Asthma is suspected from a history of key symptoms, including cough, wheezing, dyspnea, chest tightness, and increased mucus production. A positive family or personal history of atopic diseases and diseases that are comorbid with asthma, such as allergic rhinitis and rhinosinusitis, is also important. The differential diagnosis of asthma is broad and includes potentially life-threatening diseases. Pediatric asthma and psychiatric mimics require special attention to prevent misdiagnosis. Differentiating asthma from these other disease states by history alone is not always possible. Because accurate diagnosis is critical to successful treatment, objective testing by spirometry and methacholine challenge should be employed.
Diagnosis of asthma by history and presentation is essentially the process of searching for the key symptoms that indicate asthma is possible in an individual patient who has respiratory complaints. There are five key asthma symptoms: cough, wheeze, dyspnea, chest tightness, and increased mucus production. Although asthma has been known for thousands of years, the exact biochemical and cellular mechanisms that are perturbed to create these symptoms are not entirely understood. Further, there still is not a single exact test that can pinpoint asthma in all patients. Therefore, asthma remains a clinical diagnosis, and its discovery and confirmation depend totally on the suspicious and questioning mind of an astute clinician.
Historic evolution of asthma concepts
Observations and descriptions of a clinical history of asthma, the development of signs and symptoms in an affected individual, have changed substantially over time. The earliest descriptions of asthma from twenty-sixth century b.c. Chinese and sixteenth century b.c. Egyptian records recognized some major aspects of the disease: its seasonal nature, the labored, noisy, breathing, characteristic thick phlegm, and the association with nasal mucus. Until the twentieth century, however, asthma was not diagnosed accurately; rather, it frequently was confused with infectious, cardiac, and other respiratory conditions. For example, even Galen, the most influential physician during the Greco-Roman era, used the term “asthma” in three different situations: to describe panting symptoms, to label a type of acute respiratory distress, and as the syndrome name for chronic respiratory illness . It was not until the late Middle Ages, when Razi, about 925 , Maimonides, around 1180 , and others first described asthma as a specific disorder that could be diagnosed from clinical history. It remained for Laennec, in the nineteenth century, to use physical examination to begin to differentiate various chest diseases , and for Sampter in 1933, to discriminate between allergic and nonallergic asthma by histamine provocation. Finally, in the past 2 decades, the modern view of asthma was completed with the gradual realization that eosinophilic inflammation was the underlying basis for asthma clinical symptoms .
Environmental and psychologic influences
Important aspects of asthma’s clinical pattern are an association with environmental causes and with psychologic stresses . There has been debate over the degree to which environmental factors explain the marked rise in asthma incidence during the twentieth century , but there is little debate about the adverse effects of specific pollutants, such as ozone , diesel exhaust , or aeroallergens , on individual asthmatics. The exact nature of the relationship of asthma to environmental allergies was settled in 1989, with the report of an extremely strong statistical link between elevated IgE levels and the presence of asthma symptoms . This study forced a re-evaluation of the traditional dichotomy between intrinsic and extrinsic asthma: the great majority of asthma was found to be allergen influenced and therefore extrinsic.
Psychologic stress also has long been thought to play a major role in asthma attack causation and is believed to be a precipitating factor in up to 35% of asthmatics . In the first half of the twentieth century, it was common to send asthmatics to the mountains or seashore for a rest cure, but a recent systematic review failed to find solid evidence that psychologic factors increase the risk of severe or fatal asthma attacks . Nevertheless, mouse studies have shown that short-term stress reduces bronchial inflammation, whereas chronic stress enhances it . Recently, in children, low socioeconomic status and chronic stress, which are known to increase asthma incidence, were shown also to increase the levels of the proallergic cytokines interleukin 5 and interleukin 13 .
Environmental and psychologic influences
Important aspects of asthma’s clinical pattern are an association with environmental causes and with psychologic stresses . There has been debate over the degree to which environmental factors explain the marked rise in asthma incidence during the twentieth century , but there is little debate about the adverse effects of specific pollutants, such as ozone , diesel exhaust , or aeroallergens , on individual asthmatics. The exact nature of the relationship of asthma to environmental allergies was settled in 1989, with the report of an extremely strong statistical link between elevated IgE levels and the presence of asthma symptoms . This study forced a re-evaluation of the traditional dichotomy between intrinsic and extrinsic asthma: the great majority of asthma was found to be allergen influenced and therefore extrinsic.
Psychologic stress also has long been thought to play a major role in asthma attack causation and is believed to be a precipitating factor in up to 35% of asthmatics . In the first half of the twentieth century, it was common to send asthmatics to the mountains or seashore for a rest cure, but a recent systematic review failed to find solid evidence that psychologic factors increase the risk of severe or fatal asthma attacks . Nevertheless, mouse studies have shown that short-term stress reduces bronchial inflammation, whereas chronic stress enhances it . Recently, in children, low socioeconomic status and chronic stress, which are known to increase asthma incidence, were shown also to increase the levels of the proallergic cytokines interleukin 5 and interleukin 13 .
Key asthma symptoms
Asthma is a highly variable syndrome of reversible airway obstruction characterized by some combination of cough, airway hyperresponsiveness, wheezing, dyspnea, and mucus hypersecretion. The disease process is variable both from person to person and in each person from episode to episode. At one extreme, sufferers are continuously ill and are frequently in and out of the hospital; at the other extreme, symptoms are rare, intermittent, often mild, and sometimes unrecognized. Milder expressions of asthma blend, without sharp distinction, into the allergic bronchitis that often accompanies allergic rhinitis . This variation can make diagnosis of certain patients extremely challenging. Still, presumptive clinical diagnosis usually is possible by obtaining a good clinical history that includes four key symptom groups.
Cough and airway hyperreactivity
Cough may be the only symptom leading to suspicion of asthma . Cough-variant asthma patients normally do not wheeze, are not dyspneic, and often have normal spirometry but do have bronchial hyperreactivity, as shown by positive methacholine challenge tests, and respond quickly to bronchodilator treatment. Bronchodilator treatment alone does not change their bronchial hyperreactivity , and there is debate as to whether these patients may, over time, develop more symptomatic asthma. In asthmatic children, the frequency of coughing is related directly to the sputum neutrophil count rather than to the eosinophil count , a finding that suggests infection may contribute to this symptom, at least in children. Cough also may be caused, commonly, by upper airway cough syndrome (allergic bronchitis/postnasal drip/sinobronchial syndrome), nonasthmatic eosinophilic bronchitis, coexisting esophageal reflux , or, rarely, by lung cancer and other more serious ailments. In children, recurrent or chronic infections and congenital or acquired structural abnormalities also are important mimics of cough-variant asthma . A history of chronic cough, especially a seasonally recurring, nocturnal, cold air– or activity-induced, or occupationally related cough, should prompt assessment with spirometry and either methacholine challenge or determination of the diurnal variability in peak flow . In difficult diagnostic cases, CT scanning also may be useful, because cough-variant asthma and other forms of asthma, but not other causes of cough, cause measurable increases in bronchial wall thickness .
Wheezing
Wheezes, the sounds generated by air passing through narrowed bronchioles, are a second key asthma symptom. In adults who have a personal or family history of allergy, wheezes, either on examination, or by history, are a sensitive but not specific indicator of significant bronchial obstruction and possible asthma. In the general population, the situation is reversed, with wheezing being specific (0.82–0.93), but not sensitive (0.31–0.47) for asthma identification . Either auscultation or computerized lung sonography can detect wheezing, and when this information is combined with other diagnostic tests, such as a methacholine challenge, the presence of wheezes increases the certainty of an asthma diagnosis and also increases the number of identified asthmatics by about 30% . Wheeze detection during spirometry is similarly useful, because the number of recorded wheezes and the reduction in wheezes with bronchodilator use are proportionate to asthma severity . Wheezing can identify even stable asthmatics during periods of normal spirometry. Not all that wheezes is asthma, however. One of the more common conditions presenting with wheeze and also with dyspnea or cough is congestive heart failure. Congestive heart failure mimics asthma even to the extent of improving with bronchodilator use, because pulmonary edema induces bronchospasm . Another wheezing asthma mimic is vocal cord dyskinesia or spasm, which simulates nocturnal asthma attacks. In this case, diagnostic tests may be normal, unless asthma and vocal cord spasms occur together or unless spirometry is done during an attack and a flattened flow-volume loop is noted. Bronchodilators are not effective for vocal cord spasm, and the inefficacy of bronchodilators, in addition to the typical description of very brief episodes of choking, wheezing, and dyspnea, can help differentiate vocal cord spasm from asthma . Other wheezing conditions in the asthma diagnostic differential are extrinsic or intratracheal upper airway obstruction, foreign body aspiration, chronic eosinophilic pneumonia, Churg-Strauss vasculitis, and bronchiolitis obliterans .
Wheezing in young children
Children are a special case, because more than 85% of their wheezing episodes are triggered by viral infections and because it is difficult to perform objective lung function tests in children younger than 6 years. The prevalence of asthma in school-aged children in the United States is now estimated to be 9%, having doubled in about 20 years . Wheezing is extremely common, occurring in at least 50% of children , but in the absence of dyspnea or effects on sleep or activities, wheezing is not likely to be caused by asthma. Wheezing that presents in the first 3 years of life and persists into childhood, is associated with bronchial hyperreactivity and reduced lung function in later life, and may be a reason for early intervention and maintenance medication. Children who have severe intermittent wheezing usually develop atopy . There also, however, are transient wheezers, who usually clear by age 3, and nonatopic wheezers, who do not seem to develop later asthma, although they may continue to wheeze occasionally when older. The differential diagnosis of wheezing in childhood is broad and is beyond the scope of this article, other than noting that cystic fibrosis may present with wheezing and must be excluded . Suspicion of asthma is increased when any one or several historical factors are present. These relative risk factors for developing asthma by the teenage years are
Three or more episodes of otitis media (1.5 times increased risk)
Pneumonia (1.8 times increased risk),
Atopic dermatitis (1.9 times increased risk)
Family asthma history (2 times increased risk)
Laryngotracheitis (2 times increased risk)
Allergic rhinitis (2.2 times increased risk)
Any wheezing in first 3 years (3.3 times increased risk)
Sinusitis (3.5 times increased risk)
Family sinusitis history (3.9 times increased risk)
Recurrent wheezing in first 3 years (4.7 times increased risk)
Recurrent wheezing in years 4 through 6 (15 times increased risk)
In contrast, onset of symptoms at or shortly after birth suggests a congenital airway anomaly or ciliary dyskinesia, and acute onset that is not associated with an infection suggests foreign body aspiration. Finally, obtaining a history of risk factors is important, because wheezing cannot always be depended on to identify child asthmatics: school-aged asthmatics may not wheeze at all, unless their forced expiratory volume in 1 second (FEV1) is reduced by at least 30% to 40% .
Dyspnea, chest tightness, and exercise-induced dyspnea
People vary in their perception and description of the breathless sensation of bronchial obstruction. In experimental bronchoconstriction studies, lesser obstruction is more likely to be described as chest tightness and greater obstruction as increased work or effort of breathing or a sense of not being able to move enough air . People also react more to changes in their lung function than to the absolute degree of obstruction, and some are unable to express in words what they are experiencing or cannot perceive dyspnea at all. Because of these variables, subjective ratings of dyspnea during asthma attacks do not correlate with data obtained during laboratory provocation studies . Some asthmatics, hypoperceivers, have significant chronic obstruction and are only minimally aware of their deficit, which may increase their risk of suffering a serious asthma attack . In one study, hypoperceivers comprised 22% of the subjects, and another 6% were nonperceivers . There was a dramatic, counterintuitive difference in methacholine sensitivity between the groups with different degrees of dyspnea perception: those who had the poorest perception were the most sensitive to provocation. The implication from this work is that patients at risk of severe asthma attacks might be predicted by assessing their subjective responses to methacholine challenge. Similar measurements also can be used to differentiate more clearly between patients who have allergic rhinitis and asthma and those who have allergic rhinitis and bronchial hyperreactivity, because those who have asthma report significantly more subjective dyspnea for the same degree of bronchoprovocation . Aging is another significant variable, with asthmatics more than 65 years old showing only about half the level of perceived dyspnea as young adults who have the same degree of FEV1 impairment . Useful subjective dyspnea ratings also can be obtained for teenage asthmatics 12 years old or older . Importantly, hypoperception of dyspnea may be a consequence of severe asthma and seems to improve with adequate asthma therapy . In a retrospective analysis of 104 hospitalized asthmatics, older age and high total IgE were correlated with initial dyspnea hypoperception but did not prevent either a good therapeutic effect or improved perception of dyspnea with treatment.
Two simple methods for estimating dyspnea perception that do not involve methacholine provocation have been reported recently. The first technique measures breath-hold duration after completing expiration spirometry . The second method uses an incentive spirometer to test maximal breathing capacity over 3 minutes . Both methods accurately identify patients who have poor dyspnea perception.
Exercise-induced dyspnea
Exercise-induced dyspnea is a special situation. Exercise-induced asthma is clinically diagnosed based on dyspnea, with or without wheezing, during exercise. Some patients who have exercise-induced asthma respond very well to pretreatment with bronchodilators or cromolyn, but some do not improve. When nonimprovers are subjected to formal cardiopulmonary exercise testing, many are found to have nonasthmatic diagnoses: laryngomalacia, vocal cord dysfunction, chest wall restriction, hyperventilation, and supraventricular tachycardia. In over half of the nonimprovers, the dyspnea is a normal response to exercise, and no illness is present .
The presence of dyspnea is a useful symptom in identifying possible asthma, but the expressed level of dyspnea cannot be used to assess the severity of disease without additional, objective information, and dyspnea also may be absent. Dyspnea is a symptom common to many diseases, so that when objective tests are not definitive, or when therapy is not successful, the differential diagnosis is wide. One of the most difficult illnesses to differentiate is chronic obstructive pulmonary disease (COPD). Asthma and COPD may occur together, particularly in asthmatics who have smoked, and in about one third of cases may be diagnostically inseparable . In some cases of severe asthma, there may be no indication of reversible obstruction on initial spirometry, but reversibility can be detected after inhaled steroid therapy. Other asthma mimics that typically cause wheezing or cough were discussed previously. In addition, there are many causes of chronic lung inflammation that produce dyspnea: pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis, allergic bronchopulmonary Aspergillosis, Wegener’s granulomatosis, and autoimmune interstitial pneumonitis . Pulmonary emboli also present with dyspnea and, rarely, also with wheezing. Alpha-1 antitrypsin deficiency is common, may occur with or without asthma, and should be sought when dyspnea and/or spirometry are worsening.
Mucus hypersecretion
As a symptom of asthma, phlegm production has been underappreciated, although mucus hypersecretion contributes to airflow limitation, hyperreactivity, morbidity, and mortality . About 9% of asthma patients produce profuse quantities of bronchorrheic sputum during attacks , and many asthmatics complain of excessive phlegm or coughing up mucus balls. In fatal asthma, marked increases in goblet cells are seen, and the mucins secreted by these cells seem to cling to the cells, producing obstructive mucus plugs rather than being cleared by ciliary function . Rheologic properties of asthmatic mucus are altered, so that the secretions are both more adhesive and less fluid . In fact, asthmatic mucus is much more difficult to cough up than is mucus produced in patients who have COPD. Mucociliary clearance is known to be impaired in asthma, probably because of both inflammation and oxidant injury . In stable, mild asthma, mucociliary clearance is decreased significantly, and during severe attacks requiring hospital care, mucociliary clearance is not measurable . Following acute attacks, mucociliary clearance does improve, but it recovers much more slowly than does obstruction. Profuse mucus production is an indicator of poor asthma control , and mucus hypersecretion is reduced when adequate corticosteroid treatment is given . Excess mucus production is generally correlated with severe asthma and with increased morbidity and mortality . In children, cough with mucus production for longer than 6 weeks should be investigated for chronic bacterial infection, cystic fibrosis, hypogammaglobulinemia, and other nonasthmatic causes . Although mucus hypersecretion occurs in other lung diseases, complaints of excess phlegm indicate a need for spirometry and consideration of asthma, and potentially serious asthma, as the cause.
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