|
| A) | acute. | ||
| B) | subacute. | ||
| C) | chronic. | ||
| D) | post-chronic. |
CHRONIC COUGH TERMINOLOGY
| Term | Definition |
|---|---|
| Acute cough | Cough lasting less than 3 weeks |
| Subacute cough | Cough lasting 3 to 8 weeks |
| Chronic cough | Cough lasting more than 8 weeks |
| Refractory chronic cough | Cough that persists despite guideline-based treatment of the presumed underlying cause(s) |
| Unexplained chronic cough | No diagnosable cause of cough is found despite extensive investigation for common and uncommon causes |
| Allotussia | Cough triggered by innocuous stimuli (e.g., laughing, talking, changes in ambient temperature) |
| Hypertussia | Exaggerated 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 hypersensitivity | The cardinal feature of cough hypersensitivity syndrome |
| Cough hypersensitivity syndrome | Disorder characterized by cough triggered by mildly tussive or innocuous stimuli, with features of allotussia, hypertussia, and/or laryngeal paresthesia |
| 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. |
CHRONIC COUGH TERMINOLOGY
| Term | Definition |
|---|---|
| Acute cough | Cough lasting less than 3 weeks |
| Subacute cough | Cough lasting 3 to 8 weeks |
| Chronic cough | Cough lasting more than 8 weeks |
| Refractory chronic cough | Cough that persists despite guideline-based treatment of the presumed underlying cause(s) |
| Unexplained chronic cough | No diagnosable cause of cough is found despite extensive investigation for common and uncommon causes |
| Allotussia | Cough triggered by innocuous stimuli (e.g., laughing, talking, changes in ambient temperature) |
| Hypertussia | Exaggerated 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 hypersensitivity | The cardinal feature of cough hypersensitivity syndrome |
| Cough hypersensitivity syndrome | Disorder characterized by cough triggered by mildly tussive or innocuous stimuli, with features of allotussia, hypertussia, and/or laryngeal paresthesia |
| A) | Visual Analog Scale (VAS) | ||
| B) | Cough Severity Diary (CSD) | ||
| C) | Leicester Cough Monitor (LCM) | ||
| D) | Cough Quality of Life Questionnaire (CQLQ) |
COUGH MEASURES
| Name | Domains/Items, Rating and Minimal Clinically Importance Difference (MCID) | Comments | |||
|---|---|---|---|---|---|
| Health-related quality of life patient-reported outcome tools | |||||
| Leicester Cough Questionnaire (LCQ) |
| The most widely used tool for assessing quality of life impact of chronic cough | |||
| Cough Quality of Life Questionnaire (CQLQ) |
| Contains more items on physical impact of chronic cough (e.g., fractured ribs, headaches, immune deficiency, tuberculosis) | |||
| Hull Airway Reflux Questionnaire (HARQ) |
| Also used as a diagnostic tool for airway reflux, and to assess unexplained respiratory symptoms | |||
| Cough Severity Diary (CSD) |
| Captures the severity and impact of chronic cough. Developed in response to patient feedback. | |||
| Objective assessment tools | |||||
| VitaloJAK Cough Monitor |
| 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) |
| — | |||
| Numerical Rating Scale (NRS) | Score range 0 (no cough) to 10 (worst cough ever) | ||||
| A) | 1% | ||
| B) | 10% | ||
| C) | 25% | ||
| D) | 50% |
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].
| A) | Frailty | ||
| B) | Male sex | ||
| C) | Younger age | ||
| D) | Angiotensin-converting enzyme (ACE) inhibitor use |
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].
| A) | 1 and 2. | ||
| B) | 3 through 5. | ||
| C) | 5 through 7. | ||
| D) | 7 through 9. |
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].
| A) | bipolar disorder. | ||
| B) | anxiety and depression. | ||
| C) | substance use disorders. | ||
| D) | ADHD and obsessive-compulsive disorder. |
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].
| 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. |
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].
| A) | Diastole and systole | ||
| B) | Waxing, full, and waning | ||
| C) | Inspiration, compression, and expiration | ||
| D) | Latent period, contraction, and relaxation |
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.
| 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 |
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
| A) | identify its etiology. | ||
| B) | determine its duration. | ||
| C) | start empirical/diagnostic therapy. | ||
| D) | evaluate impact on patient quality of life. |
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
| A) | Hoarseness | ||
| B) | Hemoptysis | ||
| C) | History of asthma | ||
| D) | Systemic symptoms (e.g., fever, weight loss) |
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
| A) | Laryngoscopy (fiberoptic) | ||
| B) | Chest computed tomography (CT) | ||
| C) | Peripheral blood eosinophil count | ||
| D) | Bronchial challenge testing (e.g., methacholine) |
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].
| 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. |
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.
| 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. |
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.
| A) | Allergic | ||
| B) | GERD-associated | ||
| C) | Nonallergic noninfectious | ||
| D) | Chronic rhinosinusitis with or without nasal polyposis |
DISTINGUISHING CHARACTERISTICS OF RHINITIS PHENOTYPES
| Rhinitis Phenotype | Primary Symptoms | Associated Features | More Responsive to | Less Responsive to |
|---|---|---|---|---|
| Allergic | Sneezing, nasal pruritis, clear rhinitis | Ocular itching, wheezing, atopic dermatitis | INCS, INAH, FGAH, SGAH, SCS, AIT | Decongestants, ABX |
| Nonallergic noninfectious | Intermittent congestion, clear rhinitis | Physical triggers (temperature changes, food, irritants) | INCA, INAH, INAC | FGAH, SGAH, SCS, AIT, ABX |
| GERD-associated | Postnasal drip, throat clearing | Epigastric pain, heartburn, dysphagia | GERD diet and lifestyle changes, INAC | FGAH, SGAH, INCS, INAH, SCS, ABX, AIT |
| Chronic rhinosinusitis with or without nasal polyposis | Anosmia/hyposmia, unremitting congestion, facial pain/pressure | Wheezing, NSAID hypersensitivity | SCS, biologics, intermittent INCS | FGAH, SGAH, INAH |
| Infectious | Acute onset, sinus pressure, nasal congestion with purulent discharge | Viral prodrome, episodic nature lasting <2 weeks | Saline nasal lavage, INAH, decongestants, INAC | FGAH, 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. | ||||
| 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. |
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].
| A) | Baclofen | ||
| B) | Gabapentin | ||
| C) | Amitriptyline | ||
| D) | Low-dose morphine slow-release |
GUIDELINE RECOMMENDATIONS FOR NEUROMODULATOR TREATMENT OF REFRACTORY/UNEXPLAINED CHRONIC COUGH
| Drug | Guideline Organization (Year) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| ACCP (2016) | ERS (2020) | GRS (2020)a | FRS (2023) | BTS (2023) | NEURO-COUGH (2023) | ||||
| Low-dose morphine slow-release | Not reportedb | Strong recommendation | Strong recommendation | Recommended: Grade B | Recommended | Recommended, very high consensus | |||
| Codeine | Not reported | Not recommended | Not reported | Not reported | Recommended against | Not reported | |||
| Gabapentin | Recommended | Conditional recommendation | Can be used | Recommended: Grade B | Recommended | Recommended, high consensus | |||
| Pregabalin | Not reported | Conditional recommendation | Can be used | Recommended: Grade B | Recommended | Not reported | |||
| Amitriptyline | Not reported | Not reported | Can be used | Recommended: Grade C | Not reported | Recommended, high consensus | |||
| Baclofen | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | |||
| |||||||||
| A) | Nausea | ||
| B) | Fatigue | ||
| C) | Dizziness | ||
| D) | Constipation |
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].
| 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. |
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].