Leprosy Mailing List – August 28, 2020
Ref.: (LML) Transmission of HD (leprosy) is maintained by covert recurrence
From: Joel Almeida, London and Mumbai
Dear Pieter & colleagues,
Recent LML contributions (eg., Pai, LML 27 July 2020) have drawn attention to the risk of recurrent HD among patients with LL HD. Evidence from Brazil (Sartori PVU, Penna GO, Bührer-Sékula S et al 2020) lends support to the view that genetic risk factors predispose to re-infection/relapse/recurrence. The evidence below underlines the importance of recurrent HD. Implications for action are discussed.
Learning from past successes, and even past failures, can help us more rapidly and surely to end transmission while limiting disability, extreme poverty and exclusion.
Joel Almeida
= = = = = = = = = = = =
Transmission of HD (leprosy) is maintained by covert recurrence among previously treated LLp (polar lepromatous) patients
Abstract
Long-term follow-up of a cohort after 24 months of MDT (multi-drug therapy) reveals that among LLp HD (polar lepromatous leprosy) patients in an endemic area, recurrence rates are higher than previously believed: >5/100 person-years at risk from year 6 onwards following the end of MDT. Recurrent bacillary multiplication may be due to exogenous re-infection, endogenous relapse or both. Evidence suggests that genetic risk factors predispose individuals to recurrence of HD.
By contrast, during the first 5 years after the end of MDT, clinically diagnosed recurrence rates are low (less than 0.5/100 person-years at risk). However, this may be partly because it is not easy promptly to detect multiplication of bacilli. The risk of recurrence is predicted to be higher in hyper-endemic areas than elsewhere.
Transmission demonstrably and rapidly can be reduced by deliberate efforts using anti-microbial chemotherapy. This was demonstrated in both Shandong (China) and Uele (DR Congo). A 17% to 20%/year decrease in newly detected MB (multibacillary) HD patients was demonstrated there at a time when those places still had relatively low income. Prolonged anti-microbial protection for persons with LLp genomes was the critical ingredient in both places. In Uele at that time, income not only had been low for some time but also was declining. Low and declining income did not suffice to maintain transmission rates in the face of prolonged anti-microbial protection for LLp HD patients. In Shandong, prolonged anti-microbial protection for LLp HD patients (among others) was maintained until near-zero transmission. This approach, although contrary to global fashions, led to a decline of about 20%/year in newly detected MB patients. This relatively rapid decline was sustained until near-zero transmission.
At global level, in contrast to the success described above, the number of newly detected MB patients per year has stagnated compared to the 1980s. HD is known to be an important cause of extreme poverty and social exclusion, in addition to being a putative consequence of poverty. Ending HD and caring for those previously treated therefore makes a useful contribution to ending extreme poverty and breaking the downward spiral of disease leading to poverty leading to still more disease.
Persons with LLp genomes and unrecognised/untreated recurrence uniquely are capable of shedding astronomical numbers of highly concentrated viable bacilli. This can maintain transmission despite all other efforts to control HD. Further, active LLp HD is far more prevalent among previously treated MB patients than among the general population, by a factor of about 10,000 (ten thousand times more prevalent). Among previously treated MB patients known to have LLp HD, the excess risk of active LLp HD is likely to be even more frequent still, by several orders of magnitude.
Active case-finding therefore should give top priority to detecting active LLp HD among previously treated MB patients, so as to give them the highest level of protection against destitution, exclusion, further disability, and bacilli. Previously treated patients now experiencing destitution should receive the greatest priority for such protection.
The Sasakawa Health Foundation contributed financially to the rapid success in Shandong, allowing local professionals the elbow room to depart from global fashions in order to improve outcomes. Such respectful partnership between financing organisations and local professionals offers excellent prospects for ending the transmission of HD, because it enables rather than disables scientifically astute local talent that is constantly assimilating subtle front-line clues.
Based on past successes, ending the anti-microbial neglect of previously treated LLp patients is likely to close the critical gap through which HD continues to be transmitted. It would be good to join and assist the people and professionals of endemic countries in closing this critical gap (or at least allow them sufficient elbow room to succeed). By ending the too-frequent neglect of previously treated LLp HD patients, we are likely to hasten the end of HD transmission.
Voices of people afflicted by HD are important catalysts for bringing about the required changes. Words about the desirability of ending all world poverty are not an adequate substitute for actions that remedy the drop in income that too often accompanies disfiguring sequelae of HD.
Recurrence rate after MDT
The recurrence rate of clinical HD (leprosy) in years 6 to 20 following the end of MDT (multi-drug therapy) was demonstrably in the region of 5/100 person-years at risk or more, among persons with an initial BI (bacterial index in slit skin smears) of 4+ or greater. (1, 1a) MDT in that study included 24 monthly doses of rifampicin. 5/100 PYAR (person-years at risk) is more than a negligible rate of recurrence.
By contrast, during years 0 to 5 following the end of 24-month MDT in that same study, the corresponding risk was less than 0.5/100 PYAR (person-years at risk). Therefore, an insufficient duration of observation can underestimate, by a relatively large margin, the eventual cumulative recurrence rate in this group of patients.
The observed recurrence rate in excess of 5/100 PYAR, 6 or more years after the end of MDT, equates to eventual recurrence among 75% to 100% of persons with an initial BI of 4+. That assumes survival of such a treated person for 25 years or more after the end of MDT. Such survival is commonplace. 75% to 100% eventually showing recurrent HD is more than a negligible proportion of such patients.
Further, persons with LLp genomes uniquely are capable of shedding astronomical numbers of viable bacilli when left unprotected against bacilli. (2) Such unprotected persons also bear the full weight of (covert or overt) bacillary multiplication and its complications. Therefore, there is good reason for giving top priority to such persons who have ever shown high bacillary loads, and their contacts.
A previously treated LLp patient with recurrence of HD will usually take some time to show obvious clinical signs or marked increases in BI. Bacilli easily can multiply and spread to others before recurrence is recognised. Ensuring sufficient care for such patients following MDT not only would respect their human rights and help slow the deterioration of their disabilities, but also would close the critical gap in our efforts to end transmission.
The most powerful evidence supporting such action comes from highly successful programmes. A 20%/year decline in new MB patients/year, leading to near-zero transmission, was achieved (in Shandong, with the support of the Sasakawa Health Foundation). (3, 3a, 4) Therefore, such major and lasting success can be achieved again. Even Uele (DRCongo) achieved a 17%/year or greater decline in new MB patients/yr at a time of low and declining GDP per capita. (5, 5a) Prolonged anti-microbial protection for persons with LLp genomes was the critical ingredient in both Shandong and Uele, reducing transmission relatively rapidly.
Implications for action
In order to end transmission, and protect affected individuals, it seems necessary to include prolonged anti-microbial protection after MDT for persons who have ever shown a high BI.
Underestimates of recurrence risk
The risk of recurrence can be underestimated if the denominator of such estimates includes persons unlikely to have LLp (polar lepromatous) genomes. That would be like estimating the risk of ovarian cancer by studying a population of professional footballers, ignoring the fact that most professional footballers are male. Or estimating the risk of ovarian cancer by studying girls under 10 years of age, in whom the risk is very low. Similarly, most persons with even MB (multibacillary) HD starting MDT do not have LLp genomes. Therefore, their risk of recurrent HD following MDT is relatively low. Such underestimates do not justify complacency about the risk.
One study (6) compared 6 months of MDT with 12 months of MDT (historical controls). That study happened to include only three patients with a BI of 6+ at all sites. (Aung & Butlin, personal communication) All three patients happened to be in the 12-month MDT group. These three patients are likely to have had a relatively boosted risk of recurrence, owing to their genomes apparently permitting unrestrained proliferation of bacilli. The 6-month MDT group happened to have no such patients. This under-representation in the 6-month group was unintended and unplanned, but still relevant to the analysis. Accordingly, recurrence rates in the 6-month group are expected to be underestimated relative to the 12-month group.
Further, the 12-month MDT group was reported to have an average duration of 8.3 years of observation, including the 12 months of MDT. This is the same as 7.3 years of observation following the end of MDT. It amounts to an average of only 2.3 years of observation beyond the low-risk initial 5 years. During those 2.3 years the three patients with a BI of 6+ at all sites contributed roughly 7 PYAR. No recurrence of HD was detected among them. Therefore the apparent recurrence rate among these three BI 6+ patients from the sixth year of observation onwards was less than 1 in 7 PYAR . That equates to a risk of less than 14/100 PYAR in years 6 and beyond (upper 95% confidence limit <40/100 PYAR). <14/100 PYAR and <40/100 PYAR are far from trivial recurrence rates, among persons who permitted unrestrained proliferation of bacilli. On the other hand, as mentioned above, the 6-month group included not even a single patient with BI 6+ at all sites. Therefore, not a single PYAR among such patients was available from the 6-month MDT group. Given zero PYAR, the only safe conclusion is that the risk of recurrence among such patients, had any occurred in the 6-month MDT group, would have been less than 100/100 PYAR. 100% recurrence rate, the 95% upper confidence limit in this case, is more than a negligible proportion.
Implications for action
Ensure an adequate duration of MDT, not less than 12 months, in persons with a high initial BI at all sites.
Give prolonged anti-microbial protection after MDT, to persons with a high initial BI at all sites.
Detecting bacillary multiplication after MDT
Recurrence after treatment can be defined as multiplication of bacilli. WHO (the World Health Organization) uses this definition for relapse in HD. Further, recurrence may be caused by endogenous relapse or exogenous reinfection, (7, 8) or even both simultaneously. There is some evidence supporting the prediction that the human genome influences susceptibility to MB HD (9) and recurrence of HD. (10)
The occurrence and extent of bacillary multiplication can be estimated by quantitative PCR performed on serial dilutions of successive samples of bacilli compared to reference controls. Confirmation of viability can be obtained by inoculation into footpads of immunologically compromised mice. Alternatively, the samples might permit viability PCR, a technique that has apparently yet to be tried or ruled out for these bacilli.
Less sensitive approaches have often been used (understandably so, under routine programme conditions) in assessing multiplication of bacilli among previously treated patients. These include an increase in BI of 2+ (100-fold) at any one site, or the appearance of new lesions. An even less sensitive criterion of bacillary multiplication is an increase in average BI (average of four to six sites) rather than an increase at just one site. This latter criterion is conspicuously insensitive because even a spectacular increase from 0+ to 6+ BI at one skin smear site would fail to increase the average BI by more than about 1.5+. That means many, if not most, instances of early recurrence could be missed by this insensitive criterion. This "low sensitivity" criterion was used in at least one study. (6) "Low sensitivity" approaches can overlook even considerable multiplication of viable bacilli. This allows serious underestimates of the true cumulative recurrence rate, especially if the duration of observation is measured in years (6) rather than decades.(1)
Implications for action
Research: At least one cohort of patients who have high initial BI at all sites should be followed up using highly sensitive methods of detecting bacillary multiplication starting with the end of MDT and continuing for a duration well beyond 10 years.
Treatment: Give prolonged anti-microbial protection after MDT, to persons with a high initial BI at all sites.
The frequency of LLp patients among previously treated patients vs the general population
Roughly 16 million persons have ever been treated with MDT, including over 10 million persons in India. About 1% of them are likely to have genomes that readily permit unrestrained proliferation of bacilli. This is estimated from a field programme of the Schieffelin Centre in Karigiri, India, where meticulous contact tracing was done over decades (11). This would equate roughly to about 100,000 out of 10 million previously treated persons in India with genomes permitting unrestrained bacillary proliferation. They are therefore highly susceptible to re-infection after MDT. These persons are actual or potential sources of astronomical numbers of viable bacilli, as noted above.
Further, each year about 125,000 persons with signs of clinical HD are newly detected in India, including about 1,250 persons likely to have LLp genomes. If we merely treat the 1,250 newly detected while neglecting the 100,000 previously treated but probably with LLp genomes, our epidemiological impact is predicted to be disappointing. Such disappointing impact has been observed.
The figures above have implications for case-finding, as discussed now.
The incidence rate of new highly bacillated patients among the general population is in the region of (1,250/1.3 billion =) 1 per 100 million population/year.
The incidence rate of highly bacillated recurrent HD among previously treated MB patients is about (5/100 x 0.2% =) 1 per 10,000 previously treated MB patients/year.
Therefore, to discover one person with probable active LLp HD, it is necessary to examine about 100 million of the general population. Whereas it is sufficient to examine about 10,000 previously treated MB patients. Therefore, it seems important to give priority to previously treated MB patients when looking for persons with active LLp HD.
Examination of previously treated MB patients experiencing destitution in two towns of India revealed that 17% of them had positive skin smears. (12) Among those experiencing HD-related destitution, therefore, 1,700 out of 10,000 previously treated MB patients could well have recurrence of HD. They are highly important persons deserving the greatest level of ongoing protection against destitution, exclusion, further disability, and bacilli. Neglecting them would be a serious error of public health, involving also a disregard for their human rights.
Just as it is more important to examine previously treated MB patients than to examine the general population for active LLp HD, so it is more important to actually eradicate extreme poverty among destitute previously treated MB patients than to talk about the desirability of a global end to all poverty.
Implications for action
Active case-finding should give top priority to detecting active LLp HD among previously treated MB patients, so as to give them the highest level of protection against destitution, exclusion, further disability, and bacilli. Previously treated patients now experiencing destitution should receive the greatest priority for such protection.
Research: In a sample of previously treated MB patients, highly sensitive molecular techniques can be used to detect even covert bacillary multiplication in serial samples subjected to quantitative serial dilution techniques.
The consequences of neglecting previously treated LLp patients
The number of new MB patients/year has shown little or no decline in recent decades despite our best efforts.
Figure 1. Newly reported MB patients by year, globally. Relative stagnation.
See attached file
Figure 2. Newly reported MB patients by year, Shandong (China). Rapid decline at a time of low income. Decline sustained until eventual near-zero transmission.
See attached file
The number of new PB patients/year is highly sensitive to the frequency of case-finding campaigns (13, 13a), but the number of new MB patients/year less so. Similarly, financial incentives to field workers tend artificially to depress the reported proportion of newly detected patients showing grade 2 disability, but the number of new MB patients/year is less sensitive to distortion by such financial incentives. Persons with MB signs rarely self-heal. Sooner or later, they come to the attention of health services. Therefore, the number of newly detected MB patients/year is more useful than the total of all newly detected patients/year.
The number of new bacillated patients per year often has failed to decline at 20%/year in hyper-endemic areas where prolonged anti-microbial chemotherapy for LLp patients was omitted or, prior to the sulfones, unavailable. Even dramatic improvement in socio-economic conditions has so far not proved sufficient to achieve a 20%/year decline in newly detected MB patients in hyper-endemic areas. In Norway, where near-zero transmission was reached before the introduction of effective anti-microbial chemotherapy, (14) the rate of decline of newly reported bacillated patients/year remained well below the 17%/year or greater achieved in Uele, DRCongo. Uele, notably, had low and declining income.
Interestingly, the frequency of new MB patients/year is often observed to be higher around places to which previously treated LLp patients gravitate (including many institutions that have diligently served HD patients for many decades). Instead of the good work there leading to a marked local decline in transmission, it appears to have led to a local increase in transmission relative to other places. That is probably partly because LLp HD patients gravitating there generally have been denied prolonged anti-microbial protection. This not only exposes the individuals unnecessarily to harm, but also allows HD to keep spreading.
Implications for action
Give prolonged anti-microbial protection after MDT, to persons who have shown a high BI ever.
Transforming our outcomes and impact
Neglect of previously treated persons with LLp genomes not only seems disrespectful of their human rights, and damaging to those individuals, but also has serious consequences for the population. That is because it allows the spread of viable bacilli to children and others.
Prolonged anti-microbial protection of persons with LLp genomes is necessary for rapid decline in new MB patients/population/year. This requires prophylactic anti-microbial protection after MDT in the high-risk group of patients likely to have LLp genomes. Monthly doses of 3 bactericidal drugs are likely to work well for this purpose. (15, 16)
Implications for action
In endemic areas, patients who have shown a high BI (ever) should be given a full course of MDT followed by monthly doses of 3 bactericidal drugs to protect them against re-infection (eg., Rifampicin + Minocycline + Moxifloxacin or with Clarithromycin in place of Moxifloxacin)
Discussion
Prolonged anti-microbial protection for those with LLp genomes is a demonstrably effective way of shutting down a major source of transmission in HD while upholding the right of HD-affected persons to necessary and competent health care.
Analogies can aid understanding. When dealing with a flooded bathroom, it is not sufficient to focus on mopping up the water while neglecting to turn off the tap. Similarly, merely trying to protect those exposed is not as effective as interrupting transmission at source. That demonstrably can be achieved by prolonged anti-microbial protection for previously treated LLp HD patients.
Previously treated patients with LLp genomes typically have been neglected in recent decades. Using another analogy, refusing them prolonged anti-microbial protection and comprehensive care, merely because they were previously treated, is like firemen refusing to attend a wooden storage shed for inflammable fuels merely because a fire was extinguished there previously. It seems more humane to provide previously treated LLp patients with the anti-microbial protection they require. Anti-microbial neglect of previously treated LLp HD patients emerges also as one of the most important reasons maintaining transmission of HD. It seems not entirely consistent with ethics, human rights and science.
The Sasakawa Health Foundation contributed financially to the success in Shandong (China), without requiring local professionals to follow global fashions that turned out to be ineffective. This model of respectful partnership between financing organisations and local experts offers excellent prospects for ending the transmission of HD and reducing its sequelae. That is because it enables rather than disables scientifically astute local talent that is constantly assimilating subtle front-line clues.
Even low-income areas (Uele, DR Congo) rapidly have reduced transmission by using MDT backed up by prolonged anti-microbial protection for persons with LLp genomes. Ending transmission also helps shut down a significant cause of extreme poverty. Such measurable impact against extreme poverty seems worthwhile. It also seems more realistic and effective than mere words decrying global poverty.
In the landmark public interest litigation by the great lawyer Pankaj Sinha on behalf of neglected HD-afflicted persons against the Govt. of India, the advocate Colin Gonsalves described to the Supreme Court the predicament of many previously treated HD-afflicted persons: "they are driven to streets and eventually turn to begging" "compelled to live in so-called leprosy homes where they are treated as unpersons or aliens". It is remarkable that Mr. Sinha is physically blind. He apparently can see more clearly than many of us who are not physically blind.
Full respect for human rights and open scientific discussion would seem not only highly conducive to ending transmission, but also in keeping with our best selves. We are all explorers and learners, we all make mistakes but correct them eventually. When our eyes, ears and minds are kept open, the wealth of clues from the front-lines can lead us increasingly towards the truth. The truth alone can set people free from the ravages of HD.
Conclusion
We can match past successes in reducing transmission relatively rapidly even in places with as low a per capita income as Uele (DR Congo). A 20%/year decline in newly detected MB patients, leading to near-zero transmission, has been demonstrated by ensuring prolonged anti-microbial protection for highly bacillated MB patients. Such a rapid decline therefore is achievable. The people of endemic countries deserve no less. The noble values we profess permit no less. Let's do it.
References
1. 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 & analysed further in:
1a. Almeida J, Recurrence rate among MB patients following RFT. LML 2 June 2019
2. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
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. 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.
5. 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:
5a. Almeida J. Reducing transmission in poor hyperendemic areas - evidence from Uele (DRC). LML 29 Nov 2019
6. Butlin CR, Aung KJM, Withington S et al. Levels of disability and relapse in Bangladeshi MB leprosy cases, 10 years after treatment with 6m MB-MDT. Lepr Rev (2019) 90, 388–398.
7. Almeida JG, Jesudasan K, Christian M, Chacko CJG. Relapse rates in lepromatous leprosy according to treatment regularity. Int J Lepr 1986 Mar;54(1):16-20.
8. 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.
9. Chakravarti MR, Vogel F. A twin study on leprosy Georg Thieme Publishers, Stuttgart, Germany; 1973
10. Sartori PVU, Penna GO, Bührer-Sékula S et al. Human Genetic Susceptibility of Leprosy Recurrence. Scientific Reports (2020) volume 10, Article number: 1284
11. Norman G, Raja Samuel Bhushanam JD, Samuel P. Trends in leprosy over fifty years in Gudiyatham Taluk, Vellore, Tamil Nadu. Indian J Lepr. 2006 Apr-Jun;78(2):167-85.
12. 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.
13. Xiang-Sheng Chen, Wen-Zhong Li, Cheng Jiang, & Gan-Yun Ye. Leprosy in China: epidemiological trends between 1949 and 1998. Bull. WHO, 2001, 79: 306–312
reviewed & analysed further in:
13 a. Almeida J, Classification of patients and interruption of transmission. LML 14 Apr 2019
14. Irgens LM. Leprosy in Norway. An epidemiological study based on a national patient registry. Lepr Rev, Volume 51, Supplement 1, March 1980
15. Almeida J. Example protocol for safely interrupting transmission of Hansen's Disease. LML 4 Nov 2019
16. Pardillo EF, Burgos J, Fajardo TT et al. Powerful Bactericidal Activity of Moxifloxacin in Human Leprosy Antimicrob Agents Chemother. 2008 Sep; 52(9): 3113–3117. doi: 10.1128/AAC.01162-07
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