Cough-Variant Asthma and Related Diseases

many subgroups (or phenotypes), including atopic asthma, neutrophilic asthma, exercise-induced bronchoconstriction (EIB), obese asthma, the asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS), occupational asthma, aspirin-exacerbated respiratory disease (AERD), exacerbation-prone asthma, and cough-variant asthma, to name a few. While each of these asthma phenotypes has its unique pathobiology, they all share the backbone-defining feature of asthma—variable expiratory airflow limitation (and the consequent symptoms of cough, wheeze, shortness of breath, and/or chest tightness that vary over time and in intensity).

Acute airway obstruction in asthma is driven by a combination of airway smooth muscle constriction and bronchial inflammation. Airway narrowing and the mediators released as part of airway inflammation in asthma trigger the cough receptors that line the airways, stimulating the cough reflex. Bronchoconstriction can occur in response to many different environmental stimuli, including inhaled allergens, irritants, respiratory infections, cold air, and certain medications such as beta blockers. Asthmatic patients appear to have a unique infiltration of their airway smooth muscle cells by activated mast cells,8, 9 resulting in increased airway smooth muscle mass and airway hyperresponsiveness. Allergen-induced airway narrowing, one of the more common causes of bronchoconstriction, results predominantly from IgE-dependent release of the mast cell-derived mediators, including histamine, tryptase, leukotrienes, and prostaglandins.10 These mast cell mediators directly contract airway smooth muscle cells and promote airway infiltration with inflammatory cells, especially eosinophils.

Airway inflammation in asthma results from activation of mast cells and T helper 1 (Th1) and T helper 2 (Th2) lymphocytes. Th2 cell activation leads to the release of the cytokines interleukin-4 (IL-4), IL-5, and IL-13, which in turn leads to increased bone marrow release of eosinophils. Airway eosinophilia is a major contributor to the inflammatory cycle of asthma. There is developing evidence that airway and sputum neutrophilia also contribute to a corticosteroid-resistant asthma phenotype in some patients.

With persistent airway inflammation, individuals with asthma develop mucous hypersecretion, mucous plugging of the airways, and mucosal, submucosal, and adventitial edema. Mucous plugging, airway edema, subepithelial fibrosis, smooth muscle hypertrophy, and smooth muscle hyperplasia can result in permanent structural changes in the airways, referred to as remodeling. Remodeled airways can become permanently obstructed, rendering them less responsive to traditional therapy, with features akin to chronic obstructive pulmonary disease (COPD).

Interestingly, the mechanism of cough in asthma has features that are likely somewhat distinct from the above-mentioned pathways that induce bronchial hyperresponsiveness. Individuals with cough-variant asthma have a hypersensitive cough reflex but demonstrate less bronchial hyperresponsiveness to methacholine than those with classic asthma.11, 12


Of the approximately 26 million Americans with asthma (8.4% of the population), more than 75% of cases first manifest in childhood as cough, wheeze, chest tightness, or frequent chest colds.13 Persistent cough is a frequent manifestation of childhood asthma. Patients with asthma may experience a period of disease latency during their teenage years. Some then outgrow their disease, and others have a resurgence of symptoms. Poor, female, Black, and Puerto Rican individuals are disproportionately affected by asthma.14 This is likely due to a combination of genetic, environmental, and socioeconomic factors.

The typical manifestations of asthma include any combination of cough, wheeze, chest tightness, or shortness of breath that varies over time and in intensity, and improves with bronchodilators. Because of the variable nature of bronchospasm, individuals with asthma can lack airflow obstruction and be asymptomatic (including cough-free) when evaluated in a care provider’s office. A thorough history, however, should reveal fluctuating symptoms that result from usual triggers. These triggers commonly include upper respiratory tract infections, exercise, environmental allergens (including dust mites, seasonal pollens, animal dander, cockroaches, mice, molds, and work-related allergic exposures), strong emotions, cold air, cigarette smoke, and strong odors or fumes. A small percentage of adults with asthma will develop asthmatic symptoms after ingestion of aspirin or any nonsteroidal anti-inflammatory drug. They often have associated nasal symptoms and/or nasal polyps, leading to the encompassing descriptor, aspirin-exacerbated respiratory disease.

While many patients present with the classic combination of triggered cough, wheeze, chest tightness, and shortness of breath, there exists a subgroup of previously mentioned individuals with asthma who have cough-variant (or cough-predominant) asthma. These individuals frequently lack wheeze, chest tightness, and dyspnea but have heightened cough reflex sensitivity with dry or minimally productive cough. Longitudinal studies suggest that nearly 33% of patients with cough-variant asthma will develop the classical symptom of asthmatic wheeze over time.15, 16


The diagnosis of asthma is made by clinical history consistent with asthma, exclusion of alternate diagnoses, demonstration of variable airflow obstruction on spirometry, and resolution of symptoms with antiasthmatic therapy. Episodic cough, wheeze, and shortness of breath can be caused by many diseases, so it is critical to disentangle asthma signs and symptoms from those of mimicking and comorbid disorders, from the common (such as recurrent chest infections, gastroesophageal reflux, chronic rhinosinusitis, and seasonal allergies) to the uncommon (such as paradoxical vocal fold motion disorder, eosinophilic granulomatosis with polyangiitis, acute or chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and infections with associated eosinophilia, like strongyloidiasis and filariasis). This section will focus on the diagnostic modalities used to distinguish asthma from other disorders.


Spirometry is the most widely used pulmonary function test that enables the clinician to evaluate for obstructive lung disease. Patients are coached to inhale maximally and then quickly and forcefully exhale their complete breath into a spirometer. The spirometer measures the forced expiratory volume in the first second (FEV1) and total forced expired volume, or forced vital capacity (FVC). These values are used to calculate an FEV1/FVC ratio. Airflow obstruction has generally been defined as an FEV1/FVC ratio less than 0.7. More accurately (because it takes into account changes in FEV1/FVC with age), airflow obstruction is defined as a value less than the lower limit of normal, the fifth percentile of the spirometer’s electronically computed 95% confidence intervals. If airflow obstruction is present, the severity of obstruction is then determined by the percent predicted reduction in FEV1. For example, if the FEV1 is 3 L (75% of predicted) and the FVC is 5 L (95% of predicted), the FEV1/FVC ratio of 0.6 demonstrates the presence of airflow obstruction and the FEV1 at 75% of predicted is used to describe the severity of airflow obstruction as mild.

Airflow obstruction can also be identified with a classic scooped, concave shape on the expiratory limb of a flow-volume loop (Figure 2–1). As the name implies, flow-volume loops are a graphic representation of expiratory (and inspiratory) air volume versus rate of airflow.

Bronchodilator Reversibility and Bronchoprovocation Testing

Variability in measured airflow obstruction is essential to asthma diagnosis. Variability can be seen over time or in response to bronchodilator or bronchoprovocation testing.17

If a patient has verified obstruction on his or her spirometry (with FEV1/FVC less than 0.7), a diagnosis of variable airflow obstruction can be made by demonstrating significant FEV1 improvement on subsequent testing performed longitudinally or immediately following bronchodilator administration. Bronchodilator reversibility testing is performed by administering two to four puffs (or a nebulized treatment) of a short-acting bronchodilator after initial spirometry, and repeating the spirometry 10 to 15 minutes later. If a patient’s FEV1 increases by 12% with an absolute change of 200 cc, he or she is said to have a positive response to bronchodilator. There is no clearly defined bronchodilator reversibility cutoff for asthma diagnosis, though some providers look for a 15% or 20% increase in FEV1 after administration of bronchodilator. There are rare circumstances when a patient with asthma might have a false negative response (less than 12% or less than 200 cc improvement) to bronchodilator testing. The potential causes for failure of lung function to improve following bronchodilator administration in asthma are beyond the scope of this chapter.

If a patient does not have obstruction on his or her spirometry (with FEV1/FVC greater than 0.7), but a diagnosis of asthma is still suspected, bronchoprovocation testing can be performed to induce bronchoconstriction. Patients with asthma are more sensitive than normal to provocative airway stimuli and, therefore, in response to these stimuli, experience airflow obstruction with a significant decrease in FEV1. A variety of bronchoprovocative agents can be used, including methacholine, mannitol, exercise, and eucapnic hyperventilation of cold, dry air. Methacholine challenge is considered the gold standard and involves inhalation of incrementally increasing concentrations of methacholine, an analog of the neurotransmitter acetylcholine, with spirometry testing after each inhalation (Figure 2–2). The test concludes when the subject experiences a 20% relative reduction in FEV1 or reaches the maximum concentration of inhaled methacholine. The methacholine concentration at which a 20% reduction is seen is called the provocative concentration, or PC20. A PC20 greater than 16 mg/mL excludes an asthma diagnosis with reasonable certainty; a PC20 less than 8 mg/mL indicates bronchial hyperresponsiveness consistent with asthma. The test lacks specificity, unfortunately, as more than 5% of the general population without asthma may also have a significant decrease in FEV1 in response to methacholine (false positives).

Serum Biomarkers and Fractional Exhaled Nitric Oxide

A diagnostic serum or exhaled breath biomarker specific for asthma or asthma-induced cough has yet to be discovered. In Th2-driven asthma, patients may have increased peripheral eosinophils and IgE, in addition to increased airway mucosal eosinophilia. Airway mucosal eosinophilia is not limited to asthma, however; it is found in other Th2-driven airway diseases as well, like eosinophilic bronchitis and, in some patients, COPD. Mucosal eosinophilia can be approximated by measuring sputum eosinophils. Traditionally, sputum eosinophils greater than or equal to 2% to 3% of the total sputum white cell count indicate Th2 airway inflammation. However, induced sputum eosinophils are not measured in routine practice because we lack consistent standards of sputum induction, processing, and interpretation. Fractional exhaled nitric oxide (FENO), a noninvasive surrogate of mucosal eosinophilia, is used more routinely. Fractional exhaled nitric oxide correlates well with induced sputum eosinophils, presumably because eosinophilic airway inflammation leads to upregulation of inducible nitric oxide synthase in respiratory epithelial cells with release of nitric oxide into the exhaled breath. In a recent meta-analysis, FENO was shown to have 66% sensitivity and 76% specificity in detecting ≥3% induced sputum eosinophils.18 FENO > 47 ppb predicts corticosteroid responsiveness with a negative predictive value of 89%. In one study, elevated FENO correlated with corticosteroid responsiveness better than spirometry, bronchodilator response, variation in peak flow, or methacholine airway hyperresponsiveness.19

In summary, objective testing is available to rule in or rule out a diagnosis of asthma. A person with normal lung function and no evidence of airflow obstruction at a time when he or she is actively coughing almost certainly does not have asthma as the cause of cough. Similarly, a negative bronchoprovocation challenge excludes asthma as the cause of cough with at least 95% certainty. On the other hand, a person with cough and reversible airflow obstruction can be assumed to have asthma as at least one potential cause of coughing and should be treated for asthma until normal (or optimal) lung function is achieved. In general, asthma is exquisitely sensitive to treatment with corticosteroids. Cough that is not ameliorated by a course of oral corticosteroids (eg, prednisone 40 mg/day for 1–2 weeks) is probably not due to asthma. At the same time, making a diagnosis of asthma based solely on clinical impression, without confirmation based on objective (spirometric) testing, is fraught with potential for error. In a recent study of 467 adults with a physician’s diagnosis of asthma made within the previous 5 years, a full 33% were found not to have current asthma on detailed medical review and pulmonary function testing. More than half of the patients with an erroneous diagnosis of asthma had not had pulmonary function testing at the time of diagnosis.20


Patients with classic asthma and cough-variant asthma are treated similarly. The pillars to achieving asthma control are trigger avoidance, patient self-awareness and monitoring of symptoms, strong patient-physician communication, and medication compliance with correct inhaler technique and appropriate medications.21 Asthma therapy should be initiated once reversible airway obstruction has been confirmed in a patient with classic asthma symptoms or chronic cough. We understand that under certain circumstances, it may be desirable to begin an empiric trial of therapy for suspected asthma in a patient with chronic cough based on history and examination alone. However, in this circumstance when reversible airway obstruction has not been confirmed, a symptomatic response to steroid therapy cannot exclude other etiologies of steroid-responsive cough and therefore does not establish a diagnosis of asthma.

Asthma medications are divided into two classes: quick-relief bronchodilators and controller medications. These are both described in detail below.

Quick-Relief Bronchodilators

All patients with asthma, including those with mild disease, should have access to quick-relief inhalers. Inhaled short-acting beta-adrenergic agonists (referred to as short-acting beta-agonists, or SABAs) induce bronchodilation of constricted airways in less than 5 minutes. In instances of acute bronchoconstriction, SABAs therefore quickly reverse airflow obstruction and relieve debilitating symptoms of cough, wheeze, shortness of breath, and chest tightness.

Albuterol is the most commonly used short-acting bronchodilator. Its peak effect occurs 30 to 60 minutes after inhalation, and its duration of efficacy is about 4 to 6 hours.22 Patients should be instructed to take two puffs of their quick-relief inhaler at the onset of asthma symptoms, or proactively 20 to 30 minutes before an exposure to known symptom triggers to prevent bronchoconstriction.

Albuterol is a racemic mixture of dextro- and levostereoisomers. Levalbuterol is a single-isomer preparation developed with the hope of reducing the adverse stimulatory side effects of albuterol. However, most studies have found the activity and side-effect profiles of albuterol and levalbuterol to be indistinguishable.

Asthma outcomes do not improve when short-acting bronchodilators are used regularly, 4 times daily, compared to on an as-needed basis.23 A disadvantage to regular use of SABAs is the development of tolerance, or tachyphylaxis, to their bronchoprotective effect. After regular use for as little as 1 week, the ability of albuterol to protect against exercise-induced bronchoconstriction when taken prior to exercise diminishes significantly. Once a patient is using his or her SABA more than twice per week to relieve daytime asthma symptoms or more than twice per month to relieve nocturnal symptoms, consensus is to step up therapy by adding a long-acting controller medication.

Controller Agents

Refer to Table 2–1. Long-term asthma management is approached in a stepwise fashion, with medication adjustments dependent upon symptom control and exacerbation frequency. Medication regimens should be escalated (or stepped up) until adequate disease control is achieved. Conversely, patients with excellent clinical control should have their regimens evaluated for deintensification (or stepping down) to avoid excess steroid exposure.

Aug 11, 2020 | Posted by in OTOLARYNGOLOGY | Comments Off on Cough-Variant Asthma and Related Diseases
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