PAEDIATRIC RESPIRATORY REVIEWS (2006) 7, 28

MINI-SYMPOSIUM: COUGH

The physiology of cough

Anne B. Chang*
Department of Respiratory Medicine, Royal Childrens Hospital, Herston Road, Herston, Brisbane, Queensland 4029, Australia
KEYWORDS cough; physiology; children

Summary Cough is comprised of three phases (inspiratory, compressive and expiratory) and serves as a vital defensive mechanism for lung health. It prevents pulmonary aspiration, promotes ciliary activity and clears airway debris. The importance of an intact cough mechanism is reected in the occurrence of pulmonary problems when cough is inefcient. Cough efciency is dependent on physical/mechanical aspects (respiratory muscles, mucus, airway calibre and larynx) and integrity of the neurophysiological pathway of cough. The understanding of the latter has progressed signicantly (albeit mostly in animals) with the discovery of vanniloid receptors (and subtypes) and, more recently, by the characterisation of distinct cough receptors. However, the relative contributions of previously described airway afferents/receptors to cough are still disputed. Plasticity of the peripheral and central afferent pathways in cough has recently been shown to be important in pathological states associated with increased cough. To date, little is known of the developmental aspects of cough. 2005 Elsevier Ltd. All rights reserved.

INTRODUCTION
Cough, the most common symptom seen by general practitioners, has important defensive roles in health and disease. Ineffective cough is associated with respiratory morbidity such as recurrent pneumonia. However, chronic cough can be troublesome. It impairs the quality of life of adults1,2 (no paediatric data) and signicantly worries the parents of coughing children.3,4 Coughs are easily recognisable and, unlike the symptom of wheeze,5 parents are almost as good as clinicians at recognising cough quality (wet/dry) in their children.6 This article summarises the key concepts in cough physiology pertinent to clinical medicine.

COUGH MECHANICS AND SOUNDS

Physiologically, cough has three phases: inspiratory, compressive and expiratory.7 This physiological denition
* Tel.: +61 7 36369149; fax: +61 7 36361958. E-mail address: annechang@ausdoctors.net. 1526-0542/$ see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2005.11.009

appears to be unimportant clinically but is essential in animal studies where cough sounds are non-existent or difcult to identify. The inspiratory phase consists of inhaling a variable amount of air that serves to lengthen the expiratory muscles, optimising the lengthtension relationship. The compressive phase consists of a very brief (200 ms) closure of the glottis to maintain lung volume as intrathoracic pressure builds (up to 300 mmHg in adults) due to isometric contraction of the expiratory muscles against a closed glottis. The expiratory phase starts with opening of the glottis, releasing a brief (3050 ms) supramaximal expiratory ow8 (up to 12 l/s in adults, also termed the cough spike) followed by lower (34 l/s) expiratory ows lasting for a further 200 500 ms.7 Dynamic compression of the airways occurs during the expiratory phase and the high velocity expulsion of gas (air) sweeps airway debris along. Airway debris and secretions are also swept proximally by ciliary activity. Cough enhances mucociliary clearance in healthy individuals as well as those with lung disease.9 In the lung periphery, clearance is likely to occur from the mechanical effect of increased lung movement (generated from cough and hyperventilation) or

THE PHYSIOLOGY OF COUGH a milking action9,10 rather than from the direct effects of air ow. The sound of a cough is due to vibration of the large airways and laryngeal structures during turbulent ow in expiration,11,12 and is said to be individualised akin to individualised voice. Laminar airow, which occurs in smaller airways, is inaudible.13 In different cough sounds such as wet cough and brassy cough, it is not known which generation of the airways is involved nor the amount of secretions needed for the human ear to identify a wet cough. Nevertheless, wet cough in children is related to the amount of secretions in the large airways seen during exible bronchoscopy.6 In an animal model, 0.5 ml of mucus instilled into the trachea of cats altered cough quality; too little mucin had no effect on cough quality and too much mucin impaired breathing.14 Analysis of cough sounds used in research to discriminate lung pathology has no clinical applications to date. Physiologists describe two types of cough: laryngeal (a true reex, also known as expiratory reex) and tracheobronchial. In laryngeal cough, inspiration may be minimal and is initiated in clinical situations when laryngeal receptors are stimulated by aspiration of foreign material. Tracheo-

bronchial cough, on the other hand, is initiated distal to the larynx and can be volitional.

COMPONENTS OF THE COUGH PATHWAY

The knowledge of cough neurophysiology has advanced signicantly in recent years, although much of the work is based on animal models and may have limited applicability to humans due to signicant interspecies differences.15 Furthermore, much of these works were performed in animals in an altered conscious state (e.g. under anaesthesia16) or in vitro.17 Readers are referred to recent reviews15,16,1822 for in-depth aspects of cough-related neurophysiology. A summary of the current data is grossly simplied and summarised here. The cough pathway can be articially compartmentalised (Fig. 1) to facilitate understanding. The afferent (from receptors to the respiratory centre) and efferent arms (from the respiratory centre to the respiratory muscles and larynx) of the cough pathway are likely to be inuenced by a bidirectional feedback loop but this has not yet been

Figure 1 Concepts adapted from review articles16,22,28,41 grossly simplied into a schematic view. Bo t-VRG, Bo tzinger, pre-Bo tzinger and ventral respiratory group; Epi, epithelium; PRG, pontine respiratory group; RAR, rapid adapting receptor; TW, tracheal wall.

A. B. CHANG

clearly established. Receptors involved in cough are terminations of vagal afferents in airway mucosa and submucosa.15,16,18 These afferent receptors have different sensitivity to different stimuli and are unequally distributed in the airways. The larynx and proximal large airways are generally more mechanosensitive and less chemosensitive than the peripheral large airways.23,24 Thus, cough sensitivity and pattern depend on the site and type of stimulation.23,25 Laryngeal receptors are exquisitely mechanosensitive and their stimulation leads to laryngeal cough (an expiratory cough reex). Afferent airway receptors are divided into four broad classes: rapid adapting receptors (RARs), slow adapting receptors, C-bres and others (nociceptor, distinct cough receptors19). This classication is based on a variety of properties such as adaptation during sustained lung inations and conduction velocity.15,18 The relative contribution of each subtype to cough in humans is still under debate. The existence of distinct cough receptors, widely assumed to be present and rst proposed by Widdicombe,26 was only proved recently.18,19 Generation of action potentials (depolarisation of the terminal membrane) from these receptors are subclassied into ionotropic receptors (cause generator potentials by acting on ligand-gated ion channels) and metabotropic receptors (act indirectly on ligand-gated ion channels via G-protein-coupled receptors). Well-recognised cough stimuli such as capsaicin act through an ionotropic receptor (e.g. vanniloid receptors such as TRPV1).21 Since all afferent receptors are vagally mediated, cough can only be elicited by stimulation of areas innervated by the vagus nerve.25 This includes extrapulmonary sites (e.g. in the external ear in some people, as the auricular branch of the vagus nerve is present in the external ear in 2.34.2% of people27). Via the vagus nerve, the signal reaches the jugular and nodose ganglions, which have different embryological origins. The majority of RARs (which do not reach epithelium) arise from neurons in the nodose ganglion, whereas nociceptors bres (which reach the epithelium) arise from the jugular ganglion.16 These have different thresholds for different stimuli.16 From these ganglia, the rst central nervous system (CNS) synaptic contact of these afferent bres occurs at the nucleus tractus solitaris (NTS).28 Second-order neurons from the NTS have polysynaptic connections with the central cough generator, which is also the respiratory pattern generator.22,28 Hence, the NTS is postulated to be the site of greatest modulatory inuence. The brainstem networks generating and modulating the breathing pattern are also involved in producing the motor patterns of reex cough and other airway defensive reexes (sneeze, expiration reex).22 The inuence of sleep states on cough is likely to occur through the central network. The dynamic and complex brainstem network is also subject to modulation including cortical modulation. Hence, some cough can be voluntarily initiated and suppressed but there is also a reexive component of cough (the expiratory reex). The brainstem network interacts

with the efferent pathway, which includes the larynx, respiratory muscles and pelvic sphincters. Without reexive pelvic activation, incontinence would occur with coughing.

COUGH EFFICIENCY
An effective cough is dependent on generation of high linear velocities and interaction between owing gas and mucus in the airways.7 This is dependent on the integrity of the mechanisms described above. Other physical characteristics also inuence cough efciency, including adequate airway calibre (efciency decreased in the presence of ow limitation,29 e.g. severe malacia), mucus properties (sputum tenacity, adhesiveness, water content etc.)7 and respiratory muscle strength.7 When the larynx is taken out of play (e.g. tracheostomy), cough is still effective30 but its efciency is reduced.31 This efciency is related not only to these physical aspects but is also inuenced by the feedback loop from the efferent cough pathway to the central cough pathway. Efciency of ciliary clearance and expulsion of the debris is also enhanced by exercise and hyperventilation,9,10,32 although cough has been found to be more effective than exercise in total and peripheral mucus clearance in adults with chronic bronchitis.9

DEVELOPMENTAL ASPECTS OF COUGH

The central pathway for cough is a brainstem reex, linked to control of breathing28 which undergoes a maturation process so that the reference values for normal respiratory rate in children are different to adults.33 In early life, cough is related to primitive reexes (laryngeal chemoreex) that undergo maturation resulting in signicant differences in swallowing between young children and adults.34 Plasticity (modulation) of the cough reex has been shown in animals,16,28 although it is unknown if the young have greater plasticity. Other organs directly relevant to the pathology that causes prolonged cough (e.g. systemic and mucosal immune system)35,36 undergo maturation, as do some organs not directly related to cough (e.g. renal system). Thus, one can speculate that the cough reex also has maturational differences. Furthermore, the neurological system of children is more sensitive than adults to certain environmental exposures.37 The distinct differences in respiratory physiology and neurophysiology between young children and adults include maturational differences in airway, respiratory muscle and chest wall structures, sleep characteristics, respiratory reexes and respiratory control.3840 Another developmental aspect is the cortical inuence41 on cough. In adults, chronic cough is associated with anxiety as an independent factor;42 similar data are unavailable in children. However, as psychological characteristics in children are different to adults, one can speculate that the data (at least in young children) relating to cough

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would also be related to development. In the physical aspects of cough, childrens coughs generate smaller electromyogram and acoustic signal strength on cough meters, necessitating an adjustment to these devices if they are to be used in infants and young children. Given these differences, it is not surprising that many clinical aspects of paediatric cough differ to those in adults.43

COUGH PHYSIOLOGY IN PATHOLOGICAL STATES

Clinical states reecting pathophysiology of the cough pathway can be divided into: (a) increased (in response
Table 1 Mechanisms underlying some cough-related pathology. Examples of disease/clinical conditions

to a trigger, e.g. a respiratory infection) or excessive (irritating cough with little physiological value) cough; and (b) decreased cough (Table 1). In conditions related to increased cough, triggers often involve several components of the cough pathway, e.g. tobacco smoke can cause cough through its inuence on cough epithelium (ciliary, globet cells etc.) but also through the central pathway.28 The pathophysiology of cough related to airway viral infections also involves several components of the cough pathway. In the acute phase, viruses change the function of the epithelial cells. This initiates a cascade of inammatory and immune responses (eosinophils, interleukin-8, tumour necrosis factor-alpha, eotaxin etc.),44 some of which are

Key component of cough pathway Increased coughing Peripheral pathway Cough stimuli

Description of pathophysiology and/or associations found in disease process

Inammation or infection Mechano- and chemostimuli

Afferent cough or airway receptors

After infection, cough-dominant asthma, chronic cough

Airway viral infections

Jugular ganglion Central pathway Nucleus tractus solitaries

Hypertonic saline use, viral infections Tobacco-smoke exposure, ozone

Neutrophilic,50 *eosinophilic,51 +neurogenic,52 *lymphocytic,53 inammation * Foreign material aspiration, capsaicin cough sensitivity. Mechano- and chemosensitivity unequally distributed in airways24 * Upregulation of cough sensitivity measured by cough sensitivity test54,55 which is only temporally enhanced55,56 * Increased expression of transient receptor potential vanniloid-1 nerves found in bronchial biopsies of adults with chronic cough47 + Increased expression and release of tachykinins (through Ad bres and eosinophil proteins), increased NK-1 receptor, decreased expression of M2 muscarinic receptor44 + Ad bres: alteration in frequency, threshold and ring rates of neurons
+ Changes in substance-P-dependent synaptic excitability and density of transient outward currents and hyperpolarisation-activated currents of subgroup of nucleus tractus solitaris neurons28 ?Altered sensation from primary afferents, ?hormonal effects

Cortical control Decreased coughing Cough receptors and vagal nerve

Anxiety, motor or vocal tics

Laryngectomy

Hypercapnia, hypoxia Lignocaine and other similar medications Airway intubation Central pathways Parkinsons disease Cerebral palsy (or stroke in adults) Opioid medications

* Altered feedback loop resulting in reduction of cough volume acceleration as well as in the intensity of abdominal muscle contractions31 + Downregulation of chemoreceptors (in addition to CNS)57 + Inhibition of discharges in Ad bres originating from airway RARs;58 *Cough and bronchoconstriction effects can be separated59 * Downregulation of receptors possibly related from laryngeal oedema60 * Impaired recruitment of motor units from central control61 * Altered CNS state, ?loss of modulatory processes, ?loss of urge to cough + m-, k- and d-opioid receptors62

RARs, rapid adapting receptors; CNS, central nervous system; NK-1, neurokinin-1. * Refers to work based in humans. + Refers to work based in animals.

A. B. CHANG

tussogenic. Sensory nerve function change also occurs, increasing tachykinins in the lungs.44 Neurokinin-1 receptor expression is increased45 and the decreased activity of neutral endopeptidase further leads to increased airway response to cough-provoking tachykinins. In addition, viruses cause decreased expression of M2 receptors, which normally decrease sensitivity of sensory nerves44 leading to a tussogenic (hypersensitive cough) state. Why and how some of these mechanisms are switched off, whereas others persist (leading to chronic cough), is unknown. It is also unknown if triggers and/or the pathology of acute cough are similar to those for chronic cough. The relationship between cough and upper airway dysfunction is controversial in paediatric patients. The high upper airway (proximal to larynx) is not vagally innervated and hence stimulation of these areas cannot induce cough by a direct mechanism. Using a continuous infusion of 2.5 ml/min of water into the pharynx of well adults, Nishino et al. demonstrated that laryngeal irritation and cough only occurred in the presence of hypercapnia,46 in which regulation of swallowing and breathing is presumably less well co-ordinated. However, whether alterations in cough sensitivity occur due to prolonged stimulation of non-vagally-innervated areas (via the mechanism of bidirectional feedback from polysynaptic connections in the CNS) is unknown. Nasal secretions and cough are more likely to be linked by a common aetiology (infection and/or inammation causing both) or due to direct stimulation of laryngeal cough receptors by secretions. The known mechanisms of these triggers/diseases are summarised in Table 1. As for cough neurophysiology in non-diseased states, the majority of neurophysiology data on pathological cough has been gained from animal studies. However, peripheral aspects of the cough pathway in humans are being increasingly studied using bronchial biopsies.47 Plasticity of both the peripheral48 and central28 cough pathway is a key concept in cough physiology in pathological states. This concept of hypersensitivity of nerve receptors akin to hyperalgesia in pain proposed in the late 1990s41 was demonstrated recently in animals.16

ACKNOWLEDGMENTS
A.B. Chang is funded by a Practitioner Fellowship from the National Health and Medical Research Council, Australia and by the Royal Childrens Hospital Foundation, Brisbane. Dr. McElrea and Dr. van Asperens helpful comments on this manuscript are acknowledged and appreciated.

PRACTICE POINTS
 Cough is an important component for lung health maintenance.  Cough efficiency is dependent on airway characteristics and integrity of the neurophysiology of the cough pathway.  Anti-tussive mediations may be counter productive.  In a coughing illness such as an acute respiratory infection, various mechanisms account for upregulation of the cough reflex.

RESEARCH DIRECTIONS
 Developmental aspects of cough eg does the plasticity of the cough reflex alter with age?  Clinical studies on methods to improve efficiency in children.  Mechanisms of down and up regulation of the cough reflex in children.

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CLINICAL IMPLICATIONS
Knowledge of the physiology of cough is clinically relevant. For example, in conditions where cough is inefcient, recognition of the likelihood of poor mucociliary clearance may prompt the use of other mucociliary clearance techniques. Based on the knowledge that the inspiratory phase of cough is important for cough efciency, air stacking or mechanical insufation (to increase lung volume prior to the compressive phase) has been used in patients with muscle weakness to improve cough effectiveness and mucociliary clearance.49

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