Pediatric Asthma Management

Pediatric Asthma Management: Bridging the Gaps Between Knowledge and Practice

Welcome to Pediatric Asthma Management: Bridging the Gaps Between Knowledge and Practice. This program is presented by Applied Clinical Education and is accredited by Medical Education Resources. Educational support for this activity has been provided by an educational grant from Teva Pharmaceuticals.

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Part I: Pediatric Asthma: Criteria for Diagnosis Girish D. Sharma, MD Associate Professor Rush Medical College Chicago, Illinois

PART I: PEDIATRIC ASTHMA: CRITERIA FOR DIAGNOSIS By Girish D. Sharma, MD

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Definition ƒ Asthma is a chronic inflammatory disorder of the airways in which various cells and cellular elements play a role—in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells ƒ This inflammation causes recurrent episodes of wheezing, breathless chest tightness, and coughing, particularly at night or in the early morning, in susceptible individuals. These episodes are usually associated with widespread but variable airflow obstruction, which is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli National Asthma Education and Prevention Program Expert Panel Report 2007.

The definition of asthma developed by the National Asthma Education and Prevention Program Expert Panel Report1 highlights the importance of chronic inflammation in the development of asthma, in addition to episodic bronchospastic symptoms, which are usually associated with widespread but variable airway obstruction. Airway inflammation contributes to airway hyperresponsiveness, airflow limitation, respiratory symptoms, and chronicity of disease. Thus, the key features for the diagnosis are (1) the presence of episodic bronchospastic symptoms or evidence of obstruction that is at least partially reversible spontaneously or with treatment and (2) the exclusion of alternative diagnoses.

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Specific Objective Criteria For The Diagnosis Of Pediatric Asthma ƒ Episodic lower airway obstruction is present ƒ Airflow obstruction or symptoms (wheeze or cough) are at least partially reversible ƒ Alternative diagnoses are excluded ƒ Lower airway obstruction results in wheezing

Specific objective criteria for the diagnosis of asthma include the following: • episodic lower airway obstruction; • airflow obstruction or symptoms (wheeze or cough); and • exclusion of alternative diagnoses. Lower airway obstruction results in wheezing. Among all children, 20% have at least 1 episode of lower respiratory tract infection associated with wheezing during first year of life, and 70% of these episodes are associated with viral infections. Recurrent wheezing is suggestive of asthma.

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Recommended Diagnostic Methods For Asthma ƒ The recommended methods for the diagnosis of asthma are the following – Detailed medical history – physical examination focusing on upper respiratory tract, chest, and skin – Spirometry to demonstrate obstruction and assess reversibility in children older than 4 years. The reversibility is determined by an increase in FEV1 of either >12% from baseline or >10% after a dose of inhaled short-acting bronchodilator

FEV1, forced expiratory volume in 1 second

The recommended methods for the diagnosis of asthma are the following: • detailed medical history; • physical examination focusing on upper respiratory tract, chest, and skin; and • spirometry to demonstrate obstruction and assess reversibility in children older than 4 years. The reversibility is determined by an increase in forced expiratory volume in 1 second (FEV1) of either more than 12% from baseline or more than 10% after a dose of inhaled shortacting bronchodilator.

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Wheezing In Children ƒ Wheezing in young children is most commonly associated with viral infections – children younger than 2 years of age – predominantly respiratory syncytial virus – Older preschool children – other viruses such as rhinovirus and parainfluenza virus

The diagnosis of asthma in young children may be difficult because episodic wheeze and cough are also common in children who do not have asthma.1 Wheezing in children is usually associated with viral respiratory illness. Respiratory syncytial virus is the most common cause of wheezing in children younger than 2 years, whereas other viruses can cause wheezing in older children. Other viruses, such as rhinovirus, parainfluenza virus, and human metapneumovirus, are also associated with wheezing in children.

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Wheezing In Children ƒ Key indicators for considering diagnosis of asthma include the following – wheezing (note that lack of wheezing or normal physical examination findings do not exclude asthma) – cough (especially cough that is worse during night, early hours of morning) – recurrent wheezing, difficulty in breathing, or chest tightness – onset or exacerbation of symptoms caused by exercise; viral infections; exposure to animals with fur, house dust mites, molds, smoke, pollen; change in weather; strong emotional expressions; airborne chemicals, dust; menses – symptoms occur or worsen at night (early hours of morning)

Key indicators for considering a diagnosis of asthma include the following: • wheezing (note that lack of wheezing or normal physical examination findings do not exclude asthma); • cough (especially cough that is worse during night, early hours of morning); • recurrent wheezing, difficulty in breathing, or chest tightness; • onset or exacerbation of symptoms caused by exercise; viral infections; exposure to animals with fur, house dust mites, molds, smoke, pollen, airborne chemicals, dust; change in weather; strong emotional expressions; menses; and • onset or exacerbation of symptoms at night (early hours of morning).

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Wheezing In Children (Cont’d) ƒ Three Categories of wheezing in children younger than 5 years of age – transient early wheezing – persistent early-onset wheezing – Late-onset wheezing

Three categories of wheezing have been noted in children younger than 5 years of age. These include the following: Transient early wheezing: This is often outgrown in first 3 years of life. Persistent early-onset wheezing: These children tend to have recurrent wheezing associated with episodes of upper respiratory viral infections, with no evidence of atopy and no family history of atopy. The symptoms tend to persist during preschool age and in some until age 12. Late-onset wheezing: These children have asthma that tends to persist during childhood and into adult life. They are likely to have a background of atopy, often with eczema.

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Wheezing In Children (Cont’d) ƒ Alternative causes of wheezing – – – – – – – – – – –

chronic rhinosinusitis gastroesophageal reflux recurrent viral respiratory infections cystic fibrosis bronchopulmonary dysplasia tuberculosis congenital narrowing of intrathoracic airways foreign body aspiration primary ciliary dyskinesia immune deficiency congenital heart disease

Alternative causes of wheezing include the following: • chronic rhinosinusitis; • gastroesophageal reflux; • recurrent viral respiratory infections; • cystic fibrosis; • bronchopulmonary dysplasia; • tuberculosis; • congenital narrowing of intrathoracic airways; • foreign body aspiration; • primary ciliary dyskinesia; • immune deficiency; and • congenital heart disease. It should be noted that neonatal onset of wheeze with failure to thrive and focal lung and heart signs suggests alternative causes of wheeze.

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Diagnosis Of Asthma ƒ Symptoms – – – – – –

frequent episodes of wheezing activity-induced cough or wheezing nocturnal cough absence of seasonal variation persistence of symptoms beyond 3 years other symptoms

The key to successful diagnosis of asthma is to differentiate its symptoms from those of the aforementioned conditions. Common symptoms of asthma in children include the following: • frequent episodes of wheezing (more than once a week); • activity-induced cough or wheezing; • nocturnal cough (especially during early hours of morning and periods without viral infection); • absence of seasonal variation; • persistence of symptoms beyond age of 3 years; • chest tightness; and • chest pain.

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Diagnosis Of Asthma (Cont’d) ƒ Physical findings – increased anteroposterior diameter of chest – prolonged expiration, expiratory wheezing, coarse crackles – unequal breathing sounds

Physical findings vary according to whether an acute episode is present and how severe it is. During an outpatient visit between acute episodes, a child with mild asthma may have normal findings on physical examination. There may be signs of chronic respiratory distress or chronic hyperinflation, atopy, or allergic rhinitis (eg, conjunctival congestion, ocular shiners, transverse crease over the nose due to constant nose rubbing associated with allergic rhinitis, and pale violaceous nasal mucosa due to allergic rhinitis). In chronic cases, the anteroposterior diameter of the larynx may be increased, and lung examination may reveal prolongation of the expiratory phase, expiratory wheeze, coarse crackles, and unequal breath sounds. Once the diagnosis has been established, effort should be made to identify precipitating factors (eg, exposure at home, day care, or school to inhalant allergens, irritants like tobacco smoke, or viral respiratory infections) and to identify comorbidities that may aggravate asthma (eg, sinusitis, rhinitis, gastoesophageal reflux, obstructive sleep apnea, and allergic bronchopulmonary aspergillosis).

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Severity Classification of Asthma in Children

Classification of Severity of Asthma in Children

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Classification Of Asthma Severity By Clinical Features Before Treatment Intermittent

Mild Persistent

Moderate Persistent

Severe Persistent

<1/wk

>1/wk but <1/d

Daily

Daily

Brief

May affect activity or sleep

May affect activity or sleep

Frequent

Nocturnal symptoms

≤2/mo

>2/mo

>2/wk

Frequent

Short-acting β2 agonist use

>1/wk

>1/wk but <1/d

Daily

Daily

FEV1 or PEF

≥80% predicted

≥80% predicted

60%-80% predicted

≤60% predicted

FEV1 or PEF variability

<20%

<20%-30%

>30%

>30%

Symptom frequency Exacerbation characteristics

PEF, peak expiratory flow Global strategy for asthma management and prevention. The GINA report 2006. Available at: www.ginasthma.com.

Spirometry is recommended for assessing the severity of asthma. The severity (intrinsic intensity of the disease process), control (degree to which asthmatic symptoms, functional impairment, and risks for untoward events are minimized and the goals of therapy are met), and responsiveness (the ease with which asthma control is achieved by therapy) should be assessed. Asthma can be classified as follows (Table): In intermittent asthma, symptoms occur less than once a week—hence, an inhaled short-acting β2 agonist can be used. Exacerbations are brief, and nocturnal symptoms occur less than twice a month. FEV1 and peak expiratory flow (PEF) are greater than 80% of the predicted value, and FEV1 or PEF variability is less than 20%. In mild persistent asthma, symptoms occur more than once a week but less than once a day. Inhaled short-acting β2 agonists may be used accordingly. The exacerbations may affect activity or sleep, and nocturnal symptoms occur more than twice a month. FEV1 and PEF are greater than 80% of predicted value, and FEV1 or PEF variability is less than 20% to 30%. In moderate persistent asthma, symptoms occur daily, and inhaled short-acting β2 agonists must be used accordingly. Here, the exacerbations may affect activity or sleep, and nocturnal symptoms occur more than twice a week. FEV1 and PEF are 60% to 80% of predicted value, and FEV1 or PEF variability is greater than 30%. Finally, in severe persistent asthma, symptoms occur daily, and inhaled short-acting β2 agonists should be used accordingly. The exacerbations appear daily, and nocturnal symptoms are frequent. FEV1 and PEF are less than 60% of predicted value, and FEV1 or PEF variability is greater than 30%. It should be noted that because the severity of asthma depends on both the severity of the underlying disease and its responsiveness to treatment, classification is limited in terms of value in predicting what treatment may be required and what the response to that treatment will be. For example, a patient can present with severe symptoms and be classified as having severe persistent asthma at initial presentation but respond fully to the initial treatment and then be classified as having moderate persistent asthma. Hence, a periodic assessment of asthma control is relevant and useful.

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Physical Findings During An Acute Episode Mild Episode

Moderate Episode

Severe Episode

Status Asthmaticus

Respiratory rate

Increased

Increased

Increased, often >30/min

Imminent respiratory arrest

Heart rate

<100/min

100-120/min

>120/min

Bradycardia may be present

Accessory respiratory muscle use

None

Yes

Yes; may be suprasternal retractions

Yes; respiratory muscles may be fatigued

Moderate wheeze

Loud expiratory wheeze

Biphasic wheeze

May be absent

Absent

May be present (10-20 mm Hg)

Often present (20-40 mm Hg)

Heard earlier, may be absent

Normal, >95% in room air

91%-95% in room air

<91% in room air

<91% in room air, with or without cyanosis

Chest auscultation Pulsus paradoxus Oxyhemoglobin saturation

Physical examination during an acute episode may reveal different findings in mild, moderately severe, and severe episodes and in status asthmaticus with imminent respiratory arrest. During a mild episode, the respiratory rate is increased. The accessory muscles of respiration are not used. The heart rate is less than 100 beats per minute. Pulsus paradoxus is not present. Auscultation of the chest reveals moderate wheezing, which is often end-expiratory. The oxyhemoglobin saturation in room air is greater than 95%. In a moderately severe episode, the respiratory rate is increased. Typically, the accessory muscles of respiration are used, and suprasternal retractions are present. The heart rate is 100 to 120 beats per minute. Loud expiratory wheezing can be heard. Pulsus paradoxus may be present (10-20 mm Hg). The oxyhemoglobin saturation in room air is 91% to 95%. During a severe episode, the respiratory rate is often greater than 30 breaths per minute. The accessory muscles of respiration are usually used, and suprasternal retractions are commonly present. The heart rate is more than 120 beats per minute. Loud biphasic (expiratory and inspiratory) wheezing can be heard. Pulsus paradoxus is often present (20-40 mm Hg). The oxyhemoglobin saturation in room air is less than 91%. In status asthmaticus with imminent respiratory arrest, paradoxical thoracoabdominal movement occurs. Wheezing may be absent (associated with the most severe airway obstruction). Severe hypoxemia may manifest as bradycardia. Pulsus paradoxus noted earlier may be absent; this finding suggests respiratory muscle fatigue.

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Risk For Asthma In Young Children With Recurrent Wheezing A Clinical Index to Define Asthma Risk Major Criteria ƒ Parental asthma ƒ Eczema

Minor Criteria ƒ Allergic rhinitis ƒ Wheezing without colds ƒ Eosinophilia

Castro-Rodriguez JA, et al. Am J Respir Crit Care Med. 2000;162:1403-1406.

Castro-Rodreguez et al3 proposed a simple clinical index to predict the presence of asthma in late childhood. The index includes 2 major criteria (physician-diagnosed asthma in a parent and physician-diagnosed eczema in the child) and 3 minor criteria (physician-diagnosed allergic rhinitis, wheeze without cold, and eosinophilia).

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Risk For Asthma In Young Children With Recurrent Wheezing (Cont’d) ƒ The presence of asthma in later childhood is associated with the following – frequent wheezing during first 3 years+ – 1 major OR 2 minor risk factors.

The presence of 1 major risk factor or 2 of 3 minor risk factors has been shown to predict the presence of asthma in later childhood.1

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Pediatric Asthma Management ƒ Regular assessment and monitoring – control of factors that contribute to symptoms and disease severity – pharmacologic therapy – educating the child, family, and other caregivers about how to adhere to the asthma management plan

Based on these risk factors, successful pediatric asthma management should include the following: 1. Regular assessment and monitoring. 2. Control of factors that contribute to symptoms and severity of disease. 3. Pharmacologic therapy. 4. Educating the child, the family, and other caregivers on how to adhere to the asthma management plan, which includes daily management, and how to handle episodes of asthma.

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Pediatric Asthma Management Goals Of Therapy

ƒ Prevent chronic symptoms ƒ Prevent asthmatic exacerbations ƒ Maintain normal activity levels ƒ Maintain normal pulmonary function ƒ Optimize pharmacotherapy, minimize side effects ƒ Satisfy the child’s and family’s expectations/goals

The goals of therapy for the child with asthma are to: • prevent chronic symptoms; • prevent exacerbations of asthma; • maintain normal levels of activity; • maintain normal pulmonary function; • optimize pharmacotherapy, minimize side effects; and • satisfy the child’s and family’s expectations/goals for asthma care.

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Pediatric Asthma Management

Ongoing Assessment And Monitoring ƒ Signs and symptoms of asthma ƒ Pulmonary function – spirometry – PEF monitoring

ƒ ƒ ƒ ƒ

Quality of life/functional status History of asthma exacerbations Pharmacotherapy Patient–provider communication

Ongoing assessment includes monitoring in the following areas: • signs and symptoms of asthma; • pulmonary function • spirometry • peak flow monitoring; • quality of life/functional status; • history of asthma exacerbations; • pharmacotherapy; and • patient–provider communication.

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Pediatric Asthma Management Asthma Control Controlled (Any of the Following)

Partly Controlled (Any Measure Present in Any Week)

Uncontrolled

None (≤2/wk)

>2/wk

≥3 features of partly controlled asthma present in any week

Limitation of activities

None

Any

Same as above

Nocturnal symptom/awakening

None

Any

Same as above

None (≤2/wk)

>2/wk

Same as above

Lung function (FEV1 or PEF)

Normal

<80% predicted or personal best (if known)

Same as above

Exacerbations

None

≥1/y

1 in any wk

Characteristic

Daytime symptoms

Need for reliever/rescue treatment

Asthma is defined as controlled when there are no daytime symptoms or they are reported to occur less than twice a week, the patient reports no limitation of activities and/or nocturnal symptoms, there is little or no need for reliever or rescue treatment, lung function is normal, and there are no exacerbations. Asthma is defined as partially controlled if any of the following are present in any week: Daytime symptoms are reported more than twice a week, activities are limited or the patient reports nocturnal symptoms, there is need for reliever or rescue treatment more than twice a week, lung function is affected, and 1 or more exacerbations are reported over the course of a year. Asthma is considered uncontrolled if 3 or more features of partly controlled asthma are present in any given week. It should be noted that any exacerbation should prompt a review of maintenance therapy to ensure that it is adequate. Also, by definition, an exacerbation in any week makes that an uncontrolled asthma week. Finally, lung function is not a reliable test for children 5 years old or younger.

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Pediatric Asthma Management

Ongoing Assessment And Monitoring ƒ The Asthma Control Test (ACT) includes the following questions – In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school, or home? – During the past 4 weeks, how often have you had shortness of breath? – During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning? – During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication? – How would you rate your asthma control during the past 4 weeks?

Because asthma control5 refers to control of the manifestations of the disease, it is recommended that the treatment be aimed at controlling the clinical features of the disease, including abnormalities of lung function. Ideal asthma control in children will mean the following: • no coughing; • no difficulty in breathing; • no nocturnal symptoms; • normal activity, including no limitation of play, activity, sports, exercise, and school or day care activities; • no acute episodes and requirement for rescue medications; • no school absences; and • normal lung function. As you can see from this slide, the asthma control test (ACT) has been used for assessing clinical control as a continuous variable and provides numeric values to distinguish different levels of control. The ACT includes responses to the following questions: In the past 4 weeks, how much of the time did your asthma keep you from getting as much as usual done at work, school, or home? During the past 4 weeks, how often have you had shortness of breath? During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning? During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication? How would you rate your asthma control during past 4 weeks?

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Initial Evaluation In Outpatient Clinic ƒ Ask about symptom patterns over the past 2 weeks – – – – –

daytime symptoms nocturnal symptoms school absences limitation of daily activities use of rescue medications and regular medications

During initial evaluation in an outpatient clinic, ask about symptom patterns over the past 2 weeks: • daytime symptoms (coughing, wheezing, shortness of breath, rapid breathing, chest tightness); • nocturnal symptoms (nighttime or early morning cough, wheeze, breathlessness); • school absences; • limitation of daily activities; and • use of rescue medications and regular medications.

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Initial Evaluation In Outpatient Clinic (Cont’d) ƒ For infants ask about – – – – – –

difficulty in feeding changes in respiratory rate altered sleep patterns retractions irritability, lethargy decreased appetite, weight loss

For infants ask about: • difficulty in feeding (feeding with interruptions, poor sucking, grunting sounds); • changes in respiratory rate; • altered sleep patterns; • retractions; • irritability, lethargy; and • decreased appetite, weight loss.

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Initial Evaluation In Outpatient Clinic (Cont’d) ƒ For older children ask about – – – – –

fatigue increased irritability complaints about not feeling well avoidance of certain activities poor school performance

For older children ask about: • fatigue (slows down, stops playing), • increased irritability; • complaints about not feeling well; • avoidance of certain activities (eg, sports, gym class); and • poor school performance.

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Spirometry ƒ Use of spirometry is recommended – at the initial visit – after treatment has been initiated and symptoms have stabilized, to document normal lung function – in case of change in symptom pattern or severity – at least once yearly to assess maintenance airway function regardless of changes in medication – to evaluate response to change in therapy

Use of spirometry is recommended: • at the initial visit; • after treatment has been initiated and symptoms have stabilized, to document normal lung function; • in case of change in symptom pattern or severity; • at least once yearly to assess maintenance of airway function regardless of changes in medication; and • to evaluate response to change in therapy.

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Assessment During Follow-up Visits ƒ Has child’s asthma been better or worse since the last visit? ƒ In the past 2 weeks, how many days has the child had symptoms – – – –

during the day at night upon waking up in the morning during physical activity or sport activities

ƒ Since the last visit, how many times has the child missed school because of asthma?

To assess symptoms, ask parents: • Has the child’s asthma been better or worse since the last visit? • In the past 2 weeks, how many days has the child had symptoms • during the day, at night (during early part of night or after midnight during early hours of morning), • on waking up in the morning, • during physical activity or sport activities? • Since the last visit, how many times has the child missed school because of asthmatic problems?

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Assessment During Follow-up Visits (Cont’d) ƒ Exacerbations – Since the last visit, has the child had any episodes when asthmatic symptoms were a lot worse than usual? – What caused symptoms to worsen? What did the child (or caregiver) do? – Has the child had unscheduled visits to the doctor or emergency room, or hospital admissions? – Details of PEF – highest, lowest, any unusual fall

To assess whether any exacerbations have occurred, ask parents: • Since the last visit, has the child had any episodes when asthmatic symptoms were lot worse than usual? • What caused symptoms to worsen? What did the child (or caregiver) do? • Has the child had unscheduled visits to the doctor or emergency department, or has the child been admitted to a hospital? To assess PEF, ask: • What are the highest and lowest PEF measurements at home and at school since the last visit? • Has the child’s PEF dropped below 80% of personal best since the last visit? Also, check the technique of administering treatment.

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Assessment During Follow-up Visits (Cont’d) ƒ Medications – – – – –

Medications being used, dose and frequency? Medication missed, stopped or changed? If yes, why? Dose of short-acting β2-agonists? Use of β2-agonists using before exercise? Meter-dosed inhaler (MDI) with a space/holding chamber/dry powder inhaler (DPI)/nebulizer? – Is an appropriate size mask being used appropriately? Check the technique at each visit – Check for drug side effects

To assess what treatments have been used, ask parents: • What medications are being used, including dose and frequency? • Has any regular medication been missed, stopped, or changed? If yes, why? • How many puffs of short-acting β2 agonists is the child using daily? How many weekly? • How much short-acting β2 agonist medication is the child using before exercise? • Is the child using a metered-dose inhaler (MDI) with a spacer/holding chamber, a dry powder inhaler (DPI), or a nebulizer? Is a mask of the appropriate size being used appropriately? Check the technique at each visit. • Does the asthma medication have side effects (eg, cough, stomach upset, bad taste, or shakiness)? Also, periodically check the child’s/family’s technique for cleaning the device, counting doses, replacing the nebulizer and spacers/holding chambers.

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Assessment During Follow-up Visits (Cont’d) ƒ Following the care plan – What questions do you have? – Is the plan useful? – Have there been any problems following the daily management plan or the action plan? – Always review after-hours phone numbers and the rescue plan and steps for emergency care

Finally, to determine if children and their families are following the care plan, ask: • What questions do you have? • Is the plan useful? • Have there been any problems following the daily management plan or the action plan? Always review after-hours phone numbers and the rescue plan and steps for emergency care.

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Part II: Diagnosing and Assessing Asthma in Children David Skoner, MD Director, Division of Allergy, Asthma and Immunology Professor, Pediatrics Drexel University College of Medicine Vice Chair of Clinical Research Division of Allergy and Immunology Allegheny Medical Center Pittsburgh, Pennsylvania

PART II: THE CURRENT UNDERSTANDING OF ASTHMA CONTROL By David Skoner, MD

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Strategies For Asthma Control 1. Identify and control environmental triggers – smoke, allergens 2. Address effect of exercise on asthma symptoms 3. Educate patients/parents about disease, need for treatment, available treatments, environmental avoidance 4. Identify and treat concomitant diseases (allergic rhinitis, sinusitis, gastroesophageal reflux disease) 5. Provide written maintenance and action plans 6. Use anti-inflammatory treatments and develop strategies to promote long-term adherence 7. Fulfill the goals of asthma treatment

National Institutes of Health. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program Expert Panel. Clinical Practice Guidelines. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Update on Selected Topics 2007. Bethesda, MD: National Institutes of Health National Heart, Lung, and Blood Institute; 2007.

Strategies for gaining control of asthma include the following: 1. Identify and control environmental triggers: smoke, allergens. 2. Address the effect of exercise on asthma symptoms. 3. Educate patients and their parents about disease, need for treatment, available treatments, environmental avoidance. 4. Identify and treat concomitant diseases (allergic rhinitis, sinusitis, gastroesophageal reflux disease). 5. Provide written maintenance and action plans. 6. Use anti-inflammatory treatments and develop strategies to promote longterm adherence. 7. Fulfill the goals of asthma treatment.

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Classifying Asthma Severity And Assessing Asthma Control ƒ In patients not on controller medications – severity based on domains of impairment and risk – level of severity based on most severe category in which feature appears

ƒ In patients on controller medications – severity based on lowest step required to maintain clinical control – control of asthma based on domains of impairment and risk ƒ level of control based on most severe impairment of risk category ƒ validated questionnaires may be used in patients aged ≥12 years National Institutes of Health. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program Expert Panel. Clinical Practice Guidelines. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Update on Selected Topics 2007. Publication No. 02-5075. Bethesda, MD: National Institutes of Health National Heart, Lung, and Blood Institute; 2007.

In patients not on controller medications, the severity of asthma is based on domains of impairment and risk and the most severe category in which a feature appears. In patients on controller medications, severity is based on the lowest step required to maintain clinical control.

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Stepwise Approach For Managing Asthma In Children Aged 0 To 4 Years Intermittent

Step 1 Preferred: SABA as needed

Mild Persistent

Step 2 Preferred: lowlow-dose ICS Alternative: montelukastor cromolyn

Moderate to Severe Persistent

Step 3 Preferred: mediummedium-dose ICS

Step 4 Preferred: mediummedium-dose ICS and either montelukast or LABA

Step 5 Preferred: highhigh-dose ICS and either montelukast or LABA

Step 6 Preferred: highhigh-dose ICS and either montelukast or LABA and oral corticosteroid s

ICS, inhaled corticosteroid; LABA, long-acting β2 agonist; SABA, short-acting β2 agonist

According to the recently revised National Asthma Education and Prevention Program (NAEPP) guidelines for the treatment of pediatric asthma, short-acting β2 agonists are the preferred treatment for children aged 4 years and younger with intermittent asthma. For those with mild persistent asthma, low-dose inhaled corticosteroids (ICSs) are the preferred treatment. Finally, for those with moderate to severe persistent asthma, medium- or high-dose ICSs monotherapy or combination therapy with ICSs and long-acting β2 agonists or montelukast is preferred.

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Stepwise Approach For Managing Asthma In Children Aged 5 To 11 Years Intermittent

Step 1 Preferred: SABA as needed

Mild Persistent

Step 2 Preferred: lowlow-dose ICS Alternative: LTRA, cromolyn, cromolyn, nedocromil, nedocromil, or theophylline

LTRA, leukotriene receptor antagonist.

Mild Persistent Severe Persistent

Step 3 Preferred: mediummedium-dose ICS or lowlow-dose ICS and either LABA, LTRA, or theophylline

Step 4 Preferred: mediummedium-dose ICS + LABA Alternative: mediummediumdose ICS and either LTRA or theophylline

Step 5 Preferred: highhigh-dose ICS + LABA Alternative: highhigh-dose ICS and either LTRA or theophylline and omalizumab may be considered for patients who have allergies

Step 6 Preferred: highhigh-dose ICS + LABA + oral corticosteroid Alternative: highhigh-dose ICS and either LTRA or theophylline + oral corticosteroid and omalizumab may be considered for patients who have allergies

According to the recently revised NAEPP guidelines for the treatment of pediatric asthma, short-acting β2 agonists are the preferred treatment for children between the ages of 5 and 11 years with intermittent asthma. For those with mild persistent asthma, low-dose ICSs or medium-dose or low-dose ICSs with either long-acting β2 agonists or leukotriene receptor antagonists are preferred. For those with severe persistent asthma, medium-dose ICSs plus long-acting β2 agonists or high-dose ICSs plus long-acting β2 agonists and oral corticosteroids are preferred.

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Stepwise Approach For Managing Asthma In Patients Aged ≥12 Years Intermittent

Step 1 Preferred: SABA as needed

Mild Persistent

Step 2 Preferred: lowlow-dose ICS Alternative: cromolyn, cromolyn, nedocromil, nedocromil, LTRA, or theophylline

Moderate Persistent

Step 3 Preferred: mediummedium-dose ICS or lowlow-dose ICS + LABA Alternative: lowlow-dose ICS and either LTRA, theophylline, theophylline, or zileuton

Severe Persistent

Step 4 Preferred: mediummedium-dose ICS + LABA Alternative: mediummedium-dose ICS and either LTRA, theophylline, theophylline, or zileuton

Step 5 Preferred: highhigh-dose ICS + LABA and consider omalizumab for patients who have allergies

Step 6 Preferred: highhigh-dose ICS + LABA + oral corticosteroid and consider omalizumab for patients who have allergies

ICS, inhaled corticosteroid; LABA, long-acting β2 agonist; SABA, short-acting β2 agonist

According to the recently revised NAEPP guidelines for the treatment of pediatric asthma, short-acting β2 agonists are the preferred treatment for children older than 12 years with intermittent asthma. For those with mild persistent asthma, low-dose ICSs are the preferred option. For those with moderate persistent asthma, mediumdose or low-dose ICSs with long-acting β2 agonists are preferred. Finally, for those with severe persistent asthma, high-dose ICSs plus long-acting β2 agonists or highdose ICSs plus long-actiing β2 agonists and oral corticosteroids are preferred.

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Inhaled Corticosteroids

– fewer symptoms – fewer severe exacerbations – reduced use of quick-relief medicine – improved lung function – reduced airway inflammation National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 2, 1997. NAEPP Update, 2007. Barnes PJ et al. Am J Respir Crit Care Med. 1998;157:S1–S53. Suissa S et al. N Engl J Med. 2000;343:332-336.

Rate Ratio for Death From Asthma

ƒ ICSs are recommended as first-line therapy and are the most effective therapy for the treatment of persistent asthma in both adults and children ƒ Benefits of daily use 2.5 2 1.5 1 0.5 0

0 1 2 3 4 5 6 7 8 9 10 11 12 Number of Canisters of ICSs per Year

The NAEPP recommends ICS as the preferred long-term controller medication for children of all ages with persistent asthma. ICS are FDA-approved for the treatment of asthma in children as young as 1 year of age. Although clearly effective at achieving asthma control in children, ICSs pose important challenges in this population. These include issues of long-term adherence, delivery of drug to large and small airways, and the potential for systemic adverse effects. Regarding the latter, the most frequently addressed and clinically relevant systemic adverse effect in children is growth suppression. Benefits of the daily use of ICSs include fewer symptoms, fewer severe exacerbations, reduced use of quick-relief medicine, improved lung function, and reduced airway inflammation.

36

Effect Of ICSs On Inflammation E E BM

BM

Before and after 3-months of treatment with 600 mcg of BUD twice daily BUD, budesonide Laitinen LA et al. J Allergy Clin Immunol. 1992;90:32-42.

ICSs act on a variety of inflammatory and structural cells, including eosinophils, T lymphocytes, dendritic cells, mast cells, macrophages, epithelial cells, airway smooth muscle cells, endothelial cells, and mucus glands, to reduce cytokine and mediator production, vessel leakage, and mucus production and to increase β2 receptors on airway smooth muscle cells. For ICSs to be effective, adherence is clinically important, as evidenced by studies evaluating asthma control in children who do and do not adhere to ICS use. However, studies evaluating rates of adherence to ICS therapy indicate that they are very low. Therefore, the welldescribed benefits provided by the long-term use of ICSs may not be attainable. Adherence to long-term controller therapy is influenced by many factors, including ease of use, frequency of dosing, and fear of side effects. The latter has been cited as a major barrier to the long-term use of ICSs. Thus, adherence may be improved when the benefits and risks of ICS use in children are fully understood. Topically deposited corticosteroids eventually appear in the systemic circulation, with systemic bioavailability resulting from either the inhaled fraction of drug, which enters the airways (10%-60%), or the remaining portion, which is swallowed (40%-90%). The swallowed portion is absorbed from the gastrointestinal tract and subject to variable first-pass metabolism in the liver. All ICSs cause dose-related systemic adverse effects, although these are substantially less than those caused by a comparable dose of oral corticosteroids. No first-pass metabolism occurs in the lungs, and most of the drug in the blood enters via the lungs. Interestingly, the very source of efficacy (airway delivery) is also the major source of concern about any systemic side effects.

37

Analysis Of Inhaled Corticosteroids How Patients Respond

Malmstrom et al* (n=895) Adult Study* (n=470) CAMP* (n=311) ACRN* (n=336)

40

Patients, %

35 30 25 20 15 10 5 0 <–20 –20 to –10 –10 to 0 0 to 10

10 to 20 20 to 30 30 to 40

>40

FEV1 Change from Baseline, % Data include only patients who received ICS. Study of Malmstrom et al included 895 patients 15 to 85 years of age with chronic asthma; Adult study included 470 adults with asthma; CAMP study included 311 children with asthma; ACRN study included 336 adults with asthma. ACRN, Asthma Clinical Research Network; CAMP, Childhood Asthma Management Program Malmstrom K et al. Arch Intern Med. 1999;130:487-495. Tantisira KG et al. Hum Mol Genet. 2004;13:1353-1359.

An important concept to understand in the appropriate use of ICSs is dose responsiveness.

8.16

38

Dose–response Relationship In Children With Moderate And Severe Asthma

Improvement

Percentage of Maximum 100 90 80 70 60 50 40 30 20 10 0

Symptoms FEV1 Exercise (FEV1) NO FEF25%-75%

0

100

200

300

400

500

600

700

800

Daily Dose of BUD, mcg FEF25%-75%, forced expiratory flow rate; NO, nitric oxide Barnes PJ. N Engl J Med. 1995;332:868-875. Barnes PJ et al. Am J Respir Crit Care Med. 1998;157:S1-53.

Studies have shown that the dose–response curve for benefits of ICSs is steep at low doses, and that relatively little benefit is gained when a low dose is doubled or tripled. Furthermore, because the dose–response curve for adverse events is shifted to the right at higher ICS doses, doubled and tripled ICS doses are much more likely than low doses to produce systemic side effects.

39

FEV1 (Change With Montelukast, %)

Children’s Responsiveness To ICS And LTRA Is Highly Variable 40 30

22% of patients respond to montelukast

Both meds (17%)

Montelukast alone (5%)

20 10 0

40% of patients respond to fluticasone

–10 –20 –40

y tit en id f o ne Neither medication Li

–50 –50

–40 –30 –20 –10

–30

Fluticasone alone (23%)

(55%)

0

10

20

30

40

FEV1 (Change With Fluticasone, %) Szefler SJ et al. J Allergy Clin Immunol. 2005;115:233-242.

Another important concept is the heterogeneity of responses to ICSs, at least some of which may be genetically and environmentally determined. In the study of Szefler et al,16 55% of children with asthma failed to achieve an improvement in FEV1 of 7.5% or more with either montelukast or an ICS. In that same study, 17% responded to both medications, 23% responded only to an ICS, and 5% responded only to montelukast. In all, 22% responded to montelukast and 40% responded to an ICS.

40

Effect Of ICS Dosage On Therapeutic And Systemic Corticosteroid Effects

Th er ap eu tic

S (e yst g, em ↓ ic gr e ow ffe th cts )

be ne fit

Benefit/risk

Adverse effect clinical relevance Drug inhaler Rx, ~mcg/day BDP without spacer 200 BDP with spacer 200 BUD MDI 200 BUD dry powder 100 FP 100

350 400 400 200 200

500 600 800 400 400

1,000 1,200 1,600 800 800

BDP, beclomethasone diproprionate; FP, fluticasone propionate

If sufficient amounts of a corticosteroid enter the systemic circulation, systemic side effects may develop. These include cataracts and glaucoma, thinning and bruising of the skin, suppression of the hypothalamic–pituitary– adrenal axis, and suppression of growth. With the exception of growth suppression, a risk has been reported mainly with the use of high ICS doses (eg, beclomethasone dipropionate equivalent [BDP] of >400 mcg/d). In contrast, a small degree of growth suppression has been observed at lower, more frequently used ICS doses.

41

Safety Considerations With ICS Therapy ƒ Local effects – Oropharyngeal effects ƒ oral candidiasis ƒ pharyngitis ƒ hoarseness/dysphonia

ƒ Systemic effects – – – – –

adrenocortical suppression changes in bone mineral density (BMD) and bone metabolism growth suppression ophthalmologic effects: cataracts and glaucoma skin thinning and bruising

Lipworth BJ. Arch Intern Med. 1999;159:941−955.

Of the systemic adverse effects that have been observed with ICS therapy, the potential for growth suppression remains the greatest concern in pediatric patients. This concern prompted the FDA to require class labeling for ICS agents in 1998, which garnered extensive media coverage and fueled the well-known “steroid phobia” so prominent in the United States. Although numerous studies have reported relevant data on ICSs and growth, many do not meet the criteria for well-designed prospective randomized controlled trials. Additional difficulties encountered in interpreting the results of these trials include the variable growth rates occurring throughout childhood and the variable methods (eg, stadiometry, knemometry) and end points (growth velocity, height percentiles, final adult height, markers of bone formation/absorption) used to assess growth effects in studies. Despite these limitations, several prospective randomized controlled studies showed that conventional doses of ICSs were associated with mean reductions in growth velocity of about 1 cm per year. The growth-retarding effects of ICSs are more pronounced at the beginning of treatment, and prepubescent children with mild asthma appear most susceptible to these effects. Growth retardation of from 0.9 to 1.5 cm per year has been observed with beclomethasone diproprionate and of about 0.5 cm per year with fluticasone proprionate. Dose-responsiveness of the growth effect has been observed.

42

Growth Suppression ƒ Growth supression can be assessed as a short-, intermediate-, or long-term effect ƒ ICSs, as a class, can affect growth in childhood – START study showed BUD causing growth retardation over 3-year period ƒ Year 1, 0.58 cm; year 2, 0.43 cm; year 3, 0.33 cm

– Effect is small and may not be sustained with long-term therapy

ƒ Adult height attained by children treated with ICSs is not different from that of nontreated individuals – However, steroid phobia may still affect the use of ICSs START, Inhaled Steroid Treatment as Regular Therapy in Early Asthma Pederson S, O’Byrne P. Allergy. 1997;52:1-34. Leone FT et al. Chest. 2003;124:2329-2340. Sheffer AL et al. Ann Allergy Asthma Immunol. 2005;94:48-54. Pauwels RA et al. Lancet. 2003;361(9363):1071-1076.

Growth suppression can be assessed as a short-, intermediate-, or long-term effect. ICSs can affect short-term growth in childhood. In the START (Steroid Treatment as Regular Therapy in Early Asthma) study, budesonide caused growth retardation over a 3-year period. However, the effect was small and may not be sustained with long-term therapy. Data indicate that the adult height attained by children treated with ICSs is no different from that of untreated individuals. However, steroid phobia may still affect the use of ICSs

43

Standing Height Velocity, cm/y

CAMP Study Growth Velocity With Budesonide— Lower In Year 1, Similar To Placebo In Years 2-4 Budesonide 200 mcg twice daily (n=311) Nedocromil 8 mg twice daily (n=312) Placebo (n=418)

6.5 6.0 5.5 5.0 4.5 0 0

1

2

3

4

Time, year All groups had similar growth velocity by the end of the treatment period. Adapted from The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054-1063. Allen DB et al J AllergyClin Immunol 2003;112:S1-S40.

Although the long-term CAMP (Childhood Asthma Management Program) study showed only transient effects of inhaled budesonide on growth velocity throughout 4 to 6 years of follow-up, it has been proposed that the return to normal growth velocity in this and other long-term studies of ICSs may be due to waning compliance over time. In the START study, a significant but waning effect on growth was observed in all 3 years of the study. Limited data support a lack of effect of long-term ICS use on final adult height, and this important information can be used in an office setting to illustrate safety and promote long-term adherence. Following the 1998 FDA meeting to review the growth effects of ICSs, a draft guidance was published regarding the conduct of future growth studies. Recommendations included the following characteristics: 1. a population that is prepubertal and has mild, persistent asthma; 2. a study design with at least a 1-year treatment period that includes an untreated control group, the collection of baseline growth velocity data, a follow-up period, and repeat stadiometer measurements; and finally 3. a study design that uses a regression analysis of growth velocity and total length with a 95% confidence interval of 0.5 cm or less as the primary outcome.

44

Change in Height Velocity, cm ± SE

Linear Growth Stadiometry Study In Prepubertal Asthmatic Children Effect Of Montelukast Versus Beclomethasone On Linear Growth Velocity

7 6 5

Montelukast 5 mg (n=120) Beclomethasone 400 mcg (n=119) Placebo (n=121)

4 3 2 1 0 –1 –2 –3 –19–16

–8

0

8

16

24

32

40

48

56

Run-in period

Weeks on Treatment Adapted from Becker AB et al. Ann Allergy Asthma Immunol. 2006;96:800-807.

Two growth studies that followed these recommendations were subsequently conducted. The published manuscript showed, not surprisingly, that beclomethasone did have an expected effect on growth and that montelukast did not affect growth. The other study, published as yet only in abstract form, showed no growth effect with ciclesonide, a new ICS. However, in a published short-term knemometry study, ciclesonide had no effect on the short-term lower leg growth rate in children with mild asthma.

45

The Risk Pyramid Safety of Inhaled Corticosteroids for Persistent Asthma in Children STEPPED-DOWN ICS DOSES RECOMMENDED ICS DOSES

> RECOMMENDED ICS DOSES ORAL CORTICOSTEROIDS (DAILY OR EVERY OTHER DAY) UNTREATED POORLY CONTROLLED DISEASE QUOTE: J.Z., a 14-year-old asthmatic patient with growth delay, told a local pediatric endocrinologist trying to change ICS to every other day: “I would rather be short than unable to play soccer.”

This slide shows the importance of evaluating risks versus rewards in the treatment of asthma with ICS.

46

Percentage of Peripheral to Total Airway Resistance Total Airway Resistance, %

% Peripheral Airway Resistance to

Importance Of Small Airways In Asthma

60 50 40

Inspiration Expiration

*P<.01 vs normals

* *

30 20 10 0

Normal

Group A FEV1 >80%

Group B FEV1<70%

Patients in Group A were asymptomatic (FEV1 >80% predicted without apparent airflow obstruction in preceding month and without therapy). Patients in Group B had FEV1 <70% predicted during a 12-month observation period, irrespective of treatment. Range of age at onset of asthma: 19 to 30 years. Duration: >20 years. Yanai M. J Appl Physiology. 1992;72:1016-1023.

As you can see from this slide, small airways contribute significantly to total airway resistance in many patients with asthma. Newer ICS formulations using hydrofluoroalkane (HFA) rather than chlorofluoroalkane (CFC) as a propellant have improved the delivery of drug to peripheral airways because of smaller particle size. Two newer ICS formulations have been developed: BDP and ciclesonide (mentioned previously, not yet available in the United States). With HFA solution inhalers, both lung deposition (55% for HFA vs 4% for CFC BDP) and oropharyngeal deposition (29% for HFA vs 94% for CFC BDP) are better. A recently published growth study comparing CFC and HFA BDP demonstrated comparable safety profiles. A growth study of HFA flunisolide has also been published. Clinical studies indicate that ICSs may reduce bone mass in adults and children, potentially increasing the risk for fracture later in life. However, long-term ICS use had no effect on bone mineral density in the CAMP study.

47

Novel ICS Strategies ƒ Use of biomarkers to adjust ICS dose ƒ ICS dosing as needed ƒ Single inhaler

Several novel strategies for the management of asthma with ICSs have been developed, including the following: the use of biomarkers (sputum eosinophils, level of airway hyperreactivity, fraction of exhaled nitric oxide [FENO]) to adjust the ICS dose, as-needed dosing of ICS therapy, singleinhaler therapy (including an ICS and a long-acting β2 agonist), and a new ICS (ciclesonide).

48

ƒ Patients with moderate to severe asthma (N=74) ƒ ICS treatment titrated according to British Thoracic Society (BTS) guidelines or sputum eosinophils ƒ Sputum eosinophils– guided therapy: 48% reduction in ICS therapy

Severe exacerbations, No.

Asthma Management (ICS) Guided By Sputum Eosinophils 120

BTS management group Sputum eosinophil management group

100 80 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12

Time, mo

Green RH et al. Lancet. 2002;360:1715-1721. Deykin Aet al. J Allergy Clin Immunol. 2005;115:720-727.

Overall ICS use similar: sputum eosinophilia identified subjects who needed ICS therapy and those who did not.

This slide summarizes a study showing the benefit of using sputum eosinophils to adjust ICS dose. In 74 patients with moderate to severe asthma, the ICS dose was titrated according to British Thoracic Society guidelines or sputum eosinophils. The result was a 48% reduction in the use of ICS therapy.

49

Monitoring Of FENO May Reduce Exacerbations Control group

Exacerbations, No.

40 35 30 25 20 15

FENO Group

10 5 0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time, mo FENO, fraction of exhaled nitric oxide Smith AD, et al. N Engl J Med. 2005;352:2163-2173.

In a single-blind, placebo-controlled trial, 97 patients with asthma who had been regularly receiving treatment with ICSs were assigned to have their corticosteroid dose adjusted according to either FENO measurements or an algorithm based on conventional guidelines. The rates of exacerbation were 0.49 episode per patient per year in the FENO group and 0.90 episode per patient in the control group. With the use of FENO measurements, maintenance doses of ICSs may be significantly reduced without compromising asthma control.

50

Role Of Intermittent Therapy Versus Standard Therapy In Mild Persistent Asthma IMPACT

Markers of Inflammation

Outcome

Regular Budesonide

As Needed Budesonide

Regular Zafirlukast

Morning PEF

+

+

+

Asthma exacerbation rates

+

+

+

FEV1 before β2 agonist

+

O

O

FEV1 after β2 agonist

O

O

O

Degree of asthma control

+

O

O

Number of symptom-free days

+

O

O

Quality of life

O

O

O

Nitric oxide (exhaled)

+

O

O

Sputum eosinophils

+

O

O

Bronchial hyperactivity (MCH PC20)

+

O

O

IMPACT, Improving Asthma Control Trial; MCH PC20, 20% fall in FEV1 on methacholine challenge; +, positive outcome; O, no significant change from baseline •Boushey HA et al. N Engl J Med. 2005;352:1519-1528.

• Rationale: Pharmacy records indicate that most patients use their medications less than recommended. • Study observed 225 adults with mild persistent asthma for 1 year. • Included individuals aged 18 to 65 years with physician-diagnosed mild persistent asthma and an FEV1 at least 70% of the predicted value (measured more than 4 hours after the most recent use of a bronchodilator). • Excluded patients smoked cigarettes, had had a respiratory tract infection or used corticosteroids in the previous 6 weeks, or had been hospitalized or made 2 or more visits to an emergency department for asthma treatment in the previous year. • Primary outcome of efficacy selected before the study was morning peak flow. Treating mild persistent asthma intermittently is effective if the morning peak flow is used as the efficacy end point. However, other clinical outcomes of asthma control demonstrate that regular budesonide is more effective than as-needed budesonide or regular zafirlukast. Other factors to consider are the following: • The patients in the study were adults. • The setting was rigid (ie, the patients were followed closely).

51

As Needed ICS For Mild Persistent Asthma IMPACT Kaplan-Meier Estimates of Time to a First Exacerbation of Asthma

Percentage Without Exacerbation

100 80 Daily BUD Daily zafirlukast Intermittent therapy

60

P=NS

40 20 P=0.39

0

0

100

200

300

400

Days Since Randomization There were no significant differences among the groups (P=0.39). Boushey HA et al. N Engl J Med. 2005;1519-1528.

Boushey et al conducted a double-blind trial in which 225 adults were randomized to symptom-based, as-needed administration of ICS monotherapy or to daily treatment with budesonide or zafirlukast. The primary outcome was morning peak expiratory flow PEF; other outcome measures included pulmonary function test results before and following bronchodilator treatment, degree of disease control, exacerbations, symptom-free days, and quality of life.

52

Single-Inhaler Therapy ƒ Poor control may be partly due to overreliance on β2-agonist reliever at expense of regular ICS ƒ Twelve-month randomized, double-blind, parallel-group study – BUD/FORM 80 mcg bid/4.5 mcg bid plus 80 mcg prn/4.5 mcg prn (BUD/FORM maintenance + relief) – BUD/FORM 80 mcg bid/4.5 mcg bid plus terbutaline 0.4 mcg prn (BUD/FORM + SABA) – BUD 320 mcg bid plus terbutaline 0.4 mcg prn (BUD + SABA) O’Byrne PM et al. Am J Respir Crit Care Med. 2005;171:129-136.

O’Byrne et al tested the hypothesis that in children and adults treated with a low maintenance dose of budesonide-formoterol, replacing a shortacting β2 agonist reliever with as-needed budesonide-formoterol would provide rapid symptom relief and a simultaneous adjustment in antiinflammatory therapy, thereby reducing exacerbations. They conducted a double-blind randomized parallel-group study in 2,760 patients with asthma who were treated with the scheme shown on the slide. Outcome measures included time to first exacerbation, pulmonary function test results, use of daily control measures, and safety.

53

CHALLENGES

Real-World Effectiveness Oral vs inhaled

Dose frequency

Onset of action

Effectiveness = Efficacy x Compliance “Does it work?”

“Can it work?” (eg, controlled clinical trial data)

Inhaler technique

Side effects

Perceived safety

The physician must choose from a wide array of medications that are recommended in the NAEPP guidelines and have been shown to be efficacious in clinical trials. However, the efficacy of a medication in the ideal setting of a controlled clinical trial, where compliance may be enhanced by high levels of patient and parent education and follow-up, may not translate into effectiveness in the real world. In clinical practice, compliance with medical therapy is complicated by a variety of issues, including route of administration (eg, oral vs inhaled therapy), side effects, cost, perception of safety, frequency of dosing, patient education, onset of action, and inhaler technique. An otherwise efficacious drug may not be fully effective if the patient does not take it in a compliant manner.

54

Compliance Is An Essential Component Of Asthma Control Poor compliance can lead to poor outcomes

Compliance, %

100 80

P=0.008

68.2%

60 40 13.7%

20 0

Children With Stable Asthma (n=16)

Children Requiring Oral Corticosteroid Rescue (n=8)

Adapted from Milgrom H et al. J Allergy Clin Immunol. 1996;98:1051-1057.

Poor compliance in this 13-week study was strongly correlated with loss of asthma control. Among the children who required oral corticosteroid rescue, only 13.7% adhered to their regimen, compared with a compliance rate of 68.2% among the children with stable asthma—that is, the children who did not require corticosteroid rescue (P=0.008). Of 8 children who required courses of oral corticosteroid during the study, 5 were among the least compliant, including 2 who were hospitalized. These findings suggest that inadequate control of asthma may reflect noncompliance, a problem that is widespread and not confined to obviously uncooperative patients.

55

Reported Adherence Rates (Outside Clinical Trials) ƒ Medication adherence rates for asthma patients range from 30% to 70% – For inhaled corticosteroids ƒ rates range from 63% to 93% ƒ underuse (about 40%) is more common than overuse (about 10%)

– In high-risk, inner-city adults by self-report ƒ among those prescribed inhaled corticosteroids—51% ƒ β2-agonists for quick relief—100% ƒ β2-agonists for long-term control—25% Bender B et al. Ann Allergy Asthma Immunol. 1997;79:177-186. Cochrane MG et al. Chest. 2000;117:542-550. Hyland ME. Drugs. 1999;58(suppl 4):1-6. Collier MC et al. Am J Respir Crit Care Med. 2001;163:A314. Abstract.

In asthma studies, adherence varies widely depending on the population being studied and the measures being analyzed. Most studies have focused only on medication use; very few have addressed monitoring of peak flow or avoidance of triggering factors. Bender and colleagues found that rates of adherence to asthma medications in general ranged from 30% to 70%. Among patients using ICSs, adherence rates are somewhat higher, but underuse is still more common than overuse. A recent study of high-risk, inner-city adults found that self-reported adherence to long-term controllers was very limited, although virtually all patients used short-acting β2 agonists.

56

Adherence To Inhaled Asthma Therapy Decreases Over Time Adults with moderate to severe asthma (N=50) treated with twice daily ICS Actuation of inhaler monitored electronically

75

Adherence, %

70 65 60 55 50 0

1

2

3

4

5

6

Week of Study Apter AJ et al. Am J Respir Crit Care Med. 1998;157:1810-1817.

Adherence to twice-daily ICS therapy in 50 adults with moderate to severe asthma was monitored electronically for 42 days. The mean adherence rate was 63%; 54% of patients recorded at least 70% of the prescribed number of ICS actuations. Factors associated with poor adherence included the following: • less than 12 years of formal education; • poor patient–clinician communication; • household income of less than $20,000; • non–English-speaking patient; and • minority status.

57

Correlates Of Adherence Patient/Parent Factors

Disease/Treatment Factors

– Monitoring of lung function – Willingness to use drug in daily practice – Belief in active participation with physician – Belief that asthma is serious – Perception that asthma is not well controlled – Good communication with caregiver and understanding of medical instructions

– Treatment satisfaction – Moderate or severe symptoms – Written instructions on correct use of inhalers

There are many barriers to adherence, but also many intervention points at which the healthcare team can enhance the likelihood of success. Because adherence varies across people and treatment components, and because intensive efforts to promote adherence involve a great deal of time, money, and special expertise, such efforts should concentrate on the patients who are likely to need them most. Special attention should be given to patients with psychological comorbidities, those with chaotic or dysfunctional lives, and those who feel unable to control their disease. Efficacious strategies of adherence promotion include simplifying the treatment regimen, tailoring therapy to patients’ needs and preferences, and achieving a balance between providing ongoing medical support and helping patients make appropriate decisions about their own care. Patient action plans that are straightforward and easy to follow promote concordance in a therapeutic relationship. The factors that drive adherence are complex and interdependent, involving not only the beliefs and attitudes of patients and their families but also the disease characteristics and treatment properties. In general, adherence is better when patients and their families view the disease as serious, when they trust that the intervention will help them, and when the treatments are relatively simple and convenient to use. Good communication with the caregiver and a clear understanding of medical directions also are correlates of adherence. These are enhanced by the use of written instructions.

58

Correlates Of Nonadherence Patient/Parent Factors – No routine for medication use – Younger age, non-white ethnicity, low socioeconomic status – Belief that adherence is difficult – Lack of healthcare insurance – Skepticism about treatment efficacy – Fear of adverse effects – Denial or underestimation of disease severity – Shame, anger, or rebellion – Forgetfulness or complacency

Disease/Treatment Factors – – – –

High cost or complexity of regimen Dislike of medications Mild or no symptoms Difficulty or inconvenience of using inhalers – Adverse effects or failure of previous treatments

Correlates or predictors of nonadherence include a lack of routine times for administration of drug, a belief that adherence is difficult or unlikely to control the disease, and a fear of adverse effects—including steroid phobia. Past experience with drugs that were ineffective or intolerable also tends to limit a patient’s willingness to comply fully with a new therapy. A patient with mild or no symptoms is less likely to adhere to the prescribed treatment regimen, especially if it is complex or costly. This is particularly relevant among patients without healthcare coverage. However, many patients may deny or underestimate the true severity of their disease. Among children and adolescents, this is often a consequence of embarrassment or anger regarding the disease or to simple forgetfulness. Before a medication is prescribed, patients should be asked explicitly about their willingness to use it on a daily basis. Many will admit that they expect it to be difficult or impossible.

59

Conclusions ƒ ICSs are much safer than systemic steroids but continue to carry small, dose-related, manageable risks for some children (especially those with mild disease) ƒ ICSs are the guideline-preferred monotherapy for asthma of all degrees of severity, but LTRAs are viable alternatives for some children with mild asthma ƒ ICSs (at high doses) may have a role in addressing airway remodeling, but more human studies are needed ƒ LABAs are preferred adjunctive agents in patients aged ≥12 years whose disease cannot be controlled with ICS monotherapy ƒ None of the currently available therapies have been shown to change the natural history of asthma, even when started early ƒ Novel approaches to using ICSs have recently been described, the generalizability of which to children is unknown

• ICSs are much safer than systemic steroids but continue to carry small, doserelated, manageable risks for some children (especially those with mild disease). • ICSs are the guideline-preferred therapy for asthma of all severities, but leukotriene receptor antagonists are viable alternatives for some children with mild asthma. • ICSs (at high doses) may have a role in addressing airway remodeling, but more studies in humans are needed. • None of the currently available therapies have been shown to change the natural history of asthma, even when started early. • Novel approaches to using ICS therapy have recently been described, but their generalizability to children is unknown.

60

Part III: Benefits and Limitations of Available Therapies and Devices in Pediatrics Nemr S. Eid, MD Professor of Pediatrics University of Louisville School of Medicine Louisville, Kentucky

PART III: BENEFITS AND LIMITATIONS OF AVAILABLE THERAPIES AND DEVICES IN PEDIATRICS By Nemr S. Eid, MD

61

Introduction ƒ Inhaled route is preferable ƒ It is a very complex process ƒ Challenges are great in pediatrics – – – –

pharmacokinetics pharmacodynamics Patient’s physical and cognitive abilities parental acceptance

The inhaled route of administration is accepted as the optimal means of drug delivery in the treatment of asthma. The choice of delivery device and inhaler technique are key factors that influence the effectiveness of inhaled medications. The delivery of nebulized medications to the lungs is a complex process that can be affected by many factors. Studies have shown that inhaled therapy in adult patients is associated with many mishaps and difficulties, and in infants and young children the challenges are far greater because of their anatomy, physiology, and cognition are not fully developed. Besides the pharmacokinetic and pharmacodynamic complexities, the patient’s physical and cognitive abilities and the parents’ understanding and willingness to use a particular inhalation device should be considered when asthma therapy is prescribed to children. Pressurized MDIs (metered dose inhalers) are by far the most commonly prescribed inhalers in the United States, yet nearly half of patients do not use them properly, resulting in poor therapeutic benefit. Clearly, therefore, new devices are urgently needed to address these deficiencies. This presentation reviews the devices available in the US marketplace and introduces a few that are in development.

62

Available Therapies And Devices Metered-dose Inhalers

ƒ MDIs were introduced in 1956 ƒ Performance depends on inhalation technique ƒ Use difficult because of poor inhalation-actuation coordination ƒ Misuse affects drug delivery ƒ Spacers and holding chambers alleviate, but do not eliminate, problems

The traditional MDI, which was approved by the FDA and marketed in 1956, remains the most commonly prescribed device for inhalation therapy. The primary factor influencing the clinical response to medications administered with an MDI is inhalation technique. However, this technique is difficult to execute properly, and research has shown that nearly 50% of patients who use an MDI do it incorrectly because they are unable to coordinate inhalation with device actuation. Observers first commented on the issue of poor inhalation–actuation coordination as far back as 1971, yet the MDIs have remained largely unchanged.

63

Evaluation Of MDI Technique

54

>1 error No error

447

Larsen JS et al. Asthma. 1994;31:193-199.

In a large study involving a total of 500 patients from different medical specialties, Larsen et al evaluated the patients’ technique in each step of MDI use that is needed for optimum delivery. Only 54 patients (10.7%) used their MDI correctly. The percentage of errors was staggering and occurred in almost every step. Pediatric patients are frequently prescribed an MDI in combination with a spacer or a holding chamber; for children younger than 5 years of age, a mask is usually attached to these devices. But with or without spacer devices, improper technique in the use of MDIs has been demonstrated in many adults and children.

64

Error Summary By Device 80

Aerolizer Autohaler

70 60

Diskus pMDI TBH

50 40 30 20 10 0

1 Error

Critical Error

PMDI, pressurized MDI; TBH, turbuhaler Molimard M et al. J Aerosol Med. 2003;16:249-254.

In a large real-life observational study, Molimard and colleagues evaluated inhaler handling in 3,811 patients for at least 1 month. The patients used an Aerolizer, Autohaler, Diskus pressurized MDI (pMDI) or a Turbuhaler device. Inhalation errors were considered critical if they could have substantially affected drug delivery to the lung. Of the patients using a pMDI, 76% made at least 1 error, compared to 49% to 55% of patients using a breath-actuated inhaler. Critical errors were made by 28% of patients treated with a pMDI.

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Improper Use Of MDI And Holding Chambers 60

pMDI

50

pMDI+HC

40 30 20 10 0 Shake

Exhale

Actuate

Inhale

Hold

Steps were performed improperly in both groups: those using an MDI and those using a pMDI+ HC HC, holding chamber Scarfone RJ et al. Arch Pediatr Adolesc Med. 2002;156:378-383.

Scarfone et al showed that similar percentages of children performed multiple steps improperly whether they used an MDI with (60/135, 44.4%) or without (33/73, 45.2%) a holding chamber. The steps performed improperly in the 2 groups were similar.

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Available Therapies And Devices Jet Nebulizers

ƒ Can be used with all classes of asthma medications ƒ Advantageous for young children and the elderly ƒ Suited for the administration of doses of drugs ƒ Can be used with supplemental oxygen ƒ Less portable than inhalers, require a power source ƒ Longer treatment time and substantial variability

A jet nebulizer delivery system consists of a nebulizer and a source of compressed air. Airflow to the nebulizer changes the liquid medication to a mist, which can be inhaled by the patient over 5 to 10 minutes through a mask or mouthpiece. Jet nebulizers can be used with all classes of asthma medications. They are particularly advantageous for young children and for the elderly because no hand–breath coordination is required. Furthermore, nebulizers are suitable for the administration of high doses of drugs, as in continuous albuterol nebulization, which is commonly used in emergency settings and intensive care units for patients with status asthmaticus. Nebulizers can also be used with supplemental oxygen. Jet nebulizers are less portable than inhalers and require a power source. Contamination is possible if the nebulizer components are not routinely cleaned according to the manufacturer’s recommendations. Other disadvantages of nebulizers include a longer treatment time than is required with inhalers and substantial variability between nebulizers due to output variance.

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Available Therapies And Devices Dry Powder Inhalers

ƒ The powder contains micronized drug particles ƒ Requires 30 to 120 L of inspiratory flow per minute, which affects particle size and velocity ƒ May be difficult for patients with severe bronchoconstriction and/or young children ƒ No need to coordinate device actuation with inhalation ƒ Environmentally friendly and relatively easy and convenient to use ƒ Studies continue to report countless critical mistakes with DPIs Molimard M et al. J Aerosol Med. 2003;16:249-254.

DPIs have been available for more than 30 years. In general, they create aerosols by drawing air through an aliquot of dry powder. The powder contains micronized drug particles that either form loose aggregates or are loosely bound to carrier particles (such as, lactose or glucose). Aggregates of drug particles are broken up or drug particles are stripped from carrier particles by the energy of inhalation. The inspiratory flow rate required to provide sufficient energy for this process ranges from 30 to 120 L/min. Patients with severe bronchoconstriction and/or young children may find it difficult to inhale “hard” enough to achieve optimal lung deposition when they use devices requiring a high inspiratory flow rate. The ban on CFC propellants in MDIs, along with an increasing recognition of the limitations associated with MDI use, has resulted in an increased development of DPIs during the past decade. DPIs preclude the need to coordinate device actuation with inhalation. They are environmentally friendly, and are relatively easy and convenient to use.

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Error Summary By Device 80 Aerolizer Autohaler

70 60

Diskus pMDI TBH

50 40 30 20 10 0

1 Error

Critical Error

Molimard M. J Aerosol Med. 2003;16:249-254.

However, despite these developments, studies continue to report countless critical mistakes with DPIs. In a large, real-life clinical study previously mentioned, Molimard et al showed the error rate in adults using a DPI to be about 50%.

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Available Therapies And Devices New Nebulizers

ƒ ƒ ƒ ƒ ƒ ƒ

Offer a marked improvement in pulmonary drug targeting Generate aerosol only during inhalation Shorter time required for drug delivery Relatively quiet No need to add diluents to the active drug solution Three major categories are used – modified piezoelectric (vibrating mesh or aperture plate technology) – high-pressure microspray technology – electrohydrodynamic or electrostatic spray technology

Rau JL. Respir Care. 2005;50:367-382.

Nebulizer technology continues to evolve, as evidenced by several models that are being or have been developed. These new devices are more portable and offer a marked improvement in the efficiency of pulmonary drug targeting. Most of the new and efficient nebulizers are breath-actuated “dosimeters” that generate aerosol and make it available only during inhalation. These devices nebulize drug at a higher rate (0.3-0.6 mL/min), so that a shorter time is required for drug delivery. They are relatively quiet, and very little, if any, drug remains within them at the end of treatment, so that the need to add diluents to the active drug is eliminated.The newer nebulizers fall into 3 major technologic categories: (1) In the modified piezoelectric (sometimes referred to as vibrating mesh or aperture plate) technology, a low-velocity aerosol of fine particles is generated with low-frequency (180-KHz) vibration; a horn or crystal transducer pushes medication through a metal alloy mesh plate with more than 6,000 holes. (2) In high-pressure microspray technology, liquid is forced through a nozzle to form aerosol clouds. (3) In electrohydrodynamic or electrostatic spray atomization, the dispersion of liquid relies solely on its electric charges.

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Available Therapies And Devices New MDI Aerosols

ƒ New technology fostered by the elimination of CFC propellent and the advent of HFA ƒ HFA drug formulations in solution are emitted as extrafine aerosols ƒ Fine particles of ≤2 mcg have been shown to penetrate more effectively into the peripheral regions of the lung

CFC, chlorofluoroalkane; HFA, hydrofluoroalkane propellant

The elimination of chlorofluroalkane CFC propellant from MDIs and the advent of HFA propellant have made it possible to more optimally target ICSs directly at all inflammatory sites of the asthmatic lung. This shift of pulmonary deposition occurred because HFA drug formulations that are in solution are emitted as extra-fine aerosols. Fine particles of 2 micron have been shown to penetrate more effectively into the peripheral regions of the lung.

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Distribution Of BDP Particle Size In CFC Suspension And HFA Solution Percentage Total Delivered

70 60

Pulmonary

Oropharyngeal

50 40

HFA BDP CFC BDP

30 20 10

0 3 .0 .7 .0 .8 65 1.1 . 2.1 - 3. 10 -4 7-5 8-9 - 0 .65 1 3 3 0 0 2. 4. 5. 1.1 3. 0.4 9.

>1

0

at ro h T

Particle Size, µm Data from Andersen Cascade Impactor. Leach CL. Respir Med. 1998;92:3-8.

The HFA BDP inhaler reverses the pattern of deposition of the old CFC BDP product. The HFA BDP inhaler delivers approximately 60% of drug to the lungs, compared with less than 10% of the CFC BDP counterpart.

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Deposition As A Function Of HFA BDP Inhaler Coordination On time

70

Deposition, %

60

58

Early

Late

57

50 40

43 34 32

30

31 26

26 24

24

20

13

10

8

0 Lung*

Oropharynx

* Lung was divided into central, intermediate, and peripheral regions. Leach CL et al. Aerosol Med. 2005;18:379-385.

Exhaled

Relative Peripheral*

Even with suboptimal coordination of the patient in using the inhaler, more than 30% of BDP is deposited within the lungs, and and distribution is even within the lungs. The HFA BDP inhaler is FDA-approved for the treatment of asthma in children 5 years of age and older. Inhalers in development administer other drugs that have similar aerosol characteristics in HFA solution: triamcinolone acetonide, flunisolide, and ciclesonide. None has yet been approved by the FDA.

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Available Therapies And Devices New Dry Powder Inhalers

ƒ Reduce dosing variability and are not dependent on inspiratory flow rate ƒ Two types – reservoir DPI containing an active-metering cycloneseparator technology system – aerosolization chamber with inspiration-actuated, battery-powered, twin blade impeller to generate aerosol cloud

Newman SP. Expert Opin Biol Ther. 2004;4:23-33. Hirst RH et al. Respir Med. 2002;96:389-396. Keating GM et al. Drugs. 2002;62:1887-1895. Nelson H et al. Chest. 1999;115:329-335.

Most of the DPIs available today are “reservoir” devices—that is, the dry powder is contained within a cartridge and measured at the time of dosing; in other types of DPIs, the powder is contained within capsules or blister packs. Some of the new reservoir DPIs in development promise to be more practical and cost-effective systems for asthma therapy because they reduce the dosing variability seen with other DPI systems and are not so dependent on inspiratory flow rates. For example, a new DPI—not currently on the market in the United States—is a reservoir DPI that contains an active-meter cyclone separator technology system. An internal pump measures the drug dose by means of controlled air pressure. Inhalation transports the drug into the cyclone separator, where it is removed from the lactose carrier, and then into the airway. Studies have shown that deposition of BDP in the lungs with this DPI is relatively independent of the inhalation efforts of patients, and that dosing variability is reduced. Another, similar DPI, designed to function more independently of the patient’s inspiratory effort, features an aerosolization chamber containing an inspiration-actuated, battery-powered, twin-blade impeller to generate the aerosol cloud. This design is being studied with micronized albuterol sulfate and is still under development.

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Available Therapies And Devices New Breath-operated Inhalers

ƒ Improved ease of use ƒ Breath-actuated

Facilitating the use of inhalation devices, specifically MDIs, through technologic advances was the primary reason for the development of breath-operated inhalers (BOIs). A BOI obviates the need for hand–breath coordination because it automatically releases a spray of medication when the patient begins to inhale through the mouthpiece at a low inspiratory rate (about 20 L/min). Two breathoperated inhaler devices are available, although only 1 has been approved in the United States. The introduction of this device in the United States for the delivery of CFC-free albuterol will address several of the issues associated with currently available asthma therapies: ease of use and efficacy, patient and physician preferences, and cost-effectiveness. Furthermore, Phase III clinical trials are currently under way in the United States to assess the safety and efficacy of administering CFC-free BCP in a new delivery system. If approved, this product will have the added advantage of offering rescue and maintenance medications in 1 type of device.

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Cost-effectiveness Of New Devices ƒ Direct and indirect costs associated with asthma – poor control of asthma – underuse or incorrect use of available therapies

ƒ Preferred devices by patients and medical providers – increase compliance

Newer devices tend to be more expensive than traditional MDIs. However, most of the direct and indirect costs associated with asthma are the result of poor control of the disease, indicating that currently available therapies are either underused or used incorrectly. If the new devices are cost-effective and are preferred by patients and medical providers, as some of the recent studies have clearly shown, then the benefit would outweigh the cost. An ideal inhaler would be well accepted by patients, and this might facilitate compliance.

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Inhaler Use Assessment In Patients With Airflow Obstruction ƒ MDIs used by 100 patients (22-88 years old) ƒ Referred from inside and outside hospital ƒ Seven devices assessed in random order ƒ Pre-established criteria ƒ Assessment of inhaler technique and inhaler preference

Lenney J et al. Respir Med. 2000;94:496-500.

In 1 study designed to assess patients’ preferences regarding different inhaler devices, 100 patients were instructed, in randomized order, in the use of 7 different inhaler devices. After instruction, they were graded (with predetermined criteria) on their inhaler technique. After the assessment, patients were asked which 3 inhalers they most preferred and which, if any, they currently used.

77

Inhaler Use Assessment In Patients With Airflow Obstruction Device

Optimal Technique, %

Poor Technique, %

Very Poor Technique, %

pMDI

79

6

15

pMDI+spacer

87

6

7

EasiBreathe

91

5

4

Autohaler

91

3

6

Turbuhaler

87

3

10

Accuhaler/Diskus

90

4

6

Clickhaler

90

4

6

Lenney J et al. Respir Med. 2000;94:496-500.

Easi-Breathe, a new BOI, was by far the most popular device with the patients; 91% of patients demonstrated good technique with a BOI versus 79% with an MDI. This was despite the fact that 55% of the patients in the study had been using an MDI before study enrollment and had received further instruction on proper technique at enrollment in the study. Moreover, approximately 65% of the patients in this study preferred the Easi-Breathe inhaler to all other devices studied.

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Aerosol Delivery Device Selection Criteria

ƒ Drug availability, delivery mechanism ƒ Patient age, clinical setting, compliance ƒ Reimbursement/cost ƒ Patient/clinician preferences

Dolovich MB et al. Chest. 2005;127:335-371.

Choosing an aerosol system from among the many newer systems as they become available will require careful selection. Healthcare providers who are treating children with asthma often encounter difficulties in devising effective management plans. Indeed, the challenges that these healthcare providers face is that few drugs and devices are approved for the very young. Often, they have to use their imagination and translate the findings of adult studies into pediatric practice. At other times, they must apply the knowledge gained in administering 1 drug in a certain way to the administration of another, totally different class of medication given in a different way. A recently published evidence-based review of inhalation devices recommended an algorithm, which can be helpful in making a selection. The clinician should consider the following questions when selecting the appropriate device:

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Selecting An Aerosol Delivery Device ƒ In what device(s) is the desired drug available? ƒ Keeping in mind the age of the patient and the clinical setting, what device(s) is the patient likely to be able to use properly? ƒ For which device(s) is reimbursement available? ƒ Which device(s) is least costly? ƒ Can all types of inhaled asthma drugs prescribed for the patient be delivered with the same type of device? ƒ Does the patient or clinician have any specific device preferences? Dolovich MB et al. Chest. 2005;127:335-371.

1. In what device(s) is the desired drug available? 2. Keeping in mind the age of the patient and the clinical setting, what device(s) is the patient likely to be able to use properly? 3. For which device(s) is reimbursement available? 4. Which device(s) is least costly? 5. Can all types of inhaled asthma drugs prescribed for the patient be delivered with the same type of device? 6. Does the patient or clinician have any specific preferences regarding devices?

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Selecting An Aerosol Delivery Device ƒ Healthcare providers caring for children with asthma should continue to challenge industry to make devices whose use in the young age group is more intuitive ƒ They should also continue to lobby industry to study drug safety and efficacy in the very young

Healthcare providers caring for children with asthma should continue to challenge industry to make devices whose use in the very young is more intuitive. They should continue also to lobby industry to study drug safety and efficacy in the very young.

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