Leprosy Mailing List – July 17, 2024
Ref.: (LML) Visible deformity after HD (leprosy) chemoprophylaxis among India tribals
From: Joel Almeida, Mumbai, India
Dear Pieter and colleagues,
Dadra Nagar Haveli (DNH) forms part of a "Union Territory" within India. It has a population of approximately 400,000 persons. More than half the inhabitants belong to Scheduled Tribes. They have rich cultural traditions but conspicuously low incomes, mainly from agriculture..
DNH long boasted vigorous active case-finding for HD (leprosy). Repeated case-finding campaigns were carried out each year. There were typically zero deformities among newly detected HD patients in DNH, as confirmed also by a national sample survey. (1)
In 2015 as part of an initiative designed by Dutch colleagues, (2) a single dose of rifampicin (LPEP / SDR PEP / PEP RDU) was administered to contacts of newly diagnosed HD (leprosy) patients in DNH. This included household, neighbours and social contacts of newly diagnosed HD patients. What outcomes followed? (2-5)
The number of new HD patients with visible deformity (grade 2 disability) increased dramatically following the introduction of LPEP / SDR PEP in DNH. This boost was by a large factor, between 10 and 20 times (1000% to 2000%). Neighbouring non-PEP comparator states Maharashtra and Gujarat did not show any such boost in visible deformity.
Discussion
Boosting visible deformity among newly diagnosed HD patients is not the chief goal of HD control. The boost in visible deformity among newly diagnosed HD patients in DNH was observable by 2017, before the WHO treatment and prevention guidelines of 2017/2018 were issued..
A similar dramatic boost in visible deformity is observable following the introduction of LPEP / SDR PEP / PEP RDU in three Brazilian states.
LPEP study reports, too, confirm the dramatic increase in visible deformity/yr. (4, 5)
All these observations are consistent with the outcomes of a randomised controlled trial in Bangladesh where SDR PEP was compared to a non-PEP control group (6), with both groups having received a dose of BCG 8 to 12 weeks earlier.
Figure 4. SDR PEP increased the incidence rate of new MB HD within two years. As given in Table 5 of reference (6)
The investigators in DNH did not raise the alarm about the dramatic increase in visible deformity among new HD cases following the introduction of SDR PEP / LPEP. Instead, they declared publicly that LPEP was safe.
Further, some of the same investigators served as external reviewers of the WHO guidelines development in 2017. They were duly identified in Annex 1 of the said guidelines as having conflicts of interest. The conditional recommendation for the use of SDR PEP (LPEP or PEP RDU) therefore rests on sub-optimal foundations.
Brazil has since rejected LPEP / PEP RDU / SDR PEP. External pressures to reintroduce it have been resisted by Brazilian colleagues. Were our Brazilian colleagues wrong to protect their people against the boost in visible deformity that follows PEP RDU / SDR PEP?
Underlying biology
The underlying biology can be elucidated steadily, preferably by non-human experiments.
It is known that anti-mycobacterial drugs can cause massive release of TLR9 (toll-like-receptor-9) ligands from M. leprae, leading to the proinflammatory cytokines storm of ENL (erythema nodosum leprosum).(13) A variety of such mechanisms may well be triggered by anti-mycobacterial drugs, with adverse effects on nerve structure and/or function. The use of anti-mycobacterial drugs among asymptomatic persons infected with M. leprae in endemic areas appears to be more hazardous than we might like.
The other remarkable feature of DNH is the very low incidence rate of visible deformity prior to the introduction of chemoprophylaxis. This is seen in several settings where barefooted people live close to nature. It may be that environmental mycobacteria that co-infect with M. leprae serve as natural immunological protection analogous to BCG (natural vaccination). "Trained" wide-spectrum non-specific immunity is known to be elicited by BCG through the NOD2-dependent epigenetic programming of monocytes (7-12) Rifampicin is active against a variety of mycobacteria. Some of these mycobacteria are likely to be nearly as capable as BCG or MIP vaccine of inducing nonspecific protection. For example, Indian colleagues showed that mouse peritoneal macrophages treated with MIP vaccine up-regulated NOD2 mRNA expression 3- to 4-fold.(14) Killing protective environmental mycobacteria by chemoprophylaxis in asymptomatic persons might unleash the worst consequences of M. leprae infection, such as visible deformity.
Whatever the underlying biology, HD chemoprophylaxis in endemic areas was followed by an increase in visible deformity.
Shall human rights be ignored?
We are striving to defeat HD. We form a noble-minded and non-mercenary community with full respect for the Universal Declaration of Human Rights, ethical principles and various national and European legislations. People tend to recoil from causing grievous hurt to others. By contrast, the dominant concern of some SDR PEP promoters seems to be that the "reputation of SDR PEP should not be harmed" (quote from a recent meeting of experts convened by LRI in Bergen). With all due respect to LRI, people at risk of visible deformity following SDR PEP / PEP RDU might prefer that their limbs should not be harmed. Inflicting visible deformity is not the ideal way to fight HD.
Inflicting grievous hurt and visible deformity on tribals and other low income people in endemic countries seems somewhat inconsistent with the Nuremberg code on human experiments. "The scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgement required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject." (from the Nuremberg code) Further, "The voluntary consent of the human subject is absolutely essential."
Rapid epidemiological impact using other interventions
By contrast with the boost in visible deformity following LPEP / SDR PEP in DNH, rapid epidemiological impact was demonstrated elsewhere (eg., Karigiri, Tamil Nadu, India, ref. 15). 16%/year decline in the incidence rate of new LL (lepromatous) HD is demonstrably achievable. This translates to 65% reduction in incidence rate by 2030. Accelerated decline even beyond 16%/year seems possible. MIP vaccine could well help reduce recurrences in highly bacillated patients. (16)
We can rapidly reduce the incidence rate of HD using well tested interventions, instead of spreading visible deformity through chemoprophylaxis.
Informed consent
Given the greatly increased risk of visible deformity with HD chemoprophylaxis, what information is now required for sufficiently informed consent?
Joel Almeida
References
1. Katoch K, Aggarwal A, Yadav VS, Pandey A. National sample survey to assess the new case disease burden of leprosy in India. Indian Journal of Medical Research, 2017; 146(5): 585-605.
2. Barth-Jaeggi T, Steinmann P, Mieras L, et al. Leprosy Post-ExposureProphylaxis (LPEP) programme: study protocol for evaluating the feasibility and impact on case detection rates of contact tracing and single dose rifampicin. BMJ Open 2016;6:e013633.doi:10.1136/bmjopen-2016-013633.
3. Mieras L, Singh MK, Manglani PR et al. A single dose of rifampicin to prevent leprosy; quantitative analysis of impact on perception, attitudes and behaviour of persons affected, contacts and community members towards leprosy in India, Nepal and Indonesia. Lepr Rev (2020) 91, 314–327 doi:10.47276/lr.91.4.314
4. Steinmann P, Cavaliero A, Aerts A et al. The Leprosy Post-Exposure Prophylaxis (LPEP) programme: update and interim analysis. Lepr Rev (2018) 89, 102–116
5. Richardus JH, Tiwari A, Barth-Jaeggi T et al. Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme. Lancet Glob Health. Lancet Glob Health. 2021 Jan;9(1):e81-e90. doi: 10.1016/S2214-109X(20)30396-X.
6. Richardus R, Alam K, Kundu K et al. Effectiveness of single-dose rifampicin after BCG vaccination to prevent leprosy in close contacts of patients with newly diagnosed leprosy: A cluster randomized controlled trial. International Journal of Infectious Diseases 88 (2019) 65–72
7. Pinheiro RO, Schmitz V, de Andrade Silva BJ et al. Innate Immune Responses in Leprosy. Front Immunol. 2018; 9: 518. Published online 2018 Mar 28. doi: 10.3389/fimmu.2018.00518
8. Kleinnijenhuis J,Quintin J, Preijers F et al. Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012 Oct 23; 109(43): 17537–17542. Published online 2012 Sep 17. doi: 10.1073/pnas.1202870109
9. Fine PEM, Floyd S, Stanford J et al. Environmental mycobacteria in northern Malawi: implications for the epidemiology of tuberculosis and leprosy. Epidemiol Infect, 2001; 126: 379–387.
10. Denise L, Faustman AL, Hostetter ER. Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes. Cell Rep Med. 2022 Sep 20; 3(9): 100728. Published online 2022 Aug 15. doi: 10.1016/j.xcrm.2022.100728
11. Zhou,J, Jingzhu Lv, Carlson C et al. Trained immunity contributes to the prevention of Mycobacterium tuberculosis infection, a novel role of autophagy. Emerg Microbes Infect. 2021; 10(1): 578–588. Published online 2021 Mar 30. doi: 10.1080/22221751.2021.1899771
12. Jensen KJ, Larsen N, Biering-Sørensen S.Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial J Infect Dis. 2015 Mar 15; 211(6): 956–967. Published online 2014 Sep 9. doi: 10.1093/infdis/jiu508
13. Pandey RK, Sodhi A, Biswas SK, Dahiya Y, Dhillon MK. Mycobacterium indicus pranii mediates macrophage activation through TLR2 and NOD2 in a MyD88 dependent manner. Vaccine. 2012;30:5748–5754.
14. Dias AA, Silva CO, Santos JPS, Batista-Silva LR, Acosta CCD, Fontes ANB, 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
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.
16 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
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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