Leprosy Mailing List – February 12, 2020
Ref.: (LML) Why HD seldom spreads in affluent countries
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
HD (Hansen's Disease) is caused by bacilli. The probability of infection in an individual is directly related to how many viable bacilli per unit time are available to that individual, and for how long. For example, before the discovery of effective anti-microbial therapy, those who shared a bed with a patient showed a higher risk of infection than other household contacts. (1) Contacts of MB patients show a higher risk of HD disease than do contacts of PB patients or the general population. That is because untreated MB patients include LL patients who shed very high concentrations of viable bacilli per unit time. This can be as many as tens of millions of viable bacilli per day. (2)
Persons with genetically-linked anergy (polar LL, LLp) are likely to show the lowest IDh[]\50 together with the highest probability of disseminated disease. (ID50 is the number of viable bacilli necessary to infect 50% of exposed persons.) Therefore, LLp patients, with their genetically linked anergy and shedding of astronomical numbers of viable bacilli, are predicted to be clustered in families. Multiple-case families with LLp patients are predicted to be far more common than predicted by chance alone. This is likely to be especially true in former segregated colonies where opportunities for marriage with outsiders were restricted. The population of Santo Antonio do Prata in Brazil, a former segregated colony, has yielded useful clues about enrichment of genetic risk factors, although the genetic predisposition to LL disease has probably not yet been fully explored in such formerly segregated colonies. (3,4)
The clustering of all types of HD in endemic countries can be explained by the important role of untreated LLp patients (before or, with recurrences, after fixed duration MDT) as sources of highly concentrated bacilli. The relative importance of host sources of viable bacilli (even via the environment) vs long-standing environmental sources is indicated by the degree of clustering. If long-standing environmental sources were predominant, they would tend to obscure clustering. Then the distribution of newly diagnosed patients would more closely approach a random spatial distribution. Of course, untreated LLp patients are mobile and can therefore form clusters not only around their homes but also around any other places in which they frequently spend reasonably long amounts of time, such as workplaces. Once that is accounted for, the degree of true clustering around untreated LLp patients is likely to be even more marked than observed.
Clusters of HD tend to form also around former leprosy colonies or leprosy hospitals, partly due to enrichment of genetic risks among local residents, but also probably due to the denial of prolonged anti-microbial protection to persons with the LLp genome(s).
The LLp genome(s) are likely to be fairly rare, given that only about 1% of newly diagnosed patients are found to have LL disease when highly skilled personnel do periodic door-to-door surveys and intensive contact tracing. (5) Skilled and experienced personnel detect all forms of clinical disease including self-healing forms that tend to be missed altogether by passive case-finding. Only a subset of all LL patients has genetically-linked anergy, with the rest downgrading towards the lepromatous pole in response to the load of viable bacilli. Therefore, the LLp genomes are likely to occur among less than 50% of all newly diagnosed LL patients. These latter in turn form less than 1% of all newly diagnosed patients when case-finding is sufficiently intensive. Further, the cumulative incidence rate of all forms of HD tends to remain below 5000/100,000 population (5% of the population), except in small segregated populations where inter-marriage is frequent (such as Santo Antonio do Prata or endemic islands with small populations). Hence the frequency of LLp genome(s) in the general population is likely to be under (0.5 x 0.01 x 0.05 =) 0.00025 or <25 per 100,000 population. Even then, only upon exposure to the ID50 or more bacilli will these persons develop disease.
What happens when an infected but untreated person with an LLp genome, shedding astronomical numbers of bacilli, migrates to an affluent country? Their contacts might well show signs of infection. (6) However, unless the contacts include others with the LLp genome, few if any contacts are likely to develop clinical HD. The rest of the infected contacts have too high an ID50 to develop disease. For transmission to be sustained, a critical mass of infected but untreated persons with an LLp genome is likely to be required. In endemic countries, this critical mass is currently provided by previously treated LLp patients who are now neglected. The probability of contact between one infectious untreated LLp person and an uninfected LLp contact is multiplied by the prevalence of infectious untreated LLp persons. That probability, in turn, is multiplied by the availability of multiple sources of infection. Such sources include not only LLp patients but also (temporarily) the viable bacilli that they shed into the environment. In affluent countries, the infectious untreated person with an LLp genome might never encounter another person with an LLp genome either directly or indirectly. If they do, it might be too briefly to deliver a sufficient infectious dose. Further, the number of viable bacilli shed by a single LLp patient, although very high, is probably insufficient to saturate the environment in affluent countries. Therefore, for practical purposes, HD is expected to behave largely like a non-infectious disease in affluent countries.
This general rule about affluent countries is likely to be broken by multiple-case families who have more than one child with an LLp genome. Intrafamilial household transmission is then likely if even one of the persons with an LLp genome remains infectious for some time. This remains true in affluent countries, as elsewhere. Persons from the US-controlled Pacific islands migrating to the USA might well exhibit this kind of multiple-case pattern in the rare instance that one or two families have one infectious LLp parent plus one or more children with the LLp genome(s) living in one household.
In affluent countries with widespread sources of concentrated viable bacilli, however, those with an LLp genome are the most likely to be infected. Armadillos are a widespread source of concentrated viable bacilli in some parts of the USA. It can be predicted that the LL type of disease is more frequent among newly diagnosed US-born persons who have never travelled to endemic countries, compared to newly diagnosed patients in endemic countries. This is partly due to no active case-finding in the US, and missed self-healing cases. However, it is also because persons with LLp genome(s) have the lowest ID50 (infectious dose 50).
The important points in the epidemiology of HD, for interruption of transmission, may be summarised as in Figure 1. The important question is, what actions are likely to have the greatest impact in endemic areas?
Figure 1. Polar LL (LLp, de novo LL) patients, before and especially after release from anti-microbial treatment, play an overwhelmingly important role in maintaining the endemic.
The other side of this story is the spectacular success of Shandong province, and Uele (DR Congo), in reducing transmission rapidly with the use of prolonged anti-microbial treatment for LL patients (among others). This success was evident while those places were far from affluent. Once the reproductive ratio of LLp patients is reduced to below one, the endemic starts to die out. That's because one person with LLp disease who enters treatment is no longer replaced by an untreated person with LLp disease. Prolonged anti-microbial protection for LLp patients is critical for interruption of transmission. Otherwise, many treated LLp patients eventually experience recurrence and return to the pool of persons shedding astronomical numbers of viable bacilli. We have interrupted transmission before using prolonged anti-microbial protection for LL patients, and we can do it again.
The big threat to our success comes from eventual drug-resistance. (7) Monitoring drug-resistance is not the same as preventing it. Drug-resistance is a discontinuity, more like a cliff than a hillside. By the time one has fallen off a cliff, and monitored the fact, it is too late to prevent the fall. Single-dose rifampicin post-exposure prophylaxis (SDR-PEP) is a recipe for hastening the selection of drug-resistant mutants. Along with this risk brought on by SDR-PEP, the people of endemic countries can expect also an increase in the risk of MB disease and a slowing in the decline of HD if they allow SDR-PEP. It would be a double blow to them, and not entirely consistent with the high standards of ethics and compassion on which we pride ourselves.
For the past two decades we have unintentionally fooled nearly everyone, sometimes including ourselves. But we have not fooled the bacilli.
Figure 2. Newly detected MB patients reported globally, 1985-2017. The definition of MB disease has remained materially unchanged since about the year 2000. The true global decline of HD, as assessed by the number of new MB patients/year, has been modest at best. Once the backlog of undetected MB patients was cleared in the 1992-2005 period, the underlying stagnation in new cases/yr became evident.
Short-term gains in financing and glory, based on mistaken claims, are short-lived and tend to backfire. We announced that HD is not a public health problem, so the world took us at our word and started neglecting it. We turned a blind eye to evidence of high recurrence rates among highly bacillated patients after even 2-year MDT, so transmission continued. We need not keep blundering. Any organisation that adopts a defined geographical area and matches the spectacular success of Shandong will have the whole world rushing to congratulate and support them.
This new year in a new decade can be a new beginning. We can act more effectively and match the spectacular achievement of Shandong in interrupting transmission. We know how. Also, great colleagues can keep making improvements to effective field protocols. Let's do it.
Joel Almeida
References
1. Rogers L. The Incubation Period of Leprosy. Ind Med Gaz.1924 Feb; 59(2): 65–68.
2. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
3. Cambri G, Mira MT. Genetic Susceptibility to Leprosy—From Classic Immune-Related Candidate Genes to Hypothesis-Free, Whole Genome Approaches. Front. Immunol., 20 July 2018 | https://doi.org/10.3389/fimmu.2018.01674
4. Lázaro FP, Werneck RI, Mackert CCO et al. A Major Gene Controls Leprosy Susceptibility in a Hyperendemic Isolated Population from North of Brazil. The Journal of Infectious Diseases, Volume 201, Issue 10, 15 May 2010, Pages 1598–1605, https://doi.org/10.1086/652007
5. 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.
6. Dockrell HM, Young S, Macfarlane A. Possible Transmission of Mycobacterium Leprae in a Group of UK Leprosy Contacts. Lancet, 338 (8769), 739-43 1991 Sep 21
DOI: 10.1016/0140-6736(91)91454-3
7. 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
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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