Leprosy Mailing List – November 22, 2020
Ref.: (LML) Skin camps & mass multi-drug administration rapidly reduced new HD cases in year 1
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
It seems useful to study what has worked well or has not. A late '90s project in the Federated States of Micronesia seems illuminating.
Joel Almeida
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Skin camps & mass multi-drug administration rapidly reduced new HD (leprosy) cases in year 1
Introduction
The Federated States of Micronesia (FSM) includes 65 inhabited islands with more than 100,000 people. FSM is spread across more than a million square miles of the western Pacific Ocean. Travelling between islands is not easy or cheap.
The annual new case detection rate of HD (leprosy) in the FSM had stagnated above 1000 per million population/yr. In years with active case-finding, this increased to over 2000 per million population/yr. Over half the new cases were children under 15 years old, although less than half the population was aged under 15. In short, this was an area of relatively high endemicity and active transmission of HD.
A joint project was launched by the FSM government, the WHO and the Sasakawa Health Foundation to attempt a rapid reduction in the incidence rate of HD. Clinical experts were supplied for the project, bolstering local personnel.
Methods
The methods have been described in detail. (1) In brief, the whole population was to be screened by means of skin camps that also offered treatments such as ointments for non-HD skin conditions. Newly diagnosed patients were to be put on MDT and the rest of the adult population was to be given a single dose of ROM (rifampicin 600mg + ofloxacin 400mg + minocycline 100 mg), and a single dose of R (rifampicin 25 mg/kg) for the remaining children.
Approximately one year later the same process was to be repeated.
However, only 73,516 of the apparently HD-free persons received ROM/R during the first round of skin camps. 31,990 persons did not receive ROM/R. The analysis here compares outcomes in those who received ROM/R with those who did not. The outcome of interest is clinically detected signs of HD.
All newly detected patients were started on MDT. During the project the duration of MDT was shortened to only one year for all MB patients, including LL patients.
Outcomes
At the screening after a year, 12 new cases were detected out of 73,516 persons who received a single dose of ROM/R compared to 68 new cases out of 31,990 persons who did not receive ROM/R. The single dose of ROM/R accordingly showed a protective efficacy of 92.32% (95% UI 85.815% to 95.843%). Despite the non-randomised nature of the two groups, the magnitude of difference seems too great to ignore.
Figure 1. (see attached file) Effect of a single dose of ROM/R on the new case detection rate of HD in the subsequent year, Federated States of Micronesia (based on ref.1). ROM = Rifampicin + ofloxacin + minocycline in adults, R = rifampicin 25 mg/kg in children
Discussion
Mass administration of ROM/R had a dramatic impact on the number of new cases detected by screening in the following year. This single dose was given following skin camps + MDT for newly diagnosed patients. It reduced the incidence rate of clinical signs of HD by over 90% in the ROM/R treated group compared to the untreated group. Such mass administration was repeated only once, after about a year.
Following discontinuation of this approach, the incidence rate of HD crept back to pre-campaign levels. Sustained annual campaigns could well have yielded sustained near-zero transmission, especially if combined with prolonged anti-microbial protection for LL HD patients. Case finding and anti-microbial protection (if prolonged until smear negativity for LL patients) have previously sufficed for a 16% to 20% annual decline in incidence rate of LL HD in even low-income populations (2-4).
FSM adopted fixed 1-year treatment for even LL HD patients during the project, from late 1997 onwards. Recurrence (re-infection or endogenous relapse) tends to be frequent among MB patients from year 6 onwards after the withdrawal of MDT. (ref. 5, Figure 2) This was shown by 20-year follow-up of patients after 24 months of MDT in another endemic area. Recurrence rates were highest in patients who started with a BI of 4+ or more. Lack of anti-microbial protection for LL HD patients after 1 year of MDT therefore is likely to maintain transmission. It also is likely to expose individual patients to damage induced by the bacilli. By contrast, treatment till smear negativity led to very low subsequent 20-year recurrence rates among surviving LL HD and smear positive patients in another low-income area (6).
FSM, like other endemic areas, could succeed better by ensuring MDT until smear negativity for highly bacillated patients. Academic centres of excellence and private practitioners in India are known to use a combination of three bactericidal drugs given to highly bacillated patients once monthly after the end of MDT. These options for prolonged anti-microbial protection would help remedy the too-frequent anti-microbial (and other) neglect of previously treated but genetically anergic LL HD patients. Such neglect of previously treated anergic patients repeatedly has foiled all other approaches to ending transmission.
Figure 2. (see attached file) Recurrence rates (with 95% UI) during 20-year follow-up of MB HD patients (initially smear positive) who received 24 monthly doses of MDT (based on ref. 5) Recurrences were even more frequent than this among highly bacillated patients (initial BI 4+ or more)
19 of the 80 newly diagnosed patients in the second annual FSM screening claimed to have noticed signs of HD in themselves more than a year earlier. These signs had been missed in the first annual screening, one way or another. Signs of LL HD are not always conspicuous. Even experienced clinicians rely on good light, thorough physical examination and skin smear reports for evaluation of difficult diagnoses. Nevertheless, multi-drug chemoprophylaxis such as ROM is capable of delaying the selection of drug-resistant mutant bacilli in even undiagnosed LL HD patients. Multi-drugs therefore are preferable to single drugs, being better able to maintain the efficacy of MDT especially in areas where clinical expertise is scarce. Serological tests to exclude LL HD are another useful option, having over 90% negative predictive value, (7) and can be used to identify those requiring more careful examination including skin smears to rule out LL HD.
The evidence so far shows that transmission of HD could be ended rapidly by astute use of MDT, and even more rapidly by adding annual skin camps with mass multi-drug administration. The critical improvement, in epidemiological terms, is to reduce the R0 (reproductive number) of LL HD to less than 1. This is achievable by prolonged anti-microbial protection of persons with polar LL genomes, as discussed here previously. (8-13) Mass multi-drug administration amounts to a vigorous and widespread attack on bacilli in all potential human hosts. It can be a useful addition to the use of MDT till smear negativity in LL HD patients. It can almost instantly reduce the number of new HD cases to a small fraction of the previous level. Hyper-endemic zones, especially in difficult circumstances, might find this intervention particularly useful. It consists of:
Annual skin camps for all skin conditions, using visiting experts, with
MDT for newly diagnosed HD patients, plus
annual mass multi-drug administration (ROM or similar bactericidal combinations).
Skin camps can have travelling experts. Failing that, teleconsultations during skin camps can be used to assist and instruct less qualified personnel. The COVID-19 pandemic has made most expert clinicians relatively familiar with teleconsultation and tele-training. Organisations wishing to help endemic countries usefully could set up panels of expert clinicians to attend or otherwise support skin camps (for all conditions with skin manifestations) in underserved endemic areas.
90% per year is not a bad rate of decline in new cases of HD. Achieving this everywhere by annual skin camps and mass multi-drug administration would spare many children and others the ravages of HD. Integrating the skin camps and mass administration with campaigns for other diseases would reduce costs greatly. When combined with MDT until smear negativity for highly bacillated patients, this approach is likely to end transmission rapidly and enduringly. For a start, it would be good to ensure that every LL HD patient in endemic areas receives MDT until smear negativity as a part of competent care. This includes any smear positive LL HD patient who previously finished MDT but has since been neglected.
Good intentions more readily can be converted into effective action by defining a package of practical steps that have a high chance of epidemiological impact (eg., 14, 15). The measures constantly can be improved based on front-line experiences. That is how many highly successful programmes were developed for other challenging conditions.
Demonstrable past successes embolden us to aim for the end of transmission together with a more humane, respectful approach to previously treated patients. Failure to end transmission and continuing neglect of previously treated LL patients appear to be no more than self-fulfilling prophecies. It is within our power to transform the situation. Endemic countries deserve the elbow room to do what demonstrably works. As technical advice constantly is brought up to date with accumulating evidence, life is likely to improve dramatically for the patients and people we seek to serve. They deserve our best efforts.
References
1. 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)
2. 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: 2a. Almeida J. Reducing transmission in poor hyperendemic areas - evidence from Uele (DRC). LML 29 Nov 2019
3. 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: 3a. Almeida J. What really happened in Shandong? LML 16 Nov 2019
4. 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: 4a Almeida J. Karigiri, India: How transmission rapidly was reduced in a low-income population LML 29 October 2020
5. Balagon MF, Cellona RV, dela Cruz E et al. Long-Term Relapse Risk of Multibacillary Leprosy after Completion of 2 Years of Multiple Drug Therapy (WHO-MDT) in Cebu, Philippines. American Journal of Tropical Medicine and Hygiene, 2009; 81, 5: 895-9. reviewed and analysed further in 5a. Almeida J Recurrence rate among MB patients following RFT. LML 2 June 2019.
6. Norman G, Joseph G, Richard J. 2004. Relapses in multibacillary patients treated with multi-drug therapy until smear negativity: findings after twenty years. Int J. Leprosy 72:1–7
7. Leturiondo AL, Noronha AB, Oliveira do Nascimento MO et al. Performance of serological tests PGL1 and NDO-LID in the diagnosis of leprosy in a reference Center in Brazil. BMC Infectious Diseases volume 19, Article number: 22 (2019)
8. Gaschignard J, Grant AV, Thuc NV, Orlova M, Cobat A, Huong NT, et al. (2016) Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases. PLoS Negl Trop Dis 10(5): e0004345. https://doi.org/10.1371/journal.pntd.0004345
9. Chakravarti MR, Vogel F. A twin study on leprosy Georg Thieme Publishers, Stuttgart, Germany; 1973.
10. Cambri G, Mira MT. Genetic Susceptibility to Leprosy—From Classic Immune-Related Candidate Genes to Hypothesis-Free, Whole Genome Approaches. Front. Immunol., 20 July 2018 | https://doi.org/10.3389/fimmu.2018.01674
11. Sartori PVU, Penna GO, Bührer-Sékula S et al. Human Genetic Susceptibility of Leprosy Recurrence. Scientific Reports (2020) volume 10, Article number: 1284
12. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
13. Rao PS, Mozhi NM, Thomas MV. Leprosy affected beggars as a hidden source for transmission of leprosy. Indian J Med Res. 2000 Aug;112:52-5
14. Almeida JG. 8 pillars of a highly effective programme LML 18 Sept 2019
15. Almeida JG. Example protocol for safely interrupting transmission of HD LML 4 Nov 2019
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