Current Status of Leprosy: Epidemiology, Basic Science and Clinical Perspectives
Current Status of Leprosy: Epidemiology, Basic Science and Clinical Perspectives
Current Status of Leprosy: Epidemiology, Basic Science and Clinical Perspectives
REVIEW ARTICLE
Current status of leprosy: Epidemiology, basic science and
clinical perspectives
Koichi SUZUKI,1 Takeshi AKAMA,1 Akira KAWASHIMA,1 Aya YOSHIHARA,1
Rie R. YOTSU,2 Norihisa ISHII1
1
Leprosy Research Center, National Institute of Infectious Diseases, and 2Department of Dermatology, National Center for Global Health
and Medicine, Tokyo, Japan
ABSTRACT
Leprosy has affected humans for millennia and remains an important health problem worldwide, as evidenced
by nearly 250 000 new cases detected every year. It is a chronic infectious disorder, caused by Mycobacterium
leprae, that primarily affects the skin and peripheral nerves. Recent advances in basic science have improved
our knowledge of the disease. Variation in the cellular immune response is the basis of a range of clinical
manifestations. The introduction of multidrug therapy has significantly contributed to a decrease in the prevalence
of the disease. However, leprosy control activities, including monitoring and prevention programs, must be
maintained.
INTRODUCTION EPIDEMIOLOGY
Leprosy, or Hansen’s disease, is a chronic infectious disease The WHO publishes an annual report on the worldwide incidence
caused by the acid-fast bacterium Mycobacterium leprae. Norwe- of leprosy, including the number of new cases, prevalence and
gian physician Gerhard Armauer Hansen identified the bacillus in disabilities.1 The detection of new cases by the WHO has declined
the patients in 1873, making leprosy the first disease ascribed to from 514 718 in 2003 to 244 796 in 2009, but the rate of decrease
a bacterial origin. Leprosy usually affects the dermis of the skin is getting smaller each year. Among 244 796 new cases in 2009,
and peripheral nerves, but has a wide range of clinical manifesta- 16 countries that reported 1000 or more new cases accounted for
tions. It can be progressive and cause permanent damage if left 93% of the total. These countries and the number of cases
without treatment. Divided into paucibacillary (TB; tuberculoid detected in 2009 are: India (133 717 cases), Brazil (37 610 cases),
pole) or multibacillary (MB; lepromatous pole), depending on the Indonesia (17 260 cases), Bangladesh (5239 cases), the Demo-
bacillary load, the disease manifests first in discoloration of the cratic Republic of the Congo (5062 cases), Ethiopia (4417 cases),
skin and then in rashes and nodules. The introduction of dapsone Nepal (4394 cases), Nigeria (4219 cases), Myanmar (3147 cases),
(diphenyl sulfone, DDS) in 1941 brought the first effective therapy, the United Republic of Tanzania (2654 cases), Sudan (2100
and multidrug therapy (MDT) was introduced by the World Health cases), Sri Lanka (1875 cases), the Philippines (1795 cases), China
Organization (WHO) in 1981 to limit the development of drug (1597 cases), Madagascar (1572 cases) and Mozambique (1191
resistance. Endemic leprosy has declined markedly and the dis- cases).
ease is now rare in most industrialized countries. It is still a major The proportion of new cases with multibacillary leprosy ranged
public health problem in developing countries, where hundreds of from 32.70% in the Comoros in Africa to 95.04% in the Philip-
thousands of new cases are diagnosed each year. In many of pines. The proportion of females among newly detected cases
these countries, social stigmatization is an additional burden. ranged from 6.50% in Ethiopia to 59.11% in the Central African
Therefore, it is important that control activities continue if the dis- Republic. The proportion of children among new cases ranged
ease burden and damaging impacts of leprosy are to be from 0.60% in Argentina to 30.30% in Papua New Guinea. Grade
reduced. Dermatologists should be familiar with leprosy and other 2 disabilities in new cases ranged from 1.45% in Liberia to 22.8%
diseases needed for differential diagnosis. in China. As the number of new cases declines, the damaging
Correspondence: Koichi Suzuki, Ph.D., Laboratory of Molecular Diagnostics, Department of Mycobacteriology, Leprosy Research Center, National
Institute of Infectious Diseases, 4-2-1 Aoba-cho, Higashimurayama, Tokyo 189-0002, Japan. Email: koichis@nih.go.jp
Received 5 July 2011; accepted 7 July 2011.
impact of the disease on the physical, social and economic well- shows varying patterns among patients, suggesting as yet unknown
being of individuals and families affected by leprosy are also functions.13–16
expected to decline. Single nucleotide polymorphisms (SNP) and short or variable
Very few new leprosy patients are registered in developed coun- number tandem repeats have been used for M. leprae genotyping.
tries. When leprosy is detected, it is primarily found among immi- SNP analysis revealed four primitive subtypes of M. leprae and the
grants from countries where the disease is still endemic. There is an number is increasing as the analysis progresses.17–19 Some reports
association between the incidence of leprosy and socioeconomic have also presented the possibility of dual infections or phenotypi-
factors such as gross national product (GNP), personal housing cally distinct strains of M. leprae; however, these situations are still
expenditures and the number of persons per household, suggesting somewhat obscure.20,21
that improvements in socioeconomic conditions greatly contribute
to the reduction of leprosy.2 The proportion of children under the TRANSMISSION AND PATHOLOGY
age of 15 years among newly detected cases would be a good indi-
cator of the situation in a country ⁄ region. Similarly, the proportion of It is evident that humans are the major reservoir of M. leprae infec-
cases with grade 2 and visible disabilities among newly detected tion, while naturally occurring infection has been reported in wild
cases would be a reflection of early detection and treatment. animals, including the nine-banded armadillo and several species of
primates.22–32 A recent study found that the same genotypic strain
of M. leprae was detected at high incidence in wild armadillos and
BACTERIOLOGY AND GENOMICS leprosy patients in the southern USA, suggesting that leprosy may
Mycobacterium leprae is an obligate intracellular parasite that can- be a zoonosis in regions in which armadillos serve as a reservoir.33
not be cultivated in vitro. It grows very slowly with an approximate Although transmission of M. leprae is not entirely understood, it is
generation time of 12–14 days. The inability to cultivate in vitro and thought that long-term exposure of the respiratory system to air-
the lack of animal models have been major disadvantages for lep- borne droplets is the main route of infection.34,35 M. leprae is not
rosy research. However, the availability of the M. leprae genome very virulent, meaning that most people affected with leprosy are
sequence has contributed to knowledge of the disease. The first non-infectious, probably because the bacilli remain within the
genome sequence of M. leprae, completed in 2001,3 revealed that infected cells. Multibacillary patients, however, excrete M. leprae
only half of the small genome contains protein-coding genes, while from their nasal mucosa and skin.36 Close and repeated contact
the remainder consists of pseudogenes and non-coding regions with these patients is also a source of transmission. Upon MDT
(Fig. 1). The number of pseudogenes is much larger in the M. leprae treatment, however, the patients rapidly lose infectivity.
genome than in other mycobacteria,4 and the number and propor- Even if infected, a long incubation period is required before clini-
tion are exceptionally large in comparison with other pathogenic cal manifestation. The long incubation period of leprosy was demon-
and non-pathogenic bacteria and archaea.5,6 Many of the M. leprae strated by an SNP analysis of an M. leprae genome derived from one
pseudogenes are the result of stop codon insertions thought to be of four spontaneous leprosy cases in chimpanzees. The chimpanzee
caused by the dysfunction of sigma factors or the insertion of repeti- was infected with M. leprae during infancy in West Africa, but the
tive sequences derived from transposons.7–9 Despite this genetic pathogenic signs of leprosy did not appear for at least 30 years.30
damage, a specialized intracellular environment free from evolution- Mycobacterium leprae primarily infects histiocytes (or tissue
ary competition has allowed the organism to survive.3,10,11 It has macrophages) in the dermis and Schwann cells in the peripheral
been speculated that M. leprae has lost over 1500 genes from its nerves. The unique tropism for peripheral nerves can lead to defor-
genome and that non-coding regions are functionally silent and use- mities even after the pathogen is successfully treated. The outcome
less.12 However, analyses have demonstrated that some of the of infection and clinical manifestation depend on the cellular immu-
pseudogenes and non-coding regions are highly expressed at the nity of the host, which is the first line of defense against M. leprae
RNA level, and that expression of these RNA in clinical samples infection. There is a relationship between clinical manifestation and
cytokine profiles within the skin lesions. T-helper cell (Th)1 cyto-
kines, such as interleukin (IL)-2 and c-interferon, play important roles
in cellular immune responses in paucibacillary leprosy. Th2 cyto-
kines, including IL-4, IL-5 and IL-10, augment humoral immune
responses and predominate in multibacillary leprosy. Thus, there is
an inverse correlation in the cytokine profiles that create the basis of
paucibacillary and multibacillary leprosy.
Mycobacterium leprae should be recognized by the innate
immune system and phagocytized by host macrophages. Toll-like
receptor (TLR)2, in conjunction with TLR1, recognizes the cell wall
lipids of M. leprae and subsequently activates innate immune
responses.37,38 However, some bacilli escape this initial attack of
Figure 1. Only half of the Mycobacterium leprae genome contains innate immunity and successfully parasitize the phagosome of mac-
functional genes. The percentage of functional genes, pseudogenes rophages. CORO1A, an actin-binding scaffold protein in the cell
and non-coding regions are illustrated for M. leprae and Mycobacte- membrane of host cells, inhibits the phagosome ⁄ lysosome fusion,
rium tuberculosis genomes. thereby helping the pathogen escape digestion.38–40
Mycobacterium leprae parasitization of macrophages occurs in a epistaxis. The involvement of certain peripheral nerves may also
foamy or enlarged phagosome filled with lipids.40,41 Because it is be noted. In most cases of both paucibacillary and multibacillary
aerobic, it may survive in a granuloma environment with a relatively disease, the diagnosis is straightforward. However, the small pro-
low oxygen tension gradient using lipids and fatty acids as carbon portion of suspected cases that do not exhibit anesthetic patches
sources.42 M. leprae creates a lipid-rich phagosome environment require examination by a specialist to find other cardinal signs of
that is favorable for its survival.43 Adipose differentiation-related pro- the disease, including nerve involvement and a positive laboratory
tein (ADRP) and perilipin expression, which contribute to lipid intake, test for acid-fast bacilli.
significantly increase following M. leprae infection. Infection also has Patients commonly present with weakness or numbness as the
a pronounced effect on Schwann cell lipid homeostasis via regula- result of a peripheral-nerve lesion, or a burn or ulcer in an anesthetic
tion of lipid droplet biogenesis and traffic, which favors M. leprae hand or foot. In typical multibacillary leprosy, diffuse infiltration of
intracellular survival.44 the skin is evident. There may be many lesions that are not hypo-
It was long thought that leprosy might have a strong host genetic aesthetic, while only a few hypopigmented lesions with reduced
component. With the use of gene expression profiling, gene expres- sensation are seen in paucibacillary patients. Careful inspection of
sion patterns associated with host immune response in lesions of the entire body is important. The great auricular nerve, ulnar nerve,
human leprosy have been clarified.45 Genes belonging to the leuko- median nerve, radial-cutaneous nerve, posterior tibial nerve and lat-
cyte immunoglobulin-like receptor (LIR) family were significantly eral popliteal nerve are frequently involved with enlargement, with or
upregulated in lesions of lepromatous patients suffering from the without tenderness, and standard regional patterns of sensory and
disseminated form of the infection.45 A genome-wide search for loci motor loss.48 Neuritic leprosy in India and Nepal is characterized by
affecting the susceptibility to leprosy mapped a susceptibility locus asymmetrical involvement of peripheral nerve trunks without visible
to chromosome 6q25-q26.46 There is a close relationship between skin lesions.49–51
leprosy susceptibility and SNP in the genes encoding tumor necro- The Ridley–Jopling classification system,52 based on the
sis factor (TNF)-a and IL-10.47 M. leprae-specific immunological resistance status of the host, is
clinically relevant and widely used, although the WHO only distin-
guishes between paucibacillary and multibacillary for simplicity of
CLINICAL FEATURES
use in endemic countries. Ridley–Jopling divided the disease into
Leprosy is a systemic disease that primarily affects the skin, six categories based on dermatological, neurological and histopath-
nerves and eyes. M. leprae infection induces diverse clinical mani- ological findings: indeterminate (I), tuberculoid (TT), borderline tuber-
festations depending on the host immune responses. Paucibacil- culoid (BT), mid-borderline (BB), borderline lepromatous (BL) and
lary leprosy is a milder disease characterized by few (£5) lepromatous (LL) (Fig. 2). TT leprosy can be associated with rapid
hypopigmented, anesthetic skin lesions. The multibacillary form is and severe nerve damage, whereas LL is associated with chronicity
associated with multiple (>5) skin lesions, nodules, plaques, thick- and long-term complications. Borderline disease is unstable and
ened dermis or skin infiltration, and in some instances, involve- can be complicated by lepra reactions as described in the ‘‘Lepra
ment of the nasal mucosa, resulting in nasal congestion and Reactions’’ section.
Figure 2. Typical dermatological views of leprosy patients. A multibacillary case (lepromatous) showing multiple nodules in the arms (a) and ears
(b), and a paucibacillary case (borderline tuberculoid) with large erythema annulare, with discoloration in the middle of the lesion accompanied by
loss of sensation (c).
DIAGNOSIS AND LABORATORY TESTS subjected to acid-fast staining in addition to conventional histo-
pathological diagnosis in order to demonstrate the presence of
Leprosy exerts systemic effects in addition to skin lesions, which is mycobacterium; however, bacilli are not usually detected in pauci-
evident in the infiltration of bacilli into the nasal mucosa, bones and bacillary cases. The presence of neural inflammation is a histolog-
other organs of multibacillary patients.53 Severe skeletal lesions, the ical characteristic of leprosy that can differentiate it from other
hallmark of lepromatous leprosy, have been observed in excavated granulomatous disorders. The polymerase chain reaction (PCR) is
skeletal remains,54–58 and M. leprae DNA has been isolated from a sensitive method for the detection of M. leprae DNA that is
such lesions (Fig. 3).59 Eye damage is frequently seen in multibacil- widely used for differential diagnosis in advanced countries,
lary patients resulting from both nerve damage and direct bacillary although it cannot determine if viable organisms are present
invasion.60 Typically, lagophthalmos is caused by involvement of because DNA can persist long after microorganisms are
the zygomatic and temporal branches of the facial nerve. Other dead.15,30,59,63 Serum antibodies against M. leprae phenolic
facial nerve damage, such as involvement of the ophthalmic branch glycolipid-I (PGL-I) are found in multibacillary patients and some
of the trigeminal nerve, causes anesthesia of the cornea and con- household contacts, although its specificity is relatively low.30,64–66
junctiva, resulting in dryness and the risk of ulceration. Non-endemic countries do not usually consider leprosy during the
A diagnosis of leprosy is made based on cardinal signs such differential diagnosis of skin lesions; however, it should be consid-
as hypopigmented or reddish patches with definite loss of sensa- ered in a case of peripheral neuropathy or persistent skin lesions
tion, thickened peripheral nerves and acid-fast bacilli in slit-skin if patients are from endemic countries. Late diagnosis leads to
smears or biopsy materials.61,62 Smear and biopsy samples are continued transmission and increased risk of disability.67,68
(a) (b)
(c) (d)
(e)
Figure 3. Skeletal lesions of leprosy and isolation of lesion-associated Mycobacterium leprae DNA.59 Frontal view (a) and left side view (b) of
archaeological skeletal remains showing erosive deformity of the nasal aperture and disappearance of the anterior nasal spine (arrows) and
severe atrophy of the alveolar bone in the maxilla ⁄ palatal process with loss of anterior teeth (arrowheads) in panels (c) and (d). Polymerase chain
reaction detection of M. leprae DNA from skeletal samples (samples 1–4). Samples 5–7 were taken from other skeletons found in the same ceme-
tery, which had no leprous changes as a negative control. M. leprae DNA was detected in sample 1 (maxillary palate) and 4 (fibula) (e).
(a) (b)
(c) (d)
Figure 4. Female chimpanzee at leprosy diagnosis (a) and 3 months after the initiation of multidrug therapy (MDT), showing significant improve-
ment of facial lesions (b).30 Intact Mycobacterium leprae bacilli before treatment (c) fragmented and showed a granular staining pattern 6 months
after MDT (d).
multibacillary cases. Although there has been little standard moni- with missense mutations in the folP1 gene encoding dihydroptero-
toring of clinical outcomes and relapse rates, accurate diagnosis of ate synthase.73,74 Resistance to RFP is induced by a mutation in
relapse requires clinical, bacteriological and histopathological rpoB, which encodes DNA-dependent RNA polymerase sub-
evidence.70 unit-b.75 PCR analysis can provide a simple assessment for possi-
Rifampicin is an effective bactericidal agent against M. leprae. ble susceptibility to these drugs.73,74
Within a few days of administrating a single 600-mg dose to multi-
bacillary patients, the bacilli are no longer viable when inoculated
LEPRA REACTIONS
into mouse footpads.71 DDS is bacteriostatic or weakly bactericidal
against M. leprae and was the mainstay leprosy treatment for many Lepra reactions (or reactional states) are acute inflammatory compli-
years until widespread resistant strains appeared. CLF binds prefer- cations that occur in treated or untreated leprosy and often present
entially to mycobacterial DNA and exerts a slow bactericidal effect as medical emergencies. There are two major clinical types of lepra
on M. leprae by inhibiting mycobacterial growth. Skin discoloration reactions that affect 30–50% of all leprosy patients.76–78 Severe
ranging from red to black, is one of the most troublesome side- inflammation associated with these reactions results in nerve injury
effects of CLF, although the pigmentation fades slowly in most accompanied by subsequent loss of sensation, paralysis and defor-
cases after withdrawal. A characteristic ichthyosis is also some mity. The different types of reactions appear to have different under-
times evident. Other effective chemotherapeutic agents against lying immunological mechanisms; however, the factors that initiate
M. leprae include ofloxacin (OFLX), minocycline (MINO), levofloxacin them are unknown.
(LVFX), sparfloxacin (SPFX), moxifloxacin (MFLX) and clarithromycin Reversal reactions (type 1 reactions) manifest as erythema and
(CAM).72 edema of dermal lesions and tender peripheral nerves with rapid
As with most chemotherapies, drug-resistant strains are becom- loss of nerve function. It generally occurs during the first several
ing a problem in leprosy, which is a potential threat to the success months of treatment, and occasionally after MDT is completed.79,80
of current leprosy control efforts. Dapsone resistance is associated Treatment is aimed at controlling acute inflammation, easing pain,
(a) (b)
(c) (d)
Figure 5. Leprosy with peripheral nerve damage. Swelling of the great auricular nerve (a), facial nerve paralysis (b), dropped wrist, clawed fingers
with stiff joints due to ulnar and median nerve damage (c), and foot ulceration due to loss of sensation (d).
reversing nerve and eye damage, and reassuring the patient. Stan- led to increased knowledge of M. leprae genomic structure and host
dard courses of corticosteroids have been used to treat patients for responses. Health-care workers and researchers should continue to
several weeks to months. Erythema nodosum leprosum (ENL or support the intensive implementation of the elimination strategy and
type 2 reactions) occurs in lepromatous and borderline lepromatous address issues related to the detection of M. leprae-infected individ-
patients with higher bacterial loads in their lesions.81 ENL can begin uals as a matter of urgency. Sustained quality patient care that is
during the first or second year of treatment. Patients are febrile with equitably distributed, affordable and easily accessible is still
skin nodules accompanied by iritis, neuritis, lymphadenitis, orchiitis, needed. A goal of the WHO is to bring institutional and management
bone pain, dactylitis, arthritis, and proteinuria that is difficult to changes that strengthen the operational capacity of leprosy control
treat.82 CLF has an anti-inflammatory effect on ENL, and thalido- programs. Improvement is needed in efforts to provide appropriate
mide is better than steroids in controlling ENL, although thalidomide information to societies, dermatologists and patients. M. leprae is a
is not available in many countries because of its teratogenic very unique microorganism. It is expected that basic research for
effects.83 The use of monoclonal antibodies or inhibitors of TNF-a, leprosy can be sustained.
as used in rheumatoid arthritis, Crohn’s disease and psoriasis,
seems to be a logical choice for treatment, but more evidence is
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