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    Asthma Asthma Presentation Transcript

    • WHAT YOU SHOULD HAVE READ BUT….2010
      • asthma
      University of Verona, Italy Attilio Boner
    • Asthma phenotypes
    • Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams JACI 2009;124:463
      • 1380 unselected 14-year-olds.
      • Clinical history, allergic sensitization, and respiratory function.
      % SUBJECTS 60% 60 – 50 – 40 – 30 – 20 – 10 – 0 ATOPIC ASTHMATIC 10%
    • Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams JACI 2009;124:463
      • 1380 unselected 14-year-olds.
      • Clinical history, allergic sensitization, and respiratory function.
      % SUBJECTS 60% 60 – 50 – 40 – 30 – 20 – 10 – 0 ATOPIC ASTHMATIC 10% 81% of asthmatic subjects were also atopic.
    • Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling Hollams JACI 2009;124:463
      • 1380 unselected 14-year-olds.
      • Clinical history, allergic sensitization, and respiratory and immunoinflammatory function.
      % 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.
    • Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program Moore AJRCCM 2010;181:315
      • Severe Asthma Research Program cohort.
      • Cluster analysis was performed on 726 subjects.
      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.
    • Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program Moore AJRCCM 2010;181:315
      • Severe Asthma Research Program cohort.
      • Cluster analysis was performed on 726 subjects.
      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.
    • 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 "Max" 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).
    • 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
      • asthma natural history
    • 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
    • Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri JACI 2009;124:903
      • Birth cohort followed 3,963 children for 8 years .
      • Between 0 and 4 years of age, 2,171 (55%) children reported “wheezing,” “coughing at night without a cold,” or both.
      • Asthma was defined as wheezing, inhaled steroid prescription, or a doctor's diagnosis of asthma at both age 7 and 8 years of age.
      % 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
    • Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age Caudri JACI 2009;124:903
      • Male sex,
      • Post-term delivery,
      • Parental education
      • Inhaled medication,
      • Wheezing frequency,
      • Wheeze/dyspnea apart from colds,
      • Respiratory infections,
      • Eczema
      8 clinical parameters independently predicted asthma at 7 to 8 years of age:
    • 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
    • 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
      • 2,200 men and women from a general population–based study.
      • Questionnaires, blood samples, pulmonary function tests, and F E NO.
      • Follow-up 4 years later.
    • 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
      • 2,200 men and women from a general population–based study.
      • Questionnaires, blood samples, pulmonary function tests, and F E NO.
      • Follow-up 4 years later.
      Wheeze
    • 2.8 ≥ 90 percentile 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 3.2
      • 2,200 men and women from a general population–based study.
      • Questionnaires, blood samples, pulmonary function tests, and F E NO.
      • Follow-up 4 years later.
      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
    • Adulthood asthma after wheezing in infancy: a questionnaire study at 27 years of age M. Ruotsalainen, Allergy 2010;65;503
      • At the median age of 27.3 years
      • questionnaire to 59 study subjects hospitalized for wheezing at <24 months of age
      • population controls
      20% % subjects with doctor-diagnosed asthma controls 20 – 10 – 0 5% former bronchiolitis patients
    • Adulthood asthma after wheezing in infancy: a questionnaire study at 27 years of age M. Ruotsalainen, Allergy 2010;65;503
      • At the median age of 27.3 years
      • questionnaire to 59 study subjects hospitalized for wheezing at <24 months of age
      • population controls
      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
    • Remitting Periodic Persistent 55% 39% 6% Predictors of remitting, periodic, and persistent childhood asthma Covar JACI 2010;125:359
      • The Childhood Asthma Management Program ( CAMP ) in children with mild to moderate persistent asthma.
      • 4.3 years treatment
      • 4 years follow-up
      • 909 participants.
      % ADOLESCENTS WITH 60 – 50 – 40 – 30 – 20 – 10 – 0 ASTHMA
    • Remitting Periodic Persistent 55% 39% 6% Predictors of remitting, periodic, and persistent childhood asthma Covar JACI 2010;125:359
      • The Childhood Asthma Management Program ( CAMP ) in children with mild to moderate persistent asthma.
      • 4.3 years treatment
      • 4 years follow-up
      • 909 participants.
      60 – 50 – 40 – 30 – 20 – 10 – 0 anti-inflammatory treatment during the CAMP trial improved QoL, but………. % ADOLESCENTS WITH ASTHMA
    • 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
    • 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.
    • 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
    • 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
      • 28 children with remission asthma.
      • 25 with intermittent adolescent asthma.
      • 47 symptomatic adolescent.
      • 60 younger children with symptomatic asthma.
      • 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 .
      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.
    • 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
    • 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
    • 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
    • Asthma Origins
      • European Community Respiratory Health Survey participants aged 20–45 years randomly selected from general populations.
      • Spirometry in 1991–3 (n=13,359) and 9 years later (n=7,738).
      Early life origins of chronic obstructive pulmonary disease Svanes Thorax 2010;65:14–20
      • Maternal asthma,
      • Paternal asthma,
      • Childhood asthma,
      • Maternal smoking and
      • Childhood respiratory infections
      defined as ‘‘childhood disadvantage factors’’.
    • % 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
      • maternal asthma,
      • paternal asthma,
      • childhood asthma,
      • maternal smoking
      • childhood r respiratory i infections
    • 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
    • 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
    • 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
    • Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund Thorax 2010;65:146
      • Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 .
      • Information on asthma from parent-completed questionnaires at age 3-9 years.
      Prevalence of asthma according to birth weight in Danish twin pairs, 3-9 years of age.
    • Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund Thorax 2010;65:146
      • Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 .
      • Information on asthma from parent-completed questionnaires at age 3-9 years.
      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.
    • 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.
    • 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.
      • COPD is a disease of childhood that becomes manifest in adults.
      • 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.
      • 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 .
      COPD as a disease of children: hype or hope for better understanding? Mannino Thorax 2010; 65: 1-2
      • 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.
      • Some recent data support the finding that measures of lung function at a mean age of 2 months track into young adulthood.
      • Subjects entering adulthood with poor lung function are probably at an increased risk for developing COPD.
      COPD as a disease of children: hype or hope for better understanding? Mannino Thorax 2010; 65: 1-2
    • 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
    • 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 .
    • 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.
    • 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.
    • Perinatal Risk factors
    • Vacuum-assisted delivery is associated with late-onset asthma . Keski-Nisula Allergy 2009:64:1530
      • Perinatal data recorded during pregnancy and at the time of delivery.
      • 5823 children born in Northern Finland in 1985–1986.
      • Self-administered questionnaires at the ages of 7 and 15–16 yrs and skin prick tests at the age of 15–16 yrs.
      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
    • Vacuum-assisted delivery is associated with late-onset asthma . Keski-Nisula Allergy 2009:64:1530
      • 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.
      • What could be plausible reasons behind the increased tendency towards asthma in those children who were born by vacuum delivery?
      • Children born by vacuum or forceps extraction are more often exposed to intrapartal distress .
      • The levels of umbilical cord blood cortisol have been increased in those neonates.
    • Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case–control study Martel ERJ 2009:34:579
      • 8,226 children of asthmatic mothers.
      • 30,318 age-matched controls.
      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
    • Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case–control study Martel ERJ 2009:34:579
      • 8,226 children of asthmatic mothers.
      • 30,318 age-matched controls.
      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.
    • Asthma and viruses
    • 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.
    • Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up. Valkonen Allergy 2009:64:1359
      • All children <2 years of age admitted because of bronchiolitis.
      • Nasopharyngeal aspirates for viral antigens for RSV, influenza A and B viruses, parainfluenza types 1, 2, and 3 viruses, and adenovirus.
      The age distribution of children hospitalized with RSV or non-RSV bronchiolitis RSV Non-RSV
    • Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up. Valkonen Allergy 2009:64:1359
      • All children <2 years of age admitted because of bronchiolitis.
      • Nasopharyngeal aspirates for viral antigens for RSV, influenza A and B viruses, parainfluenza types 1, 2, and 3 viruses, and adenovirus.
      Development of recurrent wheezing within 3 years
    • Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up. Valkonen Allergy 2009:64:1359
      • All children <2 years of age admitted because of bronchiolitis.
      • Nasopharyngeal aspirates for viral antigens for RSV, influenza A and B viruses, parainfluenza types 1, 2, and 3 viruses, and adenovirus.
      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
    • 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.
    • INFECTED WITH HRV-16 Degree of infection evaluated 48 hours late Cells from inferior turbinates Cells from bronchial tree
      • Virus replicated more easily p<0.01
      • A 20- to 30-fold greater viral load and number of infected cells
      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
    •   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
    • Multiplex Molecular Detection of Respiratory Pathogens in Children With Asthma Exacerbation Ting Fan Leung Chest 2010;137:348
      • 209 children aged 3-18 years with asthma exacerbations
      • 77 controls with stable asthma
      • Nested multiplex polymerase chain reaction was used to detect 20 different respiratory pathogens
      % subjects with (+) results 51.0% 60 – 50 - 40 - 30 – 20 – 10 - 0 Any respiratory pathogen
    • Multiplex Molecular Detection of Respiratory Pathogens in Children With Asthma Exacerbation Ting Fan Leung Chest 2010;137:348
      • 209 children aged 3-18 years with asthma exacerbations
      • 77 controls with stable asthma
      • Nested multiplex polymerase chain reaction was used to detect 20 different respiratory pathogens
      % 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.
      • 939 children
      • primary child care setting as an infant (before 15 months)
      • and as a toddler
      • (16-36 months)
      • persistent or late-onset asthma by age 15
      % 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
      • 939 children
      • primary child care setting as an infant (before 15 months)
      • and as a toddler
      • (16-36 months)
      • persistent or late-onset asthma by age 15
      % 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
    • Asthma and bacteria, atypical bacteria
    • 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.
    • 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.
    • 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.
    • 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
    • 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.
    • 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.
      • 53 HDM-allergic children who presented to the Emergency Department with acute asthma.
      • Peripheral blood samples within 24 h of presentation.
      • A further blood sample after the acute attack, when the child was clinically well.
    • Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . Hales C EA 2010;39:1170
      • 53 HDM-allergic children who presented to the Emergency Department with acute asthma.
      • Peripheral blood samples within 24 h of presentation.
      • A further blood sample after the acute attack, when the child was clinically well.
      IgE antibody binding (ng/mL) to the outer membrane P6 antigen from Haemophilus influenzae for acute and convalescent plasma.
    • Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . Hales C EA 2010;39:1170
      • 53 HDM-allergic children who presented to the Emergency Department with acute asthma.
      • Peripheral blood samples within 24 h of presentation.
      • A further blood sample after the acute attack, when the child was clinically well.
      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.
    • Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation . Hales C EA 2010;39:1170
      • 53 HDM-allergic children who presented to the Emergency Department with acute asthma.
      • Peripheral blood samples within 24 h of presentation.
      • A further blood sample after the acute attack, when the child was clinically well.
      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.
    • 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 .
    • 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
    • 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 .
      • Impaired killing of respiratory pathogens phagocytosed by macrophages can be resolved in vitro with calcitriol administration.
      • Oral supplementation in humans may also decrease symptomatic viral infections in a non-asthmatic population.
      • 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.
      Is intrinsic asthma synonymous with infection? Dahlberg Clinical & Experimental Allergy 2009;39:1324
    • 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
      • 3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes.
      • Frequency of bleach use and information on respiratory symptoms.
      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
    • Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults Zock JACI 2009;124:731
      • 3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes.
      • Frequency of bleach use and information on respiratory symptoms.
      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.
    • Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults Zock JACI 2009;124:731
      • 3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes.
      • Frequency of bleach use and information on respiratory symptoms.
      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.
    • 1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5 OR for
      • Prospective birth cohort (n=3,863)
      • 8-year-follow-up
      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
    • 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.
    • 1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5 OR for
      • Prospective birth cohort (n=3,863)
      • 8-year-follow-up
      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
    • 1.34 1.36 1.27 PREVALENT INCIDENT ASTHMA symptoms for an interquartile increase in PM 2.5 OR for
      • Prospective birth cohort (n=3,863)
      • 8-year-follow-up
      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
    • Exposure to Traffic-related Particles and Endotoxin during Infancy Is Associated with Wheezing at Age 3 Years Ryan AJRCCM 2009:180:1068
      • Persistent wheezing at age 36 months in a high-risk birth cohort.
      • Average exposure to traffic-related particles.
      • Indoor levels of endotoxin.
      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 +
    • Exposure to Traffic-related Particles and Endotoxin during Infancy Is Associated with Wheezing at Age 3 Years Ryan AJRCCM 2009:180:1068
      • Persistent wheezing at age 36 months in a high-risk birth cohort.
      • Average exposure to traffic-related particles.
      • Indoor levels of endotoxin.
      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. +
    • Vehicle exhaust outside the home and onset of asthma among adults L. Modig E R J 2009; 33:1261
      • Three Swedish cities.
      • <50 m distance to nearest major road as a more simple indicator of exposure.
      • 3,609 participants.
      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
    • Improved Biomass Stove Intervention in Rural Mexico Romieu Am. J. Respir. Crit. Care Med 2009;180:649
      • Households were randomized to receive the Patsari stove or keep their traditional open fire.
      • 552 women were followed with monthly visits over 10 months.
      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
    • Improved Biomass Stove Intervention in Rural Mexico Romieu Am. J. Respir. Crit. Care Med 2009;180:649
      • Households were randomized to receive the Patsari stove or keep their traditional open fire.
      • 552 women were followed with monthly visits over 10 months.
      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
    • 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
    • Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study Hoppin ERJ 2009:34:1296
      • 19,704 male farmers.
      • Defined as doctor-diagnosed asthma after the age of 20 yrs.
      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
    • Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study Hoppin ERJ 2009:34:1296
      • 19,704 male farmers.
      • Defined as doctor-diagnosed asthma after the age of 20 yrs.
      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.
    • Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study Hoppin ERJ 2009:34:1296
      • Grains, hays and animals have been identified as important aetiological agents for respiratory disease among farmers for.
      • Pesticides may also be a risk factor for asthma among farmers.
      • We saw associations with lifetime days of use of individual pesticides, suggesting an exposure–response relationship.
    • 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
    • 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
      • 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.
      • Risks were estimated for interquartile range increases in pollutants.
    • 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
      • 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.
      • Risks were estimated for interquartile range increases in pollutants.
    • 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
      • 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.
      • Risks were estimated for interquartile range increases in pollutants.
    • 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
      • 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.
      • Risks were estimated for interquartile range increases in pollutants.
      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.
    • Do Endotoxin and Air Pollution Have a Synergistic Relationship to Asthma Onset or Exacerbation? Editorial Delfino AJRCCM 2009:180:1037
      • 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.
      • 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).
      • Automobile exhaust produces a similar set of compounds.
      • 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.
      • 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).
      • Automobile exhaust produces a similar set of compounds.
      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
    •  
    • Acute effects of outdoor air pollution on FEV 1 : a panel study of schoolchildren with asthma . Dales ERJ 2009:34:316
      • FEV 1 for 28 consecutive days in 182 elementary schoolchildren with physician-diagnosed asthma.
      • Ambient hourly air pollution concentrations.
      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).
    • Acute effects of outdoor air pollution on FEV 1 : a panel study of schoolchildren with asthma . Dales ERJ 2009:34:316
      • FEV 1 for 28 consecutive days in 182 elementary schoolchildren with physician-diagnosed asthma.
      • Ambient hourly air pollution concentrations.
      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.
    • Increased Levels of Outdoor Air Pollutants Are Associated With Reduced Bronchodilation in Children With Asthma Hernàndez-Cadena CHEST 2009;136:1529
      • 85 children with asthma
      • Outdoor air pollution exposure nitrogen dioxide (NO 2 ),
      • ozone (O 3 ) and [PM 2.5 ] levels
      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
    • Increased Levels of Outdoor Air Pollutants Are Associated With Reduced Bronchodilation in Children With Asthma Hernàndez-Cadena CHEST 2009;136:1529
      • 85 children with asthma
      • Outdoor air pollution exposure nitrogen dioxide (NO 2 ),
      • ozone (O 3 ) and [PM 2.5 ] levels
      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.
    • Asthma red-ox
    • 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
    • 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
    • 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
    • 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).
    • Association between antioxidant vitamins and asthma outcome measures: systematic review and meta-analysis Allen Thorax 2009;64:610–619
      • 40 studies
      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).
    • Association between antioxidant vitamins and asthma outcome measures: systematic review and meta-analysis Allen Thorax 2009;64:610–619
      • 40 studies
      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
    • Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253
      • Serum folate and total IgE levels.
      • 8083 subjects 2 years of age and older.
      Distribution of serum total IgE levels across quintiles of serum folate. P < .001 for trend
    • Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253
      • Serum folate and total IgE levels.
      • 8083 subjects 2 years of age and older.
      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
    • Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253
      • 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 .
    • Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253
      • 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 .
      • 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
      • A level of greater than 26.5 ng/mL should be considered high. Morris MS, Am J Clin Nutr. 2007;85:193–200
    • Higher serum folate levels are associated with a lower risk of atopy and wheeze Matsui JACI 2009;123:1253
      • 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 .
      • 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
      • A level of greater than 26.5 ng/mL should be considered high. Morris MS, Am J Clin Nutr. 2007;85:193–200
      DNA methylation involves the addition of a methyl group to DNA with the specific effect of reducing gene expression.
    • Has mandatory folic acid supplementation of foods increased the risk of asthma and allergic disease? Ownby JACI 2009;123:1260
      • Folate functions as an important cofactor in the transfer and use of 1-carbon moieties, primarily methyl groups.
      • 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)
    • 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
    • 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
      • allergens / atopy
    • % 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
      • Concentrations of cat allergens from the homes of 260 two-year-old children with lung function measured at birth in Oslo.
      • At 10 years.
      6.5% 10 – 5 – 0
    • 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
    • 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.
    • 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.
      • 6 asthmatic with dual sensitization to house dust mite (HDM) and grass pollen (GP)
      • challenge with these allergens on 2 occasions separated by 14 days
      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
    • 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
      • 6 asthmatic with dual sensitization to house dust mite (HDM) and grass pollen (GP)
      • challenge with these allergens on 2 occasions separated by 14 days
      EAR LAR
    • % 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
      • 6 asthmatic with dual sensitization to house dust mite (HDM) and grass pollen (GP)
      • challenge with these allergens on 2 occasions separated by 14 days
    • % 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
      • 6 asthmatic with dual sensitization to house dust mite (HDM) and grass pollen (GP)
      • challenge with these allergens on 2 occasions separated by 14 days
    • Household airborne Penicillium associated with peak expiratory flow variability in asthmatic children Bundy Ann Allergy Asthma Immunol 2009;103:26
      • 225 asthmatic c hildren (6-12 years).
      • Peak expiratory flow recorded twice daily during a 2-week period.
      • In-home airborne mold concentrations.
      Any mold 93% % of Houses with 72% 42% Cladosporium Penicillium 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 100 –
    • 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
      • 225 asthmatic c hildren (6-12 years).
      • Peak expiratory flow recorded twice daily during a 2-week period.
      • In-home airborne mold concentrations.
    • 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
      • 225 asthmatic c hildren (6-12 years).
      • Peak expiratory flow recorded twice daily during a 2-week period.
      • In-home airborne mold concentrations.
      Exposure to airborne Penicillium is associated with increased peak expiratory flow variability in asthmatic children.
    • 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 +
    • 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
    • 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.
    • 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.
    • 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)
      • Food allergy and asthma
    • Obesity
    • Obesity and allergic disease: closely related epidemics of the 21st century Warner Pediatr Allergy Immunol 2009:20:305
      • The modern allergy epidemic has followed a very similar demographic path to that of obesity and its associated metabolic syndrome.
      • There is also a remarkable concordance of the early life influences.
      • 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.
      • 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.
    • Relationship between infant weight gain and later asthma Paul Pediatr Allergy Immunol 2010:21:82
      • Birth weight, growth, pulmonary function, and symptom.
      • Ch. 2 and 3 years of age at high-risk of developing persistent enrolled in the PEAK trial. Guilbert NEJM 2006;354:1985
      Relationship between infant weight gain group and (a) systemic corticosteroid courses (p =0.01 overall group comparisons)
    • 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.
      • Birth weight, growth, pulmonary function, and symptom.
      • Ch. 2 and 3 years of age at high-risk of developing persistent enrolled in the PEAK trial. Guilbert NEJM 2006;354:1985
      • Birth weight, growth, pulmonary function, and symptom.
      • Ch. 2 and 3 years of age at high-risk of developing persistent enrolled in the PEAK trial. Guilbert NEJM 2006;354:1985
      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.
    • Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens JACI 2009;123:1312
      • 3756 children in a large birth cohort study.
      • Parents reported their children's weight and height, and wheeze, dyspnea, and prescription of ICS in yearly questionnaires.
      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
    • 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
      • 3756 children in a large birth cohort study.
      • Parents reported their children's weight and height, and wheeze, dyspnea, and prescription of ICS in yearly questionnaires.
    • 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
      • 3756 children in a large birth cohort study.
      • Parents reported their children's weight and height, and wheeze, dyspnea, and prescription of ICS in yearly questionnaires.
      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.
      • A common explanation for the increased asthma risk in overweight children is the direct mechanical effect of an increased fat mass on lung function .
      • 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
      Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens JACI 2009;123:1312
      • 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 .
      Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 yrs of age Scholtens JACI 2009;123:1312
      • 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.
      • 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 .
      • 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.
      Dyspnea in overweight children: Is it asthma? Editorial Schwartzstein JACI 2009;123:1319
    • Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649
      • Cardiovascular fitness was measured by a maximal ergometer test using Tunturi E 85 electronic cycle ergometer (Accell Fitness, Turku, Finland).
      • The workload was increased every 3 min until exhaustion.
      • The start workload and increases in workload depended on the age, gender and bodyweight.
      • 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
    • Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649
      • Body composition was measured using DEXA using a Lunar Prodygry Advance densiometer (Scanex Medical Systems, Hoersholm, Denmark).
      • Total body mass, total fat, total lean tissue, bone mineral density (BMD) and age-matched z-score were measured.
    • Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649
      • Daily physical activity measured using accelerometry.
      • Cardiovascular fitness and body composition.
      • 57 children with newly diagnosed, untreated asthma and in 157 healthy age- controls.
      CARDIOVASCULAR FITNESS 35.1 39.3 ASTHMATIC 40 – 30 – 20 – 10 – 0 HEALTHY O 2 /min/kg p<0.001 CHILDREN
    • Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649
      • Daily physical activity measured using accelerometry.
      • Cardiovascular fitness and body composition.
      • 57 children with newly diagnosed, untreated asthma and in 157 healthy age- controls.
      BODY % FAT 22.8 19.5 ASTHMATIC 25 – 20 – 15 – 10 – 0 5 – 0 HEALTHY p<0.01 CHILDREN
    • Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649
      • Daily physical activity measured using accelerometry.
      • Cardiovascular fitness and body composition.
      • 57 children with newly diagnosed, untreated asthma and in 157 healthy age- controls.
      24.6 15.2 ASTHMATIC 25 – 20 – 15 – 10 – 0 5 – 0 HEALTHY p<0.05 % OVERWEIGHT CHILDREN CHILDREN
    • Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma Vahlkvist Allergy 2009:64:1649
      • Daily physical activity measured using accelerometry.
      • Cardiovascular fitness and body composition.
      • 57 children with newly diagnosed, untreated asthma and in 157 healthy age- controls.
      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
    • 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
      • Adults with asthma (n=6,835) and without asthma (n=78,051).
      • Self-reported physical activities.
      • BMI ( kg/h 2 in metre)
      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
    • 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
      • Adults with asthma (n=6,835) and without asthma (n=78,051).
      • Self-reported physical activities.
      • BMI weight in kilograms divided by height in meters squared.
      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
        • Prevalence and severity of self-reported asthma in young adults, 1976–2004
        • Browatzki ERJ 2009:34:1046
      • 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).
      • A total of 3,285 (46% male) subjects.
      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
        • Prevalence and severity of self-reported asthma in young adults, 1976–2004
        • Browatzki ERJ 2009:34:1046
      • 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).
      • A total of 3,285 (46% male) subjects.
      FEV 1 in asthmatics ( ) and non asthmatics ( ) at the three surveys.
        • Prevalence and severity of self-reported asthma in young adults, 1976–2004
        • Browatzki ERJ 2009:34:1046
      • 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).
      • A total of 3,285 (46% male) subjects.
      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.
        • Prevalence and severity of self-reported asthma in young adults, 1976–2004
        • Browatzki ERJ 2009:34:1046
      • 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).
      • A total of 3,285 (46% male) subjects.
      The proportion of smokers declined from 60 to 38% (p<0.001). FEV 1 in asthmatics ( ) and non asthmatics ( ) at the three surveys.
    • Obesity and obesity related co-morbidities in a referral population of children with asthma Ross, Ped Pul 2009;44:877
      • 116 asthmatic children ages 4-18 years.
      • Children obese (BMI ≥ 95th percentile).
      • Not obese (BMI <95th percentile).
      50 – 40 – 30 – 20 – 10 – 0 44% Asthmatic children who were obese
      • 116 asthmatic children ages 4-18 years.
      • Children obese (BMI ≥ 95th percentile).
      • Not obese (BMI <95th percentile).
      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
    • 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
    • 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.
    • Definition of Metabolic Syndrome
      • Subjects who met at least three of the following criteria were defined as having MetSyn:
      • waist circumference ≥90th percentile for age and sex;
      • triglycerides ≥110 mg/dl;
      • HDL ≤40 mg/dl;
      • fasting glucose ≥100 mg/dl;
      • mean systolic or diastolic blood pressure ≥90th
      • percentile for age, sex, and height.
      Obesity and obesity related co-morbidities in a referral population of children with asthma Ross, Ped Pul 2009;44:877
    • % children > 85th percentile of BMI for age Asthma control, adiposity, and adipokines among inner-city adolescents Kattan JACI 2010;125:584
      • 368 adolescents with moderate-to-severe asthma .
      • Follow-up: 1 year.
      • Asthma symptoms exacerbations pulmonary function exhaled nitric oxide levels every 6 weeks.
      • Body mass index.
      61.5% female 52.3% male 80 – 60 – 40 – 20 – 0
    • % 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
      • 368 adolescents with moderate-to-severe asthma.
      • Follow-up: 1 year.
      • Asthma symptoms exacerbations pulmonary function exhaled nitric oxide levels every 6 weeks.
      • Body mass index.
      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.
      • Background:
      • 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.
      Comparison of anthropometric measures of obesity in childhood allergic asthma: Central obesity is most relevant. Musaad JACI 2009;123:1321
      • Children with allergic rhinitis with (cases) or without (control subjects) asthma were recruited.
      Comparison of anthropometric measures of obesity in childhood allergic asthma: Central obesity is most relevant. Musaad JACI 2009;123:1321
      • Central obesity was associated with asthma, asthma severity, lower lung function, and reduced atopy in asthmatic subjects.
      • 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.
    • 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.
    • 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.
    • 1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30
      • Of the 88 304 women in the analyses.
      • (n=11 500) were obese (BMI ≥ 30 kg/m 2 ) at baseline.
      • 1334 were extremely obese (BMI ≥ 40 kg/m 2 ).
      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
    • 1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30
      • Of the 88 304 women in the analyses.
      • (n=11 500) were obese (BMI ≥ 30 kg/m 2 ) at baseline.
      • 1334 were extremely obese (BMI ≥ 40 kg/m 2 ).
      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)
    • 1.40 Compared with those of normal weight, OR for adult onset asthma Overweight women Extremely obese 3.30
      • Of the 88 304 women in the analyses.
      • (n=11 500) were obese (BMI ≥ 30 kg/m 2 ) at baseline.
      • 1334 were extremely obese (BMI ≥ 40 kg/m 2 ).
      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
    • Asthma other risk factors
    • Frequent nocturnal awakening in early life is associated with nonatopic asthma in children Kozyrskyj ERJ 2009:34:1288
      • A community-based birth cohort.
      • Followed up at years 1, 2, 3, 6, 8, 10 and 14.
      • Parent-completed questionnaires.
      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
    • Frequent nocturnal awakening in early life is associated with nonatopic asthma in children Kozyrskyj ERJ 2009:34:1288
      • A community-based birth cohort.
      • Followed up at years 1, 2, 3, 6, 8, 10 and 14.
      • Parent-completed questionnaires.
      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.
      • 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.
      • 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.
      • TNF- α has been implicated in neutrophilic inflammation in neutrophilic airway inflammation has been observed in children with sleep apnoea.
      Frequent nocturnal awakening in early life is associated with nonatopic asthma in children Kozyrskyj ERJ 2009:34:1288
    • Asthma protective factors
    • Effect of breastfeeding on asthma, lung function and bronchial hyperreactivity in ISAAC Phase II Nagel Eur Respir J 2009;33:993
      • Cross-sectional studies in 27 centres in 20 countries.
      • Data from 54,000 randomly selected school children (aged 8–12 yrs, 31,759 with skin prick testing).
      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
    • Effect of breastfeeding on asthma, lung function and bronchial hyperreactivity in ISAAC Phase II Nagel Eur Respir J 2009;33:993
      • Cross-sectional studies in 27 centres in 20 countries.
      • Data from 54,000 randomly selected school children (aged 8–12 yrs, 31,759 with skin prick testing).
      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 .
    • 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.
    • 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.
    • 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.
      • 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.
      • 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.
      • Specific in vivo elimination of IMs led to overt asthmatic reactions to innocuous airborne antigens inhaled with low doses of LPS.
      Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice Bedoret J Clin Inv 2009;119:3723
      • Asma e bronchite cronica originano molto precocemente sotto l’influsso di infezioni, allergeni, fumo di sigaretta e stress ossidativo.
      • L’asma è una malattia spesso persistente e la sua storia naturale non viene modificata dalla terapia.
      • Guariscono più facilmente i soggetti esposti a basse dosi di allergeni e con poche riacutizzazioni.
      • Alcuni allergeni sono più pericolosi in relazione alla loro attività come enzimi proteolitici.
      • Altri fattori di rischio sono:
      • Bronchiolite non da RSV
      • Obesità
      • Inquinamento indoor e outdoor
      • Deficit di sostanze anti-ossidanti
      Take home
      • Asma e bronchite cronica originano molto precocemente sotto l’influsso di infezioni, allergeni, fumo di sigaretta e stress ossidativo.
      • L’asma è una malattia spesso persistente e la sua storia naturale non viene modificata dalla terapia.
      • Guariscono più facilmente i soggetti esposti a basse dosi di allergeni e con poche riacutizzazioni.
      • Alcuni allergeni sono più pericolosi in relazione alla loro attività come enzimi proteolitici.
      • Altri fattori di rischio sono:
      • Bronchiolite non da RSV
      • Obesità
      • Inquinamento indoor e outdoor
      • Deficit di sostanze anti-ossidanti
      Sono in corso numerosi studi con sostanze anti-ossidanti nella terapia/prevenzione delle malatti respiratorie croniche Take home
    • ASTHMA BHR
    • Asthma pathogenesis
    • 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
    • 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.
    • 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 .
    • 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.
      • 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.
      • Peripheral blood-derived progenitors from atopic asthmatics (n=12) and non-atopic controls (n=11).
    • 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
    • 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.
    • Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing Upham JACI 2009;124:707
      • 263 ch with
      • (+) FH of atopy.
      • Blood samples
      • at age 6 mo, 12 mo
      • and 5 years.
      • Flow cytometry.
      • SPTs.
      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 .
      • 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.
      • 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.
      Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing Upham JACI 2009;124:707
      • 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.
      • 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.
      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.
    • Regulatory cells, cytokine pattern and clinical risk factors for asthma in infants and young children with recurrent wheeze Borrego C EA 2010;39:1160
      • 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.
      • 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).
      • S ignificant reduction in the absolute number of CD4 + CD25 high in wheezy children compared with healthy controls.
      • 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.
    • 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.
    • 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
      • Atopic asthmatic (AA) n = 28
      • nonatopic asthmatics (NAA) n = 29
      • nonatopic nonasthmatic children (NANA) n = 19.
      • Skin-tested. 
      • Induced sputum.
      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
    • 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
      • Atopic asthmatic (AA) n = 28
      • nonatopic asthmatics (NAA) n = 29
      • nonatopic nonasthmatic children (NANA) n = 19.
      • Skin-tested. 
      • Induced sputum.
      *** P-values <0.0001
    • 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
    • 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.
      • 117 children with asthma
      • 77with eosinophilic bronchitis (EB)
      • 84 control subjects
      Relationship Between Amphiregulin and Airway Inflammation in Children With Asthma and Eosinophilic Bronchitis Won Kim Chest 2009;136:805
      • 117 children with asthma
      • 77with EB
      • 84 control subjects
      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
      • 117 children with asthma
      • 77with EB
      • 84 control subjects
      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
    • Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack Enomoto JACI 2009;124:913 Background: Epidermal growth factor receptor ligands, such as epidermal growth factor (EGF) and amphiregulin, may play key roles in tissue remodeling in asthma. However, the kinetics of EGF and amphiregulin secretion in the airway after an acute asthma attack and the effect of prolonged airway exposure to these ligands on airway remodeling are unknown. Objective: To measure the EGF and amphiregulin concentrations in sputa obtained from patients with asthma under various conditions, and to examine the effects of EGF and amphiregulin on the proliferation or differentiation of airway structural cells.
    • Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack Enomoto JACI 2009;124:913
      • Epidermal growth factor (EGF) and amphiregulin levels measured by ELISA in sputum.
      • 14 hospitalized children with an acute asthma attack, 13 stable outpatients with asthma, 8 healthy control children, and 7 children with respiratory tract infections.
      Concentrations of EGF (A) in the sputa of patients with asthma after an asthma attack (acute) , during the recovery phase (recovery) , and during the stable phase (stable) ; sputa of normal healthy controls; and sputa of patients with respiratory tract infection ( ∗∗ P < .01; ∗∗∗∗ P < .001).
    • Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack Enomoto JACI 2009;124:913
      • Epidermal growth factor (EGF) and amphiregulin levels measured by ELISA in sputum.
      • 14 hospitalized children with an acute asthma attack, 13 stable outpatients with asthma, 8 healthy control children, and 7 children with respiratory tract infections.
      Concentrations of EGF (A) in the sputa of patients with asthma after an asthma attack (acute) , during the recovery phase (recovery) , and during the stable phase (stable) ; sputa of normal healthy controls; and sputa of patients with respiratory tract infection ( ∗∗ P < .01; ∗∗∗∗ P < .001). The sputum levels of EGF were significantly higher for about a week after an acute asthma attack.
    • Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack Enomoto JACI 2009;124:913 Concentrations of amphiregulin (AREG) ( B ) in the sputa of patients with asthma after an asthma attack (acute) , during the recovery phase (recovery) , and during the stable phase (stable) ; sputa of normal healthy controls; and sputa of patients with respiratory tract infection. ( ∗∗ P < .01; ∗∗∗∗ P < .001).
      • Epidermal growth factor (EGF) and amphiregulin levels measured by ELISA in sputum.
      • 14 hospitalized children with an acute asthma attack, 13 stable outpatients with asthma, 8 healthy control children, and 7 children with respiratory tract infections.
    • Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack Enomoto JACI 2009;124:913 Concentrations of amphiregulin (AREG) ( B ) in the sputa of patients with asthma after an asthma attack (acute) , during the recovery phase (recovery) , and during the stable phase (stable) ; sputa of normal healthy controls; and sputa of patients with respiratory tract infection. ( ∗∗ P < .01; ∗∗∗∗ P < .001).
      • Epidermal growth factor (EGF) and amphiregulin levels measured by ELISA in sputum.
      • 14 hospitalized children with an acute asthma attack, 13 stable outpatients with asthma, 8 healthy control children, and 7 children with respiratory tract infections.
      Upregulation of amphiregulin in the sputa of patients with asthma was observed only during the acute attack.
    • EGF caused proliferation of normal human bronchial epithelial cells (NHBE), bronchial smooth muscle cells (BSMC), and normal human lung fibroblasts (NHLF) whereas amphiregulin induced proliferation of only NHBE. Prolonged exposure of NHBE to EGF and amphiregulin induced mucous cell metaplasia in an IL-13–independent manner. Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack Enomoto JACI 2009;124:913
      • a 2 -macroglobulin (an index of plasma leakage) and coagulation factors in hypertonic saline-induced sputum
      • 30 stable subjects;
      • 10 controls, 10 with moderate asthma and 10 with severe asthma.
      • The moderate cohort were weaned off their ICS, followed by further sputum induction 5 days after cessation of steroids.
      a 2 -Macroglobulin (a 2 -MG) levels demonstrating plasma exudation Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids Brims Thorax 2009;64:1037–1043 *p<0.001
    • Profibrinogenic factors in the airways of controls and asthmatics. Tissue factor Factor VII Factor X Factor XIII Fibrinogen Thrombin activity Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids Brims Thorax 2009;64:1037–1043 *p<0.05 t p<0.01
    • Profibrinogenic factors in the airways of controls and asthmatics. Tissue factor Factor VII Factor X Factor XIII Fibrinogen Thrombin activity Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids Brims Thorax 2009;64:1037–1043 *p<0.05 t p<0.01 Untreated moderate asthma is associated with increased fibrinolysis that is corrected by ICS. This study suggests that inhibition of fibrin deposition in severe asthma may be a therapeutic approach.
        • Airway smooth muscle thickness in asthma is related to severity but not duration of asthma
        • James ERJ 2009:34:1040
      • Perimeter of the basement membrane (PBM) and airway smooth muscle (ASM) area measured on transverse sections of large and small airways.
      • Post mortem cases of fatal (n = 107) and nonfatal asthma (n = 37) and from control subjects (n = 69).
      Area of the airway smooth muscle (ASMarea) relative to basement membrane perimeter (PBM) in controls (C) and cases of nonfatal asthma (NFA) and fatal asthma (FA) in large airways outliers. ***:p<0.001; ### :p=0.001; # :p=0.034; ¶ :p=0.003.
        • Airway smooth muscle thickness in asthma is related to severity but not duration of asthma
        • James ERJ 2009:34:1040
      In multivariate analyses, there was no relation to duration of asthma, age at onset of asthma, smoking or sex. These findings suggest that the increased thickness of the ASM layer is present at an early stage in the natural history of asthma and may determine clinical severity.
      • Asthma
      • Investigation
    • Accuracy of ImmunoCAP® Rapid in the diagnosis of allergic sensitization in children between 1 and 14 years with recurrent wheezing: The IReNE study Diaz-Vazquez Pediatr Allergy Immunol 2009:20:601
      • ImmunoCAP® Rapid Wheeze-Rhinitis Child (Phadia AB, Uppsala, Sweden) is a new, qualitative test designed to measure specific IgE antibodies in the blood of children with symptoms of asthma and rhinitis and for use in primary care.
      • The Wheeze-Rhinitis Child includes two control areas and 10 allergens ( 8 inhalants and 2 foods ). These are: cat (e1), birch ( Betula verrucosa ) (t3), mugwort ( Artemisia vulgaris ) (w6), timothy ( Phleum pratense ) (g6), egg white (f1), dog (e5), olive pollen ( Olea europaea ) (t9), wall pellitory ( Parietaria judaica ) (w21), house dust mite ( Dermatophagoides pteronyssinus ) (d1) and cow's milk.
    • Accuracy of ImmunoCAP® Rapid in the diagnosis of allergic sensitization in children between 1 and 14 years with recurrent wheezing: The IReNE study Diaz-Vazquez Pediatr Allergy Immunol 2009:20:601
      • ImmunoCAP® Rapid Wheeze-Rhinitis Child (Phadia AB, Uppsala, Sweden) is a new, qualitative test designed to measure specific IgE antibodies in the blood of children with symptoms of asthma and rhinitis and for use in primary care.
      • The Wheeze-Rhinitis Child includes two control areas and 10 allergens ( 8 inhalants and 2 foods ). These are: cat (e1), birch ( Betula verrucosa ) (t3), mugwort ( Artemisia vulgaris ) (w6), timothy ( Phleum pratense ) (g6), egg white (f1), dog (e5), olive pollen ( Olea europaea ) (t9), wall pellitory ( Parietaria judaica ) (w21), house dust mite ( Dermatophagoides pteronyssinus ) (d1) and cow's milk.
      Any pink–red degree on a line of an allergen is a positive result and the absence of color on such line indicates a negative test result.
    • Accuracy of ImmunoCAP® Rapid in the diagnosis of allergic sensitization in children between 1 and 14 years with recurrent wheezing: The IReNE study Diaz-Vazquez Pediatr Allergy Immunol 2009:20:601
      • ImmunoCAP® Rapid (ICR) Wheeze-Rhinitis Child.
      • 215 children (1-14 yrs) who had ≥ 3 episodes of wheezing .
      • ICR was read by two independent observers. Six classes were evaluated, negative without any color and five positive degrees of pink-red color.
      • It is estimated that at least 1 out of 3 children with recurrent wheezing is atopic .
      • Reliable diagnostic tools are needed in primary care that allow for adequate identification of these children.
    • Accuracy of ImmunoCAP® Rapid in the diagnosis of allergic sensitization in children between 1 and 14 years with recurrent wheezing: The IReNE study Diaz-Vazquez Pediatr Allergy Immunol 2009:20:601
      • ImmunoCAP® Rapid (ICR) Wheeze-Rhinitis Child.
      • 215 children (1-14 yrs) who had ≥ 3 episodes of wheezing .
      • ICR was read by two independent observers. Six classes were evaluated, negative without any color and five positive degrees of pink-red color.
      GENERAL APPEARANCE OF THE IMMUNOCAP™ RAPID DEVICE.
    • Accuracy of ImmunoCAP® Rapid in the diagnosis of allergic sensitization in children between 1 and 14 years with recurrent wheezing: The IReNE study Diaz-Vazquez Pediatr Allergy Immunol 2009:20:601 ATOPIC 50.7% % Children with sIgE ≥0.35 kU A /L (positive) (+) ONLY TO INHALANT ALLERGENS (+) ONLY TO FOOD ALLERGENS 60 – 50 – 40 – 30 – 20 – 10 – 0 (+) TO FOOD AND INHALANT ALLERGENS 39.1% 6.5% 5.1%
    • Accuracy of ImmunoCAP® Rapid in the diagnosis of allergic sensitization in children between 1 and 14 years with recurrent wheezing: The IReNE study Diaz-Vazquez Pediatr Allergy Immunol 2009:20:601
      • In the identification of a child as atopic, the positive post-test probability of ICR depended on the color degrees considered: 88.4% for any positive and 97.6% for the most intense tones.
      • ICR showed good reliability for the most prevalent allergen, the dust mite.
      • A greater intensity of color of the lines of ICR was related to higher levels of specific IgE in blood. ICR is a reliable test for the identification of atopy in children .
    • Pre-test probability of disease can be compared with the estimated later probability of disease using the information provided by a diagnostic test. The difference between the previous probability and the later probability is an effective way to analyze the efficiency of a diagnostic method. Post-test probability is calcualted using likelihood ratios of the method and pre-test probability or prevalence of the disease. Accuracy of ImmunoCAP® Rapid in the diagnosis of allergic sensitization in children between 1 and 14 years with recurrent wheezing: The IReNE study Diaz-Vazquez Pediatr Allergy Immunol 2009:20:601
    • 3.80 In children with baseline FeNO> 24.4 ppb (the 75th percentile) p<0.001 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0
      • FeNO using the off-line tidal breathing technique.
      • 89 children, (12-59 mo), with moderate-to-severe intermittent wheezing.
      Effect of elevated exhaled nitric oxide levels on the risk of respiratory tract illness in preschool-aged children with moderate-to-severe intermittent wheezing Beigelman Ann Allergy Asthma Immunol 2009;103:108 RR of respiratory tract illnesses (RTIs)
    • 3.80 In children with baseline FeNO> 24.4 ppb (the 75th percentile) p<0.001 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0
      • FeNO using the off-line tidal breathing technique.
      • 89 children, (12-59 mo), with moderate-to-severe intermittent wheezing.
      Effect of elevated exhaled nitric oxide levels on the risk of respiratory tract illness in preschool-aged children with moderate-to-severe intermittent wheezing Beigelman Ann Allergy Asthma Immunol 2009;103:108 RR of respiratory tract illnesses (RTIs) FeNO levels of >24.4 ppb were associated with more positive skin test results to aeroallergens ( P =0.03 ).
    • 3.80 In children with baseline FeNO> 24.4 ppb (the 75th percentile) p<0.001 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0
      • FeNO using the off-line tidal breathing technique.
      • 89 children, (12-59 mo), with moderate-to-severe intermittent wheezing.
      Effect of elevated exhaled nitric oxide levels on the risk of respiratory tract illness in preschool-aged children with moderate-to-severe intermittent wheezing Beigelman Ann Allergy Asthma Immunol 2009;103:108 RR of respiratory tract illnesses (RTIs) An elevated FeNO in preschool-aged children with moderate-to-severe intermittent wheezing was associated with an increased risk of RTI during a 1-year follow-up. In addition, a higher FeNO was associated with aeroallergen sensitization.
    • Effect of elevated exhaled nitric oxide levels on the risk of respiratory tract illness in preschool-aged children with moderate-to-severe intermittent wheezing Beigelman Ann Allergy Asthma Immunol 2009;103:108 Distribution of the fractional concentration of exhaled nitric oxide (FeNO) levels. Kaplan-Meier estimates of the time to a first episode of respiratory tract illness (RTI) by fractional concentration of exhaled nitric oxide (FeNO) level at randomization.
    • Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study Scott Thorax 2010;65:258–262 influence of atopy and asthma on FeNO
      • The Isle of Wight birth cohort (n=1456) reassessed at 18 years of age.
      • Questionnaires, SPTs and FeNO
    • Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study Scott Thorax 2010;65:258–262 (FeNO) and increasing SPTs positivity to aeroallergens
      • The Isle of Wight birth cohort (n=1456) reassessed at 18 years of age.
      • Questionnaires skin prick testing and FeNO
    • Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study Scott Thorax 2010;65:258–262 Wheezing attacks in atopic versus non-atopic patients with asthma
    • Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study Scott Thorax 2010;65:258–262 Conclusions: FeNO behaves as a biomarker of atopy and the “allergic asthma” phenotype rather than asthma itself. This may explain why FeNO-guided asthma treatment outcomes have proved to be of limited success where atopic status has not been considered and accounted for.
    • Background: Fraction of exhaled nitric oxide (FeNO) is considered, by some authors, to be a treatment follow-up parameter in allergic asthmatics. However, factors such as active smoking can influence NO production and must be taken into account in the interpretation of FeNO values . In children, the evidence in favour of an impact of passive smoking (PS) on FeNO values is controversial. The aim of this study was to evaluate the impact of chronic PS on FeNO in allergic asthmatic children. Passive smoking is a major determinant of exhaled nitric oxide levels in allergic asthmatic children Y. Laoudi, Allergy 2010;65;491
    • Passive smoking is a major determinant of exhaled nitric oxide levels in allergic asthmatic children Y. Laoudi, Allergy 2010;65;491
      • 70 nontreated allergic asthmatic children > 5 years of age
      • exposed and unexposed to PS
      • FeNO, spirometry, and allergic tests
      P<0.001 FeNO geometric mean
    • Passive smoking is a major determinant of exhaled nitric oxide levels in allergic asthmatic children Y. Laoudi, Allergy 2010;65;491
      • 70 nontreated allergic asthmatic children > 5 years of age
      • exposed and unexposed to PS
      • FeNO, spirometry, and allergic tests
      Negative correlation between FeNO values and the number of cigarettes smoked at home per day
    • Passive smoking is a major determinant of exhaled nitric oxide levels in allergic asthmatic children Y. Laoudi, Allergy 2010;65;491
      • 70 nontreated allergic asthmatic children > 5 years of age
      • exposed and unexposed to PS
      • FeNO, spirometry, and allergic tests
      Negative correlation between FeNO values and the number of cigarettes smoked at home per day Passive smoking lowers FeNO, and might be a major determinant of FeNO levels in nontreated allergic asthmatic children
    • The potential use of spirometry during methacholine challenge test in young children with respiratory Vilozni, Ped Pul 2009;44:720 Background :The concentration of methacholine that causes a fall of 20% from baseline forced expiratory volume in the first second (PC20-FEV 1 ) in the methacholine challenge test (MCT) is not usually considered a diagnostic tool in preschool children since PC20-FEV 1 may not be achievable <6 years of age.
      • 3- to 6-year-old children (inhaled triple-concentration increments [0.057-13.925 mg] of methacholine solution).
      • 84 children previously diagnosed with asthma (asthmatics) and 48 with prolonged cough (coughers).
      10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 1.48 9.45 Asthmatics Coughers PC25 FEV 0.5 p <0.0001 The potential use of spirometry during methacholine challenge test in young children with respiratory Vilozni, Ped Pul 2009;44:720
      • 3- to 6-year-old children (inhaled triple-concentration increments [0.057-13.925 mg] of methacholine solution).
      • 84 children previously diagnosed with asthma (asthmatics) and 48 with prolonged cough (coughers).
      10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 1.48 9.45 Asthmatics Coughers PC25 FEV 0.5 p <0.0001 The potential use of spirometry during methacholine challenge test in young children with respiratory Vilozni, Ped Pul 2009;44:720 A cut-off at 2.2 mg/ml for PC25-FEV 0.5 had 73.8% sensitivity and 72.9% specificity, for clinical diagnosis of asthma.
    • Qualitative Analysis of High-Resolution CT Scans in Severe Asthma Gupta CHEST 2009; 136:1521
      • 185 pts with difficult asthma underwent HRCT scan
      80 – 60 – 40 – 20 – 0 62 % % SUBJECTS WITH 40% Bronchial wall thickening Bronchiectasis Emphysema 8 %
    • Qualitative Analysis of High-Resolution CT Scans in Severe Asthma Gupta CHEST 2009; 136:1521
      • 185 pts with difficult asthma underwent HRCT scan
      80 – 60 – 40 – 20 – 0 62 % % SUBJECTS WITH 40% Bronchial wall thickening Bronchiectasis Emphysema HRCT scan abnormalities are common in patients with severe asthma, therefore CT scan acquisition may be required in all patients with severe asthma. 8 %
    • Qualitative Analysis of High-Resolution CT Scans in Severe Asthma Gupta CHEST 2009; 136:1521
      • Representative images of patient categories based on the presence or absence of Bronchiolar wall thickening (BWT) and
      • Bronchiectasis (BE) on HRCT scans as follows:
      • BWT-/BE-;
      • BWT-/BE+;
      • (C) BWT+/ BE+;
      • and ( D) BWT+/BE-
      • Asthma evaluation of severity
    • Background: Little is known about the perception of airflow obstruction in patients hospitalized for acute asthma. Objectives: To evaluate patient perception of airflow obstruction at hospital discharge and at a 2-week follow-up visit and to determine whether symptom control and/or severity of airflow obstruction identified patients at risk for acute asthma after discharge. Perception of airflow obstruction in patients hospitalized for acute asthma Davis Ann Allergy Asthma Immunol 2009;102:455
      • FEV 1 % predicted at discharge and 2 weeks after discharge.
      • Perception of airflow obstruction (symptom control vs FEV 1 % predicted) and perception of change in airflow obstruction (change in symptom control vs % change in FEV 1 ) between the 2 visits.
      • 51 participants.
      Change in symptom control was not significantly associated with change in airflow obstruction ( P =0.20), indicating poor perception of change in airflow obstruction . Perception of airflow obstruction in patients hospitalized for acute asthma Davis Ann Allergy Asthma Immunol 2009;102:455
      • FEV 1 % predicted at discharge and 2 weeks after discharge.
      • Perception of airflow obstruction (symptom control vs FEV 1 % predicted) and perception of change in airflow obstruction (change in symptom control vs % change in FEV 1 ) between the 2 visits.
      • 51 participants.
      Greater airflow obstruction at follow-up ( P =0.02) and a smaller improvement in airflow obstruction ( P =0.03), but not symptom control, were associated with a higher risk of acute asthma after discharge Perception of airflow obstruction in patients hospitalized for acute asthma Davis Ann Allergy Asthma Immunol 2009;102:455
    • Perception of airflow obstruction in patients hospitalized for acute asthma Davis Ann Allergy Asthma Immunol 2009;102:455 Mean Asthma Control Questionnaire symptom score and mean FEV 1 % pred in participants with and without subsequent acute asthma. AT DISCHARGE AT DISCHARGE AT FOLLOW-UP AT FOLLOW-UP ns ns ns Symptom score FEV 1 % pred
    • Perception of airflow obstruction in patients hospitalized for acute asthma Davis Ann Allergy Asthma Immunol 2009;102:455 Mean Asthma Control Questionnaire symptom score and mean FEV 1 % pred in participants with and without subsequent acute asthma. AT DISCHARGE AT DISCHARGE AT FOLLOW-UP AT FOLLOW-UP ns ns ns Symptom score FEV 1 % pred An asthmatic patients admited to hospital should have a spirometry two weeks after discharge!
      • Approximately 1 in 5 participants had an episode of acute asthma within 90 days of hospital discharge.
      • Interestingly, neither the level of asthma symptom control (evaluated with ACT) nor the severity of airflow obstruction at discharge identified participants at higher risk for an acute asthma event.
      • In contrast, more severe airflow obstruction at the 2-week follow-up visit or a smaller improvement in airflow obstruction between the visits (but not asthma symptom control) was significantly associated with an increased risk of acute asthma .
      Perception of airflow obstruction in patients hospitalized for acute asthma Davis Ann Allergy Asthma Immunol 2009;102:455
      • exacerbations
      • Parents (n=238) of children age 12 to 59 mo. with moderate-to-severe intermittent wheezing
      • signs and symptoms at the start of a respiratory tract illness
      % symptoms 50 – 40 – 30 – 20 – 10 – 0 41% nose symptoms 29% 13% Signs and Symptoms that Precede Wheezing in Children with a Pattern of Moderate-to-Severe Intermittent Wheezing Rivera-Spoljaric, J Ped 2009;154;877 significant cough insignificant cough 41%
      • Parents (n=238) of children age 12 to 59 mo. with moderate-to-severe intermittent wheezing
      • signs and symptoms at the start of a respiratory tract illness
      % symptoms 50 – 40 – 30 – 20 – 10 – 0 41% nose symptoms 29% 13% Signs and Symptoms that Precede Wheezing in Children with a Pattern of Moderate-to-Severe Intermittent Wheezing Rivera-Spoljaric, J Ped 2009;154;877 significant cough insignificant cough 41% The most reliable predictor of subsequent wheezing was significant cough , which had a specificity of 78% and a PPV of 74% for predicting wheezing
    • Detection and home management of worsening asthma symptoms. Garbutt Ann Allergy Asthma Immunol 2009;103:469 Background: Asthma guidelines recommend early home treatment of exacerbations. However, home treatment is often suboptimal and delayed. Objectives: To describe antecedent symptoms and signs of asthma exacerbations noticed by parents and to learn when and how parents intensify asthma treatment.
    • Detection and home management of worsening asthma symptoms. Garbutt Ann Allergy Asthma Immunol 2009;103:469
      • Parents of children (n=101) 2 to 12 years old with asthma exacerbations that required urgent care in the past 12 mo.
      • Telephone questionnaires.
      Respiratory symptoms 24% % Signs and Symptoms Preceding Exacerbations Cold Behaviour change Other nonspecific symptoms 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 29% 43% 79%
    • Detection and home management of worsening asthma symptoms. Garbutt Ann Allergy Asthma Immunol 2009;103:469
      • Parents of children (n=101) 2 to 12 years old with asthma exacerbations that required urgent care in the past 12 mo.
      • Telephone questionnaires.
      Cough Treatment was Most Often Intensified When the Parent Noticed Shortness of breath Wheeze 60 – 50 – 40 – 30 – 20 – 10 – 0 55% 54% 25%
    • Detection and home management of worsening asthma symptoms. Garbutt Ann Allergy Asthma Immunol 2009;103:469
      • Parents of children (n=101) 2 to 12 years old with asthma exacerbations that required urgent care in the past 12 mo.
      • Telephone questionnaires.
      Cough Shortness of breath Wheeze 60 – 50 – 40 – 30 – 20 – 10 – 0 55% 54% 25% Cold is not considered an allarming sign! Treatment was Most Often Intensified When the Parent Noticed
    • Detection and home management of worsening asthma symptoms. Garbutt Ann Allergy Asthma Immunol 2009;103:469
      • Parents of children (n=101) 2 to 12 years old with asthma exacerbations that requir ed urgent care in the past 12 mo.
      • Telephone questionnaires.
      Cough Shortness of breath Wheeze 60 – 50 – 40 – 30 – 20 – 10 – 0 55% 54% 25% and included adding: - albuterol (92%), - an oral corticosteroid (17%), - an inhaled corticosteroid (8%), or - other nonasthma medications (16%). Treatment was Most Often Intensified When the Parent Noticed
    • Detection and home management of worsening asthma symptoms. Garbutt Ann Allergy Asthma Immunol 2009;103:469 Conclusions: Although parents described antecedent symptoms and signs of impending asthma exacerbations that they consistently noticed in their children, many waited for lower respiratory signs to be present before intensifying treatment . Oral and inhaled corticosteroids were used infrequently . Interventions to improve the ability of parents and children to accurately recognize worsening symptoms and initiate timely, effective treatment are needed.
    • Recent asthma exacerbations predict future exacerbations in children with severe or difficult-to-treat asthma Haselkorn JACI 2009;124:921
      • To investigate the risk of future severe exacerbations (FSEs) in children with severe/difficult-to-treat asthma and recent severe exacerbations (RSEs).
      • Children age 6 to 11 years.
      RECENT SEVERE EXACERBATION 3.08 3-4 ALLERGY TRIGGERS POORLY CONTROLLED ASTHMA 2.05 1.59 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 OR for Future Severe Exacerbation in the Following 6 Months
    • Recent asthma exacerbations predict future exacerbations in children with severe or difficult-to-treat asthma Haselkorn JACI 2009;124:921
      • To investigate the risk of future severe exacerbations (FSEs) in children with severe/difficult-to-treat asthma and recent severe exacerbations (RSEs).
      • Children age 6 to 11 years.
      RECENT SEVERE EXACERBATION 3.08 3-4 ALLERGY TRIGGERS POORLY CONTROLLED ASTHMA 2.05 1.59 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 OR for Future Severe Exacerbation in the Following 6 Months Recent severe asthma exacerbations are an important independent predictor of FSE in children with severe/difficult-to-treat asthma and should be considered when establishing asthma management plans.
    • Recent asthma exacerbations predict future exacerbations in children with severe or difficult-to-treat asthma Haselkorn JACI 2009;124:921   PREDICTORS OF FUTURE EXACERBATIONS
    • Consistently very poorly controlled asthma,increases risk for future severe asthma exacerbations (TENOR) study Haselkorn JACI 2009;124:895
      • 82 children (6-11 years) and 725 adolescent/adult patients ≥12 years.
      • Follow-up: 24 months.
      in Children with Consistently Very Poorly Controlled Asthma OR for 6.4 HOSPITALIZATION, EMERGENCY DEPARTMENT VISIT, OR CORTICOSTEROID BURST 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0
    • Process quality measures and asthma exacerbations in the Medicaid population Yong JACI 2009;124:961
      • Medicaid beneficiaries (90,909 subjects with persistent asthma ).
      • At least 1 controller medication filling.
      • At least 4 controller medication prescription fillings.
      • A controller-to-total asthma medication ratio of at least 0.5.
      N° OF FILLED PRESCRIPTION FOR CONTROLLER MEDICATIONS 1.80 1 4 ≥50% 1.44 0.77 2.0 – 1.5 – 1.0 – 0.5 – 0 OR FOR ASTHMA EXACERBATION
    • Process quality measures and asthma exacerbations in the Medicaid population Yong JACI 2009;124:961
      • Medicaid beneficiaries (90,909 subjects with persistent asthma).
      • At least 1 controller medication filling.
      • At least 4 controller medication prescription fillings.
      • A controller-to-total asthma medication ratio of at least 0.5.
      N° OF FILLED PRESCRIPTION FOR CONTROLLER MEDICATIONS 1.80 1 4 ≥50% 1.44 0.77 2.0 – 1.5 – 1.0 – 0.5 – 0 OR FOR ASTHMA EXACERBATION A higher controller medication ratio indicated a lower likelihood of asthma exacerbations
    • Asthma morbidity among inner-city adolescents receiving guidelines-based therapy: Role of predictors in the setting of high adherence Gruchalla JACI 2009;124:213
      • 546 inner-city residents, ages 12-20 years, with persistent asthma.
      • Predictors of future symptoms and exacerbations over the subsequent 46 weeks , during which guidelines-based, optimal asthma management was offered.
      Baseline exhaled nitric oxide, total IgE, allergen-specific IgE, asthma symptoms, lung function, peripheral blood eosinophils, and airway hyperresponsiveness and sputum eosinophils accounted for only a small portion of the variance for future maximum symptom days and exacerbations—11.4% and 12.6%, respectively.
    • Asthma morbidity among inner-city adolescents receiving guidelines-based therapy: Role of predictors in the setting of high adherence Gruchalla JACI 2009;124:213
      • 546 inner-city residents, ages 12-20 years, with persistent asthma.
      • Predictors of future symptoms and exacerbations over the subsequent 46 weeks , during which guidelines-based, optimal asthma management was offered.
      Baseline exhaled nitric oxide, total IgE, allergen-specific IgE, asthma symptoms, lung function, peripheral blood eosinophils, and airway hyperresponsiveness and sputum eosinophils accounted for only a small portion of the variance for future maximum symptom days and exacerbations—11.4% and 12.6%, respectively. The usual predictors of future disease activity have little predictive power when applied to a highly adherent population with persistent asthma.
    • Asthma morbidity among inner-city adolescents receiving guidelines-based therapy: Role of predictors in the setting of high adherence Gruchalla JACI 2009;124:213 Relative importance of baseline characteristics for predicting (A) maximum symptom days and (B) exacerbations during 46 weeks follow-up RELATIVE IMPORTANCE
      • Recent asthma exacerbations
      • Poor asthma control
      • Severe airway obstruction
      • History of intensive care admissions or frequent emergency department visits
      • Elevated FENO levels
      • Allergen sensitivity and exposure
      • Depression
      • Poor attitudes about the use of asthma medicines
      The literature suggests that an increased risk of symptoms and exacerbations may be predicted by numerous factors including: Asthma morbidity among inner-city adolescents receiving guidelines-based therapy: Role of predictors in the setting of high adherence Gruchalla JACI 2009;124:213
    • Continuity of Prescribers of Short-Acting Beta Agonists among Children with Asthma K Dombkowski, J Ped 2009;155;788 B2 agonist prescribers MULTIPLE ONE 62% 70 – 60 - 50 - 40 - 30 – 20 – 10 – 0 38% % children
      • Medicaid administrative claims (2004-2005) for children ages 5 to 18 with asthma
      • SABA prescriber continuity (the number and site of prescribers)
      • Medicaid administrative claims (2004-2005) for children ages 5 to 18 with asthma
      • SABA prescriber continuity (the number and site of prescribers)
      Continuity of Prescribers of Short-Acting Beta Agonists among Children with Asthma K Dombkowski, J Ped 2009;155;788 3 – 2 – 1 – 0 OR for an emergency department visit 2.7 Children with multiple prescribers compared with those with 1 prescriber salbutamol
    • Prospective Study of Physical Activity and Risk of Asthma Exacerbations in Older Women Garcia-Aymerich Am J Respir Crit Care Med 2009;179:999
      • 2,818 women with asthma.
      • Monitored from 1998 to 2000.
      Baseline (1998) physical activity metabolic equivalent 4/wk Probability (95% Cl) of exacerbation
    • Prospective Study of Physical Activity and Risk of Asthma Exacerbations in Older Women Garcia-Aymerich Am J Respir Crit Care Med 2009;179:999
      • 2,818 women with asthma.
      • Monitored from 1998 to 2000.
      Baseline (1998) physical activity metabolic equivalent 4/wk Probability (95% Cl) of exacerbation Regular physical activity was associated with reduced risk of exacerbations in women with asthma in this longitudinal study.
    • 33% Smokers 35 – 30 – 25 – 20 – 15 – 10 – 0 5 – 0 0
      • A 63-site medical record review study of ED patients, ages 14 to 54 yrs, with a principal diagnosis of acute asthma.
      • 4,052 patient.
      Multicenter study of cigarette smoking among patients presenting to the emergency department with acute asthma Patel Ann Allergy Asthma Immunol 2009;103:121 % Patients with Acute Asthma Seen in ED
    • Multicenter study of cigarette smoking among patients presenting to the emergency department with acute asthma Patel Ann Allergy Asthma Immunol 2009;103:121 25 – 20 – 15 – 10 – 0 5 – 0 12% % Subjects Receiving Antibiotics Smokers Non Smokers Smokers Non Smokers 9% 23% 14% P<0.001 P<0.001 In ED Department At Discharge
    • Multicenter study of cigarette smoking among patients presenting to the emergency department with acute asthma Patel Ann Allergy Asthma Immunol 2009;103:121 25 – 20 – 15 – 10 – 0 5 – 0 12% % Subjects Receiving Antibiotics Smokers Non Smokers Smokers Non Smokers 9% 23% 14% P<0.001 P<0.001 A multivariate analysis confirmed that smoking status was independently associated with antibiotic administration OR= 1.6 In ED Department At Discharge
    • Changes in weather and the effects on pediatric asthma exacerbations Mireku Ann Allergy Asthma Immunol 2009;103:220
      • A retrospective study during a 2-year period.
      • The effects of climactic factors were evaluated on the day of admission (T = 0) and up to 5 days before admission (T − 5 through T − 1).
      • 25,401 asthma ED visits.
      A 10% intraday increase in humidity on day T−1 ( P <0.001) or day T−2 (P =0.01) was associated with approximately 1 additional ED visit for asthma
    • Poorly controlled asthma Difficult asthma
      • Children with difficult asthma (DA) have continued symptoms despite high-dose inhaled corticosteroids (ICS) and other therapies.
      • Confirmation of asthma diagnosis , identification and treatment of associated diagnoses is essential.
      • Potential reversible factors, such as poor treatment adherence and continued allergen exposure , should be addressed.
        • Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
        • Bossley ERJ 2009:34:1052
      • Identification of corticosteroid resistance is important, allowing the clinician to deploy alternative therapies; conversely, in the corticosteroid sensitive patient, the dose of therapy should be minimised to avoid unwanted side-effects.
      • The administration of a 2-week course of high-dose systemic corticosteroids , with investigation of noninvasive markers of inflammation before and after corticosteroids, followed by bronchoscopy at the end of the corticosteroid trial is usually performed.
        • Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
        • Bossley ERJ 2009:34:1052
    • Difficult asthma investigation protocol
        • Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
        • Bossley ERJ 2009:34:1052
        • Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
        • Bossley ERJ 2009:34:1052
      • We hypothesised that complete corticosteroid responsiveness [defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction ( F eNO) and no bronchodilator responsiveness (BDR <12%)] is uncommon in paediatric difficult asthma (DA).
      • 102 children, mean age 11.6 yrs, with DA underwent spirometry, BDR and F eNO before and after 2 weeks of systemic corticosteroids.
      51% % Patients with Alternative Diagnosis 60 – 50 – 40 – 30 – 20 – 10 – 0
        • Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
        • Bossley ERJ 2009:34:1052
      11% % Subjects with Complete Response to Corticosteroids 15 – 10 – 5 – 0
      • We hypothesised that complete corticosteroid responsiveness [defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction ( F eNO) and no bronchodilator responsiveness (BDR <12%)] is uncommon in paediatric difficult asthma (DA).
      • 102 children, mean age 11.6 yrs, with DA underwent spirometry, BDR and F eNO before and after 2 weeks of systemic corticosteroids.
        • Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
        • Bossley ERJ 2009:34:1052
      11% % Subjects with Complete Response to Corticosteroids 15 – 10 – 5 – 0
      • We hypothesised that complete corticosteroid responsiveness [defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction ( F eNO) and no bronchodilator responsiveness (BDR <12%)] is uncommon in paediatric difficult asthma (DA).
      • 102 children, mean age 11.6 yrs, with DA underwent spirometry, BDR and F eNO before and after 2 weeks of systemic corticosteroids.
      The rarity of complete corticosteroid responsiveness suggests alternative therapies are needed for children with difficult asthma.
        • Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
        • Bossley ERJ 2009:34:1052
      • In children with Difficult Asthma, males predominate and atopy is very common ;
      • Many children are exposed to environmental influences (cigarette smoke) known to cause corticosteroid resistance;
      • Associated diagnoses are common especially in nonatopic subjects;
      • Response to a corticosteroid trial is difficult to predict, with the majority of subjects exhibiting only a partial response;
      • BDR is common even after a corticosteroid trial even though most subjects were taking LABA. The latter may reflect noncompliance , tachyphylaxis or a genuine bronchodilator-resistant state.
        • Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
        • Bossley ERJ 2009:34:1052
      • Partial corticosteroid response was common, and the incomplete response may be due to ongoing exposure to environmental triggers .
      • Environmental factors are likely to play an important role in DA . We have shown that 65% of atopic children who had pets were allergic to them, and other studies have shown that persistent allergen exposure in those sensitised can lead to an IL-2 and IL-4 mediated corticosteroid resistance.
      • Thus, it is likely that the ongoing allergen exposure contributed to their poor symptom control, despite high-dose treatment .
    • 5 – 4 – 3 – 2 – 1 – 0 n° children 4/60 5/60 With different diagnosis With persisting difficult asthma despite admission to center Difficult Asthma: Can Symptoms be Controlled in a Structured Environment? De Boeck, Ped Pul 2009;44:743
      • Difficult asthma implies persistent asthma symptoms despite therapy with high doses of inhaled corticosteroids.
      • 60 children (≥ 6 years) referred because of difficult asthma to the rehabilitation centre over a period of 10 years.
    • Difficult Asthma: Can Symptoms be Controlled in a Structured Environment? De Boeck, Ped Pul 2009;44:743
      • Difficult asthma implies persistent asthma symptoms despite therapy with high doses of inhaled corticosteroids.
      • 60 children (≥ 6 years) referred because of difficult asthma to the rehabilitation centre over a period of 10 years.
      Factors contributing to poor asthma control in the home situation in children referred with a diagnosis of difficult asthma but in whom symptoms could be controlled in a residential setting (n=51/60) (85%)
    • 5/60 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 % children 85% 51/60 who improved in the resedential setting Difficult Asthma: Can Symptoms be Controlled in a Structured Environment? De Boeck, Ped Pul 2009;44:743
      • Difficult asthma implies persistent asthma symptoms despite therapy with high doses of inhaled corticosteroids.
      • 60 children (≥ 6 years) referred because of difficult asthma to the rehabilitation centre over a period of 10 years.
    • 5/60 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 % children 85% 51/60 who improved in the resedential setting
      • Poor atherence 63%
      • Environmental factor 63%
      • Psychosocial factor 70%
      Difficult Asthma: Can Symptoms be Controlled in a Structured Environment? De Boeck, Ped Pul 2009;44:743
      • Difficult asthma implies persistent asthma symptoms despite therapy with high doses of inhaled corticosteroids.
      • 60 children (≥ 6 years) referred because of difficult asthma to the rehabilitation centre over a period of 10 years.
      Causative factor of poor response at home
    • Phenotypic determinants of uncontrolled asthma Siroux JACI 2009;124:681
      • 501 adult patients with asthma.
      • Asthma control, as defined in the 2006 Global Initiative for Asthma guidelines.
      • In non-ICS users , high total IgE and sensitization to molds were associated with uncontrolled asthma.
      • In ICS users , chronic cough or phlegm were independently and significantly related to uncontrolled asthma.
    • Phenotypic determinants of uncontrolled asthma Siroux JACI 2009;124:681 Adjusted risks between asthma control and clinical characteristics, according to ICS use in the past 12 months.
      • General practitioner prescription refill records.
      • 182 patients
      % Patients Who Filled ≤ 50% Inhaled Medication Prescriptions 35% 40 – 30 – 20 – 10 – 0 The Prevalence of Nonadherence in Difficult Asthma Gamble AJRCCM 2009:180:817
      • General practitioner prescription refill records.
      • 182 patients
      % Patients Who Admitted Poor Adherence With Inhaled Therapy After Initial Denial 88% The Prevalence of Nonadherence in Difficult Asthma Gamble AJRCCM 2009:180:817 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 100 –
      • General practitioner prescription refill records.
      • 182 patients
      % Patients Who Admitted Poor Adherence With Inhaled Therapy After Initial Denial 88% The Prevalence of Nonadherence in Difficult Asthma Gamble AJRCCM 2009:180:817 51 patients (45%) prescribed oral steroids were found to be nonadherent. 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 100 –
      • Compliance
      • Asthma education
    • Monitoring adherence to beclomethasone in asthmatic children and adolescents through four different methods Jentzsch Allergy 2009:64:1458
      • 102 randomly selected asthmatic children and adolescents.
      • Followed for 12 months.
      • Adherence rate assessed every 2 months by self and/or parent report, pharmacy dispensing data, electronic device monitor, and canister weight.
      Adherence rate for each of the four different methods. 97.9% 70% 51.5% 46.3%
    • Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma Cohen Ann Allergy Asthma Immunol 2009;103:325 Background: A validated tool to assess adherence with inhaled corticosteroids (ICS) could help physicians and researchers determine whether poor asthma control is due to poor adherence or severe intrinsic asthma. Objective: To assess the performance of the Medication Adherence Report Scale for Asthma (MARS-A), a 10-item, self-reported measure of adherence with ICS. Permission to use it should be obtained by requests to Rob.horne@pharmacy.ac.uk.
    • Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma Cohen Ann Allergy Asthma Immunol 2009;103:325 MARS-A is 10-item questionnaire with several desirable characteristics for assessing ICS use. It includes both generic (&quot;I use it regularly every day&quot;) and asthma-specific questions about medication use (&quot;I only use it when I feel breathless&quot;). It also assesses both intentional (&quot;I avoid using it if I can&quot;) and nonintentional nonadherence (&quot;I forget to use it&quot;). Questions are framed as negative statements to minimize social desirability bias and set a tone of nonadherence being normal , and medication use is rated on a 5-point Likert scale (1 indicating always to 5 indicating never). Self-reported Medication Adherence
    • Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma Cohen Ann Allergy Asthma Immunol 2009;103:325
      • Self-reported Medication Adherence
      • How often do you do the following:
      • Alaways
      • Often
      • Sometimes
      • Rarely
      • Never
      High self-reported adherence was defined as a MARS score of ≥4.5
    • Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma Cohen Ann Allergy Asthma Immunol 2009;103:325
      • 318 asthmatic adults.
      • MARS-A at baseline and 1 and 3 months.
      • ICS adherence was measured electronically in 53 patients.
      52% % Days in which ICS were Used 60 – 50 – 40 – 30 – 20 – 10 – 0 According to Electronic Measurement
    • Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma Cohen Ann Allergy Asthma Immunol 2009;103:325
      • 318 asthmatic adults.
      • MARS-A at baseline and 1 and 3 months.
      • ICS adherence was measured electronically in 53 patients.
      52% % Days in which ICS were Used 60 – 50 – 40 – 30 – 20 – 10 – 0 According to Electronic Measurement Continuous MARS-A scores correlated with continuous electronic adherence ( r = 0.42, P <.001),
    • Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma Cohen Ann Allergy Asthma Immunol 2009;103:325
      • 318 asthmatic adults.
      • MARS-A at baseline and 1 and 3 months.
      • ICS adherence was measured electronically in 53 patients.
      52% % Days in which ICS were Used 60 – 50 – 40 – 30 – 20 – 10 – 0 According to Electronic Measurement High self-reported adherence predicted high electronic adherence (OR = 10.6; P <.001).
      • 433 asthmatic children aged 1-18 years discharged after asthma treatment in ED.
      • Control subjects received instructions to follow-up with a primary care provider ( PCP) within 3 to 5 days.
      • Intervention subjects received a letter to take to their PCP, viewed a video on importance of asthma control, and received a mailed reminder
      Beliefs and Barriers to Follow-up After an Emergency Department Asthma Visit: A Randomized Trial Zorc Pediatrics 2009;124;1135 RATES OF PCP FOLLOW-UP DURING THE MONTH AFTER THE ED VISIT 44.5% INTERVENTION CONTROL 50 – 40 – 30 – 20 – 10 – 0 43.8%
      • 433 asthmatic children aged 1-18 years discharged after asthma treatment in ED.
      • Control subjects received instructions to follow-up with a primary care provider ( PCP) within 3 to 5 days.
      • Intervention subjects received a letter to take to their PCP, viewed a video on importance of asthma control, and received a mailed reminder
      Beliefs and Barriers to Follow-up After an Emergency Department Asthma Visit: A Randomized Trial Zorc Pediatrics 2009;124;1135 RATES OF PCP FOLLOW-UP DURING THE MONTH AFTER THE ED VISIT 44.5% INTERVENTION CONTROL 50 – 40 – 30 – 20 – 10 – 0 43.8% An ED-based intervention increased knoledge but did not increase PCP follow-up or asthma-related outcomes.
    • 10.9 n°of canister of ICS used in 1 year SDM CDM 5.2
      • 612 adults with poorly controlled asthma
      • Randomized to shared decision making ( SDM ) or clinician decision making ( CDM )
      • Follow up:1-2 years
      Shared Treatment Decision Making Improves Adherence and Outcomes in Poorly Controlled Asthma Wilson AJRCCM 2010;181:566 15 – 10 – 5 – 0 P<0.0001
    • 70% % of Patients Saying that they Used ICS all or most of the Time when Asymptomatic Impact of positive and negative beliefs about inhaled corticosteroids on adherence in inner-city asthmatic patients. Ponieman Ann Allergy Asthma Immunol 2009;103:38 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0
      • 261 patients with high rates of: - asthma hospitalization, - ED visits, - intubation, and - oral corticosteroid use.
    • Worried about side effects % Patients 49% 37% 7% Worried about becoming addicted. Felt regimen hard to follow Impact of positive and negative beliefs about inhaled corticosteroids on adherence in inner-city asthmatic patients. Ponieman Ann Allergy Asthma Immunol 2009;103:38 50 – 40 – 30 – 20 – 10 – 0
      • 261 patients with high rates of: - asthma hospitalization, - ED visits, - intubation, and - oral corticosteroid use.
    • Felt that using ICS when asymptomatic was important OR for Adherence with ICS Use 4.5 2.23 0.52 Confident in using ICS Worries about side effects Regimen hard to follow Impact of positive and negative beliefs about inhaled corticosteroids on adherence in inner-city asthmatic patients. Ponieman Ann Allergy Asthma Immunol 2009;103:38 0.48 4.5 – 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0
    • Felt that using ICS when asymptomatic was important OR for Adherence with ICS Use 4.5 2.23 0.52 Confident in using ICS Worries about side effects Regimen hard to follow Impact of positive and negative beliefs about inhaled corticosteroids on adherence in inner-city asthmatic patients. Ponieman Ann Allergy Asthma Immunol 2009;103:38 0.48 4.5 – 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 Several positive and negative beliefs about ICS were associated with adherence. Eliciting and addressing these potentially modifiable beliefs may help improve adherence and outcomes.
    • A child's asthma quality of life rating does not significantly influence management of their asthma Mandhane, Ped Pul 2010;45:141
      • 287 (grade 2-5) children with asthma.
      • Parents and children completed a quality of life (QOL) questionnaire.
      6 – 5 – 4 – 3 – 2 – 1 – 0 5.41 4.54 Parents Children QOL score of asthmatic children p <0.001 EVALUATED BY
    • A child's asthma quality of life rating does not significantly influence management of their asthma Mandhane, Ped Pul 2010;45:141
      • 287 (grade 2-5) children with asthma.
      • Parents and children completed a quality of life (QOL) questionnaire.
      6 – 5 – 4 – 3 – 2 – 1 – 0 5.41 4.54 Parents Children QOL score of asthmatic children p <0.001 Parents rated their child's overall QOL higher than their child. EVALUATED BY
    • 0 -10 – -20 – -30 – -40 - -50 – - 46% - 36% OR=0.64 p=0.024 OR=0.54 P=0.016 For every point increase in the parent's overall QOL score, the child was less likely To receive ICS with previous 2 weeks To have missed school due to asthma
      • 287 (grade 2-5) children with asthma.
      • Parents and children completed a quality of life (QOL) questionnaire.
      A child's asthma quality of life rating does not significantly influence management of their asthma Mandhane, Ped Pul 2010;45:141
    • 0 -10 – -20 – -30 – -40 - -50 – - 46% - 36% OR=0.64 p=0.024 OR=0.54 P=0.016 For every point increase in the parent's overall QOL score, the child was less likely To receive ICS with previous 2 weeks To have missed school due to asthma
      • 287 (grade 2-5) children with asthma.
      • Parents and children completed a quality of life (QOL) questionnaire.
      A child's asthma quality of life rating does not significantly influence management of their asthma Mandhane, Ped Pul 2010;45:141 The child's QOL assessment, was not associated with the asthma management outcomes examined.
    • Improving Asthma Outcomes in Minority Children: A Randomized, Controlled Trial of Parent Mentors Flores Pediatrics 2009;124:1522 ITT Analysis of Differences Between Baseline and End Point (12-Month Follow-up) for Study Outcomes Among Control Subjects ( N= 108) and Intervention-Group Children ( N= 112)
    • Racial and Ethnic Disparities in Asthma Medication Usage and Health-Care Utilization Crocker CHEST 2009; 136:1063
      • 1,485 children surveyed
      55% % CHILDREN 60 – 50 – 40 – 30 – 20 – 10 - 0 WHITE HISPANIC BLACK 25% 20%
    • Racial and Ethnic Disparities in Asthma Medication Usage and Health-Care Utilization Crocker CHEST 2009; 136:1063 12% % CHILDREN USING A DAILY DOSE OF β 2 -AGONIST 60 – 50 – 40 – 30 – 20 – 10 - 0 WHITE HISPANIC BLACK 19% 26% P=0.001 33% % CHILDREN USING ICS 60 – 50 – 40 – 30 – 20 – 10 - 0 WHITE HISPANIC BLACK 22% 21% P=0.001
    • Racial and Ethnic Disparities in Asthma Medication Usage and Health-Care Utilization Crocker CHEST 2009; 136:1063 12% % CHILDREN USING A DAILY DOSE OF β 2 -AGONIST 60 – 50 – 40 – 30 – 20 – 10 - 0 WHITE HISPANIC BLACK 19% 26% P=0.001 33% % CHILDREN USING ICS 60 – 50 – 40 – 30 – 20 – 10 - 0 WHITE HISPANIC BLACK 22% 21% P=0.001 Black and Hispanic children compared with white children had more indicators of poorly controlled asthma, including increased emergency health-care utilization, more daily rescue medication use, and lower use of ICSs.
    • Improving Asthma Outcomes in Minority Children: A Randomized, Controlled Trial of Parent Mentors Flores Pediatrics 2009;124:1522
      • Effects of parent mentors (PMs) on asthma outcomes in minority children.
      • PMs = experienced parents of asthmatic children who received specialized training )
      • Patients were randomly assigned to PMs ( n=112) or the control group (n=108).
      • 12 month follow-up
      • Intervention children experienced:
      • significantly reduced asthma exacerbations, and emergency department (ED) visits and
      • reductions in missed parental work days.
    • Improving Asthma Outcomes in Minority Children: A Randomized, Controlled Trial of Parent Mentors Flores Pediatrics 2009;124:1522
      • Effects of parent mentors (PMs) on asthma outcomes in minority children.
      • PMs = experienced parents of asthmatic children who received specialized training )
      • Patients were randomly assigned to PMs ( n=112) or the control group (n=108).
      • 12 month follow-up
      The average monthly cost per patient for the PM program was $60.42, and net savings of $46.16 for participants.
      • Intervention children experienced:
      • significantly reduced asthma exacerbations, and emergency department (ED) visits and
      • reductions in missed parental work days.
    • Background: Complementary and alternative medicines (CAM), such as herbal remedies, are widely used by patients with chronic diseases, such as asthma. However, it is unclear whether use of the herbal remedies is associated with decreased adherence to inhaled corticosteroids (ICSs), a key component of asthma management. Objective: To examine the association among use of herbal remedies, adherence to prescribed ICSs, and medication and disease belief. Use of herbal remedies and adherence to inhaled corticosteroids among inner-city asthmatic patients Roy Ann Allergy Asthma Immunol 2010;104:118
    • % patients reported herbal remedy use 25.4% 30 - 25 - 20 - 15 - 10 - 5 - 0
      • 326 adults with persistent asthma.
      • CAM use (teas, herbs, and rubs) for the treatment of asthma in the prior 6 months.
      Use of herbal remedies and adherence to inhaled corticosteroids among inner-city asthmatic patients Roy Ann Allergy Asthma Immunol 2010;104:118
    • OR for adherence with ICS use
      • 326 adults with persistent asthma.
      • CAM use (teas, herbs, and rubs) for the treatment of asthma in the prior 6 months.
      Use of herbal remedies and adherence to inhaled corticosteroids among inner-city asthmatic patients Roy Ann Allergy Asthma Immunol 2010;104:118 0.4 Herbal remedy use 1.0 – 0.5 – 0
    • OR for adherence with ICS use
      • 326 adults with persistent asthma.
      • CAM use (teas, herbs, and rubs) for the treatment of asthma in the prior 6 months.
      Use of herbal remedies and adherence to inhaled corticosteroids among inner-city asthmatic patients Roy Ann Allergy Asthma Immunol 2010;104:118 0.4 Herbal remedy use 1.0 – 0.5 – 0 Herbal remedy users were also more likely to worry about the adverse effects of ICSs p= 0.01 .
    • ASTHMA CONTROL Guideliness
    • Seventeen Years of Asthma Guidelines: Why Hasn’t the Outcome Improved for Children? M. Weinberger, J Ped 2009;154:786 N° of hospitalizations for asthma per 10 000 children 0 to 17 years of age, 1980-2004 N° of visits to emergency departments for asthma per 10 000 children 0 to 17 years of age, 1992-2004 N° of deaths caused by asthma per 1 000 000 children 0 to 17 years of age, 1980-2004
    • Seventeen Years of Asthma Guidelines: Why Hasn’t the Outcome Improved for Children? M. Weinberger, J Ped 2009;154:786 N° of hospitalizations for asthma per 10 000 children 0 to 17 years of age, 1980-2004 N° of visits to emergency departments for asthma per 10 000 children 0 to 17 years of age, 1992-2004 N° of deaths caused by asthma per 1 000 000 children 0 to 17 years of age, 1980-2004 This lack of improvement in hospitalizations, emergency care and fatalities, cannot be argued to result from increased asthma prevalence during this period because the reported increase appears to be confined to identification of children with mild symptoms.
      • Patients with moderate asthma are symptomatic on an ongoing basis.
      • They are usually treated initially with low-dose inhaled corticosteroids (ICSs) supplemented with a short-acting bronchodilator as a rescue medication.
      • Most steroid-naive patients will achieve good control with this strategy.
      • For patients in whom adherence, inhaler technique, environmental control, and comorbidities have been addressed but who still have uncontrolled symptoms, the addition of a long-acting β -adrenergic agonist should be considered.
      • Some patients might require a higher dose of ICS.
      Achieving asthma control in patients with moderate disease FitzGerald JACI 2010;125:307
      • Leukotriene receptor antagonists might be considered as alternate initial therapy or as an add-on to maintenance therapy with an ICS.
      • All patients should receive a structured education program emphasizing the need for ongoing maintenance treatment, even when control is achieved.
      • Patients should also be provided with a written action plan that clearly explains which additional anti-inflammatory therapy should be taken if asthma symptoms worsen .
      • The most effective strategy in this situation has been shown to be the quadrupling of the maintenance dose of ICS.
      Achieving asthma control in patients with moderate disease FitzGerald JACI 2010;125:307
    • Achieving asthma control in patients with moderate disease FitzGerald JACI 2010;125:307
    • Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children Piacentini Allergy 2009:64:1753 C-ACT score≥19 = good control
    • Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children Piacentini Allergy 2009:64:1753 Relationship between C-ACT and FeNO in newly diagnosed
      • 200 asthmatic children: - 47 children with newly diagnosed asthma ('New') and without any regular controller therapy; and - 153 children with previously diagnosed asthma, treated according to GINA guidelines.
    • Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children Piacentini Allergy 2009:64:1753 Relationship between C-ACT and FeNO regularly followed-up asthmatic children .
      • 200 asthmatic children: - 47 children with newly diagnosed asthma ('New') and without any regular controller therapy; and - 153 children with previously diagnosed asthma, treated according to GINA guidelines.
    • Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children Piacentini Allergy 2009:64:1753 Correlation of C-ACT scores with other investigated parameters in newly diagnosed and regularly followed-up asthmatic children Newly Diagnosed r  = −0.51; r  = 0.34; r  = 0.32; P  <0.001 P  <0.022 P  <0.03 Regular Follow-up n.s. n.s. n.s. FeNO FEV 1 (%) FEV 1 /FVC
    • Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children Piacentini Allergy 2009:64:1753 Correlation of C-ACT scores with other investigated parameters in newly diagnosed and regularly followed-up asthmatic children Newly Diagnosed r  = −0.51; r  = 0.34; r  = 0.32; P  <0.001 P  <0.022 P  <0.03 Regular Follow-up n.s. n.s. n.s. FeNO FEV 1 (%) FEV 1 /FVC C-ACT is complementary to, but not a substitute for, other markers of disease control in asthmatic children, especially in the context of follow-up visits.
    • Asthma patients' perception of their ability to influence disease control and management Laforest Ann Allergy Asthma Immunol 2009;102:378
    • Asthma patients' perception of their ability to influence disease control and management Laforest Ann Allergy Asthma Immunol 2009;102:378
      • I nternal locus of control (LOC) orientation.
      • Patients reported their LOC orientation on a 100-mm visual analog scale (0%, “I have absolutely no influence on asthma change,” to 100%, “this change only depends on me”).
      • 163 patients.
      % Patients with an Internal LOC < 50%. 44.2% 50 – 40 – 30 – 20 – 10 – 0
    • Asthma patients' perception of their ability to influence disease control and management Laforest Ann Allergy Asthma Immunol 2009;102:378 “ How would you rate your personal influence on asthma change?” (Please insert a vertical stroke on the line below, at the place that you consider as the most appropriate to your own situation) I have absolutely no influence on asthma change Asthma change only depends on me 0% 100%
    • Asthma patients' perception of their ability to influence disease control and management Laforest Ann Allergy Asthma Immunol 2009;102:378 “ the change only depends on me”). “ I have absolutely no influence on asthma change,”
    • Asthma patients' perception of their ability to influence disease control and management Laforest Ann Allergy Asthma Immunol 2009;102:378 “ the change only depends on me”). “ I have absolutely no influence on asthma change,” Higher risk of poor control
    • Asthma patients' perception of their ability to influence disease control and management Laforest Ann Allergy Asthma Immunol 2009;102:378
      • Internal locus of control (LOC) orientation.
      • Patients reported their LOC orientation on a 100-mm visual analog scale (0%, “I have absolutely no influence on asthma change,” to 100%, “this change only depends on me”).
      • 163 patients.
      OR for a LOC <50% 2.68 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 In Patients with Inadequately Controlled Asthma
    • Asthma patients' perception of their ability to influence disease control and management Laforest Ann Allergy Asthma Immunol 2009;102:378
      • Internal locus of control (LOC) orientation.
      • Patients reported their LOC orientation on a 100-mm visual analog scale (0%, “I have absolutely no influence on asthma change,” to 100%, “this change only depends on me”).
      • 163 patients.
      2.68 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 In Patients with Inadequately Controlled Asthma Asthma control was related to internal LOC orientation (ie, perceived ability to self-care). Improved self-care efficiency is a target for adequate disease management. OR for a LOC <50%
    • Asthma patients' perception of their ability to influence disease control and management Laforest Ann Allergy Asthma Immunol 2009;102:378
      • Internal locus of control (LOC) orientation.
      • Patients reported their LOC orientation on a 100-mm visual analog scale (0%, “I have absolutely no influence on asthma change,” to 100%, “this change only depends on me”).
      • 163 patients.
      2.68 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 In Patients with Inadequately Controlled Asthma Patients with a higher internal LOC may have a more positive approach to their asthma and may want to fully participate in their disease management. Consequently, they may use their controllers regularly, provided that they had been sensitized to this issue. OR for a LOC <50%
      • All districts and schools need to have policies and plans in place for safe, effective, and efficient administration of medications at school.
      • Having full-time licensed registered nurses administering all routine and emergency medications in schools is the best situation.
      • When a licensed registered nurse is not available, a licensed practical nurse may administer medications.
      • When a nurse cannot administer medication in school, the American Academy of Pediatrics supports appropriate delegation of nursing services in the school setting on the basis of physician guidance.
      Policy Statement-Guidance for the Administration of Medication in School Council on School Health Pediatrics 2009;124;1244
      • Asthma burden
    • Prevalence of obstructive sleep apnea–hypopnea in severe versus moderate asthma Julien JACI 2009;124:371
      • Overnight home polysomnography.
      • 26 patients with severe asthma.
      • 26 patients with moderate asthma.
      • 26 controls without asthma.
      SEVERE % Subjects with Apnea–Hypopnea Index ≥15 Events/h of Sleep MODERATE CONTROLS 31% 58% 88% 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 P< 0.001 for trend ASTHMA
    • Prevalence of obstructive sleep apnea–hypopnea in severe versus moderate asthma Julien JACI 2009;124:371
      • Overnight home polysomnography.
      • 26 patients with severe asthma.
      • 26 patients with moderate asthma.
      • 26 controls without asthma.
      SEVERE % Subjects with Apnea–Hypopnea Index ≥15 Events/h of Sleep MODERATE CONTROLS 31% 58% 88% 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 P< 0.001 for trend These observations suggest potential pathophysiologic interactions between obstructive sleep apnea–hypopnea and asthma severity and control. ASTHMA
    • Functional health literacy was assessed with the Newest Vital Sign, a screening test developed specifically for use in primary care. It consists of a nutrition label for ice cream that is accompanied by 6 questions that probe the participant’s ability to read and apply information from the label and has a very high sensitivity for detecting limited health literacy, beyond that of education and age alone. Weiss BD, Quick assessment of literacy in primary care: the newest vital sign. Ann Fam Med 2005;3:514-22. Osborn CY, Measuring adult literacy in health care: performance of the Newest Vital Sign. Am J Health Behav 2007;31(suppl 1):S36-46. Inadequate health literacy is associated with increased asthma morbidity in a population sample Adams JACI 2009;124:601
    • Inadequate health literacy is associated with increased asthma morbidity in a population sample Adams JACI 2009;124:601
      • The Newest Vital Sign is scored out of 6, with:
      • a score of 4 to 6 indicating adequate health literacy,
      • a score of 2 to 3 indicating an individual is at risk of inadequate health literacy , and
      • a score of 0 to 1 indicating inadequate health literacy .
      • (Weiss BD, Ann Fam Med. 2005;3:514–522)
    • Inadequate health literacy is associated with increased asthma morbidity in a population sample Adams JACI 2009;124:601
      • 2824 participants
      • Screening test for health literacy
      % SUBJECTS WITH 21% INADEQUATE 24% AT RISK 25 – 20 – 15 – 10 – 5 – 0 HEALTH LITERACY
    • Inadequate health literacy is associated with increased asthma morbidity in a population sample Adams JACI 2009;124:601 IN ASTHMATICS SUBJECTS OR FOR HOSPITAL ADMISSION PAST YEAR 1 ADEQUATE AT RISK 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 INADEQUATE 3.7 3.0
      • 2824 participants
      • Screening test for health literacy
      HEALTH LITERACY LEVEL
    • Inadequate health literacy is associated with increased asthma morbidity in a population sample Adams JACI 2009;124:601 IN ASTHMATICS SUBJECTS OR FOR HOSPITAL ADMISSION PAST YEAR 1 ADEQUATE AT RISK 4.0 – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 INADEQUATE 3.7 3.0
      • 2824 participants
      • Screening test for health literacy
      Compared with those with adequate health literacy among people with asthma, those with inadequate health literacy were more likely to report wakening at night weekly or more often and hospitalizations in the past year , and significantly more likely to report days lost from usual activities in the past 12 months. HEALTH LITERACY LEVEL
    • Asthma disparities in urban environments Bruyant-Stephens JACI 2009;123:1199
      • African American and Latino children who live in low-socioeconomic-status urban environments experiencing higher asthma morbidity and mortality than white children.
      • Many factors have contributed to these disparities which result in inadequate treatment:
        • Housing, which leads to increased exposure to asthma allergens
        • Social and psychosocial stressors, which are often unappreciated
    • A comparison of asthma prevalence and morbidity between rural and urban schoolchildren in Arkansas Pesek Ann Allergy Asthma Immunol 2010;104:125 % children with asthma 19% 25 – 20 – 15 – 10 – 5 – 0
      • A validated survey to parents of children enrolled in urban and rural school districts in Arkansas.
      20% Rural Urban
    • A comparison of asthma prevalence and morbidity between rural and urban schoolchildren in Arkansas Pesek Ann Allergy Asthma Immunol 2010;104:125 OR in Rural children for
      • A validated survey to parents of children enrolled in urban and rural school districts in Arkansas.
      2 – 1 – 0 1.9 More asthma morbidity including recurrent trouble breathing during the preceding 2 years.
    • A comparison of asthma prevalence and morbidity between rural and urban schoolchildren in Arkansas Pesek Ann Allergy Asthma Immunol 2010;104:125 % children with symptoms suggesting moderate to severe asthma 46%
      • A validated survey to parents of children enrolled in urban and rural school districts in Arkansas.
      35% Rural Urban 50 – 40 – 30 – 20 – 10 – 0 P<0.001
    • A comparison of asthma prevalence and morbidity between rural and urban schoolchildren in Arkansas Pesek Ann Allergy Asthma Immunol 2010;104:125 % children with symptoms suggesting moderate to severe asthma 46%
      • A validated survey to parents of children enrolled in urban and rural school districts in Arkansas.
      35% Rural Urban 50 – 40 – 30 – 20 – 10 – 0 P<0.001 Many families living in rural areas have to travel long distances to access pediatric health care services, and they may not have adequate access to subspecialty providers or emergency health care services.
    • A comparison of asthma prevalence and morbidity between rural and urban schoolchildren in Arkansas Pesek Ann Allergy Asthma Immunol 2010;104:125 % children with symptoms suggesting moderate to severe asthma 46%
      • A validated survey to parents of children enrolled in urban and rural school districts in Arkansas.
      35% Rural Urban 50 – 40 – 30 – 20 – 10 – 0 P<0.001 These findings suggest that not all rural environments are protective against atopic disorders such as asthma and warrant further investigation of the impact of environmental and sociodemographic factors on high-risk rural children.
    • Asthma Morbidity Among Children Evaluated by Asthma Case Detection Gerald Pediatrics 2009;124:e927
      • A school-based asthma case detection validation study of 3539 children by questionnaire .
      • Physician evaluation of 530 case detection results yielded 420 cases of agreement: -168 children with previously diagnosed asthma, -39 with undiagnosed asthma, and -213 without asthma.
      % parents reporting cough , wheeze , and shortness of breath while the child was asleep more than twice in the past 30 days.
    • % parents reporting daytime cough , wheeze , and shortness of breath more than twice in the past 30 days.
      • A school-based asthma case detection validation study of 3539 children by questionnaire .
      • Physician evaluation of 530 case detection results yielded 420 cases of agreement: -168 children with previously diagnosed asthma, -39 with undiagnosed asthma, and -213 without asthma.
      Asthma Morbidity Among Children Evaluated by Asthma Case Detection Gerald Pediatrics 2009;124:e927
    • % PARENTS REPORTING ≥ 1 RESPIRATORY-RELATED ED VISIT AND HOSPITALIZATION IN THE PAST 12 MONTHS.
      • A school-based asthma case detection validation study of 3539 children by questionnaire .
      • Physician evaluation of 530 case detection results yielded 420 cases of agreement: -168 children with previously diagnosed asthma, -39 with undiagnosed asthma, and -213 without asthma.
      Asthma Morbidity Among Children Evaluated by Asthma Case Detection Gerald Pediatrics 2009;124:e927
    • Asthma Morbidity Among Children Evaluated by Asthma Case Detection Gerald Pediatrics 2009;124:e927 Despite similar physician-rated severity, children with undiagnosed asthma reported significantly less frequent respiratory symptoms and health care use than children with previously diagnosed asthma. These findings suggest that the potential health gains from case detection may be smaller than expected. % PARENTS REPORTING ≥ 1 RESPIRATORY-RELATED ED VISIT AND HOSPITALIZATION IN THE PAST 12 MONTHS.
    • EIA
    • Mannitol and exercise challenge tests in asthmatic children Kersten, Ped Pul 2009;44:655 5/60
      • 33 clinically stable children, aged 9-18 years.
      • Mannitol and exercise provocation challenges.
      Individual dose–response curves relating the percentage decrease in FEV 1 after mannitol to the cumulative dose of mannitol inhaled in children responsive to mannitol.
    • 5/60 Relationship between log-transformed response–dose ratio (RDR=% fall in FEV 1 /cum. dose) to mannitol and percent fall in FEV 1 after exercise. Pearsons correlation coefficient ( r p )=0.666, P<0.001.
      • 33 clinically stable children, aged 9-18 years.
      • Mannitol and exercise provocation challenges.
      Mannitol and exercise challenge tests in asthmatic children Kersten, Ped Pul 2009;44:655
    • 5/60 Relationship between log-transformed response–dose ratio (RDR=% fall in FEV 1 /cum. dose) to mannitol and percent fall in FEV 1 after exercise. Pearsons correlation coefficient ( r p )=0.666, P<0.001.
      • 33 clinically stable children, aged 9-18 years.
      • Mannitol and exercise provocation challenges.
      Mannitol challenge appears to be a suitable alternative for an exercise provocation test to assess EIB in asthmatic children. Given the negative predictive value of 91%, it is especially useful to exclude EIB. Mannitol and exercise challenge tests in asthmatic children Kersten, Ped Pul 2009;44:655
    • Take home
      • Dopo anni di linee guida….
      • ACT non risolve tutto,
      • Meglio se il paziente si sente protagonista,
      • Attenti ai pazienti con difficoltà di comprensione,
      • La spirometria va ripetuta 2 settimane dopo la dimissione
      • Il raffreddore è un sintomo premonitore di riacutizzazione d’asma ma viene sottostimato dai genitori che iniziano la terapia in ritardo e in modo inadeguato,
      • Segui con particolare attenzione il bambino che ha avuto una riacutizzazione da poco tempo, soprattutto se è allergico, se usa spesso il salbutamolo, e quando aumenta l’umidità,
      • L’adesione al regime terapeutico si aggira attorno al 50%; è disponibile un questionario affidabile per valutare la compliance che aumenta se le decisioni sono condivise e si riduce se il paziente fa uso di farmaci alternativi e nelle minoranze etniche.
      • Spacer devices
    • Lack of use of MDI device in acute asthma: An Italian survey Guala, Ped Pul 2009;44:1244 19.9 35.2
      • Two surveys, one in 2006 and one in 2008.
      • How drugs was administered in
      • acute attacks of
      • asthma.
      • 30 pediatric units of Piemonte and
      • Valle d’Aosta hospitals.
      44.4% 20% % Episodes treated with MDI and spacer 2006 2008 50 – 40 – 30 – 20 – 10 – 0
    • Lack of use of MDI device in acute asthma: An Italian survey Guala, Ped Pul 2009;44:1244 19.9 35.2
      • Two surveys, one in 2006 and one in 2008.
      • How drugs was administered in
      • acute attacks of
      • asthma.
      • 30 pediatric units of Piemonte and
      • Valle d’Aosta hospitals.
      44.4% 20% % Episodes treated with MDI and spacer 2006 2008 50 – 40 – 30 – 20 – 10 – 0 even if most of the clinicians seam to share and recognize the argumentation for their use, the approach in acute asthma therapy remains ‘‘ traditionalistic’’.
      • Mask design is a critical factor with regard to therapeutic efficacy with aerosol therapy.
      • For any given mask dead space varies considerably when different pressures are applied by care givers.
      • Masks must be tightly applied to the face to achieve an adequate seal.
      • With increasing application of force—there is a progressive decrease in the mask dead space.
      Face masks for aerosols - there is more science Amirav Pediatric Pulmonology 2009;45:221
      • Mask design is a critical factor with regard to therapeutic efficacy with aerosol therapy.
      • For any given mask dead space varies considerably when different pressures are applied by care givers.
      • Masks must be tightly applied to the face to achieve an adequate seal.
      • With increasing application of force—there is a progressive decrease in the mask dead space.
      Face masks for aerosols - there is more science Amirav Pediatric Pulmonology 2009;45:221 The smallest possible dead space would be optimal since more drug will then be delivered to the respiratory tract.
      • Acceptance of the mask is the single most important factor for achieving effective aerosol therapy in infants and toddlers .
      • Increasing pressure applied to the infant’s face frequently upsets the child who then usually screams and tries to escape.
      • These problems could be addressed making masks softer, more flexible, and inherently better fitting .
      Face masks for aerosols - there is more science Amirav Pediatric Pulmonology 2009;45:221
      • Effect of varying mask static dead volume (SDV), respiratory rate (RR), and tidal volume (VT) on albuterol captured at the mouth opening (ACMO) in an in vitro model.
      • An Aerochamber Max1 without and with three mask sizes (SDV of 10, 36, 85, and 200 ml, respectively) was.
      • ACMOwas measured at VTs = 36, 72, 145, and 290 ml and RR of 12 and 24.
      Effect of face mask dead volume, respiratory rate, and tidal volume on inhaled albuterol delivery Chavez Pediatric Pulmonology 2009;45:224 Experimental setup to measure albuterol captured at the mouth opening (ACMO).
    • Effect of face mask dead volume, respiratory rate, and tidal volume on inhaled albuterol delivery Chavez Pediatric Pulmonology 2009;45:224 Spacer and masks attached to face plate with mouth opening. From left: large, medium, small, and no mask setup.
      • Effect of varying mask static dead volume (SDV), respiratory rate (RR), and tidal volume (VT) on albuterol captured at the mouth opening (ACMO) in an in vitro model.
      • An Aerochamber Max1 without and with three mask sizes (SDV of 10, 36, 85, and 200 ml, respectively) was.
      • ACMOwas measured at VTs = 36, 72, 145, and 290 ml and RR of 12 and 24.
    • Effect of face mask dead volume, respiratory rate, and tidal volume on inhaled albuterol delivery Chavez Pediatric Pulmonology 2009;45:224 albuterol captured at the mouth opening ACMO at different tidal volume (VTs), respiratory rates (RRs), and face masks increasing tidal volumes
    • Effect of face mask dead volume, respiratory rate, and tidal volume on inhaled albuterol delivery Chavez Pediatric Pulmonology 2009;45:224 Decreasing mask static dead volume ( SDV), increasing tidal volume ( VT), and increasing respiratory rate ( RR) increase albuterol captured at the mouth opening ( ACMO). albuterol captured at the mouth opening ACMO at different tidal volume (VTs), respiratory rates (RRs), and face masks increasing tidal volumes
    • Effect of face mask dead volume, respiratory rate, and tidal volume on inhaled albuterol delivery Chavez Pediatric Pulmonology 2009;45:224 Early transition from face mask to mouthpiece should be considered in children receiving albuterol via MDI with HC. albuterol captured at the mouth opening ACMO at different tidal volume (VTs), respiratory rates (RRs), and face masks increasing tidal volumes
    • ACUTE ASTHMA TREATMENT
    • Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504
      • Guidelines by the National Asthma Education and Prevention Program (NAEPP) have recommended that caregivers of asthmatic children begin treatment for asthma exacerbations at home to avoid treatment delays and reduce the severity of the attack.
      • Up to 3 back-to-back treatments (every 20 minutes) are recommended during the first hour , with reassessment after each treatment.
      • If symptoms improve , albuterol can then be given every 3 to 4 hours for 24 to 48 hours as needed, and the primary care physician (PCP) can be contacted for follow-up instructions and further management.
      • If symptoms persist , oral corticosteroid therapy should be started and albuterol treatment continued every 2 to 4 hours as needed, with same-day evaluation by the PCP.
      Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504
      • If symptoms improve , albuterol can then be given every 3 to 4 hours for 24 to 48 hours as needed, and the primary care physician (PCP) can be contacted for follow-up instructions and further management.
      • If symptoms persist , oral corticosteroid therapy should be started and albuterol treatment continued every 2 to 4 hours as needed, with same-day evaluation by the PCP.
      Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504 + 4 X ICS
      • 114 caregivers
      • telephone interview with an asthma nurse
      • to evaluate home management of their child's acute asthma symptoms.
      Appropriately % Caregives Using Albuterol Under Use or Over Use 68% 38% 70 - 60 – 50 – 40 – 30 – 20 – 10 – 0 Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504
      • 114 caregivers completed a structured telephone interview with an asthma nurse to evaluate home management of their child's acute asthma symptoms.
      Appropriately % Caregives Using Albuterol Under Use or Over Use 68% 38% 70 - 60 – 50 – 40 – 30 – 20 – 10 – 0 Appropriate use of albuterol was more likely if the children had an ED visit or hospitalization for asthma in the prior year, Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504
      • 114 caregivers completed a structured telephone interview with an asthma nurse to evaluate home management of their child's acute asthma symptoms.
      Appropriately % Caregives Using Albuterol Under Use or Over Use 68% 38% 70 - 60 – 50 – 40 – 30 – 20 – 10 – 0 but appropriate use of albuterol was not associated with caregiver report of having an asthma action plan (AAP) or a recent primary care physician visit to discuss asthma maintenance care. Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504
      • Asthma Action Plans (AAPs) have been shown to reduce acute care visits when used in combination with education and regular management review. Gibson PG, Thorax. 2004;59:94-99; Bhogal S, Cochrane Database Syst Rev. 2006;3:CD005306 .
      • Regular monitoring of home care with education as needed appears to be the key to successful home use of albuterol.
      • Most children with asthma receive their care from their AAPs and education about asthma management are also provided in EDs and during hospitalizations .
      • The increased likelihood of appropriate albuterol use after 1 of these contacts suggests that caregivers may have learned to provide appropriate care through this experience .
      Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504
      • One in 10 caregivers in our study was unwilling to provide initial management of their child's yellow zone symptoms at home, preferring to seek emergency care immediately .
      • Their responses may have been due to discomfort with treating yellow zone symptoms, inability to distinguish yellow zone from more severe red zone symptoms, or unfamiliarity with use of albuterol.
      • Although immediate referral to the ED may be the safest option for severe symptoms, repeated use of this coping strategy may have negative psychological impacts on both children and parents. Peeters Y, Health Qual Life Outcomes 2008;6:24 Marsac ML, Child Care Health Dev 2007;33:360-367
      Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504
      • Not have an AAP.
      • Not use them.
      • Not be able to find their children's AAP at the time of exacerbations.
      • Not know how and when to use them.
      • Not be able to read or understand them.
      • Follow the given plans but fail to administer medications correctly.
      Several factors may explain the apparent lack of having an AAP on appropriate albuterol use. Home use of albuterol for asthma exacerbations Garbutt Ann Allergy Asthma Immunol 2009;102:504
    • Formoterol for acute asthma in the emergency department: a systematic review with meta-analysis Rodrigo Ann Allergy Asthma Immunol. 2010;104:247–252.
      • Formoterol fumarate vs short-acting 2-agonists (SABAs) for the treatment of asthma exacerbations;
      • 9 randomized controlled trials (including 576 participants).
      formoterol = SABAs for any of the selected time points:at 30 to 40 minutes after the first administration of study drugs.
    • Formoterol for acute asthma in the emergency department: a systematic review with meta-analysis Rodrigo Ann Allergy Asthma Immunol. 2010;104:247–252.
    • A randomized, comparative study of formoterol and terbutaline dry powder inhalers in the treatment of mild to moderate asthma exacerbations in the pediatric acute care setting Bussamra Ann Allergy Asthma Immunol 2009;103:248
      • 79 pediatric patients (mean age, 10 yrs) with mild to moderate asthma exacerbations.
      • 3 doses of formoterol aerolizer, 12 μg, or terbutaline Turbuhaler, 0.5 mg (dry powder inhalers).
      • All the patients received oral prednisolone, 1 mg/kg.
      Formoterol % Increase in FEV 1 15 min after Dosing Terbutaline +19.5% 20 – 15 – 10 – 0 5 – 0 +15.3%
    • A randomized, comparative study of formoterol and terbutaline dry powder inhalers in the treatment of mild to moderate asthma exacerbations in the pediatric acute care setting Bussamra Ann Allergy Asthma Immunol 2009;103:248
      • 79 pediatric patients (mean age, 10 yrs) with mild to moderate asthma exacerbations.
      • 3 doses of formoterol aerolizer, 12 μg, or terbutaline Turbuhaler, 0.5 mg (dry powder inhalers).
      • All the patients received oral prednisolone, 1 mg/kg.
      Formoterol % Increase in FEV 1 15 min after Dosing Terbutaline +19.5% 20 – 15 – 10 – 0 5 – 0 +15.3% Formoterol therapy was at least as effective as terbutaline therapy in children and adolescents with mild and moderate asthma exacerbations.
    • Regular vs prn nebulized treatment in wheeze preschool children Papi Allergy 2009:64:1463
      • 276 symptomatic children with frequent wheeze, aged 1–4 years.
      • 3-month nebulized treatment: 1) 400 μg beclomethasone bid plus 2500 μg salbutamol prn; 2) placebo bid plus 2500 μg salbutamol prn; 3) placebo bid plus 800 μg beclomethasone/1600 μg salbutamol combination prn.
      PRN SALBUTAMOL REGULAR BECLOMETHASONE PRN COMBINATION 69.6% 61% 64.9% % FREE DAYS 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 p=0.034 ns
      • 276 symptomatic children with frequent wheeze, aged 1–4 years.
      • 3-month nebulized treatment: 1) 400 μg beclomethasone bid plus 2500 μg salbutamol prn; 2) placebo bid plus 2500 μg salbutamol prn; 3) placebo bid plus 800 μg beclomethasone/1600 μg salbutamol combination prn.
      PRN SALBUTAMOL REGULAR BECLOMETHASONE PRN COMBINATION 69.6% 61% 64.9% % FREE DAYS 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 Results were no different in children with or without risk factors for developing persistent asthma. Regular vs prn nebulized treatment in wheeze preschool children Papi Allergy 2009:64:1463 p=0.034 ns
      • 276 symptomatic children with frequent wheeze, aged 1–4 years.
      • 3-month nebulized treatment: 1) 400 μg beclomethasone bid plus 2500 μg salbutamol prn; 2) placebo bid plus 2500 μg salbutamol prn; 3) placebo bid plus 800 μg beclomethasone/1600 μg salbutamol combination prn.
      PRN SALBUTAMOL REGULAR BECLOMETHASONE PRN COMBINATION 69.6% 61% 64.9% % FREE DAYS 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 The effect of prn combination was no different from that of regular beclomethasone on the primary and on several important secondary outcomes. Regular vs prn nebulized treatment in wheeze preschool children Papi Allergy 2009:64:1463 p=0.034 ns
    • Rescue Treatment in Asthma More Than As-Needed Bronchodilation Papi Chest 2009;135:1628
      • International guidelines recommend the use of rapid-onset inhaled 2-agonists alone for symptom relief in all asthmatic patients.
      • However, recent clinical trials have shown that the “as-required,” or PRN, use of inhaled combinations of a corticosteroid and a rapid-onset β 2 -agonist provides clinical advantages over the traditional PRN inhaled rapid-onset β 2 -agonists alone in patients with different degrees of asthma severity.
      • Asthma symptoms are associated not only with bronchoconstriction but also with increased airway inflammation .
    • Rescue Treatment in Asthma More Than As-Needed Bronchodilation Papi Chest 2009;135:1628
      • Inhaled β 2 -agonists have a rapid onset of bronchodilator action that is mainly mediated by a relaxing effect on airway smooth muscle.
      • Inhaled corticosteroids also have rapid clinical effects that can suppress lower airway inflammation, and there is a rapid synergistic potentiation of the antiinflammatory effect of corticosteroids and of the bronchodilatory action of β 2 -agonists when the two drugs are given simultaneously.
      • On the basis of this emerging evidence, we propose that the current rescue use of rapid-onset inhaled β 2 -agonists alone should now be replaced by an inhaled rapid-acting β 2 -agonists combined with a corticosteroid as preferred PRN strategy .
    • Quadrupling the Dose of Inhaled Corticosteroid to Prevent Asthma Exacerbations Oborne Am. J. Respir. Crit. Care Med 2009;180:598
      • 403 people with asthma.
      • An active or placebo corticosteroid inhaler in addition to their usual asthma treatment when their PEF fell by 15% on 2 consecutive days or by 30% on 1 day.
      • A quadrupling or no change in corticosteroid dose.
      14% PLACEBO ns ICS X 4 DOSING 9% RR=0.64 % PATIENTS WITH AN ASTHMA EXACERBATION 15 – 10 – 5 – 0 4X
    • Quadrupling the Dose of Inhaled Corticosteroid to Prevent Asthma Exacerbations Oborne Am. J. Respir. Crit. Care Med 2009;180:598 50% PLACEBO p = 0.004 ICS X 4 DOSING 21% RR = 0.43 % PATIENTS WHO REQUIRED ORAL CORTICOSTEROIDS 50 – 40 – 30 – 20 – 10 – 0
      • 403 people with asthma.
      • An active or placebo corticosteroid inhaler in addition to their usual asthma treatment when their PEF fell by 15% on 2 consecutive days or by 30% on 1 day.
      • A quadrupling or no change in corticosteroid dose.
      4X
    • Quadrupling the Dose of Inhaled Corticosteroid to Prevent Asthma Exacerbations Oborne Am. J. Respir. Crit. Care Med 2009;180:598 50% PLACEBO p = 0.004 ICS X 4 DOSING 21% RR = 0.43 % PATIENTS WHO REQUIRED ORAL CORTICOSTEROIDS 50 – 40 – 30 – 20 – 10 – 0
      • 403 people with asthma.
      • An active or placebo corticosteroid inhaler in addition to their usual asthma treatment when their PEF fell by 15% on 2 consecutive days or by 30% on 1 day.
      • A quadrupling or no change in corticosteroid dose.
      4X Although our primary outcome did not reach statistical significance, quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate appears to reduce acute exacerbations of asthma and deserves further investigation.
      • 3,798 patients with acute asthma in 62 urban EDs in 23 US states between 2003 and 2006.
      • Pattern of systemic corticosteroid (SC) use in the ED, categorized as timely use (≤60 minutes), delayed use (>60 minutes), or nonuse.
      67.4% % Patients Receiving Systemic Corticosteroids Factors associated with delayed use or nonuse of systemic corticosteroids in emergency department patients with acute asthma Tsai Ann Allergy Asthma Immunol 2009;103:318 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0
      • 3,798 patients with acute asthma in 62 urban EDs in 23 US states between 2003 and 2006.
      • Pattern of systemic corticosteroid (SC) use in the ED, categorized as timely use (≤60 minutes), delayed use (>60 minutes), or nonuse.
      67.4% % Patients Receiving Systemic Corticosteroids Factors associated with delayed use or nonuse of systemic corticosteroids in emergency department patients with acute asthma Tsai Ann Allergy Asthma Immunol 2009;103:318 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 The median door-to-SC time was 62 minutes (interquatile range, 35-100 minutes)
      • 3,798 patients with acute asthma in 62 urban EDs in 23 US states between 2003 and 2006.
      • Pattern of systemic corticosteroid (SC) use in the ED, categorized as timely use (≤60 minutes), delayed use (>60 minutes), or nonuse.
      51.5% % Patients with Delayed (>60 min) Systemic Corticosteroids Treatment Factors associated with delayed use or nonuse of systemic corticosteroids in emergency department patients with acute asthma Tsai Ann Allergy Asthma Immunol 2009;103:318 60 – 50 – 40 – 30 – 20 – 10 – 0
      • 3,798 patients with acute asthma in 62 urban EDs in 23 US states between 2003 and 2006.
      • Pattern of systemic corticosteroid (SC) use in the ED, categorized as timely use (≤60 minutes), delayed use (>60 minutes), or nonuse.
      Factors associated with delayed use or nonuse of systemic corticosteroids in emergency department patients with acute asthma Tsai Ann Allergy Asthma Immunol 2009;103:318
    • Non use of SCs was explained by markers of asthma exacerbations Factors associated with delayed use or nonuse of systemic corticosteroids in emergency department patients with acute asthma Tsai Ann Allergy Asthma Immunol 2009;103:318
      • never intubated for asthma,
      • lower respiratory rate, and
      • higher SaO 2 ).
      Delayed SC treatment was associated with
      • age ≥ 40 years,
      • female sex,
      • longer duration of symptoms,
      • ED presentation between 8
      • AM and 11:59 PM, and
      • ED with a longer average
      • patient wait time.
    • Non use of SCs was explained by markers of asthma exacerbations Factors associated with delayed use or nonuse of systemic corticosteroids in emergency department patients with acute asthma Tsai Ann Allergy Asthma Immunol 2009;103:318
      • never intubated for asthma,
      • lower respiratory rate, and
      • higher SaO 2 ).
      Delayed SC treatment was associated with
      • age ≥ 40 years,
      • female sex,
      • longer duration of symptoms,
      • ED presentation between 8
      • AM and 11:59 PM, and
      • ED with a longer average
      • patient wait time.
      A meta-analysis summarizing 12 randomized trials has shown that the use of SC within 1 hour of ED arrival significantly improves pulmonary function and reduces the odds of hospital admission by 60%. Rowe BH “Early emergency department treatment of acute asthma with systemic corticosteroids” . Cochrane Database Syst Rev. 2001(1):CD002178
    • Asthma treatment broncodilators
    • Asthma long-term treatment
      • Drug prescriptions involving 24,407 children <18 years old, dispensed during 2003 by the retail pharmacies of the local health unit in Lecco, Italy, were analysed.
      • Children ≥6 years old receiving anti-asthmatics.
      12% % Children Receiving an Anti-Asthma Prescription Anti-asthmatic drug prescriptions to an Italian paedriatic population Bianchi Pediatr Allergy Immunol 2009:20:585 15 – 10 – 0 5 – 0
      • Drug prescriptions involving 24,407 children <18 years old, dispensed during 2003 by the retail pharmacies of the local health unit in Lecco, Italy, were analysed.
      • Children ≥6 years old receiving anti-asthmatics.
      12% % Children Receiving an Anti-Asthma Prescription Anti-asthmatic drug prescriptions to an Italian paedriatic population Bianchi Pediatr Allergy Immunol 2009:20:585 15 – 10 – 0 5 – 0 58% of these children received only 1 prescription in 1 year
      • Drug prescriptions involving 24,407 children <18 years old, dispensed during 2003 by the retail pharmacies of the local health unit in Lecco, Italy, were analysed.
      • Children ≥6 years old receiving anti-asthmatics.
      12% % Children Receiving an Anti-Asthma Prescription Anti-asthmatic drug prescriptions to an Italian paedriatic population Bianchi Pediatr Allergy Immunol 2009:20:585 15 – 10 – 0 5 – 0 Inhaled steroids were the most prescribed drugs (83%). The most common of these was BDP.
    • Anti-asthmatic drug prescriptions to an Italian paedriatic population Bianchi Pediatr Allergy Immunol 2009:20:585 ONLY 1 PRESCRIPTION 58% % CHILDREN 29% 13% 2-3 PRESCRIPTION ≥ 4 PRESCRIPTION 60 – 50 – 40 – 30 – 20 – 10 – 0 RECEIVING
    • Anti-asthmatic drug prescriptions to an Italian paedriatic population Bianchi Pediatr Allergy Immunol 2009:20:585 ONLY 1 PRESCRIPTION 58% % CHILDREN 29% 13% 2-3 PRESCRIPTION ≥ 4 PRESCRIPTION 60 – 50 – 40 – 30 – 20 – 10 – 0 In Italy the prevalence of anti-asthmatic prescription is much higher than prevalence of disease. RECEIVING
    • Anti-asthmatic drug prescriptions to an Italian paedriatic population Bianchi Pediatr Allergy Immunol 2009:20:585 ONLY 1 PRESCRIPTION 58% % CHILDREN 29% 13% 2-3 PRESCRIPTION ≥ 4 PRESCRIPTION 60 – 50 – 40 – 30 – 20 – 10 – 0 Steroids, especially nebulized, are mainly prescribed only once in a year, supporting the idea that are prescribed not for asthma. RECEIVING
    • Anti-asthmatic drug prescriptions to an Italian paedriatic population Bianchi Pediatr Allergy Immunol 2009:20:585 SYSTEMIC STEROID PRESCRIPTION In Children Receiving ≥4 Prescription OR for 6.8 HOSPITAL ADMISSION FOR ASTHMA 8.6 10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0
      • Bavarian health insurance
      • from April 2005 to March 2006
      prevalence of physician diagnosed asthma 5 – 4 – 3 – 2 – 1 – 0 4.5% Persistence with asthma treatment is low in Germany especially for controller medication – a population based study of 483 051 patients J. Hasford, Allergy 2010;65;347 4.8%
      • Bavarian health insurance
      • from April 2005 to March 2006
      Persistence with asthma treatment is low in Germany especially for controller medication – a population based study of 483 051 patients J. Hasford, Allergy 2010;65;347 52.8% 60 - 50 - 40 - 30 – 20 – 10 – 0 % of asthma patients treated in accordance with guidelines
      • Bavarian health insurance
      • from April 2005 to March 2006
      Persistence with asthma treatment is low in Germany especially for controller medication – a population based study of 483 051 patients J. Hasford, Allergy 2010;65;347 Proportion of patients receiving the indicated number of DEFINED DAILY DOSES over the course of 1 year
      • Bavarian health insurance
      • from April 2005 to March 2006
      Persistence with asthma treatment is low in Germany especially for controller medication – a population based study of 483 051 patients J. Hasford, Allergy 2010;65;347 Proportion of patients receiving the indicated number of DEFINED DAILY DOSES over the course of 1 year Persistence of asthma patients with medical treatment is low, especially for controller medication.
    • Asthma long-term treatment ICS
    • Background: In a 3-year study , adult patients who recently developed asthma (symptoms for less than 1 year) were treated for 2 years with the inhaled corticosteroid (ICS) budesonide ( early therapy ) or terbutaline. During the third year  of the study, terbutaline-treated patients received budesonide ( delayed therapy ). Differences in lung function and bronchial responsiveness to histamine were observed between the 2 groups. Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma Haahtela JACI 2009:124:1180
    • Objective: We compared the effects of early versus delayed budesonide therapy after a 10-year follow-up period (13 years after the study began) and current real-life data. Methods: Of the original 103 patients, 90 were re-examined 13 years after study initiation. After the third year of the study, all patients had their medications, including the dose of ICS, individually adjusted. Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma Haahtela JACI 2009:124:1180
    • Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma Haahtela JACI 2009:124:1180
    • Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma Haahtela JACI 2009:124:1180 Patients with relatively mild asthma who received ICS within 12 months of their first asthma symptoms or after a 2-year delay achieved equally good functional control of asthma after 10 years of individualized therapy. However, the delayed therapy group exhibited slightly less optimal disease control and more signs of airway inflammation .
    • Comparison of induced sputum indices and fractionated exhaled nitric oxide concentrations at the 13-year follow-up examination in patients with early and delayed budesonide therapy Sputum samples Eosinophils (%) ECP (μg × L −1 ) Neutrophils (%) MPO (μg × L −1 ) FENO (ppb) .23 .001 .0009 .0026 .25 Variable Early therapy Delayed therapy P value 3.2 ± 0.9 1,231 ± 369 33.0 ± 3.6 6,487 ± 1,712 16.9 ± 2.5 5.8 ± 1.4 2,481 ± 537 49.5 ± 3.8 10,325 ± 1,670 18.7 ± 2.1 Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma Haahtela JACI 2009:124:1180
    • Box plot z score, specific airway conductance, for budesonide and placebo, before and after treatment
      • Functional residual capacity (FRC) and sGaw of steroid-naive children aged 3–26 months with respiratory symptoms
      • Inhaled budesonide (400 mcg/day) or placebo with NebuChamber for 6 weeks
      • Lung function measurements were repeated after 6 weeks
      BUDESONIDE IMPROVES DECREASED AIRWAY CONDUCTANCE IN INFANTS WITH RESPIRATORY SYMPTOMS Pelkonen Arch Dis Child 2009;94:536 p=0.014 45
    • Box plot z score, specific airway conductance, for budesonide and placebo, before and after treatment
      • Functional residual capacity (FRC) and sGaw of steroid-naive children aged 3–26 months with respiratory symptoms
      • Inhaled budesonide (400 mcg/day) or placebo with NebuChamber for 6 weeks
      • Lung function measurements were repeated after 6 weeks
      BUDESONIDE IMPROVES DECREASED AIRWAY CONDUCTANCE IN INFANTS WITH RESPIRATORY SYMPTOMS Pelkonen Arch Dis Child 2009;94:536 p=0.014 45 Improvement in sGaw was more pronounced in children with atopy (p=0.017)
    • High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations Blais JACI 2009:124:1229 % Infants with Congenital Malformation 9.5%
      • 13,280 pregnancies.
      • Women taking > 0 to 1000 μg/d ICS (BDP-equivalent) with women taking >1000 μg/d and those not taking ICSs.
      10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0
    • High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations Blais JACI 2009:124:1229 OR FOR HAVING A BABY WITH A MALFORMATION 1.63 IN WOMEN WHO USED >1000 ΜG/D ICS (N = 154) 2.0 – 1.5 – 1.0 – 0.5 – 0
      • 13,280 pregnancies.
      • Women taking > 0 to 1000 μg/d ICS (BDP-equivalent) with women taking >1000 μg/d and those not taking ICSs.
    • High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations Blais JACI 2009:124:1229
      • 13,280 pregnancies.
      • Women taking > 0 to 1000 μg/d ICS (beclomethasone dipropionate–equivalent) with women taking >1000 μg/d and those not taking ICSs.
      OR FOR HAVING A BABY WITH A MALFORMATION 1.63 IN WOMEN WHO USED >1000 ΜG/D ICS (N = 154) 2.0 – 1.5 – 1.0 – 0.5 – 0 On the other hand, women who used >0 to 1000 μg/d were not found to be more at risk than women who did not use ICSs during the first trimester (n = 8734).
      • teofillina
    • Theophylline inhibits the differentiation of human monocyte into dendritic cell potentially via adenosine receptor antagonism Yasui, CEA 2009;39:1857 Peripheral human blood monocytes Granulocyte/macrophage-colony stimulating factor and IL-4 The number of DCs was remarkably reduced by 60–70% when theophylline was administered at a therapeutic concentration DC differentiation
    • Theophylline inhibits the differentiation of human monocyte into dendritic cell potentially via adenosine receptor antagonism Yasui, CEA 2009;39:1857 Peripheral human blood monocytes Granulocyte/macrophage-colony stimulating factor and IL-4 The number of DCs was remarkably reduced by 60–70% when theophylline was administered at a therapeutic concentration DC differentiation These findings provide further evidence that theophylline has an anti-inflammatory action in bronchial asthma.
      • LABA basic science
    • Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting–agonists Black CHEST 2009; 136:1095
      • β 2 -Agonists can stimulate the glucocorticoid receptor (GR) and promote its translocation to the nucleus, resulting in increased CS-mediated gene transcription.
      • In structural airway cells, such as fibroblasts and smooth muscle, this gene transcription is associated with the formation of a complex between the GR and another transcription factor, CCAAT enhancer-binding protein (C/EBP)- α .
      • Airway smooth muscle cells from persons with asthma are deficient in C/EBP- α , which may explain the finding that CSs do not inhibit the proliferation of these cells in vitro.
      • CSs mitigate against the reduced transcription of β 2-receptors, which occurs as a consequence of long-term β 2-agonist administration.
    • Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting–agonists Black CHEST 2009; 136:1095 β 2 -Agonists bind to and activate β 2 -adrenoeceptors ( β 2 AR). Following activation of the β 2 AR, the stimulatory Gcoupled protein, Gs, acts to increase adenylyl cyclase (AC), which catalyzes the production of cAMP. In turn, increased cAMP activates PKA, which phosphorylates the β 2 -receptor, and, in doing so, activates other pathways. Long-term treatment with either β 2 2-agonists or steroids results in decreased or increased β 2 AR expression, respectively.
    • Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting–agonists Black CHEST 2009; 136:1095 The activation of the GR by steroids may function in the following three distinct ways: 1) two active GRs form a dimer and bind to the GRE, thereby inhibiting transcription of proinflammatory genes; 2) the GR dimer also may compete with NF-kB action and reduce histone acetylation; or 3) a single active GR molecule binds with its zinc finger motif to other transcription factors, such as C/EBPs, and exerts different functions.
    • LABA + ICS Vs ICS alone
    • Salmeterol and ICS
    • Salmeterol/fluticasone propionate vs. double dose fluticasone propionate on lung function and asthma control in children. de Blic Pediatr Allergy Immunol 2009:20:763
      • asthmatic children previously uncontrolled on low doses of ICS (FP 100 μg bd).
      • either SFC 50/100 μg bd (n =160) or FP 200 μg bd (n = 161) for 12 wks.
      Change from baseline in morning PEF
    • Salmeterol/fluticasone propionate vs. double dose fluticasone propionate on lung function and asthma control in children. de Blic Pediatr Allergy Immunol 2009:20:763
      • asthmatic children previously uncontrolled on low doses of ICS (FP 100 μg bd).
      • either SFC 50/100 μg bd (n =160) or FP 200 μg bd (n = 161) for 12 wks.
      Change from baseline in morning PEF Asthma control improved over time in both groups.
    • Salmeterol/fluticasone propionate vs. double dose fluticasone propionate on lung function and asthma control in children. de Blic Pediatr Allergy Immunol 2009:20:763
      • asthmatic children previously uncontrolled on low doses of ICS (FP 100 μg bd).
      • either SFC 50/100 μg bd (n =160) or FP 200 μg bd (n = 161) for 12 wks.
      Change from baseline in morning PEF Treatment with SFC 50/100 μg bd compared with twice the steroid dose of FP (200 μg bd), was at least as effective in improving individual clinical outcomes and overall asthma control, in asthmatic children previously uncontrolled on low doses of ICS.
    • Add-on salmeterol compared to double dose fluticasone in pediatric asthma: A double-blind, randomized trial (VIAPAED) Gappa , Ped Pul 2009;44:1132
      • Children (4-16 years)
      • During a 14-day run-in phase, all children inhaled FP 100 µg b.i.d.
      • Patients with persistent symptoms were randomized to 8 weeks treatment with a Diskus® containing either SFC 50 µg/100 µg b.i.d. or FP 200 µg b.i.d.
      • PP= per protocol
      • ITT= intention to treat
    • Add-on salmeterol compared to double dose fluticasone in pediatric asthma: A double-blind, randomized trial (VIAPAED) Gappa , Ped Pul 2009;44:1132
      • Children (4-16 years)
      • During a 14-day run-in phase, all children inhaled FP 100 µg b.i.d.
      • Patients with persistent symptoms were randomized to 8 weeks treatment with a Diskus® containing either SFC 50 µg/100 µg b.i.d. or FP 200 µg b.i.d.
      • PP= per protocol
      • ITT= intention to treat
    • Morning and evening peak expiratory flow rates during the treatment period. Patients receiving SFC had a faster and significantly larger increase during each 2-week period. Add-on salmeterol compared to double dose fluticasone in pediatric asthma: A double-blind, randomized trial (VIAPAED) Gappa , Ped Pul 2009;44:1132
    • Add-on salmeterol compared to double dose fluticasone in pediatric asthma: A double-blind, randomized trial (VIAPAED) Gappa , Ped Pul 2009;44:1132
    • Conclusions: in children with persistent asthma inadequately controlled on low dose ICS alone, adding a long acting beta-2-agonist to ICS in a single inhaler was more effective than doubling the ICS dose . These results support recommendations of adding LABA to low-dose ICS as the preferred controller option for children older than 4 years with symptomatic asthma. Add-on salmeterol compared to double dose fluticasone in pediatric asthma: A double-blind, randomized trial (VIAPAED) Gappa , Ped Pul 2009;44:1132
    • Fluticasone propionate/salmeterol and exercise-induced asthma in children with persistent asthma David Pearlman Ped Pul 2009;44:429
      • 248 subjects with persistent asthma (age 4-17 years).
      • FPS (100/50 mcg bd) or FP alone (100 mcg bd) via Diskus for 4 weeks.
      • Exercise challenge 8 hr after administration of the medication .
      % fall in FEV 1 after 4 weeks      TO P      ABSTRACT     ME THODS     RE SULTS     DI SCUSSION     Su pport statement     St atement of interest     AC KNOWLEDGEMENTS     RE FERENCES
    • Fluticasone propionate/salmeterol and exercise-induced asthma in children with persistent asthma David Pearlman Ped Pul 2009;44:429
      • 248 subjects with persistent asthma (age 4-17 years).
      • FPS (100/50 mcg bd) or FP alone (100 mcg bd) via Diskus for 4 weeks.
      • Exercise challenge 8 hr after administration of the medication.
      Chronic dosing with FP&S in a single device provides superior protection compared with an inhaled corticosteroid alone in protecting against exercise-induced asthma in children with persistent asthma. % fall in FEV 1 after 4 weeks      TO P      ABSTRACT     ME THODS     RE SULTS     DI SCUSSION     Su pport statement     St atement of interest     AC KNOWLEDGEMENTS     RE FERENCES      TO P      ABSTRACT     ME THODS     RE SULTS     DI SCUSSION     Su pport statement     St atement of interest     AC KNOWLEDGEMENTS     RE FERENCES
    • Dispensing of fluticasone propionate/salmeterol combination in the summer and asthma-related outcomes in the fall. Spahn JACI 2009:124:1197
      • A retrospective, observational study using health care claims.
      • Children (4-11 years), adolescents (12-18 years), and adults (19-55 years)
      In Summertime Dispensings of FSC OR for 1.0 – 0.5 – 0 0.54 P<0.001 Asthma-Related ED Visit in the Subsequent Fall in 4-11 Years Old pts
    • % patients with an asthma-related ED visit in the fall for patients with FSC dispensed in the summer and those not dispensed FSC. Yellow lines represent baseline (summer) rate % patients with an asthma-related hospitalization in the fall for patients dispensed and not dispensed FSC in the summer. Dispensing of fluticasone propionate/salmeterol combination in the summer and asthma-related outcomes in the fall. Spahn JACI 2009:124:1197
    • % patients with an asthma-related ED visit in the fall for patients with FSC dispensed in the summer and those not dispensed FSC. Yellow lines represent baseline (summer) rate % patients with an asthma-related hospitalization in the fall for patients dispensed and not dispensed FSC in the summer. Dispensing of fluticasone propionate/salmeterol combination in the summer and asthma-related outcomes in the fall. Spahn JACI 2009:124:1197 Summertime dispensings of FSC were associated with a decreased risk of serious asthma-related outcomes in the subsequent fall. Continuous use of FSC before seasonal viral exposure may decrease seasonally related exacerbations.
    • formoterol and ICS
    • Budesonide and formoterol inhibit inflammatory mediator production by bronchial epithelial cells infected with rhinovirus Skevaki, CEA 2009;39:1700 Human bronchial epithelial cells Rhinoviruses
      • BUD effectively suppressed RV-mediated induction of all mediators studied.
      • The combination of BUD and FORM had concentration-dependent, additive or synergistic effects.
      CCL5, CXCL10, CXCL8, IL-6 VEGF and bFGF (-)
    • Efficacy and tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler in adults and adolescents with asthma previously stable with twice-daily budesonide/formoterol dosing. Kerwin Ann Allergy Asthma Immunol 2009;103:62
      • 12-week study.
      • 619 patients ≥ 12 years with mild to moderate asthma.
      • After 4-5 weeks of twice-daily BUD/FOR (MDI), 80/4.5 μg × 2 inhalations ( 320/18 μg/d ), stable patients were randomized 1:1:1:1 to: * 2 inhalations twice daily of BUD/FOR pMDI, 80/4.5 μg - (320/18 μg/d), or - 2 inhalations once daily (evening) of BUD/FOR (MDI): * 160/4.5 μg (320/9 μg) or * 80/4.5 μg (160/9 μg/d), or * BUD pMDI, 160 μg (320 μg/d).
    • Pulmonary function and asthma control were more effectively maintained with all budesonide/formoterol regimens vs once-daily budesonide and with twice-daily budesonide/formoterol at twice the daily formoterol dose vs both once-daily budesonide/formoterol doses. Mean percent change from baseline in evening predose FEV 1 during the 12-week randomized treatment period. bid indicates twice daily; BUD, budesonide; FM, formoterol; pMDI, pressurized metered-dose inhaler; and qd, once daily. Efficacy and tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler in adults and adolescents with asthma previously stable with twice-daily budesonide/formoterol dosing. Kerwin Ann Allergy Asthma Immunol 2009;103:62 160/9 bid 320/9 qd 160/9 qd 320 qd
    • Effects of budesonide and formoterol on allergen induced airway responses, inflammation, and airway remodeling in asthma Kelly JACI 2010;125:349
      • 14 asthmatic subjects with dual responses after allergen inhalation.
      • inhaled BUD/FOR combination therapy versus inhaled BUD alone or inhaled placebo
      • Randomized, double-blind, 3-period crossover study of 11 days each.
      • Allergen-induced airway responses, airway inflammation, and airway remodeling.
      Effect of study treatment on allergen-induced early (EAR) and late (LAR) asthmatic responses.
    • Effect of study treatment on AHR ( MCh PC 20 ) before (day 8) and after (day 11) allergen challenge. Effects of budesonide and formoterol on allergen induced airway responses, inflammation, and airway remodeling in asthma Kelly JACI 2010;125:349
      • 14 asthmatic subjects with dual responses after allergen inhalation.
      • inhaled BUD/FOR combination therapy versus inhaled BUD alone or inhaled placebo
      • Randomized, double-blind, 3-period crossover study of 11 days each.
      • Allergen-induced airway responses, airway inflammation, and airway remodeling.
    • Effect of study treatment on sputum eosinophil numbers before (day 8) and 7 hours (day 9) and 48 hours (day 11) after allergen challenge. Effects of budesonide and formoterol on allergen induced airway responses, inflammation, and airway remodeling in asthma Kelly JACI 2010;125:349
      • 14 asthmatic subjects with dual responses after allergen inhalation.
      • inhaled BUD/FOR combination therapy versus inhaled BUD alone or inhaled placebo
      • Randomized, double-blind, 3-period crossover study of 11 days each.
      • Allergen-induced airway responses, airway inflammation, and airway remodeling.
    • Smooth muscle (percentage of area) and numbers of myofibroblasts in the subepithelial compartment in bronchial biopsy specimens. Diluent Placebo Budesonide Budesonide/ Formoterol Diluent Placebo Budesonide Budesonide/ Formoterol Effects of budesonide and formoterol on allergen induced airway responses, inflammation, and airway remodeling in asthma Kelly JACI 2010;125:349
    • Smooth muscle (percentage of area) and numbers of myofibroblasts in the subepithelial compartment in bronchial biopsy specimens. Diluent Placebo Budesonide Budesonide/ Formoterol Diluent Placebo Budesonide Budesonide/ Formoterol Allergen inhalation resulted in a significant increase in submucosal tissue myofibroblast numbers and produced a significant decrease in percentage smooth muscle area. Combination therapy, but not budesonide monotherapy, significantly attenuated these changes in myofibroblast numbers and smooth muscle area. Effects of budesonide and formoterol on allergen induced airway responses, inflammation, and airway remodeling in asthma Kelly JACI 2010;125:349
      • Conclusions :
      • The effects on allergen-induced changes in sputum eosinophils, airway myofibroblast numbers, and smooth muscle seen with combination therapy suggest that the benefits associated with this treatment might relate to effects on airway inflammation and remodeling.
      • The attenuation of early asthmatic responses and airway hyperresponsiveness by combination treatment was likely due to the known functional antagonistic effect of formoterol.
      Effects of budesonide and formoterol on allergen induced airway responses, inflammation, and airway remodeling in asthma Kelly JACI 2010;125:349
      • Retrospective analysis of 5 BUD/FOR maintenance and reliever therapy (Symbicort SMART Turbuhaler) studies.
      • Relationship between asthma control questionnaire (ACQ-5) and Global Initiative for Asthma-defined clinical asthma control and future risk of instability and exacerbations.
      Overall asthma control: The relationship between current control and future risk Bateman JACI 2010;125:600 Asthma control in the preceding week Asthma control in the following week
      • Retrospective analysis of 5 BUD/FOR maintenance and reliever therapy (Symbicort SMART Turbuhaler) studies.
      • Relationship between asthma control questionnaire (ACQ-5) and Global Initiative for Asthma-defined clinical asthma control and future risk of instability and exacerbations.
      Overall asthma control: The relationship between current control and future risk Bateman JACI 2010;125:600 Asthma control in the preceding week Asthma control in the following week Controlled week predicted at least Partly Controlled asthma the following week (≥80% probability).
      • Retrospective analysis of 5 BUD/FOR maintenance and reliever therapy (Symbicort SMART Turbuhaler) studies.
      • Relationship between asthma control questionnaire (ACQ-5) and Global Initiative for Asthma-defined clinical asthma control and future risk of instability and exacerbations.
      Overall asthma control: The relationship between current control and future risk Bateman JACI 2010;125:600 Asthma control in the preceding week Asthma control in the following week Bud/For maintenance and reliever therapy reduces exacerbations versus comparators and achieves at least similar control.
      • In Bateman report of 5 large clinical trials the control achieved by each patient was categorized by using the current Global Initiative for Asthma criteria. That is, patients were considered controlled when they had
      • no nocturnal symptoms of asthma,
      • daytime symptoms of asthma no more than 2 days per w week,
      • reliever use no more than 2 days per week and no more than 4 inhalations in total,
      • morning peak flow greater than 80% predicted,
      • no activity limitations attributable to asthma.
      SMART isn’t. Editorial Chapman JACI 2010;125:617
      • In Bateman report of 5 large clinical trials the control achieved by each patient was categorized by using the current Global Initiative for Asthma criteria. That is, patients were considered controlled when they had
      • no nocturnal symptoms of asthma,
      • daytime symptoms of asthma no more than 2 days per w week,
      • reliever use no more than 2 days per week and no more than 4 inhalations in total,
      • morning peak flow greater than 80% predicted,
      • no activity limitations attributable to asthma.
      SMART isn’t. Editorial Chapman JACI 2010;125:617 Patients who were not considered controlled were termed either partly controlled (if 1 or 2 of these criteria were not met) or uncontrolled (if 3 or more criteria were not met).
    • In the SMART treated patients % with asthma 17.4% CONTROLLED 38.3% PARTIALLY CONTROLLED 50 – 40 – 30 – 20 – 10 – 0 SMART isn’t. Editorial Chapman JACI 2010;125:617 44.3% UNCONTROLLED
    • In the SMART treated patients % with asthma 17.4% CONTROLLED 38.3% PARTIALLY CONTROLLED 50 – 40 – 30 – 20 – 10 – 0 SMART isn’t. Editorial Chapman JACI 2010;125:617 44.3% UNCONTROLLED If asthma control is the exception rather than the rule with SMART and if severe exacerbations remain frequent, why have early adopters argued that SMART is a superior means of preventing exacerbations?
    • In the SMART treated patients % with asthma 17.4% CONTROLLED 38.3% PARTIALLY CONTROLLED 50 – 40 – 30 – 20 – 10 – 0 SMART isn’t. Editorial Chapman JACI 2010;125:617 44.3% UNCONTROLLED Despite the availability of newer medications and formulations, there is no evidence that we should abandon the life-saving strategy of symptom prevention to return to the previously discredited approach of symptom-driven care.
    • formoterol Onset of effect
    • Formoterol for acute asthma in the emergency department: a systematic review with meta-analysis Rodrigo Ann Allergy Asthma Immunol. 2010;104:247–252.
      • Formoterol fumarate vs short-acting 2-agonists (SABAs) for the treatment of asthma exacerbations;
      • 9 randomized controlled trials (including 576 participants).
      formoterol = SABAs for any of the selected time points:at 30 to 40 minutes after the first administration of study drugs.
    • Formoterol for acute asthma in the emergency department: a systematic review with meta-analysis Rodrigo Ann Allergy Asthma Immunol. 2010;104:247–252.
    • A randomized, comparative study of formoterol and terbutaline dry powder inhalers in the treatment of mild to moderate asthma exacerbations in the pediatric acute care setting Bussamra Ann Allergy Asthma Immunol 2009;103:248
      • 79 pediatric patients (mean age, 10 yrs) with mild to moderate asthma exacerbations.
      • 3 doses of formoterol aerolizer, 12 μg, or terbutaline Turbuhaler, 0.5 mg (dry powder inhalers).
      • All the patients received oral prednisolone, 1 mg/kg.
      Formoterol % Increase in FEV 1 15 min after Dosing Terbutaline +19.5% 20 – 15 – 10 – 0 5 – 0 +15.3%
    • A randomized, comparative study of formoterol and terbutaline dry powder inhalers in the treatment of mild to moderate asthma exacerbations in the pediatric acute care setting Bussamra Ann Allergy Asthma Immunol 2009;103:248
      • 79 pediatric patients (mean age, 10 yrs) with mild to moderate asthma exacerbations.
      • 3 doses of formoterol aerolizer, 12 μg, or terbutaline Turbuhaler, 0.5 mg (dry powder inhalers).
      • All the patients received oral prednisolone, 1 mg/kg.
      Formoterol % Increase in FEV 1 15 min after Dosing Terbutaline +19.5% 20 – 15 – 10 – 0 5 – 0 +15.3% Formoterol therapy was at least as effective as terbutaline therapy in children and adolescents with mild and moderate asthma exacerbations.
    • formoterol
      • farmacoeconomia
    • Salmeterol+fluticasone vs formoterol+budesonide
      • LABA SAFETY
    • Hospitalizations for asthma in an urban population: 1995-1999 Lang Ann Allergy Asthma Immunol 2009;103:128
      • E cologic analysis, asthma hospitalization rates in individuals aged 5-64 yrs
      • In period 1 (1995-1997) and period 2 (1997-1999)
      Hospitalizations were correlated directly with prescriptions for inhaled short-acting β-agonists (SABAs) in periods 1 ( r s =0.61) and 2 ( r s =0.60) and inversely with LABA prescriptions in periods 1 ( r s =−0.56) and 2 ( r s =−0.66).
    • Hospitalizations for asthma in an urban population: 1995-1999 Lang Ann Allergy Asthma Immunol 2009;103:128
      • E cologic analysis, asthma hospitalization rates in individuals aged 5-64 yrs
      • In period 1 (1995-1997) and period 2 (1997-1999)
      Higher SABA prescription rates were also correlated with greater proportions of African Americans per zip code in periods 1 ( r s =0.58) and 2 ( r s =0.53).
    • Hospitalizations for asthma in an urban population: 1995-1999 Lang Ann Allergy Asthma Immunol 2009;103:128
      • E cologic analysis, asthma hospitalization rates in individuals aged 5-64 yrs
      • In period 1 (1995-1997) and period 2 (1997-1999)
      Higher SABA prescription rates were also correlated with greater proportions of African Americans per zip code in periods 1 ( r s =0.58) and 2 ( r s =0.53). These data do not support the contention that LABA exposure is a major cause of asthma morbidity. Risk of asthma hospitalization is strongly associated with being African American.
    • Hospitalizations for asthma in an urban population: 1995-1999 Lang Ann Allergy Asthma Immunol 2009;103:128 SABA precriptions LABA precriptions
      • We believe that recommendations to combine a β - agonist/ICS in a single inhaler should now be extended to include SABA usage in the treatment of asthma.
      • Combining the ICS with the SABA would ensure that ICS treatment is increased at times of increased disease activity, as well as potentially protecting against adverse effects of SABA overuse at the time of asthma exacerbation.
      Mechanisms of adverse effects of β 2 -agonists in asthma Johnston Thorax 2009;64;739
    • Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th aminoacid position of the β2-adrenergic receptor ( B16 Arg/Arg ) benefit less from treatment with longacting β2 agonists and inhaled corticosteroids than do those homozygous for glycine ( B16 Gly/Gly ). We investigated whether there is a genotype-specific response to treatment with a longacting β2 agonist in combination with inhaled corticosteroid. Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
      • Adult with moderate asthma;
      • B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype;
      • Salmeterol 50 μg twice a day or placebo crossover for two 18-week periods;
      • Hydrofluoroalkane beclometasone 240 μg twice a day, all patients.
      Morning PEF Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
      • Adult with moderate asthma;
      • B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype;
      • Salmeterol 50 μg twice a day or placebo crossover for two 18-week periods;
      • Hydrofluoroalkane beclometasone 240 μg twice a day.
      Morning PEF In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
      • Adult with moderate asthma;
      • B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype;
      • Salmeterol 50 μg twice a day or placebo crossover for two 18-week periods;
      • Hydrofluoroalkane beclometasone 240 μg twice a day.
      Morning PEF These findings suggest that patients should continue to be treated with longacting β2 agonists plus moderatedose inhaled corticosteroids irrespective of B16 genotype. Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
    • Methacholine responsivness
      • Adult with moderate asthma;
      • B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype;
      • Salmeterol 50 μg twice a day or placebo crossover for two 18-week periods;
      • Hydrofluoroalkane beclometasone 240 μg twice a day, all patients.
      Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
      • Adult with moderate asthma;
      • B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype;
      • Salmeterol 50 μg twice a day or placebo crossover for two 18-week periods;
      • Hydrofluoroalkane beclometasone 240 μg twice a day.
      Methacholine responsivness Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
    • Morning and Evening PEF in African-American partecipants
      • Adult with moderate asthma;
      • B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype;
      • Salmeterol 50 μg twice a day or placebo crossover for two 18-week periods;
      • Hydrofluoroalkane beclometasone 240 μg twice a day, all patients.
      Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
    • Morning and Evening PEF in African-American partecipants
      • Adult with moderate asthma;
      • B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype;
      • Salmeterol 50 μg twice a day or placebo crossover for two 18-week periods;
      • Hydrofluoroalkane beclometasone 240 μg twice a day, all patients.
      In a post-hoc subanalysis of African-American individuals the Arg/Arg group did not benefit when salmeterol was added to inhaled corticosteroid Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
    • Morning and Evening PEF in African-American partecipants
      • Adult with moderate asthma;
      • B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype;
      • Salmeterol 50 μg twice a day or placebo crossover for two 18-week periods;
      • Hydrofluoroalkane beclometasone 240 μg twice a day, all patients.
      Since our African-American subpopulation was small, this finding might be caused by beta error and should be considered exploratory; however, if confirmed, this finding might have important implications Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
      • Adult patients with moderate asthma B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype
      • Salmeterol 50 μg twice a day) or placebo for two 18-week periods.
      • Hydrofluoroalkane beclometasone 240 μg twice a day was given to all participants.
      Increase Compared to Placebo in Mean Morning PEF after 18 Weeks of Treatment 21.4 L/min ARG/ARG GLY/GLY 21.5 L/min p<0.0001 p<0.0001 25 – 20 – 15 – 10 – 5 – 0 Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
      • Adult patients with moderate asthma B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype
      • Salmeterol 50 μg twice a day) or placebo for two 18-week periods.
      • Hydrofluoroalkane beclometasone 240 μg twice a day was given to all participants.
      Increase Compared to Placebo in Mean Morning PEF after 18 Weeks of Treatment 21.4 L/min ARG/ARG GLY/GLY 21.5 L/min p<0.0001 p<0.0001 25 – 20 – 15 – 10 – 5 – 0 The improvement in PEF did not differ between genotypes. Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
      • Adult patients with moderate asthma B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype
      • Salmeterol 50 μg twice a day) or placebo for two 18-week periods.
      • Hydrofluoroalkane beclometasone 240 μg twice a day was given to all participants.
      Increase Compared to Placebo in Mean Morning PEF after 18 Weeks of Treatment 21.4 L/min ARG/ARG GLY/GLY 21.5 L/min p<0.0001 p<0.0001 25 – 20 – 15 – 10 – 5 – 0 These findings suggest that patients should continue to be treated with longacting β 2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
      • Adult patients with moderate asthma B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype
      • Salmeterol 50 μg twice a day) or placebo for two 18-week periods.
      • Hydrofluoroalkane beclometasone 240 μg twice a day was given to all participants.
      A subanalysis did reveal an interesting and important finding: 8 African American subjects with the Arg/Arg single nucleotide polymorphism did not benefit from the addition of salmeterol to inhaled corticosteroid therapy. The authors noted that this was consistent with recent findings by the US Food and Drug Administration that long-acting β2-agonists are associated with greater risk of serious side effects in African American asthmatic patients. Effect of beta2-adrenergic receptor polymorphism on response to LABA in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Wechsler Lancet 2009:374:174
    • Risk of mortality associated with formoterol: a systematic review and meta-analysis Wijesinghe ERJ 2009:34:803
      • Astra Zeneca Formoterol Clinical Trial Safety Database and Novartis Food and Drug Aministration Formoterol Briefing Document.
      • Randomised controlled clinical trials of duration ≥4 weeks that compared formoterol with a non-LABA comparator treatment in asthma.
      • There were 42 deaths (9 from asthma) recorded in 62 studies with 49,327 subjects.
      • The odds ratio for risk of mortality with formoterol for asthma death was 2.7
    • Risk of mortality associated with formoterol: a systematic review and meta-analysis Wijesinghe ERJ 2009:34:803
      • Astra Zeneca Formoterol Clinical Trial Safety Database and Novartis Food and Drug Aministration Formoterol Briefing Document.
      • Randomised controlled clinical trials of duration ≥4 weeks that compared formoterol with a non-LABA comparator treatment in asthma.
      • There were 42 deaths (9 from asthma) recorded in 62 studies with 49,327 subjects.
      • The odds ratio for risk of mortality with formoterol for asthma death was 2.7
      There are insufficient power to determine whether formoterol increase the risk of mortality
    • Kaplan-Meier probability curve for the time to first asthma-related hospitalization with formoterol-containing treatment versus non-LABA therapy Risk of asthma-related hospitalization with formoterol containing versus non-LABA therapy Safety of formoterol in patients with asthma: Combined analysis of data from double-blind, randomized controlled trials Nelson JACI 2010;125:390
    • Safety of formoterol in patients with asthma: Combined analysis of data from double-blind, randomized controlled trials Nelson JACI 2010;125:390
      • All blind, parallel-arm, randomized, active-controlled and/or placebo-controlled AstraZeneca-sponsored asthma studies with formoterol-containing and non-LABA comparator arms.
      • Data from 13,542 formoterol-randomized and 9968 non-LABA patients 4 years or older (42 trials), of whom 93% and 89%, respectively, received ICS.
      With formoterol-containing versus non-LABA treatment: 1) no evidence of increased risk of asthma-related hospitalization, 2) no asthma-related deaths, and a 3) low incidence of all- cause death and asthma-related intubation
      • It has frequently been asked: Is it biologically plausible that drugs which offer such significant benefits in the management of asthma can simultaneously cause harm? The answer is: Yes it is. This is the essence of the β-agonist &quot;paradox,&quot; and it is the critical lesson that clinicians need to bear in mind. Interestingly, there is a precedent in the Cardiac Arrhythmia Suppression Trial (CAST) study that showed that despite the suppression of major arrhythmias, the antiarrhythmic drugs flecainide and encainide were simultaneously associated with an increase in cardiac mortality.
      The β-Agonist Saga and Its Clinical Relevance: On and On It Goes Taylor Am J Respir Crit Care Med 2009;179:976
    • The β-Agonist Saga and Its Clinical Relevance: On and On It Goes Taylor Am J Respir Crit Care Med 2009;179:976
      • β-agonists: despite the short term benefits of mast cell stabilization and smooth muscle relaxation, the weight of evidence indicates that they are proinflammatory.
      • Increases IL-4 and IL-5 and decreases interferon-γ, thus enhancing the Th-2 pathway.
      • Increases in induced sputum inflammatory cells, and AHR especially to allergen .
    • The β-Agonist Saga and Its Clinical Relevance: On and On It Goes Taylor Am J Respir Crit Care Med 2009;179:976
      • How should we now approach the clinical challenges related to this issue? We should all acknowledge that the &quot;β-agonist paradox&quot; is here to stay for as long as we continue to use β-agonists! Clinicians should accept that it is no longer a matter of being for or against, but of recognizing that in addition to maximizing the benefits of LABAs and judiciously using SABAs, safe management of patients with asthma ought to take into account the potential paradoxical adverse effects to occur.
    • The β-Agonist Saga and Its Clinical Relevance: On and On It Goes Taylor Am J Respir Crit Care Med 2009;179:976
      • How should we now approach the clinical challenges related to this issue? We should all acknowledge that the &quot;β-agonist paradox&quot; is here to stay for as long as we continue to use β-agonists! Clinicians should accept that it is no longer a matter of being for or against, but of recognizing that in addition to maximizing the benefits of LABAs and judiciously using SABAs, safe management of patients with asthma ought to take into account the potential paradoxical adverse effects to occur.
      Good asthma management should include appropriate diagnosis and treatment of β-agonist toxicity where these drugs are occasionally the problem and not the solution.
    • The β-Agonist Saga and Its Clinical Relevance: On and On It Goes Taylor Am J Respir Crit Care Med 2009;179:976
      • How should we now approach the clinical challenges related to this issue? We should all acknowledge that the &quot;β-agonist paradox&quot; is here to stay for as long as we continue to use β-agonists! Clinicians should accept that it is no longer a matter of being for or against, but of recognizing that in addition to maximizing the benefits of LABAs and judiciously using SABAs, safe management of patients with asthma ought to take into account the potential paradoxical adverse effects to occur.
      We recently reported a case in which excessive β-agonist use was the chief reason for poor asthma control, and minimizing β-agonist treatment resulted in significant clinical improvements. Taylor DR, J Allergy Clin Immunol 2008;122:836–838
      • The characteristic features include unstable or intractable asthma with evidence of psychological and/or pharmacological β-agonist inhaler dependence. The need for frequent &quot;reliever,&quot; should cause alarm bells to ring.
      Management of β-agonist overuse: Why and how? Taylor JACI 2008;122:836
      • The characteristic features include unstable or intractable asthma with evidence of psychological and/or pharmacological β-agonist inhaler dependence. The need for frequent &quot;reliever,&quot; should cause alarm bells to ring.
      Management of β-agonist overuse: Why and how? Taylor JACI 2008;122:836 The management of such patients requires a structured treatment plan involving a team, as well as the cooperative involvement of the affected patient, such that β-agonist therapy is minimized or even withdrawn (yes, it is possible!). The approach is not at all new. Keighley JF. Ann Intern Med 1966;65:985–995 Eisenstadt WS Ann Allergy 1969;27:283–288 Sears MR Lancet 1991;338:1331–1332
      • The characteristic features include unstable or intractable asthma with evidence of psychological and/or pharmacological β-agonist inhaler dependence. The need for frequent &quot;reliever,&quot; should cause alarm bells to ring.
      Management of β-agonist overuse: Why and how? Taylor JACI 2008;122:836 Studies in this area will only be relevant if we also apply the important questions in individual cases especially where asthma management is difficult.
      • A 69-year-old woman with life-long asthma was referred for assessment of poorly controlled asthma.
      • Her treatment included 200 μg of budesonide/6 μg of formoterol, 3 inhalations twice daily.
      Management of β-agonist overuse: Why and how? Taylor JACI 2008;122:836
    • Management of β-agonist overuse: Why and how? Taylor JACI 2008;122:836
      • A n alternative treatment plan:
        • Symbicort containing formoterol (long-acting β-agonist) was discontinued. Inhaled fluticasone, 1000 μg/d through a Volumatic spacer, was administered.
        • Prednisone, 15 mg/d, was initiated to reduce any airway inflammation not adequately treated with inhaled steroid and, theoretically, to reverse any β-receptor tolerance.
        • Oral theophylline, 125 mg at night, was started to alleviate nocturnal symptoms.
    • Management of β-agonist overuse: Why and how? Taylor JACI 2008;122:836
      • Ad lib ipratropium (Atrovent administered through a metered-dose inhaler [MDI]) was permitted for relief of minor bronchospasm.
      • Peak flow monitoring was performed when symptoms worsened to provide feedback as to whether they were objectively related to airways narrowing.
      • Permission was granted to use albuterol administered by means of MDI only if PEF decreased by more than 25% from the baseline value.
    • Background: Regular use of inhaled β 2 -agonists has been associated with a paradoxical loss of asthma control and a deterioration of airway hyper-responsiveness, but the underlying mechanism is unknown. The neurotrophin brain-derived neurotrophic factor (BDNF) has recently been identified as a mediator of airway hyper-responsiveness in asthma. Adverse effects of salmeterol in asthma: a neuronal perspective Lommatzsch, Thorax 2009; 64: 763-769
      • 18 patients with mild allergic asthma who did not use any regular antiasthmatic therapy inhaled salmeterol for 2 weeks followed by 2 weeks of combination therapy with salmeterol and fluticasone.
      Boxplot graphs display the median (line within the box), interquartile range (edges of the box) and the range of all values less distant than 1.5 interquartile ranges from the upper or lower quartile (vertical lines). Adverse effects of salmeterol in asthma: a neuronal perspective Lommatzsch, Thorax 2009 64: 763-769 FEV 1 % pred
    • Airway responsiveness to histamine. PC20
      • 18 patients with mild allergic asthma who did not use any regular antiasthmatic therapy inhaled salmeterol for 2 weeks followed by 2 weeks of combination therapy with salmeterol and fluticasone.
      Adverse effects of salmeterol in asthma: a neuronal perspective Lommatzsch, Thorax 2009 64: 763-769
    • Brain-derived neurotrophic factor (BDNF) concentrations in serum and platelets. A B Adverse effects of salmeterol in asthma: a neuronal perspective Lommatzsch, Thorax 2009 64: 763-769
    • Association of brain-derived neurotrophic factor (BDNF) in serum (A) or platelets (B) and changes in the PC20 values Adverse effects of salmeterol in asthma: a neuronal perspective Lommatzsch, Thorax 2009 64: 763-769
    • Brain-derived neurotrophic factor (BDNF) release by monocyte-enriched human peripheral blood mononuclear cells stimulated with tumour necrosis factor a (TNFa, 50 ng/ml) for 24 h . Adverse effects of salmeterol in asthma: a neuronal perspective Lommatzsch, Thorax 2009 64: 763-769
      • 215 studies with 106 575 subjects
      Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy W eatherall Thorax 2010;65:39–43 OR for asthma death in salmeterol monotherapy 7.3 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0
    • Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy W eatherall Thorax 2010;65:39–43
      • 215 studies with 106 575 subjects
      OR for asthma death in salmeterol monotherapy 7.3 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 In 63 studies in which patients were randomised to receive the combination salmeterol/fluticasone propionate inhaler or ICS, there were no asthma deaths among 22,600 patients
    • Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy W eatherall Thorax 2010;65:39–43
      • 215 studies with 106 575 subjects
      OR for asthma death in salmeterol monotherapy 7.3 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 Salmeterol monotherapy in asthma increases the risk of asthma mortality and this risk is reduced with concomitant ICS therapy.
      • 215 studies with 106 575 subjects
      OR for asthma death in salmeterol/fluticasone propionate 2.1 3 – 2 – 1 – 0 Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy W eatherall Thorax 2010;65:39–43
    • The FDA and Safe Use of Long-Acting Beta-Agonists in the Treatment of Asthma Chowdhury, NEJM 2010;362:1
      • The FDA has conducted a comprehensive review of the benefits and risks of using LABAs to treat asthma.
      • The agency has concluded that the benefits of LABAs continue to outweigh the risks when the drugs are used appropriately
      • Background:
      • Long-acting 2-agonists (LABAs) are recommended as add-on therapy to antiinflammatory treatment in patients with chronic persistent asthma.
      • Results from individual studies evaluating the in vivo antiinflammatory effect of LABAs are conflicting.
      • The purpose of this metaanalysis was to determine whether LABAs have an in vivo antiinflammatory effect compared to placebo and whether the addition of a LABA to therapy with inhaled corticosteroids (ICSs) has a synergistic or additive antiinflammatory effect.
      Antiinflammatory Effects of Long-Acting β 2 -Agonists in Patients With Asthma A Systematic Review and Metaanalysis Mu Lee Chest 2009;136:171
      • 32 studies (n=1,105 participants)
      • There was no effect of LABA therapy on sputum, BAL fluid, or mucosal inflammatory cells in adults or in children.
      • In children, LABA therapy was associated with a small decrease in serum eosinophils and interleukin-4.
      • LABA therapy decreases BAL fluid albumin levels, suggesting a possible modulating effect on microvascular leakage .
      Antiinflammatory Effects of Long-Acting β 2 -Agonists in Patients With Asthma A Systematic Review and Metaanalysis Mu Lee Chest 2009;136:171
    • A: comparison of therapy with a LABA plus an ICS vs an ICS alone on ECP (serum, sputum) and sputum eosinophils. B: comparison of the effect of therapy with a LABA plus an ICS vs an ICS alone on ENO, by subgroup. Center of rhomboid indicates mean effect, and the width represents 95% CI. Antiinflammatory Effects of Long-Acting β 2 -Agonists in Patients With Asthma A Systematic Review and Metaanalysis Mu Lee Chest 2009;136:171
    • Safety of Long-Acting -Agonists Are New Data Really Required? Sears Chest 2009;136:604
      • A critical stratified analysis in the FDA report involving 15,192 individuals indicates that a LABA used with mandatory ICS therapy was not associated with an increased risk of asthma-related mortality , intubations, or exacerbations.
      • A new study is not practicable , nor is one needed in the light of current analyses of existing data. It is time to learn from the past, to rigorously avoid LABA monotherapy in asthma, and to use a LABA (when indicated) always in mandatory combination with appropriate doses of an ICS.
      • LABA + ICS in COPD
      • LABA vs MONTELUKAST as add-on
      • 182 children (6 to 17 yrs of age), who had uncontrolled asthma while receiving 100 µg of fluticasone twice daily ;
      • 16 weeks: 250 µg of fluticasone twice daily ( ICS step-up ), 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist twice daily ( LABA step-up ), or 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily ( LTRA step-up ).
      Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975 Relative probability of best response vs LTRA step-up 1.6 P=0.004 2 – 1 – 0 LABA step-up
    • Relative probability of best response vs ICS step-up 1.7 P=0.002 2 – 1 – 0 LABA step-up
      • 182 children (6 to 17 yrs of age), who had uncontrolled asthma while receiving 100 µg of fluticasone twice daily ;
      • 16 weeks: 250 µg of fluticasone twice daily ( ICS step-up ), 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist twice daily ( LABA step-up ), or 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily ( LTRA step-up ).
      Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975
    • Relative probability of best response vs ICS step-up 1.7 P=0.002 2 – 1 – 0 LABA step-up
      • 182 children (6 to 17 yrs of age), who had uncontrolled asthma while receiving 100 µg of fluticasone twice daily ;
      • 16 weeks: 250 µg of fluticasone twice daily ( ICS step-up ), 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist twice daily ( LABA step-up ), or 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily ( LTRA step-up ).
      Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975 Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P = 0.009).
    • Relative probability of best response vs ICS step-up 1.7 P=0.002 2 – 1 – 0 LABA step-up
      • 182 children (6 to 17 yrs of age), who had uncontrolled asthma while receiving 100 µg of fluticasone twice daily ;
      • 16 weeks: 250 µg of fluticasone twice daily ( ICS step-up ), 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist twice daily ( LABA step-up ), or 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily ( LTRA step-up ).
      Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975 However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy .
    • Pairwise comparisons of the three step-up therapies Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975
    • Primary Predictors of a Differential Response to Step-up Therapy Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975
    • Secondary Predictors of a Differential Response to Step-up Therapy Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975
      • Each child received all three therapies, and treatment success was determined on an individual basis.
      • During each treatment period, the investigators kept a close eye on each child’s asthma. They recorded asthma exacerbations requiring oral prednisone, the number of days each child’s asthma was under control, and the child’s lung function.
      • Despite a valiant effort, the investigators found no strongly compelling way of predicting which step- up therapy would work best in a given patient .
      Choosing Asthma Step-up Care Mutius Editorial NEJM 2010;362:1042
      • Do these data inform clinical practice?
      • Since any of the three step-up therapies may work in an individual patient, we would base our first choice for a given patient on three things: surety of safety , price , and convenience , in that order.
      Choosing Asthma Step-up Care Mutius Editorial NEJM 2010;362:1042
      • Do these data inform clinical practice?
      • Since any of the three step-up therapies may work in an individual patient, we would base our first choice for a given patient on three things: surety of safety , price , and convenience , in that order.
      • Our first choice would be either increasing the dose of an inhaled corticosteroid or adding a leukotriene modifier to the therapeutic regimen.
      Choosing Asthma Step-up Care Mutius Editorial NEJM 2010;362:1042
    • Asthma montelukast
      • 130 children 2 to 17 yrs with mild to moderate acute asthma stabilized with prednisolone in the emergency department
      • 5 daily treatments with either prednisolone or montelukast after discharge
      • treatment failure within 8 days:
      • asthma-related unscheduled
      • visit
      • hospitalization
      • additional systemic
      • corticosteroids
      % children with treatment failure Can Montelukast Shorten Prednisolone Therapy in Children with Mild to Moderate Acute Asthma? A Randomized Controlled Trial S Schuh, J Ped 2009;155;795 30 – 20 – 10 – 0 22.4% 7.9% prednisolone montelukast P=0.03
      • 130 children 2 to 17 yrs with mild to moderate acute asthma stabilized with prednisolone in the emergency department
      • 5 daily treatments with either prednisolone or montelukast after discharge
      • treatment failure within 8 days:
      • asthma-related unscheduled
      • visit
      • hospitalization
      • additional systemic
      • corticosteroids
      % children with treatment failure Can Montelukast Shorten Prednisolone Therapy in Children with Mild to Moderate Acute Asthma? A Randomized Controlled Trial S Schuh, J Ped 2009;155;795 30 – 20 – 10 – 0 22.4% 7.9% prednisolone montelukast P=0.03 Treatment was more likely to fail in younger patients (OR = 4.9)
      • 130 children 2 to 17 yrs with mild to moderate acute asthma stabilized with prednisolone in the emergency department
      • 5 daily treatments with either prednisolone or montelukast after discharge
      • treatment failure within 8 days:
      • asthma-related unscheduled visit
      • hospitalization
      • additional systemic corticosteroids
      % children with treatment failure Can Montelukast Shorten Prednisolone Therapy in Children with Mild to Moderate Acute Asthma? A Randomized Controlled Trial S Schuh, J Ped 2009;155;795 30 – 20 – 10 – 0 22.4% 7.9% prednisolone montelukast P=0.03 Montelukast does not represent an adequate alternative to corticosteroids after outpatient stabilization in mild to moderate acute asthma.
    • Asthma montelukast Patogenesi leucotrieni
    • MONTELUKAST Remodelling
    • MONTELUKAST Pharmacokinetics and safety
    • Reports of suicidality in clinical trials of montelukast Philip JACI 2009;124:691 Background In recent years, a number of drugs and drug classes have come under scrutiny by the US Food and Drug Administration regarding suicidality (including suicidal behavior and ideation). Objective We sought to perform 2 reviews (requested by the US Food and Drug Administration) of the number of events possibly related to suicidality reported in Merck clinical trials of montelukast.
    • Reports of suicidality in clinical trials of montelukast Philip JACI 2009;124:691
      • Review of clinical adverse experiences (AEs) from 116 studies.
      • Database described as possibly suicidality-related adverse events.
      • No completed suicides were reported in any study.
      • AES possibly related to suicidality were rare and were similar between the montelukast and placebo
      • Individuals with serious mental health disorders might be at highest risk for suicidality and behavior-related adverse events.
      • 2 .Both adults and children with more severe asthma are at increased risk for depression and behavior-related problems .
      Assessing risk: Data from montelukast clinical trials Editorial Kelsay JACI 2009;124:697
    • Background Frequencies of behavior-related adverse experiences (BRAEs) in controlled clinical studies of leukotriene modifier drugs have not been summarized. Objective We sought to compare the frequency of BRAEs in patients receiving montelukast or placebo in a retrospective analysis of Merck clinical trial data. Analysis of behavior-related adverse experiences in clinical trials of montelukast Philip JACI 2009;124:699
    • Analysis of behavior-related adverse experiences in clinical trials of montelukast Philip JACI 2009;124:699
      • 35 Adult and 11 pediatric placebo-controlled trials.
      • 11,673 patients received montelukast, 8,827 received placebo, and 4,724 received active control.
      3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 2.73% MONTELUKAST ns PLACEBO 2.27% % PATIENTS WITH BEHAVIOUR-RELATED ADVERSE EXPERIENCE (BRAE)
    • Analysis of behavior-related adverse experiences in clinical trials of montelukast Philip JACI 2009;124:699
      • 35 Adult and 11 pediatric placebo-controlled trials.
      • 11,673 patients received montelukast, 8,827 received placebo, and 4,724 received active control.
      3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 2.73% MONTELUKAST ns PLACEBO 2.27% % PATIENTS WITH BEHAVIOUR-RELATED ADVERSE EXPERIENCE (BRAE) The frequency of patients with a BRAE considered serious was 0.03% in both treatment groups .
    • Safety and tolerability of montelukast in placebo-controlled pediatric studies and their open-label extensions Bisgaard Ped Pul 2009;44:568
      • 2,751 pediatric patients 6 months to 14 years of age enrolled in 7 randomized, placebo-controlled, double-blind studies.
      • Montelukast was well tolerated in all studies.
      • Clinical and laboratory adverse experiences for patients treated with montelukast were generally mild and transient .
      • The clinical and laboratory safety profile for montelukast was similar to that observed for placebo or active control/usual care therapies.
      • The safety profile of montelukast did not change with long-term use .
           TO P      ABSTRACT     ME THODS     RE SULTS     DI SCUSSION     Su pport statement     St atement of interest     AC KNOWLEDGEMENTS     RE FERENCES      TO P      ABSTRACT     ME THODS     RE SULTS     DI SCUSSION     Su pport statement     St atement of interest     AC KNOWLEDGEMENTS     RE FERENCES
    • MONTELUKAST
        • Asthma - acute
        • - exacerbations
    • A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma Camargo JACI 2010;125:374
      • 583 adults with acute asthma treated with standard care during a ≤ 60-minute screening period.
      • Patients with FEV 1 ≤ 50% predicted were randomly allocated to intravenous montelukast 7mg (n=291) or placebo (n=292) in addition to standard care.
      Change from baseline in FEV 1 (L) over time (means ± SEs).
    • A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma Camargo JACI 2010;125:374
      • 583 adults with acute asthma treated with standard care during a ≤ 60-minute screening period.
      • Patients with FEV 1 ≤ 50% predicted were randomly allocated to intravenous montelukast 7mg (n=291) or placebo (n=292) in addition to standard care.
      Change from baseline in FEV 1 (L) over time (means ± SEs). Intravenous montelukast added to standard care in adults with acute asthma produced significant relief of airway obstruction throughout the 2 hours after administration, with an onset of action as early as 10 minutes.
    • Background: Up to 30% of patients require hospitalization for acute asthma despite standard therapy in the emergency department. In adults, intravenous montelukast added to standard therapy significantly improved forced expiratory volume in 1 second (FEV 1 ) and reduced hospital admissions compared with standard therapy . Objective: To evaluate the efficacy of intravenous montelukast added to standard therapy in children with acute asthma. A randomized, placebo-controlled study of intravenous montelukast in children with acute asthma Morris Ann Allergy Asthma Immunol 2010;104:161
    • A randomized, placebo-controlled study of intravenous montelukast in children with acute asthma Morris Ann Allergy Asthma Immunol 2010;104:161
      • Children (6-14 yrs)
      • FEV 1 ≤ 75% pred value
      • after up to 120 minutes of standard therapy (eg, oxygen, albuterol, inhaled anticholinergics, and systemic oral corticosteroids)
      • Intravenous montelukast, 5.25 mg ( n =145 ), or placebo ( n=131 ) added to standard therapy.
      Change from baseline in FEV 1 during 2 hours ns
    • A randomized, placebo-controlled study of intravenous montelukast in children with acute asthma Morris Ann Allergy Asthma Immunol 2010;104:161
      • Children (6-14 yrs)
      • FEV 1 ≤ 75% pred value
      • after up to 120 minutes of standard therapy (eg, oxygen, albuterol, inhaled anticholinergics, and systemic oral corticosteroids)
      • Intravenous montelukast, 5.25 mg ( n =145 ), or placebo ( n=131 ) added to standard therapy.
      Change from baseline in FEV 1 during 2 hours ns Large inter-individual variations in the response
    • A randomized, placebo-controlled study of intravenous montelukast in children with acute asthma Morris Ann Allergy Asthma Immunol 2010;104:161
      • Children (6-14 yrs)
      • FEV 1 ≤ 75% pred value
      • after up to 120 minutes of standard therapy (eg, oxygen, albuterol, inhaled anticholinergics, and systemic oral corticosteroids)
      • Intravenous montelukast, 5.25 mg (n =145), or placebo (n=131) added to standard therapy.
    • A randomized, placebo-controlled study of intravenous montelukast in children with acute asthma Morris Ann Allergy Asthma Immunol 2010;104:161
      • Children (6-14 yrs)
      • FEV 1 ≤ 75% pred value
      • after up to 120 minutes of standard therapy (eg, oxygen, albuterol, inhaled anticholinergics, and systemic oral corticosteroids)
      • Intravenous montelukast, 5.25 mg (n =145), or placebo (n=131) added to standard therapy.
      intravenous montelukast was not significantly better than placebo in improving FEV 1 , symptoms, or overall hospital course.
    • Single-dose desloratadine and montelukast and allergen-induced late airway responses B. E. Davis E R J 2009; 33:1302
      • Atopic asthmatics (n = 10).
      • Single-dose P lacebo, 5 mg D esloratadine, 10 mg M ontelukast and the combination.
      • Administered 2 h prior to allergen inhalation challenge.
      • Methacholine challenges 24 h before and after allergen challenge.
      Treatment-dependent inhibition of the late asthmatic response expressed as mean area under the FEV 1 curve (AUC) 3–7 h after allergen inhalation. P=0.007 P=0.042 P=0.066
    • Single-dose desloratadine and montelukast and allergen-induced late airway responses B. E. Davis E R J 2009; 33:1302 P D M D+M Treatment % increase in sputum eosinophils 24 h following allergen inhalation % increase in sputum eosinophils 7 h following allergen inhalation Treatment
      • Atopic asthmatics (n = 10).
      • Single-dose P lacebo, 5 mg D esloratadine, 10 mg M ontelukast and the combination.
      • Administered 2 h prior to allergen inhalation challenge.
      • Methacholine challenges 24 h before and after allergen challenge.
    • Single-dose desloratadine and montelukast and allergen-induced late airway responses B. E. Davis E R J 2009; 33:1302 P D M D+M Treatment % increase in sputum eosinophils 24 h following allergen inhalation % increase in sputum eosinophils 7 h following allergen inhalation Treatment
    • MONTELUKAST Asthma - chronic
      • Montelukast e cough variant asthma
      • Asma da esercizio
    • Add-on montelukast to inhaled corticosteroids protects against excessive airway narrowing Ulrik C EA 2010; 40:576
      • 31 patients with allergic asthma.
      • Montelukast 10 mg or placebo 12-week parallel study.
      • Bronchoprovocation tests with methacholine ≥40% decline in FEV 1 .
      Individual PD 20 FEV 1 methacholine values at baseline and after 12 weeks of treatment P=0.02 ns
    • Add-on montelukast to inhaled corticosteroids protects against excessive airway narrowing Ulrik C EA 2010; 40:576
      • 31 patients with allergic asthma.
      • Montelukast 10 mg or placebo 12-week parallel study.
      • Bronchoprovocation tests with methacholine ≥40% decline in FEV 1 .
      Mean decrease in maximal response plateau to methacholine -9.4% p<0.005 -10 – - 0 -1 – -2 – -3 – -4 – -5 – -6 – -7 – -8 – -9 – In Momtelukast vs Placebo
    • Add-on montelukast to inhaled corticosteroids protects against excessive airway narrowing Ulrik C EA 2010; 40:576
      • 31 patients with allergic asthma.
      • Montelukast 10 mg or placebo 12-week parallel study.
      • Bronchoprovocation tests with methacholine ≥40% decline in FEV 1 .
      Mean decrease in maximal response plateau to methacholine -9.4% p<0.005 -10 – - 0 -1 – -2 – -3 – -4 – -5 – -6 – -7 – -8 – -9 – In Momtelukast vs Placebo Add-on montelukast to ICS has disease-modifying effects in adults with persistent asthma, and hence reduces the risk of excessive airway narrowing.
      • Piccole vie aeree
    • MONTELUKAST responders non-responders
    • Randomized trial of the effect of drug presentation on asthma outcomes: The American Lung Association Asthma Clinical Research Centers. Wise JACI 2009;124:436 Background: Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma symptoms often improve with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit. Objective: The study objective was to determine whether response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit.
      • 601 asthmatic patients with poor symptom control.
      • Assigned to one of 5 study groups: (ie, placebo with enhanced messages, placebo with neutral messages, montelukast with enhanced messages, or montelukast with neutral messages) or to usual care.
      • Lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo.
      • Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants; the neutral placebo group did have improved asthma control.
      Compared with the usual care group: Randomized trial of the effect of drug presentation on asthma outcomes: The American Lung Association Asthma Clinical Research Centers. Wise JACI 2009;124:436
    • Augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Rican and Mexican children Tcheurekdjian Ann Allergy Asthma Immunol 2009;102:510
      • A cross-sectional study of 84 Mexican American and 192 Puerto Rican children with persistent asthma.
      + 11.8% p<0.001 % Increase in FEV 1 after Albuterol In LTRA Treated Puerto Rican Children 15 – 10 – 0 5 – 0
    • Augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Rican and Mexican children Tcheurekdjian Ann Allergy Asthma Immunol 2009;102:510
      • A cross-sectional study of 84 Mexican American and 192 Puerto Rican children with persistent asthma.
      + 11.8% p<0.001 % Increase in FEV 1 after Albuterol In LTRA Treated Puerto Rican Children 15 – 10 – 0 5 – 0 No effect was seen in Mexican American children.
    • Augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Rican and Mexican children Tcheurekdjian Ann Allergy Asthma Immunol 2009;102:510
      • A cross-sectional study of 84 Mexican American and 192 Puerto Rican children with persistent asthma.
      + 11.8% p<0.001 % Increase in FEV 1 after Albuterol In LTRA Treated Puerto Rican Children 15 – 10 – 0 5 – 0 This ethnic-specific, drug-drug interaction highlights the need for the further understanding of asthma pharmacogenetics among children from different ethnic groups.
      • Montelukast non-asthma
    • Combined cetirizine-montelukast preventive treatment for food-dependent exercise-induced anaphylaxis Peroni, Ann Allergy Asthma Immunol 2010;104:272-273
      • 17-year-old adolescent admitted for 2 episodes of anaphylaxis that occurred while jogging 60 minutes after eating;
      • Open food-exercise challenges with 2 peaches was associated with generalized urticaria, nausea, swelling, coughing, and wheezing within 3 minutes.
      Cetirizine 10 mg no protection Cetirizine 10 mg + Montelukast 10 mg Full protection
    • Urine Concentrations of Cysteinyl Leukotrienes in Children With Obstructive Sleep-Disordered Breathing (SDB) Kaditis Chest 2009;135:1496
      • 19 children with moderate-to-severe SDB
      • (OAHI: 14.4±9.6 episodes/h)
      • 29 subjects with mild SDB (OAHI: 2.9±0.8 episodes/h)
      • 26 children with primary snoring (PS) (OAHI: 1.1 ± 0.3episodes/h)
      • 18 control subjects (OAHI: 0.7±0.3 episodes/h)
    • Urine Concentrations of Cysteinyl Leukotrienes in Children With Obstructive Sleep-Disordered Breathing (SDB) Kaditis Chest 2009;135:1496
      • 19 children with moderate-to-severe SDB
      • (OAHI: 14.4±9.6 episodes/h)
      • 29 subjects with mild SDB (OAHI: 2.9±0.8 episodes/h)
      • 26 children with primary snoring (PS) (OAHI: 1.1 ± 0.3episodes/h)
      • 18 control subjects (OAHI: 0.7±0.3 episodes/h)
      InCysLTs correlated significantly with log-transformed OAHI in 92 children with obstructive SDB ( r =0.40; p <0.01).
    • Urine Concentrations of Cysteinyl Leukotrienes in Children With Obstructive Sleep-Disordered Breathing (SDB) Kaditis Chest 2009;135:1496
      • 19 children with moderate-to-severe SDB
      • (OAHI: 14.4±9.6 episodes/h)
      • 29 subjects with mild SDB (OAHI: 2.9±0.8 episodes/h)
      • 26 children with primary snoring (PS) (OAHI: 1.1 ± 0.3episodes/h)
      • 18 control subjects (OAHI: 0.7±0.3 episodes/h)
      This finding indicates that 5-lipoxygenase pathway products participate in the pathogenesis of obstructive sleep apnea in childhood or alternatively that SDB promotes CysLTs biosynthesis.
    • Asthma OMALIZUMAB Humanized antibodies In the simplest case, these are created by grafting the antigen-binding loops, known as complementarity-determining regions (CDRs), from a mouse mAb into a human IgG.
    • Effects of omalizumab on markers of inflammation in patients with allergic asthma Holgate Allergy 2009:64:1728
      • The role of IgE in allergic inflammation provided the rationale for developing omalizumab , a humanized monoclonal anti-IgE antibody for patients with moderate-to-severe or severe allergic asthma .
      • The reductions in circulating levels of IgE resulting from omalizumab treatment leads to reductions in FcɛRI expression on mast cells, basophils and dendritic cells.
      • This combined effect results in attenuation of several markers of inflammation, including peripheral and bronchial tissue eosinophilia and levels of GMC-SF (granulocyte macrophage colony stimulating facto)r, interleukin (IL)-2, IL-4, IL-5 and IL-13 .
    • Effects of omalizumab on markers of inflammation in patients with allergic asthma Holgate Allergy 2009:64:1728
      • The role of IgE in allergic inflammation provided the rationale for developing omalizumab , a humanized monoclonal anti-IgE antibody for patients with moderate-to-severe or severe allergic asthma .
      • The reductions in circulating levels of IgE resulting from omalizumab treatment leads to reductions in FcɛRI expression on mast cells, basophils and dendritic cells.
      • This combined effect results in attenuation of several markers of inflammation, including peripheral and bronchial tissue eosinophilia and levels of GMC-SF (granulocyte macrophage colony stimulating facto)r, interleukin (IL)-2, IL-4, IL-5 and IL-13 .
      By blocking IgE binding to its receptors and diminishing dendritic cell FcɛRI receptor expression, omalizumab may also reduce allergen presentation to T cells and the production of Th2 cytokines.
    • Effects of omalizumab on markers of inflammation in patients with allergic asthma Holgate Allergy 2009:64:1728 PROPOSED MECHANISMS OF ACTION OF OMALIZUMAB
    • Effects of omalizumab on markers of inflammation in patients with allergic asthma Holgate Allergy 2009:64:1728
    • Effects of omalizumab on markers of inflammation in patients with allergic asthma Holgate Allergy 2009:64:1728 Individual eosinophil counts at baseline and after 12 weeks of treatment. Change in eosinophil apoptosis (Annexin-positive cells) between baseline and week 12 in patients with allergic asthma.
    • Background: Many children with asthma continue to experience symptoms despite available therapies. Objective: This study evaluated the efficacy and safety of omalizumab, a humanized anti-IgE mAb, in children with moderate-to-severe persistent allergic (IgE-mediated) asthma that was inadequately controlled despite treatment with medium-dose or high-dose inhaled corticosteroids (ICSs) with or without other controller medications. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Lanier JACI 2009:124:1210
      • Children age 6 to <12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs .
      • Randomized 2:1 to receive omalizumab ( 75-375 mg sc, q2 or q4 wk ) or placebo over a period of 52 weeks .
      • 24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase .
      • Omalizumab, n = 421; placebo, n = 206.
      Rate of Clinically Significant Asthma Exacerbations over the 24-week Fixed-Steroid Phase 0 -5 – -10 – -15 – -20 – -25 – -30 – -35 – -31% p=0.007 IN OMALIZUMAB Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Lanier JACI 2009:124:1210
      • Children age 6 to <12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs.
      • Randomized 2:1 to receive omalizumab ( 75-375 mg sc, q2 or q4 wk ) or placebo over a period of 52 weeks .
      • 24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase.
      • Omalizumab, n = 421; placebo, n = 206.
      0 -5 – -10 – -15 – -20 – -25 – -30 – -35 – -31% p =0.007 IN OMALIZUMAB Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Lanier JACI 2009:124:1210 Sottocute 1 o 2 volte al mese Rate of Clinically Significant Asthma Exacerbations over the 24-week Fixed-Steroid Phase
    • Rate of Clinically Significant Asthma Exacerbations over a Period of 52 Weeks 0 -5 – -10 – -15 – -20 – -25 – -30 – -35 – -40 – -45 – -43% p<0.001 IN OMALIZUMAB Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Lanier JACI 2009:124:1210
      • Children age 6 to <12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs .
      • Randomized 2:1 to receive omalizumab ( 75-375 mg sc, q2 or q4 wk ) or placebo over a period of 52 weeks .
      • 24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase .
      • Omalizumab, n = 421; placebo, n = 206.
    • 0 -5 – -10 – -15 – -20 – -25 – -30 – -35 – -40 – -45 – -43% p<0.001 IN OMALIZUMAB Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Lanier JACI 2009:124:1210
      • Children age 6 to <12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs .
      • Randomized 2:1 to receive omalizumab ( 75-375 mg sc, q2 or q4 wk ) or placebo over a period of 52 weeks .
      • 24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase .
      • Omalizumab, n = 421; placebo, n = 206.
      Omalizumab significantly reduced severe exacerbations. Rate of Clinically Significant Asthma Exacerbations over a Period of 52 Weeks
    • Clinically significant asthma exacerbation rates over a period of 24 weeks (primary outcome; A) and 52 weeks (B) in patients with moderate-to-severe asthma treated with add-on omalizumab (n = 384) or placebo (n = 192) to an optimized asthma program (mITT population). Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Lanier JACI 2009:124:1210
    • Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Lanier JACI 2009:124:1210 INCIDENCE OF AEs (SAFETY POPULATION) Over a period of 52 weeks, omalizumab had an acceptable safety profile, with no difference in overall incidence of adverse events compared with placebo.
    • After 6 years with Xolair;a 3-year withdrawal follow-up Nopp Allergy 2010:65:56
      • 18 cat allergic asthmatics treated with Xolair for 6 years.
      • Follow-up: 3 yrs after stopping Xolair.
      ◦ ◦ ◦ ◦
    • After 6 years with Xolair;a 3-year withdrawal follow-up Nopp Allergy 2010:65:56 Changes 1 and 3 years after stopping Xolair
    • After 6 years with Xolair;a 3-year withdrawal follow-up Nopp Allergy 2010:65:56 Changes 1 and 3 years after stopping Xolair Most of the patients in this study had, still 3 years after closing of 6 years Xolair treatment, a surprisingly mild and stable asthma.
    • The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment Johansson Allergy 2009:64:1472
      • Some patients with allergic asthma treated with anti-IgE (Xolair®) do not become symptom free .
      • Better criteria for response assessment than allergy skin tests or IgE determination are needed.
      • The impact of the size of the disease relevant allergen-specific IgE antibody fraction, i.e. the percentage of IgE antibody of total IgE, was evaluated in cat allergic patients treated with the recommended doses of Xolair®. Results were measured as changes in basophil allergen threshold sensitivity (CD-sens).
    • The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment Johansson Allergy 2009:64:1472 Calculation of CD-sens Basophil allergen threshold sensitivity , CD-sens, was analysed by flow cytometry after incubation with serial dilutions of cat allergen extract and defined as the inverted value for the allergen concentration giving a 50% of maximum CD63 up-regulation multiplied by 100. There is a significant correlation between CD-sens, skin prick test titration and nasal provocation allergen sensitivity. Percentage CD63 up-regulation, after stimulation with one or a few high doses of the cat allergen, was taken as a measure of basophil reactivity.
    • The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment Johansson Allergy 2009:64:1472
      • 20 patients with a high (>3.8%) and 18 with a low (<1%) percentage of IgE antibodies to cat.
      • Xolair® for 16 weeks.
      • Change in CD-sens ( Basophil allergen threshold sensitivity ).
      CD-sens after treatment in relation to percentage of IgE antibodies to cat before start of trial in the high group receiving active (  ) or placebo (  ) compared to the low group on active (  ) or placebo (  ). <1% sIgE >3.8% sIgE
    • The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment Johansson Allergy 2009:64:1472
      • 20 patients with a high (>3.8%) and 18 with a low (<1%) percentage of IgE antibodies to cat.
      • Xolair® for 16 weeks.
      • Change in CD-sens ( Basophil allergen threshold sensitivity ).
      CD-sens after treatment in relation to percentage of IgE antibodies to cat before start of trial in the high group receiving active (  ) or placebo (  ) compared to the low group on active (  ) or placebo (  ). <1% sIgE >3.8% sIgE In the group with a low percentage of disease relevant IgE to cat receiving active treatement 13 out of 18 patients had a negative CD-sens (p<0.01).
    • The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment Johansson Allergy 2009:64:1472
      • 20 patients with a high (>3.8%) and 18 with a low (<1%) percentage of IgE antibodies to cat.
      • Xolair® for 16 weeks.
      • Change in CD-sens ( Basophil allergen threshold sensitivity ).
      CD-sens after treatment in relation to percentage of IgE antibodies to cat before start of trial in the high group receiving active (  ) or placebo (  ) compared to the low group on active (  ) or placebo (  ). <1% sIgE >3.8% sIgE In the group with a high percentage of disease relevant IgE to cat receiving active treatement no patient’s CD-sens became negative.
    • The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment Johansson Allergy 2009:64:1472 Number of CD-sens positive (  ) and negative (  ) patients in the high and low group after treatment with Xolair in relation to total serum IgE concentration before trial.
      • 20 patients with a high (>3.8%) and 18 with a low (<1%) percentage of IgE antibodies to cat.
      • Xolair® for 16 weeks.
      • Change in CD-sens ( Basophil allergen threshold sensitivity ).
    • The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment Johansson Allergy 2009:64:1472
      • 20 patients with a high (>3.8%) and 18 with a low (<1%) percentage of IgE antibodies to cat.
      • Xolair® for 16 weeks.
      • Change in CD-sens ( Basophil allergen threshold sensitivity ).
      CD-sens after treatment in relation to percentage of IgE antibodies to cat before start of trial in the high group receiving active (  ) or placebo (  ) compared to the low group on active (  ) or placebo (  ). <1% sIgE >3.8% sIgE The presently recommended dosing for Xolair® seem to be effective only in cases with a small fraction, in this study <1%, of disease-relevant IgE antibodies out of 'total IgE'. If the fraction is larger, i.e. >3–4%, a higher dose must be considered .
    • Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma Massanari JACI 2010;125:383 % patients with systemic allergic reactions to immunotherapy 13.5% 25 – 20 – 15 – 10 – 5 – 0
      • omalizumab’s effect on the tolerability of specific immunotherapy
      • patients with symptomatic persistent asthma not adequately controlled with inhaled corticosteroids
      • specific immunotherapy (cat, dog, and house dust mite)
      • 248 randomized patients (126 omalizumab, 122 placebo)
      22.5% Omalizumab Placebo P=0.017
    • % patients able to reach the target maintenance immunotherapy dose 87.3% 72.1% Omalizumab Placebo P=0.004 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma Massanari JACI 2010;125:383
      • omalizumab’s effect on the tolerability of specific immunotherapy
      • patients with symptomatic persistent asthma not adequately controlled with inhaled corticosteroids
      • specific immunotherapy (cat, dog, and house dust mite)
      • 248 randomized patients (126 omalizumab, 122 placebo)
    • % patients able to reach the target maintenance immunotherapy dose 87.3% 72.1% Omalizumab Placebo P=0.004 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma Massanari JACI 2010;125:383
      • omalizumab’s effect on the tolerability of specific immunotherapy
      • patients with symptomatic persistent asthma not adequately controlled with inhaled corticosteroids
      • specific immunotherapy (cat, dog, and house dust mite)
      • 248 randomized patients (126 omalizumab, 122 placebo)
      Use of omalizumab in patients whose asthma was symptomatic despite use of inhaled corticosteroids was associated with fewer systemic allergic reactions to specific immunotherapy and enabled more patients to achieve the target immunotherapy maintenance dose.
    • Omalizumab-associated anaphylactic reactions reported between January 2007 and June 2008 Lin Ann Allergy Asthma Immunol 2009;103:442
      • B etween January 1, 2007, and June 30, 2008
      There were 85 cases with an anaphylaxis descriptor and 33 cases without a descriptor of anaphylaxis but with multisystem allergic reactions (mostly respiratory and skin or mucosal) that were consistent with anaphylaxis. Of these 118 cases, 32 were after the first dose
    • Omalizumab-associated anaphylactic reactions reported between January 2007 and June 2008 Lin Ann Allergy Asthma Immunol 2009;103:442
      • B etween January 1, 2007, and June 30, 2008
      77 of the 118 cases were categorized as requiring hospital admission or had life-threatening reactions, underwent treatment with epinephrine.
    • Omalizumab-associated anaphylactic reactions reported between January 2007 and June 2008 Lin Ann Allergy Asthma Immunol 2009;103:442
      • B etween January 1, 2007, and June 30, 2008
      19 of the 118 cases were described as occurring within 1 hour of omalizumab injection.
    • Omalizumab-associated anaphylactic reactions reported between January 2007 and June 2008 Lin Ann Allergy Asthma Immunol 2009;103:442
      • B etween January 1, 2007, and June 30, 2008
      • The FDA investigators estimated that at least 2 of 1,000 omalizumab-treated patients develop anaphylaxis. Limb SL ,JACI. 2007;120:1378.
      • This prevalence is similar to the systemic reaction rate associated with allergen immunotherapy injections of 2.5 per 1,000.
      • Solar urticaria is divided into 2 types: type I and type II.
      • Type I defines patients who have precursors located in the serum, plasma, or cutaneous tissue fluid that become photoallergens once activated by the appropriate wavelength and bind to IgE receptors , resulting in mast cell degranulation.
      • Type II is also IgE mediated, but precursors are found in both healthy patients and patients with solar urticaria. It is hypothesized that only patients with solar urticaria have an abnormal circulating IgE autoantibody that recognizes these irradiated precursors.
      Partial improvement of solar urticaria after Omalizumab Waibel JACI 2010;125:490
      • We present a 16-year-old boy with solar urticaria who was refractory to oral antihistamines but improved partially with omalizumab.
      • Symptoms would occur within minutes and would progress to raised, confluent urticarial plaques only on sun-exposed skin. Once he returned indoors, his skin symptoms would completely resolve after 30 minutes without hyperpigmentation or eczematous changes.
      Partial improvement of solar urticaria after Omalizumab Waibel JACI 2010;125:490
      • We present a 16-year-old boy with solar urticaria who was refractory to oral antihistamines but improved partially with omalizumab.
      • Symptoms would occur within minutes and would progress to raised, confluent urticarial plaques only on sun-exposed skin. Once he returned indoors, his skin symptoms would completely resolve after 30 minutes without hyperpigmentation or eczematous changes.
      Partial improvement of solar urticaria after Omalizumab Waibel JACI 2010;125:490 He had significantly altered his social behavior because of these symptoms.
      • We present a 16-year-old boy with solar urticaria who was refractory to oral antihistamines but improved partially with omalizumab.
      • Symptoms would occur within minutes and would progress to raised, confluent urticarial plaques only on sun-exposed skin. Once he returned indoors, his skin symptoms would completely resolve after 30 minutes without hyperpigmentation or eczematous changes.
      Partial improvement of solar urticaria after Omalizumab Waibel JACI 2010;125:490 He had only tried over-the-counter sunscreen with minimal improvement.
    • Phototesting demonstrating a wheal and flare for the UV-A (5 and 10 J/cm 2 ) and UV-B (20, 30, 40, and 50 mJ/cm 2 ) spectrum within 1 minute of testing. The patient demonstrated significant sensitivity with erythema and flushing even in areas protected with a Tyvek Protective Wear Suit (DuPont, Wilmington, Del). No reaction occurred to the visible light spectrum. Partial improvement of solar urticaria after Omalizumab Waibel JACI 2010;125:490
      • The patient was unsuccessfully treated with loratadine (30 mg/d), cetirizine (20 mg/d), and diphenhydramine (up to 200 mg/d).
      • Omalizumab (Xolair). On the basis of his initial IgE level (851 IU/mL) and weight (57.7 kg), a calculated dose of 400 mg every 2 weeks for 3 months was initiated.
      • Repeat phototesting was performed 1 week after his sixth omalizumab dose.
      Partial improvement of solar urticaria after Omalizumab Waibel JACI 2010;125:490
      • The patient was unsuccessfully treated with loratadine (30 mg/d), cetirizine (20 mg/d), and diphenhydramine (up to 200 mg/d).
      • Omalizumab (Xolair). On the basis of his initial IgE level (851 IU/mL) and weight (57.7 kg), a calculated dose of 400 mg every 2 weeks for 3 months was initiated.
      • Repeat phototesting was performed 1 week after his sixth omalizumab dose.
      Partial improvement of solar urticaria after Omalizumab Waibel JACI 2010;125:490 UV-A and UV-B testing sites showed improvement with no immediate reaction that was previously seen on initial testing.
    • Asthma treatment macrolides
    • Azithromycin has an antiproliferative and autophagic effect on airway smooth muscle cells Stamatiou ERJ 2009:34:721
      • Incubation with azithromycin for 72 h reduced SMC proliferation and viability in a dose-dependent manner.
      • Azithromycin reduces proliferation and causes autophagy of airway SMCs.
      Rabbit tracheal SMCs were treated with azithromycin (10 –5 to 10 –6  M)
    • Azithromycin Attenuates Airway Inflammation in a Noninfectious Mouse Model of Allergic Asthma Beigelman Chest 2009;136:498 Intraperitoneal ovalbumin sensitization. Intranasal challenge Treated with azithromycin or phosphate-buffered saline (PBS) solution on days 13 through 16. On day 17, airway inflammation was assessed.
    • Azithromycin Attenuates Airway Inflammation in a Noninfectious Mouse Model of Allergic Asthma Beigelman Chest 2009;136:498 Intraperitoneal ovalbumin sensitization. Intranasal challenge Treated with azithromycin or phosphate-buffered saline (PBS) solution on days 13 through 16. On day 17, airway inflammation was assessed. Azithromycin attenuated allergic airway inflammation.
    • Azithromycin Attenuates Airway Inflammation in a Noninfectious Mouse Model of Allergic Asthma Beigelman Chest 2009;136:498 Azithromycin (Azithro) attenuated ovalbumin-dependent airway inflammation.
    • Azithromycin Attenuates Airway Inflammation in a Noninfectious Mouse Model of Allergic Asthma Beigelman Chest 2009;136:498
      • Azithromycin attenuated ovalbumin-dependent BAL accumulations of
      • eosinophils,
      • macrophages,
      • lymphocytes, and
      • neutrophils.
    • Asthma treatment termoplasty
    • Take home
      • Le maschere dei distanziatori devono essere piccole e soffici, meglio passare direttamente al boccaglio appena possibile,
      • I genitori attuano più efficacemente la terapia della crisi se hanno “sperimentato” che cosa succede in caso contrario,
      • I β 2 andrebbero sempre usati assieme a ICS (4X !!!),
      • Gli steroidi sistemici, se servono, vanno iniziati entro 60 min dalla richiesta di visita,
      • Nei pazienti non ben controllati da ICS meglio aggiungere LABA o LTRA piuttosto che 2X ICS anche se la risposta varia da pt. a pt.,
      • Prescrivi la terapia preventiva prima della “September epidemic”,
      • LTRA + anti-istaminico (+ ICS) può essere utile nella prevenzione delle “crisi prevedibili”,
      • Nei non responder si può ricorrere al monoclonale anti-IgE e ai macrolidi.
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