Updates in Pediatric Asthma Prevention to PICU

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Updates in Pediatric Asthma Prevention to PICU

• John D. Mark MD
• Clinical Assoc Professor of Pediatrics
• Pediatric Pulmonary Medicine
• Lucile Packard Childrens Hospital at Stanford

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Disclosure of Relevant Financial Relationships

• I do not have any relevant financial
  relationships with any commercial interests.

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Objectives

• Recent advances in determining the complex
  etiology of asthma as well as prevention,
  treatment and management
• Asthma is a complex disease that involve numerous
  mechanisms resulting in similar clinical
  manifestations
• Importance of early events in childhood in the
  development of asthma and how that may impact
  intervention.
• The genetic predisposition for developing asthma
  may be affected by the environment (epigenetics)

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Asthma Status 2007

• 9.1 of US children (6.7 million) in 2007
• Asthma related deaths increased in the 90s but
  have since leveled off or even decreased
• Highest prevalence children 11-17 yrs but the
  highest rates of asthma related health care
  visits 0-4 yr olds
• Burden of asthma is great-school/work absenteeism
  and restriction of activity
• Non-Hispanic Black have highest risk of ED visits
  and death
• Geographical differences are significant-reasons
  are not clear

Akinbami, L. et al F. Pediatrics
2009123S131-S145
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Definition of Asthma
Symptoms
Airway Obstruction
AHR
Inflammation
Asthma is a changing mix of these 4 key elements
http//www.ginasthma.com/
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Asthma Is Not a Static Disease
Poor control
Good control
Wheezing
Dyspnea
Cough
Use of rescue medication
FEV1
PEF variability
nor is asthma control
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2007 GuidelinesFinally

• Guidelines for the Diagnosis and Management of
  Asthma was developed by National Asthma Education
  and Prevention Program (NAEPP).
• This document was evidence based
• Focused on asthma severity and control concepts
  of impairment and risk
• Stepwise approach in long term management
• Emphasis on approaches to patient education,
  control of environment and co-morbid conditions
• http//www.nhlbi.nih.gov/guidelines/asthma/asthsum
  m.pdf

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NAEEP Guidelines Emphasized

• That inflammation was critical with considerable
  variability from person to person
• That gene-by-environmental interactions are
  complex and may play an important role in the
  development and expression of asthma
• That onset of asthma for most patients begins
  early in life with recognizable risk factors
  (atopic disease, recurrent wheezing, and a
  parental history of asthma)
• That current asthma treatment with
  anti-inflammatory therapy is most effective but
  does not modify progression of the disease
  severity.
• The need to consider co-morbidities
• VCD, GERD, ABPA, obesity, sinusitis, and stress

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Since the Guidelines..

• Causes of asthma are still not well understood
• Numerous extrinsic influences and intrinsic
  factors may contribute to asthma-complex
• Despite widespread support, guidelines have not
  improved asthma care!
• Canadian study of over 10,000 adult patients
  concluded that 59 of the patients were
  considered uncontrolled
• Objective measurements of lung function are
  rarely done
• Use of controller medications are often delayed
  or never started
• Action plans are seldom discussed with patients
  or families
• NAEPP starting to realize that guidelines will
  only work if those using them take part in their
  development

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Asthma- Why So Complex?

• Asthma is a disorder of the airways and improves
  with time and/or medications which suggests
  variable airway abnormalitiesasthmareversibility
  (or partial)
• Auscultation and lung function tests are used but
  are only snapshots as to the underlying process
• Currently, there is no clinical way for
  assessing, investigating, and analyzing normal or
  variability of airway size and tone before onset
  of disease-especially in children lt4 yrs.
• Total IgE, esosinophils and other lab markers are
  used but these are determinants of atopy not
  asthma
• Asthma most likely is the end product of many
  pathways

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Genetics of Asthma

• Six genes (ADAM33, GRPA, PHF11, DPP1V, HLG-G and
  CYF1P2) have been consistently identified by
  means of positional cloning as linking with
  asthma
• Asthma susceptibility genes can be grouped in 4
  categories
• 1. Associated with innate immunity and
  immunoregulation
• 2. Associated with TH2 cell differentiation
  (hygiene theory?)
• 3. Associated with epithelial biology and mucosal
  immunity
• 4. Associated with lung function, airway
  remodeling and disease severity
• Most likely a number of genes coding for products
  involved in a distinct pathway will result in an
  asthma phenotype for some patients, whereas for
  others, a constellation of genes coding a
  different pathway will play a role.

Von Mutius, E. J Allergy Clin Immunol
20091233-11
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Vercelli, D, Nat Rev Immunol. 20088(3)169-82
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Asthma Prevention?

• Knowing that asthma may be more then one disease
  makes prevention difficult
• Asthma is likely a syndrome, in which different
  pathways eventually result in various phenotypes
  of variable airway obstruction.
• These genetic effects may in part differ with
  respect to a subjects environmental exposures,
  although some genes may also exert their effect
  independently of the environment.

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Gene-by-Environment Interactions

• Defined as a situation when, because of genetic
  differences, 2 or more individuals, families or
  genotypic lines respond differently to, or to
  different extents, to a change in the
  environment.
• Smoking, air pollution, diet, microbial
  exposures, day care, allergens, pet keeping,
  moisture, chemical-exposure have been related to
  development of asthma- but little is known about
  their genetic background
• Smoking, air pollution and microbials are being
  studied but the tools for measurements are
  crude compared to the genetic studies
• Example is it the diversity of exposure to
  bacteria or the abundance of a certain species
  that is important?

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Gene-Environment Interaction

• Rural children grain dust, vegetable particles,
  microorganisms, insects, feed additives,
  avian/rodent proteins, pesticides, ozone, wood
  smoke
• Urban children dust mite, cockroach, pet dander,
  molds, tobacco smoke, gas stoves/heaters/furnaces,
  CO, volatile organic compounds, outdoor vehicle
  pollutants
• Genetic component is significant in asthma but
  the large number of candidate genes identified
  through linkage analysis and the conflicting
  results in various studies reflect the difficulty
  of classifying subsets of individuals with
  asthma.
• Since the development of asthma depends on
  interaction of multiple genes coupled with
  environmental exposures, public health may play
  an integral role in protecting the most
  susceptible children.

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Early Indicators for Asthma

• What are characteristics that can be identified
  for developing asthma beside atopy, parental
  history, wheeze apart from colds?
• Postulated indicators include
• C-section associated with increase in asthma
  (delayed gut microbial colonization) 2009
• Antibiotic use in the 1st yr of life, increases
  with courses 2009
• Delay in DPT immunizations (negative
  relationship) 2008
• Paracetamol (acetaminophen) ingestion in 1st yr
  of life 2008
• Breast feeding- may increase risk if mother has
  asthma and/or allergies 2007
• Day care attendance-reduced risk (strongest
  protection for those who entered between 6-12 mo)
  2008

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Prevention Possible?

• Genetic factors are not yet changeable but
  environmental components lends to analysis and
  modification
• Role of indoor allergens have been postulated to
  lead to atopic sensitization and subsequent
  disease
• If one can interrupt the allergen exposure, thus
  decrease the change of sensitization, then at
  least for the atopic asthma pathway, it could be
  modified
• House dust mite, mold, cockroach and mouse
  allergens, pets have been studied
• Elimination of exposure and modifying the immune
  response with specific immunotherapy have shown
  promise in prevention of asthma.

Cur Opin Allergy Clin Immunol. 2009 9128-35
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Inhalant and/or Food Allergen Reduction

• Prevention may only be effective if most or all
  relevant environmental factors are simultaneously
  avoided?
• Recent review of 3 multifaceted and 6
  mono-faceted intervention studies was done
  looking at over 3,000 children (predisposed to
  developing asthma)
• Despite trying to design such studies, there
  remains uncertainty as to whether multiple
  interventions are more effective than
  mon-component interventions

Cochrane Database of Systematic Reviews 2009,
Issue 3. CD006480
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Probiotics and Prebiotics Effect in Allergic
Disease

• Microbial colonization of the newborn intestine
  is required for normal immune development
• Altered intestinal microbiota is associated with
  increased risk of developing allergic disease
• Probiotics and prebiotics have been shown to
  modulate the composition and/or activity of this
  microbiota and thereby influence immune response
• There have been at least 8 RCT of various
  probiotics bacteria studies for the prevention of
  allergic disease and 2 studies of prebiotics for
  the prevention of eczema
• Studies suggest a promising role for probiotics,
  prebiotics in the prevention of eczema, however
  it remains uncertain if this beneficial effect
  will extent to other conditions such as food
  allergies, allergic rhinitis and asthma.

Nestle Nutr Workshop Ser Pediatr Program.
2009219-238. Epub 2009
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Diet and Asthma

• Because diet is the major source of antioxidants,
  suboptimal intake during airway growth may lead
  to airway damage and reduced airway compliance.
• Diets, such as the Mediterranean Diet, has been
  shown to be preventive (pregnancy) and protective
  in children.
• There are several large epidemiologic studies
  showing the beneficial association between
  fruits, vegetables, and other antioxidant-rich
  foods including fish.
• However, a Cochrane Review conducted in adults
  and children who had established asthma concluded
  that there was no consistent effect of omega 3
  fatty acid supplementation on asthma symptoms,
  asthma medication use, lung function, or
  bronchial hyper-responsiveness

Thorax 200863507513.
Thorax 20076267783.
Am J Epidemiol 200315857684.
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Obesity and Asthma

• Prevalence of both has increased and both may
  begin in childhood
• Common exposures may help explain the association
  (some being studied)
• Common genetic predictors
• Prenatal exposure to specific nutrients and
  maternal nutrition
• Patterns of colonization of the neonatal and
  infant gut
• Birth weight and infant weight gain
• Sedentary behaviors
• Adipokines levels early in life

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Obesity and Asthma-Mechanisms?

• Reduced lung volume and tidal volume in obesity
  may promote airway narrowing
• Low-grade inflammation seen in obesity may act on
  the lungs to exacerbate asthma
• Obesity related changes in adipose-derived
  hormones including leptin and adiponectin
• Co-morbidities dyslipidemia, GERD, sleep
  disordered breathing including sleep apnea, type
  2 diabetes and hypertension- all provoke asthma
• Early interventions to prevent excess infant
  adipostiy may reduce asthma risk?

Shore, S. J Allergy Clin Immuno 20081211087-93
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Asthma -Viruses?

• Wheezing is often associated with viral
  infections especially Respiratory Syncytial Virus
  (RSV)
• Burden RSV Rates of hospitalization- 3 times
  influenza/para-flu, gt2 million children under 5
  yr seek medical attention and most RSV infection
  occurs in previously healthy children
• More significant then RSV, rhinovirus?
• Possible defective epithelial antiviral response
• Found in the airway epithelial cells of
  asthmatics even when no URI symptoms
• Rhinovirus my up-regulate growth factors involved
  in airway remodeling
• But does it cause asthma?

Hall, C. et al. N Engl J Med 2009360588-98
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Treat Wheezing like Asthma?

• New NAEPP guidelines emphasize early diagnosis
  and treatment especially with controller
  medications such as inhaled corticosteroids
• However, nearly 1/3 of all children less then 4
  yrs of age have intermittent wheezing usually
  with a viral infection
• Some children, particularly those with atopy,
  have multiple triggers (cold air, viral
  illnesses, smoke, allergen, and exercise)-but
  some do not
• Since children lt 4 yrs who wheeze can be
  difficult to diagnose as having asthma- what to
  do?

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Wheezing Preschoolers

• Two studies investigated the role of steroids in
  virus induced wheezing and in young children
• One found no benefit of oral prednisolone in 687
  preschool children hospitalized with acute virus
  induced wheezing
• Concluded that oral steroids have been overused
  especially in children with no response to
  bronchodilator
• Other study gave high dose inhaled fluticasone to
  129 children, 1-6 yrs, with a history of
  wheezing, at the first sign of an infection.
• Fluticasone group showed modest benefit with a
  decrease duration of symptoms and less use of
  rescue meds but safety data was concerning

Panickar et al. N Engl J Med 2009360329-338
Ducharme et al. N Engl J Med 2009 360 409-410
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Other Management Issues

• Continued high emergency and urgent care visits
  for childhood asthma
• Increasing and persistent disparities in access
  to care and medication.
• Medicaid insurance, family member with asthma,
  maternal employment- associated with poor control
• Reluctance of physicians and health care
  providers to diagnose and treat asthmalike to
  call it RAD
• Ongoing studies monitoring IgE in cord blood
  (elevated in stressed mothers even without
  significant allergen exposure).
• Depression in mothers has been linked to increase
  in asthma in children.
• Reluctance of health care providers and families
  to use controller medications such as inhaled
  steroids

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Treatment?
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Inhaled Steroids Are Best

• Two long term studies (PEAK n285, and CAMP
  n941) both have shown that in high risk
  toddlers, inhaled steroids, (ICS-fluticasone and
  budesonide) improved all aspects of asthma
  management over other controllers
• Example oral steroids (29 reduction) and
  unplanned medical visits (36 reduction)
• Neither study showed a modifying effect on the
  course of asthma, and both studies showed a small
  but significant effect on growth
• No steroid sparing therapies (leukotriene
  modifiers, cromolyn) have been as effective.
  Chinese herbs that do show some promise in their
  immune modulating properties

Bacharier, L et al. J Allergy Clin Immunol 2009
in press Strunk R et al. J Pediatr 2009 in press
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Control Impairment and Risk

• Guidelines assessing impairment and risk
• Impairment recent symptoms and asthmas effects
  on quality of life (ACT and other questionnaires)
• Risk adverse events such as exacerbations
  (steroid use) and progressive loss of pulmonary
  function.
• Child may have one or both-need to consider both
  when determining medication regimen and
  environmental control
• Environmental control Important since often
  children and their families have not received
  comprehensive instruction in management of
  allergies and avoidance of household
  irritants/allergens

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Goals for Asthma Control

• Reducing impairment
• Prevent chronic and troublesome symptoms
• Require infrequent use of SABA
• Maintain (near) normal pulmonary function
• Maintain normal activity levels
• Meet patients and families expectations with
  care
• Reducing risk
• Prevent recurrent exacerbations of asthma and
  minimize the need for ED visits or
  hospitalizations
• Prevent progressive loss of lung function for
  children, prevent reduced lung growth
• Provide optimal therapy with minimal or no
  adverse effects

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Managing Asthma Exacerbations

• Exacerbations have the greatest impact on health
  utilization and treatment costs for children with
  asthma
• Use of controller medication will reduce
  exacerbations-however even with adherence up to
  30 of children will have an exacerbation in the
  1st year of treatment . Probably higher in real
  life
• Studies suggest that genetic and/or developmental
  factors may determine a pattern of immune
  response to viruses that make some patients
  susceptible to an inappropriate response to viral
  illnesses (rhinovirus)
• Three different responses neutrophilic pattern,
  eosinophilic pattern and a paucigranulocytic
  pattern-respond differently to available asthma
  medications

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Intermittent Asthma Management

• 60-70 of children with asthma have mild
  persistent asthma (MPA) and should be on a daily
  controller medication- preferably inhaled
  steroids (ICS)
• Many parents and physicians do not follow this
  guideline and there is some evidence that
  intermittent use of ICS in adults with mild
  asthma was successful
• Many investigators feel is it essential to
  determine whether children with mild persistent
  asthma can be treated as effectively with
  symptom-triggered anti-inflammatory as with
  continuous daily ICS and other controllers

Martinez, F. Pediatrics 2009123146-S150
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Asthma Exacerbation

• Classifying severity into mild, moderate, severe
  and respiratory arrest imminent
• Symptoms Breathlessness, speech alertness
• Signs Resp rate, accessory muscles use, wheeze,
  pulse and pulsus paradoxus
• Functional PEF, Pa02 and/or Sa02
• Exacerbation severity determines treatment
• ED primarily 02/beta agonists, corticosteroids,
  consider inhaled ipratropium bromide (acute tx)
• Currently insufficient evidence to recommend
  high-dose ICS
• Impending Respiratory Failure
• IV magnesium sulfate
• Heliox driven abltuterol (also decrease WOB)
• IV beta agonists (largely unproved tx)

Proc Am Thorac Soc 2009, 6357-66
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Asthma and Respiratory Failure

• Consider intubation apnea, coma, persistent or
  increasing hypercapnea, exhaustion, depressed
  mental status
• NIPPV?
• Might be a useful adjunct although the data
  available is minimal
• Consider a controlled trial in selected
  patients (cooperative and can tolerate)
• RTs, nurses and physicians need to be very
  familiar with technology
• Patients must be constantly observed and monitored

Proc Am Thorac Soc 2009, 6367-70
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Intubation in Asthma

• Alternative therapies to consider heliox,
  ketamine, glucagon, leukotriene modifiers,
  nebulized clonidine, nitroglycerin, nebulized
  calcium channel blockers, nebulized lidocaine,
  external chest compression!
• Consensus for intubation
• Clinical cardiac or respiratory arrest, altered
  sensorium (lethargy or agitation), physical
  exhaustion, silent chest
• Lab pHlt7.2, C02 increasing by 5 mm Hg/hr or
  gt55-70 and pz02lt60 on Fi02 of 1.0
• Techniques nasotracheal, awake orotracheal,
  orotracheal with sedation, orotracheal with
  sedation and neuromuscular blockade (preferred)
• Ketamine and propofol might be preferred sedation

Proc Am Thorac Soc 2009, 6371-79
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Ventilator Management

• Control of hyperinflation and auto-PEEP
• Reduction in respiratory rate, reduction in tidal
  volume, shortening of inspiration with a square
  wave and inspiratory flow rate of 60 L/min,
  monitor for auto-PEEP
• Hypercapnia is preferable to hyperinflation
• Avoid hypercapnea if increase intracranial
  pressure
• Acceptable level of hypercapnia and acidosis is a
  pH as low as 7.15 and PaC02 up to 80 mmg hg
• Continue beta agonist, steroids (no heliox),
  sedation
• Monitor for acute hypoxemia and hypotension

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Discharge from ED/Acute Setting

• Consider intramuscular corticosteroids (IMCS) in
  patients likely to have difficulty in obtaining
  oral steroids
• Consider very high-dose inhaled steroids (ICS)
  instead of oral steroids in patients with mild
  exacerbations (knowing that they can afford,
  obtain and understand use correctly)
• Budesonide-2,400 µg/day (divided 4 dose),
  flucticasone-1,000-1,500 µg/day, mometasone-
  800-1,200 µg/day
• Consider initiating daily ICS from ED/Urgent care
  if not already on ICS therapy
• Not enough evidence to support use of leukotriene
  modifiers or macrolides after acute episode of
  asthma
• Follow-up with primary provider soon (3-5 days)

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Improving Follow-up

• All patients seen in the acute care setting have
  their asthma severity characterized using the
  NAEPP guidelines
• Recommend appointment to the primary care
  physician, asthma specialist or clinic be made
  prior to leaving the acute care setting
• Recommend that follow-up be within 1 week
• Recommend that elements of the follow-up include
  controller management, inhaler technique, self
  monitoring/self-management education, action
  plan, trigger identification and avoidance
  instruction
• Recommend that all patients with severe
  persistent asthma or requiring hospitalization be
  referred to an asthma specialist

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Importance of Education

• Continue asking patients early in each visit what
  concerns they have about their asthma
• Review the short-term goals and revise the goals
  as needed.
• Review the written asthma action plan and adjust
  the plan as needed, provide plan for school and
  daycare
• Continue teaching and reinforcing key educational
  messages use meds to decrease meds
• Discuss lifestyle changes as a way to decrease
  medications stress reduction, exercise,
  nutrition/diet, exposure to environmental triggers

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Thanks!