WAO-ARIA consensus on chronic cough - Part II: Phenotypes and mechanisms of abnormal cough presentation — Updates in COVID-19

Open AccessPublished:November 21, 2021DOI:https://doi.org/10.1016/j.waojou.2021.100618

      Abstract

      Background

      Chronic cough can be triggered by respiratory and non-respiratory tract illnesses originating mainly from the upper and lower airways, and the GI tract (ie, reflux). Recent findings suggest it can also be a prominent feature in obstructive sleep apnea (OSA), laryngeal hyperresponsiveness, and COVID-19. The classification of chronic cough is constantly updated but lacks clear definition. Epidemiological data on the prevalence of chronic cough are informative but highly variable. The underlying mechanism of chronic cough is a neurogenic inflammation of the cough reflex which becomes hypersensitive, thus the term hypersensitive cough reflex (HCR). A current challenge is to decipher how various infectious and inflammatory airway diseases and esophageal reflux, among others, modulate HCR.

      Objectives

      The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on classification, epidemiology, presenting features, and mechanistic pathways of chronic cough in airway- and reflux-related cough phenotypes, OSA, and COVID-19. The interplay of cough reflex sensitivity with other pathogenic mechanisms inherent to airway and reflux-related inflammatory conditions was also analyzed.

      Outcomes

      Currently, it is difficult to clearly ascertain true prevalence rates in epidemiological studies of chronic cough phenotypes. This is likely due to lack of standardized objective measures needed for cough classification and frequent coexistence of multi-organ cough origins. Notwithstanding, we emphasize the important role of HCR as a mechanistic trigger in airway- and reflux-related cough phenotypes. Other concomitant mechanisms can also modulate HCR, including type2/Th1/Th2 inflammation, presence or absence of deep inspiration-bronchoprotective reflex (lower airways), tissue remodeling, and likely cough plasticity, among others.

      Keywords

      Introduction

      Epidemiological studies suggest the prevalence of cough ranges from 2.5% to 18%
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      Prevalence of chronic cough and possible causes in the general population based on the Korean National Health and Nutrition Examination Survey.
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      Prevalence and incidence of, and risk factors for chronic cough in the adult population: the Rotterdam Study.
      with significant impact on quality of life (QoL),
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      Prevalence and incidence of, and risk factors for chronic cough in the adult population: the Rotterdam Study.
      ,
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      Impact of chronic cough in quality of life.
      especially in the elderly.
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      Cough in the elderly population: relationships with multiple comorbidity.
      Acute cough is defined as lasting up to 3 or 4 weeks in adults,
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      and is usually self-limited.
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      Cough persisting for ≥8 weeks in adults
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      or 4 ≥ weeks in children
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      A cough algorithm for chronic cough in children: a multicenter, randomized controlled study.
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      can be defined as chronic cough. In this arbitrary classification, adult patients presenting for an interim period (ie, 4–8 weeks) may be either recovering from an acute cough-associated illness or in the pre-chronic cough stage and can be labelled as having “probable” chronic cough.
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      Cough presentation in primary care and the identification of chronic cough: a need for diagnostic clarity?.
      Chronic cough affects all ages and genders, although the typical chronic cough patient is a female in her sixth decade.
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      Worldwide survey of chronic cough: a manifestation of enhanced somatosensory response.
      Chronic cough is more prevalent in western countries compared to Asia and Africa.
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      The global epidemiology of chronic cough in adults: a systematic review and meta-analysis.
      A variety of respiratory and non-respiratory tract illnesses can trigger the condition, and the illnesses are listed in Fig. 1. Upper and lower airway etiologies of chronic cough are collectively termed upper airway cough syndrome (UACS) and lower airway cough syndrome (LACS), respectively. Other important etiologies include gastroesophageal reflux disease (GERD)-related cough and laryngeal hyperresponsiveness (LHR), obstructive sleep apnea (OSA), and COVID-19, tumors, and drugs (ie, ACE inhibitors, opioids), among others. However, chronic cough can occur in the absence of known triggers. While cough has been considered traditionally a symptomatic byproduct of these illnesses, the majority of patients do not report cough, although if asked, most patients describe it to be aggravating. Also, cough severity correlates poorly with severity of cough-associated illnesses.
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      • Morice A.H.
      Cough hypersensitivity syndrome: a few more steps forward.
      This suggests chronic cough is a distinct clinical entity. Based on clinical models, it is speculated that the underlying mechanism of chronic cough is a neurogenic inflammation of the cough reflex which becomes hypersensitive, thus the term hypersensitive cough reflex (HCR).
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      WAO-ARIA consensus ON chronic cough- part I: role of TRP channels in neurogenic inflammation of cough neuronal pathways.
      Still, the physician struggles to decipher how various infectious and inflammatory airway diseases and esophageal reflux, among others, modulate HCR. In a previous part of the consensus (Part I),
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      WAO-ARIA consensus ON chronic cough- part I: role of TRP channels in neurogenic inflammation of cough neuronal pathways.
      we reported on the role of transient receptor potential (TRP) ion channels in pathogenesis of chronic cough by mediating a crosstalk between neurogenic and inflammatory pathways in cough associated airways diseases. The current part II of the consensus (see Appendix) examines the presenting features, and mechanistic tussive pathways, in addition to the role of TRP ion channels, in airway- and reflux-related cough phenotypes, OSA, and COVID-19. Cough management in primary and cough specialty care will be further reported in part III of the consensus.
      Fig. 1
      Fig. 1Classification of chronic cough phenotypes, Abbreviations: AR (Allergic rhinitis), CA (Classic asthma), CC (Chronic cough), CVA (Cough variant asthma), COPD (Chronic obstructive pulmonary disease), GERD (gastroesophageal reflux disease), LACS (Lower airway cough syndrome), LHR (Laryngeal hyperresponsiveness), NAEB (Non-asthmatic eosinophilic bronchitis), NAR (Non allergic rhinitis), OSA (Obstructive sleep apnea), PCD (Primary ciliary dyskinesia), PND (Post-nasal drip), PVC (Post-viral cough), UACS (Upper airway cough syndrome), UCC (Unexplained chronic cough), ∗disease of rare occurrence.

      Upper airway cough syndrome

       Classification and epidemiology

      The term UACS, previously called postnasal drip syndrome (PNDS), is used to describe protracted cough triggered by common infectious, inflammatory, or neurogenic diseases involving the upper airways (Fig. 1). These can encompass several rhinitis and rhinosinusitis phenotypes, anatomic abnormalities, or chemically induced rhinitis, as well as pharyngeal diseases, among others.
      • Yu L.
      • Xu X.
      • Lv H.
      • Qiu Z.
      Advances in upper airway cough syndrome.
      • Pratter M.R.
      Chronic upper airway cough syndrome seconday to rhinosinus diseases (previously referred to as postnasal drip syndrome).
      • Papadopoulos N.G.
      • Guibas G.V.
      Rhinitis subtypes, endotypes and definitions.
      Also, diseases of the upper digestive tract can trigger cough. Mechanical manipulation of the external auditory canal can stimulate the auricular branch of the vagus nerve (Arnold's nerve) resulting in chronic dry cough.
      • Bloustine S.
      • Langston L.
      • Miller T.
      Ear-cough (arnold ’s) reflex.
      ,
      • Ryan N.M.
      • Gibson P.G.
      • Birring S.S.
      Arnold's nerve cough reflex: evidence for chronic cough as a sensory vagal neuropathy.
      A uniform definition of UACS/PNDS is lacking across the United States, Europe, and Asia. The discrepancy lies in considering postnasal drip (PND) as a symptom or a separate disease entity.
      • Yu L.
      • Xu X.
      • Lv H.
      • Qiu Z.
      Advances in upper airway cough syndrome.
      Furthermore, patients with PND do not account for a homogeneous group with respect to etiology. Other considerations, such as lack of standardized objective measures for clinical assessment of chronic cough, co-existence of more than one upper airway cough-associated disease, and absence of a uniform management protocol for chronic cough pose a great challenge to a clear definition of UACS. The characterization of UACS is even more complex in children. Challenges include age-related changes in etiologic frequencies of chronic cough in nursery, preschool, and school-age children,
      • Gao F.
      • Gu Q.L.
      • Jiang Z.D.
      Upper airway cough syndrome in 103 children.
      possibly related to differential maturation and modulation of cough reflex postnatally.
      • Ioan I.
      • Poussel M.
      • Coutier L.
      • et al.
      What is chronic cough in children?.
      Also, inability to perform invasive or noninvasive diagnostic modalities in young children, such as induced sputum analysis, bronchial provocation testing, and computed tomography (CT) scans requiring sedation, poses additional challenges to the classification and consequently to the management of chronic cough in this age group.
      • Wilson N.W.
      • Hogan M.B.
      • Harper C.B.
      • et al.
      Sinusitis and chronic cough in children.
      Epidemiological data on prevalence of upper airway-related cough among chronic cough patients is highly variable.
      • Yu X.
      • Kong L.
      • Jiang W.
      • et al.
      Etiologies associated with chronic cough and its clinical characteristics in school-age children.
      This is partly due to poor awareness amongst physicians of upper airway cough phenotypes leading to chronic cough. Enhanced diagnostic accuracy of cough etiological factors can also affect prevalence data. Other confounding variables can be type of patient population, whether studied in primary or cough-specialty care; this can overestimate or underestimate the true prevalence, respectively. In a 10-year longitudinal study (N = 1311), the reported etiological frequency for chronic cough dramatically changed as UACS and cough variant asthma (CVA) decreased by 50%, while GERD increased by 50%. Moreover, in a series of chronic cough patients, allergic rhinitis (AR), classic asthma (CA), chronic rhinosinusitis (CRS), and nasal polyposis (NP) were found in 46.5%, 31%, 12%, and 8.6% of patients with chronic cough, respectively. The high predictive value for concomitant asthma in UACS warrants a careful search for a lower airway pathology in patients presenting with chronic cough of upper airway origin.
      • Watelet J.B.
      • Van Zele T.
      • Brusselle G.
      Chronic cough in upper airway diseases.
      Cough quality that is either dry or productive cannot predict cough phenotype in adults; however, it can prove useful in determining etiological diagnosis in children.
      • Chang A.B.
      • Oppenheimer J.J.
      • Weinberger M.M.
      • et al.
      Management of children with chronic wet cough and protracted bacterial bronchitis: CHEST guideline and expert panel report.
      For example, in children with bacterial bronchitis a persistent wet cough warrants urgent attention whereas its value in adults remains questionable.
      • Mello C.J.
      • Irwin R.S.
      • Curley F.J.
      Predictive values of the character, timing, and complications of chronic cough in diagnosing its cause.
      In conclusion, the characterization of UACS in epidemiological studies lacks objective measures. This is partly due to presence of confounding variables, more so in the pediatric population.

       Pathogenesis

      It is speculated that upper airway cough-associated diseases can induce mechanical, systemic, or neurogenic stimulation of the afferent limb of cough reflex.
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      • De Blasio F.
      Anatomy and neuro-pathophysiology of the cough reflex arc.
      This includes sensory fibers of the trigeminal nerve
      • Yu L.
      • Xu X.
      • Lv H.
      • Qiu Z.
      Advances in upper airway cough syndrome.
      ,
      • Tatar M.
      • Plevkova J.
      • Brozmanova M.
      • Pecova R.
      • Kollarik M.
      Mechanisms of the cough associated with rhinosinusitis.
      and superior laryngeal and pharyngolaryngeal branch of the vagus nerve. Pathogenic mechanisms can be mechanical or chemical stimulation of the vagal afferent nerve by postnasal drip,
      • Pratter M.R.
      Chronic upper airway cough syndrome seconday to rhinosinus diseases (previously referred to as postnasal drip syndrome).
      ,
      • Yu J.L.
      • Becker S.S.
      Postnasal drip and postnasal drip-related cough.
      hematogenous spread of inflammatory mediators,
      • Yu L.
      • Xu X.
      • Lv H.
      • Qiu Z.
      Advances in upper airway cough syndrome.
      or cough reflex hypersensitivity.
      • Yu L.
      • Xu X.
      • Lv H.
      • Qiu Z.
      Advances in upper airway cough syndrome.
      As a mechanistic trigger, PND, whether subjectively reported or noted on physical examination, is not a consistent complaint/finding in patients with chronic cough.
      • Morice A.H.
      Post-nasal drip syndrome — a symptom to be sniffed at.
      Furthermore, the united airway theory speculates a hematogenous or neural spread of inflammatory mediators between upper and lower airways. This is evidenced by bidirectional involvements of both nose/sinuses and lungs in airway inflammatory diseases, such as atopy, and CRS with or without NP.
      • Braunstahl G.J.
      • Overbeek S.E.
      • KleinJan A.
      • Prins J.B.
      • Hoogsteden H.C.
      • Fokkens W.J.
      Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways.
      ,
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • et al.
      Allergic rhinitis and its impact on asthma ( ARIA ) 2008.
      Although evidence of a hypersensitive cough reflex involving vagus central and peripheral neuronal pathways is abundant, data supporting a hypersensitive cough reflex involvement of trigeminal nerve are relatively scarce. Notwithstanding, direct stimulation of trigeminal afferents in the nose can promote the cough reflex. In support of this, mechanical, thermal, and chemo-sensitive polymodal afferent receptors of the trigeminal nerve can be activated by capsaicin through its selective receptor TRPV1.
      • Mandadi S.
      • Roufogalis B.D.
      ThermoTRP channels in nociceptors: taking a lead from capsaicin receptor TRPV1.
      Clinical models involving tussigen inhalation and nasal challenges have provided great insight into the mechanism involved in UACS. It is important to note that tussive challenges reflect only a predisposition to cough under controlled conditions since experimental tussigen concentrations demonstrate only a moderate correlation with cough frequency.
      • Cho P.S.P.
      • Birring S.S.
      • Fletcher H.V.
      • Turner R.D.
      Methods of cough assessment.
      Capsaicin, a TRPV1 agonist, is an important tussigen used in animal and human models of cough inhalation challenges, where capsaicin-mediated activation of TRPV1 results in bronchospasm.
      • Yamasaki M.
      • Ebihara S.
      • Ebihara T.
      • et al.
      Cough reflex and oral chemesthesis induced by capsaicin and capsiate in healthy never-smokers.
      In healthy subjects, nasal challenge with histamine which lowers activation threshold of TRPV1 triggered sneezing and itching but no cough. One explanation for the absence of cough reflex can be insufficient lowering of the cough receptor threshold by histamine.
      • Bessac B.F.
      • Jordt S.E.
      Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control.
      At the peak of nasal itching ensuing from intranasal histamine challenge, subjects who were sequentially challenged with capsaicin inhalation reported more coughs when compared to a concomitant challenge with intranasal saline and inhaled capsaicin. This suggests nasal triggers can potentiate the cough reflex arc in the lower airways.
      • Tatar M.
      • Plevkova J.
      • Brozmanova M.
      • Pecova R.
      • Kollarik M.
      Mechanisms of the cough associated with rhinosinusitis.
      ,
      • Plevková J.
      • Poliaček I.
      • Adamkov M.
      • Svirlochová K.
      • Varga I.
      Brainstem neuronal populations activated in the model of ovalbumine induced allergic rhinitis in Guinea pigs - the c-Fos study.
      It also supports existence of a central crossover between trigeminal and vagus neuronal pathways referred to as cough plasticity or the modulation of the cough reflex by other afferent inputs within the vagal neuronal pathway and out of it.
      • Plevkova J.
      • Song W.J.
      Chronic cough in subjects with upper airway diseases - analysis of mechanisms and clinical applications.
      Hypothetically, “convergence” centers among nasal putative sensory afferents along the paratrigeminal nucleus and afferent cough fibers along the vagal second order neurons in tractus solitarius, can feature interactive activity of both afferent nerves.
      • Lucanska M.
      • Hajtman A.
      • Calkovsky V.
      • Kunc P.
      • Pecova R.
      Upper airway cough syndrome in pathogenesis of chronic cough.
      This can modulate cough response by increasing cough sensitivity to capsaicin.
      • Plevkova J.
      • Brozmanova M.
      • Pecova R.
      • Tatar M.
      The effects of nasal histamine challenge on cough reflex in healthy volunteers.
      In support of the convergence theory, capsaicin challenge in guinea pigs increased neuronal activity simultaneously in the brainstem and the trigeminal nerve, as suggested by increased expression of C-fos (proto-oncogene),
      • Yu L.
      • Xu X.
      • Lv H.
      • Qiu Z.
      Advances in upper airway cough syndrome.
      ,
      • Plevková J.
      • Poliaček I.
      • Adamkov M.
      • Svirlochová K.
      • Varga I.
      Brainstem neuronal populations activated in the model of ovalbumine induced allergic rhinitis in Guinea pigs - the c-Fos study.
      the gene group of second and higher order neurons.
      In conclusion, UACS lack a uniform definition of trigger diseases, such as PND, rhinitis, or rhinosinusitis in children or adults. Additionally, mechanistic triggers of chronic cough in UACS can involve a neurogenic or systemic communication between upper and lower airways, and likely cough reflex sensitivity. Because rhinitis or rhinosinusitis are frequent comorbidities of reactive airways and reflux disease, it is sometimes difficult to discern if chronic cough reflects HCR involving the vagus nerve, trigeminal nerve, or both.

       Infectious rhinitis

      Infectious rhinitis or common cold has been traditionally linked to chronic cough, the so-called post-viral cough (PVC). Mechanical stimulation of the chest by high frequency chest percussion in non-coughing patients with upper respiratory tract infection (URTI) increased cough when compared to healthy volunteers. This suggests airway mechanical and rapidly adapting receptors can trigger cough reflex sensitivity in patients with URTI.
      • Lee P.C.L.
      • Eccles R.
      Cough induction by high-frequency chest percussion in healthy volunteers and patients with common cold.
      Previous reports demonstrated patients with URTI have increased cough sensitivity to capsaicin but no change in airway responsiveness to methacholine challenge, when compared to healthy volunteers.
      • O'Connell F.
      • Thomas V.E.
      • Studham J.M.
      • Pride N.B.
      • Fuller R.W.
      Capsaicin cough sensitivity increases during upper respiratory infection.
      This suggests respiratory infections can induce a hypersensitive cough reflex without airway hyperresponsiveness. Also, lipopolysaccharide can activate TRPA1, independently of their activation of Toll-like receptor 4 (TLR4),
      • Meseguer V.
      • Alpizar Y.A.
      • Luis E.
      • et al.
      TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins.
      and viral mRNA is capable of stimulating purinergic receptors via TLR7.
      • Park C.K.
      • Xu Z.Z.
      • Berta T.
      • et al.
      Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1.

       Allergic and non-allergic rhinitis

      A longitudinal cohort study demonstrated non-infectious rhinitis is a significant and independent risk factor for development of chronic cough in adults.
      • Guerra S.
      • Sherrill D.L.
      • Baldacci S.
      • et al.
      Rhinitis is an independent risk factor for developing cough apart from colds among adults.
      In AR, many patients have cough, wheezing, and shortness of breath, and during the pollen season, cough is often severe with no major change in forced expiratory volume during the first second (FEV1), thereby suggesting an upper airway origin.
      • Bousquet J.
      • Boushey H.A.
      • Busse W.W.
      • et al.
      Characteristics of patients with seasonal allergic rhinitis and concomitant asthma.
      Bronchial hyperresponsiveness is more frequent in AR patients in cross-sectional studies,
      • Kim S.W.
      • Han D.H.
      • Lee S.J.
      • Lee C.H.
      • Rhee C.S.
      Bronchial hyperresponsiveness in pediatric rhinitis patients: the difference between allergic and nonallergic rhinitis.
      • Shaaban R.
      • Zureik M.
      • Soussan D.
      • et al.
      Allergic rhinitis and onset of bronchial hyperresponsiveness: a population-based study.
      • Suh D.I.
      • Koh Y.Y.
      Relationship between atopy and bronchial hyperresponsiveness.
      and compared to seasonal rhinitis, perennial rhinitis is much more important as a risk factor for developing nonspecific bronchial hyperresponsiveness.
      • Verdiani P.
      • Di Carlo S.
      • Baronti A.
      Different prevalence and degree of nonspecific bronchial hyperreactivity between seasonal and perennial rhinitis.
      Experimental data suggest that AR is a risk factor for chronic cough. Tussigen challenges in AR indicate that capsaicin-sensitive TRPV1 receptors and capsaicin-insensitive A-δ stretch receptors modulate cough sensitivity.
      • Plevkova J.
      • Song W.J.
      Chronic cough in subjects with upper airway diseases - analysis of mechanisms and clinical applications.
      Cough reflex sensitivity in the upper airways is heightened in atopic patients
      • Pecova R.
      • Vrlik M.
      • Tatar M.
      Cough sensitivity in allergic rhinitis.
      ,
      • Pecova R.
      • Zucha J.
      • Pec M.
      • Neuschlova M.
      • Hanzel P.
      • Tatar M.
      Cough reflex sensitivity testing in seasonal allergic rhinitis patients and healthy volunteers.
      when compared to healthy controls. By comparing adults
      • Plevkova J.
      • Song W.J.
      Chronic cough in subjects with upper airway diseases - analysis of mechanisms and clinical applications.
      or children
      • Plevkova J.
      • Varechova S.
      • Brozmanova M.
      • Tatar M.
      Testing of cough reflex sensitivity in children suffering from allergic rhinitis and common cold.
      with seasonal AR outside their pollen season to healthy controls, a standardized (inhaled) capsaicin challenge model demonstrated significantly increased cough in atopic patients. Using the same model, allergic patients in-season reported significantly more coughs than those out-of-season.
      • Pecova R.
      • Vrlik M.
      • Tatar M.
      Cough sensitivity in allergic rhinitis.
      These findings are also in accordance with the “priming effect” reported in the upper airways, that is, reduced activation threshold of sensory nerves in response to IgE and non-IgE related stimuli following allergen exposure.
      • Connell J.T.
      Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen exposure, and placebo challenge on the nasal membrane.
      ,
      • Connell J.T.
      Quantitative intranasal pollen challenges. 3. The priming effect in allergic rhinitis.
      As stated previously, combined challenge with inhaled capsaicin and nasal topical histamine enhanced capsaicin induced cough reflex hypersensitivity in seasonal AR.
      • Tatar M.
      • Plevkova J.
      • Brozmanova M.
      • Pecova R.
      • Kollarik M.
      Mechanisms of the cough associated with rhinosinusitis.
      ,
      • Plevkova J.
      • Brozmanova M.
      • Pecova R.
      • Tatar M.
      The effects of nasal histamine challenge on cough reflex in healthy volunteers.
      Conversely, treatment of atopic inflammation with inhaled corticosteroids or antileukotrienes in an animal model of ovalbumin-sensitive guinea pigs restored the cough sensitivity reflex to its pre-treatment values.
      • Brozmanova M.
      • Plevkova J.
      • Bartos V.
      • Plank L.
      • Tatar M.
      Antileukotriene treatment and allergic rhinitis-related cough in Guinea pigs.
      ,
      • Brozmanova M.
      • Calkovsky V.
      • Plevkova J.
      • Tatar M.
      Effects of inhaled corticosteroids on cough in awake Guinea pigs with experimental allergic rhinitis--the first experience.
      In conclusion, these results are in line with a speculated increased reactivity of cough afferent nerve endings in patients with clinical or subclinical AR.
      Non-allergic rhinitis is a collective term used to describe non-allergic non-infectious rhinitis phenotypes characterized by nonspecific nasal hyperreactivity. The latter denotes induction of rhinitis symptoms (rhinorrhea, nasal congestion) in response to nonspecific irritants such as tobacco smoke, changes in temperature and humidity, and air pollutants, among others.
      • Papadopoulos N.G.
      • Guibas G.V.
      Rhinitis subtypes, endotypes and definitions.
      ,
      • Shusterman D.
      Nonallergic rhinitis: environmental determinants.
      Idiopathic (vasomotor) rhinitis constitutes the majority of nonallergic rhinitis
      • Scarupa M.D.
      • Kaliner M.A.
      Nonallergic rhinitis, with a focus on vasomotor rhinitis.
      and features many characteristics relevant to UACS. Clinically, this is exemplified by triggering of rhinitis symptoms following nonspecific thermal, mechanical, and endogenous inflammatory triggers. In vasomotor rhinitis there is also over expression of TRPV1 and TRPM8 channels along the C-fiber sensory distribution of the trigeminal nerve endings in the nose.
      • Van Gerven L.
      • Alpizar Y.A.
      • Steelant B.
      • et al.
      Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.
      ,
      • Bernstein J.A.
      • Singh U.
      Neural abnormalities in nonallergic rhinitis.
      Along the same line, data suggest presence of neuroimmune modulation in vasomotor rhinitis as manifested by neuropeptides (substance P and calcitonin gene-related peptide [CGRP]) mediated-inflammatory response.
      • Van Gerven L.
      • Alpizar Y.A.
      • Wouters M.M.
      • et al.
      Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.
      Interestingly allergic, infectious, and nonallergic rhinitis can all have components of nasal hyperactivity, to a varying degree.
      • Van Gerven L.
      • Steelant B.
      • Hellings P.W.
      Nasal hyperreactivity in rhinitis: a diagnostic and therapeutic challenge.
      Yet, chronic cough is infrequently reported in idiopathic rhinitis,
      • Shusterman D.
      Nonallergic rhinitis: environmental determinants.
      and to our best knowledge no capsaicin inhaled challenge studies addressing chronic cough have been performed in this rhinitis phenotype.

       Chronic rhinosinusitis

      Although rhinosinusitis can constitute up to 20% of adult patients with chronic cough,
      • Arinze J.T.
      • de Roos E.W.
      • Karimi L.
      • Verhamme K.M.C.
      • Stricker B.H.
      • Brusselle G.G.
      Prevalence and incidence of, and risk factors for chronic cough in the adult population: the Rotterdam Study.
      coughing is not a major feature of chronic rhinosinusitis (CRS),
      • Fokkens W.J.
      • Lund V.J.
      • Hopkins C.
      • et al.
      European position paper on rhinosinusitis and nasal polyps 2020.
      and cough aggravation has been associated with presence of bacterial biofilms.
      • Li H.
      • Wang D.
      • Sun X.
      • Hu L.
      • Yu H.
      • Wang J.
      Relationship between bacterial biofilm and clinical features of patients with chronic rhinosinusitis.
      In one study of adult patients with rhinosinusitis presenting with chronic cough, pharmacotherapy improved lung function parameters but not subjective cough scores, probably related to the small size of the study.
      • Kariya S.
      • Okano M.
      • Higaki T.
      • Makihara S.
      • Tachibana T.
      • Nishizaki K.
      Long-term treatment with clarithromycin and carbocisteine improves lung function in chronic cough patients with chronic rhinosinusitis.
      In contrast to adults, the majority of children with CRS present with chronic cough.
      • Fokkens W.J.
      • Lund V.J.
      • Hopkins C.
      • et al.
      European position paper on rhinosinusitis and nasal polyps 2020.
      Several studies reported improvement of pediatric CRS-associated (chronic) cough with medical
      • Pham V.
      • Sykes K.
      • Wei J.
      Long-term Outcome of once daily nasal irrigation for the treatment of pediatric chronic rhinosinusitis.
      ,
      • Ozturk F.
      • Bakirtas A.
      • Ileri F.
      • Turktas I.
      Efficacy and tolerability of systemic methylprednisolone in children and adolescents with chronic rhinosinusitis : a double-blind , placebo-controlled randomized trial.
      or surgical
      • Chang P.H.
      • Lee L.A.
      • Huang C.C.
      • Lai C.H.
      • Lee T.J.
      Functional endoscopic sinus surgery in children using a limited approach.
      treatment modalities. Mechanistic analysis of cough triggers in CRS is hampered by the frequent coexistence of other cough-associated illnesses such as lower airway pathology
      • Ryu G.
      • Min C.
      • Park B.
      • Choi H.G.
      • Mo J.H.
      Bidirectional association between asthma and chronic rhinosinusitis: two longitudinal follow-up studies using a national sample cohort.
      or gastroesophageal reflux disease,
      • Poelmans J.
      • Tack J.
      Extraoesophageal manifestations of gastro-oesophageal reflux.
      which can act as confounding variables.

       Obstructive sleep apnea syndrome (OSAS)

      OSAS is an increasingly recognized important risk factor for cough in children
      • Chang A.B.
      • Oppenheimer J.J.
      • Weinberger M.
      • Grant C.C.
      • Rubin B.K.
      • Irwin R.S.
      Etiologies of chronic cough in pediatric cohorts: CHEST guideline and expert panel report.
      and adults.
      • Sundar K.M.
      • Daly S.E.
      Chronic cough and OSA: a new association?.
      OSAS can present solely with cough
      • Birring S.S.
      • Ing A.J.
      • Chan K.
      • et al.
      Obstructive sleep apnoea: a cause of chronic cough.
      and absence of daytime somnolence (normal Epworth sleepiness score).
      • Chan K.
      • Ing A.
      • Birring S.S.
      Cough in obstructive sleep apnoea.
      Other associated symptoms in patients with OSA and cough include rhinitis and GERD.
      • Birring S.S.
      • Ing A.J.
      • Chan K.
      • et al.
      Obstructive sleep apnoea: a cause of chronic cough.
      ,
      • Chan K.K.Y.
      • Ing A.J.
      • Laks L.
      • Cossa G.
      • Rogers P.
      • Birring S.S.
      Chronic cough in patients with sleep-disordered breathing.
      ,
      • Wang T.Y.
      • Lo Y.L.
      • Liu W.T.
      • et al.
      Chronic cough and obstructive sleep apnoea in a sleep laboratory-based pulmonary practice.
      The prevalence of chronic cough in OSA patients and general population is estimated at 33–39%
      • Sundar K.M.
      • Daly S.E.
      Chronic cough and OSA: a new association?.
      ,
      • Wang T.Y.
      • Lo Y.L.
      • Liu W.T.
      • et al.
      Chronic cough and obstructive sleep apnoea in a sleep laboratory-based pulmonary practice.
      ,
      • Sundar K.M.
      • Daly S.E.
      • Pearce M.J.
      • Alward W.T.
      Chronic cough and obstructive sleep apnea in a community-based pulmonary practice.
      and 2.5–18%, respectively, which suggests a strong association between cough and OSA. This has been linked to increased production of inflammatory mediators (IL-6, IL-8, INF-γ),
      • Chan K.
      • Ing A.
      • Birring S.S.
      Cough in obstructive sleep apnoea.
      exhaled nitric oxide, and sputum neutrophilia
      • Fortuna A.M.
      • Miralda R.
      • Calaf N.
      • González M.
      • Casan P.
      • Mayos M.
      Airway and alveolar nitric oxide measurements in obstructive sleep apnea syndrome.
      in OSA. Compared to normal subjects, OSA patients reported a higher incidence of chronic cough, reportedly secondary to nocturnal GERD.
      • Wang T.Y.
      • Lo Y.L.
      • Liu W.T.
      • et al.
      Chronic cough and obstructive sleep apnoea in a sleep laboratory-based pulmonary practice.
      Also, patients with OSA manifest frequent nocturnal arousal and awakening episodes concomitant with the obstructive respiratory events which can cause a dysfunctional central inhibition of cough.
      • Chan K.
      • Ing A.
      • Birring S.S.
      Cough in obstructive sleep apnoea.
      Continuous positive airway pressure (CPAP) therapy in patients with OSA and cough improves cough reflex sensitivity as measured by citric acid challenge,
      • Faruqi S.
      • Fahim A.
      • Morice A.H.
      Chronic cough and obstructive sleep apnoea: reflux-associated cough hypersensitivity?.
      cough-related QoL (Leicester cough questionnaire)
      • Birring S.S.
      • Ing A.J.
      • Chan K.
      • et al.
      Obstructive sleep apnoea: a cause of chronic cough.
      ,
      • Faruqi S.
      • Fahim A.
      • Morice A.H.
      Chronic cough and obstructive sleep apnoea: reflux-associated cough hypersensitivity?.
      ,
      • 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.
      and cough scores.
      • Birring S.S.
      • Ing A.J.
      • Chan K.
      • et al.
      Obstructive sleep apnoea: a cause of chronic cough.
      ,
      • Wang T.Y.
      • Lo Y.L.
      • Liu W.T.
      • et al.
      Chronic cough and obstructive sleep apnoea in a sleep laboratory-based pulmonary practice.
      ,
      • Faruqi S.
      • Fahim A.
      • Morice A.H.
      Chronic cough and obstructive sleep apnoea: reflux-associated cough hypersensitivity?.
      Taken together, these data suggest OSA is implicated in the pathogenesis of chronic cough. The role of CPAP titration in cough improvement requires further elucidation with large scale randomized trials.

      Laryngeal hyperresponsiveness

       Anatomical and pathophysiological considerations

      Laryngeal hyperresponsiveness (LHR) denotes inspiratory movement of vocal cords towards each other (adduction) in response to noxious chemical stimuli or inhaled histamine challenge.
      • Bucca C.B.
      • Bugiani M.
      • Culla B.
      • et al.
      Chronic cough and irritable larynx.
      LHR encompasses a range of laryngeal pathologies, including vocal cord dysfunction, muscle tension dysphonia, and globus, among others.
      • Gibson P.G.
      • Simpson J.L.
      • Ryan N.M.
      • Vertigan A.E.
      Mechanisms of cough.
      LHR is present in up to 50% of patients with chronic cough.
      • Vertigan A.E.
      • Theodoros D.G.
      • Gibson P.G.
      • Winkworth A.L.
      Voice and upper airway symptoms in people with chronic cough and paradoxical vocal fold movement.
      The laryngo-constriction chemoreflex is mediated by the afferent superior laryngeal branch of the vagus nerve and the efferent recurrent laryngeal nerve. It forms a basic defense mechanism in newborns against aspirated liquids, and is phylogenetically complemented in adults by reflex cough and bronchoconstriction.
      • Thach B.T.
      Maturation of cough and other reflexes that protect the fetal and neonatal airway.
      LHR can be measured by a decrease in extrathoracic (maximal) mid- inspiratory and expiratory airflow rates and a reduction in the size of the laryngeal inlet, as noted on endoscopic exam. Most patients with upper inflammatory airway diseases and cough displayed LHR as revealed by histamine inhalation protocol.
      • Bucca C.
      • Rolla G.
      • Scappaticci E.
      • Baldi S.
      • Caria E.
      • Oliva A.
      Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms.
      Using glottic airflow rates as index of extrathoracic hyperresponsiveness and subsequent laryngeal adduction,
      • Famokunwa B.
      • Walsted E.S.
      • Hull J.H.
      Assessing laryngeal function and hypersensitivity.
      LHR was significantly associated with sinusitis, postnasal drip, female gender, and dysphonia.
      • Bucca C.
      • Rolla G.
      • Scappaticci E.
      • Baldi S.
      • Caria E.
      • Oliva A.
      Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms.
      Also, LHR was prevalent in chronic cough patients with rhinitis/rhinosinusitis (76%), gastroesophageal reflux disease (77%), and asthma (93%); however, it was absent in non-coughing asthmatic patients.
      • Bucca C.B.
      • Bugiani M.
      • Culla B.
      • et al.
      Chronic cough and irritable larynx.
      Taken together, these data suggest LHR is associated with UACS, GERD-associated chronic cough, and cough associated with asthma. However, presence of asthma seems independent of the association of LHR and chronic cough of different etiologies.

       Clinical aspects

      Cough localized primarily to the larynx, commonly referred to as “throat” cough, is one manifestation of a hyperfunctional larynx along with episodic laryngospasm, muscle tension dysphonia, stridor, wheezes, and globus.
      • Morrison M.
      • Rammage L.
      • Emami A.J.
      The irritable larynx syndrome.
      These phenotypes of laryngeal dysfunction have overlapping symptomatology and can be induced by nonspecific triggers such as scents, emotional stress, exertion, and reflux.
      • Famokunwa B.
      • Walsted E.S.
      • Hull J.H.
      Assessing laryngeal function and hypersensitivity.
      The underlying sensory nature of these triggers is suggestive of a neural plasticity of the central laryngeal neuronal pathways,
      • Morrison M.
      • Rammage L.
      • Emami A.J.
      The irritable larynx syndrome.
      ,
      • Andrianopoulos M.V.
      • Gallivan G.J.
      • Gallivan K.H.
      PVCM, PVCD, EPL, and irritable larynx syndrome: what are we talking about and how do we treat it?.
      similar to chronic cough and chronic neuropathic pain. Laryngeal provocation models consist of incremental endoscopic insufflation of gases directly into laryngeal inlet and measuring laryngeal adductor reflex as expressed by the air pressure required to achieve glottic closure. A challenge with inhaled air
      • Aviv J.E.
      • Martin J.H.
      • Kim T.
      • et al.
      Laryngopharyngeal sensory discrimination testing and the laryngeal adductor reflex.
      or diluted acid
      • Phua S.Y.
      • McGarvey L.
      • Ngu M.
      • Ing A.
      The differential effect of gastroesophageal reflux disease on mechanostimulation and chemostimulation of the laryngopharynx.
      can reflect mechanical and sensory laryngeal hypersensitivity, respectively. These models revealed diminished laryngeal sensitivity in patients with chronic cough-associated reflux disease and paradoxical vocal fold motion.
      • Cukier-Blaj S.
      • Bewley A.
      • Aviv J.E.
      • Murry T.
      Paradoxical vocal fold motion: a sensory-motor laryngeal disorder.
      Therefore, an exaggerated laryngeal adduction reflex was proposed as a compensatory motor response to LHR.
      • Cukier-Blaj S.
      • Bewley A.
      • Aviv J.E.
      • Murry T.
      Paradoxical vocal fold motion: a sensory-motor laryngeal disorder.
      A recent review on methods of laryngeal sensory provocation confirms that endoscopic visualization of vocal fold motion, in different laryngeal pathologies and during exposure to multiple sensory triggers, is clinically appropriate to objectively assess vocal cord dysfunction;
      • Famokunwa B.
      • Walsted E.S.
      • Hull J.H.
      Assessing laryngeal function and hypersensitivity.
      it can be also assisted by computational algorithms. Comprehensive immunological and physiological data on neurogenic inflammatory pathways involved in LHR are currently lacking. Nevertheless, earlier data suggest efficacy of neuromodulators in treating chronic cough patients with laryngospasm and throat clearing.
      • Lee B.
      • Woo P.
      Chronic cough as a sign of laryngeal sensory neuropathy: diagnosis and treatment.
      Thus, laryngeal cough reflex sensitivity is an evolving concept.

      Lower airway cough syndrome

      Reactive lower airway diseases can be associated with chronic cough, most commonly classic asthma, cough variant asthma, non-asthmatic eosinophilic bronchitis and chronic obstructive pulmonary disease.
      • 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.
      Immunological and clinical highlights of these closely related cough phenotypes are shown in Table 1.
      Table 1Comparative analysis of immunological and clinical properties of cough-phenotypic traits originating from lower airways.
      Airway eosinophilia
      • Lougheed M.D.
      • Turcotte S.E.
      • Fisher T.
      Cough variant asthma: lessons learned from deep inspirations.
      ,
      • Wasilewski N.V.
      • Fisher T.
      • Turcotte S.E.
      • Fisher J.T.
      • Lougheed M.D.
      Bronchoprotective effect of deep inspirations in cough variant asthma: a distinguishing feature in the spectrum of airway disease?.
      ,
      • Hastie A.T.
      • Martinez F.J.
      • Curtis J.L.
      • et al.
      Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort.
      Deep inspiration cough broncho-protective reflex
      • Lougheed M.D.
      • Turcotte S.E.
      • Fisher T.
      Cough variant asthma: lessons learned from deep inspirations.
      ,
      • Wasilewski N.V.
      • Fisher T.
      • Turcotte S.E.
      • Fisher J.T.
      • Lougheed M.D.
      Bronchoprotective effect of deep inspirations in cough variant asthma: a distinguishing feature in the spectrum of airway disease?.
      PGE2 (bronchodilator) expression
      • Sastre B.
      • Fernández-Nieto M.
      • Mollá R.
      • et al.
      Increased prostaglandin E2 levels in the airway of patients with eosinophilic bronchitis.
      ,
      • Sastre B.
      • Del Pozo V.
      Role of PGE 2 in asthma and nonasthmatic eosinophilic bronchitis.
      ,
      • Lai K.
      • Luo W.
      • Zeng G.
      • Zhong N.
      Diagnosis and treatment of chronic cough in China: an insight into the status quo.
      • Dagouassat M.
      • Gagliolo J.M.
      • Chrusciel S.
      • et al.
      The cyclooxygenase-2-prostaglandin e2 pathway maintains senescence of chronic obstructive pulmonary disease fibroblasts.
      • Zaslona Z.
      • Peters-Golden M.
      Prostanoids in asthma and COPD actions, dysregulation, and th erapeutic opportunities.
      Bronchial hyperresponsiveness (methacholine)
      • Lougheed M.D.
      • Turcotte S.E.
      • Fisher T.
      Cough variant asthma: lessons learned from deep inspirations.
      ,
      • Wasilewski N.V.
      • Fisher T.
      • Turcotte S.E.
      • Fisher J.T.
      • Lougheed M.D.
      Bronchoprotective effect of deep inspirations in cough variant asthma: a distinguishing feature in the spectrum of airway disease?.
      ,
      • Hantera M.
      • Abdel-Hafiz H.
      Methacholine challenge test as indicator for add on inhaled corticosteroids in COPD patients.
      HCR mechanism in CC/tussigen challenge studies
      In comparison with healthy individuals
      ,
      • Satia I.
      • Tsamandouras N.
      • Holt K.
      • et al.
      Capsaicin-evoked cough responses in asthmatic patients: evidence for airway neuronal dysfunction.
      ,
      • Kanemitsu Y.
      • Fukumitsu K.
      • Kurokawa R.
      • et al.
      Increased capsaicin sensitivity in patients with severe asthma is associated with worse clinical outcome.
      ,
      • Brightling C.E.
      Chronic cough due to nonasthmatic eosinophilic bronchitis ACCP evidence-based clinical practice guidelines.
      ,
      • Nakajima T.
      • Nishimura Y.
      • Nishiuma T.
      • Kotani Y.
      • Nakata H.
      • Yokoyama M.
      Cough sensitivity in pure cough variant asthma elicited using continuous capsaicin inhalation.
      ,
      • Cho P.S.P.
      • Fletcher H.V.
      • Turner R.D.
      • Patel I.S.
      • Jolley C.J.
      • Birring S.S.
      The relationship between cough reflex sensitivity and exacerbation frequency in chronic obstructive pulmonary disease.
      ,
      • Cho P.S.P.
      • Fletcher H.V.
      • Patel I.S.
      • Turner R.D.
      • Jolley C.J.
      • Birring S.S.
      Cough hypersensitivity and suppression in COPD.
      Innate/adaptive immune system
      • Sadeghi M.H.
      • Morice A.H.
      The emerging role of the eosinophil and its measurement in.
      ,
      • Schleimer R.P.
      Innate immune responses and chronic obstructive pulmonary disease: “Terminator” or “terminator 2”.
      CANormal or increasedAbsent or impairedDecreased (Vs NAEB)PresentConfirmed/conclusive dataInnate (ILC₂) & adaptive (Th₂) response
      NAEBIncreasedLikely preservedIncreased (Vs CA)AbsentUnconfirmed/Insufficient dataInnate (ILC₂) response
      CVANormal or increasedPreserved or impairedIncreased (Vs CA)Present or BorderlineConfirmed/Preliminary dataInnate (ILC₂) response
      COPDNormal or increasedAttenuatedIncreased (Vs CA)PresentConfirmed/Preliminary dataInnate (ILC1/ILC₂) & adaptive (Th₁) response
      Abbreviations: CA (classic asthma), CC (Chronic cough), COPD (chronic obstructive pulmonary disease), CVA (cough variant asthma), HCR (hypersensitive cough reflex), ILC (innate lymphoid cell), NAEB (non-asthmatic eosinophilic bronchitis), PGE2 (prostaglandin E2), Th2 (T helper 2).
      a In comparison with healthy individuals

       Pathogenesis

      As stated earlier, HCR involves neurogenic and inflammatory dysfunction of vagus nerve cough neuronal pathways. Neurogenic dysfunction involves neuromediators, such as neurokinins (bradykinins) and neuropeptides (substance P), leukotrienes and prostaglandins (PGs) (E2 and D2), nerve growth factor (NGF), and CGRP, among others.
      • Turcotte S.E.
      • Lougheed M.D.
      Cough in asthma.
      ,
      • Niimi A.
      • Fukumitsu K.
      • Takeda N.
      • Kanemitsu Y.
      Interfering with airway nerves in cough associated with asthma.
      These powerful tussigens are associated with TRP channels and can increase cough sensitivity to bronchoconstrictor agents used in human and animal cough models, such as capsaicin, citric acid, and histamine. The inflammatory component of HCR in lower airways is characterized mainly by type 2 inflammation and airway eosinophilia reportedly noted in 50–60% of asthmatics.
      • Niimi A.
      • Fukumitsu K.
      • Takeda N.
      • Kanemitsu Y.
      Interfering with airway nerves in cough associated with asthma.
      ,
      • Drake M.G.
      • Scott G.D.
      • Blum E.D.
      • et al.
      Eosinophils increase airway sensory nerve density in mice and in human asthma.
      Type 2 cytokines such as IL-4, IL-5, and IL-13 may be expressed following stimulation of the innate immune response orchestrated by mast cells and innate lymphoid cells type 2, among others.
      • Sastre B.
      • Fernández-Nieto M.
      • Mollá R.
      • et al.
      Increased prostaglandin E2 levels in the airway of patients with eosinophilic bronchitis.
      ,
      • Wang J.L.
      • Ren Z.Y.
      • Xia J.B.
      • et al.
      The mechanism of airway inflammation in eosinophilic bronchitis and cough variant asthma.
      The resultant signal cascade can give rise to cough phenotypes such as cough variant asthma (CVA), non-asthmatic eosinophilic bronchitis (NAEB), and nonatopic asthma.
      • Brightling C.E.
      • Ward R.
      • Goh K.L.
      • Wardlaw A.J.
      • Pavord I.D.
      Eosinophilic bronchitis is an important cause of cough.
      ,
      • Lund S.
      • Walford H.
      • Doherty T.
      Type 2 innate lymphoid cells in allergic disease.
      Atopic asthma displays activation of innate and adaptive immunity where inflammatory mediators such as histamine, prostaglandins, leukotrienes and platelet activation factor can cause bronchoconstriction and cough secondary to allergen exposure.
      • Niimi A.
      • Fukumitsu K.
      • Takeda N.
      • Kanemitsu Y.
      Interfering with airway nerves in cough associated with asthma.
      Recent evidence supports that neuromechanical properties of the lungs, which are related to a change in airway caliber as occurs during bronchoconstriction, can also contribute to chronic cough in asthmatics
      • Satia I.
      • Watson R.
      • Scime T.
      • et al.
      Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma.
      (see below). However, the relationship between neurogenic and inflammatory components of cough hypersensitive reflex and their impact on inherent mechanical properties of lower airways through bronchoconstriction is still unclear. Components of neurogenic inflammation are discussed in different cough phenotypic traits of the lower airways highlighting important clinical symptomatology, tussive challenge testing, and response to medical therapy.

       Classic asthma

      Asthma is a clinical diagnosis marked by cough, variable airflow obstruction, and airway remodeling. It is one of the most common etiologies of chronic cough and accounts for up to 29% of cases.
      • Ribeiro M.
      • De Castro Pereira C.A.
      • Nery L.E.
      • Beppu O.S.
      • Silva C.O.S.
      A prospective longitudinal study of clinical characteristics, laboratory findings, diagnostic spectrum and outcomes of specific therapy in adult patients with chronic cough in a general respiratory clinic.
      Cough is a decisive symptom of asthma. Chronic cough is associated with poor asthma control;
      • Çolak Y.
      • Afzal S.
      • Lange P.
      • Laursen L.C.
      • Nordestgaard B.G.
      • Dahl M.
      Role and impact of chronic cough in individuals with asthma from the general population.
      ,
      • De Marco R.
      • Marcon A.
      • Jarvis D.
      • et al.
      Prognostic factors of asthma severity: a 9-year international prospective cohort study.
      conversely, cough control predicts prognosis of asthma.
      • Çolak Y.
      • Afzal S.
      • Lange P.
      • Laursen L.C.
      • Nordestgaard B.G.
      • Dahl M.
      Role and impact of chronic cough in individuals with asthma from the general population.
      Other factors associated with more severe disease phenotype include objective increase in cough frequency
      • Marsden P.A.
      • Satia I.
      • Ibrahim B.
      • et al.
      Objective cough frequency, airway inflammation, and disease control in asthma.
      and heightened cough response to tussigen challenges.
      • Satia I.
      • Tsamandouras N.
      • Holt K.
      • et al.
      Capsaicin-evoked cough responses in asthmatic patients: evidence for airway neuronal dysfunction.
      ,
      • Kanemitsu Y.
      • Fukumitsu K.
      • Kurokawa R.
      • et al.
      Increased capsaicin sensitivity in patients with severe asthma is associated with worse clinical outcome.
      Cough in asthma is typically dry or minimally productive. Mucus-secreting cough may be potentially associated with steeper decline of pulmonary functions
      • Ulrik C.S.
      Outcome of asthma: longitudinal changes in lung function.
      and severe asthma, bronchiectasis, or chronic bronchitis.
      • Martin M.J.
      • Harrison T.W.
      Causes of chronic productive cough: an approach to management.
      The mechanism of chronic cough in asthma is complex and features intertwined components of a hypersensitive cough reflex, IgE or non-IgE mediated eosinophilic airway inflammation, abnormal neuromechanical properties of the lungs, and presence or absence of deep inspiration reflex (Fig. 2). In healthy individuals deep-inspiration causes bronchodilation.
      • Crimi E.
      • Saporiti R.
      • Bartolini S.
      • Baroffio M.
      • Pellegrino R.
      • Brusasco V.
      Airway responsiveness to methacholine and deep inhalations in subjects with rhinitis without asthma.
      During methacholine challenge studies, deep inspiration can also protect against induced bronchoconstriction.
      • Scichilone N.
      • Kapsali T.
      • Permutt S.
      • Togias A.
      Deep inspiration-induced bronchoprotection is stronger than bronchodilation.
      It is generally agreed that the deep inspiration bronchoprotective reflex is absent or impaired in asthma.
      • Lougheed M.D.
      • Turcotte S.E.
      • Fisher T.
      Cough variant asthma: lessons learned from deep inspirations.
      Hence, testing airway hyperresponsiveness can assist in the differential diagnosis of asthma (Table 1). Evidence for neuroinflammation of cough-sensitive neurons in asthma is not fully established but supported in several reports. An increased expression of bradykinin and its effector molecules prostaglandin-E2 and leukotrienes can trigger cough in the asthmatic airways
      • Choudry N.B.
      • Fuller R.W.
      • Pride N.B.
      Effect of inflammatory mediators prostaglandin E2 , bradykinin, and histamine.
      • Maher S.A.
      • Birrell M.A.
      • Adcock J.J.
      • et al.
      Prostaglandin D2 and the role of the DP1, DP2 and TP receptors in the control of airway reflex events.
      • Grace M.S.
      • Baxter M.
      • Dubuis E.
      • Birrell M.A.
      • Belvisi M.G.
      Transient receptor potential (TRP) channels in the airway: role in airway disease.
      by activation of TRP channels (A1 and V1).
      • Turcotte S.E.
      • Lougheed M.D.
      Cough in asthma.
      Also, compared to healthy subjects or patients with mild intermittent asthma, moderate asthma was associated with increased airway innervation, substance P expression, in addition to airway and serum eosinophilia.
      • Drake M.G.
      • Scott G.D.
      • Blum E.D.
      • et al.
      Eosinophils increase airway sensory nerve density in mice and in human asthma.
      Along the same line, other data suggest asthmatics, compared to healthy subjects, have heightened cough response to capsaicin challenge, independent of inhaled corticosteroids (ICS) dose,
      • Fujimura M.
      • Sakamoto S.
      • Kamio T.
      • Bando T.
      • Kurashima K.
      • Matsuda T.
      Effect of inhaled procaterol on cough receptor sensitivity to capsaicin in patients with asthma or chronic bronchitis and in normal subjects.
      airway inflammation,
      • Satia I.
      • Tsamandouras N.
      • Holt K.
      • et al.
      Capsaicin-evoked cough responses in asthmatic patients: evidence for airway neuronal dysfunction.
      FEV1 and airway hyperresponsiveness. Similarly, the observation of a heightened capsaicin-evoked cough response in asthmatics with mild airflow obstruction was independent of fractional exhaled nitric oxide (FeNO), lung function testing or airway hyperresponsiveness.
      • Satia I.
      • Tsamandouras N.
      • Holt K.
      • et al.
      Capsaicin-evoked cough responses in asthmatic patients: evidence for airway neuronal dysfunction.
      These data suggest presence of a hypersensitive cough reflex in asthmatics independently of airway inflammation or reduction of airway caliber through induced bronchoconstriction. Furthermore, the role of atopy in the etiology of chronic cough in asthma is also revealed from capsaicin challenge models. Patients with mild to moderate stable atopic asthma have unexpectedly lower cough response to capsaicin challenge when compared to nonatopic asthmatics; although both asthmatic groups, in single or combination, had worse cough scores when compared to healthy controls.
      • Satia I.
      • Tsamandouras N.
      • Holt K.
      • et al.
      Capsaicin-evoked cough responses in asthmatic patients: evidence for airway neuronal dysfunction.
      To note, these observations ensued using a capsaicin challenge which consisted of monitoring maximal cough response following any capsaicin challenge concentration (Emax)
      • Hilton E.C.Y.
      • Baverel P.G.
      • Woodcock A.
      • Van Der Graaf P.H.
      • Smith J.A.
      Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point.
      as opposed to a model which determines the lowest capsaicin concentration triggering 2 or 5 coughs (C2, C5).
      • Dicpinigaitis P.V.
      Short- and long-term reproducibility of capsaicin cough challenge testing.
      Reportedly, the former model (Emax) can discriminate better chronic cough patients from healthy controls compared to the conventional model (C2,C5).
      • Hilton E.C.Y.
      • Baverel P.G.
      • Woodcock A.
      • Van Der Graaf P.H.
      • Smith J.A.
      Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point.
      In addition, the role of airway neuromechanical properties or change in airway caliber, length, and pressure in inducing cough through capsaicin-sensitive nerves is highlighted in both atopic and non-atopic asthmatics. In one report, asthmatics had higher cough response to capsaicin-induced cough (Emax) independently of markers of eosinophilic airway inflammation. More importantly, a decrease in FEV1 resulted in doubling of cough responses in these asthmatics.
      • Satia I.
      • Badri H.
      • Woodhead M.
      • O'Byrne P.M.
      • Fowler S.J.
      • Smith J.A.
      The interaction between bronchoconstriction and cough in asthma.
      This was also confirmed by a recent study involving combined allergen, capsaicin, and methacholine challenges in steroid-naïve stable and atopic asthmatics. These challenges also suggested cough reflex sensitivity is linked to bronchoconstriction and mechanical decrease in airway caliber in addition to type 2 inflammation.
      • Satia I.
      • Watson R.
      • Scime T.
      • et al.
      Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma.
      In summary, these data highlight the role of altered neurobiology of the afferent cough reflex in addition to atopic or nonatopic inflammatory status as modulators of cough mechanism in asthmatics. Presence of a hypersensitive cough reflex seems independent of airway eosinophilia or hyperresponsiveness. Also, both methacholine and allergen-induced bronchoconstriction or reduction in airway caliber correlates well with capsaicin-provoked cough sensitivity in asthmatics.
      Fig. 2
      Fig. 2Classic asthma: suggested mechanisms in pathogenesis of chronic cough, Abbreviations: ILC2 (group 2 innate lymphoid cells), RAR (Rapidly adapting receptors), Th2 (T helper cell type 2), TRPA1 (transient receptor potential ankyrin 1), TRPV1 (transient receptor potential cation channel subfamily V member 1).

       Non-asthmatic eosinophilic bronchitis

      Epidemiological data suggest that non-asthmatic eosinophilic bronchitis (NAEB) represents up to 35% of chronic cough patients in Asia
      • Lai K.
      • Chen R.
      • Lin J.
      • et al.
      A prospective, multicenter survey on causes of chronic cough in China.
      ,
      • Lai K.
      • Pan J.
      • Chen R.
      • Liu B.
      • Luo W.
      • Zhong N.
      Epidemiology of cough in relation to China.
      and can involve children according to a large series.
      • Kim Y.H.
      • Kim K.W.
      • Baek J.
      • et al.
      Usefulness of impulse oscillometry and fractional exhaled nitric oxide in children with Eosinophilic bronchitis.
      Clinically, NAEB is a cough phenotype which lacks bronchoconstriction and bronchial hyperresponsiveness
      • Brightling C.E.
      Chronic cough due to nonasthmatic eosinophilic bronchitis ACCP evidence-based clinical practice guidelines.
      ,
      • Yıldız T.
      • Dülger S.
      Non-astmatic eosinophilic bronchitis.
      (Table 1). Similar to asthma, it is characterized by airway eosinophilia in induced sputum and responds well to anti-inflammatory therapy.
      • Chen L.
      • Lai K.
      • Xie J.
      Establishment of airway eosinophilic bronchitis mouse model without hyperresponsiveness by ovalbumin.
      ,
      • Niimi A.
      • Matsumoto H.
      • Mishima M.
      Eosinophilic airway disorders associated with chronic cough.
      NAEB can include patients with or without atopy. In Japan, atopic patients with a dry cough who lack airway hyperresponsiveness and are resistant to bronchodilator therapy, have been designated to have an atopic cough or eosinophilic tracheobronchitis.
      • Fujimura M.
      • Ogawa H.
      • Yasui M.
      • Matsuda T.
      Eosinophilic tracheobronchitis and airway cough hypersensitivity in chronic non-productive cough.
      • Fujimura M.
      • Ogawa H.
      • Nishizawa Y.
      • Nishi K.
      Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?.
      • Fujimura M.
      • Sakamoto S.
      • Matsuda T.
      • Fujimura M.
      Bronchodilator-resistive cough in atopic patients: bronchial reversibility and hyperresponsiveness.
      In patients with NAEB, presence of a heightened cough response is studied in relation to anti-asthma medications using capsaicin challenge models. In one report evaluating the cough response in NAEB patients following anti-asthma therapy,
      • Brightling C.E.
      • Ward R.
      • Wardlaw A.J.
      • Pavord I.D.
      Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis.
      an initial increase in HCR at baseline was improved to near normal levels following inhaled corticosteroid therapy. Changes in sputum eosinophil count also correlated with improvement in cough sensitivity following therapy. In NAEB, the role of IL-17A, a Th17-pathway cytokine involved in asthma development, remains obscure.
      • Zhan C.
      • Xu R.
      • Liu J.
      • et al.
      Increased sputum IL-17a level in non-asthmatic eosinophilic bronchitis.
      Comparative analysis of immunopathological profiles of NAEB and asthma has been reviewed elsewhere and highlights mechanisms underlying the absence of airway hyperresponsiveness in NAEB.
      • Diver S.
      • Russell R.J.
      • Brightling C.E.
      Cough and eosinophilia.
      Patients with NAEB have increased mast cells in bronchial brushings, whereas asthmatics have increased mast cells in airway smooth muscle cells, a finding reported to be inversely related to airway hyperresponsiveness in asthma.
      • Gibson P.G.
      • Simpson J.L.
      • Ryan N.M.
      • Vertigan A.E.
      Mechanisms of cough.
      ,
      • Sastre B.
      • Del Pozo V.
      Role of PGE 2 in asthma and nonasthmatic eosinophilic bronchitis.
      In addition, patients with NAEB have decreased IL-13 in bronchial submucosa and sputum
      • Berry M.A.
      • Parker D.
      • Neale N.
      • et al.
      Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis.
      and less narrowing of the airway lumen compared to asthma, although both asthma and NAEB express airway remodeling.
      • Siddiqui S.
      • Gupta S.
      • Cruse G.
      • et al.
      Airway wall geometry in asthma and nonasthmatic eosinophilic bronchitis.
      Unlike asthma, there is marked expression of the endogenous bronchodilator PGE-2
      • Sastre B.
      • Del Pozo V.
      Role of PGE 2 in asthma and nonasthmatic eosinophilic bronchitis.
      ,
      • Sastre B.
      • Fernández-Nieto M.
      • López E.
      • et al.
      PGE2 decreases muscle cell proliferation in patients with non-asthmatic eosinophilic bronchitis.
      in NAEB, which may account for preservation of deep inspiration-induced bronchoprotective effect from cough,
      • Lougheed M.D.
      • Turcotte S.E.
      • Fisher T.
      Cough variant asthma: lessons learned from deep inspirations.
      ,
      • Sastre B.
      • Del Pozo V.
      Role of PGE 2 in asthma and nonasthmatic eosinophilic bronchitis.
      and an antiproliferative effect of bronchial smooth muscle.
      • Gibson P.G.
      • Simpson J.L.
      • Ryan N.M.
      • Vertigan A.E.
      Mechanisms of cough.
      In conclusion, NAEB represents a cough trait with distinct immunopathological profile in LACS. Yet, scarcity of tussigen challenge data makes it difficult to ascertain a clear role of HCR as a mechanistic trigger for cough in NAEB.

       Cough variant asthma

      Cough variant asthma (CVA) is a cough phenotypic trait which lacks wheezing or dyspnea and is associated with airway hyperresponsiveness (Table 1) and a favorable response to anti-asthma medications.
      • Vujnović S.D.
      • Domuz A.
      • Petrović S.
      Cough variant asthma as a phenotype of classic asthma.
      Patients with CVA can account for around 30% of chronic cough referrals
      • Pavord I.D.
      Cough and asthma.
      and can present solely or predominantly with cough
      • Fujimura M.
      • Ogawa H.
      • Nishizawa Y.
      • Nishi K.
      Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?.
      ,
      • Magni C.
      • Chellini E.
      • Zanasi A.
      Cough variant asthma and atopic cough.
      in response to innocuous triggers such as talking and laughing, allergens and cold air.
      • Gao J.
      • Wu F.
      • Wu S.
      • Yang X.
      Inflammatory subtypes in classic asthma and cough variant asthma.
      ,
      • Kanemitsu Y.
      • Matsumoto H.
      • Osman N.
      • et al.
      “Cold air” and/or “talking” as cough triggers, a sign for the diagnosis of cough variant asthma.
      Currently there is insufficient data to speculate if CVA is a precursor of classic asthma or a separate cough phenotype.
      • Fujimura M.
      • Ogawa H.
      • Nishizawa Y.
      • Nishi K.
      Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?.
      The discrepancy lies partly in the presence or absence of airway hyperresponsiveness which, as stated earlier, has been linked to the deep inspiration cough bronchoprotective effect.
      • Lougheed M.D.
      • Turcotte S.E.
      • Fisher T.
      Cough variant asthma: lessons learned from deep inspirations.
      ,
      • Wasilewski N.V.
      • Fisher T.
      • Turcotte S.E.
      • Fisher J.T.
      • Lougheed M.D.
      Bronchoprotective effect of deep inspirations in cough variant asthma: a distinguishing feature in the spectrum of airway disease?.
      Data suggest the absence of airway hyperresponsiveness in a subset of patients with CVA is due to preservation of cough bronchoprotective reflex.
      • Wasilewski N.V.
      • Fisher T.
      • Turcotte S.E.
      • Fisher J.T.
      • Lougheed M.D.
      Bronchoprotective effect of deep inspirations in cough variant asthma: a distinguishing feature in the spectrum of airway disease?.
      Conversely methacholine challenge data demonstrated presence of “borderline” airway hyperresponsiveness in patients with CVA compared to moderate-severe airway hyperresponsiveness in asthmatics.
      • Lougheed M.D.
      • Turcotte S.E.
      • Fisher T.
      Cough variant asthma: lessons learned from deep inspirations.
      This suggests that patients with CVA can manifest mild airway hyperresponsiveness on methacholine challenge with preservation of deep inspiration bronchoprotective reflex.
      • Wasilewski N.V.
      • Fisher T.
      • Turcotte S.E.
      • Fisher J.T.
      • Lougheed M.D.
      Bronchoprotective effect of deep inspirations in cough variant asthma: a distinguishing feature in the spectrum of airway disease?.
      In support, prospective epidemiological studies demonstrated up to one third of CVA patients can eventually develop wheezing.
      • Fujimura M.
      • Ogawa H.
      • Nishizawa Y.
      • Nishi K.
      Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?.
      Suggested mechanisms of airway hyperresponsiveness in CVA can relate to hypersensitivity of vagal neuronal pathway,
      • Wasilewski N.V.
      • Fisher T.
      • Turcotte S.E.
      • Fisher J.T.
      • Lougheed M.D.
      Bronchoprotective effect of deep inspirations in cough variant asthma: a distinguishing feature in the spectrum of airway disease?.
      although understanding the nature of the involved mediators requires further evaluation.
      • Satia I.
      • Badri H.
      • Woodhead M.
      • O'Byrne P.M.
      • Fowler S.J.
      • Smith J.A.
      The interaction between bronchoconstriction and cough in asthma.
      Other possible mechanisms to explain CVA airway hyperresponsiveness include variable cough
      • Koh Y.Y.
      • Jeong J.H.
      • Park Y.
      • Kim C.K.
      Development of wheezing in patients with cough variant asthma during an increase in airway responsiveness.
      ,
      • Nakajima T.
      • Nishimura Y.
      • Nishiuma T.
      • Kotani Y.
      • Nakata H.
      • Yokoyama M.
      Cough sensitivity in pure cough variant asthma elicited using continuous capsaicin inhalation.
      thresholds, or structural changes in respiratory smooth muscle cells secondary to small airway remodeling.
      • Lougheed M.D.
      • Turcotte S.E.
      • Fisher T.
      Cough variant asthma: lessons learned from deep inspirations.
      ,
      • Wasilewski N.V.
      • Fisher T.
      • Turcotte S.E.
      • Fisher J.T.
      • Lougheed M.D.
      Bronchoprotective effect of deep inspirations in cough variant asthma: a distinguishing feature in the spectrum of airway disease?.
      The latter has been suggested as a positive feedback mechanism for cough persistence in animal studies.
      • Nakaji H.
      • Niimi A.
      • Matsuoka H.
      • et al.
      Airway remodeling associated with cough hypersensitivity as a consequence of persistent cough: an experimental study.
      CVA patients can feature an eosinophilic airway inflammation as reflected by increased eosinophil count in induced sputum, biopsied bronchial mucosa, and bronchoalveolar lavage fluid.
      • Fujimura M.
      Pathophysiology, diagnosis and treatment of cough variant asthma.
      Eosinophilia in CVA patients has been linked to more severe disease, yet when comparing eosinophilic to non-eosinophilic patients with CVA, no significant difference in spirometry findings was noted and the bronchial hyperresponsiveness (BHR) difference was not dramatic.
      • Gao J.
      • Wu F.
      • Wu S.
      • Yang X.
      Inflammatory subtypes in classic asthma and cough variant asthma.
      Reportedly, patients with CVA express increased cough sensitivity when compared to healthy controls, but not asthmatics. To note, these observations ensued using a continuous sequential dilutions of capsaicin challenge for 1 min and determining the concentration at which the total number of coughs per minute was 10 or more (C10min).
      • Nakajima T.
      • Nishimura Y.
      • Nishiuma T.
      • Kotani Y.
      • Nakata H.
      • Yokoyama M.
      Cough sensitivity in pure cough variant asthma elicited using continuous capsaicin inhalation.
      One explanation for presence of comparable HCR among patients with CVA and asthma can be an insufficient observation period (1 year) of CVA patients prior to their enrollment in the study in order to exclude patients who transited to bronchial asthma. In patients with CVA, HCR is also studied in relation to anti-asthma medications using capsaicin challenge models.
      • Niimi A.
      • Fukumitsu K.
      • Takeda N.
      • Kanemitsu Y.
      Interfering with airway nerves in cough associated with asthma.
      Data indicate cough reflex sensitivity measured in terms of the lowest capsaicin concentration triggering 2 or 5 coughs (C2 or C5) responds well to leukotriene receptor antagonists (LTRAs) with variable effects on airway hyperresponsiveness.
      • Dicpinigaitis P.V.
      • Dobkin J.B.
      • Reichel J.
      Antitussive effect of the leukotriene receptor antagonist zafirlukast in subjects with cough-variant asthma.
      ,
      • Takemura M.
      • Niimi A.
      • Matsumoto H.
      • et al.
      Clinical, physiological and anti-inflammatory effect of montelukast in patients with cough variant asthma.
      This effect is likely attributed to the anti-inflammatory properties rather than the bronchodilator effects of LTRAs. Conversely, in CVA, bronchodilators or ICS have demonstrated insignificant improvement in capsaicin-induced cough thresholds and variable improvement in airway hyperresponsiveness.
      • Fujimura M.
      • Hara J.
      • Myou S.
      Change in bronchial responsiveness and cough reflex sensitivity in patients with cough variant asthma: effect of inhaled corticosteroids.
      Taken together, these data suggest CVA can be a precursor of asthma, and both cough phenotypes can manifest overlapping clinical symptomatology, airway inflammation and hyperresponsiveness. This may act as confounding variable in research studies comparing HCR among both cough phenotypes, despite presence of increased cough sensitivity in both CVA and classic asthma (CA) patients when compared to healthy individuals.

       Chronic obstructive pulmonary disease

      Chronic obstructive pulmonary disease (COPD) manifests predominantly as productive cough associated with airflow limitation
      • Gold
      Pocket guide to copd diagnosis, management, and prevention.
      and occasionally bronchial hyperreactivity.
      • Hantera M.
      • Abdel-Hafiz H.
      Methacholine challenge test as indicator for add on inhaled corticosteroids in COPD patients.
      Several COPD phenotypes exist, including frequent and non-frequent exacerbators, in addition to the asthma COPD overlap (ACO). The frequent exacerbator phenotype is characterized by airway (and serum) eosinophilia. The ACO phenotype represents asthmatics who later on develop COPD secondary to smoking.
      • Gold
      Pocket guide to copd diagnosis, management, and prevention.
      According to a large Korean survey, COPD constitutes 26.4% of patients with chronic cough.
      • Koo H.K.
      • Jeong I.
      • Lee S.W.
      • et al.
      Prevalence of chronic cough and possible causes in the general population based on the Korean National Health and Nutrition Examination Survey.
      Severity of airflow restriction is linked to increased epithelial Th2 signature gene expression
      • Christenson S.A.
      • Steiling K.
      • Van Den Berge M.
      • et al.
      Asthma-COPD overlap: clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease.
      in addition to blood and sputum
      • Hastie A.T.
      • Martinez F.J.
      • Curtis J.L.
      • et al.
      Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort.
      eosinophilia; the latter being also a biomarker for frequency of exacerbations
      • Hastie A.T.
      • Martinez F.J.
      • Curtis J.L.
      • et al.
      Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort.
      and corticosteroid responsiveness.
      • Brightling C.E.
      • Monteiro W.
      • Ward R.
      • et al.
      Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.
      ,
      • Bafadhel M.
      • McKenna S.
      • Terry S.
      • et al.
      Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial.
      In COPD patients, the presence of chronic cough is associated with lower FEV1,
      • Koo H.K.
      • Park S.W.
      • Park J.W.
      • et al.
      Chronic cough as a novel phenotype of chronic obstructive pulmonary disease.
      more severe dyspnea, and worse QoL compared to COPD patients without chronic cough. Chronic cough is also associated with more severe airflow limitation and higher levels of inflammatory biomarkers in blood. These include high-sensitivity C-reactive protein, fibrinogen, leukocytes, neutrophils, and eosinophils.
      • Landt E.
      • Çolak Y.
      • Lange P.
      • Laursen L.C.
      • Nordestgaard B.G.
      • Dahl M.
      Chronic cough in individuals with COPD: a population-based cohort study.
      Data also suggest chronic cough is an independent risk factor for acute exacerbation of COPD.
      • Koo H.K.
      • Park S.W.
      • Park J.W.
      • et al.
      Chronic cough as a novel phenotype of chronic obstructive pulmonary disease.
      It is speculated that this property is linked to activation of TRPV1 by oxidative stress, inflammation, hypoxia, and mechanical stress.
      • Abbott-Banner K.
      • Poll C.
      • Verkuyl J.M.
      Targeting TRP channels in airway disorders.
      In fact, TRPV4 may be implicated in the pathogenesis of COPD as revealed by data on genetic polymorphism in TRPV4-encoding genes.
      • Zhu G.
      • Gulsvik A.
      • Bakke P.
      • et al.
      Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease.
      Capsaicin challenge data in COPD patients reveal HCR improves in the recovery period (6 weeks) following an acute exacerbation of COPD. This correlated with cough frequency, severity (VAS), but not cough-related QoL questionnaire. Furthermore, improvement of HCR in the recovery period was inversely correlated with frequency of future acute exacerbations monitored over 1 year.
      • Cho P.S.P.
      • Fletcher H.V.
      • Turner R.D.
      • Patel I.S.
      • Jolley C.J.
      • Birring S.S.
      The relationship between cough reflex sensitivity and exacerbation frequency in chronic obstructive pulmonary disease.
      Despite the small size of the studied patient population, this suggests HCR is heightened in acute exacerbation of COPD and can potentially predict future ones. In another report, chronic cough, or its suppression, was studied in COPD patients and compared to patients with chronic refractory cough (CRC), or to healthy subjects.
      • Cho P.S.P.
      • Fletcher H.V.
      • Patel I.S.
      • Turner R.D.
      • Jolley C.J.
      • Birring S.S.
      Cough hypersensitivity and suppression in COPD.
      All subjects with chronic cough, being COPD or CRC patients, had increased HCR when compared to subjects without chronic cough, being COPD patients or healthy individuals. Also, non-coughing COPD patients had comparable cough reflex sensitivity to healthy subjects. This suggests HCR has an important role in COPD patients with cough but is not a general feature of COPD per se. In addition, the ability of all COPD participants, but not those with CRC, to suppress cough suggests different cough mechanisms in both diseases. In conclusion, chronic cough in COPD patients is associated with worse clinical outcomes and manifests as a heightened HCR on tussigen challenge. Yet, underlying cough mechanisms need further elucidation.

      Reflux-related cough syndrome

       Epidemiology

      In GERD, gastric regurgitation results in troublesome esophageal and extra-esophageal symptoms, including cough.
      • Vakil N.
      • Van Zanten S.V.
      • Kahrilas P.
      • Dent J.
      • Jones R.
      Global Consensus group
      The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.
      Extraesophageal symptoms can manifest in the mouth, lungs, and upper airways, and can lead to asthma (9.3–14%), laryngitis (7–14%), chronic cough (13%), dental erosions, and non-cardiac chest pain (23.1%).
      • Durazzo M.
      • Lupi G.
      • Cicerchia F.
      • et al.
      Extra-esophageal presentation of gastroesophageal reflux disease: 2020 update.
      Epidemiological data suggest GERD-related cough comprises 7%–85% of chronic cough cases with higher prevalence in western compared to Asian countries.
      • 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.
      ,
      • Lai K.
      • Pan J.
      • Chen R.
      • Liu B.
      • Luo W.
      • Zhong N.
      Epidemiology of cough in relation to China.
      ,
      • Irwin R.S.
      • Mark Madison J.
      Diagnosis and treatment of chronic cough due to gastro-esophageal reflux disease and postnasal drip syndrome.
      • Jaspersen D.
      • Kulig M.
      • Labenz J.
      • et al.
      Prevalence of extra-oesophageal manifestations in gastro-oesophageal reflux disease: an analysis based on the ProGERD Study.
      • 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 high variability in reported prevalence data may be related to different geographical population studies, lack of uniform criteria for diagnosis of chronic cough, and type of patient referral, among other factors.

       Pathogenesis

      Gastric or esophageal refluxate can be acidic or non-acidic, liquid or gaseous, and proximal or distal in location. Gastric refluxate can trigger cough or be induced by the act of coughing. Cough-induced reflux can be detected by the temporal association of a coughing episode followed by a reflux event on impedance/pH monitoring,
      • Herregods T.V.K.
      • Pauwels A.
      • Tack J.
      • Smout A.J.P.M.
      • Bredenoord A.J.
      Reflux-cough syndrome: assessment of temporal association between reflux episodes and cough bursts.
      ,
      • Sifrim D.
      • Dupont L.
      • Blondeau K.
      • Zhang X.
      • Tack J.
      • Janssens J.
      Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring.
      which is subsequently computed as a symptom association probability (SAP).
      • Weusten B.L.A.M.
      • Roelofs J.M.M.
      • Akkermans L.M.A.
      • Van Berge-Henegouwen G.P.
      • Smout A.J.P.M.
      The symptom-association probability: an improved method for symptom analysis of 24-hour esophageal pH data.
      The degree and duration of acid or non-acid exposure in esophageal and extraesophageal sites can determine the extent of mucosal injury and the presence or absence of heartburn, ie, silent reflux.
      • De Giorgi F.
      • Palmiero M.
      • Esposito I.
      • Mosca F.
      • Cuomo R.
      Pathophysiology of gastro-oesophageal reflux disease.
      Reflux events can induce coughing despite natural esophageal and laryngeal mucosal protective structures and mechanisms, such as upper/lower esophageal sphincters and esophago-glottic reflex, respectively.
      • Ates F.
      • Vaezi M.F.
      Approach to the patient with presumed extraoesophageal GERD.
      Patients with gastroesophageal and laryngopharyngeal reflux have invariably non-acid and gas reflux which is more likely located in the proximal esophagus as compared to the distal part. This suggests an overlap between laryngopharyngeal and gastroesophageal reflux-related cough.
      • Yu Y.
      • Wen S.
      • Wang S.
      • et al.
      Reflux characteristics in patients with gastroesophageal reflux-related chronic cough complicated by laryngopharyngeal reflux.
      One mechanism of GERD-related cough speculates a central crosstalk between airway and esophageal afferents (esophageal-bronchial reflex) at their site of convergence in the brainstem, the so-called “reflex theory”.
      • Smith J.A.
      • Houghton L.A.
      The oesophagus and cough: laryngo-pharyngeal reflux, microaspiration and vagal reflexes.
      Another mechanism of GERD-related cough suggests direct triggering of the chemo/stretch receptors located on the afferent limb of the laryngopharyngeal reflex by refluxate in the upper esophagus, and/or micro-aspiration into the lungs, the so-called “reflux theory”.
      • Smith J.A.
      • Houghton L.A.
      The oesophagus and cough: laryngo-pharyngeal reflux, microaspiration and vagal reflexes.
      Several reports investigated the role of HCR and neurogenic inflammation in GERD-related cough.
      • Patterson R.N.
      • Johnston B.T.
      • Ardill J.E.S.
      • Heaney L.G.
      • McGarvey L.P.A.
      Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux.
      ,
      • Chang A.B.
      • Gibson P.G.
      • Ardill J.
      • McGarvey L.P.A.
      Calcitonin gene-related peptide relates to cough sensitivity in children with chronic cough.
      Compared to healthy subjects or patients with GERD but no cough, chronic cough patients with acid or non-acid reflux had lower cough threshold and higher levels of substance P and mast cell tryptase in induced sputum. However, the latter tested parameters were comparable among chronic cough patients with acid and non-acid reflux.
      • Qiu Z.
      • Yu L.
      • Xu S.
      • et al.
      Cough reflex sensitivity and airway inflammation in patients with chronic cough due to non-acid gastro-oesophageal reflux.
      This underlines an important role of HCR in coughing patients with GERD but also suggests the acidity of the refluxate may not be of major importance in the mechanistic pathways linking reflux and cough. Discordant data on mechanisms involved in GERD-related cough also exist. Compared to healthy subjects, unselected patients with chronic cough have comparable frequency of proximal esophageal reflux events and extent of acidity. Likewise, the comparison of healthy subjects to chronic cough patients, where extraesophageal causes of chronic cough have been excluded, revealed similar findings.
      • Sifrim D.
      • Dupont L.
      • Blondeau K.
      • Zhang X.
      • Tack J.
      • Janssens J.
      Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring.
      ,
      • Smith J.A.
      • Houghton L.A.
      The oesophagus and cough: laryngo-pharyngeal reflux, microaspiration and vagal reflexes.
      More importantly, no correlation was noted between the number of proximally occurring reflux events and the frequency of coughing. This implies that frequency of proximal reflux events may not be important for provocation of cough.
      • Smith J.A.
      • Houghton L.A.
      The oesophagus and cough: laryngo-pharyngeal reflux, microaspiration and vagal reflexes.
      ,
      • Decalmer S.
      • Stovold R.
      • Houghton L.A.
      • et al.
      Chronic cough: relationship between microaspiration, gastroesophageal reflux, and cough frequency.
      However, in the same studies, a significant temporal association between cough and proximal reflux events (ie, SAP) was observed, reminiscent of hypersensitivity of esophageal-bronchial reflex, ie, reflex theory.
      • Smith J.A.
      • Houghton L.A.
      The oesophagus and cough: laryngo-pharyngeal reflux, microaspiration and vagal reflexes.
      Other comorbid conditions need be considered in coughing patients with GERD, such as ineffective esophageal peristalsis.
      • Kastelik J.A.
      • Redington A.E.
      • Aziz I.
      • et al.
      Abnormal oesophageal motility in patients with chronic cough.
      Data revealed that esophageal dysmotility is twice more prevalent in chronic cough compared with heartburn patients, irrespective of the refluxate acidity (ie, acid or non-acid).
      • Kastelik J.A.
      • Redington A.E.
      • Aziz I.
      • et al.
      Abnormal oesophageal motility in patients with chronic cough.
      This adds to the complexity of chronic cough in patients with GERD. In conclusion, pathogenic mechanisms linking chronic cough and GERD are yet unclear. Direct triggering of cough by proximal reflux events (reflux theory) in patients with chronic cough and GERD lacks clear evidence. There is seemingly an important role of HCR in GERD-related cough (reflex theory) which requires further elucidation.

      COVID-19 cough

       Epidemiology

      Three stages of COVID-19 have been described: (i) a viral infection lasting for 1 to 2 weeks; (ii) a second phase characterized by an intertwined cytokine and oxidative stress storm, independent of infection; and (iii) a recovery phase that may last for months during which cough may be persistent.
      • Halpin S.
      • O'Connor R.
      • Sivan M.
      Long COVID and chronic COVID syndromes.
      • Cortinovis M.
      • Perico N.
      • Remuzzi G.
      Long-term follow-up of recovered patients with COVID-19.
      • Gorna R.
      • MacDermott N.
      • Rayner C.
      • et al.
      Long COVID guidelines need to reflect lived experience.
      • Venkatesan P.
      NICE guideline on long COVID.
      Cough is a major COVID-19 symptom
      • Hu Y.
      • Sun J.
      • Dai Z.
      • et al.
      Prevalence and severity of corona virus disease 2019 (COVID-19): a systematic review and meta-analysis.
      but is not necessarily associated with severity.

      Blain H, Gamon L, Tuaillon E, et al. Atypical Symptoms, SARS-CoV-2 Test Results, and Immunization Rates in 456 Residents from Eight Nursing Homes Facing a COVID-19 Outbreak. Age Ageing. Published online 2021. doi:10.1093/ageing/afab050.

      To date, epidemiological data suggest that prevalence of persistent cough, beyond 2 months from COVID-19 recovery, ranges from 7% to 34%;
      • D'Cruz R.F.
      • Waller M.D.
      • Perrin F.
      • et al.
      Chest radiography is a poor predictor of respiratory symptoms and functional impairment in survivors of severe COVID-19 pneumonia.
      • Carfi A.
      • Bernabei R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • et al.
      Long-COVID”: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      it is infrequently severe or troublesome and associated with symptoms of residual fatigue, breathlessness, and dyspnea, among others.
      • Arnold D.T.
      • Hamilton F.W.
      • Milne A.
      • et al.
      Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort.
      Whether COVID-19 is a risk factor for chronic cough remains to be elucidated. Prevalence data of chronic/persistent cough in general population and in COVID-19, being 2.5–18%
      • Holden S.E.
      • Morice A.
      • Birring S.S.
      • et al.
      Cough presentation in primary care and the identification of chronic cough: a need for diagnostic clarity?.
      • Song W.J.
      • Chang Y.S.
      • Faruqi S.
      • et al.
      The global epidemiology of chronic cough in adults: a systematic review and meta-analysis.
      • Koo H.K.
      • Jeong I.
      • Lee S.W.
      • et al.
      Prevalence of chronic cough and possible causes in the general population based on the Korean National Health and Nutrition Examination Survey.
      • Arinze J.T.
      • de Roos E.W.
      • Karimi L.
      • Verhamme K.M.C.
      • Stricker B.H.
      • Brusselle G.G.
      Prevalence and incidence of, and risk factors for chronic cough in the adult population: the Rotterdam Study.
      and 7–34%
      • D'Cruz R.F.
      • Waller M.D.
      • Perrin F.
      • et al.
      Chest radiography is a poor predictor of respiratory symptoms and functional impairment in survivors of severe COVID-19 pneumonia.
      • Carfi A.
      • Bernabei R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • et al.
      Long-COVID”: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      respectively, are highly variable. Confounding variables may include the spatiotemporal variation in prevalence data of chronic cough in general population studies
      • 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.
      ,
      • Ding H.
      • Xu X.
      • Wen S.
      • et al.
      Changing etiological frequency of chronic cough in a tertiary hospital in Shanghai, China.
      and likely in COVID-19; also, prevalence data in COVID-19 cough are preliminary
      • Carfi A.
      • Bernabei R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.
      and need be constantly updated until after the pandemic is controlled.

       Pathogenesis

      Mechanistic data on cough in COVID-19 are slowly unveiling and likely involve different immune pathways. TRP channels are involved in lung injury, COVID-19 morbidity, and severity of disease. The underlying pathological events leading also to mortality may be closely linked to the TRPV1- expressing neuronal system (afferent/efferent neurons) in the lungs
      • Nahama A.
      • Ramachandran R.
      • Cisternas A.F.
      • Ji H.
      The role of afferent pulmonary innervation in ARDS associated with COVID-19 and potential use of resiniferatoxin to improve prognosis : a review.
      with TRPV1 and TRPV4 also involved in pulmonary chemical injuries.
      • Achanta S.
      • Jordt S.E.
      Transient receptor potential channels in pulmonary chemical injuries and as countermeasure targets.
      Recent proof-of-concept clinical data in COVID-19 suggest that TRP channels may play a role in cough during all 3 stages of the disease as defined above. Specifically, spices (see below), which are TRPA1 and/or TRPV1 agonists, reduce COVID-19 cough within 1 to 2 min suggesting a channel desensitization. Furthermore, there may be a crosstalk between TRP channels and the antioxidant transcription nuclear factor erythroid 2-related factor 2 (Nrf2).
      • Bousquet J.
      • Anto J.M.
      • Czarlewski W.
      • et al.
      Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19.
      • Bousquet J.
      • Cristol J.P.
      • Czarlewski W.
      • et al.
      Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies.
      • Bousquet J.
      • Wienczyslawa C.
      • Zuberbier T.
      • De-la-Torre R.
      • Anto J.M.
      Induced Cough Challenges in a Single Patient with COVID-19 Showing an Interplay between Nrf2, TRPA1 and TRPV1 Agonists.
      • Bousquet J.
      • Le V.
      • Blain H.
      • Czarlewski W.
      Efficacy of broccoli and glucoraphanin in COVID-19 : from hypothesis to proof-of- concept with three experimental clinical cases.
      • Bousquet J.
      • Czarlewski W.
      • Zuberbier T.
      • Mullol J.
      • Blain H.
      • Cristol J.P.
      • et al.
      Spices to control COVID-19 symptoms: yes, but not only….
      Activation of TRPA1 and TRPV1 channels augment sensory or vagal nerve discharges to evoke several symptoms of COVID-19, including cough, nasal obstruction, pain, vomiting, diarrhea and, at least partly, sudden and severe loss of smell and taste.
      • Talavera K.
      • Startek J.B.
      • Alvarez-Collazo J.
      • et al.
      Mammalian transient receptor potential TRPA1 channels: from structure to disease.
      Considering another mechanism for cough, the mucosal angiotensin converting enzyme-2 receptor for COVID-19 regulates metabolism of the proinflammatory bradykinin,
      • Colarusso C.
      • Terlizzi M.
      • Pinto A.
      • Sorrentino R.
      A lesson from a saboteur: high-MW kininogen impact in coronavirus-induced disease 2019.
      an important tussigen of the bronchopulmonary C fiber population of the vagus nerve. Increased expression of bradykinin in COVID-19 can induce cough, reminiscent of drug (ACE inhibitors)-induced cough.
      • Kickbusch I.
      • Leung G.
      Response to the emerging novel coronavirus outbreak.
      The “two pathways” animal model speculates that chemoreceptors have both a stimulatory and an inhibitory role on cough in proximal and distal airways, respectively.
      • Canning B.J.
      • Mazzone S.B.
      • Meeker S.N.
      • Mori N.
      • Reynolds S.M.
      • Undem B.J.
      Identification of the tracheal and laryngeal afferent neurons mediating cough in anaesthetized Guinea-pigs.
      ,
      • Chou Y.L.
      • Mori N.
      • Canning B.J.
      Opposing effects of bronchopulmonary C-fiber subtypes on cough in Guinea pigs.
      It has been suggested that COVID-19 can curtail cough by stimulating distal cough chemoreceptors and concomitantly induce peripheral lung damage resulting in breathlessness and dyspnea.
      • Dicpinigaitis P.V.
      • Canning B.J.
      Is there (will there Be) a post-COVID-19 chronic cough?.
      In summary, clear evidence on immune pathways involved in COVID-19 cough is currently lacking. Current data suggest multiple mechanistic triggers and likely an important role of TRP channels are involved in COVID-19 cough.

       Comparison with post-viral cough

      COVID-19 cough and post-viral cough (PVC) may have different characteristics in terms of clinical course, immune pathways, and pharmacological response pattern. PVC has a benign clinical symptomatology and frequently manifests solely with cough.
      • Braman S.S.
      Postinfectious cough: ACCP evidence-based clinical practice guidelines.
      COVID-19 often requires hospitalization, and residual cough is frequently associated with breathlessness and other symptoms as stated above. Immune pathways in PVC, as inferred from in vitro infectious models (human rhinovirus), reveal enhanced expression of TRP channels (A₁/V₁/M₈) mediated by increase in infected cell supernatants of IL-6 and IL-8,
      • Abdullah H.
      • Heaney L.G.
      • Cosby S.L.
      • McGarvey L.P.A.
      Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity.
      among others. Similar effects have been described in COVID-19
      • Paces J.
      • Strizova Z.
      • Smrz D.
      • Cerny J.
      COVID-19 and the immune system.
      • Chowdhurry M.A.
      • Hossain N.
      • Abul M.
      • Shahid M.A.
      • Alam A.
      Immune response in COVID-19 : a review.
      • Del Valle D.M.
      • Kim-Schulze S.
      • Huang H.H.
      • et al.
      An inflammatory cytokine signature predicts COVID-19 severity and survival.
      • Li L.
      • Li J.
      • Gao M.
      • et al.
      Interleukin-8 as a biomarker for disease prognosis of coronavirus disease-2019 patients.
      • Bousquet J.
      • Czarlewski W.
      • Zuberbier T.
      • et al.
      Potential interplay between Nrf2 , TRPA1 , and TRPV1 in nutrients for the control of COVID-19.
      • Bousquet J.
      • Czarlewski W.
      • Zuberbier T.
      Potential control of COVID-19 symptoms by Nrf2-interacting nutrients with TRPA1 (transient receptor potential ankyrin 1) agonist activity.
      which, additionally, can also manifest as hemophagocytic lymphohistiocytosis