Chronic Cough in Adults

Course #94820 - $60-


Study Points

  1. Describe the background and terminology related to chronic cough.
  2. Compare and contrast available cough severity measures.
  3. Outline the epidemiology of chronic cough and underlying etiologies.
  4. Evaluate the impact of chronic cough on various dimensions of patients' lives.
  5. Discuss the natural history and course of chronic cough.
  6. Describe the pathophysiology of chronic cough.
  7. Outline components of the initial evaluation of patients with chronic cough.
  8. Identify potential underlying etiologies of chronic cough as well as appropriate management approaches for these conditions.
  9. Analyze available treatment modalities for chronic cough of various underlying causes, including upper respiratory, lower respiratory, and reflux-associated cough.
  10. Identify appropriate modalities for the treatment of refractory chronic cough, including pharmacotherapy, nonpharmacologic approaches, and investigational agents.

    1 . A cough lasting seven weeks is categorized as
    A) acute.
    B) subacute.
    C) chronic.
    D) post-chronic.

    BACKGROUND

    CHRONIC COUGH TERMINOLOGY

    TermDefinition
    Acute coughCough lasting less than 3 weeks
    Subacute coughCough lasting 3 to 8 weeks
    Chronic coughCough lasting more than 8 weeks
    Refractory chronic coughCough that persists despite guideline-based treatment of the presumed underlying cause(s)
    Unexplained chronic coughNo diagnosable cause of cough is found despite extensive investigation for common and uncommon causes
    AllotussiaCough triggered by innocuous stimuli (e.g., laughing, talking, changes in ambient temperature)
    HypertussiaExaggerated coughing triggered by mildly tussive stimuli (e.g., strong odors, second-hand cigarette smoke)
    Urge to cough (laryngeal paresthesia)A distinct, often debilitating sensation of irritation or "itch" in the throat or chest that precede cough and is not satiated by coughing
    Cough reflex hypersensitivityThe cardinal feature of cough hypersensitivity syndrome
    Cough hypersensitivity syndromeDisorder characterized by cough triggered by mildly tussive or innocuous stimuli, with features of allotussia, hypertussia, and/or laryngeal paresthesia
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    2 . Cough hypersensitivity syndrome is
    A) cough that persists despite guideline-based treatment of the presumed underlying cause(s).
    B) cough triggered by innocuous stimuli (e.g., laughing, talking, changes in ambient temperature).
    C) a distinct, often debilitating sensation of irritation or "itch" in the throat or chest that precede cough and is not satiated by coughing.
    D) a disorder characterized by cough triggered by mildly tussive or innocuous stimuli, with features of allotussia, hypertussia, and/or laryngeal paresthesia.

    BACKGROUND

    CHRONIC COUGH TERMINOLOGY

    TermDefinition
    Acute coughCough lasting less than 3 weeks
    Subacute coughCough lasting 3 to 8 weeks
    Chronic coughCough lasting more than 8 weeks
    Refractory chronic coughCough that persists despite guideline-based treatment of the presumed underlying cause(s)
    Unexplained chronic coughNo diagnosable cause of cough is found despite extensive investigation for common and uncommon causes
    AllotussiaCough triggered by innocuous stimuli (e.g., laughing, talking, changes in ambient temperature)
    HypertussiaExaggerated coughing triggered by mildly tussive stimuli (e.g., strong odors, second-hand cigarette smoke)
    Urge to cough (laryngeal paresthesia)A distinct, often debilitating sensation of irritation or "itch" in the throat or chest that precede cough and is not satiated by coughing
    Cough reflex hypersensitivityThe cardinal feature of cough hypersensitivity syndrome
    Cough hypersensitivity syndromeDisorder characterized by cough triggered by mildly tussive or innocuous stimuli, with features of allotussia, hypertussia, and/or laryngeal paresthesia
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    3 . Which of the following is an objective tool for cough measurement?
    A) Visual Analog Scale (VAS)
    B) Cough Severity Diary (CSD)
    C) Leicester Cough Monitor (LCM)
    D) Cough Quality of Life Questionnaire (CQLQ)

    COUGH SEVERITY MEASURES

    COUGH MEASURES

    NameDomains/Items, Rating and Minimal Clinically Importance Difference (MCID)Comments
    Health-related quality of life patient-reported outcome tools
    Leicester Cough Questionnaire (LCQ)
    Seven-point Likert scale (1=all of the time; 7=none of the time); 19 items in 3 domains: physical, psychological, and social. Total score range: 3 (maximal impairment) to 21 (no quality-of-life impairment).
    MCID: 1.5 to 2.5 increase
    The most widely used tool for assessing quality of life impact of chronic cough
    Cough Quality of Life Questionnaire (CQLQ)
    Four-point Likert scale (1=strongly disagree; 4=strongly agree); 28 items over 6 domains: physical and extreme physical complaints, psychosocial issues, emotional well-being, safety fears, and functional abilities. Total score range: 28 (no adverse effect of cough) to 112 (worst possible impact).
    MCID: 10.6 to 21.9
    Contains more items on physical impact of chronic cough (e.g., fractured ribs, headaches, immune deficiency, tuberculosis)
    Hull Airway Reflux Questionnaire (HARQ)
    Six-point scale (0=no symptoms; 5=most severe) of 14 items that measure airway hypersensitivity in chronic cough. Total score range: 0 to 70
    Normal is <14
    MCID: 16
    Also used as a diagnostic tool for airway reflux, and to assess unexplained respiratory symptoms
    Cough Severity Diary (CSD)
    11-point scale (0=never; 10=constantly) of 7 items on frequency; intensity; disruptiveness
    MCID ≥1.3 total score, −1.4 to −1.1 domain scores
    Captures the severity and impact of chronic cough. Developed in response to patient feedback.
    Objective assessment tools
    VitaloJAK Cough Monitor
    Electronic cough recording monitors worn by patients to measure cough frequency, typically as coughs per hour over 24 hours
    MCID: ≥20% to 30% decrease
    Does not capture the episodic nature of chronic cough, a primary factor in patients' disease burden
    Leicester Cough Monitor (LCM)
    Subjective tools
    Visual Analogue Scale (VAS)
    Score range 0 (no cough) to 100 mm (worst cough ever)
    MCID: 30-mm reduction on the 100-mm cough severity VAS
    Numerical Rating Scale (NRS)Score range 0 (no cough) to 10 (worst cough ever)
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    4 . What is the approximate prevalence of chronic cough among U.S. adults?
    A) 1%
    B) 10%
    C) 25%
    D) 50%

    EPIDEMIOLOGY

    Chronic cough has a prevalence among U.S. adults of roughly 10%, of whom 92% visited healthcare clinicians in the past six months [32]. Chronic cough is estimated to cost $6.8 billion annually in the United States, and an estimated $3.6 billion is spent annually on over-the-counter therapies [33]. The economic implications of chronic cough include the cost of outpatient visits, plus diagnostic workups, prescription medications to treat cough, and lost work and lost school productivity [1]. While inconsistent definitions prohibit direct comparisons of chronic cough prevalence between different countries or ethnicities, chronic cough appears to be more common in Europe, North America, and Australia than in Asian countries [32,34].

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    5 . Which of the following is a risk factor for the development of chronic cough?
    A) Frailty
    B) Male sex
    C) Younger age
    D) Angiotensin-converting enzyme (ACE) inhibitor use

    EPIDEMIOLOGY

    Risk factors of chronic cough include smoking, female sex, older age, obesity, asthma, allergic rhinitis, rhinosinusitis, and angiotensin-converting enzyme (ACE) inhibitor use for hypertension treatment [34,39].

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    6 . Cough-induced rib fractures, a painful and potentially serious complication of chronic cough, often involve ribs
    A) 1 and 2.
    B) 3 through 5.
    C) 5 through 7.
    D) 7 through 9.

    PATIENT IMPACT OF CHRONIC COUGH

    Cough-induced rib fractures, another painful and potentially serious complication of chronic cough, often involve multiple ribs, particularly ribs 5 through 7. The number of ribs fractured is associated with higher mortality rates, particularly in older patients who often have decreased bone density due to osteoporosis (also an adverse effect of long-term corticosteroid treatment). However, rib fractures can also occur in patients with normal bone density [44,46].

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    7 . Studies of patients with chronic cough have reported high rates of
    A) bipolar disorder.
    B) anxiety and depression.
    C) substance use disorders.
    D) ADHD and obsessive-compulsive disorder.

    PATIENT IMPACT OF CHRONIC COUGH

    The psychological effects associated with chronic cough are highly prevalent, with an impact on mental health comparable to that of stroke or Parkinson disease. Studies of patients with chronic cough have reported high rates of anxiety (33% to 52%) and depression (16% to 91%) [28].

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    8 . Which of the following statements regarding the natural history and clinical course of chronic Cough is TRUE?
    A) The natural history of cough hypersensitivity is clearly established.
    B) Most patients with chronic Cough are diagnosed and effectively treated within months.
    C) Chronic cough is related to an accelerated FEV1 decline over time, regardless of smoking history or COPD diagnosis.
    D) The relationship between chronic cough and worse clinical outcomes has a clear pathophysiological explanation.

    NATURAL HISTORY AND DISEASE COURSE

    Little is known about the natural history of cough hypersensitivity, but the available evidence suggests that patients often suffer from it for many years [4]. In a longitudinal study of patients with unexplained chronic cough, cough severity worsened (36%) or was unchanged (23%) over 7 to 10 years. Predictors of cough persistence or improvement could not be identified. Unexpectedly, longitudinal spirometry data showed declines in forced expiratory volumes over one second (FEV1) that were well above population norms for similarly aged nonsmokers. The striking magnitude of decline argued against a chance finding. Around 10% of patients developed spirometric features of COPD [52].

    In summary, chronic cough is related to an accelerated FEV1 decline over time, regardless of smoking history or COPD diagnosis, but the relationship between chronic cough and worse clinical outcomes lacks a clear pathophysiological explanation [55].

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    9 . What are the phases of cough?
    A) Diastole and systole
    B) Waxing, full, and waning
    C) Inspiration, compression, and expiration
    D) Latent period, contraction, and relaxation

    PATHOPHYSIOLOGY OF CHRONIC COUGH

    Cough occurs in three phases [31,56]. The first is inspiratory, during which the glottis opens widely followed by rapid inhalation sufficient for generating enough air movement to be productive. The second phase is compression. This phase is characterized by the rapid closure of the glottic apparatus and contraction of abdominal and other respiratory muscles compresses the alveoli and bronchiole, increasing intrathoracic pressure to greater than 300 mm Hg. The final phase is expiration, or the sudden opening of the epiglottis and vocal cords results in rapid, high-volume expiratory airflow that may exceed 500 mph in velocity. The force of this process loosens and expels mucous secretions from the airway wall, while the rapid airflow vibrates the larynx and pharynx, inducing the characteristic sounds of cough.

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    10 . Excessive coughing is a consequence of increased activation of neuronal cough-mediating pathways due to
    A) Neuroplastic changes in the CNS
    B) Neuroplastic changes in vagal afferent fibers
    C) Excessive activation of airway vagal afferent terminals by chemical or mechanical irritants
    D) All of the above

    PATHOPHYSIOLOGY OF CHRONIC COUGH

    Chronic cough, unlike protective cough, is a pathologic state that no longer serves a physiologic role [60]. Excessive coughing is a consequence of increased activation of neuronal cough-mediating pathways due to [62,63]:

    • Excessive activation of airway vagal afferent terminals by chemical or mechanical irritants

    • Neuroplastic changes in vagal afferent fibers

    • Neuroplastic changes in the CNS

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    11 . The first step in evaluating cough is to
    A) identify its etiology.
    B) determine its duration.
    C) start empirical/diagnostic therapy.
    D) evaluate impact on patient quality of life.

    INITIAL EVALUATION OF CHRONIC COUGH

    Thus, the first step in evaluating cough is to determine its duration. This also helps to narrow the differential diagnosis based on the most common underlying causes [10,100]:

    • Acute (<3 weeks) cough:

      • Infectious etiologies, especially with viral causes

      • Exacerbations of chronic diseases (e.g., asthma, COPD)

      • Pneumonia

      • Environmental exposures

    • Subacute (3 to 8 weeks) cough:

      • Postinfectious cough

      • Exacerbations of chronic diseases (e.g., asthma, COPD)

      • Upper airway cough syndrome

    • Chronic (>8 weeks) cough:

      • Upper airway cough syndrome

      • Asthma

      • Nonasthmatic eosinophilic bronchitis

      • GERD

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    12 . All of the following are "red flag" signs/ symptoms in patients with chronic cough that warrant further evaluation, EXCEPT:
    A) Hoarseness
    B) Hemoptysis
    C) History of asthma
    D) Systemic symptoms (e.g., fever, weight loss)

    INITIAL EVALUATION OF CHRONIC COUGH

    In cough of any duration, the initial evaluation should identify any danger signs that may indicate a diagnosis requiring urgent attention. Important danger signs that will need further evaluation with chest x-ray and possibly laboratory testing and computed tomography (CT) include [44,100]:

    • Systemic symptoms (raises suspicion for chronic infection or rheumatic disease):

      • Fever

      • Night sweats

      • Weight loss

      • Peripheral edema with weight gain

    • Hemoptysis, an indicator of infection (e.g., bronchiectasis, lung abscess, tuberculosis), cancer (e.g., lung, bronchus, or larynx), rheumatologic diseases, heart failure, or foreign body inhalation

    • Prominent dyspnea, especially at rest or at night, a possible clue to airway obstruction or lung parenchymal disease

    • Possible foreign-body inhalation (requires urgent bronchoscopy)

    • Smoker older than 45 years of age with a new cough, change in cough, or co-occurring voice disturbance

    • Hoarseness

    • Trouble swallowing when eating or drinking

    • Vomiting

    • Recurrent pneumonia

    • Abnormal respiratory exam and/or abnormal chest radiograph coinciding with duration of cough

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    13 . In patients with negative physical examination and spirometry findings, what testing should be performed to confirm airway hyper-reactivity consistent with symptomatic asthma?
    A) Laryngoscopy (fiberoptic)
    B) Chest computed tomography (CT)
    C) Peripheral blood eosinophil count
    D) Bronchial challenge testing (e.g., methacholine)

    INITIAL EVALUATION OF CHRONIC COUGH

    In patients with negative physical examination and spirometry findings, bronchial challenge testing (e.g., methacholine) should be performed to confirm airway hyper-reactivity consistent with symptomatic asthma [84]. Bronchial challenge testing is recommended in patients with reactive airway diseases to help diagnosis of asthma and nonasthmatic eosinophilic bronchitis as a cause of chronic cough. A negative bronchial challenge test (defined as an FEV1 decrease of <20% at the highest methacholine challenge dose [10 mg/mL]) has a high negative predictive value of asthma as an etiological diagnosis in chronic cough [104].

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    14 . Which of the following statements best describes the treatable traits approach in managing airway disease?
    A) Traits in the treatable traits approach are defined as clinically relevant, measurable, and treatable.
    B) The treatable traits approach focuses solely on traditional diagnostic labels such as asthma and COPD to determine treatment plans.
    C) In the treatable traits approach, only phenotypes are considered for treatment, while endotypes are not relevant in identifying treatment targets.
    D) The treatable traits approach is limited to identifying and treating only those traits that are associated with conventional asthma and COPD diagnoses.

    IDENTIFICATION AND MANAGEMENT OF UNDERLYING ETIOLOGIES

    A trait is defined as clinically relevant, measurable, and treatable. These traits can be identified by their phenotypes and/or endotypes in pulmonary, extrapulmonary, and behavioral/environmental domains, and can coexist, interact, and change over time in the same patient. The treatable traits approach is agnostic to the traditional diagnostic labels of asthma or COPD and can be used in any patient with airway disease. The treatable traits approach often extends beyond the diagnostic label itself to find more treatment targets, especially in complex patients with suboptimal response to conventional guideline-based treatment [87,88]. In other words, the treatable traits approach represents a transdiagnostic model.

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    15 . In patients with chronic cough in asthma, the first-line treatment is
    A) biologics.
    B) allergy medications.
    C) inhaled corticosteroid with or without long-acting beta-agonist
    D) a leukotriene receptor antagonist or long-acting muscarinic antagonist.

    TREATMENT

    In patients with chronic cough in asthma, the first-line treatment is inhaled corticosteroid with or without long-acting beta-agonist [6]. A leukotriene receptor antagonist or long-acting muscarinic antagonist may be added in for those who do not fully respond to initial treatment. Whether biologics can treat chronic cough related to asthma has not been studied.

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    16 . Wheezing and NSAID hypersensitivity are features of which rhinitis phenotype?
    A) Allergic
    B) GERD-associated
    C) Nonallergic noninfectious
    D) Chronic rhinosinusitis with or without nasal polyposis

    TREATMENT

    DISTINGUISHING CHARACTERISTICS OF RHINITIS PHENOTYPES

    Rhinitis PhenotypePrimary SymptomsAssociated FeaturesMore Responsive toLess Responsive to
    AllergicSneezing, nasal pruritis, clear rhinitisOcular itching, wheezing, atopic dermatitisINCS, INAH, FGAH, SGAH, SCS, AITDecongestants, ABX
    Nonallergic noninfectiousIntermittent congestion, clear rhinitisPhysical triggers (temperature changes, food, irritants)INCA, INAH, INACFGAH, SGAH, SCS, AIT, ABX
    GERD-associatedPostnasal drip, throat clearingEpigastric pain, heartburn, dysphagiaGERD diet and lifestyle changes, INACFGAH, SGAH, INCS, INAH, SCS, ABX, AIT
    Chronic rhinosinusitis with or without nasal polyposisAnosmia/hyposmia, unremitting congestion, facial pain/pressureWheezing, NSAID hypersensitivitySCS, biologics, intermittent INCSFGAH, SGAH, INAH
    InfectiousAcute onset, sinus pressure, nasal congestion with purulent dischargeViral prodrome, episodic nature lasting <2 weeksSaline nasal lavage, INAH, decongestants, INACFGAH, SGAH, INCS, SCS, ABX, AIT
    ABX = antibiotics; AIT = allergen immunotherapy; FGAH = first-generation oral antihistamines; GERD = gastroesophageal reflux disease; INAC = intranasal anticholinergics; INAH = intranasal antihistamines; INCS = intranasal corticosteroids, SCS = systemic corticosteroids; SGAH = second-generation oral antihistamines.
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    17 . According to the 2016 ACCP clinical practice guideline for reflux-associated chronic cough, when should esophageal manometry and pH-metry be performed?
    A) As a first-line diagnostic test for all patients with chronic cough, regardless of response to antireflux therapy.
    B) Only in patients who have not responded to a six-month antireflux trial, regardless of their surgical management plans.
    C) In patients who have responded partially to antireflux medication but do not have a clear diagnosis of gastroesophageal reflux.
    D) In patients with suspected reflux cough who are refractory to a three-month antireflux trial and are being considered for surgical management, or in those with strong clinical suspicion warranting diagnostic testing for gastroesophageal reflux.

    TREATMENT

    The 2016 ACCP clinical practice guideline for reflux-associated chronic cough suggests that esophageal manometry and pH-metry be performed in patients with suspected reflux cough refractory to a three-month antireflux trial and being evaluated for surgical management (antireflux or bariatric); or with strong clinical suspicion warranting diagnostic testing for gastroesophageal reflux (Table 6). Esophageal manometry assesses for major motility disorder. It involves placing the pH electrode 5 cm above the lower esophageal sphincter in the pH monitoring study after the patient is off PPIs for seven days and histamine H2-receptor antagonists for three days [83].

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    18 . Which of the following agents is recommended by the American College of Chest Physicians for neuromodulator treatment of refractory/unexplained chronic cough?
    A) Baclofen
    B) Gabapentin
    C) Amitriptyline
    D) Low-dose morphine slow-release

    TREATMENT OF REFRACTORY CHRONIC COUGH

    GUIDELINE RECOMMENDATIONS FOR NEUROMODULATOR TREATMENT OF REFRACTORY/UNEXPLAINED CHRONIC COUGH

    DrugGuideline Organization (Year)
    ACCP (2016)ERS (2020)GRS (2020)aFRS (2023)BTS (2023)NEURO-COUGH (2023)
    Low-dose morphine slow-releaseNot reportedbStrong recommendationStrong recommendationRecommended: Grade BRecommendedRecommended, very high consensus
    CodeineNot reportedNot recommendedNot reportedNot reportedRecommended againstNot reported
    GabapentinRecommendedConditional recommendationCan be usedRecommended: Grade BRecommendedRecommended, high consensus
    PregabalinNot reportedConditional recommendationCan be usedRecommended: Grade BRecommendedNot reported
    AmitriptylineNot reportedNot reportedCan be usedRecommended: Grade CNot reportedRecommended, high consensus
    BaclofenNot reportedNot reportedNot reportedNot reportedNot reportedNot reported
    a"Can be used" is a weaker endorsement than "recommendation" (i.e., "should be used").
    b75% of expert panelists endorsed a recommendation of morphine, falling short of 80% required for inclusion; thus, morphine is neither recommended for nor against.
    ACCP = American College of Chest Physicians; BTS = British Thoracic Society; ERS = European Respiratory Society; FRS = French-Speaking Society of Respiratory Diseases; GRS = German Respiratory Society; NEURO-COUGH = New Understanding in the treatment Of COUGH Clinical Research Collaboration; SR = sustained-release.
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    19 . In clinical trials, what is the most common side effect of nalbuphine extended-release?
    A) Nausea
    B) Fatigue
    C) Dizziness
    D) Constipation

    TREATMENT OF REFRACTORY CHRONIC COUGH

    Nalbuphine extended-release (ER) is an opioid agonist-antagonist. In a double-blind randomized controlled trial of patients with idiopathic pulmonary fibrosis and chronic cough, nalbuphine ER tablets (titrated up to 162 mg twice daily) led to 75.1% reduction in daytime objective cough frequency, compared with 22.6% with placebo, a 50.8% placebo-adjusted reduction in 24-hour cough frequency, and similar improvements in patient reported outcomes [162]. Nalbuphine ER was the first therapy to show robust effects on chronic cough in idiopathic pulmonary fibrosis [25]. However, nalbuphine side effects of nausea (42.1%), fatigue (31.6%), constipation (28.9%), and dizziness (26.3%) led to a 24% dropout during the drug initiation phase, partially attributed to the inflexible forced-titration study design [162].

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    20 . Which of the following accurately describes the use of lidocaine in the context of treating chronic cough?
    A) Lidocaine primarily functions as a systemic analgesic and is not effective for treating coughs associated with bronchoscopy or chronic cough.
    B) Lidocaine selectively blocks specific types of sodium channels to reduce coughing during bronchoscopy, and it is not used for chronic cough.
    C) Lidocaine's main role in treating chronic cough is through its action as a central nervous system depressant rather than its local anesthetic properties.
    D) Lidocaine is a local anesthetic that non-selectively blocks voltage-gated sodium channels, which helps in reducing coughing during bronchoscopy and has been used in nebulized form to treat refractory chronic cough.

    TREATMENT OF REFRACTORY CHRONIC COUGH

    Lidocaine non-selectively blocks voltage-gated sodium channels important in the initiation of action potentials and their conduction and is a local anesthetic agent in routine topical use to reduce coughing during bronchoscopy. Case reports and case series have also described the use of nebulized lidocaine as an antitussive to treat refractory chronic cough [169].

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