Memorias X Congreso Colombiano de Neumologia y Asma Pediatrica 2012-2

Diagnostic Methods in Evaluating Respiratory Disturbances During Sleep in Children Manisha Witmans, MD, FRCPC, FAASM

Objectives ď Ź

Discuss the diagnostic challenges in evaluating children with sleep related respiratory complaints

ď Ź

Discuss practical methods of evaluating children with sleep disordered breathing

Is This All Sleep Disordered Breathing Is?

Primary or Secondary Sensory Neuro-motor impairment dysfunction

Upper airway dysfunction Inflammation

Modified from Tauman R & Gozal D. Paediatric Respiratory Reviews (2006)

Structural alteration

Pediatric PSG: What one needs?

EEG

EOG

Nasal EtCO2

Nasal Oral Airflow

Chin EMG (2)

Microphone TcCO2

SaO2

EKG Tech Observer

Video Camera Respiratory Effort (RIP)

Documents arousals, parasomnias, abnormal sleeping position, and attends to any technical problem

Leg EMG (2)

Records behavior

Courtesy of Dr. Carol Rosen with modifications by Dr. Manisha Witmans

PSG Tracing

PSG as a Test 

The knowns

 

 

Sleep Efficiency Sleep architecture and stages Type, nature and severity of respiratory events Cardiorespiratory parameters



The unknowns



   

Sleep fragmentation Work of breathing Neurocognitive dysfunction End organ dysfunction The pathophysiology and mechanisms for the abnormalities

Other Tests Ambulatory sleep testing  Clinical history and physical examination  Radiological imaging  Endoscopy (evaluation of airway)  Bloodwork for inflammatory markers  Assessment of neurobehav. functioning 

Where and what is the goal?

Validity-reliability bulls eye (Babbie, 1998)

Both valid & reliable

Reliable, but invalid

Ambulatory Testing Stardust

Embletta X100 Nox Medical

SagaTech: Snoresat

Ares

Watch-Pat 100 Nite Watch

Methods of Diagnosing SDB

**AAP guidelines, 2002

Other Investigations: ď Ź

Ancillary measures such as heart rate variability, or pulse transit time

Ambulatory Devices in Children Limited validation  Signal artifact is a real problem  Needs a dedicated personnel who know what they are doing 

Where and what is the goal?

A compromise between validity and reliability

Where and what is the goal?

A compromise between validity and reliability

What is that AND How do we get there?

OSAS-SDB Spectrum in Children 

Defining SDB: 



Symptom complex for OSAS-SDB

Symptom complex and PSG abnormalities 

PSG or ambulatory testing abnormalities  Cut-off

values for statistical significance is not the same as for clinical outcomes:  



 

Degree of hypoxemia Degree of hypercarbia Apnea-Hypopnea Index (AHI)

Degree of sleep disruption of child and/or family End organ effect (inflammation/injury)

Suggested Criteria for SDB

Gozal, 2010, Sleep Medicine

Pulse Oximetry ď Ź

Examples of oximetry tracings

Brouillette, Pediatrics, 2000

Examples 2 yr old boy with OSA with failure to thrive  Healthy  Questions? 

Pre-op

2 wks after adenotonsillectomy

Primhak, Arch Dis child Educ Prac 2005; 90

REM related sleep apnea

Patil S, Chest, July 2007 Limitations: without respiratory bands, can’t tell for sure whether it is central or obstructive apneas

Videos

Summary Polysomnography provides the most comprehensive information for sleep related respiratory complaint ď Ź It is important to consider the question one is asking to obtain the best test for the affected individual ď Ź Other methods may be feasible to diagnose sleep disordered breathing and ancillary testing may also help. ď Ź

Questions?

Impacto de la Rinitis AlĂŠrgica en la Escolaridad FernĂĄn Caballero Fonseca Caracas, Venezuela 2012

Impacto de la Rinitis Alérgica en la Escolaridad  Rinitis: Generalidades

 Importancia de la congestión y el sueño en concentración y escolaridad

 Fracaso escolar: Prevalencia, factores causales  Impacto de las formas de terapia en rendimiento y productividad

 Conclusiones

Impacto de la Rinitis Alérgica en la Escolaridad  Rinitis: Generalidades

 Importancia de la congestión y el sueño en concentración y escolaridad

 Fracaso escolar: Prevalencia, factores causales  Impacto de las formas de terapia en rendimiento y productividad

 Conclusiones

Rinitis Alérgica: Generalidades  Es la enfermedad alérgica más frecuente tanto en niños como adultos  10 a 30% en adultos  40% en niños

 Morbilidad elevada por:       

Ausentismo y bajo rendimiento laboral y escolar Infecciones agregadas Alteraciones en el sueño Respiración oral / estridor Otitis media y disminución de la agudeza auditiva Disminución del olfato y gusto Efectos secundarios de los medicamentos

Impacto de la Rinitis Alérgica en la Vida Cotidiana de los Pacientes SUEÑO Y CANSANCIO • 46% de pacientes se siente cansado1 • 77% tiene problemas para conciliar el sueño1

IMPACTO

EN ACTIVIDADES

ALTERACIÓN EN APRENDIZAJE Y FUNCIONES COGNITIVAS6

COTIDINANAS2,3

Impacto de Rinitis Alérgica PRODUCTIVIDAD EN TRABAJO Y ESCUELA

AFECCIÓN SOCIAL

• ≤90% Efectividad en trabajo4 • ≤93% Desempeño alterado en salón de clases3,5

Adolescentes apenados de usar inhaladores6

1. Scadding G et al. EAACI 2007, Abstract 1408. 2. Reilly MC et al. Clin Drug Invest 1996;11:278–88. 3.

Tanner LA et al. Am J Manag Care 1999;5(Suppl 4):S235–S247. 4. Blanc PD et al. J Clin Epidemiol 2001;54:610–18. 5.

Juniper EF et al. J Allergy Clin Immunol 1994;93:413–23. 6. Marshall PS, Colon EA. Ann Allergy 1993;71:251–8.

Impacto de la Rinitis Alérgica en la Escolaridad  Rinitis: Generalidades

 Importancia de la congestión y el sueño en concentración y escolaridad

 Fracaso escolar: Prevalencia, factores causales  Impacto de las formas de terapia en rendimiento y productividad

 Conclusiones

El Enigma de la Congestión “Bloqueo total”

Obstruido/ Sentirse obstruido

“Congestionado”

“Tapadísimo”

Qué es congestión?

Edema/ Sentimiento hinchazón

“Nariz Tapada”

No Flujo de Aire

Bloqueado “No puedo respirar”

“Taponado”

Obstruido

Definiciรณn de Congestiรณn

Edema de la mucosa causado por vasodilataciรณn y exudaciรณn debido al incremento de la permeabilidad capilar relacionada con la inflamaciรณn

Jessen and Malm. Allergy. 1997;52(suppl):3.

SĂ­ntomas que Ocasionan Mayores Molestias al Paciente con Rinitis AlĂŠrgica

% de pacientes Allergies in America, 2006.

Trastornos Respiratorios Asociados al Sueño (Sleep Disordered Breathing)  Están caracterizados por un patrón anormal respiratorio durante el sueño que incluye ronquidos, respiración bucal, y pausas en la respiración  Estos transtornos (SDB) comprenden un espectro que van desde ronquidos hasta la apnea del sueño obstructiva (OSA)

 La apnea del sueño obstructiva (OSA) se diagnostica cuando los trastornos de sueño se acompañan de anormalidades en polisomnografía en relación a eventos obstructivos

Practice Guideline: Polysomnography for Sleep-Disordered Breathing Prior to Tonsillectomy in Children.

Otolaryngology–Head and Neck Surgery 145(1S) S1–S15, 2011.

Rinitis Alérgica y Trastornos del Sueño  Lavie P, Gertner R, Zomer J, Podoshin L. Breathing disorders in sleep associated with “microarousals” in patients with allergic rhinitis. Acta Otolaryngol. 1981;92:529 – 533.  Craig TJ, Teets S, Lehman EB, Chinchilli VM, Zwillich C. Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue and the response to topical nasal corticosteroids. J Allergy Clin Immunol. 1998;101:633– 637.

 Scharf MB, Cohen AP. Diagnostic and treatment implications of nasal obstruction in snoring and obstructive sleep apnea. Ann Allergy Asthma Immunol. 1998;81:279 – 287; quiz 287–290.  McNicholas WT, Tarlo S, Cole P, et al. Obstructive apneas during sleep in patients with seasonal allergic rhinitis. Am Rev Respir Dis. 1982;126:625– 628.  Young T, Finn L, Kim H. Nasal obstruction as a risk factor for sleepdisordered breathing. The University of Wisconsin Sleep and Respiratory Research Group. J Allergy Clin Immunol. 1997;99:S757–S762.

Allergic rhinitis and its consequences on quality of sleep: An unexplored area

Leger D., Annesi-Maesano I., Carat F.,Rugina M., Chanal I., Pribil C., El Hasnaoui A., Bousquet J.

Arch Intern Med 2006;166:1744-8

Sueño Deficiente en la Rinitis Alérgica 14 pacientes con rinitis tuvieron 10 veces más (promedio de 50) micro-despertares que los controles

Lavie et al. Acta Otolaryngol. 1981;92;529.

Conclusiones: Los trastornos del sue単o, de cualquier severidad se asocian a alteraciones de conducta, pero no a deficiencias en desempe単o cognitivo.

2012 Published by Elsevier B.V.

A Clinical Overview of Sleep and Attention- deficit/Hyperactivity Disorder in Children and Adolescents  Reportes recientes han documentado un incremento significativo en los trastornos del sueño reportados por los padres, especialmente en niños siendo evaluados y/o dignosticados con ADD (ADHD)  Se ha sugerido que hasta el 25% de los niños con diagnóstico de ADD (ADHD) pudieran padecer trastornos del sueño tales como ronquidos habituales  Ronquidos habituales han sido reportados tres veces más frecuentemente en niños con ADD (ADHD) (33%) que en población psiquiatrica (11%) o en población de niños sanos (9%)

Judith A. Owens, MD, MPH J Can Acad Child Adolesc Psychiatry. 2009 May; 18(2): 92–102.

A Clinical Overview of Sleep and Attention- deficit/Hyperactivity Disorder in Children and Adolescents  No todos los estudios han encontrado la asociación entre ADD y trastornos del sueño confirmados por polisomnografia (Sangal, Owens, & Sangal, 2005)  Estudios que analizan los cambios en conducta y funcionamiento neuropsicológico en niños tratados (generalmente adeno-tonsilectomía) han tenido mejoría importante en los trastornos de sueño y en rendimiento escolar (Wei, Mayo, Smith, Reese, & Weatherly, 2007; Gozal, 1998; Ali, Pitson, & Stradling, 1996)  En un estudio el 50% de un grupo de niños con criterios para ADD no los tenian un año posterior a adenotonsilectomía(Chervinet al., 2006)

Judith A. Owens, MD, MPH J Can Acad Child Adolesc Psychiatry. 2009 May; 18(2): 92–102.

Impacto Adverso de la Congestión Sobre el Sueño: Resumen  La congestión es el síntoma más frecuente y más molesto  La congestión afecta negativamente el sueño del paciente  Dificulta ó evita que los pacientes se duerman  Despierta a los pacientes  Incrementa la somnolencia diurna  La congestión reduce la asistencia y la productividad en el trabajo/la escuela

Impacto de la Rinitis Alérgica en la Escolaridad  Rinitis: Generalidades

 Importancia de la congestión y el sueño en concentración y escolaridad

 Fracaso escolar: Prevalencia, factores causales  Impacto de las formas de terapia en rendimiento y productividad

 Conclusiones

Rinitis Alérgica: Problemas de Aprendizaje en Niños Calificación promedio de aprendizaje compuesto a las 2 semanas (%)

Calificaciones de aprendizaje compuesto en niños de 10-12 años de edad P=0.007

Niños sanos (n=13)

Niños con rinitis alérgica (n=12) Vuurman et al. Ann Allergy. 1993;71:121.

Grado de Interferencia de la Alergia en la Actividad Escolar Sólo faltó a la escuela

Interfirió

Ambas

Ninguna

100% 80%

46%

47%

52%

46%

62%

60% 40%

19% 16%

20%

28%

29%

6%

3% 41% 9%

2% 32%

18%

20%

17% 7%

0% Todos los Países AILA

Argentina

Brasil

Méjico*

Otros Países de América Latina

Q27A. ¿Ha su hijo/a faltado a la escuela en los últimos 12 meses debido a su alergia nasal?

Q28A. Además de efectivamente faltar a la escuela, ¿los síntomas de la alergia nasal en los últimos 12 meses han interfereido con su desempeño en la escuela? Base: Empleado tiempo completo, N = 418 *Méjico no preguntó Q28a si la respuesta a Q27a fue ‘sí’. Por lo tanto, se clasificó a estos hogares como ‘Ambas’.``

 1834 Estudiantes de 16 a 18 años  Comparación del desempeño en exámenes simulado (invierno) vs. el actual (verano)  662 estudiantes tuvieron un desempeño peor en verano y 1172 tuvieron uno igual o mejor  La probabilidad de un desempeño peor  Rinitis alérgica en curso: 1.4 (IC 1.1-1.8), p=0.02  Antihistamínicos sedativos: 1.7 (IC 1.1-2-8), p=0.03 Walker S et al. J Allergy Clin Immunol 2007; 120: 381-7.

 Conclusión: La rinitis alérgica sintomática y el uso de medicación para la rinitis se asocian con un riesgo significativamente aumentado de fracasar en los exámenes de grado  Implicaciones clínicas: Por primera vez se demuestra la relación entre la rinitis alérgica sintomática y un pobre desempeño en los exámenes, lo cual tiene importantes implicaciones para la práctica clínica

Walker S et al. J Allergy Clin Immunol 2007; 120: 381-7.

Impacto de la Rinitis Alérgica en la Escolaridad  Rinitis: Generalidades

 Importancia de la congestión y el sueño en concentración y escolaridad

 Fracaso escolar: Prevalencia, factores causales  Impacto de las formas de terapia en rendimiento y productividad

 Conclusiones

Antihistamínicos de 1era Generación: Impacto en Sedación y Desempeño Escolar  Sedación de hasta el 55% de pacientes pediátricos  Efectos anticolinérgicos a dosis elevadas  Automedicación común (preparados OTC)  Riesgo mayor de sobredosis  Leve: insomnio, ataxia, estimulación paradójica del CNS  Severo: convulsiones, psicósis, arritmias ventriculares, paro cardiorespiratorio

Ten Eick AP, et al. Drug Safety 2001;24:119-47.

Antihistamínicos de 2da Generación: Efecto sobre los Trastornos del Sueño Cambio medio desde la línea de base en la escala de interferencia con el sueño (Diarios AM)

ACCEPT-1 Resultados: la DL mejora los trastornos del sueño asociados con la RAI Días 2-15

Línea de base: 1.37

0

1.38

-0.1 -0.2

-0.27 -0.3

-0.37

*

-0.4

Desloratadina 5 mg

-0.5 -0.6

Placebo

*P<0.05 vs placebo.

Escala de 4 puntos (0 = ninguno, 3 = severo)

Bachert et al. Allergy. 2008;63(supl. 88):634. Resumen 1760.

Allergy Asthma Proc 29:140 â&#x20AC;&#x201C;145, 2008.

28

Corticoides Intranasales: Efecto sobre el Desmpeño Escolar  No afectan el desempeño escolar1  Mejoran el desempeño escolar2  Limitaciones en los datos clínicos: • Triamcinolona > 2 años de edad • Mometasona > 2 años de edad • Propionato de Fluticasona > 4 años de edad, • Furoato de Fluticasona >2 años • Beclometasona, budesonide > 6 años de edad • Ciclesonide > 12 años de edad 1.Sayyad JJ, et al. Biblioteca Cochrane Plus 2007;3. Oxford: Update Software Ltd. 2. Craig, et al. J Allergy Clin Immunol 2005;116:1264-6.

9

¶

*

8

*

7

* p<0.05 ¶ p<0.001

*

6

5

Pre-tto

MFNS 200 mcg QD

4

3

*

2

1

Memoria visual

Concentracion

Atencion

PV-exactitud

0

PV-capacidad

Cambio en el puntaje de funcion cognitiva

Mejoría de la Función Cognitiva en Adolescentes con Tratamiento con Corticoides Intranasales

Namazova LS et al. AAAAI Annual Meeting 2010.

30

Conclusiones  La rinitis alérgica no tratada podría ser la causa de un bajo desempeño en la escuela

 Un diagnóstico temprano y un tratamiento óptimo de la RA podrían evitar el impacto y el ausentismo escolar

 La 1era generación de anti-H1 tiene un efecto nocivo sobre la capacidad de aprendizaje de los niños

 El tratamiento farmacológico de primera línea con anti-H1 de 2da generación es verdaderamente no sedativo y los esteroides intranasales en niños en edad escolar han demostrado ser beneficiosos en los efectos negativos de esta enfermedad

Muchas Gracias!!!

Inmunoterapia en Asma - Pro

Fernรกn Caballero Fonseca Caracas, Venezuela 2012

Inmunoterapia específica con alergenos

Es la administración repetida de alergenos específicos en pacientes sensibilizados, con el propósito de inducir inmuno tolerancia a un agente pro-inflamatorio a la re-exposición a dichos alergenos

Adapted from Cox L, Li JT. Nelson H and Lockey R. Allergen Immunotherapy. A Practice Parameter Second Update.

J Allergy Clin Immunology. 2007; 120 (3): S25-85.and Third Update JACI 127, 1 2011.

ITSC, ITSL  Efectividad probada en adultos y niños en:  Rinoconjuntivitis alérgica (A)  Asma alérgica (A)



Sensibilidad al veneno de insectos (A)

 Aún no aprobada en:



Dermatitis atópica (débil)



Alergia a alimentos (débil) Radulovic S. et al. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD002893.

Ross RN, Nelson HS, Finegold I. Clin Ther 2000 Abramson M, Puy R, Weiner J. Cochrane Database Syst Rev 2003,4: CDoo1186 Durham SR,et al. Cochrane Database Syst Rev. 2003;(2):CD002893.

Prevención de progreso de enfermedades alérgicas

REVISAR

 Nuevas sensibilizaciones en pacientes monosensibilizados  Progreso a asma en pacientes con diagnóstico sólo de rinitis alérgica  Interrumpe la tendencia a formas graves de alergia. Marcha atópica  El efecto benéfico de la ITE persiste por largo tiempo después de haberse descontinuado

Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy (6 year follow-up study)  134 niños, con edades entre 5 y 8 años, con asma intermitente, con o sin rinitis, y mono-sensibilizados a dermatofagoides

 Padres de 75 niños aceptaron inmunoterapia  Padres de 63 niños rechazaron inmunoterapia  Inmunoterapia por 3 años, con 3 años de seguimiento. IgE y P/C

cada año  Resultados. 123 niños completaron el estudio. Inmunoterapia 52/69 (75.44 %) no nuevas sensibilizaciones Medicamento (control) 18/54 (33.3 %) P < 0.0002

GB Pajno et al. Clin Exp Allergy 2001;31:1392-7.

Estudio PAT:

Prevención de asma por inmunoterapia específica

 205 niños de 7-13 años de edad con rinitis alérgica y NO diagnóstico de asma  “La ITE previene el desarrollo de asma en niños?”  Inmunoterapia por 3 años con Abedul y/o Pleum pratensis  191 pacientes 94 control 97 inmunoterapia  Seguimiento por 5 y 10 años

Moller C, Jacobsen L, et. Al. JACI 2002;109:251-6.

Estudio PAT:

Desarrollo de asma a los 10 años 147 pacientes de 205 con seguimiento % de pacientes

100

80

Tasa de probabilidad= 2.50 (1.1 – 5.9) N= 46

N=29

60

N=24

40

Sin asma Asmáticos

N=16

20 0

SIT

Control Jacobsen et al Allergy 2007.

Estudio PAT:

Prevenci贸n de asma por inmunoterapia especifica

Asthma reduction with 3 yrs of SLIT Randomized controlled trial

SLIT: Metacholine challenge (+):

82 (56.9%)

After SLIT: 23 (17.7%)

p< .001

Marogna. Ann Allergy Asthma Immunol. 2008;101:206.

Asthma reduction with 3 yrs of SLIT Randomized controlled trial: 216 children * SLIT

*

Controls

NS

70

60 *

50 40

Patients, %

*

30

NS NS

20 10

0 Baseline 3rd Year Intermittent Asthma

SLIT: Metacholine challenge (+):

82 (56.9%)

Baseline 3rd Year Persistent Asthma

After SLIT: 23 (17.7%)

p< .001

*P<0.001.

Marogna. Ann Allergy Asthma Immunol. 2008;101:206.

SLIT en asma 3-18 aĂąos Puntaje de sĂ­ntomas

Penagos et al. Chest. 2008 Mar;133(3):599-609.

SLIT en asma 3-18 a帽os Puntaje de medicaci贸n

Penagos et al. Chest. 2008 Mar;133(3):599-609.

Long-lasting effects of sublingual immunotherapy according to its duration 15-year prospective study

   

78 pacientes tratados con dermatofagoides SLIT 30X dosis de SCIT Tratamiento inicial por 3, 4 o 5 años Re- tratados cuando escala de síntomas >50% de la línea basal Observación 15 años

M Marogna, et al. J Allergy Clin Immunol 2010;126:969-75.

Escalas de s鱈ntomas / Medicamentos A 3-a単os B 4-a単os C 5-a単os

400

100

2002

2000

1998

SLIT

1996

1994

1992

SLIT

2006

200

** ** * * * ** * * ** ** ** * * ** ** * * * * * * * * * * * *

2004

* *

300

M Marogna, et al. J Allergy Clin Immunol 2010;126:969-75.

Injection allergen immunotherapy for asthma (Review)  Objetivo: Estimar la eficacia general de la inmunoterapia

especifica con alérgenos sobre los síntomas de asma, requerimiento de medicamentos, función pulmonar, HRB no especifica y alérgeno-especifica

 Método:  Revisión de todos los estudios del grupo Cochrane vías respiratorias, (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED y PsycINFO, Estudios ADCCP  Tres revisores independientes evaluar criterios de inclusión  Dos revisores independientes evaluar la calidad de los estudios Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD001186. DOI: 10.1002/14651858.CD001186.pub2.

increased non-specific or AS BHR than those who received placebo (table). When compared with untreated controls, patients in the AS immunotherapy group had greater improvement in lung function (2 RCTs; weighted mean difference [WMD] 2 15.20, 95%CI 2 23.09 to 2 7.31); and greater reduction in asthma symptoms (3 RCTs; WMD 2 6.93, CI –13.83 to –0.04), medication requirements (1 RCT; WMD – 4.00, CI –4.79 to –3.21), and non-specific BHR (1 RCT; WMD –0.77, CI –1.11 to –0.43). No other comparison groups differed for lung function.

Finally, a recent European study tested the hypothesis that AS immunotherapy might prevent the development of asthma. After 3 years of therapy, children with allergic rhinitis who received AS immunotherapy were about half as likely to develop asthma as those who did not.4 ASimmunotherapy issafe and effective when administered by trained healthcare professionals who observe high standards of care.

Bernard RAdelsberg, MD Hamden Internal Medicine Associates Hamden, Connecticut, USA

Injection allergen immunotherapy for asthma (Review)

CONCLUSION In patients with asthma, allergen specific immunotherapies reduceasthma symptoms, medication requirements, allergen specific

1 Turkeltaub PC. FDA Medical Bulletin 1994;24:7.

2 Idsoe O, Guthe T, Willcox RR, et al. Nature and extent of penicillin sidereactions, with particular reference to fatalitiesfromanaphylacticshock. Bull World Health Organ 1968;38:159–88.

3 Sullivan TJ, Selner JC, Patterson R, et al. Expert careand immunotherapy for asthma. A review of published studies with emphasis on patient outcome and cost. American College of Allergy, Asthma, and Immunotherapy Monograph. Nov 1996, 1–25.

4 Mo ¨ ller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reducesthe development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251–6.

Resultado. 88 estudios incluidos 1954 - 2009 (13 nuevos) . . . . . . . . . .3792 . . . . . . . . . . .pacientes ........................................

For correspondence: Associate Professor M Abramson, Monash University,

Calificación (Escala de Jadad) 6: 5/5, 16: 4/5, 32: 3/5

Prahran, Victoria, Australia. michael.abramson@med.monash.edu.au Source of funding: Garfield Weston Foundation, UK.

Allergen specific immunotherapies (ITs) v placebo or untreated controls (UC) for reducing asthma symptoms* Outcomes

Comparisons

Number of trials

Weighted event rates

RRR(CI)

NNT(CI)

Asthmatic symptoms

Mite ITv placebo Pollen ITv placebo Animal dander ITv placebo Overall ITv placebo Overall ITv placebo

12 3 4 22 16

30%vs 51% 21%vs 62% 27%vs 69% 29%vs 60% 48%vs 72%

38%(13 to 56) 75%(10 to 93) 54%(6 to 78) 49%(35 to 59) 34%(24 to 42)

5 (1 to 3) 3 (2 to 4) 3 (2 to 17) 4 (3 to 5) 5 (4 to 7)

Overall ITv placebo Overall ITv placebo House dust v placebo

5 16 1

30%vs 64% 32%vs 63% 11%vs 39%

53%(30 to 69) 49%(37 to 59) 71%(29 to 88)

3 (2 to 6) 4 (3 to 5) 4 (3 to 13)

Asthma medication requirements Non-specific BHR Allergen specific BHR

*WMD = weighted mean difference; BHR = bronchial hyper-reactivity. Other abbreviations defined in glossary; weighted event rates, RRR, NNT, and CI calculated from data in article using a fixed effects model. Follow up not reported.

www.evidence-bas edmedicine.com Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database

of Systematic Reviews 2010, Issue 8. Art. No.: CD001186. DOI: 10.1002/14651858.CD001186.pub2.

Injection allergen immunotherapy for asthma (Review)  Magnitud de eficacia de ITE comparable a esteroide inhalado  Efectos adversos: Anafilaxia 2.45 (95% CI 1.91 a 3.13)  Conclusión: ITE es efectiva... sin embargo debe considerarse la posibilidad de efectos adversos (anafilaxia)

Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD001186. DOI: 10.1002/14651858.CD001186.pub2.

Eficacia y seguridad. ¿De qué depende?       

Selección de paciente Atención de alergenicidad cruzada Atención labilidad y contenido de proteasas Selección alérgeno(s) relevantes(s) Calidad de alérgenos Dosis efectiva de cada alérgeno Duración suficiente

Muchas Gracias!!!

Obstructive Sleep Apnea in Children Manisha Witmans, MD, FRCPC, FAASM

Objectives 

To challenge the current paradigm of OSA 

Discuss the pathophysiological mechanisms of upper airway dysfunction



Discuss end-organ dysfunction associated with OSA



Discuss challenges in diagnosing OSA

Is This All Sleep Disordered Breathing Is?

Proposed Phenotypes of OSA Symptom

Type 1 OSA

Type 2 OSA

Daytime Sleepiness

+

++++

Weight gain/Obesity

+

++++

Hyperactivity

++++

-

Lymphoid hyperplasia

++++

++

Hypertension

+

++++

LV Dysfunction

+

++++

Insulin Resistance

-

++++

Psychiatric Problems

+

+++

Gozal, Am Thor Proceedings 2008

Other proposed types: Craniofacial Neuromuscular

Primary or Secondary Sensory Neuro-motor impairment dysfunction

Upper airway dysfunction Inflammation

Modified from Tauman R & Gozal D. Paediatric Respiratory Reviews (2006)

Structural alteration

Sensory Impairment 

Cause or effect? 

Older children

Tongue Tapia, 2010, Sleep

Anterior Palate

Hypotonia and SDB

Endoscopic data Obstruction   



Deviated nasal septum Chronic rhinitis Adenoidal Tonsillar

Collapse    

Circumferential pharyngeal Lateral pharyngeal Laryngeal Tongue base

Summary for DS 

Down syndrome children exhibit a collapsing pattern more than other children with SDB



Lingual collapse is significant but not universal



Neuro-motor dysfunction overrides structural alterations in this group



SNP may direct surgery and help avoid unnecessary adeno-tonsillectomies



Fung et al. 2012, Archives of Otolaryngology

The United Airways Disease Asthma

Atopy Obstructive Sleep Apnea

Common genetic and environmental risk factors

Inflammation 

SDB 

Inflammatory markers identified  CRP,



oxidative species, cytokines, eNO

Evidence that treating inflammation improves SDB

Primary or Secondary Sensory impairment

Neuro-motor dysfunction

Upper airway dysfunction Inflammation

Structural alteration

Modified from Tauman R & Gozal D. Paediatric Respiratory Reviews (2006)

Obesity Risk factor for OSAS (OR 4.5)  Obesity more prevalent in studies evaluating SDB  Surgery (T&A) does not cure majority of those with OSAS 

Redline, AJRCCM, 2005 Bhatacharjee, AJRCCM, 2010 Mitchell, OtoHNS, 2004

Obesity 

Pathophysiology: 

Anatomic factors  Hormonal,

inflammatory  Possible soft tissues restricting airway  Craniofacial structure 

Functional factors  Increased  

airway collapsibility

Neuromotor tone, increased resistance ? Possible higher Pcrit

Chest wall mechanics  Altered ventilatory responses 

Childhood Obesity and SDB

Arens, 2010, J Appl Phys.

End Organ Dysfunction 

Metabolic Derangements



Cardiovascular dysfunction



Neurocognitive dysfunction

SDB and Metabolic Syndrome 

Adjusting for sex, age, race and prematurity, adolescents with OSA  



Adjusted OR of Met S: 6.49 ( 95% CI, 2.52, 16.70) Degree of AHI and lower minimum SaO2 increased odds of Met S

Adjusting for BMI and sex, OSA predisposed to  Increased  Higher

insulin resistance

BP  Higher LDL Redline, 2007, AJRCCM

End Organ Dysfunction 

Cardiovascular morbidity Blood pressure regulation  Cardiac function 

 End

diastolic dysfunction  Left ventricular remodelling 

Endothelial functioning  CRP,

myeoid related protein 8/14

Amin. AJRCCM, 2002; Amin. Hypertension, 2008 Wang, J Am Coll Cardiol, 2007 Bhattacharjee et al, Prog CV Disease, 2009; Bhattacharjee Circulation, 2007; Bhattacharjee, Sleep, 2010

End Organ Dysfunction

n=8 controls

ď&#x201A;§ Time to reach baseline cutaneous flow was (mean) 69 seconds

Bhattacharjee et al, Circulation, 2007

Pre and Post Adenotonsillectomy

n=26

ď&#x201A;§ Baseline cutaneous flow pre T+A was > 113 seconds ď&#x201A;§ Normalized to 60-80 seconds post surgery

Pre and Post Adenotonsillectomy Family history of CVS Disease

n=6

ď&#x201A;§ Baseline cutaneous flow pre T+A was > 113 seconds ď&#x201A;§ Did not normalise post surgery

Inflammatory Marker: sCD40L

ď&#x201A;§ sCD40L high in OSA but significantly reduced post T+A but still higher than controls

CV Dysfunction and SDB

Bhattacharjee, Sleep Medicine, 2010

OSA and Neurocognition 

Link between habitual snorers with OSA and neurocognition



Link between habitual snorers without OSA and neurocognition



Increased risks for neurobehavioural deficits in the context of OSA are Obesity  Hypoxemia and sleep fragmentation 

Beebe DW, Sleep 2006 Gruber R, Sleep 2007

OSA and Neurocognition Variable

No-snoring (n=87)

No-OSA (n=112)

OSA (n=146)

Age

6.4 ± 0.3

6.4 ± 0.2

6.3 ± 0.3

BMI

16.7 ± .04

16.9 ± 0.5

17.0 ± 0.4

AHI

0.0 ± 0.0

0.8 ± 0.3

8.6 ± 2.2 *

Minimum SaO2

93.1 ± 0.6

90.6 ± 0.7

81.6 ± 2.7 *

2 abnormal NC tests no ( %)

0

3 (2)

16 (11) *

APOE e4 no (%)

0

16 (14)

72 (49) *

 APOEe4 allele increased among children with cognitive deficits and OSA

Summary OSA is common and can affect many children with physical and neurocognitive consequences  OSA can be related to adenotonsillar hypertrophy but that is not the only factor to consider  Evaluating factors that might contribute to the OSA will help target appropriate treatment 

Rinitis Alérgica y su Relación con Asma ARIA Fernán Caballero Caracas, Venezuela 2012

La Rinitis Alérgica:  Es la enfermedad crónica respiratoria más frecuente en la infancia, se estima que afecta del 20 al 25% de la población  Su prevalencia está en aumento  El pico de incidencia y la severidad sintomática es durante la infancia y adolescencia

 Afecta del 0.8 al14.9% de los niños entre 6 y 7 años de edad, y del 1.4 al 39.7% de niños entre 13 y 14 años de edad (ISAAC)  Solamente en el 15% de los niños los síntomas de RA remiten espontáneamente a los 10 años del inicio de la enfermedad

Prevalencia de la RA

Katelaris CH et al. Clin ExpAllergy. 2012 Feb;42(2):186-207.

Gravedad de la Rinitis AlĂŠrgica Leve Intermitente 4-10%

Leve persistente 14-42% Moderada/grave persistente 5160%

Moderada/grave intermitente 317%

Bousquet J et al. Clin ExpAllergy. 2005 Jun;35(6):728-32.

Bousquet J et al. J Allergy Clin Immunol. 2006 Jan;117(1):158-62.

Bousquet J et al. IntArchAllergyImmunol. 2009;150(1):75-82.

Predominio de los Distintos Tipos de Rinitis Alérgica (RA) Prevalencia global de la rinitis alérgica perenne América Latina *2

Europa 1

* Venezuela, Ecuador, Panamá, México, Perú (n = 455)

29%

33% 67%

71% Intermitente Persistente

1 Bauchau y Durham. Eur Respir J. 2004;24:758.

2 Programa observacional abierto (V-P04141): Tratamiento de la rinitis alérgica con desloratadina en niños – En prensa 2006.

Prevalencia de Rinoconjuntivitis Alérgica Prevalencia según el tipo de presentación en Venezuela N = 603 Persistente

11%

Intermitente

89% 89%

Garmendia et al, AAAAI 2003.

Nasal allergies in the Latin American population: Results from the Allergies in Latin America survey Neffen H, Mello J, Sole D, Naspitz C, Dodero A, Garza H, Guerra E, Baez-Loyola C, Boyle J, Wingertzahn M; Allergy and Asthma Proceedings 2010; 31: S7-S29.

Prevalencia Comparativa de Rinitis Alérgica Diagnosticada en la Población Prevalencia (%)

60%

40%

20% 6.6%

8.8% 3.5%

9.8% 6.3%

11.6%

11.4%

Perú

Venezuela

6.4%

0% Todos los Argentina Países AILA*

Brasil

Méjico

Chile

Ecuador

Incluyéndolo a usted, ¿Cuántas personas, adultos y niños, viven en este hogar (aunque no estén aquí ahora)? ¿Alguna de estas personas fue diagnosticada con alergias nasales o rinitis alérgica? ¿Cuántas personas en este hogar han sido diagnosticadas con alergias nasales o rinitis alérgica?

N= 1545 personas de 22.012 hogares seleccionados. *Excluye a Colombia debido a una metodología diferente.

Underdiagnosis of Allergic Rhinitis in Latin America

Prevalence (%)

Comparison of ISAAC versus AILA results

ISAAC â&#x20AC;&#x201C; Phase 31.

1. SolĂŠ D, Mallol J, Camelo-Nunes IC, et al. Allergy and Asthma Proceedings 2010; 31: S7-S29.

Prevalencia de Pruebas Cutรกneas Positivas en Pacientes con Rinitis o Rinosinusitis N = 229

23.5%

76.4%

Sรกnchez-Borges M et al. AAIR 2012 (sometido a publicaciรณn).

Rinitis Alérgica: Comorbilidad  Asma: • 25%-35% de pacientes con RA tienen asma

• 85% de pacientes con asma tienen RA  Conjuntivitis: Prevalencia ~50%  Rinosinusitis

y

pólipos

nasales:

Prevalencia

de

rinosinusitis crónica >75%  Otitis Media

 Eccema

Bousquet et al. J Allergy Clin Immund. 2001;108:S147..

 Asma  70-90% rinitis más frecuente en asma alérgica  Rinitis  19-38% asma más frecuente en rinitis perenne

Rinitis

Rinitis y Asma

Asma

Relación Rinitis-Asma

 La prevalencia de asma es mayor en pacientes con rinitis alérgica y no-alérgica  La rinitis está casi siempre presente en los pacientes con asma  La rinitis puede ser un factor de riesgo para asma  La hiperreactividad bronquial inespecífica está aumentada en la rinitis persistente

Posibles Mecanismos que Conectan las Vías Respiratorias Superiores e Inferiores en Asma y RA Drenaje postnasal de material inflamatorio hacia las vías respiratorias inferiores Activación de los reflejos bronquiales nasofaríngeos

Cambio de respiración nasal a bucal

Absorción en las vías respiratorias inferiores de mediadores o factores quimiotácticos provenientes del proceso inflamatorio en la nariz o en los senos paranasales

Togias AG. J Allergy Clin Immunol 2003.

ARIA Allergic Rhinitis and its impact on Asthma Primera Guía en MBE en esta área en el año 2001

Objetivos de ARIA Educación e Implementación



Clasificación de rinitis



Tratamiento basado en evidencia



Información sobre interrelación de rinitis y asma (y otros procesos inflamatorios)

Asma

RA y RNA

UC

DA

RSC

Clasificación ARIA Intermitente ≤ 4 días por semana o ≤ 4 semanas

Persistente > 4 días a la semana y > 4 semanas

Leve

Moderada-grave

• sueño normal • no alteración del ocio, activitades, deporte • escuela / trabajo normal • sin síntomas molestos

uno o más ítems • sueño alterado • alteración del ocio, actividades, deporte • alteración escuela / trabajo • síntomas molestos

en pacientes no tratados Bousquet et al. J Allergy Clin Immunol 2001.

Jerarquía de la EBM Meta-análisis y revisiones sistemáticas

A Conexión de Base de Datos al Azar Estudios de cohortes, series de casos

D

Reportes de caso, Ideas Editoriales, Opinión de expertos

GRADE

 Graduación de

 Recomendaciones  Asesoría  Desarrollo y  Evaluación

Recomendaciones (2 niveles) • Fuerte • Débil

Calidad de la Evidencia (4 niveles) • Alta • Moderada • Baja • Muy baja

Guyatt.

ARIA - Tratamiento de la Rinitis Alérgica persistente moderada persistente grave leve

intermitente moderada grave intermitente leve corticoide intranasal cromona tópica antihistamínico H1 no sedante, oral o tópico descongestionante intranasal (<10 días) u oral evitación de alergenos e irritantes

valorar inmunoterapia Bousquet et al. J Allergy Clin Immunol 2001.

ARIA - Tratamiento según MBE Intervención

RAE

RAP

PER

adultos

niños

adultos

niños

anti-H1 orales

A

A

A

A

anti-H1 tópicos

A

A

A

A

CC tópicos nasales

A

A

A

A

antileucotrienos

A

A (> 6 a)

cromona tópica

A

A

A

A

IT subcutánea

A

A

A

A

IT sublingual deglutida

A

A

A

A

anti-IgE (> 12 a)

A

A (>12 a)

A

A (>12 a)

evitación alergénica

D

D

D

D

A

Evidencia de Tratamiento con Medicamentos (según GRADE) Los medicamentos para tratar la Rinitis Alérgica (AR) pueden ser administrados intranasal u oralmente (para algunos) Los medicamentos para tratar rinitis alérgica son efectivos y seguros

FUERTE

Los antihistamínicos anti H1de Segunda Generación, vía intranasal u oral, son recomendables para el tratamiento de rinitis y conjuntivitis alérgica en niños y adultos

FUERTE

Los antihistamínicos anti H1 vía oral de 1ra Generación NO son recomendables cuando los de 2da G están disponibles, por razones de seguridad

FUERTE

Los antihistamínicos anti H1 intraoculares son recomendados para el tratamiento de conjuntivitis alérgica en adultos

FUERTE

Los antihistamínicos anti H1 intraoculares son recomendados para el tratamiento de conjuntivitis alérgica en niños

DÉBIL

Rinitis Leve Intermitente ARIA Opciones (no en orden de preferencia)  anti-H1 oral o intranasal  descongestionante intranasal  descongestionante oral (no en niños)

Rinitis Moderada-Severa Intermitente Rinitis Leve Persistente

ARIA Opciones (no en orden de preferencia)  anti-H1 oral or intranasal

 anti-H1 oral + descongestionante  cc intranasal  (cromonas) El paciente debería ser re-evaluado a las 2 semanas

Rinitis Moderada-Severa Persistente ARIA Tratamiento escalonado

 cc intranasal como tratamiento de primera línea  si hay obstrucción importante: añada curso corto de CC oral o decongestionante

Re-evaluar a las 2-4 semanas  si los síntomas persisten añada:  anti-H1 oral (± descongestionantes)  ipratropium

ARIA 2008 

Los corticosteroides intranasales son las drogas de primera elección para rinitis persistente y moderadasevera



Preferencia por antihistamínicos de 2da generación



Incluye ARLTs y omalizumab



Inmunoterapia



Falta de eficacia de la medicina complementaria y alternativa (2005)

Omalizumab en Rinitis Alérgica Severa  Pinto JM et al. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronicrhinosinusitis. Rhinology. 2010 Sep;48(3):318-24.  Bobolea I et al. Omalizumab: a potential new therapeuticapproach for aspirin-exacerbatedrespiratorydisease. J InvestigAllergol Clin Immunol. 2010;20(5):448-9.  Kamin W, et al. Safety of anti-IgEtreatmentwithomalizumab in childrenwithseasonalallergicrhinitisundergoingspecificimmunothe rapy simultaneously. PediatrAllergyImmunol. 2010 Feb;21(1 Pt 2):e160-5.

Novedades ARIA 2008  Confirma la utilidad de la nueva clasificación

 Insiste en el tratamiento de acuerdo con el impacto de la rinitis sobre la calidad de vida  Introduce el concepto de control de la rinitis  Medicina basada en las evidencias científicas, evalua todos los tratamientos disponibles  Confirma la interrelación rinitis-asma Bousquet J et al. Allergy, 2008.

Bousquet j et al. JACI ,2010.

Recomendaciones  Pacientes con rinitis persistente deberían ser evaluados para asma

 Pacientes con asma persistente deberían ser evaluados para rinitis  La estrategia debería combinar el tratamiento de las vías aéreas superiores e inferiores en términos de eficacia y seguridad

Golfo de Cariaco Edo Sucre - Youenn Jacquin

Plaza Venezuela - Orlando Acosta

Isla Blanquilla - Youenn Jacquin

Los Nevados Edo Merida - Youenn Jacquin

VENEZUELA

Isla Las Aves - Youenn Jacquin

Muchas Gracias!!!

Role of Respiratory Infections in Childhood Asthma Robert F. Lemanske, Jr., M.D. Professor of Pediatrics and Medicine University of Wisconsin

Madison

Genetic Factor Atopy

(Immune Dysregulation) (Innate immunity) (Interferons)

Environmental Factors Viral LRIs (RV and RSV)

Developmental Component

PERSISTENT WHEEZING

ASTHMA

COAST

Childhood Origins of ASThma A prospective study in a high risk cohort designed to evaluate the interactions among age, patterns of immune dysfunction, and virus infections with respect to the subsequent development of asthma and allergic diseases

Funded by the NHLBI

PI: Rob Lemanske, MD Co-Is: Jim Gern, MD Carole Ober, PhD Ron Gangnon, PhD Wai-Ming Lee, PhD Kathy Roberg, RN, MS

Research Design and Methods • Target enrollment: 300 families • At least one parent with allergies or asthma • Prospective (developmental) evaluation of § Immune system – Child (annually from birth) and parent – Cytokine response profiles; antigen-specific IgE § Respiratory infections (nasal aspirates) § Wheezing phenotypes (questionnaires) § Airway physiological evaluation (ages 4-7 yrs) - Impulse oscillometry, spirometry, eNO, meth. challenge § Environmental evaluation (diet, allergens, pets) § Genotype evaluation • Minimum 12-14 year follow-up

COAST Evaluations Nasal lavage specimens collected at symptomatic illnesses

2 4 6

Birth

9

1 yr

Nasal Washes collected at â&#x20AC;&#x153;Well Child Visitsâ&#x20AC;?

2 yr

3 yr Persistent Wheezing Evaluation

4 yr

5 yr

6 yr

Asthma Evaluation

[AJRCCM 178:667, 2008]

[JACI 116:571, 2005]

Timing, severity & etiology of respiratory illnesses determined throughout childhood

What viral infections in early life are associated with the development of asthma at age 6 years?

Etiology of Wheezing Illnesses in Early Childhood 1.0

RV Rhinovirus

Asthma at 6 Years 0.8

RSV Respiratory syncytial virus

Year 1 Year 2 Year 3

PIV Parainfluenza Flu Influenza

Mean Wheezing Illnesses per Year

0.6

CV

Coronavirus

MPV Metapneumovirus 0.4

AdV Adenovirus EnV Enterovirus

0.2

0.0 No Virus RV 0.4

RSV

PIV

Flu

CV

MPV

AdV

EnV

No Asthma at 6 Years

Jackson DJ et al. AJRCCM, 178:667, 2008

0.2

0.0 No Virus RV

RSV

PIV

Flu

CV

Virus Detected

MPV

AdV

EnV

Did RV or RSV wheezing illnesses during years 1-3 impact the risk of asthma at age 6?

RV Wheezing vs. RSV Wheezing in First 3 Years and Asthma at Age 6 Years

Jackson DJ et al. AJRCCM, 178:667, 2008

RV Wheezing & Allergic Sensitization in Year 3 and Asthma at Age 6 Years

Jackson DJ et al. AJRCCM, 178:667, 2008

Which comes first?

Allergic sensitization or wheezing illnesses?

Does sensitization lead to viral wheezing, or does viral wheezing lead to sensitization?

Viral Wheeze

2

Neither

1

4

Sensitized and Viral Wheeze

3 Sensitized

Jackson et al. AJRCCM 185:281, 2012

Does sensitization lead to viral wheezing, or does viral wheezing lead to sensitization?

Viral Wheeze

If viral wheeze causes sensitization: 2→4 > 1→3

2

Neither

1

4

3 Sensitized

Sensitized and Viral Wheeze

If sensitization causes viral wheeze: 3→4 > 1→2 No causality: 2→4 = 1→3 3→4 = 1→2

Jackson et al. AJRCCM 185:281, 2012

Sensitization Leads to Viral Wheeze (the reverse does not appear to be true) Viral Wheeze

Virus

2 Any Neither

1

4

3 Sensitized

Sensitized and Viral Wheeze

HRV RSV

Ratio 3→4 1→2

2→4 1→3

1.9*

0.75

(1.2, 3.1)

(0.49, 1.1)

2.4*

0.69

(1.4, 4.3)

(0.41, 1.2)

1.6

0.8

(0.9, 2.9)

(0.52, 1.3)

Jackson et al. AJRCCM 185:281, 2012

How does allergic sensitization alter the host response to viral respiratory infections?

Hypothesis: Allergy Inhibits Innate Immune Responses Through FcεRI Allergen!

Allergen

HRV

Cross-linking of FcεRI

Expression of FcεRI

PBMCs

IFN

(Durrani et al, JACI in press)

Type I & Type III IFN

Type I & Type III IFN

More frequent and severe virus-induced wheezing Prolonged inflammation Possible airway remodeling and/or loss of lung function

Do wheezing RV infections in early life influence subsequent lung function?

Influence of Viral Etiology for Wheezing on Lung Function

Guilbert T et al. JACI 128:532, 2011

Effects of Asthma Exacerbation Severity on Lung Function

Oâ&#x20AC;&#x2122;Brian A. et al. JACI 129:1162, 2012

Innate immune development, viral respiratory tract illnesses, and loss of lung function in childhood

Innate Immune Responses and Frequency of Viral Infections during Infancy

Copenhaver C et al. AJRCCM 170:175, 2004

Cord Blood Innate Interferon-ÎłResponses and Loss of Lung Function

Do wheezing RV infections in early life cause asthma?

Host Factors ↓ antiviral responses ↓ lung function Genetic polymorphisms

Asthma “Normal ” Virus

Abnormal Host

Mechanisms • Airway epithelial cells1 – Normal: apoptosis – Asthma: viral replication • Immune dysregulation1-4 – Altered innate immune responses • Type 1-3 interferons (α, β, γ, λ) – FcεR1 numbers and bridging on antigenpresenting cells4 • Genetic polymorphisms5 – CD14_159 and Toll 3 receptors 1. Contoli M et al. Nat Med 12:1023, 2006

4. Gill M et al. JI 184:5999, 2010

2. Wark PA et al. J Exp Med 201:937, 2005

5. Hewson CA et al. J Virol 79:12273, 2005

3. Copenhaver CC et al. AJRCCM 170:175, 2004

6. Martin AC et al. AJRCCM 173:617, 2006

Pathologic Virus Normal Host

Virus Factors Lung/Airway damage Virulent strains?

Asthma

Sequencing and Analyses of All Known Human Rhinovirus Genomes Reveals Structure and Evolution

Palmenberg A and Spiro D et al.

Science 2009;324:55-59

HRVA & HRVC are similarly common in infants.

Together, they account for 94% of HRV infections.

456 HRV were typed in 451 HRV-positive samples 80

60

Detection Rate of each HRV group (% of all HRV)

49.3%

44.3%

40

20

6.4% 0 # of Isolate # of strain

HRVA 225 45

HRVB 29

HRVC 202

Total=456

8

35

Total=88

HRV Strain Virulence

HRV-­‐C and Asthma Exacerba5ons • Prospec(ve popula(on-­‐based surveillance1 Nashville TN and Rochester NY 1052 children age <5 yrs hospitalized with ARI or fever HRV-­‐C vs. HRV-­‐A: • ↑ discharge diagnosis of asthma (55% vs 36%, P = .022)

• ED Asthma Study (2-­‐16 y/o)2 Perth, Australia HRV C detected in 59% of children: • ↑ severity in HRV C vs. A or B 1 Miller EK et al. JACI 2009 2 Bizzintino J et al. ERJ 2011

The probability of inducing MSI is similar for HRVA & HRVC infections that is significantly higher than that of HRVB MSI = Moderate-Severe Illness

367 HRV only infection 20

95% confidence

15

Probability 10 of MSI (%) 5 0

A C B HRV Group

Probability of inducing MSI varied with HRV strain 84 serotypes/strains (367 HRV only infections) HRVA

50 95% confidence

HRVB HRVC

Probability of MSI (%)

20 10 5 2 1 0.5

W30, R56, W13, W20, W9, W37, W25, W26, W6, W12 Most pathogenic

R52, R86, R91, R6, R83, R27, R14, W36, W10, R78 Least pathogenic

Gene by environment interactions

GWAS and 17q21 • Two large meta-analyses of asthma GWAS have recently provided strong evidence for involvement of specific genes in asthma risk: GABRIEL and EVE • Variation at a locus spanning five genes on chromosome 17q21, including the ORMDL3 gene yielded the most significant association • The 17q21 locus is the most replicated asthma locus and represents the most significant genetic risk factor for childhood asthma known to date

17q21 Genotype and HRV Wheezing Illnesses • COAST studies of asthma candidate genes revealed significant associations between genotypes at the 17q21 asthma-susceptibility locus (rs7216389) and: – Asthma (p=0.0059) – The number of moderate-to-severe wheezing illnesses with human rhinovirus infection (HRV wheezing illness) in the first 3 years of life (p=0.00070) – Not with allergic sensitization (p=0.69) or with respiratory syncytial virus (RSV) wheezing illness (p=0.26)

Gene by Environment Interactions

HRV wheezing illness in first 3 yrs:

Yes No

This SNP is located in an intron of GSDML and is an eQTL for both ORMDL3 and GSDML.

17q21 FcεRI HRV Pathway Infection Pathway

Abnormal UPR (Epi, pDC, MΦ)

pDC: ↑FcεRI IgE cross-linking

↑ Inflammation ↑ Remodeling

↓ Virus-induced IFN ↑ Illness severity

Allergy

Asthma Inception

Developmental stage (age) Gender

Innate and adaptive immune responses

HRV infection Microbiome 2°Bacterial infection

Acute Exacerbation

Genetic Factor Atopy

(Immune Dysregulation) (Innate immunity) (Interferons)

Environmental Factors Viral LRIs (RV and RSV)

Developmental Component

PERSISTENT WHEEZING

ASTHMA

COAST Personnel Robert F. Lemanske, Jr., M.D. James E. Gern, M.D. Carole Ober, Ph.D. Ronald Gangnon, Ph.D. Kathy Roberg, R.N., M.S. Wai-Ming Lee, Ph.D. Beth Anderson, B.S.N., M.A. Michael Evans, M.S. Douglas DaSilva, B.S. Lisa Salazar, B.A. Christopher Tisler, M.T. Tressa Pappas, B.S. Chris Kleppe, M.S. Kat Sullivan Dillie, Ph.D. Fue Vang, M.S. Woo Kyung Kim, M.D., PhD. Kate Shanovich, B.A. Nicholas Hallett, B.S. Michael Possin, B.S. Rochelle Grabher, B.S.

Christine Seroogy, M.D. Kristjan Burmeister, B.S. Tuomas Jartti, M.D. Theresa Guilbert, M.D. Kirstin Carlson-Dakes, R.N. M.Ed. Sarah Sund, M.T. Kristine Grindle, B.S. HuiChuan Lai, Ph.D., R.D. Zhumin Zhang, M.S. Suzanne Shoff, M.S. R.D. Lisa Davis, M.S. R.D. Peter Shult, Ph.D. Eric Reisdorf, B.S. Sam Friedlander, M.D. Jeremy Bufford, M.D. Anne Marie Singh, M.D. Christine Virnig, M.D. Dan Jackson, M.D. Jack Bork, B.S. Gemma Gliori, M.S.

Manisha Witmans, MD, FRCPC

Objectives  Discuss the definition of SIDS

 Review the pathophysiology of SIDS  Discuss genetic, epidemiological and individual

factors that contribute to the prevalence of SIDS  Discuss risk reducing strategies

Historical Perspective “And this woman’s child died in the night;” 1 Kings 3:19-20 (950 BC)  1291 a German poster forbid mothers from taking their infants under 3 years of age to bed with them.  Research into SIDS has spanned the last 4 decades. 

Definition  Sudden Unexplained Infant Death Syndrome (SIDS):  The sudden and unexplained death of an infant under one year of age. 

 

Despite a complete investigation of the circumstances of death, clinical history, coroner’s investigation and complete autopsy, no obvious cause of death is found.

Diagnosis of exclusion Leading cause of infant mortality in infants < 12 months of age in developed countries.

Krous HF, Beckwith JB, Byard RW, Rognum TO, Bajanowski T, Corey T, Cutz E, Hanzlick R, Keens TG, and Mitchell EA. Pediatrics 2004;114:234-238.

Cot deaths. BMJ 1995;310:7–10

SIDS Autopsy Findings  Key Features:  No identifiable cause of death  No signs of severe illness

 No significant signs of stress

SIDS Death Rates: USA ď&#x201A;&#x2014; 2008: 0.5 infant deaths per 1000 live births; 2226 infants

http://www.sidscenter.org/Statistics.html#overview

SIDS Death Rates by Race/Ethnicity

International Rates of SIDS

Brainstem Neurotransmitters in SIDS  The brainstem is life support for the brain

 Autopsy findings found decreased serotonergic (5-HT)

neurotransmitter receptor binding activity in SIDS brainstems versus controls.  5-HT regulation are abnormal: synthesis, release, processing, and clearence Kinney, H.C., et al. J. Neuropath. Exp. Neurol., 60: 228-247, 2001.

Kinney, H.C., et al. J. Neuropath. Exp. Neurol., 62: 1178-1191, 2003.

Brainstem Neurotransmitters in SIDS  Abnormal regulation of 5-HT processing may be

genetic or developmental  Results in abnormal neurological control of cardiac, respiratory, and/or arousal function  Provides a biological basis for SIDS  Resulting complicated pathways between development, sleep, hypoxia, environment and autonomic nervous system dysfunction

Triple Risk Model

Filiano, J.J., and H.C. Kinney. Biol. Neonate, 65: 194-197, 1994.

Trachtenbaerg FL, et al. Pediatrics 129;630:2012.

SIDS Cause of SIDS is not known Based on what we know, we can only decrease risk factors

Environmental Risk Factors  Sleeping Position  Prone >>>>>>> Side lying> Supine

 Smoke exposure  Dose response curve and second hand smoke  Bedding and Sleep Surfaces  Soft  Temperature  How warmly the infant is dressed or bundled AAP Policy Statement, Pediatrics 116:1245-1255; 2005

Prone Sleeping and SIDS (Odds Ratios) Senecal, 1987 Beal, 1988 Lee, 1989 Jonge, 1989 Fleming, 1990 Mitchell, 1991 Dwyer, 1991 Wigfield, 1992 0

5

10

15

P.J. Fleming. Proceedings of the 12th Conference on Apnea of Infancy.

1994. Slide from Dr. Tom Keens

SIDS and Maternal Smoking During Pregnancy

10 SIDS 8 Odds Ratio 6 vs 4 No Smoking

2 0 1 to 9 10 to 19 >20 Cigarettes smoked per day P.S. Blair, et al. Br. Med. J., 313: 195-198, 1996.

Slide Courtesy of Dr. Tom Keens

SIDS and Cigarette Smoking After Pregnancy

6 5 4

SIDS Odds Ratio 3 vs No Smoking 2

Alm Fleming

1 0 Mother

Father

Proceedings of the Fourth SIDS International Conference, 1996.

Slide Courtesy of Dr. Tom Keens

SIDS and Infant Exposure to Cigarette Smoke 10

SIDS 8 Odds Ratio 6 vs No 4 Exposure 2 0

1-2 3-5 6-8 >8 Hours of Cigarette Smoke Exposure per day

P.S. Blair, et al. Br. Med. J., 313: 195-198, 1996.

Slide Courtesy of Dr. Tom Keens

Protective Factors Risk Factors  Pacifier Use at Sleep Time

 Room Sharing  Breast Feeding

Sleeping Environment and Risk of SIDS 6

5 4 3 2 1 0 Soft Surface

Pillow Use

Face/Head covered

Bed Sharing with parent

Hauck FR, Herman SM, et al. Pediatrics 111, 1207-1214: 2003

Pacifier Use

Arousal Responses  Narcotic use during pregnancy increase risk  Immature cardiorespiratory autonomic control

 Failure of arousal responsiveness from sleep  Gene polymorphisms relating to serotonin transport

and autonomic nervous system development

AAP Pediatrics 2005

Two Distinct Bedsharing Subgroups

Elective: Breast feeders Non-smokers Firm mattress

Non-Elective: Bottle fed Smokers Risk ‘factors’

Less Risk

High Risk

McKenna J. SIDS. Cambridge Handbook 2004

Bed Sharing Safe

 Eliminate all the Risk Factors  Bed is appropriate in the

middle of the room  Mattress firm  No loose fitting sheets or heavy blankets  Breastfed infant

Risky  Smoking during pregnancy  Current smoking  Heavy bedding (comforter,          

duvet) Obesity Sleeping on multiple pillows Soft bedding Not sleeping in a bed Room overheated Alcohol Use Other children Pets Baby Sleeping Prone Other stuffed animals

McKenna JJ. A Parent’s Guide to Cosleeping, and Sleeping with Your Baby 2007

Ideal BedSharing  Baby brought to bed for

breastfeeding and then back to own crib  Crib/bassinet/cradle should be safe  Mom sleeping on proper bed  FEET to FOOT

AAP Policy Statement Pediatrics 116: 1245-1255, 2005.

• • • •

Pacifiers No evidence that pacifier use inhibits breastfeeding or causes later dental complications.

Recommends pacifier use throughout the first year of life.

Do not force pacifiers if infants refuse.

Should not be coated in sweet solutions.

AAP Policy Statement. Pediatrics, 116: 1245-1255, 2005.

Summary  The cause of SIDS is not yet known  We can help by decreasing risk factors  Encourage smoking cessation whenever possible  Encourage breastfeeding  Encourage optimal sleeping environment  Education and public awareness are key

Step-up and Step-down Strategies in the Treatment of Asthma Robert F. Lemanske, Jr., M.D. Professor of Pediatrics and Medicine University of Wisconsin School of Medicine and Public Health

Madison, WI

Step-wise Approach to Asthma Therapy Choosing the initial step in therapy based upon Asthma SEVERITY Step 6 Step 5 Step 4 Step 3 Step 2 Step 1 Intermittent Asthma

Persistent Asthma

Step-wise Approach to Asthma Therapy Adjusting therapy based on asthma CONTROL Stepping down

Stepping up Step 6 Step 5 Step 4 Step 3

Step 2 Step 1 Intermittent Asthma

Persistent Asthma

Step-up Approaches in Asthma

Thomas, Lemanske & Jackson, JACI 128:915, 2011

EPR-3 Recommendations For Frequent Preschool Wheeze & + API

DAILY low-dose ICS at step-2 as preferred treatment

Step 6 Step 5 Step 4

Step 3 Step 2 Step 1

Prevention of Early Asthma in Kids Screening/ Eligibility Run-in 1 month

Treatment Years 1 & 2

Observation Year 3

Interim Efficacy Tests Randomize • Randomized, multicenter, double-blind, parallel group, placebo-controlled trial • 285 two & three y/o kids at high-risk for asthma (mAPI +) • Fluticasone 44 µg/puff vs. placebo (2 puffs b.i.d.)

Guilbert, NEJM 2006

PEAK – Outcomes EFD: No cough or wheeze, unscheduled clinic, urgent care, ED or hospital visits; no use of asthma medications including bronchodilator pre-treatment before exercise

Treatment Phase:

Observation Phase:

↓ Exacerbations

= Exacerbations

↓ Supplemental medications (ICS and LTRA)

= Supplemental medications (ICS and LTRA)

= bronchodilator use and unscheduled visits

= Bronchodilator use and unscheduled visits

Guilbert, NEJM 2006

Conundrum with Daily ICS Use n

n

n

n

Most effective and guideline preferred controller for persistent pediatric and adult asthma as it improves dayto-day asthma control and prevents exacerbations However, exacerbations occur yearly in about 30% of children with mild and 40% of children with mildmoderate asthma prescribed daily ICS in trials Long-term adherence with daily ICS is consistently low: 30-50% in general pediatric practice Growth effects small but may be permanent

ICS Options for Preschool Children with Recurrent Wheeze and Past Year Exacerbations

Daily

Intermittent

MIST Protocol: Overview Cohort (N=278): Ages 12-53 mo, frequent wheeze, modified API, past year exacerbation, intermittent illnesses Run-in: placebo respule nightly + albuterol prn

Treatment Phase: 52 Weeks Randomized Treatment Group

Nightly EXCEPT During Respiratory Tract Illnesses

During Respiratory Tract Illnesses ONLY for 7 days

Daily low-dose Budesonide

Budesonide 0.5 mg PM

Placebo AM Budesonide 0.5 mg PM

Placebo PM

Budesonide 1.0 mg AM 1.0 mg PM

Intermittent high-dose Budesonide

Time to 1st Exacerbation Similar with Daily vs Intermittent ICS B. % of Patients without a Course of Prednisolone

100 80 60 40 20

p-value=0.87

Intermittent (Rate 0.95/person yr) Daily (Rate 0.97/person yr)

0 0 Number at Risk Intermittent 139 Daily 139

50 114 114

100 100 93

150 89 84

200 250 Days 78 74

71 66

300

350

64 54

50 40

400

11

Lessons from MIST In API positive preschoolers with frequent wheeze & prior year exacerbations n n

Illness burden is substantial despite ICS therapy Intermittent high-dose budesonide started early during predefined respiratory tract illnesses and continued for 7 days, may be an alternative option to daily low-dose budesonide given its

ü similar outcomes ü less frequent use ü lower ICS exposure

Are there alternative approaches to daily ICS in school age asthma?

Is a Long Acting Beta Agonist Necessary for Control?

• Mild asthma subjects (n=455) • Six months treatment • Primary outcome: AM PEF

Results: • AM PEF and Exacerbations: Group A = C = D > B

Treatment Group

Scheduled

As needed

A

Placebo

BDP 250 mcg + Albuterol 100 mcg

B

Placebo

Albuterol 100 mcg

C

BDP 250 mcg

Albuterol 100 mcg

D

BDP 250 mcg + Albuterol 100 mcg

Albuterol 100 mcg

• Cumulative dose of ICS lower in Group A compared to C and D

Papi A et al. NEJM 356:2040, 2007

Unanswered Questions in Children with Controlled Mild Persistent Asthma Is rescue ICS (step-up intermittent) a better approach as step-down care to ICS discontinuation?

Step 6 Step 5

Step 1 Plus Step 4 Step 3 Step 2 Step 1 Intermittent Asthma

Persistent Asthma

The TReating Of Children To Prevent EXacerbations Of Asthma (TREXA) Trial Martinez FD for the CARE Network Lancet 2011; 377:650-7

TREXA Trial Design Cohort (N=288): ages 5 â&#x20AC;&#x201C; 18 years Controlled mild persistent asthma after 4-week run-in on beclomethasone 40 ug BID with placebo rescue + albuterol Randomization groups

Rescue Therapy + albuterol

Daily Therapy (BID)

Combined ICS

Beclomethasone (80 ug)

Beclomethasone (40 ug)

Daily ICS

Placebo

Beclomethasone (40 ug)

Rescue ICS

Beclomethasone (80 ug)

Placebo

Placebo

Placebo

Placebo

TREXA: Regimens on Exacerbations Requiring Oral Corticosteroids

Time to 1st Exacerbation

Daily ICS p=0.03

Placebo

p values adjusted for multiple comparisons (Hochberg-Bonferroni)

Combined ICS p=0.07 Rescue ICS p=0.07

(Martinez F, Lancet 2011;377:650-7)

TREXA: Regimens on Treatment Failures

Treatment Failure (2 oral steroid courses)

40% 30%

Placebo 23.0%

20% 10% 0%

Combined P=0.012 5.6%

N=71

Rescue P=0.024 Daily P=0.009 2.8%

8.5%

N=71

N=71

Entire +API Cohort

N=74

(Martinez F, Lancet 2011;377:650-7)

TREXA: Regimens on Linear Growth Rescue ICS P < 0.001

Placebo 1.1 cm Combined ICS Daily ICS

(Martinez F, Lancet 2011;377:650-7)

TREXA - Conclusions n

n

n

Discontinuing ICS causes an unacceptable increase in exacerbations in children with well-controlled, mild persistent asthma Daily ICS is the most effective treatment for preventing exacerbations; adding rescue ICS to daily ICS does not add benefit Rescue ICS with albuterol (step-up intermittent therapy) demonstrates benefits over albuterol alone and avoids daily ICS administration and its growth effects

Combination Therapy

More ICS or add a LABA? n

Greening, A. et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 344 (8917):219-224, 1994. n

n

Improved impairment; no difference in risk domain

Woolcock, A et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. AJRCCM 153 (5): 1481-1488, 1996. n Improved impairment; no difference in risk domain

Severe Exacerbations/Patient/yr

FACET Study: Formoterol and Budesonide in Moderate Asthma **

1.0 0.9

Budesonide 100mcg/400mcg BID Formoterol 12mcg BID

0.8 0.7

**

0.6 0.5

**p=0.01

0.4 0.3 0.2 0.1 0.0 BUD 200mcg/day (n=213)

BUD 200mcg/day+F (n=210)

BUD 800mcg/day (n=214)

Pauwels, et al. N Engl J Med 1997; 337: 1405-1411

BUD 800mcg/day+F (n=215)

Beta Agonists + ICS: Maintenance and Reliever Therapy?

Combination Therapy as both Maintenance and Reliever Therapy

Oâ&#x20AC;&#x2122;Byrne PM et al. AJRCCM 171: 129, 2005

Severe Asthma Exacerbations

Combination Therapy: STAY Study

Oâ&#x20AC;&#x2122;Byrne PM et al. AJRCCM 171:129, 2005

Step-Up Long Term in Children

BADGER Best Add-on Therapy Giving Effective Responses nď Žâ&#x20AC;Ż

In patients receiving daily low dose ICS treatment who are not well controlled, what are the next best treatment options?

Lemanske RF et al. NEJM 362:975, 2010

Unanswered Questions in Childhood Asthma

Uncontrolled on low dose ICS at Step 2 care Step 4 Step 3 Step 2 Step 1 Intermittent Asthma

Persistent Asthma

Step 6 Step 5

EPR-3 Recommendations

Step 6 Step 5 Step 4 Step 3 Step 2 Step 1 Intermittent Asthma

Persistent Asthma

BADGER: Research Question n

In children not satisfactorily controlled on low dose ICS (fluticasone 100 µg BID) therapy, what is the next best treatment approach? n n n

Increased doses of ICS (fluticasone 250 µg BID)?

Add a LABA (salmeterol/fluticasone combination)?

Add a LTRA (montelukast)?

BADGER: Novel Trial Design n

n

Each participant would receive all 3 treatment options Determine the presence or absence of a differential response among those treatments using a composite outcome that evaluated 3 components in defining asthma control: n

Impairment domain n n

n

Asthma control days Pulmonary function (FEV1)

Risk domain n

Asthma exacerbations

Research Questions n n

n

Could a differential response be demonstrable in at least 25% of participants?

If so, what was the direction of the response (i.e., which therapy had the greatest probability of producing the best response?)

Were there baseline characteristics that could predict the probability of a differential response? n n n n

Methacholine PC20 FeNO Asthma Control Test (ACT®) scores B16 genotype (Arg/Arg)

Differential Response n

n

n

At the end of the study, each child was identified as either a differential or non-differential treatment responder.

A differential responder was someone who exhibited significantly better outcomes on one treatment than on another.

Effective treatment response was based on (in order of importance): 1. Asthma exacerbations 2. Asthma control days (ACD) 3. Change in FEV1.

Definitions for Differential Response: Asthma Exacerbations n

Differential response with respect to asthma exacerbations occurrred when the total amount of prednisone prescribed to control asthma symptoms was at least 180 milligrams* greater on one treatment than on either of the other two treatments.

*Based on “prednisone burst” of 2 mg/kg/day for 2 days, 1 mg/kg/day for 2 days to a maximum of 60-60-30-30 mg

Definitions for Differential Response: Asthma Control Days

nď Žâ&#x20AC;Ż

Differential response with respect to ACD occurred when the number of annualized ACD (AACD) achieved on one treatment was at least 31 days more than on either of the other two treatments.

Asthma Control Day (ACD) n

An ACD was defined as a day without:

Albuterol rescue use (pre-exercise treatment permitted) n Use of non-study asthma medications n Nighttime awakenings n Daytime asthma symptom score more than mild n Unscheduled health care provider visits for asthma n Yellow-zone PEF or Red-zone PEF n

Definitions for Differential Response: FEV1 n

n

Differential response with respect to FEV1 occured when the FEV1 change on one treatment was at least 5% higher than on either of the other two treatments.

The FEV1 change for each treatment was defined as the percent difference between the FEV1 from the end of the run-in to the end of the treatment period FEV treatment − FEVrun-in FEVrun-in

BADGER Protocol: Overview Three Treatment Period, Double blind, 3 way cross-over Run-in period on 1xICS to demonstrate lack of control

Run-in Period 2-8 weeks

Period 1

Period 2

Period 3

Evaluation Period

Evaluation Period

Evaluation Period

2.5 x ICS or 1x ICS + LABA or 1 x ICS + LTRA

2.5 x ICS or 1x ICS + LABA or 1 x ICS + LTRA

2.5 x ICS or 1x ICS + LABA or 1 x ICS + LTRA

16 weeks

16 weeks

16 weeks

1xICS = fluticasone DPI 100 µg BID

Randomization

2.5 x ICS = fluticasone DPI 250 µg BID 1xICS+LABA = fluticasone/salmeterol DPI 100/50 BID 1xICS+LTRA = fluticasone DPI 100 µg BID + montelukast

Primary Outcome: Probability of BEST Response Based on Composite Outcome*

LABA step-up was more than 1.5 times as likely to produce the best response LABA LABA

ICS

(p = 0.002)

LTRA

(p = 0.004)

*Covariate adjusted model

Lemanske RF et al. NEJM 362:975, 2010

BADGER: Conclusions A differential response to step-up therapy was demonstrated in nearly all subjects (â&#x2030;Ľ 95%) and more than 1.5 times as likely with LABA stepup. Many children demonstrated a best response to either ICS or LTRA step-up, highlighting the need to regularly monitor and appropriately adjust each childâ&#x20AC;&#x2122;s asthma therapy.

Step 6 Step 5 Step 4 Step 3 Step 2 Step 1 Intermittent Asthma

Persistent Asthma