Leprosy Mailing List – June 14, 2021
Ref.: (LML) Predominant MB HD (multibacillary leprosy) and its significance
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
The points below concern the epidemiology of HD including in low endemic areas, including those that are affluent. Esteemed colleagues can feel free to improve on this understanding. The better our grasp of the underlying epidemiology, the more successfully can we achieve our desired outcomes in all areas.
Multibacillary HD (MB leprosy) patients include a subset known to shed as many as tens of millions of viable bacilli per day. (1) This subset consists of persons with active lepromatous (LL) HD who are not receiving anti-microbial protection. When, and only when, a person with sufficient genomic and current phenotypic susceptibility to HD bacilli becomes infected with a sufficient dose of viable bacilli, then that person eventually shows physical signs of disease. Sensitive tests reveal that people newly infected in low endemic areas can show no physical signs of disease. (2)
Prompt detection of physical signs of HD depends on:
A) the index of suspicion among health professionals and among the general population,
B) the level of knowledge and clinical excellence among health professionals, and
C) the frequency of examinations among the general population.
Areas with a low index of suspicion will tend to overlook nearly all transient forms of HD, leaving predominantly MB forms available for detection. Only those areas with frequent (e.g., monthly or annual) examinations of the general population will detect transient forms of HD whose incidence rate is a considerable multiple of that for MB forms.
This follows from the formula:
Point prevalence of physical signs of disease =
incidence rate of new cases with physical signs x duration of the physical signs
Examinations at intervals exceeding the duration of transient physical signs will depress the point prevalence of physical signs of disease.
The failure to detect transient forms of HD does not mean that they did not occur, rather that the interval between examinations exceeded the typical duration of transient physical signs. Infrequent examination of the entire population is understandable in low endemic areas, where a particularly vast number of persons would have to be examined thoroughly in order to find a single new case with physical signs. That is why in low endemic areas MB forms predominate among detected cases.
The highest reported proportion of a population recorded as ever having physical signs of HD is 350,000 per million (i.e., 35% of the entire population). (3) This was revealed by frequent examinations in the pre-sulfone era, done as frequently as monthly. Clinical skills were not conspicuously poor then, and skin smear microscopy was used routinely. One of the clinicians there even correctly discerned that temperature sensation in anaesthetic skin lesions was the first to be lost, which suggests a degree of clinical acumen that is remarkably good by today's standards. A certain proportion of the cases will have been doubtful diagnoses or wrong diagnoses, but probably not much more than would be expected among competent clinicians today. The annual incidence rate of new cases with physical signs of HD there was reported to be over 14,000 per million population. This included transient forms of HD.
Populations examined at yearly intervals still show a notable predominance of transient forms of HD among the HD cases newly detected. (4) The age-specific incidence rate of PB forms reported here exceeded that of MB forms of HD by a factor of up to 13. For every MB HD case newly detected there were as many as 13 PB HD cases newly detected by yearly examination of the entire population.
Therefore, the total number of cases newly detected with physical signs of HD can be increased or reduced at will. This happens simply by altering the frequency, coverage and competence of examinations. This holds true for children as well as adults. Therefore a zero new case detection rate (or new child case detection rate) can be achieved immediately by simply keeping our eyes closed for long enough. Conversely, the case detection rate (including among children) can be increased fairly quickly in endemic areas by simply examining a large proportion of the population frequently and repeatedly. This happened in the run-up to the year 2000..
If the case detection rate (or child case detection rate) depends largely on the intensity of case-finding activities, how are we to discern the real underlying epidemiological trend over years or decades?
MB HD holds the key. It almost never self-heals. Sooner or later, MB HD cases come to the attention of health professionals. Therefore the case detection rate of MB HD is a reasonably reliable indicator of the underlying epidemiological trend of HD in a population (or age group). Even more so once any backlog of MB HD cases is registered, as happened in the run-up to the year 2000. Stochastic variation can be smoothed out by averaging the MB HD case detection rate, over some years. The moving average of the MB HD case detection rate is more informative than short-term fluctuations.
The probability of developing physical signs among members of a population is directly related to known factors including
a) the quantum of viable bacilli available to that population (notional area under the curve of number of viable bacilli shed per unit time from any source, plus the concentration per unit surface area or unit space of viable bacilli surviving in the environment),
b) the frequency of HD-susceptible genomes in that population, (usually similar in most populations apart from small isolated populations with frequent intermarriage between persons with HD-susceptible genomes)
c) the total person-hours of direct or indirect contact between sources of concentrated viable bacilli and genomically susceptible individuals,
d) the cumulative duration for which infectious and susceptible individuals meet in poorly ventilated spaces.(given that the bacilli are sized between 1 and 8 microns, similar to several other infectious agents capable of spread by droplets and airborne routes).
e) the extent to which skin abrasions are prevalent and exposed to the environment
f) phenotypic susceptibility owing to inadequate nutrition and other features of very low income
In areas of low endemicity, especially in affluent areas, all of these tend to be of low absolute magnitude. In addition, there is an inverse relationship with
g) the coverage by effective anti-microbial protection (including MDT given till smear negativity, or even more bactericidal regimens given to anergic patients)
h) the coverage of effective vaccines (e.g., BCG or MIP) in the population
i) the fraction of the population protected by periodic mass multi-drug administration using effective regimens (e.g., ROM rifampicin + ofloxacin + minocycline).
Therefore it is predicted from a) to f) above, and observed, that in low-endemic affluent areas even undiagnosed MB HD patients rarely give rise to new cases with physical signs of HD. This does not mean that HD is a non-communicable disease, merely that the viable bacilli shed by untreated LL HD patients seldom reached "fertile soil", metaphorically speaking. The most "fertile soil" is a person with a genome conferring extreme susceptibility to bilaterally disseminated and highly bacillated forms of HD. (5. 6, 7) Susceptibility to clinical HD may be expressed in terms of the dose of viable bacilli sufficient to produce overt HD in 50% of a defined population (ID50). In persons with polar LL genomes, the ID50 is likely to be a very small number of viable bacilli.
Unless an infectious patient (or other source of concentrated viable bacilli e.g. infected armadillos) becomes the effective contact of a genomically susceptible person, few or no new cases with physical signs of HD are expected to arise. A low and declining frequency of infectious individuals reduces the probability of effective contact between them and genomically susceptible individuals. Therefore it is predicted, and observed, that in low endemic areas even undiagnosed and infectious MB HD cases seem to lead relatively rarely to physical signs of HD in other local people. This is especially true when examinations of the whole population are infrequent or absent, because then transient physical signs can easily escape detection.
There are predictable exceptions to the situation described above. Shared genomes (5-7) among twins or even siblings are predicted to enable multiple cases to occur in a single household in even low endemic areas, as long as some source of concentrated viable bacilli is available. Likewise, segregated settlements with an over-representation of people who experienced HD can show atypically high incidence rates of physical signs of HD, given a source of concentrated viable bacilli.
Esteemed colleagues can fine tune and improve this account. We can help one another better to elucidate the underlying epidemiology. That shows how and why 84% reduction of new HD cases in hyperendemic "hot spots" is achievable within 2 years, as demonstrated by the SHF/WHO project using periodic mass ROM administration (rifampicin + ofloxacin + minocycline) in FS Micronesia. Also how and why even low income high endemic areas such as that served by Karigiri (India) achieved a 16%/year decline in the incidence rate of LL HD, without relying on segregation and without waiting for incomes to increase first. The huge epidemiological impact of adequate anti-microbial protection highlights the importance of delaying drug-resistance by using only multi-drug combinations invariably, for treatment or prophylaxis. The better our epidemiological understanding, the less risk of serious mistakes and the more surely and rapidly we will spread success.
Joel Almeida
References
1. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
2. 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
3. Wade H, Ledowsky V. The leprosy epidemic at Nauru. Int J Lepr 1952; 20(1): 1-29.
4. Wardekar RV. Chemoprophylaxis in leprosy. Lepr India; 1969; XLI(2): 240-6
5. Chakravarti MR, Vogel F. A twin study on leprosy Georg Thieme Publishers, Stuttgart, Germany; 1973
6. Zhang FR, Huang W, Chen SM et al. Genomewide Association Study of Leprosy. N Engl J Med 2009; 361:2609-2618 DOI:10.1056/NEJMoa0903753
7. 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.
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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