Why can't we control Morbus Hansen?
by Bernard Naafs Foundation Global Dermatology, Munnekeburen, Friesland, The Netherlands.Instituto Lauro de Souza Lima, Bauru, SP, Brazil. KCMUco, Moshi, Tanzania. RDTC, Moshi, Tanzania.Department of Dermatology Ayder Hospital, University of Mekelle, Mekelle, Tigray, Ethiopia.
In the Middle Ages, people were aware that Morbus Hansen (MH) could spread from person to person, and sufferers were therefore banished from society. It was generally accepted that they were cursed. However, some had the feeling that persons with MH were also The Lord’s creatures, and MH hospitals such as those run by Santa Casa da Misericordia, care centres and asylums were built.
In the 19th century it became accepted that the disease ran in families and was a hereditary disease (1). Inspired in part by the writings of the Dutch physician C. L. Drognat Landré, who based his contagion theory on observations in Surinam (2), the Norwegian physician G. H. Armauer Hansen discovered the leprosy bacillus in 1873 (3). Indeed, Mycobacterium (M) leprae was the first bacillus to be associated with a disease. However, it was not until 1897, at the International Leprosy Conference in Berlin, that consensus was reached on MH being truly an infectious disease (4).
P. G. Unna in the early years of the 20th century showed that M. leprae bacilli were spread by talking and sneezing. Previously, people believed that skin to skin contact with a MH patient could pass on the disease, particularly during sexual contact. In 1977, Dick Rees was the first to show in an animal experiment how easily an infection could be acquired through the nose (5). In humans, only a small number of contacts who acquire M. leprae bacilli develop MH (6).
What we know about MH seems straightforward. MH is a chronic disease caused by a bacillus, M leprae or M. lepromatosis. The bacilli multiply slowly and the incubation period of the disease is on average five years. The disease mainly affects the skin, peripheral nerves, mucosa of the upper respiratory tract, and the eyes. A clinical spectrum is recognized, determined by the host immune response (7,8). MH is treatable with multidrug therapy (MDT).
Why are we unable to get MH under control?
The WHO was convinced that MH would cease to be a public health problem after the year 2000, a deadline which was later extended to 2005 and achieved only on paper and in public opinion. Their failure made me think that we do not know what kind of disease MH actually is. It may not be just an immunological reaction against a mycobacterium which is otherwise known to be harmless, with the immune system causing direct or collateral damage.
Similarly, it was assumed that MH infection spreads from person to person via mucous membranes or the skin, although zoonotic transmission from armadillos has also been implicated (9). But what of recent publications showing the presence of viable M. leprae in the environment, such as in soil and water (bathing pond), living in association with the free-living pathogenic protozoa, Acanthamoeba (10).
In an endemic environment, M. leprae bacilli seem to be everywhere. Most are dead, but a few are viable and able to cause the disease in humans. Dead bacteria predominate, in the form of antigens such as PGL1, lipoarabinomannan and many other specific and non-specific antigens, even as DNA and RNA. These antigens are able to enter the body, to ’infect’, and then to circulate in the blood (11).
The nose can be considered a vacuum cleaner, sucking up bacilli and antigens, which enter the nose and adhere to the nasal mucosa. There they are in close contact with circulating blood (12). When M. leprae are present in a in a pond which is visited to wash the body and clothes, living and dead bacilli, and their antigens, will surely contaminate the skin. They may penetrate the epidermis via small scratches or other breakages. Children sitting with bare buttocks on infected soil or who kneel or fall on this soil may become ’infected’. Armadillos and other animals able to harbour M. leprae will similarly be infected if they inhabit endemic areas. They are victims like human beings and contribute to the pool of infection. It is not known for how long the bacteria will survive in the environment, their survival depending on the conditions of humidity, temperature, soil or by protection by animal, protozoal or other hosts.(13).
Once the antigens or live bacilli have entered the nose or the skin, they will enter the bloodstream, where they are gobbled up by macrophages. Thereafter, they will circulate in the blood and lymph either as antigens or, far outnumbered by the dead, as living bacilli. They may multiply in the macrophages or other phagocytic cells (Schwann cells), at least in those individuals whose host cells can be turned on to sustain M. leprae bacilli. In an experiment of nature, less than 20% of HIV-infected patients with severely depressed adaptive immunity living in a highly endemic environment where they were exposed to live M. leprae developed the disease (6). This suggests there must be some factor other than cell-mediated immunity, a phenomenon first speculated on by Abrahão Rotberg, with his ‘N-factor’ (14).
When antigens and live bacilli circulate in blood and lymph they expose the immune system. Together with the innate, both the humeral as well as the cellular adaptive immune system will react to them, whether the host will develop “MH” or not. Thus, certainly immunological tests and even PCR, there is free circulating M. leprae DNA, may be positive in contacts of M. leprae. Therefore these tests cannot be used to diagnose the disease with 100% certainty. They only show contact!
It is generally believed that Schwann cells in the skin and peripheral nerves are where the bacilli multiply and survive. The question is, how do they get into these nerves? There are no lymph vessels in the endoneurium. It was Graham Weddell (personal communication) who observed that MH-related damage occurs at places where there is movement, such as the wrist, elbow, knee, and ankle. Such movements lead to micro-trauma which the body responds to by sending repair cells, including macrophages. To get these cells into the endoneurium, where the micro-trauma is located, the endothelial cells of the blood vessels in the endoneurium will express adhesion molecules (15).
Macrophages loaded with M. leprae and its antigens will adhere to the endothelial cells, entering via diapedesis into the interstitium of the endoneurium, there coming into contact with Schwann cells (Fig. 1).
M. leprae may then enter the Schwann cell the way Anura Rambukkana suggested, using PGL-1 and other surface molecules, leading to multiplication and/or demyelination (Fig. 2) (16,17). However, some researchers have shown that PGL-1 alone, expressed by macrophages, can cause demyelination (18).
Similarly, Nawal Bahia El Idrissi, Pranab Das and Frank Baas showed that another important M. leprae antigen, lipoarabinomannan, could also cause demyelination by complement activation (membrane attack complex (MAC)) (19,20). These findings suggest that the presence of antigens alone might be a sufficient cause for the segmental demyelination that is the hallmark of MH.
It is important to note that PGL-1 is broken down relatively quickly, whereas lipoarabinomannan may be present for years and continue to cause damage (21). Similarly, Toll-like receptors such as TLR9, which binds to circulating DNA, and TLR1, 2 and 4, which bind to other mycobacterial antigens, may be a persistent cause of MH-related pathology (22).
Another important way in which nerves can be damaged is by the adaptive immune response, stimulated by, and responding to M. leprae antigens or their determinants. Autoimmunity may develop during the initial bacterial infection but could also occur during the so-called reactions (23). There are two types of nerve damage reaction in HD, Type 1 Reaction is due to the cell-mediated immunity; Type 2 Reaction is an immune complex disease (24). During a reaction, damage may be caused by a bystander effect or be due to the reaction specifically directed against antigenic determinants of the cells in the nerve which are identical to M. leprae antigenic determinants (Fig 3) (23,25). An example of a collateral effect are the actions of cytokines on myelin.
M. leprae antigenic determinants may contribute to TNF-mediated inflammation and focal demyelination by rendering Schwann cells more sensitive to TNF within the nerves of affected persons (26).
MH-related damage therefore does not require live bacteria but could be induced by continuous exposure to M. leprae antigens from the environment. This could be considered an autoimmune disease (27). Another cause of damage is purely physical, such as oedema inside the nerve due to inflammation leading to compression of and damage to the axons, because the surrounding perineurium is impermeable. This type of damage can continue when venostatic oedema develops in the endoneurium due to pressure on the inelastic perineurium, where the blood vessels crossing obliquely through the perineurium are compressed, the arterioles hardly, but especially the venules (Fig 4) (28).
In 1943, Fite stated that no MH existed without nerve damage (29). Shetty and Antia reported in 1977 that nerves in early MH and in contacts showed signs of demyelination in nerve conduction studies and histopathology (30). Diogo Fernandes dos Santos presented nerve conduction findings to the 2017 Brazilian leprosy congress, indicating demyelination in contacts with and without positive anti-PGL-1 serology (31). In 2019, Glauber Voltan and Marco Andrey Frade found enlarged nerves in MH contacts using ultrasound (personal communication), with the degree of enlargement in some way associated to the extent of exposure. In these studies, no clinical symptoms related to nerve dysfunction of the involved nerves were demonstrated. It is assumed that clinical symptoms can only be detected when more than 20% of nerve fibres are not functioning.
A historical observation, made just after the Second World War by Stanley Browne in the Belgian Congo (personal communication), was that many MH contacts had hypo-pigmented patches with no obvious sensory loss. These disappeared over time in most of these contacts, and only a small percentage developed clinical MH (32). Pranab Das and Caroline Le Poole suggested that hypopigmentation in MH could be an autoimmune reaction to the melanocytes or their melanin synthesis, as in vitiligo (33).
The common theme underlying all these observations is that there is no need for live bacteria, since contact with antigens is sufficient. However, damage caused by M. leprae antigenic determinants is worse when the contact hosts live M. leprae and the bacilli multiply. Even when these patients have been treated and the treatment has discontinued, there is still remaining lipoarabinomannan and that with continued exposure to environmental M. leprae in endemic settings means further contact with antigens and live bacilli and thus continuing damage.
Regardless of these suggested mechanisms, the adage that 2 out of 3 cardinal symptoms are needed to diagnose MH still holds, namely:
1. Loss of sensation in a skin patch
2. Enlarged nerve
3. Positive skin smear
An enlarged nerve or a hypopigmented patch alone does not diagnose MH, and skin smears alone do not prove it either. Immunological tests only indicate exposure. If only one clinical sign is found the health workers should do their utmost to find a second sign. If that is not possible, the patient should be examined again after a period. If that is not feasible in the field or the health worker does not feel experienced enough (and there is no expert available), then he needs to treat. The possible side effects of treatment outweigh lasting nerve damage and disability. All of the new diagnostic methods only detect individuals who have been in contact with M. leprae, and even this imperfectly. They may detect patients with an active infection with live bacilli, but not all of them.
Serological tests for PGL-1, LID-1 and for any other M. leprae unique antigenic determinants detect antibodies against these determinants from living or dead bacilli or against circulating antigens. The same is the true with tests based on cell-mediated immunity, including the Mitsuda test, lymphocyte transformation test (LTT), and Gamma-interferon test. DNA is everywhere, and even RNA may be present for some time. Therefore, just doing PCR provides only an indication that the positive person was in contact with M. leprae.
Histopathology will show a cellular reaction considered to be specific to M. leprae antigens, but certainly not in all cases. Histopathology is only specific in multibacillary leprosy, when an acid-fast stain is unequivocally positive.
Accordingly, when an abnormality is detected in a contact of a MH patient, does it indicate MH as an infectious disease with live M. leprae or a reaction to M. leprae antigens? Should the reaction in and around nerves, as seen in histopathology, be considered a reaction to antigens or a reaction to living and dividing bacilli? Is it possible to ever be free from contact with live M. leprae and its antigenic determinants in an endemic country?
I think that I noticed fewer relapses in non-endemic than in endemic countries. However, in the non-endemic countries, relapses were present after 10 years or more. Is a patient ’cured’ having completed the prescribed treatment? This should be very much questioned, considering the presence of persisters, enhanced immune-reactivity and reactions to continuous exposure to M. leprae antigenic determinants from the host and from the bacilli in the environment.
Economic development, better medical care and living conditions with sufficient safe drinking and washing water, and less crowding may be more effective than post-exposure chemoprophylaxis and vaccination. Armauer Hansen, visiting emigrants from Bergen in North America in the early 20th Century, noticed that better housing and living conditions meant that MH was no longer spreading and behaving like an infectious disease. Until recently, immigrants in north-west European countries did not spread MH in their new countries. However, in the current situation in which immigrants are only just surviving in camps and living ‘illegally’ in crowded unhygienic locations in Europe and America, M. leprae has the potential to spread and will very likely lead to secondary cases (34).
The economic elite in Western countries must therefore create better socio-economic circumstances for immigrants or, from a human rights and dignity perspective, develop a test that indicates who may be at risk of developing infectious MH and provide curative treatment or lifelong prophylaxis.
1. Danielssen D C, Boeck W, Losting JL. Om Spedalskhed . Christiania : Chr. Gröndahl. 1847.
2. Drognat Landré CL. De la contagion, seule cause de la propagation de la Lèpre. Paris: Bailliere; 1869.
3. Hansen GHA. Undersøgelser Angående Spedalskhedens Årsager. Norsk Mag. Laegervidenskaben. 1874;1–88.
4. Menke, H. E., Faber, W. R., & Pieters, T. Contribution from a Dutch colony to the discovery of the leprosy Bacterium Leprosy Review, Charles Louis Drognat Landré and Gerhard Hendrik Armauer Hansen; 2010;82–6.
5. Rees RJ, McDougall AC. Airborne infection with Mycobacterium leprae in mice. J Med Microbiol. fevereiro de 1977;10(1):63–8.
6. Naafs B. World leprosy day 2018: How forward respecting the past? Indian J Med Res. 1o de janeiro de 2018;147(1):1.
7. Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis. 1966;34(3):255-73.
8. Leiker DL. Classification of leprosy. Lepr Rev.1966 Jan;37(1):7–15.
9. da Silva MB, Portela JM, Li W, Jackson M, Gonzalez-Juarrero M, Hidalgo AS, et al. Evidence of zoonotic leprosy in Pará, Brazilian Amazon, and risks associated with human contact or consumption of armadillos. PLoS Negl Trop Dis. 2018;12(6):e0006532.
10. Turankar RP, Lavania M, Darlong J, Siva Sai KSR, Sengupta U, Jadhav RS. Survival of Mycobacterium leprae and association with Acanthamoeba from environmental samples in the inhabitant areas of active leprosy cases: A cross sectional study from endemic pockets of Purulia, West Bengal. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis. 2019;72:199–204.Epub 2019 Jan 15.
11. Nikkari S, McLaughlin IJ, Bi W, Dodge DE, Relman DA. Does blood of healthy subjects contain bacterial ribosomal DNA? J Clin Microbiol. maio de 2001;39(5):1956–9.
12. Fokkens WJ, Nolst Trenite GJ, Virmond M, KleinJan A, Andrade VL, van Baar NG, et al. The nose in leprosy: immunohistology of the nasal mucosa. Int J Lepr Mycobact Dis Off Organ Int Lepr Assoc. setembro de 1998;66(3):328–39.
13. Wheat WH, Casali AL, Thomas V, Spencer JS, Lahiri R, Williams DL, et al. Long-term survival and virulence of Mycobacterium leprae in amoebal cysts. PLoS Negl Trop Dis. 2014;8(12):e3405. Published 2014 Dec 18. doi:10.1371/journal.pntd.0003405
14. Rotberg A. Some aspects of immunity in leprosy and their importance in epidemiology, pathogenesis and classification of forms of the disease. Rev. Bras. Leprol. 5 (1937) 45-97
15. Scollard DM. Endothelial cells and the pathogenesis of lepromatous neuritis:insights from the armadillo model. Microbes Infect. dezembro de 2000;2(15):1835–43.
16. Rambukkana A, Zanazzi G, Tapinos N, Salzer JL. Contact-dependent demyelination by Mycobacterium leprae in the absence of immune cells. Science. 3 de maio de 2002;296(5569):927–31.
17. Rambukkana A. Mycobacterium leprae-induced demyelination: a model for early nerve degeneration. Curr Opin Immunol. agosto de 2004;16(4):511–8.
18. Madigan CA, Cambier CJ, Kelly-Scumpia KM, Scumpia PO, Cheng T-Y, Zailaa J, et al. A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell. 24 de agosto de 2017;170(5):973-985.e10.
19. Bahia El Idrissi N, Das PK, Fluiter K, Rosa PS, Vreijling J, Troost D, et al. M. leprae components induce nerve damage by complement activation: identification of lipoarabinomannan as the dominant complement activator. Acta Neuropathol (Berl). maio de 2015;129(5):653–67.
20. Bahia El Idrissi N, Iyer AM, Ramaglia V, et al. In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin. PLoS One. 2017. PMID: 28505186
21. Verhagen C, Faber W, Klatser P, et al. Immunohistological analysis of in situ expression of mycobacterial antigens in skin lesions of leprosy patients across the histopathological spectrum. Association of Mycobacterial lipoarabinomannan (LAM) and Mycobacterium leprae phenolic glycolipid-I (PGL-I) with leprosy reactions. Am J Pathol. 1999 Jun;154(6):1793-804.
22. Polycarpou A, Holland MJ, Karageorgiou I, et al. Mycobacterium leprae Activates Toll-Like Receptor-4. Signaling and Expression on Macrophages Depending on Previous Bacillus Calmette-Guerin Vaccination. Front Cell Infect Microbiol. 2016;6:72. Published 2016 Jul 8. doi:10.3389/fcimb.2016.00072
23. Naafs B, Kolk AH, Chin A Lien RA, Faber WR, Van Dijk G, Kuijper S, et al. Anti-Mycobacterium leprae monoclonal antibodies cross-react with human skin: an alternative explanation for the immune responses in leprosy. J Invest Dermatol. maio de 1990;94(5):685–8.
24. Naafs B. Leprosy reactions. New knowledge. Trop Geogr Med. 1994;46(2):80–4.
25. Singh I, Yadav AR, Mohanty KK, Katoch K, Sharma P, Mishra B, et al. Molecular mimicry between Mycobacterium leprae proteins (50S ribosomal protein L2 and Lysyl-tRNA synthetase) and myelin basic protein: a possible mechanism of nerve damage in leprosy. Microbes Infect.2015;17(4):247-57
26. Andrade PR, Jardim MR, da Silva ACC, Manhaes PS, Antunes SLG, Vital R, et al. Inflammatory Cytokines Are Involved in Focal Demyelination in Leprosy Neuritis. J Neuropathol Exp Neurol. 2016;75(3):272-283. doi:10.1093/jnen/nlv027
27. Iversen R, Sollid LM. Autoimmunity provoked by foreign antigens. Science. 10 de 2020;368(6487):132–3.
28. Naafs B., Van Droogenbroeck J.B.A. Décompression des névrites réactionnelles dans la lèpre: Justification physiopathologique et méthodes objectives pour en apprécier les résultats. Méd. Trop. 37 (1977) 763-770
29. Fite GL. Leprosy from histopathologic point of view. Arch Pathol Lab Med 1943. 35:611–44.
30. Shetty VP, Mehta LN, Antia NH, Irani PF. Teased fibre study of early nerve lesions in leprosy and in contacts, with electrophysiological correlates. J Neurol Neurosurg Psychiatry. julho de 1977;40(7):708–11.
31. Santos DF dos. Aspectos clínicos, moleculares, sorológicos e neurofisiológicos no diagnóstico precoce da neuropatia hansênica. 28 de agosto de 2017 [citado 30 de julho de 2020]; Disponível em: https://repositorio.ufu.br/handle/123456789/19892
32. Leprosy. Documenta Geigy: Acta clinica , Ciba-Geigy, 1984. 1984.
33. Das PK, van den Wijngaard RM, Wankowicz-Kalinska A, Le Poole IC. A symbiotic concept of autoimmunity and tumour immunity: lessons from vitiligo. Trends Immunol. 2001;22(3):130-6
34. Alemu Belachew W, Naafs B. Position statement: LEPROSY: Diagnosis, treatment and follow-up. J Eur Acad Dermatol Venereol. 1o de julho de 2019;33(7):1205–13.