Leprosy Mailing List – November 5, 2024
Ref.: (LML) Preventing visible deformity
From: Joel Almeida, Mumbai, India
Dear Pieter and colleagues,
Preventing visible deformities of HD (leprosy) is a central goal of HD control.
Serious damage to motor nerves with dysfunction of muscles can occur within as little as few months to two years.(1) PGL-1 of HD bacilli induce their host macrophages to produce excess nitric oxide that kills the mitochondria in nerves.(2,3) By contrast, most persons exposed to HD bacilli stop the infection at the outset. This is partly because they do not have a genome that would predispose them to unrestrained growth of the HD bacilli. (4-10) However, in persons with a genome for "de novo" polar LL (lepromatous) HD, the bacilli have been known to produce protective proteins that preserve bacilli as well as host cells. (11,12) In persons with HD types other than polar LL, inflammatory host response around a nerve can damage both host cells and bacilli.(13,14) In this latter group, anti-inflammatory drugs are notably effective if given promptly.
It may be useful to think of some major groups of people in endemic areas. The overwhelming majority of people simply kill the bacilli upon first infection. Those who develop any clinical signs fall into a few groups.
a) Self-healing HD. When the interval between active surveys among contacts of HD patients in an endemic area was increased from 1 to 4 years, more than 75% of those with newly occurring signs of disease healed completely in the interval between surveys. This was without diagnosis or treatment, and the self-healed persons escaped any sequelae or stigma.(15) These self-healing types of HD typically have a well defined single lesion on only one area of the body, and no enlarged nerves. In the dapsone era, such patients were demonstrated to have a higher incidence rate of deformity with more anti-microbial treatment than with less anti-microbial treatment.(16) Even with MDT, 1% per year of TT (tuberculoid) patients in a prospective study newly developed motor impairments. (17) Therefore the advantages of anti-microbial treatment or prophylaxis in self-healing types of HD do not obviously outweigh the disadvantages.
b) Self-limiting HD definitely requiring treatment. In these types of HD, a pro-inflammatory response is mounted against the bacilli. This destroys bacilli. However, in the process it sometimes destroys the nerves where bacilli reside. Quarterly monitoring of nerve function is required so that anti-inflammatory treatment can be started promptly upon finding any impairments. Once HD bacilli are allowed to disseminate within the body, macrophages increasingly fall under the control of the bacilli. Anti-microbials therefore have a central role in these types of HD although they are often self-limiting. Where door-to-door surveys are conducted, self-limiting types of HD can form over 90% of all newly detected patients.
c) Disseminated HD definitely requiring treatment. In this group, bacilli control macrophages, turning them into factories for feeding and protecting the bacilli while suppressing signs of disease. Typically, these patients for several months or even longer show only diffuse infiltration of skin without patches. Only later in the disease do they show nerve enlargement. However, from the earliest stages of infection they shed tens of millions of viable bacilli per day. Nose blows or nasal smears are packed with bacilli. These patients replenish the environment with viable bacilli that then lose their viability within as little as five months. Anti-microbial treatment of these patients kills the bacilli. Unfortunately, this can release TLR9 ligands that produce the cytokine storm of ENL (18) often with excruciatingly painful nerves. Some patients who start off with self-limiting HD and remain untreated can develop immune deficits resembling polar LL (lepromatous) HD, but MIP vaccine is known to convert as many as 70% of LL patients to "lepromin positive".(19) Those LL patients who do not respond to MIP vaccine currently require protection against reinfection in endemic areas.(20, 21)
In groups b) and c) above, competent case management requires more than anti-microbial treatment. Quarterly monitoring for nerve damage and prompt anti-inflammatory treatment are required, backed by a full range of care and rehabilitation (physical, social, psychological, educational, vocational, financial, spiritual). In short, persons who experience(d) HD and their families require full respect as human beings so that diligent efforts can be made to serve and protect them. The persons themselves and their families know this. As their voices gain traction, opportunities for neglect or for offences against them will be reduced.
Some anti-microbials have immunomodulatory effects, in addition to interaction with other drugs. This is relevant to visible deformity. Drugs that decrease host TLR2 expression and TNF secretion, or that upregulate bacillary efflux pumps (22) tend to boost bacillary growth and virulence. Once PGL-1 is increased by growth of bacilli, macrophages tend to release excess nitric oxide that damages motor axons and hastens visible deformity, as mentioned above. Sometimes a dose of drug has been given to asymptomatic persons in endemic areas even though they do not have any signs of HD. Too often thereafter, the outcome is visible deformity. This typically occurs about a year after the use of the drug. (The Figure)
The Figure. Contacts who developed HD after receiving a single antimicrobial dose were included as new index cases.
In summary, protection against visible deformity requires not only anti-microbial treatment confined largely or wholly to infected persons who are unlikely to self-heal. It also requires quarterly monitoring of nerve function and prompt anti-inflammatory treatment, backed by availability of full care and rehabilitation for those who fall through the protective net. Asymptomatics need not be subjected to an excess risk of visible deformity at all.
With better information and an increasing voice for populations affected by HD, the risk of visible deformity can be kept very low.
Joel Almeida
References
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2. Madigan C et al., A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. 2017, Cell 170, 973–985
3. Madigan C, Cameron J, Ramakrishnan L. A Zebrafish Model of Mycobacterium leprae Granulomatous Infection. J Infect Dis. 2017 Sep 15;216(6):776-779. doi: 10.1093/infdis/jix329.
4. Zhang F-R, Huang W, Chen S-M, Sun L-D, Liu H, Li Y, et al. Genomewide association study of leprosy. N Engl J Med(2009) 361:2609–18. 10.1056/NEJMoa0903753
5. Travassos LH, Carneiro LAM, Ramjeet M, Husseym S, Kim Y-G, Magalhães JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol(2010) 11:55–62. 10.1038/ni.1823
6. Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV. Association of vitamin D receptor genotype with leprosy type. J Infect Dis(1999) 179:187–91. 10.1086/314536
7. Mira MT, Alcaïs A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, et al. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature(2004) 427:636–40. 10.1038/nature02326
8. Yuk J-M, Shin D-M, Lee H-M, Yang C-S, Jin HS, Kim K-K, et al. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe(2009) 6:231–43. 10.1016/j.chom.2009.08.004
9. Shin D-M, Yuk J-M, Lee H-M, Lee S-H, Son JW, Harding CV, et al. Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling. Cell Microbiol(2010) 12:1648–65. 10.1111/j.1462-5822.2010.01497.x
10. Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature(2013) 501:512–6. 10.1038/nature12566
11. Brito de Souza VN, Nogueira ME, Belone A, de F, Soares CT. Analysis of apoptosis and Bcl-2 expression in polar forms of leprosy. FEMS Immunol Med Microbiol(2010) 60:270–4. 10.1111/j.1574-695X.2010.00746.x
12. Moura DF, de Mattos KA, Amadeu TP, Andrade PR, Sales JS, Schmitz V, et al. CD163 favors Mycobacterium leprae survival and persistence by promoting anti-inflammatory pathways in lepromatous macrophages. Eur J Immunol(2012) 42:2925–36. 10.1002/eji.201142198
13. Montoya D, Cruz D, Teles RM, Lee DJ, Ochoa MT, Krutzik SR, et al. Divergence of macrophage phagocytic and antimicrobial programs in leprosy. Cell Host Microbe(2009) 6:343–53. 10.1016/j.chom.2009.09.002
14. Montoya D, Modlin RL. Learning from leprosy: insight into the human innate immune response. Adv Immunol(2010) 105:1–24. 10.1016/S0065-2776(10)05001-7
15. Jesudasan K, Bradley D, Smith PG, Christian M. The effect of intervals between surveys on the estimation of incidence rates of leprosy. Lepr Rev. 1984 Dec;55(4):353-9. doi: 10.5935/0305-7518.19840040.
16. Radhakrishna S, Nair NG. Association between regularity in dapsone (DDS) treatment and development of deformity. Int J Lepr 1987 Sep;55(3):425-34.
17. Solomon S, Kurian N, Ramadas P, Rao PSS. Incidence of Nerve Damage in Leprosy Patients Treated with MDT. Int J Lepr 1998 Dec;66(4):451-6
18 Dias AA, Silva CO, Santos JPS et al. DNA sensing via TLR-9 constitutes a major innate immunity pathway activated during erythema nodosum leprosum. J Immunol (2016) 197:1905–13. 10.4049/jimmunol.1600042
19. 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
20. Stefani MMA, Avanzi C, Bührer-Sékula S, et al. Whole genome sequencing distinguishes between relapse and reinfection in recurrent leprosy cases. PLoS Negl Trop Dis. 2017 Jun 15;11(6):e0005598. doi: 10.1371/journal.pntd.0005598.
21. Uaska Sartori PV, Penna GO, Bührer-Sékula S, et al. Human Genetic Susceptibility of Leprosy Recurrence Sci Rep. 2020 Jan 28;10(1):1284. doi: 10.1038/s41598-020-58079-3.
22. Machado D, Lecorche E, Mougari F et al. Efflux Pumps and Their Implications in Drug Resistance and Virulence. Insights on Mycobacterium leprae. Front. Microbiol. 9:3072. doi: 10.3389/fmicb.2018.03072
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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