Concise Clinical Review
Controversies in the Evaluation and Management
of Chronic Cough
Surinder S. Birring1
1
Division of Asthma, Allergy and Lung Biology, King’s College London, London, United Kingdom
Chronic cough that cannot be explained after basic evaluation is
a common reason for patients to be referred to respiratory out-
patient clinics. Asthma, gastroesophageal reflux, and upper airway
disorders frequently coexist with chronic cough. There is some
controversy as to whether these conditions are causes or aggravants
of cough. Heightened cough reflex sensitivity is an important fea-
ture in most patients. There is good evidence that it is reversible
when associated with upper respiratory tract infection, angiotensin-
converting enzyme inhibitor medications, and chronic cough asso-
ciated with eosinophilic airway inflammation. In many patients,
heightened cough reflex sensitivity is persistent and their cough is
unexplained. There are few therapeutic options for patients with
unexplained chronic cough. There is a pressing need to understand
the genetic, molecular, and physiological basis of unexplained
chronic cough and to develop novel antitussive drugs that down-
regulate cough reflex sensitivity.
Keywords: chronic cough; cough hypersensitivity; asthma; postnasal
drip; gastroesophageal reflux
Over the past 40 years much has been learned about how to
evaluate and treat chronic cough, but it is clear that there is much
further to go. In 1977, a systematic diagnostic approach was
proposed that encouraged evaluation of the sites of the sensory
limb of the cough reflex (1). Subsequent studies reported that
extrapulmonary conditions such as upper airway diseases and
gastroesophageal reflux disease (GERD) can cause cough. This
led to the introduction of the anatomic diagnostic paradigm,
which focuses on identifying the causes of cough (2) (Table 1).
Although many investigators have used the paradigm with a high
success rate, there are a significant number who have not. Success
rates as low as 58% have been reported and the reasons for this
are unclear (3). There is, however, agreement among clinicians
that some patients with chronic cough do not respond to therapy
despite extensive evaluation. This has led some investigators to
suggest that a new approach to chronic cough is necessary (4).
This article reviews the controversies in the evaluation of
chronic cough in adults, highlights concerns about the current
approach to cough, and suggests that therapy and future research
need more focus on important mechanisms such as cough reflex
hypersensitivity.
(Received in original form July 1, 2010; accepted in final form December 10, 2010)
Correspondence and requests for reprints should be addressed to Surinder S.
Birring, M.D., King’s College London, Division of Asthma, Allergy and Lung
Biology, Denmark Hill, London SE5 9RS, UK. E-mail: surinder.birring@nhs.net
Am J Respir Crit Care Med Vol 183. pp 708–715, 2011
Originally Published in Press as DOI: 10.1164/rccm.201007-1017CI on December 10, 2010
Internet address: www.atsjournals.org
GASTROESOPHAGEAL REFLUX–ASSOCIATED
CHRONIC COUGH
The evaluation of GER is one of the key components of the
diagnostic pathway. Cough guidelines recommend an initial trial
of therapy rather than invasive investigations to identify GER
cough (5). Proton pump inhibitors (PPIs) are the most widely
used therapy; if medical therapy fails, further investigation may
result in antireflux surgery being recommended. A Cochrane
review meta-analysis, however, concluded that the effect of
antireflux therapy such as PPIs for chronic cough was inconsistent
and of uncertain magnitude (6). A number of other observations
have also led clinicians to question the importance of GER in
chronic cough.
Are Tests for GER Necessary?
The diagnosis of GER cough on the basis of the presence of
symptoms of GER is problematic because symptoms can vary and
are not always present. Furthermore, GER can coexist in patients
with cough due to other conditions. Ideally, objective demon-
stration of a temporal association between GER and cough
should be sought. Endoscopy and barium esophagoscopy are
limited by their inability to detect the temporal relationship
between episodes of GER and cough. Furthermore, endoscopy is
often not helpful because the presence of esophagitis is un-
common in patients with chronic cough (7). Esophageal pH
monitoring has been the most studied of all tests. A significant
limitation of esophageal pH monitoring is its poor predictive
value in determining the response to therapy for GER. In a study
from Patterson and colleagues, only 28% of patients with a
chronic cough and positive esophageal pH monitoring test had
a long-term response to proton pump inhibitor therapy (8).
Esophageal manometry is often combined with pH monitoring
to detect episodes of cough objectively. Studies have led to
caution in the interpretation of cough frequency data from
esophageal manometry because it is significantly lower than that
measured with sound-based cough monitors (9). This is thought
to be due to an inhibitory effect of the esophageal probe on cough
and the insensitivity of manometry for detecting cough, particu-
larly low-intensity coughs. Nonacid (or weakly acid) GER has
been recognized as a potential cause of GERD. It can constitute
gas, liquid, solids, or a combination of these. The symptoms of
acid and nonacid GER overlap, and therefore objective tests are
necessary for detection. The advent of esophageal impedance
monitoring has allowed assessment of nonacid GER, although it
is in its infancy and not widely used at present. The limitations of
this technique are that it is considerably more expensive than
standard esophageal pH monitoring and that its usefulness in
establishing a diagnosis of GER cough and ability to predict
response to therapy have not been established; this deserves
further study. At present, the routine use of objective investiga-
tions of GER cannot be recommended.
Concise Clinical Review
TABLE 1. COMMON ASSOCIATIONS WITH CHRONIC COUGH
Gastroesophageal reflux
Rhinosinusitis (UACS/postnasal drip)
Asthma
Eosinophilic bronchitis
Upper respiratory tract infection
Obstructive sleep apnea
Chronic tonsillar enlargement
Chronic snoring
Angiotensin-converting enzyme inhibitor medications
Definition of abbreviation: UACS 5 upper airway cough syndrome.
Are Proton Pump Inhibitors Effective in Chronic Cough?
Several randomized controlled trials of PPIs in chronic cough
have not confirmed the success of earlier uncontrolled studies (6).
In the largest study, Fathi and colleagues randomized 56 patients
with chronic cough to receive esomeprazole 20 mg twice daily or
placebo for 2 months (10). The change in cough-related quality of
life, the primary outcome measure, was not significantly different
between groups but PPIs were effective in relieving gastrointes-
tinal symptoms of GER, as expected. The lack of clinical benefit
with PPIs is not limited to patients with chronic cough; it is also
seen in other airway conditions such as asthma, in which
symptoms of GER are also common (11). There are limitations
to these studies. First, objective outcome parameters such as
cough frequency monitoring were not used and it is possible that
a treatment effect was not detected. Second, it is possible that
many patients with GER cough are treated in primary care and
not referred to specialist clinics, leading to recruitment bias in
clinical trials. Third, these studies were underpowered. Further
trials are needed. These should be large, multicenter, random-
ized, placebo controlled, inclusive of patients in primary care,
and utilize both objective and subjective cough severity out-
come parameters. They should also assess the temporal relation-
ship between GER and cough with esophageal pH/impedance
monitoring to determine the selection criteria of patients suit-
able for therapy and not be limited to PPIs. Therefore, until
further data are available, a trial of PPI should still be recom-
mended (5).
Is Nonacid GER Important in Cough?
The fact that not all GER is acidic and that some patients have
a poor response to acid suppression has focused attention on
esophageal dysmotility and nonacid GER. Esophageal dysmo-
tility is a common finding in patients with chronic cough, although
its relevance to the pathogenesis is not known (12). It has been
suggested that cough and esophageal dysmotility may represent
a generalized abnormality of neural aerodigestive reflexes be-
cause of their coexistence. Decalmer and colleagues investigated
the importance of nonacid GER with esophageal impedance
studies in a large group of patients with chronic cough and
compared them with healthy subjects (13). They found no dif-
ference in the number of acid or nonacid GER episodes between
the groups. The temporal association between episodes of non-
acid GER and cough has also been studied. Blondeau and col-
leagues have developed a statistical index of temporal association
called the symptom association probability (SAP), obtained from
esophageal impedance recordings (14). In their study, a positive
SAP was found in only a small proportion (5%) of patients with
chronic cough and cough itself caused episodes of GER. Smith
and colleagues also provide important insights into the associa-
tion between GER and cough (15). In contrast to Blondeau and
colleagues, they found a positive symptom association for GER
709
preceding cough within a 2-minute time interval in a much higher
proportion of patients (48%), and the reasons for this are unclear
(15). Only 44% of all coughs in patients with a positive symptom
association followed episodes of GER. Furthermore, a significant
number of patients (56%) had episodes of GER after cough. This
suggests that factors other than GER are also important in
patients with cough associated with GER and that anti-GER
therapy alone may not lead to resolution of cough. The most
appropriate time interval between episodes of GER and cough
used to establish a causal association is not known. Episodes of
GER and cough are more likely to be causally linked if this time
interval is shorter, and hence there is a need for standardization
(15). It is not known whether the SAP is predictive of response to
therapy; this clearly needs further investigation in controlled
studies before esophageal impedance monitoring can be recom-
mended in the diagnostic algorithm for patients with cough. The
therapeutic options for nonacid GER are largely dietary modi-
fications, prokinetic drug therapy, and antireflux surgery in
selected patients. No study has evaluated the relative roles of
these therapies.
Is There a Role for Antireflux Surgery in the Management
of Chronic Cough?
Current guidelines recommend surgery such as Nissen’s fundo-
plication for selected patients with cough and persistent GER
despite optimal medical therapy (16). In practice, the use of
surgical treatment for GER cough is highly variable. A number of
case series of small numbers of patients report good success rates
with surgery but controlled trials, objective cough outcome data,
and long-term follow-up are lacking (5). Nissen’s fundoplication
is not without risks; severe dysphagia, flatulence, inability to
belch, and increased bowel symptoms are the most frequently
reported complications. Furthermore, the number of fundopli-
cations performed in the United States for GER is steadily
declining because of lower than anticipated successful outcomes
and patient dissatisfaction (17). Controlled studies of surgical
therapy for GER cough are urgently needed. A placebo in-
tervention is ethically and technically difficult to achieve but may
be possible with endoscopic therapies in future. The clinical trials
of bronchial thermoplasty for severe asthma highlight the impor-
tance of including a sham group when assessing an interventional
procedure (18). The author’s view is that there are insufficient
data to support the recommendation for antireflux surgery for
patients with chronic cough.
Does Laryngopharyngeal Reflux Cause Cough?
Laryngopharyngeal reflux (LPR), the reflux of gastric contents
into the laryngopharynx, is widely considered by otolaryngolo-
gists as a common cause of chronic cough. It can be associated
with frequent throat clearing, hoarse voice, and globus (19). LPR
cough has yet to gain widespread recognition among pulmonol-
ogists because there is significant overlap in the phenotype of
patients diagnosed with GER cough and LPR cough. There are
no pathognomonic symptoms, signs, or endoscopic findings of
LPR. The diagnosis is usually based on laryngoscopic findings of
erythema, edema, and thickening of the posterior pharynx that
can potentially be indistinguishable from the trauma from
coughing itself (20). PPIs are recommended for LPR cough,
based on limited evidence (21). Further studies are needed to
establish the importance of LPR in patients referred with chronic
cough. This needs to include the demonstration of a temporal
relationship between LPR and cough with pharyngeal impedance
monitoring and randomized controlled trials of PPIs and other
therapies.
710 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
UPPER AIRWAYS COUGH SYNDROME
Upper airways cough syndrome (UACS), also referred to as
postnasal drip syndrome or rhinosinusitis cough, is associated
with a wide range of upper airway symptoms. Allergic, infectious,
and vasomotor etiologies are most common. More recently,
chronic tonsillar enlargement and obstructive sleep apnea have
been described in association with chronic cough (22–24). The
assessment of UACS is limited by the lack of a diagnostic test;
a trial of therapy is usually the first line of investigation.
Nasendoscopy may confirm the presence of upper airway in-
flammation, but there is no evidence to suggest its routine use in
cough without suggestive symptoms. Computed tomographic
imaging of the sinuses has a poor positive predictive value in
establishing a diagnosis of UACS and hence is not routinely
recommended (16). The therapy for UACS is determined by the
nature of the upper airway pathology. Nasal corticosteroids and
first-generation sedating antihistamines are widely used.
UACS: Cause or Aggravant of Cough?
A number of observations have led some pulmonologists and
otolaryngologists to question the importance of postnasal drip
in the causation of chronic cough. Postnasal drip is a common
symptom in the general population and is not always associated
with cough. However, this observation alone is not sufficient to
dismiss UACS as a cause of chronic cough because it may affect
only susceptible patients, as seen with angiotensin-converting
enzyme (ACE) inhibitor drugs. There are no unique features in
history, examination, or investigations that identify UACS as
a cause of cough. The paucity of randomized controlled trials
of therapy for UACS is perhaps the most striking omission;
addressing this will go a long way to establishing whether there
is a causal link. Until then, patients with cough and upper air-
way symptoms should undergo a trial of nasal corticosteroids
and/or antihistamines.
Silent Postnasal Drip or Unexplained Chronic Cough?
Silent postnasal drip is a term reserved for patients with chronic
cough who do not complain of symptoms of rhinosinusitis but
respond to upper airway–specific therapy (16). The prevalence of
silent postnasal drip varies from no reported cases to significant
numbers between cough clinics. This may be due to differences in
diagnostic labeling or failure to use the correct medications. The
diagnosis of silent postnasal drip is often based on the improve-
ment in cough with a first-generation antihistamine such as
dexbrompheniramine (16). Dexbrompheniramine is available
in the United States but is not easily available in the United
Kingdom and parts of Europe. The improvement in cough with
antihistamines may, however, be due to its action on the central
and peripheral cough reflex rather than an effect on rhinosinusitis
and some investigators therefore prefer to call this condition
‘‘unexplained chronic cough’’ (25, 26). Although a randomized
controlled trial in patients with acute cough and postnasal drip
caused by upper respiratory tract infection reported a reduction
in cough severity with dexbrompheniramine when used in
combination with pseudoephedrine, there have been no con-
trolled trials conducted in patients with chronic cough (27). A
randomized controlled trial of dexbrompheniramine in chronic
cough patients with and without upper airway symptoms is
needed to determine its effectiveness. Until these data are avail-
able, a short-term trial of antihistamine is still recommended.
COUGH VARIANT ASTHMA
There is general consensus that asthma is an important cause of
cough. The controversies relate largely to its evaluation. There
VOL 183 2011
are numerous diagnostic tests and effective therapeutic options
available, in contrast to GER and UACS.
Which Diagnostic Test?
A diagnostic test for cough variant asthma should have high
sensitivity and specificity, predict response to therapy, and be safe
and affordable. Peak flow rate monitoring and bronchodilator
responsiveness testing are widely used but are limited by their
poor diagnostic sensitivity and specificity (28). Although bron-
choprovocation challenge tests have high negative predictive
value, positive predictive value is poor (29). The assessment of
airway inflammation by induced sputum eosinophil cell count
analysis and exhaled nitric oxide measurement offers high
sensitivity and specificity and is predictive of response to cortico-
steroid therapy (28, 30). They also have the potential to guide
titration of corticosteroid therapy (31). Exhaled nitric oxide
measurement has the greatest promise; it is easy to measure and
portable, and the cost has fallen considerably. Induced sputum
assessment is limited by the labor costs of sputum induction,
processing, and analysis but some institutions have demonstrated
that a favorable cost–benefit profile is possible (31). Larger
studies investigating the diagnostic accuracy and clinical useful-
ness of exhaled nitric oxide tests compared with induced sputum
and bronchoprovocation tests are needed to determine which test
is optimal for the investigation of cough variant asthma. Indirect
airway challenge tests, such as mannitol, can potentially assess
cough reflex sensitivity in addition to airway reactivity in a single
study; this deserves further investigation (32).
Limitations of Diagnostic Trials of Inhaled Corticosteroids?
Trials of inhaled corticosteroids are widely used to establish
a diagnosis of cough variant asthma. The limitation of trials of
therapy is that, when patients fail to respond, it is not clear
whether this is due to inadequate therapy for asthma or whether
the cough is due to another cause. A significant number of patients
with cough variant asthma fail to respond to an initial trial of
inhaled corticosteroids, and this may be due to inadequate dose
and duration of therapy, poor inhaler technique and compliance,
the presence of small airway inflammation, neutrophilic airway
inflammation, the need for systemic therapy, and inhaler-induced
cough (33). The assessment of airway inflammation can be used to
identify patients who are likely to respond to corticosteroids. The
presence of eosinophilic airway inflammation should prompt the
physician to explore reasons for treatment failure and initiate
a further trial or intensify treatment. A short-term diagnostic trial
of oral corticosteroids may be an alternative option.
Should Bronchodilator Therapy Be Used?
Inhaled bronchodilator therapy is recommended in combination
with inhaled corticosteroids for the treatment of cough variant
asthma (16). The evidence for the use of bronchodilators is
limited. In one study, inhaled metaproterenol was compared with
placebo in a randomized trial of nine patients with cough variant
asthma (29). There was a greater reduction in cough severity
scores with metaproterenol compared with placebo, but this was
not confirmed by objective cough frequency measurement. The
reduction in cough scores was not due to an amelioration of
airway hyperresponsiveness. Importantly, this study demon-
strated that the mere presence of airway hyperresponsiveness
by itself in chronic cough was a poor predictor of a diagnosis of
asthma and cough was independent of bronchoconstriction.
Further studies have found that bronchodilators are ineffective
in acute cough and unexplained chronic cough in children (34,
35). A large randomized controlled trial of bronchodilator
Concise Clinical Review
therapy is needed to assess their role in chronic cough; this may be
better achieved with long-acting bronchodilators.
Eosinophilic Bronchitis/Atopic Cough
Eosinophilic bronchitis (EB) is a relatively common cause of
chronic cough and accounts for up to 15% of cases (36). EB can
coexist with other airway diseases such as chronic obstructive
pulmonary disease, occupational lung disease, and bronchiectasis
(37). It is characterized by eosinophilic airway inflammation and
in contrast to asthma, there is an absence of airway hyper-
responsiveness. The latter is due to the absence of airway smooth
muscle mast cell inflammation (38). Inhaled corticosteroids are
the first-line therapy and effective. EB is seldom recognized
outside specialist clinics and this may relate to the unavailability
of diagnostic tests. EB is diagnosed by demonstrating eosinophilic
airway inflammation with induced sputum cell analysis or exhaled
nitric oxide measurement and the exclusion of airway hyper-
responsiveness. If measures of airway inflammation are not
available, a corticosteroid-responsive cough in a patient with
a negative bronchoprovocation test is likely to be caused by EB.
When both airway inflammation and reactivity testing are not
available, the distinction between asthma and EB is not always
possible in a patient with a corticosteroid-responsive cough. It is
unclear whether this distinction has clinical implications, but this
needs investigation in longitudinal studies. It is perhaps more
important to emphasize that a trial of corticosteroids is essential
in patients with chronic cough to rule out asthma and EB. Long-
term therapy for EB may be necessary because of persistent
symptoms, risk of progression to asthma, and the development of
fixed airflow obstruction (39).
Atopic cough (AC) is a cause of chronic cough reported almost
exclusively in Japan (40). The reason for this is unclear but is
thought to relate to environmental factors. AC is characterized by
the presence of an atopic phenotype and/or sputum eosinophilia
in the absence of airway hyperresponsiveness. The diagnosis is
based on the presence of atopy (skin test/IgE) or induced sputum
eosinophilia, cough reflex hypersensitivity, exclusion of airway
hyperresponsiveness, and a negative trial of bronchodilator
therapy (41). A simplified diagnostic criterion has been proposed
that recommends a trial of therapy with an antihistamine or
corticosteroid for atopic patients with a chronic cough without
wheezing (41). There is considerable overlap in the diagnostic
criteria for AC with EB. One of the differences is that bron-
choalveolar eosinophilic inflammation is less common in AC and
progression to asthma is rare (41).
UNEXPLAINED CHRONIC COUGH: DISTINCT
CONDITION OR INADEQUATE THERAPY
FOR EXPLAINED COUGH?
The cause of cough may not be identified because of a number of
reasons including inadequate assessment, poor compliance with
therapy, and ineffective therapy (42). However, many clinics
report a high prevalence of unexplained chronic cough (UCC)
after detailed investigations and treatment trials (3, 20, 43).
Moreover, patients with UCC have some unique clinical charac-
teristics that suggest their cough differs from explained cough (43).
Clinical Characteristics
There is no consensus concerning the best term by which to
identify patients whose cough is unexplained after comprehen-
sive investigations and treatment trials. The term idiopathic
chronic cough is often used, but it may inhibit physicians from
assessing patients thoroughly. Cough hypersensitivity syndrome
has also been proposed to identify this group of patients and
emphasizes that unexplained chronic cough is a condition in-
711
volving an abnormality of the cough reflex (44, 45). The terms
sensory neuropathic cough, laryngeal sensory neuropathy, sen-
sory hyperreactivity, and vagal neuropathy–associated cough
are used by otolaryngologists and it is likely that there is
considerable overlap among patients with UCC. It is preferable
that there be a consensus in terminology when describing these
patients. Most of the current terms used suggest hypersensitivity
of the cough reflex, and this deserves further consideration.
The prevalence of UCC varies between clinics and has been
reported to be as high as 42% of cases (3). Patients with UCC tend
to be female, middle-aged, and have an onset of cough around
menopause, but this also true of patients with explained chronic
cough, although to a lesser extent (43, 46). Viral illness at onset of
cough and association with airway infections with Bordetella
pertussis and basidiomycetous fungi have been reported in
patients with UCC (3, 47, 48). Patients with UCC have high levels
of anxiety and symptoms of depression (49). This is thought to be
a consequence of long-standing cough and its impact on health
status; an improvement in psychological health status with
therapy for cough supports this. Psychogenic cough is an
extremely rare diagnosis in adults.
Pathogenesis
Patients with UCC have a strikingly increased sensitivity to cough
challenge with capsaicin, which suggests an abnormality of the
airway sensory nerves because capsaicin is a potent activator of
unmyelinated C fibers (50). The importance of enhanced airway
sensory nerve sensitivity in the pathogenesis of UCC is also
supported by an increased density of sensory nerve fibers in the
airways. An increase in neuropeptide calcitonin gene–related
peptide (CGRP)–containing nerves has been reported (51).
There is also increased expression of airway receptors that
potentially mediate cough, such as the transient receptor poten-
tial vanilloid-1 (TRPV-1) ion channel present on C fibers (52).
Furthermore, both CGRP nerve density and TRPV-1 receptor
expression are related to the degree of capsaicin cough reflex
sensitivity. The hypersensitivity of airway nerves may not be
limited to just those involved in cough; enhanced sensitivity of the
laryngeal glottic closure reflex and the high prevalence of vocal
cord dysfunction and voice disorders in UCC raise the possibility
of a generalized disorder of airway nerves (50, 53).
Airway inflammation may also be important in the pathogen-
esis of UCC. A number of inflammatory mediators such as
histamine, prostaglandin E2, and cysteinyl-leukotrienes are ele-
vated in the airways of patients with UCC and many are known to
activate the cough reflex (54, 55). There is also an increased
number of inflammatory cells in the airways; neutrophilia and
lymphocytosis have been reported (43, 56, 57). Airway lympho-
cytosis has been associated with the presence of organ-specific
autoimmune disease in UCC (43, 56). One study reported that the
prevalence of autoimmune disease, particularly thyroid disease,
was eight times higher in patients with UCC compared with
control subjects (46). The prevalence of autoantibodies was also
higher in UCC. Airway lymphocytosis is thought to result from
the homing of inflammatory cells from primary sites of autoim-
mune inflammation to the airways (58, 59). The onset of cough
around menopause is thought to be due to altered lung CD41 T-
lymphocyte immunity occurring after menopause (57). It is not
known whether inflammation leads to airway remodeling in
UCC. Airway structural changes such as goblet cell hyperplasia
have been reported, but it is not clear whether they are related to
the pathogenesis or are a consequence of cough (51, 60). Most
research to date has focused on the activation of sensory nerves
that leads to a reflex cough; future studies also need to identify the
stimuli that sensitize the cough reflex.
712 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Treatment
The therapeutic options for patients with UCC are limited.
Opiates such as morphine sulfate can suppress cough but are
associated with significant side effects such as sedation, and there
is the risk of dependence (61). Their mechanism of action is likely
to be central (61). Novel antitussive drugs with a peripheral site of
action that down-regulate cough hypersensitivity are needed.
Open label studies of drugs acting on peripheral nerves used to
treat neuropathic pain, such as amitryptyline and gabapentin,
have been reported to reduce cough severity but this needs
further investigation in controlled trials (62). Antagonists to the
TRPV-1 ion channel have been developed and need evaluation in
clinical trials. A number of other molecular targets have been
identified for antitussive drug development that can potentially
down-regulate cough hypersensitivity; these include selective
cannabinoid agonists (CB2 agonists), maxi-K channel openers,
P2X3 antagonists, and p38 mitogen-activated protein (MAP)
kinase inhibitors (63). There are nonpharmacological therapeutic
options available for patients with UCC. A speech and language
therapy program that included cough suppression, vocal hygiene
maneuvers, and strategies that reduce vocal cord dysfunction was
effective at reducing cough severity in a randomized controlled
trial (53). Up to two-thirds of patients with UCC have identifiable
triggers of cough (64). Cough physiotherapy that focuses on
trigger avoidance and voluntary cough suppression is another
promising therapy and deserves further evaluation (65). A long-
term follow-up study of patients with UCC found that cough
persisted in most patients but was reduced in severity in more
than 50% of subjects (66). Patients with UCC had an increased
decline in FEV1 (63 ml/yr) and 13% developed airflow obstruc-
tion. The only independent predictor of FEV1 decline was cough
reflex sensitivity.
LIMITATIONS OF THE CURRENT APPROACH
TO CHRONIC COUGH
The emphasis of current guidelines is on the evaluation of
conditions that coexist with chronic cough, such as GER, UACS,
and asthma (16). However, the exact role of coexisting conditions
in the pathogenesis of cough is unclear. There are several
possibilities: (1) they cause cough reflex hypersensitivity; (2) they
are triggers or aggravants of cough in patients with preexisting
cough reflex hypersensitivity; (3) they, along with cough, are
a manifestation of a generalized disorder of the upper aerodiges-
tive tract; and (4) they are unrelated to the pathogenesis of cough.
The evidence for treating coexisting conditions to reduce cough
severity is not robust, as it consists largely of uncontrolled studies
(16). The lack of control groups in clinical trials is a concern
because significant placebo responses are common (4). The poor
success rates in treating cough by some investigators have led
them to propose that coexisting conditions are aggravants rather
than the cause and that a new approach is needed to encourage
further research and development in this field (4). The cause and
pathogenesis of cough need to be investigated to move forward.
Cough reflex hypersensitivity is an important feature of chronic
cough (50, 63). Future research should focus on understanding the
sensitization of the cough reflex and the mechanisms involved in
cough. A better understanding of the airway sensory nerves and
their signaling pathways will potentially lead to the identification
of novel therapies.
THE NEW COUGH PARADIGM: COUGH
REFLEX HYPERSENSITIVITY
The cough reflex has an important role in airway protection and
clearance of secretions. Most patients with unexplained chronic
VOL 183 2011
cough have an abnormally sensitive cough reflex. The sensitivity
of the cough reflex can be assessed by measuring the cough
response to a variety of airway irritants such as capsaicin, citric
acid, and fog (67). The sensory receptors that mediate cough in
humans are not fully understood, but members of the transient
receptor potential (TRP) ion channel family are strong candi-
dates (68). They are expressed on sensory neurons and are
activated by temperature, osmolarity, stretch, and many nocicep-
tive stimuli. Commonly reported triggers of cough such as scents,
odors, cold air, food, speech, and laughter are likely to activate
this pathway. Cough receptors are thought to be most concen-
trated in the laryngopharynx but are also expressed in the lower
airways. There is evidence of increased expression of TRPV-1 on
the airway nerves of patients with unexplained chronic cough
(52).
A heightened cough reflex is an important feature of chronic
cough irrespective of the diagnosis (50). Cough reflex sensitivity is
more heightened in females than males and this may be why
chronic cough is more prevalent in females (50). Cough reflex
sensitivity is reported to be stable in most patients, and therefore
variations in the number and intensity of coughs may be due to
environmental triggers such as air pollution (69). Cough reflex
hypersensitivity is also seen in healthy subjects; this is analogous
to other airway reflexes such as bronchial hyperreactivity (50).
For this reason, the positive predictive value of cough reflex
testing for a diagnosis of cough hypersensitivity is likely to be low.
The negative predictive value is not known but is likely to be good
and may be of clinical value.
Heightened cough reflex sensitivity can be considered re-
versible or persistent in patients with chronic cough, in whom the
cough is typically dry or minimally productive (Figure 1). It is
absent in pulmonary conditions associated with a productive
cough such as chronic obstructive pulmonary disease and bron-
chiectasis (70). The role of heightened cough reflex sensitivity in
the pathogenesis of cough has been most studied in patients with
angiotensin-converting enzyme inhibitor (ACE-I)–associated
chronic cough. Approximately 10% of patients taking ACE-Is
develop a chronic cough (71). The reason why only some patients
develop cough is unclear. ACE-Is heighten cough reflex sensitiv-
ity by increasing substance P, bradykinin, and prostaglandin
concentrations in airway secretions (71). The withdrawal of
ACE-I usually leads to a reduction in cough severity and cough
reflex sensitivity. ACE-I cough can also be managed with antiin-
flammatory drugs such as sodium cromoglycate and sulindac (71).
The reintroduction of ACE-I usually leads to recurrence of
cough. A reversible cough reflex sensitivity is not unique to
ACE-I–associated cough; it is also seen in patients with upper
respiratory tract infection, cough variant asthma, and eosino-
philic bronchitis (72) (Figure 1). It is not clear whether these
conditions cause cough by increasing cough reflex sensitivity or
trigger cough in a sensitized individual. In patients with GER or
UACS, the evidence for a reduction in cough reflex hypersensi-
tivity with specific therapy is not robust because this has not been
evaluated in controlled trials. Cough and heightened cough reflex
sensitivity can persist despite optimal management of coexisting
conditions such as that in patients with UCC. Research into
persistent cough hypersensitivity needs to be an area of priority.
ASSESSMENT OF COUGH SEVERITY
One of the important challenges in chronic cough is to conduct
large randomized controlled trials to address areas of controversy
in clinical practice. The key to conducting a high-quality trial is to
use validated cough severity outcome tools. Subjective tools such
as cough visual analog scales, scores, and diaries are widely used
(73) (Figure 2). The appreciation of the profound physical,
Concise Clinical Review
Figure 1. Evaluation of chronic cough. CXR 5 chest X-ray; EB 5
eosinophilic bronchitis.
psychological, and social impact of cough has led to increasing use
of health-related quality of life measures. Three validated, self-
completed, cough-specific quality of life questionnaires are avail-
able: the Cough-specific Quality of Life Questionnaire (CQLQ),
the Leicester Cough Questionnaire (LCQ), and the Chronic
Cough Impact Questionnaire (CCIQ) (74–76). The LCQ and
CQLQ have been used successfully in clinical trials evaluating
antitussive therapy (61, 74, 75, 77).
The importance of developing objective measures of cough
severity has been highlighted in the European Respiratory
Society guidelines on the assessment of cough (67). Cough reflex
sensitivity measurement is the most widely used objective test. Its
limitations are that it is relatively time-consuming and it may not
detect the effect of therapy if antitussive therapy is acting on
a different cough reflex pathway (50). Advances in digital sound
713
recording devices and improved battery life have led to the
development of several cough frequency monitors that can record
for 24 hours (78–80). Most represent work in progress. The goal is
to automate cough counting by developing customized software,
but this has been challenging because of difficulty in discriminat-
ing cough sounds from speech and other noise. Studies, however,
report promising results; it has been possible to achieve a sensi-
tivity and specificity for cough detection greater than 90% with
some automated monitors (78). More than 80% of cough occurs
during awake hours, and therefore a considerably shorter dura-
tion of cough monitoring may be sufficient to assess the efficacy
of therapy. It is likely that cough intensity is also an important
determinant of cough severity in some patients. Further stud-
ies are needed to investigate whether automated measures of
cough intensity can be derived from sound-based cough mon-
itors. Although the optimal assessment of cough severity is not
known, it is likely that a combination of subjective and objec-
tive assessments will be necessary. It is essential that future
clinical trials of antitussive drugs use well-validated cough se-
verity assessment tools.
CONCLUSIONS
Unexplained chronic cough should be considered a disorder
rather than just a symptom. Cough reflex hypersensitivity is
a feature of most patients with unexplained chronic cough. The
cause or aggravant of cough should be treated in patients with
reversible cough hypersensitivity. Cough hypersensitivity is per-
sistent in some patients, for whom there are few therapeutic
options. There is a pressing need to develop antitussive drugs that
down-regulate cough reflex sensitivity. This will be achieved by
investment in research and development that leads to a better
understanding of the genetic, molecular, and physiological basis
of cough. Future trials of therapy for cough should be designed
as randomized controlled trials and incorporate validated sub-
jective and objective outcome parameters. There are clearly
many challenges ahead for clinicians, researchers, and the
pharmaceutical industry involved in the care of patients with
cough as attempts are made to explain what is so far unexplained.
However, there have been substantial improvements, giving
us new tools and understanding. This should be a focus to go
forward.
Figure 2. Cough severity assessment
tools. QOL 5 quality of life; VAS 5 visual
analog scale.
714 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Author Disclosure: S.B. has served on an advisory board for Pfizer, consultant for
Biocopea, was compensated as a lecturer for Schering Plough, received industry-
sponsored grants from Pfizer for research and occasional payments for use of the
Leicester Cough Questionnaire in commerically sponsored clinical trials.
Acknowledgment: The author thanks Dr. Richard Irwin for input into this review
article.
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