Key points

Introduction

Asthma is a heterogeneous syndrome of cough, wheeze, dyspnea, and chest tightness that affects approximately 300 million individuals worldwide. Pathologically, airways are characterized by chronic inflammation and diminished bronchial diameter. Physiologically, spirometry demonstrates a degree of reversible airflow obstruction typically responsive to bronchodilators. Although these physiologic and pathologic distinctions contribute to the definition of asthma, the clinical symptoms of this syndrome provide practitioners little help in arriving at a specific diagnosis. Given the prevalence of asthma and the relative paucity of so-called asthma mimickers, the common constellation of cough, wheeze, dyspnea, and chest tightness usually signifies underlying asthma. However, in a subset of patients, these symptoms may represent a different underlying disease process with variable responsiveness to classic asthma therapies. In these patients, disease may progress while practitioners attempt conventional therapy. Some types of asthma may require alternative approaches to relieve symptoms successfully.

Although the aim of this article is to clarify the differential diagnosis of asthma to the otolaryngologist, the list of potential mimickers is broad ( Box 1 ). Patients with bronchial wall edema from congestive heart failure may have concomitant wheezing and dyspnea unrelated to airway inflammation, whereas obese patients may experience symptoms consistent with asthma without any significant bronchial diameter-related reduction in airflow. Similarly, there are a wide array of causes that may produce chronic wheezing, cough, and shortness of breath in any particular patient. This article addresses some of the more common medical and surgical processes that may be encountered in the practice of asthma management. For each diagnosis, awareness of the potential will increase the practitioner’s likelihood of considering (and evaluating for) an alternative pathologic condition in an at-risk patient.

Introduction

Asthma is a heterogeneous syndrome of cough, wheeze, dyspnea, and chest tightness that affects approximately 300 million individuals worldwide. Pathologically, airways are characterized by chronic inflammation and diminished bronchial diameter. Physiologically, spirometry demonstrates a degree of reversible airflow obstruction typically responsive to bronchodilators. Although these physiologic and pathologic distinctions contribute to the definition of asthma, the clinical symptoms of this syndrome provide practitioners little help in arriving at a specific diagnosis. Given the prevalence of asthma and the relative paucity of so-called asthma mimickers, the common constellation of cough, wheeze, dyspnea, and chest tightness usually signifies underlying asthma. However, in a subset of patients, these symptoms may represent a different underlying disease process with variable responsiveness to classic asthma therapies. In these patients, disease may progress while practitioners attempt conventional therapy. Some types of asthma may require alternative approaches to relieve symptoms successfully.

Although the aim of this article is to clarify the differential diagnosis of asthma to the otolaryngologist, the list of potential mimickers is broad ( Box 1 ). Patients with bronchial wall edema from congestive heart failure may have concomitant wheezing and dyspnea unrelated to airway inflammation, whereas obese patients may experience symptoms consistent with asthma without any significant bronchial diameter-related reduction in airflow. Similarly, there are a wide array of causes that may produce chronic wheezing, cough, and shortness of breath in any particular patient. This article addresses some of the more common medical and surgical processes that may be encountered in the practice of asthma management. For each diagnosis, awareness of the potential will increase the practitioner’s likelihood of considering (and evaluating for) an alternative pathologic condition in an at-risk patient.

Aspirin-exacerbated respiratory disease

Otolarygologists are familiar with Samter’s triad, in which patients present with recalcitrant sinonasal polyposis, aspirin sensitivity, and asthma. This eponymous entity is now more commonly called aspirin-exacerbated respiratory disease (AERD) or aspirin-induced asthma. The hallmark of the disease is an adverse response to ingestion of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs), after which patients can experience exacerbations of both upper and lower airway disease. The rhinosinusitis experienced by patients with AERD is severe compared with other subtypes of chronic rhinosinusitis and may be refractory to standard medical and surgical therapies.

Mucosal inflammation in AERD is related to disordered metabolism of arachidonic acid, which is metabolized by the cyclooxygenase (COX) pathway to yield prostaglandins or by the lipoxygenase pathway to yield cysteinyl leukotrienes. Aspirin and other NSAIDs block the COX pathway, shunting metabolism away from antiinflammatory prostaglandins toward proinflammatory cysteinyl leukotrienes. Cysteinyl leukotrienes are important mediators in the pathophysiology of asthma and, possibly, in the development of sinonasal polyposis in asthmatics. Patients with AERD have elevated levels of urinary cysteinyl leukotrienes compared with aspirin-tolerant asthmatics, as do aspirin-tolerant asthmatics with sinonasal polyposis compared with asthmatics without sinonasal disease.

Patients with AERD commonly develop symptoms in early adulthood. They may report an upper respiratory infection that “never went away,” or an exposure to a COX-1 inhibitor that marked the beginning of their symptoms. Nearly all patients with AERD have sinonasal symptoms, followed by adult-onset asthma.

Patients with suspected AERD are confirmed by an oral aspirin challenge. Protocols exist that typically take 2 to 3 days of outpatient supervision to complete. In a review of 300 patients referred to a tertiary center for a history of adverse reaction to aspirin-related drugs, 85% had a positive reaction to an oral aspirin provocation. Aspirin provocation followed by desensitization differs from standard immunotherapy in that a reaction is expected to occur. A reaction may include naso-ocular symptoms, lower airway reactivity measured by forced expiratory volume in 1 second (FEV ₁ ), laryngospasm, anaphylactoid reaction, or some combination of these. After a positive oral challenge, the patient can be treated either by avoidance of all COX-1 inhibitors or by desensitization, which involves continued escalation of the dose of aspirin into the therapeutic range, followed by continuous aspirin therapy.

Continuous aspirin therapy in patients with AERD results in decreased bronchial reactivity, decreased dependence on topical steroids and albuterol, and improvement in nasal symptoms. McMains and Kountakis performed a retrospective review of AERD patients undergoing endoscopic sinus surgery and showed that eight out of ten patients who did not received aspirin desensitization required revision sinus surgery, whereas no patients receiving aspirin therapy required revision in the 2-year follow-up period. Initiation of aspirin desensitization is typically performed 4 weeks following endoscopic sinus surgery.

After sinus surgery, AERD patients may benefit from treatment with a leukotriene-modifying drug combined with a topical nasal steroid. Leukotriene-modifying drugs include those that block the leukotriene receptor, currently montelukast and zafirlukast, as well as zileuton, which block the 5-lipooygenase enzyme further upstream. These drugs should be continued if the patient is to undergo aspirin oral challenge and desensitization.

Asthma in patients with AERD responds to traditional asthma therapies but can be difficult to control. The typical patient with AERD will require both a topical corticosteroid and a leukotriene-modifying drug for control of their asthma. Concomitant atopic disease should not be ignored and may be treated with allergen avoidance, antihistamines, anti-IgE therapy, or immunotherapy as indicated.

Foreign-body aspiration

In children, foreign-body aspiration can present with symptoms of bronchial asthma. Children usually present after a coughing or choking spell. Children of any age may present, though typically they are younger than 2 years of age. Most patients present to emergency rooms soon after suspected aspiration; those presenting to outpatient providers days or weeks after the event may be more easily confused with bronchial asthma. Physical examination may show unilateral decreased breath sounds or wheezing. Other findings may include tachypnea, stridor, coughing, fever, or cyanosis. Chest radiographs may show evidence of air trapping or atelectasis of distal lung parenchyma. However, a high index of suspicion should not be allayed by a normal physical examination and radiographic evaluation because neither of these is sensitive for the detection of airway foreign body in children. Patients in whom foreign-body aspiration is suspected should undergo rigid bronchoscopy for diagnosis and possible removal of the foreign body.

A delay in diagnosis can lead to inappropriate treatments for asthma or pneumonia, and can result in a prolonged hospital stay compared with a prompt diagnosis resulting in interventional bronchoscopy. A significant delay in diagnosis can result in chronic respiratory sequelae including bronchiectasis.

Cough variant asthma or nonasthmatic eosinophilic bronchitis

Asthma represents 25% to 29% of cases of chronic cough. Although the typical triad of wheezing, shortness of breath, and chest tightness often accompanies cough in cases of asthma, a subset of patients with asthma will report cough as their predominant (if not only) symptom of concern. This syndrome, termed cough variant asthma (CVA), is associated with mast cell airway infiltration, airway remodeling, and reversible airflow obstruction in a pattern consistent with other forms of asthma.

The workup of chronic cough generally includes measurement of airflow limitation by spirometry. Although some patients with CVA demonstrate abnormalities in their pulmonary function tests, many have essentially normal spirometry. Given the vague nature of an isolated cough in a nonsmoking patient with normal spirometry, diagnosis of CVA requires a high index of suspicion for the diagnosis in this population. Methacholine inhalation challenge will typically demonstrate increased bronchial reactivity, which supports a diagnosis of CVA. However, diagnosis typically requires response to a diagnostic or therapeutic trial of bronchodilators and inhaled corticosteroids. Patients with concerning symptoms should start a trial of therapy consistent with general guideline-based management of asthma. A 14-day course of the leukotriene receptor antagonist zafirlukast was demonstrated to improve subjective cough score in a series of patients with bronchodilator and inhaled-corticosteroid refractory CVA. Therefore, patients with failure of response to bronchodilator and inhaled-corticosteroid therapy should be offered second-line leukotriene-receptor antagonist therapy. In some patients with severe disease, a short course of systemic corticosteroids may be useful as an adjunct to chronic therapy. Treatment should continue in a fashion consistent with guideline-driven asthma therapy. However, even with therapy, up to 30% of patients with CVA eventually progress to classic asthma.

CVA demonstrates a sputum eosinophilia similar to that observed in classic asthma. However, up to 13% of patients with chronic cough present with sputum eosinophilia, chronic cough, and absence of spirometric markers of bronchial hyper-reactivity. This syndrome, known as nonasthmatic eosinophilic bronchitis, represents a constellation of normal spirometry, increased cough, sputum eosinophilia, and absent bronchodilator response. Patients presenting with this symptomatic array should be evaluated for occupational or environmental exposures, and be considered for a trial of inhaled corticosteroids. Inhaled budesonide has resulted in a decrease in sputum eosinophils and cough reflex sensitivity among patients with eosinophilic bronchitis.

The differential diagnosis of chronic cough is broad. Workup should include evaluation for sputum eosinophilia and bronchial hyper-reactivity. Early recognition of the diagnoses of CVA and eosinophilic bronchitis requires disease awareness and a low threshold of suspicion. Such diagnosis may result in earlier administration of appropriate therapy and shorter duration of symptoms.

Work-related asthma

Work-related asthma (WRA) is a broad term encompassing several circumstances in which asthma symptoms are either triggered or exacerbated by work exposures. Occupational asthma (OA) is a specific subset of bronchial hyper-reactivity associated with variable airflow limitation occurring de novo (or recurring in an asthmatic patient previously in remission) in the setting of a specific agent related to the workplace. This can take the form of an immediate response (ie, reactive airway dysfunction syndrome or irritant-induced OA) that is independent of allergic reaction. In other circumstances, patients may experience progressive bronchoconstriction resulting from development of an allergic response to a workplace substance (ie, sensitizer-induced OA). A separate subset of WRA called work-exacerbated asthma (WEA) is the worsening of preexisting asthma by work-related noxious exposure ( Box 2 ).

As the leading occupation-related lung disease in many countries, OA generates a significant amount of interest among employers and managers of workers’ compensation funds, and accounts for 9% to 15% of cases of adult asthma. As a result, there is much written about the cause and definition of this syndrome as well as the association between symptoms and work-related exposures. Further confounding the analysis of this complex disease, diagnostic standards are less than optimally homogeneous, particularly given the medico-legal and financial implications of a work-related diagnosis.

Typically, patients present with classic asthma symptoms of shortness of breath, chest tightness, wheezing, and cough that variably improves during periods away from work exposures. Whereas some patients may have improvement in symptoms during their daily time off, many require a more extensive period away from the trigger to induce remission of symptoms. Symptomatic improvement during weekends or on prolonged vacations has approximately 88% to 90% sensitivity for OA. Therefore, when evaluating a patient with asthma, clinicians should inquire about variations in symptoms related to time off. In patients with new onset symptoms, historical review should also include ascertainment of work tasks, specific exposures (with review of material safety data sheets), changes in work processes or work areas, adherence to personnel protection-equipment policies, unusual exposures within 24 hours of symptoms or concomitant sinonasal or conjunctival irritation. Patients should also be asked to describe any history of reactive airway disease to elucidate the potential for WEA. Physical examination should target wheezing, allergic mucosal changes, or dysphonia, though these are all nonspecific findings and do not definitively direct the clinician’s focus. Although historical assessment and physical examination are imperative to identify other potentially pathologic causes, only 50% of diagnoses of OA are likely to result from history or examination alone.

Literally hundreds of substances have been associated with WRA. Health workers have been noted to have symptom development with latex gloves, hairdressers have had symptomatic association with persulfates, and plant workers have become progressively ill with exposures to a wide variety of workplace agents. Although specific inhalational challenges may help with objectively documenting bronchial reactivity, initial workup should begin with pulmonary function testing, including bronchodilator responses and nonspecific challenges (either methacholine or histamine), to determine bronchial responsiveness.

If historical information raises suspicion of WRA, patients may be asked to provide data from serial peak expiratory flow rate (PEFR) measured both at and away from work. After training on proper performance of PEFR, patients perform measurements four times daily, ideally for 3 to 4 weeks. This is completed on both workdays and on days off. Optimally, it includes a 2-week period off for comparison to a 2-week period of work. Although there is difficulty in interpreting the significance of variability based on gross analysis of PEFR results, these measurements can be imported into the OASYS system (Occupational Asthma Expert SYStem, Vitalograph, UK) with a computer-driven differential analysis. Variability of greater than 20% to 30% in peak flow measurements as assessed by this software is associated with 78% sensitivity and 92% specificity for OA.

Additionally, physiologic measurements of airway responsiveness can be obtained sequentially after prolonged exposure (eg, the end of a workweek) and a period of prolonged avoidance (eg, a 2-week vacation). This can be accomplished using spirometry with methacholine or histamine challenges. After a week of work, a threefold decline in the concentration of provocative substance necessary to produce a 20% fall in FEV ₁ would be additional support for a diagnosis of WRA. Although allergic skin testing can be helpful in the assessment of an IgE response to protein allergens (eg, animal dander), most chemical irritants have not similarly been associated with positive results. Similarly, specific serologic IgE antibodies have been associated with many protein (but few chemical) triggers for asthma. The role of targeted immunologic testing (serologic or skin) has been addressed in several studies but remains unclear. Generally, this battery of tests may help identify specific triggers in some patients with OA symptoms, though it obviously does not exclude untested triggers.

Specific inhalation challenges (SICs) have been described by the US Agency for Healthcare Research and Quality as a “reference standard” for OA. These tests remain cumbersome, fraught with confounding technicalities, and accessible only at a few centers worldwide. Nonetheless, SIC may be a useful adjunct in the diagnosis of WRA in an otherwise unclear case. Alternatively, in a review of 10 patients with WRA, there was notation of a significant increase in median (interquartile range) sputum eosinophils during a 2-week to 4-week period of work when compared with a 2-week period away. This suggests that sputum cell counts may provide yet another clue in the workup of the patient with suspected WRA. In summary, the rational approach to the diagnosis of WRA should include historical assessment of respiratory symptoms, association of symptoms with work exposures, and physiologic assessments of response to work exposure. Although there is no gold standard, these factors can be used in combination to provide support for such a diagnosis.

Of note, occupational exposure-related lung disease may manifest in a variety of ways. Hypersensitivity pneumonitis (HP) may present in similar fashion to OA (see later discussion). However, the underlying pathophysiology of OA remains a type-1 hypersensitivity reaction (prominent IgE response), consistent with other types of asthma. In contradistinction, HP is mediated by T-lymphocytes and it represents a type-4 hypersensitivity reaction. This important difference drives the variability in therapy between two similar phenotypes with similar exposures.

Therapy for WRA is driven by subtype of disease. For all patients, irritant avoidance remains the principal mechanism for improvement in symptoms. However, this is not always easy to achieve, particularly if the diagnosis is unclear. For patients with sensitizer-induced OA, therapy should be avoidance of, or reduction in exposure to, the noxious stimulus responsible for illness. Given that this may not be possible for economic or personal reasons, bronchodilator therapy (to include inhaled corticosteroids and/or β2-agonists) may be applied in the fashion generally prescribed for non-OA. Irritant-induced asthma occurs after a very short latent period and represents an acute response to a respiratory irritant. Therefore, engineering processes and personnel protective equipment is often able to reduce burden to such a degree that symptomatic recurrence is prevented. WEA has some pathophysiologic differences from simple progression of asthma. However, very few studies have been targeted at defining variation in therapy for patients with this syndrome. As a result, management of asthma in conventional fashion with maximal exposure avoidance remains the most prudent course of therapy.