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SUPPLEMENT TO Journal of the association of physicians of india MAY 2013 VOL. 61
Chronic Cough
SP Rai*
Introduction
C ough is a normal protective mechanism of the respiratory
tract, as well as a common symptom of respiratory disease.
Chronic cough is defined as cough lasting for more than 8
weeks.1 This definition is based on fact that a cough lasting
longer than 8 weeks is unlikely to be due to post infectious
cough.2 Chronic cough is a common symptom of almost all
chronic respiratory and some non-respiratory illnesses with an
estimated prevalence of 11% to 20% of the population.3 It can be
associated with significant distress and impairment in quality of
life.4 Effective management requires accurate etiologic diagnosis.
Several recognisable causes of chronic cough, such as chronic
obstructive pulmonary disease (COPD), pulmonary tuberculosis,
sarcoidosis, interstitial lung disease, lung cancer, an inhaled
foreign body, and heart failure will be obvious after clinical
examination, chest radiography, and spirometry. However
despite extensive investigation and treatment trials, up to 46%
of patients with chronic cough have an unexplained etiology.5
Pathophysiology
Cough is a defensive reflex mechanism that clears secretions
from the upper airways of the respiratory tract; which is triggered
by the stimulation of a complex reflex arc. Cough receptors are
located in the respiratory tract from the hypopharynx and larynx
to the segmental bronchi. Several different types of sensory nerve
receptors respond to chemical, mechanical, inflammatory or
thermal stimuli activating cough receptors connected to vagal
afferent nerves. A cough centre in the medulla receives signals
from these activated cough receptors via afferent fibres in the
vagus nerve. Voluntary inhibition or production of cough is
possible because of the influence of higher cortical centres on
this cough centre. Efferent signals are then sent to the muscles
that produce the forced expiratory effort.6
Differential Diagnosis
The common causes of chronic cough in an immunocompetent
nonsmoking adult with normal chest radiograph are angiotensin-
converting enzyme (ACE) inhibitor medication,7 upper airway
cough syndrome (UACS, also known as postnasal drip
syndrome), asthma, or gastroesophageal reflux disease (GERD),
alone or in combination. Chronic cough has two or more causes
in 18 to 62 percent of patients, and three causes in up to 42
percent of patients.8,9 Empiric treatment should be initiated
sequentially for the three most common causes of chronic cough
until symptoms are resolved.
UACS
Rhinitis, often associated with sinusitis and post-nasal drip,
is frequently identified as a common cause of chronic cough.10
Mechanical stimulation of cough receptors in the hypopharynx
and larynx either directly or indirectly through inflammatory
mediators has been proposed as a mechanism of cough in
patients with UACS.11
*
Consultant in Pulmonary & Sleep Medicine, Kokilaben Dhirubhai
Ambani Hospital & Medical Research Institute, Four Bungalows,
Andheri (West), Mumbai- 400053
GERD
Gastro-esophageal reflux (GERD) is an important cause of
chronic cough that may be the sole clinical manifestation.12 LPR
refers to extraesophageal manifestations of GERD, when gastric
contents reach the larynx and pharynx. A number of symptoms
are reported with LPR, including chronic cough, throat clearing,
hoarseness, globus sensation, and vocal cord dysfunction. Up
to 75% of patients who were found to have GERD-induced
cough do not have symptoms of heartburn or acid indigestion.
Endoscopy is typically not helpful, and most patients with
chronic cough and GERD do not have evidence of esophagitis.
Asthma Syndrome
Asthma is characterized by chronic or recurrent respiratory
symptoms associated with airway inflammation and variable
airflow obstruction. Symptoms include wheeze, dyspnea, and/or
cough. Because of possible pathophysiologic differences, patients
with cough variant asthma are thought to represent a different
phenotype from those with classic asthma.13 A third cough-
predominant eosinophilic airway disorder is nonasthmatic
eosinophilic bronchitis (NAEB). These are non-smoker with
eosinophilic airway inflammation, normal chest radiographic
and spirometric results, and no evidence of variable airflow
obstruction.
Usually most coughs related to upper respiratory tract
infections resolve within 3 weeks however, cough may
persist in a small number of patients. Infection in most cases
remains unidentified; Mycoplasma pneumoniae, Chlamydia
pneumoniae, and Bordetella pertussis have been among the
organisms implicated in adults .14 Persistent cough due to
infection might be more likely in patients with pre-existing
airway problems.
Obstructive sleep apnea (OSA) at times can cause chronic
cough. Possible mechanisms of OSA-associated cough include
apnea causing increased transdiaphragmatic pressure leading
to lower esophageal sphincter insufficiency, GERD, and cough.
Airway inflammation from epithelial injury associated with OSA
can also be operative.
Psychogenic or Habitual Cough
A habitual cough is a diagnosis of exclusion. Many patients
with this condition do not cough during sleep, are not awakened
by cough, and generally do not cough during enjoyable
distractions.
Some investigators have suggested that up to 20% of patients
with chronic cough have more than one potential aggravating
factor, and all factors need to be addressed before satisfactory
control can be achieved.15
Chronic Cough in Children
In children, a cough lasting longer than four weeks is
considered chronic.16 The most common causes of chronic cough
in children are asthma, respiratory tract infections, and GERD.
The differential diagnosis for chronic isolated cough without
associated wheezing in an otherwise healthy child includes
recurrent viral bronchitis, postinfectious cough, pertussis-like
SUPPLEMENT TO Journal of the association of physicians of india MAY 2013 VOL. 61 29

or abnormal physical signs

Chronic Cough increases the probability of lung
disease requiring appropriate
History, investigations, which could
A cause of
examination, Smoking include high-resolution CT scan
Investigate cough is
Chest X-ray ACE-I Discontinue of the chest and bronchoscopy.
and Treat suggested
Onset of cough with symptoms
suggestive of an upper or lower
Upper Airway Cough Syndrome (UACS) respiratory tract infection raises
Inadequate empiric treatment No response the possibility of a post infectious
response Asthma cough; prominent whoops, a
to optimal Rx ideally evaluate (Spirometry, bronchodilator very troublesome nocturnal
reversibility, bronchial provocation challenge) cough, and cough associated
or empiric treatment with vomiting are all associated
Non-asthmatic eosinophilic bronchitis (NAEB)
with pertussis. An important next
Ideally evaluate for sputum eosinophilia
or empiric treatment step is to assess objectively cough
Gastroesophageal Reux Disease (GERD) severity, frequency, intensity
Empiric treatment and sensitivity. Cough that
Inadequate For initial treatments see box below worsens when supine suggests
response postnasal drip, esophageal reflux,
to optimal Rx bronchiectasis, chronic bronchitis
Further investigtions to consider: or heart failure. Production
24 h esophageal pH monitoring
of clear sputum suggests a
Endoscopic or Videouoroscopic
Swallow Evaluation hpersensitivity mechanism,
Barium esophagram while purulent sputum implies
Sinus imaging chronic infection (sinusitis,
HRCT bronchiectasis, tuberculosis),
Bronchoscopy and blood-tinged sputum
Echocardiogram
points to cancer, tuberculosis, or
Environmental Assessment
Consider other rare causes (see section 26) bronchiectasis. A non-productive
cough is commonly due to ACE
Initial Treatments
inhibitors. Sour taste or heartburn
Important General Considerations
Optimise therapy for each diagnosis UACS - A/D is reported by 60% of patients
Check compliance Asthma - ICS, BD, LTRA with a reflux etiology. Smoking
Due to the possibility of multiple causes NAEB - ICS history, ACE inhibitor use,
maintan all partially eective treatment GERD - PPI, diet / lifestyle presence of systemic symptoms
For futher detailed treatment see
(fever, anorexia/weight loss, night
each section recommendations
sweats, and progressive fatigue),
geographic and environmental
Fig. 1 : Evaluation and management of chronic cough
exposure to infectious or toxic
illness, cough variant asthma, UACS, psychogenic cough, and agents, and previous diagnoses
GERD. Signs suggestive of serious underlying lung disease of cancer, tuberculosis, or human immunodeficiency virus are
include neonatal onset of cough, chronic moist or purulent cough, also key historical points.
cough starting with and persisting after a choking episode, cough Physical examination focuses on the upper and lower
occurring during or after feedings, or associated failure to thrive. respiratory tract and cardiovascular system. Examining
Foreign body aspiration should be considered in young children. the nose (polyps, discharge, and obstruction), sinuses
Congenital conditions, cystic fibrosis, and immune disorders are (tenderness), oropharynx (secretions, mucosal edema and
possible diagnoses in children with chronic cough and recurrent tonsillar enlargement), ears (tympanic membrane or external
infections. Congenital abnormalities, although rare, can include canal inflammation), and neck (adenopathy) can provide
vascular rings, tracheoesophageal fistulas, and primary ciliary important confirmatory information. Diffuse wheezing implies
dyskinesia. asthma, COPD or heart failure, while localized wheezing may be
found when a tumor is present. Evidence of heart failure should
Evaluation of the Patient with Chronic also be sought. Epigastric tenderness, or reflux symptoms is
suggestive of esophageal reflux. Chest radiograph is important
Cough in the diagnostic algorithm. HRCT should be considered in
The evaluation of chronic cough includes a detail history, patients with abnormal chest radiographs. Sputum for Gram
including smoking status, environmental exposures, and stain, culture, and acid-fast staining are indicated when purulent
medication use. History of the onset of cough is important: an or blood-tinged sputum is noted, or suggestive radiograph
abrupt onset of coughing when eating raise the possibility of findings are present. Sputum cytology and examination for
foreign body aspiration and the onset of cough shortly after eosinophils may also be helpful when history and physical
introduction of ACE-inhibitor therapy raise the possibility of examination suggest a neoplastic or allergic etiology or NAEB.
ACE-inhibitor associated cough. The presence of hemoptysis, Bronchoscopy is indicated in patients with abnormal chest
sputum production, systemic symptoms, breathlessness, wheeze, radiograph, hemoptysis, obstructing lesions and infiltrates that
30 SUPPLEMENT TO Journal of the association of physicians of india MAY 2013 VOL. 61
otherwise elude diagnosis. Spirometry with bronchoprovocation
should be considered when asthma is suspected (Figure 1).
Management
Smoking should be stopped and exposure to passive
smoke eliminated in all patients. ACE inhibitors should be
stopped if possible, or dose reduced; if causative, this will
result in symptom relief in 2-4 weeks. Persistence of cough
after withdrawal of ACE inhibitors raises the possibility of
another cause of cough, such as asthma, the onset of which
has been linked to the use of ACE inhibitors. Therapeutic
trials are appropriate. Upper airway cough syndrome
may respond to removal of inhaled irritants or offending
antigens, treatment of chronic sinusitis with a course
of antibiotics, and weaning off topical decongestants.
Empiric therapy may also include a first-generation
antihistamine with or without oral pseudoephedrine;
improvement may be seen within 2 weeks, while some
patients will require several months to respond.17 Asthma
(highly suspected or proven by spirometry) should be
treated with inhaled corticosteroids and beta-2 agonists; a
clear improvement within 1 week. Sedating antihistamines
may also ease associated insomnia. 2-week trial of
oral prednisolone should be given in cases of NAEB.18
Treatment for GERD includes conservative measures (diet
manipulation), drug therapy (e.g., motility or prokinetic
agents, H2 antagonists, proton pump inhibitors (PPIs).19
A trial of treatment with acid-suppression therapy with
a PPI for 23 months would be reasonable in patients
with otherwise unexplained cough, even when there are
no suggestive upper gastrointestinal symptoms (Table).
Antitussive Treatment
In many patients, the cause of increased cough reflex will
probably remain at least partly unexplained, and treatments
directed against potential aggravating factors will not achieve
complete results. In many such patients, antitussive therapies are
needed.20 Narcotic antitussives (codeine 8-15 mg every 4 hours)
are preferred when chronic cough interferes with sleeping or
eating. Opioids, mainly acts centrally on the cough network in the
brainstem, but might also inhibit peripheral activation of cough
receptors. Such therapies are ineffective against acute cough of
the common cold and against cough in patients with COPD. A
non-narcotic antitussive, dextromethorphan, has proved to have
some effect on cough associated with upper respiratory tract
infections, although the effect on cough frequency was small
and of uncertain clinical relevance. The use of morphine and
diamorphine has been restricted to severe distressing cough in
malignant disease, in which cough is often associated with pain
and distress. There is evidence of the effectiveness of as low-
release formulation of morphine in a population with distressing,
unexplained cough. Expectorants and mucolytics (guaifenesin)
will improve symptoms by mobilizing sputum in patients with
inflammatory etiologies. Sedating antihistamines may also ease
associated insomnia.
Summary
Chronic cough is often viewed as a difficult clinical problem.
It can be physically and psychologically debilitating, occasionally
leading to serious complications. Although there are many
etiologies, an organized approach including focused history
and physical examination, directed testing in select cases, and
treatment trials lead to accurate, safe, and cost-effective diagnoses
in most patients. Additional symptomatic treatment is frequently
beneficial. Occasionally, diagnostic dilemmas, treatment failures,
or more serious causative disorders necessitate referral for
further testing and management
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