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![Global Disease Burden
of NTM (Australia)
• Projections
show cases
could more
than triple
between 2020
and 2040 [up
to 6,446 cases
a year (CI 15
just in QLD]](https://image.slidesharecdn.com/mycobakterinontb-241114114445-61ca20ef/75/The-Rise-of-Non-Tuberculosis-Mycobacterial-Lung-Disease-pptx-10-2048.jpg)
![[Micro] atypical mycobacterium](https://cdn.slidesharecdn.com/ss_thumbnails/7d5djanirg26boloifek-signature-2127a2ca5368c7fdfd023e8d90dde3fc0b9fe7d91346a4189562c9f63dc0d19d-poli-150819190753-lva1-app6891-thumbnail.jpg?width=640&height=640&fit=bounds)
The Rise of Non-Tuberculosis Mycobacterial Lung Disease.pptx
- 1. The Rise ofNon-Tuberculosis Mycobacterial Lung Disease Champa N. Ratnatunga, Viviana P. Lutzky, Andreas Kupz, Denise L. Doolan, David W. Reid, Matthew Field, Scott C. Bell, Rachel M. Thomson and John J. Miles
- 2. Prologue • Incidence andmortality of NTM disease steadily increasing globally • Was thought as saprophytics and only opportunistic now infecting immunocompetent • It is difficult to treat, and have an extremely antibiotic resistant ability • Right now has ben founded a fact that TNM can transmitted by person to person • This paper reviewing : global and economic burden, population at risk, treatment, host-bacteri interaction, immune dynamics, recent development and reasearch priorities of NTM
- 3. Introduction • NTM comefrom genus Mycobacterium --_ over 170 spesies identified right now • NTM are are ubiquitous, free living, environmental saprophytic organisms known to occupy water systems, soil, and vegetation • Microanaerob, grom in 6-12% level of oxygen, have lipid-rich cell walls, doubling time around 20-24h • Divided to : slow and rapid grower • Natural habibat : brackish and marasy waters • Right now can be found on household, municipal and even healthcare system
- 4. Pathology of PulmonaryNTM (PNTM) infection • The transmission mode of PNTM still not understood clearly • It can manifest as lymphadenopathy (commonly cervical) to aseptic meningitis • Classified to 3 groups based on distinct pathology • Fibrocavitary • Nodular bronchiectasis • Hypersensitivity pneumonitis • Low virulence, slow grwoth rate insidious or even asymtomatic on early stage • Incubation vary from months-years • Predominated by MAC and MABS infection (Etiology)
- 5. Risk Groups forNTM Disease • Patients with genetic or acquired structural lung diseases (CF, COPD, lung cancer, etc) • Patients with PIDs • Patients with acquired immunodeficiency syndromes DNTM>PNTM • Patients on medication • patients with rheumatoid arthritis on anti-TNF therapy unexpected NTM susceptibility PNTM
- 6. Risk Groups forNTM Disease
- 7. Global Disease Burdenof NTM • Studies from North America, Europe, and Asia have all shown increasing NTM disease incidence over the last two decades. • Globally, the most common NTM pathogens are the MAC organisms though prevalence varies greatly with geographic region, gender, and age • MABS have very high levels of antibiotic resistance and the disease is a growing problem in East Asian countries including Japan, Korea, and Taiwan
- 8. Global Disease Burdenof NTM (US) • Prevalance : 2.4 cases/100,000 (1980) 15.2 cases/100,000 (2013) • Prevalence in the elderly population (>65 years) : 20 cases/100,000 (1997)47 cases /100,000 (2007) • NTM culture (+) : 8.2cases/100,000 (1994) 16 cases/100,000 (2014) • Prevalence of NTM disease on NCF bronchiectasis patients 37% caused by MAC • Laboratory isolation of NTM increase 8.4% annually (1997-2003)
- 9. Global Disease Burdenof NTM (Asian) • South Korea : 62% increase in NTM lung disease (2002-2008) with a marked increase in MABS infection, contrast to europe which predominated by MAC infection • Japan : a marked increase in both NTM infection and mortality (1994-2010) • Chinese : an increase in NTM isolation rate from 3 to 8.5%(2008 to 2012)
- 10. Global Disease Burden ofNTM (Australia) • Projections show cases could more than triple between 2020 and 2040 [up to 6,446 cases a year (CI 15 just in QLD]
- 11. The Treatment, Complications,and Economic Burden Of NTM (Treatment) • PNTM treatment requires prolonged (12–18 months) multi-drug therapy • remission rates depending on infecting species, patient age and comorbidities • Side effects of antibiotics are numerous, and regimes are difficult to tolerate. • Adjuvant therapies have been tested with little success. • IFNγ therapy (by intramuscular injection showed promise but still lack of supporting studies • A phase 2 open labeled drug trial is currently underway to test the efficacy of inhaled GM-CSF in persistent NTM infection (NCT03421743)
- 12. The Treatment, Complications,and Economic Burden Of NTM (Complication) • Recurrence rates 30–50% (MAC infection) • The majority of these recurrences are due to reinfection as opposed to relapse • MABS infection is more likely to result in treatment failure and recurrence • Many patients develop persistent chronic infection despite treatment while others succumb to the disease • long term treatment +multiple antibiotics increases antibiotic resistance and there is now evidence of person-to-person transmission of NTM
- 13. The Treatment, Complications,and Economic Burden Of NTM (Economic Burden) • Treatment is at high cost (USD $14,730 for MAC infection and USD $47,240 for MABS infection) • Study of MAC infection across Canada, France, Germany and the UK (2018 ) average direct medical costs per person year ranged from $US12,200 in Canada to $US25,500 in France • In addition to direct disease related costs, patients were also shown to have six times higher secondary care utilization events
- 14. The Host-Bacterial Interaction •NTM are environmental saprophytic organisms that make use of the new living opportunity presented when human habitation and bacterial habitation overlap • These things still unknown • Percentage of a given population who are exposed • How infection occurs and by what source • What host and bacterial factors determine clearance • How NTM establishes itself as a colonizer without causing tissue invasion • Why NTM are symptomatic in only some individuals • Currently known is that specific groups of individuals are at risk, some with known immune dysfunction, and others with specific medical characteristics
- 15.
- 16. The Immune Responsein Pulmonary NTM Infection (Overview) • The immune responses seen in human NTM infection has shown similarities to TB • Immune compromise caused by genetic mutations (MSMD) and acquired defects due to infections like HIV usually lead to disseminated infection • while iatrogenic causes, defects in lung structural and functional integrity, and pulmonary alveolar proteinosis predispositions to PNTM
- 17. The Immune Responsein Pulmonary NTM Infection (Overview) • Innate defense mechanisms such as effective respiratory epithelial ciliary function are likely required to keep colonizing NTM counts under control • When airway mucociliary clearance is impaired and/or when virulent strains of bacteria can locally invade tissue, cellular defense mechanisms are activated.
- 18. The Immune Responsein Pulmonary NTM Infection (Overview) The immune cascade then follows: • macrophage activation and local recruitment of innate cells including neutrophils, iNKTs and NK cells to control early infection • migration to of APCs to lymph nodes for antigen presentation and activation of antigen specific T cells • naïve T cells Th1 type or Th2 type during mycobacterial infection • Macrophages and NK cells release IL-12/ IFNγ to guide T cells toward a Th1 type phenotype • Th1 IFNγ and IL-2 release then promote intracellular killing of mycobacteria • The exact triggers for a Th2 type response are not known • Type2 cytokines (IL-4, IL-10, and IL-13) promote suppressive pathways that increased Treg cell frequency
- 19. The Immune Responsein Pulmonary NTM Infection (Mouse Model) • RORγt induced Th17/IL-17 responses during MAC infection promote pulmonary inflammation • NTM infection have shown the importance of CCL2, CCL5, and TLR signaling via MAPK, MyD88, and NFκβ for disease protection • comparisons between immune competent and immune deficient mouse models have provided insight into immune dysfunctions associated with DNTM • For PNTM, not have been studied yet in mouse model
- 20. The Immune Responsein Pulmonary NTM Infection (Human Study)
- 21. The Immune Responsein Pulmonary NTM Infection (Human Study) • Indirect evidence suggests individuals prone to NTM infection have underlying immune dysfunction • Mutations affecting IL12β, IL12Rβ1, IFNγR1, IFNγR2, and transcription factor STAT1 and RORC • Deficiency in NFκβ essential modulator (NEMO) and other primary immunodeficiency syndromes like GATA- 2 deficiency and isolated CD4+ T cell deficiency • HIV infection ncreases the risk of NTM disease when CD4+ T cell counts drops below 50/mm3 • Broadly immunosuppressed patients with hematological malignancies, organ transplants, and stem cell transplants are at high risk
- 22. Recent Developments andResearch Priorities (Recent Development) Recent findings of increased NTM pathophysiology are cause for global concern: 1. Recent emergence of person-to person transmission of highly antibiotic resistant MABS across continents is highly alarming 2. Increasing incidence of childhood NTM disease 3. It has been postulated that that MAC infection increases tumorgenes inflammatory responses which could lead to an increased risk of breast and lung cancer 4. There are alarmingly high death rates in patients following diagnosis with NTM lung infection
- 23. Recent Developments andResearch Priorities (Research Priorities) • rapid diagnostic tools fast identification of infecting species • simple and cheap screening tool to identify patients at risk • These are considered high impact research goals that would alert clinicians to at risk patients enabling faster initiation of appropriate treatment and ultimately, superior care.
- 24. Discussion • If wecan understand potential patient risk profiles, screening tests could be efficiently deployed to identify infection at risk individuals within hours. • Screening tests as well as prognostic tests that can predict outcome during early treatment would be extremely beneficial for clinicians to make therapy decisions as soon as possible, with potential improvement of patient outcomes • Research into adjuvant immune therapies that could be used to “boost” a weakened immune system would beneficial • Disease burden is being documented in both childhood and adulthood disease in terms of both direct and indirect morbidity.
- 25. Discussion • If wecan understand potential patient risk profiles, screening tests could be efficiently deployed to identify infection at risk individuals within hours. • Screening tests as well as prognostic tests that can predict outcome during early treatment would be extremely beneficial for clinicians to make therapy decisions as soon as possible, with potential improvement of patient outcomes • Research into adjuvant immune therapies that could be used to “boost” a weakened immune system would beneficial • Disease burden is being documented in : • Both developed and developing nations • Both immune competent and immune compromised populations • Both childhood and adulthood • Both direct and indirect morbidity
- 26. Discussion • A cohesivesolution to the global challenge of NTM lung infection requires a multipronged approach involving not just epidemiological data, but also clinical and laboratorybased research for new diagnostics, prognostics, and treatments for use in machine learning. • These cohesive approaches are urgent as NTM is more common in the warmer climates • Forty percent of the world’s population live in the tropics1 and due to climate change, the tropic are expanding in area
Editor's Notes
- #5 primary immune deficiency syndromes (PIDs) such as Mendelian Susceptibility to Mycobacterial Disease (MSMD) associated with IL12-p40, IL12, IFNγ receptor abnormalities and gene deformities (IFNγR1, IFNγR2, IL12RB1, IL12B, STAT1, IKBKG, CYBB, ISG15, IRF8, GATA2) are at high risk of NTM infection