Vol. 13 •Issue 1 • Page 16
Allergy & Asthma
Curing the Cough: Diagnosing and Treating Cough-variant Asthma
Wheezing, dyspnea and chest tightness, combined with reversible airways obstruction on spirometry, are easy to diagnose as asthma. At times, due to variations in exposure and severity of asthma, symptoms and findings of obstruction may disappear, only to reappear in the future.
In the extreme, asthma may present with a single symptom – cough. Cure of the cough, with its myriad other causes, can elude the physician, unless careful consideration is given to asthma as the culprit.
The phenomenon of cough as the sole symptom of asthma was unrecognized prior to the 1970s, and patients with undiagnosed chronic cough due to asthma often were labeled with chronic bronchitis.
In 1972, a researcher described “variant asthma” in five adults with a nonproductive chronic cough that improved after bronchodilator or corticosteroid treatment.1 Three of the five subjects, however, had mild obstruction on spirometric examination.
Three years later, another investigator described seven adults with cough who improved after bronchodilator therapy.2 As with the first study’s subjects, this cohort also had obstructive lung disease, as evidenced by abnormal airways resistance and increased residual volume.
In 1979, the definitive paper defining cough-variant asthma was published.3 Six individuals with chronic cough and normal spirometry were documented to have hyperreactive airways disease after a methacholine challenge test (MCT) (PC20 at ² 25mg/ml), and all subjects had resolution of their cough after treatment with bronchodilators.
Other researchers subsequently documented the same types of findings in the pediatric population. In 1982, a study of 32 pediatric subjects, ages 3 to 17, showed their chronic cough resolved with theophylline.4
The epidemiology of cough-variant asthma is unknown, as no large-scale population studies have addressed this question. Cough as the lone symptom of asthma is estimated to occur in 6.5 percent to 57 percent of patients with asthma.5
One large population study that followed 15,000 Canadian children observed persistent wheezing in 13 percent and a persistent cough in 6 percent, compared to a history of physician-diagnosed asthma in 4.7 percent.6 However, no confirmatory studies were performed to document that cough-variant asthma caused the chronic cough.
Smaller observational studies of patient populations at referral facilities suggest that asthma is the second most common cause of chronic cough, after postnasal drip.
Over a course of 11 months, one team examined 49 adult patients who had been referred for a chronic cough.7 Asthma or asthma in combination with postnasal drip accounted for 43 percent of patients with a chronic cough.
In a similar study of 38 children with a persistent cough of at least four weeks duration, 39 percent of the population had cough-variant asthma.8 While informative, these studies aren’t likely to be representative of the general population because they evaluated patients at tertiary referral centers. Based on these and similar studies, there doesn’t appear to be an age or sex predilection for cough-variant asthma.
Presentation and Diagnosis
By definition, individuals with cough-variant asthma present only with cough and lack wheezing, dyspnea or chest tightness. However, the definition of a chronic cough is controversial.
The American Thoracic Society Consensus Panel defines a chronic cough as one lasting three weeks to eight weeks or longer.5 Other authors advocate using a definition of cough lasting more than two months.9
The cough is characteristically nonproductive and may exacerbate at night, after exercise, with exposure to cold air, or after a respiratory infection.4 There may be a seasonal variation of the cough reflecting changing environmental allergens, and many patients give a personal or family history of atopy.
Studies show a prevalence of personal atopy, documented by previous history or skin testing, ranging from 38 percent to 64 percent in these patients.4,10 Family history of atopy is documented in 48 percent to 100 percent of the cases.3,4
One group documented that the average length of chronic cough in individuals presenting to a tertiary clinic was 39.8 months prior to diagnosis, while patients with a diagnosis of asthma or asthma and postnasal drip complained of cough for an average of 11.5 months and 67.2 months, respectively.7
A criterion for the diagnosis of cough-variant asthma is the presence of normal pulmonary function studies. These should include FEV1 (³ 80 percent predicted), FEV1/FVC ratio (² 8 absolute percent points below the predicted ratio as a percent), and FEF25%-75% (³ 65 percent predicted). There also should be no significant bronchodilator response (i.e., FEV1 < 12 percent, FEF25%-75% < 23 percent improvement from the pre-bronchodilator value).
Hyperreactivity to methacholine (PC20, FEV1 < 8 mg/ml to 25 mg/ml), histamine, carbachol or adenosine monophosphate also should be documented. However, a positive MCT isn't a specific diagnostic test for asthma, and individuals with undiagnosed chronic cough and a positive MCT who don't respond to therapy with inhaled corticosteroid or bronchodilators can't be diagnosed with asthma.11
While some authors report that a negative MCT has a 100 percent negative predictive value for asthma, other studies suggest that this isn’t the case.
Researchers evaluated 39 male and 35 female children, ages 6 years to 20 years, with chronic undiagnosed cough. All the subjects had similar baseline FEV1 and a history of atopy, although peripheral eosinophilia wasn’t reported. Although 38 subjects weren’t responsive to methacholine (PC20 > 25mg/ml), 24 percent of these methacholine nonresponsive individuals had resolution of or significant improvement in their cough after bronchodilator therapy, and four of the subjects ultimately developed wheezing within a few months.
In another study, a negative MCT (PC20 > 8mg/ml) had a negative predictive value of 56 percent for the diagnosis of asthma in individuals with suspected asthma but with normal spirometry and no spirometric response to bronchodilators.12 Asthma was diagnosed after subjects clinically improved with bronchodilator or inhaled corticosteroid therapy.
Occasionally, forced exhalation can’t be used to perform a MCT due to an interfering cough. In such cases, airway resistance or specific airway conductance can be used to assess response to methacholine.
It’s not possible to perform a MCT in very young children, so the diagnosis of cough-variant asthma in this population may need to be based on response to therapy.
Ultimately, abatement of the cough after bronchodilator or anti-inflammatory therapy provides confidence in the diagnosis. Treatment with oral corticosteroids and perhaps other systemic therapies, such as anti-leukotriene agents, may be less convincing because they may be treating allergic rhinitis.
Peripheral eosinophilia may be present in patients with cough-variant asthma, and the presence of eosinophila isn’t significantly different from that seen in classic asthma. Peripheral eosinophilia is documented in approximately 50 percent of subjects with cough-variant asthma.3,4
Another group showed no difference in peripheral or sputum eosinophilia between individuals with cough-variant asthma and classic asthma.13 Other researchers found similar results and also documented comparable levels of serum eosinophilic cationic protein, as well as eosinophils in bronchoalveolar lavage and bronchial biopsy specimens in individuals with cough-variant and classic asthma.14
Airways eosinophilia and metachromatic cells also are observed in eosinophilic bronchitis. This syndrome is defined as chronic cough with normal spirometry, the presence of airways eosinophilia, and a negative MCT. It’s unclear if this syndrome represents asthma with a negative MCT or a separate entity.15
The pathophysiology specific to cough-variant asthma isn’t well understood, and most findings show airways inflammation indistinguishable from classic asthma. Theories of both large and small airways’ involvement, as well as hypersensitivity of the cough receptors, have been postulated for the variant presentation of the disease.3,16
Recent studies have shown hypersensitivity of the cough receptors in individuals with cough-variant asthma when compared to those with classic asthma or normal controls.
Investigators showed a higher density of the neuropeptide, substance P, in the bronchial epithelium of subjects with cough-variant asthma when compared to subjects with classic asthma.17 Substance P, released from the airway sensory nerve C-fibers, may play an important role in the pathophysiology of asthma by mediating bronchoconstriction, inflammation and airways edema.
In another study, mast cells harvested via .bronchoalveolar lavage from individuals with cough-variant asthma, nonasthmatic cough and normal controls were exposed to sensory neuro-peptides. Cells from individuals with cough-variant asthma and nonasthmatic cough produced more histamine in response to the sensory neuropeptide, calcitonin gene-related protein, when compared to the normal controls.18
While histopathologic features of asthma are present in individuals with cough-variant asthma, they’re less pronounced than those seen in classic asthma.
Using bronchial biopsies, researchers documented subepithelial-layer thickening consistent with remodeling in individuals with cough-variant asthma which wasn’t as severe as in the classic asthma group but was significantly more pronounced than in the normal control group.19
Treatment for cough-variant asthma is essentially identical to that for classic asthma, and therapy should be directed by established guidelines.20 Interestingly, longer therapy with oral corticosteroids that’s generally used for the short-term treatment of acute exacerbations of classical asthma may be necessary to initially control the cough in some patients with cough-variant asthma.7,21
Initial therapy can start with inhaled bronchodilators, inhaled corticosteroids or oral corticosteroids. Patients with cough-variant asthma often don’t respond solely to bronchodilator therapy, and inhaled corticosteroids may take four weeks to six weeks to reach full efficacy.22
Inhalation from an MDI without a spacer should be avoided because it may exacerbate the cough.5 If cough during administration of the inhaled medication is a problem, a dry powder inhaler without a carrier powder such as budesonide inhalation powder (Pulmicort Turbuhaler®, AstraZeneca) or a hydrofluoro-alkane-MDI with an extra-fine particle size and “soft” mist such as HFA-beclomethasone dipropionate (Qvar™, Ivax) may be better tolerated.
Research showed that nine out of 10 subjects with cough-variant asthma who didn’t improve with bronchodilators responded to oral prednisone (20 mg/day to 60 mg/day) within three days. One patient required two weeks of therapy prior to improvement.22
At long-term follow-up, seven patients required an inhaled corticosteroid for suppression of their cough, while three patients didn’t have recurrent cough after a trial of prednisone.
It’s important to remember that often there’s more than one etiology for a chronic cough, and the failure of the cough to resolve with asthma therapy, or the need for continuous high dose oral corticosteroids, should prompt an evaluation for other etiologies, such as postnasal drip secondary to rhinosinusitis, gastroesophageal reflux disease or eosinophilic bronchitis.7,9
Cough-variant asthma may precede classic asthma and exhibits similar histopathologic changes. Up to two-thirds of individuals with cough-variant asthma will subsequently develop wheezing and dyspnea and require further therapy for asthma.3,4,10,23,24
Overall, there are no clear prognostic indicators for the development of classic asthma. However, children who develop cough-variant asthma prior to age 5 appear to be at a higher risk for developing classic asthma than children who develop cough-variant asthma after the age of 5.24
The degree of airways hyperreactivity (PC20) and the duration of cough don’t correlate with progression of symptoms, but individuals who develop wheezing show a worsening of PC20 and more severe airways obstruction than individuals with cough-variant asthma who develop airways obstruction but don’t wheeze.23-26
The rate of decline of FEV1 followed over five years in 20 individuals with cough-variant asthma (0.029 +/- 0.007/year) didn’t differ from that of normal controls (0.028 +/- 0.002 L/year), nor did the rate of decline change with the use of inhaled corticosteroids.26
Using a questionnaire in 1,245 children, researchers showed that children with a chronic cough used less asthma medication and utilized health care facilities less often than children who reported chronic wheezing. While the results of this study suggest that cough-variant asthma may be a “milder” version of classic asthma, the authors suggest that further studies are needed to ascertain if chronic cough in children can be empirically diagnosed and treated as asthma.27
Cough remains the most common presenting symptom to a physician’s office in the United States and accounts for 10 percent to 38 percent of outpatient visits in pulmonology practice, resulting in more than $1 billion in health care expenditures.7,28
The timely identification and treatment of cough-variant asthma is imperative for reducing the morbidity and expense of chronic cough. Further prospective longitudinal studies are necessary to improve our understanding of the biology of cough-variant asthma, its long-term sequelae and the effect of early intervention.
Drs. Zeidler, Kleerup and Tashkin are all involved in the Asthma and Cough Center at the University of California, Los Angeles. Their research interests include small airways involvement in asthma and the therapeutics of asthma and COPD.
For a list of references, please call Mike Bederka at (610) 278-1400, ext. 1128, or visit www.Respiratory-care-sleep-medicine.advanceweb.com.
TABLE: DIAGNOSTIC CRITERIA FOR COUGH-VARIANT ASTHMA
• Chronic cough lasting longer than three weeks to eight weeks
• Normal pulmonary function tests without response to bronchodilators
• Hyperresponsiveness to methacholine inhalation challenge
• Response to specific asthma therapy