WHAT YOU SHOULD HAVE READ BUT….2010 <ul><li>asthma </li></ul>University of Verona, Italy Attilio Boner
Asthma phenotypes
Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams  JAC...
Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams  JAC...
Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams  JAC...
Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program   Moore  AJRCCM  2010;181...
Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program   Moore  AJRCCM  2010;181...
Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program   Moore  AJRCCM  2010;181...
Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program   Moore  AJRCCM  2010;181...
<ul><li>asthma natural history </li></ul>
Background:  Clinicians have difficulty in  diagnosing asthma in preschool children with  suggestive symptoms. Objective: ...
Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri  JACI 2009;124:9...
Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri  JACI 2009;124:9...
Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri  JACI 2009;124:9...
Increased Fraction of Exhaled Nitric Oxide Predicts New-Onset Wheeze in a General Population   Olin   AJRCCM  2010;181:324...
18.8 New-onset No onset 20 – 15 – 10 – 0 5 – 0  15.8 Increased Fraction of Exhaled Nitric Oxide Predicts New-Onset Wheeze ...
2.8 ≥  90 percentile 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0  3.2 <ul><li>2,200 men and women from a general pop...
Adulthood asthma after wheezing in infancy:  a questionnaire study at 27 years of age M. Ruotsalainen,   Allergy 2010;65;5...
Adulthood asthma after wheezing in infancy:  a questionnaire study at 27 years of age M. Ruotsalainen,   Allergy 2010;65;5...
Remitting Periodic Persistent 55% 39% 6% Predictors of remitting, periodic, and persistent childhood asthma  Covar  JACI 2...
Remitting Periodic Persistent 55% 39% 6% Predictors of remitting, periodic, and persistent childhood asthma  Covar  JACI 2...
55% Percentages of remitting, periodic, and persistent asthma evaluated in the follow-up phase in CAMP were similar for th...
55% Percentages of remitting, periodic, and persistent asthma evaluated in the follow-up phase in CAMP were similar for th...
FEATURES  AT ENTRY INTO CAMP  ASSOCIATED WITH   REMITTING  VERSUS PERSISTENT ASTHMA ( OR )  3.23 lack of allergen sensitiz...
55% Distribution of CAMP participants with remitting ( blue ), periodic ( purple ), and persistent ( red ) course by age a...
<ul><li>28 children with  remission asthma.  </li></ul><ul><li>25 with intermittent adolescent asthma.  </li></ul><ul><li>...
Values for the cumulative dose of methacholine at the inflection point of respiratory resistance (Dmin) and the slope of t...
Values for the cumulative dose of methacholine at the inflection point of respiratory resistance (Dmin) and the slope of t...
Values for the cumulative dose of methacholine at the inflection point of respiratory resistance (Dmin) and the slope of t...
Asthma Origins
<ul><li>European Community Respiratory Health Survey  participants aged 20–45 years randomly selected  from general popula...
% subjects with one or more childhood disadvantage factors 40% 40 – 30 – 20 – 10 – 0 associated with   lower FEV 1 at age ...
OR for FEV 1 /FVC ≤ 70% 1.7 6.3 1 1 7.2 ≥ 3 1.6 ≥ 3 n°FACTORS IN MEN n°FACTORS IN WOMEN 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 ...
OR for FEV 1 /FVC ≤ 70% 1.7 6.3 1 1 7.2 ≥ 3 1.6 ≥ 3 n°FACTORS IN MEN n°FACTORS IN WOMEN 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 ...
Associations of chronic obstructive pulmonary disease (COPD)* with  (A)  individual childhood disadvantage factors and  (B...
Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund  Thorax 2010;65:146...
Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund  Thorax 2010;65:146...
Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund  Thorax 2010;65:146...
Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund  Thorax 2010;65:146...
<ul><li>COPD is a disease of childhood that becomes manifest in  adults. </li></ul><ul><li>Combining  paediatric risk fact...
<ul><li>Some asthma phenotypes in children do look like COPD  in that they seem to be related to ‘‘irritant’’ exposure and...
Non-atopic intrinsic asthma and the 'family tree'  of chronic respiratory disease syndromes   Holt  CEA  2009;39:807  Chro...
Non-atopic intrinsic asthma and the 'family tree'  of chronic respiratory disease syndromes   Holt  CEA  2009;39:807  Chro...
Non-atopic intrinsic asthma and the 'family tree'  of chronic respiratory disease syndromes   Holt  CEA  2009;39:807  Chro...
Non-atopic intrinsic asthma and the 'family tree'  of chronic respiratory disease syndromes   Holt  CEA  2009;39:807  Chro...
Perinatal Risk factors
Vacuum-assisted delivery is associated with late-onset asthma .  Keski-Nisula  Allergy 2009:64:1530  <ul><li>Perinatal dat...
Vacuum-assisted delivery is associated with late-onset asthma .  Keski-Nisula  Allergy 2009:64:1530  <ul><li>This was not ...
Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case–control ...
Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case–control ...
Asthma and viruses
Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year...
Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year...
Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year...
Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year...
In vitro susceptibility to rhinovirus infection is greater for bronchial than for nasal airway epithelial cells in human s...
INFECTED WITH HRV-16 Degree of infection evaluated 48 hours late Cells from inferior turbinates  Cells from bronchial tree...
  Immunocytochemistry for rhinovirus RNA (HRV-16)  Micrograph of noninfected control HBE cells showing  no HRV-16.  Microg...
Multiplex Molecular Detection of Respiratory Pathogens  in Children With Asthma Exacerbation  Ting Fan Leung  Chest 2010;1...
Multiplex Molecular Detection of Respiratory Pathogens  in Children With Asthma Exacerbation  Ting Fan Leung  Chest 2010;1...
<ul><li>939 children </li></ul><ul><li>primary child care setting as an infant (before 15 months)  </li></ul><ul><li>and a...
<ul><li>939 children </li></ul><ul><li>primary child care setting as an infant (before 15 months)  </li></ul><ul><li>and a...
Asthma and bacteria,  atypical bacteria
A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prost...
A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prost...
A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prost...
Ovalbumin induced asthma Low-dose Mp in allergic mice significantly enhanced IL-4 and eotaxin-2, and lung eosinophilia.  I...
A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prost...
Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . ...
Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . ...
Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . ...
Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . ...
Is intrinsic asthma synonymous with infection? Dahlberg  Clinical & Experimental Allergy 2009;39:1324 Rackemann described ...
Is intrinsic asthma synonymous with infection? Dahlberg  Clinical & Experimental Allergy 2009;39:1324 Respiratory tract in...
Is intrinsic asthma synonymous with infection? Dahlberg  Clinical & Experimental Allergy 2009;39:1324 Intrinsic asthma may...
<ul><li>Impaired killing of respiratory pathogens phagocytosed  by macrophages can be resolved in vitro with calcitriol ad...
Cleaning  Indoor and Outdoor pollution as Risk factors
Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults   Zock JACI 2009;124:731  <u...
Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults   Zock JACI 2009;124:731  <u...
Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults   Zock JACI 2009;124:731  <u...
1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5   OR  for <ul><li>Prospective bi...
la prevalenza  misura la proporzione di &quot;eventi&quot; presenti in una popolazione  in un dato momento .  l'incidenza ...
1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5   OR  for <ul><li>Prospective bi...
1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5   OR  for <ul><li>Prospective bi...
Exposure to Traffic-related Particles and Endotoxin during Infancy Is Associated with Wheezing at Age 3 Years   Ryan   AJR...
Exposure to Traffic-related Particles and Endotoxin during Infancy Is Associated with Wheezing at Age 3 Years   Ryan   AJR...
Vehicle exhaust outside the home and onset of asthma among adults  L. Modig E R J 2009; 33:1261 <ul><li>Three Swedish citi...
Improved Biomass Stove Intervention in Rural Mexico Romieu  Am. J. Respir. Crit. Care Med 2009;180:649 <ul><li>Households ...
Improved Biomass Stove Intervention in Rural Mexico Romieu  Am. J. Respir. Crit. Care Med 2009;180:649 <ul><li>Households ...
TWO REPRESENTATIVE HOUSEHOLD KITCHEN MEXICO  Patsari chimney wood stove  Open wood fire  Improved Biomass Stove Interventi...
Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study  Hoppin  ERJ 2009:34:1296  <ul><l...
Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study  Hoppin  ERJ 2009:34:1296  <ul><l...
Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study  Hoppin  ERJ 2009:34:1296  <ul><l...
Background:  Ambient fine particles (particular matter <2.5 µm diameter [PM 2.5 ]) and ozone exacerbate respiratory condit...
Children age  6 to 18 years consistently had the highest risk.  Age-related association of fine particles and ozone with s...
for each 12µg/m 3  increase in  PM 2.5   % increase in children  6-18 years  in 26% ICU admission 19% Hospital admission 3...
for each 22ppb   increase in  ozone   % increase in children  6-18 years  in 19% ICU admission 20% Hospital admission 20 –...
for each 22ppb   increase in  ozone   % increase in children  6-18 years  in 19% ICU admission 20% Hospital admission 20 –...
Do Endotoxin and Air Pollution Have a Synergistic Relationship to Asthma Onset or Exacerbation?   Editorial Delfino   AJRC...
<ul><li>Studies using diesel exhaust particles have suggested that acute  exacerbations of asthma from air pollutant expos...
 
Acute effects of outdoor air pollution on FEV 1 :  a panel study of schoolchildren with asthma .  Dales  ERJ 2009:34:316  ...
Acute effects of outdoor air pollution on FEV 1 :  a panel study of schoolchildren with asthma .  Dales  ERJ 2009:34:316  ...
Increased Levels of Outdoor Air Pollutants Are Associated With Reduced Bronchodilation in Children With Asthma  Hernàndez-...
Increased Levels of Outdoor Air Pollutants Are Associated With Reduced Bronchodilation in Children With Asthma  Hernàndez-...
Asthma red-ox
Role of Oxidative Stress in Ultrafine Particle–induced Exacerbation of Allergic Lung Inflammation Alessandrini   Am J Resp...
Role of Oxidative Stress in Ultrafine Particle–induced Exacerbation of Allergic Lung Inflammation Alessandrini   Am J Resp...
Role of Oxidative Stress in Ultrafine Particle–induced Exacerbation of Allergic Lung Inflammation Alessandrini   Am J Resp...
Role of Oxidative Stress in Ultrafine Particle–induced Exacerbation of Allergic Lung Inflammation Alessandrini   Am J Resp...
Association between antioxidant vitamins and asthma outcome measures: systematic review and meta-analysis   Allen  Thorax ...
Association between antioxidant vitamins and asthma outcome measures: systematic review and meta-analysis   Allen  Thorax ...
Higher serum folate levels are associated  with a lower risk of atopy and wheeze Matsui  JACI 2009;123:1253  <ul><li>Serum...
Higher serum folate levels are associated  with a lower risk of atopy and wheeze Matsui  JACI 2009;123:1253  <ul><li>Serum...
Higher serum folate levels are associated  with a lower risk of atopy and wheeze Matsui  JACI 2009;123:1253  <ul><li>folic...
Higher serum folate levels are associated  with a lower risk of atopy and wheeze Matsui  JACI 2009;123:1253  <ul><li>One p...
Higher serum folate levels are associated  with a lower risk of atopy and wheeze Matsui  JACI 2009;123:1253  <ul><li>One p...
Has mandatory folic acid supplementation of foods increased the risk of asthma and allergic disease? Ownby  JACI 2009;123:...
Histone deacetylase-2 and airway disease. Barnes PJ. Ther Adv Respir Dis. 2009;3:235-43.   The  increased expression of in...
Histone deacetylase-2 and airway disease. Barnes PJ. Ther Adv Respir Dis. 2009;3:235-43.   The  increased expression of in...
<ul><li>allergens / atopy </li></ul>
% families with cat at age 2 years Childhood asthma and early life exposure to indoor allergens, endotoxin and  β (1,3)-gl...
The predicted probability of current asthma at age 10 among boys and girls based on risk calculation [odds ratio (OR)] per...
The predicted probability of current asthma at age 10 among boys and girls based on risk calculation [odds ratio (OR)] per...
The predicted probability of current asthma at age 10 among boys and girls based on risk calculation [odds ratio (OR)] per...
<ul><li>6 asthmatic with  dual sensitization  to house dust mite (HDM) and grass pollen (GP) </li></ul><ul><li>challenge w...
The allergen specificity of the late asthmatic reaction M. Hatzivlassiou,   Allergy 2010;65;355 Percentage change in FEV 1...
% fall in FEV 1  during late asthmatic reactions (LAR) The allergen specificity of the late asthmatic reaction M. Hatzivla...
% eosinophils in sputum The allergen specificity of the late asthmatic reaction M. Hatzivlassiou,   Allergy 2010;65;355 30...
Household airborne Penicillium associated with peak expiratory flow variability in asthmatic children   Bundy  Ann Allergy...
2.4 OR  for PEF  Variability >18.5% In Houses with  Penicillium 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 Household airborne Penicil...
2.4 OR  for PEF  Variability >18.5% In Houses with  Penicillium 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 Household airborne Penicil...
House Dust Mite–Promoted Epithelial-to-Mesenchymal Transition in Human Bronchial Epithelium Heijink   AJRCMB 2010;42:69   ...
House Dust Mite–Promoted Epithelial-to-Mesenchymal Transition in Human Bronchial Epithelium Heijink   AJRCMB 2010;42:69   ...
The non-proteolytic house dust mite allergen Der p2 induce NF- κ B and MAPK dependent activation of bronchial epithelial c...
The non-proteolytic house dust mite allergen Der p2 induce NF- κ B and MAPK dependent activation of bronchial epithelial c...
The non-proteolytic house dust mite allergen Der p2 induce NF- κ B and MAPK dependent activation of bronchial epithelial c...
<ul><li>Food allergy and asthma </li></ul>
Obesity
Obesity and allergic disease: closely related epidemics of the 21st century Warner   Pediatr Allergy Immunol 2009:20:305  ...
Relationship between infant weight gain and later asthma  Paul  Pediatr  Allergy Immunol 2010:21:82  <ul><li>Birth weight,...
Relationship between infant weight gain and later asthma  Paul  Pediatr  Allergy Immunol 2010:21:82  Relationship between ...
<ul><li>Birth weight, growth, pulmonary function, and symptom. </li></ul><ul><li>Ch. 2 and 3 years  of age at high-risk of...
Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens   JACI 2...
1.68 1.66 AT AGE 8 YEARS  OR  FOR Children who had a persistent  high body mass index  (BMI, weight/height 2 ) during chil...
1.68 1.66 AT AGE 8 YEARS  OR  FOR Children who had a persistent  high body mass index  (BMI, weight/height 2 ) during chil...
<ul><li>A common explanation for the increased asthma risk in overweight children is the  direct mechanical effect of an i...
<ul><li>Another reason for the increased asthma risk in overweight children might be the  immunologic changes  observed in...
<ul><li>Asthma might be overdiagnosed in obese with dyspnea. Misdiagnosis of asthma can result in inappropriate prescripti...
Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma   Vahlkvist   Allergy 2009...
Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma   Vahlkvist   Allergy 2009...
Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma   Vahlkvist   Allergy 2009...
Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma   Vahlkvist   Allergy 2009...
Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma   Vahlkvist   Allergy 2009...
Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma   Vahlkvist   Allergy 2009...
The role of physical activity and body mass index  in the health care use of adults with asthma  Dogra   Ann Allergy Asthm...
The role of physical activity and body mass index  in the health care use of adults with asthma  Dogra   Ann Allergy Asthm...
<ul><ul><li>Prevalence and severity of self-reported  asthma in young adults, 1976–2004   </li></ul></ul><ul><ul><li>Browa...
<ul><ul><li>Prevalence and severity of self-reported  asthma in young adults, 1976–2004   </li></ul></ul><ul><ul><li>Browa...
<ul><ul><li>Prevalence and severity of self-reported  asthma in young adults, 1976–2004   </li></ul></ul><ul><ul><li>Browa...
<ul><ul><li>Prevalence and severity of self-reported  asthma in young adults, 1976–2004   </li></ul></ul><ul><ul><li>Browa...
Obesity and obesity related co-morbidities in a referral population of children with asthma   Ross, Ped Pul 2009;44:877 <u...
<ul><li>116 asthmatic children ages 4-18 years. </li></ul><ul><li>Children obese (BMI ≥ 95th percentile). </li></ul><ul><l...
70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 23% 0% 0% 60% 33% Children with metabolic syndrome Snoring Obese Non obese Obese Non ...
70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 23% 0% 0% 60% 33% Children with metabolic syndrome Snoring Obese Non obese Obese Non ...
Definition of Metabolic Syndrome <ul><li>Subjects who met at least three of the following criteria were defined as having ...
% children > 85th percentile of BMI for age Asthma control, adiposity, and adipokines among inner-city adolescents  Kattan...
% children > 85th percentile of BMI for age 61.5% female 52.3% male Asthma control, adiposity, and adipokines among inner-...
<ul><li>Background: </li></ul><ul><li>Established indicators of central obesity include waist circumference, waist/height ...
<ul><li>Children with allergic rhinitis with (cases)  or without (control subjects) asthma  were recruited.  </li></ul>Com...
Comparison of anthropometric measures of obesity  in childhood allergic asthma: Central obesity is most relevant.  Musaad ...
Obesity, waist size and prevalence of current asthma in the California Teachers Study cohort   Von Behren  Thorax 2009;64:...
1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30 <ul><li>Of the ...
1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30 <ul><li>Of the ...
1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30 <ul><li>Of the ...
Asthma  other risk factors
Frequent nocturnal awakening in early life is associated with nonatopic asthma in children   Kozyrskyj   ERJ 2009:34:1288 ...
Frequent nocturnal awakening in early life is associated with nonatopic asthma in children   Kozyrskyj   ERJ 2009:34:1288 ...
<ul><li>While shorter duration of sleep has been linked to hyperactivity disorders and obesity in children, to the best of...
Asthma  protective factors
Effect of breastfeeding on asthma, lung function  and bronchial hyperreactivity in ISAAC Phase II Nagel  Eur Respir J 2009...
Effect of breastfeeding on asthma, lung function  and bronchial hyperreactivity in ISAAC Phase II Nagel  Eur Respir J 2009...
Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of a...
Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of a...
Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of a...
<ul><li>Lung interstitial macrophages  (IMs), a cell population with no previously described in vivo function,  prevent in...
<ul><li>Asma e bronchite cronica originano molto precocemente sotto l’influsso di infezioni, allergeni, fumo di sigaretta ...
<ul><li>Asma e bronchite cronica originano molto precocemente sotto l’influsso di infezioni, allergeni, fumo di sigaretta ...
ASTHMA BHR
Asthma pathogenesis
The  airway smooth muscle cell , as well as contracting and relaxing, produces myriad  inflammatory and growth factors  as...
The  airway smooth muscle cell , as well as contracting and relaxing, produces myriad  inflammatory and growth factors  as...
Intrinsic asthma: not so different from allergic asthma but driven by superantigens?   Barnes  C EA 2010;39:1145  Invasion...
Human airway smooth muscle promotes  eosinophil differentiation   Fanat  CEA  2010;39:1009  HASM cells stimulated signific...
Stimulated airway smooth muscle supernatant (ASMS) elicited an eosinophilopoietic response  by blood progenitors from (a) ...
Plasmacytoid dendritic cells during infancy  are inversely associated with childhood respiratory tract infections and whee...
Plasmacytoid dendritic cells during infancy  are inversely associated with childhood respiratory tract infections and whee...
<ul><li>The frequency of circulating pDCs was inversely correlated with LRIs, wheezing reported by a parent, and the cumul...
<ul><li>The frequency of circulating pDCs was inversely correlated with LRIs, wheezing reported by a parent, and the cumul...
Regulatory cells, cytokine pattern and clinical risk factors for asthma in infants and young children  with recurrent whee...
Regulatory cells, cytokine pattern and clinical risk factors for asthma in infants and young children  with recurrent whee...
Background:  Asthma phenotypes are well described among children. However, there are few studies comparing airway inflamma...
<ul><li>Atopic asthmatic  (AA) n = 28 </li></ul><ul><li>nonatopic asthmatics (NAA) n = 29  </li></ul><ul><li>nonatopic non...
Box plots of  absolute numbers of neutrophils  per gram of sputum.  Neutrophilic airway inflammation is a main feature of ...
AA, atopic asthma; NAA, nonatopic asthma; NANA, no asthma/no atopy.  *  Data expressed as median (minimum–maximum).    Si...
Relationship Between Amphiregulin and  Airway Inflammation in Children With  Asthma and Eosinophilic Bronchitis  Won Kim  ...
<ul><li>117 children with asthma </li></ul><ul><li>77with eosinophilic bronchitis (EB) </li></ul><ul><li>84 control subjec...
<ul><li>117 children with asthma </li></ul><ul><li>77with EB </li></ul><ul><li>84 control subjects </li></ul>Sputum amphir...
<ul><li>117 children with asthma </li></ul><ul><li>77with EB </li></ul><ul><li>84 control subjects </li></ul>Our findings ...
Tissue remodeling induced by hypersecreted epidermal growth factor  and amphiregulin in the airway after an acute asthma a...
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  1. 1. WHAT YOU SHOULD HAVE READ BUT….2010 <ul><li>asthma </li></ul>University of Verona, Italy Attilio Boner
  2. 2. Asthma phenotypes
  3. 3. Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams JACI 2009;124:463 <ul><li>1380 unselected 14-year-olds. </li></ul><ul><li>Clinical history, allergic sensitization, and respiratory function. </li></ul>% SUBJECTS 60% 60 – 50 – 40 – 30 – 20 – 10 – 0 ATOPIC ASTHMATIC 10%
  4. 4. Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams JACI 2009;124:463 <ul><li>1380 unselected 14-year-olds. </li></ul><ul><li>Clinical history, allergic sensitization, and respiratory function. </li></ul>% SUBJECTS 60% 60 – 50 – 40 – 30 – 20 – 10 – 0 ATOPIC ASTHMATIC 10% 81% of asthmatic subjects were also atopic.
  5. 5. Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams JACI 2009;124:463 <ul><li>1380 unselected 14-year-olds. </li></ul><ul><li>Clinical history, allergic sensitization, and respiratory and immunoinflammatory function. </li></ul>% SUBJECTS 60% 60 – 50 – 40 – 30 – 20 – 10 – 0 ATOPIC ASTHMATIC 10% 81% of asthmatic subjects were also atopic. BHR was associated strongly with atopic but not with nonatopic asthma, and the BHR risk profile was itself dominated by atopy-associated variables.
  6. 6. Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program Moore AJRCCM 2010;181:315 <ul><li>Severe Asthma Research Program cohort. </li></ul><ul><li>Cluster analysis was performed on 726 subjects. </li></ul>5 groups were identified. Subjects in Cluster 1 (n=110) have early onset atopic asthma with normal lung function treated with two or fewer controller medications (82%) and minimal health care utilization. Cluster 2 (n=321) consists of subjects with early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization.
  7. 7. Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program Moore AJRCCM 2010;181:315 <ul><li>Severe Asthma Research Program cohort. </li></ul><ul><li>Cluster analysis was performed on 726 subjects. </li></ul>Cluster 3 (n=59) is a unique group of mostly older obese women with late-onset nonatopic asthma, moderate reductions in FEV 1 , and frequent oral corticosteroid use to manage exacerbations. Subjects in Clusters 4 (n=120) and 5 (n=116) have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids.
  8. 8. Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program Moore AJRCCM 2010;181:315 Using three variables (baseline FEV 1 [with a bronchodilator withhold], maximal &quot;Max&quot; FEV 1 after six to eight puffs of albuterol, and age of onset of asthma), subjects can be assigned to the five clusters that range from milder asthma (Cluster 1) to more severe disease (Clusters 4 and 5).
  9. 9. Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program Moore AJRCCM 2010;181:315 50 – 40 – 30 – 20 – 10 – 0 5 – 0 % Sputum: Eosinophils , Neutrophils 1 2 3 4 5 23.3% 33.3% 37.6% 34.7% 48.3% 0.7% 0.7% 1.9% 1.5% 1.2% Cluster
  10. 10. <ul><li>asthma natural history </li></ul>
  11. 11. Background: Clinicians have difficulty in diagnosing asthma in preschool children with suggestive symptoms. Objective: We sought to develop a clinical asthma prediction score for preschool children who have asthma-like symptoms for the first time. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri JACI 2009;124:903
  12. 12. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri JACI 2009;124:903 <ul><li>Birth cohort followed 3,963 children for 8 years . </li></ul><ul><li>Between 0 and 4 years of age, 2,171 (55%) children reported “wheezing,” “coughing at night without a cold,” or both. </li></ul><ul><li>Asthma was defined as wheezing, inhaled steroid prescription, or a doctor's diagnosis of asthma at both age 7 and 8 years of age. </li></ul>% Children with Symptoms at 0 to 4 Years of Age 11% HAD ASTHMA at 7 to 8 YEARS 11 – 10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0
  13. 13. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri JACI 2009;124:903 <ul><li>Male sex, </li></ul><ul><li>Post-term delivery, </li></ul><ul><li>Parental education </li></ul><ul><li>Inhaled medication, </li></ul><ul><li>Wheezing frequency, </li></ul><ul><li>Wheeze/dyspnea apart from colds, </li></ul><ul><li>Respiratory infections, </li></ul><ul><li>Eczema </li></ul>8 clinical parameters independently predicted asthma at 7 to 8 years of age:
  14. 14. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri JACI 2009;124:903 MALE SEX 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 1.7 POST-TERM DELIVERY MEDIUM/LOW PARENTAL EDUCATION ECZEMA 3 ≥ 4 2.5 1.5 2.1 1.5 2.3 OR FOR ASTHMA AT AGE 7-8 YEARS WHEEZING FREQUENCY TIMES/Y
  15. 15. Increased Fraction of Exhaled Nitric Oxide Predicts New-Onset Wheeze in a General Population Olin AJRCCM 2010;181:324 49 subjects reported new-onset wheeze <ul><li>2,200 men and women from a general population–based study. </li></ul><ul><li>Questionnaires, blood samples, pulmonary function tests, and F E NO. </li></ul><ul><li>Follow-up 4 years later. </li></ul>
  16. 16. 18.8 New-onset No onset 20 – 15 – 10 – 0 5 – 0 15.8 Increased Fraction of Exhaled Nitric Oxide Predicts New-Onset Wheeze in a General Population Olin AJRCCM 2010;181:324 Median Concentration of FeNO at Baseline ppb p=0.03 <ul><li>2,200 men and women from a general population–based study. </li></ul><ul><li>Questionnaires, blood samples, pulmonary function tests, and F E NO. </li></ul><ul><li>Follow-up 4 years later. </li></ul>Wheeze
  17. 17. 2.8 ≥ 90 percentile 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 3.2 <ul><li>2,200 men and women from a general population–based study. </li></ul><ul><li>Questionnaires, blood samples, pulmonary function tests, and F E NO. </li></ul><ul><li>Follow-up 4 years later. </li></ul>Increased Fraction of Exhaled Nitric Oxide Predicts New-Onset Wheeze in a General Population Olin AJRCCM 2010;181:324 OR for new-onset wheeze ≥ 95 percentile Baseline FeNO
  18. 18. Adulthood asthma after wheezing in infancy: a questionnaire study at 27 years of age M. Ruotsalainen, Allergy 2010;65;503 <ul><li>At the median age of 27.3 years </li></ul><ul><li>questionnaire to 59 study subjects hospitalized for wheezing at <24 months of age </li></ul><ul><li>population controls </li></ul>20% % subjects with doctor-diagnosed asthma controls 20 – 10 – 0 5% former bronchiolitis patients
  19. 19. Adulthood asthma after wheezing in infancy: a questionnaire study at 27 years of age M. Ruotsalainen, Allergy 2010;65;503 <ul><li>At the median age of 27.3 years </li></ul><ul><li>questionnaire to 59 study subjects hospitalized for wheezing at <24 months of age </li></ul><ul><li>population controls </li></ul>20% % subjects with doctor-diagnosed asthma controls 20 – 10 – 0 5% former bronchiolitis patients An increased asthma risk in early-life wheezers continues, even after many symptom-free years at school age, at least until 27 years of age
  20. 20. Remitting Periodic Persistent 55% 39% 6% Predictors of remitting, periodic, and persistent childhood asthma Covar JACI 2010;125:359 <ul><li>The Childhood Asthma Management Program ( CAMP ) in children with mild to moderate persistent asthma. </li></ul><ul><li>4.3 years treatment </li></ul><ul><li>4 years follow-up </li></ul><ul><li>909 participants. </li></ul>% ADOLESCENTS WITH 60 – 50 – 40 – 30 – 20 – 10 – 0 ASTHMA
  21. 21. Remitting Periodic Persistent 55% 39% 6% Predictors of remitting, periodic, and persistent childhood asthma Covar JACI 2010;125:359 <ul><li>The Childhood Asthma Management Program ( CAMP ) in children with mild to moderate persistent asthma. </li></ul><ul><li>4.3 years treatment </li></ul><ul><li>4 years follow-up </li></ul><ul><li>909 participants. </li></ul>60 – 50 – 40 – 30 – 20 – 10 – 0 anti-inflammatory treatment during the CAMP trial improved QoL, but………. % ADOLESCENTS WITH ASTHMA
  22. 22. 55% Percentages of remitting, periodic, and persistent asthma evaluated in the follow-up phase in CAMP were similar for the budesonide, nedocromil, and placebo–treated groups. Predictors of remitting, periodic, and persistent childhood asthma Covar JACI 2010;125:359
  23. 23. 55% Percentages of remitting, periodic, and persistent asthma evaluated in the follow-up phase in CAMP were similar for the budesonide, nedocromil, and placebo–treated groups. Predictors of remitting, periodic, and persistent childhood asthma Covar JACI 2010;125:359 Remission of asthma in adolescence is infrequent and not affected by 4 years of anti-inflammatory controller therapy.
  24. 24. FEATURES AT ENTRY INTO CAMP ASSOCIATED WITH REMITTING VERSUS PERSISTENT ASTHMA ( OR ) 3.23 lack of allergen sensitization and less exposure to indoor allergens milder asthma higher FEV 1 1.05 1.39 less BHR 3.5 - 3.0 - 2.5 - 2.0 - 1.5 - 1.0 - 0.5 - 0 2.01 P<0.0001 P=0.03 P=0.03 P<0.02 Predictors of remitting, periodic, and persistent childhood asthma Covar JACI 2010;125:359
  25. 25. 55% Distribution of CAMP participants with remitting ( blue ), periodic ( purple ), and persistent ( red ) course by age at the end of the observational phase (N=the number within the bars). The percentage of participants having remitting asthma did not increase with age , although the numbers of older adolescents were low. Predictors of remitting, periodic, and persistent childhood asthma Covar JACI 2010;125:359
  26. 26. <ul><li>28 children with remission asthma. </li></ul><ul><li>25 with intermittent adolescent asthma. </li></ul><ul><li>47 symptomatic adolescent. </li></ul><ul><li>60 younger children with symptomatic asthma. </li></ul><ul><li>Threshold of methacholine ( Dmin ) ( bronchial sensitivity ), and speed of bronchial constriction ( Sm ) ( bronchial reactivity ) were measured by methacholine inhalation challenge using the continuous oscillation method . </li></ul>Relationship between bronchial hyperreactivity and asthma remission during adolescence Mochizuki Ann Allergy Asthma Immunol 2009;103:201 Dmin , the cumulative dose of methacholine at the inflection point of the Rrs; and Sm , the slope of the methacholine Rrs dose-response curve. Sm Dmin The inflection point of respiratory resistance (Rrs) in methacholine inhalation challenge by the oscillation method.
  27. 27. Values for the cumulative dose of methacholine at the inflection point of respiratory resistance (Dmin) and the slope of the methacholine respiratory resistance dose-response curve (Sm) in 4 groups. Relationship between bronchial hyperreactivity and asthma remission during adolescence Mochizuki Ann Allergy Asthma Immunol 2009;103:201 Dmin = bronchial sensitivity Sm = speed of bronchial constriction (bronchial reactivity) adolescent asthma adolescent asthma
  28. 28. Values for the cumulative dose of methacholine at the inflection point of respiratory resistance (Dmin) and the slope of the methacholine respiratory resistance dose-response curve (Sm) in 4 groups. Adolescents with asthma remission showed no change in Dmin, whereas a significant decrease of Sm was observed (symptom-free but bronchial hyperresponsive asthma). Dmin = bronchial sensitivity Sm = speed of bronchial constriction (bronchial reactivity) adolescent asthma adolescent asthma
  29. 29. Values for the cumulative dose of methacholine at the inflection point of respiratory resistance (Dmin) and the slope of the methacholine respiratory resistance dose-response curve (Sm) in 4 groups. Relationship between bronchial hyperreactivity and asthma remission during adolescence Mochizuki Ann Allergy Asthma Immunol 2009;103:201 Sm = speed of bronchial constriction (bronchial reactivity) adolescent asthma
  30. 30. Asthma Origins
  31. 31. <ul><li>European Community Respiratory Health Survey participants aged 20–45 years randomly selected from general populations. </li></ul><ul><li>Spirometry in 1991–3 (n=13,359) and 9 years later (n=7,738). </li></ul>Early life origins of chronic obstructive pulmonary disease Svanes Thorax 2010;65:14–20 <ul><li>Maternal asthma, </li></ul><ul><li>Paternal asthma, </li></ul><ul><li>Childhood asthma, </li></ul><ul><li>Maternal smoking and </li></ul><ul><li>Childhood respiratory infections </li></ul>defined as ‘‘childhood disadvantage factors’’.
  32. 32. % subjects with one or more childhood disadvantage factors 40% 40 – 30 – 20 – 10 – 0 associated with lower FEV 1 at age 29-44 years Early life origins of chronic obstructive pulmonary disease Svanes Thorax 2010;65:14–20 <ul><li>maternal asthma, </li></ul><ul><li>paternal asthma, </li></ul><ul><li>childhood asthma, </li></ul><ul><li>maternal smoking </li></ul><ul><li>childhood r respiratory i infections </li></ul>
  33. 33. OR for FEV 1 /FVC ≤ 70% 1.7 6.3 1 1 7.2 ≥ 3 1.6 ≥ 3 n°FACTORS IN MEN n°FACTORS IN WOMEN 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 Early life origins of chronic obstructive pulmonary disease Svanes Thorax 2010;65:14–20
  34. 34. OR for FEV 1 /FVC ≤ 70% 1.7 6.3 1 1 7.2 ≥ 3 1.6 ≥ 3 n°FACTORS IN MEN n°FACTORS IN WOMEN 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 COPD increased with increasing childhood disadvantage Early life origins of chronic obstructive pulmonary disease Svanes Thorax 2010;65:14–20
  35. 35. Associations of chronic obstructive pulmonary disease (COPD)* with (A) individual childhood disadvantage factors and (B) with the number of childhood disadvantage factors. COPD defined as FEV 1 /FVC < 0.70 and FEV 1 < 80% predicted (A) (B) Early life origins of chronic obstructive pulmonary disease Svanes Thorax 2010;65:14–20
  36. 36. Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund Thorax 2010;65:146 <ul><li>Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 . </li></ul><ul><li>Information on asthma from parent-completed questionnaires at age 3-9 years. </li></ul>Prevalence of asthma according to birth weight in Danish twin pairs, 3-9 years of age.
  37. 37. Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund Thorax 2010;65:146 <ul><li>Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 . </li></ul><ul><li>Information on asthma from parent-completed questionnaires at age 3-9 years. </li></ul>Prevalence of asthma according to birth weight in Danish twin pairs, 3-9 years of age. This finding lends support to the “fetal origins hypothesis” suggesting undisclosed prenatal determinants for the risk of asthma.
  38. 38. Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund Thorax 2010;65:146 Birth characteristics of subjects with and without asthma in a sample of Danish twin pairs, 3-9 years of age.
  39. 39. Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund Thorax 2010;65:146 Birth characteristics of subjects with and without asthma in a sample of Danish twin pairs, 3-9 years of age. This finding lends support to the “fetal origins hypothesis” suggesting undisclosed prenatal determinants for the risk of asthma.
  40. 40. <ul><li>COPD is a disease of childhood that becomes manifest in adults. </li></ul><ul><li>Combining paediatric risk factors (such as a personal history of asthma , a parental history of asthma or early respiratory infections ) with early exposure to tobacco smoke resulted in a risk that rivalled or exceeded that seen from the traditional COPD risk factor of cigarette smoking. </li></ul><ul><li>While cigarette smoking remains an undeniable risk factor, it is clear that not all smokers have the same risk of developing COPD and its complications . </li></ul>COPD as a disease of children: hype or hope for better understanding? Mannino Thorax 2010; 65: 1-2
  41. 41. <ul><li>Some asthma phenotypes in children do look like COPD in that they seem to be related to ‘‘irritant’’ exposure and show some evidence of impaired lung function. </li></ul><ul><li>Some recent data support the finding that measures of lung function at a mean age of 2 months track into young adulthood. </li></ul><ul><li>Subjects entering adulthood with poor lung function are probably at an increased risk for developing COPD. </li></ul>COPD as a disease of children: hype or hope for better understanding? Mannino Thorax 2010; 65: 1-2
  42. 42. Non-atopic intrinsic asthma and the 'family tree' of chronic respiratory disease syndromes Holt CEA 2009;39:807 Chronic respiratory inflammatory diseases – a 'family tree' Inset A : Key Inset B : Proposed partial overlap between disease risk genotypes
  43. 43. Non-atopic intrinsic asthma and the 'family tree' of chronic respiratory disease syndromes Holt CEA 2009;39:807 Chronic respiratory inflammatory diseases – a 'family tree' Inset A : Key Inset B : Proposed partial overlap between disease risk genotypes Early respiratory tract infections and atopic sensitization during the preschool years are both independently associated with risk for asthma development, but the highest risk for persistent asthma is observed in children who experience both .
  44. 44. Non-atopic intrinsic asthma and the 'family tree' of chronic respiratory disease syndromes Holt CEA 2009;39:807 Chronic respiratory inflammatory diseases – a 'family tree' Inset A : Key Inset B : Proposed partial overlap between disease risk genotypes Severe exacerbations of NAA, similar to the situation in AA, are almost invariably triggered by virus infection but requiring a longer time scale to reach a similar clinical end point.
  45. 45. Non-atopic intrinsic asthma and the 'family tree' of chronic respiratory disease syndromes Holt CEA 2009;39:807 Chronic respiratory inflammatory diseases – a 'family tree' Inset A : Key Inset B : Proposed partial overlap between disease risk genotypes Inheritance of reduced lung function is a risk factor for severe, early onset COPD.
  46. 46. Perinatal Risk factors
  47. 47. Vacuum-assisted delivery is associated with late-onset asthma . Keski-Nisula Allergy 2009:64:1530 <ul><li>Perinatal data recorded during pregnancy and at the time of delivery. </li></ul><ul><li>5823 children born in Northern Finland in 1985–1986. </li></ul><ul><li>Self-administered questionnaires at the ages of 7 and 15–16 yrs and skin prick tests at the age of 15–16 yrs. </li></ul>LATE-ONSET ASTHMA In Children Delivered by Vacuum Extraction OR for 1.80 2.41 P<0.001 P<0.001 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 DOCTOR-DIAGNOSED ASTHMA AT ANY TIME
  48. 48. Vacuum-assisted delivery is associated with late-onset asthma . Keski-Nisula Allergy 2009:64:1530 <ul><li>This was not explained by maternal demographic variables such as age or parity, or longer duration of delivery, fetal size, lower neonatal Apgar scores or neonatal need for intensive treatment after birth. </li></ul><ul><li>What could be plausible reasons behind the increased tendency towards asthma in those children who were born by vacuum delivery? </li></ul><ul><li>Children born by vacuum or forceps extraction are more often exposed to intrapartal distress . </li></ul><ul><li>The levels of umbilical cord blood cortisol have been increased in those neonates. </li></ul>
  49. 49. Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case–control study Martel ERJ 2009:34:579 <ul><li>8,226 children of asthmatic mothers. </li></ul><ul><li>30,318 age-matched controls. </li></ul>In children whose mothers had moderate-to-severe uncontrolled asthma during pregnancy versus mild controlled asthma. 1.27 OR for ASTHMA 1.5 – 1.0 – 0.5 – 0
  50. 50. Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case–control study Martel ERJ 2009:34:579 <ul><li>8,226 children of asthmatic mothers. </li></ul><ul><li>30,318 age-matched controls. </li></ul>In children whose mothers had moderate-to-severe uncontrolled asthma during pregnancy versus mild controlled asthma. 1.27 OR for ASTHMA 1.5 – 1.0 – 0.5 – 0 A significant increase in asthma risk was demonstrated among children whose mothers had poor control and increased severity of asthma during pregnancy.
  51. 51. Asthma and viruses
  52. 52. Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up. Valkonen Allergy 2009:64:1359 Background:  Recent studies have suggested that rhinovirus -associated early wheezing is a greater risk factor for development of recurrent wheezing in children than is early wheezing associated with respiratory syncytial virus (RSV). We determined the development of recurrent wheezing in young children within 3 years after hospitalization for RSV or non-RSV bronchiolitis.
  53. 53. Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up. Valkonen Allergy 2009:64:1359 <ul><li>All children <2 years of age admitted because of bronchiolitis. </li></ul><ul><li>Nasopharyngeal aspirates for viral antigens for RSV, influenza A and B viruses, parainfluenza types 1, 2, and 3 viruses, and adenovirus. </li></ul>The age distribution of children hospitalized with RSV or non-RSV bronchiolitis RSV Non-RSV
  54. 54. Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up. Valkonen Allergy 2009:64:1359 <ul><li>All children <2 years of age admitted because of bronchiolitis. </li></ul><ul><li>Nasopharyngeal aspirates for viral antigens for RSV, influenza A and B viruses, parainfluenza types 1, 2, and 3 viruses, and adenovirus. </li></ul>Development of recurrent wheezing within 3 years
  55. 55. Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up. Valkonen Allergy 2009:64:1359 <ul><li>All children <2 years of age admitted because of bronchiolitis. </li></ul><ul><li>Nasopharyngeal aspirates for viral antigens for RSV, influenza A and B viruses, parainfluenza types 1, 2, and 3 viruses, and adenovirus. </li></ul>Children hospitalized with bronchiolitis caused by other viruses than RSV develop recurrent wheezing at substantially higher rates during a 3-year follow-up period Development of recurrent wheezing within 3 years
  56. 56. In vitro susceptibility to rhinovirus infection is greater for bronchial than for nasal airway epithelial cells in human subjects Lopez-Souza JACI 2009;123:1384 Background: Human rhinoviruses (HRVs) characteristically cause upper respiratory tract infection, but they also infect the lower airways, causing acute bronchitis and exacerbating asthma. Objective: Our purpose was to study ex vivo the differences in the response to HRV infection of nasal and bronchial epithelial cultures from the same healthy and asthmatic individuals using conditions favoring development of fully differentiated, pseudostratified mucociliary epithelium.
  57. 57. INFECTED WITH HRV-16 Degree of infection evaluated 48 hours late Cells from inferior turbinates Cells from bronchial tree <ul><li>Virus replicated more easily p<0.01 </li></ul><ul><li>A 20- to 30-fold greater viral load and number of infected cells </li></ul>In vitro susceptibility to rhinovirus infection is greater for bronchial than for nasal airway epithelial cells in human subjects Lopez-Souza JACI 2009;123:1384
  58. 58.   Immunocytochemistry for rhinovirus RNA (HRV-16) Micrograph of noninfected control HBE cells showing no HRV-16. Micrograph of infected HBE cells showing a high number of HRV-16–infected cells, some with condensed chromatin/nuclei (bright green). In vitro susceptibility to rhinovirus infection is greater for bronchial than for nasal airway epithelial cells in human subjects Lopez-Souza JACI 2009;123:1384
  59. 59. Multiplex Molecular Detection of Respiratory Pathogens in Children With Asthma Exacerbation Ting Fan Leung Chest 2010;137:348 <ul><li>209 children aged 3-18 years with asthma exacerbations </li></ul><ul><li>77 controls with stable asthma </li></ul><ul><li>Nested multiplex polymerase chain reaction was used to detect 20 different respiratory pathogens </li></ul>% subjects with (+) results 51.0% 60 – 50 - 40 - 30 – 20 – 10 - 0 Any respiratory pathogen
  60. 60. Multiplex Molecular Detection of Respiratory Pathogens in Children With Asthma Exacerbation Ting Fan Leung Chest 2010;137:348 <ul><li>209 children aged 3-18 years with asthma exacerbations </li></ul><ul><li>77 controls with stable asthma </li></ul><ul><li>Nested multiplex polymerase chain reaction was used to detect 20 different respiratory pathogens </li></ul>% subjects with (+) results 51.0% 60 – 50 - 40 - 30 – 20 – 10 - 0 Any respiratory pathogen Human rhinovirus infection was more common among children with asthma exacerbation ( OR = 2.38). All other pathogens or coinfections were not associated with asthmatic attacks.
  61. 61. <ul><li>939 children </li></ul><ul><li>primary child care setting as an infant (before 15 months) </li></ul><ul><li>and as a toddler </li></ul><ul><li>(16-36 months) </li></ul><ul><li>persistent or late-onset asthma by age 15 </li></ul>% children developing asthma by 15 yrs Risk of Childhood Asthma in Relation to the Timing of Early Child Care Exposures Gurka, J Ped 2009;155;781 Day care 30 – 20 – 10 – 0 18.8% 16.2% 14.6% no before 15 mo after 15 mo P<0.05
  62. 62. <ul><li>939 children </li></ul><ul><li>primary child care setting as an infant (before 15 months) </li></ul><ul><li>and as a toddler </li></ul><ul><li>(16-36 months) </li></ul><ul><li>persistent or late-onset asthma by age 15 </li></ul>% children developing asthma by 15 yrs Risk of Childhood Asthma in Relation to the Timing of Early Child Care Exposures Gurka, J Ped 2009;155;781 Living in a clean house 30 – 20 – 10 – 0 14.8% 24.7% NO YES P<0.05 X
  63. 63. Asthma and bacteria, atypical bacteria
  64. 64. A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prostaglandin E 2 pathway Wu , CEA 2009;39:1754 Background: Over 40% of chronic stable asthma patients have evidence of respiratory Mycoplasma pneumoniae (Mp) infection as detected by PCR, but not by serology and culture, suggesting that a low-level Mp is involved in chronic asthma. However, the role of such a low-level Mp infection in the regulation of allergic inflammation remains unknown. Objective: To determine the impact of a low-level Mp infection in mice with established airway allergic inflammation on allergic responses such as eosinophilia and chemokine eotaxin-2, and the underlying mechanisms [i.e. the prostaglandin E2 (PGE2) pathway] since PGE2 inhalation before an allergen challenge suppressed the eosinophil infiltration in human airways.
  65. 65. A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prostaglandin E 2 pathway Wu, CEA 2009;39:1754 Ovalbumin induced asthma IL-4 expression, bronchoalveolar lavage (BAL) eosinophil, eotaxin-2 and PGE 2 levels.
  66. 66. A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prostaglandin E 2 pathway Wu, CEA 2009;39:1754 Ovalbumin induced asthma Low-dose Mp in allergic mice significantly enhanced IL-4 and eotaxin-2, and lung eosinophilia. IL-4 expression, bronchoalveolar lavage (BAL) eosinophil, eotaxin-2 and PGE 2 levels.
  67. 67. Ovalbumin induced asthma Low-dose Mp in allergic mice significantly enhanced IL-4 and eotaxin-2, and lung eosinophilia. IL-4 expression, bronchoalveolar lavage (BAL) eosinophil, eotaxin-2 and PGE 2 levels. High-dose Mp significantly reduced lung eosinophilia and tended to decrease IL-4 and eotaxin-2. A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prostaglandin E 2 pathway Wu, CEA 2009;39:1754
  68. 68. A low dose of Mycoplasma pneumoniae infection enhances an established allergic inflammation in mice: the role of the prostaglandin E 2 pathway Wu, CEA 2009;39:1754 CFU, colony-forming unit; Mp, Mycoplasma pneumoniae; Sal, saline.
  69. 69. Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . Hales C EA 2010;39:1170 IgE antibody binding (ng/mL) to the major Der p 1 and Der p 2 in paired acute asthma and convalescent plasma samples for each individual (n=53). The number of children with undetectable IgE antibody is shown in parenthesis. <ul><li>53 HDM-allergic children who presented to the Emergency Department with acute asthma. </li></ul><ul><li>Peripheral blood samples within 24 h of presentation. </li></ul><ul><li>A further blood sample after the acute attack, when the child was clinically well. </li></ul>
  70. 70. Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . Hales C EA 2010;39:1170 <ul><li>53 HDM-allergic children who presented to the Emergency Department with acute asthma. </li></ul><ul><li>Peripheral blood samples within 24 h of presentation. </li></ul><ul><li>A further blood sample after the acute attack, when the child was clinically well. </li></ul>IgE antibody binding (ng/mL) to the outer membrane P6 antigen from Haemophilus influenzae for acute and convalescent plasma.
  71. 71. Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . Hales C EA 2010;39:1170 <ul><li>53 HDM-allergic children who presented to the Emergency Department with acute asthma. </li></ul><ul><li>Peripheral blood samples within 24 h of presentation. </li></ul><ul><li>A further blood sample after the acute attack, when the child was clinically well. </li></ul>IgE antibodies to the P6 bacterial antigen increased in 60% of sera during convalescence and for many children achieved titres as high as IgE titres to allergens. In contrast IgE anti-HDM titres declined during convalescence. IgE antibody binding (ng/mL) to the outer membrane P6 antigen from Haemophilus influenzae for acute and convalescent plasma.
  72. 72. Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . Hales C EA 2010;39:1170 <ul><li>53 HDM-allergic children who presented to the Emergency Department with acute asthma. </li></ul><ul><li>Peripheral blood samples within 24 h of presentation. </li></ul><ul><li>A further blood sample after the acute attack, when the child was clinically well. </li></ul>This provides further support for the concept of T-helper type 2 responses to bacterial antigens playing a role in asthma pathogenesis. IgE antibody binding (ng/mL) to the outer membrane P6 antigen from Haemophilus influenzae for acute and convalescent plasma.
  73. 73. Is intrinsic asthma synonymous with infection? Dahlberg Clinical & Experimental Allergy 2009;39:1324 Rackemann described the ‘intrinsic asthma’ population over 50 years ago as a unique subgroup that was characterized by onset of progressive loss of lung function beginning later in life , possibly after a respiratory infection. It has also been associated with a female predominance , aspirin-sensitive bronchospasm , and nasal polyposis . While the aetiology is not understood, we propose that persistent respiratory infections play a central role in the development of intrinsic asthma .
  74. 74. Is intrinsic asthma synonymous with infection? Dahlberg Clinical & Experimental Allergy 2009;39:1324 Respiratory tract infections incite established asthma and likely participate in the initiation of chronic allergic pulmonary inflammation in both infancy and adulthood
  75. 75. Is intrinsic asthma synonymous with infection? Dahlberg Clinical & Experimental Allergy 2009;39:1324 Intrinsic asthma may develop in individuals who are unable to eliminate an acute respiratory infection due to previously acquired subtle immune impairments .
  76. 76. <ul><li>Impaired killing of respiratory pathogens phagocytosed by macrophages can be resolved in vitro with calcitriol administration. </li></ul><ul><li>Oral supplementation in humans may also decrease symptomatic viral infections in a non-asthmatic population. </li></ul><ul><li>As vitamin D deficiency is highly prevalent in western societies, if infection is shown to play a causal role, vitamin D levels may prove to be a modifiable factor in preventing this disease. </li></ul>Is intrinsic asthma synonymous with infection? Dahlberg Clinical & Experimental Allergy 2009;39:1324
  77. 77. Cleaning Indoor and Outdoor pollution as Risk factors
  78. 78. Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults Zock JACI 2009;124:731 <ul><li>3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes. </li></ul><ul><li>Frequency of bleach use and information on respiratory symptoms. </li></ul>2.0 – 1.5 – 1.0 – 0.5 – 0 0.75 1.24 IN SUBJECTS USING BLEACH ≥4 DAYS/W OR for RESPIRATORY SYMPTOMS ALLERGY TO CAT
  79. 79. Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults Zock JACI 2009;124:731 <ul><li>3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes. </li></ul><ul><li>Frequency of bleach use and information on respiratory symptoms. </li></ul>2.0 – 1.5 – 1.0 – 0.5 – 0 0.75 1.24 IN SUBJECTS USING BLEACH ≥4 DAYS/W OR for RESPIRATORY SYMPTOMS ALLERGY TO CAT The use of bleach was not associated with indoor allergen concentrations.
  80. 80. Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults Zock JACI 2009;124:731 <ul><li>3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes. </li></ul><ul><li>Frequency of bleach use and information on respiratory symptoms. </li></ul>2.0 – 1.5 – 1.0 – 0.5 – 0 0.75 1.24 IN SUBJECTS USING BLEACH ≥4 DAYS/W OR for RESPIRATORY SYMPTOMS ALLERGY TO CAT People who clean their homes with hypochlorite bleach are less likely to be atopic but more likely to have respiratory symptoms.
  81. 81. 1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5 OR for <ul><li>Prospective birth cohort (n=3,863) </li></ul><ul><li>8-year-follow-up </li></ul>Traffic-related Air Pollution and the Development of Asthma and Allergies during the First 8 Years of Life Gehring AJRCCM 2010;181:596–603 2.0– 1.5– 1.0– 0.5– 0 ASTHMA at AGE 8 y
  82. 82. la prevalenza misura la proporzione di &quot;eventi&quot; presenti in una popolazione in un dato momento . l'incidenza misura la proporzione di &quot;nuovi eventi&quot; che si verificano in una popolazione in un dato lasso di tempo.
  83. 83. 1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5 OR for <ul><li>Prospective birth cohort (n=3,863) </li></ul><ul><li>8-year-follow-up </li></ul>Traffic-related Air Pollution and the Development of Asthma and Allergies during the First 8 Years of Life Gehring AJRCCM 2010;181:596–603 2.0– 1.5– 1.0– 0.5– 0 Exposure to traffic-related air pollution may cause asthma in children. ASTHMA at AGE 8 y
  84. 84. 1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5 OR for <ul><li>Prospective birth cohort (n=3,863) </li></ul><ul><li>8-year-follow-up </li></ul>Traffic-related Air Pollution and the Development of Asthma and Allergies during the First 8 Years of Life Gehring AJRCCM 2010;181:596–603 2.0– 1.5– 1.0– 0.5– 0 No associations were found with atopic eczema, allergic sensitization, and BHR. ASTHMA at AGE 8 y
  85. 85. Exposure to Traffic-related Particles and Endotoxin during Infancy Is Associated with Wheezing at Age 3 Years Ryan AJRCCM 2009:180:1068 <ul><li>Persistent wheezing at age 36 months in a high-risk birth cohort. </li></ul><ul><li>Average exposure to traffic-related particles. </li></ul><ul><li>Indoor levels of endotoxin. </li></ul>Exposure to increased levels of traffic-related particles (≥75th percentile) before age 12 months. Coexposure to endotoxin Or for Persistent Non Allergic Wheezing at Age 36 Months 6.0 – 5.0 – 4.0 – 3.0 – 2.0 – 1.0 – 0 1.75 5.85 +
  86. 86. Exposure to Traffic-related Particles and Endotoxin during Infancy Is Associated with Wheezing at Age 3 Years Ryan AJRCCM 2009:180:1068 <ul><li>Persistent wheezing at age 36 months in a high-risk birth cohort. </li></ul><ul><li>Average exposure to traffic-related particles. </li></ul><ul><li>Indoor levels of endotoxin. </li></ul>Exposure to increased levels of traffic-related particles (≥75th percentile) before age 12 months. Coexposure to endotoxin Or for Persistent Non Allergic Wheezing at Age 36 Months 6.0 – 5.0 – 4.0 – 3.0 – 2.0 – 1.0 – 0 1.75 5.85 The association between traffic-related particle exposure and persistent wheezing at age 36 months is modified by exposure to endotoxin. This finding supports prior toxicological studies demonstrating a synergistic production of reactive oxygen species after coexposure to diesel exhaust particles and endotoxin. +
  87. 87. Vehicle exhaust outside the home and onset of asthma among adults L. Modig E R J 2009; 33:1261 <ul><li>Three Swedish cities. </li></ul><ul><li><50 m distance to nearest major road as a more simple indicator of exposure. </li></ul><ul><li>3,609 participants. </li></ul>3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 2.92 OR for new onset of asthma Living <50 m from a major Rood
  88. 88. Improved Biomass Stove Intervention in Rural Mexico Romieu Am. J. Respir. Crit. Care Med 2009;180:649 <ul><li>Households were randomized to receive the Patsari stove or keep their traditional open fire. </li></ul><ul><li>552 women were followed with monthly visits over 10 months. </li></ul>1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0 0.77 0.29 RELATIVE RIGH FOR Respiratory Symptoms Wheezing In women who use a stove instead of open fire
  89. 89. Improved Biomass Stove Intervention in Rural Mexico Romieu Am. J. Respir. Crit. Care Med 2009;180:649 <ul><li>Households were randomized to receive the Patsari stove or keep their traditional open fire. </li></ul><ul><li>552 women were followed with monthly visits over 10 months. </li></ul>1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0 0.77 0.29 RELATIVE RIGH FOR Respiratory Symptoms Wheezing In women who use a stove instead of open fire Actual use of the Patsari stove was associated with a lower FEV 1 decline (31 ml) compared with the open fire use (62 ml) over 1 year of follow-up ( P =0.012 ) for women 20 years of age and older
  90. 90. TWO REPRESENTATIVE HOUSEHOLD KITCHEN MEXICO Patsari chimney wood stove Open wood fire Improved Biomass Stove Intervention in Rural Mexico Romieu Am. J. Respir. Crit. Care Med 2009;180:649
  91. 91. Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study Hoppin ERJ 2009:34:1296 <ul><li>19,704 male farmers. </li></ul><ul><li>Defined as doctor-diagnosed asthma after the age of 20 yrs. </li></ul>IN SUBJECTS WITH HIGH PESTICIDE EXPOSURE EVENTS OR for Allergic and Nonallergic Asthma 2.2 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0
  92. 92. Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study Hoppin ERJ 2009:34:1296 <ul><li>19,704 male farmers. </li></ul><ul><li>Defined as doctor-diagnosed asthma after the age of 20 yrs. </li></ul>IN SUBJECTS WITH HIGH PESTICIDE EXPOSURE EVENTS OR for Allergic and Nonallergic Asthma 2.2 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 Pesticides may be an overlooked contributor to asthma risk among farmers.
  93. 93. Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study Hoppin ERJ 2009:34:1296 <ul><li>Grains, hays and animals have been identified as important aetiological agents for respiratory disease among farmers for. </li></ul><ul><li>Pesticides may also be a risk factor for asthma among farmers. </li></ul><ul><li>We saw associations with lifetime days of use of individual pesticides, suggesting an exposure–response relationship. </li></ul>
  94. 94. Background: Ambient fine particles (particular matter <2.5 µm diameter [PM 2.5 ]) and ozone exacerbate respiratory conditions including asthma. There is little documentation determining whether children are more vulnerable to the effects of ambient pollution than adults , or whether pollution causes life-threatening episodes requiring intensive care unit (ICU) admission . Objective: We investigate the relationship between severe asthma morbidity and PM 2.5 and ozone in the warm season, and determine whether there is an age-related susceptibility to pollution. Age-related association of fine particles and ozone with severe acute asthma in New York City Silverman JACI 2010;125:367
  95. 95. Children age 6 to 18 years consistently had the highest risk. Age-related association of fine particles and ozone with severe acute asthma in New York City Silverman JACI 2010;125:367 <ul><li>6008 asthma ICU admissions and 69,375 general (non-ICU) asthma admissions in 4 age groups (<6, 6-18, 19-49, and 50+ years) in 74 New York City hospitals for the months April to August from 1999 to 2006. </li></ul><ul><li>Risks were estimated for interquartile range increases in pollutants. </li></ul>
  96. 96. for each 12µg/m 3 increase in PM 2.5 % increase in children 6-18 years in 26% ICU admission 19% Hospital admission 30 - 25 - 20 - 15 - 10 - 5 - 0 Age-related association of fine particles and ozone with severe acute asthma in New York City Silverman JACI 2010;125:367 <ul><li>6008 asthma ICU admissions and 69,375 general (non-ICU) asthma admissions in 4 age groups (<6, 6-18, 19-49, and 50+ years) in 74 New York City hospitals for the months April to August from 1999 to 2006. </li></ul><ul><li>Risks were estimated for interquartile range increases in pollutants. </li></ul>
  97. 97. for each 22ppb increase in ozone % increase in children 6-18 years in 19% ICU admission 20% Hospital admission 20 – 15 – 10 – 5 – 0 Age-related association of fine particles and ozone with severe acute asthma in New York City Silverman JACI 2010;125:367 <ul><li>6008 asthma ICU admissions and 69,375 general (non-ICU) asthma admissions in 4 age groups (<6, 6-18, 19-49, and 50+ years) in 74 New York City hospitals for the months April to August from 1999 to 2006. </li></ul><ul><li>Risks were estimated for interquartile range increases in pollutants. </li></ul>
  98. 98. for each 22ppb increase in ozone % increase in children 6-18 years in 19% ICU admission 20% Hospital admission 20 – 15 – 10 – 5 – 0 Age-related association of fine particles and ozone with severe acute asthma in New York City Silverman JACI 2010;125:367 <ul><li>6008 asthma ICU admissions and 69,375 general (non-ICU) asthma admissions in 4 age groups (<6, 6-18, 19-49, and 50+ years) in 74 New York City hospitals for the months April to August from 1999 to 2006. </li></ul><ul><li>Risks were estimated for interquartile range increases in pollutants. </li></ul>Warm weather patterns of ozone and PM 2.5 disproportionately affect children with asthma and appear responsible for severe attacks that could have been avoided.
  99. 99. Do Endotoxin and Air Pollution Have a Synergistic Relationship to Asthma Onset or Exacerbation? Editorial Delfino AJRCCM 2009:180:1037 <ul><li>Studies using diesel exhaust particles have suggested that acute exacerbations of asthma from air pollutant exposures may occur in large part through oxidative stress from pollutant-induced generation of reactive oxygen or nitrogen species (ROS, RNS) either directly or through activation of neutrophils, alveolar macrophages, or respiratory epithelial cells. </li></ul><ul><li>Particulate and semivolatile components of air pollution from fossil fuel combustion have been shown to have prooxidant properties , including polycyclic aromatic hydrocarbons, quinones, and transition metals (e.g., Cu, Ni, and Zn). </li></ul><ul><li>Automobile exhaust produces a similar set of compounds. </li></ul>
  100. 100. <ul><li>Studies using diesel exhaust particles have suggested that acute exacerbations of asthma from air pollutant exposures may occur in large part through oxidative stress from pollutant-induced generation of reactive oxygen or nitrogen species (ROS, RNS) either directly or through activation of neutrophils, alveolar macrophages, or respiratory epithelial cells. </li></ul><ul><li>Particulate and semivolatile components of air pollution from fossil fuel combustion have been shown to have prooxidant properties , including polycyclic aromatic hydrocarbons, quinones, and transition metals (e.g., Cu, Ni, and Zn). </li></ul><ul><li>Automobile exhaust produces a similar set of compounds. </li></ul>This might explain the protective effect of anti-oxidants on the negative effects of pollutants Do Endotoxin and Air Pollution Have a Synergistic Relationship to Asthma Onset or Exacerbation? Editorial Delfino AJRCCM 2009:180:1037
  101. 102. Acute effects of outdoor air pollution on FEV 1 : a panel study of schoolchildren with asthma . Dales ERJ 2009:34:316 <ul><li>FEV 1 for 28 consecutive days in 182 elementary schoolchildren with physician-diagnosed asthma. </li></ul><ul><li>Ambient hourly air pollution concentrations. </li></ul>An interquartile range (IQR) increase (6.0 µg·m –3 ) in the previous 24-h PM 2.5 was associated with a 0.54% decrease in bedtime FEV 1 (p=0.027).
  102. 103. Acute effects of outdoor air pollution on FEV 1 : a panel study of schoolchildren with asthma . Dales ERJ 2009:34:316 <ul><li>FEV 1 for 28 consecutive days in 182 elementary schoolchildren with physician-diagnosed asthma. </li></ul><ul><li>Ambient hourly air pollution concentrations. </li></ul>An interquartile range (IQR) increase (6.0 µg·m –3 ) in the previous 24-h PM 2.5 was associated with a 0.54% decrease in bedtime FEV 1 (p=0.027). In children with asthma, relatively low concentrations of urban air pollution worsen lung function over a short period of time, even within a day. Of the pollutants measured, PM 2.5 appears to be the most important.
  103. 104. Increased Levels of Outdoor Air Pollutants Are Associated With Reduced Bronchodilation in Children With Asthma Hernàndez-Cadena CHEST 2009;136:1529 <ul><li>85 children with asthma </li></ul><ul><li>Outdoor air pollution exposure nitrogen dioxide (NO 2 ), </li></ul><ul><li>ozone (O 3 ) and [PM 2.5 ] levels </li></ul>0 - 5 – -10 – -15 – -15 % % REDUCED RESPONSE TO SABA FOR A SAME-DAY INTERQUARTILE INCREASE OF NO2 -11 % NO 2 NO EFFECT O 3 PM 2.5
  104. 105. Increased Levels of Outdoor Air Pollutants Are Associated With Reduced Bronchodilation in Children With Asthma Hernàndez-Cadena CHEST 2009;136:1529 <ul><li>85 children with asthma </li></ul><ul><li>Outdoor air pollution exposure nitrogen dioxide (NO 2 ), </li></ul><ul><li>ozone (O 3 ) and [PM 2.5 ] levels </li></ul>0 - 5 – -10 – -15 – -15 % % REDUCED RESPONSE TO SABA FOR A SAME-DAY INTERQUARTILE INCREASE OF NO2 -11 % NO 2 NO EFFECT O 3 PM 2.5 Recent exposure to NO 2 and possibly O 3 may reduce the response to SABAs in producing bronchodilation in children with asthma.
  105. 106. Asthma red-ox
  106. 107. Role of Oxidative Stress in Ultrafine Particle–induced Exacerbation of Allergic Lung Inflammation Alessandrini Am J Respir Crit Care Med 2009;179:984 Exposed to elemental carbon ultrafine particles (EC-UFPs) Exposed to filtered air immediately before allergen challenge and systemically treated with N-acetylcysteine or vehicle. In sensitized and challenged mice EC-UFP inhalation increased allergen-induced lung lipid peroxidation and NF- κ B activation in addition to inflammatory infiltrate, cytokine release, and airway hyperresponsiveness. Ovalbumin-sensitized mice
  107. 108. Role of Oxidative Stress in Ultrafine Particle–induced Exacerbation of Allergic Lung Inflammation Alessandrini Am J Respir Crit Care Med 2009;179:984 Exposed to elemental carbon ultrafine particles (EC-UFPs) Exposed to filtered air immediately before allergen challenge and systemically treated with N-acetylcysteine or vehicle. N-acetylcysteine treatment significantly reduced the adjuvant activity of EC-UFPs. In sensitized and challenged mice EC-UFP inhalation increased allergen-induced lung lipid peroxidation and NF- κ B activation in addition to inflammatory infiltrate, cytokine release, and airway hyperresponsiveness. Ovalbumin-sensitized mice
  108. 109. Role of Oxidative Stress in Ultrafine Particle–induced Exacerbation of Allergic Lung Inflammation Alessandrini Am J Respir Crit Care Med 2009;179:984 ( A ) Nonsensitized mice exposed for 24 hours to EC-UFPs (NS/UFP); ( B ) Sensitized and challenged mice exposed to filtered air (S/OVA); A B
  109. 110. Role of Oxidative Stress in Ultrafine Particle–induced Exacerbation of Allergic Lung Inflammation Alessandrini Am J Respir Crit Care Med 2009;179:984 C D ( C ) sensitized mice exposed to EC-UFP 24 hours before OVA challenge (S/UFP/OVA); ( D ) sensitized mice exposed to EC-UFP 24 hours before OVA challenge and treated with NAC (S/NAC/UFP/OVA).
  110. 111. Association between antioxidant vitamins and asthma outcome measures: systematic review and meta-analysis Allen Thorax 2009;64:610–619 <ul><li>40 studies </li></ul>Lower intakes levels vitamin C were also associated with an increased odds of asthma. (OR=1.21) Dietary vitamin A intake was significantly lower in people with asthma than in those without asthma (-182 μ g/day) and in people with severe asthma than in those with mild asthma (- 344 μ g/day).
  111. 112. Association between antioxidant vitamins and asthma outcome measures: systematic review and meta-analysis Allen Thorax 2009;64:610–619 <ul><li>40 studies </li></ul>Lower intakes levels vitamin C were also associated with an increased odds of asthma. (OR=1.21) Dietary vitamin A intake was significantly lower in people with asthma than in those without asthma (-182 μ g/day) and in people with severe asthma than in those with mild asthma (- 344 μ g/day). Vitamin E intake was generally unrelated to asthma status but was significantly lower in severe asthma than in mild asthma
  112. 113. Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253 <ul><li>Serum folate and total IgE levels. </li></ul><ul><li>8083 subjects 2 years of age and older. </li></ul>Distribution of serum total IgE levels across quintiles of serum folate. P < .001 for trend
  113. 114. Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253 <ul><li>Serum folate and total IgE levels. </li></ul><ul><li>8083 subjects 2 years of age and older. </li></ul>IgE LEVEL >100 KU/L ADJUSTED OR ASSOCIATED WITH THE FIFTH QUINTILE OF FOLATE RELATIVE TO THE FIRST QUINTILE 0.70 0.69 0.60 ATOPY WHEEZE 1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0
  114. 115. Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253 <ul><li>folic acid serves as a source for methyl donors for DNA methylation and thus is a particular dietary component that could directly influence the propensity for epigenetic modifications . </li></ul>
  115. 116. Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253 <ul><li>One particular dietary component that could directly influence the propensity for epigenetic modifications is folic acid , which serves as a source for methyl donors for DNA methylation . </li></ul><ul><li>The lower limit for a normal serum folate level is generally considered to be in the range of 3 to 4.5 ng/Ml. McDowell MA, NCHS data briefs no. 6. Selhub J, Food Nutr Bull. 2008;29 (suppl):S67–S73 </li></ul><ul><li>A level of greater than 26.5 ng/mL should be considered high. Morris MS, Am J Clin Nutr. 2007;85:193–200 </li></ul>
  116. 117. Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253 <ul><li>One particular dietary component that could directly influence the propensity for epigenetic modifications is folic acid , which serves as a source for methyl donors for DNA methylation . </li></ul><ul><li>The lower limit for a normal serum folate level is generally considered to be in the range of 3 to 4.5 ng/Ml. McDowell MA, NCHS data briefs no. 6. Selhub J, Food Nutr Bull. 2008;29 (suppl):S67–S73 </li></ul><ul><li>A level of greater than 26.5 ng/mL should be considered high. Morris MS, Am J Clin Nutr. 2007;85:193–200 </li></ul>DNA methylation involves the addition of a methyl group to DNA with the specific effect of reducing gene expression.
  117. 118. Has mandatory folic acid supplementation of foods increased the risk of asthma and allergic disease? Ownby JACI 2009;123:1260 <ul><li>Folate functions as an important cofactor in the transfer and use of 1-carbon moieties, primarily methyl groups. </li></ul><ul><li>Folic acid supplementation before and during pregnancy dramatically reduced the risk of neural-tube defects in newborns (85% reduction with 5000 μg of folic acid per day) </li></ul>
  118. 119. Histone deacetylase-2 and airway disease. Barnes PJ. Ther Adv Respir Dis. 2009;3:235-43. The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones , whereas histone deacetylase-2 (HDAC2) suppresses inflammatory gene expression . increased expression of inflammatory genes suppresses inflammatory gene expression
  119. 120. Histone deacetylase-2 and airway disease. Barnes PJ. Ther Adv Respir Dis. 2009;3:235-43. The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones , whereas histone deacetylase-2 (HDAC2) suppresses inflammatory gene expression . The reduction in HDAC2 appears to be secondary to increased oxidative stress in the lungs. Antioxidants such as curcumin may therefore restore corticosteroid sensitivity
  120. 121. <ul><li>allergens / atopy </li></ul>
  121. 122. % families with cat at age 2 years Childhood asthma and early life exposure to indoor allergens, endotoxin and β (1,3)-glucans Bertelsen CEA 2010;40:307 <ul><li>Concentrations of cat allergens from the homes of 260 two-year-old children with lung function measured at birth in Oslo. </li></ul><ul><li>At 10 years. </li></ul>6.5% 10 – 5 – 0
  122. 123. The predicted probability of current asthma at age 10 among boys and girls based on risk calculation [odds ratio (OR)] per increase in cat allergen exposure at age 2. asthma Childhood asthma and early life exposure to indoor allergens, endotoxin and β (1,3)-glucans Bertelsen CEA 2010;40:307 per 10 µg/g dust increase in cat allergen exposure at 2 years of age OR for 2 – 1 – 0 1.20 BHR 1.22
  123. 124. The predicted probability of current asthma at age 10 among boys and girls based on risk calculation [odds ratio (OR)] per increase in cat allergen exposure at age 2. asthma Childhood asthma and early life exposure to indoor allergens, endotoxin and β (1,3)-glucans Bertelsen CEA 2010;40:307 per 10 µg/g dust increase in cat allergen exposure at 2 years of age OR for 2 – 1 – 0 1.20 BHR 1.22 No association was seen with allergic sensitization.
  124. 125. The predicted probability of current asthma at age 10 among boys and girls based on risk calculation [odds ratio (OR)] per increase in cat allergen exposure at age 2. asthma Childhood asthma and early life exposure to indoor allergens, endotoxin and β (1,3)-glucans Bertelsen CEA 2010;40:307 per 10 µg/g dust increase in cat allergen exposure at 2 years of age OR for 2 – 1 – 0 1.20 BHR 1.22 In a community with a low prevalence of pet keeping and low mite allergen levels, exposure to cat allergens early in life increased the risk of late childhood asthma and BHR, but not the risk of allergic sensitization.
  125. 126. <ul><li>6 asthmatic with dual sensitization to house dust mite (HDM) and grass pollen (GP) </li></ul><ul><li>challenge with these allergens on 2 occasions separated by 14 days </li></ul>The allergen specificity of the late asthmatic reaction M. Hatzivlassiou, Allergy 2010;65;355 0 -10 – -20 – -30 - -25.8% -28% % fall in FEV 1 during early asthmatic reactions (EAR) MITE GRASS ns
  126. 127. The allergen specificity of the late asthmatic reaction M. Hatzivlassiou, Allergy 2010;65;355 Percentage change in FEV 1 from baseline over time following inhaled challenge <ul><li>6 asthmatic with dual sensitization to house dust mite (HDM) and grass pollen (GP) </li></ul><ul><li>challenge with these allergens on 2 occasions separated by 14 days </li></ul>EAR LAR
  127. 128. % fall in FEV 1 during late asthmatic reactions (LAR) The allergen specificity of the late asthmatic reaction M. Hatzivlassiou, Allergy 2010;65;355 0 -10 – -20 – -30 - -13% -22.8% MITE GRASS P=0.046 <ul><li>6 asthmatic with dual sensitization to house dust mite (HDM) and grass pollen (GP) </li></ul><ul><li>challenge with these allergens on 2 occasions separated by 14 days </li></ul>
  128. 129. % eosinophils in sputum The allergen specificity of the late asthmatic reaction M. Hatzivlassiou, Allergy 2010;65;355 30 – 20 – 10 – 0 MITE GRASS 11.0% 6.7% 5.4% 22.1% ns P=0.028 PRE PRE POST POST <ul><li>6 asthmatic with dual sensitization to house dust mite (HDM) and grass pollen (GP) </li></ul><ul><li>challenge with these allergens on 2 occasions separated by 14 days </li></ul>
  129. 130. Household airborne Penicillium associated with peak expiratory flow variability in asthmatic children Bundy Ann Allergy Asthma Immunol 2009;103:26 <ul><li>225 asthmatic c hildren (6-12 years). </li></ul><ul><li>Peak expiratory flow recorded twice daily during a 2-week period. </li></ul><ul><li>In-home airborne mold concentrations. </li></ul>Any mold 93% % of Houses with 72% 42% Cladosporium Penicillium 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 100 –
  130. 131. 2.4 OR for PEF Variability >18.5% In Houses with Penicillium 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 Household airborne Penicillium associated with peak expiratory flow variability in asthmatic children Bundy Ann Allergy Asthma Immunol 2009;103:26 <ul><li>225 asthmatic c hildren (6-12 years). </li></ul><ul><li>Peak expiratory flow recorded twice daily during a 2-week period. </li></ul><ul><li>In-home airborne mold concentrations. </li></ul>
  131. 132. 2.4 OR for PEF Variability >18.5% In Houses with Penicillium 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 Household airborne Penicillium associated with peak expiratory flow variability in asthmatic children Bundy Ann Allergy Asthma Immunol 2009;103:26 <ul><li>225 asthmatic c hildren (6-12 years). </li></ul><ul><li>Peak expiratory flow recorded twice daily during a 2-week period. </li></ul><ul><li>In-home airborne mold concentrations. </li></ul>Exposure to airborne Penicillium is associated with increased peak expiratory flow variability in asthmatic children.
  132. 133. House Dust Mite–Promoted Epithelial-to-Mesenchymal Transition in Human Bronchial Epithelium Heijink AJRCMB 2010;42:69 Human bronchial epithelium (16HBE cells) Fibrogenic cytokine TGF-β and protease-containing aeroallergen house dust mite induce epithelial-to-mesenchymal transition (EMT), a key process in tissue repair and remodeling +TGF- β TGF- β +
  133. 134. House Dust Mite–Promoted Epithelial-to-Mesenchymal Transition in Human Bronchial Epithelium Heijink AJRCMB 2010;42:69 Mesenchymal stem cells , or MSCs , are multipotent stem cells that can differentiate into a variety of cell types . Cell types that MSCs have been shown to differentiate in ex vivo cultures and in vitro or in vivo include: - osteoblasts (bone cells), - chondrocytes (cartilage cells) and - adipocytes (fat cells). Mesenchymal stem cells
  134. 135. The non-proteolytic house dust mite allergen Der p2 induce NF- κ B and MAPK dependent activation of bronchial epithelial cells . Österlund C EA 2010;39:1199 Der p2, a major non-proteolytic allergen of Dermatophagoides pteronyssinus , Human bronchial epithelial cell line BEAS-2B Dose-dependent up-regulation of: - granulocyte-macrophage colony-stimulating f factor (GMC-SF), - IL-6, IL-8, - monocyte-chemotactic protein-1 (MCP-1) - macrophage inflammatory protein-3 α - intercellular adhesion molecule (ICAM)-1.
  135. 136. The non-proteolytic house dust mite allergen Der p2 induce NF- κ B and MAPK dependent activation of bronchial epithelial cells . Österlund C EA 2010;39:1199 Der p2, a major non-proteolytic allergen of Dermatophagoides pteronyssinus , Human bronchial epithelial cell line BEAS-2B This non-proteolytic allergen, in addition to its immunogenic properties, can aggravate respiratory airway disease by adjuvant-like activation of the lung epithelium. Dose-dependent up-regulation of: - granulocyte-macrophage colony-stimulating f factor (GMC-SF), - IL-6, IL-8, - monocyte-chemotactic protein-1 (MCP-1) - macrophage inflammatory protein-3 α - intercellular adhesion molecule (ICAM)-1.
  136. 137. The non-proteolytic house dust mite allergen Der p2 induce NF- κ B and MAPK dependent activation of bronchial epithelial cells . Österlund C EA 2010;39:1199 Der p 2 ( μ g/mL) Der p 2 ( μ g/mL) Der p 2 ( μ g/mL)
  137. 138. <ul><li>Food allergy and asthma </li></ul>
  138. 139. Obesity
  139. 140. Obesity and allergic disease: closely related epidemics of the 21st century Warner Pediatr Allergy Immunol 2009:20:305 <ul><li>The modern allergy epidemic has followed a very similar demographic path to that of obesity and its associated metabolic syndrome. </li></ul><ul><li>There is also a remarkable concordance of the early life influences. </li></ul><ul><li>Like allergic disease, obesity also has its origins in fetal life (insulin resistance and other features of the metabolic syndrome) McMillen IC, Physiol Rev 2005: 85: 571–633. </li></ul><ul><li>A shift in the ratio of intakes of omega-6 to omega-3 polyunsaturated fatty acids has been related to the increase in prevalence of obesity and of course the same associations have been seen in relation to allergy. </li></ul>
  140. 141. Relationship between infant weight gain and later asthma Paul Pediatr Allergy Immunol 2010:21:82 <ul><li>Birth weight, growth, pulmonary function, and symptom. </li></ul><ul><li>Ch. 2 and 3 years of age at high-risk of developing persistent enrolled in the PEAK trial. Guilbert NEJM 2006;354:1985 </li></ul>Relationship between infant weight gain group and (a) systemic corticosteroid courses (p =0.01 overall group comparisons)
  141. 142. Relationship between infant weight gain and later asthma Paul Pediatr Allergy Immunol 2010:21:82 Relationship between infant weight gain group and scheduled physician visits (p <0.001 overall group comparisons) during the 3-yr study period. <ul><li>Birth weight, growth, pulmonary function, and symptom. </li></ul><ul><li>Ch. 2 and 3 years of age at high-risk of developing persistent enrolled in the PEAK trial. Guilbert NEJM 2006;354:1985 </li></ul>
  142. 143. <ul><li>Birth weight, growth, pulmonary function, and symptom. </li></ul><ul><li>Ch. 2 and 3 years of age at high-risk of developing persistent enrolled in the PEAK trial. Guilbert NEJM 2006;354:1985 </li></ul>Relationship between infant weight gain and later asthma Paul Pediatr Allergy Immunol 2010:21:82 Relationship between infant weight gain group and scheduled physician visits (p <0.001 overall group comparisons) during the 3-yr study period. fewer exacerbations occurred amongst those with a decelerated weight gain pattern.
  143. 144. Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens JACI 2009;123:1312 <ul><li>3756 children in a large birth cohort study. </li></ul><ul><li>Parents reported their children's weight and height, and wheeze, dyspnea, and prescription of ICS in yearly questionnaires. </li></ul>WHEEZED AT AGE 8 YEARS % CHILDREN 7.3% 9.6% 7.1% HAD DYSPNEA HAD ICS PRESCRIBED 10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0
  144. 145. 1.68 1.66 AT AGE 8 YEARS OR FOR Children who had a persistent high body mass index (BMI, weight/height 2 ) during childhood or a high BMI at 6 to 7 years 2.0 – 1.5 – 1.0 – 0.5 – 0 DYSPNEA BHR Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens JACI 2009;123:1312 <ul><li>3756 children in a large birth cohort study. </li></ul><ul><li>Parents reported their children's weight and height, and wheeze, dyspnea, and prescription of ICS in yearly questionnaires. </li></ul>
  145. 146. 1.68 1.66 AT AGE 8 YEARS OR FOR Children who had a persistent high body mass index (BMI, weight/height 2 ) during childhood or a high BMI at 6 to 7 years 2.0 – 1.5 – 1.0 – 0.5 – 0 DYSPNEA BHR Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens JACI 2009;123:1312 <ul><li>3756 children in a large birth cohort study. </li></ul><ul><li>Parents reported their children's weight and height, and wheeze, dyspnea, and prescription of ICS in yearly questionnaires. </li></ul>Children with a high BMI at a young age, but who developed a normal BMI at 6 to 7 years, did not have an increased risk of dyspnea or BHR at 8 years . BMI was not associated with sensitization.
  146. 147. <ul><li>A common explanation for the increased asthma risk in overweight children is the direct mechanical effect of an increased fat mass on lung function . </li></ul><ul><li>The observed increased risk of BHR in children with a high BMI might be explained by the low tidal volumes in overweight children . It has been put forward that, because of the low tidal volumes in overweight persons, airway responsiveness may be increased by changes in the airway smooth muscle . Tantisira KG Thorax. 2001;56(suppl 2):ii64–ii73; Beuther DA Am J Respir Crit Care Med. 2006;174:112–119 </li></ul>Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens JACI 2009;123:1312
  147. 148. <ul><li>Another reason for the increased asthma risk in overweight children might be the immunologic changes observed in overweight subjects. Overweight is increasingly viewed as a chronic state of low-grade systemic inflammation . White adipose tissue not only is a site of energy storage but also has endocrine functions, and it secretes several immunologic active factors. ( Kershaw EE, J Clin Endocrinol Metab. 2004; 89:2548–2556). Overweight has been associated with higher levels of leptin and proinflammatory cytokines such as TNF-α , IL-6 , IL-1β , and C-reactive protein . </li></ul>Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens JACI 2009;123:1312
  148. 149. <ul><li>Asthma might be overdiagnosed in obese with dyspnea. Misdiagnosis of asthma can result in inappropriate prescription of short-acting bronchodilators or corticosteroids in persons who are short of breath for obesity-related dyspnea that does not represent reversible airway obstruction. </li></ul><ul><li>For younger nonverbal children, parental report of physical signs (eg, increased respiratory rate, wheeze, and use of accessory muscles of ventilation ) is likely to be more reliable than report of a specific symptom, such as dyspnea . </li></ul><ul><li>The failure of Scholtens et al. to find a significant relationship between BMI and wheeze, BMI and inhaled corticosteroids, and BMI and rest dyspnea might support the hypothesis that the dyspnea being reported was primarily caused by factors other than asthma. </li></ul>Dyspnea in overweight children: Is it asthma? Editorial Schwartzstein JACI 2009;123:1319
  149. 150. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649 <ul><li>Cardiovascular fitness was measured by a maximal ergometer test using Tunturi E 85 electronic cycle ergometer (Accell Fitness, Turku, Finland). </li></ul><ul><li>The workload was increased every 3 min until exhaustion. </li></ul><ul><li>The start workload and increases in workload depended on the age, gender and bodyweight. </li></ul><ul><li>Criteria for exhaustion were at least two of the following three: (i) heart rate above 185 bpm; (ii) child unable to continue despite encouragement by observer; (iii) subjectively assessed by the observer. Hansen HS, Eur J Appl Physiol Occup Physiol 1989;58:618–624 </li></ul>
  150. 151. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649 <ul><li>Body composition was measured using DEXA using a Lunar Prodygry Advance densiometer (Scanex Medical Systems, Hoersholm, Denmark). </li></ul><ul><li>Total body mass, total fat, total lean tissue, bone mineral density (BMD) and age-matched z-score were measured. </li></ul>
  151. 152. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649 <ul><li>Daily physical activity measured using accelerometry. </li></ul><ul><li>Cardiovascular fitness and body composition. </li></ul><ul><li>57 children with newly diagnosed, untreated asthma and in 157 healthy age- controls. </li></ul>CARDIOVASCULAR FITNESS 35.1 39.3 ASTHMATIC 40 – 30 – 20 – 10 – 0 HEALTHY O 2 /min/kg p<0.001 CHILDREN
  152. 153. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649 <ul><li>Daily physical activity measured using accelerometry. </li></ul><ul><li>Cardiovascular fitness and body composition. </li></ul><ul><li>57 children with newly diagnosed, untreated asthma and in 157 healthy age- controls. </li></ul>BODY % FAT 22.8 19.5 ASTHMATIC 25 – 20 – 15 – 10 – 0 5 – 0 HEALTHY p<0.01 CHILDREN
  153. 154. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649 <ul><li>Daily physical activity measured using accelerometry. </li></ul><ul><li>Cardiovascular fitness and body composition. </li></ul><ul><li>57 children with newly diagnosed, untreated asthma and in 157 healthy age- controls. </li></ul>24.6 15.2 ASTHMATIC 25 – 20 – 15 – 10 – 0 5 – 0 HEALTHY p<0.05 % OVERWEIGHT CHILDREN CHILDREN
  154. 155. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649 <ul><li>Daily physical activity measured using accelerometry. </li></ul><ul><li>Cardiovascular fitness and body composition. </li></ul><ul><li>57 children with newly diagnosed, untreated asthma and in 157 healthy age- controls. </li></ul>24.6 15.2 ASTHMATIC 25 – 20 – 15 – 10 – 0 5 – 0 HEALTHY p<0.05 % OVERWEIGHT CHILDREN Children with untreated asthma are less fit and have a higher body per cent fat and frequency of obesity than their healthy peers. CHILDREN
  155. 156. The role of physical activity and body mass index in the health care use of adults with asthma Dogra Ann Allergy Asthma Immunol 2009;102:462 <ul><li>Adults with asthma (n=6,835) and without asthma (n=78,051). </li></ul><ul><li>Self-reported physical activities. </li></ul><ul><li>BMI ( kg/h 2 in metre) </li></ul>Overnight Hospital Stay Or in Inactive Asthmatic Patients versus Active Asthmatic Patients ≥ 3 Physician Consultations 1.68 1.23 2.0 – 1.5 – 1.0 – 0.5 – 0
  156. 157. The role of physical activity and body mass index in the health care use of adults with asthma Dogra Ann Allergy Asthma Immunol 2009;102:462 <ul><li>Adults with asthma (n=6,835) and without asthma (n=78,051). </li></ul><ul><li>Self-reported physical activities. </li></ul><ul><li>BMI weight in kilograms divided by height in meters squared. </li></ul>OR in Inactive/Obese Asthmatic Patients versus Active/Normal Weight Asthmatic Patients 2.35 2.76 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 Overnight Hospital Stay ≥ 3 Physician Consultations
  157. 158. <ul><ul><li>Prevalence and severity of self-reported asthma in young adults, 1976–2004 </li></ul></ul><ul><ul><li>Browatzki ERJ 2009:34:1046 </li></ul></ul><ul><li>Males and females aged 20–35 yrs were sampled from the population of Copenhagen for the three surveys (1976–1978, 1991–1993 and 2001–2004). </li></ul><ul><li>A total of 3,285 (46% male) subjects. </li></ul>A 1.5% 1976-1978 4.7% 6.9% Prevalence of Self-Reported Asthma 1991-1993 2001-2004 10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0
  158. 159. <ul><ul><li>Prevalence and severity of self-reported asthma in young adults, 1976–2004 </li></ul></ul><ul><ul><li>Browatzki ERJ 2009:34:1046 </li></ul></ul><ul><li>Males and females aged 20–35 yrs were sampled from the population of Copenhagen for the three surveys (1976–1978, 1991–1993 and 2001–2004). </li></ul><ul><li>A total of 3,285 (46% male) subjects. </li></ul>FEV 1 in asthmatics ( ) and non asthmatics ( ) at the three surveys.
  159. 160. <ul><ul><li>Prevalence and severity of self-reported asthma in young adults, 1976–2004 </li></ul></ul><ul><ul><li>Browatzki ERJ 2009:34:1046 </li></ul></ul><ul><li>Males and females aged 20–35 yrs were sampled from the population of Copenhagen for the three surveys (1976–1978, 1991–1993 and 2001–2004). </li></ul><ul><li>A total of 3,285 (46% male) subjects. </li></ul>From the 1991–1994 survey, increasing body mass index, especially >30 kg·m –2 , was associated with a lower percentage predicted FEV 1 (p 0.005). FEV 1 in asthmatics ( ) and non asthmatics ( ) at the three surveys.
  160. 161. <ul><ul><li>Prevalence and severity of self-reported asthma in young adults, 1976–2004 </li></ul></ul><ul><ul><li>Browatzki ERJ 2009:34:1046 </li></ul></ul><ul><li>Males and females aged 20–35 yrs were sampled from the population of Copenhagen for the three surveys (1976–1978, 1991–1993 and 2001–2004). </li></ul><ul><li>A total of 3,285 (46% male) subjects. </li></ul>The proportion of smokers declined from 60 to 38% (p<0.001). FEV 1 in asthmatics ( ) and non asthmatics ( ) at the three surveys.
  161. 162. Obesity and obesity related co-morbidities in a referral population of children with asthma Ross, Ped Pul 2009;44:877 <ul><li>116 asthmatic children ages 4-18 years. </li></ul><ul><li>Children obese (BMI ≥ 95th percentile). </li></ul><ul><li>Not obese (BMI <95th percentile). </li></ul>50 – 40 – 30 – 20 – 10 – 0 44% Asthmatic children who were obese
  162. 163. <ul><li>116 asthmatic children ages 4-18 years. </li></ul><ul><li>Children obese (BMI ≥ 95th percentile). </li></ul><ul><li>Not obese (BMI <95th percentile). </li></ul>Obese participants had: similar rates of atopy and family history of atopy, lung function, and asthma control at enrolment as their non-obese peers. Obesity and obesity related co-morbidities in a referral population of children with asthma Ross, Ped Pul 2009;44:877
  163. 164. 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 23% 0% 0% 60% 33% Children with metabolic syndrome Snoring Obese Non obese Obese Non obese Obesity and obesity related co-morbidities in a referral population of children with asthma Ross, Ped Pul 2009;44:877
  164. 165. 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 23% 0% 0% 60% 33% Children with metabolic syndrome Snoring Obese Non obese Obese Non obese Obesity and obesity related co-morbidities in a referral population of children with asthma Ross, Ped Pul 2009;44:877 Insufficient sleep and nocturnal desaturations tended to be more prevalent among obese subjects.
  165. 166. Definition of Metabolic Syndrome <ul><li>Subjects who met at least three of the following criteria were defined as having MetSyn: </li></ul><ul><li>waist circumference ≥90th percentile for age and sex; </li></ul><ul><li>triglycerides ≥110 mg/dl; </li></ul><ul><li>HDL ≤40 mg/dl; </li></ul><ul><li>fasting glucose ≥100 mg/dl; </li></ul><ul><li>mean systolic or diastolic blood pressure ≥90th </li></ul><ul><li>percentile for age, sex, and height. </li></ul>Obesity and obesity related co-morbidities in a referral population of children with asthma Ross, Ped Pul 2009;44:877
  166. 167. % children > 85th percentile of BMI for age Asthma control, adiposity, and adipokines among inner-city adolescents Kattan JACI 2010;125:584 <ul><li>368 adolescents with moderate-to-severe asthma . </li></ul><ul><li>Follow-up: 1 year. </li></ul><ul><li>Asthma symptoms exacerbations pulmonary function exhaled nitric oxide levels every 6 weeks. </li></ul><ul><li>Body mass index. </li></ul>61.5% female 52.3% male 80 – 60 – 40 – 20 – 0
  167. 168. % children > 85th percentile of BMI for age 61.5% female 52.3% male Asthma control, adiposity, and adipokines among inner-city adolescents Kattan JACI 2010;125:584 <ul><li>368 adolescents with moderate-to-severe asthma. </li></ul><ul><li>Follow-up: 1 year. </li></ul><ul><li>Asthma symptoms exacerbations pulmonary function exhaled nitric oxide levels every 6 weeks. </li></ul><ul><li>Body mass index. </li></ul>80 – 60 – 40 – 20 – 0 Higher BMI was associated with more symptom days (P =0.02) and exacerbations (P =0.06) and lower FEV 1 /FVC among female subjects only.
  168. 169. <ul><li>Background: </li></ul><ul><li>Established indicators of central obesity include waist circumference, waist/height ratio, and the conicity index. Studies using such measures (as opposed to body mass index [BMI] percentiles) to characterize the association between obesity and asthma are lacking, despite the fact that these measures have been shown to be most relevant for many other chronic diseases. </li></ul>Comparison of anthropometric measures of obesity in childhood allergic asthma: Central obesity is most relevant. Musaad JACI 2009;123:1321
  169. 170. <ul><li>Children with allergic rhinitis with (cases) or without (control subjects) asthma were recruited. </li></ul>Comparison of anthropometric measures of obesity in childhood allergic asthma: Central obesity is most relevant. Musaad JACI 2009;123:1321 <ul><li>Central obesity was associated with asthma, asthma severity, lower lung function, and reduced atopy in asthmatic subjects. </li></ul><ul><li>Measures of central obesity are more associated with the presence of asthma and asthma severity in children with allergic rhinitis when compared with standard BMI measures. </li></ul>
  170. 171. Comparison of anthropometric measures of obesity in childhood allergic asthma: Central obesity is most relevant. Musaad JACI 2009;123:1321 Health risks for obesity are most associated with fat distribution rather than body weight. Alternative measures that account for fat distribution include waist circumference, a measure of abdominal (central) obesity that, compared with BMI percentiles, better predicts risk for some diseases, such as cardiovascular disease. Similarly, waist/height ratio and the conicity index have been found to be more sensitive than BMI in predicting the risk for cardiovascular disease.
  171. 172. Obesity, waist size and prevalence of current asthma in the California Teachers Study cohort Von Behren Thorax 2009;64:889–893 Background: Obesity is a risk factor for asthma, particularly in women, but few cohort studies have evaluated abdominal obesity which reflects metabolic differences in visceral fat known to influence systemic inflammation. A study was undertaken to examine the relationship between the prevalence of asthma and measures of abdominal obesity and adult weight gain in addition to body mass index (BMI) in a large cohort of female teachers.
  172. 173. 1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30 <ul><li>Of the 88 304 women in the analyses. </li></ul><ul><li>(n=11 500) were obese (BMI ≥ 30 kg/m 2 ) at baseline. </li></ul><ul><li>1334 were extremely obese (BMI ≥ 40 kg/m 2 ). </li></ul>4 - 3 – 2 – 1 – 0 Obesity, waist size and prevalence of current asthma in the California Teachers Study cohort Von Behren Thorax 2009;64:889–893
  173. 174. 1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30 <ul><li>Of the 88 304 women in the analyses. </li></ul><ul><li>(n=11 500) were obese (BMI ≥ 30 kg/m 2 ) at baseline. </li></ul><ul><li>1334 were extremely obese (BMI ≥ 40 kg/m 2 ). </li></ul>4 - 3 – 2 – 1 – 0 Obesity, waist size and prevalence of current asthma in the California Teachers Study cohort Von Behren Thorax 2009;64:889–893 Large waist circumference (>88 cm) was associated with increased asthma prevalence, even among women with a normal BMI (OR 1.37)
  174. 175. 1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30 <ul><li>Of the 88 304 women in the analyses. </li></ul><ul><li>(n=11 500) were obese (BMI ≥ 30 kg/m 2 ) at baseline. </li></ul><ul><li>1334 were extremely obese (BMI ≥ 40 kg/m 2 ). </li></ul>4 - 3 – 2 – 1 – 0 Obesity, waist size and prevalence of current asthma in the California Teachers Study cohort Von Behren Thorax 2009;64:889–893 Visceral abdominal fat in proinflammatory and prothrombotic
  175. 176. Asthma other risk factors
  176. 177. Frequent nocturnal awakening in early life is associated with nonatopic asthma in children Kozyrskyj ERJ 2009:34:1288 <ul><li>A community-based birth cohort. </li></ul><ul><li>Followed up at years 1, 2, 3, 6, 8, 10 and 14. </li></ul><ul><li>Parent-completed questionnaires. </li></ul>In Children with Frequent Nocturnal Awakening During the First 3 Yrs OR for Non-Atopic Asthma at Age 6 and 14 Yrs 2.18 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0
  177. 178. Frequent nocturnal awakening in early life is associated with nonatopic asthma in children Kozyrskyj ERJ 2009:34:1288 <ul><li>A community-based birth cohort. </li></ul><ul><li>Followed up at years 1, 2, 3, 6, 8, 10 and 14. </li></ul><ul><li>Parent-completed questionnaires. </li></ul>In Children with Frequent Nocturnal Awakening During the First 3 Yrs OR for Non-Atopic Asthma at Age 6 and 14 Yrs 2.18 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 There was no effect on atopic asthma.
  178. 179. <ul><li>While shorter duration of sleep has been linked to hyperactivity disorders and obesity in children, to the best of our knowledge, this is the first report of frequent nocturnal awakening in early life and asthma development. </li></ul><ul><li>Several pro-inflammatory cytokines, such as IL-6, IL-1 and TNF- α , participate in sleep control. Two of these cytokines, IL-6 and TNF- α , are elevated in sleep-deprived adults. </li></ul><ul><li>TNF- α has been implicated in neutrophilic inflammation in neutrophilic airway inflammation has been observed in children with sleep apnoea. </li></ul>Frequent nocturnal awakening in early life is associated with nonatopic asthma in children Kozyrskyj ERJ 2009:34:1288
  179. 180. Asthma protective factors
  180. 181. Effect of breastfeeding on asthma, lung function and bronchial hyperreactivity in ISAAC Phase II Nagel Eur Respir J 2009;33:993 <ul><li>Cross-sectional studies in 27 centres in 20 countries. </li></ul><ul><li>Data from 54,000 randomly selected school children (aged 8–12 yrs, 31,759 with skin prick testing). </li></ul>OR for not atopic wheezing 0.87 AFFLUENT COUNTRIES 0.80 NON AFFLUENT COUNTRIES 1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0 any breast feeding
  181. 182. Effect of breastfeeding on asthma, lung function and bronchial hyperreactivity in ISAAC Phase II Nagel Eur Respir J 2009;33:993 <ul><li>Cross-sectional studies in 27 centres in 20 countries. </li></ul><ul><li>Data from 54,000 randomly selected school children (aged 8–12 yrs, 31,759 with skin prick testing). </li></ul>OR for not atopic wheezing 0.87 AFFLUENT COUNTRIES 0.80 NON AFFLUENT COUNTRIES 1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0 any breast feeding Breastfeeding was not associated with atopic wheeze and objective measures of allergy .
  182. 183. Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma Mabalirajan JACI 2010;125:626 Ovalbumin–sensitized and challenged mice. L-arginine significantly reduced AHR and airway inflammation including bronchoalveolar lavage fluid eosinophilia, T H 2 cytokines, TGF- β 1, goblet cell metaplasia, and subepithelial fibrosis. Different doses of L-arginine.
  183. 184. Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma Mabalirajan JACI 2010;125:626 Ovalbumin–sensitized and challenged mice. L-arginine significantly reduced AHR and airway inflammation including bronchoalveolar lavage fluid eosinophilia, T H 2 cytokines, TGF- β 1, goblet cell metaplasia, and subepithelial fibrosis. Different doses of L-arginine. Further, L-arginine increased exhaled nitric oxide levels and reduced the markers of nitro-oxidative stress such as nitrotyrosine, 8-isoprostane, and 8-hydroxy-2’-deoxyguanosine.
  184. 185. Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma Mabalirajan JACI 2010;125:626 Ovalbumin–sensitized and challenged mice. L-arginine significantly reduced AHR and airway inflammation including bronchoalveolar lavage fluid eosinophilia, T H 2 cytokines, TGF- β 1, goblet cell metaplasia, and subepithelial fibrosis. Different doses of L-arginine. This was associated with reduced activity and expression of arginase 1, increased expression of endothelial NOS, and reduction of inducible NOS in bronchial epithelia.
  185. 186. <ul><li>Lung interstitial macrophages (IMs), a cell population with no previously described in vivo function, prevent induction of a Th 2 response in mice challenged with LPS and an experimental harmless airborne antigen. </li></ul><ul><li>IMs, but not alveolar macrophages, were found to produce high levels of IL-10 and to inhibit LPS-induced maturation and migration of DCs loaded with the experimental harmless airborne antigen in an IL-10–dependent manner. </li></ul><ul><li>Specific in vivo elimination of IMs led to overt asthmatic reactions to innocuous airborne antigens inhaled with low doses of LPS. </li></ul>Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice Bedoret J Clin Inv 2009;119:3723
  186. 187. <ul><li>Asma e bronchite cronica originano molto precocemente sotto l’influsso di infezioni, allergeni, fumo di sigaretta e stress ossidativo. </li></ul><ul><li>L’asma è una malattia spesso persistente e la sua storia naturale non viene modificata dalla terapia. </li></ul><ul><li>Guariscono più facilmente i soggetti esposti a basse dosi di allergeni e con poche riacutizzazioni. </li></ul><ul><li>Alcuni allergeni sono più pericolosi in relazione alla loro attività come enzimi proteolitici. </li></ul><ul><li>Altri fattori di rischio sono: </li></ul><ul><li>Bronchiolite non da RSV </li></ul><ul><li>Obesità </li></ul><ul><li>Inquinamento indoor e outdoor </li></ul><ul><li>Deficit di sostanze anti-ossidanti </li></ul>Take home
  187. 188. <ul><li>Asma e bronchite cronica originano molto precocemente sotto l’influsso di infezioni, allergeni, fumo di sigaretta e stress ossidativo. </li></ul><ul><li>L’asma è una malattia spesso persistente e la sua storia naturale non viene modificata dalla terapia. </li></ul><ul><li>Guariscono più facilmente i soggetti esposti a basse dosi di allergeni e con poche riacutizzazioni. </li></ul><ul><li>Alcuni allergeni sono più pericolosi in relazione alla loro attività come enzimi proteolitici. </li></ul><ul><li>Altri fattori di rischio sono: </li></ul><ul><li>Bronchiolite non da RSV </li></ul><ul><li>Obesità </li></ul><ul><li>Inquinamento indoor e outdoor </li></ul><ul><li>Deficit di sostanze anti-ossidanti </li></ul>Sono in corso numerosi studi con sostanze anti-ossidanti nella terapia/prevenzione delle malatti respiratorie croniche Take home
  188. 189. ASTHMA BHR
  189. 190. Asthma pathogenesis
  190. 191. The airway smooth muscle cell , as well as contracting and relaxing, produces myriad inflammatory and growth factors as well as extracellular matrix proteins and adhesion molecules, which enable interactions with inflammatory cells. Asthma may arise from an intrinsic defect in the smooth muscle cell, which could then be the primary driver of inflammation and remodelling . Intrinsic asthma: is it intrinsic to the smooth muscle? Black CEA 2010;39:962
  191. 192. The airway smooth muscle cell , as well as contracting and relaxing, produces myriad inflammatory and growth factors as well as extracellular matrix proteins and adhesion molecules, which enable interactions with inflammatory cells. Asthma may arise from an intrinsic defect in the smooth muscle cell, which could then be the primary driver of inflammation and remodelling . Intrinsic asthma: is it intrinsic to the smooth muscle? Black CEA 2010;39:962 An abnormality in the airway smooth muscle cell, which is capable of producing inflammatory, immunological and growth factors as well as molecules, which facilitate interaction with inflammatory cells, is the primary or instigating event.
  192. 193. Intrinsic asthma: not so different from allergic asthma but driven by superantigens? Barnes C EA 2010;39:1145 Invasion of airway epithelial cells by Staphylococcus aureus (and other microorganisms) causes the release of Staphylococcal superantigens (Sag) (and other superantigens), which act on airway B lymphocytes to cause class-switching with the local production of polyclonal IgE, together with IgE directed against SSa (which acts as a 'superallergen'). This causes mast cell activation and release of bronchoconstrictor mediators .
  193. 194. Human airway smooth muscle promotes eosinophil differentiation Fanat CEA 2010;39:1009 HASM cells stimulated significant growth of eosinophil/basophil colony forming units (Eo/B CFUs) from blood progenitor cells from both groups of subjects. <ul><li>H uman airway smooth muscle (HASM) cells in culture synthesize cytokines and chemokines that may orchestrate the tissue homing and in situ differentiation of haemopoietic progenitor cells from the peripheral circulation. </li></ul><ul><li>Peripheral blood-derived progenitors from atopic asthmatics (n=12) and non-atopic controls (n=11). </li></ul>
  194. 195. Stimulated airway smooth muscle supernatant (ASMS) elicited an eosinophilopoietic response by blood progenitors from (a) normals (n=11) and (b) atopic asthmatics (n=12), optimal at 1/10 dilution. Eosinophil/basophil colony forming unit (Eo/B CFU) numbers. Human airway smooth muscle promotes eosinophil differentiation Fanat CEA 2010;39:1009
  195. 196. Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing Upham JACI 2009;124:707 DCs are a family of bone marrow–derived cells that can be separated into 2 major subgroups: conventional or myeloid DCs (mDCs) and plasmacytoid DCs (pDC). Animal models have highlighted the importance of mDCs in the pathogenesis of allergic airway inflammation, whereas pDCs appear to play a specialized role in host defense against viral infections at mucosal surfaces and in some circumstances might mediate immune tolerance.
  196. 197. Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing Upham JACI 2009;124:707 <ul><li>263 ch with </li></ul><ul><li>(+) FH of atopy. </li></ul><ul><li>Blood samples </li></ul><ul><li>at age 6 mo, 12 mo </li></ul><ul><li>and 5 years. </li></ul><ul><li>Flow cytometry. </li></ul><ul><li>SPTs. </li></ul>Circulating DC subsets during infancy and asthma diagnosed by a doctor up to age 5 years. Presence ( red bars , n = 13) or Absence ( blue bars , n = 39) of doctor-diagnosed asthma at age 5 years .
  197. 198. <ul><li>The frequency of circulating pDCs was inversely correlated with LRIs, wheezing reported by a parent, and the cumulative rate of asthma diagnosed by a doctor. </li></ul><ul><li>Thus fewer pDCs at 6 months of age, 12 months of age, or both was a risk factor for LRIs, asthma, and wheezing by age 5 years, whereas more frequent pDCs were correlated with relative protection against these clinical outcomes. </li></ul>Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing Upham JACI 2009;124:707
  198. 199. <ul><li>The frequency of circulating pDCs was inversely correlated with LRIs, wheezing reported by a parent, and the cumulative rate of asthma diagnosed by a doctor. </li></ul><ul><li>Thus fewer pDCs at 6 months of age, 12 months of age, or both was a risk factor for LRIs, asthma, and wheezing by age 5 years, whereas more frequent pDCs were correlated with relative protection against these clinical outcomes. </li></ul>Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing Upham JACI 2009;124:707 Animal models suggest that pDCs play a dual role in virus infections, providing important host defense against mucosal viral infections through their capacity to produce type I IFNs, such as IFN-α and IFN-β, and also by modulating the extent of inflammation and tissue damage induced by viruses.
  199. 200. Regulatory cells, cytokine pattern and clinical risk factors for asthma in infants and young children with recurrent wheeze Borrego C EA 2010;39:1160 <ul><li>Peripheral blood CD4 + CD25 + and CD4 + CD25 high T cells and their cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), GITR and Foxp3 expression were analysed by flow cytometry. </li></ul><ul><li>Cytokine (IFN-γ, TGF-β and IL-10), CTLA-4 and Foxp3 mRNA expression were evaluated (real-time PCR) after peripheral blood mononuclear cell stimulation with phorbol 12-myristate 13-acetate (PMA) (24 h) and house dust mite (HDM) extracts (7th day). </li></ul><ul><li>S ignificant reduction in the absolute number of CD4 + CD25 high in wheezy children compared with healthy controls. </li></ul><ul><li>Wheezy children at a high risk of developing asthma had a significantly lower absolute number of CD4 + CD25 + ( P =0.01) and CD4 + CD25 high ( P =0.04), compared with those at a low risk. </li></ul>
  200. 201. Regulatory cells, cytokine pattern and clinical risk factors for asthma in infants and young children with recurrent wheeze Borrego C EA 2010;39:1160 HC, healthy children; LRC, low risk for asthma wheezing children; HRC, high risk for asthma wheezing children.
  201. 202. Background:  Asthma phenotypes are well described among children. However, there are few studies comparing airway inflammation in different clinical presentations of pediatric asthma. We tested the hypothesis that nonatopic asthma is associated with a predominant noneosinophilic inflammation in the airways, as assessed by induced sputum. The objective of this study was to evaluate the cytological characteristics of induced sputum (IS) in atopic (AA), nonatopic asthmatics (NAA) and nonatopic nonasthmatic children (NANA). Neutrophilic airway inflammation is a main feature of induced sputum in nonatopic asthmatic children Drews Allergy 2009:64:1597
  202. 203. <ul><li>Atopic asthmatic (AA) n = 28 </li></ul><ul><li>nonatopic asthmatics (NAA) n = 29 </li></ul><ul><li>nonatopic nonasthmatic children (NANA) n = 19. </li></ul><ul><li>Skin-tested.  </li></ul><ul><li>Induced sputum. </li></ul>Neutrophilic airway inflammation is a main feature of induced sputum in nonatopic asthmatic children Drews Allergy 2009:64:1597 *** P-values <0.0001 for comparisons between groups
  203. 204. Box plots of absolute numbers of neutrophils per gram of sputum. Neutrophilic airway inflammation is a main feature of induced sputum in nonatopic asthmatic children Drews Allergy 2009:64:1597 <ul><li>Atopic asthmatic (AA) n = 28 </li></ul><ul><li>nonatopic asthmatics (NAA) n = 29 </li></ul><ul><li>nonatopic nonasthmatic children (NANA) n = 19. </li></ul><ul><li>Skin-tested.  </li></ul><ul><li>Induced sputum. </li></ul>*** P-values <0.0001
  204. 205. AA, atopic asthma; NAA, nonatopic asthma; NANA, no asthma/no atopy. * Data expressed as median (minimum–maximum).  Significant difference when compared with NANA, P < 0.001. ‡ Significant difference when compared with AA, P < 0.001. § Significant difference when compared with NAA and NANA, P < 0.001. ¶ Eosinophilia = if sputum eosinophils ≥3%. Differential cell counts * from induced sputum in the three clinical phenotypes Cell viability, % 86 (64–95) 84 (50–95) 88 (66–93) TCC†×10 6 /mg 3.4 (1.2–13.0) 4.0 (1.5–7.6) 2.2 (1.8–8.0) Neutrophils % 11.0 (7.0–16) 18.0 (7.0–31) ‡ 13.0 (8.0–22.0) Eosinophils % 9.0 (0.2–64.0) § 1.0 (0–66.0) 0.5 (0–1.8) Macrophages % 76.4 (29–86) 78.0 (24–84) 81.0 (74–87) Lymphocytes % 0.8 (0–4) 1.0 (0–5.0) 0.8 (0–2.0) Sputum eosinophilia ¶ , n (%) 17 (81)  5 (23.8) 0 (0) Neutrophilic airway inflammation is a main feature of induced sputum in nonatopic asthmatic children Drews Allergy 2009:64:1597
  205. 206. Relationship Between Amphiregulin and Airway Inflammation in Children With Asthma and Eosinophilic Bronchitis Won Kim Chest 2009;136:805 Background: Amphiregulin , a member of the epidermal growth factor family , has been shown to promote the growth of fibroblasts, to be associated with the T-helper type 2 cell adaptive immune response, and to up-regulate mucin gene expression. We aimed to determine whether sputum amphiregulin is expressed at elevated levels in patients with asthma or eosinophilic bronchitis (EB), and whether it is associated with eosinophilic inflammation, pulmonary function, and bronchial hyperresponsiveness in children.
  206. 207. <ul><li>117 children with asthma </li></ul><ul><li>77with eosinophilic bronchitis (EB) </li></ul><ul><li>84 control subjects </li></ul>Relationship Between Amphiregulin and Airway Inflammation in Children With Asthma and Eosinophilic Bronchitis Won Kim Chest 2009;136:805
  207. 208. <ul><li>117 children with asthma </li></ul><ul><li>77with EB </li></ul><ul><li>84 control subjects </li></ul>Sputum amphiregulin levels positively correlated with levels of sputum eosinophils ( γ =0.221; p= 0.007) Relationship Between Amphiregulin and Airway Inflammation in Children With Asthma and Eosinophilic Bronchitis Won Kim Chest 2009;136:805
  208. 209. <ul><li>117 children with asthma </li></ul><ul><li>77with EB </li></ul><ul><li>84 control subjects </li></ul>Our findings suggest that childhood asthma is associated with sputum amphiregulin, whereas EB is not, and that sputum amphiregulin would be a supportive marker of airway inflammation in asthma. Relationship Between Amphiregulin and Airway Inflammation in Children With Asthma and Eosinophilic Bronchitis Won Kim Chest 2009;136:805
  209. 210. Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack Enomoto JACI 2009;124:913 Backgroun

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