Zusammenhang zwischen. Asthma. Th.Frischer Univ.Klinik f.kinder- und Jugendheilkunde Wien

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Adolph Dieter
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1 Zusammenhang zwischen RSV Infektion und frühkindlichem Asthma Th.Frischer Univ.Klinik f.kinder- und Jugendheilkunde Wien

2 Zunahme von Virus-induziertem induziertem Wheeze Populationsstichprobe von 1650 (1990) und 2600 (1999) 1-5 Jährigen Fragebogen Alle Wheezing-Erkrankungen zeigen signifikanten Anstieg RS Virus Meta-Pneumovirus Adenovirus Influenza, Parainfluenzaviren, Viral wheeze Multiple wheeze Transient wheeze Kuehni et al Lancet 2001

signifikanten Anstieg RS Virus Meta-Pneumovirus Adenovirus Influenza,

3 RSV Bronchiolitis: Klinisches Bild Nasenflügeln Einziehungen Hypoxämie Stridor Pfeifende AG oder sehr leise AG Tachypnoe, paradoxe Atmung Netter F. The Ciba Collection of Medical Illustrations. Vol. 7, Respiratory System. CIBA, 1979.

leise AG Tachypnoe, paradoxe Atmung Netter F.

5 Bronchiolitis obliterans

6 Bronchiolitis obliterans

7 Folgen einer RSV Infektion Bronchiolitis obliterans Rezidivierende obstruktive Bronchitis Asthma bronchiale (allergisch) Reaktive Atemwege (Asthma-ähnliches Krankheitsbild) Restitutio ad integrum

Asthma bronchiale (allergisch) Reaktive Atemwege

8 Pregnancy and birth: a TH2 phenomenon Jones C et al, Allergy 2000;55:2-10

9 Attenuated & Th2 polarised Fetal life Microbial stimulation at mucosal surfaces Adult-equivalent adaptive immune function TH1 skewed

10 Postnatal maturation of Th1 function 2000 IFNg (pg/ml culture fluid) mths 4 mths 6 mths 12 mths 18 mths 6 yrs

11 Postnatal development of cytokine response capacity IL-5 (pg/ml) *** p=0.004 *** *** p= *** *** IL-13 (pg/ml) *** *** p=0.02 *** *** p=0.01 *** 0 2mth 4mth 6mth 12mth 18mth 0 2mth 4mth 6mth 12mth 18mth p= *** IFN g(pg/ml) *** *** *** *** 0 2mth 4mth 6mth 12mth 18mth PHA 1ug/ml; 48hr culture s/n

02 *** *** p=0.01 *** 0 2mth 4mth 6mth 12mth 18mth 0 2mth 4mth 6mth 12mth 18mth p=0.

12 Severe infant RSV infections which prime RSV-specific CMI are associated with slow postnatal maturation of Th1 competence PHA-induced IFNg response (pg/ml) p< mths 4 mths 6 mths 12 mths 18 mths POS RSV NEG RSV Postnatal age

PHA-induced IFNg response (pg/ml) 4500 4000 3500 3000 2500 2000 1500

13 Response to RSV infection in infant mice RSV infection of infant mice -> eosinophilic Th2-polarised 1 0 immunity + Th2 polarised T-memory Reinfection Airway eosinophilia + AHR Infection of MATURE mice -> Th1 polarised 1 0 and 2 0 immunity Openshaw, et al.:

polarised T-memory Reinfection Airway eosinophilia + AHR

14 Delayed postnatal maturation of Th1 function Increased risk for atopy,, severe LRI, and persistent wheeze? Birth Infancy Preschool Viral bronchiolitis (infancy) Acute high-intensity airway inflammation Reactive airways Occasional wheeze

Birth Infancy Preschool Viral bronchiolitis (infancy)

15 Delayed postnatal maturation of Th1 function Increased risk for atopy,, severe LRI, and persistent wheeze? Birth Infancy Preschool Viral bronchiolitis (infancy) Acute high-intensity airway inflammation Reactive airways Occasional wheeze Atopic sensitisation to inhalant allergens (Th2 memory) allergen exposure Low-moderate airway inflammation Reactive airways Occasional wheeze Inhalant repeated allergens exposure Th1 memory allergen exposure No symptoms

Occasional wheeze Atopic sensitisation to inhalant allergens (Th2 memory) allergen exposure Low-moderate airway

16 Delayed postnatal maturation of Th1 function Increased risk for atopy,, severe LRI, and persistent wheeze? Birth Infancy Preschool Viral bronchiolitis (infancy) Acute high-intensity airway inflammation Reactive airways Occasional wheeze Persistent wheeze to age 6 Atopic sensitisation to inhalant allergens (Th2 memory) allergen exposure Low-moderate airway inflammation Reactive airways Occasional wheeze Inhalant repeated allergens exposure Th1 memory allergen exposure No symptoms

Occasional wheeze Persistent wheeze to age 6 Atopic sensitisation to inhalant allergens (Th2 memory) allergen exposure

17 Delayed postnatal maturation of Th1 function Increased risk for atopy,, severe LRI, and persistent wheeze? Birth Infancy Preschool Viral bronchiolitis (infancy) Acute high-intensity airway inflammation Reactive airways Occasional wheeze + low IFNg phenotype Persistent wheeze to age 6 + Atopic sensitisation to inhalant allergens (Th2 memory) allergen exposure Low-moderate airway inflammation Reactive airways Occasional wheeze Inhalant repeated allergens exposure Th1 memory allergen exposure No symptoms

wheeze + low IFNg phenotype Persistent wheeze to age 6 + Atopic sensitisation to inhalant allergens (Th2 memory) allergen

18 Zeitpunkt der RSV Infektion bedeutsam? Birth 1 yr 2 yr 3 yr 4 yr 5 yr 6 yr RSV infection RSV infection Th1-polarised Reinfection immunity resolution resolution Th1-memory reactivation

19 Zeitpunkt der RSV Infektion bedeutsam? Birth 1 yr 2 yr 3 yr 4 yr 5 yr 6 yr RSV infection RSV infection RSV infection Th1-polarised Reinfection immunity resolution resolution Th1-memory reactivation Th2-polarised immunity Spread to Lower Resp tract Airways inflammation Wheeze

infection Th1-polarised Reinfection immunity resolution resolution

20 Reaktive Atemwege nach RSV 9 kontrollierte Studien Follow-up 2-13 Jahre Meisten retrospektiv

21 Retrospektive Studien Studie Patienten RSV/Kontrollen follow-up Statistisch signifikanter Unterschied zwischen Gruppen p Werte Sims et al (1978) Pullan & Hey (1982) McConnochie & Roghmann (1984) Mok & Simpson (1984) 35/35 8 Jahre JA 130/ Jahre JA 59/177 8 Jahre JA 100/200 7 Jahre JA p < 0.02 p < p < NA

22 Prospektive Studien 207 Kinder mit milder RSV Infektion Kontrollkinder ohne respiratorische Infekte in den ersten 3 LJ Risiko für frequent wheeze mit 11 Jahren erhöht (p 0.01) Odds Ratios (95% CI) *** *** *** ** * NS Age 6 Age 8 Age 11 Age 13 Frequent wheeze Infrequent wheeze Stein et al. Lancet. 1999;354:541. ***p **p 0.01 *p 0.05

23 Prospektive Studien 47 Kinder wegen RSV Infektion hospitalisiert im 1.LJ 93 Kontrollen ohne RSV Infektion Risiko für wheeze mit 7 Jahren signifikant erhöht (p < ) % of group * ** *** ** ** RSV Controls RSV Controls Wheezing Asthma 1 yr 3 yr 7 yr Sigurs et al. Am J Respir Crit Crit Care Med. 2000;161:1501. *p = **p < ***p < p = 0.004

24 Multivariate Test of Risk Factors for Asthma and Any Wheezing in All 140 Children Risk factor RSV bronchiolitis Asthma Odds ratio (95% CI) 12.7 ( ) Any wheezing Odds ratio (95% CI) 5.3 ( ) Hereditary asthma (parents) 3.0 ( ) Male gender 4.4 ( ) Sigurs et al. Am J Respir Crit Care Med. 2000;161:1501.

25 Prospektive Studien Risiko für Asthma mit 13 Jahren signifikant erhöht (28% vs 3.3%; p < ) Risiko für positiven SPT erhöht (50% vs 28%) Geringe Erhöhung bronchialer Reaktiviät Sigurs et al. Am J Respir Crit Crit Care Med. 2004;171:137-41

26 Prospektive Studien Kohortenstudie (n=14062) 150 Kinder mit nachweisbarer RSV infektion + Hospitalisierung Follow-up bis 7.LJ Outcomes: wheezing, asthma, Atopy Henderson et al- Ped.Allergy and Immunol. 2005;16:

27 Prospektive Studien Wheezing mit Monaten häufiger - 28% vs 13% Whezing mit Monaten häufiger % vs 9.6% Asthmadiagnose mit 91 Monaten häufiger - 38% vs 20% Atopy nicht häufiger Henderson et al- Ped.Allergy and Immunol. 2005;16:

28 RSV Bronchiolitis and Allergic Sensitization in Hospitalized Children, Studies with Control Groups No increased risk (SPT) Sims 1981, age 8 (SPT and serum IgE) Carlsen 1987, age 2 Pullan 1982, age 10 Noble 1997, age 8 10 Increased risk Murray 1992, age 6 (SPT) Sigurs 1995, age 3 (SPT and serum IgE) Sigurs 2000, age 7 (SPT and serum IgE)

29 Family History of Atopy and Clinical Course of RSV 172 patients with RSV 99 inpatients 73 outpatients Family history of atopy IP-62%; OP-29% p=0.001 Bronchiolitis 89% vs 74% p<0.02 Longer stay 7.4 vs 6.1 p< p<0.02 Atopy No Atopy <1 Week >1 Week Trefny PH, et al. Pediatr Pulmonol 2000;30:302

30 Post - RSV Wheezing 140 Kinder, hospitalisiert nach RSV Infektion 29% Frühgeboren Alter: 0-52 Wochen Follow-up bis 3.LJ Atopiebelastung: 44% Bont et al. Thorax 2004;59:

31 Prednisolone Treatment of Respiratory Syncytial Virus Infection: : A randomized controlled trial of 147 infants. Bülow et al Pediatrics 1999;104:6 N=147, < 2 years Hospitalisation due to resp. symptoms and RSV+ 2mg/kg Aprednislon 5 days Outcomes length of hospitalization length of symptoms symptoms after 1 month and 1 year Result therapy= plazebo

32 Verhindert RSV-IVIG reaktive Atemwege durch RSV Infektion? Prospektive Studie 13 Kinder mit BPD welche RSV-IVIG als Säugling erhalten haben 26 gematchte Kontrollen mit BPD 6/13 behandelten Fällen hatten eine Anamnese einer RSV Infektion vs 21/26 Kontrollen Wenzel et al. Am J Med 2002

33 Ergebnisse FEV1/FVC besser (p < 0.02) Weniger Atopie (p < 0.04) Schulfehltage (p = 0.01), Erkältungen (p < 0.03), und Asthma anfälle (p < 0.04) seltener Geringe Reduktion von Hospitalisierungen und Asthmamedikamentenverbrauch Wenzel et al. Am J Med 2002

34 FEV1/FVC is Significantly Better in the RSV IGIV Group FEV1/FVC CONTROL p=0.016 RSV IGIV Wenzel S, et al. Am J Med 2002;112:

35 Patient population Multicenter, multinational trial Preterm infants 35 wk GA 3 years of age at time of enrollment No CLD No CHD Group 1: Received palivizumab Group 2: No palivizumab + RSV hospitalization in first year of life Group 3: No palivizumab + no RSV hospitalization in first year of life

36 Statistical analysis Comparisons of: Palivizumab group vs combined control groups (groups 2 and 3) Palivizumab group vs non-hospitalized control group (group 3 only) Subgroups defined by family history of asthma Time to recurrent wheezing Time to asthma Multivariable logistic regression Multivariable proportional hazards regression

37 Zusammenfassung RSV Bronchiolitis hat bei Kleinkinder oft eine chronische Asthma-ähnliche Erkrankung (reaktive Atemwege) zur Folge, welche bis in das Schulalter bestehen bleiben kann. Die Prävention durch Synagis senkt die Häufigkeit und den Schweregrad reaktiver Atemwege nach durchgemachter RSV Infektion.

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