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The Evolving Clinical Practice of Chronic Cough

      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 therapeutics for CHS, while also ensuring that common causes of chronic cough continue to be evaluated and treated in a systematic multidisciplinary manner.

      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)
      Article Highlights
      • 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 syndrome (CHS).
      • Allotussia and hypertussia are common features in chronic cough and CHS, simulating the mechanistic pathway of chronic pain.
      • Behavioral therapy with physiotherapy speech and language therapy intervention and neuromodulators may be beneficial for CHS.
      • Novel therapeutic strategies are expected to help develop management pathways in CHS.
      • There is a need to expand and individualize treatment pathways for patients with refractory chronic cough and study impact on important patient outcomes.
      Chronic cough accounts for approximately 10% to 38% of respiratory visits in the United States.
      • Macedo P.
      • Zhang Q.
      • Saito J.
      • et al.
      Analysis of bronchial biopsies in chronic cough.
      • Chung K.F.
      • Pavord I.D.
      Prevalence, pathogenesis, and causes of chronic cough.
      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.
      • Song W.J.
      • Chang Y.S.
      • Faruqi S.
      • et al.
      The global epidemiology of chronic cough in adults: a systematic review and meta-analysis.
      • Colak Y.
      • Nordestgaard B.G.
      • Laursen L.C.
      • Afzal S.
      • Lange P.
      • Dahl M.
      Risk factors for chronic cough among 14,669 individuals from the general population.
      Almost all epidemiological studies on chronic cough suggest a strong female predilection with females accounting for more than two-thirds of patients in cohorts.
      • Morice A.H.
      • Jakes A.D.
      • Faruqi S.
      • et al.
      A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response.
      Chronic cough can have profound impact on the quality of life of patients, such as vomiting, rib pain, urinary incontinence, syncope, speech interference, fatigue, and depression.
      • Chung K.F.
      • Pavord I.D.
      Prevalence, pathogenesis, and causes of chronic cough.
      • Birring S.S.
      • Floyd S.
      • Reilly C.C.
      • Cho P.S.P.
      Physiotherapy and Speech and Language therapy intervention for chronic cough.
      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.
      • Hilton E.
      • Marsden P.
      • Thurston A.
      • Kennedy S.
      • Decalmer S.
      • Smith J.A.
      Clinical features of the urge-to-cough in patients with chronic cough.
      In addition, patients with refractory chronic cough are more likely to present with depression, anxiety, and fatigue.
      • Hulme K.
      • Deary V.
      • Dogan S.
      • Parker S.M.
      Psychological profile of individuals presenting with chronic cough.
      Addressing these psychological symptoms can improve cough-related quality of life.
      • French C.L.
      • Crawford S.L.
      • Bova C.
      • Irwin R.S.
      Change in psychological, physiological, and situational factors in adults after treatment of chronic cough.
      Whereas chronic cough has not, in particular, been observed to be a predominant feature of patients who have recovered from coronavirus disease 2019 infection,
      • Dicpinigaitis P.V.
      • Canning B.J.
      Is there (will there be) a post-COVID-19 chronic cough?.
      the pandemic has worsened the anxiety and distress from coughing in patients 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 gastroesophageal reflux disease (GERD), upper airway cough syndrome (UACS), and airway inflammatory 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 accounts for 12% to 46% of specialty clinic referrals.
      • Haque R.A.
      • Usmani O.S.
      • Barnes P.J.
      Chronic idiopathic cough: a discrete clinical entity?.
      • Vertigan A.E.
      • Kapela S.L.
      • Ryan N.M.
      • Birring S.S.
      • McElduff P.
      • Gibson P.G.
      Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial.
      • Gibson P.
      • Wang G.
      • McGarvey L.
      • et al.
      Treatment of unexplained chronic cough: CHEST guideline and expert panel report.
      This is defined by the American College of Chest Physicians (ACCP) as persistence of cough despite a thorough algorithmic approach towards testing and treating for GERD, UACS, and airway inflammatory disorders as well as ensuring avoidance of smoking, environmental triggers, and angiotensin-converting enzyme inhibitor use (Figure 1).
      • French C.T.
      • Diekemper R.L.
      • Irwin R.S.
      • et al.
      Assessment of intervention fidelity and recommendations for researchers conducting studies on the diagnosis and treatment of chronic cough in the adult: CHEST guideline and expert panel report.
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      Whereas multiple etiologies for chronic cough can coexist in the same patient,
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      many patients may not have undergone rigorous diagnostic tests and standardized therapeutic trials for their chronic cough.
      • French C.T.
      • Diekemper R.L.
      • Irwin R.S.
      • et al.
      Assessment of intervention fidelity and recommendations for researchers conducting studies on the diagnosis and treatment of chronic cough in the adult: CHEST guideline and expert panel report.
      Thus, it is imperative to undertake a thorough and complete inventory of the patient’s diagnostic as well therapeutic journey before applying the label of RCC or UCC.
      Figure thumbnail gr1
      Figure 1A 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 corticosteroid (ICS), long acting beta agonist (LABA), physiotherapy speech and language therapy intervention (PSALTI), and superior laryngeal nerve block (SLN). ACE = antiotensin-converting enzyme; MII = Multichannel intraluminal impedance.
      Refractory chronic cough has been discussed in the literature and clinical practice under several different names, including neurogenic cough, laryngeal hypersensitivity, cough hypersensitivity syndrome, irritable larynx, tic cough, habit cough, and psychogenic cough. Cough hypersensitivity refers to the laryngeal and airway sensory neuropathy that underlies this disorder
      • Chung K.F.
      • McGarvey L.
      • Mazzone S.B.
      Chronic cough as a neuropathic disorder.
      • Sundar K.M.
      • Stark A.C.
      • Hu N.
      • Barkmeier-Kraemer J.
      Is laryngeal hypersensitivity the basis of unexplained or refractory chronic cough?.
      ; 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.
      • Vertigan A.E.
      • Murad M.H.
      • Pringsheim T.
      • et al.
      Somatic cough syndrome (previously referred to as psychogenic cough) and tic cough (previously referred to as habit cough) in adults and children: CHEST guideline and expert panel report.

      What Clinical Features Are Helpful in Identifying CHS?

      Patients with CHS often present with laryngeal symptoms, although those are not specific to CHS. Laryngeal paresthesia comprises throat, airway, and chest sensations.
      • Vertigan A.E.
      • Bone S.L.
      • Gibson P.G.
      Development and validation of the Newcastle Laryngeal Hypersensitivity Questionnaire.
      Symptoms may manifest as an intermittent itch, tickle, scratch, irritation, and choking or globus sensation in the throat or a feeling of throat and/or upper chest tightness.
      • Hilton E.
      • Marsden P.
      • Thurston A.
      • Kennedy S.
      • Decalmer S.
      • Smith J.A.
      Clinical features of the urge-to-cough in patients with chronic cough.
      • Vertigan A.E.
      • Bone S.L.
      • Gibson P.G.
      Development and validation of the Newcastle Laryngeal Hypersensitivity Questionnaire.
      Other symptoms may include dysphonia, hoarseness of voice, and vocal cord dysfunction.
      • Vertigan A.E.
      • Bone S.L.
      • Gibson P.G.
      Development and validation of the Newcastle Laryngeal Hypersensitivity Questionnaire.
      This often leads to an enhanced perception or sensation of the urge to cough.
      Laryngeal hypersensitivity with symptoms of allotussia and hypertussia is also common in CHS,
      • Sundar K.M.
      • Stark A.C.
      • Hu N.
      • Barkmeier-Kraemer J.
      Is laryngeal hypersensitivity the basis of unexplained or refractory chronic cough?.
      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 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.
      • O'Neill J.
      • McMahon S.B.
      • Undem B.J.
      Chronic cough and pain: Janus faces in sensory neurobiology?.
      Figure 2 shows a possible hypothesis for understanding the differences between a “normal” cough reflex and the “hypersensitive” cough reflex. The relationship between the urge to cough (UTC), motor cough, and stimulus intensity
      • Davenport P.W.
      Clinical cough I: the urge-to-cough: a respiratory sensation.
      is shown via the interactions of three tussigenic stimuli (A, B, and C) with the patient’s sensory as well as motor 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 patient 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 motor cough in both normal as well as those with cough hypersensitivity.
      Table 1Symptoms of Cough Hypersensitivity
      Urge to coughAllotussia (cough triggered by nontussive stimulant)Hypertussia (increased sensitivity to stimulant)
      Irritation/ itch/ scratchy throatTalkingCold air
      TickleLaughingDry air
      Globus sensationSingingFumes
      “Something there”Changing positionsOdor
      Humidity changesDust
      EatingAerosols
      Figure thumbnail gr2
      Figure 2Relationship of urge to cough and stimulus intensity in normal subject and chronic cough patients. CRC = corticosteroid responsive cough; GERD = gastroesophageal reflux disease; UACS = upper airway cough syndrome.
      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.
      • Irwin R.S.
      • Ownbey R.
      • Cagle P.T.
      • Baker S.
      • Fraire A.E.
      Interpreting the histopathology of chronic cough: a prospective, controlled, comparative study.

      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 activation of airway afferents by inhaled, aspirated, or locally produced substances.
      • Mazzone S.B.
      An overview of the sensory receptors regulating cough.
      Whereas the reflex cough pathway terminates in the brainstem, voluntary cough or cough suppression likely involves higher cortical circuitries.
      • Mazzone S.B.
      • McGovern A.E.
      • Yang S.K.
      • et al.
      Sensorimotor circuitry involved in the higher brain control of coughing.
      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 resultant cough motor response.
      • Davenport P.W.
      Clinical cough I: the urge-to-cough: a respiratory sensation.
      This highlights the importance of behavioral interventions in the treatment of CHS.
      • Mazzone S.B.
      • McGovern A.E.
      • Yang S.K.
      • et al.
      Sensorimotor circuitry involved in the higher brain control of coughing.
      The majority of the vagal sensory afferents involved in the pathway of cough are the unmyelinated C- fibers from chemoreceptors as well as a subset of myelinated mechanoreceptors.
      • Canning B.J.
      • Chang A.B.
      • Bolser D.C.
      • Smith J.A.
      • Mazzone S.B.
      • McGarvey L.
      Anatomy and neurophysiology of cough: CHEST guideline and expert panel report.
      • Mazzone S.B.
      • McGovern A.E.
      Sensory neural targets for the treatment of cough.
      Transient receptor potential vanilloid-1 (TRPV-1) ion channel is a chemosensor upregulated in chronic cough, such as in the setting of a viral infection.
      • Clarke R.
      • Monaghan K.
      • About I.
      • et al.
      TRPA1 activation in a human sensory neuronal model: relevance to cough hypersensitivity?.
      P2X3 receptors which are adenosine triphosphate–gated ion channels and tachykinin receptors are other receptors of interest.
      • Mazzone S.B.
      • McGovern A.E.
      Sensory neural targets for the treatment of cough.
      • Abdulqawi R.
      • Dockry R.
      • Holt K.
      • et al.
      P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
      • Morice A.H.
      • Kitt M.M.
      • Ford A.P.
      • et al.
      The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study.
      • Smith J.A.
      • Kitt M.M.
      • Morice A.H.
      • et al.
      Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial.
      C-fibers, peripherally and centrally,
      • Mazzone S.B.
      • McGovern A.E.
      Sensory neural targets for the treatment of cough.
      release tachykinins such as substance-P and neurokinins, and calcitonin-gene-related peptides.
      • Lim K.G.
      • Rank M.A.
      • Kita H.
      • Patel A.
      • Moore E.
      Neuropeptide levels in nasal secretions from patients with and without chronic cough.
      These pathways are also involved in airway inflammatory disorders.
      • Patterson R.N.
      • Johnston B.T.
      • Ardill J.E.
      • Heaney L.G.
      • McGarvey L.P.
      Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux.
      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.
      • Chung K.F.
      • Pavord I.D.
      Prevalence, pathogenesis, and causes of chronic cough.
      • Smith J.A.
      • Woodcock A.
      Chronic cough.
      • Mazzone S.B.
      • McGovern A.E.
      • Koo K.
      • Farrell M.J.
      Mapping supramedullary pathways involved in cough using functional brain imaging: comparison with pain.
      • Mazzone S.B.
      • McLennan L.
      • McGovern A.E.
      • Egan G.F.
      • Farrell M.J.
      Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging.
      Further observations in subjects with cough hypersensitivity have noted an increased response to capsaicin inhalation in the nucleus cuneiformis area of the midbrain with diminished central suppression, analogous to pain hypersensitivity.
      • Ando A.
      • Smallwood D.
      • McMahon M.
      • Irving L.
      • Mazzone S.B.
      • Farrell M.J.
      Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control.
      • Driessen A.K.
      • McGovern A.E.
      • Narula M.
      • et al.
      Central mechanisms of airway sensation and cough hypersensitivity.
      The degree of afferent vagal as well as central hypersensitivity can be elucidated using 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.
      • Pullerits T.
      • Ternesten-Hasseus E.
      • Johansson E.L.
      • Millqvist E.
      Capsaicin cough threshold test in diagnostics.
      • Lim K.
      Neurogenic cough.
      • Mai Y.
      • Zhan C.
      • Zhang S.
      • et al.
      Arnold nerve reflex: vagal hypersensitivity in chronic cough with various causes.

      What Treatments Are Currently Available and in Use for CHS?

      The optimal treatment approach for CHS remains an area of active interest and debate as we continue to improve our understanding of the mechanisms underlying CHS.
      Neuromodulators, including amitri-ptyline,
      • Ryan M.A.
      • Cohen S.M.
      Long-term follow-up of amitriptyline treatment for idiopathic cough.
      • Norris B.K.
      • Schweinfurth J.M.
      Management of recurrent laryngeal sensory neuropathic symptoms. Ann.
      • Jeyakumar A.
      • Brickman T.M.
      • Haben M.
      Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy.
      • Bastian R.W.
      • Vaidya A.M.
      • Delsupehe K.G.
      Sensory neuropathic cough: a common and treatable cause of chronic cough.
      gabapentin,
      • Ryan N.M.
      • Birring S.S.
      • Gibson P.G.
      Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial.
      • Ryan N.M.
      • Gibson P.G.
      Gabapentin for idiopathic chronic cough: a randomised controlled trial.
      • Mintz S.
      • Lee J.K.
      Gabapentin in the treatment of intractable idiopathic chronic cough: case reports.
      baclofen,
      • Dicpinigaitis P.V.
      • Rauf K.
      Treatment of chronic, refractory cough with baclofen.
      and pregabalin
      • Halum S.L.
      • Sycamore D.L.
      • McRae B.R.
      A new treatment option for laryngeal sensory neuropathy.
      have been used successfully with improvement in cough severity,
      • Cohen S.M.
      • Misono S.
      Use of specific neuromodulators in the treatment of chronic, idiopathic cough: a systematic review.
      • Wei W.
      • Liu R.
      • ZhangTong Y.
      • Qiu Z.
      The efficacy of specific neuromodulators on human refractory chronic cough: a systematic review and meta-analysis.
      and are currently used in clinical practice. Adverse effects including dry mouth, dizziness, and fatigue typically limit optimal dosing as well as effective use of these neuromodulators in many patients (Table 2).
      • Cohen S.M.
      • Misono S.
      Use of specific neuromodulators in the treatment of chronic, idiopathic cough: a systematic review.
      Table 2Brief Overview of Key Studies on the Use of Neuromodulators in CHS in the Last 15 Years
      CHS = cough hypersensitivity syndrome; CSI = cough severity index; CQOL = Cough Quality of Life Questionnaire; HARQ = Hull Airway Reflux Questionnaire; LCQ = Leicester Cough Questionnaire; VAS = Visual Analogue Scale.
      MedicationAuthorYearLocationType of studyNo. of patientsOutcome measuresSide effects/concerns
      Gefapixant (P2X3 receptor antagonist)Smith et al
      • Smith J.A.
      • Kitt M.M.
      • Morice A.H.
      • et al.
      Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial.
      2020UKDouble-blind, randomized, placebo-controlled

      4 groups: placebo, gefapixant 7.5mg, 20 mg, 50 mg, and twice a day
      252Awake objective cough frequency

      24-h objective cough frequency

      VAS

      Cough severity diary

      LCQ score

      Significant reductions at week 12 in 50-mg group
      1 patient in 50-mg group had frost bite

      Taste disturbance in the 50-mg group
      Orvepitant (neurokinin receptor antagonist)Smith et al
      • 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 (VOLCANO-1).
      2019UKPhase 2 pilot study1326% reduction in daytime cough frequency

      Improved CQOL and VAS at 4 weeks
      Well tolerated

      Fatigue, somnolence, lethargy
      Gefapixant 100 mg (P2X3 receptor antagonist)Morice et al
      • Morice A.H.
      • Kitt M.M.
      • Ford A.P.
      • et al.
      The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study.
      2019UKDouble-blind, randomized, placebo- controlled crossover study24 chronic cough

      12 healthy volunteers
      Increased cough challenge thresholds

      Improved VAS, HARQ, cough count
      Cough frequency/counts measured by cough monitors such as VitaloJAK.
      Taste disturbance in gefapixant group
      GSK2339345 (sodium channel blocker)Smith et al
      • Smith J.A.
      • McGarvey L.P.A.
      • Badri H.
      • et al.
      Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough.
      2017UKDouble-blind, placebo-controlled, crossover study11Increased 8-h cough countWell tolerated
      Tramadol (50 mg three times daily)Dion et al
      • Dion G.R.
      • Teng S.E.
      • Achlatis E.
      • Fang Y.
      • Amin M.R.
      Treatment of neurogenic cough with tramadol: a pilot study.
      2017USAProspective case series16Improved CSI and LCQRisk of serotonin syndrome and dependence
      XEN-D0501 (TRPV-1 antagonist)Belvisi et al
      • Belvisi M.G.
      • Birrell M.A.
      • Wortley M.A.
      • et al.
      XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough.
      2017UKDouble- blind, placebo- controlled18No improvement in spontaneous cough frequency
      Azithromycin (500 mg for 3 days, then 250 mg, three times a week)Hodgson et al
      • Hodgson D.
      • Anderson J.
      • Reynolds C.
      • et al.
      The effects of azithromycin in treatment-resistant cough: a randomized, double-blind, placebo-controlled trial.
      2016UKDouble-blind, placebo- controlled44LCQ score improved only in subgroup of chronic cough related to asthma1 drop out for gastrointestinal side effects
      AF-219, 600 mg (P2X3 receptor antagonist)Abdulqawi
      • Abdulqawi R.
      • Dockry R.
      • Holt K.
      • et al.
      P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
      2015UKPhase 2, Double-blind, placebo- controlled, crossover study24Improved daytime cough frequency by 75% in study groupTaste disturbance
      a CHS = cough hypersensitivity syndrome; CSI = cough severity index; CQOL = Cough Quality of Life Questionnaire; HARQ = Hull Airway Reflux Questionnaire; LCQ = Leicester Cough Questionnaire; VAS = Visual Analogue Scale.
      b Cough frequency/counts measured by cough monitors such as VitaloJAK.
      Physiotherapy and speech and language therapy intervention (PSALTI) has emerged as an effective method in clinical practice for treating the behavioral aspect of refractory chronic cough.
      • Vertigan A.E.
      • Theodoros D.G.
      • Gibson P.G.
      • Winkworth A.L.
      Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy.
      • Chamberlain Mitchell S.A.
      • Garrod R.
      • Clark L.
      • et al.
      Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.
      The PSALTI method comprises techniques of laryngeal hygiene and hydration, cough control, mindfulness about laryngeal injurious behavior, breathing exercises, and psycho-educational counseling.
      • Birring S.S.
      • Floyd S.
      • Reilly C.C.
      • Cho P.S.P.
      Physiotherapy and Speech and Language therapy intervention for chronic cough.
      Use of the PSALTI method has shown improvement in cough frequency by 41% as compared with usual care and sustained improvement in symptoms 3 months after therapy.
      • Chamberlain Mitchell S.A.
      • Garrod R.
      • Clark L.
      • et al.
      Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.
      The addition of a neuromodulator, such as pregabalin, to speech therapy resulted in additional improvement in cough severity, cough frequency, and quality of life when compared with speech therapy alone.
      • Vertigan A.E.
      • Kapela S.L.
      • Ryan N.M.
      • Birring S.S.
      • McElduff P.
      • Gibson P.G.
      Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial.
      Nonpharmacological management strategies such as hypnosis and referral to psychiatry/psychology have not been explored systematically in adults with CHS.

      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 bilateral thyroarytenoids in 22 patients with refractory chronic cough resulted in a 50% improvement in cough severity symptoms in half the patients.
      • Sasieta H.C.
      • Iyer V.N.
      • Orbelo D.M.
      • et al.
      Bilateral thyroarytenoid botulinum toxin type A injection for the treatment of refractory chronic cough.
      Some transient unpleasant effects included liquid dysphagia and dysphonia.
      Vocal fold augmentation with injection of methylcellulose and hyaluronic acid has been described with 18 of 23 patients reporting a 50% improvement in cough at 1 month with five showing no improvement and 11 having recurrence of symptoms.
      • Litts J.K.
      • Fink D.S.
      • Clary M.S.
      The effect of vocal fold augmentation on cough symptoms in the presence of glottic insufficiency.
      More recently, superior laryngeal nerve block has shown significant improvement in retrospective studies with 15 of 18 patients in one series reporting benefit using a combination of corticosteroid and a local anesthetic.
      • Simpson C.B.
      • Tibbetts K.M.
      • Loochtan M.J.
      • Dominguez L.M.
      Treatment of chronic neurogenic cough with in-office superior laryngeal nerve block.
      Because adverse effects with superior laryngeal nerve blocks are minimal, this modality has gained interest; however, randomized sham-controlled trials of all the above interventions are lacking.

      Novel Agents — Which Have Been Tried and Which Show Promise?

      Table 2 shows experience with neuromodulators as well as some of the novel agents that are receptor specific. P2X3 receptor antagonist was studied in a phase 2 randomized placebo-controlled trial where cough frequency improved by 75%.
      • Abdulqawi R.
      • Dockry R.
      • Holt K.
      • et al.
      P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
      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.
      • Morice A.H.
      • Kitt M.M.
      • Ford A.P.
      • et al.
      The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study.
      • Smith J.A.
      • Kitt M.M.
      • Morice A.H.
      • et al.
      Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial.
      • Smith J.A.
      • Kitt M.M.
      • Butera P.
      • et al.
      Gefapixant in two randomised dose-escalation studies in chronic cough.
      • Muccino D.R.
      • Morice A.H.
      • Birring S.S.
      • et al.
      Design and rationale of two phase 3 randomised controlled trials (COUGH-1 and COUGH-2) of gefapixant, a P2X3 receptor antagonist, in refractory or unexplained chronic cough.
      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%.
      • 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 (VOLCANO-1).
      Figure 3 captures some aspects of existing and expectant treatment modalities.
      Figure thumbnail gr3
      Figure 3Clinically relevant treatment modalities in cough hypersensitivity syndrome. CRC = corticosteroid responsive cough; GERD = gastroesophageal reflux disease; NK = neurokinin; NMDA = N-methyl-D-aspartate; PSALTI = physiotherapy speech and language therapy intervention; SLN = superior laryngeal nerve; TRPV-1 = transient receptor potential vanilloid 1; UACS = upper airway cough syndrome.

      Chronic Cough Secondary to GERD

      The relationship between chronic cough and GERD is probably the most contentious with arguments on both sides of the causal relationship. Most clinicians treat patients with GERD-related cough with proton pump inhibitors. However, trials of proton pump inhibitors for GERD-related cough show no benefit when used as sole therapy without symptoms such as heartburn.
      • Kahrilas P.J.
      • Altman K.W.
      • Chang A.B.
      • et al.
      Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report.
      • Chang A.B.
      • Lasserson T.J.
      • Gaffney J.
      • Connor F.L.
      • Garske L.A.
      Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults.

      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) microaspiration, 2) vagally mediated esophagobronchial reflex, and 3) gastric refluxate reaching proximal airways provoking hypersensitivity to stimuli such as cold and dust.
      • Richter J.E.
      Role of the gastric refluxate in gastroesophageal reflux disease: acid, weak acid and bile.
      More recently, it has been observed that patients with chronic cough have swallows with long breaks in esophageal motility.
      • Bennett M.C.
      • Patel A.
      • Sainani N.
      • Wang D.
      • Sayuk G.S.
      • Gyawali C.P.
      Chronic cough is associated with long breaks in esophageal peristaltic integrity on high-resolution manometry.

      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 related to GERD.
      • Kahrilas P.J.
      • Altman K.W.
      • Chang A.B.
      • et al.
      Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report.
      The focus is on minimizing transient lower esophageal sphincter relaxation.

      What Tests Can Help Diagnose Chronic Cough Secondary to GERD?

      Gastroesophageal refluxate could be acidic or weakly acidic.
      • Kahrilas P.J.
      • Altman K.W.
      • Chang A.B.
      • et al.
      Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report.
      • Richter J.E.
      Role of the gastric refluxate in gastroesophageal reflux disease: acid, weak acid and bile.
      • Pauwels A.
      • Blondeau K.
      • Dupont L.
      • Sifrim D.
      Cough and gastroesophageal reflux: from the gastroenterologist end.
      Barium esophagram can help with evaluating mucosal defects, esophageal motility, hiatal hernia, and peptic esophageal strictures; however, it has limited sensitivity and specificity in the interpretation of GERD.
      • Tutuian R.
      Update in the diagnosis of gastroesophageal reflux disease.
      Because both acid or weakly acid reflux can result in cough, the addition of measuring impedance to the multichannel pH testing and manometry has allowed for improved diagnosis of cough related to GERD.
      • Kahrilas P.J.
      • Altman K.W.
      • Chang A.B.
      • et al.
      Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report.
      • Pauwels A.
      • Blondeau K.
      • Dupont L.
      • Sifrim D.
      Cough and gastroesophageal reflux: from the gastroenterologist end.
      • Lee J.H.
      • Park S.Y.
      • Cho S.B.
      • et al.
      Reflux episode reaching the proximal esophagus are associated with chronic cough.

      What is the Role of Acid Suppressive Therapy in Chronic Cough From GERD?

      The role of acid suppression therapy has long been debated, and in those patients without heartburn or regurgitation, there has been no improvement in symptoms of cough.
      • Kahrilas P.J.
      • Altman K.W.
      • Chang A.B.
      • et al.
      Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report.
      • Shaheen N.J.
      • Crockett S.D.
      • Bright S.D.
      • et al.
      Randomised clinical trial: high-dose acid suppression for chronic cough — a double-blind, placebo-controlled study.
      • Faruqi S.
      • Molyneux I.D.
      • Fathi H.
      • Wright C.
      • Thompson R.
      • Morice A.H.
      Chronic cough and esomeprazole: a double-blind placebo-controlled parallel study.
      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.
      • Kahrilas P.J.
      • Altman K.W.
      • Chang A.B.
      • et al.
      Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report.

      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 metoclopramide to acid suppression helped improve cough in one-third of the patients.
      • Poe R.H.
      • Kallay M.C.
      Chronic cough and gastroesophageal reflux disease: experience with specific therapy for diagnosis and treatment.
      • Hiyama T.
      • Yoshihara M.
      • Tanaka S.
      • Haruma K.
      • Chayama K.
      Effectiveness of prokinetic agents against diseases external to the gastrointestinal tract.
      Similarly, in a small cohort of 16 patients, baclofen improved cough symptom score in half of the patients at 8 weeks.
      • Xu X.H.
      • Yang Z.M.
      • Chen Q.
      • et al.
      Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough.

      Is There a Role for Antireflux Surgery?

      There are no randomized controlled trials of antireflux surgery such as with Nissen fundoplication; however, it can be considered for patients with refractory cough from GERD and normal esophageal motility.
      • Kahrilas P.J.
      • Altman K.W.
      • Chang A.B.
      • et al.
      Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report.
      Significant improvement in chronic cough was described in a prospective follow-up over 31 months of 232 patients who underwent laparoscopic antireflux surgery.
      • Park A.
      • Weltz A.S.
      • Sanford Z.
      • Addo A.
      • Zahiri H.R.
      Laparoscopic antireflux surgery (LARS) is highly effective in the treatment of select patients with chronic cough.
      Use of novel laparoscopic magnetic sphincter augmentation methods in the management of GERD has not been systematically studied for its impact on chronic cough from GERD.

      Corticosteroid Responsive Cough

      Corticosteroid responsive cough (CRC) includes cough-variant asthma (CVA), nonasthmatic eosinophilic bronchitis (NAEB) as well as allergic rhinitis. Corticosteroid responsive cough is found in approximately 24% of chronic cough patients who are nonsmokers, whereas NAEB is found in approximately 13.6%.
      • Tarlo S.M.
      • Altman K.W.
      • Oppenheimer J.
      • et al.
      Occupational and environmental contributions to chronic cough in adults: chest expert panel report.
      TH2 cell–mediated airway inflammation most likely explains the pathophysiology in CRC. However, the variable bronchial hyperresponsiveness that is found in CVA is absent in NAEB. Nonasthmatic eosinophilic bronchitis is also characterized by sputum eosinophilia of greater than 3%, which can also be present in the eosinophilic variant of asthma.
      • Tarlo S.M.
      • Altman K.W.
      • Oppenheimer J.
      • et al.
      Occupational and environmental contributions to chronic cough in adults: chest expert panel report.
      • Brightling C.E.
      Chronic cough due to nonasthmatic eosinophilic bronchitis: ACCP evidence-based clinical practice guidelines.
      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 CVA
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      and can help differentiate CVA from NAEB in those with normal spirometry. Exhaled fractional excretion of nitric oxide (FeNO) has emerged as a convenient surrogate of eosinophilic inflammation. Whereas a diagnostic cutoff for the value of FeNO has not been firmly established, a high FeNO greater than 30 ppb has been shown to have a high correlation with sputum eosinophilia
      • Yi F.
      • Chen R.
      • Luo W.
      • et al.
      Validity of fractional exhaled nitric oxide in diagnosis of corticosteroid-responsive cough.
      and blood eosinophil count.
      • Sadeghi M.H.
      • Wright C.E.
      • Hart S.
      • Crooks M.
      • Morice A.H.
      Does FeNO predict clinical characteristics in chronic cough?.
      It may also help predict corticosteroid responsiveness in a patient with chronic cough.
      • Hahn P.Y.
      • Morgenthaler T.Y.
      • Lim K.G.
      Use of exhaled nitric oxide in predicting response to inhaled corticosteroids for chronic cough.
      Treatment of CVA includes inhaled corticosteroid with bronchodilator, leukotriene receptor antagonists, or short course of oral steroids.
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      Similarly, NAEB also responds to inhaled steroids or oral steroids.
      • Brightling C.E.
      • Ward R.
      • Goh K.L.
      • Wardlaw A.J.
      • Pavord I.D.
      Eosinophilic bronchitis is an important cause of chronic cough.
      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.
      • Pratter M.R.
      Chronic upper airway cough syndrome secondary to rhinosinus diseases (previously referred to as postnasal drip syndrome): ACCP evidence-based clinical practice guidelines.
      It is often characterized by the drainage of secretions from the nose or paranasal sinuses into the pharynx, resulting in the previously known terminology of postnasal drip.

      What Are the Different Etiologies to Consider in UACS?

      Allergic rhinitis is the most common cause of UACS.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • et al.
      The diagnosis and management of rhinitis: an updated practice parameter.
      Other causes include vasomotor rhinitis, nonallergic rhinitis with eosinophilia syndrome, postinfectious UACS, allergic fungal sinusitis, bacterial sinusitis, occupational rhinitis, rhinitis secondary to medications, and rhinitis from chemical exposures and that secondary to anatomic airway abnormalities, including polyps.
      • Pratter M.R.
      Chronic upper airway cough syndrome secondary to rhinosinus diseases (previously referred to as postnasal drip syndrome): ACCP evidence-based clinical practice guidelines.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • et al.
      The diagnosis and management of rhinitis: an updated practice parameter.
      Diagnostic pathway includes allergy testing, rhinolaryngoscopy (to look for changes of nasal mucosa, lesions and secretions), and imaging including plain sinus radiography and sinus computed tomography.
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      • Pratter M.R.
      Chronic upper airway cough syndrome secondary to rhinosinus diseases (previously referred to as postnasal drip syndrome): ACCP evidence-based clinical practice guidelines.

      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.
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      Sedating properties of older-generation antihistamines limit its widespread use. Even if not sedating, it can still impair attention.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • et al.
      The diagnosis and management of rhinitis: an updated practice parameter.
      • Bolser D.C.
      Older-generation antihistamines and cough due to upper airway cough syndrome (UACS): efficacy and mechanism.
      For allergic rhinitis, nasal steroids, nasal antihistamines, cromolyn, and second-generation nonsedating antihistamines are effective first-line treatments. Nasal saline rinses are beneficial as a sole modality or as an adjunct therapy
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • et al.
      The diagnosis and management of rhinitis: an updated practice parameter.
      • Lin L.
      • Chen Z.
      • Cao Y.
      • Sun G.
      Normal saline solution nasal-pharyngeal irrigation improves chronic cough associated with allergic rhinitis.
      Immunotherapy and omalizumab are also effective interventions.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • et al.
      The diagnosis and management of rhinitis: an updated practice parameter.
      Similarly, for vasomotor rhinitis, nasal ipratropium has shown benefit.
      • Pratter M.R.
      Chronic upper airway cough syndrome secondary to rhinosinus diseases (previously referred to as postnasal drip syndrome): ACCP evidence-based clinical practice guidelines.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • et al.
      The diagnosis and management of rhinitis: an updated practice parameter.
      For chronic sinusitis, if administration of decongestion, antibiotics, and nasal steroids is not effective, endoscopic sinus surgery should be considered.
      • Pratter M.R.
      Chronic upper airway cough syndrome secondary to rhinosinus diseases (previously referred to as postnasal drip syndrome): ACCP evidence-based clinical practice guidelines.
      Nasal saline irrigation with one or a combination of nasal steroids, nasal antihistamines, and nasal ipratropium can be helpful in most scenarios of cough from UACS.

      Emerging Topics in Chronic Cough

      Among additional problems that could influence the symptom of chronic cough, obstructive sleep apnea (OSA) and excessive dynamic airway collapse have surfaced to attention. In a prospective follow-up of 99 chronic cough patients, OSA was found in more than half and tracheobronchomalacia in approximately one-third of the patients among the multitude of diagnoses of chronic cough.
      • Good Jr., J.T.
      • Rollins D.R.
      • Kolakowski C.A.
      • Stevens A.D.
      • Denson J.L.
      • Martin R.J.
      New insights in the diagnosis of chronic refractory cough.

      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 psychological and social domains when measured using the validated Leicester Cough Questionnaire.
      • Sundar K.M.
      • Daly S.E.
      • Willis A.M.
      A longitudinal study of CPAP therapy for patients with chronic cough and obstructive sleep apnoea.
      This was also observed in 22 patients randomized to undergo CPAP vs sham-CPAP.
      • Sundar K.M.
      • Willis A.M.
      • Smith S.
      • Hu N.
      • Kitt J.P.
      • Birring S.S.
      A randomized, controlled, pilot study of CPAP for patients with chronic cough and obstructive sleep apnea.
      Among a cohort of 94 patients, significant improvement in symptoms of cough, voice, and breathing disorder was observed in those who used CPAP every night.
      • Roy N.
      • Merrill R.M.
      • Pierce J.
      • Sundar K.M.
      Evidence of possible irritable larynx syndrome in obstructive sleep apnea: an epidemiologic approach.
      Events caused by GERD have been observed to be strongly related to arousals in severe OSA.
      • Suzuki M.
      • Saigusa H.
      • Kurogi R.
      • et al.
      Arousals in obstructive sleep apnea patients with laryngopharyngeal and gastroesophageal reflux.
      We have incorporated screening for OSA into our management of chronic cough.

      Excessive Dynamic Airway Collapse

      Tracheobronchomalacia is an important entity 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 techniques 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 recognize the interplay of different etiologies when evaluating for chronic cough that would enable a unique treatment pathway for the patient. Ensuring adherence to the algorithm of chronic cough as per ACCP and fidelity to interventions remains fundamental in management.

      Potential Competing Interests

      The authors report no potential competing interests.

      References

        • Macedo P.
        • Zhang Q.
        • Saito J.
        • et al.
        Analysis of bronchial biopsies in chronic cough.
        Respir Med. 2017; 127: 40-44https://doi.org/10.1016/j.rmed.2017.04.001
        • Chung K.F.
        • Pavord I.D.
        Prevalence, pathogenesis, and causes of chronic cough.
        Lancet. 2008; 371: 1364-1374https://doi.org/10.1016/s0140-6736(08)60595-4
        • Song W.J.
        • Chang Y.S.
        • Faruqi S.
        • et al.
        The global epidemiology of chronic cough in adults: a systematic review and meta-analysis.
        Eur Respir J. 2015; 45: 1479-1481https://doi.org/10.1183/09031936.00218714
        • Colak Y.
        • Nordestgaard B.G.
        • Laursen L.C.
        • Afzal S.
        • Lange P.
        • Dahl M.
        Risk factors for chronic cough among 14,669 individuals from the general population.
        Chest. 2017; 152: 563-573https://doi.org/10.1016/j.chest.2017.05.038
        • Morice A.H.
        • Jakes A.D.
        • Faruqi S.
        • et al.
        A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response.
        Eur Respir J. 2014; 44: 1149-1155https://doi.org/10.1183/09031936.00217813
        • Birring S.S.
        • Floyd S.
        • Reilly C.C.
        • Cho P.S.P.
        Physiotherapy and Speech and Language therapy intervention for chronic cough.
        Pulm Pharmacol Ther. 2017; 47: 84-87https://doi.org/10.1016/j.pupt.2017.04.001
        • Hilton E.
        • Marsden P.
        • Thurston A.
        • Kennedy S.
        • Decalmer S.
        • Smith J.A.
        Clinical features of the urge-to-cough in patients with chronic cough.
        Respir Med. 2015; 109: 701-707https://doi.org/10.1016/j.rmed.2015.03.011
        • Hulme K.
        • Deary V.
        • Dogan S.
        • Parker S.M.
        Psychological profile of individuals presenting with chronic cough.
        ERJ Open Res. 2017; 3: 00099-2016https://doi.org/10.1183/23120541.00099-2016
        • French C.L.
        • Crawford S.L.
        • Bova C.
        • Irwin R.S.
        Change in psychological, physiological, and situational factors in adults after treatment of chronic cough.
        Chest. 2017; 152: 547-562https://doi.org/10.1016/j.chest.2017.06.024
        • Dicpinigaitis P.V.
        • Canning B.J.
        Is there (will there be) a post-COVID-19 chronic cough?.
        Lung. 2020; 198: 863-865https://doi.org/10.1007/s00408-020-00406-6
        • Haque R.A.
        • Usmani O.S.
        • Barnes P.J.
        Chronic idiopathic cough: a discrete clinical entity?.
        Chest. 2005; 127: 1710-1713https://doi.org/10.1378/chest.127.5.1710
        • Vertigan A.E.
        • Kapela S.L.
        • Ryan N.M.
        • Birring S.S.
        • McElduff P.
        • Gibson P.G.
        Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial.
        Chest. 2016; 149: 639-648https://doi.org/10.1378/chest.15-1271
        • Gibson P.
        • Wang G.
        • McGarvey L.
        • et al.
        Treatment of unexplained chronic cough: CHEST guideline and expert panel report.
        Chest. 2016; 149: 27-44https://doi.org/10.1378/chest.15-1496
        • French C.T.
        • Diekemper R.L.
        • Irwin R.S.
        • et al.
        Assessment of intervention fidelity and recommendations for researchers conducting studies on the diagnosis and treatment of chronic cough in the adult: CHEST guideline and expert panel report.
        Chest. 2015; 148: 32-54https://doi.org/10.1378/chest.15-0164
        • Morice A.H.
        • Millqvist E.
        • Bieksiene K.
        • et al.
        ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
        Eur Respir J. 2020; 55: 1901136https://doi.org/10.1183/13993003.01136-2019
        • Irwin R.S.
        • French C.L.
        • Chang A.B.
        • Altman K.W.
        Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
        Chest. 2018; 153: 196-209https://doi.org/10.1016/j.chest.2017.10.016
        • Chung K.F.
        • McGarvey L.
        • Mazzone S.B.
        Chronic cough as a neuropathic disorder.
        Lancet Respir Med. 2013; 1: 414-422https://doi.org/10.1016/S2213-2600(13)70043-2
        • Sundar K.M.
        • Stark A.C.
        • Hu N.
        • Barkmeier-Kraemer J.
        Is laryngeal hypersensitivity the basis of unexplained or refractory chronic cough?.
        ERJ Open Res. 2021; 7: 00793-2020https://doi.org/10.1183/23120541.00793-2020
        • Vertigan A.E.
        • Murad M.H.
        • Pringsheim T.
        • et al.
        Somatic cough syndrome (previously referred to as psychogenic cough) and tic cough (previously referred to as habit cough) in adults and children: CHEST guideline and expert panel report.
        Chest. 2015; 148: 24-31https://doi.org/10.1378/chest.15-0423
        • Vertigan A.E.
        • Bone S.L.
        • Gibson P.G.
        Development and validation of the Newcastle Laryngeal Hypersensitivity Questionnaire.
        Cough. 2014; 10: 1https://doi.org/10.1186/1745-9974-10-1
        • O'Neill J.
        • McMahon S.B.
        • Undem B.J.
        Chronic cough and pain: Janus faces in sensory neurobiology?.
        Pulm Pharmacol Ther. 2013; 26: 476-485https://doi.org/10.1016/j.pupt.2013.06.010
        • Davenport P.W.
        Clinical cough I: the urge-to-cough: a respiratory sensation.
        Handb Exp Pharmacol. 2009; : 263-276https://doi.org/10.1016/j.pupt.2013.06.010
        • Irwin R.S.
        • Ownbey R.
        • Cagle P.T.
        • Baker S.
        • Fraire A.E.
        Interpreting the histopathology of chronic cough: a prospective, controlled, comparative study.
        Chest. 2006; 130: 362-370https://doi.org/10.1378/chest.130.2.362
        • Mazzone S.B.
        An overview of the sensory receptors regulating cough.
        Cough. 2005; 1: 2https://doi.org/10.1186/1745-9974-1-2
        • Mazzone S.B.
        • McGovern A.E.
        • Yang S.K.
        • et al.
        Sensorimotor circuitry involved in the higher brain control of coughing.
        Cough. 2013; 9: 7https://doi.org/10.1186/1745-9974-9-7
        • Canning B.J.
        • Chang A.B.
        • Bolser D.C.
        • Smith J.A.
        • Mazzone S.B.
        • McGarvey L.
        Anatomy and neurophysiology of cough: CHEST guideline and expert panel report.
        Chest. 2014; 146: 1633-1648https://doi.org/10.1378/chest.14-1481
        • Mazzone S.B.
        • McGovern A.E.
        Sensory neural targets for the treatment of cough.
        Clin Exp Pharmacol Physiol. 2007; 34: 955-962https://doi.org/10.1111/j.1440-1681.2007.04702.x
        • Clarke R.
        • Monaghan K.
        • About I.
        • et al.
        TRPA1 activation in a human sensory neuronal model: relevance to cough hypersensitivity?.
        Eur Respir J. 2017; 50: 1700995https://doi.org/10.1183/13993003.00995-2017
        • Abdulqawi R.
        • Dockry R.
        • Holt K.
        • et al.
        P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
        Lancet. 2015; 385: 1198-1205
        • Morice A.H.
        • Kitt M.M.
        • Ford A.P.
        • et al.
        The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study.
        Eur Respir J. 2019; 54: 1900439https://doi.org/10.1183/13993003.00439-2019
        • Smith J.A.
        • Kitt M.M.
        • Morice A.H.
        • et al.
        Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial.
        Lancet Respir Med. 2020; 8: 775-785https://doi.org/10.1016/s2213-2600(19)30471-0
        • Lim K.G.
        • Rank M.A.
        • Kita H.
        • Patel A.
        • Moore E.
        Neuropeptide levels in nasal secretions from patients with and without chronic cough.
        Ann Allergy Asthma Immunol. 2011; 107: 360-363https://doi.org/10.1016/j.anai.2011.07.010
        • Patterson R.N.
        • Johnston B.T.
        • Ardill J.E.
        • Heaney L.G.
        • McGarvey L.P.
        Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux.
        Thorax. 2007; 62: 491-495https://doi.org/10.1136/thx.2006.063982
        • Smith J.A.
        • Woodcock A.
        Chronic cough.
        N Engl J Med. 2016; 375: 1544-1551https://doi.org/10.1056/NEJMcp1414215
        • Mazzone S.B.
        • McGovern A.E.
        • Koo K.
        • Farrell M.J.
        Mapping supramedullary pathways involved in cough using functional brain imaging: comparison with pain.
        Pulm Pharmacol Ther. 2009; 22: 90-96https://doi.org/10.1016/j.pupt.2008.08.003
        • Mazzone S.B.
        • McLennan L.
        • McGovern A.E.
        • Egan G.F.
        • Farrell M.J.
        Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging.
        Am J Respir Crit Care Med. 2007; 176: 327-332https://doi.org/10.1164/rccm.200612-1856OC
        • Ando A.
        • Smallwood D.
        • McMahon M.
        • Irving L.
        • Mazzone S.B.
        • Farrell M.J.
        Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control.
        Thorax. 2016; 71: 323-329https://doi.org/10.1136/thoraxjnl-2015-207425
        • Driessen A.K.
        • McGovern A.E.
        • Narula M.
        • et al.
        Central mechanisms of airway sensation and cough hypersensitivity.
        Pulm Pharmacol Ther. 2017; 47: 9-15https://doi.org/10.1016/j.pupt.2017.01.010
        • Pullerits T.
        • Ternesten-Hasseus E.
        • Johansson E.L.
        • Millqvist E.
        Capsaicin cough threshold test in diagnostics.
        Respir Med. 2014; 108: 1371-1376https://doi.org/10.1016/j.rmed.2014.07.012
        • Lim K.
        Neurogenic cough.
        J Allergy Clin Immunol. 2014; 133: 1779-.e3https://doi.org/10.1016/j.jaci.2014.02.040
        • Mai Y.
        • Zhan C.
        • Zhang S.
        • et al.
        Arnold nerve reflex: vagal hypersensitivity in chronic cough with various causes.
        Chest. 2020; 158: 264-271https://doi.org/10.1016/j.chest.2019.11.041
        • Ryan M.A.
        • Cohen S.M.
        Long-term follow-up of amitriptyline treatment for idiopathic cough.
        Laryngoscope. 2016; 126: 2758-2763https://doi.org/10.1002/lary.25978
        • Norris B.K.
        • Schweinfurth J.M.
        Management of recurrent laryngeal sensory neuropathic symptoms. Ann.
        Otol Rhinol Laryngol. 2010; 119: 188-191
        • Jeyakumar A.
        • Brickman T.M.
        • Haben M.
        Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy.
        Laryngoscope. 2006; 116: 2108-2112https://doi.org/10.1097/01.mlg.0000244377.60334.e3
        • Bastian R.W.
        • Vaidya A.M.
        • Delsupehe K.G.
        Sensory neuropathic cough: a common and treatable cause of chronic cough.
        Otolaryngol Head Neck Surg. 2006; 135: 17-21https://doi.org/10.1016/j.otohns.2006.02.003
        • Ryan N.M.
        • Birring S.S.
        • Gibson P.G.
        Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial.
        Lancet. 2012; 380: 1583-1589https://doi.org/10.1016/s0140-6736(12)60776-4
        • Ryan N.M.
        • Gibson P.G.
        Gabapentin for idiopathic chronic cough: a randomised controlled trial.
        Lung. 2012; 190: 64https://doi.org/10.1007/s00408-012-9370-3
        • Mintz S.
        • Lee J.K.
        Gabapentin in the treatment of intractable idiopathic chronic cough: case reports.
        Am J Med. 2006; 119: e13-e15https://doi.org/10.1016/j.amjmed.2005.10.046
        • Dicpinigaitis P.V.
        • Rauf K.
        Treatment of chronic, refractory cough with baclofen.
        Respiration. 1998; 65: 86-88https://doi.org/10.1159/000029232
        • Halum S.L.
        • Sycamore D.L.
        • McRae B.R.
        A new treatment option for laryngeal sensory neuropathy.
        Laryngoscope. 2009; 119: 1844-1847https://doi.org/10.1002/lary.20553
        • Cohen S.M.
        • Misono S.
        Use of specific neuromodulators in the treatment of chronic, idiopathic cough: a systematic review.
        Otolaryngol Head Neck Surg. 2013; 148: 374-382https://doi.org/10.1177/0194599812471817
        • Wei W.
        • Liu R.
        • ZhangTong Y.
        • Qiu Z.
        The efficacy of specific neuromodulators on human refractory chronic cough: a systematic review and meta-analysis.
        J Thorac Dis. 2016; 8: 2942-2951https://doi.org/10.21037/jtd.2016.10.51
        • 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 (VOLCANO-1).
        Chest. 2019; 157: 111-118https://doi.org/10.1016/j.chest.2019.08.001
        • Smith J.A.
        • McGarvey L.P.A.
        • Badri H.
        • et al.
        Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough.
        Int J Clin Pharmacol Ther. 2017; 55: 712-719https://doi.org/10.5414/CP202804
        • Dion G.R.
        • Teng S.E.
        • Achlatis E.
        • Fang Y.
        • Amin M.R.
        Treatment of neurogenic cough with tramadol: a pilot study.
        Otolaryngol Head Neck Surg. 2017; 157: 77-79https://doi.org/10.1177/0194599817703949
        • Belvisi M.G.
        • Birrell M.A.
        • Wortley M.A.
        • et al.
        XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough.
        Am J Respir Crit Care Med. 2017; 196: 1255-1263https://doi.org/10.1164/rccm.201704-0769OC
        • Hodgson D.
        • Anderson J.
        • Reynolds C.
        • et al.
        The effects of azithromycin in treatment-resistant cough: a randomized, double-blind, placebo-controlled trial.
        Chest. 2016; 149: 1052-1060https://doi.org/10.1016/j.chest.2015.12.036
        • Vertigan A.E.
        • Theodoros D.G.
        • Gibson P.G.
        • Winkworth A.L.
        Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy.
        Thorax. 2006; 61: 1065-1069https://doi.org/10.1136/thx.2006.064337
        • Chamberlain Mitchell S.A.
        • Garrod R.
        • Clark L.
        • et al.
        Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.
        Thorax. 2017; 72: 129-136https://doi.org/10.1136/thoraxjnl-2016-208843
        • Sasieta H.C.
        • Iyer V.N.
        • Orbelo D.M.
        • et al.
        Bilateral thyroarytenoid botulinum toxin type A injection for the treatment of refractory chronic cough.
        JAMA Otolaryngol Head Neck Surg. 2016; 142: 881-888https://doi.org/10.1001/jamaoto.2016.0972
        • Litts J.K.
        • Fink D.S.
        • Clary M.S.
        The effect of vocal fold augmentation on cough symptoms in the presence of glottic insufficiency.
        Laryngoscope. 2018; 128: 1316-1319https://doi.org/10.1002/lary.26914
        • Simpson C.B.
        • Tibbetts K.M.
        • Loochtan M.J.
        • Dominguez L.M.
        Treatment of chronic neurogenic cough with in-office superior laryngeal nerve block.
        Laryngoscope. 2018; 128: 1898-1903https://doi.org/10.1002/lary.26914
        • Smith J.A.
        • Kitt M.M.
        • Butera P.
        • et al.
        Gefapixant in two randomised dose-escalation studies in chronic cough.
        Eur Respir J. 2020; 55: 1901615https://doi.org/10.1183/13993003.01615-2019
        • Muccino D.R.
        • Morice A.H.
        • Birring S.S.
        • et al.
        Design and rationale of two phase 3 randomised controlled trials (COUGH-1 and COUGH-2) of gefapixant, a P2X3 receptor antagonist, in refractory or unexplained chronic cough.
        ERJ Open Res. 2020; 6: 00284-2020https://doi.org/10.1183/23120541.00284-2020
        • Kahrilas P.J.
        • Altman K.W.
        • Chang A.B.
        • et al.
        Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report.
        Chest. 2016; 150: 1341-1360https://doi.org/10.1016/j.chest.2016.08.1458
        • Chang A.B.
        • Lasserson T.J.
        • Gaffney J.
        • Connor F.L.
        • Garske L.A.
        Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults.
        Cochrane Database Syst Rev. 2011; 1: CD004823https://doi.org/10.1002/14651858.CD004823.pub4
        • Richter J.E.
        Role of the gastric refluxate in gastroesophageal reflux disease: acid, weak acid and bile.
        Am J Med Sci. 2009; 338: 89-95https://doi.org/10.1097/MAJ.0b013e3181ad584a
        • Bennett M.C.
        • Patel A.
        • Sainani N.
        • Wang D.
        • Sayuk G.S.
        • Gyawali C.P.
        Chronic cough is associated with long breaks in esophageal peristaltic integrity on high-resolution manometry.
        J Neurogastroenterol Motil. 2018; 24: 387-394https://doi.org/10.1097/MAJ.0b013e3181ad584a
        • Pauwels A.
        • Blondeau K.
        • Dupont L.
        • Sifrim D.
        Cough and gastroesophageal reflux: from the gastroenterologist end.
        Pulm Pharmacol Ther. 2009; 22: 135-138https://doi.org/10.1016/j.pupt.2008.11.007
        • Tutuian R.
        Update in the diagnosis of gastroesophageal reflux disease.
        J Gastrointestin Liver Dis. 2006; 15: 243-247
        • Lee J.H.
        • Park S.Y.
        • Cho S.B.
        • et al.
        Reflux episode reaching the proximal esophagus are associated with chronic cough.
        Gut Liver. 2012; 6: 197-202https://doi.org/10.5009/gnl.2012.6.2.197
        • Shaheen N.J.
        • Crockett S.D.
        • Bright S.D.
        • et al.
        Randomised clinical trial: high-dose acid suppression for chronic cough — a double-blind, placebo-controlled study.
        Aliment Pharmacol Ther. 2011; 33: 225-234https://doi.org/10.1111/j.1365-2036.2010.04511.x
        • Faruqi S.
        • Molyneux I.D.
        • Fathi H.
        • Wright C.
        • Thompson R.
        • Morice A.H.
        Chronic cough and esomeprazole: a double-blind placebo-controlled parallel study.
        Respirology. 2011; 16: 1150-1156https://doi.org/10.1111/j.1440-1843.2011.02014.x
        • Poe R.H.
        • Kallay M.C.
        Chronic cough and gastroesophageal reflux disease: experience with specific therapy for diagnosis and treatment.
        Chest. 2003; 123: 679-684
        • 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: 537-546https://doi.org/10.1111/j.1440-1746.2009.05780.x
        • Xu X.H.
        • Yang Z.M.
        • Chen Q.
        • et al.
        Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough.
        World J Gastroenterol. 2013; 19: 4386-4392https://doi.org/10.3748/wjg.v19.i27.4386
        • Park A.
        • Weltz A.S.
        • Sanford Z.
        • Addo A.
        • Zahiri H.R.
        Laparoscopic antireflux surgery (LARS) is highly effective in the treatment of select patients with chronic cough.
        Surgery. 2019; 166: 34-40https://doi.org/10.1016/j.surg.2019.01.036
        • Tarlo S.M.
        • Altman K.W.
        • Oppenheimer J.
        • et al.
        Occupational and environmental contributions to chronic cough in adults: chest expert panel report.
        Chest. 2016; 150: 894-907https://doi.org/10.1016/j.chest.2016.07.029
        • Brightling C.E.
        Chronic cough due to nonasthmatic eosinophilic bronchitis: ACCP evidence-based clinical practice guidelines.
        Chest. 2006; 129: 116s-121shttps://doi.org/10.1378/chest.129.1_suppl.116S
        • Irwin R.S.
        • Baumann M.H.
        • Bolser D.C.
        • et al.
        Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
        Chest. 2006; 129: 1s-23shttps://doi.org/10.1378/chest.129.1_suppl.1S
        • Yi F.
        • Chen R.
        • Luo W.
        • et al.
        Validity of fractional exhaled nitric oxide in diagnosis of corticosteroid-responsive cough.
        Chest. 2016; 149: 1042-1051https://doi.org/10.1016/j.chest.2016.01.006
        • Sadeghi M.H.
        • Wright C.E.
        • Hart S.
        • Crooks M.
        • Morice A.H.
        Does FeNO predict clinical characteristics in chronic cough?.
        Lung. 2018; 196: 59-64https://doi.org/10.1007/s00408-017-0074-6
        • Hahn P.Y.
        • Morgenthaler T.Y.
        • Lim K.G.
        Use of exhaled nitric oxide in predicting response to inhaled corticosteroids for chronic cough.
        Mayo Clinic Proc. 2007; 82: 1350-1355
        • Brightling C.E.
        • Ward R.
        • Goh K.L.
        • Wardlaw A.J.
        • Pavord I.D.
        Eosinophilic bronchitis is an important cause of chronic cough.
        Am J Respir Crit Care Med. 1999; 160: 406-410https://doi.org/10.1164/ajrccm.160.2.9810100
        • Pratter M.R.
        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: 63s-71shttps://doi.org/10.1378/chest.129.1_suppl.63S
        • Wallace D.V.
        • Dykewicz M.S.
        • Bernstein D.I.
        • et al.
        The diagnosis and management of rhinitis: an updated practice parameter.
        J Allergy Clin Immunol. 2008; 122: S1-S84https://doi.org/10.1016/j.jaci.2008.06.003
        • Bolser D.C.
        Older-generation antihistamines and cough due to upper airway cough syndrome (UACS): efficacy and mechanism.
        Lung. 2008; 186: S74-S77https://doi.org/10.1007/s00408-007-9033-y
        • 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: 96-104https://doi.org/10.2500/ajra.2017.31.4418
        • Good Jr., J.T.
        • Rollins D.R.
        • Kolakowski C.A.
        • Stevens A.D.
        • Denson J.L.
        • Martin R.J.
        New insights in the diagnosis of chronic refractory cough.
        Respir Med. 2018; 141: 103-110https://doi.org/10.1016/j.rmed.2018.06.024
        • Sundar K.M.
        • Daly S.E.
        • Willis A.M.
        A longitudinal study of CPAP therapy for patients with chronic cough and obstructive sleep apnoea.
        Cough. 2013; 9: 19https://doi.org/10.1186/1745-9974-9-19
        • Sundar K.M.
        • Willis A.M.
        • Smith S.
        • Hu N.
        • Kitt J.P.
        • Birring S.S.
        A randomized, controlled, pilot study of CPAP for patients with chronic cough and obstructive sleep apnea.
        Lung. 2020; 198: 449-457https://doi.org/10.1007/s00408-020-00354-1
        • Roy N.
        • Merrill R.M.
        • Pierce J.
        • Sundar K.M.
        Evidence of possible irritable larynx syndrome in obstructive sleep apnea: an epidemiologic approach.
        J Voice. 2021; 35: 932.e29-932.e38https://doi.org/10.1016/j.jvoice.2020.02.006
        • Suzuki M.
        • Saigusa H.
        • Kurogi R.
        • et al.
        Arousals in obstructive sleep apnea patients with laryngopharyngeal and gastroesophageal reflux.
        Sleep Med. 2010; 11: 356-360https://doi.org/10.1016/j.sleep.2009.09.008