Leprosy Mailing List – November 4, 2019
Ref.: (LML) Example protocol for safely interrupting transmission of Hansen's Disease
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
It is helpful to keep our eyes fixed on demonstrable success at the front-lines. Shandong demonstrated that near-zero transmission can be achieved within a surprisingly short duration. (1) This was an unexpected success. Unexpected failures and unexpected successes are our two greatest teachers.
Based on the evidence to date, a protocol such as that outlined at the end maximises our chance of matching Shandong's success. The 3 key points are to:
A) Protect LLp patients against recurrence (endogenous relapse &/or re-infection). Shandong protected LL patients with prolonged anti-microbial treatment. That allowed Shandong to shut down a major source of concentrated viable bacilli. Shandong then achieved a 20%/year decline in incidence rate. This contrasted with Yunnan's relative stagnation or very slow decline in new cases, as is typical for fixed-duration MDT. (1) Further, we know that in two Indian towns, 17% of neglected previously treated patients, experiencing destitution, had positive skin smears.(2) Monthly chemoprophylaxis after MDT could protect all LL patients.
It is very important correctly to classify LL disease among contacts of current or former patients, for example by obtaining skin smear results. Then LL patients can be recognised and given prolonged anti-microbial protection. Otherwise recurrent disease among previously treated LL patients threatens the patients' well-being and remains a major source of concentrated HD bacilli. Allowing this source to continue and then looking for the persons infected is not an ideal way to tackle transmission.
{For those who are not from a biological background - If HD is like a fire then LLp patients are like persons who naturally perspire petrol. Protecting them against recurrent disease after MDT is crucial to their well-being, and crucial for "putting out the fire", i.e., interrupting transmission at source.}
B) Avoid selection of drug-resistant bacilli by always using multiple drugs instead of monotherapy. Drug-resistance is the single biggest long-term threat to HD control.(3,4) Multi-drug resistant microbes have undermined control of other diseases. It is better to avoid that predicament in HD. Therefore, multi-drug chemoprophylaxis, like MDT, is preferable to monotherapy (e.g., single-dose rifampicin). This is especially true because undiagnosed LL patients examined by minimally trained multi-purpose workers can easily be misclassified as disease-free contacts. Giving unrecognised LL patients monotherapy invites the selection of drug-resistant mutant bacilli.
{ For those not from a biological background, drug-resistant bacilli are like super-bugs that make HD control more difficult and eventually impossible. It is better to keep the bacilli, our enemy, manageable. We cannot afford to fight a fire by spraying it with fuel. }
C) Diagnose the often-subtle clinical signs of LL disease. Early LL signs are subtle and easily overlooked. Even door-to-door case-finding campaigns are known to miss the subtle signs of LL disease. For example, in Salaunikhurd (India), the national programme investigated an increase in new cases/year from about 30/10,000 population to over 100/10,000 population, occurring within 2 or 3 years. This increase was attributable largely to missed multiple LL patients in a household. (5) An untreated LL patient can shed up to a billion bacilli per day. Skin smear examinations are indispensable, and the Indian programme is strengthening skin smear services. That deserves appreciation.
Serology can help in an unexpected way. Absence of IgM antibodies, to specific antigens, has high negative predictive value. (6) It can help more surely to exclude LL HD among contacts who lack clear physical signs of disease.
Eventually, diagnosis of subtle LL signs might be able to rely on image capture using mobile technology linked to automated cloud-based analysis. This could assist even relatively untrained front-line staff better to recognise early LL disease. Such technology is becoming available for some other diseases. Similar technology might eventually prove very helpful in recognising subtle signs of LL HD.
{ For those here not from a biological background - HD bacilli are often camouflaged (like concealed flames) in patients who excrete tens of millions of viable bacilli per day. However, HD bacilli tend to produce easily detectable signs (like smoke) in non-infectious and self-healing patients. We cannot put out a fire by concentrating on only the smoke. }
We can succeed if we learn from Shandong's demonstrable success and keep improving our interventions.
Example protocol for safely interrupting transmission
An effective and safe protocol to interrupt transmission in hyper-endemic "hot spots" is likely to look something like the following. The "eight pillars of a highly effective programme" (LML 18 Sept 2019) provide the supportive context, enabling zero disability and reducing stigma even as we strive for zero transmission.
= = = = = = = = = = = =
A. Door-to-door surveys and/or skin camps. Treat patients as in C 1 to 3 below.
Skin camps (for all signs and symptoms, not just HD) have the advantage of on-site clinical expertise, and relatively low stigma. Confirmation of diagnosis can be immediate. Also, skin smears can be taken and BCG can be made available at skin camps. Further, given the clustering of new patients, skin camps plus contact tracing are likely to yield far more genuine new patients per worker-hour than available from door-to-door surveys. However, periodic door-to-door sample surveys remain indispensable for estimating the true magnitude of the problem.
Examine contacts of confirmed or former patients.
B. Serological testing (5) of the contacts of all current and former patients and the former patients themselves. (This needs to include all known former LL patients diagnosed even decades earlier)
IF SEROLOGICALLY POSITIVE then
C. Skin smear exam to help recognise and classify LL patients
1. a) if high BI now (4+ or greater) then
Give full MB-MDT followed by post-MDT chemoprophylaxis with 3 balanced bactericidal drugs (eg., monthly rif + moxifloxacin OR clarithromycin + minocycline) - MB MDT followed by monthly RMoxMin or RCMin
1. b) if high BI ever previously (4+ or greater) then
Give monthly RMoxMin or RCMin
2. else if smear positive with low BI or smear negative with more than 5 lesions then
Give full MB-MDT
3. else if smear negative and 1-5 lesions then
Give full PB-MDT
4. else if smear negative and no lesions then
Give a bactericidal combination (eg., single dose RMoxMin or RCMin)
PLUS for ALL the above categories as well as to all SEROLOGICALLY NEGATIVE contacts,
Give MIP vaccine. (7)
Using the protocol above, persons with anergy are unlikely to be missed, or under-treated. That is crucial for success. Otherwise, unrecognised LLp (anergic) patients given inadequate anti-microbial protection can serve as enduring sources of concentrated viable bacilli.
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In summary, the example protocol for interrupting transmission in even hyper-endemic areas relies on:
1. MDT (MB or PB) reinforced with
2. Multi-drug chemoprophylaxis for
a) LL patients (monthly doses after MDT) and for
b) contacts (single dose).
MIP vaccine can be added for all patients and contacts.
= = = = = = = = = = = =
A protocol such as the above maximises our chances of matching or even exceeding Shandong's demonstrated 20%/year decline in incidence rate, ending in near-zero transmission. Such a protocol attempts to take into account relevant evidence, known gaps are closed, and serious ethical concerns are averted. Esteemed colleagues can improve and adapt this example protocol for use in their own HD control areas.
Organisations that implement a protocol such as this in defined geographical areas and demonstrably match Shandong's success will find the whole world rushing to congratulate and support them. Shandong succeeded in ending HD, and so can we.
Joel Almeida
References
1) 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.
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) Benjak A, Avanzi C, Singh P et al. Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae. Nature Communications (2018) volume 9, Article number: 352
4) 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
5) Central Leprosy Division, India. Epidemiological investigation of multiple cases occurring in one family in village Salaunikhurd. NLEP newsletter Vol III, Issue 3, July – Sept 2018
6) 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)
7) Sharma P, Mukherjee R, Talwar GP et al. Immunoprophylactic effects of the anti-leprosy Mw vaccine in household contacts of leprosy patients: clinical field trials with a follow up of 8-10 years. Lepr Rev. 2005 Jun;76(2):127-43
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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