Virus and Asthma Renato T. Stein
Pontif铆cia Universidade Cat贸lica RGS PORTO ALEGRE, BRAZIL
Worldwide Prevalence of Asthma Symptoms: ISAAC Phase I Data
ISAAC Study. Lancet 1998; 351: 1225–32.
Genetics and the Environment: why do Babies Wheeze? “Born to burn”: the inflammatory pathway Genetics meets the viruses Low lung function since birth Viruses “hurt” the airways Bad control of Aw tone …..
Annual Mean Incidence Levels of Respiratory Diseases: Person/Year Tecumseh, Michigan, 1965–1971 7
Females
Mean annual illness incidence
6
Males
5 4 3 2 1 0
<1
1–2
3–4
5–9
10–14
15–19
20–24
25–29
30–39
40–49 50–59
≥60
Age group (yr) Monto AS, Ullman BM. JAMA. 1974;227:164.
RSV and Rhinovirus RSV is the leading infectious cause of wheezing in infants. ~ 70% of infants are infected during their first year of life, and all children have been infected at least once by age 2 RV infects the lower airway as well, and bronchiolitis (as well as asthma) symptoms may arise as a result of lower airway inflammation May be as frequent as RSV
Impact of RSV Infection 1-2% infected are hospitalized Children with RSV bronchiolitis are more likely to wheeze later in life. Conflicting results Associated with atopy? Sigurs et al. AJRCCM 2000/01/05
Rhinovirus Underestimated impact Heat-resistant strains (lower airways) More prevalent in spring and fall Older infants; more likely to have atopic dermatitis and eosinophilia (Korpi MA. PID 2004) Response to steroids in bronchiolitis: recurrent wheeze (Jartti PID 2006)
Rhinovirus In a population of children at increased risk of developing allergies and asthma the most significant risk factor for the development of preschool childhood wheezing was the occurrence of symptomatic rhinovirus illnesses during infancy (COAST Study) Lemanske R
Respiratory Viruses in First Time Wheezers
Positive detection in NPA (%) (n=35) RSV Rhinovirus Influenza
33 (94.3) 6 (17.1) 1 (2.9)
Adenovirus Parainfluenza
2 (5.7) 0
Pitrez PM et al. 2005 J Ped (Rio J)
VRIs and Hospitalizations for Asthma
Hospital admissions for asthma correlate with virus isolation peaks and school terms. URIs
20
Total pediatric and adult hospitalizations
15
School holidays
10 5 0 Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
Johnston SL et al. AJRCCM 1996
Major Questions Viral bronchiolitis contributes to asthma inception, or Identifies infants at risk for subsequent wheezing, …whether due to an atopic predisposition or preexisting abnormal lung function.
Susceptibility Period Infection in early infancy: greatest impact in the immune and/or respiratory system Infants born in winter are more likely to have asthma (Aberg N, Clin Exp Allergy 1999) (Nielsen HE Acta Paediatr 2003)
RSV Inflammatory Mediators Neuroimmune interactions: Nerve Growth Factor, neurotrophic factor protein may be associated to Aw BHR/inflammation (Piedimonte G, et al. AJRCCM 2005) Low IFNg early in life is associated with persistent wheeze and increased viral shedding (Guerra S, et al. AJRCCM 2003)
IL-10 as a predictor of subsequent wheeze (Bont L, AJRCCM 2000)
Genetic markers: IL-10 genes, TLR4 mutations,â&#x20AC;Ś are related to severe bronchiolitis (Hull J et al. J Infec Dis 2005), (Guy T et al. J Infect Dis 2004)
Data from Texas
Mejias, Chaves-Bueno, Ramilo O. Ped Infect Dis J. 2005
Host Susceptibility Low IFN-g proliferative responses to RV Increased viral shedding and symptom severity (Parry DE. JACI 2000) Weak Th1 responses in sputum: associated with greater Dx severity (Gern JE AJRCCM 2000)
Weak Th1 responses (adults): lower lung function and increased BHR (Papadopoulos NG. Thorax 2002)
Maturation of Immune Immune Responses in Infancy Non-Asthmatic Interferon gamma responses (Th1)
Atopic Asthmatic
Non-Atopic Asthmatic
24-48
0 Age (months)
Holt P, Sly P
Guerra S, et al. AJRCCM 2003
“Asthma” Phenotypes in Childhood
Stein et al. Thorax 1997
Early Transient Wheeze Phenotype Majority of wheezers falls under this category (~70%) Low lung function since birth; it tracks throughout life Not related to atopy Related to maternal smoking Virus-related Good prognosis!
Risk for Wheezing in RSV Infected Children Early in Life, Independent of Atopyâ&#x20AC;Ś
Stein et al, Lancet 1999
Predictive Score: Persistent Wheeze/Asthma Major Criteria Minor Criteria Parents/siblings w Eosinophilia asthma/allergies Sensitized to Eczema <1y foods Sensitized to More than 3 allergens wheeze episodes Hospital admission for asthma CRITERIA: 2 major or 1 major/2 minor Castro-Rodrigues JA et al. AJRCCM 2000
What is the Impact of Persistent Wheeze?
Z-Scores Aw flows height-adjusted (± ±se)
Impact of Wheeze Phenotypes on Lung Function
0,4 0,2 0,0 - 0,2 - 0,4 - 0,6
Never Wheeze Transient Wheeze
-0,8
Late Wheezers
-1,0
Persistent Wz
-1,2 0
2
4
6
10 8 Age, years
12
14
16
18
Morgan WJ, et al. AJRCCM 2005
Different Exposures, Different Asthma?
Atopic sensitisation and the international variation of asthma prevalence in children: ISAAC II Gudrum Weynmar, Stephan Weiland et al., submitted for publication
ISAAC Phase II Thirty study centres in 22 countries Parental questionnaires (n=54,439) Skin prick tests (n=31,759) Serum IgE levels (n=8,951) Economic development assessed by gross national income per capita (GNI)
Prevalence of wheeze in the past 12 months Brazil
New Zealand United Kingdom Norway Spain Turkey Georgia Sweden West Bank Netherlands Estonia Germany Italy Greece Ghana India Albania China Ecuador 0
5
10
15
Prevalence (in %)
20
25
ISAAC II, Steering Committee Data Bank, 2005
Association between wheeze in past year and skin prick test reactivity (> 3mm) Germany, Dresden Munich Greece, Athens Thessaloniki Italy, Rome Netherlands, Utrecht New Zealand, Hawkes Bay Norway, Tromso Spain, Almeria Cartagena Madrid Valencia Sweden, Linkoeping Oestersund UK, West Sussex
‘Western‘
Combined ‘Western ‘ Albania, Tirana China, Beijing Hong Kong Estonia, Tallinn Georgia, Tbilisi Ghana, Kintampo India, Bombay Turkey, Ankara West Bank, Ramallah
‘Non-Western‘
Combined ‘non-Western‘
0
2
4
O.R. (95% C.I.)
6
8
Hong Kong
Cartagena
Dresden Munich
Almeria
Athens
Madrid
Thessaloniki Reykjavik
Valencia
Rome Utrecht
Dresden
Hawkes Bay
Munich
Tromso Almeria
Athens
Cartagena Madrid
Thessaloniki
Valencia
Rome
Linköping Östersund
Utrecht
West Sussex Combined affluent
Tromso
Tirana
Linköping
Uruguaiana
Östersund
Beijing
West Sussex
58.9 [21.4;162.2]
Guangzhou Pichincha
Combined affluent
Tallinn Tbilisi
Tirana
Kintampo
Tallinn
Mumbai Riga
Mumbai
Ramallah
Tbilisi
Ankara Combined non-affluent
Combined non-affluent
Combined non-affluent, without Guangzhou 0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
12
12
10
10
8
8
Prevalence in %
Prevalence in %
Prevalence (%) of wheeze attributable to Prevalence (%) of wheeze attributable to specific IgE (≥0.35 kU/L) by GNI + skin prick test reactivity by GNI + ρ #=0.7365; p=0.0027 ρ #=0.7398; p<0.0001
6 4
6 4
2
2
0
0 0
10000
20000
30000
40000
g ro s s n a tio n a l in c o m e (in U S $ )
PAP= PAF X prevalence of disease
0
10000
20000
30000
g ro s s n a tio n a l in c o m e
40000
ISAAC â&#x20AC;&#x201C; Phase II Data, Brazil Cross sectional study with questionnaires, skin tests, stool examinations for parasites, BHR Population n=1199 Age: 10.1 (+ 0.8)
South Brazil Study Skin test +ve. (atopy): 13.7% 40% +ve. parasites; 19% helminths; Helm are inversely associated with skin tests: OR (95% CI)=0.4 (0.2-0.8) Current wheeze: 26.4% (21.3% atopic) Current asthma: 9.4% (29% atopic) Bronchiolitis <2y E.R. or hospital: 6.1%
Wheeze in previous 12m OR, 95% C.I.
Active Asthma OR, 95% C.I.
Maternal Hx Asthma
3.1 (1.8-5.3)***
5.5 (2.8-10.8)***
Paternal Hx Asthma
3.9 (2.1-7.2)***
3.4 (1.6-7.5)***
Bronchiolitis < 2y
5.4 (2.9-9.9)***
17.0 (8.6-33.4)***
Any positive skin test
2.8 (1.8-4.2)***
5.9 (3.2-10.8)***
Humid household
1.5 (1.1-2.1)**
2.4 (1.4-4.1)**
Maternal smoking
1.2 (0.9-1.7)
1.2 (0.7-2.0)
Born before term
1.4 (0.8-2.3)
0.7 (0.3-1.8)
Maternal schooling > 8y
0.7 (0.4-1.0)
0.4 (0.2-0.9)*
> 2 Siblings
1.1 (0.8-1.4)
0.6 (0.3-0.97)*
High-load Ascaris (>100eggs/g)
1.8 (0.97-3.0)
2.7 (1.1-6.6)*
Most prevalent asthma/wheeze phenotype among the poor may be nonatopic. Most significant risk factor for non-atopic asthma at age 10: bronchiolitis early in life Viral â&#x20AC;&#x153;bronchiolitisâ&#x20AC;?/early viral-related wheeze plus heminths: key risk factors for non-atopic wheeze?