Pathogenesis

  • Nontuberculous mycobacteria (NTM) are widespread in the environment and exposure is thought to be common1,2
  • However, NTM infection with clinical disease is usually limited to hosts with known predisposing risk factors1
  • NTM species have a variety of virulence factors that assist them in establishing infection and evading the host immune response, allowing for disease progression3
Pathogenesis
Risk Factors
Environmental Factors
Host Factors
Bacterial Factors

Risk Factors for Nontuberculous Mycobacteria Pulmonary Disease

NTM are widespread in the environment and exposure is thought to be common; however, exposure does not always result in infection.1,4 The risk of NTM infection is impacted by a complex interplay of host, environmental, and bacterial factors that together contribute to development of clinical disease.4,5

Risk Factors for NTM Pulmonary Disease

Environmental Factors1,5

  • Infecting load
  • Duration of exposure
  • Environmental exposure: natural and engineered sources

Host Factors2,4

  • Primary or acquired immunodeficiency
  • Structural/functional lung compromise (cystic fibrosis, bronchiectasis, COPD, malignancy)
  • Drug-induced (e.g., anti-TNFɑ, steroids)
  • Genetic

Bacterial Factors2,4,5

  • Species
  • Pathogenicity
  • Biofilm formation and persistence
  • Antibiotic and disinfectant resistance

Environmental Factors

NTM are widely distributed throughout the environment and several exposure routes have been proposed, including those from engineered and natural systems.1 NTM can live in water and soil particles; these can then become aerosolized, allowing the bacteria to be inhaled.1 People are also frequently exposed to NTM through simple, daily activities, such as showering or gardening. Environmental factors are thought to mediate disease susceptibility.2 In contrast to pulmonary tuberculosis, reports of direct human-to-human transmission of NTM are limited and inconclusive.2,6

Environmental Factors for NTM Pulmonary Disease

NTM Pathogenesis

Host Factors

While exposure to NTM is common, the development of pulmonary disease is usually limited to individuals with predisposing risk factors including structural lung disease (bronchiectasis, chronic obstructive pulmonary disease, cystic fibrosis) or treatment with immunosuppressive medications (anti-TNFα therapy,a steroids).4
 

  • Studies have demonstrated a close link between bronchiectasis and NTM pulmonary disease. Those with a reported diagnosis of bronchiectasis were 50 to 75 times more likely to have NTM infection compared with those without bronchiectasis1,2
  • Cystic fibrosis is a particularly strong risk factor for NTM pulmonary disease, with a reported prevalence of between 6% and 13% in this group3
  • In patients with rheumatoid arthritis, anti-TNFα therapy is associated with a significantly increased risk of NTM disease compared with non-users (adjusted odds ratio [OR]=2.19)4

 

Risk Factors for NTM Pulmonary Disease5

GeneticCystic fibrosis
α-1-antitrypsin deficiency
Primary ciliary dyskinesia
Pulmonary alveolar proteinosis
AcquiredBronchiectasis
Chronic obstructive pulmonary disease
Chronic aspiration
Lung malignancy
Lady Windermere SyndromePost menopausal females with slender body habitus and skeletal abnormalities
Drug inducedAnti-TNFα therapya,b
Cytotoxic therapya
Steroid therapy
OtherVitamin D deficiency
Aspergillus infection

aPatients on anti-TNFα therapy and cytotoxic therapy are predisposed to both NTM pulmonary disease and disseminated NTM infection, though lung disease is more common.

bTNFα, tumor necrosis factor alpha 
Figure adapted from Ratnatunga CN, et al. Front Immunol. 2020 Mar 3;11:303 under the Creative Commons Attribution License (CC BY)5



 

Bacterial Factors

The pathogenicity of NTM varies widely across the different species. Virulence factors present in pathogenic NTM species are crucial for the establishment of infection and progression to clinical disease.6-8

 

  • Virulence factors allow NTM to adhere to damaged areas of the respiratory mucosal surface in susceptible hosts1
  • Biofilm formation and inhibition of host inflammatory response are mechanisms by which NTM can promote colonization and subsequent invasion of the bronchial epithelium7
  • Alveolar macrophages are thought to be the main reservoir of NTM. Once inside macrophages, virulence factors also assist NTM in evading the host immune response allowing the bacteria to survive and replicate intracellularly, leading to chronic infection7,9
     
pathogenesis

Clinically Relevant Species of NTM Arranged According to Relative Pathogenicity

Image from Chalmers JD, et al. Pulmonology. 2018;24(2):120 under the Creative Commons Attribution License (CC BY).8

Learn about the epidemiology and disease burden of NTM pulmonary disease

References

  1. Park IK, Olivier KN. Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis. Semin Respir Crit Care Med. 2015;36(2):217–24. doi:10.1055/s-0035-1546751
  2. Seitz AE, Olivier KN, Adjemian J, Holland SM, Prevots DR. Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007. Chest. 2012;142(2):432–439. doi:10.1378/chest.11-2209
  3. Martiniano SL, Nick JA, Daley CL. Nontuberculous Mycobacterial Infections in Cystic Fibrosis. Clin Chest Med. 2016;37(1):83-96. doi:10.1016/j.ccm.2015.11.001
  4. Brode SK, Jamieson FB, Ng R, et al. Increased risk of mycobacterial infections associated with anti-rheumatic medications. Thorax. 2015;70(7):677–82. doi:10.1136/thoraxjnl-2014-206470
  5. Ratnatunga CN, Lutzky VP, Kupz A, et al. The Rise of Non-Tuberculosis Mycobacterial Lung Disease. Front Immunol. 2020;11:303. doi:10.3389/fimmu.2020.00303
  6. Daley CL. Mycobacterium avium Complex Disease. Microbiol Spectr. 2017;5(2)doi:10.1128/microbiolspec.TNMI7-0045-2017
  7. Honda JR, Knight V, Chan ED. Pathogenesis and risk factors for nontuberculous mycobacterial lung disease. Clin Chest Med. 2015;36(1):1–11. doi:10.1016/j.ccm.2014.10.001
  8. Chalmers JDA, T. Carvalho, A.C.C. Rendon, A. Franco, I. Non-tuberculous mycobacterial pulmonary infections. Pulmonology. 2018;24(2):120–131. 
  9. McGarvey J, Bermudez LE. Pathogenesis of nontuberculous mycobacteria infections. Clin Chest Med. 2002;23(3):569–83. doi:10.1016/s0272-5231(02)00012-6
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