Manejo de la tos y enfoque diagnóstico , Otro de Medicina. Universidad Autónoma de Bucaramanga
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Manejo de la tos y enfoque diagnóstico , Otro de Medicina. Universidad Autónoma de Bucaramanga

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Cough management in primary, secondary and tertiary settings

Accepted Manuscript

Cough management in primary, secondary and tertiary settings

Kay Wang, Nikki Milojevic, Bryan Sheinman, Omar S. Usmani

PII: S1094-5539(16)30196-1

DOI: 10.1016/j.pupt.2017.05.001

Reference: YPUPT 1618

To appear in: Pulmonary Pharmacology & Therapeutics

Received Date: 19 December 2016

Revised Date: 10 April 2017

Accepted Date: 1 May 2017

Please cite this article as: Wang K, Milojevic N, Sheinman B, Usmani OS, Cough management in primary, secondary and tertiary settings, Pulmonary Pharmacology & Therapeutics (2017), doi: 10.1016/ j.pupt.2017.05.001.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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TITLE PAGE: 2

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Cough Management in Primary, Secondary and Tertiary Settings 4

Kay Wang1, Nikki Milojevic2, Bryan Sheinman2, Omar S Usmani3 5

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1Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford 7

OX2 6GG, UK 8

2North Middlesex University Hospital NHS Trust, London N18 1QX, UK 9

3National Heart and Lung Institute, Imperial College London & Royal Brompton 10

Hospital, London SW3 6LY, UK 11

12

Corresponding author 13

Dr. Omar S. Usmani 14

National Heart and Lung Institute, Imperial College London & Royal Brompton 15

Hospital, London SW3 6LY, UK 16

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e-mail: o.usmani@imperial.ac.uk 18

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WORD COUNT: 3555 words 24

ABSTRACT 25

This review reflects upon the management of cough in primary, secondary and 26

tertiary care settings. It reviews the burden of cough, the diagnostic tools employed 27

to investigate the cause of cough and pragmatic treatment strategies. A clinical case 28

vignette presenting in primary care highlights the challenges of managing cough by 29

family practitioners. An approach to establishing a persistent cough clinic service in 30

secondary care is described. Finally, the entity of idiopathic cough in tertiary care 31

and the specialist approaches to treating recalcitrant cough are addressed. 32

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KEYWORDS: cough, family practitioners, pulmonologists 48

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MAIN TEXT 49

50

1. Management of Cough in Primary Care 51

1.1 Burden of cough 52

Cough is one of the most common reasons why patients consult in primary care,[1,2] 53

and is associated with considerable economic burden as well as physical, social and 54

psychological morbidity.[3,4] Acute cough in preschool children alone is estimated to 55

cost the UK NHS around £31.5 million annually (ref: Hollinghurst S et al. BMC Family 56

Practice 20089:10 DOI: 10.1186/1471-2296-9-10). 57

Most episodes of cough which present in primary care are caused by acute self-58

limiting viral respiratory tract infections, some of which develop into post-infectious 59

cough. Post-infectious cough is associated with severe impairment in cough-specific 60

quality of life. However, around 50% of patients with post-infectious cough recover 61

two weeks after initial presentation.[7] Asthma, chronic obstructive pulmonary 62

disease (COPD), and pneumonia are also important differential diagnoses for acute 63

or subacute cough lasting up to eight weeks. Survey data from general practitioners 64

highlight the potential utility of point-of-care tests in helping them with diagnosis, 65

management and referral decisions in these patients.[6] 66

67

In a patient with chronic cough (cough persisting for more than 8 weeks), the main 68

differential in primary care is to determine if the cause is asthma, gastro-69

oesophageal reflux disease (GERD), upper-airway cough syndrome (eg rhinitis, 70

rhinosinusitis), or exclude an underlying chest malignancy or infection. Non-acid 71

reflux is another important but less well recognised cause of chronic cough, which 72

may present in the absence of dyspepsia with symptoms such as cough on eating, 73

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drinking or speaking, a strange taste in the mouth, postural provocation of cough and 74

changes in phonation. Cough hypersensitivity syndrome is also an important cause 75

of chronic cough, which may encompass patients with chronic idiopathic cough as 76

well as individuals with other conditions associated with heightened response to 77

cough-provoking stimuli (Morice A et al. European Respiratory Journal 2014 44: 78

1132-1148) 79

80

Uncertainty around the management of chronic cough in primary care is still 81

widespread, with around 13% of coughs in children and around 4% of coughs in 82

adults having no recorded diagnosis.[8] Although direct access by primary care 83

physicians to hospital investigations, such as chest radiography, full lung-function 84

testing and computed tomography of the lungs is becoming more commonplace in 85

order to help differentiate the above diagnoses, many primary care clinicians still rely 86

predominantly on clinical symptoms and signs when assessing patients with cough, 87

and only have access to limited investigations in the community, such as spirometry 88

and peak expiratory flow. 89

90

1.2 A challenging case of cough 91

Mrs R is a 64-year-old non-smoker with a chronic persistent cough of over seven 92

months. She also has gastroesophageal reflux (treated with a proton pump inhibitor), 93

hypertension (treated with an angiotensin II receptor blocker) and Crohn’s disease 94

(treated with monthly week-long courses of ciprofloxacin). Mrs R initially consulted in 95

primary care after she had been coughing yellow sputum for one week. She did not 96

have a fever, but she felt her reflux symptoms had recently become worse. Her chest 97

was clear on auscultation. She was diagnosed with viral bronchitis and treated with 98

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an antacid in view of her reflux symptoms. However, her cough had still not resolved 99

after 2 weeks and she had developed shortness of breath on minimal exertion. 100

Auscultation of her chest on this occasion revealed inspiratory and expiratory 101

wheeze in both lower zones. Spirometry and a chest radiograph were performed, 102

and did not reveal any abnormality. She was therefore prescribed an inhaled 103

bronchodilator for likely viral wheeze. Nevertheless, her cough and wheeze 104

continued to persist, leading to prescription of a five-day course of oral 105

corticosteroids. 106

107

Mrs R’s symptoms mildly improved with oral corticosteroid treatment, but did not 108

resolve completely. In the weeks that followed, she was sequentially prescribed 109

macrolide antibiotics, an antihistamine, and a standard dose of inhaled 110

corticosteroid, none of which appeared to settle her symptoms. A second chest 111

radiograph was also normal, and blood tests showed only a mildly raised total white 112

cell count and C-reactive protein. At this stage, Mrs R was referred to a respiratory 113

specialist, who noted she had had a previous blood eosinophil count of higher than 114

0.3 x 109/L within the previous six months. Fractional exhaled nitric oxide (FeNO) 115

was 35 parts per billion. These findings were considered to be suggestive of 116

eosinophilic airway inflammation. Mrs R was therefore commenced on a high-dose 117

inhaled corticosteroid and advised to continue daily treatment with a proton pump 118

inhibitor. 119

120

1.3 Current management of cough 121

Based on retrospective reviews of medical records, many patients referred to 122

hospital respiratory clinics with chronic cough have undergone empirical trials of 123

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treatment in primary care. One case series including 100 adults referred with chronic 124

cough reported that over half had previously been prescribed antibiotics or inhaled 125

bronchodilators, and around a third had previously received treatments for 126

gastroesophageal reflux or inhaled corticosteroids. However, only around one-fifth of 127

patients had undergone spirometry testing prior to referral.[9] Another case series 128

involving 49 children with chronic cough reported that nearly one-third received 129

empirical trials of high-dose inhaled corticosteroids and/or oral corticosteroids before 130

referral, but only around 6% had undergone prior spirometry or other pulmonary 131

function testing.[10]132

133

Not only may empirical trials of treatment fail to provide clinical benefit, they may 134

also result in patients being unnecessarily exposed to the risk of medication-related 135

adverse events. Routinely collected data from UK general practices have 136

demonstrated that potential systemic corticosteroid-induced co-morbidities are 137

prevalent among patients with asthma.[11] The most prevalent co-morbidities 138

recorded were dyspeptic disorders (65% of patients with severe asthma, 34% of 139

patients with mild-to-moderate asthma), obesity (42% of patients with severe 140

asthma, 35% of patients with mild-to-moderate asthma), and hypertension (34% of 141

patients with severe asthma, 29% of patients with mild-to-moderate asthma). 142

143

Trial of treatment approaches may also generate unnecessary prescribing costs. 144

Combination inhaled corticosteroid/long-acting bronchodilator inhalers account for 145

47% of respiratory medication costs; for example, prescriptions for the pressurised 146

metered-dose inhaler combination of fluticasone/salmeterol (250 micrograms) are 147

associated with an estimated cost of £170 million per year.[12] 148

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149

However, one should be cognisant of incorrect diagnoses. Primary care data from 150

the Netherlands suggest that around 50% of children diagnosed with or receiving 151

treatment for asthma have an incorrect diagnosis.[13] Among 652 children aged 6 to 152

18 years who were coded as having asthma or receiving treatment for asthma, 349 153

had received minimal prescriptions for asthma medications during the previous 12 154

months, or had a diagnosis of asthma excluded by a respiratory specialist. Indeed a 155

possible contributory factor to this may be the considerable heterogeneity in the 156

nature of the underlying airway dysfunction, that has also been demonstrated in 157

patients with a primary care diagnosis of asthma.[14] A cross-sectional study of 262 158

patients with primary care-diagnosed asthma who were recruited from 12 UK general 159

practices found no abnormalities on spirometry, bronchodilator reversibility, or 160

methacholine challenge testing in 82 patients (31%). Evidence of airway hyper-161

responsiveness was only demonstrated in 87 patients (33%), and fully reversible 162

airway obstruction in only 31 patients (12%). The latter group included the highest 163

proportion of patients with evidence of sputum eosinophilia (55%), which was only 164

demonstrated in 14% of patients with normal pulmonary function tests. 165

166

2 Cough Management in Secondary Care 167

2.1 Persistent cough 168

The term ‘persistent cough’ has been adopted for cough which has persisted for 169

eight weeks or more,[15] and has been estimated to account for up to a third of 170

secondary care respiratory outpatient practice.[16]Cough which persists in the 171

absence of easily demonstrable underlying disease is often dismissed as an 172

aggravating but relatively trivial condition, carrying a negligible mortality. This ignores 173

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the considerable morbidity with which such cough is associated (marital, social and 174

work-place difficulties, stress incontinence, sleep disturbance, depression, for 175

example). Achieving a precise diagnosis is often a difficult and prolonged exercise in 176

secondary care, and at present may rely on empirical trials of treatment. Even in 177

specialist cough clinics, a significant proportion patients suffering from persistent 178

cough never receive a firm diagnosis.[17] 179

180

It has become increasingly evident that specialist management in a specifically-181

organised setting produces the best outcomes,[17] and yet in most developed 182

countries there remains a dearth of specialist cough clinics. This includes the UK, 183

where higher specialist training in Respiratory Medicine specifies no formal training 184

in the management of persistent cough. These salutary facts notwithstanding, 185

significant progress has been made in recent years, where guidelines for 186

investigation and management have been produced and are in continued 187

development.[18–20] 188

189

2.2 Causes of cough 190

A number of conditions have been identified as the underlying causes of cough with 191

asthma, gastro-oesophageal reflux disease (GERD), and upper-airway cough 192

syndrome (eg rhinitis, rhinosinusitis) being the most common. It has recently been 193

suggested that GERD may include non-acid reflux which accounts for patients with 194

clinical features suggestive of GERD but without heartburn,[21] and this syndrome 195

may respond to pro-peristaltic pharmacotherapy. Additionally, drugs such as 196

baclofen inhibit the lower oesophageal relaxations which facilitate both acid and non-197

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acid reflux and can be useful in patients with pH/impedance-demonstrated, lower-198

oesophageal reflux of both acid-and non-acid types.[22] 199

200

2.3 Cough hypersensitivity syndrome 201

The concept of Cough Hypersensitivity Syndrome,[23] has recently been introduced 202

in an attempt to present a unifying ‘umbrella’ construct, the common end-pathway of 203

different disease processes, such as GERD, asthma, eosinophilic bronchitis, upper 204

airway disease, which may result in chronic cough. A significant percentage of 205

patients have no conventionally-demonstrable pathology and are thought to have 206

‘neurogenic’ cough, perhaps as a result of up-regulation of cough receptors, 207

characterised in some patients by laryngeal paraesthesia and hypertussia, although 208

most often in the absence of other neurological features. [24] It has been suggested 209

that these syndromes may be analogous to other sensory neuropathic disorders 210

such as chronic pain. It is these patients who currently present the greatest clinical 211

challenge. 212

213

It is becoming increasingly evident that the investigation and management of 214

Persistent Cough requires sub-specialist expertise. Bearing in mind the huge burden 215

of chronic cough in the general population,[25] and that currently the overwhelming 216

majority of specialist cough clinics take place in a relatively small number of tertiary 217

care/research-associated settings, is there a place for effective management in 218

secondary care as represented by the District General Hospital (DGH) in the United 219

Kingdom? 220

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221

2.4 Establishing a specialist cough service 222

What is feasible in secondary care depends to some extent on the location of the 223

hospital relative to other investigation facilities and on patient demographics. We 224

(BDS, NM) describe our experience here of establishing a Persistent Cough Clinicat 225

the North Middlesex University Hospital NHS Trust, a secondary care DGH, serving 226

a catchment area with a large ethnic mix and a high social deprivation index with all 227

the attendant difficulties that these factors impose (literacy, language, culture, 228

compliance, regular clinic attendance, ability to attend for investigations at sites 229

remote from the hospital). Our dedicated clinic has been running for approximately 230

one year, addressing the described challenges with one Respiratory Consultant 231

(BDS) who has developed a special interest and one Speech and Language 232

Therapist (NM). We have thus far chosen to keep our cough questionnaires as 233

simple as possible and use the Hull Cough Hypersensitivity Questionnaire,[26]and a 234

Visual Analogue Scale,[27] as well as a Laryngeal Hypersensitivity 235

Questionnaire,[28] The questionnaires have been translated for us into a number of 236

languages. The utilisation of these questionnaires could be beneficial in primary care 237

but in real-life day-to-day practice is not usual for clinicians to use questionnaires to 238

evaluate cough in primary care. We have been granted the services of a dedicated 239

pH/impedance-manometry service at a nearby tertiary centre, and have also forged 240

links with a sub-specialist upper GI-surgeon at another tertiary centre, in order to 241

support the service. 242

243

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Our database currently lists about 75 patients many of whom have been investigated 244

and/or treated in primary and other secondary care centres (non-cough specialist 245

general respiratory clinics) previously. Many have not yet reached the end of our 246

own diagnostic/therapeutic algorithms and it is thus too early to compare and 247

contrast our results with other specialist cough centres. There is, nevertheless, a 248

clear preponderance of patients related to GERD and a large proportion of these 249

patients respond to high-dose acid suppression for cough, which had most often 250

been present for at least several months and not infrequently for years. Many of 251

them can be weaned down to conventional doses or even intermittent treatment. We 252

have also been able to identify and treat non-GERD cases; one of our patients with 253

‘neurogenic’ cough and Arnold’s Reflex reported her first relief from severe coughing 254

for thirty years in response to gabapentin where her VAS indicated an approximate 255

80% improvement. Where pharmacotherapy has failed, we have achieved success 256

with ‘laryngeal hygiene’,[29]combined with training in cough suppression. 257

258

It is our view that dedicated persistent cough clinics can be practical and effective in 259

the secondary care setting, and an organised approach is essential to effective 260

management. We advocate that specialist training for respiratory interns now needs 261

to take specific account of persistent cough which is common, disabling and of 262

considerable socioeconomic importance. 263

264

3 Challenges in Tertiary Care 265

3.1 Effective communication 266

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The challenges in tertiary care mirror those in primary and secondary care. The 267

considerable impact of the debilitating and distressing cough on the patient’s quality 268

of life should not be under-estimated and by the time a patient reaches the tertiary 269

specialist setting they will have seen several healthcare professionals, undergone 270

numerous investigations, and as described above, will have tried a variety of trials of 271

treatments, both empirical and disease-directed, with little impact on their symptoms. 272

Therein lays the problem that cough is a symptom and not a diagnosis, and patients 273

often feel perplexed and frustrated as to why a diagnosis has eluded several 274

specialists and their symptom has not responded to treatment. Indeed patients want 275

to be understood, they want a diagnosis, they want a cure, and they want to get their 276

life back. The challenge for the cough specialist is to attain the confidence of the 277

patient, while yet another attempt is undertaken to sort their cough and in this 278

respect, effective communication with the patient and also the referring doctors is 279

critical from the outset in the management of the patient’s cough. 280

281

An important discussion with the patient in the initial consultation should revisit the 282

causes of cough, address the mechanisms of cough and discuss the approach to its 283

management in that the aim is to ‘reset’ and not abolish, the pathologically 284

exaggerated cough reflex which in itself is actually a physiological protective reflex 285

for the body. A shared goal should be to focus on achieving a reduction in the 286

patient’s subjective description of their cough intensity and cough frequency. 287

288

3.2 Idiopathic cough 289

As with many ‘difficult to treat’ clinics, the tertiary cough specialist meticulously 290

revisits the history and the causes and associations with chronic cough,[30] bearing 291

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in mind that the patient may have had an insufficient diagnostic work up or an 292

inadequate treatment course. In the tertiary, setting a number of specialised 293

investigations may be readily available to help in achieving diagnosis.The 294

uncommon causes of cough should also be sought for during the patients 295

assessment,[31,32] 296

297

Patients who are referred to tertiary specialist clinics are a highly-selected 298

population, where the diagnoses have eluded other specialists, and even after 299

further assessment and investigations, clinic case series have reported that nearly 300

40% of patients referred remain undiagnosed and the discrete clinical entity 301

‘idiopathic cough’ or unexplained cough has been recognised.[33] This is another 302

challenge for the specialist, in that the patient who was so hopeful that this ‘final 303

opinion’ would determine the cause of their cough, may become confused or indeed 304

disengaged and here the specialist needs to be erudite and have effective 305

communication skills in explaining this diagnosis of exclusion in an otherwise healthy 306

patient, and the next steps in management, particularly as the medications used will 307

most likely be off label. 308

309

3.3 Treating recalcitrant cough 310

It is important to review the drug history and accurately ascertain details on ‘failed 311

previous treatment trials’ as it is recognised that in the management of cough, the 312

right drug (or drug combination), at the right dose, needs to be given for the right 313

length of time where an underlying cause for the cough exists. For example in the 314

management of GERD, the combination of a high-dose proton pump inhibitor, 315

together with a high-dose histamine-2 receptor blocker, and an alginate for at least 3 316

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to 6 months, is considered to be an optimal approach. It should be recognised 317

though that proton pump inhibitors do not treat airway reflux per se, but treat acid 318

related symptoms and two trials show they do not work in chronic cough. As in all 319

medical disciplines, the specialist needs to encourage adherence to medication by 320

the patient, particularly when re-prescribing a previous treatment strategy approach 321

(inhalation therapy, anti-reflux medication, anti-allergy therapy) where it is vital to 322

have the confidence and trust of the patient, such that the patient adheres to 323

therapy. This can often be addressed by discussing that a therapeutic anti-tussive 324

effect may not be achieved immediately after starting therapy and could take weeks 325

or months. It is important to bear in mind that there may be multiple causes of cough, 326

and this accounts for ~1/3 of patients referred to specialist cough clinics.[33] Here, 327

consideration should be given to simultaneously treat each cause in order to adopt 328

the best possible strategy to achieve resolution in the patient’s heightened cough 329

intensity and frequency. There remains however, paucity and lack of clinical trial data 330

on the most effective approach to treating the recognised underlying causes of 331

cough.[34] 332

333

By its very nature, the therapeutic strategy in patients with idiopathic cough is even 334

more difficult and most treatments utilized are off-label. In refractory cases of cough, 335

or in patients with idiopathic cough, neuromodulatory agents such as gabapentin,[35] 336

and pregabalin,[36] may be considered. Gabapentin has been shown to significantly 337

improve cough-related quality of life compared to placebo,[35] while pregabalin used 338

in combination with speech pathology treatment is associated with significantly 339

greater improvement in cough-related quality of life and cough severity than speech 340

pathology treatment alone.[36] It is recognised that opiates in low-dose (rather than 341

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high-doses as previously prescribed) may provide temporary benefit,[37] and 342

efficacy using low-doses of gabapentin has also been described.[31] Long-acting 343

muscarinic antagonists have been used by us in tertiary care (OSU) to dampen down 344

laryngeal nerve irritability as well as treat (dry) airway secretions that may be 345

aggravating the cough reflex pathways. In this respect mucolytics, such as 346

carbocisteine, may break-up tenacious mucus that may be precipitating the patient’s 347

cough and allow the patient to expectorate and clear their airways more easily. Often 348

patients will be tried on several of the above regimens through progressive follow-up 349

appointments, when the initial treatment strategy has not worked. Although such 350

treatments tend to be initiated in secondary or tertiary care settings at the moment, 351

future development of suitable shared care models may facilitate greater primary 352

care involvement in managing these patients in the community. 353

354

As can be appreciated, there is a significant need for research to understand 355

unexplained cough in order to guide effective therapy for cough. The cough reflex 356

comprises afferent and efferent arcs and a growing body of laboratory evidence has 357

begun to demonstrate the characteristics of afferent receptors, as well as afferent 358

and efferent fibre types and pathways in both upper and lower airways. Considerable 359

interest has been centred on airway afferent Transient Receptor Potential (TRP) 360

receptors which are variably amenable to pharmacological blockade in animal 361

models. However, despite continuing efforts, translational research has not yet 362

demonstrated clinical utility. Central influences on the reflex arc are clearly important 363

because behavioural cough-suppression techniques can be very effective,[38] and 364

as discussed above some patients respond to centrally-acting drugs such as 365

gabapentin, pregabalin and morphine. Indeed, the role of low dose morphine in 366

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cough may be every effective in managing refractory patients [39]. Although 367

sometimes useful, these drugs have important, use-limiting side-effects, are 368

therefore not a panacaea. 369

370

3.4 Other interventions 371

Herbal preparations, homeopathy and plant derived products are gaining popularity, 372

with patient’s often self-medicating prior to consultation.[40] Non-drug interventions 373

such as physiotherapy,[41] or speech therapy,[42] may be helpful, and indeed 374

spontaneous resolution of cough is also well-observed in clinics. Massage and 375

acupuncture are approaches that have also been tried. [43] 376

377

As can be appreciated, and highlighted in this review series, there is a critical and 378

urgent need for effective antitussive therapy in the management of patients with 379

chronic cough.[44] There is a great deal of activity directed towards the 380

development of new drugs, with a variety of agents in development,[34] and 381

particular interest in a novel P2X3 receptor antagonist.[45] 382

383

4 Future Directions - Phenotyping Cough 384

To help clinicians target treatments for cough more accurately, a more precise and 385

personalised understanding of the pathophysiological mechanisms which produce 386

cough are needed. That is, we need to identify who to treat with what, and analogies 387

with the identification of biomarkers in the treatment of asthma may help inform us. 388

Sputum eosinophilia is a well-established marker of steroid-responsiveness,[46-48] 389

but cannot be readily assessed in primary care settings. More recent evidence has 390

demonstrated that peripheral blood eosinophil counts, which are more convenient to 391

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obtain in the community, may also be useful as a marker of eosinophilic airway 392

inflammation and steroid-responsiveness.[49,50] Indeed, in patients with mild-to-393

moderate asthma, retrospective raised blood eosinophil counts have also been 394

associated with significantly greater risk of acute exacerbations in primary care.[51] 395

Fractional exhaled nitric oxide (FeNO) is a simple non-invasive breath test, which 396

also has potential for use in primary care.[52, 53] FeNO provides objective evidence 397

of steroid-responsive airway inflammation and is an independent predictor of future 398

asthma exacerbations.[54] The National Institute for Health and Care Excellence 399

(NICE) already recommends that FeNO should be used to help facilitate more 400

accurate diagnosis of asthma and suggests that a value of 40 parts per billion (ppb) 401

or higher should be considered a positive result.[55] However, a FeNO value of 31.5 402

ppb or higher was recently reported to give the best performance in diagnosing 403

steroid-responsive chronic cough, irrespective of whether this was diagnosed as 404

cough variant asthma, eosinophilic bronchitis or atopic cough (sensitivity 54%, 405

specificity, 91.4%).[56] Highly promising are the latest studies with the P2X3 406

antagonist AF219, showing highly effective results in up to 3 months therapy in 407

patients with chronic cough and there is real hope for the future in the management 408

of patients with chronic cough [57]. 409

410

5 Summary 411

In conclusion, the words of the late John Widdicombe seem as pertinent now as they 412

were over a decade ago to all those managing patients with cough; At present, 413

treatment of cough is like treating headache with a rubber hammer to the head. I 414

would like to see development of drugs known to act on particular components of the 415

cough mechanism, and ‘specific’ to particular types of cough.416

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1. Hollinghurst S, Gorst C, Fahey T, Hay AD. Measuring the financial burden of 418 acute cough in pre-school children: a cost of illness study. BMC family practice. 419 2008;9:10. DOI: 10.1186/1471-2296-9-10 420

421

2. Morice AH. Epidemiology of cough. Pulm Pharmacol Ther. 2002;15:253–9. DOI: 422 10.1006/pupt.2002.0352 423

424 3. Dicpiginaitis, PV, Colice, GL, Goolsby, MJ, Rogg GI, Spector SL, Winther B. Acute 425 cough: a diagnostic and therapeutic challenge. Cough. 2009;5:11. DOI: 426 10.1186/1745-9974-5-11 427

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