(LML) Learning from unexpected success

Leprosy Mailing List – April 23,  2019 Ref.:  (LML)   Learning from unexpected success From:  Joel Almeida, London and Mumbai Dear Pieter, Evidence about the endemic is revealing. Figure 1. Analysis of number of newly detected people with MB reported globally, by year of detection. (Almeida, based on data from: WHO, Weekly Epidemiological Records)

The average decline in newly detected people with MB is calculated to be less than 0.5% per year. Transmission continues, including to children. More people with MB were newly detected in 2017 than in 1985, although this is partly due to altered definitions of MB.

Contrast this global picture with Shandong Province.

Figure 2. Analysis of number of newly detected people with MB in Shandong Province by year of detection. (Almeida, based on data from: Li et al, Int J Lepr (1985) 53(1): 79-85)

The decline in newly detected people with MB is calculated to be about 15% per year in Shandong Province. The decline has continued relentlessly, through to near-zero transmission. (3)

What explains the enormous difference in decline between the global situation (Fig. 1) and Shandong (Fig. 2)?

The disease is initiated by bacilli. Bacilli infect hosts according to the infectious dose 50 (ID50, the inoculum required to infect 50% of a population). Hosts with genetically-linked anergy innately tend to have a much smaller ID50 than do others. Further, unprotected persons with anergy (LLp) can harbour and shed more bacilli than do hundreds of thousands of persons with a well-defined single small skin patch but no other signs of disease. A single well-defined small patch is often a sign of a healthy immune response, typically resulting in zero infectiousness and self-healing without sequelae. The bacilli have a better chance of prolonged survival outside hosts than within such self-healing persons who have a healthy immune response.

The whole of India reports about 130,000 newly detected patients each year, including many with excellent innate immunity. So, the number of bacilli that can be shed by even one unprotected person with anergy can play a hugely disproportionate and critical role in maintaining the endemic. (The lack of protection, incidentally, is not the fault of the person with anergy.) The demonstrated viability of bacilli in shaded Indian environments, for at least 5 months (4), aggravates the situation. The greater the environmental concentration of viable bacilli, the greater the risk that an unprotected person with genetically-linked anergy will be infected or re-infected. The endemic is therefore probably kept alive largely by transmission from one genetically anergic person to another, including via the environment.

Shandong Province ensured prolonged anti-microbial protection for persons with anergy. By contrast, we currently allow re-infection of persons with anergy (LLp) after withdrawal of MDT. This can, to an important extent, explain the differing rates of decline in Shandong (Fig. 2) and globally (Fig. 1).

Did BCG, too, aid the observed decline of Hanseniasis in Shandong Province? Not very much. BCG was introduced to Shandong in only about 1978.

Was the decline attributable entirely to an increase in per capita GDP? Not entirely. Compare the per capita GDPs, over time, of China and India:

Figure 3. Comparison of GDP per capita in China (top) and India (bottom) over time. (Almeida, based on data from World Bank)

Both countries achieved a USD500 GDP per capita in the 1980s. India has well over half of the world's newly detected patients, and made a dominant contribution to Figure 1 data.

The observed difference can be explained, to an important extent, by prolonged anti-microbial protection for persons with LLp in Shandong province. Therefore, anti-microbial protection for LL patients after the standard duration of MDT is likely to be, by far, the most effective and important form of chemoprophylaxis.  It protects persons with anergy against re-infection (5), and ensures that they cannot contribute to the environmental pool of bacilli. That decreases the reproductive ratio of LLp patients, the number of LLp patients arising as a consequence of one index LLp patient. Once this reproductive ratio falls and stays below one, the endemic begins its terminal decline. Shandong's success illustrates this process.

We have so far omitted the critical step that can help interrupt transmission: prolonged anti-microbial protection for persons with LLp. It would be good to provide this critically important intervention, including by identifying persons with LL at diagnosis. Slit skin smears are very helpful for such classification at diagnosis.

Funders interested in showing similar success could usefully sponsor one or more demonstration projects in endemic countries. Demonstration projects allow us to succeed, or to learn why not.

Wouldn't it be great more effectively to save human nerves, eyes, limbs, minds, livelihoods and relationships? Wouldn't it be wonderful to defeat the bacillus? Shandong succeeded. So, probably, can all of us.

शान्दोंग प्रांत ने LLpolar वाले व्यक्तियों को लंबे समय तक एंटी माइक्रोबियल सुरक्षा प्रदान की। इसके विपरीत, वैश्विक नीति ने MDT के बाद LLpolar वाले व्यक्तियों के पुन: संक्रमण की अनुमति दी। इसके कारण, शान्दोंग में बीमारी की गिरावट वैश्विक औसत से लगभग 30 गुना अधिक तेजी से हुई। शान्दोंग ने लगभग शून्य संचरण हासिल किया। हम भी शायद इस तरह से सफल हो सकते हैं।

A província de Shandong forneceu proteção antimicrobiana prolongada para pessoas com LLpolar / anergia. Pelo contrário, a política global permitiu a re-infecção de pessoas com LLpolar após a PQT. Devido a isso, o declínio da doença em Shandong foi quase 30 vezes mais rápido que a média global. Shandong conseguiu quase zero transmissão. Nós também provavelmente podemos ter sucesso dessa maneira.

La province du Shandong a fourni une protection antimicrobienne prolongée aux personnes atteintes de LLpolar / anergy. Au contraire, la politique mondiale a permis la réinfection des personnes atteintes de LLpolar après la PCT. Pour cette raison, le déclin de la maladie dans le Shandong a été presque 30 fois plus rapide que la moyenne mondiale. Le Shandong a réalisé une transmission presque nulle. Nous aussi pouvons probablement réussir de cette façon.

Joel Almeida

References

1. WHO. Weekly Epidemiological Records, various. 1997-2018

2. Li Huan-Ying, Pan Yu-Lin, and Wang Yang. Leprosy Control in Shandong Province, China,1955-1983; Some Epidemiological Features. Int J Lepr (1985) 53(1): 79-85.

3. Shumin Chen, Yunchun Zheng, Min Zheng, Demin Wang. Rapid survey on case detection of leprosy in a low endemic situation, Zhucheng County, Shandong Province, The People's Republic of China. Lepr Rev (2007) 78, 65–69.

4. Desikan KV, Sreevatsa. (1996) Extended studies on the viability of Mycobacterium leprae outside the human body. Lepr Rev 66(4):287-95 

5. Stefani MMA, Avanzi C, Bührer-Sékula S et al. Whole genome sequencing distinguishes between relapse and reinfection in recurrent leprosy cases. PLoS Negl Trop Dis (2017) 11(6): e0005598.

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LML - S Deepak, B Naafs, S Noto and P Schreuder

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