Fw: Ref.: (LML) 100% risk - multi-case families

 

 

Leprosy Mailing List �C  November 4,  2025

 

Ref.:  (LML) 100% risk - multi-case families

From: Joel Almeida, Mumbai, India

 

 

Note editor: Dear colleagues, I will be traveling till the first week of December. Nevertheless, your reactions or observations are always welcome.

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Dear Pieter & colleagues,

We know that HD (Hansen Disease) can be manifested in as many as 60% of girls/women who are genetically susceptible (homozygous for an apparent major gene effect) as well as sufficiently exposed to the bacilli. (1) Nobody is aiming for 100% disease among girls/women. However, when physical signs of disease are found among all the girls/women in a household, and indeed when a household shows 100% cumulative incidence among all its members, it seems prudent to ask what is going on. 

Typically bacilli enter the nasal epithelium with the aid of Mammalian Cell Entry protein 1A (2). Macrophages phagocytose the bacilli and eliminate them in a controlled and relatively harmless manner via mechanisms such as the vit D-induced cathelicidin system.(3) This elimination can be compromised if bacillary debris (eg. DNA) becomes available within the cytosol of macrophages, or if the concentration of bacilli is sufficiently high. (4) If macrophages with viable bacilli travel to perineural locations around the body, nerves can be damaged owing to PGL-1 mediated inducible Nitric Oxide Synthase (iNOS) and excessive NO levels that damage mitochondria in axons of peripheral nerves.(5) This can occur without any signs of inflammation (silent neuropathy). Skin signs can become detectable if melanocytes or cutaneous fibres are damaged. With aids such as high-resolution ultrasonography, nerve changes can be detected even before any signs appear in the skin. Where neglect is the rule, deformity can appear before HD is suspected.

The important lesson is that nerve function needs to be tested in all contacts of newly diagnosed patients. Further, nerve function needs to be monitored if there is any use of anti-microbials. Otherwise the bacillary debris within macrophages can activate the cGAS-STING pathway that results in OASL inhibition of the cathelicidin system, and reduced autophagy, allowing bacilli to replicate within macrophages and damaging nerves via PGL1 as noted above.

In a household where one or more individuals are shedding many bacilli in nasal discharges (6), it seems likely that all members of the household will have received bacilli in their nose or skin. If the vit D-induced cathelicidin system is allowed to do its job without interference, some or all of the infected persons will eliminate bacilli without suffering any harm, or at least will contain the bacilli in a non-replicating state within macrophages. If such persons are given chemoprophylaxis, the resulting bacillary debris in the cytosol will tend to move the macrophages to a permissive state where bacilli can replicate and cause nerve damage as described above. This can give rise to signs in the skin, anaesthesia, muscle weakness or even deformity.

Given the biology, it can be predicted that whereas formerly it was almost unheard of for more than 60% of girls/women in a household or village to develop signs of HD, this can be increased to 100% by the use of chemoprophylaxis among asymptomatic infected persons. 100% cumulative incidence has been reported in a family in Pekan, Pahang, Malaysia. (7)  The pathological processes might take a few months or a few years, but they are predicted by the biology.

It seems prudent to warn family members and other contacts to refuse chemoprophylaxis, so as to reduce their risk of HD and its serious sequelae. Otherwise the biology predicts that we will see more multi-case famiilies, with some showing even multiple members with deformity developing silently before diagnosis. This is the exact reverse of what all of us wish to achieve.

With all sincerity,

Joel Almeida

References

1.      Lázaro, F. P. et al. (2010) A major gene controls leprosy susceptibility in a hyperendemic isolated population from north of Brazil. J. Infect. Dis. 201(10), 1598�C1605 

2.      Fadlitha VB, Yamamoto F, Idris I, Dahlan H, Sato N, Aftitah VB, et al. (2019) The unique tropism of Mycobacterium leprae to the nasal epithelial cells can be explained by the mammalian cell entry protein 1A. PLoS Negl Trop Dis 13(3): e0006704. https://doi.org/10.1371/journal. pntd.0006704

3.      da Silva Prata, et al. (2019) Macrophages in the Pathogenesis of Leprosy. DOI: http://dx.doi.org/10.5772/intechopen.88754

4.      de Toledo-Pinto et al (2016) STING-Dependent 2′-5′ Oligoadenylate Synthetase�CLike Production Is Required for Intracellular Mycobacterium leprae Survival. JID 214 :311-320

5.     Madigan CA, Cambier CJ, Kelly-Scumpia et al (2017). A macrophage response to Mycobacterium leprae phenolic glycolipid initiates nerve damage in leprosy. Cell. 170(5):973-985. e10. 

6.     Davey TF, Rees RJ. The nasal discharge in leprosy: clinical and bacteriological aspects (1974). Lepr Rev. 45(2):121-34.

7.     Benedict S et al (2025) Paucibacillary leprosy in a 6-month-old infant in an endemic area of Malaysia: a clinical case report. Lepr Rev (2025) 96, e2025074

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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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