Pathophysiologie, Diagnostik und Therapie von chronischem Husten: Neuronale Reflexe und Antitussiva

Zusammenfassung

Husten ist weltweit eines der häufigsten Symptome, welches zur Konsultation eines Arztes führt. Dabei stellt Husten einen wichtigen neuronalen Reflex dar, der als Schutzfunktion vor körperfremden Mikroorganismen, thermischen und chemischen Reizstoffen, die über die Atemwege eindringen können, dient. Zudem beugt er der Retention von Schleim in den Atemwegen vor.

Der Husten-Reflex wird durch die Aktivierung verschiedener Husten-Rezeptoren initiiert. Diese Husten-Rezeptoren lassen sich hinsichtlich ihrer elektrophysiologischen Konfiguration in 3 Gruppen unterteilen, nämlich in die beiden Aδ-Fasern-Typen „schnell adaptierende (RAR) Mechanorezeptoren“ und „langsam adaptierende (SAR) Mechanorezeptoren“ und die C-Faser-Rezeptoren. Der Reiz wird durch die Husten-Rezeptoren über vagal-sensible Neuronen an das Husten-Zentrum im Gehirn weitergegeben. Der Husten selbst wird danach über Motoneuronen efferenter Nerven ausgebildet. Der Hustenreflex besteht somit aus 5 [1] funktionell aufeinander folgenden Teilen, nämlich den Husten-Rezeptoren [2], den primären afferenten Bahnen des N. vagus [3] [4] [5], N. trigeminus und N. glossopharyngeus [1], dem Hustenzentrum in der Medulla oblongata (N. tractus solitarius) [6] [7] [8], den afferenten Bahnen des N. phrenicus, des Spinalnervs und des N. laryngeus recurrens und den Muskeln des Rachens sowie dem Zwerchfell und der abdominalen, intercostalen und laryngealen Muskulatur. Die Hustenrezeptoren befinden sich hauptsächlich in Larynx, Trachea und Hauptbronchien [2].

Der Vorgang des Hustens kann in 4 Phasen eingeteilt werden. Auf die erste Phase der schnellen Inspiration mit geöffneter Glottis folgen die Kompression mit geschlossener Glottis und ansteigendem trachealen Druck, die Akzeleration, bei der sich die Glottis öffnet, und schließlich die Exspiration/Expulsion mit geöffneter Glottis [9]. Gemäß seiner Charakteristik kann Husten in zwei distinkte Typen aufgeteilt werden, zum einen den „unfreiwilligen, lauten Aspirations-Husten“, und zum anderen den kratzenden, reizenden und in seiner Intensität langsam ansteigenden kontrollierten Husten [10].

Akuter Husten entsteht häufig als Reaktion auf eine Infektion des respiratorischen Systems [11] [12] [13] und endet meist spontan nach 4 Wochen. Bis zu 8 Wochen hingegen kann Husten in chronischer Form durch einen infektiösen Befall mit Pathogenen wie Adenovirus, Bordetella pertussis und Mykoplasmen andauern [12] [13] [14]. Zur Unterteilung des Hustens nach seiner Ursache kann er auch nach Art und Weise differenziert werden. Zu unterscheiden sind trockener und Schleim-produzierender Husten.

Mit dieser Übersicht sollen die neuronalen Vorgänge und Mechanismen sowie Diagnostik und Therapie chronischen Hustens dargestellt werden. Dabei wird auch die Effizienz etablierter und potenzieller, noch nicht etablierter Antitussiva betrachtet.

Abstract

Cough is the number one symptom for patients to visit a physician worldwide. It is an important neuronal reflex which serves to protect the airways from inhaled exogenous microorganisms, thermal and chemical irritants. Moreover, it prevents the airways from mucus retention.

The cough reflex is initiated by activation of different cough receptors. These cough receptors can be divided into three groups according to their electrophysiological properties: into the two Aδ-fiber types “rapid-adapting mechanoreceptor” (RAR) and “slow-adapting mechanoreceptor” (SAR), and the C-fiber receptor.

The stimulus is detected by cough receptors which conduct the signal to the cerebral cough centre via vagal-sensory neurons. The cough itself is mediated by efferent motoneurons. Hence the cough reflex consists of 5 functionally sequential parts [1]: the cough receptors [2], the primary afferent fibres of the N. vagus [3] [4] [5], N. trigeminus and N. glossopharyngeus [1], the cough centre in the medulla oblongata (N. tractus solitarius) [6] [7] [8], the afferent fibres of the N. phrenicus, spinal nerve and N. laryngeus recurrens, as well as the diaphragm and the abdominal, intercostal and laryngeal muscles. The cough receptors are mainly located in the larynx, trachea and main bronchi [2].

The event of coughing can be divided into four subsequent parts: After the first phase of fast inspiration with an opened glottis, there is compression with a closed glottis and increasing tracheal pressure, acceleration and ultimately maximum expiration with an opened glottis [9]. According to its characteristics, cough can be split into two distinct types, “aspiration cough“, which is loud and involuntary, and “urge-to-cough sensation”, which describes an irritant, scratchy, and controlled cough of slowly increasing intensity [10].

Acute cough mostly develops because of infection of the respiratory system [11] [12] [13] and ends spontaneously after 4 weeks. In contrast to this, bacterial infection with pathogens like Adenovirus, Bordetella pertussis and Mycoplasms can last up to 8 weeks [12] [13] [14]. In additional to the division of cough according to its cause, it can also be differentiated according to its manner: dry and mucus-producing cough.

With this review we want to give an overview of neuronal processes and mechanisms, as well as diagnostics of and therapy for chronic cough. Thereby the focus is also placed on the efficiency of already established and potential future antitussive agents.

• Literatur

• 1 Kardos P, Berck H, Fuchs KH et al. [Guidelines of the german respiratory society for diagnosis and treatment of adults suffering from acute or chronic cough]. Pneumologie 2010; 64: 336-373
• 2 Widdicombe JG. Receptors in the trachea and bronchi of the cat. J Physiol 1954; 123: 71-104
• 3 Taylor-Clark TE, Nassenstein C, McAlexander MA et al. TRPA1: a potential target for anti-tussive therapy. Pulm Pharmacol Ther 2009; 22: 71-74
• 4 Canning BJ. Afferent nerves regulating the cough reflex: mechanisms and mediators of cough in disease. Otolaryngol Clin North Am 2010; 43: 15-25, vii
• 5 Dinh QT, Groneberg DA, Peiser C et al. Expression of substance P and nitric oxide synthase in vagal sensory neurons innervating the mouse airways. Regul Pept 2005; 126: 189-94
• 6 Bolser DC, DeGennaro FC, O’Reilly S et al. Central antitussive activity of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994 and SR 48968, in the guinea-pig and cat. Br J Pharmacol 1997; 121: 165-170
• 7 Bonham AC, Sekizawa S, Chen CY et al. Plasticity of brainstem mechanisms of cough. Respir Physiol Neurobiol 2006; 152: 312-319
• 8 Bonham AC, Sekizawa SI, Joad JP. Plasticity of central mechanisms for cough. Pulm Pharmacol Ther 2004; 17: 453-457
• 9 Braman SS, Corrao WM. Cough: differential diagnosis and treatment. Clin Chest Med 1987; 8: 177-188
• 10 Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008; 371: 1364-1374
• 11 Curley FJ, Irwin RS, Pratter MR et al. Cough and the common cold. Am Rev Respir Dis 1988; 138: 305-311
• 12 Footitt J, Johnston SL. Cough and viruses in airways disease: mechanisms. Pulm Pharmacol Ther 2009; 22: 108-113
• 13 McGarvey LP, Nishino T. Acute and chronic cough. Pulm Pharmacol Ther 2004; 17: 351-354
• 14 Birkebaek NH. Bordetella pertussis in the aetiology of chronic cough in adults. Diagnostic methods and clinic. Dan Med Bull 2001; 48: 77-80
• 15 Widdicombe J. Functional morphology and physiology of pulmonary rapidly adapting receptors (RARs). Anat Rec A Discov Mol Cell Evol Biol 2003; 270: 2-10
• 16 Undem BJ, Carr MJ. Targeting primary afferent nerves for novel antitussive therapy. Chest 2010; 137: 177-184
• 17 Dinh QT, Mingomataj E, Quarcoo D et al. Allergic airway inflammation induces tachykinin peptides expression in vagal sensory neurons innervating mouse airways. Clin Exp Allergy 2005; 35: 820-825
• 18 Dinh QT, Suhling H, Fischer A et al. [Innervation of the airways in asthma bronchiale and chronic obstructive pulmonary disease (COPD)]. Pneumologie 2011; 65: 283-292
• 19 Doherty MJ, Mister R, Pearson MG et al. Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. Thorax 2000; 55: 643-649
• 20 Canning BJ. Central regulation of the cough reflex: therapeutic implications. Pulm Pharmacol Ther 2009; 22: 75-81
• 21 Eccles R. Central mechanisms IV: conscious control of cough and the placebo effect. Handb Exp Pharmacol 2009; 187: 241-262
• 22 Eccles R. The powerful placebo in cough studies?. Pulm Pharmacol Ther 2002; 15: 303-308
• 23 Emonds-Alt X, Proietto V, Steinberg R et al. SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl) -2-morpholinyl]ethyl]- 4-piperidinyl)-2-methylpropanamide], a centrally active nonpeptide antagonist of the tachykinin neurokinin-1 receptor: I. biochemical and pharmacological characterization. J Pharmacol Exp Ther 2002; 303: 1171-1179
• 24 Chung KF. Cough: potential pharmacological developments. Expert Opin Investig Drugs 2002; 11: 955-963
• 25 Lee KK, Birring SS. Cough and sleep. Lung 2010; 188 (Suppl. 01) S91-S94
• 26 Grace MS, Dubuis E, Birrell MA et al. Pre-clinical studies in cough research: Role of Transient Receptor Potential (TRP) channels. Pulm Pharmacol Ther 2013; http://dx.doi.org/10.1016/j.pupt.2013.02.007 (in press)
• 27 Raemdonck K, de Alba J, Birrell MA et al. A role for sensory nerves in the late asthmatic response. Thorax 2012; 67: 19-25
• 28 Preti D, Szallasi A, Patacchini R. TRP channels as therapeutic targets in airway disorders: a patent review. Expert Opin Ther Pat 2012; 22: 663-695
• 29 O’Connell F, Thomas VE, Studham JM et al. Capsaicin cough sensitivity increases during upper respiratory infection. Respir Med 1996; 90: 279-286
• 30 O’Hara J, Jones NS. “Post-nasal drip syndrome”: most patients with purulent nasal secretions do not complain of chronic cough. Rhinology 2006; 44: 270-273
• 31 Lee PCL, Jawad MS, Eccles R. Antitussive efficacy of dextromethorphan in cough associated with acute upper respiratory tract infection. J Pharm Pharmacol 2000; 52: 1137-1142
• 32 Byard RW. Diphtheria - 'The strangling angel' of children. J Forensic Leg Med 2013; 20: 65-68
• 33 Groneberg-Kloft B, Dinh QT, Scutaru C et al. Cough as a symptom and a disease entity: scientometric analysis and density-equalizing calculations. J Investig Allergol Clin Immunol 2009; 19: 266-275
• 34 Dinh QT, Groneberg DA, Mingomataj E et al. Expression of substance P and vanilloid receptor (VR1) in trigeminal sensory neurons projecting to the mouse nasal mucosa. Neuropeptides 2003; 37: 245-250
• 35 Lee MG, Kollarik M, Chuaychoo B et al. Ionotropic and metabotropic receptor mediated airway sensory nerve activation. Pulm Pharmacol Ther 2004; 17: 355-360
• 36 Plevkova J, Brozmanova M, Pecova R et al. Effects of intranasal capsaicin challenge on cough reflex in healthy human volunteers. J Physiol Pharmacol 2004; 55 (Suppl. 03) 101-106
• 37 Plevkova J, Varechova S, Brozmanova M et al. Testing of cough reflex sensitivity in children suffering from allergic rhinitis and common cold. J Physiol Pharmacol 2006; 57 (Suppl. 04) 289-296
• 38 Pecova R, Vrlik M, Tatar M. Cough sensitivity in allergic rhinitis. J Physiol Pharmacol 2005; 56 (Suppl. 04) 171-178
• 39 Pratter MR. Chronic upper airway cough syndrome secondary to rhinosinus diseases (previously referred to as postnasal drip syndrome): ACCP evidence-based clinical practice guidelines. Chest 2006; 129: 63S-71S
• 40 Lee P, Eccles R. Cough induced by mechanical stimulation of the upper airway in humans. Acta Otolaryngol 2004; 124: 720-725
• 41 Sanu A, Eccles R. Postnasal drip syndrome. Two hundred years of controversy between UK and USA. Rhinology 2008; 46: 86-91
• 42 Macedo P, Saleh H, Torrego A et al. Postnasal drip and chronic cough: An open interventional study. Respir Med 2009; 103: 1700-1705
• 43 Phelan PD. Postnasal drip and chronic cough. Lancet 1978; 2: 1309
• 44 Fujimura M, Sakamoto S, Kamio Y et al. Cough receptor sensitivity and bronchial responsiveness in normal and asthmatic subjects. Eur Respir J 1992; 5: 291-295
• 45 Smith J, Woodcock A. Cough and its importance in COPD. Int J Chron Obstruct Pulmon Dis 2006; 1: 305-314
• 46 Terada K, Muro S, Ohara T et al. Cough-reflex sensitivity to inhaled capsaicin in COPD associated with increased exacerbation frequency. Respirology 2009; 14: 1151-1155
• 47 Fujimura M, Ogawa H, Nishizawa Y et al. Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?. Thorax 2003; 58: 14-18
• 48 Birring SS, Pavord ID. Chronic cough and gastro-oesophageal reflux. Thorax 2004; 59: 633-634
• 49 Irwin RS, Zawacki JK, Curley FJ et al. Chronic cough as the sole presenting manifestation of gastroesophageal reflux. Am Rev Respir Dis 1989; 140: 1294-1300
• 50 Kastelik JA, Jackson W, Davies TW et al. Measurement of gastric emptying in gastroesophageal reflux-related chronic cough. Chest 2002; 122: 2038-2041
• 51 Irwin RS, French CL, Curley FJ et al. Chronic cough due to gastroesophageal reflux. Clinical, diagnostic, and pathogenetic aspects. 1993. Chest 2009; 136: e30
• 52 Morice AH. Gastro-oesophageal reflux and tachykinins in asthma and chronic cough. Thorax 2007; 62: 468-469
• 53 Galmiche JP, Zerbib F, Bruley de Varannes S. Review article: respiratory manifestations of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2008; 27: 449-464
• 54 Zubairi AB, Liaquat HB, Husain SJ et al. Wegener’s granulomatosis: a diagnostic challenge. J Pak Med Assoc 2009; 59: 853-855
• 55 Brown KK. Chronic cough due to chronic interstitial pulmonary diseases: ACCP evidence-based clinical practice guidelines. Chest 2006; 129: 180S-185S
• 56 Daba MH, El-Tahir KE, Al-Arifi MN et al. Drug-induced pulmonary fibrosis. Saudi Med J 2004; 25: 700-706
• 57 Patel KN, Patel F, Hudgins L. Lofgren’s syndrome presenting as a case of fever of unknown origin. Tenn Med 2007; 100: 37-38
• 58 Javidan-Nejad C, Bhalla S. Bronchiectasis. Radiol Clin North Am 2009; 47: 289-306
• 59 Akers SM, Bartter TC, Pratter MR. Chronic cough as the sole manifestation of Hodgkin’s disease. Chest 1992; 101: 853-854
• 60 Lynch III JP, Kazerooni EA, Gay SE. Pulmonary sarcoidosis. Clin Chest Med 1997; 18: 755-785
• 61 de Jongste JC, Shields MD. Cough. 2: Chronic cough in children. Thorax 2003; 58: 998-1003
• 62 Wright AL, Stern DA, Kauffmann F et al. Factors influencing gender differences in the diagnosis and treatment of asthma in childhood: the Tucson Children’s Respiratory Study. Pediatr Pulmonol 2006; 41: 318-325
• 63 Mund E, Christensson B, Gronneberg R et al. Noneosinophilic CD4 lymphocytic airway inflammation in menopausal women with chronic dry cough. Chest 2005; 127: 1714-1721
• 64 Mund E, Christensson B, Larsson K et al. Sex dependent differences in physiological ageing in the immune system of lower airways in healthy non-smoking volunteers: study of lymphocyte subsets in bronchoalveolar lavage fluid and blood. Thorax 2001; 56: 450-455
• 65 An LC, Berg CJ, Klatt CM et al. Symptoms of cough and shortness of breath among occasional young adult smokers. Nicotine Tob Res 2009; 11: 126-133
• 66 Ford AC, Forman D, Moayyedi P et al. Cough in the community: a cross sectional survey and the relationship to gastrointestinal symptoms. Thorax 2006; 61: 975-979
• 67 Ben-Noun L. Drug-induced respiratory disorders: incidence, prevention and management. Drug Saf 2000; 23: 143-164
• 68 Rosenow III EC. Drug-induced pulmonary disease. J Pract Nurs 1979; 29: 23-26, 43
• 69 Costabel U. [Drug-induced lung changes in rheumatology]. Z Rheumatol 1990; 49: 284-290
• 70 Ludviksdottir D, Bjornsson E, Janson C et al. Habitual coughing and its associations with asthma, anxiety, and gastroesophageal reflux. Chest 1996; 109: 1262-1268
• 71 Erenberg G. Psychogenic cough. Pediatrics 2001; 108: 819-820
• 72 Niggemann B. How to diagnose psychogenic and functional breathing disorders in children and adolescents. Pediatr Allergy Immunol 2010; 21: 895-859
• 73 Ishizaki Y, Kobayashi Y, Kino M. Chronic and persistent cough related to vulnerability to psychological stress: tic or psychogenic?. Pediatr Int 2008; 50: 392-394
• 74 Ramanuja S, Kelkar P. Habit cough. Ann Allergy Asthma Immunol 2009; 102: 91-95
• 75 Christopher KL, Wood RP, Eckert RC et al. Vocal-cord dysfunction presenting as asthma. N Engl J Med 1983; 308: 1566-1570
• 76 Morice AH. Epidemiology of cough. Pulm Pharmacol Ther 2002; 15: 253-259
• 77 Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol 1992; 90: 32-42
• 78 Andre E, Gatti R, Trevisani M et al. Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents. Br J Pharmacol 2009; 158: 1621-1628
• 79 Grace MS, Belvisi MG. TRPA1 receptors in cough. Pulm Pharmacol Ther 2011; 24: 286-288
• 80 Leung SY, Niimi A, Williams AS et al. Inhibition of citric acid- and capsaicin-induced cough by novel TRPV-1 antagonist, V112220, in guinea-pig. Cough 2007; 3: 10
• 81 McLeod RL, Correll CC, Jia Y et al. TRPV1 antagonists as potential antitussive agents. Lung 2008; 186 (Suppl. 01) S59-S65
• 82 Szallasi A, Cortright DN, Blum CA et al. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 2007; 6: 357-372
• 83 Gatti R, Andre E, Barbara C et al. Ethanol potentiates the TRPV1-mediated cough in the guinea pig. Pulm Pharmacol Ther 2009; 22: 33-36
• 84 Groneberg DA, Niimi A, Dinh QT et al. Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med 2004; 170: 1276-1280
• 85 Gunthorpe MJ, Chizh BA. Clinical development of TRPV1 antagonists: targeting a pivotal point in the pain pathway. Drug Discov Today 2009; 14: 56-67
• 86 Gunthorpe MJ, Szallasi A. Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms. Curr Pharm Des 2008; 14: 32-41
• 87 Hillis BR. The assessment of cough suppressing drugs. Lancet 1952; 1: 1230-1235
• 88 Jia Y, McLeod RL, Wang X et al. Anandamide induces cough in conscious guinea-pigs through VR1 receptors. Br J Pharmacol 2002; 137: 831-836
• 89 Materazzi S, Nassini R, Gatti R et al. Cough sensors. II. Transient receptor potential membrane receptors on cough sensors. Handb Exp Pharmacol 2009; 49-61
• 90 Jia Y, McLeod RL, Hey JA. TRPV1 receptor: a target for the treatment of pain, cough, airway disease and urinary incontinence. Drug News Perspect 2005; 18: 165-171
• 91 Morice AH, Geppetti P. Cough. 5: The type 1 vanilloid receptor: a sensory receptor for cough. Thorax 2004; 59: 257-258
• 92 Trevisani M, Milan A, Gatti R et al. Antitussive activity of iodo-resiniferatoxin in guinea pigs. Thorax 2004; 59: 769-772
• 93 Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 2001; 24: 487-517
• 94 Pavord ID, Chung KF. Management of chronic cough. Lancet 2008; 371: 1375-1384
• 95 Dicpinigaitis PV, Dobkin JB. Antitussive effect of the GABA-agonist baclofen. Chest 1997; 111: 996-999
• 96 Takemura M, Quarcoo D, Niimi A et al. Is TRPV1 a useful target in respiratory diseases?. Pulm Pharmacol Ther 2008; 21: 833-839
• 97 Groneberg-Kloft B, Feleszko W, Dinh QT et al. Analysis and evaluation of environmental tobacco smoke exposure as a risk factor for chronic cough. Cough 2007; 3: 6
• 98 Moore N, Noblet C, Joannides R et al. Cough and ACE inhibitors. Lancet 1993; 341: 61
• 99 Lin CS, Sun WZ, Chan WH et al. Intravenous lidocaine and ephedrine, but not propofol, suppress fentanyl-induced cough. Can J Anaesth 2004; 51: 654-659
• 100 Slavenburg S, Heijdra YF, Drenth JP. Pneumonitis as a consequence of (peg)interferon-ribavirin combination therapy for hepatitis C: a review of the literature. Dig Dis Sci 2010; 55: 579-585
• 101 Elli A, Aroldi A, Montagnino G et al. Mycophenolate mofetil and cough. Transplantation 1998; 66: 409
• 102 Boggess KA, Benedetti TJ, Raghu G. Nitrofurantoin-induced pulmonary toxicity during pregnancy: a report of a case and review of the literature. Obstet Gynecol Surv 1996; 51: 367-370
• 103 Mitra S, Sinha PK, Anand LK et al. Propofol-induced violent coughing. Anaesthesia 2000; 55: 707-708
• 104 Roberts RJ, Wells AC, Unitt E et al. Sirolimus-induced pneumonitis following liver transplantation. Liver Transpl 2007; 13: 853-856
• 105 Mallet P, Mourdi N, Dubus JC et al. Respiratory paradoxical adverse drug reactions associated with acetylcysteine and carbocysteine systemic use in paediatric patients: a national survey. PLoS One 2011; 6: e22792