Review

© Future Drugs Ltd. All rights reserved. ISSN 1478-7210 111

CONTENTS

Pathophysiology of cough

Specific categories of cough

Postinfectious cough

Cough variant asthma

Psychogenic cough

Systemic causes of cough

Environmental causes of cough

Expert opinion

Five-year view

Key issues

References

Affiliations

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Chronic cough in children: recent advancesIoanna M Velissariou and Dimitris A Kafetzis†

Recurrent cough in children is a very common symptom of respiratory disease. Most children who cough, however, have normal pulmonary function. This article presents a diagnostic framework for chronic cough and a recommended management plan in order to avoid over investigation and over treatment of a generally benign and self-remitting condition. Pathophysiology of cough and recent advances in treatment options are also included.

Expert Rev. Anti-infect. Ther. 2(1), 111–117 (2004)

†Author for correspondenceUniversity of Athens, Second Department of Paediatrics‘P and A Kiriakou’ Children’s Hospital, Thevon and Livadias St, GR 11527, Athens, GreeceTel.: +30 210 772 6349kafetzis@ath.forthnet.gr

KEYWORDS: asthma, children, chronic cough, cough reflex, review

Persistent cough is common in childhood. It isa symptom that causes a significant degree ofdistress to the sufferer, which leads to increasedparental anxiety and frequent school absence.As a result, the public demand for cough sup-pressant agents increases. It is estimated thatUS$ 2 billion per year are spent in the USA oncough and cold preparations [1]. Kogan andcolleagues report that approximately 35% ofpreschool-age children in the USA had usedover the counter remedies for cough in a1 month period survey [1]. In Australia, thereported use of medications for coughs andcolds in a 2 week period was 167 per 1000 forchildren under the age of 5 years and 87 per1000 for children aged 5 to 14 years old. Anti-tussive remedies were the most frequently, andthe third most frequently used medicationgroup in the respective age groups [2].

However, the exact prevalence of chroniccough in children is not known. In adults, anumber of questionnaire surveys haveattempted to estimate its prevalence [3–5]. Insome studies, chronic cough is considered tobe directly related to environmental tobaccoexposure; in others, chronic cough and spu-tum production were taken as aspects of thesame syndrome and in others, chronic cough isconsidered to be the same entity as nocturnalcough. There is, therefore, a discrepancy in theperception of chronic cough which reflects thequestions asked in the above-mentioned sur-veys and biases the results. All reported studies,

however, conclude that the level of sympto-matic chronic cough within the adult popula-tion is far higher than virtually any othersymptom and certainly higher than any otherrespiratory symptom.

There is also a discrepancy in the definition ofchronic cough in children. Thomson and col-leagues define chronic cough as persistent coughlasting 4 weeks or more [6]. Chang and col-leagues consider recurrent cough as two episodesof cough or more, each lasting 2 weeks or morein a 12 month period [7]; Marguet define it ascough observed during several consecutivemonths, each episode lasting at least 1 week [8];and Bremont as cough lasting at least 3 weeks [9].

Pathophysiology of coughIn recent years, there has been extensiveresearch regarding the multifactorial patho-physiology of cough and of the cough reflex, inhumans and in animal models. Understand-ing the in-depth mechanisms of cough willfacilitate a more successful management.

In health, coughing serves to clear the air-ways of inhaled particulate matter, aspirate andother noxious stimuli, and is therefore neces-sary for the maintenance of normal airwayfunction. The cough reflex, however, canbecome excessive during exacerbations of vari-ous respiratory conditions. It appears that thesensitivity of the cough reflex is regulated byvariable neural pathways. A number of airwaysdiseases may be associated with increased levels

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of neurotrophic factors, such as nerve growth factor, providingan ideal environment to support neuronal growth of existingairway nerve fibers. It has been shown that the number of nervefibers is increased in the airways of patients suffering from idio-pathic nonproductive cough, although the exact identity ofthese fibers remains unknown [10,11]. The tuning of the coughreflex, either inhibition or enhancement of its strength, seemsto be dependent upon three sensory receptors: rapidly adaptingreceptors (RAR), C-fiber and Aδ-nociceptors. While all threeare activated by tussigenic agents, RARs cause cough directly,C-fiber receptors by local release of tachykinins that stimulateRARs and the reflex role of Aδ-nociceptors is unknown. It hasnot yet been clarified whether Aδ-nociceptors are part of theRARs since RARs are Aδ-fibers too [12–14].

The cough reflex involves forceful expiration after a build upof pressure in the thorax up to 300 mmHg by contraction ofexpiratory muscles against a closed glottis. As a result, gas isexpulsed at high velocity and airway debris sweeps towards theoral cavity [15]. Chronic cough can cause significant morbiditydue to the high intra-thoracic and intra-abdominal pressuresthat are generated by the expiratory muscles in patients withairway disease [16]. The expiratory muscles follow a unique pat-tern of intense activation, which results in the large respiratorypressures associated with cough. The brain stem initiates thisactivation by a neural network that transmits expiratory motordrive to spinal motoneurones via medullary premotor neurons.

The main components of this network are [17–19]:

• Gate cells, which, when activated open the pathways for theexpiratory efforts of cough, while suppressing the eupnoeiccontrol of breathing

• Pump cells, which when activated open the gate to allow theexpiratory reflexes to be expressed

• Expiration augmenting neurons in the ventral respiratorygroup/Botzinger complex, which control the expiratorypremotor neurons and thereby the expiratory muscles

Apart from the brain stem, however, the cortex is alsoinvolved in the complexity of the mechanisms of cough. It iscommonly known that cough can be induced voluntarily andstudies have measured the extent to which pathological coughcan be voluntarily suppressed [20]. Davenport and colleaguesintroduced a new cortical parameter, the ‘urge to cough’. Withvaried and random concentrations of capsaicin aerosol as astimulus, the subject’s urge to cough was recorded on a visualscale simultaneously with the number of coughs. The twoshowed a good correlation but the urge to cough always pre-ceded the cough and if the urge was weak, cough was usuallyabsent. Therefore, the sensory threshold was lower than thereflex threshold [21].

Specific categories of coughIt is said that virtually any pediatric lung disease can causecough. Chronic cough in children, however, can be dividedinto specific categories according to several clinical andpractical characteristics, which guide further management.

Postinfectious coughAll children cough with colds. There are some children, how-ever, who tend to cough for more prolonged periods of timethan others after a respiratory infection for reasons which arenot very well clarified.

Postviral cough is a term generally used to define the prolongedcough which follows a respiratory tract infection that is benignand self-limiting and has an arbitrarily defined duration of upto 8 weeks [22]. The cough may persist after the apparentdemise of the infectious agent, although it is possible that post-viral cough may represent patients who have persistent upperrespiratory tract infection. A more likely explanation is that theinvading organism is cleared relatively rapidly, but some aspectof the inflammatory process persists giving rise to symptomslong after the acute event. Fitch and colleagues describe a smallbut statistically significant increased percentage of neutrophils

Box 1. Questions to ask in the history.

• Is the cough productive or nonproductive?

• Are there symptoms suggesting upper airway obstruction (e.g., snoring, apnoeic pauses, restlessness, daytime somnolence, poor concentration)?

• Is the child wheezing? Is there a family history of asthma and/or atopy, is the child atopic?

• Is there a history of weight loss, lymphadenopathy, or any feature of a systemic immunodeficiency?

• Does the child suffer from night sweats, unremitting pyrexia, suppurative sputum production?

• Are the symptoms continuous, or do they occur in association with a cold?

• Does the child cough or get short of breath with exercise?

• Did the cough start from the first day of life, indicating a structural deformity of the airways?

• Does the child have symptoms associated with gastroesophageal reflux, such as irritability after feeds, worsening on lying down, vomiting, chocking on feeds?

• Is the cough of abrupt onset, indicating foreign body aspiration, or is there a specific point in time when parents first noticed the symptoms, do they recall any time when the child had been left playing unsupervised?

• Is the child allergic to anything, can the parents relate the cough to a specific environment, smoke exposure or consumption of a specific food?

• Does the child have diarrhea or other symptoms indicative of malabsorption?

• Does the cough continue when the child falls asleep, or does it stop completely? Does the child have tics, or is there a family history of psychosomatic illnesses?

• Does the child have recurrent headaches, stuffed nose, or any evidence of sinusitis or rhinitis?

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in bronchoalveolar lavage samples from children with chroniccough [23]. It is speculated that this finding represents an under-lying persistent airways infection. Infective agents that havebeen implicated with chronic cough in children are the respira-tory syncytial virus, several rhinoviruses, Mycoplasma pneumo-niae, Chlamydia pneumoniae, Bordetella pertussis, Mycobacte-rium tuberculosis and even rare parasitic agents causingtoxocariasis in school children population [24–26]. In the case ofBordetella pertussis, the infective agent adheres to multiplesites on the respiratory mucosa and causes hypersecretion andepithelial damage [26].

A practical point of note in this category of chronic cough isthat many parents do not realize the frequency with which viralinfections occur in toddlers when they first go to a child carefacility (about every 3 weeks on average). These children havechronic infective rhinitis, cough vigorously, but are well andreassurance of the family is all that is needed [27]. Cough linc-tuses are useless but many parents will not be satisfied until amedication is prescribed. Probably the best way to handle thissituation is to reassure parents that these children require notreatment, get better with time and have normal long-termlung function.

Cough variant asthmaIn the past year, there has been a lot of speculation about therelation of chronic cough and asthma. The term cough vari-ant asthma was first applied in 1972 to adults with chroniccough and increased bronchial responsiveness [28]. It was pre-viously thought to be associated with atopy in children,although more recent studies have suggested that atopy is nomore common in this group of children than in the generalpopulation [29]. The value of bronchial hyper-responsiveness todiagnose cough variant asthma in children has been questioned

since viral infections can also cause a transient increase inbronchial responsiveness [30]. Children with chronic coughwithout wheeze due to cough variant asthma should exhibitairway inflammation similar to known atopic asthmatics whohave increased eosiniphils and mast cells in their bronchoal-veolar lavage fluid, as well as increased concentrations ofeosinophil catonic protein and histamine [31,32]. Fitch andcolleagues, however, have shown that only a minority of chil-dren with chronic unexplained cough have asthmatic-typeairway inflammation [23].

The prevalence of asthma has risen exponentially over the lasttwo decades, and to a large extent this is because of childrenand adults being labeled as cough variant asthmatics. As withmany aspects in medicine, there is controversy with proponentsof cough variant asthma advocating that children with coughalone should be treated as having asthma and detractors statingthat a child with asthma must have a wheezy component [9]. Ina recent study, Thomson and colleagues demonstrated thatchildren with isolated cough were just as likely to have beendiagnosed with asthma as children with cough and wheeze [6].As a result, over-diagnosis of asthma and the overuse of asthmatreatments with significant side effects is common in childrenwith persistent cough.

Therefore, it is important to instigate strict criteria whendiagnosing asthma in children. This can be challenging, how-ever, because of the difficulties associated with young age, com-pliance and collaboration. Bush states that the diagnosis ofcough variant asthma should only be made in older childrenafter variable airflow obstruction and response to bronchodila-tor has been demonstrated physiologically. In younger children,rational diagnostic criteria are an abnormally increased cough,with no evidence of any nonasthma diagnosis, a clear-cutresponse to a therapeutic trial of asthma medication, usuallymoderate dose inhaled corticosteroids and relapse on stoppingmedications with second response to recommencing them [27].

From a practical point of view, when faced with a child withchronic cough without wheeze, an idea would be to ask thechild to keep a peak flow diary over a number of weeks (if thechild is old enough and able to collaborate). This will allow thedemonstration of significant variability consistent with a diag-nosis of asthma, even if audible wheeze has never been heard bythe parents or pediatrician.

Psychogenic coughPsychogenic cough, also known as habit cough, or honk cough,is a well-documented entity in the pediatric and adolescentpopulation. It is usually a loud, stereotyped, barking noise,quite unlike any organic cough. It is irritating to all around andcontinues unabated until the child falls asleep, unlike anycough associated with any other underlying disease. In the ado-lescent population, vocal cord dysfunction can present aschronic cough and can be easily documented via the typicalinspiratory loop of the flow–volume curve. There are casereports in the literature associating chronic cough with Gillesde la Tourette syndrome, however, it may not be appropriate to

Box 2. Physical signs in chronic cough.

• Signs of weight loss, wasted buttocks, decreased musculature or decreased subcutaneous tissue and failure to thrive

• Digital clubbing, peripheral or central cyanosis, laboured breathing

• Evidence of eczema or allergic rhinitis (e.g., allergic salute)

• Enlarged tonsils or adenoids, nasal polyps, chronic suppurative otitis media

• Chest deformity, barrel chest, Harrison's sulci, pectus carinatum

• Stridor, wheeze, bilateral or unilateral

• Peripheral edema, hepatosplenomegaly, ascites or other evidence of malabsorption

• Evidence of chronic lung disease or cor pulmonale

• Anthropometric parameters suggesting prematurity or expremature state

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treat a child’s cough with haloperidol, unless a psychiatristdeems it necessary based on other symptoms that the childexperiences [33]. Symptoms may respond to breathing tech-niques, or even more unusual methods of distraction [34]. Inthis case, the key question that will guide the clinician to thediagnosis of psychogenic cough is ‘what happens when thechild falls asleep?’

Systemic causes of coughThere is a wide list of diseases that can cause chronic cough inchildhood. Examples of these conditions would be gastro-esophageal reflux [35,36]; uvula, tracheal and laryngeal structuraldisorders [37–39]; paranasal sinus abnormalities [40]; tuberculosis[41]; and immune deficiencies, endobronchial foreign body,postnasal drip, cystic fibrosis and bronchiectasis [24].

Given the variety of diseases that can cause chronic cough, itis not difficult to understand why a significant percentage of

children get misdiagnosed. The implications of misdiagnosiscan be significant since most of these children have a treatablecause for their cough, which goes unrecognized. Instead, theyget treated with various antitussive agents, some of which havesignificant side effects. Nowadays, when medicolegal issues areencountered more and more frequently in everyday practice,it would be highly inappropriate to go on treating a child’slaryngeal cyst with a cough linctus.

Practically speaking, the best way of managing a child with achronic cough is to start with a detailed history aiming toenlighten symptoms that can go unrecognized, continue with adetailed physical examination targeting certain signs (althoughmost children will not have any physical signs), and thenorganize certain investigations, bearing in mind the findingsand the differential diagnoses. In the boxes below, we includekey questions to ask (BOX 1), specific signs to seek (BOX 2), inves-tigations to consider (BOX 3) and differential diagnoses to bearin mind (BOX 4).

Environmental causes of coughA large amount of research has been presently extrapolatedin order to assess the morbidity associated with air pollu-tion. The Institute for Social and Preventive medicine inSwitzerland concludes that there is an increased impact onthe prevalence of chronic cough in children from environ-mental tobacco smoke exposure [42]. When dealing with achild with chronic cough, every attempt should be made toevaluate any environmental triggers, and whenever feasible,attempt to eliminate them. These triggers may includesmoke from cigarettes or open fires, strong perfumes, abrupttemperature changes, exposure to furry pets, house dustmite or various foods. It is necessary to emphasize theimportance of these factors to the parents in order toincrease their level of compliance.

Expert opinionCough is universal in childhood but most children are normal[27]. The initial approach to a child with recurrent coughshould be a carefully taken history, followed by a thoroughphysical examination. This will enable the clinician to detectabnormalities, target further investigations carefully, only ifneeded and decide on treatment options individually.

In the majority of children, however, a more conservativeapproach is recommended [49]. Chronic cough can cause sig-nificant distress to the whole family, therefore, it is importantto explore the reasons for parental anxiety and reassure theparents that a watch and wait policy is probably all that isneeded. At the same time, it is necessary to detect environ-mental exacerbating factors and attempt to eliminate them.If, however, asthma medications are tried, the child should bereviewed after 2 weeks and the medication discontinued ifthere was no effect on cough. If the cough has ceased, how-ever, it should be explained to the parents that the cough hasprobably stopped irrespective of the medication given andthat it would be advisable to discontinue all treatment.

Box 3. Investigations in chronic cough.

• Structural airway disease: consider fiberoptic bronchoscopy, barium swallow to exclude a vascular ring

• Gastroesophageal reflux: consider pH monitoring, barium swallow, video fluoroscopy, milk scan

• Upper airway disease: consider sleep study, polysomnography, radiologic evaluation of sinuses (although rarely useful and debatable)

• Cystic fibrosis: consider sweat test, genotype, stool elastase, nasal potentials

• Primary ciliary dyskinesia: consider saccharin test, electron microscopy of nasal mucosa, cilia biopsy

• Tuberculosis or other infections: consider Mantoux test, bronchoscopy and lavage, high resolution computed tomography of the chest, serological testing according to speculated infectious agent, gastric lavage, induced sputum analysis

• Immunodeficiencies: consider immunoglobulins and subclasses, lymphocyte and neutrophil function tests, lymphocyte subsets, high resolution computed tomography of the chest to detect bronchiectasis

• Pulmonary hypertension: consider cardiac echocardiogram, cardiac catheterization

• Asthma: consider adenosine, histamine or metacholine challenge, exercise challenge, exhaled nitric oxide measurement, induced sputum analysis

• Endobronchial disease: foreign body, tumour, papiloma

• Bronchopulmonary dysplasia, cor pulmonale

• Interstitial lung disease: rheumatic disorders, cytotoxic drugs, irradiation

• Aspiration: altered swallow, weak cough reflex, neuromuscular disease, gastroesophageal reflux

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Five-year viewAs it has already been mentioned, children suffering from per-sistent cough frequently get overtreated with unnecessary medi-cations, some of which can have significant side effects. Anti-tussives, cough suppressants, antihistamines, decongestants andantiasthma medications are some of the categories of drugs thathave been tried for this condition. When treating chroniccough, the aim should be to unravel the underlying conditionand treat it accordingly. Most children with chronic nonspecificcough get better with time and do not need any medication.

There are, however, some conditions where cough treatmentmight help. Cough enhancers might be beneficial in childrensuffering from neuromuscular diseases or cerebral palsy byincreasing the effectiveness of muco-ciliary airway clearanceand enhancing the cough reflex, thus preventing aspiration andameliorating suppurative lung disease [43].

Currently available cough suppressants (e.g., opiates anddextromethorphan) act on the central cough pathway. Theyhave significant side effects, however, (e.g., respiratory depres-sion, drowsiness and constipation) which limit their use. Hulland colleagues have attempted to optimize the delivery of dex-tromethorphan and improve its effectiveness on a given dose[44]. The optimized formulation resulted in an increase in therate and extent of dextromethorphan absorption, an earlieronset of effect and greater overall antitussive action for a givendose compared with the conventional liquid oral formulation.

Chung and colleagues have recently published a review ofnew active antitussive agents, which act either centrally orperipherally [45]. New opioids, such as k- and d-receptor ago-nists have been developed in addition to nonopioid, nocice-ptin. Neurokinin, bradykinin and vanilloid receptor antago-nists may be beneficial by blocking effects of tachykinins and

sensory nerve activation. Local anesthetics and blockers ofsodium-dependent channels can act as inhibitors of thecough reflex. These new agents appear promising, however,large-scale clinical trials are required before they can besafely administered.

As children with persistent cough get overdiagnosed withasthma, they get treated very frequently with antiasthma med-ications. Chang and colleagues have composed a randomized,double-blind, placebo-controlled trial to test the hypothesisthat inhaled salbutamol or beclomethasone will reduce thefrequency of cough in children with recurrent cough [46].They concluded that most children with recurrent coughwithout other evidence of airway obstruction do not haveasthma and neither inhaled salbutamol, nor beclomethasoneis beneficial.

More recently, research has turned towards a newer genera-tion of antiasthma medications, the leukotriene receptor antag-onists. Multiple clinical trials have demonstrated the ability ofleukotriene modifiers to improve symptoms, pulmonary func-tion and bronchial hyperresponsiveness in chronic asthma, aswell as in exercise- and aspirin-induced asthma [47]. Research isunderway to establish their effectiveness in cough-variantasthma but so far no studies have been published to evaluatethe antitussive effects of leukotriene receptor antagonists innonasthmatic recurrent cough [48].

Box 4. Differential diagnosis of chronic cough.

• Nonspecific cough: postinfectious, cough variant asthma, functional disorders (psychogenic cough, habitual cough, tics)

• Bronchiectasis or other lung disorder: cystic fibrosis, ciliary dyskinesia, immunodeficiency, congenital lung lesion, missed foreign body, tracheoeosophageal fistula H type

• Infective causes: tuberculosis, other mycobacteria, mycoses

• Upper airway disease: adenotonsillar hypertrophy, postnasal drip, sinusitis, rhinitis

• Structural bronchial disease: tracheomalacia, bronchomalacia, vascular rings, cartilage rings, cysts

• Endobronchial disease: foreign body, tumour, papiloma

• Bronchopulmonary dysplasia, cor pulmonale

• Interstitial lung disease: rheumatic disorders, cytotoxic drugs, irradiation

• Aspiration: altered swallow, weak cough reflex, neuromuscular disease, gastroesophageal reflux

Key issues

• Recurrent cough in children is a very common symptom of respiratory disease, however most children who cough have normal pulmonary function.

• With regards to the pathophysiology of cough, the tuning of the cough reflex seems to be dependent upon three receptors: rapidly adapting fibers (RAR), C- fibers and Aδ- nociceptors.

• The brain stem initiates the activation of a complex neural network which transmits expiratory motor drive to spinal motoneurones via medullary premotor neurons.

• Apart from the brain stem, the cortex has been shown recently to play a significant role in the modulation of the urge to cough.

• With regards to treatment, new active antitussive agents are presented.

• Overtreatment with antiasthma medications is highlighted and should be discouraged.

• The antitussive effect of leukotriene receptor antagonists in nonasthmatic recurrent cough needs to be evaluated.

• The initial approach to a child with recurrent cough should be a carefully taken history and thorough physical examination with the aid of specifically targeted investigations.

• In the majority of children, a watch and wait policy is all that is required.

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• Designed to test the pharmacokinetic and clinical pharmacological characteristics of a formulation of dextromethorphan to reduce first-pass metabolism.

45 Chung KF, Chang AB. Therapy for cough:active agents. Pulm. Pharmacol. Ther. 15, 335–338 (2002).

•• Presents novel antitussive agents, some of which act centrally, or peripherally.

46 Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson CF. A randomized, placebo-controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch. Dis. Child. 79, 6–11 (1998).

•• Concludes that most children with recurrent cough without other evidence of airway obstruction, do not have asthma and neither salbutamol nor beclomethasone is beneficial.

47 Horwitz RJ, NcGill KA, Busse WW. The role of leukotriene modifiers in the treatment of asthma. Am. J. Respir. Crit. Care Med. 157, 1363–1371 (1998).

48 Dicpinigaitis PV. Antitussive effects of leukotriene receptor antagonists. Eur. Respir. Rev. 85, 275–277 (2002).

•• The role of leukotriene receptor antagonists in the chronic treatment of cough-variant asthma awaits definition.

49 Chang AB, Asher MI. A review of cough in children. J. Asthma 38, 299–309 (2001).

•• The article presents broad clinical guidelines on the approach to childhood cough and discusses current controversies of the management of cough in children.

Affiliations• DA Kafetzis, MD

Associate Professor of Paediatrics,University of Athens, Second Department of Paediatrics, ‘P and A Kiriakou’ Children’s Hospital, Thevon and Livadias St,GR 11527, Athens, GreeceTel.: +30 210 772 6349kafetzis@ath.forthnet.gr

• IM Velissariou, MD

Research Fellow in Paediatric Infectious DiseasesUniversity of Athens, Second Department of Paediatrics, ‘P and A Kiriakou’ Children’s Hospital, Thevon and Livadias StGR 11527, Athens, GreeceTel.: +30 694 486 3635jane_vel@hotmail.com.