Alyn Morice University of Hull HYMS. The diagnosis and treatment of Chronic Cough

Transcription

1 Alyn Morice University of Hull HYMS The diagnosis and treatment of Chronic Cough )

2 Cough and wheeze is not always asthma

3 Cough Hypersensitivity is the primary mechanism in cough AHM 2016

4 A Definition Cough Hypersensitivity Syndrome is a clinical syndrome characterised by troublesome coughing often triggered by low levels of thermal, mechanical, or chemical exposure AHM 2016

5 Cough Clinic Survey Participating centres from New York, China, Korea, Holland, Sweden, and 6 from the UK Now 10,000 patients A worldwide survey of chronic cough: A manifestation of enhanced somatosensory response? Morice et al ERJ 2014 ERJ

6 Urge-to-cough is associated with activations in cerebral cortex the anterior mid-cingulate and primary somatosensory cortices appear to be significantly elevated in females Stuart Mazzone personal communication Sex of Cough Clinic Attenders Total Males Total females Orbitofrontal cortex(a), inferior frontal gyrus(a,b),anterior insula(b,c), superior temporal gyrus(c), primary motor & somatosensory cortics(d,c),suplementary motor area(e), anterior midcingulate cortex(f) Mazzone SB et al. AJRCCM 2007;176: %

7 The TRP (Transient Receptor Potential) Family HOT 55 C 43 C 33 C 30 C 25 C TRPV2 TRPV1 TRPV3 TRPV4 TRPM8 17 C TRPA1 COLD VRL1 VR1 capsaicin protons VRL3 VR-OAC OTRPC4 osmotic CMR1 cold/ menthol Coexpressed with VR1 Cell :

8 Plot of Adjusted Geometric Mean Cough Counts Per Hour with 95% CI

9 Comparative anatomy Pilot Whale Cat Deer Spider Monkey Laitman and Reidenberg Am J Med 1997

10 Human anatomy Larynx and associated structures decend Epiglottis and soft palate no longer in contact Tongue forms anterior pharangeal wall Greatly expanded oropharynx

11

12 AHM 2016

13

14 High Resolution Manometry + Impedance Gaseous mist trapped in the oesophagus

15 Cough hypersensitivity syndrome: a distinct clinical entity. Morice AH, Faruqi S, Wright CE, Thompson R, Bland JM Lung Feb;189(1):73-9. Within the last MONTH, how did the following problems affect you? 0 = no problem and 5 = severe/frequent problem Hoarseness or a problem with your voice Clearing your throat Excess mucus in the throat, or drip down the back of your nose Retching or vomiting when you cough Cough on first lying down or bending over Chest tightness or wheeze when coughing Heartburn, indigestion, stomach acid coming up (or do you take medications for this, if yes score 5) A tickle in your throat, or a lump in your throat Cough with eating (during or straight after meals) Cough with certain foods Cough when you get out of bed in the morning Cough brought on by singing or speaking (for example, on the telephone) Coughing during the day rather than night A strange taste in your mouth TOTAL SCORE /70

16 Airway autophagy

17 Reflux Airway Disease CD14 CD36 IL-33 Innate lymphocyte 2 IL-4, IL-5, IL-10, IL-12. IFNγ, IL-8. IL-1, TNFα, NGF. Eosinophilic Infiltration Neutrophilic Infiltration TRP channel Up-regulation

18 AHM 2016 Non atopic allergy

19 Allergen or other IgE on mast cell The eosinophil Il33 ILC2 Epithelial damage

20 Drug treatment Not PPI (unless heartburn ++) Metaclopramide Domperidone Baclofen Azithromycin Dig Dis Sci May;54(5): Epub 2009 Feb 25. Azithromycin reduces gastroesophageal reflux and aspiration in lung transplant recipients. Mertens V, Blondeau K, Pauwels A, Farre R, Vanaudenaerde B, Vos R, Verleden G, Van Raemdonck DE, Dupont LJ, Sifrim D AHM 2016

21 Opiates in chronic cough Results of Diary Data N=27 6 Mean Cough scores Placebo: 4.97 (1.68) MST : 3.44 (1.75) P value : < placebo:diary MST:diary data Morice AH et al 2006 AJRCCM

22 Cell damage Release of extracellular ATP P2X3 receptors P2X3

23 AF -219 an antagonist of P2X3 Abdulqawi, R., et al. (2014). "P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study." Lancet.

24 TRPV4 agonist GSK A

25

26 Extracellular Agonist Ca 2+ ATP Ca 2+ TRPV4 Pannexin-1 P2X3 Membrane Intracellular ATP Sensitising Kinases Membrane Extracellular Stimuli Opening TRPV4

27 Drug development P2X3 antagonists Merck Bayer NK1 antagonists Menlo NeRRi TRPV4 antagonist - GSK AHM 2016

28 Chest X ray within the last year How to manage chronic cough AHM 2016

29 Chest X ray within the last year Look for eosinophilia How to manage chronic cough AHM 2016

30 Chest X ray within the last year Look for eosinophilia HARQ questionnaire How to manage chronic cough AHM 2016

31 How to manage chronic cough Chest X ray within the last year Look for eosinophilia HARQ questionnaire History of ACEI, associated conditions, family history AHM 2016

32 How to manage chronic cough Chest X ray within the last year Look for eosinophilia HARQ questionnaire History of ACEI, associated conditions, family history If airway reflux one month trial of each promotility agent AHM 2016

33 How to manage chronic cough Chest X ray within the last year Look for eosinophilia HARQ questionnaire History of ACEI, associated conditions, family history If airway reflux one month trial of each promotility agent If eosinophilic add steroids and montelukast AHM 2016

34 How to manage chronic cough Chest X ray within the last year Look for eosinophilia HARQ questionnaire History of ACEI, associated conditions, family history If airway reflux one month trial of each promotility agent If eosinophilic add steroids and montelukast Cough suppression with low dose morphine AHM 2016

35 How to manage chronic cough Chest X ray within the last year Look for eosinophilia HARQ questionnaire History of ACEI, associated conditions, family history If airway reflux one month trial of each promotility agent If eosinophilic add steroids and montelukast Cough suppression with low dose morphine HROM to define pathophysiology? fundoplication AHM 2016