Pediatric Asthma

Michelle M. Klinek, M.D.

Family Center for Allergy and Asthma

Overview

• Dramatic changes in our understanding and approach to asthma

New world of cell adhesion molecules which have led us to the concept of asthma being more of an inflammatory rather than a purely bronchospastic process.

• Whole new category of drugs now available - the leukotriene antagonists

Goals of Presentation

• Review Epidemiology and Pathophysiology
• Discuss NHBLI 1997 Asthma Guidelines
• Examples of Patient Management Strategies

Epidemiology

Epidemiology

• From 1982-1992 Asthma prevalence rate rose by 42% to 13 million. In the group <20yo, the rate increased by 60%.
• From 1980-1993 increased hospitalization rate by 28% especially those <4yo.
• Increased mortality rate - doubled from 1980-1993: age 5-14yo from 2.5-5.2/million.
• Asthma is the most common nonsurgical admission to pediatric hospitals.

Epidemiology (con't)

• Asthma accounts for 23% of days absent from school. Lost work income to parents who had to stay home >$900million/yr.
• Disproportionate burden among minority, poor and urban children with respect to morbidity and mortality.
• Asthma has been identified as one of the five most pressing global lung problems.

Pathophysiology

Inflammatory Cascade

Anatomic Factors

Causative Factors

Pathophysiology

• Asthma is a chronic inflammatory disorder of medium and small airways.
  • Airway inflammation contributes to hyperresponsiveness, edema and mucosal plug
  • CDEP: Chronic Desquamating Eosinophilic Bronchitis
  • Airway smooth muscle hypertrophy, Goblet Cell hyperplasia and metaplasis.
  • Airway remodeling that can lead to fixed obstruction.

Airway Inflammation

• Involves numerous cells:
  • antigen presenting cells ie. macrophages
  • lymphocytes that produce cytokines (Tcells) and IgE molecules (B cells).
  • mast cells release various mediators when Ig E receptors crosslinked by allergens.
  • eosinophils that can cause epithelial damage via Major Basic Protein.

Inflammatory Cascade -Mast Cell Mediators

• Preformed
  • Histamine (peaks in 30 minutes)
  • Tryptase (peaks in 90 minutes)
  • TNF
  • Peroxidase

Anatomic and Physiologic Factors in Pediatric Wheezing

• 1. Smaller Reservoir for Gas Exchange
  • Decrease Respiratory Surface
    • Doubles at 18 months, Triples at 3 years
  • Relatively Narrower Peripheral Airway
    • Increased total resistance
    • More likely to develop mechanical obstruction from edema, mucus and cellular infiltrates.
  • Rib cage more flexible and diaphragm placed higher in chest.

Anatomic and Physiologic Factors in Pediatric Wheezing

• 2. Increased Frequency of Atelectasis
  • Decreased collateral ventilation due to decreased Pores of Kahn (connect alveoli)
  • Less smooth muscle, but increased mucus glands/cm2 of bronchial mucosa
    • Results in poorer response to bronchodilators
  • Lower elastic recoil predisposes to early airways closure

Children Are Not Little Adults

Genetic Implications

• Atopy is the strongest identifiable predisposing factor for the developement of asthma.
• Parents with Atopy Risk of Asthma
  • 0 6.5%
  • 1 19.7%
  • 2 63.6%
• Linkage with Chrm 11q13 - High Affinitiy IgER, Chrm 5q - Cytokine Gene Cluster, Chrm14q - Tcell agR

Causative Factors

• Studies suggest a window period in development during which events can predispose a child to develop asthma.
  • 1. Dustmites: Sporik NEJM 1990 323(8):502-507
    • Der p1 levels in nursery >10ug/g of housedust associated with 4.8 relative risk of developing atopic asthma by 11yo.
    • Age of first wheezing inversely related to level of exposure of Der p1 at first year.

Causative Factors

• 2. Passive Smoke

Weitzman et al.Pediatrics 1990 85(4):505-511: Children 0-5yo whose mothers smoked > 10 cigarettes/day were 2.1 times more likely to develop asthma.

• Harlap and Davis: Smoker's infants 38% more likely to be hospitalized for bronchitis and pneumonia.
• Children have a slower rate of lung development if exposed to smoke.

Causative Factors

• 3. Viral Infections:
  • Welliver NEJM1981 305(115):841-846

Production of viral specific IgE - higher levels of IgE to RSV in children with wheezing than those children with RSV without wheezing.

In first 6 months, frequency of persistent wheezing at 7yo is proportional to level of IgE in nasal secretions during initial RSV episode.

• Damage to airway epithelium
• Altered autonomic nervous system function

Causative Factors

• 4. Exercise - exposure to airways cooling and drying
• 5. Underlying Triggers: infections, GERD, consider differential diagnosis.

Natural History

Asthma improves in most children during adolescence, though children with persistent wheezing at 14yo will continue to wheeze though adulthood.

• High Percentage of Relapse
  • 45% of child asthmatics who are wheeze free at 14yo will relapse by 21yo
  • 31% of child asthmatics who are improved by 21yo will relapse by 28yo

Natural History

• Martinez et al.: Assessment in infancy and at 6yo NEJM 1995;332:133-138.
  • 1/3 of children < 3yo had wheezing, but 60% outgrow this by 6 years old.
    • contribution from congenitally smaller airways and maternal smoking
  • If still wheezing after 6 yo, greater contribution of allergies and environmental risks.

Diagnosis of Asthma

Presentation

Differential Diagnosis

Recalcitrant Asthma

Usual History or Presentation

• wheezing
• recurrent bronchitis
• prolonged colds
• "couch potato"
• chronic cough
• chest tightness
• shortness of breath

Diagnosis

• Must be willing to entertain the diagnosis of asthma to make the diagnosis.
  • Use history, physical exam and diagnostic tools ie. CXR, lung function tests.

Differential Diagnosis of Asthma in Children

• Infancy
  • Vascular rings
  • Laryngeal webs
  • TE Fistula
  • Laryngotracheolmal.
  • Congenital Heart Dis
  • Cystic Fibrosis
  • BPD
  • Infections: RSV, Pneum. Carinii,

Recalcitrant Wheezing

• Review Compliance and Technique of Medication Administration
• Sinusitis/Mucosal Misbehavior
  • Sinonasal-bronchial reflex - inflammation in the sinus can trigger inflammation in the lower respiratory tract

Recalcitrant Asthma

• Sinusitis (continued)
  • Born with Maxillary and Ethmoid Sinuses
    • Sphenoids develop soon after 2yo
    • Frontals develop around 8yo
  • Rachelefsky et al

44 children with 3 months of daily wheezing and abnormal sinus Xray. After antibiotics 20/30 children had normalization of their PFT.

Recalcitrant Wheezing

• Gastroesophageal Reflux
  • Symptoms in children variable
    • heartburn, nausea, dyspepsia
    • hoarse throat, gagging, cough, pneumonia
    • 25% of children with GERD have clinically silent reflux. Simpson Arch Intern Med 1995;155:798

Recalcitrant Asthma

• GERD and Asthma's Vicious Cycle
  • Aspiration of refluxed material leads to enhanced bronchial reactivity secondary to acid exposure
  • Air trapping during asthma can reduce the competency of the LES, perpetuating a vicious cycle.

Recalcitrant Asthma

• Other Diagnosis to Keep in Mind
  • Aspirin Sensitivity (more common in adults)
  • Beta-Blockers (Migraines, HTN, Eye Drops)

Infections - Don't forget annual influenza vaccination. It is also important to check varicella history. If a exposure to varicella occurs during steroid burst, increased risk of disseminated disease. If hx (-),Vaccinate!

NHBLI Guidelines February 1997

NHBLI Guidelines Feb. 1997

• Message: All Patients with Asthma Deserve Expert Care, Whether Provided by a Primary Care Provider or a Specialist.
• This report is a comprehensive guide to the best care of the patient with asthma.
  • Can be used like a cookbook
• Expert Panel Team :
  • Internists, Family and ER physicians, Pediatricians, Allergists, Pulmonologists,

Purpose of Guidelines

• These Protocols have been found to
  • Decrease visits to the ER, Hospitalizations and costs of asthma care
  • Improve quality of life for patients
  • Improve satisfaction with asthma care
  • Provide prognostic insight

Key Points of Guidelines

• 1. Asthma is a Chronic Inflammatory disorder of the airways.
• 2. Spirometry and Peak Flow Meters facilitate diagnosis and monitoring.
• 3. Identification and Control of Asthma Triggers: Allergens and Irritants.
• 4. Active Partnership: Patient and Physician Focus on Education.

Classification of Asthma Severity

Step Approach

Useful reminder that when classifying asthma in one of the persistent groups, that it is a Chronic disease and requires Maintenance therapy.

• Step Up vs Step Down Philosophy
  • At this time most favor Step Down: Categorize pt. at a higher category; Step down as pt stabilizes.

Treatment Recommendations

Treatment Recommendations

• For Children < 5yo and Infants
  • Maintenance medications often begin with a trial of Cromolyn or Nedocromil; however with Step 3 - Inhaled steroids.
  • When inhaled steroids are introduced, lower doses are used (chart to follow).
  • Need to teach spacer/nebulizer devices.
  • Consultation with a specialist is advised in children with Moderate Persistent Asthma.
    

Early Intervention with Antiinflammatory Therapy

• Agertoft and Pedersen Denmark
  • Respiratory Medicine 1994 88, 373-381

Concern: Inhaled steroids are not yet widely accepted in the treatment of children due to a fear of systemic side effects, such as stunting of growth.

Controlled Prospective Study measuring growth and pulmonary function in children with asthma during long-term treatment with inhaled budesonide compared with those children not treated with corticosteroids.

Mean Height Standard Deviation with Respect to Time Started Inhaled Steroids

Change in Lung Function

Influence of Asthma Duration at the Start of Inhaled Steroids on FEV1 Increase

Conclusions of Study

• No indication that long-term therapy with inhaled budesonide (<600ug) adversely affected growth.
• Early Intervention with Inhaled Budesonide may prevent the development of irreversible airway obstruction.

Inhaled Steroids

• Most Effective long-term therapy
• Use spacers to help coordinate actuation of medicine and to decrease topical side effects: thrush, hoarseness.
• Should always monitor growth. Most studies show there is minimal effect on overall growth with proper dosing.

Inhaled Steroids - Choices

• Beclomethasone : Vanceril, Vanceril DS, Beclovent - Well studied.
• Triamcinolone: Azmacort - built in spacer.
• Flunisolide: Aerobid - safe, bitter taste
• Fluticasone: Flovent - 44mcg,110 and 220 - fast action, long t1/2
• Budesonide: Pulmicort - turbuhaler - new spacer

• Dosing Charts Clearly Outlined

New Antiinflammatory Meds.

• Zafirlukast (Accolate)
  • Leukotriene Receptor D4 Antagonist
    • Inhibits LTD4 and LTE4
  • 50% response rate in my experience
  • 20 mg BID without food
  • Multiple Drug Interactions:
    • CYP2C9, 3A4, 2C8 - Warfarin, Cisapride, Phenytoin
  • Question of an association with Churg-Strauss Syndrome JAMA

New Antiinflammatory Meds.

• Zileuton (Zyflo)
  • 5-Lipoxygenase Inhibitor
    • Inhibits LTB4, LTC4, LTD4, LTE4
  • Many good responders
  • 600mg QID without regard to food
  • Need to monitor ALT qmos x 3,q3mos x 3
  • Multiple Drug Interactions:
    • CYP1A2, 2C9, 3A4 - Theo needs to be decreased by 1/2, Warfarin, Ca Channel Blockers, Cisapride, Beta Blockers

Pulmonary Function Tools

Spirometry

Peak Flow Meters

Pulmonary Function Tools

• The use of Objective measurements, rather than relying on Subjective observations.
  • Marked phenotypic heterogeneity
  • Patients are notorious for not accurately recognizing the severity of their disease.
  • History and PE may not predict severity of obstruction. Diagnostic accuracy of 66% based on History, PE and CXR
    • Pratter et al Arch Inter Med 1989;149:2277-82

Chemosensitivity and Perception of Dyspnea in Patients with a History of Near-Fatal Asthma NEJM1994:330:1329-34 Kikuchi et al Japan

• Most patients with near-fatal asthma have:
  • decreased chemosensitvity to hypoxia
  • blunted perception of dyspnea during resistive loading
  • ?due to dysfunction of carotid chemoreceptors
• Conclusion:

Physicians should know that reliance on a patient's own assessment without the use of an objective determination of airway narrowing carries a risk of undertreatment.

Pulmonary Function Tools

• Spirometry

Diagnostic: Helps to determine whether there is airflow obstruction and whether it is reversible over the short term. Preferred over PEF due to PEF wide variability of values.

• Measures FVC, FEV1, and FEF25-75
• Significant Reversibility is an increase >12%
• Ability to perform inspiratory and expiratory flow loops

Spirometry Con't

• Expert Panel Recommends that Spirometry be done:
  • At initial assessment
  • After treatment is initiated and patient is stable to document "normal" baseline
  • At least every 1-2 years to assess maintenance of airway function

Pulmonary Function Tools

• Peak Flow Meters are designed for Monitoring, not Diagnostic

Can help establish variability - Usually lowest at first awakening and highest between 12pm and 2pm. A 20% difference between morning and afternoon suggests asthma.

• Very Useful for Patient Self-Assessment

Asthma Triggers

Irritants

Allergens

Exercise

Viruses

Control of Asthma Triggers

• Irritants
  • Avoid Smoking and Smoke Exposure
  • Avoid exercise outside when air pollution is high
  • Avoid exposure to fumes from unvented gas, oil, wood-burning stoves or fireplaces
  • Avoid strong odors such as cleaners or colognes

Control of Asthma Triggers

• Inhalant Allergens
  • General environmental control measures for dustmites, pet dander , pollens and molds.
  • Assess devices that modify indoor air.
    • Vacuum 1-2x/week - mask HEPA filters
    • Avoid humidifiers, best humidity 45%
    • Air conditioners
  • Consider skin testing and immunotherapy

Skin Testing

• Involves both prick and intradermal
  • A wheal and flare reaction after 15 minutes signifies a positive response.
  • Helps distinguish between allergic and vasomotor
  • Sensitivity: 97% Specificity: 75%; RAST Sensitivity: 50-60%
  • Severe Reaction to skin testing <0.25%

Immunotherapy

• Sigman and Mazer
  • Annals of Allergy, Asthma and Immunology 1996;76:299-309.
  • Literature Review regarding immunotherapy in the management of childhood asthma.
    • Majority of studies demonstrated improvement
    • Best with early intervention in asthma, especially in children with dustmite allergy

Exercise Induced Asthma

• Most Children Enjoy Sports
  • Any child who is a "couch potato"=Red Flag
• Who is at risk?
  • Allergies - these people have baseline inflammation and are primed to respond
    • Known asthmatics - 70-80%
    • Allergic Rhinitis - 40%

Exercise Induced Asthma

• Those with Asthma only during Exercise
  • Accounts for an additional 7% of the population. Often these people are unrecognized.
• Study at the University of Iowa
  • Evaluated student-athletes: 12% gave a history of asthma, but 19% experienced symptoms consistent with EIA

Exercise Induced Asthma

• An acute, reversible, self-limited episode of airway obstruction.
  • Normally air enters the nose where it is warmed and humidified.
  • With exercise air is inhaled through the mouth leading to cooling and drying of the airways. This leads to bronchospasm.
  • Diagnosis: Exercise Challenge Test or convincing hx with appropriate response to prophylactic or rescue meds.

Exercise Induced Asthma

• Clinical Pattern

During the first few minute of exercise, adrenaline is released. This results in airway relaxation. However, by 5-12 minutes exercise airway obstruction begins.

• Refractory Period: Once EIA has occurred, the body appears to be protected from another episode for 30-90 min. Warm Up!

Exercise Induced Asthma

• Factors That Determine Airway Response to Exercise
  • Duration of Exercise
  • Intensity of Exercise (minute ventilation)
  • Type of Exercise - soccer vs swimming
  • Interval since last episode of EIA
  • Ambient Air Conditions - temperature, humidity, air pollution
  • Baseline level of airway reactivity

Treatment for EIA

• Ensure there are no underlying problems
  • Allergies, Pulmonary abnl, Cardiac abnl
• Review of proper warming up exercise to induce refractory period and cool down
• Use of face mask or scarf over the nose and mouth to help warm and humidify air

Treatment of EIA

• Medications:
  • If no underlying inflammation, 80% respond well to inhaled bronchodilator 15 minutes prior to exercise (can consider Serevent)
  • If EIA persists consider adding Cromolyn as well just prior to the activity
  • If EIA still persists consider adding Atrovent in addition.
  • If symptoms persist, consider Spirometry, inhaled steroid and allergy evaluation.

Viruses and Asthma

• Viral infections are major causes of wheezing in all ages
  • Infants with RSV can predispose to asthma
  • In those with established asthma Rhinovirus is usually the culprit.
• Mechanisms
  • Enhancement of underlying allergic inflam.
    • Rhinovirus promotes late phase allergic rxn.
    • RSV stimulates inflammatory cytokines upregulating preexisting inflammation.

Viruses and Asthma

Epithelial destruction with increased exposure to airway irritant receptors. Also increased antigen exposure to luminal contents and subsequent development of allergy.

Patient Education

Self Management

Asthma Action Plans

Patient Education

• Basic pathophysiology
• Role of medications
• Review of skills - Inhalation technique, Spacers (Aerochambers, InspirEase) Peak Flow Meters
• Environmental control
• Recognizing symptoms
• Rescue actions - Written home treatment plan

Self Management

• From Mayo Clinic - ASTHMA
  • A: activity or lifestyle - smoking, vaccines
  • S: self-monitoring
  • T: trigger control
  • H: health-care partnership, follow-up
  • M: medications
  • A: action plan - written

Asthma Action Plans

• Green Zone: 80% or better than baseline
  • All Clear Zone Continue current regimen
• Yellow Zone: 50-80% of baseline
  • Warning Zone Increase bronchodilator and inhaled steroid
• Red Zone: Less than 50% of baseline
  • Danger Zone Repeat bronchodilator and recheck peak flow, take oral steroid, call physician or go to ER.

Referral to a Specialist

• Pt not meeting goals of therapy.
• Pt has had a life threatening exacerbation.
• Pt has severe persistent asthma.
• Pt is <3yo with moderate or severe asthma.
• Pt requires high dose inhaled steroids or > 2 burst of oral steroids/year.
• Signs are atypical.
• Pt requires additional education.

Conclusions

• Children with asthma may have increased morbidity and mortality due to physiologic differences with adults
• Focus on inflammation and triggers
• Objective tools for assessing lung function essential in treatment plan
• Partnership between family and physician