Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pathogenesis of nontuberculous mycobacterial infections

David E Griffith, MD
Section Editor
C Fordham von Reyn, MD
Deputy Editor
Allyson Bloom, MD


Mycobacteria other than Mycobacterium tuberculosis and Mycobacterium leprae are generally free-living organisms that are ubiquitous in the environment (table 1). They have been recovered from surface water, tap water, soil, domestic and wild animals, milk, and food products. Although nontuberculous mycobacteria (NTM) can inhabit body surfaces and secretions without causing disease, they can, in broad terms, induce four distinct clinical syndromes. (See "Overview of nontuberculous mycobacterial infections in HIV-negative patients".)

Progressive pulmonary disease is usually associated with bronchiectasis or chronic obstructive lung disease and caused primarily by Mycobacterium avium complex (MAC) Mycobacterium kansasii and Mycobacterium abscessus, especially in older persons.

Superficial lymphadenitis, especially cervical lymphadenitis, in children is caused mostly by MAC, Mycobacterium scrofulaceum, and, in northern Europe, Mycobacterium malmoense (M. tuberculosis is a more common cause of lymphadenitis in tuberculosis-endemic countries).

Disseminated disease can occur in severely immunocompromised patients.

Skin and soft tissue infection usually is a consequence of direct inoculation.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 26, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Thomson RM, Armstrong JG, Looke DF. Gastroesophageal reflux disease, acid suppression, and Mycobacterium avium complex pulmonary disease. Chest 2007; 131:1166.
  2. Good RC, Snider DE Jr. Isolation of nontuberculous mycobacteria in the United States, 1980. J Infect Dis 1982; 146:829.
  3. CORPE RF, STERGUS I. Is the histopathology of nonphotochromogenic mycobacterial infections distinguishable from that caused by Mycobacterium tuberculosis? Am Rev Respir Dis 1963; 87:289.
  4. von Reyn CF, Horsburgh CR, Olivier KN, et al. Skin test reactions to Mycobacterium tuberculosis purified protein derivative and Mycobacterium avium sensitin among health care workers and medical students in the United States. Int J Tuberc Lung Dis 2001; 5:1122.
  5. Bermudez LE, Young LS, Enkel H. Interaction of Mycobacterium avium complex with human macrophages: roles of membrane receptors and serum proteins. Infect Immun 1991; 59:1697.
  6. Roecklein JA, Swartz RP, Yeager H Jr. Nonopsonic uptake of Mycobacterium avium complex by human monocytes and alveolar macrophages. J Lab Clin Med 1992; 119:772.
  7. Swartz RP, Naai D, Vogel CW, Yeager H Jr. Differences in uptake of mycobacteria by human monocytes: a role for complement. Infect Immun 1988; 56:2223.
  8. Holland SM. Host defense against nontuberculous mycobacterial infections. Semin Respir Infect 1996; 11:217.
  9. Ogata K, Linzer BA, Zuberi RI, et al. Activity of defensins from human neutrophilic granulocytes against Mycobacterium avium-Mycobacterium intracellulare. Infect Immun 1992; 60:4720.
  10. Hayashi T, Catanzaro A, Rao SP. Apoptosis of human monocytes and macrophages by Mycobacterium avium sonicate. Infect Immun 1997; 65:5262.
  11. Klingler K, Tchou-Wong KM, Brändli O, et al. Effects of mycobacteria on regulation of apoptosis in mononuclear phagocytes. Infect Immun 1997; 65:5272.
  12. Honda JR, Knight V, Chan ED. Pathogenesis and risk factors for nontuberculous mycobacterial lung disease. Clin Chest Med 2015; 36:1.
  13. Rose SJ, Bermudez LE. Mycobacterium avium biofilm attenuates mononuclear phagocyte function by triggering hyperstimulation and apoptosis during early infection. Infect Immun 2014; 82:405.
  14. McGarvey J, Bermudez LE. Pathogenesis of nontuberculous mycobacteria infections. Clin Chest Med 2002; 23:569.
  15. Raulet DH, Held W. Natural killer cell receptors: the offs and ons of NK cell recognition. Cell 1995; 82:697.
  16. Dannenberg AM Jr, Rook GAW. Pathogenesis of pulmonary tuberculosis: An interplay of tissue-damaging and macrophage-activating immune responses — dual mechanisms that control bacillary multiplications. In: Tuberculosis: Pathogenesis, Protection, and Control, Bloom BR (Ed), ASM Press, Washington, DC 1994. p.459.
  17. Regev D, Surolia R, Karki S, et al. Heme oxygenase-1 promotes granuloma development and protects against dissemination of mycobacteria. Lab Invest 2012; 92:1541.
  18. O'Connell ML, Birkenkamp KE, Kleiner DE, et al. Lung manifestations in an autopsy-based series of pulmonary or disseminated nontuberculous mycobacterial disease. Chest 2012; 141:1203.
  19. Malcolm KC, Nichols EM, Caceres SM, et al. Mycobacterium abscessus induces a limited pattern of neutrophil activation that promotes pathogen survival. PLoS One 2013; 8:e57402.
  20. Fulton SA, Johnsen JM, Wolf SF, et al. Interleukin-12 production by human monocytes infected with Mycobacterium tuberculosis: role of phagocytosis. Infect Immun 1996; 64:2523.
  21. Gately MK, Renzetti LM, Magram J, et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol 1998; 16:495.
  22. Trinchieri G, Scott P. Interleukin-12: basic principles and clinical applications. Curr Top Microbiol Immunol 1999; 238:57.
  23. Blanchard DK, Michelini-Norris MB, Friedman H, Djeu JY. Lysis of mycobacteria-infected monocytes by IL-2-activated killer cells: role of LFA-1. Cell Immunol 1989; 119:402.
  24. Katz P, Yeager H Jr, Whalen G, et al. Natural killer cell-mediated lysis of Mycobacterium-avium complex-infected monocytes. J Clin Immunol 1990; 10:71.
  25. Bermudez LE, Young LS. Oxidative and non-oxidative intracellular killing of Mycobacterium avium complex. Microb Pathog 1989; 7:289.
  26. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol 1997; 15:749.
  27. Gallin JI, Farber JM, Holland SM, Nutman TB. Interferon-gamma in the management of infectious diseases. Ann Intern Med 1995; 123:216.
  28. Darnell JE Jr. Studies of IFN-induced transcriptional activation uncover the Jak-Stat pathway. J Interferon Cytokine Res 1998; 18:549.
  29. Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 2000; 11:321.
  30. van de Vosse E, Hoeve MA, Ottenhoff TH. Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae. Lancet Infect Dis 2004; 4:739.
  31. Browne SK, Burbelo PD, Chetchotisakd P, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med 2012; 367:725.
  32. Kartalija M, Ovrutsky AR, Bryan CL, et al. Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am J Respir Crit Care Med 2013; 187:197.
  33. Bermudez LE, Young LS. Tumor necrosis factor, alone or in combination with IL-2, but not IFN-gamma, is associated with macrophage killing of Mycobacterium avium complex. J Immunol 1988; 140:3006.
  34. Winthrop KL, Yamashita S, Beekmann SE, et al. Mycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: case finding through the Emerging Infections Network. Clin Infect Dis 2008; 46:1738.
  35. Bermudez LE, Young LS. Natural killer cell-dependent mycobacteriostatic and mycobactericidal activity in human macrophages. J Immunol 1991; 146:265.
  36. Flesch IE, Hess JH, Huang S, et al. Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon gamma and tumor necrosis factor alpha. J Exp Med 1995; 181:1615.
  37. Bermudez LE, Wu M, Young LS. Interleukin-12-stimulated natural killer cells can activate human macrophages to inhibit growth of Mycobacterium avium. Infect Immun 1995; 63:4099.
  38. Bermudez LE, Martinelli J, Petrofsky M, et al. Recombinant granulocyte-macrophage colony-stimulating factor enhances the effects of antibiotics against Mycobacterium avium complex infection in the beige mouse model. J Infect Dis 1994; 169:575.
  39. Denis M. Interleukin-6 is used as a growth factor by virulent Mycobacterium avium: presence of specific receptors. Cell Immunol 1992; 141:182.
  40. Bermudez LE, Champsi J. Infection with Mycobacterium avium induces production of interleukin-10 (IL-10), and administration of anti-IL-10 antibody is associated with enhanced resistance to infection in mice. Infect Immun 1993; 61:3093.
  41. Ovrutsky AR, Merkel PA, Schonteich E, et al. Patients with non-tuberculous mycobacterial lung disease have elevated transforming growth factor-beta following ex vivo stimulation of blood with live Mycobacterium intracellulare. Scand J Infect Dis 2013; 45:711.
  42. Holland SM, Eisenstein EM, Kuhns DB, et al. Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. A preliminary report. N Engl J Med 1994; 330:1348.
  43. Frucht DM, Holland SM. Defective monocyte costimulation for IFN-gamma production in familial disseminated Mycobacterium avium complex infection: abnormal IL-12 regulation. J Immunol 1996; 157:411.
  44. Guide SV, Holland SM. Host susceptibility factors in mycobacterial infection. Genetics and body morphotype. Infect Dis Clin North Am 2002; 16:163.
  45. Chan J, Fan XD, Hunter SW, et al. Lipoarabinomannan, a possible virulence factor involved in persistence of Mycobacterium tuberculosis within macrophages. Infect Immun 1991; 59:1755.
  46. Hines ME 2nd, Jaynes JM, Barker SA, et al. Isolation and partial characterization of glycolipid fractions from Mycobacterium avium serovar 2 (Mycobacterium paratuberculosis 18) that inhibit activated macrophages. Infect Immun 1993; 61:1.
  47. Tsuyuguchi I, Kawasumi H, Takashima T, et al. Mycobacterium avium-Mycobacterium intracellular complex-induced suppression of T-cell proliferation in vitro by regulation of monocyte accessory cell activity. Infect Immun 1990; 58:1369.
  48. Rhoades ER, Archambault AS, Greendyke R, et al. Mycobacterium abscessus Glycopeptidolipids mask underlying cell wall phosphatidyl-myo-inositol mannosides blocking induction of human macrophage TNF-alpha by preventing interaction with TLR2. J Immunol 2009; 183:1997.
  49. Catherinot E, Roux AL, Macheras E, et al. Acute respiratory failure involving an R variant of Mycobacterium abscessus. J Clin Microbiol 2009; 47:271.
  50. Byrd TF, Lyons CR. Preliminary characterization of a Mycobacterium abscessus mutant in human and murine models of infection. Infect Immun 1999; 67:4700.
  51. Sanguinetti M, Ardito F, Fiscarelli E, et al. Fatal pulmonary infection due to multidrug-resistant Mycobacterium abscessus in a patient with cystic fibrosis. J Clin Microbiol 2001; 39:816.
  52. Pawlik A, Garnier G, Orgeur M, et al. Identification and characterization of the genetic changes responsible for the characteristic smooth-to-rough morphotype alterations of clinically persistent Mycobacterium abscessus. Mol Microbiol 2013; 90:612.
  53. Pang L, Tian X, Pan W, Xie J. Structure and function of mycobacterium glycopeptidolipids from comparative genomics perspective. J Cell Biochem 2013; 114:1705.
  54. Shiratsuchi H, Toossi Z, Mettler MA, Ellner JJ. Colonial morphotype as a determinant of cytokine expression by human monocytes infected with Mycobacterium avium. J Immunol 1993; 150:2945.
  55. Michelini-Norris MB, Blanchard DK, Pearson CA, Djeu JY. Differential release of interleukin (IL)-1 alpha, IL-1 beta, and IL-6 from normal human monocytes stimulated with a virulent and an avirulent isogenic variant of Mycobacterium avium-intracellulare complex. J Infect Dis 1992; 165:702.
  56. Sousa S, Bandeira M, Carvalho PA, et al. Nontuberculous mycobacteria pathogenesis and biofilm assembly. Int J Mycobacteriol 2015; 4:36.
  57. Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989; 321:863.
  58. Reich JM, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest 1992; 101:1605.
  59. Huang JH, Kao PN, Adi V, Ruoss SJ. Mycobacterium avium-intracellulare pulmonary infection in HIV-negative patients without preexisting lung disease: diagnostic and management limitations. Chest 1999; 115:1033.
  60. Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis. Thoracic anomalies associated with pulmonary disease caused by Mycobacterium avium complex. Am Rev Respir Dis 1991; 144:914.
  61. Kim RD, Greenberg DE, Ehrmantraut ME, et al. Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome. Am J Respir Crit Care Med 2008; 178:1066.
  62. Szymanski EP, Leung JM, Fowler CJ, et al. Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease. Am J Respir Crit Care Med 2015; 192:618.
  63. Gelb BD. Marfan's syndrome and related disorders--more tightly connected than we thought. N Engl J Med 2006; 355:841.
  64. Melia E, Freeman AF, Shea YR, et al. Pulmonary nontuberculous mycobacterial infections in hyper-IgE syndrome. J Allergy Clin Immunol 2009; 124:617.
  65. Paulson ML, Olivier KN, Holland SM. Pulmonary non-tuberculous mycobacterial infection in congenital contractural arachnodactyly. Int J Tuberc Lung Dis 2012; 16:561.
  66. Colombo RE, Hill SC, Claypool RJ, et al. Familial clustering of pulmonary nontuberculous mycobacterial disease. Chest 2010; 137:629.
  67. Ziedalski TM, Kao PN, Henig NR, et al. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest 2006; 130:995.
  68. Knowles MR, Daniels LA, Davis SD, et al. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med 2013; 188:913.
  69. Bienvenu T, Sermet-Gaudelus I, Burgel PR, et al. Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2010; 181:1078.
  70. Swensen SJ, Hartman TE, Williams DE. Computed tomographic diagnosis of Mycobacterium avium-intracellulare complex in patients with bronchiectasis. Chest 1994; 105:49.
  71. Griffith DE, Girard WM, Wallace RJ Jr. Clinical features of pulmonary disease caused by rapidly growing mycobacteria. An analysis of 154 patients. Am Rev Respir Dis 1993; 147:1271.
  72. Wallace RJ Jr. The clinical presentation, diagnosis, and therapy of cutaneous and pulmonary infections due to the rapidly growing mycobacteria, M. fortuitum and M. chelonae. Clin Chest Med 1989; 10:419.
  73. Alberts WM, Chandler KW, Solomon DA, Goldman AL. Pulmonary disease caused by Mycobacterium malmoense. Am Rev Respir Dis 1987; 135:1375.
  74. Costrini AM, Mahler DA, Gross WM, et al. Clinical and roentgenographic features of nosocomial pulmonary disease due to Mycobacterium xenopi. Am Rev Respir Dis 1981; 123:104.
  75. Wayne LG, Sramek HA. Agents of newly recognized or infrequently encountered mycobacterial diseases. Clin Microbiol Rev 1992; 5:1.
  76. von Reyn CF, Maslow JN, Barber TW, et al. Persistent colonisation of potable water as a source of Mycobacterium avium infection in AIDS. Lancet 1994; 343:1137.
  77. Horsburgh CR Jr, Selik RM. The epidemiology of disseminated nontuberculous mycobacterial infection in the acquired immunodeficiency syndrome (AIDS). Am Rev Respir Dis 1989; 139:4.
  78. Nightingale SD, Byrd LT, Southern PM, et al. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis 1992; 165:1082.
  79. Chin DP, Hopewell PC, Yajko DM, et al. Mycobacterium avium complex in the respiratory or gastrointestinal tract and the risk of M. avium complex bacteremia in patients with human immunodeficiency virus infection. J Infect Dis 1994; 169:289.
  80. Jacobson MA, Hopewell PC, Yajko DM, et al. Natural history of disseminated Mycobacterium avium complex infection in AIDS. J Infect Dis 1991; 164:994.
  81. Torriani FJ, McCutchan JA, Bozzette SA, et al. Autopsy findings in AIDS patients with Mycobacterium avium complex bacteremia. J Infect Dis 1994; 170:1601.
  82. Torriani FJ, Behling CA, McCutchan JA, et al. Disseminated Mycobacterium avium complex: correlation between blood and tissue burden. J Infect Dis 1996; 173:942.
  83. von Reyn CF, Jacobs NJ, Arbeit RD, et al. Polyclonal Mycobacterium avium infections in patients with AIDS: variations in antimicrobial susceptibilities of different strains of M. avium isolated from the same patient. J Clin Microbiol 1995; 33:1008.
  84. Fordham von Reyn C, Arbeit RD, Tosteson AN, et al. The international epidemiology of disseminated Mycobacterium avium complex infection in AIDS. International MAC Study Group. AIDS 1996; 10:1025.
  85. von Reyn CF, Barber TW, Arbeit RD, et al. Evidence of previous infection with Mycobacterium avium-Mycobacterium intracellulare complex among healthy subjects: an international study of dominant mycobacterial skin test reactions. J Infect Dis 1993; 168:1553.