Perspective

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Therapy for cough: where

does it fall short?
Expert Rev. Respir. Med. 5(4), 503513 (2011)

Anne B Chang
Child Health Division, Menzies School
of Health Research, Charles Darwin
University, Darwin, NT, Australia
and
Queensland Childrens Respiratory
Centre and Queensland Childrens
Medical Research Institute, Royal
Childrens Hospital, Brisbane,
QLD4029, Australia
Tel.: +61 73 636 5270
Fax: +61 73 636 1958
annechang@ausdoctors.net

Studies on cough have come a long way but many shortfalls still exist. These shortfalls can be
attributed to: the lack of randomized controlled studies with a focus on cough; studies not
using robust cough outcome measures, poor definition of target groups in studies and
guidelines, the lack of safe and efficacious treatments; difficulty in defining etiological factors,
and the lack of data on the predictors of response to therapies for cough dominant etiologies.
Addressing shortfalls in cough therapy that focuses on improving the lives of people with
cough requires a systematic approach that includes better medications, high quality studies,
improved multidisciplinary guidelines and education (of both health professionals and patients).
To achieve new cough therapeutics requires an improved understanding of cough in humans
(i.e., not just in animals). Development of new medications without substantial adverse events
is long awaited for cough.

Keywords : adults children clinical studies cough therapies

Just about everyone has encountered an illness with cough at some point in their lives.
While the illness is transient in most, in some
the cough is particularly severe with complications[1] . In others, the cough becomes unrelenting. Some people seek cough therapies and some
do not. To address the issue of the shortfalls
in cough therapy, considerations to several key
questions need to be addressed:
Are therapies for cough required? If so when?
What are the available existing therapies for
cough? If so, what is the evidence for these
therapies? Do therapies for acute cough differ
to that for chronic cough?
Why do the shortfalls exist and what steps
are required to address these shortfalls in
cough therapies?
The reverse of troublesome cough is the
absence or downregulation of the cough reflex
leading to the loss or the protective cough
reflex and subsequent recurrent small volume
aspiration into the airways (i.e., silent aspiration). These are likely to occur in adults who
have had a cerebral event [2] or children with
neurological problems [3] . This article will not
be dealing with this important issue as it is
restricted to troublesome cough. In addition,
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10.1586/ERS.11.35

the article takes a broad brush to the aformentioned questions. References to in-depth
systematic reviews on particular therapies are
provided whereappropriate.
Are therapies for cough required?
Evidence for requirement of
coughtherapies

The need for cough therapies by the community is reflected in several ways, including the
high frequency of consultations for cough,
annual cost of purchased medications to relieve
cough, other economic cost from lost work
days, and the associated burden of disease.
Cough (acute and chronic) is the most common reason for acute presentation to primary
care in many countries where data are available[46] . In the USA, 29.5 million doctor visits
per year are for cough [7] . In Australia, cough
is the reason for 7.3 of every 100 visits to general practitioners [6] , equating to 1.38 million
general practitioners visits/year. These medical consultations figures do not include visits
to specialists. Furthermore, in one study that
assessed the number of prior medical consultations for coughing illness in the last 12 months
before the childs first present to a respiratory
pediatrician, >80% of children had five doctor
visits and 53% had >10 [8] .

2011 Expert Reviews Ltd

ISSN 1747-6348

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Chang

The morbidity of cough is also reflected in the community use

of medications for cough. In an attempt to ameliorate cough,
various prescription and nonprescription medications are widely
used (sometimes inappropriately)[9] . Approximately 10% of US
children use a cough and cold medication in a given week [10] .
The cost of over-the-counter medications (OTCs) for cough consumed in Australia is AUD$3.5 million/year [11] . In the USA, it
is estimated that consumption of OTCs is several billions of dollars per year [12] . In addition to cost, use of OTCs may result in
adverse events (including accidental poisoning and death[13])[14] .
In an Australian study, cough OTCs are the second most common cause of accidental poisoning in young children [14] . In
addition to OTCs, empirical treatment cough is common in
adults and the cost of prescribed medicines (e.g., that for asthma,
gastroesophageal reflux, and so on) used for cough is unknown.
Economic cost also result from loss of work days (from adults
being unwell, or in having to take time off to look after their
child). In accordance with Knutson and Braun, In the USA,
treatment costs for acute bronchitis are enormous: for each episode, patients receive an average of two prescriptions and miss
two to three days of work [15] . Data on lost work days related to
chronic cough in adults or children are unavailable.
A fourth component that reflects the need for effective therapies
for cough is reflected in the associated burden of disease. This
can be couched in terms of prevalence of cough and its impact on
quality of life (QoL) for the patient and their families.
Prevalence of acute & chronic cough
Acute cough

Data on cough prevalence is gleaned from epidemiological studies

aimed at evaluating respiratory symptoms in relation to a host
of other factors (pollution, asthma and so on). These studies in
general do not differentiate between acute and chronic cough.
Further various types (nocturnal cough, productive cough etc.)
of reported cough were used in defining cough, and these types of
cough are not interchangeable. Bearing in mind the limitations of
the data, the prevalence of cough reported in these studies ranges
from 10% (cough without asthma) [16] , 22.2% (cough lasting 2 or
more weeks [17]) up to 41.5% in remote Aboriginal communities
in Australia [18] . In Hong Kong schoolchildren, 1016% of children have a frequent cough without cold, with has been reported
to be related to level of air pollution [19] . The prevalence of cough
in epidemiological studies in adults also has a wide range. One
study that reported on the European Community Respiratory
Health (based in 16 centers) described that in young adults aged
2048 years the median prevalence of nocturnal, nonproductive
and productive cough in the different centre was 30.7, 10.2 and
10.2%, respectively [20] . Furthermore, data on isolated cough in
epidemiology studies is limited by validity of questionnaires [21] .
Chronic cough

With the limited validity of chronic cough questionnaires for

community use [21] , there is little accurate data on the prevalence
of chronic cough. The prevalence and etiologies for chronic cough
would invariably depend on definition utilized (e.g., duration of
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chronic cough) and the setting (e.g., affluent vs developing countries, remote vs urban, age of children/adult studies, prevalence of
tobacco smoke exposure, and so on). Published data describe the
community prevalence of chronic (>3 weeks) cough in primary
school-aged children (612 years) to be 510% [22] and that of
daily chronic cough productive of phlegm in 1115-year-olds as
7.2% [23] . In adults the prevalence of chronic cough (defined as
>8weeks) has been reported to be as common as 16% [24] .
The burden of cough in children & adults & its impact
onQoL

In addition to the burden reflected in visits to doctors, OTC use

and prevalence data, the symptom is also associated with significant morbidity in both children and their parents [8,22] . There
are only three studies in children that have examined parental
evaluations or concerns of their childrens coughing illness. In
the two older studies, parents main concerns were related to disturbed sleep, discomfort and that cough would cause permanent
chest damage [25,26] . An Australian study involving 190 families
described that the most significant concerns and worries expressed
by parents were: feelings of frustration, upset, sleepless nights,
awakened at night, helpless, stressed, and sorry for child. Specific
issues that bothered the parent(s) most were: the cause of cough,
cough relating to a serious illness, their child not sleeping well
and cough causing damage [8] . Concerns and worries of parents
outlined earlier, were significantly reduced when the childs cough
resolved [8] . Unlike adults with chronic cough, children with
chronic cough do not have symptoms of anxiety [8] . In addition,
parents of children with chronic cough did not have symptoms of
anxiety or depression but were stressed [8] . This is in contrast to
the data in adults with chronic cough. In adults, chronic cough
is associated with depressive symptoms and anxiety [2730] . Adults
with cough, particularly when chronic, can also suffer from one
of the many complications of cough such as syncope and urinary
incontinence, as reviewed by Irwin [1] .
Irrespective of the underlying condition, the symptom of cough
impairs QoL. In QoL questionnaires, the pioneering work of
Juniper and colleagues showed that cough is particularly troublesome, as part of the symptom complex of a disease like asthma [31] .
Of the 152 items examined for constructing the asthma-specific
QoL for adults, cough was the fourth most frequent item and
also the fourth most important impact [31] . Voll-Aanerud and
colleagues showed that irrespective of diagnosis (asthma, chronic
obstructive pulmonary disease or no diagnosis), respiratory symptoms (including cough) were a determinant of QoL in adults [32] .
In addition, cough-specific QoL scores do not differ for different
underlying etiologies of cough in adults [33] .
There is less data on QoL issues in children as cough-specific
QoL for pediatric use was only recently developed in 2008 [34] , in
contrast to that for adults, which was first available in 2002 [30] .
Pediatric data have shown that parents of children with chronic
cough have a poorer QoL that improves when the cough is
resolved [8,35] . Irrespective of the etiology, the symptom of chronic
cough is associated with significant morbidity to parents [25,36] and
children as it disrupts activities including school and sleep [22] .
Expert Rev. Respir. Med. 5(4), (2011)

Therapy for cough: where does it fall short?

When are therapies for cough required?

The aformentioned brief overview leaves little doubt that cough

is common and, when present, is a relatively troublesome symptom
for a substantial number of people. Outside of expected cough[37] ,
the presence of cough is not normal and thus the condition causing
the cough should be sought and treated. That is, when treating a
patient with a cough and in the consideration of cough therapies,
obtaining the right diagnosis (and thus treatment of it) is crucial.
Cough related to underlying disease improves or totally resolves
when the condition is treated, such as that related to protracted
bacterial bronchitis in children. The importance in obtaining the
right diagnosis in the management of cough is reflected in consequences when an underlying cause is missed or delayed, such as
airway obstruction leading to bronchiectasis [38] . Thus cough related
to an underlying disease should always be treated by addressing
therapies of the underlying disease.
In expected cough, some also seek therapies for cough. However,
in these circumstances consideration of balance of possible adverse
events (from the therapy) versus benefit (resolution of cough) should
be undertaken. Nevertheless, in some circumstances (such as when
severe complications like cough syncope occur in adults) irrespective
of the cause, therapies are also arguably required.
When determining therapies for cough, consideration of oversuppression of the protective cough reflex that is necessary for maintenance of a healthy airway is important. Loss of the protective
cough reflex potentially leads to aspiration, which may be silent.
Current therapies for cough
What are available existing therapies?

There is a wide array of (not necessarily effective) therapies available for cough. Therapies can be broadly divided to nonspecific
therapies and specific therapies. Nonspecific therapies range from
nonprescription treatments (including herbal therapy) to prescription medications (including nonspecific therapy such as codeine to
disease-specific treatment trials). Furthermore, whether any of these
therapies are equally efficacious in acute cough as for chronic cough
remains, to date, a speculation, given the lack of appropriate trials.
Given the lack of data, following the discussion will not differentiate
the two; but it remains important to differentiate treating cough
related to an underlying disease and that of cough itself.
Specific therapies refer to treatment of the underlying cause that
is, when the etiology causing the cough is treated, cough resolves.
Examples include treatment of exacerbations of bronchiectasis in
children [39] and treatment when cough is part of the symptom
complex of asthma [40] . Clear-cut examples in adults include eosinophilic bronchitis wherein treatment with corticosteroids resolves
the chronic cough [41] . As specific cough therapies cover almost
the entirety of respiratory medicine, it will not be further discussed
other than raising issues that are not yet consolidated as potential
causes (as opposed to associations) of cough.

Perspective

at the underlying condition. While this group is sometimes referred

as cough suppressants, because not all these possible therapeutics
work through suppressing cough, nonspecific therapies is a arguably
the preferred term. The list of nonspecific therapies that has been
suggested for cough is exhaustive and as such, is not provided in this
article. A Google search on nonspecific treatment for cough returns
treatments ranging from the numerous herbal therapies (such as carrot juice, turmeric, eucalyptus leaves and mints), non-oral therapies
(such as rubs, air modifications), home remedies (e.g.,pepper in
honey, lemon with pepper and salt, garlic), manufactured treatments by nonpharmaceutical companies (such as multivitamins)
and OTCs. OTCs generally include pharmacologically active
and non-active ingredients of varying combination and doses of
expectorants (e.g., guaifenesin), cough suppressants (e.g., opiates),
demulcents (e.g., sugar-based solutions), anti-histamines and decongestants (pseudoephedrine, phenylephrine, oxymetazoline) [42] .
Prescription nonspecific therapies for cough include opiates and its
derivatives (e.g., codeine, pholcodeine, dextromethorphan), sedative
antihistamines, baclofen [43] and gabapentin [44] .
The wide array of available therapies probably reflects that
there are few effective therapies. Indeed, only honey [45] and
more recently vapor rub [46] have been shown to be effective for
acute cough in children. Readers are referred to the appropriate
Cochrane reviews on acute and chronic cough in children and
adults [4749] . These and the many guidelines on the management
of chronic cough, first pioneered by Irwin [50] , including those
endorsed by major respiratory organizations [4,24,51,52] , generally
clearly define the lack of available evidence in the searches.
That there is a shortfall in cough therapies is arguably indisputable. In addition, evidence that the management of chronic cough
(by clinicians) in children could be significantly improved is reflected
in international data [5356] . What shortfall in cough therapies comprises of, is intertwined with the reasons contributing to, and steps
required for, addressing the shortfalls in therapies for cough.
Addressing the shortfalls in cough therapies

The shortfalls in therapies for cough in children and adults, and

the many reasons that contribute to it will be discussed later. The
following is not an exhaustive list but the key issues reasons can
be grouped into issues relating to:
Randomized controlled trials (RCTs);
Cough outcome measures;
Differentiating adult versus children studies and other sampling
frame issues;
Lack of availability of medications and treatments for cough;
Yet to be defined associated conditions;
Data on predictors of response to therapies.

Nonspecific therapies for cough

General research quality issues in cough

This group of therapies refer to therapies (both prescription- and

nonprescription-based) that may resolve or diminish cough in a
generic sense (i.e., symptom relief) rather than therapies targeted

Like almost all medical interventions, but even more so in conditions like cough, RCTs are essential to be certain of treatment
effects. Cough is a symptom that has a substantial period effect

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when studied [57] (i.e., spontaneously improves with time) and is

subjected to a placebo effect as high as 80% [58] . When RCTs are
not possible strict methodological criteria, particularly that for
assessing response to treatment, needs to be applied. Clinicians
need to be aware of several factors that influence validity of data
in less rigorous study designs.
First, if subjective scores are used (i.e., objective outcome measures are not used), how it is measured is important. For example,
measuring cough outcomes only by using a subjective score at
week1 and week 8 in a non-RCT [59] without applying any criteria
is methodologically substantially flawed; as by 8 weeks after a therapy is given (and assumed taken), any improvement in subjective
cough scores can be simply related to various factors that includes
a period effect [57] and/or a placebo effect (of the medication or by
seeing someone who has taken an interest in their childs cough)[8] .
The time period effect for studies on cough was described in the
1980s by Evald and colleagues [57] . In RCTs with cough as part of
another condition such as with asthma, early studies showed that
cough resolves totally (i.e., no cough) within 12 weeks [21,52] . Thus
a time factor needs to be predetermined and applied when therapies
are given and ascribing the cough to a condition.
Second, improvement needs to be defined apriori, that is, how
large a change is to constitute an improvement in cough and
what is considered resolution of cough. A change in any subjective score needs to be large enough to be clinically relevant.
There are studies published in even reputable journals that do
not have an apriori definition of what cough improvement is.
Improvement (i.e., reduction in cough) of >70% measured by
subjective or objective studies [60] for a defined number of days
(usually 23 days) [61] has generally been used in pediatric studies.
The importance of this lies in the fact that just by seeing a doctor
who takes an interest in the childs cough, the cough score and
QoL improves before treatment [62] .
Third, ascribing an etiology to the cough also needs to be
done apriori. Cough that improves months after an intervention was given may not be related to the medication but merely
to the period and/or placebo effects. Apriori defined time frame
(time-response based) on published RCTs and data needs to be
considered. In most circumstances, 23 weeks is applicable for
chronic cough in children as noted in systematic reviews [52,63] .
Adult data has yet to systematically determine if time to response
is applicable.
To address shortfalls in cough therapies requires improving
the quality of studies. Papers with many limitations and errors
including incorrect statistical analyses for example continue to be
published (even in reputable journals) in the area of cough [64] .
While some robust techniques are still limited to research, studies
on cough have come a long way with objective measures [65] and
apriori outcomes used as far back as in the 19801990s [60,66] .
Lack of randomized controlled trials

The aformentioned reasons highlight the importance of RCTs

and the use of placebo, as recently summarized by Eccles; The
placebo effect apparent in clinical trials consists of several components: natural recovery, regression of cough response toward
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mean, demulcent effect, effect of sweetness, voluntary control, and

effects related to expectancy and meaning of the treatment[67] .
Despite the known importance of placebo-controlled randomized trials, there are few RCTs and those available generally have
small sample size [52,68] . Many Cochrane reviews relevant to children have also depicted this, the sole Cochrane review in adults
with cough was combined with children with gastroesophageal
reflux [69,70] . A recent systematic review in adults [68] has also
highlighted the problem. Thus, one shortfall in cough therapies
relates to the lack of RCTs with cough as an outcome. Improving
and using robust cough outcome measurements in studies would
improve the quality of studies evaluating efficacy of therapies and
thus address some shortfalls in cough therapies.
Cough outcome measurements

Assessments of outcomes are important in the clinical setting as

well as in research. Important outcomes for assessing efficacy of
interventions for cough include objective outcomes (cough counts
and cough receptor sensitivity [CRS]) as well as subjective measures (cough score and QoL) [34,60,7173] . While these outcomes
relate to each other, they are not interchangeable [74] . In children,
CRS has a significant but modest relationship with cough frequency and subjective cough scores have a stronger and consistent
relationship with objective cough counts [74] . Adult studies later
also confirmed the relationship and further showed that coughspecific QoL correlated to objective cough counts [75] . Ideally
cough-based studies should include both subjective and objective
outcomes that are validated. Use of appropriate outcomes would
reduce a shortfall future cough therapy studies. Validated coughspecific QoL are now available for children, the pediatric chronic
cough QoL [35,76] and adults, the Cough-Specific Quality-of-Life
Questionnaire (CQLQ) [30] and Leicester Cough Questionnaire
(LCQ) [77] . These various QoLs are not interchangeable. While
validated CRS measures are also available for both children and
adults, valid automated cough counters are still in development.
Adults versus children

In papers and guidelines on cough, clarification of the sampling

frame and target group would improve cough therapies. Pediatric
cough-related issues, like most other conditions particularly in
young children, share similarities but also have substantial important differences with adults. As recently summarized [78] , these
can be understood from physiological based domains simplified
to: cough specific, general respiratory, other direct systems such
as the immune system and other general physiology. The earlier
(among other reasons), results in observed differences in etiology,
management and measurement of response (i.e., cough outcome
measures) between children and adults. Indeed, substantial differences between children and adults have been shown in underlying
etiologies for cough and CRS [61,74,79] . Recently, it has been found
that gender does not influence objective cough counts or subjective cough scores in children [80] . This is in contrast to adult data
that showed that gender significantly influenced objective cough
scores [81] . In adults with chronic cough, objective cough counts
and CRS were higher in females than males [81,82] .
Expert Rev. Respir. Med. 5(4), (2011)

Therapy for cough: where does it fall short?

Thus, pediatricians have long advocated that children should be

managed in accordance to child-specific treatments. While some
papers clearly state the target therapeutic group, some adult-based
papers include a discussion on children yet recommend interventions clearly inappropriate for children such as the prolonged use of
oral corticosteroids (30 mg/day for 2 weeks)[71,83,84] . While pediatricians and those accustomed to looking after children usually
make the distinction irrespective of what is advocated, others do
not and commonly extrapolate adult data to children. These sometimes result in delayed diagnosis of underlying lung disease[54] and
substantial side effects such as that from the inappropriate use of
corticosteroids for children with chronic cough [53,56] .
Future studies to reduce shortfalls in cough therapies

As stated in most Cochrane reviews with a focus on cough [70,85,86]

studies that are sufficiently powered, parallel and placebo controlled are required. These should include assessing time for
improvement and resolution of cough, as well as optimal duration
of therapy using valid cough outcomes. These cough outcomes
should include objective tools (e.g., ambulatory cough monitors)
and validated subjective cough instruments, such as cough-specific
QoL instruments [34,76,77,87] and cough diaries [88,89] . Studies on
prediction of response to treatment would also be useful for clinical
practice. The significant time period effect and placebo influences
on cough as a symptom would render nonrandomized studies difficult to interpret. Design of future RCTs should have sufficient
follow-up time post-trial, to evaluate the possible carry-over effect
or recurrence of cough post-cessation of therapy. Crossover studies on cough have showed the presence of a significant carry-over
effect [90,91] . Thus crossover designed studies should be avoided.
Respiratory illness and pharmacokinetics of medications in children are sufficiently different to that in adults to warrant separate
studies on children using child appropriate valid outcomes.
Limited availability of effective medications
& treatments for cough

Despite the many available pharmacological and nonpharmacological therapies available for cough, more effective therapies are
required. While these therapies may not necessarily be pharma
ceutical based as shown by Gibson and colleagues (speech therapy
techniques were useful for vocal cord dysfunction [92]), improved
medications that are effective and safe with few adverse events
are required. To achieve this, improved understanding of the
pathophysiology of cough mechanisms in humans (i.e., not just
in animals) are required. Animal work has advanced the field
substantially in recent years and readers are referred to excellent
reviews [9395] . However, while this has come a long way in the last
15 years, it is still in infancy when compared to other conditions
such as asthma.
Examples of evaluations relating etiology to cough

As discussed previously, cough can be specific (i.e., related to

an underlying illness) or nonspecific. However, in reality, it is
sometimes not clear, such as in gastroesophageal reflux disease
(GERD) [96,97] . While respiratory-based adult guidelines clearly
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accept that GERD causes cough, pediatric groups and guidelines

from gastroenterology societies are less adamant of its cough and
effect (i.e., causation) [98,99] . Indeed, recent studies using objective
measurements of cough and reflux have also cast further doubts
on the cause and effect of GERD and cough in children [96,97]
and adults [12,100] . Examples of two emerging conditions relating
cause and effect is obstructive sleep disorders and airway lesions.
Airway lesions & cough

Chronic cough has been well described in children with airway

lesions for many years [101103] . Gormley and colleagues described
that 75% of children with tracheomalacia secondary to congenital
vascular anomaly had persistent cough at presentation [103] . By
contrast, an adult study reported that none of 24 with tracheo
malacia had chronic cough as a presenting symptom [104] . Recent
prospective cohort studies in which airway malacia was quantified, and children followed for 12 months have confirmed
that compared to controls, children with airway malacia have
increased likelihood of respiratory illness frequency, severity, significant cough and a tendency for delayed recovery [105] . However,
neither the site nor severity of malacia exhibited any significant
dose effect on respiratory illness profiles [105] .
How common airway lesions are found in asymptomatic children is unknown and how the symptom of cough relates to airway
lesions can only be postulated. Airway malacia impedes clearance
of secretions [102] and it is plausible that the prolonged cough in
these children relate to a bronchitic process, probably protracted
bacterial bronchitis (Figure 1) [61] , distal to the lesion. In addition,
when chronic bronchitis is present, airway malacia is more likely
to be present. Stradling has described bronchomalacia secondary to chronic bronchitis [106] . Thus what is cause and effect is
unknown but it is highly probable that malacia itself does not
cause cough.
Obstructive sleep breathing disorders & cough

Case series on chronic cough in adults have reported that one

of the possible etiological factors is obstructive sleep apnoea
(OSA)[107] . A retrospective review of adults with chronic cough
reported that OSA was a common finding, even when another
cause of cough was identified and that interventions to optimize
the sleep disordered breathing lead to an improvement in the
cough [108] . In a cross-sectional study, snoring in preschool children was found to be significantly associated with both nocturnal
cough and asthma [109] . However, symptoms of OSA, particularly
snoring in children is also common, with a population prevalence
of habitual snoring as high as 12% [110] . Hence the symptoms
may coexist by chance alone. Furthermore, the findings of Lu and
colleagues [109] need to be interpreted in light of known findings
of respiratory symptom reporting in children [88,111,112] and respiratory symptoms [113] . In addition, atopy (rather than reporting
of hayfever) was not accounted in the odds ratio (OR), which is
a probable confounder [114] as previously shown by the Tuscon
group. Nevertheless other biologically plausible mechanisms
may also account for the association between cough and OSA.
This includes recurrent small volume aspiration in association
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Figure 1. Bronchoscopic image depicting left main stem bronchomalacia

associated with protracted bacterial bronchitis. This childs cough settled after the
child was treated with antibiotics for protracted bacterial bronchitis.

with childhood OSA and priming of cough receptors leading

to increased cough sensitivity from mechanical vibration of the
airways from snoring.
The previous two examples (airway lesions and sleep disordered
breathing) demonstrate the difficulties of relating etiology to
cough in studies without adequate controlled studies.
Lack of data on predictors of response to therapies

It is not known if nonspecific cough therapies are efficacious for

cough relating to an underlying disease. For respiratory conditions with cough as a dominant symptom, one shortfall of cough
therapies is the lack of good data on predictors of response.
There are, however, promising markers. Examining for sputum
inflammation profiles pioneered by Hargreave has substantially
improved our understanding of airway diseases [115] . It appears logical that the presence of eosinophilic airway inflammation (as seen
in eosinophilic bronchitis [116]) could predict the response of cough
to inhaled corticosteroids. In adults with asthma, management in
accordance to eosinophilia present in sputum improves asthma
outcomes [117] . However, while there are RCTs on the use of ICS
and its effect on surrogates of eosinophilic inflammation (showing
only a modest improvement in cough in the ICS group compared
to placebo) [118] , data on predicting corticosteroid response based
on eosinophilic inflammation is lacking. In chronic obstructive
pulmonary disease, fractional exhaled nitric oxide (FeNO, cutoff of 50 ppb) was a weak predictor of short-term response to
oral corticosteroids [119] . Data from cohort studies on adults with
cough (without asthma) are inconsistent. Preito and colleagues
concluded that a significant proportion of subjects with chronic
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cough respond well to ICS therapy, these

patients cannot be identified by FeNO levels
or AMP responsiveness at baseline [120] . By
contrast, Sato etal. described that FeNO is
useful as a diagnostic marker of prolonged
cough [121] . No such pediatric studies on
FeNO have as yet been published. Clearly,
RCTs are required to examine whether
FeNO is a predictor of response to ICS in
children and adults.
In children, the presence of chronic wet
cough is dominated by the presence of
endobronchial infection (protracted bacterial bronchitis) [122] . Children with chronic
wet cough are significantly more likely to
respond to antibiotics (number needed to
treat for benefit of 3; 95%CI: 24) compared to placebo [123] . While not all wet
cough has an infective element, presence
of wet cough at the time of consultation
was indicative of specific cough with an OR
of 9.34 (95%CI: 3.4925.03) [62] . Similar
data in adults are not available.
Expert commentary

There is little doubt that there is currently

a large shortfall in therapies for cough. In addition, a mismatch
between patients needs (who seek therapies for cough) and physicians (who generally do not appreciate the impact of cough on the
patients) is present. The shortfalls in therapies for cough include
the current lack of safe and efficacious treatments and the lack
of randomized controlled studies with a focus on cough. In the
absence of a control group, many cohort studies are flawed with
the lack of an apriori time frame, definition of cough improvement (i.e., improvement in cough scores is insufficient) and use of
nonvalidated outcome measures. Other contributors to shortfalls
in cough therapies relate to the lack of the use of robust cough
outcome measures, clear definition of target groups in studies and
guidelines, the difficulty in defining etiological factors, and the
lack of data on the predictors of response to therapies for cough
dominant etiologies.
Addressing shortfalls in cough therapy that focus on improving
the lives of people with the ailment requires a systematic approach
that includes better medications, high quality studies, improved
multidisciplinary guidelines and education (of health professionals and of patients). RCTs in the management of cough [52,68] is
strikingly lacking and remain an under-researched area. New
cough medications require rigorous testing for regulatory bodies
for the US FDA to approve such therapies.
Studies in primary healthcare are required [63] as the etiologies
of cough will in variably be different in different settings [61,63,124] .
However, studies, irrespective of where conducted, need to be of
high quality to contribute to clinical care. Promotion of myths
based on personal beliefs and/or flawed methodology need to be
dispelled such as that elegantly highlighted, by McKenzie 15years
Expert Rev. Respir. Med. 5(4), (2011)

Therapy for cough: where does it fall short?

ago that isolated cough in children is rarely asthma [125] . We

have a long way to go to achieve practice based on robust evidence in the respiratory care of children, even in very common
symptoms of cough [63] and/or wheeze [126] .
To achieve this, improved understanding of cough in humans
is required. To date, most of our understanding in the pathophysiology of cough has been gleaned from animal studies. Yet,
in the area of cough, animals differ substantially from humans.
Development of new medications without substantial adverse
events is long awaited for cough.
Five-year view

On the clinical front, the challenge that therapies for GERD,

asthma and upper airway syndrome are effective for most people
with isolated nonspecific chronic cough, which was first disputed
by the pediatric groups, is likely to be increasingly challenged by
adult groups. In addition, the use of the recently promoted term
cough hypersensitivity syndrome is not likely to be clinically useful, given that it does not clinically differentiate between specific
causes of cough (such as cough associated with asthma) versus
nonspecific cough.
New RCTs on therapies for cough using improved cough outcome measures will probably emerge in the next few years. With
the change in regulations in the use of OTCs in children following publication of the 2006 American College of Chest Physicians
guidelines [4] , there is now an impetus from the pharmaceutical
companies to perform RCTs in acute cough. Large multicenter

Perspective

studies will likely emerge in the coming years. Systematic reviews

using the gold standard of Cochrane reviews on cough in adults
will likely surface, further highlighting the lack of data in adults.
Improved outcome measures for cough will probably include
validated automated cough counts that will advance the field of
clinical research. Studies delineating the predictors of response
(such as FeNO levels) to medications for cough will improve clinical practice. Multi-disciplinary guidelines, as previously advocated for cough [96] , will probably emerge in the coming years.
On the pathophysiology front, studies in animals will be further
forthcoming and are expected in humans. These will improve our
understanding of the mechanisms of cough. Finally, new medications (such as TRPA1 antagonists, nociceptin opioid receptor agonists [127] , TRPV1 antagonists [95]) will continue to be developed
and tested but are unlikely to make it into routine clinical practice
within 5 years. The pharmacophysiological rationale underlying
development of these potential medications effective for cough
is described by experts in these fields and is beyond the scope of
this article.
Financial & competing interests disclosure

Grants supporting work: Australian National Health and Medical Research

Council (NHMRC) grants 490321 and 545216. The author has no other
relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
Cough (acute and chronic) is a relatively problematic symptom to many. This is reflected in the high frequency of doctor visits, use of
medications for cough and burden apparent in quality of life measures.
There is discrepancy between burden of cough to availability of research data, and between patients needs and treatment options.
Current shortfalls in cough therapies are apparent and include the lack of randomized controlled studies with a focus on cough, issues
relating to robust cough outcome measurements, unavailability of effective therapies, little data on predictors of response to therapies
and the problems ascribing etiology to the cough.
Many cohort studies are flawed with the lack of apriori time frame, definition of cough improvement (i.e., improvement in cough
scores is insufficient) and use of nonvalidated outcome measures.
While there is a multitude of possible cough therapies (both pharmaceutical and nonpharmaceutical based) most of these have not
been critically appraised.
Addressing the many shortfalls in cough therapies requires a systematic multidisciplinary approach that involves the development of
better medications, avoiding the use of medications with significant adverse effects, high quality studies, easier access to validated
tools, improved multidisciplinary guidelines and education (of health professionals and of patients).
Improved understanding of the pathophysiology of cough mechanisms in humans (i.e., not just in animals) is required for development
of new therapies for cough.
Future guidelines for management of cough that are multidisciplinary and child- and adult-specific are advocated.

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