1. Mod.1-8 – Cough: Clinical perspectives and therapy – 1
Ting Joe Li Yah
Mod.1-8 Cough: Clinical perspectives & therapy
Introduction
1. Cough affects the quality of life and have many environmental triggers
a. 2 billion pounds spend on cough medications
2. Common causes and associations with chronic cough
a. 90%: Gastro-oesophageal reflux, rhino sinusitis, asthma (eosinophilic airway disease)
b. Upper respiratory tract infection
c. ACE-inhibitors
d. COPD/Emphysema
e. These are usually ward off by CT scan: Bronchiectasia/EF, neoplasm, interstitial lung disease,
foreign body inhalation, infection e.g. TB
Gastro-oesophageal reflux (GOR)
1. Diagnosis
a. GOR symptoms vary, not always present (75% patients have no symptoms ‘clinically silent’)
b. ‘Reverse causation’, where cough causes reflux, instead of reflux causing cough
c. GOR can co-exist in patients with cough due to other conditions
d. Demonstrate temporal association (two or more events that occur around the same time but
are unrelated, chance occurrences) between GOR and cough
2. Mechanisms
a. Microaspiration?
i. Pepsin could be aspirated into the larynx.
ii. Hence, check for pepsin in the BAL, but level was not increased in people with cough
b. Laryngopharyngeal Reflux?
i. Erythema, oedema, thickened post pharynx
ii. Indistinguishable from coughing trauma, where repeated trauma from coughing
causes the redness and not the other way round
c. Distal Reflux: Significant temporal relationship between cough and distal GOR
d. Central cough
i. Physiological levels of reflux stimulate cough
ii. Distal acid infusion ↑ cough reflex sensitivity & activate cough centre in the brain
3. Treatment with proton pump inhibitor (PPI)
a. Cornerstone therapy for GOR, but the Cochrane meta-analysis did not confirm reduction in
cough severity with PPIs
b. No different on cough scores or LCQ and lack of PPI benefit in asthma
c. Need large multicentre study to provide definitive guidance, trial of PPI still recommended
4. Non-acid
a. The lack of PPI benefit could be due to non-acid GOR
b. Conventional pH-monitors are unable to determine the direction or the composition of
refluxate (air/liquid/solid)
c. Using an oesophageal impedance (OI) + pH, able to detect the change in current to identify
the level of reflux and the type of reflux (acid or non-acid) through current changes
d. Temporal relationship between non-acid GOR & cough: 5% of GOR causality related to cough
e. Furthermore studies needed, more sensitivity and specificity of impedance in diagnosis of
GOR-cough and predicting response to therapy

2. Mod.1-8 – Cough: Clinical perspectives and therapy – 2
Ting Joe Li Yah
5. Surgery
a. Guidelines recommend surgery (Nissen’s fundoplication) for selected cough patients with
persistent GOR despite treatment
b. Case-reports of success but lack of long-term follow ups. In addition, there were risks of
severe dysphagia (difficulty in swallowing), flatulence and ↑ bowel symptoms
c. Hence, patient dissatisfaction was lower than anticipated successful outcome
d. This surgical intervention requires more controlled studied
Asthma
1. Cough is an important symptoms in asthma
2. Mechanisms
a. Airway inflammation  peripheral nerve sensitisation
b. Constrictor stimuli  bronchoconstrictor induced cough
c. Coexistent triggers  nasal disease, oesophageal reflux and bronchiectasis (irreversible
dilation of part of the bronchial tree caused by destruction of the muscle and elastic tissue)
3. Eosinophilic airway diseases (EAD) consist of asthma, cough variant asthma, atopic cough and
eosinophilic bronchitis (EB)
a. Longitudinal studies needed to determine if distinction between the EAD has clinical
implications
i. Eosinophilic bronchitis (EB) always do have >3% sputum eosinophils, while the other
EAD have frequent sputum eosinophils only
ii. Asthma has higher mast cells number in ASM, while atopic cough has neurokinin (NK)
b. Studies needed to assess accuracy and clinical usefulness (response to treatment) to
determine optimal test in EAD
4. Treatment
a. Optimal asthma treatment may not be effective at reducing cough (61% still cough)
b. Need to explore reasons for treatment failure
i. Inadequate therapy (inhaler technique, compliance, DPI-cough, need for systemic
treatment (small airway disease))
ii. Other coexisting causes like smoke?
iii. Perhaps need to intensify treatment in presence of eosinophilic inflammation
c. Inhaled b/d are ineffective in children & more RCT are needed for combination with ICS
d. For EB, ICS very good response, but long term therapy may be needed
Uncommon chronic cough associations/causes
1. Obstructive sleep apnoea (OSAS)
a. 44% cough patients in the community has OSAS (diagnosed with polysomnography)
b. Mainly overweight females who snore. Snoring shreds the mucosa causing epithelial injury
leading to upper airway inflammation
c. Significant reduction in cough when CPAP is used
2. Tracheobronchopathia osteochondroplastica: Benign, submucosal nodules growing from
submucosal layer of airways, protruding into bronchial lumen
3. Arnold reflex (ear): Ear wax or foreign body impacting on the branch of the vagus nerve.
4. Autonomic dysfunction – Holmes-Adie Syndrome
a. Holmes-Adie Syndrome: A condition of unknown aetiology characterised by tonic pupillary
reactions and absent tendon reflexes, signs of autonomic neuropathy causing aniscoira
(unequal size of pupils), one more dilated than the other

3. Mod.1-8 – Cough: Clinical perspectives and therapy – 3
Ting Joe Li Yah
b. Mechanism behind cough is poorly understood, but has been proposed that selective loss of
thinly myelinated afferents in the lung, trachea and larynx leads to denervation
hypersensitivity of secondary neurons in the nucleus solitarius
5. Chronic tonsillar enlargement; Fungal-associated chronic cough (FACC) – Basidiomycetous fungi
(in Japan); Drugs – Indacaterol; Autoimmune disease (hypothyroidism)
Idiopathic Cough
1. Clinical
a. Despite detailed investigations & treatment trials in specialised clinic, 40% unexplained cases
b. Characteristics
i. Chronic cough > 8 weeks; Acute URTI preceding cough
ii. Triggers = aerosols, eating (biscuits, breads), cold/hot air
iii. Cough may cause chest pain, incontinence and social embarrassment
c. Significant impairment on quality of life
d. High levels of anxiety and symptoms of depression as a consequence of cough
2. Pathology
a. Enhanced airway sensory nerve sensitivity
i. Increased capsaicin sensitivity, activates unmyelinated C-fibres
ii. Increased density sensory nerve fibres
b. Increase expression of airway receptors mediating cough such as the transient receptor
potential vaniloid-1 ion channel  could target the channel as an intervention
c. Increase sensitivity of laryngeal glottic closure reflex and increase prevalence of vocal cord
dysfunction and voice disorders  could use speech therapy as an intervention
d. Airway inflammation
i. Increase mediators  histamine, PGE, CysLTs, activate cough reflex
ii. Increase cells  neutrophils and lymphocytes
e. Goblet cells hyperplasia
3. Treatment
a. Limited therapeutics options for idiopathic cough as recommendations could be based on
opinions or evidence. RCT shows that placebo response is significant (20%)
b. Morphine: Reduce cough severity, central mechanism of action as peripheral cough reflex
hypersensitivity not reduced. Side effects: Dependence. Hence, need novel anti-tussives.
Mainly used for patients with cough caused by lung cancers
c. Codeine: Ineffective for chronic COPD cough. Side effects: Constipation and addiction
d. NOP1 agonist: RCT for post-viral cough not superior to codeine or placebo
e. Erythromycin: RCT shows a reduction in sputum amount but ineffective
Anti-tussive  theobromine (cocoa)
1. Properties
a. Low potency as bronchodilator but unique anti-tussive effect in guinea pig cough model
b. The lack of a methyl group allows it to have an anti-tussive effect
c. Cocoa ≫≫ Tea ≫ Coffee
2. Randomised cross-over study
a. Cough challenges: Induce cough provocation method by capsaicin (extract of chilli pepper)
then measure sensitivity of cough reflex and is used as a responsive measure to intervention
and to test efficacy of new cough treatment
b. Tried with theobromine 1000mg, codeine phosphate 60mg and placebo

4. Mod.1-8 – Cough: Clinical perspectives and therapy – 4
Ting Joe Li Yah
c. Theobromine was shown to increase cough threshold significantly when compared to
codeine and placebo
d. No adverse effects on CVS, CNS and GI reported
3. Evaluation of treatment on sensory nerve depolarisation
a. It is a A1-receptor antagonist and PDE inhibitor that increase intracellular cAMP
b. A2-receptor agonist analogue that inhibit capsaicin sensitive afferent nerves in guinea pig
Cough in the Clinic
1. Obtain patient’s history
a. Patients own description of cough pattern
b. Using detailed questions: Cough on phonation, rising from bed, associated with certain food,
eating in general, throat clearing. For GOR, if there is any symptoms of heartburn/indigestion
c. ‘honking’ cough, disappears with sleep  psychogenic in children
d. Even with identifiable cough triggers, it does not provide specific diagnostic value
e. Sleep history, eczema, hay fever, family history of asthma, nasal symptoms, GI-indigestion,
drug history and smoking history
2. Examination of the oropharynx, neck/Thyroid, pupils, ankle tendon reflexes and Ear/Nose/Throat
3. Investigation:
a. Spirometry, chest radiograph and epworth score
b. Skin prick testing for atopy
c. Full PFTS with flow volume loop for lung function (check for small airway disease)
d. High-Resolution Computed-Tomography (HRCT)  to check for lung tumour
e. Histamine challenge for bronchial hyper-reactivity
f. Blood auto antibodies to check for autoimmune disease and Quality of Life through cough
questionnaires
4. Treatment
a. Cough and its associated condition
i. Asthma/EAD  ICS +/- LABA, anti-LTs
ii. GOR  PPi
iii. Post-nasal drip  nasal spray for corticosteroid, antimuscarinic and antihistamine
b. Idiopathic cough
i. Hot ginger infusion with honey
ii. Steam inhalation with Vick vaporub
- Consist of Menthol that act on TRP channel, a anti-tussive receptor
- Cooling effect on airway
iii. Gabapentin  a GABA analogue for neuropathic pain
iv. Nebulised bupivacaine  local anaesthesia
5. Non-pharmacological treatment
a. Cough physiotherapy (education)  cough trigger avoidance (strategies to reduce cough)
and have the capacity for voluntary cough suppression
b. Speech and language therapy for cough suppression
c. Reduce laryngeal irritation through increase hydration, decrease exposure to irritating stimuli
and vocal hygiene
d. Psycho-educational counselling for internalising focus of control and accept that treatment is
hard work