Bronchial asthma- Etiology, pathogenesis, clinical features, diagnostics, treatment and prophylactic

Asthma (from the Greek άσθμα, ásthma, "panting") is a common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath. Treatment of acute symptoms is usually with an inhaled short-acting beta-2 agonist (such as salbutamol). Symptoms can be prevented by avoiding triggers, such as allergens and irritants, and by inhaling corticosteroid

Add Asthma is an acquired hypersensitivity to a foreign substance or event that causes a narrowing of the bronchial airways in the lungs. Asthma attacks are triggered by a combination of factors such as allergens, pollutants, viral infections, exercise, caption

what is Asthma all about?

Asthma is a chronic inflammatory disorder of the airways characterized by an obstruction of airflow, which may be completely or partially reversed with or without specific therapy. Airway inflammation is the result of interactions between various cells, cellular elements, and cytokines. In susceptible individuals, airway inflammation may cause recurrent or persistent bronchospasm, which causes symptoms including wheezing, breathlessness, chest tightness, and cough, particularly at night or after exercise.

Two million Australians suffer from the agony of asthma. Each year, more than 700 of us die from what has become Australia's most widespread chronic disease. Fortunately, better drugs are providing much-needed relief for severe suffers. But imagine i

Source: Asthma patient

Airway inflammation is associated with airway hyperreactivity or bronchial hyperresponsiveness(BHR), which is defined as the inherent tendency of the airways to narrow in response to a variety of stimuli (eg, environmental allergens and irritants).

Approximately 500,000 annual hospitalizations (34.6% in persons <18 y) are because of asthma. The cost of illness related to asthma is around $6.2 billion. Each year, an estimated 1.81 million people (47.8% £18 y) require treatment in the emergency department. Among children and adolescents aged 5-17 years, asthma accounts for a loss of 10 million school days and costs caretakers $726.1 million because of work absence.

Pathophysiology

Interactions between environmental and genetic factors result in airway inflammation, which limits airflow and leads to functional and structural changes in the airways in the form of bronchospasm, mucosal edema, and mucus plugs.

NKT cells release cytokines in response to allergens, triggering inflammation. The air passages become inflammed and mucus filled.

Bronchial obstruction in case of Asthma

Asthma is a chronic, reversible, obstructive airway disease, characterized by wheezing. It is caused by a spasm of the bronchial tubes, or the swelling of the bronchial mucosa, after exposure to various stimuli. Asthma is the most common chronic dise

 child with inhale

Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates. These changes lead to a decreased ability to expel air and may result in hyperinflation. The resultingoverdistention helps maintain airway patency, thereby improving expiratory flow; however, it also alters pulmonary mechanics and increases the work of breathing.

Hyperinflation compensates for the airflow obstruction, but this compensation is limited when the tidal volume approaches the volume of the pulmonary dead space; the result is alveolar hypoventilation. Uneven changes in airflow resistance, the resulting uneven distribution of air, and alterations in circulation from increased intraalveolar pressure due to hyperinflation all lead to ventilation-perfusion mismatch. Hypoxic vasoconstriction also contributes to this mismatch.

In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is prevented by the ready diffusion of carbon dioxide across alveolar capillary membranes. Thus, asthmatic patients who are in the early stages of an acute episode have hypoxemia in the absence of carbon dioxide retention. Hyperventilation triggered by the hypoxic drive also causes a decrease in PaCO₂. An increase in alveolar ventilation in the early stages of an acute exacerbation prevents hypercarbia. With worsening obstruction and increasing ventilation-perfusion mismatch, carbon dioxide retention occurs. In the early stages of an acute episode, respiratory alkalosis results from hyperventilation. Later, the increased work of breathing, increased oxygen consumption, and increased cardiac output result in metabolic acidosis. Respiratory failure leads to respiratory acidosis.

Chronic inflammation of the airways is associated with increased BHR, which leads to bronchospasmand typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens, environmental irritants, viruses, cold air, or exercise. In some patients with chronic asthma, airflow limitation may be only partially reversible because of airway remodeling (hypertrophy and hyperplasia of smooth muscle, subepithelial fibrosis) that occurs with chronic untreated disease.

New insights in the pathogenesis of asthma suggest the role of lymphocytes. Airway inflammation in asthma may represent a loss of normal balance between two "opposing" populations ofTh lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and Th2. Th1 cells produce IL-2 and IFN-a , which are critical in cellular defense mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (IL-4, -5, -6, -9, and -13) that can mediate allergic inflammation. The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may explain some of the dramatic increases in asthma prevalence in Westernized countries. This hypothesis is based on the assumption that the immune system of the newborn is skewed toward Th2 cytokine generation. Following birth, environmental stimuli such as infections will activate Th1 responses and bring the Th1/Th2 relationship to an appropriate balance.

Evidence exists that the prevalence of asthma is reduced in association with certain infections (Mycobacterium tuberculosis, measles, or hepatitis A); exposure to other children (eg, presence of older siblings and early enrollment in childcare); and less frequent use of antibiotics. Furthermore, the absence of these lifestyle events is associated with the persistence of a Th2 cytokine pattern.

Under these conditions, the genetic background of the child, with a cytokine imbalance toward Th2, will set the stage to promote the production of IgE antibody to key environmental antigens (eg, dust mites, cockroaches, Alternaria, and possibly cats). Therefore, a gene-by-environment interaction occurs in which the susceptible host is exposed to environmental factors that are capable of generatingIgE, and sensitization occurs. A reciprocal interaction seems to exist between the two subpopulations in which Th1 cytokines can inhibit Th2 generation and vice versa. Allergic inflammation may be the result of an excessive expression of Th2 cytokines. Alternately, the possibility that the loss of normal immune balance arises from a cytokine dysregulation in which Th1 activity in asthma is diminished has been suggested in recent studies.

In preschool children with asthma, 2 years of inhaled corticosteroid therapy did not change the asthma symptoms or lung function during a third, treatment-free year. This suggests that no disease-modifying effect of inhaled corticosteroids is present after the treatment is discontinued.

Recent evidence suggests that rhinovirus is a significant risk factor for the development of wheeze in preschool children and a frequent trigger of wheezing illnesses in children with asthma.

Frequency

• In the US: Approximately 17.3 million Americans have asthma. The prevalence of asthma in the general population is 5%, and it has increased 40% in the past decade. Asthma accounts for more school absences and more hospitalizations than any other chronic illness. In most children's hospitals in the United States, it is the most common diagnosis at admission.

• Internationally: Worldwide, 130 million people have asthma. The prevalence is 8-10 times higher in developed countries (eg, United States, Great Britain, Australia, New Zealand) than in the developing countries. In developed countries, the prevalence is higher in low income groups in urban areas and inner cities than in other groups.

Mortality/Morbidity

Globally, morbidity and mortality associated with asthma have increased over the last 2 decades. This increase is attributed to increasing urbanization. Despite advancements in our understanding of asthma and the development of new therapeutic strategies, the morbidity and mortality rates due to asthma definitely increased between 1980 and 1995. In the United States, the mortality rate due to asthma has increased in all age, race, and sex strata. In the United States, the mortality rate due to asthma is more than 17 deaths per 1 million people (ie, 5000 deaths per y). From 1975-1993, the number of deaths nearly doubled in people aged 5-14 years. In the northeastern and midwestern United States, the highest mortality rate has been among persons aged 5-34 years.

Race

The prevalence of asthma is higher in minority groups (eg, blacks, Hispanics) than in other groups; however, findings from one study suggest that much of the recent increase in the prevalence is attributed to asthma in white children. About 5-8% of all black children have asthma at some time. The prevalence in Hispanic children is reported to be as high as 15%. In blacks, the death rate is consistently higher than in whites.

Sex

Before puberty, the prevalence is 3 times higher in boys than in girls. During adolescence, the prevalence is equal among males and females. Adult-onset asthma is more common in women than in men.

Age

In most children, asthma develops before they are aged 5 years, and, in more than half, asthma develops before they are aged 3 years.

Among infants, 20% have wheezing with only upper respiratory tract infections (URTIs), and 60% no longer have wheezing when they are aged 6 years. Many of these children were called "transient wheezers" by Martinez et al. They tend to have no allergies, although their lung function is often abnormal. These findings have led to the idea that they have small lungs. Children in whom wheezing begins early, in conjunction with allergies, are more likely to have wheezing when they are aged 6 and 11 years. Similarly, children in whom wheezing begins after they are aged 6 years often have allergies, and the wheezing is more likely to continue when they are aged 11 years.

CLINICAL MANIFESTATION

History

The National Asthma Education and Prevention Program Expert Panel Report II (EPR-2), "Guidelines for the Diagnosis and Management of Asthma," highlights the importance of correctly diagnosing asthma. To establish the diagnosis of asthma, the clinician must establish the following: (a) episodic symptoms of airflow obstruction are present, (b) airflow obstruction or symptoms are at least partially reversible, and (c) alternative diagnoses are excluded.

The severity of asthma is classified as mild intermittent, mild persistent, moderate persistent, or severe persistent, according to the frequency and severity of symptoms, including nocturnal symptoms, characteristics of acute episodes, and pulmonary function. These categories do not always work well in children. First, lung function is difficult to assess in younger children. Second, asthma that is triggered solely by viral infections does not fit into any category. While the symptoms may be intermittent, they may be severe enough to warrant hospitalization. Therefore, a category of severe intermittent asthma has been suggested. Features of the categories include the following:

• Patients with mild intermittent disease have symptoms fewer than 2 times a week, and pulmonary function is normal between exacerbations. Exacerbations are brief, lasting from a few hours to a few days. Nighttime symptoms occur less than twice a month. The variation in peak expiratory flow (PEF) is less than 20%.

• Patients with mild persistent asthma have symptoms more than 2 times a week but less than once a day. Exacerbations may affect activity. Nighttime symptoms occur more than twice a month. Pulmonary function test results (in age-appropriate patients) demonstrate that the forced expiratory volume in 1 second (FEV₁) or PEF is less than 80% of the predicted value, and the variation in PEF is 20-30%.

• Patients with moderate persistent asthma have daily symptoms and use inhaled short-acting beta2-agonists every day. Acute exacerbations in patients with moderate persistent asthma may occur more than 2 times a week and last for days. The exacerbations affect activity. Nocturnal symptoms occur more than once a week. FEV₁ and PEF values are 60-80% of the predicted values, and PEF varies by more than 30%.

• Patients with severe persistent asthma have continuous or frequent symptoms, limited physical activity, and frequent nocturnal symptoms. FEV₁ and PEF values are less than 60% of the predicted values, and PEF varies by more than 30%.

• Disease with any of their features is assigned to the most severe grade. The presence of one severe feature is sufficient to diagnose severe persistent asthma. The characteristics in this classification system are general and may overlap because asthma is highly variable. The classification may change over time. Patients with asthma of any level of severity may have mild, moderate, or severe exacerbations. Some patients with intermittent asthma have severe and life-threatening exacerbations separated by episodes with almost normal lung function and minimal symptoms; however, they are likely to have other evidence of increased BHR (exercise or challenge testing) due to ongoing inflammation.

• Symptoms of asthma may include wheezing, coughing, and chest tightness, among others.

• Wheezing

• A musical, high-pitched, whistling sound produced by airflow turbulence is one of the most common symptoms.
• In the mildest form, wheezing is only end expiratory. As severity increases, the wheeze lasts throughout expiration. In a more severe asthmatic episode, wheezing is also present during inspiration. During a most severe episode, wheezing may be absent because of the severe limitation of airflow associated with airway narrowing and respiratory muscle fatigue.
• Asthma can occur without wheezing when obstruction involves predominantly the small airways. Thus, wheezing is not necessary for the diagnosis of asthma. Furthermore, wheezing can be associated with other causes of airway obstruction, such as cystic fibrosis and heart failure.
• Patients with vocal cord dysfunction have a predominantly inspiratory monophonic wheeze (different from the polyphonic wheeze in asthma), which is heard best over the laryngeal area in the neck. Patients with bronchomalacia and tracheomalacia also have a monophonic wheeze.
• In exercise-induced or nocturnal asthma, wheezing may be present after exercise or during the night, respectively.

• Coughing: Cough may be the only symptom of asthma, especially in cases of exercise-induced or nocturnal asthma. Usually, the cough is nonproductive and nonparoxysmal. Also, coughing may be present with wheezing. Children with nocturnal asthma tend to cough after midnight, during the early hours of morning.

• Chest tightness: A history of tightness or pain in the chest may be present with or without other symptoms of asthma, especially in exercise-induced or nocturnal asthma.

• Other nonspecific symptoms: Infants or young children may have history of recurrent bronchitis,bronchiolitis, or pneumonia; a persistent cough with colds; and/or recurrent croup or chest rattling. Most children with chronic or recurrent bronchitis have asthma. Asthma is the most common underlying diagnosis in children with recurrent pneumonia. Older children may have a history of chest tightness and/or recurrent chest congestion.

• During an acute episode, symptoms vary according to the severity.

• Symptoms during a mild episode: Patients may be breathless after physical activity such as walking. They can talk in sentences and lie down, and they may be agitated.

• Symptoms during a moderate severe episode: Patients are breathless while talking. Infants havefeeding difficulties and a softer, shorter cry.

• Symptoms during a severe episode: Patients are breathless during rest, are not interested in feeding, sit upright, talk in words (not sentences), and are usually agitated.

• Symptoms with imminent respiratory arrest (in addition to the aforementioned symptoms): The child is drowsy and confused. However, adolescents may not have these symptoms until they are in frank respiratory failure.

Physical

• The clinical picture varies. Symptoms may be associated with URTIs, nocturnal or exercise-induced asthmatic symptoms, and status asthmaticus. Status asthmaticus, or an acute severe asthmatic episode that is resistant to appropriate outpatient therapy, is a medical emergency that requires aggressive hospital management. This may include admission to an ICU for the treatment of hypoxia, hypercarbia, and dehydration and possibly for assisted ventilation because of respiratory failure.

• Physical findings vary with the absence or presence of an acute episode and its severity, as follows:

• Physical examination in the absence of an acute episode (eg, during an outpatient visit between acute episodes)

• The physical findings vary with the severity of the asthma. During an outpatient visit, it is not uncommon for a patient with mild asthma to have normal findings at 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, ocular shiners, a transverse crease on the nose due to constant rubbing associated with allergic rhinitis, and pale violaceous nasal mucosa 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 prolongation of the expiratory phase, expiratory wheezing, coarse crackles, or unequal breath sounds.

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

• Physical examination during an acute episode may reveal different findings in mild, moderately severe, and severe episodes and in status asthmaticus with imminent respiratory arrest.

• Mild episode: The respiratory rate is increased. Accessory muscles of respiration are not used. The heart rate is less than 100 beats per minute. Pulsus paradoxus is not present. Auscultation of chest reveals moderate wheezing, which is often end expiratory. Oxyhemoglobin saturation withroom air is greater than 95%.

• Moderately severe episode: The respiratory rate is increased. Typically, accessory muscles of respiration are used, and suprasternal retractions are present. The heart rate is 100-120 beats per minute. Loud expiratory wheezing can be heard. Pulsus paradoxus may be present (10-20 mmHg). Oxyhemoglobin saturation with room air is 91-95%.

• Severe episode: The respiratory rate is often greater than 30 breaths per minute. Accessory muscles of respiration are usually used, and suprasternal retractions are commonly present. The heart rate is more than 120 beats per minute. Loud biphasic (expiratory and inspiratory) wheezing can be heard. Pulsus paradoxus is often present (20-40 mm Hg). Oxyhemoglobin saturation with room air is less than 91%.

• Status asthmaticus with imminent respiratory arrest: Paradoxical thoracoabdominal movement occurs. Wheezing may be absent (associated with most severe airway obstruction). Severe hypoxemia may manifest as bradycardia. Pulsus paradoxus noted earlier may be absent; this finding suggests respiratory muscle fatigue.

Causes

In most cases of asthma in children, multiple triggers or precipitants exist, and the patterns of reactivity may change with age. Treatment can also change the pattern. Certain viral infections, such as respiratory syncytial virus (RSV) bronchiolitis in infancy, predispose the child to asthma.

• Respiratory infections: Most commonly, these are viral infections. In some patients, fungi (eg, allergic bronchopulmonary aspergillosis), bacteria (eg, mycoplasmata, pertussis), or parasites may be responsible. Most infants and young children who continue to have a persistent wheeze and asthma have high immunoglobulin E (IgE) production and eosinophilic immune responses (in the airways and in circulation) at the time of the first viral URTI. They also have early IgE-mediated responses to local aeroallergens.

• Allergens: In patients with asthma, 2 types of bronchoconstrictor responses to allergens exist.

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

• 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, roach allergens, dust mites), or seasonal outdoor allergens (eg, mold spores, pollens, grass, trees).

• Irritants: Tobacco smoke, cold air, chemicals, perfumes, paint odors, hair sprays, air pollutants, and ozone can initiate BHR by inducing inflammation.

• Weather changes: Asthma attacks can be related to changes in atmospheric temperature, barometric pressure, and the quality of air (eg, humidity, allergen and irritant content).

• Exercise: Exercise can trigger an early asthmatic response. Mechanisms underlying exercise-induced asthmatic response remain somewhat uncertain. Heat and water loss from the airways can increase the osmolarity 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 rewarmingphase after exercise, the changes are magnified because the ambient air breathed during recovery is warm rather than cool.

• Emotional factors: In some individuals, emotional upsets clearly aggravate asthma.

• Gastroesophageal reflux (GER): The presence of acid in the distal esophagus, mediated via vagalor other neural reflexes, can significantly increase airway resistance and airway reactivity.

• Allergic rhinitis, sinusitis, and chronic URTI: 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.

• Nocturnal asthma: Multiple factors have been proposed to explain nocturnal asthma. Circadian variation in lung function and inflammatory mediator release in the circulation and airways (including parenchyma) have been demonstrated. Other factors, such as allergen exposure and posture-related irritation of airways (eg, GER, sinusitis), can also play a role. In some patients, abnormalities in CNS control of the respiratory drive may be present, particularly in patients with a defective hypoxic drive and obstructive sleep apnea

Laboratory Studies

• Pulmonary function test (PFT) results are not reliable in patients younger than 5 years. In young children (3-6 y) and older children who can't perform the conventional spirometrymaneuver, newer techniques, such as measurement of airway resistance using impulseoscillometry system, are being tried. Measurement of airway resistance before and after a dose of inhaled bronchodilator may help to diagnose bronchodilator responsive airway obstruction.

• Spirometry: In a typical case, an obstructive defect is present in the form of normal forced vital capacity (FVC), reduced FEV₁, and reduced forced expiratory flow over 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 central 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. Take care to ensure maximum patient effort. However, a normal peak flow rate does not necessarily mean a lack of airway obstruction.

• 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. Airwayresistance is increased when significant obstruction is present.

• Bronchial provocation tests: Bronchial provocation tests may be performed to diagnose BHR. These tests are performed in specialized laboratories by specially trained personnel to document airway hyperresponsiveness 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).

• 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 a patient of appropriate age (usually >6 y), 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. The patient should be breathing cold, dry air during the exercise to increase the yield of the study. Spirographic findings and the PEF rate (PEFR) are determined immediately after the exercise period and at 3, 5, 10, 15, and 20 minutes after the first measurement. The maximal decrease in lung function is calculated by using the lowest postexercise and highest preexercise values. The reversibility of airway obstruction can be assessed by administering aerosolized bronchodilators.

• Blood testing: Eosinophil counts and IgE levels may help when allergic factors are suspected.

• Recent evidence suggests the usefulness of measuring the fraction of exhaled nitric oxide (FeNO) as a noninvasive marker of airway inflammation, in order to adjust the dose of inhaled corticosteroids treatment. Currently FeNO measurement, due to high cost of equipment, is used primarily as a research tool.

IMAGING STUDIES

Asthma is a disease in which inflammation of the airways causes airflow into and out of the lungs to be restricted. When an asthma attack occurs, mucus production is increased, muscles of the bronchial tree become tight, and the lining of the air pas

• Chest radiography: Include chest radiography in the initial workup if the asthma does not respond to therapy as expected. In addition to typical findings of 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.

Asthma is a disease in which inflammation of the airways causes airflow into and out of the lungs to be restricted. When an asthma attack occurs, mucus production is increased, muscles of the bronchial tree become tight, and the lining of the air pas

• Paranasal sinus radiography or CT scanning: Consider using these to rule out sinusitis.

Other Tests

• Allergy testing: 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 duration of action) before allergy testing. Topical or systemic corticosteroids do not affect the skin reaction.

Histologic Findings

Asthma is an inflammatory disease characterized by the recruitment of 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. 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.

TREATMENT OF PATIENTS

Medical Care

The goals of asthma therapy are to prevent chronic and troublesome symptoms, maintain normal or near-normal pulmonary function, maintain normal physical activity levels (including exercise), prevent recurrent exacerbations of asthma, and minimize the need for emergency department visits or hospitalizations, provide optimal pharmacotherapy with minimal or no adverse effects, and meet the family's expectations for asthma care.

Medical care includes treatment of acute asthmatic episodes and control of chronic symptoms, including nocturnal and exercise-induced asthmatic symptoms. Pharmacologic management includes the use of control agents such as inhaled corticosteroids, inhaled cromolyn or nedocromil, long-acting bronchodilators, theophylline, leukotriene modifiers, and recently introduced strategies such as the use of anti-IgE antibodies. Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium. Nonpharmacologic management includes measures to improve patient compliance and adherence. 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.

A step-down approach based on the asthma severity classification system emphasizes the initiation of high-level therapy to establish prompt control and then decreasing therapy (National Asthma Education and Prevention Program Expert Panel Report II, 1997). Treatment should be reviewed every 1-6 months; a gradual stepwise reduction in treatment may be possible. If control is not maintained despite adequate medication and adherence and the exclusion of contributing environmental factors, increased therapy should be considered. Long- and short-term therapy is based on the severity of asthma, as follows:

• Mild intermittent asthma

• Long-term control: Usually, no daily medication is needed.
• Quick relief: Short-acting bronchodilators in the form of inhaled beta2-agonists should be used as needed for symptom control. The use of short-acting inhaled beta2-agonists more than 2 times a week may indicate the need to initiate long-term control therapy.

• Mild persistent asthma

• Long-term control: Anti-inflammatory treatment in the form of low-dose inhaled corticosteroids or nonsteroidal agents (eg, cromolyn, nedocromil) is preferred. Some evidence suggests that leukotriene antagonists may be useful as first-line therapy in children. Recently, the use of montelukast was approved for children aged 2 years and older.
• Quick relief: Short-acting bronchodilators in the form of inhaled beta2-agonists should be used as needed for symptom control. Use of short-acting inhaled beta2-agonists on a daily basis or increasing use indicates the need for additional long-term therapy.

• Moderate persistent asthma

• Long-term control: Daily anti-inflammatory treatment in the form of inhaled corticosteroids (medium dose) is preferred. Otherwise, low- or medium-dose inhaled corticosteroids combined with a long-acting bronchodilator or leukotriene antagonist can be used, especially for the control of nocturnal or exercise-induced asthmatic symptoms.
• Quick relief: Short-acting bronchodilators in the form of inhaled beta2-agonists should be used as needed for symptom control. The use of short-acting inhaled beta2-agonists on a daily basis or increasing use indicates the need for additional long-term therapy.

• Severe persistent asthma

• Long-term control

• Daily anti-inflammatory treatment in the form of inhaled corticosteroids (high dose) is preferred. Other medications, such as a long-acting bronchodilator leukotrieneantagonist or theophylline, can be added.
• Patients with moderate-to-severe asthma who react to perennial allergens despite inhaled corticosteroids may benefit from omalizumab treatment. Two 52-week pivotal Phase III clinical trials were designed to study asthma exacerbation reduction in 1071 patients with asthma (aged 12-76 y). The coprimary endpoint of each study was the number of asthma exacerbations per patient during the stable-steroid phase and the steroid-reduction phase. Patients were randomized to receive subcutaneousomalizumab or placebo every 2-4 weeks. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment (stable-steroid phase) and tapered during a further 12-week treatment period (steroid-reduction phase).
• In both pivotal clinical trials, when used as an add-on therapy to inhaled corticosteroids, omalizumab reduced mean asthma exacerbations (ie, asthma attacks) per patient by 33%-75% during the stable-steroid phase and 33%-50% during the steroid-reduction phase. Reduction in asthma exacerbations was confirmed by improvements in other measurements of asthma control, including symptom scores (eg, nocturnal awakenings, daytime asthma symptoms).

Quick relief: Short-acting bronchodilators in the form of inhaled beta2-agonists should be used as needed for symptom control. The use of short-acting inhaled beta2-agonists on a daily basis or increasing use indicates the need for additional long-term therapy.

• Acute severe asthmatic episode (status asthmaticus)

• Treatment goals are the following:

• Correction of significant hypoxemia with supplemental oxygen: In severe cases, alveolar hypoventilation requires mechanically assisted ventilation.
• Rapid reversal of airflow obstruction by using 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 that fails to respond promptly and completely to inhaled beta2-agonists.
• Reduction in the likelihood of recurrence of severe airflow obstruction by intensifying therapy: Often, a short course of systemic corticosteroids is helpful.

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. Use of the peak flow rate or FEV1 values, along with the patient's history, current symptoms, physical findings, to guide treatment decisions is helpful in achieving the aforementioned goals. In using the 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.

Consultations

Consider consultation with an allergist; ear, nose, and throat (ENT) specialist; or gastroenterologist.

• An allergist may help with further evaluation and management when the history and physical examination findings suggest significant allergies (especially systemic involvement and allergies to dietary products).

• An ENT specialist may help in managing chronic sinusitis.

• A gastroenterologist may help in excluding gastroesophageal reflux.

Diet

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.

Activity

One of the goals of therapy is to adequately control exercise-induced asthmatic symptoms so that physical activity is not restricted.

Medication

Current treatment of asthma includes the use of relievers, such as beta-adrenergic agonists, systemic corticosteroids, and ipratropium, and controllers, such as cromolyn, nedocromil, inhaled corticosteroids, long-acting beta-agonists, theophylline, and leukotriene modifiers.

Drug Category: Bronchodilator, beta2-agonists

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

Albuterol sulfate (Proventil, Ventolin) -- This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, metered-dose inhaler (MDI), oral solution). This is most commonly used in rescue therapy for acute asthmatic symptoms. Albuterol is used as needed, and prolonged use may be associated with tachyphylaxis due to beta2-receptordownregulation and receptor hyposensitivity.

· Adult

Oral inhaler: 1-2 inhalations q4-6h; recent guidelines suggest 8-10 inhalations for more severe symptoms
Nebulizer: Dilute 0.5 mL (2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS solution; administer 2.5-5 mg via nebulization q4-6h, diluted in 2-5 mL sterile sodium chloride solution or water

Pediatric

Oral inhaler: 90 mcg per inhalation, 2 inhalations q4-6h; more inhalations may be used in severe, acute episodes; more frequent dosing can be used to treat acute symptoms
Nebulizer: 2.5 mg via nebulization of 0.5% solution in 2-3 mL of sodium chloride solution q4-6h

Pirbuterol acetate (Maxair) -- Available as a breath-actuated or ordinary inhaler. The ease of administration with the breath-actuated device makes it an attractive choice in the treatment of acute symptoms in younger children who otherwise cannot use an MDI. Strength is 200 mcg per inhalation.

· Adult

Oral inhalation: 1-2 inhalations q4-6h; not to exceed 12 inhalations q24h

Pediatric

Administer as in adults

Drug Category: Nonracemic form of the beta2-agonist albuterol

-- This nonracemic form of albuterol was recently introduced. One advantage is better efficacy; hence, lower doses have a therapeutic effect, and a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia, hyperglycemia, hypokalemia) is reported.

Levalbuterol (Xopenex) -- Nonracemic form of albuterol, 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).

· Adult

0.63-1.25 mg by nebulizer q8h

Pediatric

0.63 mg by nebulizer q8h

Drug Category: Long-acting beta2-agonist

-- Long-acting bronchodilators 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. Currently, 2 long-acting beta2-agonists are available in the United States: salmeterol (Serevent) andformoterol (Foradil). Salmeterol is discussed below. Salmeterol is available as a combination ofsalmeterol and fluticasone (Advair) in the United States. Advair has an expiration date of 30 days once the protective wrapper is removed.

Salmeterol (Serevent Diskus) -- 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 reduce the potential adverse effects of the steroids.

· Adult

Serevent Diskus: 1 inhalation (50 mcg) q12h

Pediatric

<12 years: Not established
>12 years: 1 inhalation of inhalation powder (50 mcg) q12h; data in children are limited

Drug Category: Methylxanthines

-- These agents are used for long-term control and prevention of symptoms, especially nocturnal symptoms.

Theophylline (Theo-24, Theolair, Theo-Dur, Slo-bid) -- Available in short- and long-acting formulations. Because of the need to monitor the drug levels (see Precautions below), this agent is used infrequently.

· Adult

200-600 mg PO q12-24h

Pediatric

Initial dose: 10 mg/kg PO sustained-release tablets and capsules; not to exceed 300 mg/d
First dose adjustment: 13 mg/kg PO; not to exceed 450 mg/d
Second dose adjustment: 16 mg/kg PO; not to exceed 600 mg/d

Drug Category: Mast cell stabilizers

-- These agents block early and late asthmatic responses, interfere with chloride channels, stabilize the mast cell membrane, and inhibit the activation and release of mediators from eosinophils and epithelial cells. They inhibit acute responses to cold air, exercise, and sulfur dioxide.

Cromolyn sodium (Intal), nedocromil sodium (Tilade) -- These nonsteroidal anti-inflammatory agents are used primarily in preventive therapy.

· Adult

Cromolyn: 20 mg in 2 mL nebulizer solution q6-8h
Nedocromil: 2-4 inhalations bid/tid; 1.75 mg/actuation

Pediatric

Cromolyn: Administer as in adults
Nedocromil: Administer as in adults

Drug Category: Corticosteroids

-- Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed, and least likely to cause adverse effects. No study has shown significant toxicity with inhaled steroid use in children at doses less than the equivalent of 400 mcg of beclomethasone per day. They are used for long-term control of symptoms and for the suppression, control, and reversal of inflammation. Inhaled forms reduce the need for systemic corticosteroids. They block late asthmatic response to allergens; reduce airway hyperresponsiveness; inhibit cytokine production, adhesion protein activation, and inflammatory cell migration and activation; and reverse beta2-receptor downregulation and subsensitivity (in acute asthmatic episodes with long-term beta2-agonist use).

Inhaled steroids include beclomethasone, triamcinolone, flunisolide, fluticasone, and budesonide.

Beclomethasone (Beclovent, Vanceril, QVAR) -- Inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation; and may decrease the number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness.

· Adult

Low dose: 168-504 mcg/d (42 mcg/inhalation, 4-12 oral inhalations q24h)
Medium dose: 504-840 mcg/d (42 mcg/oral inhalation, 12-20 inhalations q24h)
High dose: >840 mcg/d (42 mcg/oral inhalation, >20 inhalations q24h)

Pediatric

Low dose: 84-336 mcg/d (42 mcg/oral inhalation, 2-8 inhalations q24h)
Medium dose: 336-672 mcg/d (42 mcg/oral inhalations, 8-16 inhalations q24h)
High dose: >672 mcg/d (42 mcg/oral inhalation, >16 inhalations q24h)

Fluticasone (Flovent) -- Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically.

·Adult

Low dose: 88-264 mcg/d (44 mcg/oral inhalation, 2-6 inhalations q24h or 110 mcg/inhalation, 2 inhalations q24h)
Medium dose: 264-660 mcg/d (110 mcg/oral inhalation, 2-6 inhalations q24h)
High dose: >660 mcg/d (110 mcg/oral inhalation, >6 inhalations q24h or 220 mcg/oral inhalations, >3 inhalations q24h)

Pediatric

Low dose: 88-176 mcg/d (44 mcg/oral inhalation, 2-4 inhalations q24h)
Medium dose: 176-440 mcg/d (110 mcg/oral inhalation, 2-4 inhalations q24h)
High dose: >440 mcg/d (110 mcg/oral inhalation, >4 inhalations q24h or 220 mcg/oral inhalation, 2 inhalations q24h)

Budesonide (Pulmicort Turbuhaler or Respules) -- Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. Pulmicort is available in a powder inhaler (200 mcg per oral inhalation) or as anebulized susp (ie, Respules).

·Adult

Low dose: 200-400 mcg/d (1-2 inhalations/d)
Medium dose: 400-600 mcg/d (2-3 inhalations/d)
High dose: >600 mcg/d (>3 inhalations/d)

Pediatric

MDI:
Low dose: 100-200 mcg/d (1 inhalation q24h)
Medium dose: 200-400 mcg/d (1-2 inhalation q24h)
High dose: >400 mcg/d (>2 inhalations q24h)
Nebulizer (inhalation susp): 0.25-0.5 mg bid; not to exceed 1 mg/d

Drug Category: Systemic corticosteroids

-- 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 subsensitivity anddownregulation; 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 gastrointestinal transit time or absorption is not impaired. The usual regimen is to continue frequent multiple daily dosing until the FEV₁ or PEF is 50% of the predicted or personal best values; then, the dose is changed to twice daily. This usually occurs within 48 hours.

Prednisone (Deltasone, Orasone) and prednisolone (Pediapred, Prelone, Orapred) -- Immunosuppressants for the treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

· Adult

5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve

Pediatric

1-2 mg/kg/d PO for 3-10 d; not to exceed 60-80 mg/d

Methylprednisolone (Solu-Medrol) -- May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

· Adult

0.5-1 mg/kg/dose IV q6h; not to exceed 5 d

Pediatric

1 mg/kg IV q6h

Drug Category: Leukotriene modifier

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

Zafirlukast (Accolate) -- Selective competitive inhibitor of LTD4, LTE4 receptors.

· Adult

20 mg PO bid

Pediatric

5-11 years: 10 mg PO bid
>12 years: Administer as in adults

Montelukast (Singulair) -- Last agent introduced in its class. The advantages are that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.

·Adult

10 mg PO hs

Pediatric

12-23 months: 1 packet of 4 mg oral granules PO hs
2-6 years: 4 mg PO hs
6-14 years: 5 mg PO hs
>14 years: Administer as in adults

Drug Category: Monoclonal antibody

-- These agents bind selectively to human IgE on the surface of mast cells and basophils.

Omalizumab (Xolair) -- Recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on surface of mast cells and basophils. Reduces mediator release, which promotes allergic response. Indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.

· Adult

150-375 mg SC q2-4wk; inject slowly over 5-10 s because of viscosity; not to exceed 150 mg per injection site
Precise dose and frequency established by serum total IgE level (IU/mL)

Pediatric

<12 years: Not established

Further Inpatient Care

• Admit patients for treatment of acute severe episodes if they are unresponsive to outpatient care (eg, they have worsening bronchospasm, hypoxia, evidence of respiratory failure).

• Once the patient is admitted, further investigations (eg, PFTs, allergy testing, and investigations to rule out other associated conditions and complications) can be performed.

Further Outpatient Care

• Regular follow-up visits (1-6-mo intervals) are essential to ensure control and appropriate therapeutic adjustments.

• Outpatient visits should include the following:

• Interval history of asthmatic complaints, including history of acute episodes (eg, severity, measures and treatment taken, response to therapy)

• History of nocturnal symptoms

• History of symptoms with exercise and exercise tolerance

• Review of medications, including use of rescue medications

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

• 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)

• 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 episode, which includes instructions about identifying signs of acute episode, using rescue medications, monitoring, and contacting the asthma care team. These items are reviewed at eachvisit.

Inpatient & Outpatient Medications

• Bronchodilators (short- and long-acting)

• Controlling medications (nonsteroidal, steroidal, newer agents such as leukotriene modifiers)

• Medications for the treatment of associated conditions (antiallergy medications, nasal steroids for allergic rhinitis)

• Rescue medications for use in acute episodes (short burst of steroids)

Transfer

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

• History of sudden severe exacerbations

• History of prior intubation for asthma

• Admission to an ICU because of asthma

• Two or more hospitalizations for asthma in the past year

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

• Hospitalization or an emergency department visit for asthma within the past month
• Use of 2 or more canisters of inhaled short-acting beta2-agonists per month
• Current use of systemic corticosteroids or recent withdrawal from systemic corticosteroids

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

Prevention

• 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.

Complications

• Pneumothorax status asthmaticus with respiratory failure

• Fixed (nonreversible) airway obstruction

• Death

Prognosis

• Of infants who wheeze with URTIs, 60% are asymptomatic by age 6 years; however, children who have asthma (recurrent symptoms continuing at age 6 y) 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.

• Individuals who have asthma during childhood have significantly lower FEV₁ and airway reactivity and more persistent bronchospastic symptoms than those with infection-associated wheezing.

• 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.

Patient Education

• Patient and parent education should include instructions on how to use medications and devices (eg, spacers, nebulizers, MDIs). The patient's MDI technique should be assessed on every visit.

• Discuss the management plan, which includes instructions about 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.

• Write and discuss in detail a rescue plan for an acute episode. This plan should include instructions for identifying signs of an acute attack, using rescue medications, monitoring, and contacting the asthma care team.

• 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.

• Emphasize the importance of compliance with and adherence to treatment.

• Incorporate the concept of expecting full control of symptoms, including nocturnal and exercise-induced symptoms, in the management plans and goals (for all but the most severely affected patients).

• Avoid unnecessary restrictions in the lifestyle of the child or family. Expect the child to participate in recreational activities and sports and to attend school as usual.

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