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Interrupting the Cough Reflex in Asthma

http://www.medscape.com/viewarticle/715989

Interrupting the Cough Reflex in Asthma

Jaclyn A.

Posted: 03/16/2010; Curr Opin Allergy Clin Immunol. 2010;10(1):77-81. © 2010

Lippincott & Wilkins

Abstract and Introduction

Abstract

Purpose of review Although cough is one of the defining symptoms of asthma,

wheeze, chest tightness and breathlessness have generally received more

attention. The impact of coughing for patients may be more important than

currently appreciated and has been rated more troublesome than wheeze, chest

tightness or disturbance of sleep.

Recent findings Studies objectively measuring cough in asthma reveal that cough

frequencies vary from those similar to healthy volunteers to cough counts

comparable to patients presenting with chronic cough, but the potential triggers

for cough in asthma are poorly understood. This review discusses our current

knowledge of cough in asthma, potential mechanisms that may provoke coughing,

the effect of current treatments and possible future therapeutics.

Summary Cough in some asthma patients is a significant problem, deserving

further attention in both clinical practice and clinical research.

Introduction

Cough is one of the defining symptoms of asthma[1] and although as such is

frequently used in the diagnosis and monitoring of asthma, the symptoms of

wheeze, chest tightness and breathlessness have generally received more

attention. Some patients with asthma present with cough as an isolated

troublesome symptom and so-called cough-variant asthma[2] is recognized as one

of the three commonest causes of chronic cough alongside rhinosinusitis (or

upper airways cough syndrome) and gastroesophageal reflux disease.[3–6] Why in

some individuals asthma leads to such profound coughing but not significant

wheeze is unclear.

The importance of cough in patient presenting with cough-variant asthma goes

without question; however, the importance of this common symptom in patients

with classical asthma may have been underestimated. A study by Osman et al. [7]

performed a conjoint analysis of patients' symptom weightings in asthma and

surprisingly found that cough and breathlessness were rated more troublesome

than wheeze, chest tightness or disturbance of sleep. In this study, cough was

the most troublesome symptom and patients were willing to trade higher levels of

other symptoms for a reduction in coughing. There are a number of potential

explanations for this: perhaps cough responds less well to current medications

than wheeze or breathlessness; cough is a distinct, easily identified problem

and may correlate closely with other symptoms; and in some patients, cough is a

dominant severe symptom and, therefore, results in the significant psychosocial

and physical complications described in patients presenting with chronic

cough.[8] A recent study[9] examined cough-specific quality of life in patients

attending a general respiratory outpatient clinic and did not find significant

differences in this setting between patients who had presented with asthma,

chronic obstructive pulmonary disease bronchiectasis or even chronic cough.

In addition to its importance to patients, some evidence from epidemiological

studies suggests that chronic cough may predict poor outcomes in asthma. In a

study[10] that followed a cohort of asthma patients over a 9-year period,

worsening of cough had the highest predictive weight for severe asthma.

The present review summarizes our current knowledge of the mechanisms underlying

cough in asthma, the effectiveness of existing treatments and the potential

targets for future treatments to interrupt the cough reflex in asthma.

Measuring Cough in Asthma

One of the barriers to a better understanding of the role of cough in asthma may

be the lack of well validated measures. Current outcome measures may not

adequately emphasize the impact of cough as perceived by patients relative to

their other asthma symptoms. Furthermore, when cough is assessed in both

clinical practice and in clinical trials, subjective reporting using visual

analogue scales or scoring systems has generally been relied upon. We have

recently shown that subjective patient reports of cough frequency in asthma

poorly represent objective cough rates.[11•] In some small studies, cough reflex

sensitivity to tussive agents such as capsaicin or citric acid has been

determined, and although mechanistically interesting, again we found these

measures do not well represent the actual amount of coughing or its impact on

patients.[11•]

As can be seen in Fig. 1,[11•,12] objective ambulatory measurement of cough

using a digital sound recording device reveals a wide range in cough frequency

in patients with classical asthma. Although cough frequencies for many asthma

patients were similar to those in healthy volunteers, the higher cough rates in

classical asthma were comparable to those we have observed in a cohort of

patients presenting with chronic cough.[12] Cough-related quality of life was

correlated with objective cough frequency in classical asthma,[11•] implying

that for patients with high objective frequencies, the impact of coughing was

significant.

Figure 1. Comparison of objective cough frequency in healthy controls,

patients with classical asthma and patients presenting with chronic cough

Note logarithmic scale on Y-axis. Data adapted from previous

publications.[11•,12]

Mechanisms Underlying Cough in Asthma

There are several possible mechanisms by which coughing in asthma might be

triggered, and potentially provide targets for the treatment of cough in asthma.

These may, however, differ considerably between individual patients.

Sensitization of the Cough Reflex

It is controversial whether hypersensitivity of the cough reflex contributes to

cough in patients with either classical asthma or cough-variant asthma. Some

studies have suggested that asthma patients have a sensitized cough reflex[13]

compared with healthy volunteers and that cough reflex sensitivity improves

following asthma treatment,[9] whereas several studies by Fujimura[14,15] have

suggested that asthma patients have similar cough reflex sensitivity to that in

normal volunteers. In patients with cough-variant asthma, the cough reflex

sensitivity was reduced by zafirlukast[16] but in a separate study of classical

asthma, this effect was not seen.[17] In contrast, a recent study[18] found

improvement in cough was not associated with improved cough reflex sensitivity

in cough-variant asthma. Many of these studies contain a small number of

patients and patient selection likely explains the contradictory findings. In

our experience, cough reflex sensitivity in classical asthma is correlated

moderately with objective cough counts;[11•] hence, if patients with high cough

rates happen to be selected, cough reflex sensitivity will probably be

heightened compared with healthy volunteers. Until cough reflex sensitivity is

measured in a large group of unselected well characterized patients and compared

with that in healthy volunteers of similar age and sex, this issue will not be

resolved.

Airway Inflammation

Asthma is a chronic inflammatory disease of the airways and is usually

associated with eosinophilic inflammation, which can be demonstrated in sputum

and airway biopsies. Cough in patients with classical and cough-variant asthma

is generally reported to respond well to treatment with antiinflammatory

agents,[5] which produce reductions in eosinophil counts. Furthermore,

eosinophilic bronchitis, a condition defined by eosinophilic airway inflammation

in the absence of airway hyperresponsiveness, may account for up to 13% of

patients presenting with chronic cough.[19] These observations raise the

possibility that eosinophilic inflammation may be responsible for cough via

influences on airway afferent nerves.

In addition to cellular inflammation, asthma patients exhibit increases in

concentrations of mediators known to be involved in the activation and

sensitization of airway nerves, for example, prostaglandin E2[20] and

bradykinin.[21] One study[22] has suggested that mast cell-derived mediators

histamine and PGD2 are increased in chronic cough patients of all causes

compared with healthy controls. In a separate study, these mediators were not

elevated in classical asthma, suggesting these mediators could be involved in

provoking excessive coughing.

Airway Mucus

Patients with classical asthma generally expectorate only small volumes of

sputum and the precise role of mucus hypersecretion as a trigger for symptoms

such as cough is unknown.[23••] In the small airways, excessive mucus produced

by the epithelium may become impacted leading to closure of the small airways

and contributing to airflow obstruction. These smaller airways are thought to

have a lower density of afferent fibers capable of responding to the mechanical

effects of mucus plugging;[24] however, coughing may be required to clear such

impactions by a squeezing action on the airway wall.

Comorbidities

It is frequently reported that apart from asthma, nasal disease and

gastroesophageal reflux disease constitute the two other commonest diagnoses

found in patients presenting with chronic cough. Both of these conditions are

known to have an increased prevalence in asthma and it is interesting to

speculate that high cough rates in asthma may be due to these comorbidities. The

mechanisms via which nasal disease and reflux provoke coughing and why some

patients present with severe coughing as a consequence of these conditions,

whereas many do not are poorly understood. Recent studies on asthma have failed

to demonstrate a role for reflux in poorly controlled asthma but have not

specifically assessed cough or weakly acid reflux events (pH 4–7).[25]

Bronchiectasis is another complicating condition in asthma patients, which may

affect up to a quarter of patients with severe asthma,[26] with larger volumes

of mucus leading to increased cough and expectoration.

Asthma Exacerbations

Exacerbations of asthma are common and are clearly associated with increased

coughing, which is likely to be due to many of the mechanisms described above,

that is, increased airway inflammation, mucus production and possibly also

heightening of cough reflex sensitivity. The majority are related to viral

infections, which even in the absence of asthma, can produce severe and

sometimes prolonged coughing.[27] In experimental rhinovirus infections, lower

respiratory symptoms (including cough) are markedly increased for asthma

patients compared with healthy volunteers.[28••] The precise mechanisms via

which viruses induce coughing and whether this is a direct or indirect effect on

airway nerves are not known.[29]

Cough and Measures of Asthma Severity

The severity of asthma involves not only the severity of the underlying disease

process but also how well the disease responds to therapy. As such Global

Initiative for Asthma (GINA) guidelines suggest asthma severity is based upon

the frequency of symptoms, number of exacerbations, medication use and

impairments/variability in forced expiratory volume in 1 s (FEV1) or peak

expiratory flow rate (PEFR).[1] In a recent cross-sectional study[11•] of

patients, we explored the relationships between objective cough frequency and

standard measures of asthma severity, including pulmonary function and airway

responsiveness. We found no significant correlations between cough frequency and

FEV1 or methacholine challenge. A number of studies[30–32] have demonstrated

that the underlying mechanisms of cough and bronchospasm are mediated by

different sensory pathways in keeping with this finding.

There was, however, a weak association between increasing nocturnal cough

frequency and dose of inhaled corticosteroid, which may be explained by poor

asthma control correlating with both greater treatment requirements and higher

cough frequency. Alternatively, patients with higher cough rates may be given

additional asthma treatment in an unsuccessful attempt to control the cough. Of

interest, cough frequency in this group of asthma patients was more influenced

by age and sex than by standard measures of asthma, with cough rates tending to

be higher in female patients and older patients, similar to that we have

observed in chronic cough.[12]

Cough and Asthma Control

Asthma control may be defined as how the symptoms and pathophysiological

features of the disease are suppressed by therapy and therefore may vary over

time. As such objective cough frequency may be a useful surrogate objective

indicator of asthma control. We have recently investigated this hypothesis by

examining the relationships between objective cough rates and disease control in

89 asthma patients using both a clinical measure (GINA classification:

'controlled', 'partly controlled' and 'uncontrolled')[33] and a validated

questionnaire-based measure (Asthma Control Questionnaire, ACQ) of asthma

control.[34] We found statistically significant differences in log total cough

rates across GINA control groups with 'uncontrolled' asthma patients having

significantly higher cough rates than those 'partly controlled' or 'controlled'.

There were also weak but statistically significant positive correlations between

ACQ score and objective cough rates over 24 h and for day and night cough rates

individually. Indeed, British Thoracic Society (BTS) treatment step,[35] smoking

history (pack years), sputum eosinophil count and log total cough rate all

significantly independently predicted ACQ scores. This observation suggests

cough frequency and eosinophilic inflammation may be operating a different

paradigm.

Current and Future Treatments for Cough in Asthma

As already mentioned, it is generally accepted that cough in both classical

asthma and cough-variant asthma responds well to treatment with inhaled

corticosteroids and bronchodilators. If this impression is correct, it might be

assumed that patients with treated asthma, who still have cough, have poorly

controlled disease. Further work is required to better understand to what extent

cough rates in asthma may be a consequence of inadequate treatment, comorbid

conditions or a failure of existing treatments to fully control the mechanisms

driving cough in asthma. It is noteworthy that a recent observational study[36]

of asthma patients in France found over a quarter were dispensed antitussive

agents. In patients in whom a diagnosis of asthma is confirmed but cough remains

refractory to standard treatment, there is some evidence to suggest that

leukotriene receptor antagonists may be of benefit, by reducing cough reflex

sensitivity.[16]

In recent years, considerable progress has been made in animal models

identifying specific airway afferent nerve subtypes and the channels which they

express.[37••,38••] This has allowed the identification of a number of potential

targets for novel antitussive agents, including transient receptor potential

receptors (TRPV1 and TRPA1), Nociceptin Opioid 1 (NOP1) receptors, tachykinin

receptors, cannabinoid receptors and a variety of modulators of ions channels

(for a recent comprehensive review, see reference[39••]). Whether promising

results using drugs targeting these receptors in animal studies will translate

into effective human treatments and whether such treatments will have a role in

the management of classical asthma remain to be seen.

Conclusion

In summary, rates of cough in asthma are extremely variable and the potential

triggers for cough numerous. In the patients with higher cough rates, the impact

upon patients is currently underestimated and further investigation is required

to understand the mechanisms driving cough in these patients and hence identify

targets to improve treatment.

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•• Refs. [37••-39••] provide a comprehensive review of current knowledge of

mechanisms underlying cough and how these may translate into future novel

therapies: Ref. [37••] describes the afferent nerves initiating and regulating

cough, Ref. [38••] the agents that modulate the activity of these nerves and

Ref. [39••] potential new cough therapies.

Papers of particular interest, published within the annual period of review,

have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current

World Literature section in this issue (p. 92).

[CLOSE WINDOW]

Authors and Disclosures

Jaclyn A.

Respiratory Research Group, University of Manchester, Manchester, UK

Correspondence to

Dr Jaclyn , 2nd Floor Education and Research Centre, University Hospital

South Manchester, Southmoor Rd, Manchester M23 9LT, UK Tel: +44 ;

fax: +44 ; e-mail: jacky.smith@...

Acknowledgements

Dr Jaclyn is currently funded by an MRC Clinician Scientist Award. She has

received remuneration for advice/lectures and the department has also received

financial support from GlaxoKline, Pfizer, Astra Zeneca, Schering Plough,

Procter & Gamble, Vectura and Sound Biotech. Her department has also received

funding to support studies from the Moulton Charitable Trust and a Manchester

University Stepping Stones Award.

J.A.S. is an inventor on a patent describing a novel method for cough detection,

filed by the University Hospital of South Manchester and licensed to Vitalograph

Ltd, UK. J.A.S. has an industrial collaboration with Vitalograph Ltd, UK to

develop a commercial cough monitoring system.

Curr Opin Allergy Clin Immunol. 2010;10(1):77-81. © 2010 Lippincott &

Wilkins