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The physiology of cough
PAEDIATRIC RESPIRATORY REVIEWS (2006) 7, 2–8
MINI-SYMPOSIUM: COUGH
The physiology of cough Anne B. Chang* Department of Respiratory Medicine, Royal Children’s 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 reflected in the occurrence of pulmonary problems when cough is inefficient. Cough efficiency 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 significantly (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. ß 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 significantly 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 definition * Tel.: +61 7 36369149; fax: +61 7 36361958. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 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 difficult to identify. The inspiratory phase consists of inhaling a variable amount of air that serves to lengthen the expiratory muscles, optimising the length–tension 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 (30–50 ms) supramaximal expiratory flow8 (up to 12 l/s in adults, also termed the ‘cough spike’) followed by lower (3–4 l/s) expiratory flows 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 action’9,10 rather than from the direct effects of air flow. The sound of a cough is due to vibration of the large airways and laryngeal structures during turbulent flow in expiration,11,12 and is said to be individualised akin to individualised voice. Laminar airflow, 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 flexible 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 reflex, also known as ‘expiratory reflex’) 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-
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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 significantly in recent years, although much of the work is based on animal models and may have limited applicability to humans due to significant 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 reviews15,16,18–22 for in-depth aspects of cough-related neurophysiology. A summary of the current data is grossly simplified and summarised here. The cough pathway can be artificially 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 influenced by a bidirectional feedback loop but this has not yet been
Figure 1 Concepts adapted from review articles16,22,28,41 grossly simplified 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.
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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 reflex). Afferent airway receptors are divided into four broad classes: rapid adapting receptors (RARs), slow adapting receptors, C-fibres and others (nociceptor, distinct cough receptors19). This classification is based on a variety of properties such as adaptation during sustained lung inflations 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 first proposed by Widdicombe,26 was only proved recently.18,19 Generation of action potentials (depolarisation of the terminal membrane) from these receptors are subclassified 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 2.3–4.2% 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 fibres (which reach the epithelium) arise from the jugular ganglion.16 These have different thresholds for different stimuli.16 From these ganglia, the first central nervous system (CNS) synaptic contact of these afferent fibres 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 influence. ‘The brainstem networks generating and modulating the breathing pattern are also involved in producing the motor patterns of reflex cough and other airway defensive reflexes (sneeze, expiration reflex)’.22 The influence 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 reflexive component of cough (the expiratory reflex). The brainstem network interacts
A. B. CHANG
with the efferent pathway, which includes the larynx, respiratory muscles and pelvic sphincters. Without reflexive pelvic activation, incontinence would occur with coughing.
COUGH EFFICIENCY An effective cough is dependent on generation of high linear velocities and interaction between flowing gas and mucus in the airways.7 This is dependent on the integrity of the mechanisms described above. Other physical characteristics also influence cough efficiency, including adequate airway calibre (efficiency decreased in the presence of flow 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 efficiency is reduced.31 This efficiency is related not only to these physical aspects but is also influenced by the feedback loop from the efferent cough pathway to the central cough pathway. Efficiency 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 reflex, 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 reflexes (laryngeal chemoreflex) that undergo maturation resulting in significant differences in swallowing between young children and adults.34 Plasticity (modulation) of the cough reflex 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 reflex 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 reflexes and respiratory control.38–40 Another developmental aspect is the cortical influence41 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
THE PHYSIOLOGY OF COUGH
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would also be related to development. In the physical aspects of cough, children’s 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
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 influence 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 inflammatory and immune responses (eosinophils, interleukin-8, tumour necrosis factor-alpha, eotaxin etc.),44 some of which are
COUGH PHYSIOLOGY IN PATHOLOGICAL STATES Clinical states reflecting pathophysiology of the cough pathway can be divided into: (a) increased (in response Table 1
Mechanisms underlying some cough-related pathology.
Key component of cough pathway
Examples of disease/clinical conditions
Description of pathophysiology and/or associations found in disease process
Increased coughing Peripheral pathway Cough stimuli
Inflammation 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
Cortical control Decreased coughing Cough receptors and vagal nerve
Hypertonic saline use, viral infections Tobacco-smoke exposure, ozone
*
Anxiety, motor or vocal tics
Laryngectomy
Hypercapnia, hypoxia Lignocaine and other similar medications Airway intubation Central pathways
Parkinson’s disease Cerebral palsy (or stroke in adults) Opioid medications
Neutrophilic,50 *eosinophilic,51 +neurogenic,52 *lymphocytic,53 inflammation * 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 fibres and eosinophil proteins), increased NK-1 receptor, decreased expression of M2 muscarinic receptor44 + Ad fibres: alteration in frequency, threshold and firing 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
* 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 fibres 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.
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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 nerves’44 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 inflammation 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
CLINICAL IMPLICATIONS Knowledge of the physiology of cough is clinically relevant. For example, in conditions where cough is inefficient, 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 efficiency, air stacking or mechanical insufflation (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
A. B. CHANG
ACKNOWLEDGMENTS A.B. Chang is funded by a Practitioner Fellowship from the National Health and Medical Research Council, Australia and by the Royal Children’s Hospital Foundation, Brisbane. Dr. McElrea and Dr. van Asperen’s 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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10. Wolff RK, Dolovich MB, Obminski G, Newhouse MT. Effects of exercise and eucapnic hyperventilation on bronchial clearance. J Appl Physiol 1977; 43: 46–50. 11. Korpas J, Sadlonova J, Salat D, Masarova E. The origin of cough sounds. Bull Eur Physiopathol Respir 1987; 23(Suppl 10): 47s–50s. 12. Hashimoto Y, Murata A, Mikami M, Nakamura S, Yamanaka E, Kudoh S. Influence of the rheological properties of airway mucus on cough sound generation. Respirology 2003; 8: 45–51. 13. Nunn JF. Non-elastic resistance to gas flow. Applied Respiratory Physiology. London: Butterworths, 1993. pp. 61–89. 14. Korpas J, Widdicombe JG, Vrabec M. Influence of simulated mucus on cough sounds in cats. Respir Med 1993; 87: 49–54. 15. Canning BJ. Anatomy and neurophysiology of the cough reflex. Chest 2006; in press. 16. Undem BJ, Carr MJ, Kollarik M. Physiology and plasticity of putative cough fibres in the Guinea pig. Pulmon Pharmacol Ther 2002; 15: 193– 198. 17. Smith JA, Calverley PMA. Cough in chronic obstructive pulmonary disease. Pulmon Pharmacol Ther 2004; 17: 393–398. 18. Mazzone SB. Sensory regulation of the cough reflex. Pulmon Pharmacol Ther 2004; 17: 361–368. 19. Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, Undem BJ. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 2004; 557: 543–558. 20. Smith AD, Cowan JO, Filsell S et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med 2004; 169: 473–478. 21. Lee MG, Kollarik M, Chuaychoo B, Undem BJ. Ionotropic and metabotropic receptor mediated airway sensory nerve activation. Pulmon Pharmacol Ther 2004; 17: 355–360. 22. Shannon R, Baekey DM, Morris KF, Nuding SC, Segers LS, Lindsey BG. Production of reflex cough by brainstem respiratory networks. Pulmon Pharmacol Ther 2004; 17: 369–376. 23. Karlsson J-A, Sant’Ambrogio G, Widdicombe J. Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1988; 65: 1007–1023. 24. Hansson L, Wollmer P, Dahlback M, Karlsson J-A. Regional sensitivity of human airways to capsaicin-induced cough. Am Rev Respir Dis 1992; 145: 1191–1195. 25. Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J 1995; 8: 1193–1202. 26. Widdicombe J. The race to explore the pathway to cough: who won the silver medal? Am J Respir Crit Care Med 2001; 164: 729–730. 27. Bloustine S, Langston L, Miller T. Ear-cough (Arnold’s) reflex. Ann Otol Rhinol Laryngol 1976; 85: 406–407. 28. Bonham AC, Sekizawa S, Joad JP. Plasticity of central mechanisms for cough. Pulmon Pharmacol Ther 2004; 17: 453–457. 29. Smaldone GC, Messina MS. Flow limitation, cough, and patterns of aerosol deposition in humans. J Appl Physiol 1985; 59: 515– 520. 30. Young S, Abdul-Sattar N, Caric D. Glottic closure and high flows are not essential for productive cough. Bull Eur Physiopathol Respir 1987; 23(Suppl 10): 11s–17s. 31. Fontana GA, Pantaleo T, Lavorini F, Mutolo D, Polli G, Pistolesi M. Coughing in laryngectomized patients. Am J Respir Crit Care Med 1999; 160: 1578–1584. 32. Bennett WD, Foster WM, Chapman WF. Cough-enhanced mucus clearance in the normal lung. J Appl Physiol 1990; 69: 1670– 1675. 33. Hay AD, Schroeder K, Fahey T. Acute cough in children. BMJ 2004; 328: 1062. 34. Thach BT. Maturation and transformation of reflexes that protect the laryngeal airway from liquid aspiration from fetal to adult life. Am J Med 2001; 111(Suppl 8A): 69S–77S.
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35. Gleeson M, Cripps AW, Clancy RL. Modifiers of the human mucosal immune system. Immunol Cell Biol 1995; 73: 397–404. 36. Smart JM, Suphioglu C, Kemp AS, Age-related. T cell responses to allergens in childhood. Clin Exp Allergy 2003; 33: 317–324. 37. Brenner DJ. Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative. Pediatr Radiol 2002; 32: 228– 231. 38. Nunn JF. Applied Respiratory Physiology. London: Butterworths, 1993. 39. Polgar G, Weng T. The functional development of the respiratory system from the period of gestation to adulthood. Am Rev Respir Dis 1979; 120: 625–695. 40. Haddad GG, Abman SH, Chernick V. Basic Mechanisms of Pediatric Respiratory Disease. 2nd ed. Hamilton: BC Decker Inc, 2002. 41. Chang AB. State of the art: cough, cough receptors, and asthma in children. Pediatr Pulmonol 1999; 28: 59–70. 42. Ludviksdottir D, Bjornsson E, Janson C, Boman G. Habitual coughing and its associations with asthma, anxiety, and gastroesophageal reflux. Chest 1996; 109: 1262–1268. 43. Chang AB. Cough: are children really different to adults? Cough 2005; 1–7. 44. Jacoby DB. Pathophysiology of airway viral infections. Pulmon Pharmacol Ther 2004; 17: 333–336. 45. Hu C, Wedde-Beer K, Auais A, Rodriguez MM, Piedimonte G. Nerve growth factor and nerve growth factor receptors in respiratory syncytial virus-infected lungs. Am J Physiol Lung Cell Mol Physiol 2002; 283: L494–L502. 46. Nishino T, Hasegawa R, Ide T, Isono S. Hypercapnia enhances the development of coughing during continuous infusion of water into the pharynx. Am J Respir Crit Care Med 1998; 157: 815–821. 47. Groneberg DA, Niimi A, Dinh QT et al. Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med 2004; 170: 1276–1280. 48. Carr MJ. Plasticity of vagal afferent fibres mediating cough. Pulmon Pharmacol Ther 2004; 17: 447–451. 49. Sivasothy P, Brown L, Smith IE, Shneerson JM. Effect of manually assisted cough and mechanical insufflation on cough flow of normal subjects, patients with chronic obstructive pulmonary disease (COPD), and patients with respiratory muscle weakness. Thorax 2001; 56: 438–444. 50. White AJ, Gompertz S, Bayley DL et al. Resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis. Thorax 2003; 58: 680–685. 51. Brightling CE, Symon FA, Birring SS, Bradding P, Wardlaw AJ, Pavord ID. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax 2003; 58: 528–532. 52. Hamamoto J, Kohrogi H, Kawano O et al. Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs. J Appl Physiol 1997; 82: 738–745. 53. Birring SS, Brightling CE, Symon FA, Barlow SG, Wardlaw AJ, Pavord ID. Idiopathic chronic cough: association with organ specific autoimmune disease and bronchoalveolar lymphocytosis. Thorax 2003; 58: 1066–1070. 54. Shimizu T, Mochizuki H, Morikawa A. Effect of influenza A virus infection on acid-induced cough response in children with asthma. Eur Respir J 1997; 10: 71–74. 55. Chang AB, Phelan PD, Robertson CF. Cough receptor sensitivity in children with acute and non-acute asthma. Thorax 1997; 52: 770–774. 56. Chang AB, Phelan PD, Sawyer SM, Del Brocco S, Robertson CF. Cough sensitivity in children with asthma, recurrent cough, and cystic fibrosis. Arch Dis Child 1997; 77: 331–334. 57. Tatar M, Korpas J, Polacek H, Zahradny V. Changes induced by severe hypoxia in respiratory defence reflexes in anaesthetized cats. Respiration 1986; 49: 114–121.
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58. Adcock JJ, Douglas GJ, Garabette M et al. RSD931, a novel anti-tussive agent acting on airway sensory nerves. Br J Pharmacol 2003; 138: 407– 416. 59. Choudry NB, Fuller RW, Anderson N, Karlsson J-A. Separation of cough and reflex bronchoconstriction by inhaled local anaesthetics. Eur Respir J 1990; 3: 579–583. 60. Tanaka A, Isono S, Ishikawa T, Nishino T. Laryngeal reflex before and after placement of airway interventions: endotracheal
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tube and laryngeal mask airway. Anesthesiology 2005; 102: 20– 25. 61. Fontana GA, Pantaleo T, Lavorini F, Benvenuti F, Gangemi S. Defective motor control of coughing in Parkinson’s disease. Am J Respir Crit Care Med 1998; 158: 458–464. 62. Kamei J. Delta-opioid receptor antagonists as a new concept for central acting antitussive drugs. Pulmon Pharmacol Ther 2002; 15: 235– 240.
MINI-SYMPOSIUM: COUGH
The physiology of cough Anne B. Chang* Department of Respiratory Medicine, Royal Children’s 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 reflected in the occurrence of pulmonary problems when cough is inefficient. Cough efficiency 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 significantly (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. ß 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 significantly 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 definition * Tel.: +61 7 36369149; fax: +61 7 36361958. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 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 difficult to identify. The inspiratory phase consists of inhaling a variable amount of air that serves to lengthen the expiratory muscles, optimising the length–tension 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 (30–50 ms) supramaximal expiratory flow8 (up to 12 l/s in adults, also termed the ‘cough spike’) followed by lower (3–4 l/s) expiratory flows 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 action’9,10 rather than from the direct effects of air flow. The sound of a cough is due to vibration of the large airways and laryngeal structures during turbulent flow in expiration,11,12 and is said to be individualised akin to individualised voice. Laminar airflow, 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 flexible 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 reflex, also known as ‘expiratory reflex’) 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-
3
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 significantly in recent years, although much of the work is based on animal models and may have limited applicability to humans due to significant 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 reviews15,16,18–22 for in-depth aspects of cough-related neurophysiology. A summary of the current data is grossly simplified and summarised here. The cough pathway can be artificially 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 influenced by a bidirectional feedback loop but this has not yet been
Figure 1 Concepts adapted from review articles16,22,28,41 grossly simplified 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.
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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 reflex). Afferent airway receptors are divided into four broad classes: rapid adapting receptors (RARs), slow adapting receptors, C-fibres and others (nociceptor, distinct cough receptors19). This classification is based on a variety of properties such as adaptation during sustained lung inflations 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 first proposed by Widdicombe,26 was only proved recently.18,19 Generation of action potentials (depolarisation of the terminal membrane) from these receptors are subclassified 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 2.3–4.2% 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 fibres (which reach the epithelium) arise from the jugular ganglion.16 These have different thresholds for different stimuli.16 From these ganglia, the first central nervous system (CNS) synaptic contact of these afferent fibres 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 influence. ‘The brainstem networks generating and modulating the breathing pattern are also involved in producing the motor patterns of reflex cough and other airway defensive reflexes (sneeze, expiration reflex)’.22 The influence 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 reflexive component of cough (the expiratory reflex). The brainstem network interacts
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with the efferent pathway, which includes the larynx, respiratory muscles and pelvic sphincters. Without reflexive pelvic activation, incontinence would occur with coughing.
COUGH EFFICIENCY An effective cough is dependent on generation of high linear velocities and interaction between flowing gas and mucus in the airways.7 This is dependent on the integrity of the mechanisms described above. Other physical characteristics also influence cough efficiency, including adequate airway calibre (efficiency decreased in the presence of flow 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 efficiency is reduced.31 This efficiency is related not only to these physical aspects but is also influenced by the feedback loop from the efferent cough pathway to the central cough pathway. Efficiency 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 reflex, 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 reflexes (laryngeal chemoreflex) that undergo maturation resulting in significant differences in swallowing between young children and adults.34 Plasticity (modulation) of the cough reflex 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 reflex 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 reflexes and respiratory control.38–40 Another developmental aspect is the cortical influence41 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, children’s 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
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 influence 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 inflammatory and immune responses (eosinophils, interleukin-8, tumour necrosis factor-alpha, eotaxin etc.),44 some of which are
COUGH PHYSIOLOGY IN PATHOLOGICAL STATES Clinical states reflecting pathophysiology of the cough pathway can be divided into: (a) increased (in response Table 1
Mechanisms underlying some cough-related pathology.
Key component of cough pathway
Examples of disease/clinical conditions
Description of pathophysiology and/or associations found in disease process
Increased coughing Peripheral pathway Cough stimuli
Inflammation 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
Cortical control Decreased coughing Cough receptors and vagal nerve
Hypertonic saline use, viral infections Tobacco-smoke exposure, ozone
*
Anxiety, motor or vocal tics
Laryngectomy
Hypercapnia, hypoxia Lignocaine and other similar medications Airway intubation Central pathways
Parkinson’s disease Cerebral palsy (or stroke in adults) Opioid medications
Neutrophilic,50 *eosinophilic,51 +neurogenic,52 *lymphocytic,53 inflammation * 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 fibres and eosinophil proteins), increased NK-1 receptor, decreased expression of M2 muscarinic receptor44 + Ad fibres: alteration in frequency, threshold and firing 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
* 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 fibres 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.
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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 nerves’44 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 inflammation 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
CLINICAL IMPLICATIONS Knowledge of the physiology of cough is clinically relevant. For example, in conditions where cough is inefficient, 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 efficiency, air stacking or mechanical insufflation (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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ACKNOWLEDGMENTS A.B. Chang is funded by a Practitioner Fellowship from the National Health and Medical Research Council, Australia and by the Royal Children’s Hospital Foundation, Brisbane. Dr. McElrea and Dr. van Asperen’s 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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