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Update on the epidemiology, diagnosis, and

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DOI: 10.1016/j.medmal.2015.09.002

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Médecine et maladies infectieuses 45 (2015) 383–393

General review

Update on the epidemiology, diagnosis, and treatment of leprosy

La lèpre : actualités épidémiologiques, diagnostiques et thérapeutiques
F. Reibel a,b,c , E. Cambau d,e,f , A. Aubry a,b,c,∗
a Sorbonne universités, UPMC Univ Paris 06, CR7, Centre d’immunologie et des maladies infectieuses, CIMI, team E13 (Bacteriology), 75013 Paris, France
b Inserm, U1135, centre d’immunologie et des maladies infectieuses, CIMI, team E13 (Bacteriology), 75013 Paris, France
c Bactériologie-hygiène, hôpital Pitié-Salpêtrière, AP–HP, 75013 Paris, France
d Centre national de référence des mycobactéries et de la résistance des mycobactéries aux antituberculeux, bactériologie-hygiène, 75013 Paris, France
e Université Paris Diderot, Sorbonne Paris Cité, Inserm, UMR 1137 IAME, 75018 Paris, France
f Service de bactériologie, hôpital Lariboisière, AP–HP, 75010 Paris, France

Received 23 January 2015; received in revised form 1st June 2015; accepted 2 September 2015
Available online 1 October 2015

Abstract
Leprosy is an infectious disease that has now been reported for more than 2000 years. The leprosy elimination goal set by the World Health
Organization (WHO), i.e. a global prevalence rate < 1 patient per 10,000 population, was achieved in the year 2000, but more than 200,000 new
case patients are still reported each year, particularly in India, Brazil, and Indonesia. Leprosy is a specific infection: (i) it is a chronic infection
primarily affecting the skin and peripheral nerves, (ii) Mycobacterium leprae is one of the last bacterial species of medical interest that cannot be
cultured in vitro (mainly because of its reductive genome evolution), and (iii) transmission and pathophysiological data is still limited. The various
presentations of the disease (Ridley-Jopling and WHO classifications) are correlated with the patient’s immune response, bacillary load, and by the
delay before diagnosis. Multidrug therapy (dapsone, rifampicin, with or without clofazimine) has been recommended since 1982 as the standard
treatment of leprosy; 6 months for patients presenting with paucibacillary leprosy and 12 months for patients presenting with multibacillary leprosy.
The worldwide use of leprosy drugs started in the 1980s and their free access since 1995 contributed to the drastic decline in the number of new
case patients. Resistant strains are however emerging despite the use of multidrug therapy; identifying and monitoring resistance is still necessary.
© 2015 Elsevier Masson SAS. All rights reserved.

Keywords: Leprosy; Mycobacterium leprae; Multidrug therapy

Résumé
La lèpre est une maladie infectieuse décrite depuis plus de 2 millénaires. Bien que l’objectif d’élimination (prévalence mondiale inférieure à 1
pour 10 000 habitants) affiché par l’OMS ait été atteint au niveau mondial en 2000, plus de 200 000 nouveaux cas sont encore observés chaque
année, en particulier en Inde, au Brésil et en Indonésie. La lèpre et l’agent infectieux qui en est responsable sont remarquables à plus d’un titre :
(i) c’est une infection chronique qui atteint en priorité la peau et les nerfs périphériques, (ii) Mycobacterium leprae est une des dernières espèces
bactériennes d’intérêt médical à ne pas être cultivable in vitro, en particulier du fait d’une évolution réductrice de son génome, et (iii) les données
de transmission et de physiopathologie sont encore mal connues. Il existe différentes formes de la maladie (classifications de Ridley et Jopling,
de l’OMS) déterminées par la qualité de la réponse immunologique de l’individu atteint, la charge bacillaire et la précocité du diagnostic. La
polychimiothérapie (dapsone, rifampicine, plus ou moins clofazimine) est le traitement standard recommandé pour le traitement de la lèpre depuis
1982 avec une durée de traitement de 6 mois pour la forme pauci-bacillaire et 12 mois pour la forme multi-bacillaire. La diffusion en masse
des médicaments, commencée dès les années 1980, et leur distribution gratuite à partir de 1995 ont permis une baisse drastique du nombre de

∗ Corresponding author. Laboratoire de bactériologie, faculté de médecine Pitié-Salpêtrière, 91, boulevard de l’Hôpital, 75634 Paris cedex 13, France.
E-mail address: alexandra.aubry@upmc.fr (A. Aubry).

http://dx.doi.org/10.1016/j.medmal.2015.09.002
0399-077X/© 2015 Elsevier Masson SAS. All rights reserved.
384 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393

nouveaux cas. Cependant, malgré l’introduction de la polychimiothérapie, des souches résistantes émergent, ce qui montre que le diagnostic et la
surveillance de la résistance sont encore cruciaux.
© 2015 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Lèpre ; Mycobacterium leprae ; Polychimiothérapie

1. Introduction of leprosy in Asia. The disease would then have progressively

Leprosy is a chronic infectious disease caused by Mycobac-
terium leprae, also known as Hansen’s bacillus. This
incapacitating disease was first described in Indian treaties dat-
ing from 600 BC. Leprosy was an endemic disease in Europe
from the 12th century to the 13th century, but has now almost
entirely disappeared from that region of the world. One of the
first goals set by WHO, and reached in the year 2000, was to
reduce the global disease prevalence to less than 1 case patient
per 10,000 population [1]. Leprosy is however still reported in
various countries of the world; 215,656 new case patients were
registered by WHO in 2013 [2]. Significant geographic dispar-
ities can be observed: Southeast Asia alone accounted for 72%
of case patients reported in 2013 (155,385/215,656) and more
than 10,000 new case patients are reported each year in India,
Brazil, and Indonesia (Fig. 1).
2. Leprosy over the years
Leprosy is a very old disease, which spreads through the
centuries via the various populations of the world. The first
3 large clusters of leprosy were found in India, China, and
Egypt.
The first medical description of leprosy was found in an
Indian treaty, known as the Sushruta Samhita, dating from 600
BC. In China, the first clinical description consistent with lep-
rosy dates from the 3rd century BC. In India, 4 skulls with
leprosy-specific lesions were found and dated to be from the
2nd century BC [3]. The first biological evidence of leprosy
found in humans was identified thanks to paleontology and its
use of molecular biology. The DNA of M. leprae was isolated
from the bones of a man skeleton dating from the 1st century
BC and found in a grave near Jerusalem [4].
For a long time, the analysis of ancient texts was the only way
to make assumptions about the progressive spread of M. leprae
in the world. Leprosy is believed to have spread to the Mediter-
ranean region through the Greek soldiers of Alexander the Great
returning from their Indian military campaign. This hypothesis
is now being called into question considering epidemiological
data obtained by molecular typing [5]. Two hypotheses have thus
been put forward to explain the worldwide spread of leprosy. The
first hypothesis points out to the East African origin of the dis-
ease and suggests that leprosy might have simultaneously spread
towards the East (Asia) and the West (Europe) before reaching
the Americas and West Africa through human migration waves
due to colonialism and slave trade. The second hypothesis is
rather more consistent with ancient texts and places the origin
spread towards the West starting with East Africa, Europe, and
the Americas to finally reach the West of Africa [5] (Fig. 2).
3. Epidemiology
The first WHO Expert Committee on Leprosy got together
in 1953 in Rio de Janeiro (Brazil), but the first global data
on the disease prevalence was published in 1966. At the time,
WHO estimated the global number of leprosy case patients at
10,786,000, even though well aware that this figure was proba-
bly under-estimated. The global number of leprosy case patients
reported between 1960 and 1980 remained stable, ranging from
10 to 12 million [6,7]. The approval and wide use of a multidrug
therapy from 1982 onwards contributed to the drastic reduction
in the number of case patients. In 1991, the global number of lep-
rosy patients dropped to 5.5 million [8]. This promising figure
led the members of the 44th session of the World Health Assem-
bly to approve the WHA 44.9 resolution (Elimination of leprosy
as a public health problem by the year 2000), i.e. the reduction of
the disease prevalence to a level below 1 case patient per 10,000
population [1].
The number of leprosy case patients detected every year
between 2000 and 2006 significantly decreased from 719,219
case patients in 2000 to 265,661 in 2006. The decrease was
mainly due to the lower number of leprosy case patients iden-
tified in the regions of the world that are still reporting the
highest number of case patients (i.e., Southeast Asia and Africa).
Unfortunately, this decrease in annual case patients started to
drastically slow down in 2006: 265,661 case patients were
reported in 2006 and 215,656 in 2013.
The latest available data suggests that the overall prevalence
of leprosy case patients in countries that are still reporting case
patients is 0.32 per 10,000 population (first trimester of 2014).
This figure is lower than the goal set by WHO in 1991, i.e.
less than 1 case patient per 10,000 population. However, the
prevalence of leprosy differs from one region to another: 0.04
per 10,000 population in the Western Pacific Region and 0.63
per 10,000 population in Southeast Asia.
The following observations can be drawn from analyzing the
gender and age distribution of case patients reported in 2013:
• the proportion of women among newly detected leprosy
case patients in countries reporting more than 100 new case
patients per year was lower than that of men, ranging from
0.5% (Pakistan) to 56.4% (South Sudan). These figures may
reflect the difficult access to medical care for women living
in these countries;
 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393 385

Fig. 1. New case detection rates of leprosy case patients, WHO, January 2013.
Taux d’incidence des cas de lèpre détectés annuellement par l’OMS, janvier 2013.

Fig. 2. Worldwide spread of leprosy. The circles indicate the country of origin of the analyzed samples and their distribution into the 4 SNP types. SNP-type 1 is in
yellow, SNP-type 2 in orange, SNP-type 3 in purple, and SNP-type 4 in green. The colored arrows indicate the direction of human migrations predicted by the SNP
analysis. Gray arrows indicate the human migration routes derived from genetic, archaeological, and anthropological studies.
Dissémination de la lèpre à travers le monde. Les cercles colorés correspondent aux pays d’origine des souches examinées et leurs distributions à travers 4 SNPs-
types. Le SNP-type 1 apparaît en jaune, le 2 en orange, le 3 en violet et le 4 en vert. Les flèches colorées indiquent les migrations de populations déduites de l’analyse
des SNPs-types. Les flèches grises correspondent aux migrations de populations déduites des études génétiques, archéologiques et anthropologiques.
From Monot et al. [5].

• the proportion of children among newly detected leprosy
case patients in countries reporting more than 100 new case
patients per year ranged from 0.6% in Argentina and Mexico
to 39.5% in the Federated States of Micronesia. These figures
are good indicators of the disease infectiousness and of the
persistence of undiagnosed contaminating patients.
4. Bacteriology
M. leprae was identified in 1873 by Gerhard Henrik Armauer
Hansen [9], 9 years before the identification of M. tuberculosis
by Robert Koch (Table 1).
M. leprae belongs to the Mycobacterium genus and to
the Mycobacteriaceae family. The rod-shaped bacillus appears
motionless at microscopic analysis, and is 1 to 8 ␮m long for
0.3 ␮m large (Fig. 3). M. leprae is a micro-aerophilic bacterium
and ideally grows at a temperature ranging from 30 to 35 ◦ C. The
bacilli group together in highly infected tissues to form clumps
of bacilli (known as globi) that can contain hundreds of bacilli.
The inability to culture M. leprae in vitro is one of the
main specificities of that bacterium, and can be explained by
its very long doubling time (14 days). For matters of com-
parison, the doubling time of M. tuberculosis is 24 hours and
that of Escherichia coli is 20 minutes. Laboratory research on
386 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393
Table 1
Key dates of significant importance in the history of leprosy.
Principales dates associées à un évènement marquant dans l’histoire de la lèpre.
600 BC 1st clinical description of leprosy in an Indian treaty
1873 Armauer Hansen identifies the disease-causing agent of
leprosy [9]
1941 1st publication by Faget supporting the effectiveness of
dapsone [54]
1960 Shepard succeeds in quantifying the multiplication of the leprosy
bacillus in a mouse footpad [10]
1964 First reported case of resistance to dapsone [65]
1970 A new and effective agent in the treatment of leprosy is identified:
rifampicin [56]
1971 Kirchheimer and Storrs manage to obtain a significant
multiplication of the leprosy bacillus inoculating the disease to
the nine-banded armadillo [11]
1981 WHO recommends the use of multidrug therapy [57]
1997 A “single dose” regimen is suggested for patients presenting with
a single nodular lesion: ROM (rifampicin/ofloxacin/minocycline)
[64]
2001 Whole genome sequencing of an Indian strain of M. leprae
isolated from the Tamil Nadu (TN) region [15]
2008 A new species of Mycobacterium causing lepromatous leprosy is
identified: M. lepromatosis [12]
M. leprae was, and still is, made difficult by that very long dou-
bling time, but in 1960 Charles C. Shepard proved that the culture
of M. leprae could be done by inoculating the bacterium into
the footpad of female Swiss mice (white) [10]. The culture of
M. leprae allowed studying and developing antibiotic therapies,
and later studying and identifying antibiotic resistance.
In 1971, Kirchheimer and Storrs proved that massive mul-
tiplication of M. leprae could be done by inoculating the
bacterium to the nine-banded armadillo, a perfect animal model
due to its body temperature (between 30 ◦ C and 35 ◦ C) and its
susceptibility to M. leprae [11]. The experiment of Kirchheimer
and Storrs enabled scientists to obtain a large number of lep-
rosy bacilli. It was then fundamental for the many antigenic and
Fig. 3. M. leprae acid-fast bacilli, isolated or grouped in globi, following Ziehl-
Neelsen staining.
Bacilles acido-alcoolo-résistants de M. leprae après coloration par Ziehl-
Neelsen. Les bacilles apparaissent isolés ou groupés en globi.
genetic studies conducted in the 1980s and 1990s, eventually
leading to the first sequencing of the M. leprae genome in 2001.
In 2008, the team led by Han et al. identified a new species of
mycobacteria, known as M. lepromatosis, which was isolated
from 2 deceased patients who presented with diffuse lepro-
matous leprosy. This type of leprosy was initially reported in
Mexico by Lucio and Alvarado and is best known as Lucio’s
phenomenon [12]. The results of the whole genome sequenc-
ing of that new species of mycobacteria revealed that M. leprae
and M. lepromatosis are quite similar in terms of phylogenetics.
They both derive from the same ancestor [13], and must have
separated more than 13.9 million years ago. M. lepromatosis
was recently isolated from carriers of tuberculoid leprosy, with
or without M. leprae [14].
5. Genetics
The results of the whole genome sequencing of M. leprae
(TN strain) were first published in 2001 [15]. The results of
the whole genome sequencing of 3 other strains revealed the
reductive genome evolution of M. leprae as a sequence identity
of 99.99% was found in 3 strains isolated from 3 very distant
regions [16]. The genome of M. leprae was found to contain
3,268,203 base pairs (3.2 Mb) and to have a G + C content lower
than that of other mycobacteria: 57.8% vs. 65.6% for M. tuber-
culosis. M. leprae shares 90% of its protein-coding genes with
M. tuberculosis, the remaining 10% being specific to M. leprae
[15]. The results of the genome analysis revealed that only half
of the transcripts were actual genes; the other half being pseudo-
genes or non-coding regions. Among bacteria and archaea, M.
leprae is the bacterium with the highest number of pseudogenes
as 50% of its genome seems to be lacking biological functions
[17]. The function of those pseudogenes, which have a signifi-
cant impact on the bacterium metabolism, is still unknown but
several hypotheses have been suggested to explain it. Pseudo-
genes and non-coding regions could be involved in the regulation
of the infection, intracellular parasitism, or in the replication of
the bacterium [18].
The small size of M. leprae, the mosaic structure of its
genome, and the significant deletions all point out to a reductive
evolution. The number of genes involved in the respiratory and
metabolic pathways is reduced [15,19]. The loss of those genes
may be related to the loss of many metabolic functions and to
the intracellular parasitic development of M. leprae [20].
6. Transmission of leprosy
The exact method of transmission of leprosy is still unknown.
The human being is the main reservoir of infection even
though transmission through African green monkeys [21,22] and
armadillos in Louisiana [23] has been reported. The most con-
tagious presentation of the disease is the lepromatous leprosy
as patients usually carry a very large number of leprosy bacilli.
Some patients can carry up to 7 billion leprosy bacilli per one
gram of tissue.
At the first International Congress of Leprosy held in Berlin
(1897), Schäffer proved that the infection could spread through
 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393
nasal discharge. During the congress, Schäffer asked 2 infected
patients to speak, cough, and sneeze for about 10 minutes in
front of microscope slides that were then stained and ana-
lyzed. The results were conclusive; at the end of the experiment
up to 185,000 bacilli had been spread. Schäffer’s experiment
was however disregarded and the transmission of leprosy by
direct contact only was accepted by the scientific commu-
nity. In the 1960s, Shepard proved once again that lesions
in the nasal mucosa could lead to the discharge of 10,000
to 10,000,000 bacilli [10] and Pedley estimated that tens of
millions bacilli could be discharged from the nasal mucosa
on a daily basis [24]. In 2013, M. leprae was identified
in the buccal mucosa of 94% of patients presenting with
multibacillary and paucibacillary leprosy (PCR analysis and
antigenic markers) [25]. The main dissemination route of the
leprosy bacillus therefore seems to be the upper respiratory
tract.
Other dissemination routes were suspected but their role in
the transmission of leprosy was not clearly defined (mosquitos,
breast milk, etc.).
7. Pathophysiology
Leprosy is probably transmitted through nasal or sputum
excretions. The results of experimental studies conducted on
mice pointed out to the respiratory tract as a potential portal of
entry for bacilli instead of the digestive tract or the skin [26,27].
No pathophysiological model has however been established so
far.
Studying the incubation period of leprosy is not easy because
of (i) the insidious nature of the disease, especially in the early
phase, (ii) its slow evolution, and (iii) the absence of sensitive
and specific diagnostic tests for the sub-clinical phase of the
infection. Various incubation periods have been reported: very
short ones in young children (3 and 6 months old) [28], or very
long ones (up to 30 years) [29]. The short incubation period was
observed in 2 leprosy patients with a bacilli count respectively
performed 4 months and 15 days before the first signs of lepro-
matous skin lesions [28]. The longer incubation periods were
observed in American war veterans who used to be stationed
in endemic countries for short periods of time. These incuba-
tion periods ranged from 2.9 to 5.3 years for patients presenting
with tuberculoid leprosy and from 9.3 to 11.6 years for patients
presenting with lepromatous leprosy.
Patients living in endemic countries are probably contami-
nated during childhood and leprosy is most frequently detected
in adulthood. The details of the transition from the latent infec-
tion to the symptomatic infection are still unknown; a clear
understanding of the pathophysiology of leprosy is therefore
impossible.
8. Immunology
Immunology is a key aspect of leprosy as the host’s immune
response determines the clinical expression of the disease.
Immunodepression leads to the most severe presentations of lep-
rosy. The clinical presentation is correlated with the quality of the
387
immune response. Tuberculoid leprosy is the result of high cell-
mediated immunity with a strong Th1 type immune response,
limiting the disease progression to skin lesions and well-defined
nerve damage (no humoral response in that case). Lepromatous
leprosy is however characterized by low cell-mediated immu-
nity with a predominant humoral Th2 response (high production
of IgG or IgM antibodies), leading to an inadequate immune
response to an intracellular bacterium and to the uncontrolled
multiplication of the bacilli.
Leprosy is known to occur at all ages but most patients do
not contract the disease, even after a prolonged contact with M.
leprae [30].
9. Clinical signs and classifications
Leprosy is a chronic disease that is not immediately life
threatening. M. leprae has a tropism for the skin and Schwann
cells of the peripheral nerves. Patients first present with sensory
neuritis, but untreated patients seeking medical care at a later
stage present with more severe motor disorders. Plantar ulcers,
lytic bone lesions (nose, phalanxes, etc.), and paralyses (ulnar
nerve, lagophthalmos) can be named as frequent complications;
they define the clinical picture of leprosy that has now been
described for centuries [31].
Various clinical signs can be observed during the early phase
of leprosy, known as the indeterminate phase, making it difficult
to diagnose the disease.
Various more advanced presentations of leprosy have been
reported and classified as tuberculoid leprosy and leproma-
tous leprosy. Many other clinical presentations, known as
intermediate or borderline leprosy, have been identified and
classified in between those 2 types. The Ridley and Jopling
(RJ) system defines [32] 5 clinical presentations of leprosy:
polar tuberculoid leprosy (TT), borderline tuberculoid leprosy
(BT), borderline–borderline leprosy (BB), borderline lepro-
matous leprosy (BL), and polar lepromatous leprosy (LL)
(Fig. 4).
WHO recently adopted a new classification to make the treat-
ment choice easier. Paucibacillary leprosy is defined by the
presence of 1 to 5 skin lesions and/or 1 impaired nerve, and multi-
bacillary leprosy by the presence of more than 5 skin lesions or
impaired nerves [33]. The relation between those different clini-
cal presentations is represented in Fig. 4. The relative frequency
of each of these leprosy presentations differs across affected
countries and populations [2].
9.1. Tuberculoid leprosy
Tuberculoid leprosy is defined by skin lesions and nerve
damage. Skin manifestations either include large hypochromic
macules with well-defined edges that can sometimes be infil-
trated, or large thickened and infiltrated plaques. Tuberculoid
leprosy presents with very few lesions (hyposensitivity or anes-
thetic lesions). Nerve damage is usually observed around skin
lesions and is associated with sensory and/or motor impairment
when the hands and feet are affected.
388 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393
Fig. 4. Clinical, biological, and therapeutic classification of leprosy [32,33]. TT: tuberculoid; BT: borderline–borderline; BL: borderline lepromatous; LL: lepro-
matatous.
Classification clinique, biologique et thérapeutique de la lèpre [32,33].
9.2. Lepromatous leprosy
The initial skin lesions are small-sized hypochromic mac-
ules with indistinct edges. If left untreated, they form copper
colored papules or nodules known as leproma. Lepromatous
leprosy patients present with a high number of bilateral and
symmetrical leproma (20 to 100) that can develop everywhere
on the skin but most frequently on the face, earlobes, fingers,
and toes. Those lesions are not anesthetic.
Peripheral nerve damage is often bilateral, diffuse, and sym-
metrical. It is associated, to various extents, with peripheral
nerve hypertrophy, sensory and/or motor impairment.
9.3. Borderline leprosy
Borderline leprosy is defined by various clinical signs and
corresponds to a transition status. Its classification depends
on the number of clinical signs consistent with tuberculoid or
lepromatous lesions. The borderline tuberculoid (BT) presen-
tation of leprosy is defined by the presence of several large
asymmetrical and hypoesthetic lesions with peripheral mac-
ules or infiltration of the skin. Smaller lesions can usually
be observed near the larger ones. The borderline–borderline
(BB) presentation is defined by the presence of several non-
anesthetic annular lesions with indistinct edges. The borderline
lepromatous (BL) presentation is defined by the presence of
more than 10 bilateral and non-anesthetic lepromas and annular
lesions [34].
10. Disease progression
Leprosy is a slowly progressing disease. The neurological
impairment leads to chronic complications, such as sensory loss,
amyotrophy, deformations, and chronic wounds on the hands
and feet that can sometimes be irreversible. In 2012, 6.2% of
newly diagnosed patients presented with grade 2 disabilities
according to the WHO scale [35]. This figure points out to the
delay in diagnosing the disease and to the poor access to medical
care of those populations.
Two types of spontaneous acute complications (leprosy reac-
tions) associated with the patient’s immune response can be
observed. Type 1 reaction is known as reversal reaction and type
2 reaction as erythema nodosum leprosum. They are defined
by severe activation/reactivation of the immune and inflamma-
tory systems and primarily affect peripheral nerves. Patients can
present with leprosy reactions before being diagnosed with lep-
rosy, during treatment, or once an adequate treatment has been
completed.
Fifteen to 65% of leprosy patients present with irreversible
nerve damage during the course of the disease, mainly during
leprosy reactions [36].
11. Risk factors
Leprosy is associated with poverty and lower socio-economic
status, but without any additional specific factor. There is no
relation between the frequency of leprosy and that of other infec-
tious diseases (including HIV), unlike what is currently being
observed with tuberculosis [37,38]. Patients with genetic predis-
position seem more likely to contract leprosy [39]. Of the many
identified genes that could be associated with a higher risk of
contracting leprosy very few were validated in large studies and
in various populations [39]. Among genes increasing the risk of
leprosy, we can name as an example a region on chromosome
6 regulating the expression of the genes PARK2 and PACRG
(Parkin co-regulated gene). The function of the PACRG gene is
currently unknown. The parkin-coding PARK2 gene is involved
in one of the cellular proteins degradation pathways (ubiquit-
ination) and is responsible for some clinical presentations of
Parkinson’s disease [40,41].
 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393
12. Diagnosis
The diagnosis of leprosy remains clinical and easy to make for
health workers used to treat those patients. The biggest challenge
is to suspect the diagnosis of leprosy, especially in industrialized
countries where the disease has now almost entirely disappeared.
Choosing the right lesion that will then be sent for pathological
and biological analyses is crucial and requires clinical expertise
of leprosy lesions.
Paraclinical tests can help confirm the clinical diagnosis of
leprosy, i.e. bacteriological (Section 12.2) and pathological anal-
yses. No other biological analysis can be recommended.
12.1. Clinical diagnosis
The patient’s medical history is the first indicator of lep-
rosy, especially if the patient is coming from or used to live
in an endemic country. Skin lesions with hypoesthesia are usu-
ally the hallmark sign of leprosy as no other dermatological
condition is theoretically associated with sensory disorders. Der-
matological signs are the clinical indicators of leprosy in 90%
of patients; the remaining 10% present with neurological signs
only [42].
The clinical analysis of the skin lesions and nerve damage
must be performed by an experienced leprosy clinician. The
results will help diagnose and classify the patient’s disease pre-
sentation according to both RJ and WHO classifications, which
will then inform the choice of an adequate treatment, determine
the patient’s infectiousness, and help prevent potential reversal
reactions.
Microbiological and pathological analyses should be per-
formed whenever possible to support the clinical diagnosis. Such
analyses should preferably be performed using a skin biopsy or a
nerve biopsy when the patient is mainly presenting with neuritis
signs.
12.2. Bacteriological diagnosis
12.2.1. Samples
M. leprae has a tropism for skin; skin lesions must therefore
be sampled (smear tests and biopsies). A rapid diagnosis can be
established with little iatrogenic effects with a tissue fluid smear
test performed on the earlobe; experience is however needed to
successfully perform this test. The result is usually negative for
most paucibacillary and tuberculoid presentations of leprosy.
Taking a sample from the nasal mucosa is not recommended,
especially for patients presenting with lepromatous leprosy as
their mucus membrane is fragile. It is also not recommended to
sample nasal discharge collected through nose blows because
of their low specificity (presence of other commensal mycobac-
teria of the mucus membrane) and of the difficulty to collect
a large quantity of secretions. Skin biopsy known as “punch
biopsy” is preferred, using if possible a 4 mm punch to collect
enough tissue for microscopic and molecular analyses. Surgical
biopsy (≥ 6 mm) is only needed for relapsing cases of leprosy
or suspicion of resistance.
389
12.2.2. Microscopic analysis and acid-fast bacilli
M. leprae cannot be cultured in vitro; researching resistant
acid-fast bacilli with an optical microscope remains the standard
diagnostic technique [33]. Tissue fluid smear tests or biopsy cell
suspensions, once crushed and spread out onto the slide, are
stained with the Ziehl-Neelsen staining technique. Bacilli take
a fuchsia color on a blue background (Fig. 3).
The number of bacilli contained in each microscopic field or
bacterial index (BI) is calculated with the Ridley index [43] for
skin smears (earlobe and skin lesions). Tuberculoid leprosy is
associated with a negative BI in the tissue fluid of the earlobe and
a negative or equal to “1+” BI in skin lesions. In lepromatous
leprosy, the BI is positive, always > “2” with bacilli grouping
together to form globi. An initially high BI (≥ “4+”) is consistent
with a higher risk of transmission and relapse [44,45]. Compliant
patients have a decreasing BI, but most patients with a high BI
still have a positive BI at the end of the treatment course as the
clearance of non-viable residual bacilli can take years.
12.2.3. Molecular techniques
The analysis of the DNA of M. leprae is done with the PCR
technology. Several target genes and antigens have been sug-
gested to detect it in smear tests: pra-36 KDa, pra-18 KDa,
RLEP, Ag85B, 16S RNA, folP, rpoB, and gyrA [46]. Specialized
laboratories perform those analyses on the skin lesion biopsies
presenting the highest bacilli count as they are associated with
the best detection rate [47].
PCR sensitivity is close to 100% in patients presenting with
a positive bacteriological index, but it is significantly lower in
patients presenting with a negative bacteriological index. Sen-
sitivity figures vary between studies and methods, ranging from
87% to 100% for lepromatous patients and from 30% to 83%
for tuberculoid patients [46]. PCR sensitivity makes it possible
to confirm a leprosy diagnosis, highlighting the presence of the
DNA of M. leprae in the lesions [42,48,49].
12.3. Pathological diagnosis
The biological diagnosis of leprosy must include a patholog-
ical analysis of the skin biopsies.
Tuberculoid leprosy presents with nodular and histio-
lymphocytic infiltrations surrounding the adnexa and nerves;
an infiltration or even destruction of the nervules and sudorifer-
ous glands can also be observed, leading to the hypoesthesia or
anesthesia of the lesions.
Lepromatous infiltrations are dense with histiocytic cells
characterized by foamy cytoplasm (Virchow’s cells). They usu-
ally surround hair, adnexa, and nerves without invading them.
They are separated from the superficial part of the dermis by the
band of Unna [50]. Infiltrations have no destruction potential
and patients do not present with any sensory impairment.
12.4. Immunological diagnostic
Infection by M. leprae leads to a cell-mediated humoral
response and to the production of non-protective antibod-
ies. One of the antigens of M. leprae, known as phenolic
390 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393
glycolipid-1 (PGL1), was studied for diagnostic test purposes.
Several epidemiological studies used a specific serology test to
detect anti-PGL1 IgM or a more recently developed test that
can detect both anti-PGL1 IgM and anti-LID1 IgG (fusion pro-
tein specific to M. leprae) [51]. This serology test is neither
marketed nor recommended because of its low sensitivity, espe-
cially for paucibacillary presentations of leprosy (thus offering
a limited added value), and its inadequate specificity for popu-
lation of patients frequently infected by other tuberculoid and
non-tuberculoid mycobacteria [52].
13. Treatments
M. leprae, just like any other mycobacteria, is naturally resis-
tant to most of the frequently prescribed antibiotics because of
the high number of lipids in its cell wall, thus preventing antibi-
otic penetration and especially hydrophilic ones (␤-lactams,
glycopeptides, fusidic acid, and chloramphenicol).
Chaulmoogra oil, extracted from the fruit of the Taraktogenos
kurzii tree, was the first leprosy treatment. One of its compounds,
hydnocarpic acid (C16 H28 O2 ), has an in vitro activity against
some mycobacteria species. It is however inactive against M.
leprae [53].
13.1. First-line antibiotics: dapsone, clofazimine, and
rifampicin
The discovery of dapsone, a sulfamide antibiotic, was a mile-
stone for millions of leprosy patients. The antimycobacterial
activity of dapsone was first demonstrated in the treatment of
tuberculosis in 1940. In 1941, the physician Guy Faget was
in charge of the national leper colony of the United States in
Carville (Louisiana) and decided to contact the Parke-Davies
company to further study the results obtained with dapsone. The
year before, the researchers of the Parke-Davies company had
synthetized the agent derived from dapsone, Promin® , which led
to the discovery of the first effective treatment against leprosy
more than 60 years after the identification of the disease-causing
agent [54].
Clofazimine, B663 or Lamprene® , is a red/orange phenazine
which was synthetized in 1956. It was first proposed as a tuber-
culosis treatment, and later its usefulness in the treatment of
leprosy was demonstrated [55].
Rifampicin belongs to the rifamycin group and was first used
as a tuberculosis treatment, just like all the other leprosy treat-
ments. The first studies supporting the efficacy of rifampicin
against susceptible M. leprae strains, but also on resistant strains
to dapsone, were conducted in 1970 [56]. A daily dose of 600 mg
of rifampicin was administered to patients enrolled in the first
clinical trials [56], but in 1982 WHO recommended the use of
a monthly dose of rifampicin because: (i) “the better efficacy
of the 600 mg daily dose of rifampicin as compared with the
600 mg monthly dose” had not be proven [57,58] and because
(ii) of the need to control the use of rifampicin as it was at the
time more expensive than dapsone, but mainly because it was
the most effective (bactericidal activity) agent to treat leprosy.
13.2. Second-line agents: fluoroquinolones, minocycline,
and clarithromycin
Fluoroquinolones (ofloxacin, levofloxacin, and moxi-
floxacin), minocycline, and clarithromycin are intended as
potential therapeutic alternatives. These antibiotics have the
same broad-spectrum activity as rifampicin and target many
Gram-positive and Gram-negative bacteria. They can be admin-
istered to patients presenting with an intolerance, resistance,
or clinical failure to first-line agents. Patients presenting with
rifampicin-resistant leprosy need to take those antibiotics daily,
and treatment duration must be extended to 24 months because of
a lower bactericidal activity compared with rifampicin [33,59].
13.3. New therapeutic approaches
Very few new agents active against M. leprae are currently
being developed. Bedaquiline (diarylquinoline, R207910, or
TMC207) is a new tuberculosis treatment that inhibits the ATP
synthase [60,61]. The bactericidal activity of bedaquiline against
M. leprae observed in mice is similar to that of moxifloxacin and
rifampicin [62]. Bedaquiline has not yet been tested on leprosy
patients.
13.4. Therapeutic strategies
Multidrug therapy was recommended as the standard treat-
ment of tuberculosis (i.e., the other mycobacterial infection) as
early as the 1970s but its use for leprosy patients was only rec-
ommended by WHO in 1982. The use of the multidrug therapy
was progressive; its geographical coverage was less than 1%
between 1982 and 1985, 50% in 1992, and is now 100% since
1997 [63].
The recommended treatment duration for multibacillary lep-
rosy is 12 months. Patients presenting with LL, BL, and BB
leprosy according to the Ridley and Jopling system belong to
that treatment group. The recommended treatment duration for
paucibacillary leprosy is 6 months. Patients presenting with I,
TT, and BT leprosy according to the Ridley and Jopling system
belong to that treatment group [32] (Table 2 and Fig. 4). WHO
recommends administering treatment to patients presenting with
only one lesion, even though most of them usually recover spon-
taneously, because there is no diagnostic method to differentiate
which patients will or will not be cured.
In 1997, WHO recommended treating patients presenting
with only one lesion with a single dose regimen containing
600 mg of rifampicin, 400 mg of ofloxacin, and 100 mg of
minocycline [64]. This therapeutic strategy was however not
renewed in the 2012 recommendations.
Leprosy relapses are first treated with the standard multidrug
therapy-dosing regimen as patients who have been on the mul-
tidrug therapy for more than 30 years face a minor risk of
relapses. Relapses are rather associated with a treatment dura-
tion, which is not long enough [33]. Trying to identify any
acquired resistance is required when the multidrug therapy is
clinically inefficient (see below).
 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393
Table 2
Standard multidrug therapy regimens for paucibacillary and multibacillary leprosy in adults and children (WHO recommendation, 2013) [33].
Schémas thérapeutiques préconisés par l’OMS en 2013 dans les lèpres pauci-bacillaire et multi-bacillaire chez les adultes et les enfants [33].
Clinical presentations Population Agents
Paucibacillary leprosy Adults Rifampicin
Dapsone
Children Rifampicin
Dapsone
Multibacillary leprosy Adults Rifampicin
Clofazimine
Dapsone
Children Rifampicin
Clofazimine
Dapsone
Corticosteroids must be administered to patients presenting
with leprosy reactions because of their anti-inflammatory and
immunomodulatory activity. Treatment duration > 12 weeks is
recommended only if the patient is followed by a specialist.
Treatment duration differs for type 1 and type 2 leprosy reactions
[33].
14. Treatment resistance
As M. leprae cannot be cultured in vitro, studying antibiotic
resistance is difficult and available data is limited. Inoculating
the bacillus into the mouse footpad has long been the only avail-
able method to assess the antibiotic susceptibility of a strain;
this technique is however long and difficult to perform (1.5 to
2 years).
The first case of dapsone resistance was reported in 1964 [65].
Dapsone resistance is due to mutations of the folP1 gene, which
encodes dihydropteroate synthase. This enzyme is involved in
the synthesis of folates [66]. The first cases of rifampicin resis-
tance were reported in 1976, especially in patients previously
treated with a monotherapy [67]. Rifampicin resistance is due
to mutations of the rpoB gene, which encodes the sub-unit B of
the RNA polymerase [68]. Quinolone resistance is due to muta-
tions of the gyrA gene, which encodes the sub-unit A of DNA
gyrase [69–71].
International data on resistance is very limited and heteroge-
neous as the rate of resistant strains differs from one study to
another, ranging from 4.3% to 41% [72,73]. Previously treated
patients are faced with a higher resistance rate than newly diag-
nosed patients (22.6% vs. 5.2%) [74]. Resistance to dapsone
is more frequently observed, followed by rifampicin resistance.
Fluoroquinolone resistance is rare and has first been observed
in strains resistant to both dapsone and rifampicin; this is why
this type of strains is defined as “multidrug resistant” [75]. Mul-
tidrug resistant strains now pose a real threat to the treatment
of leprosy. M. leprae strains that are only resistant to fluoro-
quinolones [49], with a resistance selection occurring during
the long-term treatment of other infections, have recently been
observed. The excessive global use of fluoroquinolones could
lead to the greater emergence of such strains.
The development of molecular biology revolutionized the
bacteriological diagnosis of leprosy and identification of
391
Dosing regimen Treatment duration
600 mg/month 6 months
100 mg/day
450 mg/month 6 months
50 mg/day
600 mg/month 12 months
300 mg/month and 50 mg/day
100 mg/day
450 mg/month 12 months
150 mg/month and 50 mg/day
50 mg/day
Fig. 5. Molecular detection of resistance in M. leprae strains using the
GenoType Leprae DR (Hain® ) test. Profile 1: rifampicin, oflaxacin and dapsone-
susceptible strain (WT); profile 2: rifampicin (MUT2), oflaxacin (MUT), and
dapsone-susceptible strain (WT). Dapsone resistance has not been detected by
that test. Gene sequencing is required.
Détection moléculaire des résistances de M. leprae par le test GenoType Leprae
DR (Hain® ).
resistance to leprosy agents. The molecular detection of resis-
tance uses the sequencing of the genes involved in the antibiotic
mechanism of action: the rpoB gene for rifampicin, the folP
gene for dapsone, and the gyrA gene for quinolones [47]. A
new test has recently been developed to detect the most frequent
mutations: GenoType® Leprae DR (Hain) [49]. More easily per-
formed and less expensive than the mouse inoculation technique,
this test is not limited to reference laboratories and can be used
in endemic regions (Fig. 5).
Several preventive strategies have been evaluated (BCG
primary immunization, BCG immunoprophylaxis and chemo-
prevention of “contact patients” of leprosy patients with
antileprosy drugs such as dapsone and rifampicin). None of them
is currently recommended by WHO as their mid-term effective-
ness and suitability to other populations than the one studied
have not been proven [33].
Leprosy is usually thought of as an old and remote disease but
healthcare professionals should consider leprosy as a diagnosis,
especially when confronted to patients coming from endemic
countries and presenting with hypoesthetic skin lesions. Scien-
tific research, access to treatment, and preventive strategies must
keep on being supported so that every region of the world can
reach the elimination goal of leprosy.
392 F. Reibel et al. / Médecine et maladies infectieuses 45 (2015) 383–393
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
Acknowledgement
We would like to thank the Raoul Follereau Foundation for
the support given to the fight against leprosy, and particularly for
the support given to the work conducted by the bacteriological
laboratory of the Pitié-Salpêtrière Hospital.
AA, FR, and EC wrote the article.
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