Asthma is a chronic inflammation of the bronchial tubes (airways) that causes swelling and narrowing (constriction) of the airways. The result is difficulty breathing. The bronchial narrowing is usually either totally or at least partially reversible with treatments.

Bronchial tubes that are chronically inflamed may become overly sensitive to allergens (specific triggers) or irritants (non-specific triggers). The airways may become "twitchy" and remain in a state of heightened sensitivity. This is called "Bronchial Hyperreactivity" (BHR). It is likely that there is a spectrum of bronchial hyperreactivity in all individuals. However, it is clear that asthmatics and allergic individuals (without apparent asthma) have a greater degree of bronchial hyperreactivity than non-asthmatic and non-allergic people. In sensitive individuals, the bronchial tubes are more likely to swell and constrict when exposed to triggers such as allergens, tobacco smoke, or exercise. Amongst asthmatics, some may have mild BHR and no symptoms while others may have severe BHR and chronic symptoms.

This Continuing Education Unit is intended to aid health care professionals in diagnosing and managing patients with asthma. The recommendations found here for diagnosis and pharmacologic therapy are strictly intended as general guidelines for making therapeutic decisions, and are not intended to be prescriptions for individual treatment. Specific therapies should be tailored to the needs and circumstances of individual patients.

Upon successful completion of this continuing education module, you will be able to:

• Define the term “asthma” and identify its etiology, epidemiology, and pathogenesis
• Explain how asthma is diagnosed, listing its symptoms, signs, and classifications
• Identify the “triggers” associated with asthma, and discuss how to limit patients” exposure to
• List and discuss techniques and protocols for monitoring and treating asthma

Asthma Today

Recently, asthma has been getting quite a bit of attention in the popular news media. One example can be seen in a newspaper report:

CHICAGO -- Northwestern football player Rashidi Wheeler had the stimulant ephedrine in his system when he collapsed during a grueling Aug. 3, 2001 workout, but the banned substance did not cause his death, the Cook County medical examiner said Monday. "We do not think this contributed to his death," Dr. Edmund Donoghue said. "We think this is a classic case of exercise-induced bronchial asthma."

Wheeler, a chronic asthmatic, collapsed during a preseason conditioning drill involving a series of wind sprints and was pronounced dead a short time later at an Evanston hospital. Wheeler's mother, Linda Will, has said the university wasn't prepared to deal with such an emergency during what was supposed to be a voluntary preseason workout. She has enlisted the help of Rev. Jesse Jackson and attorney Johnnie Cochran Jr. The university is investigating the incident, including questions about whether Wheeler took a nutritional supplement containing a form of ephedrine, a substance banned by the NCAA that has been linked to strokes and heart attacks.

The amount of the stimulant in Wheeler's system was "well below toxic or lethal levels," Donoghue said. "The levels are consistent with what someone might have if you had taken that supplement the day he died," Donoghue said. A Northwestern spokesman reiterated Monday that university officials, coaches and players would not comment on the circumstances surrounding Wheeler's death until its review panel's report is released.

The spokesman said no date has been determined for the release of the report.

Attorneys for Wheeler's family have videotapes of his final practice. The tapes supplied by the university's athletic staff show Wheeler wobbling and dropping to his knees during wind sprints. During the sprints, unidentified persons are heard encouraging Wheeler to pick up the pace. The tape also shows paramedics trying unsuccessfully to save Wheeler's life -- while teammates continued a conditioning drill.

There were also stories about the Minnesota Vikings player Korie Stringer’s death being somehow linked to an asthmatic condition. Those types of stories, and more focus on adult onset asthma have led to considerably more attention being paid to this potentially deadly disease condition.

The statistics surrounding asthma are also astounding:

Statistics

Statistics related to asthma and allergies:

According to the latest available from the National Institute of Allergy and Infectious Diseases (NIAID), consider the following statistics:

Asthma:

• More than 17 million people in the US have been diagnosed with asthma.
• Asthma is the sixth most common chronic condition in the US.
• Asthma affects more than 4.8 million US children, making it the most common serious and chronic disease among children.
• Asthma accounts for 10 million absences from school each year.
• Asthma is 26 percent more prevalent in African-American children than in Caucasian children.
• African-American children with asthma, most often from inner city populations, generally experience more severe disability from asthma and have more frequent hospitalizations than do Caucasian children.
• Asthma is the third most common cause of childhood hospitalizations under the age of 15.
• More than 200,000 children with asthma experience more severe symptoms due to exposure to secondhand smoke.
• About 10 million visits annually to office-based physicians result in a diagnosis of asthma.
• Asthma cases and asthma deaths have been on the rise. From 1979 to 1996, asthma deaths have risen 120 percent from 2,598 to 5,667.
• Hospitalizations for asthma have increased 256 percent from 1979 to 1996, to 474,100 people annually.
• Asthma treatment costs an estimated $11.3 billion, including direct and indirect expenditures each year.
• Asthma causes nearly 3 million lost workdays each year for people over age 18.

Allergy:

• Previous surveys estimate that allergies affect as many as 40 to 50 million people in the US.
• Pollen allergy (hay fever or allergic rhinitis) affects nearly 10 percent of the people in the US (26 million people), not including those with asthma.
• Allergic dermatitis (itchy rash) is the most common skin condition in children younger than 11 years of age.
• Urticaria (hives; raised areas of reddened skin that become itchy) and angioedema (swelling of throat tissues) together affect approximately 15 percent of the US population every year.
• Chronic sinusitis, most often caused by allergies, affects nearly 35 million people in the US.
• Allergic drug reactions, commonly caused by antibiotics such as penicillin and cephalosporins, occur in 2 to 3 percent of hospitalized patients.
• Eight percent of children younger than 6 years old experience food intolerances. Of this group, 2 to 4 percent appear to have reproducible allergic reactions to food. In adults, an estimated 1 to 2 percent are sensitive to foods or food additives.
• A severe allergic reaction known as anaphylaxis occurs in 3.3 percent of the US population as a result of insect stings. At least 40 deaths each year result from insect sting anaphylaxis.

:

The clinician, physiologist, immunologist, and pathologist all may have different perspectives on asthma based on their individual viewpoints and experience. The merging of these different perspectives into an acceptable definition of asthma has begun to occur and is important for more specific and effective treatment of this disease and for investigation into its pathogenesis. Furthermore, even though this disorder affects virtually the entire spectrum of life, asthma has certain age-specific characteristics and differential diagnosis issues that need to be considered in both its treatment and its etiology.

Based on current knowledge, a working definition of asthma is:
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli (NHLBI 1995).
Moreover, recent evidence indicates that subbasement membrane fibrosis may occur in some patients with asthma and that these changes contribute to persistent abnormalities in lung function (Roche 1991).

This working definition and its expanded recognition of key features of asthma have been derived from studying how airway changes in asthma relate to various factors associated with the development of allergic inflammation (e.g., allergens, respiratory viruses, and some occupational exposures, as illustrated in figure 1). From this approach has come a more comprehensive understanding of asthma pathogenesis, the development of persistent airway inflammation, and the profound implications these issues have for the diagnosis, treatment, and potential prevention of asthma.

Figure 1: Mechanisms underlying the definition of asthma.

AIRWAY PATHOLOGY AND ASTHMA

Until recently, information on airway pathology in asthma has come largely from post-mortem examination (Dunnill 1960), which shows that both large and small airways often contain plugs composed of mucus, serum proteins, inflammatory cells, and cellular debris. Viewed microscopically, airways are infiltrated with eosinophils and mononuclear cells, and there is vasodilation and evidence of microvascular leakage and epithelial disruption. The airway smooth muscle is often hypertrophied, which is characterized by new vessel formation, increased numbers of epithelial goblet cells, and deposition of interstitial collagens beneath the epithelium. These features of airway wall remodeling further underscore the importance of chronic, recurrent inflammation in asthma and its effects on the airway. Moreover, these morphologic changes may not be completely reversible. Consequently, research is currently focused on determining whether these changes can be prevented or modified by early diagnosis, avoidance of factors that contribute to asthma severity, and pharmacologic therapy directed at suppressing airway inflammation.

Establishing the relationship between the pathologic changes and the clinical features of asthma has been difficult. Fiberoptic bronchoscopy with lavage and biopsy provide new insight into mechanisms of airway disease and features that link altered lung function to a specific type of mucosal inflammation (Laitinen et al. 1985; Beasley et al. 1989; Jeffery et al. 1989). From such studies, evidence has emerged that mast cells, eosinophils, epithelial cells, macrophages, and activated T cells are key features of the inflammatory process of asthma (Djukanovic et al. 1990), as illustrated in figure 2. These cells can influence airway function through secretion of preformed and newly synthesized mediators that act either directly on the airway or indirectly through neural mechanisms (Emanuel and Howarth 1995).

Furthermore, with the use of cellular and molecular biological techniques, subpopulations of T lymphocytes (TH2) have been identified as important cells that may regulate allergic inflammation in the airway through the release of selective cytokines and also establish disease chronicity (Robinson et al. 1992). In addition, constituent cells of the airway, including fibroblasts, endothelial cells, and epithelial cells, also contribute to this process by releasing cytokines and chemokines.

Figure 2: Cellular Mechanisms Involved in Airway Inflammation.

The above factors may be important in both initiating and maintaining the level of airway inflammation (Robinson et al. 1993). It is hypothesized that airway inflammation can be acute, subacute, and chronic. The acute inflammatory response is represented by the early recruitment of cells to the airway. In the subacute phase, recruited and resident cells are activated to cause a more persistent pattern of inflammation. Chronic inflammation is characterized by a persistent level of cell damage and an ongoing repair process, changes that may cause permanent abnormalities in the airway.

Finally, it is recognized that specific adhesion proteins, found in the vascular tissue, lung matrix, and bronchial epithelium, may be critical in directing and anchoring cells in the airway, thus causing the inflammatory changes noted (Albelda 1991). From these studies of the histological features associated with asthma has come evidence of an association between airway inflammation and markers of airway disease severity and an indication that this process is multicellular, redundant, and self-amplifying. Cell-derived mediators can influence airway smooth muscle tone, modulate vascular permeability, activate neurons, stimulate mucus secretion, and produce characteristic structural changes in the airway (Horwitz and Busse 1995). These mediators can target ciliated airway epithelium to cause injury or disruption. As a consequence, epithelial cells and myofibroblasts—present beneath the epithelium—proliferate and begin to deposit interstitial collagens in the lamina reticularis of the basement membrane. This may explain apparent basement membrane thickening and the irreversible airway changes that may occur in some asthma patients (Roche 1991). Other changes, including hypertrophy and hyperplasia of airway smooth muscle, increases in goblet cell number, enlargement of submucous glands, and remodeling of the airway connective tissue, are components of asthma that need to be recognized in both its pathogenesis and treatment. This inflammatory process is redundant in its ability to alter airway physiology and architecture.

Child-Onset Asthma

Asthma often begins in childhood, and when it does, it is frequently found in association with atopy, which is the genetic susceptibility to produce IgE directed toward common environmental allergens, including house-dust mites, animal proteins, and fungi (Larsen 1992). With the production of IgE antibodies, mast cells and possibly other airway cells (e.g., lymphocytes) are sensitized and become activated when they encounter specific antigens. Although atopy has been found in 30 to 50 percent of the general population, it is frequently found in the absence of asthma. Nevertheless, atopy is one of the strongest predisposing factors in the development of asthma (Sporik et al. 1990). Furthermore, among infants and young children who have wheezing with viral infections, allergy or family history of allergy is the factor that is most strongly associated with continuing asthma through childhood (Martinez et al. 1995).

Adult-Onset Asthma

Although asthma begins most frequently in childhood and adolescence, it can develop at anytime in life. Adult-onset asthma can occur in a variety of situations. In adult-onset asthma, allergens may continue to play an important role. However, in some adults who develop asthma, IgE antibodies to allergens or a family history of asthma are not detected. These individuals often have coexisting sinusitis, nasal polyps, and sensitivity to aspirin or related nonsteroidal anti-inflammatory drugs. The mechanisms of nonallergic, or intrinsic, asthma are less well established, although the inflammatory process is similar (but not identical) to that seen in atopic asthma (Walker et al. 1992). Occupational exposure to workplace materials (animal products; biological enzymes; plastic resin; wood dusts, particularly cedar; and metals) can cause airway inflammation, bronchial hyperresponsiveness, and clinical signs of asthma (Chan-Yeung and Malo 1994; Fabbri et al. 1994). Identification of the causative agent and its removal from the workplace can reduce symptoms; however, some individuals will have persistent asthma even though exposure to the causative agent is eliminated. The mechanisms of this form of asthma are not clearly established.

RELATIONSHIP OF AIRWAY INFLAMMATION AND LUNG FUNCTION

Airway Hyperresponsiveness

An important feature of asthma is an exaggerated bronchoconstrictor response to a wide variety of stimuli. The propensity for airways to narrow too easily and too much is a major, but not necessarily unique, feature of asthma. Airway hyperresponsiveness leads to clinical symptoms of wheezing and dyspnea after exposure to allergens, environmental irritants, viral infections, cold air, or exercise. Research indicates that airway hyperresponsiveness is important in the pathogenesis of asthma and that the level of airway responsiveness usually correlates with the clinical severity of asthma.

Airway hyperresponsiveness can be measured by inhalation challenge testing with methacholine or histamine, as well as after exposure to such nonpharmacologic stimuli as hyperventilation with cold dry air, inhalation of hypotonic or hypertonic aerosols, or after exercise (O’Connor et al. 1989). In addition, variability between morning and evening peak expiratory flow (PEF) appears to reflect airway hyperresponsiveness and may serve as a measure of airway hyperresponsiveness, asthma instability, or asthma severity. The factors contributing to airway inflammation in asthma are multiple and involve a variety of different inflammatory cells (as illustrated in figure 2) (Busse et al. 1993). It is also apparent that asthma is not caused by either a single cell or a single inflammatory mediator but rather results from complex interactions among inflammatory cells, mediators, and other cells and tissues resident in airways. An initial trigger in asthma may be the release of inflammatory mediators from bronchial mast cells, macrophages, T lymphocytes, and epithelial cells. These substances direct the migration and activation of other inflammatory cells, such as eosinophils and neutrophils, to the airway where they cause injury, such as alterations in epithelial integrity, abnormalities in autonomic neural control of airway tone, mucus hypersecretion, change in mucociliary function, and increased airway smooth muscle responsiveness.

The importance of the airway inflammatory response to airway hyperresponsiveness is substantiated by several observations. First, airway markers of inflammation correlate with bronchial hyperresponsiveness. Second, treatment of asthma and modification of airway inflammatory markers not only reduce symptoms but also diminish airway responsiveness. However, the relationship between airway inflammation and airway responsiveness is complex. Some investigations have shown that although anti-inflammatory therapy reduced airway hyperresponsiveness, it did not eradicate it. A small study found that control of airway inflammation did not control bronchial hyperresponsiveness (Lundgren et al. 1988). Thus, factors in addition to inflammation may contribute to airway hyperresponsiveness.

Airflow Obstruction

Airflow limitation in asthma is recurrent and caused by a variety of changes in the airway. These include:

• Acute bronchoconstriction. Allergen-induced acute bronchoconstriction results from an IgE-dependent release of mediators from the mast cell that include histamine, tryptase, leukotrienes, and prostaglandins (Marshall and Bienenstock 1994), which directly contract airway smooth muscle. Aspirin and other nonsteroidal anti-inflammatory drugs can also cause acute airflow obstruction in some patients, and evidence indicates that this non-IgE-dependent response also involves mediator release from airway cells (Fischer et al. 1994). In addition, other stimuli, including exercise, cold air, and irritants, can cause acute airflow obstruction. The mechanisms regulating the airway response to these factors are less well defined, but the intensity of the response appears related to underlying airway inflammation (Busse et al. 1993). There is emerging evidence that stress can play a role in precipitating asthma exacerbations. The mechanisms involved have yet to be established and may include enhanced generation of pro-inflammatory cytokines (Friedman et al. 1994).
• Airway edema. Airway wall edema, even without smooth muscle contraction or bronchoconstriction, limits airflow in asthma. Increased microvascular permeability and leakage caused by released mediators also contribute to mucosal thickening and swelling of the airway. As a consequence, swelling of the airway wall causes the airway to become more rigid and interferes with airflow.
• Chronic mucus plug formation. In severe intractable asthma, airflow limitation is often persistent. In part, this change may arise as a consequence of mucus secretion and the formation of inspissated mucus plugs.
• Airway remodeling. In some patients with asthma, airflow limitation may be only partially reversible. The etiology of this component is not as well studied as other features of asthma but may relate to structural changes in the airway matrix that may accompany longstanding and severe airway inflammation. There is evidence that a histological feature of asthma in some patients is an alteration in the amount and composition of the extracellular matrix in the airway wall (Djukanovic et al. 1990; Laitinen and Laitinen 1994). As a consequence of these changes, airway obstruction may be persistent and not responsive to treatment. Regulation of this repair and remodeling process is not well established, but both the process of repair and its regulation are likely to be key events in explaining the persistent nature of the disease and limitations to a therapeutic response. Although yet to be fully explored, the importance of airway remodeling and the development of persistent airflow limitation suggest a rationale for early intervention with anti-inflammatory therapy.

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RELEVANCE OF CHRONIC AIRWAY INFLAMMATION TO ASTHMA THERAPY

Although inflammation can be used to describe a variety of conditions in various diseases, the inflammatory response in asthma has special features that include eosinophil infiltration, mast cell degranulation, interstitial airway wall injury, and lymphocyte activation. Furthermore, there is evidence that a TH2 lymphocyte cytokine profile (i.e., IL-4 and IL-5) is instrumental in initiating and sustaining the inflammatory process (James and Kay 1995; Ricci et al. 1993) (see figure 2). These observations also have become important in directing treatment in asthma. It is hypothesized that inflammation is an early and persistent component of asthma. As a consequence, therapy to suppress the inflammation must be long term. Furthermore, preliminary evidence suggests that early intervention with anti-inflammatory therapy may modify the disease process (Agertoft and Pedersen 1994; Laitinen et al. 1992; Djukanovic et al. 1992). Observations into the basic mechanisms of asthma have had tremendous impact and influence on therapy. Studies have shown that improvements in asthma control achieved with high doses of inhaled corticosteroids are associated with improvement in markers of airway inflammation (Laitinen et al. 1992; Djukanovic et al. 1992). These observations indicate that a strong link may exist between features of airway inflammation, bronchial hyperresponsiveness, and asthma symptoms and severity. Furthermore, insight into the mechanisms of asthma with airway inflammation and bronchial wall repair has become a driving factor in designing logical, and hopefully effective, treatment paradigms. Another area that needs clarification is the classification of compounds as anti-inflammatory in nature. Because many factors contribute to the inflammatory response in asthma, many drugs may fit this category. At present, corticosteroids are the anti-inflammatory compounds that have been demonstrated to modify histopathological features of asthma (Barnes 1995). It may be necessary to evaluate each new compound for the specificity of its “anti-inflammatory" action and determine from appropriate observations whether the compound is indeed anti-inflammatory and what consequences this has on the clinical features of the disease.

REFERENCES

Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994;88:373-81.

Albelda SM. Endothelial and epithelial cell adhesion molecules. Am J Respir Cell Mol Biol 1991;4:195-203.

Barnes PJ. Inhaled glucocorticosteroid for asthma. N Engl J Med 1995;332:868-75.

Beasley R, Roche WR, Roberts TA, Holgate ST. Cellular events in the bronchi in mild asthma and bronchial provocation. Am Rev Respir Dis 1989;139:806-17.

Busse WW, Calhoun WJ, Sedgwick JD. Mechanisms of airway inflammation in asthma. Am Rev Respir Dis 1993;147:S20-S24.

Chan-Yeung M, Malo JL. Etiological agents in occupational asthma. Eur Respir J 1994;7:346-71.

Djukanovic R, Roche WR, Wilson JW, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990;142:434-57.

Djukanovic R, Wilson TW, Britten KM, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms of asthma. Am Rev Respir Dis 1992;145:669-74.

Dunnill MS. The pathology of asthma, with special reference to changes in the bronchial mucosa. J Clin Pathol 1960;13:27-33.

Emanuel MB, Howarth PH. Asthma and anaphylaxis: a relevant model for chronic disease? An historical analysis of directions in asthma research. Clin Exp Allergy 1995;25:15-26.

Fabbri LM, Maestrelli P, Saetta M, Mapp CM. Mechanisms of occupational asthma. Clin Exp Allergy 1994;24:628-35.

Fischer AR, Rosenberg MA, Lilly CM, et al. Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma. J Allergy Clin Immunol 1994;94:1046-56.

Friedman EM, Coe CL, Ershler WB. Bidirectional effects of interleukin-1 on immune responses in rhesus monkeys. Brain Behav Immunol 1994;8:87-99.

Horwitz RJ, Busse WW. Inflammation and asthma. Clin Chest Med 1995;16:583-602.

James DG, Kay AB. Are you TH-1 or TH-2? [editorial] Clin Exp Allergy 1995;25:389-90.

Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma. An ultrastructural, qualitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989;140:1745-53.

Laitinen A, Laitinen LA. Airway morphology: endothelium/basement membrane. Am J Respir Crit Care Med 1994;150:S14-S17.

Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985;131:599-606.

Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a ? 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol 1992;90:32-42.

Larsen GL. Asthma in children. N Engl J Med 1992;326:1540-5.

Lundgren R, Söderberg M, Horstedt P, et al. Morphological studies of bronchial biopsies from asthmatics before and after 10 years of treatment with inhaled steroids. Eur Respir J 1988;1:883-9.

Marshall JS, Bienenstock J. The role of mast cells in inflammatory reactions of the airways, skin and intestine. Curr Opin Immunol 1994;6:853-9.

Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ, Group Health Medical Associates. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133-8.

National Heart, Lung, and Blood Institute. Global Initiative for Asthma. National Institutes of Health pub no 95-3659. 1995.

O’Connor GT, Sparrow D, Weiss ST. The role of allergy and nonspecific airway hyperresponsiveness in the pathogenesis of chronic obstructive pulmonary disease. Am Rev Respir Dis 1989;140:225-52.

Ricci M, Rossi O, Bertoni M, Matucci A. The importance of TH2-like cells in the pathogenesis of airway allergic inflammation. Clin Exp Allergy 1993;23:360-9.

Robinson DS, Durham SR, Kay AB. Cytokines in asthma. Thorax 1993;48:845-53.

Robinson DS, Hamid Q, Ying S, et al. Predominant TH2-like broncheoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992;326:298-304.

Roche WR. Fibroblasts and asthma. Clin Exp Allergy 1991;21:545-8.

Sporik R, Holgate ST, Platts-Mills TA, Cogswell JJ. Exposure to house-dust mite allergen (Der pI) and the development of asthma in childhood. A prospective study. N Engl J Med 1990;323:502-7.

Walker C, Bode E, Boer L, Hausel TT, Blaser K, Virchow JC Jr. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis 1992;146:109-15.

Section A: Initial Assessment and Diagnosis of Asthma

Key Points:

To establish a diagnosis of asthma, the health care practitioner should determine that:

• Episodic symptoms of airflow obstruction are present.
• Airflow obstruction is at least partially reversible.
• Alternative diagnoses are excluded.

Recommended mechanisms to establish the diagnosis are:

• Detailed medical history
• Physical exam focusing on the upper respiratory tract, chest, and skin
• Spirometry to demonstrate reversibility

Additional studies may be considered to:

• Evaluate alternative diagnoses
• Identify precipitating factors
• Assess severity
• Investigate potential complications

Recommendations are presented for referral for consultation or care to a specialist in asthma care.

The guidelines to help establish a diagnosis of asthma presented in this Unit are based on the opinion of the Expert Panel. The health care professional trying to establish a diagnosis of asthma should determine that:

• Episodic symptoms of airflow obstruction are present.
• Airflow obstruction is at least partially reversible.
• Alternative diagnoses are excluded.

A careful medical history, physical examination, pulmonary function tests, and additional tests will provide the information needed to ensure a correct diagnosis of asthma (see Box 1). Each of these methods of assessment is described in this section. Clinical judgment is needed in conducting the assessment for asthma. Patients with asthma are heterogeneous and present signs and symptoms that vary widely from patient to patient as well as within each patient over time.

Box 1

Consider asthma and performing spirometry if any of these indicators are present.* These indicators are not diagnostic by themselves, but the presence of multiple key indicators increases the probability of a diagnosis of asthma. Spirometry is needed to establish a diagnosis of asthma.

• Wheezing—high-pitched whistling sounds when breathing out—especially in children. (Lack of wheezing and a normal chest examination do not exclude asthma.)
• History of any of the following:
• Cough, worse particularly at night
• Recurrent wheeze
• Recurrent difficulty in breathing
• Recurrent chest tightness
• Reversible airflow limitation and diurnal variation as measured by using a peak flow meter, for example:
• Peak expiratory flow (PEF) varies 20 percent or more from PEF measurement on arising in the morning (before taking an inhaled short-acting beta2 -agonist) to PEF measurement in the early afternoon (after taking an inhaled short-acting beta2 -agonist).
• Symptoms occur or worsen in the presence of:
• Exercise
• Viral infection
• Animals with fur or feathers
• House-dust mites (in mattresses, pillows, upholstered furniture, carpets)
• Mold
• Smoke (tobacco, wood)
• Pollen
• Changes in weather
• Strong emotional expression (laughing or crying hard)
• Airborne chemicals or dusts
• Menses
• Symptoms occur or worsen at night, awakening the patient.

*Eczema, hay fever, or a family history of asthma or atopic diseases are often associated with asthma, but they are not key indicators.

MEDICAL HISTORY

A detailed medical history of the new patient known or thought to have asthma should address the items listed in figure 1-1. The medical history can help:

• Identify the symptoms likely to be due to asthma. See figure 1-2 for sample questions.
• Support the likelihood of asthma (e.g., patterns of symptoms, family history of asthma or allergies).
• Assess the severity of asthma (e.g., symptom frequency and severity, exercise tolerance, hospitalizations, current medications). See figure 1-3 for a description of the levels of asthma severity or have the computer score your patient's severity.
• Identify possible precipitating factors (e.g., viral respiratory infections; exposure at home, work, day care, or school to inhalant allergens or irritants such as tobacco smoke). See Unit 2, Control of factors Contributing to Asthma Severity, for more details.

Figure 1-1: Suggested Items for Medical History ?

A detailed medical history of the new patient who is known or thought to have asthma should address the following items:

1. Symptoms

• Cough
• Wheezing
• Shortness of breath
• Chest tightness
• Sputum production

2. Pattern of Symptoms

• Perennial, seasonal, or both
• Continual, episodic, or both
• Onset, duration, frequency (number of days or nights, per week or month)
• Diurnal variations, especially nocturnal and on awakening in early morning

3. Precipitating and/or aggravating factors

• Viral respiratory infections
• Environmental allergens, indoor (e.g., mold, house-dust mite, cockroach, animal dander or secretory products) and outdoor (e.g., pollen)
• Exercise
• Occupational chemicals or allergens
• Environmental change (e.g., moving to new home; going on vacation; and/or alterations in workplace, work processes, or materials used) Irritants (e.g., tobacco smoke, strong odors, air pollutants, occupational chemicals, dusts and particulates, vapors, gases, and aerosols)
• Emotional expressions (e.g., fear, anger, frustration, hard crying or laughing)
• Drugs (e.g., aspirin; beta-blockers, including eye drops; nonsteroidal anti-inflammatory drugs; others)
• Food, food additives, and preservatives (e.g., sulfites)
• Changes in weather, exposure to cold air
• Endocrine factors (e.g., menses, pregnancy, thyroid disease)

4. Development of disease and treatment

• Age of onset and diagnosis
• History of early-life injury to airways (e.g., bronchopulmonary dysplasia, pneumonia, parental smoking)
• Progress of disease (better or worse)
• Present management and response, including plans for managing exacerbations
• Need for oral corticosteroids and frequency of use
• Comorbid conditions

5. Family history

• History of asthma, allergy, sinusitis, rhinitis, or nasal polyps in close relatives

6. Social history

• Characteristics of home including age, location, cooling and heating system, wood-burning stove, humidifier, carpeting over concrete, presence of molds or mildew, characteristics of rooms where patient spends time (e.g., bedroom and living room with attention to bedding, floor covering, stuffed furniture)
• Smoking (patient and others in home or day care)
• Day care, workplace, and school characteristics that may interfere with adherence
• Social factors that interfere with adherence, such as substance abuse
• Social support/social networks
• Level of education completed
• Employment (if employed, characteristics of work environment)

7. Profile of typical exacerbation

• Usual prodromal signs and symptoms
• Usual patterns and management (what works?)

8. Impact of asthma on patient and family

• Episodes of unscheduled care (emergency department, urgent care, hospitalization)
• Life-threatening exacerbations (e.g., intubation, intensive care unit admission)
• Number of days missed from school/work
• Limitation of activity, especially sports and strenuous work
• History of nocturnal awakening
• Effect on growth, development, behavior, school or work performance, and lifestyle
• Impact on family routines, activities, or dynamics
• Economic impact

9. Assessment of patient’s and family’s perceptions of disease

• Patient, parental, and spouse’s or partner’s knowledge of asthma and belief in the chronicity of asthma and in the efficacy of treatment
• Patient perception and beliefs regarding use and long-term effects of medications
• Ability of patient and parents, spouse, or partner to cope with disease
• Level of family support and patient’s and parents’, spouse’s, or partner’s capacity to recognize severity of an exacerbation
• Economic resources
• Sociocultural beliefs

Figure 1-2: Sample Questions for the Diagnosis and Initial Assessment of Asthma ?

A "yes" answer to any question suggests that an asthma diagnosis is likely.

In the past 12 months, . . .

• Have you had a sudden severe episode or recurrent episodes of coughing, wheezing (high-pitched whistling sounds when breathing out), or shortness of breath?
• Have you had colds that "go to the chest" or take more than 10 days to get over?
• Have you had coughing, wheezing, or shortness of breath during a particular season or time of the year?
• Have you had coughing, wheezing, or shortness of breath in certain places or when exposed to certain things (e.g., animals, tobacco smoke, perfumes)?
• Have you used any medications that help you breathe better? How often?
• Are your symptoms relieved when the medications are used?

In the past 4 weeks, have you had coughing, wheezing, or shortness of breath:

• At night that has awakened you?
• In the early morning?
• After running, moderate exercise, or other physical activity?

Figure 1-3: Chronic Disease Severity ?

Clinical Features before Treatment*

Goals of Asthma Treatment

• Prevent chronic and troublesome symptoms (e.g., coughing or breathlessness at night, in the early morning, or after exertion)
• Maintain (near) "normal" pulmonary function
• Maintain normal activity levels (including exercise and other physical activity)
• Prevent recurrent exacerbations of asthma and minimize the need for emergency department visits or hospitalizations
• Provide optimal pharmacotherapy with minimal or no adverse effects
• Meet patients' and families' expectations of and satisfaction with asthma care

* The presence of one of the features of severity is sufficient to place a patient in that category. An individual should be assigned to the most severe grade in which any feature occurs. The characteristics noted in this figure are general and may overlap because asthma is highly variable. Furthermore, an individual's classification may change over time.

** Patients at any level of severity can have mild, moderate, or severe exacerbations. Some patients with intermittent asthma experience severe and life-threatening exacerbations separated by long periods of normal lung function and no symptoms.

PHYSICAL EXAMINATION

The upper respiratory tract, chest, and skin are the focus of the physical examination for asthma. Physical findings that increase the probability of asthma include:

• Hyperexpansion of the thorax, especially in children; use of accessory muscles; appearance of hunched shoulders; and chest deformity.
• Sounds of wheezing during normal breathing, or a prolonged phase of forced exhalation (typical of airflow obstruction). Wheezing during forced exhalation is not a reliable indicator of airflow limitation. In mild intermittent asthma, or between exacerbations, wheezing may be absent.
• Increased nasal secretion, mucosal swelling, and nasal polyps.
• Atopic dermatitis/eczema or any other manifestation of an allergic skin condition.

PULMONARY FUNCTION TESTING (SPIROMETRY)

Spirometry measurements (FEV , FVC, FEV1 /FVC) before and after the patient inhales a short-acting bronchodilator should be undertaken for patients in whom the diagnosis of asthma is being considered (Bye et al. 1992; Li and O’Connell 1996). This helps determine whether there is airflow obstruction and whether it is reversible over the short term (see Box 2 for further information). Spirometry is generally valuable in children over age 4; however, some children cannot conduct the maneuver adequately until after age 7.

Box 2-a: Importance of Spirometry in Asthma Diagnosis ?

Objective assessments of pulmonary function are necessary for the diagnosis of asthma because medical history and physical examination are not reliable means of excluding other diagnoses or of characterizing the status of lung impairment. Although physicians generally seem able to identify a lung abnormality as obstructive (Russell et al. 1986), they have a poor ability to assess the degree of airflow obstruction (Shim and Williams 1980) or to predict whether the obstruction is reversible (Russell et al. 1986).

For diagnostic purposes, spirometry is generally recommended over measurements by a peak flow meter in the clinician’s office because there is wide variability even in the best published peak expiratory flow reference values. Reference values need to be specific to each brand of peak flow meter, and such normative brand-specific values currently are not available for most brands. Peak flow meters are designed as monitoring, not as diagnostic, tools in the office (see Unit 1-Periodic Assessment and Monitoring). However, peak flow monitoring can establish peak flow variability and thus aid in the determination of asthma severity when patients have asthma symptoms and normal spirometry.

Spirometry typically measures the maximal volume of air forcibly exhaled from the point of maximal inhalation (forced vital capacity, FVC) and the volume of air exhaled during the first second of the FVC (forced expiratory volume in one second, FEV1 ). Airflow obstruction is indicated by reduced FEV1 and FEV1 /FVC values relative to reference or predicted values. Significant reversibility is indicated by an increase of >12 percent and 200 mL in FEV1 after inhaling a short-acting bronchodilator (American Thoracic Society 1991) (see figure 1-4 for examples of a spirometric curves for this test). A 2- to 3-week trial of oral corticosteroid therapy may be required to demonstrate reversibility. The spirometry measures that establish reversibility may not indicate the patient’s best lung function.

Figure 1-4: Sample Spirometry Curves ?

NORMAL

AIRWAY OBSTRUCTION

Figure 1-4a. Sample Spirometry Volume Time and Flow Volume Curves

Figure 1-4b. Report of Spirometry Findings Pre and Post Bronchodilator ?