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Internal and Emergency Medicine

, Volume 14, Issue 1, pp 39–43 | Cite as

The pathogenetic mechanisms of cough in idiopathic pulmonary fibrosis

  • Elena BargagliEmail author
  • Maria Di Masi
  • Marco Perruzza
  • Lucia Vietri
  • Laura Bergantini
  • Elena Torricelli
  • Giulia Biadene
  • Giovanni Fontana
  • Federico Lavorini
IM - REVIEW

Abstract

Idiopathic pulmonary fibrosis is a peripheral subpleural interstitial lung disorder limited to the lung not involving the airways. It has a poor prognosis (survival less than 5 years) and commonly an interstitial pneumonia radiological pattern. Patients complain of a chronic dry cough in 80% of cases. A cough is often the first symptom of this rare disease, preceding dyspnea by years, and is associated with a poor prognosis, high dyspnea scores and low FVC percentages. The pathogenetic mechanisms leading to coughing in IPF are unclear. This review focuses on recent evidence of cough pathophysiology in this disease. Gastroesophageal reflux may promote coughing in IPF patients; bile salts and pepsin may be abundant in BAL of these patients, inducing overproduction of TGF-β by airway epithelial cells and mesenchymal transition with fibroblast recruitment/activation and extracellular matrix deposition. Patients have an enhanced cough reflex to capsaicin and substance P with respect to control subjects. Moreover, patients with the MUC5B polymorphism show more severe coughing as MUC5B encodes for the dominant mucin in the honeycomb cysts of IPF patients. Comorbidities, including asthma, gastroesophageal reflux, hypersensitivity pneumonitis, bronchiectasis, chronic obstructive pulmonary disease and emphysema, can induce coughing in IPF patients. There is no clear explanation of the causes of coughing in IPF. Further research into the pathophysiology of IPF and the pathogenetic mechanisms of coughing is necessary to improve survival and quality of life.

Keywords

Idiopathic pulmonary fibrosis Cough Pathogenesis 

Abbreviations

IPF

Idiopathic pulmonary fibrosis

ILD

Interstitial lung diseases

HRCT

High resolution computed tomography

BAL

Bronchoalveolar lavage

GER

Gatroesophageal reflux

NSIP

Non specific interstitial pneumonia

FVC

Forced vital capacity

TGF-β

Tumour growth factor

UIP

Usual interstitial pneumonia

GPCR

G-Protein coupled receptor

Notes

Funding

The study was unfunded.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest related to this topic.

Statement of human and animal rights

All procedures were in accordance with the ethical standard of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Ryerson CJ, Abbritti M, Ley B et al (2011) Cough predicts prognosis in idiopathic pulmonary fibrosis. Respirology 16(6):969–975CrossRefGoogle Scholar
  2. 2.
    Hope-Gill BDM, Hilldrup S, Davies C et al (2003) A study of the cough reflex in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 168:995–1002CrossRefGoogle Scholar
  3. 3.
    Vigeland CL, Hughes AH, Horton MR et al (2017) Etiology and treatment of cough in idiopathic pulmonary fibrosis. Respir Med 123:98–104CrossRefGoogle Scholar
  4. 4.
    Kilduff CE, Counter MJ, Thomas GA et al (2014) Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study. Cough 10:4CrossRefGoogle Scholar
  5. 5.
    Madison JM, Irwin RS (2005) Chronic cough in adults with interstitial lung disease. Curr Opin Pulm Med 11(5):412–416CrossRefGoogle Scholar
  6. 6.
    Key AL, Holt K, Hamilton A et al (2010) Objective cough frequency in idiopathic pulmonary fibrosis. Cough 6:4CrossRefGoogle Scholar
  7. 7.
    Sumner H, Woodcock A, Kolsum U et al (2013) Predictors of objective cough frequency in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 187:943–949CrossRefGoogle Scholar
  8. 8.
    Horton MR, Santopietro V, Mathew L et al (2012) Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med 157:398–406CrossRefGoogle Scholar
  9. 9.
    Lavorini F, Spina D, Walker MJ et al (2016) Antitussive effect of carcainium chloride in patients with chronic cough and idiopathic interstitial pneumonias: a pilot study. Pulm Pharmacol Ther 40:91–94CrossRefGoogle Scholar
  10. 10.
    Birring SS, Wijsenbeek MS, Agrawal S et al (2017) A novel formulation of inhaled sodium cromoglycate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial. Lancet Respir Med 5(10):806–815CrossRefGoogle Scholar
  11. 11.
    Fahim A, Dettmar PW, Morice AH et al (2011) Gastroesophageal reflux and idiopathic pulmonary fibrosis: a prospective study. Medicina (Kaunas) 47(4):200–205Google Scholar
  12. 12.
    Lee JS, Song JW, Wolters PJ et al (2012) Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J 39(2):352–358CrossRefGoogle Scholar
  13. 13.
    Raghu G, Yang ST, Spada C, Hayes J et al (2006) Treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. Chest 129(3):794–800CrossRefGoogle Scholar
  14. 14.
    Lee JS, Ryu JH, Elicker BM et al (2011) Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 184(12):1390–1394CrossRefGoogle Scholar
  15. 15.
    Lee JS, Collard HR, Anstrom KJ et al (2013) Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 1(5):369–376CrossRefGoogle Scholar
  16. 16.
    Pillai M, Olson AL, Huie TJ et al (2012) Obstructive sleep apnea does not promote esophageal reflux in fibrosing interstitial lung disease. Respir Med 106:1033–1039CrossRefGoogle Scholar
  17. 17.
    Lee JS, Collard HR, Raghu G et al (2010) Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 123:304–311CrossRefGoogle Scholar
  18. 18.
    Ing AJ, Ngu MC, Breslin AB (1994) Pathogenesis of chronic persistent cough associated with gastroesophageal reflux. Am J Respir Crit Care Med 149:160–167CrossRefGoogle Scholar
  19. 19.
    Hoppo T, Jarido V, Pennathur A et al (2011) Antireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantation. Arch Surg 146(9):1041–1047CrossRefGoogle Scholar
  20. 20.
    Linden PA, Gilbert RJ, Yeap BY et al (2006) Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg 131(2):438–446CrossRefGoogle Scholar
  21. 21.
    Harrison NK (2004) Idiopathic pulmonary fibrosis: a nervous cough? Pulm Pharmacol Ther 17:347–350CrossRefGoogle Scholar
  22. 22.
    Jones RM, Hilldrup S, Hope-Gill BD et al (2011) Mechanical induction of cough in idiopathic pulmonary fibrosis. Cough 7:2CrossRefGoogle Scholar
  23. 23.
    Harrison NK (2013) Cough, sarcoidosis and idiopathic pulmonary fibrosis: raw nerves and bad vibrations. Cough 9:9CrossRefGoogle Scholar
  24. 24.
    Doherty MJ, Mister R, Pearson MG et al (2000) Capsaicin induced cough in cryptogenic fibrosing alveolitis. Thorax 55:1028–1032CrossRefGoogle Scholar
  25. 25.
    Mazzone SB, McLennan L, McGovern AE et al (2007) Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med 176:327–332CrossRefGoogle Scholar
  26. 26.
    Alexis NE, Hu SC, Zeman K et al (2001) Induced sputum derives from the central airways: confirmation using a radiolabelled aerosol bolus delivery technique. Am J Respir Crit Care Med 164:1964–1970CrossRefGoogle Scholar
  27. 27.
    Birring SS, Parker D, McKenna S et al (2005) Sputum eosinophilia in idiopathic pulmonary fibrosis. Inflamm Res 54:51–56CrossRefGoogle Scholar
  28. 28.
    Kinder BW, Brown KK, Schwarz MI et al (2008) Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest 133:226–232CrossRefGoogle Scholar
  29. 29.
    Ricci A, Felici L, Mariotta S et al (2004) Neurotrophin and neurotrophin receptor protein expression in the human lung. Am J Respir Cell Mol Biol 30:12–19CrossRefGoogle Scholar
  30. 30.
    Donnerer J, Schuligoi R, Stein C (1992) Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in-vivo. Neuroscience 49:693–698CrossRefGoogle Scholar
  31. 31.
    Braun A, Lommatzsch M, Mannsfeldt A et al (1999) Cellular sources of enhanced brain-derived neurotrophic factor production in a mouse model of allergic inflammation. Am J Respir Cell Mol Biol 21:537–546CrossRefGoogle Scholar
  32. 32.
    Yao L, Zhang D, Bernd P (1997) Differential regulation of substance P by all members of the nerve growth factor family of neurotrophins in avian dorsal root ganglia throughout development. Neuroscience 79:1197–1206CrossRefGoogle Scholar
  33. 33.
    Undem BJ, Hunter DD, Liu M et al (1999) Allergen-induced sensory neuroplasticity in airways. Int Arch Allergy Immunol 118:150–153CrossRefGoogle Scholar
  34. 34.
    Koltzenburg M (1999) The changing sensitivity in the life of the nociceptor. Pain 6:S93–S102CrossRefGoogle Scholar
  35. 35.
    Ricci A, Graziano P, Bronzetti E et al (2007) Increased pulmonary neurotrophin protein expression in idiopathic interstitial pneumonias. Sarcoidosis Vasc Diffuse Lung Dis 24:13–23Google Scholar
  36. 36.
    Harrison NK, Dawes KE, Kwon OJ et al (1995) Effects of neuropeptides on human lung fibroblast proliferation and chemotaxis in vitro. Am J Physiol 268:L278–L283CrossRefGoogle Scholar
  37. 37.
    Scholand MB, Wolff R, Crossno PF et al (2014) Severity of cough in idiopathic pulmonary fibrosis is associated with MUC5 B genotype. Cough 10:3CrossRefGoogle Scholar
  38. 38.
    Seibold MA, Smith RW, Urbanek C (2013) The idiopathic pulmonary fibrosis honeycomb cyst contains a mucocilary pseudostratified epithelium. PLoS one 8(3):e58658CrossRefGoogle Scholar
  39. 39.
    Seibold MA, Wise AL, Speer MC et al (2011) A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 364(16):1503–1512CrossRefGoogle Scholar
  40. 40.
    Zhang Y, Noth I, Garcia JG, Kaminski N (2011) A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med 364(16):1576–1577CrossRefGoogle Scholar
  41. 41.
    Jiang Haiming, Yejia Hu, Shang Li et al (2015) Association between MUC5B polymorphism and susceptibility and severity of idiopathic pulmonary fibrosis Int J. Clin Exp Pathol 8(11):14953–14958Google Scholar
  42. 42.
    Andoh Y, Aikawa T, Shimura S et al (1992) Morphometric analysis of airways in idiopathic pulmonary fibrosis patients with mucous hypersecretion. Am Rev Respir Dis 145(1):175–179CrossRefGoogle Scholar
  43. 43.
    Jaimchariyatam N, Tantipornsinchai W, Desudchit T et al (2016) Association between respiratory events and nocturnal gastroesophageal reflux events in patients with coexisting obstructive sleep apnea and gastroesophageal reflux disease. Sleep Med 22:33–38CrossRefGoogle Scholar
  44. 44.
    Mermigkis C, Bouloukaki I, Antoniou K et al (2015) Obstructive sleep apnea should be treated in patients with idiopathic pulmonary fibrosis. Sleep Breath 19:385–391CrossRefGoogle Scholar
  45. 45.
    Jung HK, Choung RS, Talley NJ (2010) Gastroesophageal reflux disease and sleep disorders: evidence for a causal link and therapeutic implications. J Neurogastroenterol Motil 16:22–29CrossRefGoogle Scholar
  46. 46.
    Chan KK, Ing AJ, Laks L et al (2010) Chronic cough in patients with sleep-disordered breathing. Eur Respir J 35:368–372CrossRefGoogle Scholar
  47. 47.
    Chilosi M, Poletti V, Murer B et al (2002) Abnormal re-epithelialization and lung remodelling in Idiopathic pulmonary fibrosis: the role of deltaN-p63. Lab Invest 82(10):1335–1345CrossRefGoogle Scholar
  48. 48.
    Caliò A, Lever V, Rossi A et al (2017) Increased frequency of bronchiolar histotypes in lung carcinomas associated with idiopathic pulmonary fibrosis. Histopathology 71(5):725–735CrossRefGoogle Scholar
  49. 49.
    Prasse A, Binder H, Schupp JC et al. (2018) BAL cell gene expression is indicative of outcome and airway basal cell involvement in IPF. Respir Crit Care Med (in press) Google Scholar
  50. 50.
    Van Manen MJ, Birring SS, Vancheri C et al (2016) Cough in idiopathic pulmonary fibrosis. Eur Respir Rev 25(141):278–286CrossRefGoogle Scholar

Copyright information

© Società Italiana di Medicina Interna 2018

Authors and Affiliations

  • Elena Bargagli
    • 1
    Email author return OK on get
  • Maria Di Masi
    • 2
  • Marco Perruzza
    • 1
  • Lucia Vietri
    • 1
  • Laura Bergantini
    • 1
  • Elena Torricelli
    • 2
  • Giulia Biadene
    • 2
  • Giovanni Fontana
    • 2
  • Federico Lavorini
    • 2
  1. 1.Section of Respiratory Diseases and Lung Transplantation, Department of Clinical Medicine and NeurosciencesSiena University HospitalSienaItaly
  2. 2.Section of Respiratory Medicine, Department of Clinical and Experimental MedicineUniversity of FlorenceFlorenceItaly

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