Approach to chronic cough

Approach to
Chronic Cough
Pannipa Kittipongpattana, MD.
14 June 2019
Division of Pediatric Allergy and Immunology
Department of Pediatrics, Faculty of Medicine
King Chulalongkorn Memorial Hospital

Outline
- Definition & Pathophysiology of cough
- Epidemiology & Etiologies of chronic cough
- Approach to chronic cough in adults
- Approach to chronic cough in children

Definition and
Pathophysiology
of Cough

Definition: What is Cough?
● Physiologic temporary reconfiguration in breathing pattern to:
- protect the lung from inhalation of noxious agents
- clear excessive secretion
● Defined as a triphasic event:
- inspiratory phase
- compressive phase
- expulsive phase
● Distinguish from other protective reflexes such as an “expiratory reflex”:
expulsive effort without a preceding inspiration
McGarvey L, Gibson PG. J Allergy Clin Immunol Pract. 2019 Apr 17.

Pathogenesis: Mechanism of Cough
Inspiratory phase
Brief inspiration:
- Glottis opens
- Diaphragms contract
- Thoracic cage expands
Compressive phase
Abdominal and thoracic
muscles compress air
against a closed glottis
Expulsive phase
- Abrupt glottis opens
- Rapid exhalation
- High velocity and shear
force allow airway clearance
Irritation phase
- Neural activation
from solitary nucleus
- Can be cortically
suppressed
Middleton’s 8th edition
ข้อแนะนำกำรปฏิบัติสำธำรณสุข กำรรักษำผู้ป่วยไอเรื้อรังในผู้ใหญ่ พ.ศ.2559

Pathogenesis: Cough stimulation
Vagus n.
Cough receptors
- C-fiber
- Myelinated fiber
- Slowly adapting receptors
- Rapidly adapting receptors
Cough center
Nucleus of tractus
solitarius in medulla
Mechanical
- particulates
- nicotine
- low Cl-
Irritant
- capsaicin
- acid
Cough stimuli
Inflammatory
- bradykinin
- prostaglandin E2
Cough sensitivity
Receptors may be more sensitive in
chronic airway inflammation
(partly regulated by transient receptor
potential [TRP] family of receptors)
Airway mucosa
Voluntary
control
Respiratory
center
Emotion
Pain

Clinical Terms
McGarvey L, Gibson PG. J Allergy Clin Immunol Pract. 2019 Apr 17.
Laryngeal
hypersensitivity
Cough
hypersensitivity
2009 2013 2018Characteristic Duration
Treatment response Pathophysiology
Etiology

Acute
< 3 weeks
Subacute
3-8 weeks
Chronic
> 8 weeks
Adults
Common cold
Exacerbation of chronic disease
Acute environmental exposure
Acute cardiopulmonary disease
Postinfectious cough
Pertussis
ACEI therapy
Smoking
Chronic bronchitis
Asthma
Upper airway cough syndrome (UACS)
Non-asthmatic eosinophilic bronchitis (NAEB)
GERD
Underlying lung disease
Children
Common cold
Acute cardiopulmonary disease
Asthma
Protracted bacterial bronchitis
Tracheobronchomalacia
Chronic rhinosinusitis
Recurrent aspiration
GERD
Pulmonary infection (e.g., pertussis)
Underlying lung disease
Acute
< 4 weeks
Chronic
> 4 weeks
Definitions and Common Causes of Cough in Adults and Children

Epidemiology and
Etiologies
of Chronic Cough

Epidemiology of ‘Chronic Cough’
Chest. 1999 Feb;115(2):434-9.
Prevalence of persistent cough
not associated with wheezing in children
5 - 10%
Estimated adults
Global Prevalence
9.6%

Etiologies: intrathoracic
1
2
3
5
4

Etiologies: extrathoracic

GERD, Gastroesophageal reflux disease
LPR, laryngopharyngeal reflux.
ALTMAN et al. J Allergy Clin Immunol Pract. 2019 May 8.
The interrelatedness of factors contributing to cough

Approach to
Chronic Cough in Adults

Review: Etiologies and Pathophysiology
Trigger Sensitivity Center Cough

Approach in Adults
Identify obvious causes
- Diagnosis based on Hx, PE, CXR → specific treatment
- Often multiple etiologies
- Consider exacerbation of chronic diseases
Red Flags Smoking
ACEI
4 Most common
- Hemoptysis
- Voice disturbance
- Dysphagia
- Vomiting
- Dyspnea
- Systemic symptoms
● Fever
● Weight loss
● Edema
- Recurrent pneumonia
- Abnormal PE / CXR
- Smoker
● Age>45 + new symptom
● Age>55 + smoke>30PY
Upper airway cough syndrome
Asthma
NonAsthmatic eosinophilic bronchitis
Gastroesophageal reflux disease
1
2
Investigation +/- empirical treatment for
common causes
3 Further investigation
4 “Unexplained chronic cough”
- no obvious cause found
- not fully response after
optimal & adequate treatment
- negative study
- not fully response after treatment
- negative study
May not helpful in diagnosis
- character: paroxysmal, loose, productive, dry
- sound quality: barking, honking
- timing: nocturnal
- Allergy Asthma Immunol Res. 2018 Nov;10(6):591-613.
- CHEST Guideline and Expert Panel Report. Chest 2018;153:196-209.
- ข้อแนะนำกำรปฏิบัติสำธำรณสุข กำรรักษำผู้ป่วยไอเรื้อรังในผู้ใหญ่ พ.ศ.2559

Chronic Bronchitis (Smoking)
Diagnosis
- History of exposure to irritant: dust, fumes, smoke
- Expectorate phlegm on most days x 3-month x 2-year
- Spirometry: obstructive pattern (COPD)
Management
- Eliminating exposure
- Smoking abstinence
- At least 4 weeks to show symptom improvement

ACEI induced Cough
Incidence
- 5% - 35% of patient taking ACEI
- Onset: hours - months after initiation
Management
- Switching to Angiotensin II receptor
antagonist
- Cough usually resolves
within 4 weeks, may up to 3 months
https://www.lecturio.com/magazine/
antihypertensives/#the-
angiotensin-converting-enzyme-
inhibitors

Upper Airway Cough Syndrome (UACS)
Formerly called ‘Post Nasal Drip Syndrome’ (PNDS)
Any disease that cause irritation of the larynx or hypopharynx
Diagnostic investigation according to primary disease
Confirmed as the cause of chronic cough after cough resolve with treatment
Common UACS

Cough in Asthma
Inflammatory mediators directly induce cough or sensitize vagal afferent
*** independent from bronchospasm
28% of asthma patients present with cough only (Cough variant asthma)***
Diagnosis
- Bronchial challenge test (high sensitivity, low specificity for asthma)
- Reversible of bronchoconstriction with bronchodilator
Management: per asthma guideline
- Cough from asthma will start to response within 1 - 3 weeks
- Complete resolution after 6 - 8 weeks

Non Asthmatic Eosinophilic Bronchitis (NAEB)
10% - 30% of chronic cough
Diagnosis
- Sputum eosiniophilia
- Increased exhale nitric oxide
- Negative metacholine challenge test / No variable airflow obstruction
- Mast cells are prominent in mucosa, and not submucosa (distinct from
asthma)
Management
- Budesonide 400 mcg BID shows response within 4 weeks

Cough in Gastroesophageal Reflux Disease
10% of chronic cough
Refluxate induces cough by
- aspiration
- irritating hypopharynx and supraglottic larynx
- distal esophageal-bronchial reflex (depends on volume > acidity)
*** 43% - 75% of GERD patients present with cough only (Silent GERD) ***
Diagnosis
- Symptom of GERD: heartburn, sour taste
- Barium swallow: demonstrate reflux to the level of the mid-esophagus or higher
- 24-hr pH and impedance monitoring: gold standard
(usually performed after treatment failure)

Cough in Gastroesophageal Reflux Disease
Management
- Cough will response to treatment 23 - 25 weeks on average
- Full treatment regimen consists of
- High protein, low fat (<45g/d) TID
- Avoidance of food/beverage high in acid, or reduce lower esophageal tone
- No eating between meals and 2-hour prior to reclining
- Head elevation
- Proton pump inhibitors + Prokinetic agents
- If cough persist despite treatment and positive 24-hr pH/impedance
monitoring → consider antireflux surgery

Approach in Adults
Red Flags Smoking
ACEI
4 Most common
- Hemoptysis
- Voice disturbance
- Dysphagia
- Vomiting
- Dyspnea
- Systemic symptoms
● Fever
● Weight loss
● Edema
- Abnormal PE / CXR
- Smoker
Asthma
1
2
common causes
- negative study
- negative study
Profile predictive of having common cause
- Age > 15 year
- Cough > 2 months
- Immunocompetent
- Normal CXR
- Not exposed to irritants
- Not taking ACEI
- CHEST Guideline and Expert Panel Report. Chest 2018;153:196-209.
- ข้อแนะนำกำรปฏิบัติสำธำรณสุข กำรรักษำผู้ป่วยไอเรื้อรังในผู้ใหญ่ พ.ศ.2559

Further investigations
● Swallow evaluation
● Sinus imaging
● High resolution chest CT
● Bronchoscopy
● Cardiac evaluation
● Occupational assessment
● Uncommon causes
● Recurrent aspiration
● Chronic bronchiectasis
● Bronchogenic carcinoma
● Interstitial lung disease
● Chronic lung infection
● Laryngeal lesion
● Heart failure
● Psychogenic cough
CHEST Guideline and Expert Panel Report. Chest 2018;153:196-209.

Irwin RS, French CL, Chang AB, Altman KW. Classification of cough as a symptom in adults and management algorithms: CHEST Guideline and Expert Panel Report. Chest 2018;153:196-209.
Subacute cough algorithm for the management of patients ≥ 15 years of age with cough lasting 3 to 8 weeks
AECB = acute exacerbation of chronic bronchitis
GERD = gastroesophageal reflux disease
NAEB = nonasthmatic eosinophilic bronchitis

Irwin RS, French CL, Chang AB, Altman KW. Classification of cough as a symptom in adults and management algorithms: CHEST Guideline and Expert Panel Report. Chest 2018;153:196-209.
Chronic cough algorithm for the management of patients
≥ 15 years of age with cough lasting > 8 weeks
ACEI = angiotensin-converting enzyme inhibitor
A/D = antihistamine/decongestant
BD = bronchodilator
HRCT = high-resolution CT
ICS = inhaled corticosteroid
LTRA = leukotriene antagonist
PPI = proton pump inhibitor

Approach in Adults
Red Flags Smoking
ACEI
4 Most common
- Hemoptysis
- Voice disturbance
- Dysphagia
- Vomiting
- Dyspnea
- Systemic symptoms
● Fever
● Weight loss
● Edema
- Abnormal PE / CXR
- Smoker
Asthma
1
2
common causes
- negative study
- negative study
- CHEST Guideline and Expert Panel Report. Chest 2018;153:196-
209.
- ข้อแนะนำกำรปฏิบัติสำธำรณสุข กำรรักษำผู้ป่วยไอเรื้อรังในผู้ใหญ่
พ.ศ.2559
Profile predictive of having common cause
- Age > 15 year
- Cough > 2 months
- Immunocompetent
- Normal CXR
- Not exposed to irritants
- Not taking ACEI

Unexplained Chronic Cough
0 - 46% of chronic cough unexplained in overall studies
Only 0 - 10% unexplained
if evidence-based diagnostic
protocol were strictly followed
● FAIL TO DIAGNOSIS
validated diagnostic protocol not followed
● Correct diagnosis
but INADEQUATE TREATMENT
● Correct diagnosis & treatment
but REFRACTORY TO TREATMENT
chronically
heightened
cough reflex
sensitivity

Common Pitfalls in Diagnosis
Failure to recognize that
- Etiologies of chronic cough may be multifactorial
- GERD and UACS can also produce phlegm
- Cough can be the only manifestation of:
- Cough variant asthma
- Silent UACS
- Silent GERD

Common Pitfalls in Management
- Premature abortion of treatment
- Asthma, UACS: up to 4 weeks
- GERD: up to 6 months
- Fail to recognize environmental exposure & co-morbids
- Asthma, UACS, NAEB: Allergen avoidance
- GERD: OSA, CCB treatment, foods, lifestyle
- Premature labelling of
- Psychogenic cough
- Idiopathic cough
- Unexplained cough

Approach to
Chronic Cough in Children

Chronic cough in children is different from adults because
- Respiratory tract structure matures from infancy to adulthood
- Cough reflex is fully matured in early childhood
- The immune system is also developing
- Children have limited cognitive function and ability to self-express
Pulm Pharmacol Ther. 2007;20(4):365.

Specific cough pointers
symptoms or physical
examination findings that
suggest the presence of
underlying disease
usually dry

Specific Cough Pointers
History: pulmonary symptoms, timing and triggers
- Productive cough … protracted bacterial bronchitis, aspiration, lung abscess
- Hemoptysis … TB, ILD, bronchiectasis, autoimmune lung disease
- Wheezing … asthma, bronchiectasis
- Dyspnea … asthma, severe lung disease
- Recurrent pneumonia … immunodeficiency, structural disease
- Neonatal symptom … immunodeficiency, congenital anomaly
- Episode of choking … inhaled retained foreign body
- Situation-anxiety related, suppressible … tic, psychogenic cough
- Environmental exposure
Chang AB, Glomb WB. Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest 2006; 129:260S.
Chang AB, Landau LI, Van Asperen PP, et al. Cough in children: Definitions and clinical evaluation. Position statement of the Thoracic Society of Australia and New Zealand.
Med J Australia 2006; 184:398

Associated symptoms or conditions
- Cardiac disease … tracheomalacia, primary ciliary dyskinesia
- Neurological disease … aspiration
- Feeding intolerance … laryngeal/tracheal disorder, aspiration
- Failure to thrive … severe lung disease, cystic fibrosis, indolent infection
- Autoimmune disease … Interstitial lung disease (ILD)
- Immunodeficiency … opportunistic infections, deep infections
- Chronic fever … indolent infections

Examination
- Clubbing finger … ILD, bronchiectasis
- Chest wall abnormality … neuromuscular disease, lung disease
- Hypoxia … lung disease
- Abnormal breath sound … lung disease, heart failure
Routine investigations
- Abnormal CXR … lung disease
- Abnormal spirometry … obstructive / restrictive lung disease

Classic Cough Sounds
- Barking or brassy cough … Tracheomalacia, tic (if acute: Croup)
- Honking or 'goose-like' cough … Tracheomalacia, tic, psychogenic cough
- Paroxysmal cough (+/-inspiratory whoop) … Pertussis and parapertussis
- Staccato cough … Chlamydia in infants
- Cough productive of casts … Plastic bronchitis, mucous plugs (e.g., ABPA)
- Wet cough in the mornings … Suppurative lung diseases
- Productive cough … Presence of endobronchial secretions

Chest. 2012 Oct;142(4):943-950.
A. Kantar et al. / Early Human Development 89 (2013) S19–S24
% by age group 0-2 y 2-6 y 6-12 y >12 y
PBB 53 40 27 28
Asthma/RAD 27 19 11 7
Bronchiectasis 5 13 10 0
Non-specific 11 11 20 28
Tracheomalacia 5 7 6 7
Psychogenic 0 0 15 21
Pertussis 1 5 5 7
Aspiration 6 0 1 0
Primary etiology of chronic cough
PBB: Protracted bacterial bronchitis

A.LAmas et al. Arch Bronconeumol. 2014 Jul;50(7):294-300.

Approach to Chronic Cough in Children
Specific Cough Pointer
Non-specific WET Cough
Non-specific DRY Cough
Diagnostic test
Provision Dx: PBB
ATB trial 2-4 weeks
Watch & Wait
2 weeks
Therapeutic trial
as Asthma
Budesonide
400 mcg/d
Not improve
ReassessmentSpecific treatment
PBB likely
Reassess in 3-4 m
Not improve
Asthma likely
Not improve
Chest 2017; 151:875.
Chest 2006; 129:260S.
improve
2-4 wk
improve

A. Lamas et al. / Arch Bronconeumol. 2014;50(7):294–300
History and physical examination

Primary ciliary dyskinesia (PCD)
- “Immotile-cilia syndrome”
- Congenital impairment of mucociliary clearance
- Rare, autosomal recessive
- Clinical phenotype:
- Newborn period: neonatal respiratory distress
- Infancy to childhood period: chronic wet cough, recurrent lower respiratory tract
infections and bronchiectasis, chronic rhinosinusitis ± polyps, recurrent otitis media
- Adult: infertility due to reduced sperm motility in male, ectopic pregnancy due to
abnormal fallopian transit of oocyte.
- Kartagener’s syndrome (one of PCD)
Triad = situs inversus, chronic sinusitis, bronchiectasis
Pediatric Pulmonary. 2016; 51:115-132

Leigh MW, Pittman JE, Carson JL, et al. Clinical and Genetic Aspects of Primary Ciliary Dyskinesia/Kartagener Syndrome. Genet Med 2009; 11:473.
Primary ciliary dyskinesia (PCD)
- Diagnosis
- Confirmation test:
- Electron microscopic ultrastructural analysis of nasal scrape/bronchial brush biopsy
(gold standard)
- High-speed videomicroscopy analysis (HSVA)
- Screening test: nasal nitric oxide (extremely low), Saccharin test (normal ≤ 20 min)
- Genetic test: mutations in the outer/inner dynein arms (DNAH5, DNAL1)
Transmission electron microscopy

Cystic fibrosis (CF)
● Fatal inherited, 1:2,000 live birth, white
● Autosomal recessive
● Mutation in the cystic fibrosis
transmembrane conductance regulator
(CFTR) protein regulating the chloride
transport in epithelial cell
● Multisystem disease involving several
organ: RS, GI, GU, osteoporosis,
pseudotumor cerebri
● Decrease in apical chloride transport and
a thickening of mucus secretion
● There is no known cure for cystic fibrosis
Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017; 181S:S4.
Diagnostic criteria: 1 + 1 criterias
One or more typical phenotypic features of CF
● Chronic pulmonary disease
● Chronic sinusitis
● Characteristic gastrointestinal and nutritional abnormalities
● Salt loss syndromes
● Obstructive azoospermia
History of cystic fibrosis in a sibling
Positive newborn screening test
Elevated sweat chloride concentration (≥60 mmol/L) ≥2 occasions
2 mutations known to cause CF on separate alleles
Nasal potential difference (NPD) testing that are typical for CF

Protracted Bacterial bronchitis (PBB)
● Common in young children < 5yrs
● Often misdiagnosed as asthma
→ inappropriate and often high doses of inhaled corticosteroids
● Definition: All 3 of the following criterias are fulfilled
1) Presence of continuous chronic wet cough (>4 weeks duration)
2) Absence of specific cough pointers suggestive of other causes
3) Cough resolved following a 2– 4-week of appropriate oral antibiotic
Kantar A, Chang AB, Shields MD, et al. ERS statement on protracted bacterial bronchitis in children. Eur Respir J 2017

Typical respiratory pathogens
- H. influenzae
- Streptococcus pneumoniae
- Moraxella catarrhalis
"Recurrent PBB": > 3 episodes/year
Should evaluate for bronchiectasis or
an underlying disorder that predisposes to
chronic lung disease
- Retained foreign body
- Congenital abnormalities
- Others: cystic fibrosis, primary ciliary dyskinesia, immunodeficiency
Kantar A, Chang AB, Shields MD, et al. ERS statement on protracted bacterial bronchitis in children. Eur Respir J 2017

Chest. 2016 Nov;150(5):1101-1108.

Treatment
- Antibiotics with a minimum course of 2 weeks (up to 4 weeks).
- Oral amoxicillin-clavulanate
- active against beta-lactamase-producing strains of H. influenzae
- Alternatives include: oral second or third generation cephalosporins, trimethoprim-
sulfamethoxazole or macrolide
- Azithromycin is not recommended
- a lack of studies demonstrating efficacy for chronic wet cough, and
- concerns about increasing resistance of S. pneumoniae and H. influenzae
Eur Respir J. 2017;50(2) Epub 2017 Aug 24.

Thorax. 2012 Aug;67(8):689-93. Epub 2012 May 24.
Amoxi-Clav
22.5 mg/kg/dose bid
Placebo

Role of bronchoscopy
- Appropriate prior to antibiotic if:
- atypical features
- suspicion of an inhaled foreign body
- fail to respond completely after 4 weeks of empirical ATB
+/- children with a very long duration of cough (eg, ≥12 months)
Arch Dis Child. 2014 Jun;99(6):522-5. Epub 2014 Feb 12.

Post-infectious cough
- No definite pathogenesis, likely transient cough hypersensitivity due to airway
inflammation
- The specific infection remains unidentified in most cases
- Respiratory viruses (human rhinoviruses, influenza viruses, respiratory
syncytial viruses, and human metapneumovirus)
- Mycoplasma pneumoniae
- Chlamydia pneumoniae
- Bordetella pertussis
Pediatric Respiratory reviews(2018). https://doi.org/10.1016/j.prrv.2018.08.002
Pediatr Infect Dis J. 2011 Dec;30(12):1047-51.

Bordetella pertussis
Clinical: Causes paroxysmal cough associated with vomiting or apnoeas in infants
Catarrhal phase → Paroxysmal phase → Convalescent phase
Diagnostic test: Bacterial culture and PCR testing are the most useful
Treatment: Macrolide, ideally in the first 2 weeks to reduce infectivity
Pediatric Respiratory reviews (2018). https://doi.org/10.1016/j.prrv.2018.08.002

Age group Primary agents Alternate agent
Azithromycin Erythromycin Clarithromycin TMP-SMX
<1 month Recommended agent; 10 mg/kg per
day in a single dose for 5 days (only
limited safety data available)
Not preferred; erythromycin is associated
with infantile hypertrophic pyloric stenosis;
use if azithromycin is unavailable; 40 mg/kg
per day in 4 divided doses for 14 days
Not recommended (safety data
unavailable)
Contraindicated for infants aged <2
months (risk for kernicterus)
1-5 months 10 mg/kg per day in a single dose for 5
days
40 mg/kg per day in 4 divided doses for 14
days
15 mg/kg per day in 2 divided doses
for 7 days
Contraindicated at age <2 months; for
infants aged ≥2 months, TMP 8 mg/kg
per day, SMX 40 mg/kg per day in 2
divided doses for 14 days
Infants (aged
≥6 months)
and children
10 mg/kg in a single dose on day 1
(maximum: 500 mg); then 5 mg/kg per
day (maximum: 250 mg) on days 2
through 5
40 mg/kg per day in 4 divided doses for 7 to
14 days (maximum: 2 g per day)
15 mg/kg per day in 2 divided doses
for 7 days (maximum: 1 g per day)
TMP 8 mg/kg per day, SMX 40 mg/kg
per day in 2 divided doses for 14 days
(maximum TMP 320 mg, SMX 1600 mg
per day)
Adults 500 mg in a single dose on day 1 then
250 mg per day on days 2 through 5
2 g (base) per day in 4 divided doses for 7 to
14 days
1 g per day in 2 divided doses for 7
days
TMP 320 mg per day, SMX 1600 mg per
day in 2 divided doses for 14 days
Recommended oral antimicrobial treatment and postexposure prophylaxis for pertussis, by age group
1.American Academy of Pediatrics. Pertussis (whooping cough). In: Red Book: 2018 Report of the Committee on Infectious Diseases, 31st ed, Kimberlin DW, Brady MT, Jackson MA, Long SS
(Eds), American Academy of Pediatrics, Itasca, IL 2018. p.620.
2.Centers for Disease Control and Prevention. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis. 2005 CDC guidelines. MMWR 2005; 54:10.

Tic cough (habit cough)
Somatic cough disorder (psychogenic cough)
Tic cough a cough with features similar to a vocal tic, especially suppressibility, distractibility, and
suggestibility
Somatic cough disorder is a diagnosis of exclusion and fulfills criteria for somatic disorder in DSM-5
Both coughs have distinctive nature
- may consist of short, single dry coughs (tics) or
- may be loud and repetitive (barking/honking)
- more prominent during office visits and absent at night
- a history of antecedent URI is common and may be a triggering event
Treatment
- suggestion therapy: employs a distractor, such as sipping warm water, as an alternative to the cough
- explanation and reassurance (directed primarily to the child) also may be effective
- referral to a psychologist if unresponsive to suggestion therapy
Chest. 2015 Jul;148 (1):24-31

Management Consideration in nonspecific dry cough
- Empirical treatment of UACS, GERD, asthma should not be routinely used
- If an empirical trial is used, the trial should be of a defined limited duration
- Family education: good prognosis
- Avoidance of tobacco smoke
- Cough suppressants: Codeine and derivatives are not recommended due to
lack of efficacy and potential adverse events of respiratory suppression and
opioid‐toxicity
Chest. 2017;151(4):875. Epub 2017 Jan 16.
Cochrane Database Syst Rev. 2016 Jul 13;7

Allergy Asthma Immunol Res. 2018 Nov;10(6):591-613.
Summary of recommendations

Allergy Asthma Immunol Res. 2018 Nov;10(6):591-613.

Approach to chronic cough

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