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Asthma The Challenge of Children, Minorities, and Low-Income Populations Thomas Owens, MD Asthma: A Chronic Lung Disease • Characterized by recurrent cough and wheeze that is increasing in prevalence among children • From 1980 to 1996 – the number of Americans afflicted with asthma more than doubled to 15 million – with children under 5 experiencing the highest rate of increase This constitutes an epidemic Review of Asthma A.D.A.M., 2007 Objectives • Describe the highest risk asthma populations • Outline the significant features of the asthma management guidelines • Describe adherence issues and methods to overcome difficulties • Describe new advances in the diagnosis and pharmacological treatments of asthma Objectives • Describe the highest risk asthma populations • Outline the significant features of the asthma management guidelines • Describe adherence issues and methods to overcome difficulties • Describe new advances in the diagnosis and pharmacological treatments of asthma Prevalence in High-Risk Populations Nearly 5 million children (<5% population 18 & younger) African-Americans & Hispanic Americans (Highest rates of asthma) Urban areas with poor living conditions (near transportation and industrial activity) Low SES (<$20,000/yr) (Carmago,2007) (poor access to healthcare and education) (Morris, 2007) Children with Asthma • Usually begins in early childhood (Carmago, 2007) – 80-90% have symptoms by age 6 – > ½ develop by age 3 – < 10 yrs. male-to-female ratio is 2:1 • Between the ages of 18 and 54 years the ratio is reversed (University of Aberdeen, 2007) Ethnicity Prevalence • Caucasian children lowest at risk (Sharma,2007) – African-Americans 44% higher • 5-8% have asthma at sometime • 20-25% of inner-city children – Hispanics 15% higher • 20-25% of inner-city children • U.S. average prevalence: – 7.6%, with ethnic minority prevalence of 3-14% Caucasian A fr ican A mer ican H ispanic African-American Child Hospitalizations • African-American children are hospitalized 3 times more than Caucasians (Bolte, 2007) – 1998 statistics: African-Americans more than 4 times likely to die – Mortality rates doubled 1980 to 1996 – More deaths occur in inner city areas Mortality Rates in Pediatric Asthma • More than doubled between 1980 and 1996 – disproportionate number of deaths occur in inner city areas • There are 5,000 deaths annually from asthma – some have been linked to management failure (especially in younger persons) – highest mortality rates occur in adolescents – persons who have had prior asthmatic exacerbation requiring intubations are at significantly increased risk for subsequent fatal exacerbations (Morris, 2007) Significant Factors in Pediatric Asthma Deaths • Inappropriate delay in seeking medical attention • Limited access to care • Under-use of anti-inflammatory agents • Overuse of beta agonists (Morris, 2007) Barriers to Healthcare: Inner City Residents • Inner city inhabitants may: – – – – low income medically underserved less likely to have routine doctor visits poor access to the availability of medications (Morris, 2007) The source of primary and follow-up care for this population is often in the hospital emergency department. Barriers to Healthcare: Ethnic Minorities • Lower quality health care – even when insurance, age, income and severity of conditions are the same • Tend to use inhaled corticosteroid suppressants less than Caucasians • Results from cost, inadequate literacy or competing priorities – These patients also received less follow-up after hospital emergency department visits (Morris, 2007) Barriers to Asthma Management • Asthma is a disease that requires maximum cooperation of the patient and family • Parents must oversee a complicated regimen of inhalers, pills, and breathing exercises (Morris, 2007) – this type of supervision and assistance may not be available in poverty situations Cultural Asthma Research • Cultural competence policies and other predictors of asthma care quality for Medicaid-insured children (Lieu, 2004) – evaluated medical clinics serving primarily inner city patients – best management of asthma was rendered where: • • • • • • physicians and caregivers improved their communication skills were trained in cultural differences utilized bilingual or low-literacy instructions, posters, teaching medication feedback was encouraged asthma case managers were utilized ethnic minority caregivers were employed Latino Populations • Puerto Ricans having highest mortality rates – followed by Cuban Americans and Mexican Americans (Homa et al. 2000; Sly, 2006) The Effect of Urbanization • Asthma emergency visits account for approximately 2% of all emergency visits – In urban centers acute asthma may comprise up to 10% of all emergency visits • Worldwide, 130 million people have asthma – The prevalence is 8-10 times higher in developed, industrialized countries (like Canada, England, Australia, Germany and New Zealand; prevalence rate = 2-10%) than in the developing countries. (Morris, 2007) – In developed countries, the prevalence is higher in low income groups in urban areas and inner cities than in other groups – Prevalence increases as a developing country becomes more Westernized and urbanized Environmental Factors • Exposure to maternal environmental tobacco smoke – which during pregnancy or the first year appears to predispose children to reactive airway disease • Efforts to mitigate cockroach and mold reduced symptoms successfully and significantly for urban children (Morgan et al., 2004) Status Asthmaticus • Appears to be on the rise • Several retrospective studies reflect an increase in hospital admissions – particularly in those younger than 4 years • Fewer hospital and emergency visits are needed in children using inhaled corticosteroid therapy Urbanization Pollution • Main contributor to the development of this disease – Gasoline (car) & diesel fuel (truck) combustion engines produce similar and yet different types of respiratory toxins (Pandya, 2001) Gasoline Exhaust • Produces known pollutants and several components of air pollution have been linked to asthma • U.S. Clean Air Act requires the EPA to monitor: – nitrogen dioxide, sulfur dioxide, lead, carbon monoxide and ozone particulate matter (both PM(10 microns (um)) and PM(2.5) – diesel exhaust and diesel exhaust particles (DEPs) also appear to play a role in respiratory and allergic diseases (Pandya, 2001) Diesel Exhaust • Smog-forming and toxic air pollutant vapors and gases that you get when you burn gasoline – also composed of small particles of carbon, known as fine particulate matter and also referred to as Diesel Exhaust Particles (DEPs) (Johnson, 2007; Graham, 2007) Diesel Particulates • EPA classifies and measures these particulate matter according to their size – (PM2.5 = 2.5 microns (micromenter, um), PM 10 = 10 microns) • Unfortunately, the average diameter of diesel particulates is 0.2 microns, and nearly 94% of diesel particulates have diameters less than 2.5 micrometers (um) (Johnson, 2007; Graham, 2007) Tiny Toxins EPA, 2007 DEPs • Hundreds of chemicals adsorbed to their surfaces • Cooked but unburned hydrocarbons could combine in thousands of combinations or permutations – are large, complex, carbon-ringed, planar, lipid soluble – similar to those we find in nature or design to penetrate the cell walls and enter the nucleus to interact with DNA (Pandya, 2001) DEPs • Bind to airborne allergens and other debris – may alter these complex organic allergen molecules further (Pandya, 2001) One could not design a more effective delivery method or toxic product to enter the deepest of our lungs Diesel Emissions • Include over 40 substances that are listed by the EPA as hazardous air pollutants • Federal agencies have classified diesel exhaust as a probable human carcinogen • Benzene, an important component of the fuel and exhaust – is designated to be a known human carcinogen (Pandya, 2001) Polyaromatic Hydrocarbons • Contain larger, more complex – (anthracene, fluoranthene, pyrene, phenanthrene) • In addition, DEPs contain – aldehydes (formaldehyde, acetaldehyde, acrolein), benzene, 1,3-butadiene, polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and hundreds of others Diesel exhaust ranks among the air pollutants that EPA believes pose the greatest public health risks (Pandya, 2001) Diesel Exhaust Components • Genotoxic and mutagenic – can produce symptoms of allergy • including inflammation and irritation of airways • Exposure to diesel exhaust can cause lung damage and respiratory problems – diesel exhaust can also exacerbate asthma and existing allergies – long-terms exposure is thought to increase the risk of lung cancer (Pandya, 2001) Children & Air Pollution There is no known safe level of exposure to diesel exhaust for children, especially those with respiratory illness • May be more susceptible to air pollution – they breathe 50 % more air per lb. of body weight than adults • May be especially susceptible to DEPs due to the small size of the particle – Smaller particles are able to penetrate children’s narrower airways reaching deeply within the lung, where they are more likely to be retained (Pandya, 2001) DEPs • DEPs act as generic respiratory irritant at high concentrations • At lower levels: – DEPs act as pro-inflammatory agents – promote release of specific cytokines, chemokines, immunoglobulins, and oxidants in the upper and lower airway – DEPs cause formation of reactive oxygen species that trigger pro-inflammatory cytokine release (Takizawa, 2007) Immunologic Evidence • May help explain the epidemiologic studies indicating that children living along major trucking thoroughfares are at increased risk for: – asthmatic and allergic symptoms – more likely to have objective evidence of respiratory dysfunction (Pandya, 2001) New & Emerging Factors U.S. Trends in Diesel Fuel Consumption 30 Billion Gallons Per Year This figure demonstrates a 45% increase in diesel fuel consumption in the U.S. over the past decade. As newer diesel engines emit less pollution, total pollution may still increase in response to increasing numbers of vehicles on the highway, and increasing miles driven by diesel vehicles. Wargo, 2002 School Bus Study Statistics • U.S. nearly 600,000 school buses transport 24 million students to school daily • Each year buses travel 4.3 billion miles – nearly 10 billion school bus rides – students will spend 180 hours on buses each year – children spend 3 billion hours on school buses each year • More than 99% of U.S. school buses are powered by diesel fuel • Fine particulate concentrations measured on buses in this study were often 5-10 times higher than average levels (Morris, 2007) School Bus DEPs • Levels of DEP often higher under certain circumstances: (Morris, 2007) – – – – were idling with windows opened ran through their routes with windows closed moved through intense traffic queued to load or unload students while idling • Some studies show there would have been less exposure if you ride in the vehicle directly behind the bus than to ride in it NRDC & Coalition for Clean Air Study (2001) • Shows that children who ride a diesel school bus may be exposed to up to four times more toxic diesel exhaust than someone traveling in a car directly behind it • Excess exhaust levels on school buses were 23 to 46 times higher than levels considered to be a significant cancer risk – according to the U.S Environmental Protection Agency and federal guidelines (Morris, 2007) Additional Causes of Asthma • Exposure to: – passive smoking – changes in exposure to environmental allergens • cockroaches, house dust mites, and the mold Alternaria Tenuis • other aeroallergens like pet dander, gas and woodburning stoves and tobacco smoke – viral respiratory infections • caused by respiratory syncytial virus • possibly rhinovirus are a significant risk factor for the development of childhood wheezing in the first decade of life (Morris, 2007) Chronic Noise Levels • During sleep caused stress and resulted in higher cortisol levels in the first half of the night • Noise may have an adjuvant effect on the pathogenesis of allergies Genetics • Found more often in patients with a personal or family history of atopy • Family history of asthma (Risk) – 7% if neither parent has asthma – 20% if one parent has asthma – 64% if both parents have asthma (Chin, 2001) Allergic March • Infants exhibiting – atopic dermatitis – food intolerance • Followed in time by allergic rhinoconjunctivitis • Ending with development of asthma Hygiene Hypothesis • Proposes that newborns are armed with an immune system ready to respond to natural environmental and infectious stimuli • If not exposed to these – the balance of T lymphocytes will be tilted towards a more ‘angry’ reactive population TH2 – as opposed to a ‘relaxed’ TH1 population with all their cytokine messenger signal proteins Measles Infection • BCG vaccine administration • Hepatitis A seropositivity • Other stimuli that increase production of interferon-gamma • IL-12 may inhibit the TH2 allergic response Increased Atopy & Asthma • Increased atopy and asthma associated with: – Vaccinations, fewer childhood infections, liberal use of antibiotics, more processed food in diets, smaller families, and less exposure to day care environments – Prevalent in western Germany, while bronchitis from power plants is more common in eastern Germany • Chinese from Hong Kong had higher atopy/allergy levels than those living on the mainland • Traffic police officers had higher atopy/allergy levels than those with desk jobs (Polosa, 2002) Further Asthma Study Results • Twins raised separately – farm-reared sibs had lower asthma levels than town-raised sibs • Asthma-free areas are present in certain subSaharan areas – Somalia, where hookworm disease is endemic • The parasitic system (eosinophiles) is fully engaged Questions • Could it be that the reactive immune system engages what it has available, (eg. cockroach, mold, cat antigens)? • And the adjuvant effect of air pollution and DEPs turns on the immune reaction to a high level? Let’s Review! Children may be more susceptible to diesel exhaust particles (DEPs) because: A. Small size of the DEP particles B. Pro-inflammatory agents in the DEPs C. High breathing rate Objectives • Describe the highest risk asthma populations • Outline the significant features of the asthma management guidelines • Describe adherence issues and methods to overcome difficulties • Describe new advances in the diagnosis and pharmacological treatments of asthma National Asthma Education & Prevention Program (NAEPP) • National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes Health has assembled: • Best practice guidelines for diagnosis and treatment of asthma – 2007 revision available: • http://www.nhlbi.nih.gov/guidelines/asthma/epr 3/resource.pdf Asthma Diagnosis • Confirmed with recurrent wheezing, coughing, dyspnea – Objective PEFR reversibility with medication • Asthma staging helps define management, continued monitoring of symptoms – PEFR helps adjust medication Goals of Treatment 1. Reduce wheeze and cough 2. Reduce the risk and number of acute exacerbations 3. Minimize adverse effects – medications – sleep disturbances – absences from school NAEPP Effective Asthma Management Components 1. Objective measurement of lung function 2. Environmental control measures 3. Comprehensive pharmacology therapy 4. Patient education Peak Flow Meter • Peak flow readings (PEFR) twice daily and as needed – Green > 80% • Okay – Yellow 50 - 80% • Action plan – Red < 50% • Emergency call Digital Peak Flow Meter • Electronic peak flow meters – will collect and monitor the data for the patient – data can be reviewed manually or electronically • Results can be downloaded to a computer and produced in a graph or tabular format – ability to track and trend data Microlife Digital Peak Flow Meter, 2007 Indoor Pollutants (northernnaturals.com, 2007) Environmental Control • Removal of carpeting and the use of pillow and mattress covers – However, recent evidence from better quality studies has shown that dust-mite avoidance measures did not improve symptoms or reduce medication use in adults with moderate to severe asthma. • Air filtration systems – There is insufficient evidence to recommend for or against the use of air filtration units to reduce allergen levels in an effort to improve asthma symptoms. Halken, et al., 2003; Woodcock,, et al., 2003; Terreehorst,, et al., 2003; Kilburn, 2004 Other Allergen Controls • Cockroach trappings • Remove moisture to lessen mold • Washing pets – cats twice a week • Skin testing • Immunotherapy Halken, et al., 2003; Woodcock,, et al., 2003; Terreehorst,, et al., 2003; Kilburn, 2004 Long-Term Management of Asthma in Children Go into objective Asthma classification* Medications required to maintain long-term control Symptom frequency Lung function† Mild intermittent Daytime: 2 days per week or less Nighttime: 2 nights per month or less PEF or FEV1: 80 percent or more of predicted function No daily medication needed Mild persistent Daytime: more than 2 days per week, but less than 1 time per day Nighttime: more than 2 nights per month PEF or FEV1: 80 percent or more of predicted function Low-dosage inhaled corticosteroid delivered by nebulizer or metered-dose inhaler with holding chamber, with or without a face mask, or by dry-powder inhaler in children 5 years and younger Moderate persistent Daytime: daily Nighttime: more than 1 night per week PEF or FEV1: 60 to 80 percent of predicted function Children 5 years and younger: low-dosage inhaled corticosteroid and long-acting beta2 agonist or mediumdosage inhaled corticosteroid Children older than 5 years: low- to medium-dosage inhaled corticosteroid and long-acting inhaled beta2 agonist. Severe persistent Daytime: continual Nighttime: frequent PEF or FEV1: 60 percent or less of predicted function High-dosage inhaled corticosteroid and long-acting beta2 agonist PEF = peak expiratory flow; FEV1 = forced expiratory volume in one second. *-Clinical features before treatment or adequate control. †-Lung function measurements are used only in patients older than five years. Adapted from National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma: update on selected topics, 2002. Bethesda, Md.: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 2003; NIH publication no. 02- Usual Dosages for Quick-Relief Asthma Medications Medication Dosage Form Child Dosage* HFA MDI with spacer: 90 mcg per puff, 200 puffs 1 to 2 puffs every 4 to 6 hours as needed. Nebulizer solution: 5 mg per mL (0.5 percent), 3.5 mg per 3 mL, 1.25 mg per 3 mL, 0.63 mg per 3 mL 0.05 mg per kg (minimum 1.25 mg, maximum 2.5 mg) in 3 mL of saline every 4 to 6 hours. MDI with spacer: 18 mcg per puff, 200 puffs 1 to 2 puffs every 6 hours Nebulizer solution: 0.25 mg per mL (0.025 percent) 0.25 to 0.5 mg every 6 hours Nebulizer solution: 0.31 mg per 3 mL, 0.63 mg per 3 mL, 1.25 mg per 3 mL 0.025 mg per kg (minimum 0.63 mg; maximum 1.25 mg) every 4 to 8 hours Methylprednisolone (Medrol) 2-, 4-, 8-, 16-, and 32-mg tablets 0.25 to 2 mg per kg in the morning or every other day, as needed for control Short-course "burst”: 1 to 2 mg per kg per day (maximum 60 mg per day) for 3 to 10 days Prednisolone (Delta-Cortef) 5-mg tablets Syrup: 5 mg per 5 mL, 15 mg per 5 mL Same as methylprednisolone Prednisone 1-, 2.5-, 5-, 10-, 20-, and 50-mg tablets Syrup: 5 mg per mL, 5 mg per 5 mL Same as methylprednisolone Inhaled medications Albuterol (Proventil) Ipratropium (Atrovent) Levalbuterol (R-albuterol, Xopenex) Systemic corticosteroids HFA = hydrofluoroalkane; MDI = metered dose inhaler. *-Dosages are for children 12 years or younger unless otherwise specified. Adapted from National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma: update on selected topics, 2002. Bethesda, Md.: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 2003. NIH publication no. 02-5074:120-1. Let’s Review! Part of the treatment for all 4 levels of asthma include: A. B. C. D. Quick acting beta2 agonist Leukotriene inhibitors Theophylline Long-acting beta2 agonist Objectives • Describe the highest risk asthma populations • Outline the significant features of the asthma management guidelines • Describe adherence issues and methods to overcome difficulties • Describe new advances in the diagnosis and pharmacological treatments of asthma Adherence Issues • The patient’s understanding of asthma treatment and exacerbating factors is key to asthma control Patient education is key in this chronic disease Prevalence Methods • Education – Patient and caregiver empowerment • Emphasize controller medications – Enact an action plan • (Patients do not like to take meds when they are feeling well) • Overcome cultural and communication barriers – Use available tools • Clean Air Act – Now LAW • Pollution activism – Where you live! Asthma Tool Kit • Inner City Asthma Intervention (NIH) – www.achp.org • Select ACHP foundation • Then click “tool kit” Offers advice based on “best practices” Cross-Cultural Competence Communication Skills • Promote bilingual or illiterate education – Handouts, posters, etc. • Ethnic minority caregivers-language ability, understand cultural barriers – Highly important!! • Emphasize controller medications – Monitor beta2 agonists (Lieu, 2004) Encouraging Action • Case managers – reports to clinicians – provide support for self-care – use asthma management guidelines • Encourage patient empowerment & selfmanagement with feedback • Encourage – primary care access, continuity, coordination Managed care can support and benefit from this activity (Lieu, 2004) Educational Empowerment • • • • Recognize and avoid triggers Understand use of prescribed medications Proper use of inhalation devices Importance of compliance and monitoring: – shown to improve lung function – decrease school absenteeism and visits to the emergency department – children with moderate to severe asthma receive the most benefit from educational programs (Haby, 2004) However, education for children who have received emergency department care for asthma does not reduce subsequent emergency department care, hospitalizations, or unscheduled doctor visits. Let’s Review! Features of best practice asthma management for all persons include: A. B. C. D. Education in your language about disease process and methods of monitoring and treatment Peak flow meter education and usage in disease monitoring and treatment Action plan based on PEFR Follow up for disease Rx adjustment as needed Objectives • Describe the highest risk asthma populations • Outline the significant features of the asthma management guidelines • Describe adherence issues and methods to overcome difficulties • Describe new advances in the diagnosis and pharmacological treatments of asthma Latest Rx Advancements • Rescue beta2 agonists – Use MDI with spacer-paper cup or plastic soda bottle if must (NAEPP, 2002) • (as good as nebulizer) **Use facemasks in under 5 (Cleveland Clinic Health System, 2007) Latest Rx Advancements • More severe attacks – Use anticholinergics with beta2 agonists (NAEPP, 2002) (www.asthme-queec.ce, 2007) Latest Rx Advancements • To keep controller inhaled steroids at lowest required dose – Use leukotriene modifiers and nedocromil (NAEPP, 2002) (www.asthme-queec.ce, 2007) Latest Rx Advancements • To reduce the likelihood of hospital admission (NAEPP, 2002) – Give oral corticosteroids early during an acute asthma exacerbation • (i.e., within 45 minutes of the onset of symptoms) (www.asthme-queec.ce, 2007) Oral Corticosteroids • More effective than inhaled or nebulized corticosteroids – children hospitalized with severe acute asthma • Treatment of acute flares of asthma with repeated short courses of oral corticosteroids (NAEPP, 2002) – (at a dose of 1-2 mg per kg per day) – do not appear to cause any lasting changes in bone metabolism, bone mineralization, or adrenal function No evidence that intravenous corticosteroids are any more effective than oral corticosteroids in children with an intact and functioning digestive tract Inhaled Corticosteroids • High doses reduce hospital admission rates – In patients with acute asthma (Courtney, 2005) However, there is insufficient evidence that inhaled corticosteroids alone are as effective as systemic steroids Inhaled Corticosteroids • As a single agent in a medium dosage are more effective than: – Inhaled long-acting beta2 agonists – Inhaled nedocromil (Tilade), and leukotriene inhibitors • (In improving asthma symptoms and lung function in children with mild to moderate asthma) • Use of maintenance inhaled corticosteroids – Less use of bronchodilators and oral corticosteroids in patients using reduced growth velocity (NAEPP, 2002) However, multiple studies have found no evidence that children treated prophylactically with inhaled corticosteroids fail to reach their full adult height. Inhaled Corticosteroids • Unlike adults, children whose asthma is inadequately controlled with standard dosages of inhaled corticosteroids have: – not been shown to benefit from the addition of a long-acting beta2 agonist – or from an increase in the dosage of inhaled corticosteroids (NAEPP, 2002) Rx Research Findings • Doubling the dosage of beclomethasone – did not change objective measures of lung function – or symptom scores but did result in a significant reduction of growth velocity (NAEPP, 2002) Some benefit can be achieved with the addition of oral theophylline, but long-term effects have not been assessed. • A brief, four-week study of oral montelukast (Singulair) added to standard dosages of inhaled budesonide (Rhinocort Aqua) in children whose asthma was not adequately controlled demonstrated: – improved lung function – reduction in the number of days with asthma exacerbations Leukotriene Inhibitors • Studies have shown that: – optimizing the dosage of inhaled corticosteroids provides better control of asthma than oral montelukast • However another study found: – montelukast and inhaled corticosteroids were equally effective • possibly because of significantly better adherence with oral montelukast therapy • Compared with placebo: – oral montelukast reduces • total daily use of beta2 agonists • the need for rescue oral corticosteroids • daytime symptom scores Ducharme & Di Salvio, 2004; Knorr et. at., 1998, 2001, 2003 Nedocromil & Cromolyn • Inhaled nedocromil reduces: – – – – – asthma symptom scores asthma severity bronchodilator use improves lung function compared with placebo However, it is not as effective as inhaled corticosteroids • There is insufficient evidence to recommend prophylactic treatment with inhaled cromolyn (Intal) in children – Although it has been studied for use in children with asthma, it is less effective than inhaled corticosteroids in improving symptoms and lung function Armenio, 1993; Tasche, 2000 Levalbuterol R-albuterol (Xopenex) (xopenex.com, 2007) Levalbuterol R-albuterol (Xopenex) • Bronchodilator that contains R and S isomers of albuterol – The R-albuterol is responsible for the bronchodilator effect – The S-albuterol provides no benefit and may be responsible for the albuterol side effects • Several pediatric studies have supported the use of levalbuterol over racemic albuterol – (increase FEV1, more favorable safety profile with fewer side effects) (Carl, 2003) – Two conflicting studies do not support these findings Overall, a review of levalbuterol for the treatment of asthma in children found no clinically significant advantage over racemic albuterol. Omalizumab (Xolair) (Xolair.com, 2007) Omalizumab (Xolair) • Recombinant DNA-derived humanized IgG monoclonal antibody that selectively binds to human immunoglobulin E (IgE) – Inhibits the binding of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils, limiting release of allergic mediators – Omalizumab is approved for use in children 12 years and older with moderate to severe persistent asthma • who have a positive skin test or in vitro reactivity to a perennial aeroallergen • and whose symptoms are inadequately controlled with inhaled corticosteroids (Corren, 2003) Omalizumab (Xolair) • In children with moderate to severe asthma it reduces the rate of serious asthma exacerbations – and the need for physician or emergency department visits and hospitalizations – improves asthma quality-of-life scores • Although this new agent seems promising, its use is likely to be limited because it has an estimated cost of $10,000 per patient per year – Its use may be cost-effective if limited to allergic asthmatics who are poorly controlled on maximal therapy – and who are hospitalized five or more times (or for 20 days or longer) per year (Corren, 2003) Sublingual Immunotherapy (SLIT) (www.allergycapital.com, 2007) Sublingual Immunotherapy (SLIT) • Improves asthma symptoms and reduces medication use compared with placebo in children with asthma – Who are allergic to house dust mites and in children with allergic rhinitis that is related to a variety of common inhalant allergens (Courtney, 2005) It appears to be safe, with unwanted effects being as low as 9.6% and no life-threatening adverse effects reported. Sublingual Immunotherapy (SLIT) • However, SLIT has not been compared directly with standard immunotherapy – While it is a procedure and therefore is not regulated by the U.S. Food and Drug Administration (FDA), the extracts used for SLIT are FDA-approved for diagnosis and injectable immunotherapy only (Courtney, 2005) • Use of FDA-approved allergic extracts for SLIT is an off-label use – Health insurers consider SLIT investigational and do not cover its use Long-Acting Beta2 Agonists (www.asthme-queec.ce, 2007) Long-Acting Beta2 Agonists • Compared with placebo, salmeterol (Serevent) produces improved lung function in children – but there is conflicting evidence about whether it reduces the use of rescue or short-acting beta2 agonists • Associated with a significant increase in bronchial hyper-reactivity compared with inhaled corticosteroids • Not recommended for use as monotherapy in children with asthma – However, limited evidence from a single three-month study with 210 patients shows that the combination of a longacting beta2 agonist and inhaled corticosteroids may increase the number of symptom-free days (Simons, 1997) Oral Theophylline • Initially seemed promising in the prophylactic treatment of childhood asthma – When compared with placebo • significantly increased the mean morning peak expiratory flow rate • reduced the mean number of acute nighttime attacks and doses of bronchodilator used • However, it proved to be less promising when its use over one year was compared with the use of inhaled corticosteroids (Simons, 1997) Oral Theophylline • Although there was no significant difference between theophylline and inhaled corticosteroids in reduction of asthma symptoms – There was an increased use of short-acting beta2 agonists and oral corticosteroids in children receiving theophylline In summary, its use in children cannot be recommended because of the potential for serious side effects, such as cardiac arrhythmias or convulsions, if therapeutic blood levels are exceeded. (Simons, 1997) Immunotherapy • Can be used as an adjunct to standard drug therapy in allergic asthmatic children • Sublingual (allergy drops) and injectable (allergy shots) therapies – have been shown to reduce the presence of asthma and the overall use of asthma medication (Pifferi, 2002) Immunotherapy • Standard immunotherapy has a 1.7 to 15 % reported range of adverse effects – between 1985 and 1989, there were 17 standard immunotherapy-related deaths reported in the United States Usual Dosages for Medications Used in the Long-Term Control of Asthma in Children (part 1) Medication Dosage form Dosage* Formoterol (Foradil Aerolizer) DPI: 12 mcg per single-use capsule 1 capsule every 12 hours Salmeterol (Serevent) MDI: 21 mcg per puff 1 to 2 puffs every 12 hours DPI: 50 mcg per blister 1 blister every 12 hours DPI: 100, 250, or 500 mcg of fluticasone with 50 mcg of salmeterol 1 inhalation twice daily; dosage depends on severity of asthma MDI: 1 mg per puff 1 to 2 puffs 3 to 4 times daily Nebulizer solution: 20 mg per ampule 1 ampule 3 to 4 times daily MDI: 1.75 mg per puff 1 to 2 puffs 2 to 4 times daily Long-acting inhaled beta2 agonists† Combined medication Fluticasone/salmeterol (Advair Diskus) Cromolyn and nedocromil Cromolyn (Intal) Nedocromil (Tilade) DPI = dry-powder inhaler; MDI = metered-dose inhaler.*-Dosages are for children 12 years or younger unless otherwise specified. †-Should not be used for symptom relief or exacerbations. Use with an inhaled corticosteroid. ‡-Serum monitoring is important (serum concentration of 5 to 15 mcg per mL at steady state). Adapted from National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma: update on selected topics, 2002. Bethesda, Md.: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 2003; NIH publication no. 02-5074:133-5. Usual Dosages for Medications Used in the Long-Term Control of Asthma in Children (part 2) Medication Dosage form Dosage* Montelukast (Singulair) 4- or 5-mg chewable tablets, 4-mg packet of oral granules, 10-mg tablets Age 12 to 23 months: 4 mg oral granules at bedtime Age 2 to 5 years: 4 mg at bedtime Age 6 to 14 years: 5 mg at bedtime Older than 14 years: 10 mg at bedtime Zafirlukast (Accolate) 10- and 20-mg tablets Age 7 to 11 years: 20 mg daily in divided doses (i.e., one 10-mg tablet twice daily) 12 years and older: 20 mg twice daily Liquids, sustained-release tablets, and capsules Starting dosage is 10 mg per kg per day Usual maximums: Age < 1 year: (0.2 x [age in weeks]) + 5 = mg per kg per day Age >= 1 year: 16 mg per kg per day Leukotriene modifiers Methylxanthines‡ Theophylline DPI = dry-powder inhaler; MDI = metered-dose inhaler.*-Dosages are for children 12 years or younger unless otherwise specified. †-Should not be used for symptom relief or exacerbations. Use with an inhaled corticosteroid. ‡-Serum monitoring is important (serum concentration of 5 to 15 mcg per mL at steady state). Adapted from National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma: update on selected topics, 2002. Bethesda, Md.: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 2003; NIH publication no. 02-5074:133-5. Estimated Comparative Daily Dosages of Inhaled Corticosteroids in Children 12 Years and Younger Agent Low daily dose Medium daily dose High daily dose Beclomethasone CFC (Beclovent, Vanceril), 42 or 84 mcg per puff 84 to 336 mcg 336 to 672 mcg > 672 mcg Beclomethasone HFA, 40 or 80 mcg per puff 80 to 160 mcg 160 to 320 mcg > 320 mcg DPI: 200 mcg per inhalation 100 to 200 mcg 200 to 400 mcg > 400 mcg Nebulizer solution: 0.25 or 0.5 mg per ampule 0.5 mg 1.0 mg 2.0 mg Flunisolide (Aerobid), 250 mcg per puff 500 to 750 mcg 1,000 to 1,250 mcg > 1,250 mcg MDI: 44, 110, or 220 mcg per puff 88 to 176 mcg 176 to 440 mcg > 440 mcg DPI: 50, 100, or 250 mcg per inhalation 100 to 200 mcg 200 to 400 mcg > 400 mcg Triamcinolone acetonide (Azmacort), 100 mcg per puff 400 to 800 mcg 800 to 1,200 mcg > 1,200 mcg Budesonide (Pulmicort) Fluticasone (Flovent) CFC = chlorofluorocarbon; HFA = hydrofluoroalkane; DPI = dry-powder inhaler; MDI = metered-dose inhaler. Adapted from National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma: update on selected topics, 2002. Bethesda, Md.: U.S. Department of Health and Human Services, Public Health Service, National Institutes Key Clinical Recommendations A spacer with a metered-dose inhaler is as effective as a nebulizer for delivery of a bronchodilator in the treatment of an acute asthma exacerbation and for the delivery of chronic prophylactic medications. Physicians should consider adding inhaled ipratropium bromide (Atrovent) with each inhalation of a beta2 agonist, particularly in the treatment of a more severe asthma exacerbation. If possible, oral corticosteroids should be administered within 45 minutes of the onset of symptoms in an acute asthma exacerbation. Modest doses of an inhaled corticosteroid are more effective than inhaled long-acting beta2 agonists, inhaled nedocromil (Tilade), and leukotriene inhibitors in improving asthma symptoms and lung function in children with moderate persistent asthma and are recommended as the first-line treatment. Parents and caregivers of children with asthma, particularly those with moderate to severe disease, should be taught to recognize and avoid triggers and to understand the use of prescribed medications and inhalation devices, and the importance of compliance and monitoring. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, opinion, or case series. Adapted from National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma: update on selected topics, 2002. Bethesda, Md.: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 2003. NIH publication no. 02-5074:135. Let’s Review! Management of severe persistent asthma might include: A. B. C. D. E. Long-acting beta2 agonist High dose inhaled corticosteroid Leukotriene modifier Anticholinergic inhaler All of the above