Section 2 -

Changing Definitions of Leprosy: Inclusion, Exclusion, and Elimination David Scollard National Hansen's Disease Programs Laboratory Research Branch at LSU Baton Rouge, LA

What is leprosy? The definitions of this disease provide benchmarks in the evolving medical and scientific understanding of leprosy. These definitions, however, are sometimes at odds with popular understanding of the disease, and occasionally with the science itself. Stigmatized for millennia as a curse, leprosy has affected all major racial groups and inhabited continents. Scandinavian countries were highly endemic in the mid1800's, and so the first definition of leprosy in modern Western medicine came from Norway in 1847, in the form of an Atlas of Leprosy, by Daniellsen and Boeck [1]. They recognized that a wide variety of dermatological findings were all manifestations of this single disease. They did not have an explanation for its etiology, however, and concluded that it was familial based on the fact that it was often observed to cluster in families. (The molecular genetic basis for this observation began to be elucidated more than 100 years later, with major contributions from laboratories at McGill University, here in Montreal [2, 3] ). The microbiological basis for leprosy was identified by G.A. Hansen, also in Norway , in 1874 [4]. Leprosy could now be defined as a disease caused by a germ, not a divine curse. Today this is heralded as a scientific milestone but, providing no remedy, it was of little value to patients at the time. The degree of contagiousness of leprosy was heatedly debated in medical and scientific meetings in the late 1800's – early 1900's [5]. However, being incurable, and assumed by social and political leaders to be highly contagious, harsh segregation/ quarantine laws were passed in many countries in the following decades. The draconian nature of these segregation policies still remains the subject of scholarly research, fictional and non-fiction accounts, and popular journalism [6, 7]. The definitive epidemiologic studies of the natural course of leprosy were conducted by Doull & Guinto and colleagues in Cebu, Philippines , in the 1930's [8]. They found that leprosy had a long incubation time, and was not highly contagious. Changes in quarantine laws lagged decades behind these observations, however. Leprosy was still an incurable infectious disease, and M. leprae remained non-cultivable, hampering efforts to test newly developed anti-microbial agents. In the mid 1940's, clinicians at the USPHS Hospital at Carville, La, first observed the remarkable efficacy of a sulfone, promine [9], and later it's orally administered derivative, dapsone. Initially, world experts were hesitant to accept the results, but by 1950 it was recognized that leprosy was curable. Soon dapsone was employed around the world: the drug was effective, well tolerated, and inexpensive, although lifetime treatment was required for many patients. These characteristics led to unwarranted assumptions of easy victory over this disease, and control efforts were often poorly organized and supervised. Although the infection was now curable, its widely diverse clinical and pathological manifestations and neurological complications remained a tangled, scientific puzzle. Numerous clinical classification schemes were promulgated, but they were all descriptive and lacked an organizing principle. In 1964, Skinsnes [10] provided the first full formulation of the concept of an immunopathologic spectrum of host responses to M. leprae. This provided a sound theoretical foundation for understanding this disease, and remains the organizing concept for leprosy research as well as the yardstick against which all new immunological hypotheses about leprosy are tested. In 1966, Drs. Ridley and Jopling published a practical classification syste [11], using reproducible clinical and histological criteria and based on the concept of the immunopathologic spectrum. Almost simultaneously, cellular immunologists discovered T cells, and they found the immunopathologic spectrum of leprosy to be an inviting and extraordinary model. An 'immunologic defect' was added to the definition of leprosy. Research on leprosy flourished in the 1970's and 80's [12]: numerous publications purported to explain the immunologic defect, and funding agencies were assured that a leprosy vaccine was imminent [13, 14]. The difficulty of immunizing individuals with an immunologic defect was often discussed informally but was not a critique welcomed by medical journals. The World Health Organization's leprosy office had long collected global data on leprosy registries, but the data were widely considered unreliable; a major concern was that once added to a registry, patients were never removed, even after they were cured. Monotherapy with dapsone was the global standard, and in the 1960's the first reports of resistance to dapsone were published [15], confirmed by later studies using the newly developed mouse footpad technique [16]. In 1982 a WHO expert committee recommended multi-drug treatment [17] to forestall the development of widespread primary dapsone resistance. The MDT campaign emphasized training (concerning diagnosis, treatment, and follow up), implementation of MDT, and removal of cured patients from the registries. Initial results were highly encouraging: 'prevalence' (the number of registered cases) fell dramatically. Further analysis, however, indicated that 'incidence' (the number of new cases identified) had not declined [18]. Buoyed by the apparent success of the MDT program, the WHO proposed the Elimination of Leprosy as a Public Health Problem by the year 2000 [19]. "Elimination' was defined as prevalence <1/10,000. A case of leprosy was defined as "a person with characteristic clinical signs and symptoms . . . who had not received a full course of recommended treatment". The WHO determined what constituted a full course of treatment, and has shortened it more than once since the inception of the campaign. Disabilities were not considered in this definition. Leprosy had not been eliminated by 2000, nor by 2005. In 2005 India had the greatest number of cases of any country in the world [20]. In early 2006, the government of India reported that the country had met WHO goals, and officially declared that leprosy had been eliminated as a public health problem. The operating definition of leprosy for the last several years has been WHO's definition, applied in the context of great pressures to reach bureaucratically determined 'elimination' goals. These efforts are sometimes at odds with local conditions, and with scientific evidence -- epidemiological, microbiological, and immunological. Although molecular and genomic research have made remarkable advances [21], major medical and scientific challenges remain [21]. Clinically, for example, HIV-AIDS has not been associated with an increase in leprosy, although other modes of immunosuppression clearly do increase susceptibility. An immune reconstitution syndrome occurs in patients with AIDS and leprosy after treatment with HAART, and also after discontinuing infliximab treatment in patients with leprosy and arthritis [22]. Worldwide support for research and treatment programs has declined markedly [12]. Due to reduced resources and related factors, available epidemiological data are now probably less and less accurate, reprising the situation in the 1950's. Some African countries which had 'eliminated' leprosy are now observing a rising number of new cases. Best estimates are that this year, 500-700,000 new cases will occur globally, but most endemic countries are reducing services for diagnosis, treatment, and follow up based on official estimates that the number of patients in their country is declining [23]. This pattern of action is highly reminiscent of the failed global campaigns to eliminate malaria and tuberculosis. References Daniellsen , D.C., and Boeck, CW. Om Spedalskhed. Christiana , Norway, 1847. Abel, L., F. O. Sanchez, J. Oberti, N. V. Thuc, L. V. Hoa, V. D. Lap, E. Skamene, P. H. Lagrange, and E. Schurr. 1998. Susceptibility to leprosy is linked to the human NRAMP1 gene. J Infect Dis 177:133-45. Mira MT, Alcais A, Nguyen VT, Moraes MO, et al. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature. 427: 636-40, 2004. Hansen, G.A. Spedalskhedens Arsager. Norsk Mag Laegevidensk 4: 36-79, 1874. Pandya, S.S. The first international leprosy conference, Berlin, 1897: the politics of segregation. Historia, Ciencias, Saude – Manguinbos, 10 (Suppl. 1): 161-177, 2003. Gussow, Z. Leprosy, Racism, and Public Health. Westview Press, Boulder, CO, 1989. Sato, H., and Narita, M. Politics of leprosy segregation in Japan: the emergence, transformation, and abolition of the patient segregation policy. Social Science and Medicine 56: 2529-2539, 2003. Doull, JA, Guinto, RS, Rodriguez, JN, and Bancroft, H. Risk of attack in leprosy in relation to age at exposure. Am J. Trop. Med. 25: 435-44, 1945. Faget, G.H., Pogge, RC, Johansen, FA, Dinan, JF, Prejean, BM, and Eccles, CG. The promin treatment of leprosy. Public Health Reports 58: 1729-41, 1943. Skinsnes, O.K. The Immunological Spectrum of Leprosy. In Leprosy in Theory and Practice, R. G. Cochrane and T. F. Davey, eds, John Wright & Sons Ltd., Bristol, 1964, p 156-189. Ridley, D.S., and Jopling, W.H. "Classification of leprosy according to immunity. A five-group system." Int. J. Lepr. 34: 255-273. 1966. Scollard, DM Leprosy research declines, but most of the basic questions remain unanswered. Int. J. Lepr. 73:25-27, 2005. Bloom , BR. Learning from leprosy: a perspective on immunology and the Third World. J. Immunol. 137: i-x, 1986. Bloom BR, Jacobs WR Jr, Clark-Curtiss JE. Leprosy Vaccine. Nature 368: 579, 1994. Petit, JH, and Rees, RJW. Sulfone resistance in leprosy. Lancet ii: 673-674, 1964 Shepard, C. C., R. J. Rees, L. Levy, S. R. Pattyn, J. Baohong, and E. C. Dela Cruz . 1986. Susceptibility of strains of Mycobacterium leprae isolated prior to from patients with previously untreated lepromatous leprosy. Int J Lepr Other Mycobact Dis 54:11-5, 1977. World Health Organization Study Group on Leprosy. Chemotherapy of leprosy control programmes (WHO Technical Report Series 675). Geneva , WHO, 1982. Lockwood, D. N. and S. Suneetha. Leprosy: too complex a disease for a simple elimination paradigm. Bull World Health Organ 83:230-5, 2005. World Health Assembly. Elimination of leprosy. Resolution 44.9, 13 May, 1991. Handbook of resolutions and decisions of the World Health Assembly and the executive board. Vol III, 1985-92, 3rd ed, Geneva , WHO, 117-118, 1993. WHO. Weekly Epidemiological Record No. 34: 80: 289-296, 2005. Scollard DM, Adams LB, Gillis TP, Krahenbuhl JL, Truman RW, Williams DL. The continuing challenges of leprosy. Clin Microbiol Rev. 19: 338-81, 2006. Scollard, D.M., Joyce, M.P., and Gillis, T. P. Development of Leprosy and Type 1 Leprosy Reactions After Treatment with Infliximab: A report of two cases. Clin. Inf. Dis., in press, 2006. Rao, PN. Leprosy program in India at the crossroads. Int J. Lepr. 73: 211-215, 2005.