Leprosy Mailing List – April 26, 2021
Ref.: (LML) ENL prevention
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
Thanks to Profs. Walker and Lockwood for their communication "ENL prevention is better than cure" (LML 22 April 2021). Approaching the data with an open mind, and with careful attention, can help.
There is an observable dose-response relationship between bacillary load and the incidence rate of ENL. LL patients with the highest bacillary load also show the highest incidence rate of ENL. Bacilli appear to underlie the pathophysiology. Does anti-microbial protection help to prevent or treat ENL? The evidence indicates that it does, to an important extent. The evidence may be summarised as follows.
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. (1,2, see the Figure here) Therefore it seems ethical and humane to ensure more than 12 monthly doses of MDT for highly bacillated patients in endemic areas.
Further, it is known that when nothing else worked (including a range of anti-inflammatory or immunomodulatory drugs), anti-microbial treatment resulted in dramatic relief of ENL symptoms and signs.(3) Plus, anti-microbial drugs were reported to have a dramatic impact on the prevention of ENL.(4-6) In patients currently suffering the excruciating pain of ENL, it would seem needlessly cruel to withhold anti-microbial drugs.
Drugs and vaccines have adverse effects. They still are used because the adverse effects of the disease typically outweigh the adverse effects of the drug or vaccine. Self-healing persons with HD might require no more than a very short course of treatment. By contrast, in persons with LL genomes, lack of treatment can lead to severe disfiguration, reinfection/recurrence, social exclusion, extreme poverty, excruciatingly painful ENL provoking suicidal ideation etc. In such persons, withholding prolonged anti-microbial protection does not seem easily justifiable, especially because troublesome drugs can be substituted with others.
Prolonged anti-microbial protection in highly bacillated patients goes further. It helps also to prevent re-infection of anergic (polar) LL patients, which in turn reduces sources of highly concentrated viable bacilli. This was critical for reducing transmission dramatically in endemic areas such as Karigiri and Shandong. (7,8 analysed here and here, see Figures). The presence in a household of a patient previously treated with even 24 months of MDT multiplied the risk of HD in "newcomer" children who joined the household of a current "index" patient, despite this being after the start of treatment in the index patient. (9, analysed here, see Figure) This excess risk associated with a previously treated patient indicates the importance of prolonged anti-microbial protection for highly bacillated patients. It is needed especially in polar LL patients who show genetically-related anergy (10-12) that can persist despite MIP vaccine immunotherapy (although MIP has good efficacy in sub-polar LL). (13)
In Shandong, (8) prolonged anti-microbial protection (MDT) of all highly bacillated patients helped reduce transmission to near-zero levels, with a 20%/year decline in new HD cases. When transmission is reduced, all types of HD decline. Then the incidence rate of ENL too declines. In this wider epidemiological sense too, prolonged anti-microbial protection of highly bacillated HD patients helps prevent ENL. It is not necessary to keep people trapped in a continuing cycle of reinfection/recurrence, transmission, drug resistance, and highly distressing complications of HD including ENL. Simply by protecting LL patients against reinfection, using prolonged anti-microbial treatment, sources of concentrated viable bacilli can be reduced and consequently transmission can be reduced dramatically.
A powerful solution for hyperendemic hot spots is to control nearly all sources of concentrated viable bacilli instantly. The most successful approach (14, 15) achieved an 84% decline of new HD cases in FS Micronesia within only 2 years, by using:
a) Integrated skin camps for all conditions, with expert clinicians assisting, so that the risk of missed LL patients was reduced yet stigma was minimised;
b) MDT prolonged beyond 12 monthly doses for LL patients (e.g., until smear negativity) so that the risk of reinfection was reduced in even high endemic zones;
c) Mass multi-drug administration (rifampicin + ofloxacin + minocycline was used) repeated at intervals in hyperendemic areas, so that nearly all sources of highly concentrated viable bacilli were instantly controlled, plus the selection of drug-resistant mutants was delayed
The intervention was stopped after two annual rounds, which turned out to be too short for permanent suppression of infections. This highly impactful intervention probably needs to be repeated in known hot spots (e.g., Santo Antonio do Prata and similar hyperendemic hot spots) until no new child case of HD can be found for a few years.
The measured epidemiological impact of this intervention was immediate and dramatic. It is by far the world's most effective known intervention for reducing transmission surely and rapidly while helping to delay drug resistance. It can even be administered alongside skin camps and mass drug administration campaigns for other diseases. Incidentally, prolonged MDT was a key component of this, the most impactful of all known interventions against HD.
A further level of intervention against ENL, HD, and all diseases, is available from efforts to remedy illiteracy, lack of schooling, training, gainful employment, land ownership rights, other legal rights, safe water, sanitation and more, among people who have experienced HD and among other people in endemic areas. However, poor people need not be kept waiting until they are rich before enjoying interventions that protect them against impoverishing diseases. HD itself pushes too many people into social exclusion and extreme poverty. Highly impactful interventions that reduce transmission of HD, and so reduce the incidence rate of ENL in the population, strike an important blow against severe distress and extreme poverty.
Conclusions
Highly bacillated patients in endemic areas need prolonged anti-microbial protection beyond 12 months of MDT because this helps prevent ENL to an important extent. This helps also to reduce reinfection and consequent transmission of HD bacilli, which in itself helps reduce the incidence rate of HD in a population, and therefore reduces the incidence rate of ENL. Transmission of HD bacilli can be reduced rapidly in hyperendemic hot spots by using the Sasakawa Health Foundation/WHO intervention that demonstrated a major immediate impact on the incidence rate of new HD cases in FS Micronesia. This highly impactful intervention almost instantly suppresses nearly all sources of concentrated viable bacilli in hot spots. It rapidly reduces new cases of HD (84% decline demonstrated in only 2 years) and therefore rapidly reduces the incidence rate of distressing complications of HD including ENL.
Withholding prolonged anti-microbial protection from highly bacillated patients with genetically linked anergy (unresponsive to MIP immunotherapy) would seem needlessly cruel to the patients, apart from unnecessarily increasing the transmission of HD bacilli to children and others. Prolonged anti-microbial protection for polar LL patients in endemic areas is the least costly and most effective way of reducing the incidence rate of new HD cases reasonably rapidly, with a demonstrably achievable decline of 16% to 20% per year.
ENL is preventable, as is HD. The key is to remedy the current widespread anti-microbial neglect of polar LL patients.
Joel Almeida
PS The various options for prolonged anti-microbial protection of polar LL patients, besides prolonged MDT, deserve a separate discussion. The important role of prolonged anti-microbial protection in controlling drug resistance also needs its own discussion. All this complements and strengthens adequate medical care, work and other entitlements under the Universal Declaration of Human Rights for persons who experienced leprosy and are left with permanent sequelae.
References
1. 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.2010.09-0586LR analysed in LML 7 Jan 2020
2. 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
3. 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
4. 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
5. 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
6. 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.
7. 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. analysed in LML 29 Oct 2020
8. 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 analysed in LML 16 Nov 2019
9. Vijayakumaran P, Jesudasan K, Mozhi NM, Samuel JD. Does MDT arrest transmission of leprosy to household contacts? Int J Lep 1998; Jun;66(2):125-30. analysed in LML 31 Dec 2020
10. Chakravarti MR, Vogel F. A twin study on leprosy Georg Thieme Publishers, Stuttgart, Germany; 1973 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.
11. 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
12. Wang N, Wang Z, Wang C et al. Prediction of leprosy in the Chinese population based on a weighted genetic risk score. PLoS Negl Trop Dis. 2018 Sep 19;12(9):e0006789. doi: 10.1371/journal.pntd.0006789.
13. Talwar GP, Gupta J C, Mustafa AS et al. Development of a potent invigorator of immune responses endowed with both preventive and therapeutic properties Biologics. 2017; 11: 55–63. doi: 10.2147/BTT.S128308
14. Workshop on the prevention of leprosy, Pohnpei, Federated States of Micronesia. 25-27 MAY 1999 sponsored by the Sasakawa Memorial Health Foundation Tokyo, Japan and the Western Pacific Regional Office of the World Health Organization. Int J Lepr, 67(4) (SUPPLEMENT)
15. Diletto C, Blanc L, Levy L. Leprosy chemoprophylaxis in Micronesia. Lepr Rev. 2000;71(Suppl):S21–3
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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