Non-tuberculous Mycobacteria in Cystic Fibrosis

  • Robert Burkes
  • Peadar G. NooneEmail author
Part of the Respiratory Medicine book series (RM)


Cystic fibrosis is a systemic disease caused by autosomal recessive inheritance of defective genes that encode the cystic fibrosis transmembrane conductance regulator. Cystic fibrosis is systemic, but its hallmark is poor pulmonary mucociliary clearance leading to mucous impaction and chronic lung inflammation and infection. Because of defective airway host defenses inherent in the disease, the lung microenvironment creates an inviting milieu for infection with non-tuberculous mycobacterium. Identification and treatment is difficult because of the multitude of bacterial pathogens cystic fibrosis patients may harbor. Diagnosis is centered around excluding other causes of infection, identifying symptoms of non-tuberculous mycobacterial disease, recognizing related imaging findings, and recovering non-tuberculous mycobacterium microbiologic specimens. Treatment is complex, prolonged, and hindered by side effects of treatment medications. In this chapter we discuss the facets on non-tuberculous mycobacterial disease unique to the cystic fibrosis patient.


Cystic fibrosis Non-tuberculous mycobacteria Mycobacterium avium complex Mycobacterium abscessus 


  1. 1.
    Elborn JS. Cystic fibrosis. Lancet (London, England). 2016;388(10059):2519–31.CrossRefGoogle Scholar
  2. 2.
    Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med. 2015;372(4):351–62.CrossRefGoogle Scholar
  3. 3.
    Stewart CS, Pepper MS. Cystic fibrosis in the African diaspora. Ann Am Thorac Soc. 2016;14(1):1–7.CrossRefGoogle Scholar
  4. 4.
    Davies JC, Alton EWFW, Bush A. Cystic fibrosis. BMJ Br Med J. 2007;335(7632):1255–9.CrossRefGoogle Scholar
  5. 5.
    Olivier KN, Weber DJ, Wallace RJ Jr, Faiz AR, Lee JH, Zhang Y, et al. Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis. Am J Respir Crit Care Med. 2003;167(6):828–34.CrossRefGoogle Scholar
  6. 6.
    Olivier KN, Weber DJ, Lee JH, Handler A, Tudor G, Molina PL, et al. Nontuberculous mycobacteria. II: nested-cohort study of impact on cystic fibrosis lung disease. Am J Respir Crit Care Med. 2003;167(6):835–40.CrossRefGoogle Scholar
  7. 7.
    Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367–416.CrossRefGoogle Scholar
  8. 8.
    Olivier KN, Yankaskas JR, Knowles MR. Nontuberculous mycobacterial pulmonary disease in cystic fibrosis. Semin Respir Infect. 1996;11(4):272–84.PubMedGoogle Scholar
  9. 9.
    Donohue MJ, Wymer L. Increasing prevalence rate of nontuberculous mycobacteria infections in five states, 2008–2013. Ann Am Thorac Soc. 2016;13(12):2143–50.CrossRefGoogle Scholar
  10. 10.
    Adjemian J, Olivier KN, Prevots DR. Epidemiology of Pulmonary Nontuberculous Mycobacterial Sputum Positivity in Patients with Cystic Fibrosis in the United States, 2010–2014. Annals of the American Thoracic Society. 15(7):2018.Google Scholar
  11. 11.
    Pierre-Audigier C, Ferroni A, Sermet-Gaudelus I, Le Bourgeois M, Offredo C, Vu-Thien H, et al. Age-related prevalence and distribution of nontuberculous mycobacterial species among patients with cystic fibrosis. J Clin Microbiol. 2005;43(7):3467–70.Google Scholar
  12. 12.
    Adjemian J, Olivier KN, Prevots DR. Nontuberculous mycobacteria among patients with cystic fibrosis in the United States: screening practices and environmental risk. Am J Respir Crit Care Med. 2014;190(5):581–6.CrossRefGoogle Scholar
  13. 13.
    Prevots DR, Adjemian J, Fernandez AG, Knowles MR, Olivier KN. Environmental risks for nontuberculous mycobacteria. Individual exposures and climatic factors in the cystic fibrosis population. Ann Am Thorac Soc. 2014;11(7):1032–8.CrossRefGoogle Scholar
  14. 14.
    Qvist T, Gilljam M, Jonsson B, Taylor-Robinson D, Jensen-Fangel S, Wang M, et al. Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia. J Cyst Fibros Off J Eur Cyst Fibros Soc. 2015;14(1):46–52.CrossRefGoogle Scholar
  15. 15.
    Levy I, Grisaru-Soen G, Lerner-Geva L, Kerem E, Blau H, Bentur L, et al. Multicenter cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Israel. Emerg Infect Dis. 2008;14(3):378–84.CrossRefGoogle Scholar
  16. 16.
    Martiniano SL, Sontag MK, Daley CL, Nick JA, Sagel SD. Clinical significance of a first positive nontuberculous mycobacteria culture in cystic fibrosis. Ann Am Thorac Soc. 2014;11(1):36–44.CrossRefGoogle Scholar
  17. 17.
    Renna M, Schaffner C, Brown K, Shang S, Tamayo MH, Hegyi K, et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J Clin Invest. 2011;121(9):3554–63.CrossRefGoogle Scholar
  18. 18.
    Bryant JM, Grogono DM, Greaves D, Foweraker J, Roddick I, Inns T, et al. Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study. Lancet (London, England). 2013;381(9877):1551–60.CrossRefGoogle Scholar
  19. 19.
    Bryant JM, Grogono DM, Rodriguez-Rincon D, Everall I, Brown KP, Moreno P, et al. Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium. Science (New York, NY). 2016;354(6313):751–7.CrossRefGoogle Scholar
  20. 20.
    Kunimoto DY, Peppler MS, Talbot J, Phillips P, Shafran SD. Analysis of Mycobacterium avium complex isolates from blood samples of AIDS patients by pulsed-field gel electrophoresis. J Clin Microbiol. 2003;41(1):498–9.CrossRefGoogle Scholar
  21. 21.
    Johnson MM, Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis. 2014;6(3):210–20.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Foundation CF. Infection prevention and control guidelines for cystic fibrosis: 2013 update. Infect Control Hosp Epidemiol. 2014;35(S1):S1–S67.CrossRefGoogle Scholar
  23. 23.
    Martin C, Burgel PR, Lepage P, Andrejak C, de Blic J, Bourdin A, et al. Host-microbe interactions in distal airways: relevance to chronic airway diseases. Eur Respir Rev: Off J Eur Respir Soc. 2015;24(135):78–91.CrossRefGoogle Scholar
  24. 24.
    Tang AC, Turvey SE, Alves MP, Regamey N, Tummler B, Hartl D. Current concepts: host-pathogen interactions in cystic fibrosis airways disease. Eur Respir Rev: Off J Eur Respir Soc. 2014;23(133):320–32.CrossRefGoogle Scholar
  25. 25.
    Matsui H, Verghese MW, Kesimer M, Schwab UE, Randell SH, Sheehan JK, et al. Reduced three-dimensional motility in dehydrated airway mucus prevents neutrophil capture and killing bacteria on airway epithelial surfaces. J Immunol. 2005;175(2):1090–9.CrossRefGoogle Scholar
  26. 26.
    Hartl D, Latzin P, Hordijk P, Marcos V, Rudolph C, Woischnik M, et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med. 2007;13(12):1423–30.CrossRefGoogle Scholar
  27. 27.
    Pezzulo AA, Tang XX, Hoegger MJ, Abou Alaiwa MH, Ramachandran S, Moninger TO, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature. 2012;487(7405):109–13.CrossRefGoogle Scholar
  28. 28.
    Orme IM, Ordway DJ. Host response to nontuberculous mycobacterial infections of current clinical importance. Infect Immun. 2014;82(9):3516–22.CrossRefGoogle Scholar
  29. 29.
    Kelley TJ, Drumm ML. Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells. J Clin Invest. 1998;102(6):1200–7.CrossRefGoogle Scholar
  30. 30.
    SenGupta S, Hittle LE, Ernst RK, Uriarte SM, Mitchell TC. A Pseudomonas aeruginosa hepta-acylated lipid A variant associated with cystic fibrosis selectively activates human neutrophils. J Leukoc Biol. 2016;100(5):1047–59.CrossRefGoogle Scholar
  31. 31.
    Assani K, Shrestha CL, Robledo-Avila F, Rajaram MV, Partida-Sanchez S, Schlesinger LS, et al. Human cystic fibrosis macrophages have defective calcium-dependent protein kinase C activation of the NADPH oxidase, an effect augmented by Burkholderia cenocepacia. J Immunol. 2017;198(5):1985–94.CrossRefGoogle Scholar
  32. 32.
    Catherinot E, Clarissou J, Etienne G, Ripoll F, Emile JF, Daffe M, et al. Hypervirulence of a rough variant of the Mycobacterium abscessus type strain. Infect Immun. 2007;75(2):1055–8.CrossRefGoogle Scholar
  33. 33.
    Nick JA, Pohl K, Martiniano SL. Nontuberculous mycobacterial infections in cystic fibrosis: to treat or not to treat? Curr Opin Pulm Med. 2016;22(6):629–36.CrossRefGoogle Scholar
  34. 34.
    Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary. Thorax. 2016;71(1):88–90.CrossRefGoogle Scholar
  35. 35.
    Whittier S, Olivier K, Gilligan P, Knowles M, Della-Latta P. Proficiency testing of clinical microbiology laboratories using modified decontamination procedures for detection of nontuberculous mycobacteria in sputum samples from cystic fibrosis patients. The Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. J Clin Microbiol. 1997;35(10):2706–8.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Caverly LJ, Carmody LA, Haig SJ, Kotlarz N, Kalikin LM, Raskin L, et al. Culture-independent identification of nontuberculous mycobacteria in cystic fibrosis respiratory samples. PLoS One. 2016;11(4):e0153876.CrossRefGoogle Scholar
  37. 37.
    Qvist T, Pressler T, Katzenstein TL, Hoiby N, Collins MT. Evaluation of a bovine antibody test for diagnosing Mycobacterium avium complex in patients with cystic fibrosis. Pediatr Pulmonol. 2016;52(1):34–40.CrossRefGoogle Scholar
  38. 38.
    Park IK, Olivier KN. Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis. Semin Respir Crit Care Med. 2015;36(2):217–24.CrossRefGoogle Scholar
  39. 39.
    Kwak N, Lee CH, Lee HJ, Kang YA, Lee JH, Han SK, et al. Non-tuberculous mycobacterial lung disease: diagnosis based on computed tomography of the chest. Eur Radiol. 2016;26(12):4449–56.CrossRefGoogle Scholar
  40. 40.
    Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax. 2016;71(Suppl 1):i1–22.CrossRefGoogle Scholar
  41. 41.
    van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, et al. The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment. Am J Respir Crit Care Med. 2012;186(6):559–65.CrossRefGoogle Scholar
  42. 42.
    Ribeiro CM, Hurd H, Wu Y, Martino ME, Jones L, Brighton B, et al. Azithromycin treatment alters gene expression in inflammatory, lipid metabolism, and cell cycle pathways in well-differentiated human airway epithelia. PLoS One. 2009;4(6):e5806.CrossRefGoogle Scholar
  43. 43.
    Chmiel JF, Aksamit TR, Chotirmall SH, Dasenbrook EC, Elborn JS, LiPuma JJ, et al. Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi. Ann Am Thorac Soc. 2014;11(8):1298–306.CrossRefGoogle Scholar
  44. 44.
    Olivier KN, Shaw PA, Glaser TS, Bhattacharyya D, Fleshner M, Brewer CC, et al. Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease. Ann Am Thorac Soc. 2014;11(1):30–5.CrossRefGoogle Scholar
  45. 45.
    Olivier KN, Griffith DE, Eagle G, McGinnis Ii JP, Micioni L, Liu K, et al. Randomized trial of liposomal amikacin for inhalation in nontuberculous mycobacterial lung disease. Am J Respir Crit Care Med. 2016;195(6):814–23.CrossRefGoogle Scholar
  46. 46.
    Field SK, Cowie RL. Treatment of Mycobacterium avium-intracellulare complex lung disease with a macrolide, ethambutol, and clofazimine. Chest. 2003;124(4):1482–6.CrossRefGoogle Scholar
  47. 47.
    Koh WJ, Jeon K, Lee NY, Kim BJ, Kook YH, Lee SH, et al. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med. 2011;183(3):405–10.CrossRefGoogle Scholar
  48. 48.
    Jeon K, Kwon OJ, Lee NY, Kim BJ, Kook YH, Lee SH, et al. Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients. Am J Respir Crit Care Med. 2009;180(9):896–902.CrossRefGoogle Scholar
  49. 49.
    Lobo LJ, Chang LC, Esther CR Jr, Gilligan PH, Tulu Z, Noone PG. Lung transplant outcomes in cystic fibrosis patients with pre-operative Mycobacterium abscessus respiratory infections. Clin Transpl. 2013;27(4):523–9.CrossRefGoogle Scholar
  50. 50.
    Maurer FP, Castelberg C, Quiblier C, Bottger EC, Somoskovi A. Erm(41)-dependent inducible resistance to azithromycin and clarithromycin in clinical isolates of Mycobacterium abscessus. J Antimicrob Chemother. 2014;69(6):1559–63.CrossRefGoogle Scholar
  51. 51.
    van Ingen J, Totten SE, Helstrom NK, Heifets LB, Boeree MJ, Daley CL. In vitro synergy between clofazimine and amikacin in treatment of nontuberculous mycobacterial disease. Antimicrob Agents Chemother. 2012;56(12):6324–7.CrossRefGoogle Scholar
  52. 52.
    Kar HK, Gupta R. Treatment of leprosy. Clin Dermatol. 2015;33(1):55–65.CrossRefGoogle Scholar
  53. 53.
    Malouf MA, Glanville AR. The spectrum of mycobacterial infection after lung transplantation. Am J Respir Crit Care Med. 1999;160(5 Pt 1):1611–6.CrossRefGoogle Scholar
  54. 54.
    Skolnik K, Kirkpatrick G, Quon BS. Nontuberculous mycobacteria in cystic fibrosis. Curr Treat Options Infect Dis. 2016;8(4):259–74.CrossRefGoogle Scholar
  55. 55.
    Milanes-Virelles MT, Garcia-Garcia I, Santos-Herrera Y, Valdes-Quintana M, Valenzuela-Silva CM, Jimenez-Madrigal G, et al. Adjuvant interferon gamma in patients with pulmonary atypical Mycobacteriosis: a randomized, double-blind, placebo-controlled study. BMC Infect Dis. 2008;8:17.CrossRefGoogle Scholar
  56. 56.
    Rolla M, D’Andrilli A, Rendina EA, Diso D, Venuta F. Cystic fibrosis and the thoracic surgeon. Eur J Cardio-thorac Surg: Off J Eur Assoc Cardio-thorac Surg. 2011;39(5):716–25.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.The Division of Pulmonary MedicineUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations