Chronic cough: new insights and future prospects

Alyn Morice; Peter Dicpinigaitis; Lorcan McGarvey; Surinder S. Birring

doi:10.1183/16000617.0127-2021

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FIGURE 1
a) Ascending and descending neural pathways involved in the cough reflex. b) Stimulation and activation of airway sensory neurons. Essentially, noxious stimuli or inflammation cause an increase in intracellular calcium which opens the pannexin channel and releases ATP to activate P2X3 channels on sensory nerves. This leads to cell depolarisation potentially triggering the opening of NaVs and generating an action potential which is carried through the vagus nerve to the central nervous system. Mechanisms for the cough reflex still have to be fully established in humans; many other pathways and receptors are probably involved. Ca²⁺: calcium; NaV: voltage-gated sodium channel; Na⁺: sodium; TRPA: transient receptor potential ankyrin; TRPM: transient receptor potential melastatin; TRPV: transient receptor potential vanilloid. Reproduced and modified from [5, 13].

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TABLE 1

Patient report-based outcome (PRO) to assess disease burden or treatment efficacy in adults with chronic cough

HRQoL tools
Name	Domains/items	Rating	MCID	Comments
LCQ [74]	19 items over three domains: physical; psychological; social.	Seven-point Likert scale (1=all of the time; 7=none of the time).	1.5–2.5 [75, 76, 77]	Developed and validated in chronic cough [74]. Used to assess treatment efficacy in clinical trials [78–81]. Recommended in guidelines [82]. Well validated [77]. MCID defined [76, 77]. Translations are available in 60 languages, including a range of European languages, Thai [83], Mandarin Chinese [84] and Korean [85].
CQLQ score [86]	28 items over six domains: physical complaints; extreme physical complaints; psychosocial issues; emotional wellbeing; personal safety fears; functional abilities.	Four-point Likert scale (1=strongly disagree; 4=strongly agree).	10.6 [87] 10.6–21.9 [77, 82]	Developed and validated in chronic cough [86]. Used to assess treatment efficacy in clinical trials [88, 89]. Recommended in guidelines [82]. Well validated [77]. MCID defined [77].
ACOS [45]	29 items over two domains (physical; psychosocial).	Yes or no.	10.6–21.9 [82]	Superseded by CQLQ [82].
CSS [90]	Two items: cough severity in daytime and night-time.	Six-point scale (0=no symptoms; 5=most severe).		Little clinical experience [77]. MCID not defined [77]. Has been translated into Korean [91].
CSD [92]	Seven items: frequency (three items); intensity (two items); disruptiveness (two items).	11-point scale (0=never; 10=constantly).	≥1.3 CSD (total score) −1.4 to −1.1 (domain scores) [93]	Developed in response to patient feedback [92]. Validated and MCID defined [93]. Widely used in clinical trials.
HARQ [94]	14 items covering major components of chronic cough	Six-point scale (0=no symptoms; 5=most severe)	16 [94]	Designed as a diagnostic test for chronic cough based on the symptoms of airway reflux [94]. High sensitivity and specificity [94]. Used in clinical trials [95, 96]. Translations are available in over 20 languages, including Mandarin Chinese [97] and Swedish [98]. Available for download at https://issc.info/

ACOS: Adverse Cough Outcome Survey; CQLQ: Cough-specific QoL Questionnaire; CSD: Cough Severity Diary; CSS: Cough Symptom Score; HARQ: Hull Airway Reflux Questionnaire; HRQoL: health-related quality of life; LCQ: Leicester Cough Questionnaire; MCID: minimal clinically important difference; RCC: refractory chronic cough. Adapted from [77].

TABLE 2

Summary of current treatments recommended by the European Respiratory Society [2]

Treatment	Evidence of efficacy/treatment recommendations	Side-effects
Non-pharmacological cough control therapy, such as physiotherapy and speech therapy	Few studies of non-pharmacological therapies. Physiotherapy/speech and language (2 months) [101]: reduced subjective cough score compared with placebo treatment (MD 2.8 points; 95% CI 1.3–4.0). Physiotherapy/speech and language (weekly for 4 weeks) [102]: improved LCQ (+1.53 points; 95% CI 0.21–2.85); reduced cough frequency per hour (fold change, 0.59; 95% CI 0.36–0.95); no significant effect on VAS severity or QoL outcomes.	None.
Non-opioid and non-anaesthetic antitussives	Evidence is limited and of variable quality [2, 3, 25].	Vary depending on the treatment used: see literature for details.
ICS and antileukotrienes	Evidence supporting the use of ICS or antileukotrienes is weak [2]. Available trial data are affected by incomplete assessments of asthma, allergy and non-asthmatic eosinophilic bronchitis [3]. ERS recommends a short trial (2–4 weeks).	Sore and dry throats (ICS) [103]. Headache, gastrointestinal disturbances, increased mucus production [104]; neuropsychiatric events (antileukotrienes) [105].
ICS and an LABA	Moderate evidence supporting use in patients with fixed airway obstruction. Salmeterol+fluticasone twice daily [106]: improved cough severity score compared with placebo (scale: 0–4) (MD −0.09; 95% CI −0.17, −0.01). Short-term trials of 2–4 weeks are recommended.	Sore and dry throat (ICS) [103], muscle cramps and muscle twisting (LABA) [103], potential risk of pneumonia with fluticasone in patients comorbid with COPD [107].
*Macrolides, e.g.* azithromycin**	Limited evidence for routine use. Can be considered if chronic bronchitis refractory to other therapy for a 4-week trial [2]. COPD GOLD stage ≥2 and chronic productive cough [108]: improved cough-specific QoL (LCQ; MD 1.3; 95% CI 0.3–2.3; p=0.01).	Nausea, diarrhoea, headaches or changes to sense of taste [109].
Opioids	In a double-blind, placebo-controlled study, slow-release morphine sulphate, 5 mg twice daily, improved the LCQ score by 3.2 points (p<0.01 versus baseline; p<0.02 versus placebo) and reduced cough severity recorded in a daily cough diary (p<0.01 versus baseline) [78].	Constipation, drowsiness, risk of dependency [2, 3, 110].
Tricyclic antidepressants	In a small case series, 72% of patients responded to treatment, as determined by subjective physician assessment of percentage improvement in cough symptoms [111].	Sedation, dry mouth, anxiety [111].
Gabapentin	Significant improvement in LCQ versus placebo in a randomized, double-blind, placebo-controlled trial. Mean between-group difference: 1.80 (95% CI 0.56–3.04; p=0.004) [80]. Reduction in cough frequency versus placebo (1 h of observation). Mean between-group difference: −27.3% (95% CI −51.8 to −2.9; p=0.028) [80]. Reduction in cough severity versus placebo. Mean difference on VAS: −12.23 points (95% CI −23.2 to −1.3; p=0.029) [80].	Confusion, dizziness, dry mouth, fatigue, nausea, blurred vision, cognitive changes [2, 3].
Pregabalin	Improvement in LCQ versus placebo in a randomized, controlled trial (both arms received speech pathology therapy). Mean difference: 3.5 points (95% CI 1.1–5.8; p=0.024) [81]. Improvement in cough severity. Mean difference on VAS: 25.1 (95% CI 10.6–39.6; p=0.002) [81].	Dizziness, fatigue, cognitive changes, nausea, blurred vision [2].

CI: confidence interval; COPD: chronic obstructive pulmonary disease; ERS: European Respiratory Society; GOLD: Global Initiative for Chronic Obstructive Lung Disease; ICS: inhaled corticosteroids; LABA: long-acting bronchodilator; LCQ: Leicester Cough Questionnaire; MD: mean difference; QoL: quality of life; VAS: visual analogue scale.

TABLE 3

Clinical phase II and phase III trial results assessing effects of P2X3 receptor antagonists versus placebo on awake cough frequency in patients with refractory chronic cough (RCC)

Drug	Dose regimen (n); design, duration	Cough frequency time period	Baseline coughs per hour, mean±sd		End of treatment coughs per hour, mean±sd		Mean % change in *cough frequency versus* placebo, (95% CI)**	Taste AEs, % (dysgeusia, hypogeusia)
Drug	Dose regimen (n); design, duration	Cough frequency time period	Placebo	Active	Placebo	Active		Placebo	Active
Gefapixant, (phase II) [42]	600 mg twice daily (n=24); 2 weeks	Awake	65.5±163.4 (n=21)	37.1±32.2 (n=19)	43.6±51.4 (n=21)	11.0±8.3 (n=19)	−75 (−88, −50), p=0.0003	0, 0	88, 54
Gefapixant, (phase II) [42]	600 mg twice daily (n=24); 2 weeks	24 h	44.7±105.2 (n=20)	26.6±22.6 (n=18)	28.9±31.2 (n=20)	7.7±6.0 (n=18)	−74 (−87, −46), p=0.001	0, 0	88, 54
Gefapixant dose escalation, (phase II) [43]	Part 1: 50–200 mg twice daily (n=29); crossover, 16 days Part 2: 7.5–50 mg twice daily (n=30); crossover, 16 days	Awake	Part 1: 52.8±40.4 Part 2: 46.1±39.8	Part 1: 54.5±41.1 Part 2: 49.6±44.0	Part 1: 54.0±39.3 Part 2: 50.6±34.4	Part 1: 28.0±23.8 Part 2: 27.0±27.4	Part 1: −41 (−59, −15), p<0.05 to −57 (−73, −31), p<0.05 Part 2: −15 (−35, 13) to −56 (−72, −31), p<0.05	0, 0	Part 1: 46–85, 7–15 Part 2: 7–53, NA
Gefapixant dose escalation, (phase II) [43]		24 h	Part 1: 37.9±27.5 Part 2: 32.2±28.0	Part 1: 39.7±28.4 Part 2: 36.3±32.3	Part 1: 40.6±28.4 Part 2: 37.3±25.9	Part 1: 21.3±18.0 Part 2: 20.8±20.5	NA, p<0.05 NA, p<0.05
Gefapixant, (phase IIb) [126]	7.5–50 mg twice daily (n=253); 12 weeks	Awake	27.6±2.3^#	24.1±3.0^# to 28.8±2.2^#	18.2±3.1^#	11.3±2.8^# to 14.5±3.7^#	−22 (−42, −5), p=0.097 to −37 (−53, −15), p=0.0027	5, 2	10–48, 0–24
Gefapixant, (phase IIb) [126]	7.5–50 mg twice daily (n=253); 12 weeks	24 h	20.5±2.2^#	17.6±3.0^# to 21.9±2.2^#	13.7±2.9^#	8.5±2.8^# to 10.8±3.6^#	−21 (−40, 5), p=0.10 to −38 (−53, −17), p=0.0014	5, 2	10–48, 0–24
Gefapixant (phase III) [138]	15 mg twice daily; 45 mg twice daily COUGH-1 (n=730): 12 weeks COUGH-2 (n=1314): 24 weeks	24 h	COUGH-1: 22.8^¶ COUGH-2: 19.5^¶	COUGH-1: 19.9^¶; 18.2^¶ COUGH-2: 19.4^¶; 18.6^¶	COUGH-1: 10.3^¶ COUGH-2: 8.3^¶	COUGH-1: 9.7^¶; 7.1^¶ COUGH-2: 8.1^¶; 6.8^¶	COUGH-1: 2 (−16, 23), ns −18 (−33, −1), p=0.041 COUGH-2: −1 (−14, −14), ns −15 (−26, −1), p=0.031	COUGH- 1: 3 COUGH-2: 8	COUGH-1: 11, 58 COUGH-2: 20, 69
Eliapixant (phase IIa) [128]	10–750 mg twice daily (n=40); crossover, 3 weeks	Awake	33.3±2.5^#	35.4±2.5^# (n=39)	30.5±2.5^#	10 mg: 30.0±2.7 (n=39) 50 mg: 25.6±2.8 (n=39) 200 mg: 22.9±2.7 (n=39) 750 mg: 22.6±2.4 (n=38)	10 mg: 5 (−11, 24)⁺, ns 50 mg: –16 (−29, 0.3)⁺, p<0.05 200 mg: −24 (−36, −11)⁺, p=0.002 750 mg: −26 (−38, −13)⁺, p=0.002	3, 0	0–10, 0–3
Eliapixant (phase IIa) [128]	10–750 mg twice daily (n=40); crossover, 3 weeks	24 h	25.5±2.5^#	26.6±2.5^#	22.6±2.5	10 mg: 22.8±2.6 (n=39) 50 mg: 18.8±2.8 (n=39) 200 mg: 17.1±2.6 (n=39) 750 mg: 16.6±2.4 (n=38)	10 mg: 10 (−7, 29)⁺, ns 50 mg: −15 (−28, 0.4)⁺, ns 200 mg: −23 (−34, −9)⁺, p=0.004 750 mg: −25 (−37, −12)⁺, p=0.002	3, 0	0–10, 0–3
Filapixant (phase IIa) [129]	20–250 mg twice daily (n=23); crossover, ascending-dose, 4 days per dose	24 h	NA	NA	NA	NA	20 mg: NA, ns 80 mg: −17, p=0.015 150 mg: −28, p<0.001 250 mg: −37, p<0.001	12	4−57
Sivopixant (phase IIa) [131]	150 mg every day (n=31); crossover, 2 weeks	Awake	NA	NA	NA	NA	−32 (−54, 1), p=0.055	NA	3, 3
Sivopixant (phase IIa) [131]	150 mg every day (n=31); crossover, 2 weeks	24 h	NA	NA		NA	−31, (p=0.0386)

Data are arithmetic mean±sd unless otherwise stated. ^#: Geometric mean±geometric sd. ^¶: Geometric mean. ⁺: 90% credible limits. AE: adverse event; CI: confidence interval; NA: not available; ns: non-significant; RCC: refractory chronic cough.

TABLE 4

Clinical phase II and phase III trial results assessing effects of P2X3 receptor antagonists versus placebo on cough severity (VAS) in patients with refractory chronic cough (RCC)

Drug	Dose regimen (n); design, duration	Baseline cough severity (VAS) mm, mean±sd		End of treatment cough severity (VAS) mm, mean±sd		Estimated mean difference from baseline in cough severity (VAS) mm, (95% CI)		*Mean change in cough severity versus* placebo, (VAS) mm, (95% CI)**
Drug	Dose regimen (n); design, duration	Placebo	Active	Placebo	Active	Placebo	Active
Gefapixant, (phase II) [42]	600 mg twice daily (n=24); 2 weeks	52.7±16.1	48.8±20.7	52.0±20.7	27.4±28.0	NA	NA	−25.6 (−41.5, −9.6), p=0.003
Gefapixant dose escalation (phase II) [43]	Part 1: 50–200 mg twice daily (n=29); crossover, 16 days Part 2: 7.5–50 mg twice daily (n=30); crossover, 16 days	Part 1: 52.2±19.2 Part 2: 57.2±23.7	Part 1: 58.4±18.7 Part 2: 54.5±24.3	Part 1: 55.6±24.1 Part 2: 48.0±27.0	Part 1: 28.0±26.2 Part 2: 30.4±25.3	NA	NA	Part 1: −20.0 (−33.6, −6.3) to −33.8 (−48.4, −19.1) Part 2: −15.6 (−27.6, −3.6) to −15.4 (−30.4, −0.5)
Gefapixant (phase IIb) [126]	7.5–50 mg twice daily (n=253); 12 weeks	57.4±23.1	56.7±20.7 to 58.3±25.1	39.3±28.1	27.9±22.4 to 35.0±23.6	−16.7 (−22.7, −10.7)	−21.1 (−27.2, −15.1) to −27.9 (−34.1, −21.6)	–4.4 (–12.9, 4.0), p=0.3 to –11.2 (–19.7, –2.6), p=0.0108
Eliapixant (phase IIa) [128]	10–750 mg twice daily (n=40); crossover, 3 weeks	70.6±17.3	71.4±16.3 (n=39)	66.4±19.1 (n=39)	10 mg: 67.2±21.8 (n=38) 50 mg: 61.0±21.4 (n=39) 200 mg: 58.5±23.2 (n=39) 750 mg: 53.0±23.3 (n=38)	2.9 (−1.7, 7.5)^#, ns	10 mg: −4.2 (1.3, −9.7)^#, ns 50 mg: −9.6 (−4.3, −15.1)^#, p<0.05 200 mg: −12.2 (−6.8, −17.6)^#, p<0.05 750 mg: −17.4 (−12.1, −22.9)^#, p<0.05	10 mg: −1.4 (3.9, −6.4)^#, ns 50 mg: −6.7 (−1.7, −11.7)^#, p<0.05 200 mg: −9.3 (−4.1, −14.4)^#, p<0.05 750 mg: −14.5 (−9.4, −19.6)^#, p<0.05
Filapixant (phase IIa) [129]	20–250 mg twice daily (n=23); crossover, ascending-dose, 4 days per dose	NA	NA	NA	NA	NA	NA	20 mg: NA, ns 80 mg: −8.1 (−1.9, −14.3), p=0.017 150 mg: −14.3 (−8.0, −20.7), p<0.001 250 mg: −20.8 (−14.7, −27.0), p<0.001
Sivopixant (phase IIa) [132]	150 mg every day (n=31); crossover, 2 weeks	NA	NA	NA	NA	−12.4	−18.8	−6.4, p=0.1334

Data are mean±sd unless otherwise stated. ^#: 90% credible limits. CI: confidence interval; NA: not available; ns: non-significant; VAS: visual analogue scale.