Wheeze

Zusammenhang zwischen
RSV Infektion und frühkindlichem
Asthma
Th.Frischer
Univ.Klinik f.Kinderund Jugendheilkunde Wien
Zunahme von Virus-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,..
Kuehni et al Lancet 2001
20
15
10
5
0
1990
1998
Viral wheeze
Multiple wheeze
Transient wheeze
RSV Bronchiolitis: Klinisches Bild
Nasenflügeln
Einziehungen
Hypoxämie
Stridor
Pfeifende AG oder sehr
leise AG
Netter F. The Ciba Collection of Medical Illustrations. Vol. 7,
Respiratory System. CIBA, 1979.
Tachypnoe,
paradoxe Atmung
Bronchiolitis obliterans
Bronchiolitis obliterans
Folgen einer RSV Infektion
„
„
„
„
„
Bronchiolitis obliterans
Rezidivierende obstruktive Bronchitis
Asthma bronchiale (allergisch)
Reaktive Atemwege (Asthma-ähnliches
Krankheitsbild)
Restitutio ad integrum
Pregnancy and birth:
a TH2 phenomenon
Jones C et al, Allergy 2000;55:2-10
Attenuated & Th2 polarised
Fetal life
Microbial stimulation
at mucosal surfaces
Adult-equivalent
adaptive immune function
TH1 skewed
Postnatal maturation of Th1 function
(pg/ml culture fluid)
IFNg
2000
1500
1000
500
2 mths
4 mths
6 mths
12 mths
18 mths
6 yrs
Postnatal development of cytokine response
capacity
160
225
***
120
150
***
p=0.004
80
60
40
***
***
IL-13 (pg/ml)
175
100
***
***
***
125
100
***
75
***
50
***
20
0
p=0.01
200
140
25
2mth
4mth
6mth
12mth
0
18mth
2mth
4mth
6mth
12mth
18mth
p=0.0008
2000
***
1750
IFN g (pg/ml)
IL-5 (pg/ml)
p=0.02
p=0.0005
180
1500
1250
1000
750
500
***
***
6mth
12mth
***
***
250
0
2mth
4mth
18mth
PHA 1ug/ml; 48hr culture s/n
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<0.05
4500
4000
3500
3000
2500
POS RSV
2000
NEG RSV
1500
1000
500
0
-500
2 mths
4 mths
6 mths
Postnatal age
12 mths
18 mths
Response to RSV infection in infant mice
RSV infection of infant mice -> eosinophilic Th2-polarised 10 immunity
+
Th2 polarised T-memory
Reinfection
Airway eosinophilia + AHR
Infection of MATURE mice -> Th1 polarised 10 and 20 immunity
Openshaw, et al.:
Delayed postnatal maturation of Th1 function
Increased risk for atopy, severe LRI, and persistent wheeze?
Birth
Viral
bronchiolitis
(infancy)
Infancy
Acute high-intensity
airway
inflammation
Preschool
Reactive
airways
Occasional
wheeze
Delayed postnatal maturation of Th1 function
Increased risk for atopy, severe LRI, and persistent wheeze?
Birth
Infancy
Viral
bronchiolitis
(infancy)
Acute high-intensity
airway
inflammation
Preschool
Reactive
airways
Low-moderate
Atopic sensitisation allergen
airway
to inhalant allergens exposure
inflammation
(Th2 memory)
Reactive
airways
Inhalant repeated
allergens exposure
Th1 memory
allergen
exposure
No symptoms
Occasional
wheeze
Occasional
wheeze
Delayed postnatal maturation of Th1 function
Increased risk for atopy, severe LRI, and persistent wheeze?
Birth
Infancy
Viral
bronchiolitis
(infancy)
Acute high-intensity
airway
inflammation
Preschool
Reactive
airways
Occasional
wheeze
Persistent
wheeze
to age 6
Low-moderate
Atopic sensitisation allergen
airway
to inhalant allergens exposure
inflammation
(Th2 memory)
Reactive
airways
Inhalant repeated
allergens exposure
Th1 memory
allergen
exposure
No symptoms
Occasional
wheeze
Delayed postnatal maturation of Th1 function
Increased risk for atopy, severe LRI, and persistent wheeze?
Birth
Infancy
Viral
bronchiolitis
(infancy)
Acute high-intensity
airway
inflammation
Preschool
Reactive
airways
Occasional
wheeze
Persistent
wheeze
to age 6
+
low IFNg phenotype
+
Low-moderate
Atopic sensitisation allergen
airway
to inhalant allergens exposure
inflammation
(Th2 memory)
Reactive
airways
Inhalant repeated
allergens exposure
Th1 memory
allergen
exposure
No symptoms
Occasional
wheeze
Zeitpunkt der RSV Infektion
bedeutsam?
Birth
1 yr
2 yr
3 yr
4 yr
RSV
infection
RSV
infection
Th1-polarised
immunity
resolution
Reinfection
Th1-memory
reactivation
resolution
5 yr
6 yr
Zeitpunkt der RSV Infektion bedeutsam?
Birth
1 yr
2 yr
3 yr
4 yr
RSV
infection
RSV
infection
RSV
infection
Th1-polarised
immunity
resolution
Th2-polarised Spread to
immunity
Lower
Resp tract
Reinfection
Th1-memory
reactivation
Airways
inflammation
resolution
Wheeze
5 yr
6 yr
Reaktive Atemwege nach RSV
„
„
„
„
9 kontrollierte Studien
1978 - 2000
Follow-up 2 - 13 Jahre
Meisten retrospektiv
Retrospektive Studien
Patienten
RSV/Kontrollen
follow-up
Statistisch signifikanter
Unterschied
zwischen Gruppen
35/35
8 Jahre
JA
p < 0.02
Pullan & Hey
(1982)
130/111
10 Jahre
JA
p < 0.001
McConnochie &
Roghmann
(1984)
59/177
8 Jahre
JA
p < 0.0001
Mok & Simpson
(1984)
100/200
7 Jahre
JA
NA
Studie
Sims et al
(1978)
p Werte
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)
***
4
Odds Ratios (95% CI)
„
***
3
*** **
2
*
1
0
Age 6
Age 8
Frequent wheeze
Stein et al. Lancet. 1999;354:541.
NS
***p ≤ 0.001
Age 11
Age 13
Infrequent wheeze
**p ≤ 0.01
*p ≤ 0.05
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 < 0.0001)
Sigurs et al. Am J Respir Crit Crit
Care Med. 2000;161:1501.
35
* **
***
30
% of group
„
40
25
** **
20
15
†
10
5
0
RSV Controls
Wheezing
1 yr 3 yr
RSV
Controls
Asthma
7 yr
*p = 0.003
***p < 0.0001
**p < 0.001
†p
= 0.004
Multivariate Test of Risk Factors for Asthma
and “Any Wheezing” in All 140 Children
Asthma
Any wheezing
Odds ratio (95% CI)
Odds ratio (95% CI)
12.7
5.3
(3.4 - 47.1)
(2.2 - 12.5)
Hereditary asthma
(parents)
—
3.0
Male gender
—
Risk factor
RSV bronchiolitis
(1.2 - 7.8)
4.4
(2.0 - 9.8)
Sigurs et al. Am J Respir Crit Care Med. 2000;161:1501.
Prospektive Studien
„
„
„
Risiko für Asthma mit 13 Jahren signifikant
erhöht (28% vs 3.3%; p < 0.0001)
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
Prospektive Studien
„
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„
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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;16:386-392
Prospektive Studien
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„
Wheezing mit 30-42 Monaten häufiger
- 28% vs 13%
Whezing mit 69-81 Monaten häufiger
- 22.6% vs 9.6%
Asthmadiagnose mit 91 Monaten häufiger
- 38% vs 20%
Atopy nicht häufiger
Henderson et al- Ped.Allergy and Immunol. 2005;16:386-392
RSV Bronchiolitis and Allergic Sensitization in
Hospitalized Children, Studies with Control Groups
No increased risk (SPT)
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Sims 1981, age 8
(SPT and serum IgE)
Carlsen 1987, age 2
Pullan 1982, age 10
Noble 1997, age 8–10
Increased risk
„
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Murray 1992, age 6 (SPT)
Sigurs 1995, age 3
(SPT and serum IgE)
Sigurs 2000, age 7
(SPT and serum IgE)
Family History of Atopy and Clinical
Course of RSV
p<0.02
• 172 patients with RSV
Atopy
– 99 inpatients
– 73 outpatients
No Atopy
35
30
• 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<0.04
25
20
15
10
5
0
<1 Week
Trefny PH, et al. Pediatr Pulmonol 2000;30:302
>1 Week
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;59:512-516
Prednisolone Treatment of Respiratory Syncytial Virus
Infection: A randomized controlled trial of 147 infants.
Bülow et al Pediatrics 1999;104:6
„
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„
„
„
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
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
Ergebnisse
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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
FEV1/FVC is Significantly Better in the
RSV IGIV Group
100
FEV1/FVC
90
80
70
p=0.016
60
CONTROL
Wenzel S, et al. Am J Med 2002;112:627–33.
RSV IGIV
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
„
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
„
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.