INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: 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.

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.

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 resulting overdistention 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 bronchospasm and 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 of Th 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 generating IgE, 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	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

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 have feeding 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 with room 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 mm Hg). 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 rewarming phase 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 vagal or 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.