Leprosy Mailing List – August 24, 2019
Ref.: (LML) Epidemiology of Hansen's Disease for interruption of transmission
From: Joel Almeida, London and Mumbai
Dear Pieter & colleagues,
At the recent symposium of the Indian Association of Leprologists, I was invited to talk about "Burning Issues" in Hansen's Disease (HD). Following the talk, there were probing questions and thoughtful discussion. Based on that, I have modified some of the slides from the talk. A small selection of slides is displayed below.
Figure 1. The thick red arrow at upper right shows how transmission continues despite MDT and all our other current efforts and innovations. Neglected LL patients with recurrent disease can shed up to a billion bacilli per day, including tens of millions of viable bacilli (1). No other sources apart from armadillos show such a high concentration of viable bacilli. In two Indian towns, 17% of previously treated patients experiencing destitution were found to show positive skin smears (2). Shandong ensured prolonged anti-microbial protection for LL patients after the recommended duration of MDT. This led to near-zero transmission. That's because one protected LL patient could no longer be replaced by a new LL patient. In epidemiological terms, the reproductive ratio of LL patients fell below one. That's what it takes to interrupt transmission. We can match Shandong's success by adding monthly post-MDT chemoprophylaxis for all known LL patients, as part of competent case management. 3 bactericidal drugs (e.g. rifampicin+moxifloxacin+minocycline or similar) given monthly are likely to exceed the efficacy of the prolonged MDT that was demonstrated to be so highly effective in Shandong.
Figure 2. Researchers in India have reported findings strongly suggesting that viable M. leprae are implicated in type 1 reactions (4) and ENL (5). Viable M. leprae can turn neural cells into stem cells, macrophages into slaves, and can evade digestion by lysosomes in LL patients. Given this remarkable range of powerful effects, viable M. leprae could well play a role in reactions too. Therefore, post-MDT chemoprophylaxis for all LL patients, together with other interventions, is likely to help avert further nerve damage caused by recurrent disease. Patients with signs of type 1 reaction or ENL need not be denied anti-microbial treatment, alongside other appropriate treatment.
Figure 3. Our neglect of LL patients not only maintains transmission but also allows new visible deformities to develop despite MDT. These deformities tend to increase fear and stigma in the community. A pilot survey in two rural communities in India revealed that 15% to 33% of persons who previously received MDT showed visible deformity (6). This happens even in areas with active case-finding where fewer than 5% of newly diagnosed patients show visible deformity. Despite MDT, over 2300 persons per million of the general population in a rural area of Maharashtra state (India) showed visible deformity caused by HD (7). By now, that figure is probably higher.
The solution lies in competent case management. Competent case management includes quarterly nerve function assessment for all MB patients during 2 years after the start of MDT (with prednisolone used as necessary), and monthly post-MDT chemoprophylaxis for all LL patients. Rehabilitation and inclusion services too are part of competent case management.
Figure 4. 85% of nerve function impairment in South Asia occurs without any signs or symptoms of reaction ("silent neuritis / silent neuropathy / quiet nerve damage") (8).
Asymptomatic patients rarely can afford to lose wages just to travel to a clinic for nerve function assessment. Trained, mobile personnel can transform the situation. One trained paramedical worker equipped with transport can serve all the MB patients in a large population, as is being done in Dadra Nagar Haveli (India). However, in some states of India, it is not easy for the government to attract and train sufficient skilled staff. NGOs can play a particularly important role in such areas, training and sponsoring staff who can take competent services to the patient's doorstep. Some NGOs are already starting such effective action.
Figure 5. The use of single drugs accelerates the selection of multiple-drug resistant (MDR) bacilli. Combined with a high recurrence rate among neglected LLp patients, that could cause the equivalent of an epidemiological tsunami of HD, setting us back decades. Drug resistance is, in mathematical terms, a discontinuity. Like a cliff rather than a slope. In one former HD colony in Brazil, MDR bacilli and recurrent disease interacted despite even MDT (9). This is a foretaste of what could happen elsewhere.
Therefore, it is prudent and ethical to use only combinations of drugs, of roughly equivalent bactericidal potency, and to give them for an adequate duration. This is true even for prophylaxis among contacts. If attempting prophylaxis among contacts, PGL-1 Ig antibody (10) can help identify those contacts who require further investigation and, if their skin smears are positive, require full MB-MDT. In the remaining PGL-1 Ig positive contacts, with negative skin smears, full PB-MDT could suffice. If contacts with sub-clinical disease and anergy are under-treated, recurrence and drug resistance are highly likely.
Conclusion
Neglect of LL patients after MDT explains why transmission has continued during the past two decades. This has happened even in Cuba (10) where nearly all our promising interventions have been implemented for nearly 20 years (including serological tests, MDT, contact tracing, BCG and chemoprophylaxis among contacts). Competent case management for MB patients during and after MDT is the missing key to zero transmission, zero new disability and zero stigma. It can unlock the efficacy of all our other interventions. Neglect of LL patients after MDT may be expedient in the short run, because patients are generally quite trusting. But such expedient neglect has allowed the bacilli to continue spreading and damaging patients, during the past two decades. We can change that. Shandong demonstrated how.
Epidemiological impact at the front lines is the ultimate test of effectiveness for an intervention. That was what Shandong provided, demonstrating near-zero transmission by protecting LL patients after the usual duration of MDT. That's what we all can strive to achieve. By adding post-MDT chemoprophylaxis and competent case management, we can create zones of near-zero transmission and near-zero new disability in our own areas. These measurable successes will be like candles in the darkness. This light can keep expanding from endemic area to endemic area until it encircles the globe with competent, compassionate, impactful practice.
Congratulations to the Indian Association of Leprologists for organising this symposium, and for the inspiring work of its members. They keep spotting subtle clues, questioning shaky assumptions and predictions, improving interventions at the front lines, while educating and inspiring a new generation of experts and supplying expertise to the national programme. India's national motto is "satyameva jayate" (truth alone triumphs). We can keep improving the quality of our scientific analysis so that our errors are all short-lived and our interventions become steadily more impactful. Shandong's local experts deviated from global fashions, but that was necessary for their world-leading success. The frontlines are where the battle is ultimately won or lost. We cannot afford to sideline the insights of patients and experts in endemic countries and endemic areas, lest we lose touch with reality. Together with them, we all can succeed.
Joel Almeida
References
1. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
2. 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.
3. 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.
4. Save MP, Dighe AR, Natrajan M & Shetty VP. Association of viable Mycobacterium leprae with Type 1 reaction in leprosy. Lepr Rev (2016) 87, 78–92
5. 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
6. Aggarwal A, Pandey A. Inverse sampling to study disease burden of leprosy. Indian J Med Res 132, October 2010, 438-441.
7. Ganapati R, Pai VV, Tripathi A. Can primary health centres offer care to the leprosy disabled after integration with general health services? - a study in rural India. Lepr Rev 2008, 79:340–341
8. Croft RP, Nicholls PG, Richardus JH, Smith WC. Incidence rates of acute nerve function impairment in leprosy: a prospective cohort analysis after 24 months (The Bangladesh Acute Nerve Damage Study). Lepr Rev. 2000 Mar;71(1):18-33
9. Rosa PS, D'Espindula HRS, Melo ACL et al. Emergence and transmission of drug/multidrug-resistant Mycobacterium leprae in a former leprosy colony in the Brazilian Amazon. Clinical Infectious Diseases. 1 July 2019, ciz570, https://doi.org/10.1093/cid/ciz570
10. Nagao-Dias AT, de Macedo AC, Rodrigues RO et al. Serum Anti-PGL-1 IgG, IgM, and IgA in a 3-Year Follow-up Study of 4–15-Year-old Leprosy Contacts. The Pediatric Infectious Disease Journal: September 2019 - Volume 38 - Issue 9 - p e193–e198 doi: 10.1097/INF.0000000000002337
11. Beldarraín-Chaple E. Historical Overview of Leprosy Control in Cuba. MEDICC Rev. 2017 Jan;19(1):23-30.
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LML - S Deepak, B Naafs, S Noto and P Schreuder
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