REVIEW

The Evolving Clinical Practice of Chronic

Cough
Sumera R. Ahmad, MBBS, and Vivek N. Iyer, MD, MPH

Abstract

Chronic cough, defined as a cough lasting for greater than 8 weeks, accounts for a substantial number
of primary care and specialist consultations in the United States. Although cough can arise from a
myriad number of serious respiratory diseases, attention has traditionally focused on diagnosing and
treating gastroesophageal reflux, upper airway cough syndrome, and eosinophilic airway inflammation
(asthma and nonasthmatic eosinophilic bronchitis) in patients with normal chest imaging. The newly
described paradigm and entity of cough hypersensitivity syndrome (CHS) becomes useful when the
etiology of cough remains elusive or when the cough remains refractory despite appropriate therapy
for underlying causes. We present an update on the evolving understanding of refractory chronic
cough and/or unexplained chronic cough as manifestations of laryngeal hypersensitivity and CHS.
This includes a focus on understanding the pathophysiology underlying current and novel thera-
peutics for CHS, while also ensuring that common causes of chronic cough continue to be evaluated
and treated in a systematic multidisciplinary manner.
ª 2022 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2022;97(6):1164-1175

From the Division of Pulmo-

C
hronic cough accounts for approxi-
nary and Critical Care, Mayo
Clinic, Rochester, MN, USA. mately 10% to 38% of respiratory
visits in the United States.1,2 Global
estimates suggest a prevalence of chronic
cough of approximately 10% to 12% with
higher rates among smokers. Prevalence
rates appear to be higher in Europe and
North America as compared with Asia and
Africa.3,4 Almost all epidemiological studies
on chronic cough suggest a strong female
predilection with females accounting for
more than two-thirds of patients in cohorts.5
Chronic cough can have profound
impact on the quality of life of patients,
such as vomiting, rib pain, urinary inconti-
nence, syncope, speech interference, fatigue,
and depression.2,6 Even the sensation of the
urge to cough, which precedes the actual
cough motor response, has been observed
to result in embarrassment, anxiety, and
distress.7 In addition, patients with refrac-
tory chronic cough are more likely to pre-
sent with depression, anxiety, and fatigue.8
Addressing these psychological symptoms
can improve cough-related quality of life.9
Whereas chronic cough has not, in
particular, been observed to be a
predominant feature of patients who have
recovered from coronavirus disease 2019
infection,10 the pandemic has worsened the
anxiety and distress from coughing in pa-
tients with chronic cough. Further clinical
observations of patient with chronic cough
during this pandemic are awaited.
In this review, we explore the current
understanding of refractory chronic cough
(RCC) and/or unexplained chronic cough
(UCC) as understood through the lens of
cough hypersensitivity syndrome (CHS).
We also provide an update on gastroesopha-
geal reflux disease (GERD), upper airway
cough syndrome (UACS), and airway in-
flammatory causes as fundamental causes
of chronic cough in clinical practice.
COUGH HYPERSENSITIVITY SYNDROME AS
A PARADIGM TO UNDERSTAND
REFRACTORY CHRONIC COUGH
Refractory chronic cough and/or UCC ac-
counts for 12% to 46% of specialty clinic re-
ferrals.11-13 This is defined by the American
College of Chest Physicians (ACCP) as
persistence of cough despite a thorough
algorithmic approach towards testing and

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www.mayoclinicproceedings.org n ª 2022 Mayo Foundation for Medical Education and Research
CHRONIC COUGH
treating for GERD, UACS, and airway in-
flammatory disorders as well as ensuring
avoidance of smoking, environmental trig-
gers, and angiotensin-converting enzyme in-
hibitor use (Figure 1).14,15 Whereas multiple
etiologies for chronic cough can coexist in
the same patient,16 many patients may not
have undergone rigorous diagnostic tests
and standardized therapeutic trials for their
chronic cough.14 Thus, it is imperative to
undertake a thorough and complete inven-
tory of the patient’s diagnostic as well thera-
peutic journey before applying the label of
RCC or UCC.
Refractory chronic cough has been dis-
cussed in the literature and clinical practice
under several different names, including
neurogenic cough, laryngeal hypersensitiv-
ity, cough hypersensitivity syndrome, irrita-
ble larynx, tic cough, habit cough, and
psychogenic cough. Cough hypersensitivity
refers to the laryngeal and airway sensory
neuropathy that underlies this disorder17,18;
hence, the term CHS can be useful by which
to understand the pathophysiology thought
to underlie RCC and/or UCC in most cases.
Thus, we will use the term CHS and avoid
terms such as habit cough and psychogenic
cough as per ACCP guidelines.19
What Clinical Features Are Helpful in
Identifying CHS?
Patients with CHS often present with laryn-
geal symptoms, although those are not spe-
cific to CHS. Laryngeal paresthesia
comprises throat, airway, and chest sensa-
tions.20 Symptoms may manifest as an inter-
mittent itch, tickle, scratch, irritation, and
choking or globus sensation in the throat
or a feeling of throat and/or upper chest
tightness.7,20 Other symptoms may include
dysphonia, hoarseness of voice, and vocal
cord dysfunction.20 This often leads to an
enhanced perception or sensation of the
urge to cough.
Laryngeal hypersensitivity with symp-
toms of allotussia and hypertussia is also
common in CHS,18 even if not specific to it
(Table1). Allotussia is defined as cough
that occurs in response to nontussive stimuli
such as talking, laughing, singing, deep
Mayo Clin Proc. n June 2022;97(6):1164-1175 n https://doi.org/10.1016/j.mayocp.2022.02.005
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ARTICLE HIGHLIGHTS
d Workup for gastroesophageal reflux disease, upper airway
cough syndrome, and corticosteroid responsive cough should
be adhered to per American College of Chest Physicians
guidelines before consideration of cough hypersensitivity syn-
drome (CHS).
d Allotussia and hypertussia are common features in chronic
cough and CHS, simulating the mechanistic pathway of chronic
pain.
d Behavioral therapy with physiotherapy speech and language
therapy intervention and neuromodulators may be beneficial for
CHS.
d Novel therapeutic strategies are expected to help develop
management pathways in CHS.
d There is a need to expand and individualize treatment pathways
for patients with refractory chronic cough and study impact on
important patient outcomes.
breathing, changes in body position, changes
in air temperature/humidity, perfumes,
chemical odors, or certain types of foods.
Hypertussia is the increased sensitivity or
lowering of threshold to tussive stimulants,
such as is seen with capsaicin and citric
acid and experienced with stimulants such
as inhalation of aerosols, fumes, or dust.21
Figure 2 shows a possible hypothesis for un-
derstanding the differences between a
“normal” cough reflex and the “hypersensi-
tive” cough reflex. The relationship between
the urge to cough (UTC), motor cough, and
stimulus intensity22 is shown via the interac-
tions of three tussigenic stimuli (A, B, and
C) with the patient’s sensory as well as mo-
tor threshold for cough. We observe that
stimulus A is weakly tussigenic and is unable
to elicit even a UTC in a “normal” subject
(green line) but can induce an UTC in a pa-
tient with cough hypersensitivity (red line).
The moderately tussigenic stimulus B elicits
a UTC (but not a motor cough) in a
“normal” subject but is strong enough to
elicit a motor cough in a patient with cough
hypersensitivity. Stimulus C, on the other
hand, is strongly tussigenic resulting in
1165
 MAYO CLINIC PROCEEDINGS

History, physical exam, chest radiograph, ±computed

• Nasal steroids
tomography chest, smoking cessaton, discontinuation
• Topical vs. oral of ACE-inhibitors othen focus on the big 3 (UACS, CRC,
decongestants GERO) and big 1 (CHS) • PSALTI
• Saline rinses • Neuromodulators
• +/-allergy treatment • SLN block
• +/-antibiotics •±vocal cord injection
• Await novel therapies

UACS
• Rhinoscopy CHS
• Sinus imaging
• Allergy testing

GERD
Triggers • Barium esophagram
• UACS/CRC/GERD • MII-pH with
manometry testing

CRC •Diet and lifestyle

• Spirometry & modification
bronchodilator/ • ±acid suppression
bronchoprovocation • ±prokinetics
• Exhaled NO •Selective consideration
• Sputum eosinophils for anti-reflux surgery
• +/-allergy testing

• ICS+/-LABA
• Asthma education
• Allergy treatment

FIGURE 1. A clinical algorithmic approach to chronic cough upper airway cough syndrome (UACS), gastroesophageal reflux disease
(GERD), corticosteroid responsive cough (CRC), cough hypersensitivity syndrome (CHS), NO nitric oxide (NO), inhaled cortico-
steroid (ICS), long acting beta agonist (LABA), physiotherapy speech and language therapy intervention (PSALTI), and superior
laryngeal nerve block (SLN). ACE ¼ antiotensin-converting enzyme; MII ¼ Multichannel intraluminal impedance.

motor cough in both normal as well as those
with cough hypersensitivity.
Because mucosal trauma from the very
act of coughing may perpetuate laryngeal
hypersensitivity, symptoms of allotussia
and hypertussia alone cannot be used to
predict the presence or absence of untreated
or undertreated etiologies of chronic
cough.23
What Is Our Current Understanding of the
Pathophysiology of CHS?
The sensory receptors and neural pathways
involved in explained chronic cough and
CHS are similar. Reflex cough is the activa-
tion of airway afferents by inhaled, aspirated,
or locally produced substances.24 Whereas
the reflex cough pathway terminates in the
brainstem, voluntary cough or cough

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CHRONIC COUGH
TABLE 1. Symptoms of Cough Hypersensitivity
Allotussia (cough Hypertussia
Urge to triggered by nontus- (increased sensi-
cough sive stimulant) tivity to stimulant)
Irritation/ Talking Cold air
itch/
scratchy
throat
Tickle Laughing Dry air
Globus Singing Fumes
sensation
“Something Changing positions Odor
there”
Humidity changes Dust
Eating Aerosols
suppression likely involves higher cortical
circuitries.25 A hypothesized perspective is
that the sensation of the urge-to-cough is
distinct from reflex cough because it requires
cortical sensory processing before the resul-
tant cough motor response.22 This highlights
the importance of behavioral interventions
in the treatment of CHS.25
The majority of the vagal sensory affer-
ents involved in the pathway of cough are
the unmyelinated C- fibers from chemore-
ceptors as well as a subset of myelinated
mechanoreceptors.26,27 Transient receptor
potential vanilloid-1 (TRPV-1) ion channel
is a chemosensor upregulated in chronic
cough, such as in the setting of a viral infec-
tion.28 P2X3 receptors which are adenosine
triphosphateegated ion channels and tachy-
kinin receptors are other receptors of inter-
est.27,29e31 C-fibers, peripherally and
centrally,27 release tachykinins such as
substance-P and neurokinins, and
32
calcitonin-gene-related peptides. These
pathways are also involved in airway inflam-
matory disorders.33 Capsaicin, or hot chili
pepper, is a direct agonist of most of the
TRPV-1 receptor. It has been observed in
functional brain imaging to result in urge-
to-cough sensation, causing activation of
multiple central cortical and cerebellar
areas.2,34e36 Further observations in subjects
with cough hypersensitivity have noted an
increased response to capsaicin inhalation
Mayo Clin Proc. n June 2022;97(6):1164-1175 n https://doi.org/10.1016/j.mayocp.2022.02.005
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in the nucleus cuneiformis area of the
midbrain with diminished central suppres-
sion, analogous to pain hypersensitivity.37,38
The degree of afferent vagal as well as
central hypersensitivity can be elucidated us-
ing capsaicin challenge as well as the Arnold
nerve reflex. The latter is done by inserting a
cotton tip in the external auditory canal to
elicit cough response. Both tests have a
limited role in differentiating explained
chronic cough from CHS.39e41
What Treatments Are Currently Available
and in Use for CHS?
The optimal treatment approach for CHS re-
mains an area of active interest and debate as
we continue to improve our understanding
of the mechanisms underlying CHS.
Neuromodulators, including amitri-
ptyline,42e45 gabapentin,46e48 baclofen,49
and pregabalin50 have been used successfully
with improvement in cough severity,51,52 and
are currently used in clinical practice. Adverse
effects including dry mouth, dizziness, and fa-
tigue typically limit optimal dosing as well as
effective use of these neuromodulators in
many patients (Table 2).51
Physiotherapy and speech and language
therapy intervention (PSALTI) has emerged
as an effective method in clinical practice
for treating the behavioral aspect of refrac-
tory chronic cough.58,59 The PSALTI method
comprises techniques of laryngeal hygiene
and hydration, cough control, mindfulness
about laryngeal injurious behavior, breath-
ing exercises, and psycho-educational coun-
seling.6 Use of the PSALTI method has
shown improvement in cough frequency by
41% as compared with usual care and sus-
tained improvement in symptoms 3 months
after therapy.59 The addition of a neuromo-
dulator, such as pregabalin, to speech ther-
apy resulted in additional improvement in
cough severity, cough frequency, and quality
of life when compared with speech therapy
alone.12
Nonpharmacological management strate-
gies such as hypnosis and referral to psychi-
atry/psychology have not been explored
systematically in adults with CHS.
1167

Triggers
• Viral infection
• Cold/dry air
• Smoke
• Odor
• Untreated UACS/
CRC/GERD
FIGURE 2. Relationship of urge to cough and stimulus intensity in normal subject and chronic cough patients. CRC ¼ corticosteroid
responsive cough; GERD ¼ gastroesophageal reflux disease; UACS ¼ upper airway cough syndrome.
Experience With Direct Vocal Cord
Therapies
Vocal cord therapy could be considered in a
specialized multidisciplinary environment if
behavioral therapy with PSALTI and use of
neuromodulators remain ineffective.
Botulinum toxin type A injection of bilat-
eral thyroarytenoids in 22 patients with re-
fractory chronic cough resulted in a 50%
improvement in cough severity symptoms
in half the patients.60 Some transient un-
pleasant effects included liquid dysphagia
and dysphonia.
Vocal fold augmentation with injection
of methylcellulose and hyaluronic acid has
been described with 18 of 23 patients report-
ing a 50% improvement in cough at 1 month
with five showing no improvement and 11
having recurrence of symptoms.61
More recently, superior laryngeal nerve
block has shown significant improvement
in retrospective studies with 15 of 18 pa-
tients in one series reporting benefit using
a combination of corticosteroid and a local
anesthetic.62 Because adverse effects with su-
perior laryngeal nerve blocks are minimal,
this modality has gained interest; however,
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MAYO CLINIC PROCEEDINGS
Chronic cough
Normal
Urge to cough
Motor
threshold
Sensory
threshold
A B C
Stimulus intensity
randomized sham-controlled trials of all the
above interventions are lacking.
Novel Agents d Which Have Been Tried and
Which Show Promise?
Table 2 shows experience with neuromodu-
lators as well as some of the novel agents
that are receptor specific. P2X3 receptor
antagonist was studied in a phase 2 random-
ized placebo-controlled trial where cough
frequency improved by 75%.29 Because taste
disturbance is a dose-dependent side effect,
studies continue to further explore optimal
dose of selective P2X3-R antagonists, and
have shown promise in randomized
placebo-controlled trials.30,31,63,64
Tachykinins receptor antagonists are also
being explored as antitussives. In a phase 2
pilot study, neurokinin-1 receptor antagonist
improved daytime cough frequency by
26%.53
Figure 3 captures some aspects of exist-
ing and expectant treatment modalities.
CHRONIC COUGH SECONDARY TO GERD
The relationship between chronic cough and
GERD is probably the most contentious with
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CHRONIC COUGH

TABLE 2. Brief Overview of Key Studies on the Use of Neuromodulators in CHS in the Last 15 Yearsa
No. of Side effects/
Medication Author Year Location Type of study patients Outcome measures concerns
Gefapixant (P2X3 receptor Smith et al31 2020 UK Double-blind, randomized, 252 Awake objective cough 1 patient in 50-mg
antagonist) placebo-controlled frequency group had frost
4 groups: placebo, 24-h objective cough bite
gefapixant 7.5mg, 20 mg, frequency Taste disturbance
50 mg, and twice a day VAS in the 50-mg
Cough severity diary group
LCQ score
Significant reductions at
week 12 in 50-mg group
Orvepitant (neurokinin Smith et al53 2019 UK Phase 2 pilot study 13 26% reduction in daytime Well tolerated
receptor antagonist) cough frequency Fatigue,
Improved CQOL and VAS somnolence,
at 4 weeks lethargy
Gefapixant 100 mg (P2X3 Morice 2019 UK Double-blind, randomized, 24 chronic Increased cough challenge Taste disturbance
receptor antagonist) et al30 placebo- controlled cough thresholds in gefapixant
crossover study 12 healthy Improved VAS, HARQ, group
volunteers cough countb
GSK2339345 (sodium Smith et al54 2017 UK Double-blind, placebo- 11 Increased 8-h cough count Well tolerated
channel blocker) controlled, crossover
study
Tramadol (50 mg three Dion et al55 2017 USA Prospective case series 16 Improved CSI and LCQ Risk of serotonin
times daily) syndrome and
dependence
XEN-D0501 (TRPV-1 Belvisi et al56 2017 UK Double- blind, placebo- 18 No improvement in
antagonist) controlled spontaneous cough
frequency
Azithromycin (500 mg for 3 Hodgson 2016 UK Double-blind, placebo- 44 LCQ score improved only in 1 drop out for
days, then 250 mg, three et al57 controlled subgroup of chronic gastrointestinal
times a week) cough related to asthma side effects
AF-219, 600 mg (P2X3 Abdulqawi29 2015 UK Phase 2, Double-blind, 24 Improved daytime cough Taste disturbance
receptor antagonist) placebo- controlled, frequency by 75% in study
crossover study group
a
CHS ¼ cough hypersensitivity syndrome; CSI ¼ cough severity index; CQOL ¼ Cough Quality of Life Questionnaire; HARQ ¼ Hull Airway Reflux Questionnaire;
LCQ ¼ Leicester Cough Questionnaire; VAS ¼ Visual Analogue Scale.
b
Cough frequency/counts measured by cough monitors such as VitaloJAK.

arguments on both sides of the causal rela-
tionship. Most clinicians treat patients with
GERD-related cough with proton pump in-
hibitors. However, trials of proton pump in-
hibitors for GERD-related cough show no
benefit when used as sole therapy without
symptoms such as heartburn.65,66
microaspiration, 2) vagally mediated esopha-
gobronchial reflex, and 3) gastric refluxate
reaching proximal airways provoking hyper-
sensitivity to stimuli such as cold and dust.67
More recently, it has been observed that pa-
tients with chronic cough have swallows
with long breaks in esophageal motility.68

What Are the Prevailing Theories About
GERD and Chronic Cough?
Several mechanisms have attempted to
describe the causal effect of GERD on
chronic cough. This includes 1)
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What is the Role of Diet and Lifestyle
Modification?
Diet and lifestyle modification including
smoking cessation and weight loss remains
at the cornerstone of treatment of cough
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 MAYO CLINIC PROCEEDINGS

Neuromodulators
• Amitriptyline Cortical/subcortical area-central
• Gabapentin “Urge-to-cough”
• Pregabalin

PSALTI

Brainstem-central
• Nucleus tractus solitarius
• Paratrigeminal nucleus
NK release

Triggers
• Viral infection Vagal afferents-neural
• Cold/dry air sensory pathway
Orvepitant
• Smoke
• Odor Vocal cord
• Untreated UACS/ therapies
CRC/GERD SLN block

Gefapixant
Airway/laryngeal
receptors-peripheral
• P2X3
• TRPV-1
• Na+ channel
• NMDA

FIGURE 3. Clinically relevant treatment modalities in cough hypersensitivity syndrome. CRC ¼ corticosteroid responsive cough;
GERD ¼ gastroesophageal reflux disease; NK ¼ neurokinin; NMDA ¼ N-methyl-D-aspartate; PSALTI ¼ physiotherapy speech and
language therapy intervention; SLN ¼ superior laryngeal nerve; TRPV-1 ¼ transient receptor potential vanilloid 1; UACS ¼ upper
airway cough syndrome.

related to GERD.65 The focus is on mini- interpretation of GERD.70 Because both

mizing transient lower esophageal sphincter acid or weakly acid reflux can result in
relaxation. cough, the addition of measuring impedance
to the multichannel pH testing and manom-
What Tests Can Help Diagnose Chronic etry has allowed for improved diagnosis of
Cough Secondary to GERD? cough related to GERD.65,69,71
Gastroesophageal refluxate could be acidic
or weakly acidic.65,67,69 Barium esophagram What is the Role of Acid Suppressive
can help with evaluating mucosal defects, Therapy in Chronic Cough From GERD?
esophageal motility, hiatal hernia, and peptic The role of acid suppression therapy has
esophageal strictures; however, it has limited long been debated, and in those patients
sensitivity and specificity in the without heartburn or regurgitation, there
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CHRONIC COUGH
has been no improvement in symptoms of
cough.65,72,73 Hence, after reviewing results
of 14 randomized controlled studies, acid
suppression alone is not recommended for
treatment of chronic cough secondary to
GERD in the absence of heartburn or
regurgitation.65
What is the Role of Prokinetics in Cough
Secondary to GERD?
Prokinetics are a potential consideration
when cough is definitively secondary to
GERD. In a cohort of 56 patients, addition
of a prokinetic agent such as metoclopra-
mide to acid suppression helped improve
cough in one-third of the patients.74,75 Simi-
larly, in a small cohort of 16 patients, baclo-
fen improved cough symptom score in half
of the patients at 8 weeks.76
Is There a Role for Antireflux Surgery?
There are no randomized controlled trials of
antireflux surgery such as with Nissen fun-
doplication; however, it can be considered
for patients with refractory cough from
GERD and normal esophageal motility.65
Significant improvement in chronic cough
was described in a prospective follow-up
over 31 months of 232 patients who under-
went laparoscopic antireflux surgery.77
Use of novel laparoscopic magnetic
sphincter augmentation methods in the
management of GERD has not been system-
atically studied for its impact on chronic
cough from GERD.
CORTICOSTEROID RESPONSIVE COUGH
Corticosteroid responsive cough (CRC) in-
cludes cough-variant asthma (CVA), non-
asthmatic eosinophilic bronchitis (NAEB)
as well as allergic rhinitis. Corticosteroid
responsive cough is found in approximately
24% of chronic cough patients who are non-
smokers, whereas NAEB is found in approx-
imately 13.6%.78
TH2 cellemediated airway inflammation
most likely explains the pathophysiology in
CRC. However, the variable bronchial hyper-
responsiveness that is found in CVA is ab-
sent in NAEB. Nonasthmatic eosinophilic
bronchitis is also characterized by sputum
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eosinophilia of greater than 3%, which can
also be present in the eosinophilic variant
of asthma.78,79 It can also be found in the
eosinophilic lung or systemic disease.
What is the Role of Fractional Excretion of
Nitric Oxide in CRC?
Methacholine challenge test is a cornerstone
in the diagnosis of CVA80 and can help
differentiate CVA from NAEB in those with
normal spirometry. Exhaled fractional excre-
tion of nitric oxide (FeNO) has emerged as a
convenient surrogate of eosinophilic inflam-
mation. Whereas a diagnostic cutoff for the
value of FeNO has not been firmly estab-
lished, a high FeNO greater than 30 ppb
has been shown to have a high correlation
with sputum eosinophilia81 and blood eosin-
ophil count.82 It may also help predict corti-
costeroid responsiveness in a patient with
chronic cough.83 Treatment of CVA includes
inhaled corticosteroid with bronchodilator,
leukotriene receptor antagonists, or short
course of oral steroids.80 Similarly, NAEB
also responds to inhaled steroids or oral ste-
roids.84 Management of allergic rhinitis is
discussed in the following section.
UPPER AIRWAY COUGH SYNDROME
Upper airway cough syndrome encompasses
a group of upper airway abnormalities that
result in chronic cough.85 It is often charac-
terized by the drainage of secretions from the
nose or paranasal sinuses into the pharynx,
resulting in the previously known terminol-
ogy of postnasal drip.
What Are the Different Etiologies to
Consider in UACS?
Allergic rhinitis is the most common cause
of UACS.86 Other causes include vasomotor
rhinitis, nonallergic rhinitis with eosino-
philia syndrome, postinfectious UACS,
allergic fungal sinusitis, bacterial sinusitis,
occupational rhinitis, rhinitis secondary to
medications, and rhinitis from chemical ex-
posures and that secondary to anatomic
airway abnormalities, including polyps.85,86
Diagnostic pathway includes allergy
testing, rhinolaryngoscopy (to look for
changes of nasal mucosa, lesions and
1171

secretions), and imaging including plain si-
nus radiography and sinus computed
tomography.80,85
What Medications and Interventions Have
Shown Efficacy in UACS?
Older-generation antihistamines (such as
brompheniramine) with decongestants such
as pseudoephedrine have shown efficacy
and been recommended in the ACCP
guidelines.80 Sedating properties of older-
generation antihistamines limit its
widespread use. Even if not sedating, it can
still impair attention.86,87 For allergic rhinitis,
nasal steroids, nasal antihistamines, cromolyn,
and second-generation nonsedating antihista-
mines are effective first-line treatments. Nasal
saline rinses are beneficial as a sole modality
or as an adjunct therapy86,88 Immunotherapy
and omalizumab are also effective interven-
tions.86 Similarly, for vasomotor rhinitis, nasal
ipratropium has shown benefit.85,86
For chronic sinusitis, if administration of
decongestion, antibiotics, and nasal steroids
is not effective, endoscopic sinus surgery
should be considered.85
Nasal saline irrigation with one or a com-
bination of nasal steroids, nasal antihista-
mines, and nasal ipratropium can be helpful
in most scenarios of cough from UACS.
EMERGING TOPICS IN CHRONIC COUGH
Among additional problems that could influ-
ence the symptom of chronic cough, obstruc-
tive sleep apnea (OSA) and excessive dynamic
airway collapse have surfaced to attention. In a
prospective follow-up of 99 chronic cough pa-
tients, OSA was found in more than half and
tracheobronchomalacia in approximately one-
third of the patients among the multitude of
diagnoses of chronic cough.89
Obstructive Sleep Apnea
In a longitudinal study of 19 patients with
OSA and chronic cough, treatment for OSA
with continuous positive airway pressure
(CPAP) suggested improvement in the psy-
chological and social domains when
measured using the validated Leicester
Cough Questionnaire.90 This was also
observed in 22 patients randomized to
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MAYO CLINIC PROCEEDINGS
undergo CPAP vs sham-CPAP.91 Among a
cohort of 94 patients, significant improve-
ment in symptoms of cough, voice, and
breathing disorder was observed in those
who used CPAP every night.92 Events
caused by GERD have been observed to be
strongly related to arousals in severe
OSA.93 We have incorporated screening for
OSA into our management of chronic cough.
Excessive Dynamic Airway Collapse
Tracheobronchomalacia is an important en-
tity that can be recognized with computed
tomography of the chest while evaluating
chronic cough. Tracheobronchomalacia falls
under the spectrum of excessive dynamic
airway collapse. This can be diagnosed with
an expiratory phased computed tomography
of the upper airways or a bronchoscopy to
look for more than 50% of collapse of the
airway lumen during passive respiration
(without coughing or forced exhalation).
Nocturnal CPAP and airway clearance tech-
niques are potentially helpful in preventing
airway contact irritation and repeated cycles
of bronchitis.
CONCLUSION
Patients may have one or a combination of
etiologies resulting in explained chronic
cough or CHS. It is most important to recog-
nize the interplay of different etiologies
when evaluating for chronic cough that
would enable a unique treatment pathway
for the patient. Ensuring adherence to the al-
gorithm of chronic cough as per ACCP and
fidelity to interventions remains funda-
mental in management.
POTENTIAL COMPETING INTERESTS
The authors report no potential competing
interests.
Abbreviations and Acronyms: CHS, cough hypersensitivity
syndrome; CRC, corticosteroid responsive cough; GERD,
gastroesophageal reflux disease; PSALTI, physiotherapy
speech and language therapy intervention; RCC, refractory
chronic cough; UACS, upper airway cough syndrome
Correspondence: Address to Sumera R. Ahmad, MBBS, Di-
vision of Pulmonary and Critical Care, Mayo Clinic, 200 First
Street, Rochester, MN 55905 USA (ahmad.sumera@mayo.
edu).
June 2022;97(6):1164-1175 https://doi.org/10.1016/j.mayocp.2022.02.005
www.mayoclinicproceedings.org
CHRONIC COUGH

REFERENCES 19. Vertigan AE, Murad MH, Pringsheim T, et al. Somatic cough
syndrome (previously referred to as psychogenic cough) and
1. Macedo P, Zhang Q, Saito J, et al. Analysis of bronchial biopsies
tic cough (previously referred to as habit cough) in adults
in chronic cough. Respir Med. 2017;127:40-44. https://doi.org/
and children: CHEST guideline and expert panel report. Chest.
10.1016/j.rmed.2017.04.001
2015;148(1):24-31. https://doi.org/10.1378/chest.15-0423
2. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of
20. Vertigan AE, Bone SL, Gibson PG. Development and valida-
chronic cough. Lancet. 2008;371(9621):1364-1374. https://doi.
tion of the Newcastle Laryngeal Hypersensitivity Question-
org/10.1016/s0140-6736(08)60595-4
naire. Cough. 2014;10(1):1. https://doi.org/10.1186/1745-
3. Song WJ, Chang YS, Faruqi S, et al. The global epidemiology of
9974-10-1
chronic cough in adults: a systematic review and meta-analysis.
21. O’Neill J, McMahon SB, Undem BJ. Chronic cough and pain: Ja-
Eur Respir J. 2015;45(5):1479-1481. https://doi.org/10.1183/
nus faces in sensory neurobiology? Pulm Pharmacol Ther. 2013;
09031936.00218714
26(5):476-485. https://doi.org/10.1016/j.pupt.2013.06.010
4. Colak Y, Nordestgaard BG, Laursen LC, Afzal S, Lange P,
22. Davenport PW. Clinical cough I: the urge-to-cough: a respira-
Dahl M. Risk factors for chronic cough among 14,669 individ-
tory sensation. Handb Exp Pharmacol. 2009;(187):263-276.
uals from the general population. Chest. 2017;152(3):563-573.
https://doi.org/10.1016/j.pupt.2013.06.010
https://doi.org/10.1016/j.chest.2017.05.038
23. Irwin RS, Ownbey R, Cagle PT, Baker S, Fraire AE. Interpreting
5. Morice AH, Jakes AD, Faruqi S, et al. A worldwide survey of
the histopathology of chronic cough: a prospective, controlled,
chronic cough: a manifestation of enhanced somatosensory
comparative study. Chest. 2006;130(2):362-370. https://doi.org/
response. Eur Respir J. 2014;44(5):1149-1155. https://doi.org/
10.1378/chest.130.2.362
10.1183/09031936.00217813
24. Mazzone SB. An overview of the sensory receptors regulating
6. Birring SS, Floyd S, Reilly CC, Cho PSP. Physiotherapy and
cough. Cough. 2005;1:2. https://doi.org/10.1186/1745-9974-1-2
Speech and Language therapy intervention for chronic cough.
25. Mazzone SB, McGovern AE, Yang SK, et al. Sensorimotor cir-
Pulm Pharmacol Ther. 2017;47:84-87. https://doi.org/10.1016/j.
cuitry involved in the higher brain control of coughing. Cough.
pupt.2017.04.001
2013;9(1):7. https://doi.org/10.1186/1745-9974-9-7
7. Hilton E, Marsden P, Thurston A, Kennedy S, Decalmer S,
26. Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB,
Smith JA. Clinical features of the urge-to-cough in patients
McGarvey L. Anatomy and neurophysiology of cough: CHEST
with chronic cough. Respir Med. 2015;109(6):701-707. https://
guideline and expert panel report. Chest. 2014;146(6):1633-
doi.org/10.1016/j.rmed.2015.03.011
1648. https://doi.org/10.1378/chest.14-1481
8. Hulme K, Deary V, Dogan S, Parker SM. Psychological profile of
27. Mazzone SB, McGovern AE. Sensory neural targets for the
individuals presenting with chronic cough. ERJ Open Res. 2017;
treatment of cough. Clin Exp Pharmacol Physiol. 2007;34(10):
3(1):00099-2016. https://doi.org/10.1183/23120541.00099-2016
955-962. https://doi.org/10.1111/j.1440-1681.2007.04702.x
9. French CL, Crawford SL, Bova C, Irwin RS. Change in psycho-
28. Clarke R, Monaghan K, About I, et al. TRPA1 activation in a hu-
logical, physiological, and situational factors in adults after treat-
man sensory neuronal model: relevance to cough hypersensi-
ment of chronic cough. Chest. 2017;152(3):547-562. https://doi.
tivity? Eur Respir J. 2017;50(3):1700995. https://doi.org/10.
org/10.1016/j.chest.2017.06.024
1183/13993003.00995-2017
10. Dicpinigaitis PV, Canning BJ. Is there (will there be) a post-
29. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist
COVID-19 chronic cough? Lung. 2020;198(6):863-865.
(AF-219) in refractory chronic cough: a randomised, double-
https://doi.org/10.1007/s00408-020-00406-6
blind, placebo-controlled phase 2 study. Lancet. 2015;
11. Haque RA, Usmani OS, Barnes PJ. Chronic idiopathic cough: a
385(9974):1198-1205.
discrete clinical entity? Chest. 2005;127(5):1710-1713. https://
30. Morice AH, Kitt MM, Ford AP, et al. The effect of gefapixant, a
doi.org/10.1378/chest.127.5.1710
P2X3 antagonist, on cough reflex sensitivity: a randomised
12. Vertigan AE, Kapela SL, Ryan NM, Birring SS, McElduff P,
placebo-controlled study. Eur Respir J. 2019;54(1):1900439.
Gibson PG. Pregabalin and speech pathology combination ther-
https://doi.org/10.1183/13993003.00439-2019
apy for refractory chronic cough: a randomized controlled trial.
31. Smith JA, Kitt MM, Morice AH, et al. Gefapixant, a P2X3 recep-
Chest. 2016;149(3):639-648. https://doi.org/10.1378/chest.15-
tor antagonist, for the treatment of refractory or unexplained
1271
chronic cough: a randomised, double-blind, controlled,
13. Gibson P, Wang G, McGarvey L, et al. Treatment of unex-
parallel-group, phase 2b trial. Lancet Respir Med. 2020;8(8):
plained chronic cough: CHEST guideline and expert panel
775-785. https://doi.org/10.1016/s2213-2600(19)30471-0
report. Chest. 2016;149:27-44. https://doi.org/10.1378/chest.
32. Lim KG, Rank MA, Kita H, Patel A, Moore E. Neuropeptide
15-1496
levels in nasal secretions from patients with and without
14. French CT, Diekemper RL, Irwin RS, et al. Assessment of inter-
chronic cough. Ann Allergy Asthma Immunol. 2011;107(4):360-
vention fidelity and recommendations for researchers con-
363. https://doi.org/10.1016/j.anai.2011.07.010
ducting studies on the diagnosis and treatment of chronic
33. Patterson RN, Johnston BT, Ardill JE, Heaney LG, McGarvey LP.
cough in the adult: CHEST guideline and expert panel report.
Increased tachykinin levels in induced sputum from asthmatic
Chest. 2015;148(1):32-54. https://doi.org/10.1378/chest.15-
and cough patients with acid reflux. Thorax. 2007;62(6):491-
0164
495. https://doi.org/10.1136/thx.2006.063982
15. Morice AH, Millqvist E, Bieksiene K, et al. ERS guidelines on the
34. Smith JA, Woodcock A. Chronic cough. N Engl J Med. 2016;
diagnosis and treatment of chronic cough in adults and children.
375(16):1544-1551. https://doi.org/10.1056/NEJMcp1414215
Eur Respir J. 2020;55(1):1901136. https://doi.org/10.1183/
35. Mazzone SB, McGovern AE, Koo K, Farrell MJ. Mapping supra-
13993003.01136-2019
medullary pathways involved in cough using functional brain im-
16. Irwin RS, French CL, Chang AB, Altman KW. Classification of
aging: comparison with pain. Pulm Pharmacol Ther. 2009;22(2):
cough as a symptom in adults and management algorithms:
90-96. https://doi.org/10.1016/j.pupt.2008.08.003
CHEST guideline and expert panel report. Chest. 2018;
36. Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ.
153(1):196-209. https://doi.org/10.1016/j.chest.2017.10.016
Representation of capsaicin-evoked urge-to-cough in the hu-
17. Chung KF, McGarvey L, Mazzone SB. Chronic cough as a
man brain using functional magnetic resonance imaging. Am J
neuropathic disorder. Lancet Respir Med. 2013;1(5):414-422.
Respir Crit Care Med. 2007;176(4):327-332. https://doi.org/10.
https://doi.org/10.1016/S2213-2600(13)70043-2
1164/rccm.200612-1856OC
18. Sundar KM, Stark AC, Hu N, Barkmeier-Kraemer J. Is laryngeal
37. Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB,
hypersensitivity the basis of unexplained or refractory chronic
Farrell MJ. Neural correlates of cough hypersensitivity in
cough? ERJ Open Res. 2021;7(1):00793-2020. https://doi.org/
humans: evidence for central sensitisation and dysfunctional
10.1183/23120541.00793-2020

Mayo Clin Proc. n June 2022;97(6):1164-1175 n https://doi.org/10.1016/j.mayocp.2022.02.005 1173

www.mayoclinicproceedings.org

inhibitory control. Thorax. 2016;71(4):323-329. https://doi.org/
10.1136/thoraxjnl-2015-207425
38. Driessen AK, McGovern AE, Narula M, et al. Central mecha-
nisms of airway sensation and cough hypersensitivity. Pulm Phar-
macol Ther. 2017;47:9-15. https://doi.org/10.1016/j.pupt.2017.
01.010
39. Pullerits T, Ternesten-Hasseus E, Johansson EL, Millqvist E.
Capsaicin cough threshold test in diagnostics. Respir Med.
2014;108(9):1371-1376. https://doi.org/10.1016/j.rmed.2014.
07.012
40. Lim K. Neurogenic cough. J Allergy Clin Immunol. 2014;133(6):
1779-.e3. https://doi.org/10.1016/j.jaci.2014.02.040
41. Mai Y, Zhan C, Zhang S, et al. Arnold nerve reflex: vagal
hypersensitivity in chronic cough with various causes. Chest.
2020;158(1):264-271. https://doi.org/10.1016/j.chest.2019.11.
041
42. Ryan MA, Cohen SM. Long-term follow-up of amitriptyline
treatment for idiopathic cough. Laryngoscope. 2016;126(12):
2758-2763. https://doi.org/10.1002/lary.25978
43. Norris BK, Schweinfurth JM. Management of recurrent laryngeal
sensory neuropathic symptoms. Ann. Otol Rhinol Laryngol. 2010;
119(3):188-191.
44. Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitrip-
tyline versus cough suppressants in the treatment of chronic
cough resulting from postviral vagal neuropathy. Laryngoscope.
2006;116(12):2108-2112. https://doi.org/10.1097/01.mlg.
0000244377.60334.e3
45. Bastian RW, Vaidya AM, Delsupehe KG. Sensory neuropathic
cough: a common and treatable cause of chronic cough. Otolar-
yngol Head Neck Surg. 2006;135(1):17-21. https://doi.org/10.
1016/j.otohns.2006.02.003
46. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory
chronic cough: a randomised, double-blind, placebo-controlled
trial. Lancet. 2012;380(9853):1583-1589. https://doi.org/10.
1016/s0140-6736(12)60776-4
47. Ryan NM, Gibson PG. Gabapentin for idiopathic chronic cough:
a randomised controlled trial. Lung. 2012;190(1):64. https://doi.
org/10.1007/s00408-012-9370-3
48. Mintz S, Lee JK. Gabapentin in the treatment of intractable idio-
pathic chronic cough: case reports. Am J Med. 2006;119(5):e13-
e15. https://doi.org/10.1016/j.amjmed.2005.10.046
49. Dicpinigaitis PV, Rauf K. Treatment of chronic, refractory cough
with baclofen. Respiration. 1998;65(1):86-88. https://doi.org/10.
1159/000029232
50. Halum SL, Sycamore DL, McRae BR. A new treatment option
for laryngeal sensory neuropathy. Laryngoscope. 2009;119(9):
1844-1847. https://doi.org/10.1002/lary.20553
51. Cohen SM, Misono S. Use of specific neuromodulators in the
treatment of chronic, idiopathic cough: a systematic review.
Otolaryngol Head Neck Surg. 2013;148(3):374-382. https://doi.
org/10.1177/0194599812471817
52. Wei W, Liu R, ZhangTong Y, Qiu Z. The efficacy of specific
neuromodulators on human refractory chronic cough: a sys-
tematic review and meta-analysis. J Thorac Dis. 2016;8(10):
2942-2951. https://doi.org/10.21037/jtd.2016.10.51
53. Smith J, Allman D, Badri H, et al. The neurokinin-1 receptor
antagonist orvepitant is a novel antitussive therapy for chronic
refractory cough: results from a phase 2 pilot study (VOL-
CANO-1). Chest. 2019;157(1):111-118. https://doi.org/10.
1016/j.chest.2019.08.001
54. Smith JA, McGarvey LPA, Badri H, et al. Effects of a novel so-
dium channel blocker, GSK2339345, in patients with refractory
chronic cough. Int J Clin Pharmacol Ther. 2017;55(9):712-719.
https://doi.org/10.5414/CP202804
55. Dion GR, Teng SE, Achlatis E, Fang Y, Amin MR. Treatment of
neurogenic cough with tramadol: a pilot study. Otolaryngol Head
Neck Surg. 2017;157(1):77-79. https://doi.org/10.1177/
0194599817703949
56. Belvisi MG, Birrell MA, Wortley MA, et al. XEN-D0501, a novel
transient receptor potential vanilloid 1 antagonist, does not
n n
1174 Mayo Clin Proc. June 2022;97(6):1164-1175
MAYO CLINIC PROCEEDINGS
reduce cough in patients with refractory cough. Am J Respir
Crit Care Med. 2017;196(10):1255-1263. https://doi.org/10.
1164/rccm.201704-0769OC
57. Hodgson D, Anderson J, Reynolds C, et al. The effects of azi-
thromycin in treatment-resistant cough: a randomized,
double-blind, placebo-controlled trial. Chest. 2016;149(4):
1052-1060. https://doi.org/10.1016/j.chest.2015.12.036
58. Vertigan AE, Theodoros DG, Gibson PG, Winkworth AL. Effi-
cacy of speech pathology management for chronic cough: a
randomised placebo controlled trial of treatment efficacy. Tho-
rax. 2006;61(12):1065-1069. https://doi.org/10.1136/thx.2006.
064337
59. Chamberlain Mitchell SA, Garrod R, Clark L, et al. Physio-
therapy, and speech and language therapy intervention for pa-
tients with refractory chronic cough: a multicentre randomised
control trial. Thorax. 2017;72(2):129-136. https://doi.org/10.
1136/thoraxjnl-2016-208843
60. Sasieta HC, Iyer VN, Orbelo DM, et al. Bilateral thyroarytenoid
botulinum toxin type A injection for the treatment of refractory
chronic cough. JAMA Otolaryngol Head Neck Surg. 2016;142(9):
881-888. https://doi.org/10.1001/jamaoto.2016.0972
61. Litts JK, Fink DS, Clary MS. The effect of vocal fold augmenta-
tion on cough symptoms in the presence of glottic insufficiency.
Laryngoscope. 2018;128(6):1316-1319. https://doi.org/10.1002/
lary.26914
62. Simpson CB, Tibbetts KM, Loochtan MJ, Dominguez LM. Treat-
ment of chronic neurogenic cough with in-office superior laryn-
geal nerve block. Laryngoscope. 2018;128(8):1898-1903. https://
doi.org/10.1002/lary.26914
63. Smith JA, Kitt MM, Butera P, et al. Gefapixant in two rando-
mised dose-escalation studies in chronic cough. Eur Respir J.
2020;55(3):1901615. https://doi.org/10.1183/13993003.
01615-2019
64. Muccino DR, Morice AH, Birring SS, et al. Design and rationale of
two phase 3 randomised controlled trials (COUGH-1 and
COUGH-2) of gefapixant, a P2X3 receptor antagonist, in refrac-
tory or unexplained chronic cough. ERJ Open Res. 2020;6(4):
00284-2020. https://doi.org/10.1183/23120541.00284-2020
65. Kahrilas PJ, Altman KW, Chang AB, et al. Chronic cough due to
gastroesophageal reflux in adults: CHEST guideline and expert
panel report. Chest. 2016;150(6):1341-1360. https://doi.org/10.
1016/j.chest.2016.08.1458
66. Chang AB, Lasserson TJ, Gaffney J, Connor FL, Garske LA. Gas-
tro-oesophageal reflux treatment for prolonged non-specific
cough in children and adults. Cochrane Database Syst Rev.
2011;1:CD004823. https://doi.org/10.1002/14651858.
CD004823.pub4
67. Richter JE. Role of the gastric refluxate in gastroesophageal
reflux disease: acid, weak acid and bile. Am J Med Sci. 2009;
338(2):89-95. https://doi.org/10.1097/MAJ.0b013e3181ad584a
68. Bennett MC, Patel A, Sainani N, Wang D, Sayuk GS,
Gyawali CP. Chronic cough is associated with long breaks in
esophageal peristaltic integrity on high-resolution manometry.
J Neurogastroenterol Motil. 2018;24(3):387-394. https://doi.org/
10.1097/MAJ.0b013e3181ad584a
69. Pauwels A, Blondeau K, Dupont L, Sifrim D. Cough and gastro-
esophageal reflux: from the gastroenterologist end. Pulm Phar-
macol Ther. 2009;22(2):135-138. https://doi.org/10.1016/j.pupt.
2008.11.007
70. Tutuian R. Update in the diagnosis of gastroesophageal
reflux disease. J Gastrointestin Liver Dis. 2006;15(3):243-
247.
71. Lee JH, Park SY, Cho SB, et al. Reflux episode reaching the prox-
imal esophagus are associated with chronic cough. Gut Liver.
2012;6(2):197-202. https://doi.org/10.5009/gnl.2012.6.2.197
72. Shaheen NJ, Crockett SD, Bright SD, et al. Randomised clin-
ical trial: high-dose acid suppression for chronic cough d a
double-blind, placebo-controlled study. Aliment Pharmacol
Ther. 2011;33(2):225-234. https://doi.org/10.1111/j.1365-
2036.2010.04511.x
https://doi.org/10.1016/j.mayocp.2022.02.005
www.mayoclinicproceedings.org
CHRONIC COUGH
73. Faruqi S, Molyneux ID, Fathi H, Wright C, Thompson R,
Morice AH. Chronic cough and esomeprazole: a double-blind
placebo-controlled parallel study. Respirology. 2011;16(7):
1150-1156. https://doi.org/10.1111/j.1440-1843.2011.02014.x
74. Poe RH, Kallay MC. Chronic cough and gastroesophageal reflux
disease: experience with specific therapy for diagnosis and
treatment. Chest. 2003;123(3):679-684.
75. Hiyama T, Yoshihara M, Tanaka S, Haruma K, Chayama K.
Effectiveness of prokinetic agents against diseases external to
the gastrointestinal tract. J Gastroenterol Hepatol. 2009;24(4):
537-546. https://doi.org/10.1111/j.1440-1746.2009.05780.x
76. Xu XH, Yang ZM, Chen Q, et al. Therapeutic efficacy of bac-
lofen in refractory gastroesophageal reflux-induced chronic
cough. World J Gastroenterol. 2013;19(27):4386-4392. https://
doi.org/10.3748/wjg.v19.i27.4386
77. Park A, Weltz AS, Sanford Z, Addo A, Zahiri HR. Laparoscopic
antireflux surgery (LARS) is highly effective in the treatment of
select patients with chronic cough. Surgery. 2019;166(1):34-40.
https://doi.org/10.1016/j.surg.2019.01.036
78. Tarlo SM, Altman KW, Oppenheimer J, et al. Occupational and
environmental contributions to chronic cough in adults: chest
expert panel report. Chest. 2016;150(4):894-907. https://doi.
org/10.1016/j.chest.2016.07.029
79. Brightling CE. Chronic cough due to nonasthmatic eosinophilic
bronchitis: ACCP evidence-based clinical practice guidelines.
Chest. 2006;129(1 suppl 1):116s-121s. https://doi.org/10.1378/
chest.129.1_suppl.116S
80. Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and man-
agement of cough executive summary: ACCP evidence-based
clinical practice guidelines. Chest. 2006;129(1 suppl):1s-23s.
https://doi.org/10.1378/chest.129.1_suppl.1S
81. Yi F, Chen R, Luo W, et al. Validity of fractional exhaled nitric
oxide in diagnosis of corticosteroid-responsive cough. Chest.
2016;149(4):1042-1051. https://doi.org/10.1016/j.chest.2016.
01.006
82. Sadeghi MH, Wright CE, Hart S, Crooks M, Morice AH. Does
FeNO predict clinical characteristics in chronic cough? Lung.
2018;196(1):59-64. https://doi.org/10.1007/s00408-017-0074-6
83. Hahn PY, Morgenthaler TY, Lim KG. Use of exhaled nitric ox-
ide in predicting response to inhaled corticosteroids for chronic
cough. Mayo Clinic Proc. 2007;82(11):1350-1355.
Mayo Clin Proc. n June 2022;97(6):1164-1175 n https://doi.org/10.1016/j.mayocp.2022.02.005
www.mayoclinicproceedings.org
84. Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID. Eosin-
ophilic bronchitis is an important cause of chronic cough. Am J
Respir Crit Care Med. 1999;160(2):406-410. https://doi.org/10.
1164/ajrccm.160.2.9810100
85. Pratter MR. Chronic upper airway cough syndrome secondary
to rhinosinus diseases (previously referred to as postnasal drip
syndrome): ACCP evidence-based clinical practice guidelines.
Chest. 2006;129(1 suppl):63s-71s. https://doi.org/10.1378/
chest.129.1_suppl.63S
86. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis
and management of rhinitis: an updated practice parameter.
J Allergy Clin Immunol. 2008;122(2 suppl):S1-S84. https://doi.
org/10.1016/j.jaci.2008.06.003
87. Bolser DC. Older-generation antihistamines and cough due to
upper airway cough syndrome (UACS): efficacy and mecha-
nism. Lung. 2008;186(suppl 1):S74-S77. https://doi.org/10.
1007/s00408-007-9033-y
88. Lin L, Chen Z, Cao Y, Sun G. Normal saline solution nasal-
pharyngeal irrigation improves chronic cough associated with
allergic rhinitis. Am J Rhinol Allergy. 2017;31(2):96-104. https://
doi.org/10.2500/ajra.2017.31.4418
89. Good JT Jr, Rollins DR, Kolakowski CA, Stevens AD, Denson JL,
Martin RJ. New insights in the diagnosis of chronic refractory
cough. Respir Med. 2018;141:103-110. https://doi.org/10.1016/
j.rmed.2018.06.024
90. Sundar KM, Daly SE, Willis AM. A longitudinal study of CPAP
therapy for patients with chronic cough and obstructive sleep
apnoea. Cough. 2013;9(1):19. https://doi.org/10.1186/1745-
9974-9-19
91. Sundar KM, Willis AM, Smith S, Hu N, Kitt JP, Birring SS.
A randomized, controlled, pilot study of CPAP for patients
with chronic cough and obstructive sleep apnea. Lung. 2020;
198(3):449-457. https://doi.org/10.1007/s00408-020-00354-1
92. Roy N, Merrill RM, Pierce J, Sundar KM. Evidence of possible
irritable larynx syndrome in obstructive sleep apnea: an epide-
miologic approach. J Voice. 2021;35(6):932.e29-932.e38. https://
doi.org/10.1016/j.jvoice.2020.02.006
93. Suzuki M, Saigusa H, Kurogi R, et al. Arousals in obstructive
sleep apnea patients with laryngopharyngeal and gastroesopha-
geal reflux. Sleep Med. 2010;11(4):356-360. https://doi.org/10.
1016/j.sleep.2009.09.008
1175