The American Journal of Medicine
Volume 123, Issue 4 , Pages 304-311 , April 2010

Does Chronic Microaspiration Cause Idiopathic Pulmonary Fibrosis?

  • Joyce S. Lee, MD

      Affiliations

    • Department of Medicine, University of California San Francisco
    • Corresponding Author InformationRequests for reprints should be addressed to Joyce Lee, MD, Department of Medicine, University of California, 505 Parnassus Avenue, Box 0111, San Francisco, CA 94143
    • ,
  • Harold R. Collard, MD

      Affiliations

    • Department of Medicine, University of California San Francisco
    • ,
  • Ganesh Raghu, MD

      Affiliations

    • Department of Medicine, University of Washington, Seattle
    • ,
  • Matthew P. Sweet, MD, MS

      Affiliations

    • Department of Surgery, University of California San Francisco
    • ,
  • Steven R. Hays, MD

      Affiliations

    • Department of Medicine, University of California San Francisco
    • ,
  • Guilherme M. Campos, MD, FACS

      Affiliations

    • Department of Surgery, University of California San Francisco
    • ,
  • Jeffrey A. Golden, MD

      Affiliations

    • Department of Medicine, University of California San Francisco
    • ,
  • Talmadge E. King Jr., MD

      Affiliations

    • Department of Medicine, University of California San Francisco

References 

  1. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment (International consensus statement). American Thoracic Society (ATS) and the European Respiratory Society (ERS) Am J Respir Crit Care Med. 2000;161:646–664
  2. Bjoraker JA, Ryu JH, Edwin MK, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;157:199–203
  3. Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007;104:7552–7557
  4. Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356:1317–1326
  5. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176:636–643
  6. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344:665–671
  7. Gleeson K, Eggli DF, Maxwell SL. Quantitative aspiration during sleep in normal subjects. Chest. 1997;111:1266–1272
  8. Ebert EC. Esophageal disease in scleroderma. J Clin Gastroenterol. 2006;40:769–775
  9. Savarino E, Bazzica M, Zentilin P, et al. Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring. Am J Respir Crit Care Med. 2009;179:408–413
  10. Travis WD, Colby TV, Koss MN, et al. Lipoid pneumonia and chronic fibrosis. In:  Travis WD,  Colby TV,  Koss MN, et al. editor. Non-Neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and the Armed Forces Institute of Pathology; 2002;p. 187–196
  11. Warner MA, Warner ME, Weber JG. Clinical significance of pulmonary aspiration during the perioperative period. Anesthesiology. 1993;78:56–62
  12. Napierkowski J, Wong RK. Extraesophageal manifestations of GERD. Am J Med Sci. 2003;326:285–299
  13. Sweet MP, Patti MG, Hoopes C, et al. Gastro-oesophageal reflux and aspiration in patients with advanced lung disease. Thorax. 2009;64:167–173
  14. Barnes TW, Vassallo R, Tazelaar HD, et al. Diffuse bronchiolar disease due to chronic occult aspiration. Mayo Clin Proc. 2006;81:172–176
  15. D'Ovidio F, Mura M, Tsang M, et al. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg. 2005;129:1144–1152
  16. Cantu E, Appel JZ, Hartwig MG, et al. J. Maxwell Chamberlain Memorial Paper (Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease). Ann Thorac Surg. 2004;78:1142–1151discussion 1151
  17. Davis RD, Lau CL, Eubanks S, et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. 2003;125:533–542
  18. Hamelberg W, Bosomworth PP. Aspiration pneumonitis: experimental studies and clinical observations. Anesth Analg. 1964;43:669–677
  19. Teabeaut JR. Aspiration of gastric contents; an experimental study. Am J Pathol. 1952;28:51–67
  20. Greenfield LJ, Singleton RP, McCaffree DR, Coalson JJ. Pulmonary effects of experimental graded aspiration of hydrochloric acid. Ann Surg. 1969;170:74–86
  21. Amigoni M, Bellani G, Scanziani M, et al. Lung injury and recovery in a murine model of unilateral acid aspiration: functional, biochemical, and morphologic characterization. Anesthesiology. 2008;108:1037–1046
  22. Kwan M, Xu YD, Raghu G, Khalil N. Acid treatment of normal rat lungs releases transforming growth factor-beta1 (TGF-beta1) and increases connective tissue synthesis (Proceedings of the American Thoracic Society (PATS)). Am J Respir Crit Care Med. 2007;A967
  23. Appel JZ, Lee SM, Hartwig MG, et al. Characterization of the innate immune response to chronic aspiration in a novel rodent model. Respir Res. 2007;8:87
  24. Downing TE, Sporn TA, Bollinger RR, et al. Pulmonary histopathology in an experimental model of chronic aspiration is independent of acidity. Exp Biol Med (Maywood). 2008;233:1202–1212
  25. Perng DW, Chang KT, Su KC, et al. Exposure of airway epithelium to bile acids associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-beta1 production and fibroblast proliferation. Chest. 2007;132:1548–1556
  26. Pearson JE, Wilson RS. Diffuse pulmonary fibrosis and hiatus hernia. Thorax. 1971;26:300–305
  27. Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration (A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology). Chest. 1976;69:512–515
  28. Patti MG, Tedesco P, Golden J, et al. Idiopathic pulmonary fibrosis: how often is it really idiopathic?. J Gastrointest Surg. 2005;9:1053–1056discussion 1056-1058
  29. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27:136–142
  30. Salvioli B, Belmonte G, Stanghellini V, et al. Gastro-oesophageal reflux and interstitial lung disease. Dig Liver Dis. 2006;38:879–884
  31. Sweet MP, Patti MG, Leard LE, et al. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg. 2007;133:1078–1084
  32. Tobin RW, Pope CE, Pellegrini CA, et al. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158:1804–1808
  33. Raghu G, Yang ST, Spada C, et al. Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. Chest. 2006;129:794–800
  34. Linden PA, Gilbert RJ, Yeap BY, et al. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg. 2006;131:438–446
  35. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998;157:1301–1315
  36. Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol. 2008;39:1275–1294
  37. Trahan S, Hanak V, Ryu JH, Myers JL. Role of surgical lung biopsy in separating chronic hypersensitivity pneumonia from usual interstitial pneumonia/idiopathic pulmonary fibrosis: analysis of 31 biopsies from 15 patients. Chest. 2008;134:126–132
  38. Stoeckli SJ, Huisman TA, Seifert B, Martin-Harris BJ. Interrater reliability of videofluoroscopic swallow evaluation. Dysphagia. 2003;18:53–57
  39. Ravelli AM, Panarotto MB, Verdoni L, et al. Pulmonary aspiration shown by scintigraphy in gastroesophageal reflux-related respiratory disease. Chest. 2006;130:1520–1526
  40. Crausaz FM, Favez G. Aspiration of solid food particles into lungs of patients with gastroesophageal reflux and chronic bronchial disease. Chest. 1988;93:376–378
  41. Schraufnagel DE, Michel JC, Sheppard TJ, et al. CT of the normal esophagus to define the normal air column and its extent and distribution. AJR Am J Roentgenol. 2008;191:748–752
  42. Ginalski JM, Schnyder P, Moss AA, Brasch RC. Incidence and significance of a widened esophageal hiatus at CT scan. J Clin Gastroenterol. 1984;6:467–470
  43. Emerenziani S, Sifrim D. New developments in detection of gastroesophageal reflux. Curr Opin Gastroenterol. 2005;21:450–453
  44. Oelschlager BK, Chang L, Pope CE, Pellegrini CA. Typical GERD symptoms and esophageal pH monitoring are not enough to diagnose pharyngeal reflux. J Surg Res. 2005;128:55–60
  45. Tutuian R. Update in the diagnosis of gastroesophageal reflux disease. J Gastrointestin Liver Dis. 2006;15:243–247
  46. Kahrilas PJ, Sifrim D. High-resolution manometry and impedance-pH/manometry: valuable tools in clinical and investigational esophagology. Gastroenterology. 2008;135:756–769
  47. Ufberg JW, Bushra JS, Patel D, et al. A new pepsin assay to detect pulmonary aspiration of gastric contents among newly intubated patients. Am J Emerg Med. 2004;22:612–614
  48. Stovold R, Forrest IA, Corris PA, et al. Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med. 2007;175:1298–1303
  49. Farrell S, McMaster C, Gibson D, et al. Pepsin in bronchoalveolar lavage fluid: a specific and sensitive method of diagnosing gastro-oesophageal reflux-related pulmonary aspiration. J Pediatr Surg. 2006;41:289–293
  50. Starosta V, Kitz R, Hartl D, et al. Bronchoalveolar pepsin, bile acids, oxidation, and inflammation in children with gastroesophageal reflux disease. Chest. 2007;132:1557–1564
  51. Potluri S, Friedenberg F, Parkman HP, et al. Comparison of a salivary/sputum pepsin assay with 24-hour esophageal pH monitoring for detection of gastric reflux into the proximal esophagus, oropharynx, and lung. Dig Dis Sci. 2003;48:1813–1817
  52. Metheny NA, Chang YH, Ye JS, et al. Pepsin as a marker for pulmonary aspiration. Am J Crit Care. 2002;11:150–154
  53. D'Ovidio F, Mura M, Waddell TK, et al. Bile acids in bronchoalveolar lavage after lung transplantation as a marker of pulmonary aspiration associated with alveolar neutrophilia. J Heart Lung Transplant. 2004;23:42S
  54. Kim DS, Park JH, Park BK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J. 2006;27:143–150
  55. Horvath I, Hunt J, Barnes PJ, et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J. 2005;26:523–548
  56. Hunt J. Exhaled breath condensate: an overview. Immunol Allergy Clin North Am. 2007;27:587–596v
  57. Jackson AS, Sandrini A, Campbell C, et al. Comparison of biomarkers in exhaled breath condensate and bronchoalveolar lavage. Am J Respir Crit Care Med. 2007;175:222–227
  58. Psathakis K, Mermigkis D, Papatheodorou G, et al. Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis. Eur J Clin Invest. 2006;36:362–367
  59. Raghu G. The role of gastroesophageal reflux in idiopathic pulmonary fibrosis. Am J Med. 2003;115(Suppl 3A):60S–64S
  60. Han MK. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;28:884–885author reply 885
  61. Gulmez SE, Holm A, Frederiksen H, et al. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med. 2007;167:950–955
  62. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947–2953
  63. Pellegrini CA, DeMeester TR, Johnson LF, Skinner DB. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of surgical therapy. Surgery. 1979;86:110–119
  64. Patti MG, Debas HT, Pellegrini CA. Esophageal manometry and 24-hour pH monitoring in the diagnosis of pulmonary aspiration secondary to gastroesophageal reflux. Am J Surg. 1992;163:401–406
  65. Patti MG, Debas HT, Pellegrini CA. Clinical and functional characterization of high gastroesophageal reflux. Am J Surg. 1993;165:163–166discussion 166-168
  66. Locke GR. Current medical management of gastroesophageal reflux disease. Thorac Surg Clin. 2005;15:369–375
  67. Raghu G, Weycker D, Edelsberg J, et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174:810–816
  68. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:136–151
  69. Laurent GJ, McAnulty RJ, Hill M, Chambers R. Escape from the matrix: multiple mechanisms for fibroblast activation in pulmonary fibrosis. Proc Am Thorac Soc. 2008;5:311–315

 Funding: NHLBI HL086516.

 Conflict of Interest: Dr. Lee has no conflicts of interest to disclose. Dr. Collard has provided consulting services to Actelion, Amira, InterMune, Gilead Science, Genzyme, CV Therapeutics, Nektar Therapeutics, and Roche, has served on an advisory committee for InterMune, and speaks regularly about idiopathic pulmonary fibrosis. Dr. Raghu has given lectures on the diagnosis and management of interstitial lung diseases and has discussed the potential role of chronic silent microaspiration in the pathogenesis of idiopathic pulmonary fibrosis. Dr. Sweet has no conflicts of interest to disclose. Dr. Hays has no conflicts of interest to disclose. Dr. Campos has no conflicts of interest to disclose. Dr. Golden has no conflicts of interest to disclose. Dr. King has given lectures on the diagnosis and management of interstitial lung diseases and has discussed the recent papers that have discussed the potential role of chronic silent microaspiration in the pathogenesis of idiopathic pulmonary fibrosis and as a potential cause of the acute respiratory decompensation manifested by some patients with idiopathic pulmonary fibrosis. In 2007, Dr. King provided expert testimony that a patient's diffuse parenchymal lung disease (lung fibrosis) was, more likely than not, caused by chronic aspiration.

 Authorship: This manuscript represents original work, and all authors meet the criteria for authorship.

PII: S0002-9343(09)01061-4

doi: 10.1016/j.amjmed.2009.07.033

The American Journal of Medicine
Volume 123, Issue 4 , Pages 304-311 , April 2010

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