Several studies identified candidate genes in a pathway that initiates type 2 helper T-cell (Th2) inflammation in response to epithelial damage and points to other candidate genes that may act in a pathway that down-regulates airway inflammation and remodeling. Our study also shows that asthma is heterogeneous: later-onset cases are influenced more by the MHC (major histocompatibility complex) than are childhood-onset cases. There is a

SNPs at the chromosome 17q21 locus associated with asthma are also strongly associated with variation in the

The locus chromosome at 2, implicating 1L1RL1 and IL 18R1 is also associated with asthma. The effect at this locus has been attributed to IL 1RL1 (encoding the receptor for interleukin) 6 and synergizes with IL 12 to induce the production of interferon-y and to promote Th1 responses. The expression of IL 18R1 is also concentrated

SMAD3 is a transcriptional modulator activated by transforming growth factor β, a polypeptide that controls

HLA-DQ was the first identified asthma susceptibility locus. Extended haplotypes encompassing HLA-DQ and HLA-DR have been studied for their effects on specific allergen sensitization and on the formation of tumor

Two other genes, SLC22A5 and RORA. SLC22A5 encodes a carnitine transporter and, like ORMDL3/GSDMB

proliferation, differentiation, and other functions in many cell types, including regulatory T cells. 40

Evidence suggests that the prevalence of asthma is less in children who experience:

Certain infections (Mycobacterium tuberculosis, measles, or hepatitis A)

cytokine dysregulation in which Th1 activity in asthma is diminished .

strong and specific effect of the chromosome 17q locus on childhood-onset disease.37

There is an association between SNPs flanking IL33 on chromosome 9 and atopic asthma. 38

Less frequent use of antibiotics

Th2 cytokine pattern (Allergy).

capable of generating IgE, and sensitization.34

**5. Genetic factors and asthma**

**Genetic Factors**

medications) and health care utilization. 35

now been replicated in several populations.

expression of ORMDL3 and GSDMB.

within the respiratory epithelium.39

and IL18R1/IL1RL1.41

necrosis factor and related gene products.

childcare) Rural living Cluster 2 comprises mostly older obese women with late-onset non-atopic asthma, moderate reductions in pulmonary function, and frequent oral corticosteroid use to manage exacerbations. Cluster 3 and cluster 4 patients have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids. 36

#### **6. Specific and non-specific triggers**

Specific immune-response to triggers entails 2 types of bronchoconstrictor responses to allergens: early and late. 42

Early asthmatic responses occur via IgE-induced mediator release from mast cells within minutes of exposure and last for 20-30 minutes. 43-45

Late asthmatic responses occur 4-12 hours after antigen exposure and result in more severe symptoms that can last for hours and contribute to the duration and severity of the disease. Inflammatory cell infiltration and inflammatory mediators play a role in the late asthmatic response. Allergens can be foods, household inhalants (eg, animal allergens, molds, fungi, cockroach allergens, dust mites), or seasonal outdoor allergens (eg, mold spores, pollens, grass, trees).

Non-specific response e.g. tobacco smoke, cold air, chemicals, perfumes, paint odors, hair sprays, air pollutants, and ozone can initiate BHR by inducing inflammation. 9

Sudden changes in ambient temperature, barometric pressure, and the quality of air (eg, humidity, allergen and irritant content) can also induce asthma exacerbations.10

Exercise can trigger an early asthmatic response. Different mechanisms are hypothesized to play a role. Heat and water loss from the airways can increase the osillolarity of the fluid lining the airways and result in mediator release. Cooling of the airways results in congestion and dilatation of bronchial vessels. During the rewarming phase after exercise, the changes are magnified because the ambient air breathed during recovery is warm rather than cool.

Emotional factors are sometimes incriminate to trigger asthma exacerbation (stress, emotional upsets a.o.)

Management of Asthma in Children 155

control of the respiratory drive may be present, particularly in patients with a defective

Wheezing, cough and dyspnea are worse during the late night and early morning hours3. Most dyspneic episodes occurring nocturnally, with a 50-fold increase in the number of attacks between 4 am and 5 am compared with the number of attacks between 4 pm and 5 pm.4 Objective indicators of disease severity correlate closely with subjective dyspnea PEFR begins declining rapidly at midnight, and at 4 am is between 8% and 40% below its mean 24-hour value at 9 am. The PEFR then increases sharply and reaches its mean 24 hour value at 8 am.5 Normal subjects also show circadian changes in airflow, with mild nocturnal bronchoconstriction, although

The pathophysiology of nocturnal asthma exacerbation is not completely understood and appears to be multifactorial. Plasma cortisol levels vary markedly, reaching a nadir at midnight and peaking at 8 am. Serum histamine levels peak dramatically at about 4 am, dropping to baseline levels by 8 am. Plasma cyclic AMP(cAMP) levels reaches a nadir at 4 am, as do the density and responsiveness of beta-adrenergic receptors located on circulating leukocytes. A nocturnal increase in vagal tone has been described. All of these factors appear to play a role in destabilizing the inflammatory environment of the airways at night. Additionally, sleepinduced oxygen dessaturation, gastroesophageal reflux, and body temperature decline during sleep may all

The circadian nature of asthma has led to the argument that nocturnal presentation of asthma is marker of more severe disease, warranting more aggressive therapy and lower threshold for hospitalization than for other asthmatic patients. Data demonstrating increased asthma mortality between midnight and 4 am, although limited to inpatient settings, appear to support this argument. However, some studies of asthmatic patients in the emergency department failed to validate this hypothesis. Several studies however demonstrate no significant

disease severity between asthmatic patients who presented during late night/early-morning hours.58-56

It is well known that there is a circadian variation in asthma severity and exacerbation.

the variation is far less pronounced than that seen in asthmatic subjects.52

predispose to nocturnal airway hyperresponsiveness.55-53

Children with mild asthma who are asymptomatic between attacks are likely to improve

Children with asthma appear to have less severe symptoms as they enter adolescence, but half of these children continue to have asthma. Asthma has a tendency to remit during puberty, with a somewhat earlier remission in girls. However, compared with men, women have more BHR. 59 Of infants who wheeze with URTls, 60% are asymptomatic by age 6 years. However, children who have asthma (recurrent symptoms continuing at age 6 years) have airway reactivity later in childhood. Some findings suggest a poor prognosis if asthma develops in children younger than 3 years, unless it occurs solely in association with viral infections. 60-62 Individuals who have asthma during childhood have significantly lower forced expiratory volume in 1 second (FEV1), higher airway reactivity, and more persistent bronchospastic

Patient and parent on how to use medications and devices (eg, spacers, nebulizers, metereddose inhalers [MDls]). The patient's MOl technique should be assessed on every visit.63

Instruction should also includes the use of medications, precautions with drug and/or device usage, monitoring symptoms and their severity (peak flow meter reading), and

hypoxic drive and obstructive sleep apnea. 51

**10. Asthma outcome**

**11. Patient education**

and be symptom-free later in life.

symptoms than those with infection-associated wheezing.

**11.1 Pediatrician and/or asthma educator should instruct**

identifying potential adverse effects and necessary actions. 64

#### **7. Gastroesophageal reflux**

The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can significantly increase airway resistance and airway reactivity.

#### **8. Upper respiratory tract: conditions**

Inflammatory conditions of the upper airways (eg, allergic rhinitis, sinusitis, or chronic and persistent infections) must be treated before asthmatic symptoms can be completely controlled.

#### **9. Circadian rhythm**

Circadian variation in lung function and inflammatory mediator release in the circulation and airways (including parenchyma) have been demonstrated to explain nocturnal asthma. Other factors, such as allergen exposure and posture-related irritation of airways (eg, gastroesophageal reflux, sinusitis), can also play a role. In some cases, abnormalities in CNS

The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can

Inflammatory conditions of the upper airways (eg, allergic rhinitis, sinusitis, or chronic and persistent infections) must be treated before asthmatic symptoms can be completely

Circadian variation in lung function and inflammatory mediator release in the circulation and airways (including parenchyma) have been demonstrated to explain nocturnal asthma. Other factors, such as allergen exposure and posture-related irritation of airways (eg, gastroesophageal reflux, sinusitis), can also play a role. In some cases, abnormalities in CNS

**7. Gastroesophageal reflux**

controlled.

**9. Circadian rhythm**

**8. Upper respiratory tract: conditions**

significantly increase airway resistance and airway reactivity.

control of the respiratory drive may be present, particularly in patients with a defective hypoxic drive and obstructive sleep apnea. 51

It is well known that there is a circadian variation in asthma severity and exacerbation.

Wheezing, cough and dyspnea are worse during the late night and early morning hours3. Most dyspneic episodes occurring nocturnally, with a 50-fold increase in the number of attacks between 4 am and 5 am compared with the number of attacks between 4 pm and 5 pm.4 Objective indicators of disease severity correlate closely with subjective dyspnea PEFR begins declining rapidly at midnight, and at 4 am is between 8% and 40% below its mean 24-hour value at 9 am. The PEFR then increases sharply and reaches its mean 24 hour value at 8 am.5 Normal subjects also show circadian changes in airflow, with mild nocturnal bronchoconstriction, although the variation is far less pronounced than that seen in asthmatic subjects.52

The pathophysiology of nocturnal asthma exacerbation is not completely understood and appears to be multifactorial. Plasma cortisol levels vary markedly, reaching a nadir at midnight and peaking at 8 am. Serum histamine levels peak dramatically at about 4 am, dropping to baseline levels by 8 am. Plasma cyclic AMP(cAMP) levels reaches a nadir at 4 am, as do the density and responsiveness of beta-adrenergic receptors located on circulating leukocytes. A nocturnal increase in vagal tone has been described. All of these factors appear to play a role in destabilizing the inflammatory environment of the airways at night. Additionally, sleepinduced oxygen dessaturation, gastroesophageal reflux, and body temperature decline during sleep may all predispose to nocturnal airway hyperresponsiveness.55-53

The circadian nature of asthma has led to the argument that nocturnal presentation of asthma is marker of more severe disease, warranting more aggressive therapy and lower threshold for hospitalization than for other asthmatic patients. Data demonstrating increased asthma mortality between midnight and 4 am, although limited to inpatient settings, appear to support this argument. However, some studies of asthmatic patients in the emergency department failed to validate this hypothesis. Several studies however demonstrate no significant disease severity between asthmatic patients who presented during late night/early-morning hours.58-56

#### **10. Asthma outcome**

Children with mild asthma who are asymptomatic between attacks are likely to improve and be symptom-free later in life.

Children with asthma appear to have less severe symptoms as they enter adolescence, but half of these children continue to have asthma. Asthma has a tendency to remit during puberty, with a somewhat earlier remission in girls. However, compared with men, women have more BHR. 59

Of infants who wheeze with URTls, 60% are asymptomatic by age 6 years. However, children who have asthma (recurrent symptoms continuing at age 6 years) have airway reactivity later in childhood. Some findings suggest a poor prognosis if asthma develops in children younger than 3 years, unless it occurs solely in association with viral infections. 60-62

Individuals who have asthma during childhood have significantly lower forced expiratory volume in 1 second (FEV1), higher airway reactivity, and more persistent bronchospastic symptoms than those with infection-associated wheezing.

#### **11. Patient education**

#### **11.1 Pediatrician and/or asthma educator should instruct**

Patient and parent on how to use medications and devices (eg, spacers, nebulizers, metereddose inhalers [MDls]). The patient's MOl technique should be assessed on every visit.63

Instruction should also includes the use of medications, precautions with drug and/or device usage, monitoring symptoms and their severity (peak flow meter reading), and identifying potential adverse effects and necessary actions. 64

Management of Asthma in Children 157

Vascular rings are unusual congenital anomalies that occur early in the development of the aortic arch and great vessels. The primary symptomatology associated with vascular rings relates to the structure that are encircled by the ring, chiefly the trachea, large

anomal

Cystic fibrosis; chronic lung disease of prematurity; ciliary dyskinesia; developmental

Cystic fibrosis; bronchiectasis; protracted bronchitis; recurrent aspiration; host defence

syndrome; bronchiectasis; tuberculosis

disorder; ciliary dyskinesia

gastroesophageal

with parental smoking

PERINATAL AND FAMILY HISTORY POSSIBLE DIAGNOSIS

Family history of unusual chest disease Cystic fibrosis; neuromuscular disorder Severe upper respiratory tract disease Defect of host defence; ciliary dyskinesia

Excessive vomiting Gastroesophageal reflux (+-aspiration) Dysphagia Swallowing problems (+- aspiration)

Focal signs in chest Developmental anomaly; post-infective

Failure to thrive Cystic fibrosis; host defense disorder;

Transient infant wheezing Onset in infancy; no associated atopy associated

peripheral tingling Hyperventilation/panic attacks Inspiratory stridor Tracheal or laryngeal disorder

Finger clubbing Cystic fibrosis; bronchiectasis

Abnormal voice or cry Laryngeal problem

Inhaled foreign body Suddent onset

Continuous or intermittent

 Environmental allergens Changes in weather

Irritants (eg, smoke exposure, chemicals, vapors, dust)

Home environment (eg, carpets, pets, mold)

Gastroesophageal reflux disease (GERD)

Symptoms present from birth or perinatal

Breathlessness with light-headedness and

Drugs (eg, aspirin, beta blockers)

 Exercise Viral infections

 Emotions Stress Foods

 Rhinitis Sinusitis

Thyroid disease

lung problem

Symptoms and signs

Persistent moist cough

Other conditions

airways and esophagus.

Parents should understand that asthma is a chronic disorder with acute exacerbations; hence, continuity of management with active participation by the patient and/or parents and interaction with asthma care medical personnel is important. Adherence to treatment is the key to full control of symptoms including nocturnal and exercise-induced symptoms. Emphasize the importance of adherence to treatment.65

Parents caregiver and teachers should expect the child to participate in recreational activities and sports and to attend school as usual. 66

### **12. Differential diagnoses**

#### **12.1 Problems to be considered include the following**

### **13. Clinical presentation**

#### **13.1 History is very important in asthma the clinician should confirm**

Obtaining a good patient history is crucial when diagnosing asthma and excluding other causes, symptoms, aggravating factors and co-existing conditions should be asked.

Parents should understand that asthma is a chronic disorder with acute exacerbations; hence, continuity of management with active participation by the patient and/or parents and interaction with asthma care medical personnel is important. Adherence to treatment is the key to full control of symptoms including nocturnal and exercise-induced symptoms.

Parents caregiver and teachers should expect the child to participate in recreational activities

Emphasize the importance of adherence to treatment.65

**12.1 Problems to be considered include the following**

**13.1 History is very important in asthma the clinician should confirm**

Obtaining a good patient history is crucial when diagnosing asthma and excluding other

causes, symptoms, aggravating factors and co-existing conditions should be asked.

Airflow obstruction or symptoms are at least partially reversible

Episodic symptoms of airflow obstruction are present

and sports and to attend school as usual. 66

**12. Differential diagnoses**

 Vocal cord dysfunction Tracheobronchomalacia Pulmonary edema Gastroesophageal Reflux Bronchopulmonary Dysplasia

 Aspiration Syndromes Airway Foreign Body Allergic Rhinitis Aspergillosis Cystic Fibrosis

Primary Ciliary Dyskinesia 67

Alternative diagnoses are excluded

Cough at night or with exercise

 Perennial, seasonal, or both Daytime or nighttime

**13. Clinical presentation**

Shortness of breath

 Chest tightness Sputum production Onset and duration

 Cough Wheezing

Vascular ring

Bronchiectasis

Vascular rings are unusual congenital anomalies that occur early in the development of the aortic arch and great vessels. The primary symptomatology associated with vascular rings relates to the structure that are encircled by the ring, chiefly the trachea, large airways and esophagus.

Management of Asthma in Children 159

Auscultation of chest reveals moderate wheezing, which is often end expiratory

The heart rate is less than 100 beats per minute

**13.3 Moderately severe asthma include the following**

Accessory muscles of respiration typically are used

 Pulsus paradoxus may be present (10-20 mm Hg) Oxyhemoglobin saturation with room air is 91-95%

 Accessory muscles of respiration are usually used Suprasternal retractions are commonly present The heart rate is greater than 120 beats per minute

Pulsus paradoxus is often present (20-40 mm Hg)

**13.5 Status asthmaticus may include the following**

Severe hypoxemia may manifest as bradycardia

may be the only abnormality in a child with mild disease.

Paradoxical thoracoabaominal movement

**14. Workup**

using oscillometry is applied.

Oxyhemoglobin saturation with room air is greater than 95%

The respiratory rate is often greater than 30 breaths per minute

Loud biphasic (expiratory and inspiratory) wheezing can be heard

Wheezing may be absent (in patients with the most severe airway obstruction)

Pulsus paradoxus may disappear; this finding suggests respiratory muscle fatigue

Spirometry is indicated in children >6 years, as younger children < 6 years are unable to perform spirometry, unless modern techniques such as measurement of airway resistance

In a typical case, an obstructive defect is present in the form of normal forced vital capacity (FVC), reduced forced expiratory volume in 1 second (FEV1), and reduced forced expiratory flow more than 25-75% of the FVC (FEF 25-75). The flow-volume loop can be concave. Documentation of reversibility of airway obstruction after bronchodilator therapy is essential to the definition of asthma. FEF 25-75 is a sensitive indicator of obstruction and

In an outpatient or office setting, measurement of the peak flow rate by using a peak flow

meter can provide useful information about obstruction in the large airways.

Oxyhemoglobin saturation with room air is less than 91 %.

Pulsus paradoxus is not present

 Suprasternal retractions are present The heart rate is 100-120 beats per minute Loud expiratory wheezing can be heard

**13.4 Severe asthma include the following:**

Increased respiratory rate

The family history should include any history of asthma, allergy, sinusitis, rhinitis, eczema, or nasal polyps in close relatives, and the social history should cover factors that may contribute to non adherence of asthma medications, as well as any illicit drug use.68-72

Physical findings vary with the absence or presence of an acute episode and its severity.

A patient with mild asthma may have normal findings on physical examination. Patients with more severe asthma are likely to have signs of chronic respiratory distress and chronic hyperinflation.

Signs of atopy or allergic rhinitis, such as conjunctival congestion and inflammation, allergic shiners, a transverse crease on the nose due to constant rubbing associated with allergic rhinitis, and pale nasal mucosa covered with transparent mucus due to allergic rhinitis, may be present.

The anteroposterior diameter of the chest may be increased because of hyperinflation. Hyperinflation may also cause an abdominal breathing pattern.

Lung examination may reveal prolonged expiratory phase, expiratory wheezing, coarse crackles, or unequal breath sounds.

Clubbing of the fingers is not a usual feature of asthma and indicates a need for more extensive evaluation and work-up to exclude other conditions, such as cystic fibrosis. 73-77

A child with an acute episode may reveal different findings in mild, moderately severe, and severe episodes and in status asthmaticus with imminent respiratory arrest.

#### **13.2 Mild episode asthma reveals**

Differential Diagnosis of Asthma in Children 5 years and younger

Recurrent Respiratory tract infections

Chronic rhino-sinusitis

Bronchopulmonary dysplasia

Primary ciliary dyskinesia syndrome

 Tuberculosis. Congenital problems:

> Tracheomalacia Cystic Fibrosis

 Immune deficiency Congenital heart disease

*Adopted from GINA Guide 2011*

 Foreign body aspiration Gastroesophageal reflux

Mechanical Problems

The family history should include any history of asthma, allergy, sinusitis, rhinitis, eczema, or nasal polyps in close relatives, and the social history should cover factors that may contribute to non adherence of asthma medications, as well as any illicit drug use.68-72 Physical findings vary with the absence or presence of an acute episode and its severity.

Congenital malformation causing narrowing of the intratoracic airways.

A patient with mild asthma may have normal findings on physical examination. Patients with more severe asthma are likely to have signs of chronic respiratory distress and chronic

Signs of atopy or allergic rhinitis, such as conjunctival congestion and inflammation, allergic shiners, a transverse crease on the nose due to constant rubbing associated with allergic rhinitis, and pale nasal mucosa covered with transparent mucus due to allergic rhinitis, may be present. The anteroposterior diameter of the chest may be increased because of hyperinflation.

Lung examination may reveal prolonged expiratory phase, expiratory wheezing, coarse

Clubbing of the fingers is not a usual feature of asthma and indicates a need for more extensive evaluation and work-up to exclude other conditions, such as cystic fibrosis. 73-77

A child with an acute episode may reveal different findings in mild, moderately severe, and

severe episodes and in status asthmaticus with imminent respiratory arrest.

Hyperinflation may also cause an abdominal breathing pattern.

hyperinflation.

Infections:

crackles, or unequal breath sounds.

**13.2 Mild episode asthma reveals**

Increased respiratory rate

Accessory muscles of respiration are not used

#### **13.3 Moderately severe asthma include the following**

#### **13.4 Severe asthma include the following:**

#### **13.5 Status asthmaticus may include the following**

#### **14. Workup**

Spirometry is indicated in children >6 years, as younger children < 6 years are unable to perform spirometry, unless modern techniques such as measurement of airway resistance using oscillometry is applied.

In a typical case, an obstructive defect is present in the form of normal forced vital capacity (FVC), reduced forced expiratory volume in 1 second (FEV1), and reduced forced expiratory flow more than 25-75% of the FVC (FEF 25-75). The flow-volume loop can be concave. Documentation of reversibility of airway obstruction after bronchodilator therapy is essential to the definition of asthma. FEF 25-75 is a sensitive indicator of obstruction and may be the only abnormality in a child with mild disease.

In an outpatient or office setting, measurement of the peak flow rate by using a peak flow meter can provide useful information about obstruction in the large airways.

Management of Asthma in Children 161

to document airway hyper-responsiveness to substances (eg, methacholine, histamine). Increasing doses of provocation agents are given, and FEV1 is measured. The endpoint is a

In a patient with a history of exercise-induced symptoms (eg, cough, wheeze, chest tightness or pain), the diagnosis of asthma can be confirmed with the exercise challenge. In children >6 years old, the procedure involves baseline spirometry followed by exercise on a treadmill or bicycle to a heart rate greater than 60% of the predicted maximum, with monitoring of the

Spirographic findings and the peak expiratory flow (PEF) rate (PEFR) are determined immediately after the exercise period and at 3 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after the first measurement. The maximal decrease in lung function is calculated by using the lowest post-exercise and highest pre -exercise values. The reversibility of airway obstruction can be assessed by administering aerosolized

Chest X-ray is indicated in the initial work-up of asthmatic patients. Typical findings are hyperinflation and increased bronchial markings, a chest radiograph may reveal evidence of

In a patient with an acute asthmatic episode that responds poorly to therapy, a chest radiograph helps in the diagnosis of complications such as pneumothorax or

Consider sinus radiography and CT scanning to rule out sinusitis, co-existing with allergic

CBC, Eosinophil counts, total IgE and RAST may be useful when allergic factors are

Allergy testing can be used to identify allergic factors that may significantly contribute to the asthma. Once identified, environmental factors (eg, dust mites, cockroaches, molds, animal dander) and outdoor factors (eg, pollen, grass, trees, molds) may be controlled or

Allergens for skin testing are selected on the basis of suspected or known allergens identified from a detailed environmental history. Antihistamines can suppress the skin test results and should be discontinued for an appropriate period (according to the particular

parenchymal disease, atelectasis, pneumonia, congenital anomaly, or a foreign body.

20% decrease in FEV1 (PD20). 90-92

electrocardiogram and oxyhemoglobin saturation.93

**17. Exercise challenge**

bronchodilators.94-95

pneumomediastinum.

rhinitis and asthma.

**20. Blood testing**

**21. Skin prick test**

suspected.

**19. Paranasal sinus and CT scanning**

avoided to reduce asthmatic symptoms.

**18. Chest X-ray**

ADAPTED GINA 2008

An individual's asthma pattern (infrequent intermittent, frequent intermittent, mild persistent, moderate persistent or severe persistent) is determined by the level of the table that corresponds to the most severe feature present. Other features associated with that pattern need not be present.

\*Predicted values are based on age, sex, and height.

\*Difference between morning and evening values.

FEV1: Forced expiratory volume in 1 second: PEF: Peak expiratory flow.

#### **15. Plethysmography**

Patients with chronic persistent asthma may have hyperinflation, as evidenced by an increased total lung capacity (TLC) at plethysmography. Increased residual volume (RV) and functional residual capacity (FRC) with normal TLC suggests air trapping. Airway resistance is increased when significant obstruction is present.

#### **16. Bronchial provocation tests**

Bronchial provocation tests may be performed to diagnose bronchial hyper-responsiveness (BHR). These tests are performed in specialized laboratories by specially trained personnel

Brief Mild Occur less than every 4- 6 weeks

per month

May affect activity and sleep

At least twice per week Restricts activity or affects sleep

Frequent restricts activity

Exacerbations PEF or

FEV1\*

More than 80% predicted

At least 80% predicted

At least 80% predicted

60%-80% predicted

60% predicted or less

PEF

variability\*\*

Less than 20%

Less than 20%

20%-30%

More than 30%

More than 30%

Night-time symptoms between exacerbations

More than twice per month but not every week

More than once per week

FEV1: Forced expiratory volume in 1 second: PEF: Peak expiratory flow.

intermittent Nil Nil More than 2

Patients with chronic persistent asthma may have hyperinflation, as evidenced by an increased total lung capacity (TLC) at plethysmography. Increased residual volume (RV) and functional residual capacity (FRC) with normal TLC suggests air trapping. Airway

An individual's asthma pattern (infrequent intermittent, frequent intermittent, mild persistent, moderate persistent or severe persistent) is determined by the level of the table that corresponds to the most severe feature present. Other features associated with

Bronchial provocation tests may be performed to diagnose bronchial hyper-responsiveness (BHR). These tests are performed in specialized laboratories by specially trained personnel

resistance is increased when significant obstruction is present.

\*Predicted values are based on age, sex, and height. \*Difference between morning and evening values.

**15. Plethysmography**

**16. Bronchial provocation tests**

Daytime symptoms between exacerbations

intermittent Nil Nil

More than once per week but not every day

presistent Continual Frequent

Infrequent

Frequent

Mild persistent

Moderate

Severe

persistent Daily

ADAPTED GINA 2008

that pattern need not be present.

to document airway hyper-responsiveness to substances (eg, methacholine, histamine). Increasing doses of provocation agents are given, and FEV1 is measured. The endpoint is a 20% decrease in FEV1 (PD20). 90-92

### **17. Exercise challenge**

In a patient with a history of exercise-induced symptoms (eg, cough, wheeze, chest tightness or pain), the diagnosis of asthma can be confirmed with the exercise challenge. In children >6 years old, the procedure involves baseline spirometry followed by exercise on a treadmill or bicycle to a heart rate greater than 60% of the predicted maximum, with monitoring of the electrocardiogram and oxyhemoglobin saturation.93

Spirographic findings and the peak expiratory flow (PEF) rate (PEFR) are determined immediately after the exercise period and at 3 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after the first measurement. The maximal decrease in lung function is calculated by using the lowest post-exercise and highest pre -exercise values. The reversibility of airway obstruction can be assessed by administering aerosolized bronchodilators.94-95

#### **18. Chest X-ray**

Chest X-ray is indicated in the initial work-up of asthmatic patients. Typical findings are hyperinflation and increased bronchial markings, a chest radiograph may reveal evidence of parenchymal disease, atelectasis, pneumonia, congenital anomaly, or a foreign body.

In a patient with an acute asthmatic episode that responds poorly to therapy, a chest radiograph helps in the diagnosis of complications such as pneumothorax or pneumomediastinum.

#### **19. Paranasal sinus and CT scanning**

Consider sinus radiography and CT scanning to rule out sinusitis, co-existing with allergic rhinitis and asthma.

#### **20. Blood testing**

CBC, Eosinophil counts, total IgE and RAST may be useful when allergic factors are suspected.

#### **21. Skin prick test**

Allergy testing can be used to identify allergic factors that may significantly contribute to the asthma. Once identified, environmental factors (eg, dust mites, cockroaches, molds, animal dander) and outdoor factors (eg, pollen, grass, trees, molds) may be controlled or avoided to reduce asthmatic symptoms.

Allergens for skin testing are selected on the basis of suspected or known allergens identified from a detailed environmental history. Antihistamines can suppress the skin test results and should be discontinued for an appropriate period (according to the particular

Management of Asthma in Children 163

bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin E (lgE) antibodies (omalizumab). Relief medications include

For all but the most severely affected patients, the ultimate goal is to prevent symptoms, minimize morbidity from acute episodes, and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle appropriate to the age of child. 108 A stepwise approach to pharmacologic therapy is recommended to gain and maintain control of asthma in both the impairment and risk domains. The type, amount, and scheduling of medication is dictated by asthma severity (for initiating therapy) and the level of asthma control (for adjusting therapy). Step-down therapy is essential to identify the

For pharmacotherapy, children with asthma are divided into 3 groups based on age: 0-4 y,

For all patients, quick-relief medications include rapid-acting beta2-agonists as needed for symptoms. The intensity of treatment depends on the severity of symptoms. If rapid acting beta2-agonists are used more than 2 days a week for symptom relief (not including use of rapid-acting beta2-agonists for prevention of exercise induce symptoms), stepping up treatment may be considered. See the stepwise approach to asthma medications in Table 1,

> Medium-dose ICS plus either longacting beta2 agonist (LABA) or montelukast

> Medium-dose ICS plus LABA

> Medium-dose ICS

plus LABA High-dose ICS

Alternate regimen: medium-dose ICS plus either LTRA or theophylline

Alternate regimen: medium-dose ICS plus either LTRA, theophylline, or zileuton

High-dose ICS plus either LABA or montelukast

High-dose ICS plus LABA

plus LABA (and consider omalizumab for patients with allergies)

Alternate regimen: highdose ICS plus either LABA or theophylline

High-dose ICS plus either LABA or montelukast; Oral systemic corticosteroid

High-dose ICS plus LABA plus oral systemic corticosteroid

Alternate regimen: high-dose ICS plus LRTA or theophylline plus systemic corticosteroid

High-dose ICS plus either LABA plus oral corticosteroid (and consider omalizumab for patients with allergies)

Age Step 1 Step 2 Step 3 Step 4 Step 5 Step 6

Either low-dose ICS plus either LABA, LTRA, or theophylline OR Medium-dose

Low-dose ICS plus LABA OR Medium-dose ICS

Alternate regimen: lowdose ICS plus either LTRA, theophylline, or zileuton

short-acting bronchodilators, systemic corticosteroids, and ipratropium. 106-107

minimum medication necessary to maintain control. See table below.

5-11 y, 12 Y and older. 109

**Intermittent Asthma Persistent Asthma: Daily Medication**

Low-dose inhaled corticosteroid

Alternate regimen: cromolyn or montelukast

Low-dose ICS

Low-dose ICS

Alternate regimen: cromolyn, LTRA, or theophylline

Table 1. Stepwise Approach to Asthma Medications

Alternate regimen: cromolyn, leukotriene receptor antagonist (LTRA), or theophylline

(ICS) Medium-dose ICS

below.

< 5 y

5-11 y

12 y or older

Rapidacting beta2 agonist prn

Rapidacting beta2 agonist prn

Rapidacting beta2 agonist as needed

agent's duration of action) before allergy testing. Topical or systemic corticosteroids do not affect the skin reaction.

### **22. Fraction of Exhaled Nitric Oxide testing**

Measuring the fraction of exhaled nitric oxide (FeNO) has proved useful as a non-invasive marker of airway inflammation, in order to guide adjustment of the dose of inhaled corticosteroids. 96-98

### **23. Histologic findings**

Asthma is an inflammatory disease characterized by inflammatory cells, vascular congestion, increased vascular permeability, increased tissue volume, and the presence of an exudate.

Eosinophilic infiltration, a universal finding, is considered a major marker of the inflammatory activity of the disease.

Histologic evaluations of the airways in a typical patient reveal infiltration with inflammatory cells, narrowing of airway lumina, bronchial and bronchiolar epithelial denudation, and mucus plugs. 99-104

Additionally, a patient with severe asthma may have a markedly thickened basement membrane and airway remodeling in the form of subepithelial fibrosis and smooth muscle hypertrophy or hyperplasia.

#### **24. Management**

#### **24.1 Goal for therapy**

Reduction in risk can be achieved by preventing recurrent exacerbations of asthma and minimizing the need for emergency room visits and hospitalizations, and preventing progressive loss of lung growth and function providing optimal pharmacotherapy with minimal or no adverse effects is important.

#### **24.2 Pharmacologic treatment**

Pharmacologic management includes the use of agents for control and agents for relief. Control agents include inhaled corticosteroids, inhaled cromolyn or nedocromil, long acting

agent's duration of action) before allergy testing. Topical or systemic corticosteroids do not

Measuring the fraction of exhaled nitric oxide (FeNO) has proved useful as a non-invasive marker of airway inflammation, in order to guide adjustment of the dose of inhaled

Asthma is an inflammatory disease characterized by inflammatory cells, vascular congestion, increased vascular permeability, increased tissue volume, and the presence of an

Eosinophilic infiltration, a universal finding, is considered a major marker of the

Histologic evaluations of the airways in a typical patient reveal infiltration with inflammatory cells, narrowing of airway lumina, bronchial and bronchiolar epithelial

Additionally, a patient with severe asthma may have a markedly thickened basement membrane and airway remodeling in the form of subepithelial fibrosis and smooth muscle

 Control asthma by reducing impairment through prevention of chronic and troublesome symptoms (eg, coughing or breathlessness in the daytime, in the night, or

Maintain normal activity levels (including exercise and other physical activity and

Reduce the need for a short-acting beta2-agonist (SABA) for quick relief of symptoms

Reduction in risk can be achieved by preventing recurrent exacerbations of asthma and minimizing the need for emergency room visits and hospitalizations, and preventing progressive loss of lung growth and function providing optimal pharmacotherapy with

Pharmacologic management includes the use of agents for control and agents for relief. Control agents include inhaled corticosteroids, inhaled cromolyn or nedocromil, long acting

(not including prevention of exercise-induced bronchospasm) Satisfy patients' and families' expectations for asthma care105

affect the skin reaction.

corticosteroids. 96-98

exudate.

**23. Histologic findings**

inflammatory activity of the disease.

denudation, and mucus plugs. 99-104

hypertrophy or hyperplasia.

**24. Management 24.1 Goal for therapy**

after exertion)

Maintain near-normal pulmonary function

attendance at work or school)

minimal or no adverse effects is important.

**24.2 Pharmacologic treatment**

**22. Fraction of Exhaled Nitric Oxide testing**

bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin E (lgE) antibodies (omalizumab). Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium. 106-107

For all but the most severely affected patients, the ultimate goal is to prevent symptoms, minimize morbidity from acute episodes, and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle appropriate to the age of child. 108

A stepwise approach to pharmacologic therapy is recommended to gain and maintain control of asthma in both the impairment and risk domains. The type, amount, and scheduling of medication is dictated by asthma severity (for initiating therapy) and the level of asthma control (for adjusting therapy). Step-down therapy is essential to identify the minimum medication necessary to maintain control. See table below.

For pharmacotherapy, children with asthma are divided into 3 groups based on age: 0-4 y, 5-11 y, 12 Y and older. 109

For all patients, quick-relief medications include rapid-acting beta2-agonists as needed for symptoms. The intensity of treatment depends on the severity of symptoms. If rapid acting beta2-agonists are used more than 2 days a week for symptom relief (not including use of rapid-acting beta2-agonists for prevention of exercise induce symptoms), stepping up treatment may be considered. See the stepwise approach to asthma medications in Table 1, below.

#### **Intermittent Asthma Persistent Asthma: Daily Medication**

Table 1. Stepwise Approach to Asthma Medications

Management of Asthma in Children 165

corticosteroids as rescue medication with albuterol might be an effective step down strategy, for children as it is more effective at reducing exacerbations than is use of rescue albuterol alone. A recent Cochrane review concluded that more research is needed to assess the effectiveness of increased inhaled corticosteroid doses at the onset of asthma exacerbation] In children, long-term use of high-dose steroids (systemic or inhaled) may lead to adverse effects, including growth failure. Recent data from the Childhood Asthma Management Program (CAMP) study and results of the long-term use of inhaled steroids (budesonide) suggest that the long-term use of inhaled steroids has no sustained adverse effect on growth

> Low Daily Doses of Inhaled Glucocorticosteroids for Children 5 years and younger

Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody that binds to the IgE molecule at the same epitope on the Fc region that binds to FcεRL, Omalizumab binds to circulating IgE regardless of allergen specificity, forming small, biologically inert IgE-anti-IgE complexes without activating the complement cascade. An 89 to 99 percent reduction in free serum IgE (i.e., IgE not bound to Omalizumab) occurs soon after the administration of omalizumab and low levels persist throughout treatment with appropriate doses. Proof-of-concept studies have shown that Omalizumab reduces both early-and late –phase asthmatic responses after allergen inhalation challenge, has a marked effect on late-phase as compared with early-phase skin responses, decreases eosinophil numbers in sputum and submucosal bronchial specimens and also down-regulates FcεRI on basophils, mast cells, and dendritic cells. A reduction in the expression of FcεRI on basophils and mast cells decreases the binding of circulating IgE, thus, preventing the release of inflammatory mediators. A reduction in the expression of FcεRI on dendritic cells may decrease allergen

200 500

Drug Low Daily Dose (μg)

Beclomethasone dipropianate 100

Fluticasone propionate 100

A review by Rodrigo et al looked at 8 studies of omalizumab in children with moderateetosevere asthma and elevated IgE levels. Children treated with omalizumab were more significantly able to reduce their use of rescue inhalers and their inhaled and/or oral steroid dose than patients in the placebo group. Although no significant differences in pulmonary function were observed, patients receiving omalizumab had fewer exacerbations than the

Several randomized, double-blind clinical trials compared omalizumab, administered subcutaneously, with

the trials evaluated patients with moderate-t0-severe persistent asthma (requiring doses of inhaled bleclomethasone, or its equivalent, ranging from 168-1200 μg per day). Two of these tree trials included adolescents and adults, and one was a study of children 6-12 years of age. Treatment with Omalizumab as compared with placebo was associated with significantly fewer exacerbations of asthma per patient, and a significantly lower percentage of patients had an exacerbation, the dose of inhaled corticosteroids required to control symptoms was significantly less among patients treated with Omalizumab than among those who

These trials demonstrated a clinical benefit from Omalizumab, although the specific findings varied. Three of

in children. 114-116

Budesonide MDI+spacer Budesonide nebulized

*GINA Guidelines*

processing.

received placebo.

placebo.

In the Salmeterol Multicenter Asthma Research Trial (SMART), salmeterol use in asthma patients, particularly African Americans, was associated with a small but significantly increased risk of serious asthma-related events. This trial was a large, double-blind, randomized, placebo-controlled, safety trial in which salmeterol 42 mcg twice daily or placebo was added to usual asthma therapy for 28 weeks. 110

The study was halted following interim analysis of 26,355 participants because patients exposed to salmeterol (n = 13,176) were found to experience a higher rate of fatal asthma events compared with individuals receiving placebo (n = 13,179); the rates were 0.1 % and 0.02%, respectively. This resulted in an estimated 8 excess deaths per 10,000 patients treated with salmeterol. 111

In the post-hoc subgroup analysis, the relative risks of asthma-related deaths were similar among whites and blacks, although the corresponding estimated excess deaths per 10,000 patients exposed to salmeterol were higher among blacks than whites.

A meta-analysis by Salpeter et al found that LABAs increased the risk for asthma related intubations and deaths by 2-fold, even when used in a controlled fashion with concomitant inhaled corticosteroids. However, the absolute number of adverse events remained small. The large pooled trial included 36,588 patients, most of them adults. 112

The US Food and Drug Administration (FDA) has reviewed the data and the issues and has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when LABAs are used appropriately with an asthma controller medication in patients who need the addition of LABAs. The FDA recommends the following measures for improving the safe use of these drugs :

Concerns about the safety of long-acting beta2-agonists and resultant drug safety communications create a question as to the course of treatment if asthma is not controlled by inhaled corticosteroidsY4] A study by Lemanske et al addressed this question and concluded that addition of long-acting beta2-agonist was more likely to provide the best response than either inhaled corticosteroids or leukotriene-receptor antagonists. Asthma therapy should be regularly monitored and adjusted accordingly.

A systematic review of 18 placebo-controlled clinical trials evaluating monotherapy with inhaled corticosteroids supports their safety and efficacy in children with asthma. In addition, the data provide new evidence linking inhaled corticosteroids use in children with asthma to improved asthma control. A recent study to assess the effectiveness of an inhaled corticosteroid used as rescue treatment recommends that children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. This study suggests that inhaled

In the Salmeterol Multicenter Asthma Research Trial (SMART), salmeterol use in asthma patients, particularly African Americans, was associated with a small but significantly increased risk of serious asthma-related events. This trial was a large, double-blind, randomized, placebo-controlled, safety trial in which salmeterol 42 mcg twice daily or

The study was halted following interim analysis of 26,355 participants because patients exposed to salmeterol (n = 13,176) were found to experience a higher rate of fatal asthma events compared with individuals receiving placebo (n = 13,179); the rates were 0.1 % and 0.02%, respectively. This resulted in an estimated 8 excess deaths per 10,000 patients treated

In the post-hoc subgroup analysis, the relative risks of asthma-related deaths were similar among whites and blacks, although the corresponding estimated excess deaths per 10,000

A meta-analysis by Salpeter et al found that LABAs increased the risk for asthma related intubations and deaths by 2-fold, even when used in a controlled fashion with concomitant inhaled corticosteroids. However, the absolute number of adverse events remained small.

The US Food and Drug Administration (FDA) has reviewed the data and the issues and has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when LABAs are used appropriately with an asthma controller medication in patients who need the addition of LABAs. The FDA recommends the following measures

LABAs should be used long-term only in patients whose asthma cannot be adequately

 LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved;

 Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled

Concerns about the safety of long-acting beta2-agonists and resultant drug safety communications create a question as to the course of treatment if asthma is not controlled by inhaled corticosteroidsY4] A study by Lemanske et al addressed this question and concluded that addition of long-acting beta2-agonist was more likely to provide the best response than either inhaled corticosteroids or leukotriene-receptor antagonists. Asthma

A systematic review of 18 placebo-controlled clinical trials evaluating monotherapy with inhaled corticosteroids supports their safety and efficacy in children with asthma. In addition, the data provide new evidence linking inhaled corticosteroids use in children with asthma to improved asthma control. A recent study to assess the effectiveness of an inhaled corticosteroid used as rescue treatment recommends that children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. This study suggests that inhaled

patients should then be switched to an asthma controller medication

corticosteroid and a LABA to ensure compliance with both medications

therapy should be regularly monitored and adjusted accordingly.

placebo was added to usual asthma therapy for 28 weeks. 110

patients exposed to salmeterol were higher among blacks than whites.

The large pooled trial included 36,588 patients, most of them adults. 112

for improving the safe use of these drugs :

controlled on inhaled steroids 113

with salmeterol. 111

corticosteroids as rescue medication with albuterol might be an effective step down strategy, for children as it is more effective at reducing exacerbations than is use of rescue albuterol alone. A recent Cochrane review concluded that more research is needed to assess the effectiveness of increased inhaled corticosteroid doses at the onset of asthma exacerbation]

In children, long-term use of high-dose steroids (systemic or inhaled) may lead to adverse effects, including growth failure. Recent data from the Childhood Asthma Management Program (CAMP) study and results of the long-term use of inhaled steroids (budesonide) suggest that the long-term use of inhaled steroids has no sustained adverse effect on growth in children. 114-116

Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody that binds to the IgE molecule at the same epitope on the Fc region that binds to FcεRL, Omalizumab binds to circulating IgE regardless of allergen specificity, forming small, biologically inert IgE-anti-IgE complexes without activating the complement cascade. An 89 to 99 percent reduction in free serum IgE (i.e., IgE not bound to Omalizumab) occurs soon after the administration of omalizumab and low levels persist throughout treatment with appropriate doses. Proof-of-concept studies have shown that Omalizumab reduces both early-and late –phase asthmatic responses after allergen inhalation challenge, has a marked effect on late-phase as compared with early-phase skin responses, decreases eosinophil numbers in sputum and submucosal bronchial specimens and also down-regulates FcεRI on basophils, mast cells, and dendritic cells. A reduction in the expression of FcεRI on basophils and mast cells decreases the binding of circulating IgE, thus, preventing the release of inflammatory mediators. A reduction in the expression of FcεRI on dendritic cells may decrease allergen processing.

Several randomized, double-blind clinical trials compared omalizumab, administered subcutaneously, with placebo.

These trials demonstrated a clinical benefit from Omalizumab, although the specific findings varied. Three of the trials evaluated patients with moderate-t0-severe persistent asthma (requiring doses of inhaled bleclomethasone, or its equivalent, ranging from 168-1200 μg per day). Two of these tree trials included adolescents and adults, and one was a study of children 6-12 years of age. Treatment with Omalizumab as compared with placebo was associated with significantly fewer exacerbations of asthma per patient, and a significantly lower percentage of patients had an exacerbation, the dose of inhaled corticosteroids required to control symptoms was significantly less among patients treated with Omalizumab than among those who received placebo.

A review by Rodrigo et al looked at 8 studies of omalizumab in children with moderateetosevere asthma and elevated IgE levels. Children treated with omalizumab were more significantly able to reduce their use of rescue inhalers and their inhaled and/or oral steroid dose than patients in the placebo group. Although no significant differences in pulmonary function were observed, patients receiving omalizumab had fewer exacerbations than the

Management of Asthma in Children 167

In pediatric asthma, inhaled treatment is the cornerstone of asthma management. Inhaler devices currently used to deliver inhaled corticosteroids (ICSs) fall into the following 4

Pressurized metered dose inhaler (pMDI) - Propellant used to dispense steroid when

Go to Use of Metered Dose Inhalers, Spacers, and Nebulizers for complete information on

In pediatric patients, the inhaler device must be chosen on the basis of age, cost, safety,

Based on current research, the preferred device for children younger than 4 years is a pMDI with a valved holding chamber and age-appropriate mask. Children aged 4-6 years should use a pMDI plus a valved holding chamber. Lastly, children older than 6 years can use either a pMDl, a DPI, or a breath-actuated pMDI. For all 3 groups, a nebulizer with a valved holding chamber (and mask in children younger than 4 y) is recommended as alternate

Valved holding chambers are important. The addition of a valved holding chamber can increase the amount of drug reaching the lungs to 20%. The use of a valved holding chamber helps reduce the amount of drug particles deposited in the oropharynx, thereby helping to reduce systemic and local effects from oral and gastrointestinal absorption.

A Cochrane review on the use of valved holding chambers versus nebulizers for inhaled steroids found no evidence that nebulizers are better than valved holding chamber. Nebulizers are expensive, inconvenient to use, require longer time for administration,

Newer devices such as…. have been associated with a greater efficacy (as evidenced by…). For MDls, chlorofluorocarbon (CFC) propellants (implicated in ozone depletion) have been phased out in favor of the hydrofluoroalkane-134a (HFA) propellant. Surprisingly, the HFA component is more environmentally friendly and has proven to be more effective, due to its smaller aerosol particle size, which results in better drug delivery. MDls with HFA propellant have better deposition of drug in the small airways and greater efficacy at

Regular follow-up visits are essential to ensure control and appropriate therapeutic adjustments. In general, patients should be assessed every 1-6 months. At every visit,

If patients have good control of their asthma for at least 3 months, treatment can be stepped down. However, the patient should be reassessed in 2-4 weeks to make sure that control is

adherence, environmental control, and comorbid conditions should be checked.

require maintenance, and have been shown to have imprecise dosing.

 Dry powder inhaler (DPI) - Does not require hand-breath coordination to operate Breath-actuated pMDI - Propellant used to dispense steroid when patient inhales

**25. Delivery devices and best route of administration**

categories:64

this topic.

therapy.

canister is pressed manually

convenience, and efficacy of drug delivery

equivalent doses compared with CFC-MDls.117

**26. Long-term monitoring**

Nebulized solution devices

children receiving placebo. These studies lasted a year or less and did not reveal any significant adverse effects of the omalizumab.

#### Clinical Use

The role of Omalizumab in the management of asthma has not yet been precisely defined. Patients with persistent asthma (defined as asthma with symptoms that occur more than two days a week or nocturnal symptoms that occur more than twice a month) have several treatment options in addition to the use of inhaled β-adrenergic agonist. These include environmental control (i.e., the elimination or minimization of exposure to aeroallergens), pharmacologic control (i.e., the use of inhaled corticosteroids, leukotriene modifiers, or both), and possibly, immunologic control (i.e., immunotherapy for relevant antigens). In addition, evaluation for coexisting conditions such as allergic rhinitis, sinusitis, and gastroesophageal reflux disease may prove beneficial.

Patients who are particularly likely to benefit from the use of Omalizumab include those with evidence of sensitization to perennial aeroallergens who require high doses of inhaled corticosteroids that have a potential for adverse side effects, those with frequent exacerbations of asthma associated with unstable disease and possibly, those with severe symptoms related in part to poor adherence to daily medication. Analysis of pooled data from published clinical trials have indicated that patients who had a response to Omalizumab had a ration of observed to expected forced expiratory volume in one second (FEV1) of less than 65 percent, were taking doses of inhaled corticosteroids equivalent to more than 800 μg of beclomethasone dipropionate per day, and had at least one visit to the emergency department in the past year. Patients requiring daily oral corticosteroids to control their stamina may be less likely to have response to Omalizumab.

A total serum IgE level should be measured in all patients who are being considered for treatment with Omalizumab, because the dose of Omalizumab is determined on the basis of the IgE level and body weight. The recommended dose is 0.016 mg per kilogram of body weight per international unit of IgE every four weeks, administered subcutaneously at either two-week or four-week intervals. This dose is based on the estimated amount of drug that is required to reduce circulating free IgE levels to less than 10 IU per milliliter.

Monitoring of total serum IgE levels during the course of therapy with Omalizumab is not indicated, because these levels will be elevated as a result of the presence of circulating IgE-anti-IgE complexes. No other laboratory tests seems to be necessary, since there have been no clinically significant laboratory abnormalities noted during treatment.

#### Cost

Omalizumab is considerably more expensive than conventional asthma therapy, with an average of approximately \$12,000 per year. This compares with approximate cosets per year of \$1,289 for montelukast, \$2,160 for the combination of fluticasone dipropionate and salmeterol, \$680 for extended-release theophylline.

A randomized trial of omalizumab for asthma in inner-city children showed improved asthma control, elimination of seasonal peaks in asthmatic exacerbations, and reduced need for other medications for asthma control.

children receiving placebo. These studies lasted a year or less and did not reveal any

The role of Omalizumab in the management of asthma has not yet been precisely defined. Patients with persistent asthma (defined as asthma with symptoms that occur more than two days a week or nocturnal symptoms that occur more than twice a month) have several treatment options in addition to the use of inhaled β-adrenergic agonist. These include environmental control (i.e., the elimination or minimization of exposure to aeroallergens), pharmacologic control (i.e., the use of inhaled corticosteroids, leukotriene modifiers, or both), and possibly, immunologic control (i.e., immunotherapy for relevant antigens). In addition, evaluation for coexisting conditions such as allergic rhinitis, sinusitis, and gastroesophageal reflux disease may

Patients who are particularly likely to benefit from the use of Omalizumab include those with evidence of sensitization to perennial aeroallergens who require high doses of inhaled

corticosteroids that have a potential for adverse side effects, those with frequent exacerbations of asthma associated with unstable disease and possibly, those with severe symptoms related in part to poor adherence to daily medication. Analysis of pooled data from published clinical trials have indicated that patients who had a response to Omalizumab had a ration of observed to expected forced expiratory volume in one second (FEV1) of less than 65 percent, were taking doses of inhaled corticosteroids equivalent to more than 800 μg of beclomethasone dipropionate per day, and had at least one visit to the emergency department in the past year. Patients

requiring daily oral corticosteroids to control their stamina may be less likely to have response to

A total serum IgE level should be measured in all patients who are being considered for treatment with Omalizumab, because the dose of Omalizumab is determined on the basis of the IgE level and body weight. The recommended dose is 0.016 mg per kilogram of body weight per international unit of IgE every four weeks, administered subcutaneously at either two-week or four-week intervals. This dose is based on the estimated amount of drug that is required to

Monitoring of total serum IgE levels during the course of therapy with Omalizumab is not indicated, because these levels will be elevated as a result of the presence of circulating IgE-anti-IgE complexes. No other laboratory tests seems to be necessary, since there have been no

reduce circulating free IgE levels to less than 10 IU per milliliter.

clinically significant laboratory abnormalities noted during treatment.

A randomized trial of omalizumab for asthma in inner-city children showed improved asthma control, elimination of seasonal peaks in asthmatic exacerbations, and reduced need

Omalizumab is considerably more expensive than conventional asthma therapy, with an average of approximately \$12,000 per year. This compares with approximate cosets per year of \$1,289 for montelukast, \$2,160 for the combination of fluticasone dipropionate and salmeterol, \$680 for

for other medications for asthma control.

extended-release theophylline.

significant adverse effects of the omalizumab.

Clinical Use

prove beneficial.

Omalizumab.

Cost

### **25. Delivery devices and best route of administration**

In pediatric asthma, inhaled treatment is the cornerstone of asthma management. Inhaler devices currently used to deliver inhaled corticosteroids (ICSs) fall into the following 4 categories:64

Go to Use of Metered Dose Inhalers, Spacers, and Nebulizers for complete information on this topic.

In pediatric patients, the inhaler device must be chosen on the basis of age, cost, safety, convenience, and efficacy of drug delivery

Based on current research, the preferred device for children younger than 4 years is a pMDI with a valved holding chamber and age-appropriate mask. Children aged 4-6 years should use a pMDI plus a valved holding chamber. Lastly, children older than 6 years can use either a pMDl, a DPI, or a breath-actuated pMDI. For all 3 groups, a nebulizer with a valved holding chamber (and mask in children younger than 4 y) is recommended as alternate therapy.

Valved holding chambers are important. The addition of a valved holding chamber can increase the amount of drug reaching the lungs to 20%. The use of a valved holding chamber helps reduce the amount of drug particles deposited in the oropharynx, thereby helping to reduce systemic and local effects from oral and gastrointestinal absorption.

A Cochrane review on the use of valved holding chambers versus nebulizers for inhaled steroids found no evidence that nebulizers are better than valved holding chamber. Nebulizers are expensive, inconvenient to use, require longer time for administration, require maintenance, and have been shown to have imprecise dosing.

Newer devices such as…. have been associated with a greater efficacy (as evidenced by…). For MDls, chlorofluorocarbon (CFC) propellants (implicated in ozone depletion) have been phased out in favor of the hydrofluoroalkane-134a (HFA) propellant. Surprisingly, the HFA component is more environmentally friendly and has proven to be more effective, due to its smaller aerosol particle size, which results in better drug delivery. MDls with HFA propellant have better deposition of drug in the small airways and greater efficacy at equivalent doses compared with CFC-MDls.117

#### **26. Long-term monitoring**

Regular follow-up visits are essential to ensure control and appropriate therapeutic adjustments. In general, patients should be assessed every 1-6 months. At every visit, adherence, environmental control, and comorbid conditions should be checked.

If patients have good control of their asthma for at least 3 months, treatment can be stepped down. However, the patient should be reassessed in 2-4 weeks to make sure that control is

Management of Asthma in Children 169

Inactivated influenza vaccine may be helpful in those who are older than 6 months.

Patient education continues to be important in all areas of medicine and is particularly important in asthma. Self-management education should focus on teaching patients the importance of recognizing their own their level of control and signs of progressively

Both peak flow monitoring and symptom monitoring have been shown to be equally effective; however, peak flow monitoring may be more helpful in cases in which patients have a history of difficulty in perceiving symptoms, a history of severe exacerbations, or

Educational strategies should also focus on environmental control and avoidance strategies and medication use and adherence (eg, correct inhaler techniques and use of other devices). Using a variety of methods to reinforce educational messages is crucial in patient understanding. Providing written asthma action plans in partnership with the patient (making sure to review the differences between long-term control and quick-relief medications), education through the involvement of other members of the healthcare team (eg, nurses, pharmacists, physicians), and education at all points of care (eg, clinics, hospitals, schools) are examples of various educational tools that are available and valuable

Treatment goals for acute severe asthmatic episodes (status asthmaticus) are as follows:

Acute exacerbation of asthma induces the release of inflammatory mediators prime adhesion molecules in the airway epithelium and capillary endothelium, which then allows inflammatory cells, such as eosinophils neutrophils, and basophils, to attach to the epithelium and endothelium and subsequently migrate into the tissues of the airway. Eosinophils release eosinophilic cationic protein (ECP) and major basic protein (MBP). Both ECP and MBP induce deqsquamation of the airway epithelium and expose nerve endings. This interaction promotes further airway hyperresponsiveness in asthma. This inflammatory component may even occur in individuals with mild asthma

Correction of significant hypoxemia with supplemental oxygen; in severe cases,

alveolar hypoventilation requires mechanically assisted ventilation

Obesity

 Rhinitis Sinusitis Depression Stress

**30. Education**

Obstructive sleep apnea

worsening asthma symptoms.

moderate-to-severe asthma.

**31. Status asthmaticus**

exacerbation.

for good patient adherence and understanding.

maintained with the new regimen. If patients require step 2 asthma medications or higher, consultation with an asthma specialist should be considered.

#### **27. Outpatient visits should include the following**

#### **28. Patient evaluation should include the following**

Address issues of treatment adherence and avoidance of environmental triggers and irritants.

Long-term asthma care pathways that incorporate the aforementioned factors can serve as roadmaps for ambulatory asthma care and help streamline outpatient care by different providers.

In the author's asthma clinic, a member of the asthma care team sits with each patient to review the written asthma care plan and to write and discuss in detail a rescue plan for acute episodes, which includes instructions about identifying signs of an acute episode, using rescue medications, monitoring, and contacting the asthma care team. These items are reviewed at each visit.

One study using directly observed administration of daily preventive asthma medications by a school nurse showed significantly improved symptoms among urban children with persistent asthma.

#### **29. Control of environmental factors and comorbid conditions**

As mentioned above, environmental exposures and irritants can play a strong role in symptom exacerbations. Therefore, in patients who have persistent asthma, the use of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is important. Once the offending allergens are identified, counsel patients on avoidance from these exposures. In addition, education to avoid tobacco smoke (both first-hand and second-hand exposure) is important for patients with asthma. 118

Lastly, comorbid conditions that may affect asthma must be appropriately managed. These include the following:

Obesity

168 Bronchial Asthma – Emerging Therapeutic Strategies

maintained with the new regimen. If patients require step 2 asthma medications or higher,

Interval history of asthmatic complaints, including history of acute episodes (eg,

Review of home-monitoring data (eg, symptom diary, peak flow meter readings, daily

Address issues of treatment adherence and avoidance of environmental triggers and

Long-term asthma care pathways that incorporate the aforementioned factors can serve as roadmaps for ambulatory asthma care and help streamline outpatient care by different

In the author's asthma clinic, a member of the asthma care team sits with each patient to review the written asthma care plan and to write and discuss in detail a rescue plan for acute episodes, which includes instructions about identifying signs of an acute episode, using rescue medications, monitoring, and contacting the asthma care team. These items are

One study using directly observed administration of daily preventive asthma medications by a school nurse showed significantly improved symptoms among urban children with

As mentioned above, environmental exposures and irritants can play a strong role in symptom exacerbations. Therefore, in patients who have persistent asthma, the use of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is important. Once the offending allergens are identified, counsel patients on avoidance from these exposures. In addition, education to avoid tobacco smoke (both first-hand and second-hand

Lastly, comorbid conditions that may affect asthma must be appropriately managed. These

**29. Control of environmental factors and comorbid conditions**

exposure) is important for patients with asthma. 118

consultation with an asthma specialist should be considered.

**27. Outpatient visits should include the following**

 History of symptoms with exercise, and exercise tolerance Review of medications, including use of rescue medications

**28. Patient evaluation should include the following**  Assessment for signs of bronchospasm and complications Evaluation of associated conditions (eg, allergic rhinitis) Pulmonary function testing (in appropriate age group)

History of nocturnal symptoms

treatments)

irritants.

providers.

reviewed at each visit.

persistent asthma.

include the following:

Bronchopulmonary aspergillosis

Gastroesophageal reflux disease (GERD)

severity, measures and treatment taken, response to therapy)

Inactivated influenza vaccine may be helpful in those who are older than 6 months.

#### **30. Education**

Patient education continues to be important in all areas of medicine and is particularly important in asthma. Self-management education should focus on teaching patients the importance of recognizing their own their level of control and signs of progressively worsening asthma symptoms.

Both peak flow monitoring and symptom monitoring have been shown to be equally effective; however, peak flow monitoring may be more helpful in cases in which patients have a history of difficulty in perceiving symptoms, a history of severe exacerbations, or moderate-to-severe asthma.

Educational strategies should also focus on environmental control and avoidance strategies and medication use and adherence (eg, correct inhaler techniques and use of other devices).

Using a variety of methods to reinforce educational messages is crucial in patient understanding. Providing written asthma action plans in partnership with the patient (making sure to review the differences between long-term control and quick-relief medications), education through the involvement of other members of the healthcare team (eg, nurses, pharmacists, physicians), and education at all points of care (eg, clinics, hospitals, schools) are examples of various educational tools that are available and valuable for good patient adherence and understanding.

#### **31. Status asthmaticus**

Treatment goals for acute severe asthmatic episodes (status asthmaticus) are as follows:

Acute exacerbation of asthma induces the release of inflammatory mediators prime adhesion molecules in the airway epithelium and capillary endothelium, which then allows inflammatory cells, such as eosinophils neutrophils, and basophils, to attach to the epithelium and endothelium and subsequently migrate into the tissues of the airway. Eosinophils release eosinophilic cationic protein (ECP) and major basic protein (MBP). Both ECP and MBP induce deqsquamation of the airway epithelium and expose nerve endings. This interaction promotes further airway hyperresponsiveness in asthma. This inflammatory component may even occur in individuals with mild asthma exacerbation.

 Correction of significant hypoxemia with supplemental oxygen; in severe cases, alveolar hypoventilation requires mechanically assisted ventilation

Management of Asthma in Children 171

The goal of long-term therapy is to prevent acute exacerbations. The patient should avoid exposure to environmental allergens and irritants that are identified during the evaluation.

Recurrent acute exacerbation of asthma cause the following histoopathological change in the airways. The airways becomes blocked by viscous, tenacious mucus distended lung parenchyma are composed of eosinophils and epithelial cells. There is an increase in smooth airway muscle with hyperplasia and hypertrophy in the major airways. Shedding of the cilated bronchial wall cells, mainly eosinophils. Apart from the bronchial infiltration of eosinophils there is dilatation of the capillary blood cells. The connective

Numerous vasoactive agents have been found in broncoalveolar lavage of \_\_\_ with recurrent acute exacerbation of asthma including cell-derived mediators, such as histamine, the cysteinyl leukotriene, LTC4, LTD4 and LTE4, and PAF, and also neural-derived mediators, e.g. substance P(SP), neurokinin A and B (NKA, NKB), and calcitonin gene-related peptide (CGRP), PAF is a phospholipid that induces neutropenia, bronchocosntriction,

and abnormal airway microvascular leakage, possibly through postcapillary venoconstriction in the tracheobroncial circulation. Thus microvascular leakage of plasma is an inflammatory hallmark of paramount relevance n asthma, generally referred to as abnormally increased vascular permeability. A substantially

tissue in which these vessels lie consists of strands of widely separated collagen.

increased number of PAF receptors are reported in the lungs of asthmatic individuals.

When a patient has major allergies to dietary products, avoidance of particular foods may help. In the absence of specific food allergies, dietary changes are not necessary. Unless compelling evidence for a specific allergy exists, milk products do not have to be avoided.

Any patient with high-risk asthma should be referred to a specialist. The following may

Hospitalization or an emergency department visit for asthma within the past month

Current use of systemic corticosteroids or recent withdrawal from systemic

Referral to an asthma specialist for consultation or co-management of the patient is also recommended if additional education is needed to improve adherence or if the patient requires step 4 care or higher (step 3 care or higher for children aged 0-4 y). Consider referral if a patient requires step 3 care (step 2 care for children aged 0-4 y) or if additional

The choice between a pediatric pulmonologist and an allergist may depend on local availability and practices. A patient with frequent ICU admissions, previous intubation, and a history of complicating factors or comorbidity (eg, cystic fibrosis) should be referred to a

**32. Prevention of asthma**

**33. Dietary adjustments**

 History of sudden severe exacerbations History of prior intubation for asthma Admission to an ICU because of asthma

testing for the role of allergy is indicated.

Two or more hospitalizations for asthma in the past year

Three or more emergency department visits for asthma in the past year

Use of 2 or more canisters of inhaled short-acting beta2-agonists per month

**34. Consultations**

corticosteroids

suggest high risk:

	- 1. Yes, See British Guidelines on Management of Asthma (revised 2009). : second line treatment of acute asthma in children aged over 2 years.
	- 2. Indications for admission to intensive care or high-dependency units include patients requiring ventilator support and those with severe acute or life threatening asthma who are failing to respond to therapy, as evidenced by:
		- Deteriorating PEF
		- Persisting or worsening hypoxia
		- Hypercapnea
		- Arterial blood gas analysis showing fall in pH or rising H+ concentration
		- Exhaustion, feeble respiration
		- Drowsiness, confusion, altered conscious state
		- Respiratory arrest.

Not all patients admitted to the Intensive Care Unit (ICU) need ventilation, but those with worsening hypixia or hypercapnea, drowsiness or uncousciousness and those who have had a respiratory arrest require intermittent positive pressure ventilation, intubation in such patients is very difficult and should ideally be performed by an anaesthetist or ICU consultant.

 Reduction in the likelihood of recurrence of severe airflow obstruction by intensifying therapy: Often, a short course of systemic corticosteroids is helpful 119-120

Achieving these goals requires close monitoring by means of serial clinical assessment and measurement of lung function (in patients of appropriate ages) to quantify the severity of airflow obstruction and its response to treatment. Improvement in FEV1 after 30 minutes of treatment is significantly correlated with a broad range of indices of the severity of asthmatic exacerbations, and repeated measurement of airflow in the emergency department can help reduce unnecessary admissions.

The use of the peak flow rate or FEV1 values, patient's history, current symptoms, and physical findings to guide treatment decisions is helpful in achieving the aforementioned goals. When using the peak expiratory flow (PEF) expressed as a percentage of the patient's best value, the effect of irreversible airflow obstruction should be considered. For example, in a patient whose best peak flow rate is 160 L/min, a decrease of 40% represents severe and potentially life-threatening obstruction.

An Australian study by Vuillermin et al found that asthma severity decreased in school aged children when parents initiated a short course of prednisolone for acute asthma. Children who received parent-initiated prednisolone for episodes of asthma had lower daytime and nighttime asthma scores, reduced risk of health resource use, and reduced school absenteeism compared with children who received placebo.

 Rapid reversal of airflow obstruction with repeated or continuous administration of an inhaled beta2-agonist; early administration of systemic corticosteroids (eg, oral prednisone or intravenous methylprednisolone) is suggested in children with asthma

2. Indications for admission to intensive care or high-dependency units include patients requiring ventilator support and those with severe acute or life threatening asthma

Arterial blood gas analysis showing fall in pH or rising H+ concentration

Reduction in the likelihood of recurrence of severe airflow obstruction by intensifying

Achieving these goals requires close monitoring by means of serial clinical assessment and measurement of lung function (in patients of appropriate ages) to quantify the severity of airflow obstruction and its response to treatment. Improvement in FEV1 after 30 minutes of treatment is significantly correlated with a broad range of indices of the severity of asthmatic exacerbations, and repeated measurement of airflow in the emergency

The use of the peak flow rate or FEV1 values, patient's history, current symptoms, and physical findings to guide treatment decisions is helpful in achieving the aforementioned goals. When using the peak expiratory flow (PEF) expressed as a percentage of the patient's best value, the effect of irreversible airflow obstruction should be considered. For example, in a patient whose best peak flow rate is 160 L/min, a decrease of 40% represents severe and

An Australian study by Vuillermin et al found that asthma severity decreased in school aged children when parents initiated a short course of prednisolone for acute asthma. Children who received parent-initiated prednisolone for episodes of asthma had lower daytime and nighttime asthma scores, reduced risk of health resource use, and reduced

therapy: Often, a short course of systemic corticosteroids is helpful 119-120

very difficult and should ideally be performed by an anaesthetist or ICU consultant.

Not all patients admitted to the Intensive Care Unit (ICU) need ventilation, but those with worsening hypixia or hypercapnea, drowsiness or uncousciousness and those who have had a respiratory arrest require intermittent positive pressure ventilation, intubation in such patients is

department can help reduce unnecessary admissions.

school absenteeism compared with children who received placebo.

potentially life-threatening obstruction.

that fails to respond promptly and completely to inhaled beta2-agonists

1. Yes, See British Guidelines on Management of Asthma (revised 2009). : second line treatment of acute asthma in children aged over 2 years.

who are failing to respond to therapy, as evidenced by:

Drowsiness, confusion, altered conscious state

Persisting or worsening hypoxia

Exhaustion, feeble respiration

Deteriorating PEF

Respiratory arrest.

Hypercapnea

### **32. Prevention of asthma**

The goal of long-term therapy is to prevent acute exacerbations. The patient should avoid exposure to environmental allergens and irritants that are identified during the evaluation.

Recurrent acute exacerbation of asthma cause the following histoopathological change in the airways. The airways becomes blocked by viscous, tenacious mucus distended lung parenchyma are composed of eosinophils and epithelial cells. There is an increase in smooth airway muscle with hyperplasia and hypertrophy in the major airways. Shedding of the cilated bronchial wall cells, mainly eosinophils. Apart from the bronchial infiltration of eosinophils there is dilatation of the capillary blood cells. The connective tissue in which these vessels lie consists of strands of widely separated collagen.

Numerous vasoactive agents have been found in broncoalveolar lavage of \_\_\_ with recurrent acute exacerbation of asthma including cell-derived mediators, such as histamine, the cysteinyl leukotriene, LTC4, LTD4 and LTE4, and PAF, and also neural-derived mediators, e.g. substance P(SP), neurokinin A and B (NKA, NKB), and calcitonin gene-related peptide (CGRP), PAF is a phospholipid that induces neutropenia, bronchocosntriction, and abnormal airway microvascular leakage, possibly through postcapillary venoconstriction in the tracheobroncial circulation. Thus microvascular leakage of plasma is an inflammatory hallmark of paramount relevance n asthma, generally referred to as abnormally increased vascular permeability. A substantially increased number of PAF receptors are reported in the lungs of asthmatic individuals.

#### **33. Dietary adjustments**

When a patient has major allergies to dietary products, avoidance of particular foods may help. In the absence of specific food allergies, dietary changes are not necessary. Unless compelling evidence for a specific allergy exists, milk products do not have to be avoided.

#### **34. Consultations**

Any patient with high-risk asthma should be referred to a specialist. The following may suggest high risk:

Referral to an asthma specialist for consultation or co-management of the patient is also recommended if additional education is needed to improve adherence or if the patient requires step 4 care or higher (step 3 care or higher for children aged 0-4 y). Consider referral if a patient requires step 3 care (step 2 care for children aged 0-4 y) or if additional testing for the role of allergy is indicated.

The choice between a pediatric pulmonologist and an allergist may depend on local availability and practices. A patient with frequent ICU admissions, previous intubation, and a history of complicating factors or comorbidity (eg, cystic fibrosis) should be referred to a

Management of Asthma in Children 173

Nonracemic form of albuterol (xopenex), levalbuterol (R isomer) is effective in smaller doses and is reported to have fewer adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation). It is available as an MOl (45 mcg per actuation)

Long-acting bronchodilators (LABA) are not used for the treatment of acute bronchospasm. They are used for the preventive treatment of nocturnal asthma or exercise-induced

There are 2 LABA are available: salmeterol and formoterol. Both are available as

LABA may increase the chance of severe asthma episodes and death when those episodes occur. Most cases have occurred in patients with severe and/or acutely deteriorating

LABAs are not considered first-line medications to treat asthma. LABAs should not be used as isolated medications and should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low- or medium-dose corticosteroids. If used as isolated medication, LABAs should be prescribed by pulmonologist / allergist.

This long-acting preparation of a beta2-agonist is used primarily to treat nocturnal or exercise-induced symptoms. It has no anti-inflammatory action and is not indicated in the treatment of acute bronchospastic episodes. It may be used as an adjunct to inhaled corticosteroids to re9uce the potential adverse effects of the steroids. The medication is

Formoterol is a long-acting B2-agonist. It is marketed in dry powder inhalation, a metered-

Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. They are used for long-term control and prevention of

Theophylline is available in short-acting and long-acting formulations. Because of the need to monitor serum concentrations, this agent is used infrequently. The dose and frequency

depend on the particular product selected. The actions of theophylline involve:

asthma; they have also occurred in a few patients with less severe asthma.

**35.3 Xopenex**

**35.5 Salmeterol**

**35.6 Formoterol**

**35.7 Methylxanthines 35.7.1 Theophylline**

delivered via a Diskus DPI.

or solution for nebulized inhalation.

**35.4 Long-Acting Beta2-Agonists**

asthmatic symptoms, for example.

combination products with inhaled corticosteroids.

dose inhaler, an inhalation solution and oral tablet.

symptoms, especially nocturnal symptoms.

pediatric pulmonologist. When allergies are thought to significantly contribute to the morbidity, an allergist may be helpful.

Consider consultation with an ear, nose, and throat (ENT) specialist for help in managing chronic rhinosinusitis. Consider consultation with a gastroenterologist for help in excluding and/or treating gastroesophageal reflux.

### **35. Appendix: Specific pharmacologic treatment**

#### **35.1 Bronchodilators, Beta2-Agonists**

These agents are used to treat bronchospasm in acute asthmatic episodes, and used to prevent bronchospasm associated with exercise-induced asthma or nocturnal asthma. Recent studies have suggested that short-acting beta2-agonists may produce adverse outcomes (eg, decreased peak flow or increased risk of exacerbations) in patients homozygous for arginine (Arg/Arg) at the 16th amino acid position of beta-adrenergic receptor gene compared with patients homozygous for glycine (Gly-Gly). Similar findings are reported for long-acting beta2-agonists, such as salmeterol. 121-122

#### **35.2 Salbutamol sulfate (Proventil HFA, Ventolin HFA, ProAir HFA)**

This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, MOl, PO solution, butalin, ventolin, asthalin, salamol, a.o.). This is most commonly used in rescue therapy for acute asthmatic symptoms. Used as needed. Prolonged use: may be associated with tachyphylaxis due to beta2-receptor down regulation and receptor hyposensitivity.

Some MD is/are available as a breath-actuated inhalers. The ease of administration with the breath-actuated devices make it an attractive choice in the treatment of acute symptoms in younger children who otherwise cannot use an ordinary MDl. The Autohaler delivers 200 mcg per actuation.

Terbutalin, a partial beta-2-agonist is short-acting bronchodilator. The inhaled form of terbutalin starts working within 15 minutes and can last for up to 6 hours.

This nonracemic form of beta-2-agonist (albuterol) offers a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia, hyperglycemia, hypokalemia).

The noncarcemic form of albuterol Levabuterol offers a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia, hyperglycemia, Hypokalemia.

The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation). It is available as an MDI (45 mcg per actuation) or solution for nebulized inhalation).

#### **35.3 Xopenex**

172 Bronchial Asthma – Emerging Therapeutic Strategies

pediatric pulmonologist. When allergies are thought to significantly contribute to the

Consider consultation with an ear, nose, and throat (ENT) specialist for help in managing chronic rhinosinusitis. Consider consultation with a gastroenterologist for help in excluding

These agents are used to treat bronchospasm in acute asthmatic episodes, and used to prevent bronchospasm associated with exercise-induced asthma or nocturnal asthma. Recent studies have suggested that short-acting beta2-agonists may produce adverse outcomes (eg, decreased peak flow or increased risk of exacerbations) in patients homozygous for arginine (Arg/Arg) at the 16th amino acid position of beta-adrenergic receptor gene compared with patients homozygous for glycine (Gly-Gly). Similar findings

This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, MOl, PO solution, butalin, ventolin, asthalin, salamol, a.o.). This is most commonly used in rescue therapy for acute asthmatic symptoms. Used as needed. Prolonged use: may be associated with tachyphylaxis due to beta2-receptor down

Some MD is/are available as a breath-actuated inhalers. The ease of administration with the breath-actuated devices make it an attractive choice in the treatment of acute symptoms in younger children who otherwise cannot use an ordinary MDl. The Autohaler delivers 200

Terbutalin, a partial beta-2-agonist is short-acting bronchodilator. The inhaled form of

This nonracemic form of beta-2-agonist (albuterol) offers a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia,

The noncarcemic form of albuterol Levabuterol offers a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia,

The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation). It is available as an MDI (45 mcg per actuation) or

morbidity, an allergist may be helpful.

and/or treating gastroesophageal reflux.

**35.1 Bronchodilators, Beta2-Agonists**

regulation and receptor hyposensitivity.

mcg per actuation.

hyperglycemia, hypokalemia).

hyperglycemia, Hypokalemia.

solution for nebulized inhalation).

**35. Appendix: Specific pharmacologic treatment**

are reported for long-acting beta2-agonists, such as salmeterol. 121-122

**35.2 Salbutamol sulfate (Proventil HFA, Ventolin HFA, ProAir HFA)**

terbutalin starts working within 15 minutes and can last for up to 6 hours.

Nonracemic form of albuterol (xopenex), levalbuterol (R isomer) is effective in smaller doses and is reported to have fewer adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation). It is available as an MOl (45 mcg per actuation) or solution for nebulized inhalation.

#### **35.4 Long-Acting Beta2-Agonists**

Long-acting bronchodilators (LABA) are not used for the treatment of acute bronchospasm. They are used for the preventive treatment of nocturnal asthma or exercise-induced asthmatic symptoms, for example.

There are 2 LABA are available: salmeterol and formoterol. Both are available as combination products with inhaled corticosteroids.

LABA may increase the chance of severe asthma episodes and death when those episodes occur. Most cases have occurred in patients with severe and/or acutely deteriorating asthma; they have also occurred in a few patients with less severe asthma.

LABAs are not considered first-line medications to treat asthma. LABAs should not be used as isolated medications and should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low- or medium-dose corticosteroids. If used as isolated medication, LABAs should be prescribed by pulmonologist / allergist.

#### **35.5 Salmeterol**

This long-acting preparation of a beta2-agonist is used primarily to treat nocturnal or exercise-induced symptoms. It has no anti-inflammatory action and is not indicated in the treatment of acute bronchospastic episodes. It may be used as an adjunct to inhaled corticosteroids to re9uce the potential adverse effects of the steroids. The medication is delivered via a Diskus DPI.

#### **35.6 Formoterol**

Formoterol is a long-acting B2-agonist. It is marketed in dry powder inhalation, a metereddose inhaler, an inhalation solution and oral tablet.

Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. They are used for long-term control and prevention of symptoms, especially nocturnal symptoms.

#### **35.7 Methylxanthines**

#### **35.7.1 Theophylline**

Theophylline is available in short-acting and long-acting formulations. Because of the need to monitor serum concentrations, this agent is used infrequently. The dose and frequency depend on the particular product selected. The actions of theophylline involve:

Management of Asthma in Children 175

Beclomethasone inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation, decrease the number and activity of inflammatory cells, and decreases airway

Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adolescent patients aged 12 y and older. Not indicated for

Corticosteroids have wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids,

After asthma stability is achieved, it is best to titrate to lowest effective dosage to reduce the possibility of adverse effects. For patients who do not adequately respond to the starting dose after 4 wk of therapy, higher doses may provide additional asthma control. It is

Mometasone is a corticosteroid for inhalation. It is indicated for asthma as prophylactic

Corticosteroids are the most potent anti-inflammatory used in asthma. Systemic corticosteroids (SCS) are effective in acute asthma, pulmonary function slowly improves beginning within 6-12 hours, SCS reduces to relapse rate and admission ranks. Several studies suggest duration of 3-5 days. The anti-inflammatory effects of corticosteroids are mediated to a major extent via TRANSREPRESSION, while many side-effects are due to TRANSACTIVATION. New generations of corticosteroids are being developed that

These agents are used for short courses (3-10 d) to gain prompt control of inadequately controlled acute asthmatic episodes. They are also used for long-term prevention of symptoms in severe persistent asthma as well as for suppression, control, and reversal of inflammation. Frequent and repetitive use of beta2-agonists has been associated with beta2 receptor sub-sensitivity and down regulation; these processes are reversed with

Higher-dose corticosteroids have no advantage in severe asthma exacerbations, and intravenous administration has no advantage over oral therapy, provided that 81 transit time or absorption is not impaired. The usual regimen is to continue frequent multiple daily dosing until the FEV1 or peak expiratory flow (PEF) is 50% of the predicted or personal best values; then, the dose is changed to twice daily. This usually occurs within

preferentially induce TRANSREPRESSION with little or no TRANSACTIVATION.

Maximum benefit may not be achieved for 4 wk or longer after initiation of therapy.

**35.8.5 Mometasone furoate inhalation powder (Asmanex Twisthaler)**

**35.8.3 Beclomethasone**

**35.8.4 Ciclesonide**

available as MDI.127

**35.9 Systemic corticosteroids**

therapy.

corticosteroids.

48 hours.

relief of acute bronchospasm.

hyperresponsiveness. It is available as MDI.

leukotrienes, cytokines) involved in inflammation.

Parenteral methylxanthines (aminophylline, theophylline) may circumvent the dimininshed delivery of aerosolized β-agonists in acute asthma and young children thus augmenting submaximal bronchial smooth-muscle relaxation. Molecular mechanisms specific to theophylline that may be responsible for its beneficial effect include phosphodiesterase enzyme inhibition, adenosine receptor antagonism, enhanced catecholamine secretion, and modulation of transmembrane calcium fluxes in muscle cells. The influence on calcium may be respoinsble for an increase in respiratory muscle contractility and resistance to diaphragmatic fatigue particularly advantageous in asthmatics with early respiratory failure. Methylxanthines may also assume greater importance during β-receptor desensitization where the response to β agonist drugs is attenuated but a response to aminophylline persists. Clinical trials involving submaximal bronchodialation have shown that the benefit from combinations of methylxanthines and βagnosits are more likely additive and synergistic.

The use of theophylline is complicated by its interaction with other drugs, chiefly cimetidine and phenytoin, erythromycin, ciprofloxacin and fluoroquinolones and that it has a narrow therapeutic index. It can cause nausea, diarrhea, tachycardia, headache, insomnia

#### **35.8 Inhaled corticosteroids**

Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed and thus less likely to cause adverse effects. They are used for long-term control of asthma symptoms and airway inflammation. Inhaled forms reduce the need for systemic corticosteroids.

Inhaled steroids block late asthmatic response to allergens; reduce airway hyper responsiveness; inhibit inflammatory process e.g. cytokine production, adhesion protein activation, and inflammatory cell migration and activation; and reverse beta2-receptor downregulation and subsensitivity (in acute asthmatic episodes with LABA use). 126-127

#### **35.8.1 Fluticasone**

Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as an MDl aerosolized product (HFA) or DPI (Diskus).

#### **35.8.2 Budesonide**

Budesonide has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as a DPI, MDI and nebulized susp (ie, Respules).

#### **35.8.3 Beclomethasone**

174 Bronchial Asthma – Emerging Therapeutic Strategies

central nervous system stimulatory effect mainly on medullary respiratory center.123-125

Parenteral methylxanthines (aminophylline, theophylline) may circumvent the dimininshed delivery of aerosolized β-agonists in acute asthma and young children thus augmenting submaximal bronchial smooth-muscle relaxation. Molecular mechanisms specific to theophylline that may be responsible for its beneficial effect include phosphodiesterase enzyme inhibition, adenosine receptor antagonism, enhanced catecholamine secretion, and modulation of transmembrane calcium fluxes in muscle cells. The influence on calcium may be respoinsble for an increase in respiratory muscle contractility and resistance to diaphragmatic fatigue particularly advantageous in asthmatics with early respiratory failure. Methylxanthines may also assume greater importance during β-receptor desensitization where the response to β agonist drugs is attenuated but a response to aminophylline persists. Clinical trials involving submaximal bronchodialation have shown that the benefit from combinations of methylxanthines and β-

The use of theophylline is complicated by its interaction with other drugs, chiefly cimetidine and phenytoin, erythromycin, ciprofloxacin and fluoroquinolones and that it has a narrow

Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed and thus less likely to cause adverse effects. They are used for long-term control of asthma symptoms and airway inflammation. Inhaled forms reduce the need for

Inhaled steroids block late asthmatic response to allergens; reduce airway hyper responsiveness; inhibit inflammatory process e.g. cytokine production, adhesion protein activation, and inflammatory cell migration and activation; and reverse beta2-receptor downregulation and subsensitivity (in acute asthmatic episodes with LABA use). 126-127

Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically.

Budesonide has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically.

It is available as an MDl aerosolized product (HFA) or DPI (Diskus).

It is available as a DPI, MDI and nebulized susp (ie, Respules).

therapeutic index. It can cause nausea, diarrhea, tachycardia, headache, insomnia

increasing heart muscle contractility and efficiency as a positive inotropic

relaxing bronchial smooth muscle

 increasing blood pressure increasing renal blood flow some anti-inflammatory effects

**35.8 Inhaled corticosteroids**

systemic corticosteroids.

**35.8.1 Fluticasone**

**35.8.2 Budesonide**

increasing heart rate positive chronotrope

agnosits are more likely additive and synergistic.

Beclomethasone inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation, decrease the number and activity of inflammatory cells, and decreases airway hyperresponsiveness. It is available as MDI.

#### **35.8.4 Ciclesonide**

Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adolescent patients aged 12 y and older. Not indicated for relief of acute bronchospasm.

Corticosteroids have wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in inflammation.

Maximum benefit may not be achieved for 4 wk or longer after initiation of therapy.

After asthma stability is achieved, it is best to titrate to lowest effective dosage to reduce the possibility of adverse effects. For patients who do not adequately respond to the starting dose after 4 wk of therapy, higher doses may provide additional asthma control. It is available as MDI.127

#### **35.8.5 Mometasone furoate inhalation powder (Asmanex Twisthaler)**

Mometasone is a corticosteroid for inhalation. It is indicated for asthma as prophylactic therapy.

#### **35.9 Systemic corticosteroids**

Corticosteroids are the most potent anti-inflammatory used in asthma. Systemic corticosteroids (SCS) are effective in acute asthma, pulmonary function slowly improves beginning within 6-12 hours, SCS reduces to relapse rate and admission ranks. Several studies suggest duration of 3-5 days. The anti-inflammatory effects of corticosteroids are mediated to a major extent via TRANSREPRESSION, while many side-effects are due to TRANSACTIVATION. New generations of corticosteroids are being developed that preferentially induce TRANSREPRESSION with little or no TRANSACTIVATION.

These agents are used for short courses (3-10 d) to gain prompt control of inadequately controlled acute asthmatic episodes. They are also used for long-term prevention of symptoms in severe persistent asthma as well as for suppression, control, and reversal of inflammation. Frequent and repetitive use of beta2-agonists has been associated with beta2 receptor sub-sensitivity and down regulation; these processes are reversed with corticosteroids.

Higher-dose corticosteroids have no advantage in severe asthma exacerbations, and intravenous administration has no advantage over oral therapy, provided that 81 transit time or absorption is not impaired. The usual regimen is to continue frequent multiple daily dosing until the FEV1 or peak expiratory flow (PEF) is 50% of the predicted or personal best values; then, the dose is changed to twice daily. This usually occurs within 48 hours.

Management of Asthma in Children 177

The last agent introduced in its class, montelukast has the advantages that it is chewable, it

Omalizumab is a recombinant, DNA-derived, humanized IgG 1K monoclonal antibody that selectively binds to human Immunoglobulin (IgE). Omalizumab's cost is very high as compared with other drugs used for asthma, and hence is mainly prescribed for patients with severe persistent asthma, which can not be controlled even with high doses of corticosteroids like other protein drugs, omalizumab may cause anaphylaxis in 1 to 2 patients per 1000.

These combinations may de\crease asthma exacerbations when inhaled short-acting beta2 agonists and corticosteroids have failed. Refer to previous discussion in the LABAs section regarding increased risk of severe asthma episodes and death with LABAs. In a recent study, use of combination therapy using fluticasone propionate and salmeterol prolonged

Budesonide is an inhaled corticosteroid that alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. Available as MDl in 2 strengths; each

Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. Budesonide is an inhaled corticosteroid that alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. This combination is available as an MOl in 2 strengths; each actuation delivers formoterol

This is a combination corticosteroid and LABA metered-dose inhaler. Mometasone elicits local anti-inflammatory effects in the respiratory tract with minimal systemic absorption.

This combination is indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled with other asthma controller medications (eg, low-dose to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 2 strengths; each

This is a combination corticosteroid and LABA metered-dose inhaler. Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may

actuation delivers mometasone/formoterol 100 mcg/5 mcg or 200 mcg/5 mcg.

has a once-a-day dosing, and it has no significant adverse effects.

**35.12 Combination inhaled steroids/Long-Acting Beta2-Agonists**

actuation delivers formoterol 4.5 mcg with either 80 mcg or 160 mcg.

4.5-mcg with either 80-mcg or 160-mcg of budesonide.

Formoterol elicits bronchial smooth muscle relaxation.

**35.11.2 Montelukast**

**35.11.3 Omalizumab**

time to first severe asthma exacerbation.

**35.12.1 Budesonide and formoterol**

**35.12.2 Mometasone and formoterol**

**35.12.3 Fluticasone and salmeterol**

#### **35.9.1 Prednisone**

An immunosuppressant for the treatment of autoimmune disorders, prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity.

#### **35.9.2 Methylprednisolone**

Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

#### **35.10 Leukotriene modifiers**

Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and inflammatory cell infiltration has led to the concept of modifying their action by using pharmacologic agents. These are either 5-lipoxygenase inhibitors or leukotriene-receptor antagonists.

#### **35.11 Leukotriene antagonists**

These are drugs that inhibit leukotrienes and thus suppress inflammation. Leukotriene antagonists such as montelukast, zafirlukast are used in asthma to block the actions of leukotrienes, either by inhibition of the cysteinyl-leukotriene type 1 receptors. (Montelukast, Zafirlukast)

#### **35.11.1 Zafirlukast**

Zapirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.

The leukotriene-antagonist zafirlukast (Accolate), and montelukast (Singulaire) are proving to be effective for long-term prevention of asthma, including exercise-induced asthma and aspirin (or NSAID)-induced asthma. Their anti-inflammatory actions are different from those of steroids.

Studies suggest that montelukast, wheich comes in a chewable tablet, may be particularly useful for managing asthma in small children (ages two to five) with asthma, since they have trouble with inhaled steroids. Zafirlukast may also reduce the severity of cat allergies, regardless of whether or not asthma is also present.

Of some concern are reports of Churg-Satrauss syncrome in a few people taking zafirlukast or montelukast. Churg-Strauss syndrome is very rare, but it causes blood vessel inflammation in the lungs and can be life threatening. Oral steroids quickly resolve the problem. In fact, usually the syndrome has occurred in patients who were tapering off steroids and changing over to the leukotrines-antagonist. Some experts believe that, in such cases, the steroids may simply have masked the presence of the disorder, which then developed when the steroid drugs were withdrawn. Symptoms include severe sinusitis, flu-like symptoms, rash, and numbness in the hands and feet.

#### **35.11.2 Montelukast**

176 Bronchial Asthma – Emerging Therapeutic Strategies

An immunosuppressant for the treatment of autoimmune disorders, prednisone may decrease inflammation by reversing increased capillary permeability and suppressing

Methylprednisolone may decrease inflammation by reversing increased capillary

Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and inflammatory cell infiltration has led to the concept of modifying their action by using pharmacologic agents. These are either 5-lipoxygenase inhibitors or

These are drugs that inhibit leukotrienes and thus suppress inflammation. Leukotriene antagonists such as montelukast, zafirlukast are used in asthma to block the actions of leukotrienes, either by inhibition of the cysteinyl-leukotriene type 1 receptors. (Montelukast,

The leukotriene-antagonist zafirlukast (Accolate), and montelukast (Singulaire) are proving to be effective for long-term prevention of asthma, including exercise-induced asthma and aspirin (or NSAID)-induced asthma. Their anti-inflammatory actions are

Studies suggest that montelukast, wheich comes in a chewable tablet, may be particularly useful for managing asthma in small children (ages two to five) with asthma, since they have trouble with inhaled steroids. Zafirlukast may also reduce the

Of some concern are reports of Churg-Satrauss syncrome in a few people taking zafirlukast or montelukast. Churg-Strauss syndrome is very rare, but it causes blood vessel inflammation in the lungs and can be life threatening. Oral steroids quickly resolve the problem. In fact, usually the syndrome has occurred in patients who were tapering off steroids and changing over to the leukotrines-antagonist. Some experts believe that, in such cases, the steroids may simply have masked the presence of the disorder, which then developed when the steroid drugs were withdrawn. Symptoms include severe sinusitis, flu-like symptoms, rash, and numbness in the hands and feet.

severity of cat allergies, regardless of whether or not asthma is also present.

Zapirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.

**35.9.1 Prednisone**

**35.9.2 Methylprednisolone**

**35.10 Leukotriene modifiers**

leukotriene-receptor antagonists.

**35.11 Leukotriene antagonists**

different from those of steroids.

Zafirlukast)

**35.11.1 Zafirlukast**

polymorphonuclear neutrophil (PMN) activity.

permeability and suppressing PMN activity.

The last agent introduced in its class, montelukast has the advantages that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.

#### **35.11.3 Omalizumab**

Omalizumab is a recombinant, DNA-derived, humanized IgG 1K monoclonal antibody that selectively binds to human Immunoglobulin (IgE). Omalizumab's cost is very high as compared with other drugs used for asthma, and hence is mainly prescribed for patients with severe persistent asthma, which can not be controlled even with high doses of corticosteroids like other protein drugs, omalizumab may cause anaphylaxis in 1 to 2 patients per 1000.

#### **35.12 Combination inhaled steroids/Long-Acting Beta2-Agonists**

These combinations may de\crease asthma exacerbations when inhaled short-acting beta2 agonists and corticosteroids have failed. Refer to previous discussion in the LABAs section regarding increased risk of severe asthma episodes and death with LABAs. In a recent study, use of combination therapy using fluticasone propionate and salmeterol prolonged time to first severe asthma exacerbation.

Budesonide is an inhaled corticosteroid that alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. Available as MDl in 2 strengths; each actuation delivers formoterol 4.5 mcg with either 80 mcg or 160 mcg.

#### **35.12.1 Budesonide and formoterol**

Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. Budesonide is an inhaled corticosteroid that alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. This combination is available as an MOl in 2 strengths; each actuation delivers formoterol 4.5-mcg with either 80-mcg or 160-mcg of budesonide.

#### **35.12.2 Mometasone and formoterol**

This is a combination corticosteroid and LABA metered-dose inhaler. Mometasone elicits local anti-inflammatory effects in the respiratory tract with minimal systemic absorption. Formoterol elicits bronchial smooth muscle relaxation.

This combination is indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled with other asthma controller medications (eg, low-dose to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 2 strengths; each actuation delivers mometasone/formoterol 100 mcg/5 mcg or 200 mcg/5 mcg.

#### **35.12.3 Fluticasone and salmeterol**

This is a combination corticosteroid and LABA metered-dose inhaler. Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may

Management of Asthma in Children 179

decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis and can relieve bronchospasms. Its effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at high or more frequent doses than recommended. Two delivery mechanisms are available (ie, powder for inhalation [Diskus], metered-dose inhaler [MDl]). Diskus is available as a combination of salmeterol 50 mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. The MDl is available as 21 mcg salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg.

#### **35.13 Anticholinergic drugs**

Anticholinergic drugs are group of bronchodilators that block the neurotransmitter acetylcholine on the muscarinic receptor on bronchial smooth muscle.

#### **35.13.1 Ipratropium bromide**

Chemically related to atropine, protropium has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. The MDl delivers 17 mcg/actuation. Solution for inhalation contains 500 mcg/2.5 mL (ie, 0.02% solution for nebulization).

decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis and can relieve bronchospasms. Its effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at high or more frequent doses than recommended. Two delivery mechanisms are available (ie, powder for inhalation [Diskus], metered-dose inhaler [MDl]). Diskus is available as a combination of salmeterol 50 mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. The MDl is available as 21 mcg

Anticholinergic drugs are group of bronchodilators that block the neurotransmitter

Chemically related to atropine, protropium has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. The MDl delivers 17 mcg/actuation. Solution for inhalation contains 500 mcg/2.5 mL (ie, 0.02%

salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg.

acetylcholine on the muscarinic receptor on bronchial smooth muscle.

**35.13 Anticholinergic drugs**

**35.13.1 Ipratropium bromide**

solution for nebulization).

Source: Management of Asthma in Children aged 1-15 years (Ped. Society of New Zealand)

Source: Management of Asthma in Children aged 1-15 years (Ped. Society of New Zealand)

Management of Asthma in Children 185

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