Research Article: Leprosy Diagnostic Test Development As a Prerequisite Towards Elimination: Requirements from the User’s Perspective

Date Published: February 11, 2016

Publisher: Public Library of Science

Author(s): Edith Roset Bahmanyar, William Cairns Smith, Patrick Brennan, Ray Cummings, Malcolm Duthie, Jan Hendrik Richardus, Paul Saunderson, Tin Shwe, Steven Rosen, Annemieke Geluk, Christian Johnson.

Abstract: None

Partial Text: Leprosy is the complex disease manifestation of Mycobacterium leprae infection. Although prevalence has declined from 5.2 million globally in the 1980s, new annual case detection rates (CDRs) remain high, at more than 200,000 new cases per year [1], indicating that additional leprosy control strategies are required to halt transmission.

Currently, leprosy is mainly diagnosed by expert clinicians using defined criteria, along with the use of slit-skin smears and biopsies [5]. As the prevalence of the disease is decreasing, clinical expertise is diminishing, leading to extended delays between onset of clinical signs and diagnosis and consequent maintenance of transmission of M. leprae. Hence, efforts to achieve elimination are undermined. In recognition of the need to move from leprosy control to preventing infection, an ideal test would identify M. leprae-infected individuals at risk of developing disease and/or who contribute to transmission. However, given the challenge of developing such a test in the absence of a gold standard, a two-step approach could prove to be a more expeditious strategy: first, obtaining a test to help health care workers in their clinical diagnosis and decision-making process for treatment while, over a longer term, another test to identify infected individuals would be developed. As part of the requirements, two intended uses (IU) for the tests were defined, based on end-user requirements (Table 1).

Receiving a leprosy diagnosis bears significant social implications related to stigma and medical implications due to the long treatment duration. Therefore, deploying a diagnostic test (for IU1 or IU2) that is not perfect requires a coherent strategy to manage positive results. An example of recommendations for programme guidelines is defined in Table 2.

Based on SIMCOLEP (individual-based mathematical model), analyses targeting household contacts have shown that the effects on disease incidence in the whole population vary with type of intervention, such as contact tracing, provision of chemoprophylaxis, Bacillus Calmette-Guerin (BCG) vaccination, and early (preclinical) diagnosis [6]. The model has been developed to include the indirect effect of interventions targeting contacts on the transmission of M. leprae in the whole population [7].

High-risk populations have been identified as an optimal target for a diagnostic test. This would require national leprosy programmes to intensify their surveillance systems in order to trigger prompt and targeted testing of high-risk clusters. Individual geographic information and spatial analysis have already been evaluated to define spatiotemporal patterns of leprosy [9], but they would need to become integrated into systematic national surveillance systems, requiring substantial investment. Introducing a new diagnostic test with IU2 could certainly help to achieve leprosy elimination, but it would require a strong commitment from policy makers and donors.

The required attributes for the two IUs of a leprosy diagnostic test, derived mainly from the results of the discussion in the meeting, are summarised in Table 4. The test would diagnose both Multi-bacillary (MB) and Pauci-bacillary (PB) forms of leprosy [5].

A review of leprosy biomarkers reveals that the ideal diagnostic biomarker is not currently available to fulfill the requirements of the target product profile [13]. Past and ongoing research is covering markers for different ends of the leprosy spectrum. Lepromatous Leprosy (LL/BL) is characterised by a very robust antibody response, whereas Tuberculoid Leprosy (TT/BT) is characterised by hardly any humoral immunity but much stronger cellular immunity. In addition, M. leprae-infected individuals without disease symptoms may vary in their biomarker profile [14,15]. Both cellular and humoral immunity against M. leprae determine the outcome of infection. Thus, tests that simultaneously detect biomarkers specific for both types of immune responses are the targets for a test for detection of asymptomatic M. leprae infection and hence progression of infection to clinical disease [16].

In conclusion, in the absence of a perfect test to detect all M.leprae-infected individuals, a diagnostic test to confirm leprosy disease at an early stage among symptomatic patients would be an acceptable and certainly useful shorter-term compromise. In parallel, it is critical that stakeholders continue promoting the concept that zero transmission is only attainable if M.leprae infection can be measured, and correspondingly invest in longitudinal research to identify biomarkers for the diagnosis of asymptomatic infection as well as for the risk of developing disease.



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