Leprosy Mailing List – October 13, 2024
Ref.: (LML) Highly bacillated lesions despite treatment of drug-susceptible bacilli
From: Joel Almeida, Mumbai, India
Dear Pieter & colleagues,
Continuing the interesting discussions:
Should training be confined to urban professionals?
Probably not. Training professionals, especially those who have settled in poorly served highly endemic rural areas, seems necessary for many reasons. One of the most important reasons is that missed LL (lepromatous) patients can otherwise suffer eventual damage, as well as shed millions of viable bacilli per day.(1) This is sufficient to maintain transmission regardless of all other efforts. Without constant replenishment of concentrated viable bacilli, the viability of environmental extracellular bacilli is lost within as little as five months in dry, shady locations or 1.5 months in moist soil.(2) Our job is to protect all patients from current or lasting damage, and to shut down sources of concentrated viable bacilli. Shutting down sources of bacilli can be achieved by competent diagnosis and sufficient treatment of infected LL patients, including the prevention of re-infection.(3) In armadillo territory, contact with armadillos and armadillo-infected soil can be avoided altogether or minimised using protective gear.
Training is also necessary for quarterly monitoring of nerve function, because about 85% of nerve function impairment during treatment occurs without any signs or symptoms ("silent" nerve damage). (4)
Is this challenge to HD control well known?
Colleagues in endemic countries have shared examples of highly bacillated forms of HD (leprosy) in patients who faithfully completed fixed duration therapy including 12 monthly doses of rifampicin. (personal communications from Brazil and India) This happened even in some patients whose bacilli did not show mutations in the usual gene loci associated with drug-resistance. Better anti-microbial protection for highly bacillated LL (lepromatous) patients can be explored to protect such patients from damage and to help stop transmission. Bacilli with only the wild type rpoB gene can still show epigenetic tolerance to rifamycins, inversely related to drug concentration. These variant bacilli are genomically rifampicin-susceptible but phenotypically tolerant, being able to grow and divide in the presence of rifampicin.(5) It even seems likely that up-regulation by rifamycins of the rpoB gene in a sub-population of mycobacteria can lead to accelerated growth and division, with accompanying increased virulence of this sub-population of M. leprae.
Tolerance to rifamycins can also arise from up-regulation of genes for efflux pumps. (6,7) Efflux pumps are proteins that actively translocate chemicals across the bacillary membrane, affecting not only tolerance to rifamycins but also virulence.
Alongside this, dormancy of most of an M. leprae population seems probable, and could be the main explanation for the long observed doubling time of the bacillary population. The transition rate to dormancy (sometimes called the natural "death rate" of M. leprae) can result in a long doubling time despite a much shorter generation time. Hastings and Morales (8) treated the transition to dormancy as death and showed that a doubling time of more than one week is explicable by a generation time of only about 26 hours plus a relatively high "death" (transition to dormancy) rate. Accordingly, upon exposure to rifamycins, most of the M. leprae population could well be dormant with sporadic growth and division in a genomically drug-susceptible but phenotypically rifamycin-tolerant sub-population. This could well explain the highly bacillated types of LL HD sometimes observed in endemic countries despite faithful ingestion of 12 monthly doses of rifampicin + daily dapsone and clofazimine, even when known drug-resistance mutations are not detectable.
Incidentally, until recently we had never witnessed exactly how mycobacteria grow and divide. Now, a microscopic movie of the fascinating process can be viewed in Hannebelle et al.(9) The process turns out to occur at poles of the bacilli, and to be bi-phasic. This is consistent with dormancy interspersed with bursts of growth and division in a sub-population of bacilli. This, along with up-regulation of efflux pumps, may well explain why the anti-microbial efficacy of rifampicin declines markedly after the initial dose. Daily rifampicin has markedly lower efficacy against M. leprae when compared to the initial dose of rifampicin, and monthly rifampicin has less efficacy than even daily dapsone or daily clofazimine.(10,11)
Responding to the challenges
The practical implication of such efflux pumps and bacillary dormancy alongside growth and division of rifampicin-tolerant bacilli is that MIP vaccine (12) is advisable in highly bacillated patients, and alternative drugs deserve testing against M. leprae. Every drug known to be active against every mycobacterium, and every micro-organism, can be tested against M. leprae in animal models using rapid quantitative assessment of viability. Telacebec and bedaquiline are well known active molecules, but there may be others including older molecules not usually considered for use against M. leprae or mycobacteria. After testing for safety including safety of nerves during drug treatment in models such as zebra fish (13) and armadillos (14), use of alternative drugs in humans could help reduce the clinical impact of genomically drug-susceptible but phenotypically drug-tolerant M. leprae. Growth of M. leprae within macrophages is known to increase PGL-1 and so provoke the release of nitric oxide from macrophages that damages mitochondria in nerve axons.(13) That is why up-regulation of rpoB genes and efflux pump genes by rifamycins with consequent bacillary growth, division and shedding can too often be followed by an increased risk of virulence, transmission and nerve damage among previously asymptomatic persons.
Preventing re-infection in endemic areas
Enlightened colleagues in centres of excellence in endemic areas have already been protecting LL patients against (re)infection or endogenous relapse, using fully supervised monthly administration of potent bactericidal drugs in combination (eg., rifapentine + moxifloxacin + minocycline, sometimes clarithromycin has been added). Unresponsiveness to MIP vaccine is a useful indicator of the need for such prolonged protection. Careful recording and reporting from such initiatives would be instructive.
Is rapid decline of MB HD unachievable?
None of the above alters the fact that rapid decline in new MB (multibacillary) and LL HD is demonstrably achievable in even low income highly endemic populations near the equator, using mobile expert services and prolonged anti-microbial protection against (re)infection of anergic LL patients (15,16) Without expertise, either in person or via telemedicine, and in the absence of nasal smears for bacilloscopy, LL patients can be missed because they lack skin patches or nerve enlargement. Successful projects in low income areas established a benchmark of >15%/year decline in incidence rate of MB HD. That would permit about 65% decline in the incidence rate of MB HD by 2030. The rate of decline can probably be accelerated by using MIP vaccine in highly bacillated patients. Is there some reason to avoid demonstrably effective methods?
Bright young talent in endemic countries
Finally, it seems important to create opportunities and invite the brightest young people in endemic countries to participate in the battle against HD. There is no substitute for immersion in the epidemiological, clinical, laboratory and socio-economic context of HD in endemic countries, using well-established as well as rapidly advancing technology and knowledge. Counter-intuitive but crucial clues can then be more readily identified and woven together. Action can steadily be tweaked to defeat M. leprae more rapidly and to protect patients and their families more securely. The brightest young people in endemic countries currently gravitate to working in, or even leading, large global corporations (Microsoft, Alphabet/Google, Adobe etc,) or organizations such as the World Bank. If even a few of the most gifted can be encouraged to participate to some extent in the fight against HD, they will probably strengthen the capability of us all while bringing nearer the defeat of HD. Gaurav et al (6) are one example of such bright young talent in endemic countries. The more, the better.
With all sincerity,
Joel Almeida
References
1. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
2. Desikan KV, Sreevatsa A. Extended studies on the viability of Mycobacterium leprae outside the human body. Lepr Rev, 1995; 66: 287–295.
3. Stefani MMA, Avanzi C, Buhrer-Sekula S, Benjak A, Loiseau C, Singh P Whole genome sequencing distinguishes between relapse and reinfection in recurrent HD cases. PLoS Negl Trop Dis 2017; 11: e0005598
4. Croft RP, Nichols P, Richardus J, Smith WCS. Incidence rates of acute nerve function impairment in leprosy : a prospective cohort analysis after 24 months (The Bangladesh Acute Nerve Damage Study). Lepr Rev (2000) 71,18-33.
5. Zhu J-H, Wang B-W, Pan M. Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription Nature Commun. 2018 Oct 11;9(1):4218. doi: 10.1038/s41467-018-06667-3.
6. Gaurav A, Bakht P, Saini M et al. Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors. Microbiology 2023;169:001333 DOI 10.1099/mic.0.001333
7. Machado D, Lecorche E, Mougari F. Insights on Mycobacterium leprae Efflux Pumps and Their Implications in Drug Resistance and Virulence. Insights on Mycobacterium leprae. Front. Microbiol. 9:3072. doi: 10.3389/fmicb.2018.03072
8. Hastings, R. C. and Morales, M. J. Observations,calculations and speculations on the growth and death of M. leprae in vivo. Int. J. Lepr. 50 (1982) 579-582.
9. Hannebelle MT, Ven JX, Toniolo C et al. A biphasic growth model for cell pole elongation in mycobacteria. NATURE COMMUNICATIONS | (2020) 11:452 | https://doi.org/10.1038/s41467-019-14088-z
10. Grosset, J. H. and Guelpas-Lauras, C.-C. Activity of rifampin in infections of normal mice with M. leprae. Int. J. Lepr. 55 (1987) 847-851.
11. Colston, M. J., Hilson, G. R. F. and Banerjee, D.K. The "proportional bactericidal test": a method for assessing bactericidal activity of drugs against M. leprae in mice. Lepr. Rev. 49 (1978) 7-15.
12. Sharma P, Kar HK, Misra RS. Induction of lepromin positivity following immuno-chemotherapy with Mycobacterium w vaccine and multidrug therapy and its impact on bacteriological clearance in multibacillary leprosy: report on a hospital-based clinical trial with the candidate antileprosy vaccine. Int J Lepr 1999 Sep;67(3):259-69
13. Madigan, Cressida A. et al. A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell, Volume 170, Issue 5, 973 - 985.e10
14. Truman RW, Ebenezer GJ, Pena MT et al. The armadillo as a model for peripheral neuropathy in leprosy. ILAR J 54(2014):304–314.
15. Norman G, Bhushanam JDRS, Samuel P. Trends in leprosy over 50 years in Gudiyatham Taluk, Vellore, Tamil Nadu. Ind J Lepr 2006. 78(2): 167-185. reviewed and analysed further in: 3a. Almeida J. Karigiri, India: How transmission rapidly was reduced in a low-income population. LML 29 Oct 2020
16. Tonglet R, Pattyn SR, Nsansi BN et al. The reduction of the leprosy endemicity in northeastern Zaire 1975/1989 J.Eur J Epidemiol. 1990 Dec;6(4):404-6 reviewed in: 13a. Almeida J. Reducing transmission in poor hyperendemic areas - evidence from Uele (DRC). LML 29 Nov 2019
LML - S Deepak, B Naafs, S Noto and P Schreuder
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Contact: Dr Pieter Schreuder << editorlml@gmail.com
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