PAEDIATRIC RESPIRATORY REVIEWS (2006) 7, 2630

MINI-SYMPOSIUM: COUGH

Cough and asthma

Peter P. van Asperen*
Department of Respiratory Medicine, The Childrens Hospital at Westmead, Locked Bag 4001, Westmead, Sydney 2145, Australia
KEYWORDS recurrent cough; non-specic cough; wheeze; asthma; children

Summary The relationship between cough and asthma is complex. Epidemiological studies now suggest that most children with recurrent cough who do not wheeze do not have asthma. These children are commonly described as having non-specic cough that appears to be due to increased cough receptor sensitivity during the coughing episode. Children with asthma who cough have also been shown to have increased cough receptor sensitivity during an acute exacerbation. Cough severity does not generally correlate with asthma severity. Apart from wheeze and dyspnoea, there are no clear distinguishing features to separate asthma from non-specic cough. To date, no specic treatment has clearly been shown to benet children with non-specic cough. Although a trial of asthma treatment may be justied in these children, it is preferable to cease rather than escalate treatment if there is no response. In children with asthma who cough, cough should not be used as the predominant symptom to direct asthma therapy. 2005 Elsevier Ltd. All rights reserved.

INTRODUCTION
While cough has been recognised as an associated symptom of asthma in children, it has become increasingly clear that the relationship between cough and asthma is complex.13 Chang1 has summarised some of the difculties encountered when interpreting studies on cough and asthma, which include the poor reproducibility and unreliability (compared with objective measures) of reported cough, the lack of validated scoring systems and the difculty of evaluating a therapeutic trial for a symptom that usually resolves spontaneously. All three recent reviews13 also highlight how this has led to the labelling of children presenting with recurrent cough (RC) as having cough-variant asthma (CVA), which in turn has led them to be inappropriately treated for asthma. While persistent cough (usually arbitrarily dened as cough lasting for more than 3 weeks) may have other important aetiologies, there is considerable overlap between RC and persistent cough in relation to asthma, as will be highlighted in this review. Furthermore, two separate but inter-related
* Tel.: +61 2 98453397; fax: +61 2 98453396. E-mail address: peterv@chw.edu.au. 1526-0542/$ see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2005.11.006

issues need to be considered in addressing the complex relationship between cough and asthma, namely: (1) what is the likelihood of asthma in a child presenting with RC? and (2) in a child with asthma, is cough severity a reection of asthma severity? These two issues will be explored in more detail in this review and the therapeutic implications of the current evidence will be discussed.

EPIDEMIOLOGICAL AND OTHER RESEARCH EVIDENCE

Recurrent cough is it asthma?
The epidemiology of children presenting with RC has been well reviewed.1,3 However, it is worth highlighting some more recent studies which have consistently suggested that RC in the absence of wheeze is much less likely to be due to asthma, although many of these children were being labelled as asthmatic.48 Clifford et al.4 examined the prevalence of wheeze and cough in 7 and 11 year olds and noted differences in both the sex distribution (wheeze

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27 with their acute exacerbations.11 This suggests that the mechanism of the cough reects the CRS rather than being directly related to the asthmatic airway pathology. This view is supported by the nding that although eosinophilic inammation was dominant and cough often heralded the onset of an exacerbation, cough scores and CRS did not reect airway inammation in mild asthma exacerbations in children.12 Chang and Gibson,2 in their recent review of the relationship between cough, CRS and asthma in children, concluded that Children with classical asthma who cough as a dominant symptom represent a different wheezing phenotype. Cough is currently in asthma management guidelines yet little is known of its signicance and relation to childhood asthma severity and exacerbations. While more research is clearly required to better understand the mechanism and management of cough in children with asthma, it would seem prudent, based on our current knowledge, to use wheeze and breathlessness rather than cough as the major indicators of the acute and interval severity of asthma.

being more common in boys) and the natural history. They concluded that the fall in the prevalence of cough between the two age groups was unlikely to be related to asthma prevalence and, when not associated with wheeze, may be an indicator of a different pathology.4 Ninan et al.5 investigated the validity of persistent nocturnal cough (PNC) as an independent marker of childhood asthma and concluded that, in the absence of wheeze, shortness of breath or tightness in the chest, PNC is only likely to be a manifestation of atypical asthma in a minority of cases. Kelly et al.6 reported on two cross-sectional surveys of primary school children in 1991 and 1993. They concluded that the respiratory symptoms of cough alone and cough, wheeze and breathlessness represent clinical responses to different specic risk factors. They also felt that the diagnosis of asthma on the basis of cough alone partly explained the increase in doctor-diagnosed asthma reported between the 1991 and 1993 surveys.6 Wright et al.7 reported on risk factors for RC in childhood from analysis of prospective data collected as part of the Tuscon Childrens Respiratory Study. They reported that children having RC without wheeze did not differ from children with neither symptom in measures of atopy, lung function or bronchial responsiveness, whereas children with RC and wheeze had signicantly more respiratory illness, atopy, reduced lung function and bronchial responsiveness.7 They also noted that those with RC without wheeze were more likely to resolve with time and concluded that RC in the absence of wheeze differs in important respects from classic asthma, inferring different pathophysiologies.7 Finally, Faniran et al.,8 in an Australian community survey, reported that children with persistent cough had less morbidity and less atopy compared with children with wheeze. They also demonstrated that a signicant number of children with persistent cough were being diagnosed with and treated for asthma and questioned the value of labelling these children as having CVA, particularly as it may lead to overtreatment.8 In conclusion, recent epidemiological evidence suggests that children presenting with RC in the absence of wheeze do not usually have asthma. These children appear to have increased cough receptor sensitivity (CRS) to capsacin during their coughing episodes,9,10 although a small number have airway hyper-responsiveness (AHR) and no evidence of increased CRS.10 While viral infections are the most common trigger, other triggers may precipitate coughing episodes, so these children are now commonly labelled as having non-specic RC of childhood.1

DISTINGUISHING NON-SPECIFIC RECURRENT COUGH FROM ASTHMA

As highlighted previously, the main distinguishing feature between these two conditions is the presence or absence of wheeze or other symptoms, such as dyspnoea, suggestive of signicant airway obstruction.1,37 However, the major challenge for the clinician is whether one can identify those children who may have asthma (and therefore respond to asthma treatment) from children with cough as the sole or predominant symptom. RC is a feature of both non-specic cough and asthma but persistent cough over a prolonged period may be more suggestive of asthma (in the absence of other aetiologies). Given the poor reproducibility and reliability of reported cough,1 it seems unlikely that a description of the cough would be a useful diagnostic tool. In addition, the presence of nocturnal cough does not appear to be a distinguishing feature.5,7 While a report of cough with vigorous exercise appeared to be a distinguishing feature in the Tuscon study,7 this may not necessarily be true in children presenting with cough alone. In addition, cough with exercise has been shown to be a poor predictor of a positive exercise challenge.13 While a history of other atopic features in the child and a family history of asthma,5,7 as well as objective evidence of atopy,7,8,14 is seen more commonly in children with associated wheeze, it is also unclear whether it will correctly identify asthma in a child with cough alone. The Tuscon study demonstrated a signicant reduction in airow in children with RC and wheeze but not in children with RC alone.7 The presence of airow reduction, particularly if there is associated bronchodilator reversibility, may be a useful diagnostic test for asthma. However, McKenzie et al.14 reported that bronchodilator reversibility failed to

Cough as a marker of asthma severity

While cough is a frequent symptom in children with asthma, it is now clear that it may have a different mechanism. Therefore, cough severity may not be a good measure of asthma severity.2 While CRS in children with asthma is not increased during a non-acute phase,9,11 it is increased during the acute phase in children with asthma who cough

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distinguish between children with RC or persistent cough and those with wheeze, even though the coughers had signicantly lower immunoglobulin E levels. Theoretically, the demonstration of diurnal peak expiratory ow (PEF) variability may also be suggestive of asthma; however, PEF monitoring as a measure of airway obstruction is often unreliable in children with cough because of the cough interfering with the PEF technique. The value of AHR as a diagnostic feature of asthma in a child presenting with RC also remains unclear. Although some investigators15,16 have suggested that methacholine challenge may be helpful in evaluating children with chronic cough and in guiding therapy, it does not appear to predict clinical response to asthma treatment15 or the development of classic asthma.16 Chang et al.10 demonstrated that some children with RC (without wheeze) demonstrated AHR to hypertonic saline. They hypothesised that this group may represent those with CVA. However, a subsequent randomised controlled trial (RCT) of inhaled salbutamol and beclomethasone failed to demonstrate any relationship between the presence of AHR and the clinical response to either drug.17 In addition, the likelihood of response to active or placebo treatment was no different,17 emphasising the natural history of resolution of cough in these children. As discussed previously, non-specic cough is usually associated with increased CRS9,10 but may also be seen during an acute exacerbation of asthma in children who also cough.11 A number of studies have investigated the inammatory airway response in children with RC.1820 In contrast to children with recurrent wheeze, only a minority of children with RC or persistent cough alone showed evidence of eosinophilic bronchitis.1820 While conrming that children with non-specic RC are likely to represent a different population to those with asthma, the role of induced sputum or bronchoalveolar lavage in distinguishing these two conditions is likely to be limited in the clinical setting. The features distinguishing non-specic RC from asthma are summarised in Table 1. There is clearly some overlap between the two conditions, with the most useful distinguishing feature being the presence or absence of wheeze. While other features may be helpful (in the absence of wheeze) in directing a trial of asthma therapy,

the natural history of the cough should always be considered when assessing the therapeutic response.

THERAPEUTIC IMPLICATIONS
Non-specic recurrent cough
The treatment of RC (in the absence of wheeze) is quite problematic for a number of reasons. While, as highlighted previously, RC may occasionally be the presenting feature of asthma, there is limited evidence of benet of asthma medication for non-specic cough. This relates mainly to the paucity and quality of published studies and highlights the urgent need for RCTs to properly evaluate therapy for children with non-specic cough. Recent Cochrane reviews have concluded that there is currently no evidence to support the use of inhaled anticholinergics or cromones in non-specic cough in children,21,22 or b2 agonists for acute bronchitis23 or non-specic chronic cough24 in children. There have been two RCTs examining the role of inhaled corticosteroids in children with RC. Chang et al.17 demonstrated no difference in the likelihood of response to 45 weeks of beclomethasone 200 mg bd or placebo. In contrast, Davies et al.25 demonstrated some benet from high-dose uticasone propionate (1 mg bd for 3 days then 500 mg bd for 11 days) over placebo in children with PNC who did not wheeze. However, they also noted a signicant improvement over time in the placebo group, highlighted the potential problems of continued high-dose prescribing and concluded that further investigation was required to see if regular conventional-dose inhaled steroids had a role in children with persistent cough without wheeze.25 The issue of the potential problem of overtreatment with inhaled corticosteroids is further highlighted by reports of adrenal crises in children who did not have asthma or whose asthma was treated on the basis of symptoms unrelated to airway obstruction, including cough.26,27 This situation may be further exacerbated by the use of frequent courses of oral steroids for perceived asthma exacerbations. In view of these issues, non-steroidal preventive asthma treatment may deserve further consideration because of a reduced likelihood of side-effects, although RCTs are required to

Table 1 Asthma vs non-specic recurrent cough distinguishing features. Asthma Wheeze Dyspnoea Cough Atopy Family history of asthma Bronchodilator responsiveness Airway hyper-responsiveness Cough receptor sensitivity Eosinophilic inammation Present Present Recurrent/persistent Usually present More often present More often present Usually present May be present during acute exacerbation Usually present Non-specic recurrent cough Absent Absent Usually recurrent Occasionally present Less often present Less often present Occasionally present Usually present Occasionally present

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establish proven benet. Nedocromil sodium has been shown to have some benet in children with persistent cough in a non-placebo-controlled study28 but this has not been substantiated by an RCT. Theophylline has been shown to attenuate CRS to capsacin and relieve symptoms in an RCT on adults with cough related to angiotensin-converting-enzyme inhibitors.29 A number of uncontrolled paediatric studies have suggested that theophylline does attenuate cough within 214 days of commencing treatment, although many of these subjects with cough also had features suggestive of asthma.30 A small cross-over RCT of 14 days of zarlukast in eight adults with CVA demonstrated both clinical efcacy on cough and improvement in CRS on active treatment.31 A more recent 4-week non-placebo-controlled trial of montelukast in 22 children with chronic cough demonstrated resolution of cough in two-thirds of subjects, although response seemed to be linked to high levels of serum eosinophilic cationic protein, suggesting that these children may have had asthma.32 Finally, the view that cough suppressants have little benet in children with non-specic RC is supported by a recent Cochrane review on over-thecounter medications for acute cough in children.33 In conclusion, given the lack of evidence of benet of medication for non-specic RC and the fact that it is a selflimiting problem in most situations, the need to consider a trial of treatment will depend on how frequent or how troublesome the cough is. A trial of therapy could be considered in children with troublesome symptoms or where associated features suggest asthma as a possible underlying problem. The important message in children with RC who do not respond to a trial of treatment is not to consider this a treatment failure and escalate treatment; rather, one should cease treatment and see if the child is any worse without treatment. The issue for the child with RC who does respond to treatment is whether this should be continued in the long term. Again, we have no evidence to help us answer this question. The pragmatic approach in the child with previously troublesome symptoms is to continue regular treatment until there is a 36-month period free of signicant problems.

is directed on the basis of cough rather than symptoms and signs of airway obstruction.

PRACTICE POINTS
 Although there is some overlap in diagnostic features, the majority of children with RC in the absence of wheeze have non-specific cough due to increased CRS and not asthma.  In children with asthma who cough, cough severity does not correlate with asthma severity and therefore should not be used as the primary determinant of directing therapy.  Treatment of non-specific cough in children is problematic because of lack of evidence of efficacy of both asthma medication and cough suppressants.  If preventive asthma therapy is used as a trial in children with non-specific cough, cease rather than escalate treatment if there is no response.

RESEARCH DIRECTIONS
 Distinguishing asthma from non-specific cough in children presenting with RC or persistent cough.  Further assessing the value of cough as a marker of asthma severity and guide to treatment in children with asthma.  Randomised controlled trials to establish the benefit of medications in children with non-specific cough.

REFERENCES
1. Chang AB. Cough, cough receptors, and asthma in children. Pediatr Pulmonol 1999; 28: 5970. 2. Chang AB, Gibson PG. Relationship between cough, cough receptor sensitivity and asthma in children. Pulm Pharmacol Ther 2002; 15: 287 291. 3. de Benedictis FM, Selvaggio D, de Benedictis D. Cough, wheezing and asthma in children: lesson from the past. Pediatr Allergy Immunol 2004; 15: 386393. 4. Clifford RD, Radford M, Howell JB, Holgate ST. Prevalence of respiratory symptoms among 7 and 11 year old schoolchildren and association with asthma. Arch Dis Child 1989; 64: 11181125. 5. Ninan TK, Macdonald L, Russell G. Persistent nocturnal cough in childhood: a population based study. Arch Dis Child 1995; 73: 403407. 6. Kelly YJ, Brabin BJ, Milligan PJM, Reid JA, Heaf D, Pearson MG. Clinical signicance of cough and wheeze in the diagnosis of asthma. Arch Dis Child 1996; 75: 489493. 7. Wright AL, Holberg CJ, Morgan WJ, Taussig LM, Halonoen M, Martinez FD. Recurrent cough in childhood and its relation to asthma. Am J Respir Crit Care Med 1996; 153: 12591265. 8. Faniran AO, Peat JK, Woolcock AJ. Persistent cough: is it asthma? Arch Dis Child 1998; 79: 411414.

Cough in an asthmatic child

Given the previously presented evidence that the mechanism of cough in the child with asthma is likely to be due to CRS and that cough severity may not reect asthma severity,2,11,12 cough should not be used as the major indicator for the level of asthma treatment, particularly in the acute episode. Although symptoms of nocturnal or exercise-induced cough may improve in children with asthma commenced on preventer treatment, the complete absence of cough may not be essential for asthma control. Escalation of treatment may potentially lead to overtreatment and unwanted side-effects.26,27 Children with acute asthma who cough are also at risk of overtreatment with unnecessarily prolonged courses of oral steroids if therapy

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9. Chang AB, Phelan PD, Sawyer SM, Del Brococo S, Robertson CF. Cough sensitivity in children with asthma, recurrent cough, and cystic brosis. Arch Dis Child 1997; 77: 331334. 10. Chang AB, Phelan PD, Sawyer SM, Roberson CF. Airway hyperresponsiveness and cough-receptor sensitivity in children with recurrent cough. Am J Respir Crit Care Med 1997; 155: 19351939. 11. Chang AB, Phelan PD, Robertson CF. Cough receptor sensitivity in children with acute and non-acute asthma. Thorax 1997; 52: 770774. 12. Chang AB, Harrhy VA, Simpson J, Masters IB, Gibson PG. Cough, airway inammation, and mild asthma exacerbation. Arch Dis Child 2002; 86: 270272. 13. De Baets F, Bodart E, Dramaix-Wilmet M et al. Exercise-induced respiratory symptoms are poor predicators of bronchoconstriction. Pediatr Pulmonol 2005; 39: 301305. 14. McKenzie SA, Mylonopoulou M, Bridge PD. Bronchodilator responsiveness and atopy in 510 year old coughers. Eur Respir J 2001; 18: 977981. 15. Galvez RA, McLaughlin FJ, Levison H. The role of methacholine challenge in children with chronic cough. J Allergy Clin Immunol 1987; 79: 331335. 16. Todokoro M, Mochizuki H, Tokuyama K, Morikawa A. Childhood cough variant asthma and its relationship to classic asthma. Ann Allergy Asthma Immunol 2003; 90: 652659. 17. Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson CF. A randomised, placebo-controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 1998; 79: 611. 18. Zimmerman B, Silverman FS, Tarlo SM, Chapman KR, Kubay JM, Urch B. Induced sputum: comparison of postinfectious cough with allergic asthma in children. J Allergy Clin Immunol 2000; 105: 495499. 19. Fitch PS, Brown V, Schock BC, Taylor R, Ennis M, Shields MD. Chronic cough in children: bronchalveolar lavage ndings. Eur Respir J 2000; 16: 11091114. 20. Gibson PG, Simpson JL, Chalmers AC. Airway eosinophilia is associated with wheeze but is uncommon in children with persistent cough and frequent chest colds. Am J Respir Crit Care Med 2001; 164: 977 981.

21. Chang AB, McKean M, Morris P. Inhaled anti-cholinergics for prolonged non-specic cough in children. Cochrane Database Systemat Rev 2003; 4: CD004358. 22. Chang AB, Marchant JM, McKean M, Morris P. Inhaled cromones for prolonged non-specic cough in children. Cochrane Database Systemat Rev 2004; 1: CD004436. 23. Smucny J, Flynn C, Becker L, Glazier R. Beta2-agonists for acute bronchitis. Cochrane Database Systemat Rev 2004; 1: CD001726. 24. Tomerak AAT, Vyas H, Lakenpaul M, McGlashan JJM, McKean M. Inhaled beta2-agonists for treating non-specic chronic cough in children (Review). Cochrane Database Systemat Rev 2005; 3: CD005373. 25. Davies MJ, Fuller P, Picciotto A, McKenzie SA. Persistent nocturnal cough: randomised controlled trial of high dose inhaled corticosteroid. Arch Dis Child 1999; 81: 3844. 26. Todd GRG, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002; 87: 457461. 27. Macdessi JS, Randell TL, Donoghue KC, Ambler GR, van Asperen PP, Mellis CM. Adrenal crises in children treated with high-dose inhaled corticosteroids for asthma. Med J Aust 2003; 178: 214216. 28. Chan PW, Debruyne JA. Inhaled nedocromil sodium for persitent cough in children. Med J Malaysia 2001; 56: 408413. 29. Cazzola M, Matera MG, Liccardi G, De Prisco F, DAmato G, Rossi F. Theophylline in the inhibition of angiotensin-converting enzyme inhibitor-induced cough. Respiration 1993; 60: 212215. 30. Chang AB, Halstead RA, Petsky HL. Methylxanthines for prolonged non-specic cough in children. Cochrane Database Systemat Rev 2005; 2: CD005310. 31. Dicpinigaitis PV, Dobkin JB, Reichel J. Antitussive effect of the leukotriene receptor antagonists Zarlukast in subjects with cough-variant asthma. J Allergy 2002; 39: 291297. 32. Kopriva F, Sobolova L, Szotkowska J, Zapalka M. Treatment of chronic cough in children with Montelukast, a leukotriene receptor antagonist. J Asthma 2004; 41: 715720. 33. Shroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Systemat Rev 2004; 4: CD001831.