Journal of Asthma, 28(2) 85-90 (1991)
REVIEW ARTICLE
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Cough Variant Asthma: A Review of the Clinical Literature David Johnson, M.D. and Lucy M. Osborn, M.D. Department of Pediatrics University of Utah Medical Center Salt Lake City, Utah 84132
ABSTRACT Cough variant asthma is an occult form of asthma of which the only sign or symptom is chronic cough. This review examines 15 clinically oriented research articles on cough variant asthma and summarizes what is known about its frequency of occurrence, clinical presentation, diagnosis, treatment, and natural history. Cough variant asthma is a common problem among all ages that frequently goes unrecognized. Pulmonary function, as measured by spirometry, is often within normal limits. Any patient with a nonproductive, nocturnal cough lasting more than two weeks, should receive an empiric trial of bronchodilators. The natural history of cough variant asthma i s variable. A significant proportion of patients followed over time develop the classic signs and symptoms of asthma, whereas for many patients, cough resolves without need for further treatment. Address reprint requests to: David Johnson, M.D., Clinical Pharmacology and Toxicology,Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1x8, Canada.
85 Copyright 0 1991 by Marcel Dekker, Inc.
Johnson and Osborn
86
J Asthma Downloaded from informahealthcare.com by University of Otago on 01/06/15 For personal use only.
INTRODUCTION Chronic cough, as the presenting symptom, is the fifth most common problem seen by office-basedphysicians (1).Of those patients whose chronic cough goes undiagnosed, as many as a third to half of these patients have unrecognized asthma (2,3)In many of these undiagnosed cases, the only symptom or sign is the cough. When cough is the sole manifestation of reactive airway disease, it is termed cough variant asthma. First described in 1972 by Glauser, cough variant asthma is now widely accepted as a legitimate clinical entity (4). This review examines the clinical literature on cough variant asthma for adults and children in the English language, clarifying what is known and highlighting questions which remain unanswered. Seven general questions are addressed. How frequently does cough variant asthma occur? What is the age and sex distribution? What are the clinical signs of the disease? What laboratory findings are helpful? How is the diagnosis made? What is the natural history? How is cough variant asthma treated? METHODOLOGY Articles were initially located by completing a MEDLINE Search using “chronic cough” and “cough” cross-referenced with “asthma” in all languages and for all ages from 1966 through the present. Bibliographies from articles obtained through this search were screened for additional references. These additional articles’ reference lists were also cross-checkedfor pertinent studies. Articles were selected for review if they involved research which specifically targeted cough variant asthma, or if in addressing the larger question of chronic cough, they singled out the topic of asthma-related cough. The 15 articles identified for review include nine from the pediatric and six from the adult literature. Three additional articles, not directly related to cough variant asthma, but containing pertinent information, are also included in this review (5-7).
RESULTS Frequency of Occurrence
Wynder reviewed 15 studies that examined chronic cough in adult males. Of nonsmokers, between 8 and 30% reported a persistent cough of unspecified duration (5).In 43% of all adult patients referred to Irwin et al. for chronic cough, the coughing was subsequently found to be caused by asthma (2).In 57% of those patients diagnosed to have asthma, the only manifestation of the disease was coughing and a positive methacholine inhalation challenge (MIC)(see below). This percentage, however, may not be representative since the study examined a selected population: namely, only those patients referred to a tertiary center for evaluation. Kerrebijn followed 817 children, randomly selected from two towns in the Netherlands, over 5 years (6).At the beginning of the study, 428 children were 6 years old and 389 children were 11 years old. Between 2 and 12% of the children had a persistent cough lasting for 3 or more months of each year. In contrast, between 0.4 and 3.7% of the children had at least one asthmatic attack each year. It is not clear, however, in this study what proportion of those children with chronic cough had classic asthma, cough variant asthma, or some other cause for their cough. Holinger reported 38 pediatric patients referred to a tertiary center for chronic cough of at least 4 weeks duration (3).Overall 39% of the infants and children with chronic cough had cough variant asthma. Just as with the Irwin article, this study also represents a selected population and may not be representative. Age of Occurrence and Sex Distribution
While epidemiological studies of cough variant asthma are incomplete, the studies reviewed provide some indication of age and sex distribution. Some degree of bias is likely, however, since most studies report on patients referred to a tertiary medical center. Combining results from the three pediatric studies in which the exact age distribution
J Asthma Downloaded from informahealthcare.com by University of Otago on 01/06/15 For personal use only.
Cough Variant Asthma: Literature Review was available and younger children were not excluded because of inability to perform pulmonary spirometry (8-101, the age ranged from 3 to 17 years (mean age was 7.4 years) 33%were less than 6 years, and 81%were less than 10 years. In a primary care-based study, 68%of those children thought to have cough variant asthma were less than 6 years of age (11). In a tertiary center study, 33%of those children with cough variant asthma were less than 18 months of age (3). In one study of adults with cough variant asthma (121, the age ranged up to 65 years of age. These patients had no known prior history of asthma, a normal physical examination, and a chronic cough which responded to bronchodilators. In this study, 13% of the adults with cough variant asthma were older than 50 years of age. Combining results from all of the pediatric studies which contained data on sex distribution (8-10,13-15), 83 of 157 children were male (53%).In the four adult studies with data on the subject’s sex (3 included some adolescents as well), 26 of 57 patients (46%) were male. Clinical Manifestations and laboratory
As might be expected, the type and pattern of cough described in patients with cough variant asthma was similar to the cough associated with classic asthma. The cough was described as nonproductive, commonly nocturnal (72%),exercise-induced(78%),cold air-induced (44%), and triggered by upper respiratory infections (100%)(8).The cough was frequently long-standing, from several weeks through many years. There was usually a family history of atopy (40-100%),and frequently a personal history of atopy as well (8,9,16). Patients with a chronic cough caused by reactive airways, but without history of asthma or evidence of wheezing, clinically are said to have cough variant asthma. However, the exact definition of cough variant asthma was not constant from study to study. Inclusion criteria for many of the studies included normal pulmonary auscultation, normal baseline spirometry, and a normal chest roent-
87
genogram. However, a third of the children in Hannaway’s study had expiratory wheezing or prolongation on auscultation (8). Patients in four of the studies (4,9,10,12,15)had abnormalities in baseline spirometry indicative of obstructive lung disease. More than half of the subjects in Yahav’s study showed hyperinflation on chest radiographs, while 4%of patients in Galvez’s study had abnormal radiographs. As noted above, patients with cough variant asthma in most of the studies, by definition, had normal routine spirometry (1,8,13,14,16). Also, forced expiratory volume over one second (FEV,) and peak expiratory flow rate (PEFR) usually did not improve with bronchodilators. However, even with normal baseline spirometry, many investigators found that patients had significant changes in pulmonary function with either exercise or MIC. In one study, exercise significantly dropped the maximum expiratory velocity at 75%of vital capacity (V,,75%VC) (14). In another study, exercise also increased the Exercise Lability Index (the percent difference between trough and peak PEFR during exercise) (9). Both these phenomena are typically associated with mild asthma. Methacholine inhalation challenge produced significant drops in FEVl ( > 20%)in most patients tested (1,13,16).In Irwin’s study of patients presenting with chronic cough, an abnormal MIC was the sole indicator of reactive airways in 57% of patients. It is thought by some investigators to be the definitive method for the diagnosis of cough variant asthma (16). Galvez, however, found that similar percentages of those patients with a chronic cough who were MIC positive and negative resolved their cough with bronchodilator treatment and then later developed episodic wheezing (15). Galvez also reported that some patients who were initially MIC negative, on rechallenge, became positive. On the other hand, Braman found in long-term follow-up, patients initially positive, subsequently became negative (1). Chest roentgenograms were, by definition, normal (except in the studies of Yahav and Galvez) (10,151. In Yahav’s study, 8 of 15
Johnson and Osborn
88 showed hyperinflation despite normal chest auscultation on physical examination. However, these patients showed improvement of FEVl with bronchodilators. These two findings suggest that in these patients, asthma was less occult than patients in the other studies. Other laboratory tests, including serum IgE, nasal smears for eosinophils, and total eosinophil counts, were inconsistently positive in all studies and, hence, do not appear to be useful for screening.
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Diagnosis
A complete history, careful physical examination, and basic laboratory and radiologic screening were performed by most investigators t o rule out nonasthmatic causes (2,3, 8-10,12-16). If indicated by history and examination, more extensive studies, such as bronchoscopy, were performed. Two studies of patients, one in adults and one in children referred to specialty clinics for a chronic cough of unknown etiology, demonstrate a clear and logical approach to identifying a diagnosis (2,3). In children, the etiology varied markedly with age. Overall, however, cough variant asthma was the most common cause of chronic cough (as previously noted). Sinusitis, aberrant innominate artery, subglottic stenosis, and psychogenic cough were also common diagnoses (3). In adults, chronic postnasal drip secondary to sinusitis or rhinitis was the most common single cause, with asthma a close second. Other common diagnoses were chronic bronchitis due to cigarette smoking and gastroesophageal reflux (2). Following exclusion of nonasthmatic causes of a chronic cough, most investigators advocate performance of baseline spirometry, followed by either exercise or methacholine inhalation challenge. As noted above, however, Galvez’s study suggests that even a negative MIC does not rule out occult asthma. Natural History
Not surprisingly, a significant portion of patients diagnosed as having cough variant asthma eventually develop wheezing,
sometimes severe enough to require continuous treatment with bronchodilators. Corrao reported that 2 of 6 patients began wheezing within 18 months of completing the study (16). Braman studied 16 patients diagnosed t o have cough variant asthma between 3 and 5 years earlier, and found that 37% had intermittent wheezing (1). Children may be even more likely than adults to progress to overt asthma. Five of the nine pediatric studies reported that children with cough variant asthma developed wheezing later in follow-up(8,10,11,13,14).Between 9 and 75% of these patients developed wheezing over a follow-upperiod of 6 to 96 months. Treatment
The effectiveness of treatment has been measured predominantly by self-report. All studies judging outcome in this way, reported a 100%response with either complete resolution or significant improvement of symptoms (2,4,8-11,13,14,16,17). In adults, gross changes or abolition of symptoms are reliably reported. But for children, reliance on parental impressions of nocturnal cough severity may be misleading (7). Some investigators relied on indirect measures of outcome to assess treatment efficacy. Cloutier repeated pulmonary studies after three to five days on theophylline, then again off bronchodilator therapy. She found that exercise-induced changes in Vmax76aoVC, noted prior treatment, had resolved on therapy. These changes returned when treatment was stopped. This pattern correlated well with the findings that, after exercise testing, 66% coughed without treatment, whereas on theophylline, only 7% coughed. In similar fashion, McFadden demonstrated a change in pulmonary function parameters before and after treatment (17). Only two investigators assessed treatment effectiveness by randomized, double-blind trials. Ellul-Micallef studied 30 adults who presented with chronic cough. Patients kept a daily log of day and night cough (scale of 1 to 10) and performed daily PEFR. During a three-week period with either terbutaline or placebo. While there was no improvement
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Cough Variant Asthma: Literature Review
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with placebo, 70% of patients had their symptoms completely resolve with terbutaline. Toop studied 34 children with nocturnal cough, assessing cough frequency with a n automatic voice-activated tape (18).The children were randomized into three groups, receiving either placebo, salbutamol, or triprolidine for two nights. There were no significant differences in cough frequency among the three groups. Toop’s findings are questionable because he included any child who had a night cough for longer than 3 nights, hence many of the children may have had only prolonged viral upper respiratory tract infection. Further, the observation period of two nights is too short to provide a n adequate trial. No trials have compared the effectiveness of beta-agonists with theophylline. Several adult studies reported that a significant portion of their patients did not respond to either beta-agonists or theophylline and required systemic steroids to achieve remission of the cough. The 30% of patients in EllulMicallef s study who did not respond to terbutaline cleared completely with a three-week course of prednisolone. Twenty-nine percent of Irwin’s patients in whom reactive airway disease was diagnosed, required prednisone to resolve their cough. Notably, all pediatric patients responded to either theophylline or beta-agonists, except for those in Toop’s study and two patients in Yahav’s study. It is not clear from Yahav’s article whether these two patients actually failed bronchodilator therapy or were initially started on steroids for some unexplained reason.
that is constantly changing. Careful epidemiological studies of chronic cough and cough variant asthma have not been completed; hence the true incidence, age, and sex distribution are not known. However, the studies reviewed provide a n approximate estimation of these epidemiologic parameters. These studies suggest that people of all ages, infants to the elderly, can have cough variant asthma, and that there is a roughly equal distribution between males and females. Using statistics from a number of studies, we can crudely estimate that between 1 in 20 and 1in 130 children have cough variant asthma [assumes that 2 to 12% have a chronic cough (6)and that 40%of these children’s coughs are due to cough variant asthma (3)l. The diagnosis of cough variant asthma should be considered in any patient with a cough lasting longer than two weeks without a n obvious cause, especially if the cough is nonproductive, nocturnal, induced by exercise or cold air, or if there is a family or personal history of atopy. In the absence of abnormal findings on physical examination confirming reactive airway disease, the diagnosis can be definitively made by exercise or a methacholine inhalation challenge dropping FEVl by 20%. However, a negative MIC does not rule out reactive airways. Consequently, any patient with a chronic cough who has a suggestive history for cough variant asthma deserves a n empiric trial of bronchodilators to establish the diagnosis. Randomized, double-blind assessments of treatment effectiveness are lacking (except for Ellul-Mecallef s study). Only Toop used a n objective outcome measure. Unfortunately, however, his study was flawed, as previously discussed. Despite the lack of well-designed, randomized, double-blind therapeutic trials with objective outcome measures, treatment with either beta-agonists or theophylline appears to be effective in most cases, especially in children. However, based on self-report, a significant number of adults and a few children responded to steroids after failing bronchodilators. Several topics merit further study. First, a large epidemiological study based in a
DISCUSSION Cough variant asthma is a n occult form of asthma whose only symptom or sign is chronic cough. Practically, there is not a clear division between cough variant and classic asthma. This is clear from the varying definitions used by investigators. More importantly, if patients with “cough variant” asthma are followed over time, many develop wheezing, whereas others resolve completely. Reactive airway disease is a dynamic process
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primary care practice would clarify the frequency of chronic cough and cough variant asthma for both adults and children. Second, patients obviously have differing severities of cough secondary to reactive airway disease. Presumably, some patients cough only for several weeks after an upper respiratory tract infection while others are never free from cough. The benefit of bronchodilators in these milder cases remains unclear and needs further study. Last and most importantly, there is a need for well-designed, randomized, double-blind cross-over studies using objective measures of cough frequency comparing placebo with beta-agonists, theophylline, and steroids.
REFERENCES 1. Braman SS, Corrao WM: Chronic cough: diagnosis and treatment. Primary Care 12:217,1985. 2. Irwin RS, Corrao WM, b a t t e r M R Chronic persistent cough in the adult: The spectrum and frequency of causes and successful outcome of specific therapy. A m Rev Resp Dis 123:413,1981. 3. Holinger LD: Chronic cough in infants and children. Laryngoscope 96:316,1986. 4. Glauser FL: Variant asthma. Ann Allergy 30:457, 1972. 5. Wynder EL, Lemon FR, Mantel N: Epidemiology of persistent cough. A m Rev. Resp Dis 91:679, 1965. 6. Kerrebijn KF, Hoogeveen-Schroot HCA, Van der
7.
8. 9. 10.
11.
12. 13.
14.
15.
16.
17.
18.
Wal MC: Chronic nonspecific respiratory disease in children, a five-year follow-up study. Acta Paediatr Scand 261(euppl):7, 1977. Archer LNJ, Simpson H: Night cough counts and diary card scores in asthma. Arch Dis Child 60:473, 1985. Hannaway PJ, Hopper GDK: Cough variant asthma in children. JAMA 247:206,1982. Konig P Hidden asthma in children. A m J Dis Child 135:1053,1981. Yahav Y, Katznelson D, Benzaray S: Persistent cough-a forme-fruste of asthma. Eur J Respir Dis 63:43,1982. Spelman R: Chronic or recurrent cough in children: A presentation of asthma? J R Coll Gen Pract 32:205, 1982. Ellul-Micallef R: Sffect of terbutaline sulphate in chronic “allergic” cough. Br Med J 287940, 1983. Sacha RE,Tremblay NF,Jacobs FtL: Chronic cough, sinusitis, and hyperreactive airways in children: An often overlooked association. Ann Allergy 54:195, 1985. Cloutier MM, Loughlin GM. Chronic cough in children: A manifestation of airway hyperreactivity. Pediatrics 676, 1981. Galvez RA, McLaughlin FJ, Levison H: The role of the methacholine challenge in children with chronic cough. J Allergy Clin Immunol 79:331,1987. Corrao WM, Braman SS, Irwin R S Chronic cough as the sole presenting manifestation of bronchial asthma. N Engl J Med 300:633, 1979. McFadden E R Exertional dyspnea and cough as preludes to acute attacks of bronchial asthma. N Engl J Med 292:555,1975. Toop LF, Howie JGR, Paxton FM: Night cough and general practice research. J R Coll Gen Pract36:74, 1986.
REVIEW ARTICLE
J Asthma Downloaded from informahealthcare.com by University of Otago on 01/06/15 For personal use only.
Cough Variant Asthma: A Review of the Clinical Literature David Johnson, M.D. and Lucy M. Osborn, M.D. Department of Pediatrics University of Utah Medical Center Salt Lake City, Utah 84132
ABSTRACT Cough variant asthma is an occult form of asthma of which the only sign or symptom is chronic cough. This review examines 15 clinically oriented research articles on cough variant asthma and summarizes what is known about its frequency of occurrence, clinical presentation, diagnosis, treatment, and natural history. Cough variant asthma is a common problem among all ages that frequently goes unrecognized. Pulmonary function, as measured by spirometry, is often within normal limits. Any patient with a nonproductive, nocturnal cough lasting more than two weeks, should receive an empiric trial of bronchodilators. The natural history of cough variant asthma i s variable. A significant proportion of patients followed over time develop the classic signs and symptoms of asthma, whereas for many patients, cough resolves without need for further treatment. Address reprint requests to: David Johnson, M.D., Clinical Pharmacology and Toxicology,Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1x8, Canada.
85 Copyright 0 1991 by Marcel Dekker, Inc.
Johnson and Osborn
86
J Asthma Downloaded from informahealthcare.com by University of Otago on 01/06/15 For personal use only.
INTRODUCTION Chronic cough, as the presenting symptom, is the fifth most common problem seen by office-basedphysicians (1).Of those patients whose chronic cough goes undiagnosed, as many as a third to half of these patients have unrecognized asthma (2,3)In many of these undiagnosed cases, the only symptom or sign is the cough. When cough is the sole manifestation of reactive airway disease, it is termed cough variant asthma. First described in 1972 by Glauser, cough variant asthma is now widely accepted as a legitimate clinical entity (4). This review examines the clinical literature on cough variant asthma for adults and children in the English language, clarifying what is known and highlighting questions which remain unanswered. Seven general questions are addressed. How frequently does cough variant asthma occur? What is the age and sex distribution? What are the clinical signs of the disease? What laboratory findings are helpful? How is the diagnosis made? What is the natural history? How is cough variant asthma treated? METHODOLOGY Articles were initially located by completing a MEDLINE Search using “chronic cough” and “cough” cross-referenced with “asthma” in all languages and for all ages from 1966 through the present. Bibliographies from articles obtained through this search were screened for additional references. These additional articles’ reference lists were also cross-checkedfor pertinent studies. Articles were selected for review if they involved research which specifically targeted cough variant asthma, or if in addressing the larger question of chronic cough, they singled out the topic of asthma-related cough. The 15 articles identified for review include nine from the pediatric and six from the adult literature. Three additional articles, not directly related to cough variant asthma, but containing pertinent information, are also included in this review (5-7).
RESULTS Frequency of Occurrence
Wynder reviewed 15 studies that examined chronic cough in adult males. Of nonsmokers, between 8 and 30% reported a persistent cough of unspecified duration (5).In 43% of all adult patients referred to Irwin et al. for chronic cough, the coughing was subsequently found to be caused by asthma (2).In 57% of those patients diagnosed to have asthma, the only manifestation of the disease was coughing and a positive methacholine inhalation challenge (MIC)(see below). This percentage, however, may not be representative since the study examined a selected population: namely, only those patients referred to a tertiary center for evaluation. Kerrebijn followed 817 children, randomly selected from two towns in the Netherlands, over 5 years (6).At the beginning of the study, 428 children were 6 years old and 389 children were 11 years old. Between 2 and 12% of the children had a persistent cough lasting for 3 or more months of each year. In contrast, between 0.4 and 3.7% of the children had at least one asthmatic attack each year. It is not clear, however, in this study what proportion of those children with chronic cough had classic asthma, cough variant asthma, or some other cause for their cough. Holinger reported 38 pediatric patients referred to a tertiary center for chronic cough of at least 4 weeks duration (3).Overall 39% of the infants and children with chronic cough had cough variant asthma. Just as with the Irwin article, this study also represents a selected population and may not be representative. Age of Occurrence and Sex Distribution
While epidemiological studies of cough variant asthma are incomplete, the studies reviewed provide some indication of age and sex distribution. Some degree of bias is likely, however, since most studies report on patients referred to a tertiary medical center. Combining results from the three pediatric studies in which the exact age distribution
J Asthma Downloaded from informahealthcare.com by University of Otago on 01/06/15 For personal use only.
Cough Variant Asthma: Literature Review was available and younger children were not excluded because of inability to perform pulmonary spirometry (8-101, the age ranged from 3 to 17 years (mean age was 7.4 years) 33%were less than 6 years, and 81%were less than 10 years. In a primary care-based study, 68%of those children thought to have cough variant asthma were less than 6 years of age (11). In a tertiary center study, 33%of those children with cough variant asthma were less than 18 months of age (3). In one study of adults with cough variant asthma (121, the age ranged up to 65 years of age. These patients had no known prior history of asthma, a normal physical examination, and a chronic cough which responded to bronchodilators. In this study, 13% of the adults with cough variant asthma were older than 50 years of age. Combining results from all of the pediatric studies which contained data on sex distribution (8-10,13-15), 83 of 157 children were male (53%).In the four adult studies with data on the subject’s sex (3 included some adolescents as well), 26 of 57 patients (46%) were male. Clinical Manifestations and laboratory
As might be expected, the type and pattern of cough described in patients with cough variant asthma was similar to the cough associated with classic asthma. The cough was described as nonproductive, commonly nocturnal (72%),exercise-induced(78%),cold air-induced (44%), and triggered by upper respiratory infections (100%)(8).The cough was frequently long-standing, from several weeks through many years. There was usually a family history of atopy (40-100%),and frequently a personal history of atopy as well (8,9,16). Patients with a chronic cough caused by reactive airways, but without history of asthma or evidence of wheezing, clinically are said to have cough variant asthma. However, the exact definition of cough variant asthma was not constant from study to study. Inclusion criteria for many of the studies included normal pulmonary auscultation, normal baseline spirometry, and a normal chest roent-
87
genogram. However, a third of the children in Hannaway’s study had expiratory wheezing or prolongation on auscultation (8). Patients in four of the studies (4,9,10,12,15)had abnormalities in baseline spirometry indicative of obstructive lung disease. More than half of the subjects in Yahav’s study showed hyperinflation on chest radiographs, while 4%of patients in Galvez’s study had abnormal radiographs. As noted above, patients with cough variant asthma in most of the studies, by definition, had normal routine spirometry (1,8,13,14,16). Also, forced expiratory volume over one second (FEV,) and peak expiratory flow rate (PEFR) usually did not improve with bronchodilators. However, even with normal baseline spirometry, many investigators found that patients had significant changes in pulmonary function with either exercise or MIC. In one study, exercise significantly dropped the maximum expiratory velocity at 75%of vital capacity (V,,75%VC) (14). In another study, exercise also increased the Exercise Lability Index (the percent difference between trough and peak PEFR during exercise) (9). Both these phenomena are typically associated with mild asthma. Methacholine inhalation challenge produced significant drops in FEVl ( > 20%)in most patients tested (1,13,16).In Irwin’s study of patients presenting with chronic cough, an abnormal MIC was the sole indicator of reactive airways in 57% of patients. It is thought by some investigators to be the definitive method for the diagnosis of cough variant asthma (16). Galvez, however, found that similar percentages of those patients with a chronic cough who were MIC positive and negative resolved their cough with bronchodilator treatment and then later developed episodic wheezing (15). Galvez also reported that some patients who were initially MIC negative, on rechallenge, became positive. On the other hand, Braman found in long-term follow-up, patients initially positive, subsequently became negative (1). Chest roentgenograms were, by definition, normal (except in the studies of Yahav and Galvez) (10,151. In Yahav’s study, 8 of 15
Johnson and Osborn
88 showed hyperinflation despite normal chest auscultation on physical examination. However, these patients showed improvement of FEVl with bronchodilators. These two findings suggest that in these patients, asthma was less occult than patients in the other studies. Other laboratory tests, including serum IgE, nasal smears for eosinophils, and total eosinophil counts, were inconsistently positive in all studies and, hence, do not appear to be useful for screening.
J Asthma Downloaded from informahealthcare.com by University of Otago on 01/06/15 For personal use only.
Diagnosis
A complete history, careful physical examination, and basic laboratory and radiologic screening were performed by most investigators t o rule out nonasthmatic causes (2,3, 8-10,12-16). If indicated by history and examination, more extensive studies, such as bronchoscopy, were performed. Two studies of patients, one in adults and one in children referred to specialty clinics for a chronic cough of unknown etiology, demonstrate a clear and logical approach to identifying a diagnosis (2,3). In children, the etiology varied markedly with age. Overall, however, cough variant asthma was the most common cause of chronic cough (as previously noted). Sinusitis, aberrant innominate artery, subglottic stenosis, and psychogenic cough were also common diagnoses (3). In adults, chronic postnasal drip secondary to sinusitis or rhinitis was the most common single cause, with asthma a close second. Other common diagnoses were chronic bronchitis due to cigarette smoking and gastroesophageal reflux (2). Following exclusion of nonasthmatic causes of a chronic cough, most investigators advocate performance of baseline spirometry, followed by either exercise or methacholine inhalation challenge. As noted above, however, Galvez’s study suggests that even a negative MIC does not rule out occult asthma. Natural History
Not surprisingly, a significant portion of patients diagnosed as having cough variant asthma eventually develop wheezing,
sometimes severe enough to require continuous treatment with bronchodilators. Corrao reported that 2 of 6 patients began wheezing within 18 months of completing the study (16). Braman studied 16 patients diagnosed t o have cough variant asthma between 3 and 5 years earlier, and found that 37% had intermittent wheezing (1). Children may be even more likely than adults to progress to overt asthma. Five of the nine pediatric studies reported that children with cough variant asthma developed wheezing later in follow-up(8,10,11,13,14).Between 9 and 75% of these patients developed wheezing over a follow-upperiod of 6 to 96 months. Treatment
The effectiveness of treatment has been measured predominantly by self-report. All studies judging outcome in this way, reported a 100%response with either complete resolution or significant improvement of symptoms (2,4,8-11,13,14,16,17). In adults, gross changes or abolition of symptoms are reliably reported. But for children, reliance on parental impressions of nocturnal cough severity may be misleading (7). Some investigators relied on indirect measures of outcome to assess treatment efficacy. Cloutier repeated pulmonary studies after three to five days on theophylline, then again off bronchodilator therapy. She found that exercise-induced changes in Vmax76aoVC, noted prior treatment, had resolved on therapy. These changes returned when treatment was stopped. This pattern correlated well with the findings that, after exercise testing, 66% coughed without treatment, whereas on theophylline, only 7% coughed. In similar fashion, McFadden demonstrated a change in pulmonary function parameters before and after treatment (17). Only two investigators assessed treatment effectiveness by randomized, double-blind trials. Ellul-Micallef studied 30 adults who presented with chronic cough. Patients kept a daily log of day and night cough (scale of 1 to 10) and performed daily PEFR. During a three-week period with either terbutaline or placebo. While there was no improvement
J Asthma Downloaded from informahealthcare.com by University of Otago on 01/06/15 For personal use only.
Cough Variant Asthma: Literature Review
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with placebo, 70% of patients had their symptoms completely resolve with terbutaline. Toop studied 34 children with nocturnal cough, assessing cough frequency with a n automatic voice-activated tape (18).The children were randomized into three groups, receiving either placebo, salbutamol, or triprolidine for two nights. There were no significant differences in cough frequency among the three groups. Toop’s findings are questionable because he included any child who had a night cough for longer than 3 nights, hence many of the children may have had only prolonged viral upper respiratory tract infection. Further, the observation period of two nights is too short to provide a n adequate trial. No trials have compared the effectiveness of beta-agonists with theophylline. Several adult studies reported that a significant portion of their patients did not respond to either beta-agonists or theophylline and required systemic steroids to achieve remission of the cough. The 30% of patients in EllulMicallef s study who did not respond to terbutaline cleared completely with a three-week course of prednisolone. Twenty-nine percent of Irwin’s patients in whom reactive airway disease was diagnosed, required prednisone to resolve their cough. Notably, all pediatric patients responded to either theophylline or beta-agonists, except for those in Toop’s study and two patients in Yahav’s study. It is not clear from Yahav’s article whether these two patients actually failed bronchodilator therapy or were initially started on steroids for some unexplained reason.
that is constantly changing. Careful epidemiological studies of chronic cough and cough variant asthma have not been completed; hence the true incidence, age, and sex distribution are not known. However, the studies reviewed provide a n approximate estimation of these epidemiologic parameters. These studies suggest that people of all ages, infants to the elderly, can have cough variant asthma, and that there is a roughly equal distribution between males and females. Using statistics from a number of studies, we can crudely estimate that between 1 in 20 and 1in 130 children have cough variant asthma [assumes that 2 to 12% have a chronic cough (6)and that 40%of these children’s coughs are due to cough variant asthma (3)l. The diagnosis of cough variant asthma should be considered in any patient with a cough lasting longer than two weeks without a n obvious cause, especially if the cough is nonproductive, nocturnal, induced by exercise or cold air, or if there is a family or personal history of atopy. In the absence of abnormal findings on physical examination confirming reactive airway disease, the diagnosis can be definitively made by exercise or a methacholine inhalation challenge dropping FEVl by 20%. However, a negative MIC does not rule out reactive airways. Consequently, any patient with a chronic cough who has a suggestive history for cough variant asthma deserves a n empiric trial of bronchodilators to establish the diagnosis. Randomized, double-blind assessments of treatment effectiveness are lacking (except for Ellul-Mecallef s study). Only Toop used a n objective outcome measure. Unfortunately, however, his study was flawed, as previously discussed. Despite the lack of well-designed, randomized, double-blind therapeutic trials with objective outcome measures, treatment with either beta-agonists or theophylline appears to be effective in most cases, especially in children. However, based on self-report, a significant number of adults and a few children responded to steroids after failing bronchodilators. Several topics merit further study. First, a large epidemiological study based in a
DISCUSSION Cough variant asthma is a n occult form of asthma whose only symptom or sign is chronic cough. Practically, there is not a clear division between cough variant and classic asthma. This is clear from the varying definitions used by investigators. More importantly, if patients with “cough variant” asthma are followed over time, many develop wheezing, whereas others resolve completely. Reactive airway disease is a dynamic process
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primary care practice would clarify the frequency of chronic cough and cough variant asthma for both adults and children. Second, patients obviously have differing severities of cough secondary to reactive airway disease. Presumably, some patients cough only for several weeks after an upper respiratory tract infection while others are never free from cough. The benefit of bronchodilators in these milder cases remains unclear and needs further study. Last and most importantly, there is a need for well-designed, randomized, double-blind cross-over studies using objective measures of cough frequency comparing placebo with beta-agonists, theophylline, and steroids.
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