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The management of persistent isolated cough in childhood
Current Paediatrics (2002) 12, 1d6 ^ 2002 Harcourt Publishers Ltd doi:10.1054/cupe.2001.0239, available online at http://www.idealibrary.com on
The management of persistent isolated cough in childhood Sejal Saglani* and Sheila A. McKenzieR *Specialist Registrar Respiratory Paediatrics and RConsultant Respiratory Paediatrician and Honorary Senior Lecturer, Queen Elizabeth Children’s Services, Royal London Hospital, 2nd Floor Fielden House, Whitechapel, London E1 1BB, UK KEYWORDS persistent cough, isolated cough, chronic cough, cough-variant asthma, diagnosis, management
Summary Persistent isolated cough is a distinct clinical entity, separate from asthma. It is empirically defined as a non-productive cough of at least 3 weeks duration, in the absence of any identifiable respiratory disease. It is usually nocturnal. An accurate diagnosis rests on a good history and examination. Investigations are rarely needed. Management consists of reassuring parents that the symptom is predominantly selflimiting, and will not result in long-term morbidity. ^ 2002 Harcourt Publishers Ltd
PRACTICE POINTS E Persistent isolated cough is not asthma E Asthma therapy should be avoided E The natural history is spontaneous resolution in most children E The likely mechanism is an increase in cough receptor sensitivity E Most persistent coughs occur with RTIs, and symptoms increase during RTIs
RESEARCH DIRECTIONS E E E E
E E
Why do some children cough persistently? What is the link with cough receptor sensitivity? Is there an association with persistence of rhinovirus or chlamydia? Is the main problem in the upper airway, and associated with parasympathetic receptors there? What is the role of menthol vapour rub? Why do children with PIC have bronchodilator reversibility and bronchial hyperresponsiveness, during periods of coughing?
Correspondence to: SS. Tel./Fax: #44-20-7377-7325; E-mail: [email protected]
INTRODUCTION Cough is a very common symptom, and with upper respiratory tract infections, accounts for numerous general practitioner consultations. Persistent isolated cough (PIC) is defined as a non-productive cough in the absence of identifiable respiratory disease, or disease of the upper airway, of at least 3 weeks duration. It is common for the cough to be present mainly at night. Other terms used interchangeably with PIC include nonspecific cough,1 persistent cough, isolated cough,2, 3 recurrent cough and chronic cough. A productive cough is always abnormal and requires further investigation. The aetiology of a productive cough, or cough resulting from underlying respiratory disease, becomes apparent from the presence of additional symptoms and signs related to chronic lung disease such as bronchiectasis. There are a number of causes of a productive cough, e.g. cystic fibrosis, bronchiectasis, recurrent milk and food aspiration, cardiac disease and inhaled foreign body. Investigations should therefore address the underlying suspected disease, which should be evident after a good history and examination. Investigation and management of cough with other symptoms, and with abnormal signs will not be addressed in this review as each cause has its own guidelines for management. The biggest breakthrough in the last 10 years is the understanding that PIC in the absence of difficulty in breathing is not asthma. This will be addressed here.
2
CURRENT PAEDIATRICS
Figure 1 The cough pathway involves cough receptors, mediators of sensory nerves, and the efferent pathway. (Taken from Chang A B, cough, cough receptors and asthma in children. Pediatr Pulmonology 1999; 28: 59d70. Fig. 1, p. 61.)
Cough, cough receptors and the cough pathway Cough has an extremely important function in maintaining the normal health of the respiratory system. It is one of the several mechanisms by which the lungs are protected and the airways cleared. This occurs in two ways: enhanced mucociliary clearance, and forced expiratory efforts following stimulation of the larynx, allowing clearance of inhaled material. The importance of the cough reflex becomes apparent when considering children with a defective cough, such as those with neuromuscular disorders who are unable to protect their airways and frequently develop recurrent pneumonia from retained secretions. The cough pathway (Fig. 1) involves cough receptors, mediators of sensory nerves, an afferent limb, the vagus nerve, the central cough centre, and an efferent limb. Cough receptors respond to various stimuli, of both a chemical and mechanical nature. The stimuli may be endogenous (airway secretions, inflammatory mediators) or exogenous (aspirated foreign material, cigarette smoke). The pattern of cough depends on the site and type of stimulation.4 The more proximal airways (larynx to trachea) are mechanosensitive, whereas the distal airways are more chemosensitive. See Fig. 2.
Figure 2 Cough receptors. (Taken from: ‘Childhood asthma and other wheezing disorders’. Edited by: Michael Silverman, Publishers: Chapman and Hall Medical. Fig. 7.1, p. 176, chapter 7eSymptoms and signs.)
Cough in healthy children Healthy children, even in the absence of a respiratory tract infection (RTI), cough up to 34 times a day.5 The
MANAGEMENT OF PERSISTENT ISOLATED COUGH IN CHILDHOOD presence of an upper RTI is associated with increased cough, but in the majority of cases the cough is selflimiting, i.e. less than 2 weeks duration. However, in some cases the cough is prolonged, or persistent, i.e. greater than 3 weeks duration. This may be because of increased cough receptor sensitivity.3 Although the cough can persist for months, it is usually self-limiting,6 and the most important aspect of management is making an accurate diagnosis, in order to avoid false labelling, and to prevent unnecessary prescribing. Children with a history of recurrent cough, of several weeks duration, without wheeze or evidence of systemic disease, are often referred to the general paediatrician. The majority of these children probably have post-RTI cough, although it is often difficult for parents to remember whether an RTI was the trigger. Despite this, there is pressure on general practitioners and paediatricians to make a more definitive diagnosis. The main concern of parents who repeatedly consult about their child’s cough seems to be the child’s risk of dying from choking as a result of coughing.7 If this anxiety cannot be allayed by reassurance, the tendency to seek alternative diagnoses will continue, and may ultimately lead to inappropriate prescribing.8
Persistent isolated cough (PIC) and asthma Early epidemiological studies, which assessed the prevalence of asthma in childhood, used the presence of wheeze as the symptom with which to make a diagnosis of asthma. Subsequently, it has been suggested that cough alone may be a presentation of asthma, and that asthma in children was being under-diagnosed because of the failure to recognize the entity of ‘cough-variant asthma’.9,10 The most recent guidelines (albeit quite dated) from the British Thoracic Society for the diagnosis of asthma acknowledge that the definition of asthma in the presence of just recurrent or chronic cough needs to be clarified.11 Much research has been carried out since these guidelines were published, to describe better the entity of persistent isolated cough, and whether it is related to asthma.
Biological distinctions It has been shown that there is no correlation between cough severity and airway calibre.12 Also, sites in the cough pathway for eliciting cough are confined to structures innervated by the vagus nerve.4 This is in contrast to sites that induce bronchoconstriction. Therefore, the pathways for cough and bronchoconstriction are distinctly different.3 Histologically, it has been found from examination of bronchoalveolar lavage (BAL)
3
fluid of children with chronic cough, that their inflammatory cell profile is similar to that of controls, and not associated with the cell profile suggestive of asthma. Asthma was associated with a high median ratio of eosinophils to neutrophils.13
Epidemiological issues It is possible that part of the apparent rise in the prevalence of asthma has resulted from the labelling of persistent cough as asthma. In one study, the prevalence of doctor-diagnosed asthma increased from 17.4% in 1991 to 22.1% in 1993. In the same period, the number of children with cough alone diagnosed as having asthma doubled from one in eight to one in four.14
Clinical features Persistent coughers do not resemble asthmatics.14,15 Children with PIC have less morbidity and less atopy compared to those with wheeze.16 Conversely, children with the triad of cough, wheeze and breathlessness, the clinical features characteristic of asthma, have an increased association with allergies, family history of atopy and preterm birth. Children with PIC do not share this profile.14
Lung function tests Lung function tests in preschool children with isolated cough have shown that coughers do not differ significantly from controls in their lung function.2 Recently, bronchodilator responsiveness (BDR), which may be interpreted as representing asthma, has been shown on lung function testing in coughers.17 The presence of BDR does not necessarily indicate asthma, although it is easy to understand the confusion. It is important to remember that BDR is also found in other conditions, such as bronchiectasis, and its presence alone does not always indicate asthma. While it is true that most patients with moderate and severe atopic asthma have very reactive airways, in a study in New Zealand only 50% of children with mild asthma were shown to have reactive airways, 26% of children with cough and no wheeze and 8% of children with no symptoms at all were reactive.18 Increased bronchial hyperresponsiveness (BHR) during coughing episodes is significantly less during cough-free periods.19 This suggests that as far as BHR is concerned coughers are intermediate between controls and wheezers, as has also been shown for BDR.2 More work needs to be done in understanding why coughers have BHR and BDR, which may be confused with asthma, while they are coughing. Epithelial damage, inflammatory mediator release and increased sensitivity of parasympathetic reflexes (including the cough reflex) are known to occur in rhinoviral infection.20 These
4 mechanisms could explain the increase in airways responsiveness and increased cough receptor sensitivity in some individuals. The increased cough receptor sensitivity that has been shown in children with persistent cough21 may be linked to increased parasympathetic reflex sensitivity and may be linked to rhinovirus presence and epithelial damage in the upper airways.
Atopy A prospective, longitudinal study16 has shown that children with recurrent cough and no wheeze did not differ from those who were asymptomatic in terms of their immunoglobulin E (IgE) levels, skin prick tests and percentage decline in lung function following cold air challenge. This was in contrast to children with both cough and wheeze, who had more atopy and greater decline in lung function with cold air challenge. What, then, distinguishes PIC from asthma is the single-symptom history and the atopic status?
Inappropriate treatment If PIC is a variant of asthma, then a response to therapy with anti-asthma medication would be expected. However, it has been shown that children with recurrent or persistent cough do not benefit from bronchodilators.6 Of two studies looking at the effect of inhaled corticosteroids (ICS) in children with PIC,6, 22 only one which used very high doses demonstrated modest benefit.22 However, it was also shown that those receiving placebo improved after 2 weeks as well.22 This suggests that the natural history of PIC is that it gets better, and prescribing medication is of no benefit, at least in the first instance. ICS are known to have significant side-effects on growth and bone mineral density and, if used, high doses should be prescribed for only the briefest period. It has recently been shown that even on relatively ‘safe’ doses of ICS, adults with mild asthma, and therefore less airways inflammation, have a significantly higher rate of systemic absorption, as the ‘protective’ effect of inflammatory changes in the airways is absent.23
Cost The increased willingness to diagnose asthma on the basis of cough alone means an increased tendency to prescribe treatment. Prescription of ICS is considered by over 60% of GPs for children with PIC.8 Inappropriate prescribing results in unwanted side-effects and diagnostic misclassification. If ICS are prescribed, then an assumption is made that asthma is the diagnosis. Children are thus given a ‘label’ and of course this has resource implications.
CURRENT PAEDIATRICS
Table 1 Useful distinguishing features of PIC and asthma PIC
Asthma
Non-atopic Cough, only symptom
Atopic (!IgE and/or SPT#ve) Wheeze and difficulty in breathing reported Good response to bronchodilators and inhaled steroids
NO response of cough to bronchodilators or inhaled steroids BDR may be demonstrated
BDR
In summary, the available evidence to date indicates that PIC is a separate entity from asthma. It is acknowledged, however, that children with asthma may present with cough, but prior to making the diagnosis, it is important to consider the facts which illustrate that cough alone, without other symptoms or risk factors, is a poor marker of asthma. Whereas all that wheezes probably coughs, all that coughs certainly does not wheeze. In asthma, cough may be the only complaint because the child and his parents are unaware of wheeze. Features that may help to distinguish PIC from asthma are highlighted in Table 1.
Cough and gastro-oesophageal reflux (GOR) The link between cough and GOR remains debatable. The prevalence of cough in children with GOR, but no underlying neurodevelopmental abnormality, is unknown. It has been shown that treatment of GOR in infants with cough fails to relieve their symptoms of cough, although the GOR may improve.24 This is therefore an unlikely cause of persistent cough.
Cough and post-nasal drip There are no cough receptors in the pharynx or postnasal space,25 so the relationship of the two conditions is controversial. It may be that post-nasal drip is associated with cough, but is unlikely to be a cause of persistent cough,4 especially as both conditions have the same trigger of viral RTI.
OUR APPROACH TO THE MANAGEMENT OF PIC IN CHILDREN History Listen to the parent carefully for symptoms other than cough, such as noisy breathing and difficulty in breathing,
MANAGEMENT OF PERSISTENT ISOLATED COUGH IN CHILDHOOD and for anything which could suggest a productive cough. Ask about upper airway noises such as snoring and stridor. A useful question is ‘can you hear the noise outside the room?’ Wheeze cannot usually be heard beyond the bed. Did the cough start with a cold, runny nose, choking episode or chesty illness. Consider pertussis, with its crescendo cough, tussive vomiting and whoop. It may be useful to imitate the cough to the parents. PIC is commonly present only at night, or often worse at night. Any other associated nocturnal symptoms should be noted. Ask about sleeping arrangements, as parents or siblings sleeping in the same room are more likely to hear the cough and be disturbed.
Examination The examination should be guided by the history, but specific things to look for are a chest wall deformity and signs of respiratory distress. It is important to examine the nose for polyps and the tonsils to look for evidence of upper airway disease. Assess growth accurately, and exclude failure to thrive. PIC is a very clear entity. However, there may be some confusion about management if cough is present with other symptoms. In this case, further evaluation is required. Management is outlined below in two sections, PIC alone, and cough with other symptoms.
Management of PIC Initially, explain that you appreciate the considerable difficulty the parents must be experiencing in dealing with this problem. But emphasize that this is a well-described symptom, which is not asthma and does not represent an underlying sinister condition such as tuberculosis. This is especially important for an immigrant Asian population. Acknowledge the sleep disturbance that is associated, but also explain that current evidence in inner-city children has shown that parents of children with PIC suffer the most sleep disturbance, and children are minimally affected.26 Also that the natural history of the symptom is a tendency to improve. Next explain that any treatment the child is on should be stopped for 7 days in order to assess any change in symptoms, and to show that treatment is of no benefit. To ensure compliance with this request, tell them that to date there is no evidence for any benefit from over-thecounter treatments, or asthma therapy for cough in children.6, 27 Offer an open appointment to re-attend if symptoms worsen or do not improve in 3 weeks. Finally, it is extremely important to explain the benign nature of PIC to the parents. Reassurance is the key to a successful outcome to avoid repeated consultation. It is likely that most will have improved within 3 weeks and are unlikely to return.
5
If, after excluding all other causes of cough, and allowing enough time to achieve natural resolution, coughing still persists, and parental anxiety is extreme, then it may be worth considering a 2-week course of high-dose inhaled fluticasone propionate (500 lg b.d.), which may hasten resolution of symptoms.22 The number needed to treat (NNT) to see any benefit is three.28 BUT prolonged or repeated courses of ICS are NOT justified for PIC.28 In order to ensure that the ICS are not over used, a small dose per inhalation device should be prescribed. The other treatment that can be tried is a 2-week trial of menthol vapour rub, such as ‘Vick’s’. Although there is no evidence of its benefit in PIC in the current literature, laboratory evidence shows that it may downregulate cough receptors29 and thus reduce the increased receptor sensitivity seen in children with PIC.
Management of cough with other symptoms Other symptoms that may be present include difficulty in breathing or noisy breathing. If the history is unclear, then we advise that the child is seen again when the additional symptoms are actually present. This should be done before bronchodilators or inhaled corticosteroids are prescribed ‘blindly’. If a strong family history of asthma or atopy is present, the child’s atopic status should be assessed, with an IgE level and skin prick tests to aeroallergens, as this may be a patient with asthma presenting with cough as the predominant symptom. Lung function tests may be helpful if asthma is suspected, but only if evidence of BDR is sustained when the child is not coughing, and if the child is atopic. If cough is present with a history of fever, the possibility of bronchitis, tracheitis, pneumonia or pulmonary tuberculosis, especially in high-risk populations, should not be forgotten, and a chest X-ray is important. Other investigations, such as pH study and barium swallow, are usually unnecessary in an otherwise well child, as there is no good evidence that GOR is related to cough.
Summary Persistent isolated cough is a defined clinical entity. A good history and examination contribute the most towards the diagnosis. A temporary increase in cough receptor sensitivity is the most likely explanation for the onset. The increased sensitivity may be predominantly in the large airways, but the precise sites affected are not known. The natural history is towards spontaneous resolution, and management includes reassurance and
6 support for the family, with the specific advice that children do not choke to death from coughing. Also that there is little evidence that sleep is lost; however, there is no evidence about the impact on quality of sleep.
REFERENCES 1. Chang A B, Robertson C F. Cough in children. Med J Aust 2000; 172: 122d125. 2. McKenzie S A, Bridge P D, Healy M J R. Airway resistance and atopy in preschool children with wheeze and cough. Eur Respir J 2000; 15: 833d838. 3. Chang A B. Cough, cough receptors, and asthma in children. Pediatr Pulmonol 1999; 28: 59d70. 4. Widdicombe J G. Sensory neurophysiology of the cough reflex. J Allergy Clin Immunol 1996; 98: 84d90. 5. Munyard P, Bush A. How much coughing is normal? Arch Dis Child 1996; 74: 531d534. 6. Chang A B, Phelan P D, Carlin J B, Sawyer S M, Robertson C F. A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 1998; 70: 6d11. 7. Cornford C S, Morgan M, Ridsdale L. Why do mothers consult when their children cough? Family Practice 1993; 10: 193d196. 8. Picciotto A, Hubbard M, Sturdy P, Naish J, McKenzie S A. Prescribing for persistent cough in children. Respir Med 1998; 92: 638d641. 9. Hannaway P J, Hopper D K. Cough variant asthma in children. JAMA 1982; 247: 206d208. 10. Jones A. Coughing, wheezing and the diagnosis of asthma. Practitioner 1990; 234: 274d276. 11. British Thoracic Society, National Asthma Campaign, Royal College of Physicians of London et al. British Guidelines on Asthma Management. Review and Position Statement. Thorax 1995; 52 (Suppl. 1): S9. 12. Hoskyns E W, Beardsmore C S, Simpson H. Chronic night cough and asthma severity in children with stable asthma. Eur J Pediatr 1995; 154: 320d325. 13. Marguet C, Jouen-Boedes F, Dean T P, Warner J O. Bronchoalveolar cell profiles in children with asthma, infantile wheeze, chronic cough, or cystic fibrosis. Am J Respir Crit Care Med 1999; 159: 1533d1540.
CURRENT PAEDIATRICS
14. Kelly Y J, Brabin B J, Milligan P J, Reid J A, Heaf D, Pearson M G. Clinical significance of cough and wheeze in the diagnosis of asthma. Arch Dis Child 1996; 489d493. 15. Faniran A O, Peat J K, Woolcock A J. Persistent cough: is it asthma? Arch Dis Child 1998; 79: 411d414. 16. Wright A L, Holberg C J, Morgan W J, Taussig L M, Halonen M, Martinez F D. Recurrent cough in childhood and its relation to asthma. Am J Respir Crit Care Med 1996; 153: 1259d1265. 17. McKenzie S A, Mylonopolou M, Bridge P D. Bronchodilator responsiveness and atopy in 5d10 year old coughers. Eur Resp J 2001 (in press). 18. Chang A B, Phelan P D, Sawyer S M, Del Brocco S, Robertson C F. Cough sensitivity in children with asthma, recurrent cough, and cystic fibrosis. Arch Dis Child 1997; 77: 331d334. 19. Sears M R, Jones D T, Holdaway M D et al. Prevalence of bronchial reactivity to inhaled metacholine in New Zealand children. Thorax 1986; 41: 283d289. 20. Gwaltney J M J. Rhinovirus infection of the normal human airway. Am J Respir Crit Care Med 1995; 152: S36dS39. 21. Chang A B, Phelan P D, Sawyer S M, Robertson C F. Airway hyperresponsiveness and cough-receptor sensitivity in children with recurrent cough. Am J Respir Crit Care Med 1997; 155: 1935d1939. 22. Davies M J, Fuller P, Picciotto A, McKenzie S A. Persistent nocturnal cough: randomised controlled trial of high dose inhaled corticosteroids. Arch Dis Child 1999; 81: 38d44. 23. Tattersfield A E, Town G I, Johnell O et al. Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroids treatment for two years. Thorax 2001; 56: 272d278. 24. Dordal M T, Baltazar M A, Roca I et al. Nocturnal spasmodic cough in the infant. Evolution after antireflux treatment. Allergie Immunol 1994; 26: 53d58. 25. Lalloo U G, Barnes P J, Chung F K. Pathophysiology and clinical presentations of cough. J Allergy Clin Immunol 1996; 98: S91dS97. 26. Fuller P, Picciotto A, Davies M, McKenzie SA. Cough and sleep in inner-city children. Eur Resp J 1998; 12: 426d431. 27. Smith M B, Feldman W. Over-the-counter cold medications. A critical review of clinical trials between 1950 and 1991. JAMA 1993; 269: 2258d2263. 28. Paton J Y. Comment re: ref 22. EBM 2000; 5: 19. 29. Maurice A H, Marshall A E, Higgins K S, Grattan T J. Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax 1994; 49: 1024d1026.
The management of persistent isolated cough in childhood Sejal Saglani* and Sheila A. McKenzieR *Specialist Registrar Respiratory Paediatrics and RConsultant Respiratory Paediatrician and Honorary Senior Lecturer, Queen Elizabeth Children’s Services, Royal London Hospital, 2nd Floor Fielden House, Whitechapel, London E1 1BB, UK KEYWORDS persistent cough, isolated cough, chronic cough, cough-variant asthma, diagnosis, management
Summary Persistent isolated cough is a distinct clinical entity, separate from asthma. It is empirically defined as a non-productive cough of at least 3 weeks duration, in the absence of any identifiable respiratory disease. It is usually nocturnal. An accurate diagnosis rests on a good history and examination. Investigations are rarely needed. Management consists of reassuring parents that the symptom is predominantly selflimiting, and will not result in long-term morbidity. ^ 2002 Harcourt Publishers Ltd
PRACTICE POINTS E Persistent isolated cough is not asthma E Asthma therapy should be avoided E The natural history is spontaneous resolution in most children E The likely mechanism is an increase in cough receptor sensitivity E Most persistent coughs occur with RTIs, and symptoms increase during RTIs
RESEARCH DIRECTIONS E E E E
E E
Why do some children cough persistently? What is the link with cough receptor sensitivity? Is there an association with persistence of rhinovirus or chlamydia? Is the main problem in the upper airway, and associated with parasympathetic receptors there? What is the role of menthol vapour rub? Why do children with PIC have bronchodilator reversibility and bronchial hyperresponsiveness, during periods of coughing?
Correspondence to: SS. Tel./Fax: #44-20-7377-7325; E-mail: [email protected]
INTRODUCTION Cough is a very common symptom, and with upper respiratory tract infections, accounts for numerous general practitioner consultations. Persistent isolated cough (PIC) is defined as a non-productive cough in the absence of identifiable respiratory disease, or disease of the upper airway, of at least 3 weeks duration. It is common for the cough to be present mainly at night. Other terms used interchangeably with PIC include nonspecific cough,1 persistent cough, isolated cough,2, 3 recurrent cough and chronic cough. A productive cough is always abnormal and requires further investigation. The aetiology of a productive cough, or cough resulting from underlying respiratory disease, becomes apparent from the presence of additional symptoms and signs related to chronic lung disease such as bronchiectasis. There are a number of causes of a productive cough, e.g. cystic fibrosis, bronchiectasis, recurrent milk and food aspiration, cardiac disease and inhaled foreign body. Investigations should therefore address the underlying suspected disease, which should be evident after a good history and examination. Investigation and management of cough with other symptoms, and with abnormal signs will not be addressed in this review as each cause has its own guidelines for management. The biggest breakthrough in the last 10 years is the understanding that PIC in the absence of difficulty in breathing is not asthma. This will be addressed here.
2
CURRENT PAEDIATRICS
Figure 1 The cough pathway involves cough receptors, mediators of sensory nerves, and the efferent pathway. (Taken from Chang A B, cough, cough receptors and asthma in children. Pediatr Pulmonology 1999; 28: 59d70. Fig. 1, p. 61.)
Cough, cough receptors and the cough pathway Cough has an extremely important function in maintaining the normal health of the respiratory system. It is one of the several mechanisms by which the lungs are protected and the airways cleared. This occurs in two ways: enhanced mucociliary clearance, and forced expiratory efforts following stimulation of the larynx, allowing clearance of inhaled material. The importance of the cough reflex becomes apparent when considering children with a defective cough, such as those with neuromuscular disorders who are unable to protect their airways and frequently develop recurrent pneumonia from retained secretions. The cough pathway (Fig. 1) involves cough receptors, mediators of sensory nerves, an afferent limb, the vagus nerve, the central cough centre, and an efferent limb. Cough receptors respond to various stimuli, of both a chemical and mechanical nature. The stimuli may be endogenous (airway secretions, inflammatory mediators) or exogenous (aspirated foreign material, cigarette smoke). The pattern of cough depends on the site and type of stimulation.4 The more proximal airways (larynx to trachea) are mechanosensitive, whereas the distal airways are more chemosensitive. See Fig. 2.
Figure 2 Cough receptors. (Taken from: ‘Childhood asthma and other wheezing disorders’. Edited by: Michael Silverman, Publishers: Chapman and Hall Medical. Fig. 7.1, p. 176, chapter 7eSymptoms and signs.)
Cough in healthy children Healthy children, even in the absence of a respiratory tract infection (RTI), cough up to 34 times a day.5 The
MANAGEMENT OF PERSISTENT ISOLATED COUGH IN CHILDHOOD presence of an upper RTI is associated with increased cough, but in the majority of cases the cough is selflimiting, i.e. less than 2 weeks duration. However, in some cases the cough is prolonged, or persistent, i.e. greater than 3 weeks duration. This may be because of increased cough receptor sensitivity.3 Although the cough can persist for months, it is usually self-limiting,6 and the most important aspect of management is making an accurate diagnosis, in order to avoid false labelling, and to prevent unnecessary prescribing. Children with a history of recurrent cough, of several weeks duration, without wheeze or evidence of systemic disease, are often referred to the general paediatrician. The majority of these children probably have post-RTI cough, although it is often difficult for parents to remember whether an RTI was the trigger. Despite this, there is pressure on general practitioners and paediatricians to make a more definitive diagnosis. The main concern of parents who repeatedly consult about their child’s cough seems to be the child’s risk of dying from choking as a result of coughing.7 If this anxiety cannot be allayed by reassurance, the tendency to seek alternative diagnoses will continue, and may ultimately lead to inappropriate prescribing.8
Persistent isolated cough (PIC) and asthma Early epidemiological studies, which assessed the prevalence of asthma in childhood, used the presence of wheeze as the symptom with which to make a diagnosis of asthma. Subsequently, it has been suggested that cough alone may be a presentation of asthma, and that asthma in children was being under-diagnosed because of the failure to recognize the entity of ‘cough-variant asthma’.9,10 The most recent guidelines (albeit quite dated) from the British Thoracic Society for the diagnosis of asthma acknowledge that the definition of asthma in the presence of just recurrent or chronic cough needs to be clarified.11 Much research has been carried out since these guidelines were published, to describe better the entity of persistent isolated cough, and whether it is related to asthma.
Biological distinctions It has been shown that there is no correlation between cough severity and airway calibre.12 Also, sites in the cough pathway for eliciting cough are confined to structures innervated by the vagus nerve.4 This is in contrast to sites that induce bronchoconstriction. Therefore, the pathways for cough and bronchoconstriction are distinctly different.3 Histologically, it has been found from examination of bronchoalveolar lavage (BAL)
3
fluid of children with chronic cough, that their inflammatory cell profile is similar to that of controls, and not associated with the cell profile suggestive of asthma. Asthma was associated with a high median ratio of eosinophils to neutrophils.13
Epidemiological issues It is possible that part of the apparent rise in the prevalence of asthma has resulted from the labelling of persistent cough as asthma. In one study, the prevalence of doctor-diagnosed asthma increased from 17.4% in 1991 to 22.1% in 1993. In the same period, the number of children with cough alone diagnosed as having asthma doubled from one in eight to one in four.14
Clinical features Persistent coughers do not resemble asthmatics.14,15 Children with PIC have less morbidity and less atopy compared to those with wheeze.16 Conversely, children with the triad of cough, wheeze and breathlessness, the clinical features characteristic of asthma, have an increased association with allergies, family history of atopy and preterm birth. Children with PIC do not share this profile.14
Lung function tests Lung function tests in preschool children with isolated cough have shown that coughers do not differ significantly from controls in their lung function.2 Recently, bronchodilator responsiveness (BDR), which may be interpreted as representing asthma, has been shown on lung function testing in coughers.17 The presence of BDR does not necessarily indicate asthma, although it is easy to understand the confusion. It is important to remember that BDR is also found in other conditions, such as bronchiectasis, and its presence alone does not always indicate asthma. While it is true that most patients with moderate and severe atopic asthma have very reactive airways, in a study in New Zealand only 50% of children with mild asthma were shown to have reactive airways, 26% of children with cough and no wheeze and 8% of children with no symptoms at all were reactive.18 Increased bronchial hyperresponsiveness (BHR) during coughing episodes is significantly less during cough-free periods.19 This suggests that as far as BHR is concerned coughers are intermediate between controls and wheezers, as has also been shown for BDR.2 More work needs to be done in understanding why coughers have BHR and BDR, which may be confused with asthma, while they are coughing. Epithelial damage, inflammatory mediator release and increased sensitivity of parasympathetic reflexes (including the cough reflex) are known to occur in rhinoviral infection.20 These
4 mechanisms could explain the increase in airways responsiveness and increased cough receptor sensitivity in some individuals. The increased cough receptor sensitivity that has been shown in children with persistent cough21 may be linked to increased parasympathetic reflex sensitivity and may be linked to rhinovirus presence and epithelial damage in the upper airways.
Atopy A prospective, longitudinal study16 has shown that children with recurrent cough and no wheeze did not differ from those who were asymptomatic in terms of their immunoglobulin E (IgE) levels, skin prick tests and percentage decline in lung function following cold air challenge. This was in contrast to children with both cough and wheeze, who had more atopy and greater decline in lung function with cold air challenge. What, then, distinguishes PIC from asthma is the single-symptom history and the atopic status?
Inappropriate treatment If PIC is a variant of asthma, then a response to therapy with anti-asthma medication would be expected. However, it has been shown that children with recurrent or persistent cough do not benefit from bronchodilators.6 Of two studies looking at the effect of inhaled corticosteroids (ICS) in children with PIC,6, 22 only one which used very high doses demonstrated modest benefit.22 However, it was also shown that those receiving placebo improved after 2 weeks as well.22 This suggests that the natural history of PIC is that it gets better, and prescribing medication is of no benefit, at least in the first instance. ICS are known to have significant side-effects on growth and bone mineral density and, if used, high doses should be prescribed for only the briefest period. It has recently been shown that even on relatively ‘safe’ doses of ICS, adults with mild asthma, and therefore less airways inflammation, have a significantly higher rate of systemic absorption, as the ‘protective’ effect of inflammatory changes in the airways is absent.23
Cost The increased willingness to diagnose asthma on the basis of cough alone means an increased tendency to prescribe treatment. Prescription of ICS is considered by over 60% of GPs for children with PIC.8 Inappropriate prescribing results in unwanted side-effects and diagnostic misclassification. If ICS are prescribed, then an assumption is made that asthma is the diagnosis. Children are thus given a ‘label’ and of course this has resource implications.
CURRENT PAEDIATRICS
Table 1 Useful distinguishing features of PIC and asthma PIC
Asthma
Non-atopic Cough, only symptom
Atopic (!IgE and/or SPT#ve) Wheeze and difficulty in breathing reported Good response to bronchodilators and inhaled steroids
NO response of cough to bronchodilators or inhaled steroids BDR may be demonstrated
BDR
In summary, the available evidence to date indicates that PIC is a separate entity from asthma. It is acknowledged, however, that children with asthma may present with cough, but prior to making the diagnosis, it is important to consider the facts which illustrate that cough alone, without other symptoms or risk factors, is a poor marker of asthma. Whereas all that wheezes probably coughs, all that coughs certainly does not wheeze. In asthma, cough may be the only complaint because the child and his parents are unaware of wheeze. Features that may help to distinguish PIC from asthma are highlighted in Table 1.
Cough and gastro-oesophageal reflux (GOR) The link between cough and GOR remains debatable. The prevalence of cough in children with GOR, but no underlying neurodevelopmental abnormality, is unknown. It has been shown that treatment of GOR in infants with cough fails to relieve their symptoms of cough, although the GOR may improve.24 This is therefore an unlikely cause of persistent cough.
Cough and post-nasal drip There are no cough receptors in the pharynx or postnasal space,25 so the relationship of the two conditions is controversial. It may be that post-nasal drip is associated with cough, but is unlikely to be a cause of persistent cough,4 especially as both conditions have the same trigger of viral RTI.
OUR APPROACH TO THE MANAGEMENT OF PIC IN CHILDREN History Listen to the parent carefully for symptoms other than cough, such as noisy breathing and difficulty in breathing,
MANAGEMENT OF PERSISTENT ISOLATED COUGH IN CHILDHOOD and for anything which could suggest a productive cough. Ask about upper airway noises such as snoring and stridor. A useful question is ‘can you hear the noise outside the room?’ Wheeze cannot usually be heard beyond the bed. Did the cough start with a cold, runny nose, choking episode or chesty illness. Consider pertussis, with its crescendo cough, tussive vomiting and whoop. It may be useful to imitate the cough to the parents. PIC is commonly present only at night, or often worse at night. Any other associated nocturnal symptoms should be noted. Ask about sleeping arrangements, as parents or siblings sleeping in the same room are more likely to hear the cough and be disturbed.
Examination The examination should be guided by the history, but specific things to look for are a chest wall deformity and signs of respiratory distress. It is important to examine the nose for polyps and the tonsils to look for evidence of upper airway disease. Assess growth accurately, and exclude failure to thrive. PIC is a very clear entity. However, there may be some confusion about management if cough is present with other symptoms. In this case, further evaluation is required. Management is outlined below in two sections, PIC alone, and cough with other symptoms.
Management of PIC Initially, explain that you appreciate the considerable difficulty the parents must be experiencing in dealing with this problem. But emphasize that this is a well-described symptom, which is not asthma and does not represent an underlying sinister condition such as tuberculosis. This is especially important for an immigrant Asian population. Acknowledge the sleep disturbance that is associated, but also explain that current evidence in inner-city children has shown that parents of children with PIC suffer the most sleep disturbance, and children are minimally affected.26 Also that the natural history of the symptom is a tendency to improve. Next explain that any treatment the child is on should be stopped for 7 days in order to assess any change in symptoms, and to show that treatment is of no benefit. To ensure compliance with this request, tell them that to date there is no evidence for any benefit from over-thecounter treatments, or asthma therapy for cough in children.6, 27 Offer an open appointment to re-attend if symptoms worsen or do not improve in 3 weeks. Finally, it is extremely important to explain the benign nature of PIC to the parents. Reassurance is the key to a successful outcome to avoid repeated consultation. It is likely that most will have improved within 3 weeks and are unlikely to return.
5
If, after excluding all other causes of cough, and allowing enough time to achieve natural resolution, coughing still persists, and parental anxiety is extreme, then it may be worth considering a 2-week course of high-dose inhaled fluticasone propionate (500 lg b.d.), which may hasten resolution of symptoms.22 The number needed to treat (NNT) to see any benefit is three.28 BUT prolonged or repeated courses of ICS are NOT justified for PIC.28 In order to ensure that the ICS are not over used, a small dose per inhalation device should be prescribed. The other treatment that can be tried is a 2-week trial of menthol vapour rub, such as ‘Vick’s’. Although there is no evidence of its benefit in PIC in the current literature, laboratory evidence shows that it may downregulate cough receptors29 and thus reduce the increased receptor sensitivity seen in children with PIC.
Management of cough with other symptoms Other symptoms that may be present include difficulty in breathing or noisy breathing. If the history is unclear, then we advise that the child is seen again when the additional symptoms are actually present. This should be done before bronchodilators or inhaled corticosteroids are prescribed ‘blindly’. If a strong family history of asthma or atopy is present, the child’s atopic status should be assessed, with an IgE level and skin prick tests to aeroallergens, as this may be a patient with asthma presenting with cough as the predominant symptom. Lung function tests may be helpful if asthma is suspected, but only if evidence of BDR is sustained when the child is not coughing, and if the child is atopic. If cough is present with a history of fever, the possibility of bronchitis, tracheitis, pneumonia or pulmonary tuberculosis, especially in high-risk populations, should not be forgotten, and a chest X-ray is important. Other investigations, such as pH study and barium swallow, are usually unnecessary in an otherwise well child, as there is no good evidence that GOR is related to cough.
Summary Persistent isolated cough is a defined clinical entity. A good history and examination contribute the most towards the diagnosis. A temporary increase in cough receptor sensitivity is the most likely explanation for the onset. The increased sensitivity may be predominantly in the large airways, but the precise sites affected are not known. The natural history is towards spontaneous resolution, and management includes reassurance and
6 support for the family, with the specific advice that children do not choke to death from coughing. Also that there is little evidence that sleep is lost; however, there is no evidence about the impact on quality of sleep.
REFERENCES 1. Chang A B, Robertson C F. Cough in children. Med J Aust 2000; 172: 122d125. 2. McKenzie S A, Bridge P D, Healy M J R. Airway resistance and atopy in preschool children with wheeze and cough. Eur Respir J 2000; 15: 833d838. 3. Chang A B. Cough, cough receptors, and asthma in children. Pediatr Pulmonol 1999; 28: 59d70. 4. Widdicombe J G. Sensory neurophysiology of the cough reflex. J Allergy Clin Immunol 1996; 98: 84d90. 5. Munyard P, Bush A. How much coughing is normal? Arch Dis Child 1996; 74: 531d534. 6. Chang A B, Phelan P D, Carlin J B, Sawyer S M, Robertson C F. A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 1998; 70: 6d11. 7. Cornford C S, Morgan M, Ridsdale L. Why do mothers consult when their children cough? Family Practice 1993; 10: 193d196. 8. Picciotto A, Hubbard M, Sturdy P, Naish J, McKenzie S A. Prescribing for persistent cough in children. Respir Med 1998; 92: 638d641. 9. Hannaway P J, Hopper D K. Cough variant asthma in children. JAMA 1982; 247: 206d208. 10. Jones A. Coughing, wheezing and the diagnosis of asthma. Practitioner 1990; 234: 274d276. 11. British Thoracic Society, National Asthma Campaign, Royal College of Physicians of London et al. British Guidelines on Asthma Management. Review and Position Statement. Thorax 1995; 52 (Suppl. 1): S9. 12. Hoskyns E W, Beardsmore C S, Simpson H. Chronic night cough and asthma severity in children with stable asthma. Eur J Pediatr 1995; 154: 320d325. 13. Marguet C, Jouen-Boedes F, Dean T P, Warner J O. Bronchoalveolar cell profiles in children with asthma, infantile wheeze, chronic cough, or cystic fibrosis. Am J Respir Crit Care Med 1999; 159: 1533d1540.
CURRENT PAEDIATRICS
14. Kelly Y J, Brabin B J, Milligan P J, Reid J A, Heaf D, Pearson M G. Clinical significance of cough and wheeze in the diagnosis of asthma. Arch Dis Child 1996; 489d493. 15. Faniran A O, Peat J K, Woolcock A J. Persistent cough: is it asthma? Arch Dis Child 1998; 79: 411d414. 16. Wright A L, Holberg C J, Morgan W J, Taussig L M, Halonen M, Martinez F D. Recurrent cough in childhood and its relation to asthma. Am J Respir Crit Care Med 1996; 153: 1259d1265. 17. McKenzie S A, Mylonopolou M, Bridge P D. Bronchodilator responsiveness and atopy in 5d10 year old coughers. Eur Resp J 2001 (in press). 18. Chang A B, Phelan P D, Sawyer S M, Del Brocco S, Robertson C F. Cough sensitivity in children with asthma, recurrent cough, and cystic fibrosis. Arch Dis Child 1997; 77: 331d334. 19. Sears M R, Jones D T, Holdaway M D et al. Prevalence of bronchial reactivity to inhaled metacholine in New Zealand children. Thorax 1986; 41: 283d289. 20. Gwaltney J M J. Rhinovirus infection of the normal human airway. Am J Respir Crit Care Med 1995; 152: S36dS39. 21. Chang A B, Phelan P D, Sawyer S M, Robertson C F. Airway hyperresponsiveness and cough-receptor sensitivity in children with recurrent cough. Am J Respir Crit Care Med 1997; 155: 1935d1939. 22. Davies M J, Fuller P, Picciotto A, McKenzie S A. Persistent nocturnal cough: randomised controlled trial of high dose inhaled corticosteroids. Arch Dis Child 1999; 81: 38d44. 23. Tattersfield A E, Town G I, Johnell O et al. Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroids treatment for two years. Thorax 2001; 56: 272d278. 24. Dordal M T, Baltazar M A, Roca I et al. Nocturnal spasmodic cough in the infant. Evolution after antireflux treatment. Allergie Immunol 1994; 26: 53d58. 25. Lalloo U G, Barnes P J, Chung F K. Pathophysiology and clinical presentations of cough. J Allergy Clin Immunol 1996; 98: S91dS97. 26. Fuller P, Picciotto A, Davies M, McKenzie SA. Cough and sleep in inner-city children. Eur Resp J 1998; 12: 426d431. 27. Smith M B, Feldman W. Over-the-counter cold medications. A critical review of clinical trials between 1950 and 1991. JAMA 1993; 269: 2258d2263. 28. Paton J Y. Comment re: ref 22. EBM 2000; 5: 19. 29. Maurice A H, Marshall A E, Higgins K S, Grattan T J. Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax 1994; 49: 1024d1026.