Leprosy Mailing List – December 1, 2021
Ref.: (LML) Closing the gaps in protection for LL HD patients in endemic areas
From: Joel Almeida, London and Mumbai
Note editor: several centres in the (leprosy) world are giving prolonged anti-micro bacterial protection of anergetic LLp patients against reinfection. We would like to request them to react and inform the LML readers about their opinion and experience.
Dear Pieter and colleagues,
It is useful to understand why some programs in low-income areas showed good epidemiological impact while other areas experience stagnation in the number of new cases. Many esteemed colleagues at the front lines are concerned about the accumulating number of previously treated LL HD patients who require re-treatment. They have an important point.
Best,
Joel Almeida
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Closing the gaps in protection for LL HD patients in endemic areas
Patients at the lepromatous pole (LLp) lack an effective immunological response against the HD (leprosy) bacilli. Anergy among LLp patients appears to be genomically related (1-5) and is long-lasting, while fixed duration MDT (multi-drug therapy) offers only temporary protection against reinfection. That is why fixed duration MDT is inadequate for genomically anergic LLp patients who live in endemic areas. A rapid decline in incidence rate of MB (multibacillary) HD has been achieved, but only when prolonged anti-microbial protection was ensured among LLp patients. (6-8)
LL patients, if denied anti-microbial protection against infection or reinfection, are capable of shedding as many as ten million viable bacilli per day. (9) This is sufficient to drive transmission despite all other efforts. The LLp patients are forced to serve unknowingly and unwillingly as super-spreaders. The ratio of accumulated reinfected LLp HD patients to previously untreated LL HD patients is more important than the absolute recurrence/reinfection rate among MB patients. Typically, the detection rate of previously untreated LL patients remains below 100 per million population per year, once the backlog of cases has been detected. This means that even so-called "low" recurrence/reinfection rates among previously treated LLp patients can make them important drivers of transmission. Since the incidence rate of LL HD is so low in absolute terms, the number of previously treated but reinfected LL patients could well exceed the number of newly diagnosed LL patients in endemic areas. HD transmission in endemic areas therefore could well be maintained to an important extent by reinfected previously treated LL patients. That is likely why only those projects ensuring prolonged anti-microbial protection against reinfection, for LLp patients, achieved a rapid decline in the incidence rate of MB HD. (6-8) Every endemic area can succeed similarly.
ENL (erythema nodosum leprosum) shows a dose-response relationship with bacillary load and shows a part response to anti-microbials (11-16). It also responds partly to anti-reaction (anti-inflammatory) drugs. (17-19) Therefore, response to "anti-reaction" medication does not in itself preclude bacillary proliferation. The use of this criterion to exclude recurrence/reinfection can underestimate the risk of recurrence/reinfection among LLp patients.
There is another important reason for continuing MDT (or other anti-microbial protection) beyond 12 months in LLp patients. A one-year MDT group in an endemic area showed a 600% increase in the risk of ENL with neuritis compared to a two-year MDT group, during months 13 to 24 after the start of MDT. (20-21) ENL with neuritis is known to be excruciatingly painful. Therefore, it would be good to continue MDT beyond 12 months in LL patients. This would help to avert a greatly multiplied risk of the painful, swollen and tender nerves found in the neuritis of ENL episodes.
Signs of reinfection can be subtle and are not easy to detect promptly. Prevention is better than surveillance because expert clinicians are not available everywhere, and experts detect signs of recurrence/reinfection in five times as many patients compared to even well trained but non-expert health workers. (10, 22) Without prolonged anti-microbial protection of anergic LLp patients against reinfection, the people of endemic areas remain trapped in transmission of HD. Reinfection of anergic LLp patients can be prevented by ensuring prolonged anti-microbial protection. It is a simple thing to do for LLp patients, and it consistently leads to a decline in the incidence rate of MB HD (Shandong vs Yunnan, ref 6, Karigiri, ref 7, Uele, ref 8). This dramatic epidemiological success can be replicated in every endemic area simply by ensuring prolonged anti-microbial protection for LLp patients, beyond 12 months of MDT. Prolonging MDT is the lowest-cost option. Monthly doses of 3 bactericidal drugs following MDT are another option if sufficient finance is available, enabling full supervision and therefore improved regularity of ingestion.
The evidence from successful programs is that prolonged anti-microbial protection of LL HD patients in endemic areas is critical for interrupting transmission as well as for greatly reducing the risk of painful, swollen nerves found in ENL episodes. Such protection of anergic LL HD patients after 12 months of MDT could replace anti-microbial neglect. This would respect Article 25 of the Universal Declaration of Human Rights, that enshrines the right to adequate medical care.
References
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2. Zhang FR, Huang W, Chen SM et al. Genomewide Association Study of Leprosy. N Engl J Med 2009; 361:2609-2618 DOI:10.1056/NEJMoa0903753
3. Sartori PVU, Penna GO, Bührer-Sékula S et al. Human Genetic Susceptibility of Leprosy Recurrence. Scientific Reports 2020 volume 10, Article number: 1284
4. Gaschignard J, Grant AV, Thuc NV et al. Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases. PLoS Negl Trop Dis. 2016 May 24;10(5):e0004345. doi: 10.1371/journal.pntd.0004345
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6. 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 and analysed further in Almeida JG. What really happened in Shandong? LML 16 Nov 2019
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8. 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 and analysed further in Almeida JG. Reducing transmission in poor hyperendemic areas - evidence from Uele (DRC). LML 29 Nov 2019
9. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
10. Balagon MF, Cellona RV, Cruz E, Burgos JA, Abalos RM, Walsh GP, et al. 2009. Long-term relapse risk in multibacillary leprosy after completion of 2 years of multiple drug therapy (WHO-MDT) in Cebu, Philipplines. Am. J Trop. Med. Hyg. 81(5), 895-899. reviewed and analysed further in Almeida JG. Recurrence rate among MB patients following RFT. LML 2 June 2019
11. Pocaterra L, Jain S, Reddy R, Muzaffarullah S, Torres O, Suneetha S, Lockwood DN. Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg (2006) 74(5):868–879.
12. Manandhar R, LeMaster JW, Roche PW. Risk factors for erythema nodosum leprosum. Int J Lepr 1999 Sep;67(3):270-8
13. Lastoria JC, deAlmeida TSC, Putlinatti MSdMA, Padovani CR. Effectiveness of the retreatment of patients with multibacillary leprosy and episodes of erythema nodosum leprosum and/or persistent neuritis: a single-center experience An Bras Dermatol. 2018 Mar-Apr; 93(2): 181–184. doi: 10.1590/abd1806-4841.20185387
14. Narang T, Bishnoi A, Dogra S et al. Alternate Anti-Leprosy Regimen for Multidrug Therapy Refractory Leprosy: A Retrospective Study from a Tertiary Care Center in North India . Am J Trop Med Hyg. 2019 Jan; 100(1): 24–30. doi: 10.4269/ajtmh.18-0256
15. Narang T, Sawatkar GU, Kumaran MS, Dogra S. Minocycline for Recurrent and/or Chronic Erythema Nodosum Leprosum JAMA Dermatol 2015 Sep;151(9):1026-8. doi: 10.1001/jamadermatol.2015.0384.
16. Arora P, Sardana K, Agarwal A, Lavania M. Resistance as a cause for chronic steroid dependent ENL - a novel paradigm with potential implications in management. Lepr Rev (2019) 90, 201– 205
17. Kar HK, Gupta L. Comparative efficacy of four treatment regimens in Type 2 leprosy reactions (prednisolone alone, thalidomide alone, prednisolone plus thalidomide and prednisolone plus clofazimine). Indian J Lepr 2016 88(1):29–38
18. Kaur I, Dogra S, Narang T, De D. 2009. Comparative efficacy of thalidomide and prednisolone in the treatment of moderate to severe erythema nodosum leprosum: a randomized study. Australas J Dermatol 50(3):181–185.
19. Lambert SM, Nigusse SD, Alembo DT, Walker SL, Nicholls PG, Idriss MH, Yamuah LK, Lockwood DN. 2016. Comparison of efficacy and safety of ciclosporin to prednisolone in the treatment of erythema nodosum leprosum: two randomised, double blind, controlled pilot studies in Ethiopia. PLoS Negl Trop Dis 10(2):e0004149.
20. Balagon MVF, Gelber RH, Abalos RM, Cellona RV. Reactions following completion of 1 and 2 year multidrug therapy (MDT) Am J Trop Med Hyg 2010 Sep;83(3):637-44. doi: 10.4269/ajtmh.2010.09-0586 reviewed and analysed further in Almeida JG. MDT duration and ENL neuritis risk. LML 7 January 2020
21. Balagon M, Saunderson PR, Gelber RH. Does clofazimine prevent Erythema Nodosum Leprosum (ENL) in leprosy? A retrospective study, comparing the experience of multibacillary patients receiving either 12 or 24 months WHO-MDT. Lepr Rev (2011) 82, 213– 221
22. Gelber RH, Balagon VF, Cellona RV. The relapse rate in MB leprosy patients treated with 2-years of WHO-MDT is not low. Int J Lepr 2004; 72: 493-500.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
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