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

Leg EMG (2)

Microphone

Chin EMG (2)

EEG EOG

Nasal EtCO2

Records behavior Documents arousals,

parasomnias, abnormal

sleeping position, and attends

to any technical problem

Respiratory Effort

Nasal Oral Airflow

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)

valid & reliable Reliable,

but invalid

Where and what is the goal?

Ambulatory Testing

Embletta X100 Stardust

Ares Watch-Pat 100

Embletta X100 Embletta X100

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

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

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

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

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

Conclusiones

El Enigma de la Congestión

Qué es

congestión?

Obstruido

Bloqueado No Flujo de

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 –

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–

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

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)

a las 2

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%

46% 52%

Todos los Países

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

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

*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.

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

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.

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

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)

SIT Control

Sin asma

Asmáticos

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

Baseline 3rd Year Baseline 3rd Year

Controls

*P<0.001.

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

Intermittent Asthma Persistent Asthma

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.

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

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

* * * * * * *

SLIT SLIT

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. michael.abramson@med.monash.edu.au

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

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)

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

(2006)

Structural

alteration

Sensory

dysfunction

Upper airway

dysfunction

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

Asthma

Obstructive Sleep Apnea

Common genetic and environmental risk factors

Inflammation

Inflammatory markers identified

CRP, oxidative species, cytokines, eNO

Evidence that treating inflammation improves SDB

Inflammation

(2006)

Structural

alteration

Sensory

dysfunction

Upper airway

dysfunction

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

Adjusting for BMI and sex, OSA predisposed to

Increased insulin resistance

Higher BP

Higher LDL

Redline, 2007, AJRCCM

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

Time to reach baseline cutaneous flow was (mean) 69 seconds

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

Pre and Post Adenotonsillectomy

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)

(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

Fernán Caballero

Caracas, Venezuela

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-

Moderada/grave intermitente 3-

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

29% 33%

Europa 1 América Latina *2

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

Garmendia et al, AAAAI 2003.

Persistente

Intermitente

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

6.6% 3.5%

8.8% 6.3%

9.8% 6.4%

11.6% 11.4%

Todos los

Países

Argentina Brasil Méjico Chile Ecuador Perú Venezuela

Underdiagnosis of Allergic Rhinitis in Latin America Comparison of ISAAC versus AILA results

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

Rinitis Alérgica: Comorbilidad

• 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

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

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

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

Meta-análisis

y revisiones

sistemáticas

Conexión de Base

de Datos al Azar

Jerarquía de la EBM

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

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

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

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 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

Year 1 Year 2 Year 3

No Asthma at 6 Years

Virus Detected

No Virus RV RSV PIV Flu CV MPV AdV EnV0.0

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

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

Which comes first?

Allergic sensitization or

wheezing illnesses?

Neither

Viral Wheeze

Sensitized

Sensitized and Viral Wheeze

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

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

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

Neither

Viral Wheeze

Sensitized

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)

How does allergic sensitization alter the host

response to viral respiratory infections?

Allergen!

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

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

49.3% 44.3%

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

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)

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

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.

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

Smoking

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

Slide Courtesy of Dr. Tom Keens

Cigarettes smoked per day

1 to 9 10 to 19 >20

Mother Father

Fleming

SIDS and Cigarette Smoking After Pregnancy

Smoking

Proceedings of the Fourth SIDS International Conference, 1996.

SIDS and Infant Exposure to Cigarette Smoke

Exposure

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

Hours of Cigarette Smoke Exposure per day

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

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

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

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

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

s with

139 114 100 89 78 71 64 50139 114 93 84 74 66 54 40

Number at RiskIntermittentDaily

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

Rescue ICS

Daily ICS

Combined ICS

Daily Therapy (BID)

Rescue Therapy + albuterol

Randomization groups

TREXA: Regimens on Exacerbations Requiring Oral Corticosteroids

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)

5.6%2.8%

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)

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

BUD 200mcg/day (n=213)

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

BUD 800mcg/day (n=214)

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

** 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

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

Step 1

Step 2

Step 3

Step 4

Step 5

Step 6 Uncontrolled on low dose ICS at Step 2 care

EPR-3 Recommendations

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

Evaluation Period Evaluation Period Evaluation Period

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

*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)

Lemanske RF et al. NEJM 362:975, 2010

BADGER: Conclusions

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.

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

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