Memorias X Congreso Colombiano de Neumologia y Asma Pediatrica 2012-2
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Transcript of 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
Discuss the diagnostic challenges in evaluating children with sleep related respiratory complaints
Discuss practical methods of evaluating children with sleep disordered breathing
Is This All Sleep Disordered Breathing Is?
Inflammation
Modified from Tauman R & Gozal D. Paediatric Respiratory Reviews
(2006)
Structural
alteration
Sensory
impairment Neuro-motor
dysfunction
Upper airway
dysfunction
Primary or Secondary
Courtesy of Dr. Carol Rosen with modifications by Dr. Manisha Witmans
Pediatric PSG: What one needs?
Tech Observer Video Camera
SaO2
Leg EMG (2)
Microphone
EKG
Chin EMG (2)
EEG EOG
Nasal EtCO2
Records behavior Documents arousals,
parasomnias, abnormal
sleeping position, and attends
to any technical problem
Respiratory Effort
(RIP)
Nasal Oral Airflow
TcCO2
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
Validity-reliability bulls eye
(Babbie, 1998)
Both
valid & reliable Reliable,
but invalid
Where and what is the goal?
Ambulatory Testing
Embletta X100 Stardust
Ares Watch-Pat 100
Nite
Watch
Embletta X100 Embletta X100
Ares
Embletta X100
Ares
Embletta X100
Ares
Embletta X100
Watch-Pat 100 Ares
Embletta X100
Watch-Pat 100 Ares
Embletta X100
Watch-Pat 100 Ares
Embletta X100
Watch-Pat 100 Ares
Embletta X100 Stardust
Watch-Pat 100 Ares
Embletta X100 Stardust
Watch-Pat 100 Ares
Embletta X100
Nite
Watch
Stardust
Nox Medical
Watch-Pat 100 Ares
SagaTech:
Snoresat
Methods of Diagnosing SDB
Other Investigations: Ancillary measures such as heart rate variability,
or pulse transit time
**AAP guidelines, 2002
Ambulatory Devices in Children
Limited validation
Signal artifact is a real problem
Needs a dedicated personnel who know what they are doing
A compromise between validity
and reliability
Where and what is the goal?
A compromise between validity
and reliability
Where and what is the goal?
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
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
It is important to consider the question one is asking to obtain the best test for the affected individual
Other methods may be feasible to diagnose sleep disordered breathing and ancillary testing may also help.
Questions?
Impacto de la Rinitis
Alérgica en la Escolaridad
Fernán 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
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.
SUEÑO Y CANSANCIO
• 46% de pacientes se siente cansado1
• 77% tiene problemas para conciliar el sueño1
PRODUCTIVIDAD EN TRABAJO Y
ESCUELA
• ≤90% Efectividad en trabajo4
• ≤93% Desempeño alterado en salón de clases3,5
AFECCIÓN SOCIAL
Adolescentes apenados de usar
inhaladores6
Impacto de
Rinitis
Alérgica
IMPACTO EN ACTIVIDADES COTIDINANAS2,3 ALTERACIÓN EN APRENDIZAJE Y
FUNCIONES COGNITIVAS6
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
Qué es
congestión?
Obstruido
Bloqueado No Flujo de
Aire
Obstruido/ Sentirse obstruido
Edema/ Sentimiento hinchazón
“Congestionado”
“Bloqueo total”
“Nariz Tapada”
“Tapadísimo”
“Taponado”
“No puedo
respirar”
Definición de Congestión
Edema de la mucosa causado por vasodilatación y
exudación debido al incremento de la permeabilidad
capilar relacionada con la inflamación
Jessen and Malm. Allergy. 1997;52(suppl):3.
Síntomas que Ocasionan Mayores
Molestias al Paciente con Rinitis Alérgica
% de pacientes
Allergies in America, 2006.
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
Trastornos Respiratorios Asociados al
Sueño (Sleep Disordered Breathing)
Practice Guideline: Polysomnography for Sleep-Disordered Breathing Prior to Tonsillectomy in Children.
Otolaryngology–Head and Neck Surgery 145(1S) S1–S15, 2011.
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.
Rinitis Alérgica y Trastornos del Sueño
Arch Intern Med 2006;166:1744-8
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.
Lavie et al. Acta Otolaryngol. 1981;92;529.
Sueño Deficiente en la Rinitis Alérgica
14 pacientes con rinitis tuvieron 10 veces más (promedio de 50)
micro-despertares que los controles
Conclusiones: Los trastornos del sueño, de cualquier severidad se asocian a
alteraciones de conducta, pero no a deficiencias en desempeño cognitivo.
2012 Published by Elsevier B.V.
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.
A Clinical Overview of Sleep and
Attention- deficit/Hyperactivity Disorder in
Children and Adolescents
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
Calificaciones de aprendizaje compuesto en niños de 10-12 años de edad
Vuurman et al. Ann Allergy. 1993;71:121.
Niños con rinitis
alérgica (n=12)
Ca
lific
ació
n p
rom
ed
io d
e
ap
rend
izaje
com
pu
esto
a las 2
sem
an
as (
%)
Niños sanos (n=13)
P=0.007
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’.``
Grado de Interferencia de la Alergia en la
Actividad Escolar
18% 20%
32%
17%
6% 2%
3%
7%
9%
29%
16%
19%
41%
28%
47%
62%
46% 52%
46%
0%
20%
40%
60%
80%
100%
Todos los Países
AILA
Argentina Brasil Méjico* Otros Países de
América Latina
Sólo faltó a la escuela Interfirió Ambas Ninguna
Walker S et al. J Allergy Clin Immunol 2007; 120: 381-7.
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
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
ACCEPT-1 Resultados:
la DL mejora los trastornos del sueño asociados con la RAI
Línea de base:
1.37 1.38
Ca
mb
io m
ed
io d
esd
e la
lín
ea
de
ba
se
en
la
esca
la d
e in
terf
ere
ncia
co
n e
l su
eñ
o (
Dia
rio
s A
M)
-0.37
*
-0.27
*P<0.05 vs placebo.
Escala de 4 puntos (0 = ninguno, 3 = severo)
Días 2-15
Bachert et al. Allergy. 2008;63(supl. 88):634. Resumen 1760.
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Desloratadina 5 mg
Placebo
Allergy Asthma Proc 29:140 –145, 2008.
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
28
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.
0
1
2
3
4
5
6
7
8
9
PV
-ca
pa
cid
ad
PV
-ex
ac
titu
d
Ate
nc
ion
Co
nc
en
tra
cio
n
Me
mo
ria
vis
ua
l
Ca
mb
io e
n e
l p
un
taje
de
fu
nc
ion
co
gn
itiv
a
Pre-tto MFNS 200 mcg QD
Namazova LS et al. AAAAI Annual Meeting 2010.
Mejoría de la Función Cognitiva en Adolescentes
con Tratamiento con Corticoides Intranasales
*
*
*
*
¶ * p<0.05
¶ p<0.001
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
30
Muchas Gracias!!!
Inmunoterapia en Asma - Pro
Fernán 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.
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
Prevención de progreso de enfermedades alérgicas
REVISAR
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
Moller C, Jacobsen L, et. Al. JACI 2002;109:251-6.
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
147 pacientes de 205 con seguimiento
Tasa de probabilidad= 2.50 (1.1 – 5.9)
0
20
40
60
80
100
SIT Control
% d
e p
acie
nte
s
Sin asma
Asmáticos
N= 46
N= 16
N= 29
N= 24
Jacobsen et al Allergy 2007.
Estudio PAT: Desarrollo de asma a los 10 años
Estudio PAT: Prevención de asma por inmunoterapia especifica
Marogna. Ann Allergy Asthma Immunol. 2008;101:206.
Asthma reduction with 3 yrs of SLIT Randomized controlled trial
SLIT: Metacholine challenge (+): 82 (56.9%) After SLIT: 23 (17.7%) p< .001
0
10
20
30
40
50
60
70
Baseline 3rd Year Baseline 3rd Year
SLIT
Controls
*P<0.001.
Marogna. Ann Allergy Asthma Immunol. 2008;101:206.
NS
NS
NS
*
*
*
*
Intermittent Asthma Persistent Asthma
Pat
ien
ts, %
Asthma reduction with 3 yrs of SLIT Randomized controlled trial: 216 children
SLIT: Metacholine challenge (+): 82 (56.9%) After SLIT: 23 (17.7%) p< .001
SLIT en asma 3-18 años
Puntaje de síntomas
Penagos et al. Chest. 2008 Mar;133(3):599-609.
Penagos et al. Chest. 2008 Mar;133(3):599-609.
SLIT en asma 3-18 años
Puntaje de medicación
Long-lasting effects of sublingual immunotherapy according to its duration
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.
15-year prospective study
Escalas de síntomas / Medicamentos
* *
* * * * * * * * * * * * * * *
* * *
*
* * *
* * * * * * *
* * *
* * *
* *
* *
1992
1994
1998
1996
2000
2002
2004
2006
400
SLIT SLIT
300
200
100
A 3-años B 4-años C 5-años
M Marogna, et al. J Allergy Clin Immunol 2010;126:969-75.
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
Injection allergen immunotherapy for asthma (Review)
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.
Review: allergen specific immunotherapies reduce symptoms,medicationrequirements, andbronchial hyper-reactivity inasthmaAbramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003;(4):CD001186.
GP/ FP/ Primary care wwwwwq q IM/ Internal medicine wwwwwq q Allergy wwwwwwq Respirology wwwwwq qImmunology wwwwwwq. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Q In patients with asthma, how do different allergen specific (AS) immunotherapies compare for reducing asthmasymptoms, medication requirements, and improving bronchial hyper-reactivity (BHR)?
METHODS
Data sources: Medline(1966 toDecember 2001), theCochrane
AirwaysGroup trials register (up to June 2001), EMBASE/
Excerpta Medica, CINAHL, Current Contents, abstractsof
dissertations, and reference lists.
Study selection and assessment: studies in any language were
selected if they were randomised controlled trials (RCTs)
comparing ASimmunotherapy with placebo, antigenically
inactivecontrols, untreated controls, or inhaled steroids; or
comparing house dust extract with placebo. Studieswere
assessed for methodological quality using the Jadad scale.
Outcomes: asthma symptoms, medication requirements, lung
function (including peak expiratory flow rate, FEV1, and thoracic
gasvolume), non-specific BHR(to histamine or methacholine),
and ASBHR.
MAIN RESULTS75 RCTsmet theselection criteria (n= 3506). Patients who received
AS immunotherapy (particularly mite, pollen, and animal dander
allergens) had greater symptomatic improvement, had reduced
asthma medication requirements, and were less likely to develop
increased non-specific or ASBHR than those who received placebo
(table). When compared with untreated controls, patients in theAS
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(1RCT; 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.
CONCLUSIONIn patients with asthma, allergen specific immunotherapies
reduceasthmasymptoms, medication requirements, allergen specific
bronchial hyperreactivity (BHR), and the development of increased
non-specific BHR.
Abstract andcommentaryalsoappear in ACPJournal Club.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .For correspondence: Associate Professor M Abramson, Monash University,
Prahran, Victoria, Australia. [email protected]
Source of funding: Garfield Weston Foundation, UK.
Commentary
The updated review by Abramson et al ‘‘confirms the efficacy of
immunotherapy in termsof a reduction inasthma symptomsand use
of asthma medication.’’
Thisreview discussesinformationabout thebenefitsof immunotherapy
but doesnot assesstherisksor costs. Thebiggest concern isanaphylaxis.
Using data from1985–1992, the FDA estimated that the crude annual
death rate for allergenic extracts is low at 0.7 per million injections,1
which is roughly similar to fatal reactions to injected penicillin, which
range from 0.13–0.4 fatalities per million injections.2 Clearly, precau-
tions are needed. Although local reactions for AS immunotherapy
injectionsare common, they are simple to manage.
The second relevant consideration regarding AS immunotherapy is
cost. In 1996, the cost of AS immunotherapy for the first year was
estimated tobeUS$800 per year and $170 for eachyear thereafter.3 In
contrast, thenewest therapy for asthma(Xolair)maycostUS$12000per
year. Immunotherapy decreases asthma medication use, offsetting its
own cost, and may also further decrease costs by limiting the need for
concurrent treatment of allergic rhinitis.
Finally, a recent European study tested the hypothesis that AS
immunotherapy might prevent thedevelopment of asthma. After 3 years
of therapy, children with allergic rhinitis who received ASimmunother-
apy were about half as likely to develop asthma asthose who did not.4
ASimmunotherapy issafeand effectivewhen administered by trained
healthcare professionals who observe high standards of care.
Bernard RAdelsberg, MD
Hamden Internal Medicine Associates
Hamden, Connecticut, USA1 Turkeltaub PC. FDA Medical Bulletin 1994;24:7.2 Idsoe O, Guthe T, Willcox RR, et al. Natureand extent of penicillin side-
reactions, withparticular referenceto fatalitiesfromanaphylacticshock. BullWorld Health Organ 1968;38:159–88.
3 SullivanTJ, Selner JC, PattersonR, etal. Expertcareand immunotherapy forasthma. A review of published studieswith emphasison patient outcomeand cost. American College of Allergy, Asthma, and ImmunotherapyMonograph. Nov 1996, 1–25.
4 Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reducesthedevelopment of asthma in children with seasonal rhinoconjunctivitis (thePAT-study). JAllergy Clin Immunol 2002;109:251–6.
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 12 30%vs51% 38%(13 to 56) 5 (1 to 3)
Pollen ITv placebo 3 21%vs62% 75%(10 to 93) 3 (2 to 4)
Animal dander ITv placebo 4 27%vs69% 54%(6 to 78) 3 (2 to 17)
Overall ITv placebo 22 29%vs60% 49%(35 to 59) 4 (3 to 5)
Asthma medication
requirements
Overall ITv placebo 16 48%vs72% 34%(24 to 42) 5 (4 to 7)
Non-specific BHR Overall ITv placebo 5 30%vs64% 53%(30 to 69) 3 (2 to 6)
Allergen specific BHR Overall ITv placebo 16 32%vs63% 49%(37 to 59) 4 (3 to 5)
House dust v placebo 1 11%vs39% 71%(29 to 88) 4 (3 to 13)
*WMD = weighted mean difference; BHR = bronchial hyper-reactivity. Other abbreviations defined in glossary; weighted event rates, RRR, NNT, and CI
calculated fromdata in article using a fixed effectsmodel. Follow up not reported.
114 THERAPEUTICS
www.evidence-basedmedicine.com
Resultado. 88 estudios incluidos 1954 - 2009 (13 nuevos) 3792 pacientes
Calificación (Escala de Jadad) 6: 5/5, 16: 4/5, 32: 3/5
Injection allergen immunotherapy for asthma (Review)
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.
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)
Injection allergen immunotherapy for asthma (Review)
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.
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
Eficacia y seguridad. ¿De qué depende?
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
Inflammation
Modified from Tauman R & Gozal D. Paediatric Respiratory Reviews
(2006)
Structural
alteration
Sensory
impairment Neuro-motor
dysfunction
Upper airway
dysfunction
Primary or Secondary
Sensory Impairment
Cause or effect?
Older children
Tongue Anterior Palate
Tapia, 2010, Sleep
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
Atopy
Asthma
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
Inflammation
Modified from Tauman R & Gozal D. Paediatric Respiratory Reviews
(2006)
Structural
alteration
Sensory
impairment Neuro-motor
dysfunction
Upper airway
dysfunction
Primary or Secondary
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 insulin resistance
Higher 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
Time to reach baseline cutaneous flow was (mean) 69 seconds
n=8
controls
Bhattacharjee et al, Circulation, 2007
Pre and Post Adenotonsillectomy
Baseline cutaneous flow pre T+A was > 113 seconds
Normalized to 60-80 seconds post surgery
n=26
Pre and Post Adenotonsillectomy
n=6
Baseline cutaneous flow pre T+A was > 113 seconds
Did not normalise post surgery
Family history of CVS Disease
Inflammatory Marker: sCD40L
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
Katelaris CH et al. Clin ExpAllergy. 2012 Feb;42(2):186-207.
Prevalencia de la RA
Gravedad de la Rinitis Alérgica
Moderada/grave persistente 51-
60%
Moderada/grave intermitente 3-
17%
Leve persistente 14-42%
Leve Intermitente 4-10%
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
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.
Persistente
Intermitente
71%
29% 33%
67%
Europa 1 América Latina *2
* Venezuela, Ecuador, Panamá, México, Perú (n = 455)
Garmendia et al, AAAAI 2003.
89%
Persistente
Intermitente
89%
11%
Prevalencia de
Rinoconjuntivitis Alérgica
Prevalencia según el tipo de presentación en Venezuela
N = 603
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.
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.
Prevalencia Comparativa de Rinitis
Alérgica Diagnosticada en la Población
Pre
va
len
cia
(%
)
6.6% 3.5%
8.8% 6.3%
9.8% 6.4%
11.6% 11.4%
0%
20%
40%
60%
Todos los
Países
AILA*
Argentina Brasil Méjico Chile Ecuador Perú Venezuela
Underdiagnosis of Allergic Rhinitis in Latin America Comparison of ISAAC versus AILA results
Pre
vale
nce (
%)
ISAAC – Phase 31.
1. Solé D, Mallol J, Camelo-Nunes IC, et al. Allergy and Asthma Proceedings 2010; 31: S7-S29.
Sánchez-Borges M et al. AAIR 2012 (sometido a publicación).
Prevalencia de Pruebas Cutáneas Positivas
en Pacientes con Rinitis o Rinosinusitis
N = 229
76.4%
23.5%
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
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
Relación Rinitis-Asma
Posibles Mecanismos que Conectan
las Vías Respiratorias Superiores e
Inferiores en Asma y RA
Drenaje postnasal de
material inflamatorio hacia
las vías respiratorias
inferiores
Cambio de
respiración nasal a
bucal
Activación de los
reflejos bronquiales
nasofaríngeos
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 RSC
UC DA
Persistente
> 4 días a la semana
y > 4 semanas
Leve • sueño normal
• no alteración del ocio, activitades, deporte
• escuela / trabajo normal
• sin síntomas molestos
Intermitente
≤ 4 días por semana
o ≤ 4 semanas
Clasificación ARIA
en pacientes no tratados
Moderada-grave uno o más ítems
• sueño alterado
• alteración del ocio, actividades, deporte
• alteración escuela / trabajo
• síntomas molestos
Bousquet et al. J Allergy Clin Immunol 2001.
Reportes de caso, Ideas
Editoriales, Opinión de expertos
Estudios de cohortes, series de
casos
Meta-análisis
y revisiones
sistemáticas
Conexión de Base
de Datos al Azar
D
A
Jerarquía de la EBM
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
intermitente leve
persistente leve intermitente
moderada grave
persistente moderada
grave
valorar inmunoterapia
cromona tópica
antihistamínico H1 no sedante, oral o tópico
evitación de alergenos e irritantes
descongestionante intranasal (<10 días) u oral
corticoide intranasal
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 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
Evidencia de Tratamiento con
Medicamentos (según GRADE)
DÉBIL Los antihistamínicos anti H1 intraoculares son recomendados para el tratamiento de conjuntivitis alérgica en niños
FUERTE Los antihistamínicos anti H1 intraoculares son recomendados para el
tratamiento de conjuntivitis alérgica en 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 H1de Segunda Generación, vía intranasal u
oral, son recomendables para el tratamiento de rinitis y conjuntivitis
alérgica en niños y adultos
FUERTE Los medicamentos para tratar rinitis alérgica son efectivos y seguros
Los medicamentos para tratar la Rinitis Alérgica (AR) pueden ser administrados intranasal u oralmente (para algunos)
Opciones (no en orden de preferencia)
anti-H1 oral o intranasal
descongestionante intranasal
descongestionante oral (no en niños)
Rinitis Leve Intermitente
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 Intermitente
Rinitis Leve 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
Rinitis Moderada-Severa Persistente
ARIA
ARIA 2008
Los corticosteroides intranasales son las drogas de
primera elección para rinitis persistente y moderada-
severa
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.
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
Recomendaciones
VENEZUELA
Golfo de Cariaco Edo Sucre - Youenn Jacquin
Isla Blanquilla - Youenn Jacquin
Isla Las Aves - Youenn Jacquin
Plaza Venezuela - Orlando Acosta
Los Nevados Edo Merida - 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)
ASTHMA
Developmental Component
PERSISTENT WHEEZING
COAST Childhood Origins of ASThma
Funded by the NHLBI
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
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
Nasal lavage specimens collected at symptomatic illnesses
1 yr Birth 6 yr
Asthma Evaluation [AJRCCM 178:667, 2008]
Timing, severity & etiology of respiratory illnesses determined throughout childhood
3 yr 2 yr 4 yr 5 yr
2 4 6 9
Nasal Washes collected at “Well Child Visits”
COAST Evaluations
Persistent Wheezing Evaluation
[JACI 116:571, 2005]
What viral infections in early life are
associated with the development of asthma at age 6
years?
Etiology of Wheezing Illnesses in Early Childhood
Asthma at 6 Years
No Virus RV RSV PIV Flu CV MPV AdV EnV
Mea
n W
heez
ing
Illne
sses
per
Yea
r
0.0
0.2
0.4
0.6
0.8
1.0
Year 1 Year 2 Year 3
No Asthma at 6 Years
Virus Detected
No Virus RV RSV PIV Flu CV MPV AdV EnV0.0
0.2
0.4
RV Rhinovirus
RSV Respiratory syncytial virus
PIV Parainfluenza
Flu Influenza
CV Coronavirus
MPV Metapneumovirus
AdV Adenovirus
EnV Enterovirus
Jackson DJ et al. AJRCCM, 178:667, 2008
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?
Neither
Viral Wheeze
Sensitized
Sensitized and Viral Wheeze
1 4
3
2
Does sensitization lead to viral wheezing, or does viral wheezing lead to sensitization?
Jackson et al. AJRCCM 185:281, 2012
Does sensitization lead to viral wheezing, or does viral wheezing lead to sensitization?
Neither
Viral Wheeze
Sensitized
Sensitized and Viral Wheeze
1 4
3
2 If viral wheeze causes sensitization: 2→4 > 1→3
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)
Neither
Viral Wheeze
Sensitized
Sensitized and Viral Wheeze
1 4
3
2
Virus Ratio 3→4 1→2
2→4 1→3
Any 1.9* (1.2, 3.1)
0.75 (0.49, 1.1)
HRV 2.4* (1.4, 4.3)
0.69 (0.41, 1.2)
RSV 1.6 (0.9, 2.9)
0.8 (0.52, 1.3)
Jackson et al. AJRCCM 185:281, 2012
How does allergic sensitization alter the host
response to viral respiratory infections?
Allergen!
IFN
Hypothesis: Allergy Inhibits Innate Immune Responses Through FcεRI
Cross-linking of FcεRI
More frequent and severe virus-induced wheezing Prolonged inflammation
Possible airway remodeling and/or loss of lung function
PBMCs
HRV
Type I & Type III IFN Type I & Type III IFN
Allergen
Expression of FcεRI
(Durrani et al, JACI in press)
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
O’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-γResponses and Loss of Lung Function
Do wheezing RV infections in
early life cause asthma?
“Normal” Virus
Abnormal Host
Asthma
Host Factors ↓ antiviral responses
↓ lung function
Genetic polymorphisms
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 antigen-
presenting cells4 • Genetic polymorphisms5
– CD14_159 and Toll 3 receptors 1. Contoli M et al. Nat Med 12:1023, 2006
2. Wark PA et al. J Exp Med 201:937, 2005
3. Copenhaver CC et al. AJRCCM 170:175, 2004
4. Gill M et al. JI 184:5999, 2010
5. Hewson CA et al. J Virol 79:12273, 2005
6. Martin AC et al. AJRCCM 173:617, 2006
Normal Host
Pathologic Virus
Asthma Virus Factors
Lung/Airway damage
Virulent strains?
Palmenberg A and Spiro D et al. Science 2009;324:55-59
Sequencing and Analyses of All Known Human
Rhinovirus Genomes Reveals
Structure and Evolution
HRVA & HRVC are similarly common in infants. Together, they account for 94% of HRV infections.
456 HRV were typed in 451 HRV-positive samples
Detection Rate of each HRV group
(% of all HRV)
HRVA HRVB HRVC 225 29 202 # of Isolate
# of strain 45 8 35
0
20
40
60
80
49.3% 44.3%
6.4%
Total=456 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 367 HRV only infection MSI = Moderate-Severe Illness
0
5
10
15
20
A C B HRV Group
Probability of MSI (%)
95% confidence
Probability of inducing MSI varied with HRV strain 84 serotypes/strains (367 HRV only infections)
Prob
abili
ty
of M
SI (%
) 50
20
10
0.5
2
1
5
R52, R86, R91, R6, R83, R27, R14, W36, W10, R78
W30, R56, W13, W20, W9, W37, W25, W26, W6, W12
HRVA HRVB HRVC
Most pathogenic
Least pathogenic
95% confidence
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.
pDC: ↑FcεRI IgE cross-linking
Abnormal UPR (Epi, pDC, MΦ)
↓ Virus-induced IFN ↑ Illness severity
HRV Infection
17q21 Pathway
FcεRI Pathway
Asthma Inception
Allergy
↑ Inflammation ↑ Remodeling
HRV infection
2°Bacterial infection
Acute Exacerbation
Microbiome
Innate and adaptive immune responses
Developmental stage (age) Gender
Genetic Factor Atopy
(Immune Dysregulation) (Innate immunity)
(Interferons)
Environmental Factors
Viral LRIs (RV and RSV)
ASTHMA
Developmental Component
PERSISTENT WHEEZING
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 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)
0 5 10 15
Wigfield, 1992
Dwyer, 1991
Mitchell, 1991
Fleming, 1990
Jonge, 1989
Lee, 1989
Beal, 1988
Senecal, 1987
P.J. Fleming. Proceedings of the 12th Conference on Apnea of Infancy. 1994. Slide from Dr. Tom Keens
SIDS and Maternal Smoking During Pregnancy
SIDS
Odds
Ratio
vs
No
Smoking
P.S. Blair, et al. Br. Med. J., 313: 195-198, 1996.
Slide Courtesy of Dr. Tom Keens
Cigarettes smoked per day
0
2
4
6
8
10
1 to 9 10 to 19 >20
0
1
2
3
4
5
6
Mother Father
Alm
Fleming
SIDS and Cigarette Smoking After Pregnancy
SIDS
Odds
Ratio
vs
No
Smoking
Proceedings of the Fourth SIDS International Conference, 1996.
Slide Courtesy of Dr. Tom Keens
SIDS and Infant Exposure to Cigarette Smoke
SIDS
Odds
Ratio
vs
No
Exposure
P.S. Blair, et al. Br. Med. J., 313: 195-198, 1996.
Slide Courtesy of Dr. Tom Keens
Hours of Cigarette Smoke Exposure per day
0
2
4
6
8
10
1-2 3-5 6-8 >8
Protective Factors Risk Factors Pacifier Use at Sleep Time
Room Sharing
Breast Feeding
Sleeping Environment and Risk of SIDS
0
1
2
3
4
5
6
Soft Surface Pillow Use Face/Headcovered
Bed Sharingwith parent
Pacifier Use
Hauck FR, Herman SM, et al. Pediatrics 111, 1207-1214: 2003
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
Less Risk High Risk
Elective: Breast feeders Non-smokers Firm mattress
Non-Elective: Bottle fed Smokers
Risk ‘factors’
McKenna J. SIDS. Cambridge Handbook 2004
Bed Sharing Safe Risky 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
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
Intermittent Asthma Persistent Asthma
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Choosing the initial step in therapy based upon Asthma SEVERITY
Step-wise Approach to Asthma Therapy
Intermittent Asthma Persistent Asthma
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Adjusting therapy based on asthma CONTROL
Stepping down Stepping up
Step-up Approaches in Asthma
Thomas, Lemanske & Jackson, JACI 128:915, 2011
EPR-3 Recommendations For Frequent Preschool Wheeze & + API
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6 DAILY low-dose ICS at step-2 as
preferred treatment
Prevention of Early Asthma in Kids
Guilbert, NEJM 2006
• 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.)
Year 3
Screening/ Eligibility
Run-in
Interim Efficacy Tests
Years 1 & 2 1 month
Randomize
Treatment Observation
PEAK – Outcomes
Treatment Phase:
↓ Exacerbations
↓ Supplemental medications (ICS
and LTRA)
= bronchodilator use and
unscheduled visits
Observation Phase:
= Exacerbations
= Supplemental medications (ICS
and LTRA)
= Bronchodilator use and
unscheduled visits
Guilbert, NEJM 2006
EFD: No cough or wheeze, unscheduled clinic, urgent care, ED or hospital visits; no use of asthma medications including bronchodilator pre-treatment before exercise
Conundrum with Daily ICS Use
n Most effective and guideline preferred controller for persistent pediatric and adult asthma as it improves day-to-day asthma control and prevents exacerbations
n However, exacerbations occur yearly in about 30% of children with mild and 40% of children with mild-moderate asthma prescribed daily ICS in trials
n Long-term adherence with daily ICS is consistently low: 30-50% in general pediatric practice
n Growth effects small but may be permanent
ICS Options for Preschool Children with Recurrent Wheeze and Past
Year Exacerbations
Daily Intermittent
MIST Protocol: Overview
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
Intermittent high-dose
Budesonide Placebo PM
Budesonide 1.0 mg AM 1.0 mg PM
Cohort (N=278): Ages 12-53 mo, frequent wheeze, modified API, past year exacerbation, intermittent illnesses
Run-in: placebo respule nightly + albuterol prn
IntermittentDaily
p-value=0.87
0 50 100 150 200 250 300 350 4000
20
40
60
80
100
B.
Days
% o
f Pat
ient
s with
out a
Cour
se o
f Pre
dniso
lone
139 114 100 89 78 71 64 50139 114 93 84 74 66 54 40
Number at RiskIntermittentDaily
11
Time to 1st Exacerbation Similar with Daily vs Intermittent ICS
(Rate 0.95/person yr) (Rate 0.97/person yr)
Lessons from MIST In API positive preschoolers
with frequent wheeze & prior year exacerbations
n Illness burden is substantial despite ICS therapy n 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?
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
Papi A et al. NEJM 356:2040, 2007
• Mild asthma subjects (n=455)
• Six months treatment
• Primary outcome: AM PEF • AM PEF and Exacerbations:
Group A = C = D > B
• Cumulative dose of ICS lower in Group A compared to C and D
Results:
Unanswered Questions in Children with Controlled Mild Persistent Asthma
Persistent Asthma
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Intermittent Asthma
Step 1 Plus
Is rescue ICS (step-up intermittent) a better approach as step-down care to ICS discontinuation?
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 – 18 years
Controlled mild persistent asthma after 4-week run-in on beclomethasone 40 ug BID with placebo rescue + albuterol
Placebo Placebo
Placebo Beclomethasone
(80 ug)
Beclomethasone (40 ug)
Placebo
Beclomethasone (40 ug)
Beclomethasone (80 ug)
Placebo
Rescue ICS
Daily ICS
Combined ICS
Daily Therapy (BID)
Rescue Therapy + albuterol
Randomization groups
TREXA: Regimens on Exacerbations Requiring Oral Corticosteroids
Tim
e to
1st E
xace
rbat
ion
Daily ICS p=0.03 Combined ICS
p=0.07
Rescue ICS p=0.07 Placebo
p values adjusted for multiple comparisons (Hochberg-Bonferroni) (Martinez F, Lancet 2011;377:650-7)
8.5%
23.0%
5.6%2.8%
0%
10%
20%
30%
40%
Entire +API Cohort
TREXA: Regimens on Treatment Failures
N=71 N=71 N=71 N=74
Rescue P=0.024
Placebo
Combined P=0.012 Daily
P=0.009
(Martinez F, Lancet 2011;377:650-7)
Trea
tmen
t Fai
lure
(2
ora
l ste
roid
cou
rses
)
TREXA: Regimens on Linear Growth
Rescue ICS
Combined ICS
Daily ICS
1.1 cm
Placebo P < 0.001
(Martinez F, Lancet 2011;377:650-7)
TREXA - Conclusions
n Discontinuing ICS causes an unacceptable increase in exacerbations in children with well-controlled, mild persistent asthma
n Daily ICS is the most effective treatment for preventing exacerbations; adding rescue ICS to daily ICS does not add benefit
n 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 Improved impairment; no difference in risk domain
n 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
FACET Study: Formoterol and Budesonide in Moderate Asthma
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
BUD 200mcg/day (n=213)
BUD 200mcg/day+F (n=210)
BUD 800mcg/day (n=214)
BUD 800mcg/day+F (n=215)
Seve
re E
xace
rbat
ions
/Pat
ient
/yr
**
** Budesonide 100mcg/400mcg BID Formoterol 12mcg BID
Pauwels, et al. N Engl J Med 1997; 337: 1405-1411
**p=0.01
Beta Agonists + ICS: Maintenance
and Reliever Therapy?
Combination Therapy as both Maintenance and Reliever Therapy
O’Byrne PM et al. AJRCCM 171: 129, 2005
Combination Therapy: STAY Study
O’Byrne PM et al. AJRCCM 171:129, 2005
Seve
re A
sthm
a Ex
acer
batio
ns
Step-Up Long Term in Children
n In patients receiving daily low dose ICS treatment who are not well controlled, what are the next best treatment options?
BADGER Best Add-on Therapy Giving
Effective Responses
Lemanske RF et al. NEJM 362:975, 2010
Unanswered Questions in Childhood Asthma
Intermittent Asthma Persistent Asthma
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6 Uncontrolled on low dose ICS at Step 2 care
EPR-3 Recommendations
Intermittent Asthma Persistent Asthma
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
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 Increased doses of ICS (fluticasone 250 µg BID)?
n Add a LABA (salmeterol/fluticasone combination)?
n Add a LTRA (montelukast)?
BADGER: Novel Trial Design
n Each participant would receive all 3 treatment options
n 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 Asthma control days n Pulmonary function (FEV1)
n Risk domain n Asthma exacerbations
Research Questions n Could a differential response be demonstrable in at least
25% of participants? n If so, what was the direction of the response (i.e., which
therapy had the greatest probability of producing the best response?)
n Were there baseline characteristics that could predict the probability of a differential response? n Methacholine PC20 n FeNO n Asthma Control Test (ACT®) scores n B16 genotype (Arg/Arg)
Differential Response n At the end of the study, each child was identified
as either a differential or non-differential treatment responder.
n A differential responder was someone who exhibited significantly better outcomes on one treatment than on another.
n 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
n 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.
Definitions for Differential Response: Asthma Control Days
Asthma Control Day (ACD)
n An ACD was defined as a day without: n 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 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.
n 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
FEVFEVFEVinrun-
inrun-treatment −
Definitions for Differential Response: FEV1
BADGER Protocol: Overview
Period 1 Period 2 Period 3 Run-in period on 1xICS to demonstrate lack of control
16 weeks 16 weeks 16 weeks
Run-in Period 2-8 weeks
Randomization
Three Treatment Period, Double blind, 3 way cross-over
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
1xICS = fluticasone DPI 100 µg BID
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
Evaluation Period Evaluation Period Evaluation Period
LABA
ICS
Primary Outcome: Probability of BEST Response Based on Composite Outcome*
LTRA
*Covariate adjusted model
LABA step-up was more than 1.5 times as likely to produce the best response
(p = 0.002)
(p = 0.004)
LABA
Lemanske RF et al. NEJM 362:975, 2010
BADGER: Conclusions
Intermittent Asthma Persistent Asthma
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
A differential response to step-up therapy was demonstrated in nearly all subjects (≥ 95%) and more than 1.5 times as likely with LABA step-up. Many children demonstrated a best response to either ICS or LTRA step-up, highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy.