Disease Watch Focus: Leprosy
BACKGROUND
CAUSATIVE AGENT. Leprosy is a chronic disease caused by the noncultivable, slow-growing, acid-fast bacterium Mycobacterium leprae. It is thought to be transmitted from human to human by nasal droplets, as distinct from the transmission of Mycobacterium tuberculosis. Leprosy lesions have been reported to develop at the site of skin abrasions. Naturally occurring M. leprae infection has been reported in wild animals, including the nine-banded armadillo in the New World, and several species of monkeys in Africa. In humans, M. leprae primarily infects macrophages, endothelial cells and Schwann cells. The unique tropism of M. leprae for peripheral nerves leads to the classical deformities that have been described over the ages.
DISTRIBUTION. In 1992, 88 countries reported more than one leprosy patient receiving treatment per 10,000 population. In 2003, leprosy is still found in nine high-burden countries, which report prevalence rates between 2.0–4.1 per 10,000 population. In an additional three countries, the prevalence rates are between 1 to 2 cases per 10,000 population. The recent prevalence figures represent a drastic reduction from the World Health Organization (WHO) estimates of 10–12 million cases globally in the early 1980s — the time when multi-drug therapy (MDT) was recommended to treat leprosy. More than 12 million leprosy patients have been cured by MDT treatment since 1981.
CURRENT GLOBAL STATUS. The implementation of the WHO-recommended MDT for leprosy treatment has been very successful over the past 22 years. At present, more than 99% of registered patients are receiving MDT, and no drug resistance or significant relapses have been reported. As the average incubation time from initial infection to clinical disease is unknown, it is assumed that a significant number of ‘subclinical’ or the detection rates of new cases have remained approximately stable over the past decade. In January 2003, there were 534,311 cases globally, and during 2002, 620,672 new cases were reported. The global mortality from leprosy is estimated to be ~4,000 individuals per year.
RECENT DEVELOPMENTS
NEW BASIC KNOWLEDGE. The inability to cultivate M. leprae in vitro and the lack of a suitable animal model have hampered leprosy research. However, the availability of the M. leprae genome sequence [1] has stimulated several research studies and new approaches to improve our understanding of leprosy [2].On the basis of recently available human genome sequence data, gene expression patterns associated with an ongoing host immune response in lesions of human leprosy have been defined [3]. Recently, a genome-wide search for loci controlling susceptibility to leprosy in a Vietnamese population provided evidence for a susceptibility gene on chromosome region 6q25 (REF. 4).A relationship between singlenucleotide polymorphisms in the genes encoding tumour necrosis factor-a interleukin-10 and the development of paucibacillary leprosy has been shown [5].We now have a greater appreciation of the functions of mycobacterial lipids, including the knowledge that mycobacterial lipoproteins can trigger host-defence mechanisms through Toll-like receptors [6–8] and that the M. leprae-specific phenolic glycolipid has a specific role in determining tissue tropism, leading to Schwann cell infection [9,10].
NEW TOOLS AND INTERVENTION METHODS. The development of new tools to diagnose exposure to, or infection with, M. leprae has been boosted by the availability of the M. leprae genome sequence [1]. It has been shown that there are variable numbers of TTC repeats in a non-coding region of the genome of M. leprae strains [11]; strain differentiation based on these TTC repeats or single-nucleotide polymorphisms could be of great epidemiological value in identifying the infectious sources of leprosy and gaining a better understanding of transmission patterns. Leprosy-specific proteins and peptides are showing great potential as T-cell reagents that could be formulated either as skin-test reagents or as antigens to be used in in vitro testing, and which could be used to monitor exposure to M. leprae within communities. A simple, robust and rapid lateral-flow test for the detection of immunoglobulin M antibodies to the M. leprae-specific phenolic glycolipid I has recently been proposed for use in the classification of leprosy patients and the identification of contacts at a high risk of developing leprosy [12]. A genotypic method for the rapid detection of rifampicin-resistant isolates of M. leprae has been rigorously tested in the laboratory but remains to be validated under field conditions [13].
NEW STRATEGIES, POLICIES AND PARTNERSHIPS. The present WHO strategy for the elimination of leprosy as a public health problem is based on the early detection and cure of cases with MDT.An important problem is that leprosy diagnosis and treatment is often a highly centralized activity, conducted by specialized staff. Implementation of a more simplified approach to diagnosis and treatment is needed, using general health workers at the village level. A uniform MDT regimen of 6 months for the treatment of all leprosy patients would facilitate integration and help ensure the sustainability of leprosy control. Its evaluation is under way, but the results will not be available for at least 5 years. The concept of ‘accompanied MDT’ has been proposed as a means of helping integrate leprosy control activities, and would entail the patient taking some or all of their medication home to be taken under supervision. Again, this approach must be validated through formal research studies. The private-public partnership that presently exists between the WHO and Novartis to provide free anti-leprosy drugs to all leprosy patients globally provides an excellent example of teamwork in the public health arena.
CONCLUSIONS AND FUTURE OUTLOOK
The WHO-recommended MDT regimen has had a significant impact in reducing the global burden of leprosy. However, the risk remains that governments and health workers will become complacent, delaying or jeopardizing the final steps in the elimination strategy. Healthcare workers and researchers should continue to support the intensive implementation of the elimination strategy and address the issues related to the detection of M. leprae-infected individuals as a matter of urgency.
Leprosy research should be focused on developing new tools to support elimination efforts, in particular the development of tests for leprosy exposure (both skin tests and simple blood tests), tests for the prediction of reactions and a better means of controlling nerve damage. Leprosy researchers should strengthen links with the tuberculosis research community, as many of the concepts and challenges are the same. In the long term, research could provide tools for monitoring transmission, the reactivation of disease, the detection of sources of infection, and the emergence of drug-resistant leprosy strains.
References:
- Cole, S. T. et al. Nature 409, 1007–1011 (2001).
- Vissa, V. D. and Brennan, P. J. in Genomics of GC-Rich Gram-Positive Bacteria. (ed. A. Danchin) 84–118 (Caister Academic Press, UK, 2002).
- Bleharski, J. R. et al. Science 301, 1527–1530 (2003).
- Mira, M. T. et al. Nature Genet. 33, 412–415 (2003).
- Santos, A. R. et al. J. Infect. Dis. 186, 1687–1691 (2002).
- Brightbill, H. D. et al. Science 285, 732–736 (1999).
- Oliveira, R. B. et al. Infect. Immun. 71, 1427–1433 (2003).
- Krutzik, S. R. et al. Nature Med. 9, 525–532 (2003).
- Ng, V. et al. Cell 103, 511–524 (2000).
- Rambukkana, A. et al. Science 296, 927–931 (2002).
- Shin, Y. C. et al. J. Clin. Microbiol. 38, 4535–4538 (2000).
- Bührer-Sékula, S. et al. J. Clin. Microbiol. 41, 1991–1995 (2003).
- Honore, N. et al. Lepr. Rev. 72, 441–448 (2001).