1. Identify immune system factors involved in lung inflammation and asthma.

2. Recommend appropriate environmental interventions for treatment of allergic symptoms.

3. Identify common childhood asthma phenotypes and risks for asthma.

4. Assess and manage patients across different age groups and severities of asthma.

5. Identify poorly controlled and well-controlled patients and adjust therapy accordingly.

The Immunopathogenesis of Asthma in Childhood
Thomas A.E. Platts-Mills, MD, PhD, Professor of Medicine and Microbiology, and Division Head, Division of Allergy and Clinical Immunology, University of Virginia School of Medicine, Charlottesville

Overview: most cases seen in hospital triggered by virus, eg, respiratory syncytial virus (RSV) infection, metapneumovirus infection; children 0 to 10 yr of age increasingly sensitized to inhaled allergens; sensitization important in managing patients; allergy testing important in asthmatics; prevalence—most studies show increase since 1960s (presently plateauing); especially high in Australia, New Zealand, and United Kingdom; most studies use subjective questionnaire data; objective evidence (Columbia University study) of asthma in ≈20% of children in Harlem (section of New York City, largely African-American); stabilized in some populations; still present in inner cities

Determinants of asthma: increase in prevalence not explained by increasing allergen exposure alone; genes—association studies give no clear answers; genes involved in multiple factors (including bronchial hyperreactivity, underlying immune response); of 100 asthma genes indicated across multiple studies, ≥20 have been found in >1 study; however, no single gene linked to asthma across all studies; environment—dust mite, cockroach, and other allergen exposures important to consider

Asthma cascade: involves genetic predispositions; inducers (eg, indoor allergen) trigger immune response (increase in helper T cell type 2 [TH 2], IgE, IgG4 , IgG1 ); inflammation (increase in TH 2, mast cells, eosinophils); wheezing

Bronchiole anatomy: outer to inner layer—smooth muscle; basement membrane plus collagen deposition; epithelium; mucus; air space; influence of asthma—increases collagen in basement membrane; no evidence that thickening equals remodeling (causing progressive decreases in size of lungs); also, little to no evidence that thickening decreases lung function; inflammation, however, important

Bronchiole provocation with particles: dust mite fecal particles 30 µm in diameter (same size as pollen grain); do not stay airborne; pollen grains (airborne) cause ≈90% of allergic conjunctivitis cases; 10% of inhaled pollen grains and mite fecal particles enter lungs; fecal particles and pollen grains 1000 times larger than penicillin spores; single mite fecal particle will produce small focus of inflammation in lung, yielding positive skin test; not true that inhaled particles must be 5 µm

Environmental interventions: dramatic effects (ie, reversal of bronchial reactivity) occur over months to one year; study (Kerrebijn 1970)—32 mite-allergic children moved from Amsterdam, Netherlands (mite-infested), to Davos, Switzerland (mite-free) for 1 yr; bronchial hyperreactivity reversed; speaker’s study (Platts-Mills 1982)—severe dust mite-allergic adult asthmatics moved from London homes to hospital unit; took months to reverse bronchial reactivity (some even got to state of normal lungs, eg, exercise possible); study (Boner)—asthmatic children moved from Verona, Italy, to sanatorium in mountains; inflammation markers, eg, eosinophil levels, nasal eosinophil cationic protein (ECP), exhaled nitric oxide, steadily decreased; allergen avoidance plus exercise involved; conclusion that allergen avoidance can be anti-inflammatory; less dramatic interventions—vacuum bedding and sofas weekly; wooden floors; second-floor apartments; allergen-resistant fabrics; compliance key

Asthma control: guidelines (speaker on panel) recommend that omalizumab (Xolair) be considered in patients ≥11 yr of age; anti-IgE (monoclonal antibody that decreases IgE in circulation); anti-interleukin-5 (anti-IL5) drugs do not work; always consider environment (eg, basement mold, cat and dog allergies); allergen immunotherapy can help in patients with rhinitis plus asthma combination; allergies not just matter of “yes” or “no”—not that one-half of population allergic, and other half nonallergic, and particular patient switches; rather, amount of IgE antibody matters; monitor serum IgE antibodies using CAP assay (immunoassay based on cellulose polymer encased in capsule

Cat and dog allergies: very different allergen effects than with dust mites; in New Zealand, 35/110 allergic asthmatics not allergic to cats but highly allergic to dust mites; several studies suggest children raised in home with cats less likely to become sensitized to cat; immune response—modified TH 2 response, no TH 1 response; combination of cats and dogs or multiple animals linked to nonspecific decrease in allergy comparable to effects of farm animals; children raised in house with cat and dog have less asthma and better lung function; in Northern Sweden (no dust mites), triggering IgE responses increases risk for asthma

Asthma Management Update
Hary T. Katz, MD, Pediatric Allergist/Immunologist, Department of Pediatrics, Division of Pediatric Allergy/Immunology, Nemours Children’s Clinic, Jacksonville, FL

Pathophysiology of asthma

Definition: chronic inflammatory disease of airways; many cell types and cellular elements mediate inflammation

Effects of inflammation: increased bronchial hyperresponsiveness to certain stimuli (eg, upper respiratory tract infection [URT; most common] laughing, crying); recurrent coughing, wheezing, and chest tightness; widespread and variable airflow obstruction (through disruption of epithelium, thickening of subbasement membranes, increased collagen deposition, increased cell infiltrate), which is often reversible

Wheezing occurrences in children: single episode in 30% to 50% of children before 5 yr of age; 40% who wheeze before 3 yr of age continue at 6 yr (“persistent wheezers”); 50% of infants who wheeze once will wheeze again within several months

Common childhood asthma phenotypes: for each phenotype, different risk factors, biomarkers, and natural history; findings based on prospective study of >1200 children followed from birth until 11 yr of age; transient early wheezers—wheeze sometime during first year of life; risk factors include prematurity, history of parental smoking during pregnancy, and passive exposure to tobacco smoke; such patients do not respond to inhaled bronchodilators or inhaled corticosteroids (ICS); wheezing tends to remit as child’s airway gets larger (between ages 2-3 yr); nonatopic wheezers—0 to 6 yr of age; wheeze associated exclusively with viral infection; usually no eczema or other comorbidities, usually no family history; wheezing tends to remit by ≈6 yr of age; atopic wheezers—past 5 yr of age, ≈80% of wheezers asthmatics (ie, allergic [have positive blood and skin testing to inhalant allergens]); tend to present within 2 to 3 yr of age, and continue to wheeze; wheezing not related to URTI

Asthma in children ≤5 yr of age: history critical; chest x-ray does not define asthma; peribronchial thickening and hyperinflammation common but not diagnostic; spirometry results unreliable; give short-acting bronchodilators and ICS; monitor response to support diagnosis

Modified Asthma Predictive Index (API): based on Tucson Respiratory Children’s Study; if 3 wheezing exacerbations in past year, with one physician-confirmed episode, plus one major criteria or 2 minor criteria, then 10 times more likely to have persistent asthma; major criteria—physician-diagnosed atopic eczema, parental history (includes, eg, mother who had childhood asthma only, father with exercise-induced asthma), allergic sensitization to one aeroallergen; minor criteria—wheezing unrelated to respiratory illness (ie, cold); blood eosinophilia 4% of total white blood cell (WBC) count; allergic sensitization to milk, eggs, or peanuts (positive skin or blood test sufficient)

When to consider long-term treatment: positive API and >3 wheezing episodes in previous 12 mo lasting >1 day and affecting sleep; consistent requirement for treatment (>2 times/wk, on average, over 1-2 mo); 2 exacerbations in 6 mo requiring oral corticosteroids

Key Updates in Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3, 2007)

Commissioned by the National Asthma Education and Prevention Program (NAEPP) Coordinating Committee (CC), and coordinated by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health

Degrees of evidence for recommendations: category A—randomized controlled trials (RCTs; rich body of data); category B—RCTs (limited body of data); category C—nonrandomized trials and observational studies; category D— consensus panel judgment (tends to apply to 0- to 4-yr-old age group)

Severity: emphasized for initiating therapy; previous guidelines (2002) emphasized severity reclassification every visit; assess impairment (ie, frequency and intensity of symptoms)—symptoms (eg, nighttime awakenings, work/school days missed, ability to engage in normal activity) and lung function (guidelines promote spirometry for patients ≥5 yr of age, peak flow); assess risk—likelihood of negative events (ie, exacerbations requiring corticosteroids); severity classification age groups—0 to 4 yr of age; 5 to 11 yr of age; 12 yr of age (new guidelines recommend looking at lung function ratio (forced expiratory volume in 1 second [FEV1 ]/forced vital capacity [FVC] {FEV1 / FVC}) to guide therapy

Management: limited age-specific data available for children, especially those in 0- to 4-yr-old age group; use step- wise approach for each group; 0 to 4 yr of age—ICS preferred therapy for mild persistent asthma; cromolyn sodium and montelukast alternatives (although no data available to indicate whether montelukast better than ICS); as severity increases, increase ICS dose (eg, budesonide inhalation suspension [eg, Pulmicort Respules], fluticasone propionate [eg, Flovent], mometasone tripattern inhaler [eg, Asmanex Twisthaler]) and begin adjunctive therapy; 5 to 11 yr of age—low-dose ICS (budesonide dry powder inhaler [DPI]) or inhalation suspension, beclomethasone hydrofluoroalkane [HFA]) preferred for mild persistent patients; add long-acting β agonist (LABA) or leukotriene receptor antagonists (LTRA); guidelines also recommend consultation with asthma specialist if patient requires more than median dose of ICS; 12 yr of age—ICS therapy; for patients requiring more than low-dose ICS, add LABA or double-dose of ICS (due to Black Box warning associated with LABAs; however, no data to support superior efficacy of double-dosing ICS); for step 5 (more severe patients), consider IgE reduction using omalizumab (Xolair) or budesonide plus formoterol (Symbicort); ICS preferred for cases of mild or moderate persistent asthma—preferred controller therapy, according to guidelines from National Institutes of Health (NIH); strong evidence that children treated with ICS (compared to as-needed β2 -agonists) show FEV1 improvement, reduced hyperresponsiveness, improvements in symptom scores, fewer courses of oral corticosteroids, and fewer urgent-care visits or hospitalizations

Control: strongly emphasized in guidelines; no universal method of measuring; includes asking patients about daytime symptoms and nighttime awakening, lung function (exacerbations key), and effects on normal activity; goals—preventing chronic and troublesome symptoms; maintaining near normal lung function; preventing recurrent exacerbations; minimizing need for emergency department (ED) visits or hospitalization; pharmacotherapy with minimal or no adverse effects; “Rule of 2s” to determine level of control—daytime symptoms >2 days/wk; nighttime symptoms >2 nights/mo; >2 rescue β2 -agonist canisters/yr; rescue β2 -agonist use >2 times per week; if patient well-controlled for 3 mo, consider stepping down therapy; if patient not well-controlled, step up therapy and reevaluate in 2 to 6 wk; if patient very poorly controlled, step up therapy 2 steps, consider short course of steroids, and reassess in 2 wk

Case example: history—9-yr-old boy with history since infancy of wheezing and prolonged coughing with URI; symptomatic with daily exertion and nighttime awakening, despite treatment with montelukast [Singulair] 5 mg/ day for past 5 mo; patient received 2 bursts of oral corticosteroids within 6-mo period; highly sensitized to dust mites; spirometry 76% of predicted; 17% improvement seen with bronchodilator use (12% improvement diagnostic of asthma); lungs obstructed (77% FEV1 /FVC ratio); classification—moderate persistent asthma; patient not well controlled (has allergic rhinitis and eczema); treatment—prescribed fluticasone plus salmeterol (Advair Diskus); educated patient on how to use; albuterol as needed; educated on dust mite control; patient trialed off montelukast; follow-up several weeks later—patient complying with medications; no side effects; no exacerbations, no ED visits or hospitalizations, no exercise-induced symptoms, nocturnal awakenings acceptable; using albuterol <2 days/wk, lung function normalized; plan to continue current management; in further follow-up, will consider stepping down therapy

Conclusions: severity, control, and responsiveness to treatment key for assessment and monitoring; goal of therapy to achieve control; monitor control through clinical assessment and patient self-assessment; ICS preferred monotherapy for controller therapy in patients with persistent asthma across all ages; LABAS are preferred adjunctive agents in patients ≥12 yr who are not well-controlled on ICS monotherapy