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 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.
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: 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
difficult 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 flow8
(up to 12 l/s in adults, also termed the cough spike) followed
by lower (34 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 action9,10 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-

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
reviews15,16,1822 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. Bot-VRG, Botzinger, pre-Botzinger
and ventral respiratory group; Epi, epithelium; PRG, pontine respiratory group; RAR, rapid adapting receptor; TW, tracheal wall.

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 2.34.2%
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 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.3840 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

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

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

Parkinsons 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.

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 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 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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