PRIMER

Cough hypersensitivity and

chronic cough
Kian Fan Chung 1,2, Lorcan McGarvey3, Woo-​Jung Song 4, Anne B. Chang 5,6
,
Kefang Lai7, Brendan J. Canning8, Surinder S. Birring9, Jaclyn A. Smith10 and
Stuart B. Mazzone 11 ✉
Abstract | Chronic cough is globally prevalent across all age groups. This disorder is challenging
to treat because many pulmonary and extrapulmonary conditions can present with chronic
cough, and cough can also be present without any identifiable underlying cause or be refractory
to therapies that improve associated conditions. Most patients with chronic cough have cough
hypersensitivity, which is characterized by increased neural responsivity to a range of stimuli that
affect the airways and lungs, and other tissues innervated by common nerve supplies. Cough
hypersensitivity presents as excessive coughing often in response to relatively innocuous stimuli,
causing significant psychophysical morbidity and affecting patients’ quality of life. Understanding
of the mechanisms that contribute to cough hypersensitivity and excessive coughing in different
patient populations and across the lifespan is advancing and has contributed to the development
of new therapies for chronic cough in adults. Owing to differences in the pathology, the organs
involved and individual patient factors, treatment of chronic cough is progressing towards a
personalized approach, and, in the future, novel ways to endotype patients with cough may prove
valuable in management.

Cough is one of the most common symptoms for which levels of thermal, mechanical or chemical exposure11.
people present to primary care and is a chief complaint The considerable burden of persistent chronic cough
for patients seeking medical attention in respiratory or has led to an appreciation of cough hypersensitivity as
allergy specialist clinics1,2. The definition of chronic a distinct clinical entity in adults. Distinct mechanisms
cough in clinical guidelines is cough persisting for that involve both peripheral and central neural path-
>8 weeks in adults and >4 weeks in children3–5; how- ways have a role in this hypersensitivity, and have moti-
ever, in many epidemiological studies, chronic cough is vated advances in cough suppressant (antitussive) drug
defined as cough that lasts >3 months6. The definition of discovery12. The aetiology and management of chronic
chronic cough is guided by expert opinion, as definitive cough differs in children from that in adults, and the
clinical criteria to distinguish acute cough from chronic relevance of cough hypersensitivity as an underpinning
cough are lacking. mechanism in children remains unclear.
In practice, chronic cough is often a long-​lasting This Primer discusses the global prevalence and
and burdensome condition, persisting for several mechanisms of cough, with a focus on the most common
years and sometimes decades for a substantial number causes of cough hypersensitivity. This Primer provides
of patients, despite exhaustive medical intervention7–9. an overview of the current state-​of-​the-​art recommenda-
Many pulmonary and some extrapulmonary diseases tions for cough diagnosis and management, and presents
and disorders can present with chronic cough, making a viewpoint of recent advances in cough hypersensitivity
diagnosis and treatment challenging. Moreover, 40% of and chronic cough that may have a future effect on
adults with chronic cough referred for specialist evalu- treatment.
ation have no identified cause (known as unexplained
chronic cough) or have persistent cough despite optimal Epidemiology
treatment of conditions associated with chronic cough Chronic cough affects ~10% of adults in various gen-
✉e-​mail: [Link]@ (known as refractory chronic cough)10. eral populations13. The prevalence of chronic cough
[Link] Chronic cough of any aetiology in adults is widely is higher in Europe, America and Australia (10–20%)
[Link] believed to reflect a hypersensitivity condition, char- than in Asia (<5%)13 (Fig. 1). In the general population
s41572-022-00370-​w acterized by coughing that is often triggered by low of Copenhagen, Denmark, the prevalence of chronic

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Author addresses cough and are potential risk factors for chronic cough22,23.
Biological traits, such as age or sex hormonal status,
1
Experimental Studies Unit, National Heart & Lung Institute, Imperial College London, also interact with these triggers in developing chronic
London, UK. cough24–26. However, the definition of chronic cough used
2
Department of Respiratory Medicine, Royal Brompton and Harefield Hospital, London, UK. in population-​based studies is based on cough duration,
3
Wellcome-​Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry
does not differentiate protective cough responses from
and Biomedical Sciences, Queen’s University Belfast, Belfast, UK.
4
Department of Allergy and Clinical Immunology, University of Ulsan College of Medicine, hypersensitivity and does not represent the key nature
Asan Medical Center, Seoul, Korea. that defines cough as the disease, such as the impact,
5
Australian Centre for Health Services Innovation, Queensland’s University of Technology severity and hypersensitivity, and thus the epide­
and Department of Respiratory and Sleep Medicine, Queensland Children’s Hospital, mio­logical research definition should be refined for
Brisbane, Queensland, Australia. elucidating the risk factors6,27–29.
6
Division of Child Health, Menzies School of Health Research, Darwin, Northern Territory,
Australia. Patient factors. Age and sex underlie the burden and
7
The First Affiliated Hospital of Guangzhou Medical University, National Center of prevalence of chronic cough, although the mechanisms
Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State that underlie this association are unknown. In one sur-
Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health,
vey, two-​thirds of the patients presenting with chronic
Guangzhou, China.
8
Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA. cough to specialist clinics were female, and the most
9
Centre for Human & Applied Physiological Sciences, School of Basic & Medical common decade for presentation was 60–69 years24. The
Biosciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK. high proportion of women in specialist clinics may be
10
Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, due to greater effects of cough in older women, as they
University of Manchester, Manchester, UK. have more frequent complications such as stress urinary
11
Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia. incontinence30. Another possible explanation for the
increased prevalence of chronic cough in female adults
cough was 4% overall, with a prevalence of 3% in is that women have a more sensitive cough reflex than
never-​smokers, 4% in former smokers and 8% in current men, as demonstrated by inhalation capsaicin cough
smokers14. Moreover, the prevalence of chronic cough in reflex sensitivity tests25 or that women have greater acti-
a meta-​analysis was 6.2% in adults in China15. vation of the somatosensory brain cortex in response to
The incidence of chronic cough ranges from 1.2 to capsaicin inhalation than men24.
5.7 per 100 person-​years in population-​based studies Notably, sex differences in capsaicin cough reflex
of adults ≥45 years of age in Belgium and Canada16,17. sensitivity are not observed during prepubertal ages26,31,
However, no global or continental-​level data are availa- suggesting that mechanisms that predispose to hyper-
ble. The longitudinal epidemiology of chronic cough and sensitivity do not occur in children. In support of this,
cough hypersensitivity is largely unknown, but cough the prevalence of Arnold’s nerve cough reflex (evoked
may persist for longer than 5 years despite treatment by mechanical stimulation of vagal fibres innervating the
in adults with chronic cough8,9,18. Certain patient traits, external auditory canal) is 11-​fold higher in adults with
such as comorbid obesity, gastro-​oesophageal reflux chronic cough than in healthy adults and those with res-
disease (GERD) and genetic background are associ- piratory disease without cough, indicative of vagal hyper-
ated with longer disease duration but warrant further sensitivity, whereas prevalence of this reflex is similar in
investigation9,18. children with chronic cough and in healthy children32.
The prevalence of chronic cough in children is not as Other populations can have unique cough epidemi-
clearly defined as in adults. Overall, prevalence of chronic ology. For example, in China, most patients with chronic
cough in children ranges from 1.1% to 21.9%19,20; the cough are ~40 years of age, with an equal sex proportion,
difference in these estimates is likely due to differences despite the enhanced cough sensitivity in women24,33.
in the method of data collection, definition of chronic Relatively few studies have identified specific genetic
cough used, setting studied (such as high-​income ver- risk factors for chronic cough. Identified genetic risk fac­
sus low-​income country) and age of children studied tors include mutations in TRPV1 (encodes transient recep-
(Table 1). Few data are available on the incidence of tor potential cation channel subfamily V member 1)34
chronic cough following an acute respiratory infection; and TAC2R (encodes neurokinin 2 receptor)35 and
one study21 reported that 171 of the 839 children (20.4%, a RFC1 (encodes replication factor complex subunit 1)
95% CI 17.7–23.1) recruited from the emergency depart- expansion associated with sensory neuropathy36,37.
ment of a specialist children’s hospital had chronic cough
(defined as cough for >4 weeks) but 63 of these children Clinical factors. Cigarette smokers are three times more
already had chronic cough at presentation. Thus, the likely to report chronic cough than never-​smokers and
incidence is likely 108 of 839 (12.9%). Of the children ex-​smokers, and the cough is usually due to chronic
with chronic cough who were reviewed by paediatric pul- bronchitis38. However, most patients in cough specialist
monologists, 30.8% had a new and serious chronic lung clinic are non-​smokers.
disease and 47.0% had protracted bacterial bronchitis21. Infection with respiratory viruses (such as rhino­
virus or severe acute respiratory syndrome coronavirus
Risk factors 2 (SARS-​CoV-2)) is a common cause of acute cough and
Various environmental and host factors, such as respira- is usually self-​limiting, but post-​infectious cough may
tory infection, air pollutants, occupational irritants, aller- persist for months in some individuals. For example,
gens, eosinophils or refluxate, can sensitize and trigger 10–20% of patients after SARS-​CoV-2 infection39 and

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Prevalence of chronic cough

in adult populations (%)
0–5
5–10
10–15
15–20
>20
Data not available

Fig. 1 | Global prevalence of chronic cough. Map showing the results of a meta-​analysis of 90 published studies assessing
the regional pooled prevalence of chronic cough in adult populations. Reprinted with permission from ref.13, ERS.

8.5–43% of patients after H1N1 influenza40,41 have per- Chronic cough is widely recognized as an adverse effect
sistent cough, which may be related to cough hypersensi- of angiotensin-​converting enzyme (ACE) inhibitors,
tivity. The viruses that are likely to induce post-​infectious which are prescribed as anti-​hypertensives or for heart
cough are unclear. Infection with Bordetella pertussis failure53.
may also be associated with a prolonged and debilitat- Rare causes of chronic cough in adults account for
ing cough (whooping cough), which can be difficult to <15% of cases and commonly include protracted bac-
treat42,43. terial bronchitis, somatic cough syndrome (which is
Common pulmonary causes of chronic cough in more common in children), diffuse panbronchiolitis
non-​smokers with normal chest X-​rays and spiro­ and obstructive sleep apnoea syndrome54. However,
metry are corticosteroid-​responsive cough such as only limited high-​quality evidence is available regard-
eosinophilic conditions, including cough variant ing their prevalence and clinical implications in adults
asthma, non-​asthmatic eosinophilic bronchitis and with chronic cough. Less common extrapulmonary
atopic cough 44,45. Extrapulmonary conditions are conditions include atypical cardiac failure and cardiac
also commonly associated with cough, including arrhythmias and tracheobronchomalacia (Table 2).
GERD and upper airway cough syndrome (previously
called ‘post-​nasal drip syndrome’) due to rhinitis or Environmental factors. Occupational irritants such as
rhinosinusitis22. Indeed, cough variant asthma, eosin- fumes, gases, cleaning products or dust55 may cause
ophilic bronchitis, upper airway cough syndrome and cough, either by triggering cough reflex or by induc-
GERD account for 51–92% of cases of adult chronic ing oxidative stress and eosinophilic inflammation56–58.
cough globally45,46. However, the existence of upper However, the precise effect of environmental factors
airway cough syndrome as a distinct clinical entity has on chronic cough remains elusive. Air pollution is an
been debated and is proposed to reflect generalized important risk factor for chronic cough particularly
airway inflammation resulting from asthma or airway in East Asia where air pollution levels are high15,59,60.
reflux4, potentially underestimating the true incidence At the population level, the annual level of fine par-
of cough in these conditions. Of note, the proportion of ticulate matter with a diameter of ≤2.5 μm (known as
patients with chronic cough with GERD is lower in PM2.5) is higher in Asian countries than in European or
East Asia than in Europe and the USA45,46. Chronic North American countries, but the prevalence of chronic
obstructive pulmonary disease (COPD), bronchiecta- cough is lower61. Data from within-​population studies
sis, lung cancer, interstitial lung disease and obstructive suggest that the degree of air pollution is associated with
sleep apnoea are also associated with chronic cough and the incidence of chronic cough or bronchitis62,63, high-
cough hypersensitivity but chest radiology and/or lung lighting potential host–environmental interactions in
physiology measurements are usually abnormal47–52. developing chronic cough.

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Table 1 | Prevalence of chronic cough in children

Setting Chronic cough definition Age, years (n) Prevalence, % Ref.
Cross-​sectional survey of Seattle middle Chronic productive cough: “daily cough 11–15 (2,397) 7.2 (all), 3.4 (excluding 220

school students using written and video productive of phlegm for at least 3 months out those with asthma)
respiratory-​symptom questionnaires of the year”
Two groups of children: one enrolled from “In the last 12 months has your child had a cough 5–7 (511) 10.4 221

public schools within a 10 km radius of Royal that lasted more than 3 weeks and was not
Prince Alfred Hospital, Sydney, Australia, and associated with a cold or flu?” 8–11 (654) 9.6
another enrolled from six schools in Nigeria; 8–11 (566) 5.1
both questionnaire based
Suva City schoolchildren, Fiji; questionnaire “Has this child coughed mucus on most mornings Mean 9.6 (2,173) 21.9 20

based in the last 12 months”

12 centres in northern, central and southern Cough or phlegm for ≥4 days a week (in the 6–7 (20,016); 6.8 222

Italy; self-​administered questionnaires absence of a cold) for ≥1 month per year 13–14 (13,616)
completed by parents
Whole-​population prospective study Parent-​reported daily wet cough for ≥4 weeks Median 3.5 (203) 13 223

undertaken in four remote communities with clinician researcher confirmation (with

in north Western Australia physiotherapist using non-​invasive techniques
to elicit a cough if necessary)
18 districts of six cities in Liaoning province, Cough on most days (>4 days per week) for as 3–12 (11,860) 9.5 (persistent cough) 60

China; Chinese language translation of the long as 3 months per year, either together with
Epidemiologic Standardization Project or separately from colds
Questionnaire of American Thoracic Society;
self-​completed by parents Seemed congested or brought up phlegm or 4.6 (persistent phlegm)
mucus from the chest on most days (>4 days per
week) for as long as 3 months per year, either
together with or separately from colds
Children who participated in CAPS and “Does your child usually have a cough when they Mean 7.1 (804) 8 224

BOLD-​Chikhwawa studies, Chikhwawa don’t have a cold?” and “Are there months in
District, rural Malawi; electronic questionnaire which they cough on most days?”
in Chichewa, the local language
Five villages in Dehlon Block of Ludhiana, Cough lasting for >3 weeks 1–15 (2,275) 1.1 19

Punjab, India
Follow-​up of a birth cohort in which parents Score of ≥3 to question “How often has this child Mean 1.1 (1,064) 6.7 225

completed questionnaires or survey in various been bothered by cough?” at least 2–3 episodes
years Mean 2.1 (945) 4.5
in the past year
Mean 5.8 (1,024) 12.2
Mean 8.1 (841) 12.1
Mean 10.4 (956) 12.4

Mechanisms/pathophysiology Cough in these species can be reliably induced with

The sensorimotor phenomenology of cough (Box 1) sug- stimuli that also evoke cough in humans64, and, as such,
gests the involvement of a complex suite of neurobiologi- studies in these models have identified mechanisms that
cal processes involving the peripheral nervous system, lead to sensory nerve activation, normal cough induc-
brainstem and higher brain in this phenomenon. Cough tion and neural pathways that mediate reflex coughing65.
can be a reflex or can be under volitional and cognitive However, the use of animals to model the development
control. It is typically initiated by irritant stimuli that and maintenance of cough hypersensitivity in humans
activate airway mucosal sensory nerve fibres. These has been debated64 as animals used to study pathological
fibres convey this information to brainstem circuitry, cough are largely devoid of any spontaneous coughing,
which alters the normal breathing cycle to a cough motor requiring cough induction with an inhaled stimulus to
pattern. Volitional and cognitively controlled cough is assess the hypersensitivity. Moreover, although reflex
often accompanied by an irritant sensation known as the cough hypersensitivity can be demonstrated in animal
urge to cough. Volitional and cognitive control of cough models, therapies that reverse this hypersensitivity have
and the perception of an urge to cough involve neural mostly not been clinically effective in humans12.
processing in subcortical and cortical brain sites.
Peripheral neurophysiology
Studying cough and cough hypersensitivity In guinea pigs, two peripheral sensory fibre subtypes
Human neurophysiological studies have contributed to can initiate cough when stimulated: thinly myeli-
our understanding of cough and cough hypersensitivity, nated Aδ-​fibre subtype and nociceptive unmyelinated
but they are limited by the types of measurements and C-​fibre subtype65–68 (Fig. 2). The cell bodies of cough Aδ
interventions possible. Detailed mechanistic studies into fibres and C fibres arise from distinct vagal ganglia65,66
cough neurophysiology have, therefore, relied heavily (nodose ganglion for Aδ fibres and jugular ganglion
on laboratory animals, especially guinea pigs and cats. for C fibres), and their peripheral terminations are

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believed to reside predominantly in the major airways chronic cough51. Molecular analyses show differing
(larynx, trachea and large bronchi)65, although termi- patterns of gene expression and novel mechanisms of
nations in the lung parenchyma cannot be discounted, regulation69,70. Aδ-​fibre-​mediated cough is triggered
as several parenchymal lung diseases present with by aspirated particulates, accumulated secretions and

Table 2 | Additional conditions associated with chronic cough in adults and children
Condition Possible mechanism Clinical picture
Obstructive sleep Airway inflammation associated with Presence of nocturnal cough, snoring and nocturnal heartburn. Raised BMI
apnoea excessive snoring, GERD, increased and excessive daytime somnolence in older children or adults. Behavioural
cough reflex sensitivity (cough issues, tonsillar adenohypertrophy and facial abnormality in young children.
hypersensitivity) and tracheobron- Prevalence range 33–68% in patients with confirmed obstructive sleep
chomalacia, a condition in which the apnoea52. CPAP therapy may be effective in alleviating cough52
walls of the trachea and bronchi are
weak, leading to dilation and easy
collapsibility of the airways
Ear diseases or Activation of Arnold’s nerve cough Cough is triggered by mechanical stimulation of the external auditory meatus.
obstructions, including reflex and vagal neuropathy This occurs in 2% of the adult population but in 25% of people with chronic
excessive wax or foreign cough32. Can occasionally be identified as a cause of chronic cough when
body mechanical stimulation of the external auditory meatus is accompanied by
features of cough hypersensitivity such as throat irritation and allotussia226
‘Cardiac cough’: Haemodynamic changes in the Ventricular arrhythmia-​induced cough and of cough syncope may be present
premature ventricular pulmonary circulation, activation of in 5% of cases of ventricular arrhythmia227. Nocturnal cough can be a symptom
contractions, cardiac cardiopulmonary C fibres or effect of patients with cardiac failure and could represent the effect of airway
arrhythmias and heart of pulmonary oedema oedema on cough receptors in large airways or the pressure of enlarged left
failure atrium on cough receptors in airways
Peripheral sensory Genetic mutations and/or nerve A rare autosomal dominant hereditary sensory neuropathy associated with
neuropathy with or pathology leading to altered sensory chronic cough, cough hypersensitivity and gastro-​oesophageal reflux228
without ataxia neuron function
Tracheobronchomalacia Possible problems clearing airway An excessive dynamic airway collapse of the posterior membrane presenting
or expiratory central secretions or changes in mechanical with a seal-​like barking cough caused by excessive vibration of posterior
airway collapse properties of the trachea during tracheal wall. This condition can mimic or coexist with asthma, COPD and
breathing bronchiectasis. This condition is often associated with poor airway clearance
of secretions
Diffuse panbronchiolitis Airway and lung inflammation Chronic cough may be the sole or predominant symptom. Patients can have
normal respiratory function or mild airflow limitation, normal chest X-​ray
findings and mild dilation of the bronchiolar passages and a ‘tree-​in-​bud’
pattern on chest high-​resolution CT. Cough can improve with long-​term
macrolide antibiotic therapy in some patients
Lung and airway Lung cancer causes of cough include A change in cough pattern in a smoker can indicate lung cancer
tumours the direct effect of tumour mass leading
to obstruction, collapse of lung or
pleural or pericardial effusion, treatment
of cancer with thoracic irradiation and
chemo- and/or immunotherapy229
ILDs including Airway and lung inflammation or Cough and dyspnoea are the main presenting features with, often, chronic
interstitial pulmonary activation of cough receptors in fibrosis cough being the main distressing symptom. Other causes of chronic cough
fibrosis and systemic by neuroinflammatory factors need to be excluded such as GERD, obstructive sleep apnoea, emphysema,
sclerosis-​associated ILD lung cancer and asthma. Often accompanied by features of cough
hypersensitivity with an increase in capsaicin cough sensitivity
Somatic cough Tic or habit cough in children (rare Tic cough is a single repetitive cough, of maybe barking/honking character,
syndrome (psychogenic in adults) is possibly anxiety related, usually absent in sleep. DSM-5 diagnostic criteria must be met for a diagnosis
cough) and tic cough whereas somatic cough syndrome could of somatic cough syndrome: “disruption of daily life; excessive thoughts about
(habit cough) be caused by psychological–functional the seriousness of the symptoms, persistent anxiety about health or symptoms,
disorder (transfer of psychological or excessive time and energy devoted to symptoms or health concerns; and
distress into a physical symptom) persistence of symptoms (typically more than six months)”109
Parasitosis Airway and lung eosinophilic Parasitosis such as paragonimiasis, caused by a lung fluke, Paragonimus
inflammation and mechanical westermani, which infects the lungs after eating an infected raw or undercooked
stimulation crab or crayfish, or mammomonogamosis, caused by Mammomonogamus
laryngeus, which inhabits the upper respiratory region in the human trachea,
bronchi or larynx, is a rare but relevant cause in some tropical regions or in
travellers. These disorders can often present as a dry persistent cough with
normal chest X-​rays. Blood eosinophilia is frequent230,231
Hypereosinophilic Airway eosinophilic inflammation with Presents with chronic cough as the sole or predominant symptom,
syndrome or without FIP1L1–PDGFRA fusion gene hypereosinophilia in blood and sputum, and responds well to imatinib118.
and aberrant tyrosine kinase activity
COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th edition;
GERD, gastro-​oesophageal reflux disease; ILD, interstitial lung disease.

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Box 1 | Sensorimotor phenomenology Glutamate (mediated by post-​s ynaptic NMDA

(N-​methyl-​d-​aspartate) receptors)76,77 and, possibly,
• Cough is an observable respiratory event in which the pattern of normal eupneic neurokinin (NK) receptors67,75,78 are involved in cough in
breathing is temporarily altered to allow for a forceful expiration, the normal purpose guinea pigs. Indeed, NMDA and NK1 receptor blockade
of which is to clear the airways of foreign materials, chemicals or secretions. in animals and humans has antitussive actions, support-
• A typical cough consists of three respiratory phases: first, a brief inspiratory phase ing a role for these receptors in cough79,80. In rodents,
to prime the lungs with a volume of air; second, a compression phase characterized brainstem neurons receiving cough sensory inputs
by expiratory muscle contraction against a closed glottis, needed to ramp up
are involved in autonomic, limbic and somatosensory
intrapulmonary pressure; and finally third, the expiratory phase during which the
glottis opens and high-​velocity expiratory airflow occurs233. processing73 (Fig. 2). In humans, functional brain imag-
ing studies have found widely distributed brain activity
• Some types of cough may not include an inspiratory phase, especially during bouts
of repetitive coughing. In events with glottic closure and expiratory effort, without
accompanying inhalation of cough-​evoking stimuli,
preceding inspiration, the event is referred to as an expiration reflex. In the clinic, in primary and secondary sensory cortical areas, and in
expiration reflexes cannot be distinguished from cough as they both produce similar the cingulate, insula and orbitofrontal cortices. This
sounds. The identification of an expiration reflex requires assessment of airflow with activity likely reflects the diverse autonomic responses,
a pneumotachograph in the laboratory. The clinical relevance of the expiration reflex and the affective, hedonic and discriminative sensory
has therefore been difficult to study233. experiences that accompany cough81.
• The induction of cough motor patterning is often linked to a reflex action, initiated by
sensory detection of irritant stimuli in the airways leading to a brainstem-​mediated Peripheral sensitization of cough
activation of cough motor pathways234, in much the same way that painful stimuli Experimental induction of lung inflammation, for exam-
initiate spinal withdrawal reflexes. However, cough can also be a purely volitional act, ple, with allergens or respiratory viruses, in animals and
initiated at will in the absence of any peripheral sensory stimuli. Similarly, voluntary in several airway diseases or treatments in humans,
control can be exerted to behaviourally change the intensity of an evoked cough
is accompanied by alterations in the excitability of the
effort, or to suppress coughing entirely107,235,236.
peripheral terminals of vagal sensory fibres that regulate
• Airway irritation can also give rise to perceivable sensations (such as an itchy or scratchy
cough65 (Fig. 3). For example, impaired metabolism of
throat) referred clinically as the urge to cough. These sensations are thought to provide
an awareness of the presence of irritating airway stimuli, and often contribute as much
bradykinin, a potent activator of vagal C fibres is linked to
to patient morbidity as does cough itself. The urge to cough may be an important coughing in patients using ACE inhibitor antihyperten-
determinant of behavioural cough induction or regulation81,237. sive therapy82. Similarly, excess release and/or impaired
metabolism of ATP is associated with refractory chronic
cough12.
mucosal acidification66, as might happen after aspiration Inflammation can also cause plasticity of airway
of gastric contents. Conversely, C-​fibre-​mediated cough mucosal innervation, including changes in receptors, ion
is triggered by a range of irritant environmental chemi- channels, neurochemistry, fibre density or the cells that
cals and mediators of inflammation or tissue damage65. contribute to fibre excitation65,83,84. For example, patients
Cough challenge studies and histochemical staining with chronic cough had a ~30-​fold increase in cough
of airway biopsy samples suggest that these two cough responsiveness to inhaled capsaicin that was accom-
pathways also exist in humans64,68,71. A combination of panied by an increased density of TRPV1-​expressing
animal and human studies has provided a comprehen- fibres in bronchial biopsy samples85. In accordance with
sive understanding of the functioning of ion channels these data, studies in animal models have demonstrated
and receptors responsible for excitation of cough sensory a central role of upregulated TRP channel expression
fibres12 (Fig. 2). or activity, including TRPV1, TRPA1 and TRPV4,
in development of hypersensitivity to inhaled cough
Central neurophysiology challenges86,87. Of note, however, clinical trials of TRPV1,
In mammals, many vagal sensory neurons terminate in TRPA1 and TRPV4 antagonists have failed to demon-
the nucleus of the solitary tract, an important sensory strate any benefit against natural cough in patients12,87,
processing nucleus in the medulla oblongata65 (Fig. 2). suggesting a disparity between animal and patient studies.
Studies in guinea pigs suggest that the regions involved Animal studies also suggest that neural plasticity
in integrating signals from cough sensory neurons have during pulmonary pathologies may relate to neuroin-
little overlap with other vagal neuronal subtypes that flammation within the vagus nerve or ganglia, character-
innervate the airways and lungs65,72. The paratrigeminal ized by increased inflammatory cell influx, upregulated
nucleus also receives inputs from vagal cough sensory inflammatory gene transcription and the release of
neurons73. Different subtypes of vagal sensory neu- inflammatory molecules from sensory neurons and res-
ron terminate in the nucleus of the solitary tract and ident or infiltrating immune cells88–90. The cause of this
the paratrigeminal nucleus, and neurons from these neuroinflammation is unclear, but likely relates to both
brain regions have differing output connectivity65,72,74,75. peripheral vagal detection of tissue inflammation and
In guinea pigs, cough mediated by jugular C fibres adverse effects of inflammation-​induced persistent fir-
is reduced by targeted lesioning of the paratrigem- ing of action potentials in sensory neurons88,91. Whether
inal nucleus, whereas Aδ-​f ibre-​mediated cough is this occurs in humans is not proven, but is hypothesized
unaffected75. Although precision mapping of sensory as a cause of cough in some patients92.
terminations in the human brainstem is not feasible, Functional interactions between sensory fibre sub-
functional brain imaging studies using stimuli that dif- types in the brainstem can also affect cough. In humans,
ferentially activate nodose and jugular neural pathways mechanical stimulation of the external ear can evoke
support the conservation of this wiring in humans71. coughing (Arnold’s reflex)32, which is attributed to

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activation of the auricular branch of the vagus nerve, are involved. The specific aetiology of cough hyper­
which projects to the paratrigeminal nucleus 74,93. sensitivity and chronic cough likely differs both between
Co-​activation of cough Aδ fibres and C fibres may and within patient groups, indicating that unique cough
induce cough hypersensitivity94, whereas coughing endotypes exist81. However, several general processes are
is inhibited by activation of nasal menthol-​sensitive thought to be important (Fig. 3).
sensory fibres, lung stretch receptors and a subtype of
C fibres innervating the lungs76,95,96. Direct sensitization or activation of cough. In asthma, the
mediators of bronchopulmonary inflammation might
Central sensitization of cough directly affect airway nerve fibre activity (Fig. 3). In some
Airway inflammation in animal models of lung disease patients with asthma, chronic cough is the sole present-
is accompanied by altered synaptic transmission, and ing symptom (known as cough variant asthma), whereas
glial cell mobilization and activation within the nucleus other patients with chronic cough have eosinophilic dis-
of the solitary tract, resulting in elevated inflammatory ease but not asthma, including non-​asthmatic eosino-
mediators in the brainstem, including neurotrophic philic bronchitis and hypereosinophilic syndrome117,118.
factors (NGF, BDNF and GDNF) and cytokines (IL-1β, Whether different inflammatory processes contribute to
IL-6 and TNF)97–100. These processes are expected to con- cough across this spectrum of patients is unclear (Box 2).
tribute to cough hypersensitivity via amplifying inputs In patients with GERD, chronic cough could occur
from cough sensory fibres. Consistent with this, upregu­ directly through refluxate stimulating vagal sensory
lated cough network activity in the midbrain has been fibres in the larynx and airways. However, studying this
demonstrated in patients with cough hypersensitivity101, theory is difficult as the detection of laryngopharyngeal
in regions reportedly involved in the development of reflux is technically challenging with no objective meas-
other sensory hypersensitivities102,103. ures for validation119,120, and detection of microaspiration
In humans, cough and the urge to cough are highly through pepsin or bile acids in saliva, sputum or airway
responsive to placebo104,105. The mechanisms of this phe- samples may not be reliable121. Of note, pepsin levels in
nomenon are comparable to those of placebo analgesia patients with chronic cough are not different from those
and involve recruitment of a descending neural path- in healthy controls122–124. Gaseous reflux might also be
way enacting opioid-​dependent suppression of sensory important in chronic cough, but supportive evidence is
processing in the brainstem105,106. lacking. In patients with upper airway cough syndrome,
Cough in humans can be voluntarily induced (or inflammation or mucus from the nose or sinuses may
enhanced) and suppressed through higher brain motor extend or drip down the pharyngeal wall to the larynx
control pathways107,108. In some patients, especially and activate cough sensory fibres. However, although
children, behavioural coughing (somatic cough syn- many patients with chronic cough complain of a sen-
drome) may be the primary cause of chronic cough109. sation of post-​nasal drip, there is a paucity of research
Volitional cough suppression involves a brain network exploring the relevance of these processes125.
important for general motor response inhibition107,110,111.
Patients with refractory chronic cough have attenuated Indirect facilitation of cough. Direct stimulation of the
volitional cough suppression112,113 and impaired engage- oesophagus or nose rarely evokes coughing. However,
ment of this cough inhibition network101. Cough and activating extrapulmonary sensory fibres can act syn-
related brain activity are also modulated by acute pain- ergistically with cough sensory fibres to produce cough
ful stimuli applied to the skin86,114, via an extension of hypersensitivity65,126–128 (Fig. 3). Oesophageal acid instil-
the conditioned pain modulation (CPM) phenomenon lation, for example, via a naso-​oesophageal catheter,
whereby noxious stimuli applied to one part of the body sensitizes cough evoked by inhaled capsaicin in healthy
inhibit the processing of noxious stimuli applied else- volunteers and causes coughing in patients with chronic
where. CPM of cough is also reduced in patients with cough129,130, while application of capsaicin to the nose of
refractory chronic cough114. These observations suggest healthy volunteers sensitizes cough, and nasal menthol
that the pathophysiology of refractory chronic cough inhibits coughing95,131. Coughing follows reflux events
involves altered efficacy of multiple central cough sup- in patients with chronic cough more often than would
pression processes. Components of these inhibitory be expected by chance alone132–134, of which both acid
systems that regulate cough use the inhibitory neuro- and non-​acid reflux events are equally likely to precede
transmitter GABA, and GABA receptor agonists mod- coughing whereas reflux events extending to the prox-
ify evoked coughing in animals and in humans115,116. imal oesophagus are not more likely to precede cough-
Patients with COPD do not have altered volitional cough ing than distal events. These observations suggest that
suppression112, suggesting that distinct neural endotypes reflux, mucus or inflammatory mediators need not reach
contribute to chronic cough81. the airways to modulate coughing.

Cough in common diseases Diagnosis, screening and prevention

Chronic cough in adults is commonly associated with Initial evaluation of patients with chronic cough gen-
asthma, non-​asthmatic eosinophilic bronchitis, GERD, erally occurs in primary care, where treatment is com-
upper airway conditions (including nasal and sinus menced in those with symptoms, clinical signs and/or
disease) and laryngeal dysfunction46. However, chronic investigations that point to one or more potential under-
cough does not occur in all patients with these diseases, lying causes. Referral to secondary care specialists often
suggesting that additional pathophysiological processes occurs for more detailed investigation in those with an

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Cerebrum

Cingulate,
orbitofrontal and
prefrontal cortices

4 Somatosensory cortex

Medial and lateral thalamus

Insula cortex

Amygdala
5

Nucleus of the solitary tract

Medulla oblongata
Paratrigeminal nucleus

Respiratory Na+
centres
Unknown receptor Mechanical

Nav1.8 Nav1.7 H+
TRPV1
Capsaicin

Particulate matter, Inflammatory mediators TRPA1 AITC

mucus and aspirate and irritant chemicals
TRPM8 Menthol
2 Vagal cough
sensory nerve P2X3 ATP
Laryngeal fibre terminal

P2X2/3 ATP
1
Tracheal
ASICs H+
Na +

K+ B2 BK
Cl–

Bronchial TRKA NGF

NKCC1 CLC
PGR PGs

Cl–

Lung

Jugular Nodose Jugular neuron Nodose neuron Both nodose and

pathway pathway specific specific jugular neurons

elusive cause of cough and in those who do not respond persistent cough despite detailed evaluation and further
to treatment in primary care. Referrals are typically to treatment trials in secondary care can be referred to spe-
pulmonary specialists, but may also be to allergists, cialist cough clinics. These clinics review the patients’
ear, nose and throat specialists or gastroenterologists, work-​up to ensure optimal treatment of comorbid condi-
depending on the clinical presentation. Adults with tions that might be driving cough. In adults, attendance
multiple comorbid conditions can be referred to multi- at a specialist cough clinic is often required to confirm
ple specialities, making the patient journey from diag- a diagnosis of refractory cough or unexplained chronic
nosis to assessment and treatment long. Patients with cough, to use therapies that are of benefit in this patient

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◀ Fig. 2 | Neural pathways and mechanisms that contribute to the generation of cough. to known tussive stimuli such as smoke, fumes and
(1) Vagal sensory neurons that are involved in cough innervate the larynx, trachea and bleach11,120. Another common symptom of cough hyper-
main bronchi and, possibly, the lung parenchyma (blue and green dashed lines). Vagal Aδ sensitivity is the presence of an uncontrollable urge to
fibres (whose cell bodies reside in the nodose ganglia) are activated by mechanical cough. Sensations in the larynx (laryngeal paraesthesia)
stimuli (such as inhaled particulate matter, mucus and aspirated gastric contents)
or chest such as tickle, itch or irritation can trigger
and protons whereas vagal C fibres (whose cell bodies reside in the jugular ganglia)
are activated by irritant chemicals and inflammatory mediators. (2) Vagal fibres involved
coughing and can be more bothersome than the cough
in cough express several ion channels and receptors needed for transduction of diverse itself137. The presence of triggers and sensory symptoms
sensory stimuli and the formation, conduction and regulation of action potentials and may be the only feature to suggest the diagnosis of cough
(3) project to brainstem nuclei to coordinate cough motor patterning. (4) Distinct networks hypersensitivity. Although sensory symptoms are pres-
in the higher brain are involved in the behavioural regulation of cough, encoding of ent in most adults with chronic cough, <5% report no
the urge to cough and for cognitive and affective processing. (5) Central mechanisms triggers or urge to cough138. Many patients with chronic
allow for volitional and cognitive modulation of cough through top-​down regulation of cough, in addition to showing signs of cough hyper-
brainstem processing (black dashed lines). AITC, allyl isothiocyanate; ASICs, acid sensing sensitivity, also display laryngeal hypersensitivity139.
ion channel subtypes; B2, bradykinin type 2 receptor; CLC, chloride channel subtypes; Laryngeal hypersensitivity and dysfunction often pres-
H+, protons/acid; Nav, voltage-​gated sodium channel subtypes; NGF, nerve growth factor;
ent with chronic cough that is associated with vocal
NKCC1, sodium (Na+) potassium (K+) chloride (Cl−) co-​transporter; P2X, purinergic receptor
subtypes; PG, prostaglandin; PGR, prostaglandin receptor; TrkA, tyrosine receptor
cord dysfunction, muscle tension dysphonia and globus
kinase A; TRP, transient receptor potential cation channel. (a sensation of a ‘lump’ in the throat (Box 3)).

Diagnostic work-​up
group and often to provide opportunities for patients to Recommendations for the evaluation of adults with
participate in clinical research including trials of novel chronic cough (Fig. 4) are based on the anatomical diag-
therapies. However, the provision of such services varies nostic protocol first proposed more than 40 years ago125
substantially between countries. and founded on the principle that structures innervated
by vagal sensory fibres represent potential sites for
Clinical characteristics generation of chronic cough3,140. This remains a useful
Cough is an explosive effort associated with a character- approach as it can assist with identifying possible treat-
istic sound (Box 1). The distinct quality of the sound can able conditions in some patients. Any comorbid condi-
be characterized, for example, wet cough (moist, loose, tions involving these structures are initially presumed
productive or rattling) or dry (barking or hoarse). Wet to be the cause of cough, recognizing that treatment of
chronic cough is thought to be associated with diagno- the presumed cause does not always improve the cough.
ses characterized by mucus production such as chronic Consequently, initial clinical assessment, investigations
bronchitis, COPD and bronchiectasis. Although clini- and trials of therapy tend to be focused on asthma,
cians can distinguish reliably wet from dry cough, the GERD and upper airway conditions (notably rhinitis,
ability to diagnose the cause of cough from sound is rhinosinusitis). A clinical history, focused on cough
poor; only 34% of cases in one case series135. In some characteristics, associated sensations (such as urge to
patients, two or more distinct types of cough can coexist, cough and need to clear throat), common cough trig-
for example, a wet and dry cough. In the clinic, the fre- gers, concomitant symptoms, combined with physical
quency of cough sounds can be counted and the inten- examination, represent the first important steps in eval-
sity of individual cough efforts measured136. However, uation of a patient with chronic cough3,140. Concomitant
patients seldom describe the frequency of cough and symptoms associated with gastro-​oesophageal reflux,
are more likely to describe clusters of cough or bouts, and rhinosinusitis may indicate the causes of chronic
cough intensity and cough triggers, typically providing cough, but a reliance solely on symptoms to guide man-
subjective accounts of when they occur and how much agement may be misleading. For example, the presence
it bothers them. The pattern of chronic cough may show of upper airway symptoms may reflect only co-​existent
waxing and waning over weeks or months. rhinitis or rhinosinusitis, and the absence of heartburn
Adults with chronic cough also frequently report does not exclude reflux as the cause of the cough3,141.
throat clearing. Throat clearing, like cough, is thought to Clinical findings are frequently unremarkable in patients
be an action to clear an unpleasant sensation or irritation referred with chronic cough but finger clubbing, evi-
and may represent an aspect of laryngeal dysfunction dence of inflamed and/or obstructed nasal passages or
in chronic cough. Throat clearing may also result from the presence of wheeze or crackles on chest ausculta-
the feeling of mucus stuck at the back of the throat that tion should inform consequent investigations and treat-
needs to be cleared, leading to mucus being swallowed. ment. Chest radiography and spirometry are mandatory
Throat clearing may be part of the spectrum of cough for patients undergoing assessment for chronic cough3.
events but whether its presence is associated with spe- Measurement of markers of type 2 inflammation, such as
cific diagnoses is not known. Whether patients distin- fractional exhaled nitric oxide (FeNO) or sputum eosin-
guish throat clearing from cough, and the effect of this ophil count, may be useful in the early stage of work-​ups
on patients’ perception of their morbidity is unknown. of patients with chronic cough. Additional tests such as
Adults with chronic cough often display characteristic chest CT, polysomnography and bronchoscopy should
signs of cough hypersensitivity. Clinically this presents be requested depending on the physician’s review of the
as allotussia, with patients reporting cough triggered by case as set out in Supplementary Table 1.
innocuous stimuli such as talking, eating and perfumes, To help identify the underlying cause of chronic
and/or hypertussia, a heightened cough sensitivity cough in children, paediatricians use the basic constructs

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of cough characterization, pointers (such as traits) and clinics145 and primary care144. Further details of the pae-
red flags (Fig. 5). These concepts are useful in current diatric diagnostic protocols are contained in the current
clinical practice, evidenced by calculation of likelihood guidelines3,143.
ratios142 and incorporation of these facets in paediatric
cough algorithms143,144. Using cough algorithms to man- Cough assessment tools
age paediatric chronic cough is efficacious in improving Several validated tools are available to assess cough in
clinical outcomes, demonstrated in cohort studies145, clinical practice (Supplementary Box 1). Subjective assess-
randomized controlled trials (RCTs) based in specialist ments of cough evaluate the patient’s perspective and

Possible cortical reorganization,

altered sensory perception and/or
cognitive responses to airway inputs

Altered midbrain
processing
4

3
Synergistic convergent
Altered descending and sensory inputs, synaptic
inhibitory modulation plasticity and possible
neuroinflammation

Sensitization and excessive activation

of vagal sensory fibres, terminal 2
sprouting, phenotypic plasticity and
possible neuroinflammation

Trigeminal
nerve

Arnold’s
nerve
1

Nasal
Bronchopulmonary disease
nerves

Tongue
Lung
diseases Laryngeal nerves

Gastro-oesophageal
reflux disease

Oesophageal
nerves

Fig. 3 | Peripheral and central processes contributing to cough hyper­ hypersensitivity have (3) increased activity in midbrain areas, and
sensitivity. (1) Preclinical studies have described potential mechanisms that (4) a reduced ability to suppress coughing owing to a failure to recruit
affect vagal sensory nerve fibres that are driven by the inflammatory descending brain networks that subserve cough suppression. (5) Patients
pathology of the underlying diseases and potentially reversed by with chronic cough have a range of effects in the cognitive domain,
disease-​specific therapy. (2) Functional synergy may also exist between suggestive of altered cortical processing of airway sensory information.
sensory neurons innervating the various tissues shown. These interactions Drugs that target vagal sensory neurons and inhibit their activity,
likely occur at the level of the brainstem, where convergence of vagal neuromodulatory drugs that target brain processes involved in maintaining
and/or trigeminal inputs leads to enhanced cough sensitivity. Peripheral hypersensitive states, and speech and language therapy aimed at improving
organ pathologies have also been shown to alter synaptic efficacy in the cough control, are all clinically useful antitussive options for patients with
brainstem, indicative of state of central sensitization. Patients with cough troublesome cough.

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Box 2 | Cough in asthma and related disorders They are often not useful for assessing the efficacy of
treatment as they are not predictive of a reduction in
• Cough is a common symptom of asthma. Patients with less well-​controlled asthma coughing in patients149. Although patients with cough
than those with well-​controlled asthma usually cough more frequently238, and bron- have significantly lower thresholds for coughing during
choconstriction and allergen exposure are known to sensitize and/or provoke challenge tests compared with healthy individuals, the
coughing in people with asthma239,240. However, in the laboratory, bronchoconstriction
ranges can overlap, limiting their diagnostic potential150.
and cough pathways can be separately inhibited241,242, and the severity of cough does
not always reflect asthma severity. Some patients with well-​controlled asthma may Improving the sensitivity and specificity of cough chal-
experience chronic cough. Chronic cough is the primary presenting symptom in lenge tests might be possible by standardizing equipment,
patients with cough variant asthma238, while in the paediatric literature isolated protocols and analysis methods151.
cough is rarely asthma143.
• Patients with classical asthma have heightened responses to inhaled irritants such as Screening and prevention
capsaicin compared with healthy controls, although not to the same degree as those Screening for chronic cough is not carried out in clini-
presenting with chronic cough240,243. The mechanisms leading to this remain elusive. cal practice. How screening could be done and whether
Airway nerve density and neuronal branching are increased in bronchoscopy samples it would lead to clinical benefit is unclear. Screening
obtained from patients with classical asthma, like those seen in patients with chronic patients with chronic respiratory disease may be ben-
cough without asthma84,244. eficial as cough is often overlooked during clinical
• The precise mechanisms that underlie why some patients develop cough variant evaluation. Moreover, early identification may improve
asthma as opposed to other asthma phenotypes is unclear, and few studies have the quality of life (QOL) of patients and possibly avoid
compared cough variant asthma with other phenotypes. Sputum eosinophilia might over-​treatment by specifically targeting cough. One
be less in cough variant asthma than in typical asthma, and patients with cough
simple screening method is a numerical rating scale
variant asthma have normal ventilation function or less severe impairment of lung
function245,246. However, patients with non-​asthmatic eosinophilic bronchitis, without
that assesses cough severity and ascertains the duration
variable airway obstruction or hyper-​responsiveness characteristic of asthma, also of cough. Screening the general population could iden-
present with chronic cough247. tify patients with respiratory disorders such as COPD,
• The localization of mast cells within airway smooth muscle in patients with asthma asthma, lung cancer and smoking-​related chronic bron-
but not in patients with non-​asthmatic eosinophilic bronchitis has been proposed chitis at an earlier stage. The most important diagnosis is
as an explanation for the lack of bronchial hyper-​responsiveness in non-​asthmatic that of lung cancer, where development of a cough may
eosinophilic bronchitis. However, as other histological features are similar, it is unclear be the first symptom, particularly in a smoker.
why patients with non-​asthmatic eosinophilic bronchitis present with chronic cough Whether non-​smoking-​related chronic cough is pre-
without airway obstruction and hyper-​responsiveness248. The difference in airway ventable is unknown. A greater understanding of the
function observed in subjects with eosinophilic bronchitis and asthma could be due mechanism of cough, particularly cough hypersensitivity,
to differences in mediator (such as prostaglandin E2 (ref.249)) production in the airways. is needed.
Eosinophils may interact with airway sensory nerve fibres in people with asthma
and promote increased airway sensory fibre density, nerve remodelling and airway
hyper-​reactivity244, while no relationship between eosinophils and increased nerve
Management
fibre density was noted in patients with chronic cough without asthma84. The management of patients with chronic cough can
be prolonged and complex, especially in patients with
multiple comorbidities requiring treatment and when
include cough severity, intensity, effects on health-​related the cough may ultimately be refractory to such inter-
quality of life (HRQOL) and triggers and symptoms sug- ventions. Therefore, management includes treatment of
gestive of cough hypersensitivity. Objective assessments comorbid conditions that are potentially driving chronic
of cough measure cough frequency with sound or physi- cough and therapies directed at cough hypersensitivity
ological measures (electromyography (EMG), airflow or in patients with refractory or unexplained cough.
chest wall movement), intensity and the sensitivity of the
cough reflex. Objective measures are important to ensure Disease-​specific therapy
that measurements are specific to the disease and not For many adults with chronic cough, treatment of com­
influenced by comorbid conditions or traits such as anx- orbid asthma, GERD or nasal disease (upper airway
iety and depression. The objective assessment of cough is cough syndrome) improves their cough. However, few
largely confined to research and clinical trial use because RCTs have assessed the efficacy of treatments compared
the tools involve time-​consuming analysis, are expensive, with placebo in reducing cough in those with these
and their clinical usefulness has not been established. The conditions.
relationship between objective and subjective measures
of cough is moderate at best146, suggesting that subjective Asthma. Several RCTs have assessed the efficacy of
and objective measures assess unique aspects of cough and asthma therapies in patients with asthma and chronic
should be viewed as complementary and equally valuable cough, but few trials have been performed in the past
tools for evaluation of patients. decade, so more recent inhaled therapies are poorly
Cough monitoring tools have been useful to evaluate represented44. The CHEST and European Respiratory
the efficacy of cough medicines, owing to the smaller Society guidelines suggest increasing inhaled corticos-
sample size required for studies than for subjective tools. teroid dose and considering trials of leukotriene inhib-
Moreover, monitoring tools address the preference of itors and β-​agonists in those for whom the treatment
some medicines regulatory agencies to include objective response to inhaled corticosteroids is incomplete, on
end points in clinical trials147. Cough reflex sensitivity the basis of evidence obtained in classical asthma3,44. The
tests have been used extensively in preclinical mecha- use of inhaled corticosteroid is considered the first-​line
nistic studies and for drug development and dosing148. treatment in adults with cough variant asthma. Of note,

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the efficacy of inhaled therapies for asthma in patients (a peripherally acting GABAB agonist with fewer adverse
with chronic cough can be subverted if the inhaled treat- effects) did not reduce cough frequency in patients with
ment evokes coughing. In this situation, a short course refractory chronic cough in a RCT. Laparoscopic fun-
of oral prednisolone can be the simplest means of assess- doplication, a keyhole surgical procedure whereby the
ing the response of chronic coughing to asthma therapy. upper part of the stomach is wrapped around the lower
In children, chronic cough should not be attributed to oesophagus so as to prevent the reflux of acid from the
asthma unless other symptoms or signs are present152, stomach into the oesophagus, in patients with GERD
and cough in paediatric asthma should not be regarded and chronic cough is rarely indicated owing to lim-
as a marker of severity. ited evidence for efficacy and high risk of long-​term
complications.
GERD. Treatments for GERD include proton pump The management of children with GERD is depend-
inhibitors (PPIs, which reduce the acidity of refluxate), ent on age and disease severity. Acid-​suppressive therapy
histamine (H2) receptor blockers (which have a similar, should not be used solely for chronic cough in children
but more prolonged, effect to PPIs) and lifestyle meas- with GERD and chronic cough157. Also, treatment of
ures such as weight loss, elevating the head of the bed children with chronic cough is dependent on their age,
and avoidance of eating before bedtime. Small RCTs of feeding regimen and symptoms. PPIs and H2 receptor
acid-​suppressing therapy (PPIs and H2 receptor block- antagonists should not be used for longer than 4–8 weeks
ers) in patients with chronic cough have been performed in paediatric patients, regardless of effectiveness, without
but did not report positive results; a pooled analysis of further evaluation157. Should they prove to be success-
these data suggests that adults with acid reflux on 24 h ful in controlling the cough, they can be continued for
pH monitoring or symptoms of heartburn are most longer periods, although the guidelines for managing
likely to experience benefit, which is now reflected in paediatric GERD recommend a gastroscopy with bio­
clinical guidelines4,141,153. Observational data support psies and other tests to confirm anatomy and exclude
this approach, but response rates were low (28%) even in other causes by histology of the biopsy samples158.
patients with chronic cough who reported heartburn154.
Treatments for non-​acid reflux are limited. Promotility Upper airway cough syndrome. The treatment of
agents (such as the dopamine antagonists metoclopr- patients with chronic cough and nasal disease is stand-
amide and domperidone) can be prescribed only for ard care for the diagnosed nasal condition. Allergic or
short-​term use owing to their adverse effects and lack nonallergic rhinitis is treated with nasal corticosteroids,
of evidence of efficacy in reflux-​related chronic cough. first or second generation and intranasal antihistamines,
Macrolide antibiotics promote gastric emptying, but decongestants and, if sinusitis is present, antibiotics. The
small studies in patients with refractory chronic cough potential role of nasal surgery in patients with chronic
failed to show benefit155,156. Baclofen, a GABAB agonist, cough is unclear159,160. Clinical trials evaluating the
blocks relaxation of the lower oesophageal sphincter, effectiveness of targeting concurrent nasal diseases to
and therefore all types of reflux, but has unacceptable control chronic cough are lacking; therefore, predictors
adverse effects for long-​term use, whereas lesogaberan of improvement in chronic cough remain uncertain161.

COPD, bronchiectasis and interstitial lung disease.

Box 3 | Laryngeal hypersensitivity and dysfunction in chronic cough Cough, typically productive, is a common first symptom
of COPD and is usually attributed to cigarette smok-
• Laryngeal hypersensitivity refers to the excessive, abnormal, laryngeal adduction
ing and also as a result of exposure to environmental
of the vocal cords during breathing or exercise, resulting in laryngeal dysfunction250.
pollutants162. Chronic bronchitis is a distinct pheno-
Laryngeal hypersensitivity and dysfunction represent an increased responsiveness
of laryngeal protective reflexes triggered by mechanical or chemical stimuli and are type of COPD and is defined as chronic cough produc-
considered to be part of the cough hypersensitivity syndrome. tive of sputum for 3 months over the course of a year for
• Laryngeal hypersensitivity and dysfunction are present in many patients with chronic two consecutive years163. In established disease, cough
cough and cough hypersensitivity139,251. They are often associated with comorbid is reported in 70% of patients47 and many consider it
post-​nasal drip, rhinosinusitis, gastro-​oesophageal reflux disease and asthma252. to be extremely severe. Moreover, cough is a prominent
• Symptoms are usually localized to the laryngeal area, for example, ‘scratchy’ or ‘tickly’ feature of disease exacerbations and is associated with
feeling of an urge to cough, or sometimes inspiratory stridor of airflow or feeling of adverse clinical outcomes48,164,165. Measuring the sever-
suffocation or difficulty in breathing. ity and burden of cough using symptom-​based ques-
• Laryngeal dysfunction in patients with refractory chronic cough has been associated tionnaires is now recommended in the routine clinical
with paradoxical vocal fold movement manifesting as vocal cord dysfunction with evaluation of patients with COPD166. Chronic cough
episodes of suffocation or difficulty in breathing or laryngospasm253. Other aspects of accompanied by the expectoration of large quantities
laryngeal dysfunction include muscle tension dysphonia that can be revealed during of mucopurulent sputum is a central clinical feature of
vocalization250. bronchiectasis. Typically coughing is much worse dur-
• Investigations include direct laryngoscopic examination of vocal fold motion during ing exacerbations and contributes to impaired health
challenge (using external triggers such as exercise or scents), laryngeal electromyogram status167. Impaired airway clearance, mucus retention
and voice assessment254. and bacterial colonization cause inflammation and lung
• Laryngeal hypersensitivity and dysfunction in patients with chronic refractory cough damage, which contribute to cough severity but are inde-
may respond to speech pathology intervention and behavioural management of pendent of cough reflex sensitivity168. Cough is a com-
cough, with the use of voice therapy techniques and breathing exercises255. Cough mon and disabling symptom in idiopathic pulmonary
neuromodulators such as amitriptyline and gabapentin might also be beneficial.
fibrosis and may be due to inflammatory consequences

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Adult with cough lasting >8 weeks (chronic cough)

History and physical examination focused on cough Review current chest radiology and
characteristics, triggers and clinical features to determine spirometry ± reversibility testing or fractional
evidence for common pulmonary and extrapulmonary causes exhaled nitric oxide measurement

No Any obvious primary pulmonary or

extrapulmonary cause for cough?

Yes

Any remaining investigations Manage according to current

to be undertaken? guidelines and review

Yes

Order investigations, review Yes Cause of cough

Cough resolved? confirmed
with results and treat as
indicated No
No
No Were treatment Optimize treatment and manage adherence
Cough resolved? trials optimal and
patient adherent?
Yes Cause of cough
Cough resolved?
Yes Yes confirmed
No
Cause of cough Refractory chronic No
confirmed cough diagnosis Any remaining investigations to be undertaken?

Yes
Yes No Yes Cause of cough
Cough resolved? Cough resolved? confirmed
No
Consider
• Speech and language intervention
Unexplained • Refer to specialist cough clinic
chronic cough • Trial of neuromodulatory agents or low-dose opiates
diagnosis • Recruit to clinical trial

Fig. 4 | Evaluation and management of chronic cough in adults. A proposed algorithm for the clinical management of
patients with chronic cough, including recommendations for managing difficult-​to-​treat cough. The algorithm was devised
using recommendations contained in existing clinical guidelines and other reference material3,4,10,46,232.

of the fibrosis itself or to comorbid reflux disease. No receptors are also localized to vagal sensory neurons,
medicines are approved to treat cough in these patients, and their activation can suppress sensory fibre activity;
and current consensus is based on limited evidence51. however, unlike oral codeine or intravenous morphine,
inhaled morphine or codeine does not inhibit inhaled
Nonspecific pharmacological therapies capsaicin-​induced cough, arguing against a peripheral
Pharmacological therapies directed at eliminating cough antitussive effect of opiates171. Opiates have no role in
are required in cases in which treatment of comorbid the management of children with chronic cough as they
disease associated with cough is unsuccessful at relieving can cause death143.
coughing, or in those with no obvious cause for a chronic Codeine has a rapid onset of action. Although
cough. These therapies are restricted to use in adults as, widely used, the efficacy of codeine is not supported
for cough management purposes, the age cut-​off for use by clinical studies. Several placebo-​controlled RCTs
in children is usually 14 years. Whether patients other for cough have been published without objective
than those with refractory or unexplained chronic cough cough measurements172,173, and other trials did not
would benefit from adjunct nonspecific cough therapy is report significant benefits of codeine over placebo174,175.
unclear, and controlled trials are needed. Moreover, codeine has several concerns regarding
safety, inter-​individual variability in metabolism and
Opiates. Codeine and morphine are commonly used dependence176, although risk of dependence may be low
antitussives in adult-​based clinical practice and have in those without vulnerability to dependence177. Adverse
antitussive effects via central opioid receptors 169. effects of codeine, such as nausea, constipation, dys-
Accordingly, effective antitussive doses of opiates are pepsia, dizziness or somnolence, occur in up to 50% of
likely to cause sedation. The opioid subtype by which patients and are mostly non-​critical in adults178.
opiates inhibit cough remains debatable, as μ-, κ- or Morphine is ~10 times more potent than codeine
δ-​opioid receptor agonists are all antitussive170. Opioid and is most often considered in patients with severe

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Child with cough lasting >4 weeks (chronic cough)

History and physical examination focused on cough Review current chest radiology and
characteristics and clinical features to determine evidence spirometry or consider fractional
for common pulmonary and extrapulmonary causes exhaled nitric oxide measurement

No
Any obvious primary pulmonary or
extrapulmonary cause for cough?

Assess evidence for non-specific cough Yes

Evaluate tobacco smoke and other pollutants
Manage according to current
guidelines and review

Watch, wait and review in 2 weeks

• Usually postviral cough or acute bronchitis No Yes Cause of cough
• Rarely foreign body asthma, upper airway Cough resolved? confirmed
disorders, adverse reaction to medicines,
functional disorders, pertussis, No
Mycoplasma, GERD or ear problems
If wet cough, treat as
protracted bacterial
No bronchitis with antibiotics
Cough resolved?
Yes
Yes Cause of cough
Cause of cough Cough resolved? confirmed
confirmed
No

Consider and manage as required

Discuss options with parents • Bronchiectasis or recurrent pneumonia
• Aspiration
• Chronic infection
Trial inhaled corticosteroids • Interstitial lung disease
• Airway abnormality
• Cardiac disorder
No • Other less common pulmonary conditions
Cough resolved?

Yes

Cause of cough confirmed

• Asthma or asthma-like Cease therapy

Fig. 5 | Evaluation and management of chronic cough in children. A proposed algorithm for the clinical management of
paediatric patients with chronic cough. The algorithm was devised using recommendations contained in existing clinical
guidelines3,143. GERD, gastro-​oesophageal reflux disease.

intractable cough. One trial demonstrated that low-​dose cough measures and objective cough frequency in
slow-​release morphine therapy was associated with sig- patients with chronic refractory cough; however, clinical
nificant improvements in subjective cough measures benefits were not sustained after treatment cessation. No
(Leicester Cough Questionnaire and daily cough sever- improvement in capsaicin cough reflex sensitivity was
ity scores) in patients with refractory chronic cough179. observed, suggesting a lack of effect on cough hyper-
The most common adverse effects were constipation sensitivity. Of note, some patients do not experience any
and drowsiness. The effects of morphine were mostly improvement in cough with gabapentin. Pregabalin, as
observed within a week, but benefit was observed in an add-​on to speech therapy, significantly improved sub-
<50% of patients. Morphine is associated with sev- jective cough measures compared with speech therapy
eral safety concerns, including respiratory depression, alone at week 14 (ref.184). However, the effects of pregab-
drowsiness and addiction, depending on the dose180. alin on objective cough frequency were not significant.
Gabapentinoids cause common, and sometimes intol-
Gabapentinoids. The GABA derivatives gabapentin erable, adverse effects, including dizziness, disorienta-
and pregabalin are inhibitors of α2δ subunit-​containing tion, confusion, fatigue and blurred vision. The benefit
voltage-​d ependent calcium channels and possibly of long-​term use of gabapentinoids is difficult to predict
NMDA receptors181,182. Gabapentinoids freely pass the given these adverse events.
blood–brain barrier and are commonly used for treat-
ment of seizures and neuropathic pain, although the sites Tricyclic antidepressants. Amitriptyline increases nora­
of central action are poorly understood. In one 10-​week drenergic or serotonergic neurotransmission by block-
RCT183, gabapentin significantly improved subjective ing presynaptic noradrenaline or serotonin transporters

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and has strong binding affinities for α-​adrenergic, his- more prone to dystussia (such as the elderly and patients
tamine (H1) and muscarinic (M1) receptors185. In one with spinal trauma or neurological disease) may be more
randomized trial, treatment with low-​dose amitripty- susceptible to generalized cough suppression by centrally
line at bedtime was significantly more effective than acting nonspecific cough therapies197,198. At least one
codeine and guaifenesin combinatorial treatment in new peripherally acting nonspecific cough therapy in
improvement of subjective measures of cough in those clinical trial (the P2X3 antagonist, gefapixant) has been
with post-​viral cough hypersensitivity186. Moreover, shown not to produce generalized cough suppression at
one small observational study found an improvement therapeutic doses148.
of >50% in 67% of patients with idiopathic (refractory
or unexplained) cough 2–3 months after starting treat- Speech and language therapy
ment; however, only one-​third of patients were still on Speech and language therapy consists of education,
the treatment after 2–3 years, with 53% reporting an cough control and suppression techniques, breath-
improvement of >50%187. A controlled, double-​blind ing exercises, vocal hygiene, hydration strategies and
study of amitriptyline in chronic cough is needed. The counselling 199 (Box 4) . Two randomized controlled
most common adverse effects of amitriptyline are dry studies have evaluated the effectiveness of speech and
mouth, dizziness, headache and somnolence. language therapy for adults with unexplained or refrac-
tory chronic cough. One study200 found that 88% of par-
Nonspecific cough suppression and the risk of dystussia. ticipants in the treatment group showed improvement
Cough has an important protective function in the res- in symptom frequency and severity scores for breath-
piratory tract in healthy individuals and patients as it ing, cough, voice and upper airway symptoms, com-
is needed to expel excessive airway secretions, prevent pared with 14% of participants in the placebo group.
aspiration and protect against inhaled irritant stimuli, Another multicentre RCT201 found an improvement in
such as smoke. An ideal cough suppressant, therefore, cough-​specific QOL and a reduction in cough frequency
would reduce unwanted, excessive coughing without in the treatment group compared with the control group.
suppression of protective cough, essentially targeting No significant difference was found between therapy and
the hypersensitive state. Studies in laboratory animals control groups regarding subjective measures of cough
and humans have demonstrated that opiates and other and cough reflex sensitivity.
centrally acting neuromodulators (gabapentin and The antitussive mechanisms of action of speech and
baclofen) can inhibit cough evoked by a broad range of language therapy remain unclear. One hypothesis is
chemical and mechanical stimuli188–191. This action is a that improved understanding of the condition through
dose-​dependent generalized suppression of the nervous education and counselling, along with training in sup-
system (sedation), inhibition of the brainstem neurons pression strategies, may affect the decreased inhibitory
involved in generating respiratory rhythm and/or direct control of cough that is present in such patients65,92,101.
suppression of cough sensory nerve activity169,192,193. However, empirical studies to address this have not
Consequently, some nonspecific cough suppressants been conducted. An improvement in paradoxical vocal
might cause dystussia, although the prevalence of this is fold movement and dysfunctional breathing may also
not well documented. One post hoc analysis of patients contribute to control of cough202.
receiving morphine and codeine for cough suppression
suggests that sedation is unlikely to contribute to their Treatment of children
cough-​suppressing properties194, whereas gabapentin Successfully managing a child with chronic cough (lead-
improved cough-​specific QOL in patients with refrac- ing to cough resolution) is dependent on identifying the
tory cough without suppressing capsaicin cough reflex aetiology of the cough and treating it (see current clini-
sensitivity183. Risk of dystussia and aspiration is likely cal guidelines3,143). Therefore, the suggested approach for
related to dosing195,196, and some patient groups who are managing children with chronic cough aims to identify
the underlying cause, provide attention to contributing
factors (such as tobacco smoke exposure) and under-
Box 4 | Speech and language therapy management of chronic cough stand the effect of the cough on the child and their par-
The approach to cough-​specific speech and language therapy involves four steps. ents or guardians3,143,145. Children aged >14 years are
• Education. Patients are provided education on the biology of coughing, chronic usually managed in accordance with adult pathways.
cough and cough hypersensitivity, and the negative effects of repeated coughing
and throat clearing are explained. Quality of life
• Vocal hygiene. Vocal and laryngeal hygiene and hydration are advised with a QOL is one of the key end points in clinical trials with
reduction in caffeine and alcohol intake. Nasal breathing with nasal douching novel antitussives, and it also aids clinical practice guide-
may be recommended with nasal steam inhalation. line decision-​making3. Cough has significant effects on
• Cough control/suppression training. Following identification of patient cough physical and mental health. Effects in adults include
triggers, patients are taught a range of suppression strategies including forced/dry urinary incontinence, pain, sleep disturbance, interfer-
swallow, sipping water, chewing gum or sucking non-​medicated sweets. Breathing ence with speech, anxiety and depression, avoidance of
pattern re-​education is used to promote relaxed abdominal breathing while inhaling social situations and inability to work203. Less common
through the nose. but severe complications include syncope and head
• Psycho-​educational counselling. Behaviour modification is used to reduce over- injury, hernia, suicidal ideation and rib fracture203. Stress
awareness of the need to cough and facilitate an individual’s internalization of control urinary incontinence is under-​recognized in adults
over their cough and to help manage stress and anxiety.
with cough: ~65% of patients with chronic cough are

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female and 65% will experience cough-​induced urinary HRQOL assessments are also valuable in the paedi-
incontinence204. Patients with cough-​induced urinary atric setting and are performed using acute cough215
incontinence are often too embarrassed to mention it or child-​specific chronic cough205 HRQOL tools. As
to their physician. In some patients, the inability to con- a child’s illness and management affects the QOL of
trol the urge to cough or throat tickle sensation can be their family, 27-​item and 8-​item generic parent-​proxy
worse than the cough itself138. In children, the key effects HRQOL tools are available for use in conjunction with
of chronic cough are annoyance, frustration, tiredness cough-​specific HRQOL assessments206,216.
and effects on activities205, whereas effects on parents of Little is known about the long-​t erm outcomes
children with chronic cough are worries on aetiology of patients with chronic cough. In a study following
of cough, helplessness and sleep disturbance206. Data on patients for 7 years, only 14% of patients had resolution
the economic burden of chronic cough are lacking. of cough although 26% reported a reduction in cough
QOL can be assessed informally in the clinic by ask- severity. No predictors of improvement in cough were
ing patients about the effects that are known to be associ- found8. Chronic cough may be associated with long-​term
ated with cough. HRQOL questionnaires can be used to health risks, such as risks of mortality, morbidity or drug
quantify QOL in a validated and standardized manner. adverse effects, although these have not been elucidated
QOL tools have broad applicability, even in conditions in patients with chronic cough.
with considerable heterogeneity that can limit the use-
fulness of objective tools. They capture aspects of disease Outlook
severity that is not possible with objective tools, such as Key gaps in knowledge
general health effects like fatigue and sleep disturbance, Despite advances in understanding the mechanisms of
among others. In patients with cough, QOL tools can chronic cough and improvements in therapeutic devel-
assess intensity and urge to cough, which cannot be opment, our understanding of the relationship between
assessed with cough frequency monitors207. This is par- cough hypersensitivity and chronic cough is incomplete.
ticularly important for patients who cough infrequently For example, although some therapeutic benefit has
but are greatly bothered by it. been shown using treatments that target mechanisms
Studies of QOL in patients with chronic cough using putatively involved in establishing or maintaining hyper-
validated tools have found significantly worse QOL in sensitivity, these treatments do not work for all patients
women than in men30. Women had lower QOL owing and they do not provide complete resolution of cough
to physical complaints, psychosocial issues and severe in most patients who do show responsivity12. Whether
physical complaints. The greatest disparity between the this observation reflects the existence of multiple con-
sexes was due to stress urinary incontinence in women. current processes involved in cough hypersensitivity,
Patients with a longer duration of cough, depression, yet-​to-​be-​discovered ‘lynch pin’ processes or a lack of
younger age and interference with speech owing to involvement of cough hypersensitivity in all patients is
cough also have worse QOL208. The presence of urge unclear. This is notable in children where evidence for
to cough is also highly correlated with impairment in cough hypersensitivity is lacking and targeting specific
QOL208. One longitudinal study of patients undergoing clinical conditions results in effective cough resolution.
treatment for chronic cough found that improvement in We do not know whether any relationships exist with
cough was associated with a significant improvement respect to the presentation of chronic cough across the
in QOL at 3 months and continued improvement at lifespan. For example, an important question to answer is
6 months208–210. This improvement was associated with whether cough hypersensitivity evolves in some patients
improvements in urinary incontinence, urge to cough owing to the presence of a troublesome cough earlier in
and anxiety symptoms208. Future studies to address life. As such, whether children with chronic cough have
gaps in knowledge should establish the frequency and a higher risk of cough hypersensitivity in adulthood is
characteristics of complications of cough to improve unknown. Indeed, genetic determinants might affect
management and understand the direction of the rela- the risk of cough hypersensitivity, although this area of
tionship between cough, anxiety and depression. The research is understudied. One challenge in investigat-
economic impact of cough on individuals also needs to ing future health effects of chronic cough lies in the lack
be investigated. of a distinct diagnostic code for chronic cough in the
The Leicester Cough Questionnaire is the most International Classification of Diseases (ICD) system217.
widely used HRQOL tool in adults. This tool consists Establishment of a code that categorizes chronic cough
of 19 items that address physical, psychological and as a disease will facilitate large-​scale routinely collected
social domains211, has good repeatability and respon- health data to further understand the burden and
siveness, and the minimal important clinical difference epidemiology of chronic cough.
has been established212. This questionnaire was used to The answers to many of the lingering questions
demonstrate improvement in HRQOL in a randomized, are dependent on improved understanding of the
placebo-​controlled and double-​blind phase III trial multiple clinical dimensions of cough. As mentioned
assessing antitussive activity of the P2X3 receptor antag- earlier, subjective patient reports of disease severity
onist, gefapixant213. The Cough QOL Questionnaire and effects on QOL do not always track linearly with
(CQLQ) is another validated tool for adult patients with objective measures of cough frequency. Moreover, the
chronic cough210. The CQLQ comprises 28 items, has aspects of chronic cough that have the greatest effects
good repeatability and responsiveness, and the minimal on patients’ lives are poorly understood. This lack of
important clinical difference has been established214. knowledge is problematic in trials of therapies that rely

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on only one output as the primary end point measure; Emerging therapies
for example, only short-​term (≤24 h) objective cough Improved understanding of cough neurophysiology has
frequency is used by drug regulators in clinical trials advanced the development of new antitussive therapies,
of new antitussive therapies, meaning that drugs that several of which are progressing through clinical trials
bring about clinically important improvements in (Supplementary Table 2). Molecules targeting P2X3
patient-​reported outcomes, but not cough frequency, and P2X2/3 ATP receptors have demonstrated efficacy
are unlikely to advance. Yet in other clinical hypersensi- in reducing cough counts, and at least four companies
tivities, for example, chronic pain, subjective measures have molecules in advanced clinical trials. Gefapixant
of pain severity and QOL are accepted as gold standard is the first such compound to have completed phase III
end point measures. Newer, less-​invasive, devices for trials and demonstrated efficacy in adults with refrac-
counting coughs over longer periods of time in natu- tory chronic cough213, while three other molecules have
ral settings, potentially assessing other aspects of cough completed phase II trials (Supplementary Table 2).
including the variability of cough, and analysis of the Trials have also been conducted with centrally acting
sound, intensity, cough bout duration and the time neurokinin 1 receptor antagonists, which have demon-
of day218 may disentangle the relationships between strated some clinical benefit, notably in patients with
objective and subjective measures, but ultimately an lung cancer presenting with chronic cough80. Drugs in
acceptance of the clinical importance of the subjective earlier phases of clinical development are those target-
dimensions of cough is needed. ing sodium channels involved in cough sensory neuron
action potential conduction219. Whether these thera-
Endotypes and personalized medicine pies will show efficacy in patients is unknown. Trials
Multiple mechanisms and aetiologies may underlie with various TRP channel agents have been negative
cough hypersensitivity. Recent suggestions of cough (Supplementary Table 2), and enthusiasm for these
endotypes may help clinical management of cough. drugs as therapeutic targets has waned.
Conventionally, these endotypes relate to the underly- One challenge for these antitussive studies is over-
ing clinical condition (such as asthma, GERD or upper coming the large placebo effect that accompanies cur-
airway cough syndrome)81 but there may be other ways rent trial designs. The development of improved animal
to endotype patients with cough; however, this needs to models that better recapitulate the processes that under-
be explored. Clinical trials with P2X3 antagonists sug- pin chronic cough and cough hypersensitivity, along
gest that a subset of patients with refractory chronic with reimagined clinical trial designs and/or improved
cough respond well to purinergic inhibition, perhaps end point measures may be required to identify true
reflecting a currently unrecognized endotype213. Trials therapeutic efficacies. Furthermore, clinical trials for
of other antitussives have similarly shown heterogene- new compounds have only been assessed in adults,
ity in responsivity that may reflect differing pathological mostly those with refractory chronic cough, and it will
processes driving cough in different patients. A more be important to ascertain the clinical use of these new
careful assessment of this heterogeneity may identify antitussives in other patients and in children.
clear endotypes, which then allows more personalized
approaches to cough management. Published online xx xx xxxx

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237. Davenport, P. W. Urge-​to-cough: what can it teach us 250. Vertigan, A. E., Bone, S. L. & Gibson, P. G. Laryngeal fees to her institution as IDMC Member of an unlicensed vac-
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240. Satia, I. et al. Capsaicin-​evoked cough responses hypersensitivity syndrome: a cross-​sectional and Merck. B.J.C. has received honoraria from Merck,
in asthmatic patients: evidence for airway observational study. J. Allergy Clin. Immunol. Pract. GSK, Nocion, Axalbion, Menlo and Attenua, and grant sup-
neuronal dysfunction. J. Allergy Clin. Immunol. 6, 2087–2095 (2018). port from Site One and Merck. S.S.B. reports honoraria from
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Effects of methacholine induced bronchoconstriction Laryngeal dysfunction: assessment and management Xention Ltd, Ario Pharma Ltd, Glenmark, Almirall,
and procaterol induced bronchodilation on cough for the clinician. Am. J. Respir. Crit. Care Med. 194, AstraZeneca, Axalbion, Patara, Verona Pharma, NeRRe
receptor sensitivity to inhaled capsaicin and tartaric 1062–1072 (2016). Pharmaceuticals, Menlo Pharmaceuticals and Attenua Inc.
acid. Thorax 47, 441–445 (1992). 255. Chamberlain, S., Birring, S. S. & Garrod, R. S.B.M. declares honoraria from Merck, NeRRe Therapeutics,
243. Hilton, E. C., Baverel, P. G., Woodcock, A., Nonpharmacological interventions for refractory Reckitt Benckiser and Bellus Health and grant support from
Van Der Graaf, P. H. & Smith, J. A. Pharmacodynamic chronic cough patients: systematic review. Lung 192, Merck and Bellus Health. None of the disclosed entities
modeling of cough responses to capsaicin inhalation 75–85 (2014). above had any involvement in the conceptualization, design,
calls into question the utility of the C5 end point. data collection, analysis, decision to publish or preparation of
J. Allergy Clin. Immunol. 132, 847–855.e1–5 (2013). Author contributions the manuscript.
244. Drake, M. G. et al. Eosinophils increase airway Introduction (S.B.M. and K.F.C.), Epidemiology (W.J.-​S .,
sensory nerve density in mice and in human asthma. A.B.C. and K.L.), Mechanisms/pathophysiology (S.B.M., B.J.C. Peer review information
Sci. Transl. Med. 10, eaar8477 (2018). and J.A.S.), Diagnosis, screening and prevention (K.F.C., L.M., Nature Reviews Disease Primers thanks Jonathan Abram
245. Gao, J., Wu, F., Wu, S. & Yang, X. Inflammatory A.B.C. and S.S.B.), Management (K.F.C. and J.A.S.), Quality Bernstein, Lu-​Yuan Lee, Anne Vertigan and the other, anony-
subtypes in classic asthma and cough variant asthma. of life (S.S.B. and A.B.C.), Outlook (S.B.M.). mous, reviewer(s) for their contribution to the peer review of
J. Inflamm. Res. 13, 1167–1173 (2020). this work.
246. Gao, J., Wu, H. G. & Wu, F. Small airways dysfunction Competing interests
and bronchial hyper-​responsiveness in cough variant K.F.C. has received honoraria for participating on Advisory Publisher’s note
asthma. Int. J. Gen. Med. 13, 1427–1434 (2020). Board meetings of GSK, AstraZeneca, Novartis, Merck, Springer Nature remains neutral with regard to jurisdictional
247. Gibson, P. G., Dolovich, J., Denburg, J., Ramsdale, E. H. Nocion, Shionogi and Reckitt Benckiser and on the Scientific claims in published maps and institutional affiliations.
& Hargreave, F. E. Chronic cough: eosinophilic Advisory Board of the Clean Breathing Institute supported by
bronchitis without asthma. Lancet 1, 1346–1348 GSK Health Care Consumer Products. He has also been remu- Supplementary information
(1989). nerated for speaking engagements by AstraZeneca, Novartis The online version contains supplementary material available
248. Brightling, C. E. et al. Mast-​cell infiltration of airway and Merck. L.M. reports honoraria from Chiesi, GSK, Merck, at [Link]
smooth muscle in asthma. N. Engl. J. Med. 346, NeRRe Therapeutics, and Shionogi Inc.; grant support from
1699–1705 (2002). Merck; and other support from AstraZeneca, Boehringer © Springer Nature Limited 2022

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