Wheeze and Asthma Mark Minor, M.D. Section of Pulmonary Medicine Dayton Children’s Hospital

Conflicts of Interest / Disclaimers None

Question 1 What is the timeframe for onset of action of systemic prednisone (orapred)? A. 30 minutes B. 1-2 hours C. 4-6 hours D. 12 hours

Question 2 Which 2 year old child has a positive asthma predictive index? 3 episodes of wheezing/year and allergic rhinitis 3 episodes of wheezing/year and 7% blood eosinophils 3 episodes of wheezing/year and eczema 3 episodes of wheezing/year and wheezing outside of colds

Objectives Overview of causes of wheezing Define natural course of wheezing in infants Review risk factors for asthma Review step method for asthma treatment Review alternatives for uncontrolled persistent asthma

Case 9 year old with recurrent wheeze and persistent dry cough Cough present for about two years, day and night Multiple visits to PCP, ED, Urgent Care with complaint of cough Documentation of wheeze and use of Albuterol and/or systemic steroids on separate occasions Multiple courses of systemic steroids for wheeze / cough with subjective improvement Usually accompanied with URI symptoms Minimal improvement with use of Albuterol On exam: Dry cough, mild inspiratory and expiratory wheeze

Causes of wheezing Asthma Vascular rings or slings Tracheomalacia, Bronchomalacia Viruses Chronic aspiration Cystic Fibrosis Foreign body Mediastinal or airway mass

Wheezing in infancy Common problem Approximately 1/3 of infants (Kuehni et al. Eur Resp Journal; 2000 16(1):81-5) Recurrent wheeze in about 1:5 infants (Alvarez et al. Aller Immun; 2018, 209-310) Kuehni et al. Eur Resp Journal, 2000

Risk factors for recurrent wheeze Viral respiratory tract infections (RSV, rhinovirus etc.) Atopic sensitization Family history of asthma Pre-natal and Post-natal exposure to maternal smoking Gastroesophageal reflux/Aspiration Exposure to environmental pollution Prematurity (BPD), Male gender Structural airway anomalies < 24 months of age

Foreign body aspiration Toddlers at special risk Peanuts, hotdogs, hard candies, toys Can result in: Complete airway obstruction Stridor Wheeze Persistent pneumonia Hemoptysis

Foreign body aspiration Persistent cough, asymmetric wheeze refractory to treatment Dx: X-ray, Bronchoscopy Hyperinflation, ball valve obstruction

Peanut in Right Mainstem Bronchus

Virus induced wheezing Strong association between viral bronchiolitis and recurrent wheezing during infancy Infants in daycare have more wheezing episodes than infants who are not in daycare due to increased exposure to viruses

Virus induced wheezing 20% of all children have at least one episode of lower respiratory illness associated with wheezing in the first year of life Rhino Virus infection leading to hospitalization during infancy is an early predictor of the subsequent development of asthma Kotaneimi-syrjanen A. et al. JACI 2003, 111: 66 Risk of asthma after viral bronchiolitis is increased in the presence of allergic sensitization in early life and if the infection is more severe

Childhood asthma

Epidemiology of Childhood Asthma Most important chronic respiratory disorder in childhood Affects approximately 5-15% of all children Boys > Girls in young children Girls > Boys in adolescents Adverse outcomes significantly determined by race and ethnicity Akinbami L. Centers for Disease Control 2006; 381:1

Evaluation and Treatment of Atopy in Childhood Asthma Atopy is present in > 75% of children with persistent asthma Role in exacerbations based on age: < 3 years: viral respiratory infections > 3 years: viral infections + allergen exposure Sensitization pattern based on age: < 1 year: eczema/milk, soy, egg, wheat, peanut > 3 years: dust mite, molds, pollen, ragweed Heymann et al, J Allergy Clin Immunol 2004; 114:239 Atopy refers to the genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema). Atopy is typically associated with heightened immune responses to common allergens, especially inhaled allergens and food allergens.

Diagnosing asthma in infancy Infants and toddlers who present with frequent early wheeze is a challenge Almost 80% of asthma starts before 5 years of age

Diagnosing asthma in infancy Asthma Predictive Index > 3 episodes of wheeze in one year, AND 1 Major Criteria Diagnosis of asthma in parent, maternal > paternal Diagnosis of eczema in infant Allergic sensitization to aeroallergen OR 2 Minor Criteria Peripheral eosinophilia (4%) Wheezing episodes not associated with URI Diagnosis of allergic rhinitis Positive Index: 65% chance of asthma by age 6 Castro-Rodriguez JA, et al. J Allergy Clin Immunol. 2016:1111-1122 Aeroallergen: House dust mite, cockroach, dog, cat, mold, grass, tree, and weed.

Other predictors increasing risk of asthma Maternal overweight or obesity during pregnancy Prenatal maternal smoking Postnatal maternal smoking, < 5 years of age Other household smoking Preterm birth and low birth weight RSV infection Household mold BMI > 95th % Maternal obesity 1.21 x increase odds of current asthma or wheeze Prenatal smoking 1.3-1.5 x increase Postnatal smoking 1.65-1.7 x Preterm, 1.46

Approach to acute asthma exacerbation, or status asthmaticus Administer treatment of inhaled SABA, repeat times three, and promptly give oral corticosteroids if needed Addition of Ipratropium Bromide (Atrovent) is effective Prednisone 2 mg/kg/day up to 40-60 mg for 3-7 days, or Dexamethasone 0.6 mg/kg (maximum 12 mg), repeat x1 in 24 hours Prednisone has onset of action: 4 to 6 hours IV Fluids if dehydrated, watch for SIADH, hypokalemia Keep Oxygen saturation > 95%

Approach to acute asthma exacerbation, or status asthmaticus Chest xray? Severe respiratory distress Unilateral wheeze Focally diminished breath sounds No antibiotics unless reasonable evidence of an acute bacterial infection

Beta-Agonists Can Worsen Hypoxemia in Acute Asthma

Nebulizer vs MDI with Spacer

Changes/Updated in 2018 to GINA Guidelines Step 1 It is explained that the reason ICS should be considered for patients with mild asthma (rather than prescribing SABA alone) is to reduce their risk of serious exacerbations (Pauwels, Lancet 2003; O’Byrne AJRCCM 2001; Reddel Lancet 2017) Steps 3-4 From the large FDA LABA safety studies: adding LABA to ICS in a combination inhaler reduces risk of exacerbations and improves symptoms and lung function, compared with the same dose of ICS alone, but with only a small reduction in reliever use (Stempel NEJM 2016, Peters NEJM 2016) Step 5 management of severe asthma Subcutaneous benralizumab (monoclonal anti-IL5 receptor α antibody) is another add-on treatment for patients aged ≥12 years with severe eosinophilic asthma

Uncontrolled asthma Co-morbidities (GERD, rhinitis, etc) Poor adherence Ineffective delivery of treatment, ie poor inhaler technique Severe therapy-resistant disease Ongoing exacerbating triggers (smoke, allergens, pollutants) Misdiagnosis Inadequate treatment

Persistent asthma Consider Biologic Therapy (injection therapy) if appropriate Xolair Nucala Dupixent – newest for certain types

Biologic targeting IgE Omalizumab (Xolair) Binds to free IgE Approved for above age 6 years Shown to decrease: symptoms, exacerbations, ICS dose Shown to increase: FEV1, quality of life

Biologic targeting eosinophils Mepolizumab (Nucala) IL-5 binding to eosinophils Approved for age 12 years and above Decreases exacerbations, symptoms, ICS dose Increases FEV1 and quality of life

Biologic targeting IL-4 and IL-13 Dupilumab (Dupixent) Recently approved for asthma control For treatment of atopic dermatitis, eczema, and persistent asthma Approved for ages 12 years and above

Summary of key points Asthma is a complex disease with significant phenotypic heterogeneity Control of exacerbating factors can improve symptoms Treatment of asthma is based on severity-based guidelines New therapies are available to treat severe/uncontrolled asthma

Case continued

Case continued 9 year old with recurrent wheeze and persistent dry cough

Case continued Spirometry

Case continued Normal chest x-ray Lateral neck x-ray

Case continued Lateral neck x-ray

Case continued

Case continued Granular cell tumor Required removal and tracheal reconstruction

Thank You! Mark Minor, MD Section of Pulmonary Medicine Dayton Children’s Hospital