(LML) Protecting cured LLp patients

Leprosy Mailing List – May 12,  2019

Ref.:   (LML) Protecting cured LLp patients

From:  Joel Almeida, London and Mumbai

---

Dear Pieter,

Interruption of transmission is understandably of great interest.

How important are previously cured persons with anergy (LLp)? Could they explain the continuing transmission in places such as Dadra Nagar Haveli (India) where the decline is disappointing despite intensive active case-finding, short-term chemoprophylaxis and MDT? Or in Cuba, which shows continued transmission despite many years of similarly intensive measures including MDT, BCG, chemoprophylaxis and even serological pre-clinical diagnosis (1)?

It has been demonstrated that an unprotected person with LL disease frequently sheds bacilli through the nose. Such a person can shed as many as 1 billion (10^9) bacilli per day in nasal discharges, including tens of millions of viable bacilli, while persons with borderline disease shed none or only a trivial number of viable bacilli (2). Shedding of bacilli was demonstrated to be even more frequent among persons with "recrudescent" LL (recurrence or relapse or re-infection).

We currently detect no more than 250,000 new patients annually across the world. The majority of newly detected patients shed few or no bacilli. Therefore, a single person with anergy shedding tens of millions of viable bacilli per day is of overwhelming importance to the endemic. For example, the Indian Central Leprosy Division reported a puzzling, rapid three-fold increase in the new case detection rate in one endemic hot spot. On careful investigation, they found missed lepromatous patients, multiple cases in one family. These were described as "de novo" MB, likely to be persons with genetically determined anergy. Intensive door-to-door case-finding had overlooked them. Corrective action has since been taken (partly as a result of LML correspondence forwarded to India). The Indian programme now displays pictures of skin nodules on ears, alongside skin patches, in its public education materials. This is a small but helpful step, no doubt accompanied by even more effective measures such as steadily restoring reliable skin smear services.

Among persons with anergy, how important are re-infected persons compared to newly detected patients in maintaining transmission?

Re-infection of persons with MB disease is demonstrable in endemic areas (3). Anergy appears to have a genetic basis (4, 5, 6). Once MDT is withdrawn, persons with anergy in endemic areas currently remain unprotected against re-infection. This is clearly dangerous for the person with anergy. How important is it for transmission?

Previously-cured persons with anergy accumulate according to their remaining life expectancy. The average age at diagnosis of LL patients in India is about 35 years (7). The average life expectancy at birth is about 70 years. The average 35-year-old in India can expect to live beyond age 70 because they have already evaded infant mortality. Therefore, a previously cured person with anergy might well hope to live for longer than another 35 years. In practice, we have tended to abandon many of them to destitution, homelessness, under-nutrition, lack of basic amenities, legalised discrimination and ostracism. They tend to suffer excess mortality (8).

Therefore, the accumulated prevalence of persons with anergy is likely to be no more than 35 times the annual incidence rate of newly diagnosed persons with anergy. In other words, for every newly diagnosed person with anergy, there is likely to be a maximum of about 35 previously cured persons with anergy. Even if the actual ratio is lower than 35, these persons offer important and fertile ground for re-infection.

Observed recurrence rates (relapse and/or re-infection) among MB patients after MDT range from 0.1/100 persons/yr in the Philippines (9) to 2/100 persons/yr (10) to even 4.29/100 persons/year in an endemic area of India (11). Therefore, every 35 persons with anergy, following completion of MDT in an endemic area of India, are likely to produce 1 to 2 relapses/re-infections per year. This number could be somewhat higher in reality because the recurrence rates above included patients without anergy.

Accordingly, re-infected persons with innate anergy could equal or even outnumber newly diagnosed persons with anergy in endemic areas. Given the astronomically high numbers of bacilli that can be shed by a single person with anergy, re-infected persons, left unprotected after standard-duration MDT, are likely to be a major source of bacilli in endemic areas. They could well prove to be the major source of bacilli.

Shandong Province avoided this error by ensuring prolonged anti-microbial protection. Shandong achieved near-zero transmission (12, 13). We usefully could follow Shandong's successful example.

Improved understanding of the underlying epidemiology also helps us to bring a realistic narrative to taxpayers and private donors. They have seen us alternate between exaggerated claims of success and failure. Now they are mostly indifferent to our noises. But our past epidemiological fog needs no longer sink us. Interruption of transmission has been achieved in Shandong using specific interventions, and therefore can very likely be achieved again. Under-financing can be remedied, as it has been for other diseases.

We usefully could provide anti-microbial protection to persons with LL disease after the standard duration of MDT, in endemic areas. Monthly doses of 2 or 3 highly bactericidal drugs in combination are likely to work well, after the standard duration of MDT.

There is another very weighty reason for protecting previously treated persons who have anergy. They are human beings just like all of us, and deserve protection against not only destitution, homelessness and ostracism, but also against re-infection and worsening of physical and psychological sequelae. It is only how we would like them to treat us if our positions were reversed.

We need to bring our best selves to this challenge, and keep tying together all the epidemiological clues from the front-lines. The bacillus is an ancient and formidable foe. We need to widen our horizons and keep our minds open to better science, warmer compassion and continuous improvement. Shandong achieved victory and so, probably, can all of us.

Joel Almeida

Translations

दादरा नगर हवेली कई अच्छी प्रथाओं का उपयोग करता है, लेकिन फिर भी रोग संचरण जारी है। क्यों होता है ऐसा? 

जीन कुछ लोगों में (बेसिलस के खिलाफ) एनर्जी पैदा करते हैं। एनर्जी वाला एक असुरक्षित व्यक्ति नाक से प्रति दिन 1 बिलियन (1,000,000,000) बेसिली तक बहा सकता है। इसमें करोड़ों व्यवहार्य बेसिली शामिल हैं। जब एमडीटी के बाद फिर से संक्रमित होते हैं, तो ऐसे व्यक्ति संभवतः बेसिली का एक प्रमुख स्रोत होते हैं। ऐसे व्यक्ति जमा होते हैं और नए निदान किए गए एनर्जिक व्यक्तियों की संख्या से अधिक होते हैं। 

सुरक्षा की यह विफलता रोगी की गलती नहीं है। यह हमारी गलती है।

शानदोंग प्रांत ने ऐसे एनर्जिक व्यक्तियों के लिए लंबे समय तक एंटी-माइक्रोबियल सुरक्षा प्रदान की और लगभग शून्य संचरण हासिल किया। हम एमडीटी के बाद एलएल रोग वाले व्यक्तियों को एंटी-माइक्रोबियल सुरक्षा प्रदान कर सकते हैं। यह शायद बैसिलस के खिलाफ हमारी ढाल में सबसे बड़ी खाई को बंद कर देगा। इस तरह से शानदोंग ने जीत हासिल की। हम भी, दादरा नगर हवेली में और पूरे भारत में, इसी तरह जीत हासिल कर सकते हैं।

Locais como Dadra Nagar Haveli (Índia) e Cuba usam muitas boas práticas antimicrobianas, incluindo descoberta ativa de casos, PQT, BCG e quimioprofilaxia de curta duração. A transmissão da doença ainda continua. Por que isso acontece?

Os genes são responsáveis pela anergia em algumas pessoas. Uma pessoa desprotegida com anergia pode eliminar 1 bilhão (1.000.000.000) de bacilos por dia do nariz. Isso inclui dezenas de milhões de bacilos viáveis. Quando infectada após a MDT, tal pessoa é provavelmente uma importante fonte de bacilos. Tais indivíduos acumulam e superam em número as pessoas anérgicas recentemente diagnosticadas.

Esta falha de segurança não é culpa do paciente. Isso é culpa nossa.

A província de Shandong forneceu proteção antimicrobiana a longo prazo e alcançou quase zero de transmissão. Nós podemos fornecer proteção antimicrobiana para pessoas com doença LL após a duração normal da MDT. Isso provavelmente fechará a lacuna mais importante em nossa defesa contra o bacilo. Shandong conseguiu a vitória e nós provavelmente podemos fazer o mesmo.

Des villes telles que Dadra Nagar Haveli (Inde) et Cuba utilisent de nombreuses bonnes pratiques antimicrobiennes, notamment la recherche active de cas, la PCT, le BCG et la chimioprophylaxie à court terme. La transmission de la maladie continue toujours. Pourquoi?

Les gènes sont responsables de l'anergie chez certaines personnes. Une personne souffrant d'anergie et non protégée peut se débarrasser d'un milliard (1 000 000 000) de bacilles par jour du nez. Cela comprend des dizaines de millions de bacilles viables. Lorsqu'elle est infectée après la PCT, une telle personne est probablement une source majeure de bacilles. Ces personnes accumulent et sont plus nombreuses que les personnes anergiques nouvellement diagnostiquées.

Cette défaillance de la sécurité n'est pas la faute du patient. C'est notre faute.

La province du Shandong a fourni une protection antimicrobienne à long terme et a ainsi atteint une transmission presque nulle. Nous pouvons fournir une protection antimicrobienne aux personnes atteintes de la maladie LL après la durée normale de la PCT. Cela peut fermer le trou le plus important de notre défense contre le bacille. Le Shandong a remporté la victoire et nous pouvons probablement faire de même.

References

1) Beldarraín-Chaple E. Historical Overview of Leprosy Control in Cuba. MEDICC Rev. 2017 Jan;19(1):23-30.

2) Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.

3) 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 Jun 15;11(6):e0005598. doi: 10.1371/journal.pntd.0005598

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

5) 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.

6) Palermo ML, Pagliari C, Trindade MA et al. Increased expression of regulatory T cells and down-regulatory molecules in lepromatous leprosy. Am J Trop Med Hyg. 2012 May;86(5):878-83. doi: 10.4269/ajtmh.2012.12-0088.

7) Sehgal VN, Rege VL, Singh KP. The age of onset of leprosy.Int J Lepr Other Mycobact Dis. 1977 Jan-Mar;45(1):52-5.

8) Noordeen SK. Mortality in leprosy. Indian J Med Res. 1972 Mar;60(3):439-45.

9) Maghanoy A, Mallari I, Balagon M, Saunderson P. Relapse study in smear positive multibacillary (MB) leprosy after 1 year WHO-multi-drug therapy (MDT) in Cebu, Philippines. Lepr Rev. 2011 Mar;82(1):65-9.

10) Kumar A, Girdhar A, Girdhar BK. Twelve months fixed duration WHO multidrug therapy for multibacillary leprosy: incidence of relapses in Agra field based cohort study. Indian J Med Res. 2013 Oct; 138(4): 536–540

11) Girdhar B, Girdhar A, Kumar A. Relapses in multibacillary leprosy patients: effect of length of therapy. Lepr Rev (2000) 71: 144- 153.

12) Li HY, Pan YL, Wang Y. Leprosy control in Shandong Province, China, 1955-1983; some epidemiological features. Int J Lepr Other Mycobact Dis. 1985 Mar;53(1):79-85.

13) Chen S, Zheng Y, Zheng M et al.  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.

---

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

LML blog link: http://leprosymailinglist.blogspot.it/

Contact: Dr Pieter Schreuder << editorlml@gmail.com