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Leprosy continues to be a challenge to health worldwide, with about 250 000 new cases being detected every year.
Despite widespread implementation of eective multidrug therapy, leprosy has not been eliminated. A third of newly
diagnosed patients have nerve damage and might develop disabilities, although the proportion varies according to
several factors, including level of self-care. Women who develop leprosy continue to be especially disadvantaged, with
rates of late diagnosis and disability remaining high in this subgroup. Leprosy was not a specied disease in the
Millennium Development Goals, but improvements in the other areas they cover, such as education and levels of
poverty, will help leprosy patients and services. We review data and make recommendations for research on diagnosis,
treatment, and prevention, such as further use of molecular analysis of the Mycobacterium leprae genome,
implementation of BCG vaccination, and administration of chemoprophylaxis to household contacts. We also suggest
development of tools for early diagnosis and detection of infection and nerve damage, and formulation of strategies
to manage the chronic complications of leprosy, such as immune-mediated reactions and neuropathy.
Introduction
Leprosy is the leading infectious cause of disability.1
Prevalence has fallen substantially in the past 50 years,2 but
transmission continues and leprosy remains a public health
problem.3 Various hindrances remain to reducing this
prevalence further. The mode of transmission of leprosy is
not well understood, although it is probably person to
person via nasal droplets.4 How many infected people
develop clinical disease and whether reactivation of past
infections is important are unknown. Although making a
clinical diagnosis is frequently straightforward, no good
point-of-care test is available for conrming it. Delay in
diagnosis can have important negative outcomes, such as
increased risk of nerve damage. Various factors contribute
to delay, but stigma is an important feature in many
cultures.5 Additionally, the immune responses and the
mechanisms involved in nerve damage are not clearly
understood; there is no predictive test for the extent of nerve
damage and no good evidence on the best treatment. Type 1
and type 2 immune-mediated reactions continue to be
major complications, and aect around 30% of patients.
WHO has set a target for reducing the number of cases
with grade 2 disability at diagnosis, but the feasibility of
reporting disability accurately needs to be assessed. The
integration of leprosy services into general health services
has led to a loss of skills in the diagnosis and management
of leprosy. WHO recommends multidrug therapy for
6 months in patients with paucibacillary disease (up to
ve skin lesions) and for 12 months in patients with
multibacillary disease (more than ve skin lesions).3 These
regimens might, however, be insucient for patients with
lepromatous disease and high bacterial indices, and no
alternative drug regimens are currently recommended.6
Drug resistance has not so far been an issue with
multidrug therapy,7 but monitoring is essential.
Various areas of research are a priority in the worldwide
management of leprosy. Contacts of leprosy patients are
at increased risk of infection;8 chemoprophylaxis and
BCG vaccination reduce this risk but the logistics, ethics,
Review
Epidemiology
The new case detection rate for leprosy remains high,
with about 250 000 new cases being registered each year.
Around 15 million people have been treated with
multidrug therapy, and an estimated 2 million people
have been prevented from developing disabilities.12
Although the leprosy prevalence values fell strikingly
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Prevalence
Incidence
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Figure: Incidence (new-case detection rate) and prevalence of leprosy in (A) India22 and (B) Brazil23
Review
Transmission
Leprosy is caused by M leprae. Most people infected with
this organism are thought not to develop clinical disease,
although there are no tools to diagnose subclinical
infection. M leprae is slow growing and the incubation
period of leprosy is long at 212 years. The mode of
transmission is still not conclusively proven, although
person-to-person spread via nasal droplets is believed to
be the main route.4
Human beings are the principal reservoir of infection,
except in the Americas, where armadillos also provide a
reservoir;26 the proportion of cases attributable to
armadillos is unknown, but progress is being made in the
estimation and two-thirds of acquired cases in southern
USA have armadillo-derived strains of M leprae in the
lesions.27 Most people with leprosy are non-infectious as
the mycobacterium remains intracellular. Patients with
lepromatous leprosy, however, excrete M leprae from their
nasal mucosa and skin28 and are infectious before starting
treatment with multidrug therapy. Contacts of these
patients are, therefore, at increased risk of developing
leprosy.7 The magnitude of this risk depends on the
closeness of contact,7 with close household contacts being
at the highest risk. The risk of disease in contacts is also
related to the bacterial load of the primary case, with the
risk being twice as high in contacts of multibacillary cases
as in those of paucibacillary cases.
Whether genetic predisposition has a role in the
development of leprosy is unclear.7 Gene candidates for
susceptibility to leprosy infection have been reported, but
replication of these ndings has been dicult. A genomewide association study of leprosy patients and healthy
controls identied new associations between variants of
genes in the NOD2-mediated signalling pathway, which
regulates the innate immune response, and determines
the risk and form of disease.7
The genome sequence of M leprae has been available
since 2001.29 Work on strain typing of M leprae has used
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Clinical disease
Infection with M leprae leads to chronic granulomatous
inammation in skin and peripheral nerves. The type of
leprosy that patients develop is determined by their cellmediated immune response to infection. Types may be
categorised according to the Ridley-Jopling classication,33
which is based on skin lesion type and bacterial load.
Patients with tuberculoid disease have good cell-mediated
immune response and few lesions with no detectable
mycobacteria. Patients with lepromatous leprosy are
anergic towards M leprae and have multiple lesions with
mycobacteria present. Between these two classications
are the borderline leprosy types, in which patients have
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Review
Treatment
WHO recommends multidrug therapy with rifampicin
and dapsone for paucibacillary disease, or with
rifampicin, dapsone, and clofazimine for patients with
multibacillary disease. The recommended duration of
therapy is 6 months for patients with paucibacillary
disease and 12 months for those with multibacillary
disease, and these regimens will eectively eradicate
M leprae in most patients. The 2009 report of the WHO
Technical Advisory Group on Leprosy Control stated
clearly that in public health terms, it is reasonable to
conclude that infectiousness becomes unlikely after
starting multidrug therapy.6 Longer treatment might,
however, be required in some patients with a high
bacterial index at diagnosis to prevent relapse.6 At least
one current trial is comparing dierent durations of
treatment for multibacillary leprosy.6
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Review
Diagnosis
Late diagnosis leads to continued transmission and to
increased risk of disability.15 Factors associated with late
diagnosis include delay by patients in presenting and delay
by health services in making a diagnosis. Reasons behind
patients delaying presentation vary from setting to setting,56
but stigma is likely to play a part in many cases.5 In some
countries stigma is promoted by legislation against leprosy
patients.5 Other inequalities also aect people with this
disease. Reports from Ethiopia and Bangladesh57,58 have
shown that women experience longer delays than men in
diagnosis and, therefore, frequently have a higher degree
of nerve damage and disability at diagnosis.
With decentralisation of treatment and monitoring
and decreasing numbers of cases, the maintenance of
expertise in leprosy at the peripheral level is a major
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Prevention
Chemoprophylaxis eectively lowers the incidence of
leprosy in household contacts.61 Whether to use this
approach more widely is under discussion. Single-dose
rifampicin can prevent progression of disease in people
infected with leprosy but only in non-close contacts
with low bacterial loads.61 Fears of resistance with use of
monotherapy, however, have led to the suggestion that
one or two doses of 600 mg rifampicin, 400 mg
ooxacin, and 100 mg minocycline should be used.5
This regimen would, however, be far more expensive.
The extension of chemoprophylaxis to close nonhousehold contacts is supported by a good
epidemiological argument, but various practical issues
could hinder implementation of this policy. For
example, disclosure of leprosy in the index case required
for identication of contacts, especially outside the
home, might be undesirable or unethical.61 The current
recommendation in WHOs Enhanced Global Strategy
for Further Reducing the Disease Burden due to
Leprosy10 is to examine household contacts of patients
for evidence of leprosy, if none is found to educate the
contacts on early signs of disease, and to return if these
develop. The latest report from WHOs Technical
Advisory Group on Leprosy Control6 recommends that
a working group be formed to review the present data
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Review
Conclusions
Priorities for research in leprosy cover a wide range of
areas, from basic science to health services. Further
understanding is needed of the epidemiology, including
transmission, the role of the armadillo, and relative
contributions of transmission and reinfection to the
overall disease burden, and of the pathogenesis of nerve
damage. Eective tools must be developed for detection
of early infection, for point-of-contact diagnosis, to
predict nerve damage, and to grade disability. New
treatment regimens for leprosy and for immune-mediated
reactions need to be developed and thoroughly tested.
Finally, eective methods for monitoring drug resistance
have to be implemented. For prevention and health
services research, development of a new vaccine or
incorporation of a leprosy component into new
antituberculosis vaccines is crucial. Delivery strategies
for chemoprophylaxis of contacts need to be assessed,
and delays to diagnosis, discrimination, and stigma must
be substantially reduced. We hope that researchers and
funding will be available to take up these challenges.
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