A Double-Blind, Randomized, Placebo Controlled Study of the Efficacy and Safety of Three Doses of Orvepitant in Subjects With Chronic Refractory Cough
Phase: PHASE2
Conditions: Chronic Refractory Cough
Sponsor: Nerre Therapeutics Ltd.

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CLINICAL STUDY PROTOCOL 
 
A DOUBLE-BLIND, RANDOMIZED, PLACEBO CONTROLLED STUDY OF THE 
EFFICACY AND SAFETY OF THREE DOSES OF ORVEPITANT IN SUBJECTS WITH 
CHRONIC REFRACTORY COUGH 
 
 
 
 
 
 
IND No:  
EudraCT No: 
ClinicalTrials.gov No: 
132343 
2016-004979-49 
NCT02993822
Protocol No.: 
VOLCANO-2  
Version No:  
Final 5.0
Date of Protocol:  
21 February 2018
 
Sponsor:            
 
NeRRe Therapeutics Ltd,  
 
 
 
 
SBC, Incubator Building,  
 
 
 
 
Gunnels Wood Rd.,  
 
 
 
 
Stevenage, 
 
 
 
 
SG1 2FX 
 
 
 
 
United Kingdom  
 
 
Confidentiality Statement: 
This protocol contains information which is the property of NeRRe Therapeutics Ltd and 
therefore is provided to you in confidence for review by you, your staff, an applicable ethics 
committee/institutional review board and regulatory authorities. It is understood that this 
information will not be disclosed to others without the written approval from NeRRe 
Therapeutics Ltd. 
This study will be conducted in compliance with Good Clinical Practice (GCP), the General 
Principles of the Declaration of Helsinki (with amendments), and in accordance with local 
legal and regulatory requirements. 
 
 
 
 
 
 
 
 
 

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1. 
PROTOCOL SYNOPSIS 
 
PROTOCOL TITLE 
A 
DOUBLE-BLIND, 
RANDOMIZED, 
PLACEBO 
CONTROLLED STUDY OF THE EFFICACY AND 
SAFETY OF THREE DOSES OF ORVEPITANT IN 
SUBJECTS WITH CHRONIC REFRACTORY COUGH 
 
PROTOCOL No. 
VOLCANO-2 
CHIEF INVESTIGATOR 
Professor Jaclyn Smith MB ChB PhD FRCP 
 
SPONSOR 
NeRRe Therapeutics Ltd 
INVESTIGATIONAL MEDICINAL 
PRODUCT   
Orvepitant and placebo 
PHASE OF DEVELOPMENT 
Phase 2 
INDICATION AND RATIONALE 
Chronic Refractory Cough 
STUDY DESIGN 
A multi-center, double-blind, randomized, parallel group, 
placebo-controlled dose range study in subjects with 
chronic refractory cough (CRC).  
Doses of orvepitant (10 mg/day, 20 mg/day and 30 
mg/day) and placebo will be investigated in four parallel 
groups. Subjects will be randomized 1:1:1:1 to each of the 
groups.  
All subjects will enter a three-week Screening period to 
determine eligibility. Eligible subjects will be randomized 
at the Baseline/Day 1 visit and enter a 12-week double-
blind dosing period. During this period there will be four 
visits at Weeks 2, 4, 8 and 12. There will be a final safety 
follow-up visit at Week 14.   
 

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• Change in the Urge-to-Cough VAS at Weeks 2, 4, 8, 
and 12 compared to Baseline  
• Change in the Leicester Cough Questionnaire (LCQ) 
score (total and three domain scores) at Weeks 2, 4, 8, 
and 12 compared to Baseline 
• Global Rating of Change in Cough Frequency and 
Severity at Weeks 2, 4, 8, and 12 
Safety 
• Change 
from 
Baseline 
in 
clinical 
laboratory 
assessments 
(hematology, 
clinical 
chemistry, 
urinalysis) 
• Change from Baseline in vital signs (temperature, 
sitting/standing Blood Pressure (BP), pulse, respiration 
rate, weight) 
• Change from Baseline in 12-lead Electrocardiogram 
(ECG) variables (heart rate and rhythm and RR, PR, 
QRS, QT, QTcF and QTcB intervals) 
• Nature and severity of Adverse Events (AE) 
• Withdrawals due to an AE 
• Use of concomitant medications  
Pharmacokinetics 
• PK exposure-response relationship for the orvepitant 
groups (10 mg, 20 mg, and 30 mg) will be carried out 
to examine the possible relationship over time between 
clinical efficacy and plasma levels of the drug 
PLANNED SAMPLE SIZE AND 
STATISTICAL 
CONSIDERATIONS 
The initial planned sample size for this study was 55 
subjects per treatment group (220 subjects in total). As a 
result of the planned sample size re-estimation the sample 
size is increased to 65 subjects per group (260 in total) 
The sample size calculation is based on pairwise 
comparisons of the primary endpoint for each active dose 
versus placebo. Objective cough frequency will be 
analyzed on a log scale. A two-sided type I error of 0.05, 
not adjusted for multiple comparisons against placebo, 
will be used for this exploratory study. Assuming a 
revised standard deviation of change from Baseline (after 
taking logs) of 0.285 (based on the sample size re-
estimate and increased from the original assumption of 
0.261), a reduction in the placebo group of 10% and a 
reduction in the orvepitant group of 35%, 65 subjects per 
arm will provide a power of 80%. This new standard 
deviation estimate has been obtained (at the first sample 
size review) by considering the revised full analysis set of 

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subjects.  
After at least 100 subjects have completed the Week 12 
ACM assessment (and in addition to the now completed 
first sample size re-estimate) the cough frequency data 
will be reviewed to check the estimate of variability 
assumed for the primary efficacy variable. This sample-
size re-estimation will be done on a blinded basis and 
may result in an increase in the sample size.   
Assuming no further changes to the sample size estimate, 
approximately 292 subjects will be randomized to ensure 
at least 260 completers (assuming approximately 10% 
drop out rate). The sample size may be adjusted again 
after the second re-estimate and provided no more than 
320 subjects (approximately 80 per group) are required 
the precise number will be documented in a non-
substantial (administrative) amendment to the protocol.   
SUBJECT POPULATION 
 
Inclusion Criteria 
 
 
 
1. Male and female subjects ≥18 years of age 
2. Able to understand and comply with the requirements 
of the study and sign Informed Consent forms 
3. Diagnosis of CRC or unexplained cough for at least 1 
year prior to Screening (see American College Chest 
Physicians/British Thoracic Society [ACCP/BTS] 
guidelines Section 17) 
4. An 
awake 
average 
cough 
frequency 
of 
≥10 
coughs/hour, as assessed using an ACM during the 
Screening period (note, the ACM will be worn for a 
24-hour period and the average waking cough 
frequency determined) 
5. Females must be non-pregnant and non-lactating with 
no intention of pregnancy during study treatment 
6. Women of child-bearing potential (WOCP) (i.e. not 
surgically sterilised or post-menopausal*) must have a 
negative blood serum pregnancy test performed at the 
Screening visit and agree to use two methods of birth 
control, one of which must be a barrier method (note: 
the double barrier method is not considered 
acceptable) for the duration of participation in the 
study.  
* Post-menopausal is defined as >1 year since the last 
menstrual period for women >55 years of age or >1 
year since their last menstrual period and have an 

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FSH level in the menopausal range for women 
<55years of age. 
Acceptable methods of birth control are: 
a. Surgical sterilization of the subject’s male partner 
(vasectomy with documented azoospermia) if he 
is the sole partner of that subject 
b. Established hormonal contraception (implantable, 
patch, oral or intramuscular [IM]) administered 
for at least one month prior to IMP administration 
and to continue for at least 4 weeks after the last 
dose of IMP 
c. An intrauterine device (IUD) or intrauterine 
system (IUS) with failure rate of less than 1% per 
year inserted by qualified physician at least one 
month prior to IMP administration and to remain 
in place for at least 4 weeks after the last dose of 
IMP 
d. Barrier methods such as male condom or cap, 
diaphragm or sponge with spermicide 
7. Male subjects and their partners of child-bearing 
potential must use two methods of acceptable birth 
control, one of which must be a barrier method; male 
subjects must make no donation of sperm from 
Screening until 90 days after the last dose of IMP 
Exclusion Criteria 
 
1. Subjects with recent respiratory tract infection (<4 
weeks prior to Screening) 
2. Females who are breast feeding or pregnant 
3. Current smokers or ex-smokers with <6 months’ 
abstinence prior to Screening 
4. Treatment with Angiotensin Converting Enzyme 
(ACE) inhibitors within 3 months of Screening 
5. A history of drug or alcohol abuse within 12 months 
of Screening 
6. Both FEV1 <80% predicted and FEV1/FVC ratio 
< 0.7, measured at Screening using spirometry 
7. History of cystic fibrosis, idiopathic pulmonary 
fibrosis, 
clinically 
significant 
bronchiectasis, 
moderate to severe asthma, chronic obstructive 
pulmonary disease (COPD) 

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8. Evidence of uncontrolled hypertension at Screening 
or Baseline1  
9. Recent myocardial infarction (within 1 year prior to 
Screening), or history of congestive cardiac failure 
10. Any clinically significant abnormalities on 12-lead 
ECG at Screening or Baseline/Day 1 
11. Subjects with prior renal transplant, current renal 
dialysis, or history of renal tubular acidosis 
12. Any clinically significant neurological disorder 
13. Any clinically significant or unstable medical or 
psychiatric condition that would interfere with the 
subject's ability to participate in the study 
14. Subjects with a prior medical history of or an 
increased risk of seizures (except febrile seizures in 
infancy), or who have a history of recent head trauma 
(within the last 6 months prior to Screening) that 
resulted in a loss of consciousness or concussion 
15. Any malignancy in the past 5 years unless non-
invasive and in remission (disease-free for >5 years 
prior to Screening) and written approval has been 
obtained from Sponsor, with the exception of skin 
cancers not including malignant melanoma 
16. Any clinically significant abnormal laboratory test 
result(s), measured at Screening2 
17. Inability to comply with the use of prohibited and 
allowed medications as described below: 
a. The use of opioids, dextromethorphan, gabapentin, 
pregabalin, baclofen, antihistamines or tricyclic 
antidepressants (e.g. amitriptyline) for treatment of 
cough is not allowed throughout the study. 
Subjects must have discontinued these drugs at 
least 1 month prior to Screening. Subjects may, 
however, be permitted to continue to use these 
drugs if they have been prescribed solely for the 
management of another disorder (e.g. neuropathic 
pain, depression). 
b. The use of other drugs taken solely for the 
treatment of cough (including those used on an as 
needed basis) is also prohibited from at least 1 
                                                 
1 as guidance, systolic >160 mm Hg or diastolic >90 mmHg should result in further evaluation which may include 
repeat measurements after a period of rest 
2 The investigator should judge the clinical relevance of any abnormal laboratory parameters in the context of the 
subject’s current and past medical history and any know contributing factors (e.g., strenuous exercise resulting in 
elevated AST or CK) 

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month prior to Screening. 
c. Concomitant respiratory medication (other than for 
management of cough) is allowed, but subjects 
must be stable on such medication and take it for 
the duration of the study 
d. Use of digoxin is not allowed from Screening until 
1 week after the last dose of IMP 
e. Use of known CYP3A4 substrates with a narrow 
therapeutic range is not allowed from Screening 
until 1 week after the last dose of IMP (including 
but not limited to alfentanil. cyclosporine, 
dihydroergotamine, 
ergotamine, 
fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus) 
f. Use of strong or moderate inhibitors of CYP3A4 is 
not allowed from Screening until 1 week after the 
last dose of IMP (including but not limited to 
clarithromycin, erythromycin, grapefruit juice, 
indinavir, 
lopinavir, 
ritonavir, 
saquinavir, 
atazanavir, 
itraconazole, 
ketoconazole, 
voriconazole, 
fluconazole, 
posaconazole, 
cimetidine, cyclosporine, diltiazem, fluvoxamine, 
imatinib, 
verapamil, 
troleandomycin 
and 
ciprofloxacin) 
g. Use of inducers of CYP3A4 is not allowed from 
Screening until 1 week after the last dose of IMP 
(including 
but 
not 
limited 
to 
rifampicin, 
carbamazepine, efavirenz, bosentan, modafinil, St. 
John's Wort) 
h. Use of known P-glycoprotein inhibitors is not 
allowed from Screening until 1 week after the last 
dose of IMP (including but not limited to 
amiodarone, 
azithromycin, 
carvedilol, 
clarithromycin, 
conivaptan, 
cyclosporine, 
diltiazem, dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir and ritonavir, 
quinidine, ranolazine, verapamil) 
18. Participation in any clinical research study evaluating 
another investigational drug or therapy within 30 days 
or within 5 half-lives (whichever is longer) of the 
investigational drug prior to Screening. If the subject 
is in an observational clinical study no washout is 
required 
19. Subjects receiving aprepitant (Emend®) or 
fosaprepitant (Ivemend®), NK-1 antagonists licensed 
as anti-emetics <4 weeks before the Screening visit 
20. Subjects who have previously received orvepitant at 

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any time 
21. Known allergy to any of the excipients (see Section 
9.2) used in the investigational medicinal product 
(IMP) (orvepitant or placebo tablets) 
22. Subjects who, in the opinion of the Investigator, 
should not participate in the study for any other 
reason 
ORVEPITANT 
FORMULATION/DOSE 
Orvepitant 10 mg, 20 mg, 30 mg tablets  
REFERENCE 
FORMULATION/DOSE 
Matching placebo 
ROUTE OF ADMINISTRATION 
Oral 
DURATION/FREQUENCY OF 
TREATMENT 
Once daily dosing for 12 weeks 
EFFICACY ASSESSMENTS 
• Subjects will be fitted with an ACM 
 
to record objective cough frequency over 24 hours at 
Screening, Weeks 2, 4, and 12 
• Subjects will complete the LCQ at the clinic at 
Baseline/Day 1 and Weeks 2 ,4 ,8, and 12  
• Subjects will complete the Global Rating of Change 
for Cough Frequency & Severity Scale at the clinic at 
Weeks 2, 4, 8, and 12 
• Subjects will complete both the Cough Severity VAS 
and Urge-to-Cough VAS at the clinic at Baseline/Day 
1 and Weeks 2, 4, 8, and 12  
SAFETY ASSESSMENTS 
Safety and tolerability will be assessed by the following: 
• Physical Examinations 
• Change from Baseline in ECG variables (heart rate 
and rhythm and RR, PR, QRS, QT, QTcF and QTcB 
intervals) 
• Change 
from 
Baseline 
in 
clinical 
laboratory 
assessments 
(hematology, 
clinical 
chemistry, 
urinalysis) 
• Change from Baseline in vital signs  
• Adverse events 
• Use of concomitant medications 

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PHARMACOKINETICS 
Plasma levels of orvepitant will be measured by analysis 
of samples collected at the clinic visits on Weeks 2, 4, 8 
and 12. 
STATISTICAL METHODS 
Relevant Screening and Baseline data (i.e. data collected 
prior to the treatment administration) and demographic 
characteristics will be summarized descriptively for each 
treatment group. Efficacy and safety endpoints will be 
summarized by descriptive statistics for each treatment 
group and for each time point. 
All statistical hypothesis tests and confidence intervals 
will be two sided, using a type I error rate of 0.05. No 
adjustment for multiple comparisons will be used for this 
study. 
The primary analysis of log transformed awake objective 
cough frequency will be conducted via a mixed model for 
repeated measures (MMRM) with the model including 
terms for region, baseline log-transformed awake 
objective cough frequency, treatment group, week, 
week*region, 
week*baseline 
and 
week*treatment 
interactions. Subject will be included as a random effect. 
Dose response analyses will be conducted. The other 
secondary endpoints will be analyzed using a MMRM 
except for the global rating of change in cough frequency 
and in severity which will be analyzed using Mantel-
Haenszel methodology. 
The safety and tolerability profile will be assessed versus 
Baseline conditions and differences between treatment 
groups and descriptive statistics will be produced, where 
applicable. 
Plasma concentrations of orvepitant will be summarized 
descriptively; possible exposure-response relationships 
will be explored. 
PLANNED DATE OF FIRST 
SUBJECT ENROLLED 
01-Apr-2017 
 
 
 
 

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2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ........................................................................................................ 2 
2. 
TABLE OF CONTENTS ...................................................................................................... 11 
3. 
LIST OF ABBREVIATIONS ............................................................................................... 14 
4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE .......................................... 17 
5. 
BACKGROUND INFORMATION ..................................................................................... 19 
5.1 
Orvepitant .............................................................................................................................. 19 
5.2 
Pre-clinical research .............................................................................................................. 19 
5.3 
Clinical experience ................................................................................................................ 19 
5.4 
Chronic Cough background and rationale for this study ...................................................... 20 
5.5 
Rationale for endpoints ......................................................................................................... 23 
6. 
STUDY OBJECTIVES AND PURPOSE ............................................................................. 23 
6.1 
Primary objectives ................................................................................................................. 23 
6.2 
Secondary objectives ............................................................................................................. 23 
6.3 
Pharmacokinetic objectives ................................................................................................... 24 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................................ 24 
7.1 
Subject numbers .................................................................................................................... 24 
7.2 
Inclusion criteria.................................................................................................................... 24 
7.3 
Exclusion criteria .................................................................................................................. 25 
7.4 
Withdrawal criteria................................................................................................................ 27 
7.5 
Criteria for Stopping the Study ............................................................................................. 28 
8. 
STUDY DESIGN .................................................................................................................. 28 
8.1 
Primary endpoint ................................................................................................................... 28 
8.2 
Secondary efficacy endpoints ............................................................................................... 28 
8.3 
Pharmacokinetic endpoints ................................................................................................... 29 
8.4 
Safety endpoints .................................................................................................................... 29 
8.5 
Study design .......................................................................................................................... 29 
8.5.1 
Screening .............................................................................................................................. 30 
8.5.2  
Baseline Visit / Day 1........................................................................................................... 30 
8.5.3 
Interim and Final Study Visits ............................................................................................. 31 
9. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION ......................................... 32 
9.1 
Selection of doses in the study .............................................................................................. 32 
9.2 
Investigational medicinal product ......................................................................................... 33 
9.3 
Allocation to Treatment ........................................................................................................ 34 
9.4 
Study Treatment and Administration .................................................................................... 34 
9.5 
Duration of Subject Participation .......................................................................................... 35 
9.6 
Treatment Accountability and Compliance Checks .............................................................. 35 
9.7 
Treatment Blinding Code ...................................................................................................... 36 
9.8 
Permitted Concomitant Medications ..................................................................................... 36 
9.9 
Prohibited Concomitant Medication ..................................................................................... 36 
9.10 
Other Study Restrictions ....................................................................................................... 37 
10. 
STUDY SCHEDULE ........................................................................................................... 38 
10.1 
Volume of Blood sampling ................................................................................................... 40 
10.2 
Efficacy assessments ............................................................................................................. 40 
10.2.1 
Ambulatory Cough Monitor ................................................................................................. 40 

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10.2.2 
Leicester Cough Questionnaire ............................................................................................ 40 
10.2.3 
Cough Severity Visual Analogue Scale ............................................................................... 41 
10.2.4 
Urge-to-Cough ..................................................................................................................... 41 
10.2.5 
Global Rating of Change Questionnaire for Cough Frequency and Severity ...................... 41 
10.3 
Safety Assessments ............................................................................................................... 41 
10.3.1 
Medical history and concomitant diseases ........................................................................... 41 
10.3.2 
Physical examinations .......................................................................................................... 42 
10.3.3 
Spirometry ............................................................................................................................ 42 
10.3.4 
12-Lead ECGs ...................................................................................................................... 42 
10.3.5 
Clinical chemistry ................................................................................................................ 43 
10.3.6 
Hematology .......................................................................................................................... 43 
10.3.7 
Urinalysis ............................................................................................................................. 43 
10.3.8 
Vital signs ............................................................................................................................. 44 
10.3.9 
Pregnancy Testing, Contraception and Pregnancy ............................................................... 44 
10.4 
Pharmacokinetics .................................................................................................................. 45 
10.5 
Adverse events ...................................................................................................................... 45 
10.5.1 
Definitions ............................................................................................................................ 45 
10.5.2 
Assessment of Severity ........................................................................................................ 47 
10.5.3 
Assessment of Causality....................................................................................................... 47 
10.5.4 
Adverse Event Reporting ..................................................................................................... 47 
11. 
STATISTICAL CONSIDERATIONS .................................................................................. 48 
11.1 
Estimated Sample Size .......................................................................................................... 49 
11.2 
Analysis Sets ......................................................................................................................... 49 
11.3 
Data Analysis ........................................................................................................................ 50 
11.4 
Demographics and Baseline Characteristics ......................................................................... 50 
11.5 
Statistical Methods for Efficacy Parameters ......................................................................... 50 
11.5.1 
Primary Efficacy Analysis ................................................................................................... 50 
11.5.2 
Secondary Efficacy Analysis ............................................................................................... 51 
11.6 
Statistical Methods for Safety Parameters ............................................................................ 51 
11.7 
Pharmacokinetics Analysis ................................................................................................... 52 
11.8 
Missing Data ......................................................................................................................... 52 
12. 
END OF THE STUDY ......................................................................................................... 52 
13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT .............................................. 52 
13.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and Relevant 
Authorities ............................................................................................................................. 52 
13.2 
Ethical Conduct of the Study ................................................................................................ 52 
13.3 
Informed Consent .................................................................................................................. 52 
14. 
STUDY AND DATA MANAGEMENT .............................................................................. 53 
14.1 
Protocol Amendments ........................................................................................................... 53 
14.2 
Monitoring ............................................................................................................................ 53 
14.3 
Quality Assurance ................................................................................................................. 54 
14.4 
Data Recording...................................................................................................................... 54 
14.4.1 
Data to be Considered as Source Data ................................................................................. 54 
14.5 
Confidentiality ...................................................................................................................... 54 
14.6 
Retention of Study Data ........................................................................................................ 55 
14.7 
Communication and Publication of Results .......................................................................... 55 

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14.8 
Indemnification ..................................................................................................................... 56 
15. 
REFERENCES ...................................................................................................................... 57 
16. 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ........................................ 63 
17. 
APPENDICES ...................................................................................................................... 65 
 

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3. 
LIST OF ABBREVIATIONS 
ACCP 
American College of Chest Physicians 
ACM 
Ambulatory Cough Monitor 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ALT 
Alanine amino transferase 
ACE 
Angiotensin Converting Enzyme 
AST 
Aspartate amino transferase 
BP 
Blood Pressure 
BTS 
British Thoracic Society 
COPD 
Chronic Obstructive Pulmonary Disease 
eCRF 
Electronic Case Report Form 
CRC 
Chronic Refractory Cough 
CSR 
Clinical Study Report 
CQLQ 
Cough specific Quality-of-Life Questionnaire 
CRO 
Contract Research Organization 
cVRG 
caudal Ventral Respiratory Group 
DAP 
Data Analysis Plan 
ECG 
Electro cardiogram 
EGFRi 
Epidermal Growth Factor Receptor inhibitor 
ERS 
European Respiratory Society 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
H0 
Null Hypothesis 
H1 
Alternative Hypothesis 
IB 
Investigators Brochure 

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ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IM 
Intramuscular 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
IWRS 
Interactive Web Response Services 
LCQ 
Leicester Cough Questionnaire 
MCV 
Mean Corpuscular Volume 
MDD 
Major Depressive Disorder 
MeDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MMRM 
Mixed model for repeated measures 
NK 
Neurokinin 
NONMEM® 
Nonlinear mixed effects modeling  
NTS 
Nucleus Tractus Solitarius 
PET 
Positron Emission Tomography 
PIS 
Participant Information Sheet 
PK 
Pharmacokinetic 
Pop PK 
Population PK 
PTSD 
Post-Traumatic Stress Disorder 
QD 
One a day 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 

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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Events 
TMF 
Trial Master File 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WOCP 
Women of Child-bearing Potential 
 
 

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4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE 
Chief Investigator 
Prof Jaclyn Smith MB ChB PhD FRCP 
Professor of Respiratory Medicine and Honorary 
Consultant 
Division of Infection, Immunity and Respiratory 
Medicine, University of Manchester, 
Director, South Manchester Respiratory and 
Allergy Clinical Research Facility, 
 
 
  
 
 
Medical Expert (Sponsor) 
Stephen Pawsey MBBS FRCA FFPM 
NeRRe Therapeutics Ltd 
SBC, Incubator Building,  
Gunnels Wood Rd.,  
Stevenage, SG1 2FX, UK 
 
 
 
Contract Research Organization / 
Monitors 
 
 
 
 
 
Statistical Consultants 
 
 
 
 
 
  
 
 
 

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GENERAL INFORMATION (continued) 
 
Central Clinical Laboratories 
 
 
  
 
 
 
  
 
 
 
 
Pharmacokinetic  Laboratory 
 
  
 
 
 
Ambulatory Cough Monitor Provision 
and Reading Centre 
  
  
  
 
 
 
 
 

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5. 
BACKGROUND INFORMATION 
5.1 
Orvepitant 
NeRRe is developing orvepitant as a treatment for Chronic Refractory Cough (CRC), also known 
as chronic idiopathic cough or unexplained chronic cough (Irwin et al., 1998; Gibson et al., 
2016). Cough in these subjects is a difficult symptom to manage and there remains a substantial 
need for new and effective treatments (Gibson & Vertigan, 2015). It is hypothesized that chronic 
cough results from hypersensitivity of peripheral airway sensory afferent neurones and neurones 
centrally in the brainstem that together govern the cough reflex, resulting in enhanced cough in 
either response to otherwise trivial stimuli or in the absence of an initiating event (reviewed in 
Canning et al., 2014; Gibson & Vertigan, 2015). Substance P and its cognate neurokinin (NK)-1 
receptor have been implicated as having a role in induction and maintenance of the peripheral and 
central cough reflex hypersensitivity; thus NK-1 antagonism has the potential to provide a novel 
and effective approach to address the CRC subject population (Canning, 2009; Lavinka & Dong, 
2013; Harle et al., 2016). 
Therefore, the overall anticipated benefits of orvepitant as a centrally penetrant, potent and 
selective NK-1 receptor antagonist include rapid and sustained control of CRC together with 
associated enhanced general Quality-of-Life. 
Refer to the Investigator’s Brochure (IB) for additional information related to the physical, 
chemical and pharmaceutical properties and formulation of orvepitant. 
5.2 
Pre-clinical research 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3 
Clinical experience 
 

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5.4 
Chronic Cough background and rationale for this study 
Cough is a defensive reflex action of the respiratory system that is activated to clear the upper 
airways (Chung & Pavord, 2008). Excessive coughing is the leading reason for ambulatory care 
visits by subjects in the US (Hsiao et al., 2010) and has a significant impact on subject Quality-
of-Life (French et al., 1998; Chamberlain et al., 2015). Chronic coughing has been shown to have 
significant physical, social and psychological consequences (Birring et al., 2003; French et al., 
2002, Dicpinigaitis et al., 2006). Subjects often suffer complications such as chest and abdominal 
pains, retching and vomiting, urinary incontinence and even cough syncope. Many are 
embarrassed and stigmatized by this symptom and therefore avoid public places and social 
gatherings. Guidelines from the American College of Chest Physicians (ACCP) define chronic 
cough as being of duration ≥8 weeks (Irwin et al., 2006). A recent meta-analysis found the 
worldwide epidemiological prevalence of chronic cough to be 7.9% (Song et al., 2015) and was 
significantly more frequent in Europe (12.7%) and America (11.0%). Chronic cough afflicts 
women more often than men and generally has an onset from middle age (Irwin et al., 1981; 
Janson et al., 2001; Ford et al., 2006; Irwin et al., 2006; Everett et al., 2007).  
CRC represents a particular problem to physicians as the management is difficult with symptoms 
persisting despite guideline based treatment (Gibson & Vertigan, 2015). For example, in a 
community based chronic cough survey, 60% of respondents reported that their symptoms had 
not improved despite treatment (Everett et al., 2007).   
The cough pathway is complex; it is activated by sensory afferent nerve fibers in the airways that 
converge into vagus nerves to a central cough-reflex centre in the brain stem called the Nucleus 

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Tractus Solitarius (NTS). The NTS is connected in turn to respiratory related neurones that are 
involved in coordinating the cough response; higher cortical centers also provide a controlling 
influence enabling either voluntary production or inhibition of cough. A cough activating reflex 
event may occur as a result of inflammatory or mechanical changes or be triggered due to the 
inhalation of irritants. It is hypothesized that the pathological basis of chronic cough is plastic 
changes in peripheral airway sensory afferent neurones and neurones centrally in the brainstem 
that hypersensitizes the cough reflex resulting in enhanced cough in either response to otherwise 
trivial stimuli or in the absence of an initiating event (reviewed in Canning et al., 2014; Gibson & 
Vertigan, 2015). Current thinking is that a mechanism that can target both peripheral and central 
cough reflex hypersensitivity could therefore provide an optimum approach to address the CRC 
subject population. 
One such potential mechanism that could be targeted is the NK-1 receptor and its cognate ligand 
Substance P. Peripherally in the airways, hypersensitivity could result by activation of lung mast 
cells that degranulate, releasing mediators which in turn stimulate unmyelinated C-fibers to 
release Substance P creating a neuro-inflammatory state (Lavinka & Dong, 2013). Such a 
mechanism is consistent with emerging data that has shown that in isolated vagal nerves from 
both guinea-pig and humans, Substance P can cause depolarization that is blocked by the NK-1 
antagonist aprepitant (Harle et al., 2016). Centrally the hypersensitization could be due to the key 
role that the NK-1 receptor system plays as a controlling excitatory transmitter regulator in the 
cough reflex centre in the NTS (Joad et al., 2004; Mazzone et al., 2005; Mutulo et al., 2007; 
Canning, 2009; Chen et al., 2009; Sekizawa et al., 2011). Recently NK-1 receptors have been 
shown to be implicated in the cough reflex pathway in another brainstem location, the caudal 
Ventral Respiratory Group (cVRG) (Mutolo et al., 2010). In vivo in animal models, NK-1 
receptor antagonists have demonstrated to be effective anti-tussive agents in five different 
species, namely: guinea pigs (Bolser et al., 1997; El-Hashim et al., 2004; Mazzone et al., 2005), 
rabbits (Mutolo et al., 2008; Mutolo et al., 2010), cats (Bolser et al., 1997; Bolser et al., 1999), 
dogs (Chapman et al., 2004) and pigs (Moreaux et al., 2000). In these experiments, the NK-1 
antagonists were administered by different routes: systemically, by intracerebroventricular 
injection, via the central artery or by direct injection into both the NTS and cVRG. In canine 
chronic bronchitis, which is a self-perpetuating, inflammatory disease of airways, characterized 
by cough >2 months in duration, treatment with the NK-1 antagonist maropitant in a small 14-
day study, significantly decreased cough frequency (p < 0.001) and cough VAS scores (p = 
0.005) (Grobman & Reinero, 2016). 
Clinically, raised plasma levels of Substance P have been reported in humans suffering with both 
asthmatic and non-asthmatic persistent cough (Otsuka et al., 2011). Substance P was also 
elevated in induced sputum from cough subjects with acid reflux (Patterson et al., 2007), and 
chronic cough subjects with non-acid gastro-esophageal reflux (Qiu et al., 2011). Substance P has 
also been reported to be increased in nasal secretions from subjects with chronic cough (Lim et 
al., 2011) and those whose cough has been demonstrated to be hypersensitive to capsaicin 
challenge (Bae et al., 2012). Subjects with idiopathic pulmonary fibrosis (Hope-Gill et al., 2003) 

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5.5 
Rationale for endpoints 
A combination of objective and subjective tools will be used to assess the impact of orvepitant on 
subjects’ CRC.  
The primary endpoint will be change from Baseline to Week 12 in awake objective cough 
frequency measured with an automated cough monitor (ACM), 
 The use of 
acoustic cough counting to objectively assess cough frequency is recognized as a valid and 
increasingly preferred tool for primary endpoint determination in cough clinical studies (Spinou 
& Birring, 2014; Boulet et al., 2015). 
Secondary endpoint measures to be utilized that will aim to further characterize the CRC 
treatment outcomes will include awake objective cough frequency changes at other clinic visits 
and the validated Quality-of-Life assessment tool the Leicester Cough Questionnaire (LCQ) 
(Birring et al., 2003; Spinou & Birring, 2014; Boulet et al., 2015). Other patient-reported 
outcome instruments that will be deployed are the Cough Severity visual analogue scale (VAS), a 
simple to use tool that is widely utilized in cough clinical studies (Morice et al., 2007), the Urge-
to-Cough VAS (Spinou & Birring, 2014) and the Global Rating of Change for Cough Frequency 
and Severity. Safety and tolerability will be evaluated through conventional assessments used in 
the evaluation of investigational medicinal products (IMP).  
The pharmacokinetic (PK) profile of orvepitant in the target population will be characterized 
through collection of sparse samples from all subjects. Sparse sampling is a well-established 
method of collecting PK data that avoids the need for multiple blood draws and extended clinic 
visits.  
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1 
Primary objectives 
• To evaluate the efficacy of once daily doses of 10 mg, 20 mg, and 30 mg orvepitant 
versus placebo in reducing awake objective cough frequency. 
6.2 
Secondary objectives 
• To evaluate the efficacy of once daily dosing of 10 mg, 20 mg, and 30 mg orvepitant 
versus placebo in:  
• Reducing 24-hour objective cough frequency 
• Reducing night-time (non-waking time) objective cough frequency 
• Reducing subject assessed cough severity and Urge-to-Cough 
• Improving Quality-of-Life and subject perception of change 
• To evaluate the dose-response relationship of 10 mg, 20 mg, and 30 mg orvepitant  

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• To assess the safety and tolerability of 10 mg, 20 mg, and 30 mg orvepitant versus placebo 
over 12 weeks dosing 
6.3 
Pharmacokinetic objectives  
• To evaluate the exposure-response relationship of orvepitant using population PK with 
sparse sampling 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Subject numbers 
Participants in the clinical investigation shall be referred to as “subjects”. 
It is anticipated that approximately 292 subjects will be enrolled to ensure approximately 260 
completers (~ 65 subjects per group; assuming approximately 10% drop out rate). The number of 
subjects enrolled may, however, be increased to a maximum of 320 in the event that the interim 
sample size re-estimation indicates that 292 is insufficient (see Section 11.1). 
Subjects will be enrolled at approximately 50 sites across North America and Europe. Additional 
sites and regions may be added. 
7.2 
Inclusion criteria 
The following inclusion criteria will apply to all subjects: 
1. Male and female subjects ≥18 years of age  
2. Able to understand and comply with the requirements of the study and sign Informed 
Consent forms 
3. Diagnosis of CRC or unexplained cough for at least 1 year prior to Screening (see 
ACCP/BTS guidelines in section 17) 
4. An awake average cough frequency of ≥10 coughs/ hour, as assessed using an ACM 
during the Screening period (note, the ACM will be worn for a 24-hour period and the 
average waking cough frequency determined) 
5. Females must be non-pregnant and non-lactating with no intention of pregnancy during 
study treatment 
6. Women of child-bearing potential (WOCP) (i.e. not surgically sterilised or post-
menopausal*) must have a negative blood serum pregnancy test performed at the 
Screening visit and agree to use two methods of birth control, one of which must be a 
barrier method (note: the double barrier method is not considered acceptable) for the 
duration of participation in the study  
* Post-menopausal is defined as >1 year since the last menstrual period for women >55 
years of age or >1 year since their last menstrual period and have an FSH level in the 
menopausal range for women <55years of age. 
Acceptable methods of birth control are: 

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a. Surgical sterilization of the subject’s male partner (vasectomy with documented 
azoospermia) if he is the sole partner of that subject 
b. Established hormonal contraception (implantable, patch, oral or intramuscular 
[IM]) administered for at least one month prior to IMP administration and to 
continue for at least 4 weeks after the last dose of IMP 
c. An intrauterine device (IUD) or intrauterine system (IUS) with failure rate of less 
than 1% per year inserted by qualified physician at least one month prior to IMP 
administration and to remain in place for at least 4 weeks after the last dose of 
IMP 
d. Barrier methods such as male condom or cap, diaphragm or sponge with 
spermicide 
7. Male subjects and their partners of child-bearing potential must use two methods of 
acceptable birth control, one of which must be a barrier method; male subjects must make 
no donation of sperm from Screening until 90 days after the last dose of IMP 
7.3 
Exclusion criteria 
The following exclusion criteria will apply to all subjects: 
1. Subjects with respiratory tract infection (<4 weeks prior to Screening) 
2. Females who are breast feeding or pregnant 
3. Current smokers or ex-smokers with <6 months’ abstinence prior to Screening 
4. Treatment with Angiotensin Converting Enzyme (ACE) inhibitors within 3 months of 
Screening 
5. A history of drug or alcohol abuse within 12 months of Screening 
6. Both FEV1 <80% predicted and FEV1/FVC ratio < 0.7, measured at Screening using 
spirometry 
7. History of cystic fibrosis, idiopathic pulmonary fibrosis, clinically significant 
bronchiectasis, moderate to severe asthma, chronic obstructive pulmonary disease 
(COPD) 
8. Evidence of uncontrolled hypertension at Screening or Baseline3  
9. Recent myocardial infarction (within 1 year prior to screening), or history of congestive 
cardiac failure 
10. Any clinically significant abnormalities on 12-lead ECG at Screening or Baseline/Day 1 
11. Subjects with prior renal transplant, current renal dialysis, or history of renal tubular 
acidosis. 
12. Any clinically significant neurological disorder 
13. Any clinically significant or unstable medical or psychiatric condition that would interfere 
with the subject's ability to participate in the study 
                                                 
3 As guidance, systolic >160 mm Hg or diastolic >90 mmHg should result in further evaluation which may include 
repeat measurements after a period of rest 

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14. Subjects with a prior medical history of or an increased risk of seizures (except febrile 
seizures in infancy), or who have a history of recent head trauma (within the last 6 months 
prior to Screening) that resulted in a loss of consciousness or concussion 
15. Any malignancy in the past 5 years unless non-invasive and in remission (disease-free for 
>5 years prior to Screening) and written approval has been obtained from Sponsor, with 
the exception of skin cancers not including malignant melanoma 
16. Any clinically significant abnormal laboratory test result(s) measured at Screening4 
17. Inability to comply with the use of prohibited and allowed medications as described 
below: 
a. The use of opioids, dextromethorphan, gabapentin, pregabalin, baclofen, 
antihistamines or tricyclic antidepressants (e.g. amitriptyline) for treatment of 
cough is not allowed throughout the study. Subjects must have discontinued these 
drugs at least 1 month prior to Screening. Subjects may, however, be permitted to 
continue to use these drugs if they have been prescribed solely for the 
management of another disorder (e.g. neuropathic pain, depression). 
b. The use of other drugs taken solely for the treatment of cough (including those 
used on an as needed basis) is also prohibited from at least 1 month prior to 
Screening. 
c. Concomitant respiratory medication (other than for management of cough) is 
allowed, but subjects must be stable on such medication and take it for the 
duration of the study 
d. 
 
 
e. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
4 The investigator should judge the clinical relevance of any abnormal laboratory parameters in the context of the 
subject’s current and past medical history and any know contributing factors (e.g., strenuous exercise resulting in 
elevated AST or CK) 

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18. Participation in any clinical research study evaluating another investigational drug or 
therapy within 30 days or within 5 half-lives (whichever is longer) of the investigational 
drug prior to Screening. If the subject is in an observational clinical study no washout is 
required 
19. Subjects receiving aprepitant (Emend®) or fosaprepitant (Ivemend®), NK-1 antagonists 
licensed as anti-emetics <4 weeks before the Screening visit 
20. Subjects who have previously received orvepitant at any time 
21. Known allergy to any of the excipients used in the IMP (orvepitant or placebo tablets), see 
Section 9.2 
22. Subjects who, in the opinion of the Investigator, should not participate in the study for any 
other reason 
7.4 
Withdrawal criteria 
The subjects will be informed that they have the right to withdraw from the study at any time 
without stating a reason and without prejudice to further treatment.  
The Investigator may withdraw subjects from the study or may discontinue study treatment at any 
time. 
Withdrawal from the study or early discontinuation from the IMP is to be registered in the 
Interactive Web Response Service (IWRS). 
Early withdrawal or early discontinuation from the IMP of any subject who has given informed 
consent to participate will be recorded including the reason for withdrawal. The primary reason 
will be selected from the following standard categories of early discontinuations or withdrawals: 
• Failed to meet randomization criteria (screen failure) 
• Adverse Event: Clinical events occurred or laboratory results are reported that in the 
medical judgment of the investigator are grounds for discontinuation from participation in 
the best interests of the subject 
• Withdrawal of Consent: The subject desired to withdraw from further participation in the 
study. The subject is not obliged to provide any reason for withdrawal of consent, but 
where a reason is given this will be recorded on the electronic Case Report Form (eCRF) 
• Protocol Violation: The subject failed to adhere to the protocol requirements, at the 
investigator’s discretion e.g. the subject requires to start taking a medication from the 
prohibited medications list (Section 9.9) 
• Lost to Follow-Up: The subject stopped coming for visits and study personnel were 
unable to contact the subject 

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• Pregnancy: Any subject becoming pregnant during the study will be withdrawn from 
dosing.  
• Other: The subject was terminated for a reason other than those listed above, such as theft 
or loss of study drugs or termination of study by Sponsor 
Subjects who withdraw or are withdrawn from participation in the study should attend an Early 
Termination visit at which the procedures scheduled for the Week 14 Follow Up visit will be 
undertaken. If the subject withdraws due to an adverse event (AE), the event should be followed 
until resolution or care is transferred to the subject’s general practitioner or primary care 
physician. 
Subjects who are withdrawn after randomization will not be replaced.  
In some circumstances, the Investigator may discontinue study treatment without the need to 
withdraw the subject from participation in the study. When subjects permanently discontinue 
IMP, effort should be made to continue following the subject through to the end of scheduled 
visits for safety and to obtain efficacy assessments that can be assigned to the originally 
randomized treatment. 
7.5 
Criteria for Stopping the Study 
The Sponsor may terminate the study for safety or administrative reasons at any time. If, in the 
opinion of an Investigator in consultation with the Sponsor, the clinical safety observations in the 
study suggest that it may be unwise to continue, the study may be terminated either at that 
Investigator’s site or overall. 
8. 
STUDY DESIGN 
8.1 
Primary endpoint 
The primary endpoint will be change from Baseline to Week 12 in awake objective cough 
frequency measured with an ACM, 
  
8.2 
Secondary efficacy endpoints 
The secondary efficacy endpoints include: 
Objective awake cough frequency changes: 
• Change in awake objective cough frequency at Weeks 2, and 4 compared to Baseline 
• Change in 24-hour objective cough frequency at Weeks 2, 4, and 12 compared to Baseline 
• Change in night-time (non-waking time) objective cough frequency at Weeks 2, 4 and 12 
compared to Baseline 
The validated Quality-of-Life assessment tool the LCQ.  

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• Change in the LCQ score (total and three domain scores) at Weeks 2, 4, 8, and 12 
compared to Baseline 
The Cough Severity VAS, the Urge-to-Cough VAS and the Global Rating of Change for Cough 
Frequency and Severity.  
• Change in the Cough Severity VAS at Weeks 2, 4, 8, and 12 compared to Baseline  
• Change in the Urge-to-Cough VAS at Weeks 2, 4, 8, and 12 compared to Baseline 
• Global Rating of Change in Cough Frequency and Severity at Weeks 2, 4, 8, and 12 
8.3 
Pharmacokinetic endpoints 
PK exposure-response relationship for the orvepitant groups (10 mg, 20 mg, and  
30 mg) will be carried out to examine the possible relationship over time between clinical 
efficacy and plasma levels of the drug.  
8.4 
Safety endpoints 
• Change from Baseline in clinical laboratory assessments (hematology, clinical chemistry, 
urinalysis) 
• Change from Baseline in vital signs (temperature, sitting/standing BP, heart rate, 
respiration rate, weight) 
• Change from Baseline in 12-lead ECG variables (heart rate and rhythm, and RR, PR, 
QRS, QT, QTcF and QTcB intervals) 
• Nature and severity of AEs 
• Withdrawals due to an AE 
• Use of concomitant medications 
8.5 
Study design 
This is a multi-center, double blind, randomized, parallel group, placebo-controlled dose range 
study in subjects with CRC. 
Subjects will be recruited into four parallel groups, 10 mg once per day orvepitant, 20 mg once 
per day orvepitant, 30 mg once per day orvepitant, and placebo once per day. See Figure 1 for 
study design schematic. 
Subjects will enter a Screening period of up to three weeks to determine eligibility.  
Subjects will be provided the Participant Information Sheet (PIS) and Informed Consent Form 
(ICF) for their prior review. Informed consent to participation in the study will be obtained for all 
subjects before any study related procedures are performed (subjects must personally sign and 
date the approved ICF and, where applicable, privacy statement).  

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8.5.1 Screening 
The Screening visit will include the following assessments to determine the subject’s eligibility 
for inclusion into the study: 
• Full physical examination, 12 lead ECG, vital signs and spirometry (FEV1 and FVC) 
• Recording of the subject’s medical history, and prior and concomitant medication use, in 
particular other concomitant respiratory medications, both prescribed and/or over the 
counter medications 
• Blood sampling and urine sample collection for both Clinical Safety labs and serum 
pregnancy test (WOCP only) 
• Subjects will be fitted with an ACM, which will be initiated prior to the subject leaving 
the clinic to monitor cough frequency over the next 24 hours. Immediately after the end of 
this period the subjects will either return the ACM to the clinic or collection of the ACM 
from the subjects will be organised 
The digital recording data from the ACM will be uploaded and read centrally by 
and 
the cough frequency determined. 
If the ACM fails during the Screening assessment and no useable recording is generated, the 24hr 
Screening ACM may be repeated provided this is done at least 10 days prior to the planned 
Baseline/Day 1 visit and under these circumstances the Screening period may be extended by up 
to one week (so a maximum of 28 days). 
8.5.2  Baseline Visit / Day 1 
At the Baseline visit a physician must assess the Baseline eligibility criteria then sign and date 
supportive documentation at the time of the subject’s visit. 
Limited data will be collected for subjects who withdraw from the study after providing informed 
consent but prior to randomization onto the study (Screen Failures). 
Eligibility for randomization will be reviewed based on the results of the 24-hour cough 
frequency measured using the ACM following the Screening visit. To be eligible for inclusion, 
subjects must have an awake average cough frequency of ≥10 coughs/ hour.  
The Baseline visit will be Day 1. Prior to dosing on Day 1, the following assessments will be 
completed:  
• Symptom directed physical examination 
• Vital signs (after resting for ≥ 5 mins per Section 10.3.8) 
• 12-lead ECG  
• Safety labs: blood samples for clinical chemistry and hematology and urine sample for 
urinalysis  

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• Opiate drug screen 
• Urine pregnancy test for WOCP  
• Subjects will be asked to complete the LCQ, Cough Severity VAS and Urge-to-Cough 
VAS 
Eligible subjects will be randomized on Day 1 in a 1:1:1:1 ratio to orvepitant (10 mg/day,  
20 mg/day, 30 mg/day) or placebo. Randomization will be performed centrally via an IWRS. 
Subjects will be given their first dose of IMP in the clinic and take all subsequent doses every day 
in the morning for a total of 12 weeks.  
8.5.3 Interim and Final Study Visits 
During the double-blind treatment phase, subjects will return to the Clinic on Weeks, 2 4, 8 and 
12. All clinic visits must occur in the morning. The Weeks 2 and 4 visits should be scheduled 
within ±3 days of the target visit day and the Weeks 8 and 12 visits within ±5 days of the target 
visit day. 
Subjects will be instructed to attend these visits not having taken their dose of IMP. At the start of 
each visit a blood sample will be taken for determination of plasma levels of orvepitant. At the 
same time, if required per the Schedule of Events in Section 10, blood samples for safety 
laboratory assessments will be taken. Subjects will be asked to provide the time they took their 
morning dose on the previous day. After this sample subjects will take their dose of IMP in the 
clinic. At all these visits subjects will complete LCQ, Cough Severity VAS, Urge-to-Cough VAS, 
and Global Rating of Change and safety assessments will be performed.  
All assessments will be performed according to the Schedule of Events in Section 10. The order 
of assessments at these visits should be as follows:  
• Blood sampling (PK, safety labs, as applicable) 
• Dosing 
• Vital signs (after resting for ≥ 5 mins per Section 10.3.8) 
• 12-lead ECG (after resting semi-recumbent for 5 mins) 
• Questionnaires (LCQ, VAS assessments, Global Rating of Change) 
The urine sample for urinalysis, pregnancy testing and opiate drug screen can be provided at any 
time.  
At the end of the Weeks 2, 4 and 12 visits they will be fitted with an ACM, which will be 
initiated prior to the subject leaving the clinic to monitor cough frequency over the next 24 hours. 
Immediately after the end of this period the subjects will either return the ACM to the clinic or it 
will be collected from the subjects. The digital recording data from the ACM will be uploaded 
and read centrally by 
and the cough frequency determined. 

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At Week 14 a safety follow-up visit will be performed.  
All Week 14 assessments will be performed according to the Schedule of Events in Section 10. 
The following assessments will be completed:  
• Symptom directed physical examination 
• Vital signs (after resting for ≥ 5 mins per Section 10.3.8) 
• 12-lead ECG 
• Safety labs 
• Urine pregnancy test for WOCP  
Throughout the study, subjects will be monitored for safety including assessments of AEs and 
concomitant medication recordings.  
Please see Section 10 for the complete list of assessments. 
Figure 1: Study schematic 
 
 
 
9. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION 
9.1 
Selection of doses in the study 
 
 
 
 
 
 
 
 

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9.2 
Investigational medicinal product 
The IMP will consist of orvepitant 10 mg, 20 mg and 30 mg tablets or matching placebo. The 
tablets are white film-coated round tablets containing orvepitant as the maleate salt or matching 
placebo to be taken orally once-daily.  
Excipients in the tablets are as follows: 
Orvepitant 10 mg, 20 mg and 30 mg tablets:  
• 
 
 
 
 
Placebo tablets: 
• 
 
 
 
 
The physical, chemical, pharmaceutical formulation properties and characteristics of the IMP are 
described in the IB.  
IMP (i.e. orvepitant 10 mg. orvepitant 20 mg, orvepitant 30 mg or placebo) will be provided in 
white, opaque, high density polyethylene bottles with white opaque, plastic, child-resistant 
closures that include induction seal liners. A desiccant is also utilized for the IMP. Each bottle 
will contain 36 tablets (enough for a 4-week dosing period plus overage). 

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The IMP bottles will be labelled according to Annex 13, Volume 4 of EudraLex and will be in 
accordance with US regulatory requirements. 
All IMP must be stored in a secure area with access limited to the Investigator and authorized site 
staff. The IMP is to be stored at ambient room temperature up to a maximum of 30oC. 
Only authorized investigational site study staff members are to dispense the IMP. 
9.3 
Allocation to Treatment 
The study will be conducted in a double-blind manner, with the subjects, Investigators and 
Sponsor all blinded to the treatment allocated. Both orvepitant (10 mg, 20 mg, and 30 mg) and 
placebo will be presented as white tablets, identical in size and shape. 
Following the Screening period and confirmation of eligibility, subjects in each cohort will be 
randomized in a 1:1:1:1 ratio to receive either orvepitant 10 mg/day, 20 mg/day 30 mg/day or 
placebo. Randomization will be stratified by region, namely North America and Europe. 
The IMP each subject will receive will be allocated by an IWRS tool provided by 
 on 
behalf of the Sponsor. 
9.4 
Study Treatment and Administration 
IMP will be taken once daily during the 12-week double-blind treatment phase (i.e. Day 1 
through Week 12). IMP doses are fixed and will not be adjusted for individual subjects during the 
study. 
At each visit subjects will be dispensed IMP for self-administration for daily dosing until the 
subsequent visit, with overage included to allow for visit windows. 
Subjects will be required to take one tablet of IMP once-daily in the morning upon waking with 
or without food. 
Subjects will receive their first dose (Day 1) whilst at the clinic and will also take the daily dose 
at the clinic at each of the Week 2, 4, 8 and 12 visits.  
At Day 1 subjects will be dispensed sufficient supply to cover the period from Day 2 to Week 4. 
An interim check of compliance will be made during the Week 2 visit (subjects will be instructed 
to bring their IMP bottle with them to this visit). 
At Week 4 subjects will be dispensed sufficient supply to cover the period from Week 4 to 
Week 8. 
At Week 8 subjects will be dispensed sufficient supply from Week 8 to Week 12. 
At each visit an overage will be included to allow for visit windows. 

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On the days of clinic visits (Weeks 2, 4, 8, and 12) subjects will be instructed to attend the clinic 
not having taken their morning dose. The dose on these days will be taken in the clinic after a 
blood sample for analysis of blood levels of orvepitant is taken. At each clinic visit subjects will 
be asked to provide the time that they took their dose the previous morning and this will be 
documented in the eCRF; after the PK sample has been taken subjects will take their dose of IMP 
and the time recorded in the eCRF. 
All doses are to be taken at approximately the same time each morning. In the event that a subject 
forgets to take a dose in the morning then the dose can be taken at any time up until 6:00pm. 
After this time, the dose should not be taken and will be considered a missed dose.  Subjects will 
return any unused medication at each clinic visit.  
9.5 
Duration of Subject Participation 
The planned duration of participation in the study for an individual subject is up to 18 weeks, 
which includes the following: 
• Initial Screening phase of up to three weeks (can be extended to up to four weeks in the 
event that the ACM fails and the 24-hour cough monitoring must be repeated) 
• 12-week double blind treatment phase 
• Two-week safety follow-up 
9.6 
Treatment Accountability and Compliance Checks 
In accordance with regulatory requirements, the Investigator or designated site staff must 
document the amount of IMP dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to the Sponsor (or 
representative) when applicable. IMP accountability records must be maintained throughout the 
course of the study. The accountability unit for this study is a tablet. Discrepancies are to be 
reconciled or resolved. Procedures for final disposition of unused IMP will be provided in the 
Pharmacy Manual. 
The Investigator has overall responsibility in ensuring that the study treatment is received and 
managed at the study site in accordance with GCP. 
Limited responsibility may be delegated to a nominated study site representative and this 
delegation must be documented. Study treatment will be dispensed by a nominated person at each 
study site. 
The Sponsor will be permitted upon request to audit supplies, storage and dispensing records and 
procedures. 
Every effort should be made to encourage subject compliance with the dosage regimen as per the 
protocol. All subjects will be instructed to return their medication bottle with any unused tablets 
at each visit (at the Week 2 visit the same bottle will be given back to the subject for continuation 

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of dosing up to Week 4). A record of the tablets dispensed, taken, and returned will be recorded 
at each visit and compliance calculated.   
9.7 
Treatment Blinding Code 
Study investigators will be given access to the IWRS system for the purposes of emergency 
unblinding. Investigators are permitted to unblind treatment for a subject if it is deemed that 
knowledge of the subject’s treatment will impact subject’s future medical care. If possible, the 
medical monitor or Sponsor medical expert should be notified prior to the blind being broken. If 
this is not possible, the medical monitor or Sponsor medical expert must be notified as soon as 
possible if a code break was performed.  
If a suspected unexpected serious adverse reaction (SUSAR) occurs that requires expedited 
reporting to the relevant regulatory agency/Institutional Review Board (IRB) /Independent Ethics 
Committee (IEC), then the blind will be broken for the relevant subject by the 
safety 
group, in order to provide the Regulators the knowledge of the event and the causal agent. This is 
in agreement with ICH E2A and a blinded copy of the report will be provided to the investigators 
and the relevant IRB/IEC. 
If unblinding occurs accidentally this will be considered a protocol deviation, this must be 
documented in the subject’s medical notes and in the trial master file (TMF), and the Sponsor 
must be informed. 
9.8 
Permitted Concomitant Medications 
All concomitant medications taken during the study will be recorded in the eCRF with indication, 
dose information, and dates of administration. 
Concomitant respiratory medication is allowed, but subjects must have been on a stable 
dose/regimen for the three months prior to Screening and must continue to take the same 
dose/regimen for the duration of the study.  
9.9 
Prohibited Concomitant Medication 
Due to their potential effect on cough reflex sensitivity, the use of opioids, dextromethorphan, 
gabapentin, pregabalin, baclofen, antihistamines or tricyclic antidepressants (e.g. amitriptyline) 
for treatment of cough is not allowed throughout the study. Subjects must have discontinued 
these drugs at least 1 month prior to Screening and should not have them started during the study. 
Subjects may, however, be permitted to continue to use these drugs if they have been prescribed 
solely for the management of another disorder (eg neuropathic pain, depression). 
The use of other drugs taken solely for the treatment of cough (including those used on an as 
needed basis) is also prohibited from at least 1 month prior to Screening. 
 
 

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9.10 
Other Study Restrictions 
 

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10. 
STUDY SCHEDULE 
 Table 1: Schedule of Events 
 
Screening 
Day -21 to 1j 
Baseline / 
Day 1 
Wk 2 
(± 3 days)k 
Wk 4 
(± 3 days)k 
Wk 8 
(± 5 days)k 
Wk 12 
(± 5 days)k 
Early 
Termination 
Wk 14 
follow-up 
(± 5 daysk) 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Examinationi 
X 
Xc 
 
 
 
 
X 
X 
Spirometry  
X 
 
 
 
 
 
 
 
Incl/Excl Criteria 
X 
Xc 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Vital Signsa 
X 
Xc 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
Xc 
X 
X 
X 
X 
X 
X 
Ambulatory cough 
monitoringb 
Xg 
 
X 
X 
 
X 
 
 
LCQ 
 
Xc 
X 
X 
X 
X 
 
 
Global Rating of Change 
 
 
X 
X 
X 
X 
 
 
Cough Severity VAS  
 
Xc 
X 
X 
X 
X 
 
 
Urge-to-Cough VAS 
 
Xc 
X 
X 
X 
X 
 
 
PK sample 
 
 
Xh 
Xh 
Xh 
Xh 
 
 
Safety labse 
X 
Xc 
 
Xh 
Xh 
Xh 
X 
X 
Opiate drug screen 
 
Xc 
Xh 
Xh 
Xh 
Xh 
 
 
Pregnancy testf 
X 
Xc 
 
X 
X 
X 
X 
X 
Dosingd 
 
X --------------------------------------------------------------------------------------X 
 
 
AE recording 
X ------------------------------------------------------------------------------------------------------------------------------------------X 
Con Med recording 
X ------------------------------------------------------------------------------------------------------------------------------------------X 
a Vital signs: systolic and diastolic blood pressure, pulse, temperature; weight (weight at Baseline/Day 1, Week 12 and Follow-up only) 
b ACM 
to be fitted during the visit and initiated prior to the subject leaving the clinic, monitoring will be continuous for 24hrs and device switched off after this period. Subjects will either 
return the ACM to the clinic (during Screening this must be done the following day) or collection from the subjects will be organized 
c Performed prior to start of dosing 
d Subjects are given their first dose of IMP in the clinic. All doses to be taken at approximately the same time each day; on clinic visits subjects will take their dose in the clinic after the pre-dose PK and 
safety samples, as applicable, have been taken. All other assessments can be performed post-dose 
e Safety labs include blood samples and urine samples 
f Pregnancy test in women of child-bearing potential only; serum pregnancy test at Screening, urine pregnancy at Baseline/Day 1, Wks 4, 8, and 12 

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g If the ACM fails during the Screening assessment and no useable recording is generated, the 24hr Screening ACM may be repeated and in this circumstance the Screening period may be extended by 
up to 1 week (to a maximum of 28 days) 
h All blood and urine samples are taken immediately prior to the dose 
i Full physical examination at Screening; symptom directed physical examination at subsequent visits 
j Screening period may be extended for up to 1 week should the original ACM fail and this need to be repeated 
k All visits and visit windows relate to Day 1 
 
 

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10.1 
Volume of Blood sampling 
Approximate blood sample volumes are detailed below. The volumes for individual samples may 
vary accordingly to laboratory requirements and the number of samples taken may increase due 
to unscheduled visits, lost or damaged samples where additional blood draws are needed, 
however, the total volume is not expected to exceed 150 mL per subject 
Clinical chemistry 
5 mL 
Hematology 
3 mL 
PK 
6 mL 
 
10.2 
Efficacy assessments 
10.2.1 
Ambulatory Cough Monitor 
Subjects will be fitted with an ACM 
 to record objective cough frequency over 
24 hours at the Screening, Weeks 2, 4, and 12 Visits. 
The ACM will be initiated prior to the subject leaving the clinic to monitor cough frequency over 
24 hours. After this period, the subjects will either return the ACM to the clinic (during Screening 
this must be done the following day) or collection from the subjects will be organized; and the 
cough frequency will be determined. 
The digitally recorded data from the ACM will be forwarded to 
who will undertake 
cough counting for all subjects using a standardised process. 
The awake period is considered to be the time between subjects rising from their beds in the 
morning and retiring to their beds in the evening. This can be determined from the 24-hour 
acoustic recordings and approximates to waking hours when cough rates are highest. Analysed 
data will be transferred to 
 for statistical analysis. 
 will be provided with 
subject identifier information but will not have access to the randomisation code.  
10.2.2 
Leicester Cough Questionnaire 
The LCQ is a 19-item questionnaire that assesses cough-related Quality-of-Life. It has three 
domains (physical, psychological and social). The total score range is 3-21 and domain scores 
each range from 1-7; a higher score indicates a better Quality-of-Life.  
Subjects will complete the LCQ whilst in the clinic at Baseline/Day 1 (pre-dose), Weeks 2, 4, 8, 
and 12. 

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10.2.3 
Cough Severity Visual Analogue Scale 
The cough VAS is a 100-mm scale on which subjects indicate the severity of cough in the 
previous 24 hours, both during the daytime (awake time) and during night-time (non-awake time) 
separately. The VAS ranges from “no cough” on the left to “worst cough” on the right. 
Subjects will complete the cough severity VAS at Baseline/Day 1, Weeks 2, 4, 8, and 12. 
10.2.4 
Urge-to-Cough 
The Urge-to-Cough VAS is a 100-mm scale on which subjects indicate their Urge-to-Cough over 
the previous 24 hours (day/awake time and night time combined). The VAS ranges from “no 
Urge-to-Cough” on the left to “severe Urge-to-Cough” on the right. 
Subjects will complete the Urge-to-Cough VAS at Baseline/Day 1, Weeks 2, 4, 8, and 12.  
10.2.5 
Global Rating of Change Questionnaire for Cough Frequency and Severity 
In the Global Rating of Change Scale subjects will indicate if there has been a change in their 
symptoms (cough frequency and, separately, cough severity) since starting the IMP. They will 
respond with “worse”, “about the same” or “better”. If they indicate a change (either “worse” or 
“better”) they will then further indicate on a 7-point scale the degree of change ranging from 1 
(almost the same, hardly any change) to 7 (a very great deal changed). 
Subjects will document their Global Rating of Change in Cough Frequency and Cough Severity 
at Weeks 2, 4, 8, and 12. 
10.3 
Safety Assessments 
10.3.1 
Medical history and concomitant diseases 
A review of medical and medication history will be performed at Screening to confirm subject 
eligibility. This must be confirmed by an investigator. 
• The investigator must record all medically and clinical relevant information regardless of 
the time since the date of diagnosis 
History should include (but is not limited to): 
• All current and past medications taken during three months before the Screening Visit  
• Relevant history of respiratory, cardiovascular, renal, gastro-intestinal, hepatic, endocrine, 
hematological, neurological, psychiatric and any other diseases 
• The specific history related to diagnosis of CRC according to either the ACCP guidelines 
(for subjects at US sites) or the BTS guidelines (for subjects at UK sites). Evidence of 
diagnosis (i.e. exclusion of other etiology) will be documented in the source data. 

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10.3.2 
Physical examinations 
A full physical examination will be conducted at the Screening visit and a symptom directed 
physical examination at the time points indicated in the Study Schedule in Table 1: Schedule of 
Events. This will be completed by a physician or an appropriately qualified delegate. 
A full physical examination is composed of a review of the following body systems: 
• General appearance 
• Skin 
• Head, eyes, ears, nose and throat 
• Respiratory 
• Cardiovascular 
• Abdomen (including liver and kidneys) 
• Musculoskeletal 
• Neurological 
Any abnormalities that are identified at the Screening Visit will be documented on the medical 
history eCRF page. Any changes (including new and worsening findings) between the Screening 
Visit and Final study visit should be captured as AEs on the AE eCRF page, as determined by the 
Investigator and documented in the subject’s notes. 
If an improvement/resolution of a physical examination finding documented in the subject’s 
medical history occurs during the study, it should be recorded in the source document. If there is 
resolution of a physical examination finding previously noted as an AE, then the event resolution 
and stop date should be recorded on the AE eCRF page and documented in the subject’s notes. 
10.3.3 
Spirometry 
Spirometry measurements will be conducted in accordance to local practice, adjusting for race, 
gender and age. For patients of mixed race, the “predominant race” as self-reported by the patient 
will be used and if this is not possible to determine, the predicted values for Caucasians will be 
used. 
Spirometry will be performed at the Screening visit. The highest values (FEV1 and FVC) from 
three technically satisfactory attempts will be recorded and used for the purpose of eligibility. 
10.3.4 
12-Lead ECGs 
Resting 12-lead ECG data will be captured at all study visits, as indicated in Table 1: Schedule of 
Events. 

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All ECGs will be performed after the patient has rested for five minutes in a semi-recumbent 
position. The same model of ECG recorder will be used throughout the study for any given 
subject. 
All ECG reports must be reviewed, signed and dated by the Investigator or delegated physician. 
Reports will then be filed with the subject’s medical record. The Investigator will comment on all 
abnormal findings and determine whether they are clinically significant. These assessments will 
be recorded in the eCRF and clinically significant findings must also be reported as AEs in the 
eCRF. 
10.3.5 
Clinical chemistry 
Blood for clinical chemistry assessments will be collected as indicated in the Study Schedule in 
Table 1: Schedule of Events and sent to a central laboratory for analysis. The following clinical 
chemistry parameters will be assessed: sodium, potassium, glucose, urea, creatinine, creatine 
kinase, albumin, calcium, phosphate, bilirubin (total), alkaline phosphatase, aspartate 
transaminase (AST), alanine transaminase (ALT), gamma glutamyl transferase (GGT), 
bicarbonate, magnesium, chloride, total protein. Subjects do not need to fast before clinical 
chemistry samples are taken. 
All clinical chemistry test reports must be reviewed, signed and dated by the Investigator or 
delegated physician. Reports will then be filed with the subject’s medical record. The Investigator 
will comment on all abnormal results and determine whether they are clinically significant. 
Clinically significant findings must also be reported as adverse events in the eCRF. 
10.3.6 
Hematology 
Blood for hematology assessments will be collected as indicated in in the Study Schedule inn 
Table 1: Schedule of Events and sent to a central laboratory for analysis. The following 
hematology parameters will be assessed: red blood cell (RBC) count, white blood cell (WBC) 
count, hematocrit, hemoglobin, MCV, platelet count and WBC differentials. 
All hematology test reports must be reviewed, signed and dated by the Investigator or delegated 
physician. Reports will then be filed with the subject’s medical record. The Investigator will 
comment on all abnormal results and determine whether they are clinically significant. Clinically 
significant findings must also be reported as adverse events in the eCRF. 
10.3.7 
Urinalysis 
Urine for urinalysis assessments will be collected as indicated in the Study Schedule in Table 1: 
Schedule of Events and sent to a central laboratory for analysis. Urinalysis will include glucose, 
bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrites, leucocyte esterase, 
sedimentation.  

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All urinalysis test reports must be reviewed, signed and dated by the Investigator or delegated 
physician. Reports will then be filed with the subject’s medical record. The Investigator will 
comment on all abnormal results and determine whether they are clinically significant. Clinically 
significant findings must also be reported as adverse events in the eCRF.  
A urine sample will also be collected to perform the opiate drug screen. 
10.3.8 
Vital signs 
Vital signs will be measured at the time points indicated in Table 1: Schedule of Events and will 
include systolic and diastolic BP, pulse, temperature and weight. Weight will be measured at 
Baseline/Day 1, Week 12 and Follow-up only. 
Blood pressure will be measured using a standardized process: 
• Subject should sit for ≥5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level 
• Use an automatic blood pressure device with an appropriately sized cuff with the bladder 
centered over the brachial artery 
• Measure and record the blood pressure using the same arm throughout the study 
All measurements are to be recorded on the Vital Signs eCRF. 
All vital signs must be reviewed by the Investigator or delegated physician. The Investigator will 
comment on all abnormal results and determine whether they are clinically significant. These 
assessments will be recorded in the eCRF and clinically significant findings must also be reported 
as adverse events in the eCRF. 
10.3.9 
Pregnancy Testing, Contraception and Pregnancy  
10.3.9.1 Pregnancy Testing 
Female subjects of childbearing potential (WOCP) will have a serum pregnancy test at initial 
Screening to confirm a negative result for subject eligibility, and a dipstick urine pregnancy test 
will be performed at Baseline/Day1 and must be negative for the subject to remain eligible. A 
dipstick urine pregnancy test will be performed at Weeks 4, 8 12, and 14. Tests must be negative 
for the subject to continue with dosing.  
10.3.9.2 Contraception 
Female subjects of childbearing potential and male subjects with female partners of childbearing 
potential must follow the permitted contraceptive methods outlined in Section 7.2 for the duration 
of their participation in the study. 
Male subjects will also be reminded to continue to use the permitted contraception methods for 
90 days following discontinuation of IMP. 

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10.3.9.3 Pregnancy 
The Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this study and for up to 30 days after the last dose of IMP. The Investigator 
will record pregnancy information on the appropriate form and submit it to the Medical Monitor 
within 24-hours of learning of a subject's pregnancy through the same process as reporting an 
SAE. The subject will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to the Medical Monitor. Generally, 
follow-up will be no longer than six to eight weeks following the estimated delivery date. Any 
premature termination of the pregnancy will be reported. 
Female subjects will be instructed that if they become pregnant during the study or up to 30 days 
after their last dose of IMP, this should be reported to the investigator. The investigator should 
also be notified of pregnancy occurring during the study but confirmed after completion of the 
study.  
Any female subject reporting a pregnancy during the study will be withdrawn from the study. 
If the partner of a male study subject becomes pregnant during the subject’s participation in the 
study and for up to 90 days after the last dose of IMP, this should be reported to the investigator. 
Consent will be sought from the partner and, if granted, any pregnancy will be followed and the 
status of mother and/or child will be reported to the sponsor after delivery.  
10.4 
Pharmacokinetics 
Blood samples for analysis of plasma orvepitant concentrations will be collected at the clinic 
visits at Weeks 2, 4, 8 and 12, immediately prior (<15 mins) to the dose to be taken in the clinic.  
The actual date and time of each blood sample collection will be recorded, together with the date 
and time of the most recent dose of IMP.  
Approximately 6 mL of blood will be collected at each time point. Details of PK blood sample 
collection (including volume to be collected), processing, storage and shipping procedures will be 
provided in the Study Manual. 
10.5 
Adverse events 
10.5.1 
Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a subject or clinical trial subject administered a IMP and 
which does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a IMP, whether or not considered 
related to the IMP. 

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Adverse Drug Reaction (ADR) 
All AEs considered to be untoward and unintended responses to a IMP related to any dose should 
be considered ADRs. The definition covers also medication errors and uses outside what is 
foreseen in the protocol, including misuse and abuse of the product. The phrase “responses to a 
IMP” means that a causal relationship between a IMP and an AE is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
Serious Adverse Event (SAE) 
An adverse event that: 
• Results in death 
• Is life-threatening (i.e. the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe) 
• Requires in-subject hospitalization or prolongation of existing hospitalization (see 
explanation below) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is considered to be an important medical event 
Based upon medical and scientific judgment, important medical events that may not be 
immediately life-threatening, or result in death or hospitalization, but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above 
may be considered a SAE. 
Hospitalizations are defined as initial or prolonged admissions that include an overnight stay. 
Hospitalization or prolonged hospitalization for technical, practical or social reasons, in the 
absence of an adverse event is not an SAE and neither is attendance at an Emergency Room / 
Accident and Emergency Department that takes place in the evening or night and does not result 
in admission to the hospital. 
Pregnancy 
Pregnancy itself is not considered an AE. However, any pregnancy complication, spontaneous or 
elective abortion (for medical reasons), still birth, neonatal death, or congenital anomaly will be 
recorded as an AE or SAE. 
Unexpected Adverse Drug Reaction 
An adverse reaction, the nature or severity of which is not consistent with applicable product 
information (e.g., IB for an unapproved IMP). 
Reports which add significant information on the specificity, increase of occurrence, or severity 
of a known, already documented serious adverse reaction constitute unexpected events. 

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Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse event that is suspected to be related to the administered medicinal product and 
the nature or severity of which is not consistent with applicable product information. 
10.5.2 
Assessment of Severity 
The severity (intensity) of each adverse event will be classified as: 
• Mild  
Awareness of sign or symptom, but easily tolerated 
• Moderate 
Sign or symptom causes discomfort, but does not interfere with normal  
 
 
activities 
• Severe  
Sign or symptom of sufficient intensity to interfere with normal activities 
10.5.3 
Assessment of Causality 
A determination will be made of the relationship (if any) between an AE and the study drug. A 
causal relationship is present if a determination is made that there is a reasonable possibility that 
the AE may have been caused by the drug or study procedure. AEs will be classified as either 
related or unrelated.  
10.5.4 
Adverse Event Reporting 
Adverse events may be volunteered spontaneously by the subject, or discovered as a result of 
general, non-leading questioning. Adverse events occurring from the time of consent up to the 
final study visit will be recorded. All AEs should be recorded in the eCRF and in the subjects’ 
source notes. 
Any SAE occurring from the time the subject signs informed consent until 30 days after the last 
dose of IMP must be reported immediately (within 24 hours of the investigator becoming aware 
of it) and recorded on the SAE Form. Detailed instructions for the reporting of SAEs can be 
found in the Study Manual. All patients with a SAE must be followed up and the outcomes 
reported. The investigator must supply the Sponsor and the relevant agency/IRB/IEC with any 
additional requested information (e.g., autopsy reports and terminal medical reports). Any follow-
up information on a previously reported SAE will also be reported within 24 hours of awareness. 
If the Investigator does not have all information regarding an SAE, he/ she will not wait to 
receive additional information before reporting the event and completing the appropriate data 
collection form. The Investigator will always provide a preliminary assessment of causality at the 
time of the initial report as described in Section 10.5.3. 
The primary mechanism for reporting SAEs will be a paper collection form. 
Fax transmission or ‘scan & email’ of the SAE form is the preferred method to transmit this 
information to the project contact for SAE receipt. In rare circumstances and in the absence of fax 
equipment, notification by telephone is acceptable, with a copy of the SAE data collection form 

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sent by overnight mail. Initial notification via the telephone does not replace the need for the 
Investigator to complete and sign the SAE data collection form within the designated reporting 
periods. 
NeRRe is required to expedite to worldwide regulatory authorities reports of SUSARs in line 
with the relevant legislation. Fatal or life-threatening SUSARs must be reported within 7 calendar 
days and other SUSARs within 15 calendar days. 
In accordance with the European Commission Directive 2001/20/EC, NeRRe will notify the 
relevant Ethics Committees in concerned Member states of applicable SUSARs as individual 
notifications or through a periodic line listing. 
NeRRe will submit to the regulatory authorities all safety updates and periodic reports, as 
required by applicable regulatory requirements. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. Each 
Investigator must then notify his or her relevant agency/IRB/IEC of the SAE as required by local 
regulatory authorities and in accordance with IRB/IEC policy. NeRRe will submit to the 
regulatory authorities all safety updates and periodic reports, as required by applicable regulatory 
requirements. 
11. 
STATISTICAL CONSIDERATIONS 
The primary objective of the study is to evaluate the efficacy of 10 mg, 20 mg, and 30 mg 
orvepitant versus placebo in reducing awake objective cough frequency. The corresponding 
primary endpoint is the change in objective awake cough frequency at Week 12 compared to 
Baseline and will be analyzed after taking logs (to base 10). 
The primary objective will be assessed by testing the following hypotheses for each orvepitant 
group separately: 
Null hypothesis (H0): There is no difference in the mean change in log transformed objective 
awake cough frequency at Week 12 compared to Baseline for the orvepitant treatment group 
compared to placebo. 
H0: µ (active) = µ (placebo) 
Alternative hypothesis (H1): There is a difference in the mean change in log transformed 
objective awake cough frequency at Week 12 compared to Baseline for the orvepitant treatment 
group compared to placebo. 
H1: µ (active) ≠ µ (placebo) 
Each comparison will be carried out at the two-sided 5% level of statistical significance. No 
adjustment will be made for the multiple orvepitant versus placebo group comparisons in this 

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phase 2 study (three in total: 10 mg versus placebo, 20 mg versus placebo and 30 mg versus 
placebo) with the understanding that this increases the overall type I error rate of the study. 
11.1 
Estimated Sample Size 
The initial planned sample size for this study was 55 subjects per treatment group (220 subjects in 
total). As a result of the planned sample size re-estimation the sample size is increased to 65 
subjects per group (260 in total). The sample size calculation is based on pairwise comparisons of 
the primary endpoint for each active dose versus placebo. Objective cough frequency will be 
analysed on a log scale. A two-sided type I error of 0.05, not adjusted for multiple comparisons 
against placebo, will be used for this exploratory study. Assuming a revised standard deviation of 
change from Baseline (after taking logs) of 0.285 (based on the sample size re-estimate and 
increased from the original assumption of 0.261) a reduction in the placebo group of 10% and a 
reduction in the orvepitant group of 35%, 65 subjects per arm will provide a power of 80%. This 
new standard deviation estimate has been obtained (at the first sample size review) by 
considering the full analysis set subjects (as revised, See Section 11.2).  
After at least 100 subjects have completed the Week 12 ACM assessment (and in addition to the 
now completed first sample size re-estimate) the cough frequency data will be reviewed to check 
the estimate of variability assumed for the primary efficacy variable. This interim sample-size re-
estimation will be done on a fully blinded basis using an overall pooled estimate of standard 
deviation and may result in an increase in the sample size (Kieser and Friede, 2000). Only the 
awake cough frequency data will be reviewed.  
Assuming no further changes to the sample size estimate, approximately 292 subjects will be 
randomized to ensure at least 260 completers (assuming approximately 10% drop out rate). The 
sample size may be adjusted again after the second re-estimate and provided no more than 320 
subjects (approximately 80 per group) are required the precise number will be documented in a 
non-substantial (administrative) amendment to the protocol. Any possible impact on the type I 
error due to this blinded sample size re-assessment procedure is believed to be negligible (Kieser 
and Friede, 2003). 
11.2 
Analysis Sets 
The following data sets will be used for the statistical analysis. 
1. Safety Set: All subjects who receive at least one dose of double-blind study drug 
irrespective of treatment received. Subjects will be analyzed according to treatment 
received 
2. Full Analysis Set (FAS): All randomized subjects who received at least one dose of 
double-blind study drug, irrespective of treatment received, satisfy inclusion criterion 
number 4 (awake cough frequency of >=10 coughs/hour during the Screening period), and 
have awake cough frequency data from the ACM for at least one post-treatment 
assessment. Subjects will be analyzed according to randomized treatment. This is the 
primary efficacy analysis set for the study. 

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3. Per Protocol (PP) Set: All subjects in the FAS excluding those identified as relevant 
protocol violators. 
4. Exposure-Response (ER) Set: all subjects who received at least one dose of double-blind 
study drug and for whom the PK data are considered sufficient. 
Analysis Sets will be identified prior to the unblinding of the study data. 
11.3 
Data Analysis 
More details of the proposed statistical analysis will be documented in the statistical analysis plan 
(SAP), which will be written following finalization of the protocol and finalized prior to the 
breaking of the blind.  
For continuous data and for ordered categorical data, if appropriate, the number of non-missing 
observations, mean, standard deviation, median, first and third quartiles, minimum and maximum 
will be calculated. For ordered categorical data and nominal data, absolute counts and relative 
frequencies (in %) will be calculated. 
All statistical hypothesis tests and confidence intervals will be two sided, using a type I error rate 
of 0.05. No adjustment for multiple comparisons will be used for this study. 
Raw data will be listed. 
11.4 
Demographics and Baseline Characteristics 
Relevant Screening and Baseline data (i.e. data collected prior to the treatment administration) 
and demographic characteristics will be summarized descriptively for each treatment group. 
There will be no formal comparison of Baseline data, that is, no statistical hypothesis testing. 
11.5 
Statistical Methods for Efficacy Parameters 
11.5.1 
Primary Efficacy Analysis 
Awake objective cough frequency at Baseline and Weeks 2, 4 and 12, along with change from 
Baseline, will be summarized for each treatment group and for each time point on the original 
scale (including percent change from Baseline) and after log (base 10) transformation.  
NB: The Baseline for objective cough frequency outcomes is the measurement obtained during 
the Screening period. 
The primary analysis of log transformed awake objective cough frequency will be conducted via 
a mixed model for repeated measures (MMRM) with the model including terms for region, 
baseline log-transformed awake objective cough frequency, treatment group, week, week*region, 
week*baseline and week*treatment interactions. Subject will be included as a random effect. The 
estimated treatment means and differences (orvepitant versus placebo) at Week 12 (primary 
endpoint) will be reported as part of this analysis, along with 95% confidence intervals and 
associated p-values. Dose response analyses will be conducted. 

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11.5.2 
Secondary Efficacy Analysis 
The analysis of change from Baseline in awake objective cough frequency at Weeks 2 and 4 will 
be conducted as part of the analysis model for the primary endpoint. The analysis of change from 
Baseline in both 24 hour and night-time (non-waking time) objective cough frequency will be 
analyzed in the same way as for the primary endpoint. The other secondary endpoints will be also 
be analyzed using the MMRM except for the global rating of change in cough frequency and in 
severity. These shall be summarized as categorical endpoints (“worse”, “about the same” and 
“better”) and analyzed using Mantel-Haenszel methodology. The 7-point scale for degree of 
change (if they indicate a change) will also be summarized. 
11.6 
Statistical Methods for Safety Parameters 
Safety data will be summarised descriptively for each treatment group. No formal inferential tests 
will be performed on safety data. 
The number of treatment emergent AEs (TEAEs), and subjects with TEAEs, will be compared 
between groups. TEAEs are defined as AEs that first occurred or worsened in severity after the 
first dose of IMP.  
TEAEs will be summarised for all causality AEs and for treatment-related AEs (those with 
related relationship to IMP and missing). TEAEs will be summarised by MeDRA body system 
and preferred term. TEAEs will also be reported by severity. 
Any deaths, SAEs and AEs leading to discontinuation of IMP administration will also be 
summarised by treatment group. 
SAEs will be presented in a similar way to AEs. 
Vital signs will be summarised for each treatment group by visit. Summary statistics will be 
presented for absolute values and the change from Baseline. 
ECGs will be assessed by the Investigator for abnormal findings. These will be categorised and 
summarised as normal, abnormal-not clinically significant or abnormal-clinically significant. 
ECG intervals will be recorded and summarised as absolute values and changes from Baseline.  
Clinical laboratory data for individual subjects will be listed and any out of range values will be 
highlighted. Laboratory data will be summarised for each treatment group by visit. Summary 
statistics will be presented for absolute values and change from Baseline, as well as an analysis of 
shifts from Baseline. 
Extent of exposure and compliance will be evaluated. 

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11.7 
Pharmacokinetics Analysis 
The plasma orvepitant concentrations will be analyzed using a population pharmacokinetic (Pop 
PK) approach by nonlinear mixed effects modeling (NONMEM®). The Pop PK model will be 
used to evaluate the relationship between orvepitant exposure and clinical endpoints. The details 
of the analysis will be described in a Pop PK Data Analysis Plan (DAP). 
11.8 
Missing Data 
Summary statistics will be based primarily on non-missing values. For hypothesis tests, estimates 
and confidence intervals, missing values for continuous efficacy endpoints analyzed via 
likelihood methods (e.g. repeated measures mixed models) will not be directly imputed as they 
are handled within the analysis itself, under the assumption that the model specification is correct 
and that the data is missing at random. Sensitivity analyses may be conducted to check the 
robustness of the analysis results under alternative assumptions with regards to missing data. 
Further details on the handling of missing values, including rules applied to incomplete 
questionnaires and any planned sensitivity analyses will be defined in the SAP. 
12. 
END OF THE STUDY 
The end of the study will be defined as the last subject’s last visit. 
13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT 
13.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and 
Relevant Authorities 
The final study protocol, the subject information and consent form and any other subject facing 
materials (e.g. questionnaires, advertisements) will be approved by an appropriately constituted 
IRB/IEC. Approval will be received in writing before initiation of the study. 
Clinical Study Authorization will be obtained prior to initiation of the study from the relevant 
Regulatory Authority. 
13.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the local regulations, the principals of Good 
Clinical Practice (GCP) as described by the International Council for Harmonization (ICH), and 
the ethical principles that have their origins in the Declaration of Helsinki. 
13.3 
Informed Consent 
For each study subject, written informed consent will be obtained prior to any protocol-related 
activities. As part of this procedure, the principal investigator or one of his/her associates will 
explain orally and in writing the nature, duration, purpose of the study, and the action of the study 
drug in such a manner that the subject is aware of the potential risks, inconveniences, or adverse 

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effects that may occur. They will be informed that their medical records may be reviewed by 
appropriately qualified monitors of the Sponsor or Sponsor Representative, and by auditors or 
regulatory authorities to ensure the accuracy of the details recorded as part of the study. They will 
be informed that they may withdraw from the study at any time without prejudice to further 
treatment. They will receive all information that is required by local regulations and ICH 
guidelines.  
14. 
STUDY AND DATA MANAGEMENT 
14.1 
Protocol Amendments 
Once approved by the applicable Regulatory Authorities and IRBs/IECs, the protocol must not be 
amended without approval by NeRRe. Unless an amendment is required to be implemented 
urgently in the interests of safety, or is deemed administrative by NeRRe, any amendments to the 
protocol must be authorized by the applicable Regulatory Authorities and IRB/IEC prior to 
implementation. 
14.2 
Monitoring 
In accordance with applicable regulations including GCP and NeRRe or delegated CRO’s 
Standard Operating Procedures (SOP), approved clinical research monitors will contact the site 
prior to the start of the study to review with the site staff the protocol, study requirements, and 
their responsibilities to satisfy regulatory, ethical, and NeRRe requirements. When reviewing data 
collection procedures, the discussion will also include identification, agreement and 
documentation of data items for which the eCRF will serve as the source document. A list of 
what is to be classed as ‘source documentation’ will be documented in the Study Monitoring 
Manual. 
NeRRe will monitor the study and sites to verify: 
• Data are authentic, accurate and complete 
• Safety and right of the subjects are being protected 
• IMP accountability 
• SAE reporting 
• Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP and all applicable regulatory requirements 
The investigator[s]/institution[s] will permit study-related monitoring, providing direct access to 
source data/documents. 

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14.3 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the 
investigator[s]/institution[s] will permit study-related audits, IRB/IEC review, and regulatory 
inspection[s], providing direct access to source data/documents. 
14.4 
Data Recording 
14.4.1 
Data to be Considered as Source Data 
An eCRF will be used to capture subject data into a secure, validated database. Access to enter 
data in the eCRF will be limited to delegated and trained investigator site staff only. ACM, PK 
and safety laboratory data will be transferred electronically into the database periodically during 
the study.  
Source data may be defined as information from an original record or certified copy of the 
original record containing patient information for use in the trial.  The information may include, 
but is not limited, to clinical findings, observations, or other activities necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in source documents 
(original records or certified copies) (ICH E2A Guideline). Examples of source data include 
subject identification and randomization identification.  
14.5 
Confidentiality 
The Investigator must assure that the subjects’ anonymity will be maintained. On all study 
documentation, with the exception of the consent form and subject ID logs, subjects will only be 
identified by their unique identification code and initials and will not be referred to by name. 
Study data will be handled with utmost discretion within the context of physician’s 
confidentiality. On the eCRFs and other study specific documents, subjects are not identified by 
their names, but by a unique subject number. Names of participating subjects and data generated 
as a result of this study will not be passed on to unauthorized persons. 
The Investigator must assure that the subjects are properly anonymized throughout the study. On 
all study documentation which is supposed to leave the site (i.e., to be transmitted to NeRRe, 
CRO or third parties), subjects will only be identified by their unique identification code and will 
not be referred to by name. 
NeRRe may transfer some data collected during the study to a different company or regulatory 
authority outside of the US or EU for the purpose of processing, review, analysis or storage. 
Whenever the subject’s personal data is transferred, it will be kept confidential and secure, and 
will used only for the purpose for which it was collected. 
Safety analysis samples collected during the study will be analyzed at a central laboratory. 
Samples will be identified by the subjects’ unique identification code. All safety samples will be 
destroyed after the assays have been completed. 

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Blood samples for analysis of orvepitant concentrations will be shipped to Aptuit Srl, Italy for 
analysis. Samples will be identified by the subjects’ unique identification code. Following 
completion of the analysis, all samples will be destroyed. 
14.6 
Retention of Study Data 
Following closure of the study, the Investigator must maintain all site study records, except for 
those required by local regulations to be maintained by someone else, in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., 
audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and staff. Where permitted by 
local laws/ regulations or institutional policy, some or all of these records can be maintained in a 
format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The Investigator must assure that all reproductions are 
legible and are a true and accurate copy of the originals, and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required. Furthermore, the Investigator must 
ensure there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
NeRRe will inform the Investigator of the time period for retaining these records to comply with 
all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by any institutional requirements or local 
laws or regulations, or NeRRe, or delegated CRO’s SOPs; otherwise, the retention period will 
default to 15 years. 
The Investigator must notify NeRRe of any changes in the archival arrangements, including, but 
not limited to, archival at an off-site facility or transfer of ownership of the records in the event 
the Investigator leaves the site. The Investigator may not dispose of any records without prior 
approval from NeRRe. 
14.7 
Communication and Publication of Results 
Where required by applicable regulatory requirements, an Investigator signatory will be identified 
for the approval of the clinical study report (CSR). The Investigator will be provided appropriate 
access to statistical tables, figures, and relevant reports and will have the opportunity to review 
the complete study results at NeRRe or another mutually agreeable location. 
The original eCRFs and all data generated during the study under this protocol will become the 
property of the Sponsor. 
Upon completion of the CSR, NeRRe will ensure public disclosure of the clinical trial research 
results according to the NeRRe’s SOP and provide the Investigator with the full summary of the 
study results. The Investigator is encouraged to share the summary results with the study subjects, 
as appropriate.  

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It is the intent of all parties that the results of the study be published in a timely manner consistent 
with academic standards and with due consideration given to the protection of intellectual 
property rights. The Principal Investigator and NeRRe will be responsible for assembling the 
proposed publication; this must happen with due diligence and with minimal delay.  
Any proposed publication or presentation (including a manuscript, abstract or poster) for 
submission to a journal or scientific meeting should be sent to the Sponsor for review at least 
sixty (60) days prior to submission. The Sponsor's comments on the proposed publication shall be 
considered in good faith by the authors. Sponsor may delay such submission by a maximum of 
six months if it reasonably believes that publication of results may compromise its intellectual 
property rights or else insist that such information or data is removed from the proposed 
publication. Publication of the results will not include confidential information without the 
permission of the Sponsor. 
14.8 
Indemnification 
In the event of study-related damage or injuries, the clinical trial insurance of the Sponsor 
provides compensation for claims that arise in accordance with the regulatory requirements of the 
countries involved, except for claims that arise from willful misconduct or gross negligence. A 
copy of the country-specific insurance certificates will be held in the TMF and in the Investigator 
Site File. 

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Janson C, Chinn S, Jarvis D, Burney P.  
Determinants of cough in young adults participating in the European Community Respiratory 
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Passive smoke effects on cough and airways in young guinea pigs: role of brainstem substance P. 
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Katsumata U, Sekizawa K, Inoue H, Sasaki H, Takishima T. 
Inhibitory actions of procaterol, a beta-2 stimulant, on substance P-induced cough in normal 
subjects during upper respiratory tract infection. 
Tohoku J Exp Med. 1989 May;158(1):105-6. 
Kieser M, Friede T.  
Blinded sample size re-estimation in multi-armed clinical trials.  
Drug Information Journal 2000; 34:455– 460. 
Kieser M, Friede T 
Simple procedures for blinded sample size adjustment that do not affect the type 1 error rate. 
Statist. Med 2003; 22:3571-3581 
Lavinka PC, Dong X.  
Molecular signaling and targets from itch: lessons for cough.  
Cough. 2013 Mar 6; 9(1):8. 
Lim KG, Rank MA, Kita H, Patel A, Moore E.  
Neuropeptide levels in nasal secretions from subjects with and without chronic cough.  
Ann Allergy Asthma Immunol. 2011 Oct; 107(4): 360-3. 
Mazzone SB, Mori N, Canning BJ. 
Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in 
guinea-pigs. 
J Physiol. 2005 Dec 1;569(Pt 2):559-73.  
Moreaux B, Nemmar A, Vincke G, Halloy D, Beerens D, Advenier C, Gustin P.  
Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs.  
Eur J Pharmacol. 2000 Nov 24; 408(3):305-12. 
Morice AH, McGarvey L, Pavord I, on behalf of the British Thoracic Society Cough Guideline 
Group 
Recommendations for the management of cough in adults. 
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McGarvey LP, Smith JA, Tatar M, Widdicombe J; European Respiratory Society (ERS). 
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Eur Respir J. 2007 Jun;29(6):1256-76. 
Mutolo D, Bongianni F, Fontana GA, Pantaleo T. 
The role of excitatory amino acids and substance P in the mediation of the cough reflex within 
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Mutolo D, Bongianni F, Cinelli E, Fontana GA, Pantaleo T.  
Modulation of the cough reflex by antitussive agents within the caudal aspect of the nucleus 
tractus solitarii in the rabbit.  
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Mutolo D, Bongianni F, Cinelli E, Pantaleo T.  
Depression of cough reflex by microinjections of antitussive agents into caudal ventral 
respiratory group of the rabbit.  
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A randomised, double-blind, placebo-controlled study to evaluate the efficacy of orvepitant 
compared with placebo on EGFRi-induced intense pruritus in oncology subjects (2016). 
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Increased tachykinin levels in induced sputum from asthmatic and cough subjects with acid 
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Qiu Z, Yu L, Xu S, Liu B, Zhao T, Lü H, Qiu Z.  
Cough reflex sensitivity and airway inflammation in subjects with chronic cough due to non-acid 
gastro-oesophageal reflux.  
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Sekizawa S, Joad JP, Pinkerton KE, Bonham AC. 
Distinct tachykinin NK(1) receptor function in primate nucleus tractus solitarius neurons is 
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Br J Pharmacol. 2011 Jun;163(4):782-91. 

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Song WJ, Chang YS, Faruqi S, Kim JY, Kang MG, Kim S, Jo EJ, Kim MH, Plevkova J, Park 
HW, Cho SH, Morice AH. 
The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. 
Eur Respir J. 2015 May;45(5):1479-81.  
Spinou A, Birring SS. 
An update on measurement and monitoring of cough: what are the important study endpoints? 
J Thorac Dis. 2014 Oct; 6(Suppl 7): S728–S734. 
Trower MK, Fisher A, Upton N, Ratti E. 
Neurokinin-1 receptor antagonist orvepitant is an effective inhibitor of itch-associated response in 
a Mongolian gerbil model of scratching behaviour. 
Exp Dermatol. 2014 Nov;23(11):858-60. 
. 

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Principal Investigator Agreement 
 
I agree to conduct the study according to the terms and conditions of this protocol, current Good 
Clinical Practice and with applicable regulatory requirements. All information pertaining to the 
study shall be treated in a confidential manner. 
 
 
 
 
Signature: 
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Title: 
 
 
 
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17. 
APPENDICES 
 
Appendix A:  
ACCP Guidelines (Irwin et al 2006) 
 
Appendix B:  
BTS Guidelines (Morice et al 2006) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Diagnosis and Management of Cough
Executive Summary
ACCP Evidence-Based Clinical Practice Guidelines
Richard S. Irwin, MD, FCCP, Chair;
Michael H. Baumann, MD, FCCP (HSP Liaison); Donald C. Bolser, PhD;
Louis-Philippe Boulet, MD, FCCP (CTS Representative);
Sidney S. Braman, MD, FCCP; Christopher E. Brightling, MBBS, FCCP;
Kevin K. Brown, MD, FCCP; Brendan J. Canning, PhD;
Anne B. Chang, MBBS, PhD; Peter V. Dicpinigaitis, MD, FCCP;
Ron Eccles, DSc; W. Brendle Glomb, MD, FCCP; Larry B. Goldstein, MD;
LeRoy M. Graham, MD, FCCP; Frederick E. Hargreave, MD;
Paul A. Kvale, MD, FCCP; Sandra Zelman Lewis, PhD;
F. Dennis McCool, MD, FCCP; Douglas C. McCrory, MD, MHSc;
Udaya B.S. Prakash, MD, FCCP; Melvin R. Pratter, MD, FCCP;
Mark J. Rosen, MD, FCCP;
Edward Schulman, MD, FCCP (ATS Representative);
John Jay Shannon, MD, FCCP (ACP Representative);
Carol Smith Hammond, PhD; and Susan M. Tarlo, MBBS, FCCP
(CHEST 2006; 129:1S–23S)
Abbreviations: ACE  angiotensin-converting enzyme; ACP  American College of Physicians; A/D  antihistamine/
decongestant; ATS  American Thoracic Society; BPC  bronchoprovocation challenge; CTS  Canadian Thoracic
Society; DPB  diffuse panbronchiolitis; dTap  acellular pertussis; FEES  fiberoptic endoscopic evaluation of
swallowing; GERD  gastroesophageal reflux disease; HRCT  high-resolution CT; HSP  Health and Science Policy
Committee; IBD  inflammatory bowel disease; ICS  inhaled corticosteroid; ILD  interstitial lung disease;
NAEB  nonasthmatic eosinophilic bronchitis; NSCLC  non-small cell lung cancer; SLP  speech-language pathol-
ogist; TB  tuberculosis; UACS  upper airway cough syndrome; URI  upper respiratory infection; VC  voluntary cough;
VSE  videofluoroscopic swallow evaluation
R
ecognition of the importance of cough in clinical
medicine was the impetus for the original evi-
dence-based consensus panel report on “Managing
Cough as a Defense Mechanism and as a Symptom,”
published in 1998,1 and this updated revision. Com-
pared to the original cough consensus statement, this
revision (1) more narrowly focuses the guidelines on
the diagnosis and treatment of cough, the symptom,
in adult and pediatric populations, and minimizes the
discussion of cough as a defense mechanism; (2)
improves on the rigor of the evidence-based review
and describes the methodology in a separate section;
(3) updates and expands, when appropriate, all pre-
vious sections; and (4) adds new sections with topics
that were not previously covered. These new sections
include nonasthmatic eosinophilic bronchitis (NAEB);
acute bronchitis; nonbronchiectatic suppurative air-
way diseases; cough due to aspiration secondary to
oral/pharyngeal dysphagia; environmental/occupa-
tional causes of cough; tuberculosis (TB) and other
infections; cough in the dialysis patient; uncommon
causes of cough; unexplained cough, previously re-
ferred to as idiopathic cough; an empiric integrative
approach to the management of cough; assessing
cough severity and efficacy of therapy in clinical
research; potential future therapies; and future di-
rections for research.
To mitigate future diagnostic confusion, two new
diagnostic terms have been introduced to replace two
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Richard S. Irwin, MD, FCCP, University of
Massachusetts Medical School, Room S6-842, 55 Lake Ave North,
Worcester, MA 01655; e-mail address: Irwinr@ummhc.org
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older terms that may represent misnomers. The com-
mittee unanimously recommends that the term upper
airway cough syndrome (UACS) be used in preference
to postnasal drip syndrome (PNDS) when discussing
cough that is associated with upper airway conditions
because it is unclear whether the mechanism of cough
is postnasal drip, direct irritation, or inflammation of
the cough receptors in the upper airway. The commit-
tee also recommends using the term unexplained cough
rather than idiopathic cough because it is likely that
more than one unknown cause of chronic cough will be
discovered. The term idiopathic implies that one is
dealing with only one disease.
For managing adult patients with cough, the com-
mittee recommends an empiric, integrative diagnos-
tic approach, which is presented in the section
entitled “An Empiric Integrative Approach to the
Management of Cough”.3 Guidelines for managing
acute, subacute, and chronic cough are presented in
algorithmic form (Fig 1–3). Guidelines with algo-
rithms for evaluating chronic cough in pediatric
patients  15 years of age are presented in the
section entitled “Guidelines for Evaluating Chronic
Cough in Pediatrics”2,4 [Fig 4, 5]. For a full discus-
sion on how to use the algorithms, please refer to
these sections.
Summary and Recommendations
Recommendations for each section of these guide-
lines are listed under their respective section titles.
For an in-depth discussion or clarification of each
recommendation, readers are encouraged to read
the specific section in question in its entirety.
Methodology and Grading of the Evidence for the
Diagnosis and Management of Cough5
• The recommendations were graded, by consensus
by the panel, using the American College of Chest
Physicians Health and Science Policy Grading
System, which is based on the following two compo-
nents: quality of evidence; and the net benefit of the
diagnostic and therapeutic procedure.
• The quality of evidence is rated according to the
study design and strength of other methodologies
used in the included studies.
• The net benefit of the recommendations is based
on the estimated benefit to the specific patient
population described in each recommendation
and not for an individual patient. Usually, the net
benefit is a clinical benefit to the population of
patients defined in the first phrase of the recom-
mendation, but, in recommendations for future
research or other nonclinical recommendations, it
may be a societal benefit.
• Both the quality of evidence and the net benefit
components are listed after each recommenda-
tion; their interaction defines the strength of the
recommendations.
• The recommendations scale is as follows: A,
strong; B, moderate; C, weak; D, negative; I,
inconclusive (no recommendation possible); E/A,
Figure 1. Acute cough algorithm for the management of patients  15 years of age with cough lasting
 3 weeks. For diagnosis and treatment recommendations refer to the section indicated in the
algorithm. PE  pulmonary embolism; Dx  diagnosis; Rx  treatment; URTI  upper respiratory
tract infection; LRTI  lower respiratory tract infection. Section 7  Irwin8; Section 8  Pratter9;
Section 9  Pratter10; Section 10  Pratter11; Section 11  Dicpinigaitis12; Section 12  Irwin13;
Section 13  Braman14; Section 14  Braman15; Section 16  Rosen17; Section 22  Irwin et al.23
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strong recommendation based on expert opinion
only; E/B, moderate recommendation based on
expert opinion only; E/C, weak recommendation
based on expert opinion only; and E/D, negative
recommendation based on expert opinion only
Anatomy and Neurophysiology of the Cough Reflex6
• There is clear evidence that vagal afferent nerves
regulate involuntary coughing.
• Coughing, like swallowing, belching, urinating,
and defecating, is unique because there is higher
cortical control of this visceral reflex.
• Cortical control can manifest as cough inhibition
or voluntary cough. The implications of this are
several-fold: because placebos can have a pro-
found effect on coughing, treatment studies must
be placebo-controlled. Because cough can be an
affective behavior, psychological issues must be
considered as a cause or effect of coughing.
• There is a need to study the roles of consciousness
and perception in coughing.
Global Physiology and Pathophysiology of Cough7
1. In patients with endotracheal tubes, tra-
cheostomy need not be performed to improve
cough effectiveness. Level of evidence, expert
opinion; net benefit, substantial; grade of recom-
mendation, E/A
2. Individuals with neuromuscular weakness
and no concomitant airway obstruction may
benefit from mechanical aids to improve cough.
Level of evidence, low; net benefit, intermediate;
grade of recommendation, C
3. In patients with ineffective cough, the cli-
nician should be aware of and monitor for
possible complications, such as pneumonia, at-
electasis, and/or respiratory failure. Level of
evidence, low; net benefit, substantial; grade of
recommendation, B
Complications of Cough8
1. In patients complaining of cough, evaluate
for a variety of complications associated with
coughing (eg, cardiovascular, constitutional, GI,
genitourinary, musculoskeletal, neurologic, oph-
thalmologic, psychosocial, and skin complica-
tions), which can lead to a decrease in a patient’s
health-related quality of life. Level of evidence, low;
benefit, substantial; grade of recommendation, B
2. Patients with cough should have a thor-
Figure 2. Subacute cough algorithm for the management of patients  15 years of age with cough
lasting 3 to 8 weeks. For diagnosis and treatment recommendations refer to the section indicated in the
algorithm. AECB  acute exacerbation of chronic bronchitis. See the legend of Figure 1 for
abbreviations not used in the text. See Figure 1 for references to Sections.
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ough diagnostic evaluation, according to the
guidelines set forth in this document, to miti-
gate or prevent these complications. Level of
evidence, low; net benefit, substantial; grade of
recommendation, B
Overview of Common Causes of Chronic Cough9
1. In patients with chronic cough and a nor-
mal chest roentgenogram finding who are non-
smokers and are not receiving therapy with an
Figure 3. Chronic cough algorithm for the management of patients  15 years of age with cough
lasting  8 weeks. ACE-I  ACE inhibitor; BD  bronchodilator; LTRA  leukotriene receptor antago-
nist; PPI  proton pump inhibitor. See the legend of Figure 1 for abbreviations not used in the text.
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angiotensin-converting enzyme (ACE) inhibi-
tor, the diagnostic approach should focus on the
detection and treatment of UACS (formerly
called PNDS), asthma, NAEB, or GERD, alone
or in combination. This approach is most likely
to result in a high rate of success in achieving
cough resolution. Level of evidence, low; benefit,
substantial; grade of recommendation, B
2. In all patients with chronic cough, regard-
less of clinical signs or symptoms, because
Figure 4. Approach to a child  15 years of age with chronic cough. There are limitations of the
algorithm, which should be read with the accompanying text. Spirometry can usually be reliably
performed in children  6 years of age and in some children  3 years of age if trained pediatric
personnel are present. CXR  chest radiograph.2
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UACS (formerly called PNDS), asthma, and
GERD each may present only as cough with no
other associated clinical findings (ie, “silent
PNDS,” “cough variant asthma,” and “silent
GERD”), each of these diagnoses must be con-
sidered. Level of evidence, low; benefit, substantial;
grade of recommendation, B
3. In patients with chronic cough, neither the
patient’s description of his or her cough in
terms of its character or timing, nor the pres-
ence or absence of sputum production, should
be used to rule in or rule out a diagnosis or to
determine the clinical approach. Level of evi-
dence, low; benefit, substantial; grade of recommen-
dation, B
Chronic Upper Airway Cough Syndrome Secondary
to Rhinosinus Diseases (Previously Referred to as
Postnasal Drip Syndrome)10
1. In patients with chronic cough that is re-
lated to upper airway abnormalities, the com-
mittee considers the term UACS to be more
accurate, and it should therefore be used in-
stead of the term PNDS. Level of evidence, expert
opinion; benefit, substantial; grade of recommenda-
tion, E/A
2. In patients with chronic cough, the diag-
nosis of UACS-induced cough should be deter-
mined by considering a combination of criteria,
including symptoms, physical examination find-
ings, radiographic findings, and, ultimately, the
response to specific therapy. Because it is a
syndrome, no pathognomonic findings exist.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
3. In patients in whom the cause of the
UACS-induced cough is apparent, specific ther-
apy directed at this condition should be insti-
tuted. Level of evidence, low; benefit, substantial;
grade of recommendation, B
4. For patients with chronic cough, an em-
piric trial of therapy for UACS should be admin-
istered because the improvement or resolution
of cough in response to specific treatment is the
Figure 5. Approach to a child  14 years of age with chronic specific cough (ie, cough associated with
other features suggestive of an underlying pulmonary and/or systemic abnormality). Children  14
years of age should be managed as outlined in adult guidelines but there is no good evidence where the
age cutoff should be. TEF  tracheal esophageal fistula. See the legend of Figure 4 for abbreviation
not used in the text.
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pivotal factor in confirming the diagnosis of
UACS as a cause of cough. Level of evidence, low;
benefit, substantial; grade of recommendation, B
5. A patient suspected of having UACS-in-
duced cough who does not respond to empiric
antihistamine/decongestant (A/D) therapy with
a first-generation antihistamine should next un-
dergo sinus imaging. Although chronic sinusitis
may cause a productive cough, it may also be
clinically silent, in that the cough can be rela-
tively or even completely nonproductive and
none of the typical findings associated with
acute sinusitis may be present. Level of evidence,
low; benefit, substantial; grade of recommendation, B
6. In patients for whom a specific etiology of
chronic cough is not apparent, empiric therapy
for UACS in the form of a first-generation A/D
preparation should be prescribed before begin-
ning an extensive diagnostic workup. Level of
evidence, low; benefit, intermediate; grade of rec-
ommendation, C
Cough and the Common Cold11
1. Patients with acute cough (as well as PND
and throat clearing) associated with the com-
mon cold can be treated with a first-genera-
tion A/D preparation (brompheniramine and
sustained-release pseudoephedrine). Naproxen
can also be administered to help decrease
cough in this setting. Level of evidence, fair;
benefit, substantial; grade of recommendation, A
2. In patients with the common cold, newer
generation nonsedating antihistamines are inef-
fective for reducing cough and should not be
used. Level of evidence, fair; benefit, none; grade of
recommendation, D
3. In patients with cough and acute URTI,
because symptoms, signs, and even sinus-imag-
ing abnormalities may be indistinguishable
from acute bacterial sinusitis, the diagnosis of
bacterial sinusitis should not be made during
the first week of symptoms. (Clinical judgment
is required to decide whether to institute anti-
biotic therapy.) Level of evidence, fair; benefit,
none; grade of recommendation, D
Chronic Cough Due to Asthma12
1. In a patient with chronic cough, asthma
should always be considered as a potential eti-
ology because asthma is a common condition
with which cough is commonly associated. Qual-
ity of evidence, fair; net benefit, substantial; grade of
recommendation, A
2. In a patient suspected of having CVA but
in whom physical examination and spirometry
findings are nondiagnostic, MIC testing should
be performed to confirm the presence of
asthma. However, a diagnosis of CVA as the
cause of cough is established only after the
resolution of cough with specific antiasthmatic
therapy. If MIC testing cannot be performed,
empiric therapy should be administered; how-
ever, a response to steroid therapy will not
exclude NAEB as an etiology of the patient’s
cough. Quality of evidence, good; net benefit, sub-
stantial; grade of recommendation, A
3. Patients with cough due to asthma should
initially be treated with a standard antiasth-
matic regimen of inhaled bronchodilators and
inhaled corticosteroids (ICSs). Quality of evi-
dence, fair; net benefit, substantial; grade of recom-
mendation, A
4. In patients whose cough is refractory to
treatment with ICSs, an assessment of airway
inflammation should be performed whenever
available and feasible. The demonstration of
persistent airway eosinophilia during such an
assessment will identify those patients who may
benefit from more aggressive antiinflammatory
therapy. Quality of evidence, low; net benefit,
substantial; grade of recommendation, B
5a. For patients with asthmatic cough that is
refractory to treatment with ICSs and broncho-
dilators, in whom poor compliance or another
contributing condition has been excluded, a
leukotriene receptor antagonist may be added
to the therapeutic regimen before the escala-
tion of therapy to systemic corticosteroids. Qual-
ity of evidence, fair; net benefit, intermediate; grade
of recommendation, B
5b. Patients with severe and/or refractory
cough due to asthma should receive a short
course (1 to 2 weeks) of systemic (oral) cortico-
steroids followed by ICSs. Quality of evidence,
low; net benefit,: substantial; grade of recommenda-
tion, B
Chronic Cough Due to Gastroesophageal Reflux
Disease13
1. In patients with chronic cough due to
gastroesophageal reflux disease (GERD), the
term acid reflux disease, unless it can be defin-
itively shown to apply, should be replaced by
the more general term reflux disease so as not to
mislead the clinicians into thinking that all
patients with cough due to GERD should im-
prove with acid-suppression therapy. Level of
evidence, expert opinion; benefit, substantial; grade
of recommendation, E/A
2. In patients with chronic cough who also
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complain of typical and frequent GI complaints
such as daily heartburn and regurgitation, es-
pecially when the findings of chest-imaging
studies and/or clinical syndrome are consistent
with an aspiration syndrome, the diagnostic
evaluation should always include GERD as a
possible cause. Level of evidence, low; benefit,
substantial; grade of recommendation, B
3. Patients with chronic cough who have GI
symptoms that are consistent with GERD or
who fit the clinical profile described in Table 1
in Irwin13, should be considered to have a high
likelihood of having GERD and should be pre-
scribed antireflux treatment even when they
have no GI symptoms. Level of evidence, low;
benefit, substantial; grade of recommendation, B
4. In patients with chronic cough, it should
not be assumed that GERD has been defini-
tively ruled out as a cause of cough simply
because there is a history of antireflux surgery.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
5. In patients with chronic cough, while tests
that link GERD with cough suggest a potential
cause-effect relationship, a definitive diagnosis
of cough due to GERD requires that cough
nearly or completely disappear with antireflux
treatment. Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
6. In patients with chronic cough being eval-
uated for GERD, the 24-h esophageal pH-mon-
itoring test is the most sensitive and specific
test; however, it is recommended that the test
results be interpreted as normal only when
conventional indices for acid reflux are within
the normal range and no reflux-induced coughs
appear during the monitoring study. Level of
evidence, low; benefit, substantial; grade of recom-
mendation, B
7. In patients with cough who are undergoing
24-h monitoring, a low percentage of coughs
associated with (or induced by) reflux does not
exclude a diagnosis of cough due to GERD. Level
of evidence, low; benefit, substantial; grade of recom-
mendation, B
8. In patients with cough due to GERD, the
degree of abnormality noted in the esophageal
pH-monitoring variables, such as the frequency
and duration of reflux events, does not directly
correlate with the severity of the patients’
cough. Level of evidence, low; benefit, substantial;
grade of recommendation, B
9. In diagnosing nonacid GERD as the cause
of cough, barium esophagography may be the
only available test to reveal GER of potential
pathologic significance in this setting (see the
“Discussion” section regarding esophageal im-
pedance monitoring). When this is the case,
barium esophagography is the test of choice to
reveal GER of potential pathologic significance.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
10. In patients with cough due to GERD, a
normal esophagoscopy finding does not rule out
GERD as the cause of cough. Level of evidence,
low; benefit, substantial; grade of recommendation, B
11. For patients fitting the clinical profile for
cough due to GERD, it is recommended that
treatment be initially started in lieu of testing.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
12. For patients fitting the clinical profile for
cough due to GERD, the performance of 24-h
esophageal pH monitoring is recommended on
therapy when cough does not improve or re-
solve to assist in determining whether the ther-
apy needs to be intensified or if medical therapy
has failed. Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
13. For patients with chronic cough, the fol-
lowing tests are not routinely recommended to
link cough with GERD: (a) assessing for lipid-
laden macrophages in BAL fluid and induced
sputum, because this test has not been studied
in patients with chronic cough and because a
positive test result is not specific for aspiration;
(b) exhaled nitric oxide measurements, because
they do not appear to be helpful in diagnosing
cough due to GERD; (c) a Bernstein test, be-
cause a negative Bernstein test result cannot be
used to exclude the diagnosis of cough due to
GERD; and (d) inhaled tussigenic challenges
with capsaicin, because they are not specific for
coughs due to GERD and because the test
result can be positive in patients with GERD
without cough. Level of evidence, low; benefit,
conflicting; grade of recommendation, I
14. In patients who meet the clinical profile
predicting that silent GERD is the likely cause
of chronic cough or in patients with chronic
cough who also have prominent upper GI symp-
toms consistent with GERD, an empiric trial of
medical antireflux therapy is recommended.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
15. For treating the majority of patients with
chronic cough due to GERD, the following
medical therapies are recommended: (a) di-
etary and lifestyle modifications; (b) acid sup-
pression therapy; and (c) the addition of proki-
netic therapy either initially or if there is no
response to the first two therapies. The re-
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sponse to these therapies should be assessed
within 1 to 3 months. Level of evidence, expert
opinion; benefit, substantial; grade of recommenda-
tion, E/A
16. In patients in which this empiric treat-
ment fails, it cannot be assumed that GERD has
been ruled out as a cause of chronic cough;
rather, the objective investigation for GERD is
then recommended because the empiric ther-
apy may not have been intensive enough or
medical therapy may have failed. Level of evi-
dence, expert opinion; benefit, substantial; grade of
recommendation, E/A
17. In some patients, cough due to GERD
will favorably respond to acid suppression ther-
apy alone; proton pump inhibition may be ef-
fective when H2-antagonism has been ineffec-
tive; prokinetic therapy and diet, when added to
proton pump inhibition, may be effective when
proton pump inhibition alone has been ineffec-
tive. Level of evidence, low; benefit, substantial;
grade of recommendation, B
18. Patients requiring an intensive medical
treatment regimen should be treated with the
following: (a) antireflux diet that includes no
> 45 g of fat in 24 h and no coffee, tea, soda,
chocolate, mints, citrus products, including to-
matoes, or alcohol, no smoking, and limiting
vigorous exercise that will increase intraab-
dominal pressure; (b) acid suppression with a
proton pump inhibitor; (c) prokinetic therapy;
and (d) efforts to mitigate the influences of
comorbid diseases such as obstructive sleep
apnea or therapy for comorbid conditions (eg,
nitrates, progesterone, and calcium channel
blockers) whenever possible. Level of evidence,
expert opinion; benefit, substantial; grade of recom-
mendation, E/A
19. In patients with chronic cough due to
GERD that has failed to improve with the most
maximal medical therapy, which includes an
intensive antireflux diet and lifestyle modifica-
tion, maximum acid suppression, and prokinetic
therapy, and the rest of the spectrum of treat-
ment options in Table 3 in Irwin,13 cough may
only improve or be eliminated with antireflux
surgery. Level of evidence, low; benefit, substantial;
grade of recommendation, B
20. In patients who meet the following crite-
ria, antireflux surgery is the recommended
treatment: (a) findings of a 24-h esophageal
pH-monitoring study before treatment is posi-
tive, as defined above; (b) patients fit the clini-
cal profile suggesting that GERD is the likely
cause of their cough (Table 1 in Irwin13); (c)
cough has not improved after a minimum of 3
months of intensive therapy (Table 3 in Irwin13),
and serial esophageal pH-monitoring studies or
other objective studies (eg, barium esophagog-
raphy, esophagoscopy, and gastric-emptying
study with solids) performed while the patient
receives therapy show that intensive medical
therapy has failed to control the reflux disease
and that GERD is still the likely cause of cough;
and (d) patients express the opinion that their
persisting cough does not allow them a satisfac-
tory quality of life. Level of evidence, expert
opinion; benefit, substantial; grade of recommenda-
tion, E/A
Chronic Cough Due to Acute Bronchitis14
1. In a patient with an acute respiratory infec-
tion manifested predominantly by cough, with or
without sputum production, lasting no more than
3 weeks, a diagnosis of acute bronchitis should not
be made unless there is no clinical or radio-
graphic evidence of pneumonia, and the common
cold, acute asthma, or an exacerbation of COPD
have been ruled out as the cause of cough. Quality
of evidence, expert opinion; benefit, substantial; grade
of recommendation, E/A
2. In patients with the presumed diagnosis of
acute bronchitis, viral cultures, serologic assays,
and sputum analyses should not be routinely
performed because the responsible organism is
rarely identified in clinical practice. Quality of
evidence, low; benefit, intermediate; grade of rec-
ommendation, C
3. In patients with acute cough and sputum
production suggestive of acute bronchitis, the
absence of the following findings reduces the
likelihood of pneumonia sufficiently to elimi-
nate the need for a chest radiograph: (1) heart
rate > 100 beats/min; (2) respiratory rate > 24
breaths/min; (3) oral body temperature of
> 38°C; and (4) chest examination findings of
focal
consolidation,
egophony,
or
fremitus.
Quality of evidence, low; benefit, substantial; grade
of recommendation, B
4a. For patients with the putative diagnosis
of acute bronchitis, routine treatment with an-
tibiotics is not justified and should not be of-
fered. Quality of evidence, good; benefit, none;
grade of recommendation, D
4b. For these patients, the decision not to use
an antibiotic should be addressed individually
and explanations should be offered because
many patients expect to receive an antibiotic
based on previous experiences and public ex-
pectation. Quality of evidence, expert opinion; ben-
efit, intermediate; grade of recommendation, E/B
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5. Children and adult patients with con-
firmed and probable whooping cough should
receive a macrolide antibiotic and should be
isolated for 5 days from the start of treatment;
early treatment within the first few weeks will
diminish the coughing paroxysms and prevent
spread of the disease; the patient is unlikely to
respond to treatment beyond this period. Level
of evidence, good; net benefit, substantial; grade of
evidence, A
6a. In most patients with a diagnosis of acute
bronchitis, 2-agonist bronchodilators should
not be routinely used to alleviate cough. Quality
of evidence, fair; benefit, none; grade of recommen-
dation, D
6b. In select adult patients with a diagnosis of
acute bronchitis and wheezing accompanying
the cough, treatment with 2-agonist broncho-
dilators may be useful. Quality of evidence, fair;
benefit, small/weak; grade of recommendation, C
7. In patients with a diagnosis of acute bron-
chitis, antitussive agents are occasionally useful
and can be offered for short-term symptomatic
relief of coughing. Quality of evidence, fair; bene-
fit, small/weak; grade of recommendation, C
8. In patients with a diagnosis of acute bron-
chitis, because there is no consistent favorable
effect of mucokinetic agents on cough, they are
not recommended. Quality of evidence, fair; ben-
efit, conflicting; grade of recommendation, I
Chronic Cough Due to Chronic Bronchitis15
1. Adults who have a history of chronic
cough and sputum expectoration occurring on
most days for at least 3 months and for at least
2 consecutive years should be given a diagnosis
of chronic bronchitis when other respiratory or
cardiac causes of chronic productive cough are
ruled out. Level of evidence, low; net benefit,
substantial; grade of recommendation, B
2. The evaluation of patients with chronic
cough should include a complete history re-
garding exposures to respiratory irritants in-
cluding cigarette, cigar, and pipe smoke; passive
smoke exposures; and hazardous environments
in the home and workplace. All are predispos-
ing factors of chronic bronchitis. Level of evi-
dence, low; net benefit, substantial; grade of recom-
mendation, B
3. Smoke-free workplace and public place
laws should be enacted in all communities.
Level of evidence, expert opinion; net benefit, sub-
stantial; grade of recommendation, E/A
4. Stable patients with chronic bronchitis
who have a sudden deterioration of symptoms
with increased cough, sputum production, spu-
tum purulence, and/or shortness of breath,
which are often preceded by symptoms of an
upper respiratory tract infection, should be
considered to have an acute exacerbation of
chronic bronchitis, as long as conditions other
than acute tracheobronchitis are ruled out or
are considered unlikely. Level of evidence, expert
opinion; net benefit, substantial; grade of recom-
mendation, E/A
5. In patients with chronic cough who have
chronic exposure to respiratory irritants, such
as personal tobacco use, passive smoke expo-
sure,
and
workplace
hazards,
avoidance
should always be recommended. It is the most
effective means to improve or eliminate the
cough of chronic bronchitis. Ninety percent of
patients will have resolution of their cough
after smoking cessation. Level of evidence,
good; net benefit, substantial; grade of recommen-
dation, A
6. In stable patients with chronic bronchi-
tis, there is no role for long-term prophylactic
therapy with antibiotics. Level of evidence, low;
benefit, none; grade of recommendation, I
7. In patients with acute exacerbations of
chronic bronchitis, the use of antibiotics is rec-
ommended; patients with severe exacerbations
and those with more severe airflow obstruction
at baseline are the most likely to benefit. Level
of evidence, fair; net benefit, substantial; grade of
recommendation, A
8. In stable patients with chronic bronchitis,
the clinical benefits of postural drainage and
chest percussion have not been proven, and
they are not recommended. Level of evidence,
fair; net benefit, conflicting; grade of recommenda-
tion, I
9. In patients with an acute exacerbation of
chronic bronchitis, the clinical benefits of pos-
tural drainage and chest percussion have not
been proven, and they are not recommended.
Level of evidence, fair; net benefit, conflicting; grade of
recommendation, I
10a. In stable patients with chronic bronchi-
tis, therapy with short-acting -agonists should
be used to control bronchospasm and relieve
dyspnea; in some patients, it may also reduce
chronic cough. Level of evidence, good; net bene-
fit, substantial; grade of recommendation, A
10b. In stable patients with chronic bronchi-
tis, therapy with ipratropium bromide should
be offered to improve cough. Level of evidence,
fair; net benefit, substantial; grade of recommenda-
tion, A
10c. In stable patients with chronic bronchi-
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tis, treatment with theophylline should be con-
sidered to control chronic cough; careful mon-
itoring for complications is necessary. Level of
evidence, fair; net benefit, substantial; grade of
recommendation, A
11. For patients with an acute exacerbation
of chronic bronchitis, therapy with short-acting
-agonists or anticholinergic bronchodilators
should be administered during the acute exac-
erbation. If the patient does not show a prompt
response, the other agent should be added after
the first is administered at the maximal dose.
Level of evidence, good; net benefit, substantial;
grade of recommendation, A
12. For patients with an acute exacerbation
of chronic bronchitis, theophylline should not
be used for treatment. Level of evidence, good;
net benefit, none; grade of recommendation, D
13. For stable patients with chronic bronchi-
tis, there is no evidence that the currently
available expectorants are effective and there-
fore they should not be used. Level of evidence,
low; net benefit, none; grade of recommendation, I
14. In stable patients with chronic bronchitis,
treatment with a long-acting -agonist when
coupled with an ICS should be offered to con-
trol chronic cough. Level of evidence, good; net
benefit, substantial; grade of recommendation, A
15. For stable patients with chronic bronchi-
tis and an FEV1 of < 50% predicted or for those
patients with frequent exacerbations of chronic
bronchitis, ICS therapy should be offered. Level
of evidence, good; net benefit, substantial; grade of
recommendation, A
16. For stable patients with chronic bronchi-
tis, long-term maintenance therapy with oral
corticosteroids such as prednisone should not
be used; there is no evidence that it improves
cough and sputum production, and the risks of
serious side effects are high. Level of evidence,
expert opinion; net benefit, negative; grade of rec-
ommendation, E/D
17. For patients with an acute exacerbation of
chronic bronchitis, there is no evidence that the
currently available expectorants are effective,
and therefore they should not be used. Level of
evidence, low; net benefit, none; grade of recommen-
dation, I
18. For patients with an acute exacerbation
of chronic bronchitis, a short course (10 to 15
days) of systemic corticosteroid therapy should
be given; IV therapy in hospitalized patients
and oral therapy for ambulatory patients have
both proven to be effective. Level of evidence,
good; net benefit, substantial; grade of recommen-
dation, A
19. In patients with chronic bronchitis, cen-
tral cough suppressants such as codeine and
dextromethorphan are recommended for short-
term symptomatic relief of coughing. Level of
evidence, fair; benefit, intermediate; grade of evi-
dence, B
Chronic Cough Due to Nonasthmatic Eosinophilic
Bronchitis16
1. In patients with chronic cough who have
normal chest radiograph findings, normal spi-
rometry findings, and no evidence of variable
airflow obstruction or airway hyperresponsive-
ness, the diagnosis of NAEB should be consid-
ered. Level of evidence, expert opinion; benefit,
substantial; grade of recommendation, E/A
2. In patients with chronic cough with nor-
mal chest radiograph findings, normal spirom-
etry findings, and no evidence of variable
airflow obstruction or airway hyperresponsive-
ness, the diagnosis of NAEB as the cause of the
chronic cough is confirmed by the presence of
airway eosinophilia, either by sputum induction
or bronchial wash fluid obtained by bronchos-
copy, and an improvement in the cough follow-
ing corticosteroid therapy. Level of evidence,
expert opinion; benefit, substantial; grade of recom-
mendation, E/A
3. In patients with chronic cough due to
NAEB, the possibility of an occupation-related
cause needs to be considered. Level of evidence,
expert opinion; benefit, substantial; grade of recom-
mendation, E/A
4. For patients with chronic cough due to
NAEB, the first-line treatment is ICSs (except
when a causal allergen or sensitizer is identified
[see recommendation 5]). Level of evidence, low;
benefit, substantial; grade of recommendation, B
5. For patients with chronic cough due to
NAEB, when a causal allergen or occupational
sensitizer is identified, avoidance is the best
treatment. Level of evidence, expert opinion; ben-
efit, substantial; grade of recommendation, E/A
6. For patients with chronic cough due to
NAEB, if symptoms are persistently trouble-
some and/or the natural history of eosinophilic
airway inflammation progresses despite treat-
ment with high-dose ICSs, oral corticosteroids
should be given. Level of evidence, expert opinion;
benefit, substantial; grade of recommendation, E/A
Chronic Cough Due to Bronchiectasis17
1. In patients with suspected bronchiectasis
without a characteristic chest radiograph find-
ing, an high-resolution CT (HRCT) scan of the
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chest should be ordered because it is the diag-
nostic procedure of choice to confirm the diag-
nosis. Level of evidence, low; benefit, substantial;
grade of recommendation, B
2. In patients for whom there is no obvious
cause, a diagnostic evaluation for an underlying
disorder causing bronchiectasis should be per-
formed, because the results may lead to treat-
ment that may slow or halt the progression of
disease. Level of evidence, low; benefit, substantial;
grade of recommendation, B
3. In patients with bronchiectasis with air-
flow obstruction and/or bronchial hyperreactiv-
ity, therapy with bronchodilators may be of
benefit. Level of evidence, expert opinion; benefit,
small; grade of recommendation, E/C
4. In patients with bronchiectasis caused by
cystic fibrosis (CF), rhDNase should be used to
improve spirometry. Level of evidence, low; ben-
efit, small; grade of recommendation, C
5. In patients with CF, prolonged treatment
with systemic corticosteroids should not be of-
fered to most patients because of significant
side effects. Level of evidence, low; benefit, con-
flicting; grade of recommendation, I
6. In patients with CF, prolonged courses of
ibuprofen should not be used. Level of evidence,
low; benefit, conflicting; grade of recommendation, I
7. In patients with idiopathic bronchiectasis,
the prolonged systemic administration of anti-
biotics may produce small benefits in reducing
sputum volume and purulence, but may also be
associated with intolerable side effects. Level of
evidence, low; benefit, conflicting, grade of recom-
mendation, I
8. In patients with CF, therapy with aerosol-
ized antipseudomonal antibiotics are recom-
mended. Level of evidence, low; benefit, interme-
diate; grade of recommendation, C
9. In patients with idiopathic bronchiectasis,
aerosolized antibiotics should not be used. Level
of evidence, low; benefit, negative; recommendation, D
10. In patients with conditions associated
with the hypersecretion of mucus and the in-
ability to expectorate effectively, chest physio-
therapy should be used and patients should be
monitored for symptom improvement. Level of
evidence, expert opinion; benefit, small/weak; grade
of recommendation, E/C
11. In selected patients with localized bron-
chiectasis that causes intolerable symptoms de-
spite maximal medical therapy, surgery should
be offered. Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
12. In patients with exacerbations of bronchi-
ectasis, antibiotics should be used, with the
selection of agents depending on the likely
pathogens. Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
Chronic Cough Due to Nonbronchiectatic
Suppurative Airway Disease (Bronchiolitis)18
1. In patients with cough and incomplete or
irreversible airflow limitation, direct or indirect
signs of small airways disease seen on HRCT
scan, or purulent secretions seen on bronchos-
copy, nonbronchiectatic suppurative airways
disease (bronchiolitis) should be suspected as
the primary cause. Level of evidence, expert opin-
ion; benefit, substantial; grade of recommendation,
E/A
2. In patients with cough in whom more
common causes have been excluded, because
bacterial suppurative airways disease may be
present and clinically unsuspected, bronchos-
copy is required before excluding it as a cause.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
3. In patients in whom bronchiolitis is sus-
pected, a surgical lung biopsy should be per-
formed when the combination of the clinical
syndrome, physiology, and HRCT findings do
not provide a confident diagnosis. Level of evi-
dence, expert opinion; benefit, substantial; grade of
recommendation, E/A
4. In patients with bacterial bronchiolitis,
prolonged antibiotic therapy improves cough
and is recommended. Level of evidence, low;
benefit, substantial; grade of recommendation, B
5. In patients with toxic/antigenic exposure
or drug-related bronchiolitis, cessation of the
exposure
or
medication
plus
corticosteroid
therapy for those with physiologic impairment
is appropriate. Level of evidence, expert opinion;
benefit, substantial; grade of recommendation, E/A
6. In the inflammatory bowel disease (IBD)
patient with cough, bronchiolitis should be sus-
pected as a potential cause. Level of evidence,
low; benefit, substantial; grade of recommendation, B
7. In patients in whom IBD-related bronchi-
olitis is suspected, both adverse drug reaction
and infection should be specifically considered.
Level of evidence, expert opinion; benefit, substan-
tial; grade of recommendation, E/A
8. In patients with IBD, therapy with both
oral corticosteroids and ICSs may improve
cough, and a trial of therapy is suggested. Level
of evidence, low; benefit, substantial; grade of rec-
ommendation, B
9. In patients with chronic cough who have
recently lived in Japan, Korea, or China, diffuse
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panbronchiolitis (DPB) should be considered in
the evaluations of the cause. Level of evidence,
low; benefit, substantial; grade of recommendation, B
10. In patients with suspected DPB, an ap-
propriate clinical setting and characteristic
HRCT scan findings may obviate the need for
invasive testing and a trial of macrolide therapy
(erythromycin or other 14-member ring macro-
lides such as clarithromycin and roxithromycin)
is appropriate. Level of evidence, expert opinion;
benefit, substantial; grade of recommendation, E/A
11. In patients with DPB, prolonged treat-
ment (> 2 to 6 months) with erythromycin (or
other 14-member ring macrolides such as clar-
ithromycin
and
roxithromycin)
is
recom-
mended. Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
Postinfectious Cough19
1. When a patient complains of cough that
has been present following symptoms of an
acute respiratory infection for at least 3 weeks,
but not more than 8 weeks, consider a diagnosis
of postinfectious cough. Quality of evidence, ex-
pert opinion; net benefit, intermediate; strength of
recommendation, E/B
2. In patients with subacute postinfectious
cough, because there are multiple pathogenetic
factors that may contribute to the cause of cough
(including postviral airway inflammation with its
attendant complications such as bronchial hyper-
responsiveness, mucus hypersecretion and im-
paired mucociliary clearance, upper airway cough
syndrome [UACS], asthma, and gastroesophageal
reflux disease), judge which factors are most
likely provoking cough before considering ther-
apy. Quality of evidence, expert opinion; net benefit,
intermediate; strength of recommendation, E/B
3. In children and adult patients with cough
following an acute respiratory tract infection, if
cough has persisted for > 8 weeks, consider
diagnoses
other
than
postinfectious
cough.
Quality of evidence, low; net benefit, intermediate;
strength of recommendation, C
4. For
adult
patients
with
postinfectious
cough, not due to bacterial sinusitis or early on
in a Bordetella pertussis infection, while the
optimal treatment is not known:
4a. Therapy with antibiotics has no role, as
the cause is not bacterial infection. Level of
evidence, expert opinion; net benefit, none; grade of
evidence, I
4b. Consider a trial of inhaled ipratropium as
it may attenuate the cough. Level of evidence,
fair; net benefit, intermediate; grade of evidence, B
4c. In patients with postinfectious cough,
when the cough adversely affects the patient’s
quality of life and when cough persists despite
use of inhaled ipratropinin, consider the use of
inhaled corticosteroids. Level of evidence, expert
opinion; net benefit, intermediate; grade of evi-
dence, E/B
4d. For severe paroxysms of postinfectious
cough, consider prescribing 30 to 40 mg of
prednisone per day for a short, finite period of
time when other common causes of cough (eg,
UACS due to rhinosinus diseases, asthma, or
gastroesophageal reflux disease) have been
ruled out. Level of evidence, low; net benefit,
intermediate; grade of evidence, C
4e. Central acting antitussive agents such as
codeine and dextromethorphan should be con-
sidered when other measures fail. Level of evi-
dence, expert opinion; net benefit, intermediate;
grade of evidence, E/B
5. When a patient has a cough lasting for > 2
weeks without another apparent cause and it is
accompanied by paroxysms of coughing, post-
tussive vomiting, and/or an inspiratory whoop-
ing sound, the diagnosis of a B pertussis infec-
tion should be made unless another diagnosis is
proven. Level of evidence, low; net benefit, sub-
stantial; grade of evidence, B
6a. For all patients who are suspected of
having whooping cough, to make a definitive
diagnosis order a nasopharyngeal aspirate or
polymer (Dacron; INVISTA; Wichita, KS) swab
of the nasopharynx for culture to confirm the
presence of B pertussis. Isolation of the bacteria
is the only certain way to make the diagnosis.
Level of evidence, low; net benefit, substantial;
grade of evidence, B
6b. PCR confirmation is available but is not
recommended as there is no universally ac-
cepted, validated technique for routine clinical
testing. Level of evidence, low; net benefit, conflict-
ing; grade of evidence, I
7. In patients with suspected pertussis infec-
tion, to make a presumptive diagnosis of this
infection, order paired acute and convalescent
sera in a reference laboratory. A fourfold in-
crease in IgG or IgA antibodies to PT or FHA is
consistent with the presence of a recent B
pertussis infection. Level of evidence, low; net
benefit, intermediate; grade of evidence, C
8. A confirmed diagnosis of pertussis infec-
tion should be made when a patient with cough
has B pertussis isolated from a nasopharyngeal
culture or has a compatible clinical picture with
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an epidemiologic linkage to a confirmed case.
Level of evidence, low; net benefit, substantial;
grade of evidence, B
9. Children and adult patients with con-
firmed or probable whooping cough should
receive a macrolide antibiotic and should be
isolated for 5 days from the start of treatment
because early treatment within the first few
weeks will diminish the coughing paroxysms
and prevent spread of the disease; treatment
beyond this period may be offered but it is
unlikely the patient will respond. Level of evi-
dence, good; net benefit, substantial; grade of evi-
dence, A
10. Long-acting -agonists, antihistamines,
corticosteroids, and pertussis Ig should not be
offered to patients with whooping cough be-
cause there is no evidence that they benefit
these patients. Level of evidence, good; net benefit,
none; grade of evidence, D
11. All children should receive prevention
against pertussis infection as part of a complete
diphtheria, tetanus, acellular pertussis (DTap)
primary vaccination series. This should be fol-
lowed by a single dose DTap booster vaccina-
tion early in adolescence. Level of evidence, good;
net benefit, substantial; grade of evidence, A
12. For all adults up to the age of 65, vacci-
nation with the stronger formulation of TDap
vaccine should be administered according to
CDC guidelines. Level of evidence, expert opinion;
net benefit, substantial; grade of evidence, E/A
Chronic Cough Due to Lung Tumors20
1. In a patient with cough who has risk fac-
tors for lung cancer or a known or suspected
cancer in another site that may metastasize to
the lungs, a chest radiograph should be ob-
tained. Level of evidence, expert opinion; benefit,
substantial; grade of recommendation, E/A
2. In patients with a suspicion of airway in-
volvement by a malignancy (eg, smokers with
hemoptysis), even when the chest radiograph
findings are normal, bronchoscopy is indicated.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
3. For patients with stage I and II non-small
cell lung cancer (NSCLC), surgery to remove the
NSCLC is the treatment of choice. If cough was
caused by a NSCLC that can be surgically re-
moved, the cough will typically cease. Level of
evidence, low; benefit, substantial; grade of recommen-
dation, B
4. For patients with more advanced NSCLC
(stages III and IV), external beam radiation
and/or chemotherapy should usually be offered.
Level of evidence, good; benefit, intermediate; grade
of recommendation, A
5. For patients with dyspnea or hemoptysis
due to endobronchial tumors, cough may also
be present. Endobronchial methods should be
considered for the palliation of these symptoms,
but cough alone is seldom a reason to offer such
treatment. Level of evidence, fair; benefit, small;
grade of recommendation, C
6. For patients with cough and lung cancer,
the use of centrally acting cough suppressants
such as dihydrocodeine and hydrocodone is
recommended. Level of evidence, low; benefit,
intermediate; grade of recommendation, C
Cough and Aspiration of Food and Liquids Due to
Oral-Pharyngeal Dysphagia21
1. In patients with cough, a medical history
particularly directed at identifying conditions
increasing the likelihood of oral-pharyngeal
dysphagia and aspiration (as indicated in Table
1 in Smith Hammond and Goldstein21) should
be obtained. Patients with high-risk conditions
should be referred for an oral-pharyngeal swal-
lowing evaluation. Level of evidence, low; benefit,
substantial; grade of recommendation, B
2a. Patients with cough and their caregivers
should be questioned regarding perceived swal-
lowing problems, including an association of
cough while eating or drinking and a fear of
choking while eating and drinking. If a patient
with cough reports swallowing problems, further
evaluation for oral-pharyngeal dysphagia is indi-
cated. Level of evidence, low; benefit, substantial;
grade of recommendation, B
2b. Further evaluation, including a chest ra-
diograph and a nutritional assessment, should
be considered in patients with cough or condi-
tions associated with aspiration. Level of evi-
dence, low; benefit, substantial; grade of recommen-
dation, B
3. Patients with oral-pharyngeal dysphagia
and cough should be referred, ideally to a
speech-language pathologist (SLP), for an oral-
pharyngeal swallow evaluation. Level of evi-
dence, low; benefit, substantial; grade of recommen-
dation, B
4. Patients with cough related to pneumonia
and bronchitis who have received medical diag-
noses and conditions associated with aspiration
(Table 1 in Smith Hammond and Goldstein21)
should be referred, ideally to an SLP, for an
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oral-pharyngeal swallow evaluation. Level of ev-
idence, low; benefit, substantial; grade of recommen-
dation, B
5. Patients with a reduced level of conscious-
ness are at high risk for aspiration and should
not be fed orally until the level of consciousness
has improved. Level of evidence, low; benefit,
substantial; grade of recommendation, B
6. Alert patients with cough who are in high-
risk groups for aspiration (Table 1 in Smith
Hammond and Goldstein21) should be observed
drinking small amounts of water (3 oz). If the
patient coughs or shows clinical signs that are
associated with aspiration (Tables 2, 3 in Smith
Hammond and Goldstein21), the patient should
be referred for a detailed swallowing evalua-
tion, preferably to an SLP. Level of evidence, low;
benefit, substantial; grade of recommendation, B
7. In patients with cough, the value of the
subjective assessment of voluntary cough (VC)
as the sole predictor of aspiration is uncertain
because of poor reliability and an unclear asso-
ciation with evaluation. Level of evidence, low;
benefit, conflicting; grade of evidence, I
8. The assessment of the reflexive cough re-
sponse to inhaled irritants as a predictor of
aspiration risk and subsequent pneumonia is
not recommended due to a lack of adequate
supportive studies. Level of evidence, low; benefit,
conflicting; grade of evidence, I
9. In acute stroke patients, the expulsive
phase rise time of VC may predict aspiration.
The use of this test has not been validated in
other patient groups, and further studies com-
paring the accuracy of objective measures of
VC to the clinical swallow evaluation to identify
aspiration risk are needed. Level of evidence, low;
benefit, small; grade of recommendation, C
10. Patients with dysphagia should undergo
videofluoroscopic swallow evaluation (VSE) or
fiberoptic endoscopic evaluation of swallowing
(FEES) to identify appropriate treatment. Level
of evidence, low; benefit, substantial; grade of rec-
ommendation, B
11. Patients with dysphagia should be man-
aged by organized multidisciplinary teams that
may include a physician, a nurse, an SLP, a
dietitian, and physical and occupational thera-
pists. Level of evidence, low; benefit, substantial;
grade of recommendation, B
12. In patients with dysphagia, VSE or FEES
can be useful for determining compensatory
strategies enabling patients with dysphagia to
safely swallow. Level of evidence, low; benefit,
substantial; grade of recommendation, B
13. In patients with dysphagia, dietary rec-
ommendations should be prescribed when indi-
cated, and can be refined by testing with foods
and liquids simulating those in a normal diet
during the VSE or FEES. Level of evidence, low;
benefit, substantial; grade of recommendation, B
14. For patients with muscular weakness dur-
ing swallowing, muscle strength training, with
or without electromyographic biofeedback, and
electrical stimulation treatment of the swallow-
ing musculature are promising techniques but
cannot be recommended at this time until fur-
ther work in larger populations is performed.
Level of evidence, low; benefit, conflicting; grade of
evidence, I
15. Patients with intractable aspiration may
be considered for surgical intervention. Level of
evidence, low; benefit, substantial; grade of recom-
mendation, B
Angiotensin-Converting Enzyme Inhibitor-Induced
Cough22
1. In patients presenting with chronic cough,
in order to determine that the angiotensin-
converting enzyme (ACE) inhibitor is the cause
of the cough, therapy with ACE inhibitors
should be discontinued regardless of the tem-
poral relation between the onset of cough and
the initiation of ACE inhibitor therapy. The
diagnosis is confirmed by the resolution of
cough, usually within 1 to 4 weeks of the cessa-
tion of the offending agent; however, the reso-
lution of cough may be delayed in a subgroup of
patients for up to 3 months. Quality of evidence,
low; net benefit, substantial; grade of recommenda-
tion, B
2. In patients presenting with chronic ACE
inhibitor-induced cough, discontinue therapy
with the drug because it is the only uniformly
effective treatment. Quality of evidence, low; net
benefit, substantial; grade of recommendation, B
3. In patients whose cough resolves after the
cessation of therapy with ACE inhibitors, and
for whom there is a compelling reason to treat
with these agents, a repeat trial of ACE inhibi-
tor therapy may be attempted. Quality of evi-
dence, fair; net benefit, substantial; grade of recom-
mendation, A
4. In patients for whom the cessation of ACE
inhibitor therapy is not an option, pharmacologic
therapy, including that with sodium cromogly-
cate, theophylline, sulindac, indomethacin, amlo-
dipine, nifedipine, ferrous sulfate, and picota-
mide that is aimed at suppressing cough should
be attempted. Quality of evidence, fair; net benefit,
intermediate; grade of recommendation, B
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5. In patients in whom persistent or intoler-
able ACE inhibitor-induced cough occurs, ther-
apy should be switched, when indicated, to an
angiotensin receptor blocker, with which the
incidence of associated cough appears to be
similar to that for the control drug, or to an
appropriate agent of another drug class. Quality
of evidence, good; net benefit, substantial; grade of
recommendation, A
Habit Cough, Tic Cough, and Psychogenic Cough
in Adult and Pediatric Populations23
1a. In adult patients with chronic cough, the
diagnoses of habit cough or psychogenic cough
can only be made after an extensive evaluation
has been performed that includes ruling out tic
disorders and uncommon causes (as described
in the section “Uncommon Causes of Cough”),
and cough improves with specific therapy such
as behavior modification or psychiatric therapy.
Level of evidence, expert opinion; benefit, substan-
tial; grade of recommendation, E/A
1b. In adult patients with chronic cough that
remains persistently troublesome despite an
extensive and thorough evidence-based evalua-
tion, and after behavior modification and/or
psychiatric therapy have failed, unexplained
cough should be diagnosed rather than a habit
cough or psychogenic cough. Level of evidence,
expert opinion; benefit, substantial; grade of recom-
mendation, E/A
1c. In children with chronic cough, the diag-
noses of habit cough or psychogenic cough can
only be made after tic disorders and Tourette
syndrome have been evaluated and cough im-
proves with specific therapy such as behavior
modification or psychiatric therapy. Level of
evidence, expert opinion; benefit, substantial; grade
of recommendation, E/A
2. In adult patients with cough, the diagnosis
of habit cough should not be made unless bio-
logical and genetic tic disorders associated with
coughing such as Tourette syndrome have been
ruled out. Level of evidence, expert opinion; bene-
fit, substantial; grade of recommendation, E/A
3. In adults with chronic cough, the presence
or absence of nighttime cough or cough with a
barking or honking character should not be
used to diagnose or exclude a diagnosis of
psychogenic cough. Level of evidence, low; bene-
fit, substantial; grade of recommendation, B
4. In children with chronic cough, the char-
acteristics of the cough may be suggestive of,
but are not diagnostic of, psychogenic cough.
The presence or absence of nighttime cough
should not be used to diagnose or exclude
psychogenic cough. Level of evidence, expert
opinion; benefit, substantial; grade of recommenda-
tion, E/A
5. In adult and pediatric patients with chronic
unexplained cough, common psychosocial prob-
lems such as anxiety, depression, domestic vio-
lence, and child abuse/neglect that are often as-
sociated with somatization disorders should be
evaluated. Level of evidence, expert opinion; benefit,
substantial; grade of recommendation, E/A
6. In
adult
and
pediatric
patients
with
chronic cough associated with troublesome psy-
chological manifestations, psychological coun-
seling or psychiatric intervention should be
encouraged, after other causes have been ruled
out. Level of evidence, expert opinion; benefit,
small/weak; grade of recommendation, E/C
Chronic Cough Due to Chronic Interstitial
Pulmonary Diseases24
1. In patients with chronic cough, before
diagnosing interstitial lung disease (ILD) as the
sole cause, common etiologies such as UACS,
which was previously referred to as PNDS,
asthma, and GERD should be considered. As
these common causes may also share clinical
features with specific ILDs, a diagnosis of ILD
as the cause of cough should be considered a
diagnosis of exclusion. Level of evidence, expert
opinion; benefit, substantial; grade of recommenda-
tion, E/A
2. In patients with cough secondary to an
ILD, because of the prognostic implications,
primary treatment should be dictated by the
specific disorder. Level of evidence, low; benefit,
substantial; grade of recommendation, B
3. In patients with cough secondary to idio-
pathic pulmonary fibrosis, corticosteroids may
lead to symptomatic improvement; however, as
they have been shown to neither prolong survival
nor improve quality of life and may be associated
with significant side effects, their use requires an
individualized analysis of the overall benefits and
risks. Level of evidence, expert opinion; benefit, inter-
mediate; grade of recommendation, E/B
4. In patients with cough and characteristic
clinical and radiographic features, sarcoidosis
should be considered as a cause. Level of evi-
dence, expert opinion; benefit, substantial; grade of
recommendation, E/A
5. In patients with cough secondary to sarcoid-
osis, although therapy with oral corticosteroids
may lead to symptomatic improvement, as they
have not been proven to have a durable benefit
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and are associated with significant side effects, an
individualized analysis of the overall benefit and
risk is necessary. Level of evidence, fair; benefit,
intermediate; grade of recommendation, B
6. In patients with cough secondary to sar-
coidosis, therapy with oral corticosteroids fol-
lowed by ICSs may improve symptoms. Level of
evidence, fair; benefit, conflicting; grade of recom-
mendation, I
7. In patients with cough, ILD, and a con-
cerning environmental, occupational, or avoca-
tional exposure, hypersensitivity pneumonitis
should be considered as a potential cause. Level
of evidence, expert opinion; benefit, substantial;
grade of recommendation, E/A
8. In patients with cough due to hypersensi-
tivity pneumonitis, treatment should include
the removal of the offending exposure and
systemic corticosteroid therapy in those with
evidence of physiologic impairment. Level of
evidence, low; benefit, substantial; grade of recom-
mendation, B
Cough: Occupational and Environmental
Considerations25
1. In every patient with cough, when taking a
medical history, ask about occupational and
environmental causes. Level of evidence, expert
opinion; benefit, substantial; grade of recommenda-
tions, E/A
2. In every patient with cough who has po-
tentially significant exposures to suspicious en-
vironmental or occupational causes, determine
the relationship of these occupational and envi-
ronmental factors to confirm or refute their
role in cough and to modify or eliminate expo-
sure to the relevant agents. Level of evidence,
expert opinion; benefit, substantial; grade of recom-
mendations, E/A
3. Because outdoor environmental pollution
and occupational exposures can be important
factors in causing cough, physicians should play
a role in developing and supporting enforce-
able standards for safe workplace and outdoor
air pollution exposure limits. Level of evidence,
expert opinion; benefit, substantial; grade of recom-
mendations, E/A
4. In patients with a high suspicion of cough
due to environmental or occupational expo-
sures, consider referring the patient to a
specialist in this area or consult evidence-
based guidelines. Level of evidence, expert opin-
ion; net benefit, substantial; grade of recommen-
dation, E/A
Chronic Cough Due to Tuberculosis and Other
Infections26
1. In areas where there is a high prevalence
of TB, chronic cough should be defined as it is
in the World Health Organization Practical Ap-
proach to Lung Health program as being 2 to 3
weeks in duration. Level of evidence, low; benefit,
substantial; grade of recommendation, B
2. In patients with chronic cough who live in
areas with a high prevalence of TB, this diagnosis
should be considered, but not to the exclusion of
the more common etiologies. Sputum smears and
cultures for acid-fast bacilli and a chest radio-
graph should be obtained whenever possible.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
3. In patients with suspected TB, future in-
vestigations are needed to refine the criteria for
suspecting TB and initiating a diagnostic evalu-
ation, to utilize resources in a cost-effective
manner and to improve patient and caregiver
adherence
to
diagnostic
recommendations.
Level of evidence, expert opinion; benefit, substan-
tial; grade of recommendation, E/A
4. In populations at increased risk of becom-
ing infected with TB and transmitting it to
others by cough (eg, those persons in prisons
and nursing homes), special measures to pre-
vent outbreaks must be made by public health
agencies to screen for new cases, maintain sur-
veillance of existing populations, and establish
effective diagnostic and treatment programs
early in the evaluation. Level of evidence, good;
benefit, substantial; grade of recommendation, A
5. In patients with unexplained chronic cough
who have resided in areas of endemic infection
with fungi or parasites, a diagnostic evaluation for
these pathogens should be undertaken when
more common causes of cough have been ruled
out. Level of evidence, low; benefit, substantial; grade
of recommendation, B
Peritoneal Dialysis and Cough27
1. In patients receiving long-term peritoneal
dialysis with cough, evaluate the patient for the
potential causes with increased prevalence in
this population such as GERD, ACE inhibitors,
pulmonary edema, asthma that may be exacer-
bated by -adrenergic-blocking medications,
and infection. Level of evidence, expert opinion;
benefit, substantial; grade of recommendation, E/A
Cough in the Immunocompromised Host28
1. In patients with immune deficiency, the
initial diagnostic algorithm for patients with
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acute, subacute, and chronic cough is the same
as that for immunocompetent persons, taking
into account an expanded list of differential
diagnoses that considers the type and severity
of immune defect and geographic factors. Level
of evidence, expert opinion; benefit, substantial;
grade of recommendation, E/A
2. In HIV-infected patients, CD4 lympho-
cyte counts should be used in constructing the
list of differential diagnostic possibilities poten-
tially causing cough. Level of evidence, low; ben-
efit, substantial; grade of recommendation, B
3. HIV-infected patients with CD4 lympho-
cyte counts of < 200 cells/L or those patients
with counts of > 200 cells/L with unexplained
fever, weight loss, or thrush who have unex-
plained cough should be suspected of having
Pneumocystis
pneumonia,
tuberculosis,
and
other opportunistic infections, and should be
evaluated accordingly. Level of evidence, low;
benefit, substantial; grade of recommendation, B
Uncommon Causes of Cough29
1. In patients with chronic cough, uncommon
causes should be considered when cough per-
sists after evaluation for common causes and
when the diagnostic evaluation suggests that an
uncommon cause, pulmonary as well as ex-
trapulmonary (see Table 1 in section 28), may
be contributing. Level of evidence, low; benefit,
substantial; grade of recommendation, B
2. In patients with chronic cough, until un-
common causes that potentially may be contrib-
uting to the patient’s cough have been ruled
out, the diagnosis of unexplained cough should
not be made. Level of evidence, low; benefit,
substantial; grade of recommendation, B
3. If cough persists after consideration of the
most common causes, perform a chest CT scan
and, if necessary, a bronchoscopic evaluation.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
4. In patients who present with abrupt onset of
cough, consider the possibility of an airway for-
eign body. Level of evidence, low; benefit, substantial;
grade of recommendation, B
5. In patients with unexplained cough, eval-
uate the possibility of drug-induced cough.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
6. In patients with unexplained cough, con-
sider a therapeutic trial of withdrawing the
drug that is suspected to cause the cough. Level
of evidence, low; benefit, substantial; grade of rec-
ommendation, B
Unexplained (Idiopathic) Cough30
1. The diagnosis of unexplained (idiopathic)
cough is a diagnosis of exclusion. It should not
be made until a thorough diagnostic evaluation
is performed, specific and appropriate treat-
ment (according to the management protocols
that have performed the best in the literature)
has been tried and has failed, and uncommon
causes have been ruled out. Level of evidence,
expert opinion; benefit, substantial; grade of recom-
mendation, E/A
An Empiric Integrative Approach to the
Management of Cough3
1. In patients with cough, the starting point
is the medical history and physical examination.
Although the timing and characteristics of the
cough are of little diagnostic value, the medical
history is important to determine whether the
patient is receiving an ACE inhibitor, is a
smoker, or has evidence of a serious life-threat-
ening or systemic disease. Level of evidence,
expert opinion; benefit, substantial; grade of recom-
mendation, E/A
2. In patients with an acute cough, first de-
termine whether the acute cough is a reflection
of a serious illness such as pneumonia or pul-
monary embolism, or, as is usually the case, a
manifestation of a non-life-threatening disease
such as a respiratory tract infection (eg, com-
mon cold or lower respiratory tract infection),
an exacerbation of a preexisting condition (eg,
COPD, UACS, asthma, or bronchiectasis), or an
environmental or occupational exposure to
some noxious or irritating agent (eg, allergic or
irritant-induced rhinitis). Level of evidence, ex-
pert opinion; benefit, substantial; grade of recom-
mendation, E/A
3. In patients with a subacute cough, first
determine whether it is a postinfectious cough
or not. If it is postinfectious, determine whether
it is a result of UACS, transient bronchial hy-
perresponsiveness, asthma, pertussis, or an
acute exacerbation of chronic bronchitis. If it is
noninfectious, manage the cough the same way
as chronic cough. Level of evidence, expert opin-
ion; benefit, substantial; grade of recommendation,
E/A
4a. In patients with chronic cough, systemat-
ically direct empiric treatment at the most com-
mon causes of cough (ie, UACS, asthma, NAEB,
and GERD). Level of evidence, low; benefit, sub-
stantial; grade of recommendation, B
4b. In patients with chronic cough, therapy
should be given in sequential and additive steps
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because more than one cause of cough may be
present. Level of evidence, low; benefit, substantial;
grade of recommendation, B
5. Patients with a chronic cough who smoke
should be counseled and assisted with smoking
cessation. Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
6. In a patient with cough who is receiving an
ACE inhibitor, therapy with the drug should be
stopped and the drug should be replaced. Level
of evidence, low; benefit, substantial; grade of rec-
ommendation, B
7. In patients with chronic cough, initial em-
piric treatment should begin with an oral first-
generation A/D. Level of evidence, low; benefit,
substantial; grade of recommendation, B
8a. In patients whose chronic cough persists
after treatment for UACS, the possibility that
asthma is the cause of cough should be worked
up next. The medical history is sometimes sug-
gestive, but is not reliable in either ruling in or
ruling out asthma. Therefore, ideally, broncho-
provocation challenge (BPC), if spirometry does
not
indicate
reversible
airflow
obstruction,
should be performed in the evaluation for
asthma as a cause of cough. In the absence of
the availability of BPC, an empiric trial of
antiasthma therapy should be administered (see
section on the treatment of asthma in this
guideline). Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
8b. In patients with chronic cough, in whom
the diagnoses of UACS and asthma have been
eliminated or treated without the elimination of
cough, NAEB should be considered next with a
properly performed induced sputum test for
eosinophils. If a properly performed induced
sputum test to determine whether eosinophilic
bronchitis is present cannot be performed, an
empiric trial of corticosteroids should be the
next step. Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
9. In the majority of patients with suspected
cough due to asthma, ideally, before starting an
oral corticosteroid regimen, a BPC should be
performed and, if the result is positive, some
combination therapy of ICSs, inhaled -ago-
nists, or oral leukotriene inhibitors should be
administered. A limited trial of oral corticoste-
roids, however, should be administered in some
patients who are suspected of having asthma-
induced cough before eliminating the diagnosis
from further consideration. Level of evidence,
low; benefit, substantial; grade of recommendation, B
10. In patients whose cough responds only
partially or not at all to interventions for UACS
and asthma or NAEB, treatment for GERD
should be instituted next. Level of evidence, low;
benefit, substantial; grade of recommendation, B
11. In patients with cough whose condition
remains undiagnosed after all of the above has
been done, referral to a cough specialist is indi-
cated. Level of evidence, expert opinion; benefit,
substantial; grade of recommendation, E/A
Assessing Cough Severity and Efficacy of Therapy
in Clinical Research31
1. In patients with chronic cough, to opti-
mally evaluate the efficacy of cough-modifying
agents, investigators should use both subjective
and objective methods because they have the
potential to measure different things. A pa-
tient’s subjective response is likely to be the
only one that measures the impact of the inten-
sity of cough. Level of evidence, expert opinion;
benefit, substantial; grade of recommendation, E/A
2. In patients with chronic cough, with re-
spect to subjective methods, it is recommended
that a valid and reliable cough-specific health-
related quality-of-life instrument be utilized.
Level of evidence, fair; benefit, substantial; grade of
recommendation, A
3. When
assessing
patients
with
chronic
cough, even though visual analog scales have
not been psychometrically tested, they are rec-
ommended because they are commonly used
and valid, and they are likely to yield different
but complementary results to cough-specific
health-related quality-of-life instruments. Level
of evidence, low; benefit, intermediate; grade of
recommendation, C
4. When assessing patients with chronic cough,
because health-related quality-of-life instruments
have been psychometrically tested and visual an-
alog scales have not, the cough-specific health-
related quality-of-life instruments are recom-
mended as the primary subjective outcome
measure. Level of evidence, fair; benefit, intermedi-
ate; grade of recommendation, B
5. In patients with chronic cough, with re-
spect to objective methods, tussigenic chal-
lenges should be used before and after the
intervention to assess the effect of therapy on
cough sensitivity only in disease states in which
cough reflex sensitivity is known to be height-
ened. Level of evidence, low; benefit, small/weak;
grade of recommendation, C
6. In patients with chronic cough, because
the act of coughing has the potential to trauma-
tize the upper airway (eg, the vocal cords),
assessing the presence of upper airway edema
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before and after therapy with flow-volume
loops is useful. Level of evidence, low; benefit,
intermediate; grade of recommendation, C
7. In
patients
undergoing
treatment
for
chronic cough, cough counting over 24 h is
recommended with a computerized methodol-
ogy that is reliable and accurate, noninvasive
and portable, and easy to use in unattended,
ambulatory, real-life settings within a patient’s
home environment. Level of evidence, low; bene-
fit, intermediate; grade of recommendation, C
Cough Suppressant and Pharmacologic Protussive
Therapy32
1. In
patients
with
chronic
bronchitis,
agents that have been shown to alter mucus
characteristics are not recommended for cough
suppression. Level of evidence, good; benefit,
none; grade of recommendation, D
2. In patients with cough due to upper respi-
ratory infection (URI) or chronic bronchitis, the
only inhaled anticholinergic agent that is rec-
ommended for cough suppression is ipratro-
pium bromide. Level of evidence, fair; benefit,
substantial; grade of recommendation, A
3. In patients with chronic or acute bronchi-
tis, peripheral cough suppressants, such as levo-
dropropizine
and
moguisteine,
are
recom-
mended for the short-term symptomatic relief
of coughing. Level of evidence, good; benefit,
substantial; grade of recommendation, A
4. In patients with cough due to URI, periph-
eral cough suppressants have limited efficacy
and are not recommended for this use. Level of
evidence, good; benefit, none; grade of recommen-
dation, D
5. In patients with chronic bronchitis, central
cough suppressants, such as codeine and dex-
tromethorphan,
are
recommended
for
the
short-term symptomatic relief of coughing.
Level of evidence, fair; benefit, intermediate; grade
of recommendation, B
6. In patients with cough due to URI, central
cough suppressants have limited efficacy for
symptomatic relief and are not recommended
for this use. Level of evidence, good; benefit, none;
grade of recommendation, D
7. In patients with chronic or acute cough
requiring symptomatic relief, drugs that affect
the efferent limb of the cough reflex are not
recommended. Level of evidence, low; benefit,
none; grade of recommendation, D
8. In patients requiring intubation during
general anesthesia, the use of neuromuscular
blocking agents is recommended to suppress
coughing. Level of evidence, good; benefit, sub-
stantial; grade of recommendation, A
9. In patients with acute cough due to the
common cold, preparations containing zinc are
not recommended. Level of evidence, good; ben-
efit, none; grade of recommendation, D
10. In patients with acute cough due to the
common cold, over the counter combination
cold medications, with the exception of an older
antihistamine-decongestant,
are
not
recom-
mended
until
randomized
controlled
trials
prove they are effective cough suppressants.
Level of evidence, fair; benefit, none; grade of
recommendation, D
11. In patients with acute or chronic cough
not due to asthma, albuterol is not recom-
mended. Level of evidence, good; benefit, none;
grade of recommendation, D
12. In patients with neuromuscular impair-
ment, protussive pharmacologic agents are in-
effective and should not be prescribed. Level of
evidence, good; benefit, none; grade of recommen-
dation, D
13. In patients with bronchitis, hypertonic
saline
solution
and
erdosteine
are
recom-
mended on a short-term basis to increase cough
clearance. Level of evidence, good; benefit, sub-
stantial; grade of recommendation, A
14. In adult patients with CF, amiloride is
recommended to increase cough clearance.
Level of evidence, good; benefit, substantial; grade
of recommendation, A
15. In adult patients with CF, while recombi-
nant DNase does improve spirometry it is not
recommended to increase cough clearance.
Level of evidence, good; benefit, none; grade of
recommendation, D
Nonpharmacologic Airway Clearance Therapies33
1. In patients with CF, chest physiotherapy is
recommended as an effective technique to in-
crease mucus clearance, but the effects of each
treatment are relatively modest and the long-
term benefits unproven. Level of evidence, fair;
benefit, small; grade of recommendation, C
2. In patients with expiratory muscle weak-
ness, manually assisted cough should be consid-
ered to reduce the incidence of respiratory
complications. Level of evidence, low; benefit,
small; grade of recommendation, C
3. In persons with airflow obstruction caused
by disorders like COPD, manually assisted cough
may be detrimental and should not be used. Level
of evidence, low; benefit, negative; grade of recommen-
dation, D
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4. In patients with COPD and CF, huffing
should be taught as an adjunct to other methods
of sputum clearance. Level of evidence, low; ben-
efit, small; grade of recommendation, C
5. In patients with CF, autogenic drainage
should be taught as an adjunct to postural
drainage as a method to clear sputum because it
has the advantage of being performed without
assistance and in one position. Level of evidence,
low; benefit, small; grade of recommendation, C
6. In patients with neuromuscular weakness
and impaired cough, expiratory muscle training
is recommended to improve peak expiratory
pressure, which may have a beneficial effect on
cough. Level of evidence, expert opinion; benefit,
small; grade of recommendation, E/C
7. In patients with CF, positive expiratory
pressure is recommended over conventional
chest physiotherapy because it is approximately
as effective as chest physiotherapy, and is inex-
pensive, safe, and can be self-administered.
Level of evidence, fair; benefit, intermediate; grade
of recommendation, B
8. In patients with CF, devices designed to
oscillate gas in the airway, either directly or by
compressing the chest wall, can be considered
as an alternative to chest physiotherapy. Level of
evidence, low; benefit, conflicting; grade of recom-
mendation, I
9. In patients with neuromuscular disease
with impaired cough, mechanical cough assist
devices are recommended to prevent respira-
tory complications. Level of evidence, low; benefit,
intermediate; grade of recommendation, C
10. The effect of nonpharmacologic airway
clearance techniques on long-term outcomes
such as health-related quality of life and rates of
exacerbations, hospitalizations, and mortality is
not known at this time. The committee recom-
mends that future investigations measure these
outcomes in patients with CF, and in other
populations with bronchiectasis, COPD, and
neuromuscular diseases. Level of evidence, expert
opinion; benefit, substantial; grade of recommenda-
tion, E/A
Guidelines for Evaluating Cough in Pediatrics4
1. Children with chronic cough require
careful and systematic evaluation for the pres-
ence of specific diagnostic indicators. Level of
evidence, expert opinion; benefit, substantial; grade
of recommendation, E/A
2. Children with chronic cough should un-
dergo, as a minimum, a chest radiograph and
spirometry (if age appropriate). Level of evi-
dence, expert opinion; benefit, intermediate; grade
of recommendation, E/B
3. In children with specific cough, further
investigations may be warranted, except when
asthma is the etiologic factor. Level of evidence,
expert opinion; benefit, intermediate; grade of rec-
ommendation, E/B
4. Children with chronic productive purulent
cough should always be investigated to docu-
ment the presence or absence of bronchiectasis
and to identify underlying and treatable causes
such as cystic fibrosis and immune deficiency.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
5. In children with chronic cough, the etiol-
ogy should be defined and treatment should be
etiologically based. Level of evidence, expert opin-
ion; benefit, substantial; grade of recommendation,
E/A
6. In children with nonspecific cough, cough
may spontaneously resolve, but children should
be reevaluated for the emergence of specific
etiologic pointers (see Table 1 in Chang and
Glomb4). Level of evidence, low; benefit, substan-
tial; grade of recommendation, B
7. In children with nonspecific cough and risk
factors for asthma, a short trial (ie, 2 to 4 weeks) of
beclomethasone, 400 g/d, or the equivalent dos-
age with budesonide may be warranted. How-
ever, most children with nonspecific cough do not
have asthma. In any case, these children should
always be reevaluated in 2 to 4 weeks. Level of
evidence, fair; benefit, intermediate; grade of recom-
mendation, B
8. In children who have started therapy with a
medication, if the cough does not resolve during
the medication trial within the expected response
time, the medication should be withdrawn and
other diagnoses considered. Level of evidence, low;
benefit, intermediate; grade of recommendation, C
9. In children with cough, cough suppressants
and other over-the-counter cough medicines
should not be used as patients, especially young
children, may experience significant morbidity
and mortality. Level of evidence, good; benefit, none;
grade of recommendation, D
10. In children with nonspecific cough, parental
expectations should be determined, and the specific
concerns of the parents should be sought and ad-
dressed. Level of evidence, low; benefit, intermediate;
grade of recommendation, E/B
11. In all children with cough, exacerbating fac-
tors such as exposure to tobacco smoke should be
determined and interventional options for the ces-
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sation of exposure advised or initiated. Level of
evidence, low; benefit, substantial; grade of recommenda-
tion, B
12. Children should be managed according to
the studies and guidelines for children (when
available), because etiologic factors and treat-
ments in children are sometimes different from
those in adults. Level of evidence, low; benefit,
substantial; grade of recommendation, B
13. In
children
< 14
years
of
age
with
chronic cough, when pediatric-specific cough
recommendations are unavailable, adult recom-
mendations should be used with caution. Level
of evidence, expert opinion; benefit, intermediate;
grade of recommendation, E/B
Potential Future Therapies for the Management of
Cough34
• Currently available cough-suppressant therapy is se-
verely limited by a dearth of effective agents and their
unacceptable side affects. Several classes of pharmaco-
logic agents are currently under investigation in an
attempt to develop clinically useful cough suppression.
Future Directions in the Clinical Management of
Cough35
1. As suggested in the various sections of this
guideline, further research should be con-
ducted to elucidate the mechanisms of the pro-
duction of cough in various diseases and condi-
tions, the optimal methods of assessment, and
treatment, specific to the suspected cause. Level
of evidence, expert opinion; benefit, substantial;
strength of recommendation, E/A
2. Research is particularly needed in areas
such as the treatment of postinfectious cough,
the characterization of psychogenic cough, the
methods of assessment of cough, and pharma-
cotherapy. Level of evidence, expert opinion; ben-
efit, substantial; strength of recommendation, E/A
ACKNOWLEDGMENT: This clinical practice guideline re-
ceived the endorsements of the ATS and the CTS.
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Asthma/eosinophic bronchitis
Key points
N Cough may be the only manifestation of these syndromes.
N No currently available tests of airway function can reliably exclude a corticosteroid responsive cough.
Recommendation
N Cough is unlikely to be due to eosinophilic airway inflammation if there is no response to a two week oral steroid trial.
(Audit)
Drugs
Recommendation
N No patient with a troublesome cough should continue on ACE inhibitors.
Environment
Key point
N One of the commonest causes of persistent cough is smoking and appears to be dose related.
Recommendation
N Smoking cessation should be encouraged as it is accompanied by significant remission in cough symptoms.
Gastro-oesophageal reflux disease (GORD)
Key points
N Failure to consider GORD as a cause for cough is a common reason for treatment failure.
N Reflux associated cough may occur in the absence of gastrointestinal symptoms.
Recommendations
N Intensive acid suppression with proton pump inhibitors and alginates should be undertaken for a minimum of 3 months.
(Audit)
N Antireflux therapy may be effective in treating cough in carefully selected cases.
Upper airway pathology
Key points
N Rhinosinusitis is commonly associated with chronic cough.
N There is an association between upper airway disease and cough but a poor association between the various symptoms
and cough.
N There is disparity in the reported efficacy of antihistamines.
Recommendations
N In the presence of prominent upper airway symptoms a trial of topical corticosteroid is recommended.
Undiagnosed or idiopathic cough
Key points
N Chronic cough should only be considered idiopathic following thorough assessment at a specialist cough clinic.
N The clinical history of reflux cough is often present in patients with idiopathic cough.
N A typical lymphocytic airways inflammation is seen in idiopathic cough.
Treatment of cough due to other common respiratory diseases
Key point
N Cough can be a debilitating symptom in many common acute and chronic respiratory diseases.
Recommendation
N Suppression may be relatively contraindicated especially when cough clearance is important.
Specialist cough clinics
Key points
N A systematic approach to diagnosis and treatment remains the most effective way to manage chronic cough.
N Important questions remain as to the complexity and cost effectiveness of existing diagnostic algorithms.
BTS recommendations for cough management in adults
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Recommendations
N No single existing diagnostic protocol can be recommended.
N A combination of selected diagnostic testing and empirical trials of treatment is likely to be most cost effective.
N Referral to a specialist cough clinic should be encouraged and a directory of specialist centres should be made available.
Specialist investigations
Key point
N Debate remains as to the interpretation and clinical utility of more complex investigations.
Bronchial provocation testing
Recommendations
N Bronchial provocation testing should be performed in patients without a clinically obvious aetiology referred to a
respiratory physician with chronic cough and normal spirometry.
N A negative test excludes asthma but does not rule out a steroid responsive cough.
Oesophageal studies
Recommendations
N Empirical treatment should be offered to patients with cough and typical reflux symptoms before oesophageal testing.
N No current test of oesophageal function predicts treatment response.
Upper airway investigations
Recommendations
N Examination of ear, nose and throat should be performed in preference to sinus imaging in patients suspected of having
rhinosinusitis, but with persisting cough despite an adequate trial of treatment directed at the upper airway.
N Specialist cough clinics should have access to fibreoptic laryngoscopy, preferably within the clinic setting.
Cough provocation testing
Recommendations
N There is no current evidence to support the routine use of cough challenge testing in the management of chronic cough.
N For research purposes, standardisation of methodology is required and accurate data on the distribution of cough
responsiveness within the population are needed.
Measurement and monitoring of cough
Recommendations
N Accurate measurement of cough helps determine cough severity, assess treatment efficacy, and may provide diagnostic
information.
N Ambulatory cough recording currently offers most promise in the objective assessment of cough, although further
technical refinement is required if it is to be broadly accessible to physicians.
Assessing airway inflammation
Recommendations
N The demonstration of sputum eosinophilia has important treatment implications and should be available in cough clinics.
N Induced sputum should be requested after exclusion of the other common causes.
N There is insufficient evidence to recommend the routine use of exhaled breath measurements in the clinical evaluation of
chronic cough.
Potential new treatments for cough
Key point
N There are no effective treatments controlling the cough response per se with an acceptable therapeutic ratio.
Recommendation
N There is a need for multicentre clinical trials on new drugs carried out across specialist centres using objective methods of
cough counting as well as subjective quality of life and symptom indexes.
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1.5 Updating of recommendations
It is envisaged that the Executive Committee of the Guideline
Group will meet every two years to review any new published
evidence obtained from a subsequent structured literature
search. An additional purpose of these update meetings will
be to formulate key clinical and research priorities.
1.6 Audit
A number of quality indicators were chosen from recom
mendations made in this document against which the quality
of management of cough could be measured. The key
indicators were:
N Chest radiography and spirometry are mandatory in the
evaluation of chronic cough.
N The severity of the cough should be quantified.
N Treatment effects should be formally quantified.
N Intensive acid suppression with proton pump inhibitors
should be undertaken for a minimum of 2 months.
N Decision to continue steroids made on the basis of a
2 week trial of oral corticosteroids.
2. DEFINITIONS
2.1. Cough
Debate exists as to the most appropriate clinical definition of
a cough event.8 For the purposes of this document, the
members of the Task Force agreed the following definition:
‘‘Cough is a forced expulsive manoeuvre, usually against a closed
glottis and which is associated with a characteristic sound.’’
2.2 Acute and chronic cough
Recommendations
N Acute cough is defined as one lasting less than 3 weeks.
N Chronic cough is defined as one lasting more than
8 weeks.
Classification of cough based on symptom duration is
somewhat arbitrary. A cough lasting less than 3 weeks is
termed acute and one lasting longer than 8 weeks is defined
as chronic. Acute cough is usually a result of a viral upper
respiratory tract infection as almost all such coughs resolve
within this time period.9 A post infective cough may,
however, persist for a considerable period of time. An upper
respiratory tract infection (URTI) cough lingering for more
than 3 weeks is usually termed ‘‘post viral cough’’. The grey
area between 3 and 8 weeks of cough is difficult to define
aetiologically since all chronic cough will have started as an
acute cough, but the clear diagnostic groups of chronic cough
are diluted by those patients with post viral cough.
3. ACUTE COUGH
3.1 Epidemiology
Key points
N Acute cough is the commonest new presentation in
primary care.
N It is most commonly associated with viral upper respira
tory tract infection.
N In the absence of significant co morbidity, it is normally
benign and self limiting.
N It is one of the commonest symptoms associated with
acute exacerbations and hospitalisations with asthma and
chronic obstructive pulmonary disease (COPD).
Acute cough is usually caused by a viral URTI but may arise
from other aetiologies such as pneumonia or aspiration of a
foreign body. The duration of a single episode of URTI
associated cough varies but is rarely more than 2 weeks. A
cut off of 2 months for chronic cough has been arbitrarily
agreed in both American10 and European guidelines.6 The
economic impact of acute cough may be usefully thought of
in terms of a series of patient thresholds that trigger
interventions such as the purchase of a cough medicine or
consultation with a general practitioner (GP).
3.1.1 Incidence of URTI
Symptomatic URTI occur at rates of 2 5 per adult person per
year, with school children suffering 7 10 episodes per year.11
If one accepts the lowest rate of URTI of two episodes per
person per year, then this translates into a conservative
estimate of an incidence of 120 million episodes of URTI per
year in the UK (fig 1).
3.1.2 Incidence of acute cough
Only a proportion of cases of URTI are associated with cough
as a symptom. In naturally acquired URTI, cough was present
in 40 50% of patients.12 13 This translates into an incidence of
approximately 48 million cases of acute cough per year in the
UK. The severity and duration of acute cough will vary widely
but many will reach a threshold of severity that precipitates
self medication.
3.1.3 Incidence of self medication
The sale of non prescription liquid cough medicines grossed
£96.5 millions in 2001 in the UK.14 This sales figure is an
underestimate of total sales as it is for sales from pharmacy
and grocery outlets only, and does not include sales from
outlets such as supermarkets and convenience stores. With
cough medicines averaging £3 4 per unit, this represents at
least 24 million episodes per year in the UK.
3.1.4 Consultations with a general practitioner
Morbidity statistics from general practice for the period 1991
2 reported that more people consulted for respiratory illnesses
(31%) than for any other single disease category.15 With 20%
of patients consulting for URTI, this translates into 12 million
consultations per year, with acute cough representing ‘‘the
largest single cause of consultation in primary care’’.16
3.1.5 Hospital admissions
In normal subjects acute cough associated with URTI is not
usually a cause of hospital admission. However, in patients
with co morbidity such as asthma11 and COPD,17 viral URTI is
the commonest cause of admission. Cough is a common
symptom in this group of patients as well as those admitted
URTI
Acute cough
Self medication
GP consultation
Hospitalisation
120 million
48 million
24 million
12
?
Figure 1
Pyramid of incidence of acute cough. The base represents the
population with an upper respiratory tract infection (URTI), some of
whom will suffer from acute cough. Level 2 represents all those suffering
from acute cough. Level 3 is the proportion of those suffering from acute
cough who reach the threshold of severity of cough to trigger the
purchase of a cough medicine. Level 4 is the proportion of those
suffering from acute cough who reach the threshold of severity of cough
to trigger a GP consultation. Level 5 is the proportion of those suffering
from acute cough who are admitted to hospital. It is not possible to
estimate the number of this latter group (see text).
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(c) Characteristics of the cough
N Interpretation of the diagnostic characteristics of the
cough should be done with caution.
Published evidence
One study has suggested that the character and timing of a
cough are not diagnostically helpful.53 However, others have
suggested a characteristic pattern in reflux cough.54
Important areas of inquiry may establish that the cough is
associated with frequent throat clearing or the sensation of
post nasal drip, occurs mainly at night or after meals, or is
made worse with exercise or cold air. However, the symptoms
of post nasal drip in a patient may reflect only coexistent
rhinitis and the absence of dyspepsia does not rule out reflux
as the cause of cough. In one study the predictive values for
cough characteristics and associated symptoms were calcu
lated.55
A cough with a ‘‘honking’’ or ‘‘barking’’ quality and which
disappears with sleep has been suggested as typical of a
psychogenic or habit cough. Such characteristics have been
frequently reported in the paediatric literature and may
represent a tic cough.56
Consensus would suggest the following areas should be
covered in the history in relation to the cough. It may be
easier to ask the patients to complete a history questionnaire
around which to structure the consultation (see Appendix 3
for suggested questionnaire framework).
(i) Onset
N Did coughing begin gradually or suddenly?
Published evidence
Cough of sudden onset may be clinically associated with
foreign body aspiration.
(ii) Duration
N When did the cough start? How long have you had your
cough?
Published evidence
There is no evidence linking the duration of cough to a
particular association.
(iii) Relation to infection
N Did coughing begin after an initial upper respiratory tract
infection
for example, a cold or sore throat?
Published evidence
Although patients commonly describe their persistent cough
as starting after an infection, there are no data specifically
linking ongoing viral infection to persistent cough. Viral
infection enhances the cough reflex sensitivity57 and may
make subclinical bronchial hyperresponsiveness or reflux
clinically apparent.
(iv) Sputum
N Is the cough dry/productive?
N Significant sputum production suggests primary pulmon
ary pathology
Published evidence
Numerous studies link chronic cough and sputum produc
tion. In a cross sectional study in 18 000 Italian adults there
was a 11.9% prevalence of cough and phlegm for a minimum
of 3 months per year.58 Primary pulmonary disease is more
likely in patients attending a specialist cough clinic with a
productive cough.
(v) Diurnal variation in cough
N Patients cough less at night.
N A cough which abates overnight may be due to reflux
(closure of the lower oesophageal sphincter).
N Asthma, infection, or heart failure can cause coughing
which wakes patients.
Published evidence
Sleep is known to suppress the cough reflex. In a series of
patients with lung disease and nocturnal cough, spontaneous
cough was almost abolished during sleep stages 3 and 4.59
In an observational study in coughers, asthmatics and non
coughers, ambulatory recordings have shown a marked
reduction in cough overnight.60
(vi) Severe coughing spasms/paroxysms
N Severe coughing paroxysms may be associated with
syncope.
N The Driver and Vehicle Licensing Agency (DVLA) stipu
lates that those at risk of syncope should not be driving.
Published evidence
www.dvla.gov.uk
(vii) Incontinence
N Women with cough are often troubled by stress incon
tinence and this may be one of their major concerns.
Published evidence
In a questionnaire survey 55% of women reported urinary
incontinence in association with chronic cough.54
(viii) Origin of sensation
N It is unlikely to be of diagnostic value to enquire where the
sensation that leads to cough arises.
N Whatever the aetiology, the irritation leading to cough is
usually localised to the throat or upper chest.
Published evidence
The site where cough sensations arise in the thorax tends to
be poorly localised. One case study reported cough and tickly
throat occurring during ventricular pacing.61 62 These C fibre
sensations can be reproduced by systemic injections in both
the throat and chest.
(ix) Cough triggers and aggravants
N Persistent cough may be perpetuated because the cough
reflex is abnormally sensitive.
N A sensitised cough reflex is suggested if there is triggering
of cough with change in air temperature, scent, sprays,
aerosols, exercise.
Published evidence
Cough reflex sensitivity may vary from time to time,
particularly when intercurrent respiratory infection occurs.57
Other known cough aggravants have been shown to alter the
sensitivity of the cough reflex
for example, angiotensin
converting enzyme (ACE) inhibitors63
and diseases includ
ing asthma and gastro oesophageal reflux disease (GORD).55
The effect of air temperature, scent, sprays, aerosols, and
exercise has not been studied.
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(x) Posture
N Reflux is known to be related to posture, e.g. bending or
lying down. However, there is no evidence demonstrating
a connection between posture and reflux related cough.
Published evidence
See Bonnet et al.64
(xi) Food
N Cough on eating and postprandially may indicate reflux
cough.
Published evidence
Maximum stimulation for transient opening of the lower
oesophageal sphincter is gastric distention which typically
occurs 10 minutes postprandially.65 In a retrospective review
of patients with proven reflux cough, three quarters had
cough with food or postprandial cough.66
(xii) Cough on phonation
N Cough on phonation such as talking on the telephone,
laughing, or singing may indicate reflux because of lack of
diaphragmatic closure of the lower oesophageal sphincter
(LOS).
Published evidence
A retrospective review again showed that 90% of patients
with reflux cough associated the symptom with phonation.66
(d) Medications
N Note all medications, particularly ACE inhibitors, and
consider which might be causing or potentiating the
cough. The cough may take some months to settle
following withdrawal of ACE inhibitors.
Published evidence
Cough associated with ACE inhibitors was first reported with
captopril in 1985.67 It is a class effect, but the reported
incidence variable may be as high as 16%. It is not dose
related and time to onset is variable, occurring within hours
or more than a year after start of treatment.68 Studies
identifying predisposing factors for the development of cough
associated with ACE inhibitors have been largely inconclu
sive. A recent large retrospective cohort study has identified
smoking, East Asian ethnicity, and previous ACE inhibitor
associated
cough
as
risk
factors.69
ACE
inhibitors
are
associated with an increased sensitivity of the cough reflex,
so they may aggravate cough due to other causes.63 The cough
invariably resolves on cessation of the drug. The median time
to resolution is 26 days although it may be longer (up to
40 weeks) in some patients.68 70 Most patients with ACE
inhibitor
associated
cough
can
tolerate
angiotensin
II
receptor blockers.71
There are only occasional reports of cough as a troublesome
side effect of other drug treatments. One case report has
attributed chronic cough to antiretroviral therapy in an HIV
positive woman.72 Dry cough has also been reported as a rare
complication of interferon alpha treatment in chronic viral
gastroenteritis.73
(e) Occupation/hobbies/pets
N A thorough occupational history should be sought as work
place sensitisers can lead to chronic cough. The same is
true of dust/chemical exposure at home.
Published evidence
Numerous studies and case reports provide accounts of
persistent cough as a presenting feature of occupational
sensitisation of the airways.74 Significant excess cough was
reported in workers exposed to hot acidic conditions in a
bottle factory75 and in workers exposed to hot chilli peppers.76
(f) Past medical history and the association of cough
with underlying disease
(i) Respiratory disease
N Chronic cough is a common association of respiratory
diseases and a thorough respiratory history should be
sought.
Persistent
cough is
commonly associated with asthma
including eosinophilic bronchitis and upper airway disease.
These will be detailed in subsequent sections of this
document. Common respiratory diseases which are readily
appreciated as being associated with chronic cough will be
addressed below.
(ii) COPD
Although patients with COPD commonly report cough, it is
usually in association with production of phlegm and
breathlessness.
Published evidence
Smokers with persistent cough may be at risk of developing
COPD (GOLD).77 A productive cough in patients with
established airflow obstruction is predictive of lung function
decline.
(iii) Bronchiectasis
Although usually associated with sputum production, ‘‘dry’’
bronchiectasis can cause persistent cough and a history of
past respiratory insult as a potential trigger should be sought.
Published evidence
Patients with productive cough may have the same range of
aetiologies as those with dry cough. The prevalence of
bronchiectasis among patients attending specialist cough
clinics is low, estimated at 4%.78
(iv) Lung cancer
Cough may arise as a consequence of the cancer itself, the
treatment, or other co existent disease.
Published evidence
Cough is the fourth commonest presenting feature of lung
cancer.79
Persistent
cough
contributes
significantly
to
impaired quality of life. In one study, 39% of patients with
inoperable non small cell lung cancer scored cough promi
nently.80
(v) Pertussis infection
N Persistent pertussis infection can lead to chronic cough.
Published evidence
An increasing body of circumstantial evidence implicates
pertussis as a cause of persistent cough. In a series of 180
prospective cases of chronic cough, 10% had nasal swabs
positive for Bordetella.81 In a case control study of 201 patients
with cough lasting up to 3 months, a significant increase in
positive serology was reported for Bordetella in the patient
group.82
(vi) Atopic disease
N There is an increase in respiratory symptoms in atopic
individuals.
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Published evidence
In a longitudinal comparative study in 620 adults, atopy was
associated with bronchial hyperresponsiveness in sympto
matic patients.83 In Japan a separate syndrome of atopic
cough is described,84 although whether this is indeed a
separate syndrome has been called into doubt.85
(vii) Cardiovascular disease
N Patients with heart disease can develop chronic cough and
are at risk of myocardial infarction.
Published evidence
Analysis of the Framingham Heart Study data identified both
chronic non productive cough and productive cough as
independent risk factors for myocardial infarction.86
(viii) Organ-specific autoimmune disease
N An association between chronic cough and organ specific
autoimmunity has been reported.
Published evidence
An association between organ specific autoimmune dis
ease
in particular thyroid disease
has been reported.87 In
a case control study, there was more autoimmune disease
and a higher proportion of organ specific autoantibodies in
patients with cough than in age and sex matched controls.87
(f) Family history
N Chronic cough may be familial, suggesting either an
inherited anatomical abnormality or neurological condi
tion.
Published evidence
A kinship of autonomic sensory neuropathy prevalence with
reflux cough (possibly vagal) followed by peripheral sensory
neuropathy was recently described.88
4.3.2 Physical examination
Recommendation
N Physical examination should concentrate on the afferent
sites of the vagus nerve most commonly associated with
the irritation leading to chronic cough.
The physical examination of the patient with chronic cough
may demonstrate clinical signs of obstructive lung disease,
lung cancer, bronchiectasis, pulmonary fibrosis, or cardiac
failure. However, more often the examination reveals less
specific findings.
Physical examination should concentrate on the afferent
sites identified as most commonly associated with chronic
cough.
An ear, nose and throat (ENT) examination may reveal
evidence of nasal obstruction due to inflamed turbinates or
the presence of polyps. The appearance of secretions draining
in the posterior pharynx may be apparent. A ‘‘cobblestone’’
appearance of the oropharyngeal mucosa has been suggested
but is an uncommon finding in the routine examination of
patients with chronic cough.89 Tonsillar enlargement is seen
in some patients with chronic cough. Tonsillectomy can
improve cough reflex sensitivity.90
Evidence of irritation of the larynx and pharynx on indirect
laryngoscopy could suggest proximal gastro oesophageal
reflux.91
Examination of the chest is not useful in differentiating
reversible airflow obstruction from fixed or partially rever
sible airflow limitation. Likewise, there are no features which
easily distinguish cough variant asthma. Asking the patient
to
inhale
may
trigger
paroxysms
of
coughing.
Chest
auscultation may reveal wheezes and a prolonged expiratory
phase on auscultation. Coarse crackles may be a prominent
finding on examination of a patient with bronchiectasis,
while widespread fine late inspiratory crackles are typical of
diffuse parenchymal lung disease.
The presence of finger clubbing in a smoker together with
evidence of a pleural effusion or lobar collapse on examina
tion almost certainly points to a diagnosis of bronchogenic
carcinoma.
In patients with a family history of chronic cough,
neurological examination of the legs should be performed
to look for signs of familial neuropathy.88
4.3.3 Baseline investigations: primary care
Cough is one of the most common symptoms of patients
presenting to primary care, yet there are few studies
investigating its management. One descriptive study found
that 46% of patients presenting with a cough of more than
2 weeks’ duration (28% of whom had a cough of more than
3 months’ duration) had a diagnosis of asthma or chronic
obstructive pulmonary disease.92 This contrasts markedly
with studies in secondary care and specialist cough clinics in
which
gastro oesophageal
reflux,
cough
predominant
asthma, and rhinitis are the main causes. A number of
reviews outlining the diagnosis and management of chronic
cough in primary care have been published.93 95 However, the
evidence for these is predominately based on descriptive
cohort studies and case studies/clinical experience from
specialist centres.
(a) Chest radiography
Recommendations
N A chest radiograph should be undertaken in all patients
with chronic cough and those with acute cough demon
strating atypical symptoms (see table 2).
Published evidence
There are numerous causes of chronic cough, many of which
can be diagnosed from abnormalities on the chest radio
graph. A study from a general respiratory clinic found that
31% of chest radiographs requested for the diagnosis of
persistent cough were abnormal or yielded a diagnosis.2
Studies using algorithms for the diagnosis of chronic cough
have been validated in patients with normal chest radio
graphs.55 78 96 100 If the patient has an abnormality on the chest
radiograph that would account for his/her symptoms, this
should be investigated appropriately and use of a diagnostic
algorithm for chronic cough is not appropriate.
(b) Assessment of pulmonary function
Recommendation
N Spirometry should be performed in all patients with
chronic cough.
N Patients with normal spirometry and bronchodilator
response in whom the diagnoses of cough predominant
asthma or eosinophilic bronchitis are being considered
should be offered a therapeutic trial of prednisolone.
Published evidence
Spirometry is helpful in identifying cough caused by chronic
airways obstruction.101 If an obstructive pattern is identified
on spirometry, forced expiratory volume in 1 second (FEV1)
should be measured before and after inhalation of a short
acting b2 agonist (for example, salbutamol 400 mg by metered
dose inhaler and spacer or 2.5 mg by nebuliser).102 Normal
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spirometry does not exclude asthma as a cause of chronic
cough. In addition, many patients with asthma may not have
spirometric reversibility sufficient to be defined as having
asthma for the purpose of clinical studies.103
Single peak expiratory flow (PEF) measurements and, in
particular, PEF to assess bronchodilator response are not as
accurate as FEV1 in diagnosing airflow obstruction as a cause
of cough in primary care and should be avoided.104 The role of
serial PEF has not been studied in patients with persistent
cough. Patients with ‘‘cough variant’’ or ‘‘cough predomi
nant’’ asthma may not exhibit airways obstruction.99 105 In
addition, patients with cough due to eosinophilic bronchitis
exhibit neither bronchial obstruction nor bronchial hyperre
sponsiveness.106 Patients in whom the diagnosis is in doubt
should be referred to a specialist centre.107
4.3.4 Baseline investigations: secondary care
Studies from general respiratory clinics have reported poor
diagnostic and treatment outcomes compared with specialist
cough clinics that use comprehensive management algo
rithms.2 108 110 Extrapulmonary causes, particularly gastro
oesophageal reflux, are frequently overlooked. The investiga
tion of these conditions is dealt with under the specialist
clinic section.
(a) Bronchoscopy
Recommendation
N Bronchoscopy should be undertaken in all patients in
whom inhalation of a foreign body is suspected.
N Bronchoscopy may be useful in patients in whom other
more targeted investigations are normal.
Published evidence
Bronchoscopy should be undertaken as an initial investiga
tion in all patients suspected of having cough as a result of
inhalation of a foreign body or aspiration. A retrospective
study of 15 420 patients undergoing bronchoscopy without a
history of inhalation of a foreign body, 91% of whom had a
persistent cough and 63% of whom had normal chest
radiographs, found that a foreign body was identified in
only 0.3%.111
Descriptive studies have shown its diagnostic yield as part
of a diagnostic algorithm for chronic cough is low (1
6%),78 98 100 112 although in carefully selected cases the yield
may
be
higher.113 114
In
addition,
bronchoscopy
allows
inspection of the larynx for signs of chronic inflammation
that may be a result of gastro oesophageal reflux.91 115
(b) High resolution computed tomographic (HRCT)
scanning of the thorax
Recommendation
N High resolution computed tomographic (HRCT) scanning
may be of use in patients with persistent atypical cough in
whom other more targeted investigations are normal.
Published evidence
The role of HRCT scanning of the thorax in the diagnosis of
cough has not been properly evaluated. In a prospective study
of patients with chronic cough and normal radiographs who
had undergone a complex diagnostic protocol, HRCT scan
ning was claimed to be diagnostic in 24% of patients;
however, multiple diagnoses were frequently reported in this
study.100 In carefully selected patients the diagnostic rate may
be higher.116 117 HRCT scanning is more sensitive and specific
than plain chest radiography in diagnosing bronchiectasis
and diffuse pulmonary diseases that may present with
chronic cough. Studies have shown abnormalities on HRCT
scans in up to 42% of patients thought to have had a normal
chest radiograph.118 120
4.4 Diganosis and management of specific cough
syndromes
4.4.1 Cough variant asthma and eosinophilic
bronchitis
(a) Definition
An isolated cough in a patient without objective evidence of
asthma
that is, variable airflow obstruction and evidence of
eosinophilic inflammation. In cough variant asthma bron
chial hyperresponsiveness is present, whereas in eosinophilic
bronchitis it is absent.
These syndromes are a common cause of isolated cough,
accounting for around 30% of cough referrals to cough
clinics.50 121 Clinical indicators of cough variant asthma
include cough occurring nocturnally, after exercise, or after
allergen exposure, although how reliable these features are is
unclear. Some studies have highlighted overdiagnosis of
cough variant asthma in children.122
(b) Diagnosis of cough variant asthma
Recommendations
Current methodology for measurement of airway hyperre
sponsiveness is well standardised and widely accepted. A
negative test excludes asthma but does not rule out a steroid
responsive cough.
Published evidence
This requires the demonstration of variable airflow obstruc
tion and/or airway hyperresponsiveness. In patients with
normal or near normal spirometric values (that is, FEV1
.70% predicted), tests of airway responsiveness are more
sensitive and specific than bronchodilator reversibility studies
and PEF records.107 123
(c) Asthma syndromes and cough
Key points
N The presence of non asthmatic corticosteroid responsive
cough syndromes emphasises the importance of assess
ment of airway inflammation or, if this is not available, a
trial of corticosteroids in all patients with chronic cough,
irrespective of the results of tests of variable airflow
obstruction and airway hyperresponsiveness.
N The test box provides clear guidance on interpretation of
the results of treatment trials.
N The type of corticosteroid used in a trial and the duration
of treatment is unclear; expert opinion is that cough is
unlikely to be due to eosinophilic airway inflammation if
there is no response to treatment with prednisolone
30 mg/day for 2 weeks.
N In patients with apparently corticosteroid resistant cough
variant asthma, an alternative diagnosis should be
considered.
Published evidence
Eosinophilic bronchitis is a common cause of cough.124 It
presents as an isolated chronic cough and is characterised by
eosinophilic airway inflammation associated with increased
Th2 cytokine expression125 in the absence of airway hyperre
sponsiveness or variable airflow obstruction. It is unclear
whether eosinophilic bronchitis represents a distinct clinical
entity. Some patients with cough and asthma have non
eosinophilic airway inflammation.126 This pattern of airway
inflammation
has
been
associated
with
corticosteroid
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resistance;126 127 theoretically it might be associated with a
bronchodilator responsive but corticosteroid resistant cough.
The prevalence of non eosinophilic asthma in patients
presenting with cough variant asthma is unclear.
(d) Management
Recommendation
N Management of cough variant asthma should follow
national guidelines, except at step 3 where there is no
evidence for use of a long acting b agonist.
N At step 3, evidence exists for the use of leukotriene
receptor antagonists. Eosinophilic bronchitis and atopic
cough respond to inhaled corticosteroids.
N There is insufficient evidence to give guidance on dose,
preparation, and duration of inhaled corticosteroid ther
apy but use of the BTS asthma guidelines is recommended.
N There is some evidence to support the role of antihista
mines and anti leukotrienes in cough due to asthma and
its variants, but larger scale studies are required.
Published evidence
Cough variant asthma responds to treatment with cortico
steroids.128 Leukotriene receptor antagonists have also been
reported to be effective in reducing cough in this condition.129
High dose antihistamines have been shown to dramatically
reduce cough in seasonal asthma130 but have not been
specifically
investigated
in
cough
variant
asthma.
Eosinophilic
bronchitis
is
characteristically
resistant
to
treatment with inhaled bronchodilators but responds to
inhaled steroids.131
Longitudinal studies have shown that up to one third of
patients who present with cough variant asthma later
develop the typical wheezing of classical asthma.84 132 133 In
contrast, the development of wheezing or airway hyper
responsiveness
is
extremely
uncommon
in
eosinophilic
bronchitis.134
4.4.2 Gastro oesophageal reflux disease (GORD)
(a) Background
Chronic cough due to gastro oesophageal disorders has been
reported in prospective studies in 5 41% of cases.97 100 110
Confusion between different diagnostic criteria, symptoms
of dyspepsia, extra oesophageal reflux, and pH monitoring
make quantification of cough due to GORD difficult.
Patients with GORD have an increased cough reflex
sensitivity which improves with antireflux therapy.135 137
GORD related cough may be induced by microaspiration
of gastric content into the larynx and tracheobronchial
tree.138 140 A second proposed mechanism is through a vagally
mediated oesophageal reflex stimulated by acid or non acid
volume reflux.141 143 Oesophageal motor dysfunction144 148 and
reduced oesophageal clearance149
but not delayed gastric
emptying150
can contribute to both of these mechanisms.
The presence of a self perpetuating cough reflux cycle has
also been suggested.143 151
(b) Does antireflux therapy improve cough
associated with GORD?
Recommendations
N Proton pump inhibitors (PPIs) such as omeprazole 20
40 mg twice daily or equivalent taken before meals for at
least 8 weeks.
N Prokinetic agents such as metoclopramide 10 mg three
times daily may be required in a proportion of patients.
N Elimination of medications that potentially can worsen
GORD should be considered.
Published evidence
A number
of uncontrolled studies
have reported that
antireflux therapy produces an improvement in chronic
reflux
cough
in
75 100%
of
cases.98 99 135
In
contrast,
randomised controlled trials suggest that proton pump
inhibitors (PPIs) twice daily improve cough in 36 57% of
patients with gastro oesophageal reflux related cough when
given for 8 weeks.152 153 Ranitidine 300 mg daily for 2 weeks
improved cough in 54% of patients.154 However, PPIs may be
superior to H2 antagonists.99 155 Twice daily dosing and dosing
before meals may be more appropriate.156 157 Full acid
suppression may only be achieved by a combination of twice
daily PPIs and nocturnal H2 antagonists.158 A trial of
treatment should be at least 8 weeks.96 98 152 153 159 Prokinetic
agents may be helpful in a proportion of patients.78 96 98 160
Elimination of medications potentially worsening reflux
(bisphosphonates, nitrates, calcium channel blockers, theo
phylline, progesterones) may also help.160
The GABA agonist baclofen increases lower oesophageal
tone and decreases lower oesophageal opening and, in an
open study, decreased the incidence of GORD related cough
resistant to other treatment.161 A non specific effect on the
cough reflex has also been demonstrated.162
(c) What is the role of antireflux surgery?
Recommendation
N Antireflux surgery may be effective in treating cough in
carefully selected cases.
Published evidence
Some patients with GORD related cough may benefit from
surgical
intervention
such
as
fundoplication.160 163 164
However, the timing and indications for surgery remain
undefined. Prior to surgery a careful evaluation should be
undertaken including exclusion of other causes of cough,
oesophageal ambulatory 24 hour pH measurement (measur
ing acid and alkaline reflux and the temporal association
between cough and reflux events), oesophageal manometry,
barium
meal,
gastric
emptying
studies,
Bernstein
acid
infusion tests, trial of PPI treatment, and elimination of
medications potentially worsening reflux.160 164 165 Abnormal
oesophageal motility may be associated with a less satisfac
tory outcome following surgery.145
4.4.3 Upper airway disease and cough
(a) Definition
Upper airway disease causes a cough commonly accompanied
by nasal stuffiness, sinusitis, and the sensation of secretions
draining into the posterior pharynx from the nose or sinuses,
sometimes termed post nasal drip.
Key points
N There is an association between upper airway disease and
cough but a poor association between the various
symptoms and cough.
N There is disparity in the reported efficacy of antihista
mines.
N In the presence of prominent upper airway symptoms, a
1 month trial of topical corticosteroid is recommended.
Published evidence
Post nasal drip syndrome (PNDS) has been reported in the
American literature as the most common cause of chronic
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cough,97 99 although this is not a universal finding.110 A broad
range of diseases of the upper airway are associated with
post nasal drip and cough. In contrast, many patients with
observable post nasal secretion do not cough. Whether PNDS
is a distinct syndrome or merely a symptom has been
debated.166
Symptoms89 and clinical findings99 are not reliable dis
criminators in establishing post nasal drip upper airways
disease as a cause of cough. A successful response to
treatment directed at the upper airway is one recommended
diagnostic approach.5
In the USA, recommended treatment involves a first line
approach with a sedating antihistamine/decongestant com
bination.5 The first generation antihistamines recommended
in this document are not available in the UK and there is
conflicting evidence as to the efficacy of second generation
(less sedating) antihistamines in the treatment of cough.167 168
There have been no randomised controlled studies evaluating
the role of topical steroids in chronic cough, although one
randomised placebo controlled trial has suggested that
intranasal steroids given for 2 weeks are effective in the
treatment of cough due to allergic rhinitis.169 Intranasal
steroids appear to be ineffective in the treatment of common
cold symptoms including cough.170 A number of prospective
studies suggest that topical nasal steroids given for 2
8 weeks to patients with cough and post nasal drip are
effective.55 171
4.4.4 Undiagnosed or idiopathic chronic cough
Key points
N Chronic cough should only be considered idiopathic
following thorough assessment at a specialist cough clinic.
N The clinical history of reflux cough is often present in
patients with idiopathic cough.
N A typical lymphocytic airways inflammation is seen in
idiopathic cough.
Published evidence
In up to 20% of referrals to cough clinics55 87 172 173 the cause of
cough remains unclear after extensive investigations and
treatment trials. It has been suggested that these patients
represent a separate subgroup that should be labelled as
idiopathic chronic cough. However, the clinical history
usually suggests non acid reflux and opinion is divided as
to whether, in the absence of a definitive diagnostic or
therapeutic intervention, this represents the underlying
aetiology. If reflux is the underlying cause, then the airway
changes seen in these patients represent the response to the
refluxate. The alternative view that there is a separate
syndrome is discussed below.
Patients with idiopathic cough are predominantly middle
aged women who typically present with a long standing
chronic dry cough which starts around the time of the
menopause87 172 174 and often appears to follow a viral
respiratory tract infection.173 Organ specific autoimmune
disease is present in up to 30%; autoimmune hypothyroidism
is particularly common.87 172 Patients have objective evidence
of abnormal airways with a heightened cough reflex,175
evidence
of
lymphocytic
airway
inflammation,87 174 176 177
increased numbers of mast cells in bronchoalveolar lavage
fluid,178 179 and increased concentrations of tussive mediators
such as histamine, prostaglandin (PG)D2 and PGE2 in
induced sputum.180 A plausible explanation for the develop
ment of cough is amplification of previously subclinical
airway inflammation at the time of the menopause.174 181 182 In
some cases this airway inflammation may be as a result of
aberrant homing of inflammatory cells to the lungs from a
primary site of autoimmune inflammation.87 183 185
When evaluating a patient with idiopathic cough, it is
important to recognise common pitfalls in managing chronic
cough. Treatment for idiopathic chronic cough is disappoint
ing and is largely limited to non specific antitussive therapy
such as dextromethorphan and drugs with weak evidence of
benefit such as baclofen and nebulised local anaesthetics
(lidocaine, mepivicaine).186 Low dose morphine has recently
been shown to be helpful.187
4.4.5 Treatment of cough due to other common
respiratory diseases
Cough may be a prominent and debilitating symptom in a
number of common respiratory diseases including lower
respiratory tract infections (acute tracheobronchitis and
pneumonia) COPD, lung cancer, diffuse parenchymal lung
disease, and bronchiectasis.
Key points
N Cough can be a debilitating symptom in many common
acute and chronic respiratory diseases.
N Suppression may be relatively contraindicated, especially
when cough clearance is important.
Published evidence
In some conditions, in particular pneumonia and bronch
iectasis, cough clearance is important and its suppression
would be undesirable. The treatment of COPD is mainly
directed at the control of symptoms and reduction of
exacerbations, but no studies have evaluated the effective
ness of a particular treatment on the cough itself.188 The
majority
of
lung
cancer
patients
experience
cough.189
Radiotherapy and both opioid and non opioid antitussives
have
been
recommended
(www.rcseng.ac.uk).
Breathlessness is usually the most distressing symptom for
patients with diffuse parenchymal lung disease. However,
cough is frequently reported and can be debilitating;190 only
limited information is available on its treatment.191 There are
no randomised trials evaluating the benefit of treatment
directed solely at cough. The treatment of diffuse parench
ymal lung disease is outside the scope of this document and
the reader is referred to the appropriate BTS guidelines on
this topic (www.brit thoracic.org.uk).
5. GUIDELINES FOR SPECIALIST COUGH CLINICS
General recommendation
N A systematic approach to diagnosis and treatment remains
the most effective way to manage chronic cough.
Important questions remain as to the complexity and cost
effectiveness of existing diagnostic algorithms.
5.1 Introduction
The evaluation and management of cough in specialist clinics
has been widely reported in the literature. Patients attending
specialist cough clinics generally comprise non smokers with
a female preponderance of approximately 2:1.50 They have
often had a combination of baseline investigations and trials
of empirical treatment before referral.
Studies in the primary literature from specialist cough
clinics consist mainly of descriptive cohort studies and
reports of clinical experience from centres with recognised
expertise in cough evaluation and management. There have
been no comparative studies of diagnostic methodology
within or between specialty clinics. The recommendations
for specialist clinics in this document will therefore comprise
a review of the published evidence and the clinical experience
of the Guideline Development Group.
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5.2 Do specialist cough clinics offer superior
diagnostic/management outcomes?
Recommendations
N All clinics managing patients with chronic cough should
ensure management protocols consider pulmonary and
extrapulmonary causes of cough.
Published evidence
Three studies have reported poor diagnostic and treatment
outcomes in hospital based clinics where no established
management algorithm for cough existed.2 108 109 The experi
ence in such clinics markedly contrasts with the generally
high
treatment
success
attributed
to
the
specialist
approach.55 98 99 171 192 In non specialist clinics extrapulmonary
causes, particularly GORD, appears to be overlooked.
5.2.1 Comparison of specialist cough clinic
protocols and outcomes
Recommendation
N Specialist protocols should continue to evaluate pulmon
ary and extrapulmonary causes for cough. Comparative
studies of cough algorithms are required. No single
existing diagnostic protocol can be recommended. A
combination of therapeutic trials and targeted investiga
tion is recommended when diagnostic doubt exists.
Published evidence
No direct comparisons of management protocols between
specialty clinics have been published. However, treatment
success reported from specialist clinics ranges from 68% to
100%.55 97 100 171 192 Thus, despite the specialist evaluation of
cough, a significant number of patients remain undiagnosed.
It is not clear whether this variance reflects differences in
referral population.
5.2.2 Cost effectiveness of diagnostic cough
algorithms employed by specialist cough clinics
Recommendation
N A combination approach of selected diagnostic testing and
empirical trials of treatment is likely to be most cost
effective.
Published evidence
Algorithms for cough evaluation typically used in specialist
clinics range from sequential trials of empirical treatment99 to
exhaustive diagnostic testing in all cases before any trial of
treatment.100 Only one study has explored the cost efficacy of
such diagnostic cough algorithms.193 The ‘‘investigate all then
treat’’ approach was the most expensive, but with the
shortest time to success compared with sequential trials of
empirical treatment.
5.2.3 Is there a specific role for specialist cough
clinics and when to refer?
Recommendation
N Referral to a specialist cough clinic should be encouraged
when there has been a failure of empirical treatment.
N A directory of specialist centres should be made available.
The specialist cough clinics from Europe,55 124 148 194 Asia
Pacific,84 192 195 and the Americas98 100 broadly report successful
outcomes when comprehensive diagnostic protocols are
implemented. It would be desirable if all physicians were
able to refer to a specialist cough clinic. Advice on how to set
up
a
specialist
cough
clinic
is
given
in
Appendix
4.
Appropriate referral criteria are:
N lack of availability of relevant diagnostic testing in primary
or secondary care;
N failed trials of empirical treatment directed at asthma,
GORD, and rhinosinusitis;
N a history suggestive of serious cough complication such as
syncope or chest wall trauma;
N patient preference; and
N recruitment and participation in clinical trials of anti
tussive therapy.
5.3 Specialist investigations
5.3.1 Background
Mandatory investigations in patients with chronic cough are
chest radiography and spirometry. This section will deal with
more complex diagnostic tests where the interpretation
remains open to debate, tests with largely research implica
tions, and new innovations.
5.3.2 Bronchial provocation testing
Key points
N Current methodology for measurement of airway hyperre
sponsiveness is standardised and widely accepted. A
negative test excludes asthma but does not rule out a
steroid responsive cough.
Recommendations
N Bronchial provocation testing should be performed in
patients without a clinically obvious aetiology referred to a
respiratory physician with chronic cough and normal
spirometric values.
Published evidence
Most of the published accounts from specialist cough clinics
have described their experience with bronchial provocation
testing. The methods of measurement of airway hyperre
sponsiveness have been well standardised. In cough clinics,
direct methods using methacholine or histamine are most
commonly employed,55 98 171 although indirect methods have
been described.196 There is broad agreement between cough
centres that a positive test is suggestive of asthma and should
prompt treatment with inhaled steroids.55 98 192 The positive
predictive value of this test ranges from 78% to 88%.55 98
While a negative test in a patient with cough rules out
asthma, it does not eliminate a cough which may respond to
steroids. A number of independent centres have reported
steroid responsive cough in patients with no evidence of
airway hyperresponsiveness.124 195 196
Extrathoracic airway responsiveness can be assessed by
recording the maximal inspiratory flow/volume curve during
conventional bronchial challenge testing. Three groups have
used this method in the assessment of cough.192 197 198 There is
no wide agreement as to the interpretation of this test.
5.3.3 Oesophageal testing
Key point
N Failure to consider GORD as a cause of cough is a common
reason for treatment failure.
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Recommendation
N Empirical treatment should be offered to patients with
cough and typical reflux symptoms before oesophageal
testing.
N 24 hour pH monitoring poorly predicts the therapeutic
response but may be indicated in cases of diagnostic doubt
and in patients thought to require fundoplication.
Published evidence
Objective investigation for GORD
including barium stu
dies,96 100 upper gastrointestinal endoscopy,141 and ambulatory
oesophageal pH testing55 84 98 100 141 149
have been described.
Ambulatory oesophageal pH monitoring is often regarded as
the most sensitive and specific investigation for the diagnosis
of GORD. A long term follow up study (median 30 months)
has recently reported that less than 30% of patients with a
‘‘positive’’ oesophageal pH study respond to antireflux
therapy, and no features on pH monitoring accurately predict
the response.199 One study has described a high prevalence of
motility disorders in cough patients using oesophageal
manometry testing.148 As cough may arise as a consequence
of non acid reflux, impedance testing may offer new insights
into GORD related cough.200 No published reports of its
application in cough currently exist. One study has advocated
the use of empirical therapy in place of oesophageal testing.152
5.3.4 Sinus imaging
Key point
N Rhinosinusitis is commonly associated with chronic
cough.
Recommendation
N Examination of ear, nose and throat should be performed
in preference to sinus imaging in patients suspected of
having rhinosinusitis but with persisting cough, despite an
adequate trial of treatment directed at the upper airway.
Published evidence
Existing cough guidelines make few recommendations on the
role of sinus imaging, preferring to observe the response to a
course of specific treatment for nasal disease.10 In selected
patients (chronic cough and excess sputum production) a
sinus radiograph has a reported positive predictive value of
81% and negative predictive value of 95%.78 However, sinus
radiographs are less sensitive than CT imaging of the
sinuses.201 In a prospective study, routine CT sinus scanning
was no better than an ENT examination in accurately
identifying upper airway disease as a cause of the cough.55
5.3.5 Fibreoptic laryngoscopy
Recommendation
N Specialist cough clinics should have access to fibreoptic
laryngoscopy, preferably within the clinic setting.
Published evidence
Pernasal fibreoptic laryngoscopy provides a quick and simple
method of viewing the laryngeal apparatus without sedation.
The presence of laryngopharyngeal reflux may be determined
by the characteristic changes associated with laryngeal
inflammation and oedema.202 These include pseudosulcus
(subglottic oedema), obliteration of the laryngeal ventricle,
erythema of the arytenoids, oedema of the posterior laryngeal
wall, and laryngeal mucus.
5.3.6 Cough provocation testing
Recommendations
N There is no current evidence to support the routine use of
cough challenge testing in the management of chronic
cough.
N For research purposes, standardisation of methodology is
required and accurate data on the distribution of cough
responsiveness within the population are needed.
Published evidence
A variety of methods to measure cough reflex sensitivity have
been described in the specialist cough clinic setting. These
include tidal breathing challenge with low chloride solutions,
and single breath challenges with capsaicin55 171 203 and citric
acid.37 Although safe and relatively simple to perform, a
review of cough provocation testing has highlighted the need
for consensus on methodology.204
Unlike bronchial hyperresponsiveness, cough challenge
reveals a wide range of normal cough reflex sensitivity.
Cough provocation testing therefore has no clear diagnostic
applications and is likely to be confined to the clinical
research of cough.
5.4 Measurement and monitoring of cough
Key points
N Accurate measurement of cough helps determine cough
severity, assess treatment efficacy, and may provide
diagnostic information.
N Ambulatory cough recording currently offers most promise
in the objective assessment of cough, although further
technical refinement is required if it is to be broadly
accessible to physicians.
Published evidence
A number of methods to measure cough frequency, intensity
and severity have been described. Visual analogue scales and
self report cough diary cards have been used but do not
consistently
correlate
with
objective
methods
such
as
ambulatory cough monitoring.205 The use of a series of
different ambulatory cough recording monitors has been
reported in both adult60 206 and paediatric207 209 literature.
Although some technical limitations currently exist, they
offer the best objective means of recording cough. Differences
in the characteristics of the cough sound and flow pattern
between asthma, bronchitis, and interstitial fibrosis have
been reported.210 Recently, analysis of overnight cough
recording determined differences in character and intensity
of cough sounds between patients with cystic fibrosis and
those with cryptogenic fibrosing alveolitis.211 These observa
tions open the diagnostic possibilities for cough monitoring.
5.5 Assessing airway inflammation
5.5.1 Induced sputum
Recommendations
N The demonstration of sputum eosinophilia has important
treatment implications and should be available in cough
clinics.
N Induced sputum should be requested after exclusion of
other common causes.
Published evidence
A number of independent groups have adapted conventional
diagnostic strategies for chronic cough to include induced
sputum.84 124 195 The demonstration of airway eosinophilia
(.3% sputum eosinophil count) in patients without the
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functional abnormalities (particularly bronchial hyperreac
tivity) associated with asthma has helped define eosinophilic
bronchitis as a distinct cause for chronic cough. Eosinophilic
bronchitis may account for up to 15% of cases of cough
referred for specialist attention,124 although debate remains as
to whether eosinophilic bronchitis exists as a separate
diagnostic entity.212
5.5.2 Exhaled breath
Recommendations
N There is insufficient evidence to recommend the routine
use of exhaled breath measurements in the clinical
evaluation of chronic cough.
Published evidence
Exhaled nitric oxide (NO) levels appear to be lower in non
asthmatic coughers, allowing some differentiation from
asthmatic patients with cough.213 Exhaled NO may represent
a simpler alternative to induced sputum tests but currently it
has no clear diagnostic role in the management of chronic
cough. An increase in nitrite levels has been reported in
exhaled breath condensate from asthmatic children with
cough but not from non asthmatic children with cough.214
Measurement of many different inflammatory molecules in
breath condensate, although currently a research procedure,
may have a place in the future diagnosis of chronic cough.
5.6 Recommended diagnostic protocol (see Appendix
2, Parts 1 and 2)
The evaluation and management of cough in an adult should
comprise two phases. The approach suggested in phase 1 is
applicable to all physicians (primary and secondary care)
encountering the patient for the first time. Treatment failure
should prompt phase 2 of the evaluation algorithm. The
algorithm is available online only at http://www.thoraxjnl.
com/supplemental.
6. POTENTIAL NEW TREATMENTS FOR COUGH
Recommendations
N There is an urgent need for multicentre phase II trials on
new drugs carried out across specialist centres using
objective methods of cough counting as well as subjective
quality of life and symptom indices.
6.1 Background
Chronic cough is associated with many inflammatory airways
diseases
such
as
asthma,
COPD,
post viral
infections,
pulmonary fibrosis, and bronchiectasis.10 In some cases
certain
drugs
can
be
used
to
inhibit
the
underlying
inflammatory process that, under certain conditions, cause
cough
for example, corticosteroids for the treatment of
asthma or COPD, or PPIs as treatment for gastro oesophageal
reflux. However, there are patients who cough who do not
respond to treatments directed at the cause of the cough, and
there are patients in whom there is no identifiable cause to
treat. Therefore, there is also a requirement to develop
compounds that are targeted to inhibit sensory nerve activity
directly (by inhibition of peripheral or central mechanisms),
which should in theory inhibit cough of any aetiology.
6.2 New treatments under investigation
6.2.1 Opioids
Attempts have been made to improve the therapeutic index
by topical administration of a peripherally acting polar
enkephalin analogue, BW443C81, which was shown to
inhibit citric acid induced cough in guinea pigs.215 However,
in humans there was no effect on capsaicin induced cough in
normal volunteers.215 A novel opioid peptide, nociceptin,
which binds to the opioid receptor like 1 receptor (NOP) has
been shown to suppress capsaicin induced cough in guinea
pigs and mechanically induced cough in the cat, but so far no
data exist in humans.216 217
6.2.2 Neurokinin receptor (NK) antagonists
The NK2 receptor antagonist SR 48968 has been shown to
inhibit
citric
acid
induced
cough
in
conscious
guinea
pigs,218 219 and an antitussive effect of NK1 receptor antago
nists is still under debate. Although there is a report
suggesting an antitussive effect of a dual NK1/NK2 receptor
antagonist (FK224) on bradykinin induced cough in asth
matics,220 other studies have failed to demonstrate any
antitussive action of compounds of this type.221 Recent data
have implicated a role for NK3 receptor activation in evoking
a tussive response possibly via a peripheral mechanism of
action,222 223 even though there have been no reports of the
presence of functional NK3 receptor antagonists in the
human lung.
6.2.3 Gamma aminobutyric acid (GABAB) receptor
agonists
GABAB agonists (such as baclofen) have been shown to
inhibit capsaicin induced cough in the conscious guinea
pig224 225 and in normal volunteers,226 and provided some
benefit in patients with chronic cough.227
6.2.4 Cannabinoid CB2 receptor agonists
CB2 receptor agonists inhibit guinea pig and human sensory
nerve activation in vitro and the cough reflex in guinea pigs,
which suggests that the development of CB2 agonists, devoid
of CB1 mediated central effects, will provide a new and safe
antitussive treatment for chronic cough.228 No clinical data
exist in humans.
6.2.5 Local anaesthetics
Local anaesthetics such as lignocaine are delivered locally to
the airways and have been shown to attenuate capsaicin
induced cough in man.229 However, the effect is transient and
the antitussive effect is accompanied by oropharyngeal
anaesthesia leading to an increased risk of aspiration of
airway secretions and food.
6.2.6 Transient receptor potential (TRP) channels
The cold and menthol sensitive receptor (CMR1) has recently
been characterised and cloned.230 Interestingly, menthol has
been proposed as an antitussive therapy and has been shown
to inhibit citric acid induced cough in normal volunteers.28
The heat sensitive channel TRPV1 is activated by capsaicin,
the main pungent ingredient in hot chilli peppers,231 232 and
capsazepine, a blocker of this channel, inhibits capsaicin and
citric acid induced cough in the guinea pig.233 An increase in
epithelial nerve profiles expressing TRPV1 has been reported
in patients with non asthmatic chronic cough.234 Compounds
of this type are currently in clinical development.
6.2.7 Potassium channel openers
NS1619, an opener of large conductance calcium activated
potassium (BKCa) channels, has been shown to inhibit
sensory nerve function and cough induced by citric acid in
the guinea pig.235 ATP sensitive potassium channels may also
be a good target.
6.3 Conclusions
Treatment of the causes of cough can often be an effective
treatment strategy. However, at the moment there are no
effective treatments controlling the cough response per se
with an acceptable therapeutic ratio. The future looks
promising
with
several
novel
mechanisms
identified;
BTS recommendations for cough management in adults
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BTS recommendations for cough management in adults
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APPENDIX 1 PATIENT INFORMATION SHEET
APPENDIX 2 PROTOCOL FOR THE EVALUATION OF CHRONIC COUGH IN AN ADULT
Appendix 2 Parts 1 and 2 is available online only at http://www.thoraxjnl.com/supplemental.
Most short term coughs are due to a virus infection. Antibiotics won’t help, even if you are bringing up phlegm,
and you probaly don’t need to see a doctor.
You can get treatment from a pharmacist (chemist). Cough remedies that contain dextromethorphan may be the
most effective. Take some paracetamol. Menthol lozenges or vapour might help too.
You’ll probably feel tired, with a running or blocked nose, and perhaps have a mild fever and aching bones.
Patient information sheet
We recommend a home remedy, such as honey and lemon if you feel the need for treatment.
Remember, coughs and sneezes do spread diseases, try not to infect others! Use a handkerchief and don’t forget
to wash your hands.
Stop making it worse  STOP SMOKING
You should see your doctor if
You’ve got a 
cough
You cough up blood
You are breathless
You have prolonged fever and feeling unwell
You have a medical condition such as chronic bronchitis (COPD), heart disease, diabetes, asthma
You have recently been in hospital
Your symptoms persist for more than three weeks
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Name
Age
Smoker:
Occupation:
Duration of cough:
Preceding URTI:
Describe cough (patients’ words)
y / n / never                         packyears:
y / n
Dry / Productive
Sudden onset ? aspiration
Phlegm (if produced):
Nocturnal:
Wakes from sleep:
Difficulty getting to sleep:
y / n 
y / n
y / n
Typical precipitants
Exercise:
Cold air:
Aerosols:
Cough on rising:
y / n 
y / n
y / n
y / n
Talking/laughing/singing:
Eating:
Positional:
Eating and postprandial:
y / n 
y / n
y / n
y / n
Associated symptoms
Heartburn/epigastric pain:
Postnasal drip:
Voice change:
y / n 
y / n
y / n
Associated respiratory symptoms
Wheeze:
SOB:
y / n 
y / n
Chest pain:
y / n 
PMHx (respiratory)
Childhood wheeze:
Atopy:
y / n 
y / n
 cats / dogs / grasses / foods
PMHx (non respiratory)
DHx (particularly ACE I / β blocker/NSAID):
Family history of cough
Systematic questions
Examination
Investigations to date
Relieving medication (tick if tried y / n for response)
Over the counter:
Oral steroids course:
Antibiotics:
Codeine/opiates:
y / n 
y / n
y / n
y / n
Inhaled medication:
Anti reflux:
Nasal sprays:
Homeopathic:
y / n  (give details) 
y / n  (give details) 
y / n  (give details) 
y / n  (give details) 
APPENDIX 3 COUGH ASSESSMENT QUESTIONNAIRE
BTS recommendations for cough management in adults
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APPENDIX 4 SETTING UP A SPECIALIST COUGH
CLINIC SERVICE
Why set up a cough clinic service?
A specialist cough clinic service offers a number of distinct
advantages
(1) Improved patient outcomes: treatment success is con
siderably higher for patients managed in a specialist
cough clinic than in general respiratory clinics.
(2) Avoidance of inappropriate prescribing: diagnostic uncer
tainty often leads to inappropriate use of antibiotics and
inhaled corticosteroids.
(3) Training: specialist cough clinics provide an environment
for training and skill development for physicians (often
specialist registrars in respiratory training programmes),
pulmonary function technicians, and respiratory nurse
specialists.
(4) Clinical research: an improved understanding of the
pathophysiology of cough and need to develop and
evaluate new cough treatments requires the collaboration
of clinicians, scientists, and the pharmaceutical industry.
Specialist cough clinics ensure the accurate characterisa
tion of patients with cough and provide opportunities for
trusts with an interest in clinical research and pharma
ceutical trial participation.
Where to set up a cough clinic service?
A specialist cough clinic should provide a combination of
diagnostic testing and treatment trials. Although specialist
cough clinics have generally been set up in secondary care,
they could be developed within a Primary Care Trust. There
are no comparisons of treatment outcome or cost to
recommend one or other.
Core requirements
(1) A named consultant or GP should have responsibility for
the service.
(2) All staff should be provided with training appropriate to
their role in providing care.
(3) To adequately supervise trials of treatment including
assessment of cough severity (visual analogue scales and
quality of life questionnaires).
(4) Pulmonary function testing with spirometry as a mini
mum requirement.
(5) Access to chest radiography and bronchial provocation
challenge testing (methacholine inhalation challenge
testing).
(6) Facility to refer for oesophageal testing in appropriate
circumstances.
(7) Ear, nose and throat (ENT) assessment either on site
(facility for direct laryngoscopy) or direct access to ENT
clinic.
(8) Access to bronchoscopy and chest CT scanning in
appropriate circumstances.
(9) The outcomes of the service should be subject to regular
review.
Desirable requirements
(1) Facility to obtain and analyse induced sputum samples.
(2) Cough provocation testing.
Cost implications
Capital costs
N Essential items: spirometer (£200 2500)
N Non essential: flexible laryngoscope (approximately
£7000); cough provocation testing, dosimeter and nebu
liser (approximately £4000).
Recurring costs
N Staff costs should include physician, pulmonary function
technician, nurse specialist, and clerical time.
N Consumables
for example, methacholine challenge test
ing (approximately £50 per test).
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