Leprosy Mailing List – October 12, 2022
Ref.: (LML) Reinfection of previously treated LL patients and HD transmission
From: Joel Almeida, Mumbai, India
Dear Pieter and colleagues,
A recent paper offers some clues about transmission of M. leprae (Ortuño-Gutierrez N, Mzembaba A, et al. High yield of retrospective active case finding for leprosy in Comoros. PLoS Negl Trop Dis. 2022;16 : e0010158).
Introduction
Transmission of HD continues even in many well-implemented programs. Understanding the underlying processes can help transform epidemiological stagnation into reliably declining transmission.
Recent evidence
A recent paper raises interesting questions about transmission. When 668 contacts of previously treated patients were screened in Anjouan, Comoros, 12 new patients were found. (1) That is remarkable. It equates to a previously undiagnosed prevalence of about 18,000 per million persons (or 180/10,000) among contacts of previously treated patients. That is about 32 times the reported annual incidence rate of only 550 cases per million (or about 5.5/10,000) persons among the general population of Anjouan in 2019. It is a remarkably large multiple (95% UI 13 to 51 times), even allowing for a possible accumulated backlog of incidence and enrichment of genomic risk factors among contacts.
This evidence offers a clue about why transmission continues relatively unabated despite well-implemented programmes in parts of the Comoros, Indonesia, Nepal, Bangladesh etc.(2) Those places show only disappointing decline in HD (leprosy) even in areas using active case finding and rifampicin prophylaxis for contacts alongside fixed duration MDT. Likewise, Cuba has been using not only fixed duration MDT but also BCG and single dose rifampicin for contacts, since about 2003, but with only disappointing impact on transmission. (3)
Epidemiological limitations of "fixed duration treatment" for LL patients
Although transmission continued largely unabated in some low-income areas, rapid decline of HD was carefully documented in other low-income areas. (4-6) Further, a classic paper (7) reported the risk of HD among contacts of patients who already completed fixed duration MDT in Gudiyatham Taluk (Schieffelin Centre, Karigiri, India). Fixed duration treatment failed to eliminate infectiousness from households with previously treated patients. What explains this? It is likely that previously treated LL patients in the household (or even neighbourhood) were reinfected after they completed fixed duration treatment. A newly diagnosed LL patient typically sheds bacilli before treatment. That is sufficient to reinfect previously treated LL patients in the surroundings. Thereafter, once the newly diagnosed LL patient completes 12 monthly doses of MDT, they in turn can be reinfected by the previously treated LL patient.
Such "ping pong" reinfection can continue indefinitely, between unprotected LL patients before and after MDT. In this way, multiple-LL-case households, or multiple-LL-case neighbourhoods, can maintain transmission indefinitely in their surrounding areas. Given such relentless supply of concentrated viable bacilli from reinfected LL patients, transmission is predicted (and observed) to continue. Even vigorous active case-finding and chemoprophylaxis for contacts are predicted (and observed) to have only disappointing epidemiological impact.
Interestingly, the risk of recurrent HD was reported to be associated with the incidence rate of new cases of HD in an area. (8) This association is more consistent with exogenous reinfection than endogenous relapse.
Incomplete training of health workers leads to missed LL cases
Health workers too often are taught to expect only skin patches in HD. However, LL HD can develop without any skin patches. Diffuse infiltration of the earlobe may be the first and only early sign of LL HD. Even nerve enlargement might be absent in early LL HD. Owing to such gaps in the training of health workers, LL cases tend to be missed while mainly single TT lesion types of HD tend to be diagnosed by active case-finding campaigns. These largely non-infectious persons with a single TT lesion are then needlessly exposed to the risk of social ostracism, job loss and extreme poverty. Meanwhile, the most highly bacillated patients too often are missed until they suffer visible deformity, having been forced to serve as major sources of bacilli in their surroundings. After MDT is withdrawn from the LL patients, they are exposed to reinfection. Once reinfected, they can remain as long-term untreated sources of concentrated viable bacilli, until the damaging effects of reinfection finally drive them to seek care.
Underlying biology
"Ping pong" reinfection between LL patients is a central fact in the epidemiology of HD wherever anti-microbial protection is withdrawn from LL patients in endemic areas. The underlying biology is relevant. A genetic basis for reinfection/recurrence among LL patients was suggested by analysis of genetic markers from patients with recurrence (9). MIP vaccine after MDT given till smear negativity was reported to convert as many as 90% of LL patients to lepromin positive status, whereas only about 40% converted to lepromin positive when MIP was replaced by placebo.(10) The 10% of LL patients who do not convert to lepromin positive status, despite MIP vaccine, may be regarded for practical purposes as polar LL patients. They remain the most fertile ground of all for M. leprae. To the bacilli, polar LL patients are merely an extremely hospitable part of the bacillary environment. Unprotected polar LL patients can develop 10 billion bacilli per g of tissue. (11) Nasal discharges of unprotected LL patients can yield 10 million viable bacilli per day. Unprotected LL patients form, by far, the main source of concentrated viable bacilli for most humans. No soil or water samples have ever been reported to yield 10 billion bacilli per g. Only susceptible armadillos, apart from LL patients, have been reported to yield such astronomical numbers of bacilli.
Solutions
The most affordable way to protect LL patients against reinfection is to prolong MDT in LL patients. A study from India demonstrated that the recurrence rate in patients with a BI >4 was significantly higher (P < 0·01) after 24 months of MDT than after MDT continued till smear negativity. (12) Further, several areas that ensured prolonged anti-microbial protection for polar LL patients documented a relatively rapid decline in the incidence rate of even MB (multibacillary) HD. These areas included Uele - DRC (5), Weifang/Shandong - China (6), Karigiri - India (7), all reviewed here previously, and all with relatively low incomes at the time of the decline. Since the late 1990s, fixed duration treatment of only 24 months, or even 12 months, has become fashionable. Fixed duration treatment may well be adequate for most patients but apparently not for polar LL patients. Withdrawal of anti-microbial protection from polar LL patients ended the earlier rapid decline of HD. Widespread epidemiological stagnation has ensued. Rapid decline in MB HD proved achievable even in low-income endemic areas of the tropics, but it apparently relied on anti-microbial protection of LL patients against reinfection.
Promising alternatives to continued MDT in LL patients include combinations of bactericidal drugs, such as ROM (rifampicin + ofloxacin + minocycline). That combination has been recommended, tried and tested by various organisations over the years. (13) It could usefully be repurposed and trialled as post-MDT chemoprophylaxis for LL patients, fully supervised wherever possible. Substituting rifapentine for rifampicin and moxifloxacin for ofloxacin (rifapentine + moxifloxacin + minocycline, PMM) (14) is likely to yield an even more effective fully supervised regimen for post-MDT chemoprophylaxis among LL patients in endemic areas.
Conclusion
Withdrawal of anti-microbial protection from LL patients in endemic areas appears to be the fundamental flaw in our programmes since the late 1990s. It has led to epidemiological stagnation evident from about 5 to 10 years later (2005-2010 onwards). Stagnation replaced the documented earlier rapid decline of incidence rate in some low-income areas. Unprotected LL patients in endemic areas can develop 10 billion bacilli per g of tissue, before or after MDT, and their nasal discharges can yield as many as 10 million viable bacilli per day. They deserve protection against reinfection.
Stopping reinfection of LL patients is the most effective way to prevent new infections in otherwise well-implemented programmes. It is also very good for the LL patients who would otherwise suffer all the damaging consequences of reinfection.
Post-MDT chemoprophylaxis for LL patients is essential in endemic areas if transmission is to be reduced. Even prolonging MDT in LL patients, as allowed and advised by WHO, is a good start in protecting them against reinfection in endemic areas. It shuts off a major neglected source of concentrated viable bacilli while sparing the patients the ill-effects of re-infection.
References
1. Ortuño-Gutierrez N, Mzembaba A, et al. High yield of retrospective active case finding for leprosy in Comoros. PLoS Negl Trop Dis. 2022;16 : e0010158
2. WHO. Weekly Epidemiological Record 2010 to 2019 (before the pandemic)
3. Beldarraín-Chaple E. Historical Overview of Leprosy Control in Cuba. MEDICC Rev. 2017 Jan;19(1):23-30. doi: 10.37757/MR2017.V19.N1.5.
4. 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: 4a. Almeida J. Reducing transmission in poor hyperendemic areas - evidence from Uele (DRC). LML 29 Nov 2019
5. Li HY, Weng XM, Li T et al. Long-Term Effect of Leprosy Control in Two Prefectures of China, 1955-1993. Int J Lepr Other Mycobact Dis. 1995 Jun;63(2):213-221. reviewed & analysed further in: 5a. Almeida J. What really happened in Shandong? LML 16 Nov 2019
6. 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: 6a. Almeida J. Karigiri, India: How transmission rapidly was reduced in a low-income population LML 29 Oct 2020
7. Vijayakumaran P, Jesudasan K, Mozhi NM, Samuel JDR. Does MDT arrest transmission of M. leprae to household contacts? Int J Lepr 1998; 66(2):125-130.
8. Gonçalves, F.G., Belone, A.d., Rosa, P.S. et al. Underlying mechanisms of leprosy recurrence in the Western Amazon: a retrospective cohort study. BMC Infect Dis 19, 460 (2019). https://doi.org/10.1186/s12879-019-4100-6
9. Uaska Sartori, P.V., Penna, G.O., Bührer-Sékula, S. et al. Human Genetic Susceptibility of Leprosy Recurrence. Sci Rep 10, 1284 (2020). https://doi.org/10.1038/s41598-020-58079-3
10. Sharma P, Misra RS, Kar HK et al. Mycobacterium w. vaccine, a useful adjuvant to multidrug therapy in multibacillary leprosy: A report on hospital based immunotherapeutic clinical trials with a follow up of 1-7 years after treatment. Lepr Rev 2000; 71 : 179-92.
11. Hastings RC, Gillis TP, Krahenbuhl JL. Leprosy. Clin Micro Rev 1988; 1(3): 330-48.
12. Girdhar BK, Girdhar A, Kumar A. Relapses in multibacillary HD patients: effect of length of therapy. Lepr Rev. 2000;71:144-53.
13. WHO Technical Report Series 1998: 874
14. Ji B, Grosset J. Combination of rifapentine-moxifloxacin-minocycline (PMM) for the treatment of leprosy. Lepr Rev. 2000 Dec;71 Suppl:S81-7. doi: 10.5935/0305-7518.20000074.
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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