78.2% of all viral positive cases. Adenoviruses were detected in 2.5% of the cases, parainfluenza in 2.2%, influenza A in 2.1%, and influenza B in 0.2%. Compared with other viruses, the higher RSV frequency was statistically significant (P < 0.000). Most RSV cases were detectedbetween May and September with a significant peak in July (P < 0.000). Pneumoniawas observed in 46% of the patients, bronchiolitis in 41% and other entities in 13%. The case fatality rate observed during the 2 year study was 0.73%. Most of theabove respiratory viruses were detected in the four cities, however, the frequency ofRSV and influenza were different in the southern city.



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Etiología.

• El VSR fue el agente etiológico más frecuentemente aislado en lasmuestras de niños < 5 años con infección aguda del tractorespiratorio inferior.

0.7%6.5%6.8%7.8%

78.2%

RSV

Adenovirus

Parainfluenza

Influenza A

Influenza B



Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection andreinfection with respiratory syncytial virus. Am J Dis Child. 1986 Jun;140: 6: 543-6.

Respiratory syncytial virus is the most important cause of serious lowerrespiratory tract infection in children. For children followed up from birth in theHouston Family Study, the infection rate was 68.8/100 children less than 12 months of age and 82.6/100 during the second year of life. Virtually all childrenhad been infected at least once by 24 months of age, and about one half hadexperienced two infections. Although lower respiratory tract disease (LRD) wascommon (22.4/100 during year 1 and 13.0/100 during year 2), most children hadonly one LRD illness. The risk of reinfection was inversely related to the level ofneutralizing antibodies in the serum. Reinfection illnesses were generally mild, and risk of reinfection decreased to only 33.3/100 during year 4. Studies ofchildren with LRD and surveys of hospitalizations provide the basis for anestimate of the number of children hospitalized each year during the respiratorysyncytial virus epidemics. Almost 100,000 children in the United Statesexperience an illness of sufficient severity to require hospitalization.



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Prevalencia de la infección por VSR.

• En un estudio de 125 niños seguidos desde el nacimiento hasta los12 meses de edad, y 92 niños hasta los 24- 36 meses, virtualmentetodos los niños estaban infectados por el VSR a los 24 meses.

100.0%97.1%

68.0%

0

20

40

60

80

100

0-12 13-24 25-36Edad (meses)

Niños coninfecciónpor VSR(%)



Fisiopatología.

• Comparte características fisiopatológicas con el asma.

• Datos que evidencian el papel de los cyst- leucotrienos en la fisiopatología de los síntomas respiratorios.

• Aumento de LTC4 en secreciones de la vía aérea en la fase aguda de la bronquiolitis (>> inducida por VSR).



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Clínica.

Fase I Fase II Fase III Largo plazo

InfecciónViral

Faseaguda

Sibilanciaspersistentes

Sibilancias y asma

Dias Semanas Meses

Curso clCurso clíínico mnico máás prolongado que la infeccis prolongado que la infeccióón real.n real.

A largo plazo, los niA largo plazo, los niñños que presentan una bronquiolitis inducida os que presentan una bronquiolitis inducida por VSR parece que estpor VSR parece que estáán en riesgo significativo de desarrollar asma.n en riesgo significativo de desarrollar asma.



Korppi M, Reijonen T, Poysa L, Juntunen-Backman K. A 2- to 3-yearoutcome after bronchiolitis. Am J Dis Child. 1993 Jun;147(6):628-31.

OBJECTIVE- - Todetermine the risk factors and short- term outcome until 3 years ofage for subsequent wheezing in children with early childhood bronchiolitis orpneumonia. DESIGN- - Prospective follow- up of a patient group. SETTING- - Universityhospital providing primary care for all pediatric patients of a defined area. PATIENTS- -One hundred twenty- seven children under 2 years of age hospitalized owing towheezing (n = 83) or pneumonia (n = 44) during 12 months in 1981 to 1982. Onehundred eight children completed the prospective follow- up until 3 years of age. INTERVENTIONS- - None. MAIN RESULTS- - The wheezing and pneumonia groupshad equal viral and bacterial etiologic findings. History of wheezing, atopic eczema, and elevated serum IgE levels were more common in patients with wheezing than withpneumonia. Subsequent wheezing was seen after bronchiolitis in 76% (61 of 80) of thechildren at 1 to 2 years of age and in 58% (44 of 76) at 2 to 3 years of age. Therespective figures were significantly lower, 9% (three of 33) and 16% (five of 32), in patients with pneumonia. An analysis of risk factors did not reveal any with a significant effect on subsequent wheezing. CONCLUSIONS- - Subsequent wheezing iscommon after bronchiolitis, but rare after early childhood pneumonia, although causedby the same viruses or bacteria. Atopic diathesis is the host factor associated withinitial wheezing. No genetic or environmental risk factor had significant associationwith later wheezing.



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Evolución.

• En un estudio de 83 niños < 2 años hospitalizados por bronquiolitis, una gran proporción tuvieron sibilancias recurrentes.

Niñoscon sibilancias (%)

58%

76%

0

20

40

60

80

100

1- 2(n=83)

2- 3(n=76)

Edad (años)



Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytialvirus bronchiolitis in infancy is an important risk factor for asthma andallergy at age 7. Am J Respir Crit Care Med 2000 May; 161: 5: 1501-7.

We previously reported an increased risk for bronchial obstructive disease and allergicsensitization up to age 3 in 47 children hospitalized with a respiratory syncytial virus (RSV) bronchiolitis in infancy compared with 93 matched control subjects recruited during infancy. The aims of the present study were to evaluate the occurrences of bronchial obstructivedisease and allergic sensitization in these children at age 7(1)/ (2). All 140 children reportedfor the follow- up, which included physical examination, skin prick tests, and serum IgE testsfor common food and inhaled allergens. The cumulative prevalence of asthma was 30% in the RSV group and 3% in the control group (p < 0.001), and the cumulative prevalence of"any wheezing" was 68% and 34%, respectively (p < 0.001). Asthma during the year prior tofollow- up was seen in 23% of the RSV children and 2% in the control subjects (p < 0.001). Allergic sensitization was found in 41% of the RSV children and 22% of the control subjects(p = 0.039). Multivariate evaluation of possible risk factors for asthma and sensitizationusing a stepwise logistic statistical procedure for all 140 children showed that RSV bronchiolitis had the highest independent risk ratio for asthma (OR: 12.7, 95% CI 3.4 to47.1) and a significantly elevated independent risk ratio for allergic sensitization (OR: 2.4, 95% CI 1.1 to 5.5). In conclusion, RSV bronchiolitis in infancy severe enough to cause hospitalization was highly associatied with the development of asthma and allergicsensitization up to age 7(1)/ (2). The results support the theory that the RSV influences themechanisms involved in the development of asthma and allergy in children.



21



Bronquiolitis por VSR y asma.

3%

30%

0

5

10

15

20

25

30

35

RSV (n=47)

Control (n=93)

Niñoscon asmaa los 7.5 años (%)

• En un estudio de 140 niños, la incidencia de asma a los 7.5 añosfue mayor en los que habían sido infectados por VSR comparadocon los controles.



• Los CysLT ¿son dianas terapéuticaspotenciales en el tratamiento de la bronquiolitis porVSR?.

• ¿Los antileucotrienos pueden modificar el proceso patológicosubyacente?.

Leukotrienereceptor

CysLT

Célula vía aérea(eosinófilo, célula músculo liso, etc.)

CysLTCysLT

LTRALTRA

Bronquiolitis.Papel de los antileucotrienos.



22



Bisgaard H; Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med. 2003; 167: 3: 379-83.

Infants often develop reactive airway disease after respiratory syncytial virus (RSV) bronchiolitis. Cysteinyl- leukotrienes (cys- LT) are released during RSV infection and may contribute to the inflammation. We hypothesized that a cys-LT receptor antagonist would ameliorate reactive airway disease subsequent toRSV bronchiolitis. One hundred and thirty infants who were 3 to 36 monthsold, hospitalized with acute RSV bronchiolitis, were randomized into a double-blind, parallel comparison of 5-mg montelukast chewable tabletsor matching placebo given for 28 days starting within 7 days of symptomdebut. Infants with a suspected history of asthma were excluded. One hundredsixteen infants provided diary card data for the treatment period. Median agewas 9 months. Infants on montelukast were free of any symptoms on 22% ofthe days and nights compared with 4% of the days and nights in infants onplacebo (p = 0.015). Daytime cough was significantly reduced on active treatment (p = 0.04). Exacerbations were significantly delayed frommontelukast compared with placebo (p < 0.05). In conclusion, cys- LT antagonist treatment reduces lung symptoms subsequent to RSV bronchiolitis.



Bronquiolitis y montelukast.

• Montelukast aumentó significantivamente los días y noches libres de síntomas.

Mediana de díasy noches libresde síntomas (%)

Días

30

20

10

0

0 7 14 21 28

Montelukast (n=61)

Placebo (n=55)

p=0.015



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Prevention of Viral- Induced Asthma

Montelukast en la prevención de las exacerbaciones inducidaspor virus en niños de 2–5 años de edad con síntomas asmáticosintermitentes.



Diseño del estudio

Semana 48

Visitas 7 8

Tanteo con placebo

Placebo

Montelukast 4 mg (o 5 mg en función de la edad)*

Período I Período II

36

1 2 3 4 5 6

241680-2-3



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Montelukast redujo la tasa de exacerbaciones.

2.34

1.60

0

1

2

3

Montelukast 4 mg (n=265)

Placebo (n=257)

Tasa deepisodios deexacerbación/ año

32%

p0.001



Montelukast redujo el recuento de célulasinflamatorias (Eosinófilos en sangre)

3.7%

- 4.0%-5

-4

-3

-2

-1

0

1

2

3

4

5

Montelukast 4 mg(n=214)

Placebo(n=216)

Cambiomediodesdebasal (%)

p=0.01



25



Resumen del estudio PREVIA

• Redujo significativamente la frecuencia de las exacerbaciones en un 32 % (p 0,001) y los ciclos de corticosteroides inhaladosen un 40 % (p = 0,027)

• Redujo numéricamente la frecuencia de los ciclos de corticosteroides orales y aumentó el porcentaje de días sin asma

• No influyó sobre la duración media ni la gravedad media de las exacerbaciones

• Generalmente fue bien tolerado

En niños de 2- 5 años de edad con síntomasepisódicos de asma, el tratamiento con montelukastdurante 12 meses


nuevas perspectivas en el tratamiento del asma · • los pacientes con rinitis alérgica...

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