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Management of chronic non-specific cough in childhood: an evidence-based review
  1. Atul Gupta1,
  2. Michael McKean1,
  3. Anne B Chang2
  1. 1Paediatric Respiratory Unit, Freeman Hospital, Newcastle upon Tyne, UK
  2. 2Department of Respiratory Medicine, Royal Children’s Hospital, Brisbane, Queensland, Australia; Menzies School of Health Research, Darwin, NT, Australia
  1. For correspondence:
    Dr A Gupta
    Paediatric respiratory Unit, Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne NE7 7DN, UK; atulgupta{at}doctors.org.uk

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Cough and sneezes spread diseases … so why do we have to cough? Cough is an important protective reflex enabling us to clear secretions aspirated into the airway. We understand many of the causes of acute and chronic cough in children, but for some children cough persists without any obvious reasons as to why. In the past it has often been assumed to be due to childhood asthma but increasingly chronic “non-specific cough” of childhood is recognised as a separate entity albeit without any identifiable cause. Paediatricians are frequently faced with a child with chronic non-specific cough. How then should these children be managed? This article focuses on the approach to assessment and investigations of chronic non-specific cough in children and includes a systematic review of common therapies.

EPIDEMIOLOGY AND MORBIDITY OF COUGH ON THE PARENTS/CHILDREN

Cough is perhaps one of the commonest symptoms in childhood and, although most acute cough is related to viral infections, there are a great number of differential diagnoses (table 1) to consider when cough frequency or severity are abnormal. Questionnaire data which rely on the subjective impression of parents suggest that up to 10% of preschool and early school aged children have chronic cough without wheeze at some time.1–3

Table 1

 Differential diagnosis of chronic cough in children

It is unknown whether the primary stimulus for chronic cough in many children is identical to that for acute cough. Further, it is unknown why the cough associated with common acute viral upper respiratory tract infection resolves in most, yet persists in a significant minority. It may be that both specific virus and host factors play a role.

In chronic non-specific cough, the aetiology is ill defined and it is suspected that the majority are related to post viral cough and/or increased cough receptor sensitivity.4,5 Wright in 1996 identified a cohort of children with chronic non-specific cough who were not atopic and did not suffer the disability that asthmatic children suffered.6 More recent studies have described children with non-specific cough to have slightly more reactive airways than controls but their airways are not as reactive as those of asthmatic children.7,8

For patient and parents, a cough which persists can be associated with considerable distress and impaired quality of life. In 1993, Cornford interviewed a group of mothers, who had consulted a doctor because of cough. He found the major concern for mothers was their fear that their child was going to die, usually because “the cough was on their chest” leading to choking on phlegm or vomit, but also through an asthma attack or cot death. Mothers were also worried that their child would develop long-term chest damage. Particularly important in mothers’ assessments were their experiences of disturbed sleep because of worries about their child dying at night.9 Similar findings were later found by Fuller et al in 1998.10 Chronic non-specific cough is certainly a common and troublesome paediatric problem.

CLINICAL ASSESSMENT

Despite advances in the understanding of cough, the clinical assessment of patients with a chronic cough can be difficult. There are a number of reasons why the cough may be difficult to treat. In some cases, it may reflect an inadequate approach to diagnostic evaluation and failure to appreciate both pulmonary and extrapulmonary causes for chronic cough (table 1). In other cases, trials of therapy may be inappropriate or of inadequate dose and of insufficient duration.

The accuracy and reliability of symptom reporting are key factors in any assessment of cough. Studies using overnight audio recordings have shown that parental reporting of cough does not correlate well with the frequency, duration, or intensity of the actual cough.1–3 It would appear in many cases that the reported “severity” of coughing in a child is related to how it affects the parents or teachers. Parental reporting of wet/dry cough has good reliability11 in contrast to the poor reliability of reporting of wheeze and stridor.12,13 However the presence/absence of nocturnal cough is unreliable when compared to objective monitoring.14 Reporting of cough is prone to time-period effects (spontaneous resolution of cough) and large placebo effect as the therapeutic benefit of placebo treatment for cough has been reported to be as high as 85%.15 Non-placebo controlled intervention studies must be interpreted with caution.

The definition of chronic cough varies from duration of three weeks16 to 12 weeks.17,18 There are no studies that have clearly defined when cough should be defined chronic or persistent. As studies have shown that cough related to acute respiratory infections (ARI) resolves within 1–3 weeks in most children11,19 it would be logical to define chronic cough as daily cough lasting four or more weeks. Cough in isolation of other clinical features is known as non-specific cough, which has been defined as non-productive cough in the absence of identifiable respiratory disease or any known aetiology.17 When any of the symptoms and signs of an underlying respiratory or systemic disease (table 1) are present, the cough is referred to as “specific cough”.

As chronic cough can be associated with significant consequences (for example, retained foreign body causing bronchiectasis), each child with chronic cough should be thoroughly evaluated, with a detailed history, followed by a thorough physical examination (table 2). This will enable the doctor to identify abnormalities suggestive of a more severe underlying disease (table 3), target further investigations as necessary and decide on treatment options individually. For most children evaluation with a history and examination will be sufficient to reassure the family that there is no serious underlying pathology (fig 1). Clinical evaluation of cough in all children should include an assessment of environmental factors, in particular tobacco smoke, parental concerns and parental expectations.

Table 2

 Points in the history and examination suggestive of alternative diagnosis

Table 3

 Worrying features suggestive of serious underlying lung disease in children with chronic cough

Figure 1

 Diagnostic algorithm for use in children with chronic cough.

In some children the quality of cough is recognisable and suggestive of specific aetiology (table 4). In the “pertussis-like” illnesses the cough is often spasmodic and choking in nature, and may result in the classical whoop or in vomiting. Pertussis, parapertussis, adenovirus, mycoplasma and Chlamydia have all been implicated in causing this pattern of coughing. Although pertussis, pertussis-like and Mycoplasma infections classically cause cough associated with other symptoms (for example, Mycoplasma may be associated with other symptoms of a respiratory infection such as pharyngitis), these infections can also cause persistent cough without other symptoms, especially in the presence of process modifiers such as antibiotics and vaccination. The possibility of tuberculosis should also be considered. Tuberculosis may cause chronic cough, especially if there is secondary infection due to airways obstruction by protruding or perforating lymph nodes.

Table 4

 Classical recognisable cough

The use of isolated cough as a marker of asthma is controversial, with more recent evidence suggesting that in most children isolated cough (that is, without wheeze/dyspnoea) does not represent asthma.20–22 In older children, cough is also subjected to psychological influences23 because, as in adults, cough can be cortically modulated.20 Rietveld and colleagues showed that children were more likely to cough under certain psychological settings.23 So called psychogenic cough should always be considered a differential, especially in the older child. A suggested diagnostic algorithm for children with chronic cough is shown in fig 1.

INVESTIGATIONS

In children with chronic cough, the type and depth of the investigations depends on clinical findings and suspected aetiology. The symptom of cough can be a marker of the involvement of many thoracic diseases and may reflect psychological functions that may be in isolation or exacerbate an underlying pulmonology process.23,24 Hence possible relevant investigations range from no or simple tests (for example, oxygen saturations) to invasive tests (for example, chest HRCT scan, bronchoscopy, barium swallow, sleep study, etc). The role of specific tests for evaluation of lung disease is beyond the scope of this paper as it would encompass the entire spectrum of paediatric respiratory illness. Summary of studies that describes yield of specific investigations for cough in children was recently published by Chang and colleagues in Chest.25

Spirometry

Spirometry is valuable in the diagnosis of reversible airway obstruction in children with chronic cough if an abnormality is present.26,27 Spirometry can usually be reliably performed in children aged >6 years and in some children >3 years if trained paediatric personnel are present.28

Tests for airway hyper-responsiveness

In paediatrics, tests for airway hyper-responsiveness (AHR) are not used in routine practice in most paediatric pulmonary laboratories to diagnose asthma.29 Presence of AHR does not mean asthma is present in children.30 Furthermore the demonstration of AHR in a child with isolated cough is unlikely to be helpful in predicting the later development of asthma31 or the response to asthma medications.32 There are older studies that have stated that the presence of AHR in children with cough is said to be representative of asthma. These studies were not placebo-controlled studies or confounders were not adjusted for, or unconventional definitions of AHR were used.22,33–35

Flexible bronchoscopy

Indications for flexible bronchoscopy in children with chronic cough include suspicion of airway abnormality, localised changes on radiology of the chest, suspicion of inhaled foreign body, evaluation of aspiration lung disease and, microbiological and lavage purposes. Utility for flexible bronchoscopy is dependent on the child’s medical history and available expertise.

Use of chest and sinus CT scans

Chest HRCT scan is a useful tool for evaluating small airway structural integrity. As radiation exposure and indications for conventional, spiral and HRCT chest scans are different and dependent on the type of suspected lesion(s), prior consultation with a paediatric pulmonologist is recommended.

Airway fluid/lavage and cellular assessment

Currently, other than assessment of airway specimens for microbiological purposes, the use of airway cellular and inflammatory profile in children with chronic cough is currently limited to supportive diagnosis and research rather than definitive diagnosis.

Other investigatory techniques

Airways resistance by the interrupter technique (Rint) is not yet established in clinical practice but may prove to be useful in detecting isolated cough associated with asthma. Despite its application in research, there are still problems with intersubject variability and hence validity of its measurements when undertaken by different investigators.36 To date there are no studies that have evaluated the role of nitric oxide or breath condensate in determining the aetiology of chronic cough in children. Tests for cough sensitivity are currently non-diagnostic, its sensitivity and specificity undefined and its use is still limited to research purposes.

TREATMENT OF “NON-SPECIFIC COUGH”

In order to give an up to date review of common treatments we performed a structured search and selection process before assessing available published literature.

METHODOLOGY OF SEARCH

Two authors (AG and MM) searched MEDLINE (from January 1951 to December 2005), CINAHL (from January 1982 to December 2005), EMBASE (from January 1974 to December 2005) and the online Cochrane databases (2005) for the subject headings cough and children (aged up to and including 16 years). All randomised (randomised and quasi-randomised) controlled trials (RCTs) or systematic reviews of RCTs were included. The search was limited to chronic, recurrent or persistent cough. References were reviewed and additional relevant articles were identified. We excluded studies where there was another apparent cause for chronic cough, such as infective causes (for example, whooping cough, immunodeficiency, cystic fibrosis, tuberculosis), cardiovascular disease, other respiratory symptoms (for example, productive cough, dyspnoea, aspiration), associated systemic illness for example, failure to thrive, lymphadenopathy) and presence of lung function abnormality. Children with associated wheezy chests were also excluded in order to help eliminate studies of asthma.

RESULTS

Inhaled β2-agonists

A Cochrane systemic review found that inhaled salbutamol was no different from placebo in reducing the frequency of cough measured objectively or scored subjectively.37 Only, one relevant paediatric RCT was reported.32 The Cochrane review highlighted that on the basis of one small trial, they cannot exclude the possibility that a subgroup of children with recurrent cough without other evidence of airway obstruction might benefit from inhaled β2-agonist.37

Mast cell stabilisers

Cromoglycate and nedocromil (commonly grouped together as cromones) are attractive medications for non-specific cough as these medications are much less likely to cause significant side effects than inhaled corticosteroids. Nedocromil and cromoglycate increase cough threshold 38 and reduce neurogenic inflammation which is believed to be the most important peripheral inflammation process involved in human cough.20,39 However, a Cochrane systemic review found no RCT that examined the efficacy of inhaled cromones in the management of prolonged non-specific cough in children.40 In a single cohort study a small effect was seen within two weeks of therapy.

Methylxanthines

A Cochrane systemic review found absence of reliable evidence to support the routine use of methylxanthines for symptomatic control of non-specific cough in children.41 If methylxanthines were to be trialled in children with prolonged non-specific cough, cohort data suggest a clinical response (subjective cough severity) would be seen within 2–5 days (and certainly within 14 days) of therapy.26,27 However methylxanthine use has to be balanced against the well known risk of toxicity and its low therapeutic range in children.

Anticholinergics

A Cochrane systemic review found no RCTs to support the use of inhaled anticholinergics in children with non-specific cough.42 The known adverse events (for example, paradoxical bronchospasm, paralytic ileus, tachycardia) must also be considered if inhaled cholinergics medications are used.

Corticosteroids

There are no RCTs on use of oral steroids for non-specific chronic cough in children. A Cochrane systemic review found that only two published RCTs (123 participants) on inhaled corticosteroids (ICS) for chronic non-specific cough in children exist.43 One compared inhaled beclomethasone dipropionate (400 μg per day) with placebo32 and the other compared fluticasone propionate (2 mg per day for 3 days followed by 1 mg per day for 11 days) with placebo.44 Both studies used metered dose inhalers via a spacer. With the lower dose of inhaled corticosteroid there was no significant difference between the beclomethasone and placebo groups.32 With the higher dose there was a significant improvement in nocturnal cough frequency after two weeks in children presenting with persistent nocturnal cough. However, a significant but smaller improvement was also seen with placebo.44 Therefore, the clinical impact of this is questionable.

GORD treatment

There are many gastrointestinal (abdominal pain, halitosis, water brash, etc) and extra-gastrointestinal symptoms (cough, hoarseness, laryngeal problems, ear disease, dental erosion, etc) attributed to GORD.45 Cohort studies in adults suggest that GORD related to acid causes 21–41% of chronic non-specific cough, including many with no gastrointestinal symptoms of GORD.46,47

A Cochrane systemic review found the data inconclusive in children. Three relevant paediatric RCTs were reported; two using thickened feeds and one using motility agents (cisapride or domperidone). Thickened feeds had an inconsistent effect, motility agents had no effect and there were no relevant studies that examined proton pump inhibitors (PPI) or fundoplication for cough and GORD. In adult studies where meta-analysis on the use of PPI was possible, the Cochrane review highlighted the significant contrast between highly positive results described in cohort studies to the low effect found in the meta-analysis of the five included RCTs.48

Others

Mucolytic agents

There is no place for mucolytic agents including bromhexine or acetylcysteine as treatment for chronic cough, because there is no evidence that they work. They may cause additional airway irritation.

Over the counter cough medications

There are no RCTs on the use of over-the-counter medications for non-specific chronic cough in children. However, systematic reviews for children have concluded that over-the-counter cough medications have little, if any, benefit in the symptomatic control of acute cough in children.49,50

Antimicrobials

There is no evidence to support the use of antibiotics in children with chronic non-specific cough. A recent Cochrane systemic review found antibiotics are likely to be beneficial in the treatment of children with chronic “moist” cough.51 When considering implications for practice of this review one must remember that the data are based on two small studies with methodological flaws. Clearly, further high-quality studies are needed before this evidence can be accepted as conclusive. Acknowledging this, the available evidence suggests that antibiotics are efficacious in young children, aged 7 years or less, with prolonged wet cough with three or four patients cured for every 10 treated.51 The use of antibiotics in children with prolonged wet cough is also associated with a reduction in the progression of illness whereby children on antibiotics are less likely to require further antibiotics for treatment of complications. One must remember antibiotics are not without side effects when considering this treatment option. The conclusions of this review are applicable only to children with persistent wet cough which must be differentiated from chronic non-specific (dry) cough.

Indoor air modifications

There is no evidence to support the use of air-modification modalities, (ionisers, vapourisers, humidifiers, air filters, regular vacuuming), in treating children with non-specific chronic cough.

Herbal antitussive therapy

There is no evidence to support the use of herbal antitussive therapy), in treating children with non-specific chronic cough.

Discussion

There are unfortunately few data available to provide a complete evidence-based approach in the management of non-specific cough in children. A suggested sequential approach to the management of the patient with non-specific chronic cough is provided in fig 2. Chronic cough in childhood is known to have a wide range of causes, hence treatment should always be preceded by a systematic effort to exclude serious underlying illness and establish the cause for the cough. Management of the otherwise well child with a persistent dry non-productive cough will include reassurance with watchful anticipation. Because of the favourable natural history of cough, if medication trials are undertaken, a “positive” response should not be assumed to be due to the medication tried.

Figure 2

 Management algorithm for the non-specific chronic cough.

Reporting of cough is likely to be biased,52 and Hutton et al described that “parents who wanted medicine at the initial visit reported more improvement at follow-up, regardless of whether the child received drug, placebo, or no treatment”.15 Given that low dose ICS have been shown to be effective in the management of the majority of childhood asthmatics, and the reported significant adverse events on high doses, we suggest the use of 400 μg/day equivalent of budesonide (or beclomethasone) if a trial of asthma therapy is warranted. As the earlier studies in adults and children that used medications for asthma reported that cough related to asthma completely resolved by 2–7 days it would seem sensible to reassess early (that is, in 2–3 weeks). Cough unresponsive to ICS should not be treated with increased doses of ICS. If cough resolved with ICS use, clinicians should remain aware that the child may not necessarily have asthma and should be re-evaluated off asthma treatment. In this way spontaneous resolution of cough can be distinguished from persistent asthma where symptoms will recur.

In the management of any child with cough irrespective of the aetiology, attention to exacerbation factors is encouraged. The cessation of parental smoking has been found to be a successful form of therapy for the children’s cough.53 Behavioural counselling for smoking mothers has been shown to reduce young children’s exposure to environmental tobacco smoke (ETS) in both reported and objective measures of ETS.54

Chronic cough can cause significant distress to the whole family; therefore, it is important to explore the reasons for parental anxiety and reassure the parents that a watch and wait policy is probably all that is needed. Simultaneously, it is necessary to detect environmental exacerbating factors and attempt to eliminate them. Providing parents with information on the expected time to resolution of acute respiratory infections may reduce anxiety in parents and the need for medication use and additional consultation. Appreciation of specific concerns and anxieties, and an understanding of why they present are thus important when consulting children with non-specific cough.

IMPLICATIONS FOR RESEARCH

Chronic non-specific cough is a common condition. An increased awareness of its impact on the child, their development and their family would assist in continuing to promote the importance of research into this area.

There is a need for more detailed study of cough response in chronic non-specific cough, as it might one day lead to more effective treatments being trailed. Questions continue to be raised as to the interaction between cough receptors and inhaled irritants or allergens and the associated inflammatory response. Exploring these issues, however, may prove challenging in children where invasive sampling is difficult to justify in a condition that is not life threatening. The application of non-invasive methods for assessing the function of the lower airways in non-specific cough should continue to be explored. It may also be beneficial to consider the argument of nature versus nurture. With increased understanding of human genetics, it may be that studies aimed at understanding genetic predisposition to cough would prove informative.

In summary, cough in children is very common and, in the majority, is reflective of expected childhood respiratory infections. However, chronic cough may also be representative of a significant serious disorder and all children with chronic cough should have a thorough clinical review to identify worrying features suggestive of an underlying respiratory and/or systemic illness.

REFERENCES