Dermatologic Therapy, Vol.

22, 2009, 518537

Printed in the United States All rights reserved

2009 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPY
ISSN 1396-0296

Treatment of leprosy/Hansens
disease in the early 21st century

dth_1274

518..537

Sophie M. Worobec
Department of Dermatology, College of Medicine, University of Illinois at
Chicago, Chicago, Illinois

ABSTRACT: Leprosy, or Hansens disease (HD), is caused by Mycobacterium leprae, a slowly dividing
mycobacterium that has evolved to be an intracellular parasite, causing skin lesions and nerve damage.
Less than 5% of people exposed to M. leprae develop clinical disease. Host cell-mediated resistance
determines whether an individual will develop paucibacillary or multibacillary disease. Hansens
disease is a worldwide disease with about 150 new cases reported annually in the United States.
Effective anti-mycobacterial treatments are available, and many patients experience severe reversal
and erythema nodosum leprosum reactions that also require treatment. Leprosy has been the target of
a World Health Organization multiple drug therapy campaign to eliminate it as a national public health
problem in member countries, but endemic regions persist. In the United States, the National Hansens
Disease Program has primary responsibility for medical care, research, and information.
KEYWORDS: borderline, erythema nodosum leprosum, lepromatous, leprosy, Lucio phenomenon,
Hansens disease, multibacillary, paucibacillary, reversal reactions, multiple drug therapy, tuberculoid

Introduction
Leprosy (synonyms: Hansens disease (HD), Hanseniasis, elephantiasis grecorum) is a chronic infectious disease with neural, skin, and upper airway
mucosal involvement caused by Mycobacterium
leprae. This bacillus was discovered by Dr. Gerhard
Armauer Hansen in skin lesions of a leprosy patient
in 1873, when leprosy was endemic in Norway (1).

Etiology
M. leprae is an acid-fast rod-shaped bacterium with
parallel sides and rounded ends, 18 mm long and
0.3 mm in diameter. It is an obligate intracellular
parasite that reproduces by binary fission slowly,
every 1213 days in the early logarithmic growth
Address correspondence and reprint requests to: Sophie M.
Worobec, MD, Associate Professor of Clinical Dermatology,
Department of Dermatology, College of Medicine, University
of Illinois at Chicago, 1801 W. Taylor Street, Suite 3E, Chicago,
IL 60612-7300, or email: drsophie@sbcglobal.net.

518

phase (mouse footpads), reaching the early plateau

growth phase in 2040 days (2,3). Despite many
attempts, researchers have been unable to culture
it in vitro on any culture medium. It grows best at
temperatures 2730C (8186F), below the core
temperature of humans, and can remain viable for
up to 5 months in the environment (4).
M. leprae has been grown experimentally in
normal mouse foot pads; in nine-banded armadillos, in monkeys, and in foot pads of immunodeficient mice for investigational drug studies,
including drug resistance and screening of new
antibacterial treatments.
Humans are the major host and reservoir of
M. leprae but it has also been rarely isolated
from chimpanzees, sooty mangabey monkeys, and
cynomolgus macaques. It is also present in about
15% of wild nine-banded armadillos in the
southern United States. Armadillos develop multibacillary disease and are the only verified environmental reservoir of M. leprae.
Armadillos are mammals with a core body temperature in the 2833C range compared with 37C
in humans. Armadillos dig in the soil, preferring

Leprosy/Hansens disease treatment

moist soil near riverbeds and lakes in arid areas (5).

Armadillo contact, especially eating armadillos,
has been associated with development of human
disease (6,7). Recent M. leprae genomic studies
support the idea that humans migrating from
Europe and Africa brought the European/North
African SNP type 3 strain of M. leprae to the Americas (8) including the southern United States, long
before the arrival of armadillos into the southern
United States. Wild armadillos from Louisiana,
naturally infected with M. leprae, have the
European/North African SNP type 3 strain, consistent with their becoming infected after human
migration brought leprosy to the Americas (9).
M. leprae is unique among bacteria in its ability
to infect peripheral nerves, with nonmyelinated
Schwann cells being more susceptible to infection
than myelinated ones. M. leprae has a specific cell
wall phenolic glycolipid-1 (PGL-1) containing a
trisaccharide that binds to the a2 side chain of
laminin-2 on the basal lamina of Schwann cells.
The M. leprae surface exposed protein, LBP21, also
binds to laminin-2. Together, the combined
binding of PGL-1 and LBP21 suffices to allow entry
of M. leprae into the Schwann cell. M. leprae then
causes early nerve demyelination by turning off
myelin gene transcription as well as promoting
myelin-free Schwann cell growth that triggers an
inflammatory response (10).
The M. leprae genome was completely
sequenced in 2001. It has undergone severe reductive evolution which renders it largely inactive
(only 49.5% is protein coding), having 1600 genes
encoding proteins, compared with the related
Myobacterium tuberculosis genome being 91%
protein coding and having 4000 genes producing
proteins (11). The M. leprae genome has lost genes
for catabolic and respiratory enzymes and other
systems, explaining its limited ability to survive
extracellularly (12). Several polymerase chain reaction (PCR) and reverse transcription PCR techniques can detect M. leprae DNA in tissue from
patients, but despite being 100% specific for recognition of M. leprae DNA, such probes are no more
sensitive than microscopic confirmation of M.
leprae for diagnosing patients (13,14). The molecular basis for rifampin-, dapsone-, and ofloxacinresistance has also been identified, and resistant
mutant M. leprae isolates can be identified by PCR
DNA amplification of specific DNA fragments from
skin biopsy specimens followed by molecular
analyses (1315).
In all M. leprae strains isolated worldwide, no
variation of the 16S ribosomal RNA (rRNA) gene
had been found until 2008, when a variant myco-

bacterium with a proposed name of Mycobacterium lepromatosis was isolated and identified by
molecular techniques in tissue samples from two
patients who had died in Arizona. The two patients
had diffuse multibacillary disease of a leprosy
variant called diffuse lepromatous leprosy (DLL),
diffuse leprosy of Lucio and Latapi, or leprosy
with the Lucio phenomenon (LP) (16). The same
bacillus genome has also been identified in two
previously reported fatal DLL cases from Singapore
(16,17). The M. lepromatosis (sp. nom. prov.)
genome differs from previously reported M. leprae
genome strains in 2.1% of the 16S rRNA gene and
in 614% mismatches among five less conserved
genes (16). Researchers have not yet reached a consensus to classify it as a new species, subspecies, or
as a separate strain of M. leprae.

Epidemiology
Less than 5% of people exposed to M. leprae
develop clinical disease, although subclinical infection with antibody formation to PGL-1 occurs in
1.735% of people living in endemic areas. These
tests are reflective of past exposure in an endemic
area and are not helpful in making a diagnosis of
leprosy. The modes of leprosy transmission are not
known, but could possibly occur by: (i) exposure
to nasal and oral secretions of patients harboring
bacilli, (ii) skin to skin contact, (iii) congenital
transmission (18), (iv) dermal inoculation via
tattoo needles (19), (v) from infected soil or sphagnum moss, and (vi) exposure to insect or arthropod
vectors (12). Nasal inhalation of M. leprae with
bacilli lodging on the inferior turbinates, followed
by a brief bacteremia, followed by bacilli binding
to Schwann cells and macrophages, is a widely
accepted leprosy transmission hypothesis (14,20).
Epidemiological studies show that household
contact with a person with untreated multibacillary disease in an endemic area carries an eventual
risk of disease of up to 10% with children being at
greater risk. Brazil reports 80% of HD cases in the
Americas. A recent case-control study in northeastern Brazil (21) showed a low level of education (correlating with poverty); having ever experienced
food shortage; bathing weekly in open water
(creek, river, or lake); hunting or fishing 10 years
previously; low frequency (< biweekly) of changing
bed linens or hammocks (indicating lack of access
to fresh water); and living in a house with a sand
or mud floor were significantly associated with
leprosy. These risk factors indicate that both direct
and indirect modes of transmission can occur.

519

Worobec

Prior BCG vaccination was protective, corresponding to a vaccine effectiveness of 52%, which
matches the protective effect seen in other studies.
In 1991, the World Health Assembly passed a
resolution to eliminate leprosy as a public health
problem by the year 2000. Elimination per countrywide status was defined as a prevalence of less
than 1 case per 10,000 people in any single country.
The World Health Organization (WHO) leprosy
elimination campaign mobilized leprosy control
programs in the developing world and provided
anti-mycobacterial chemotherapy to at least 11
million patients. In 2007, the WHO reported that
leprosy was eliminated from 118 countries out of
122 countries where leprosy was considered as a
public health problem in 1985 (22), with leprosy
remaining prevalent above elimination levels in
only four countries.
As shown in FIG. 1, by the start of 2008, both D.R.
Congo and Mozambique had reached WHO elimination status. Timor-Leste, not an independent
country in 1985, was added to the list of countries
not achieving elimination status (23).
The WHO reported that the number of registered
patients fell from 5 million in 1985 to 700,000 in
2001 and to 212,802 in early 2008 (23). This drop

was accompanied by a change in case definition to

include only those patients with active disease who
are undergoing multidrug therapy, and a halving of
treatment duration time (24). Patients completing
the official WHO treatment regimen are considered
free of the disease. However, at least 14 million
people worldwide who have finished antimicrobial
treatment still suffer complications as a result of
leprosy, and leprosy remains a leading cause of
neurological disability in developing countries.
The WHO criterion for elimination does not equate
to eradication (24); leprosy remains endemic in
many areas (25) (FIG. 2).
In 2009, leprosy is still present (i.e., not eradicated) in Asia, the Caribbean, parts of North
America; Central and South America, parts of
Europe (Spain, Portugal, Italy, Greece), parts of
Australia, and Africa. India, which has the worlds
highest number of patients who have had or have
leprosy, reached WHO national level elimination
status in December 2005 (26). Pockets of high
endemicity remain in some areas of Angola, Brazil,
Central African Republic, Democratic Republic
of Congo, India, Madagascar, Mozambique,
Nepal, and United Republic of Tanzania (25). In
endemic areas, leprosy is still a public health

FIG. 1. Countries with leprosy less than WHO elimination levels: 1985 and 2008 (used by permission of The Nippon Foundation).

520

FIG. 2. Leprosy prevalence, beginning of 2007 (25).

Leprosy/Hansens disease treatment

521

Worobec

FIG. 3. Annual incidence of new Hansens disease cases in

the United States: 19762007.

FIG. 4. Location of 137 new cases of Hansens disease in the

problem requiring attention to early diagnosis,

adequate anti-mycobacterial chemotherapy, early
management of nerve damage, and follow-up postchemotherapy with attention to possible relapses,
reactional states, and care of disabilities and rehabilitation as needed (27). Although eradication of
leprosy may yet require generations to achieve,
control is now possible through sustained efforts at
early detection and treatment (28,29).
It is a mystery why in some countries such as
Norway, leprosy completely disappeared prior to
effective chemotherapy and despite lack of total
isolation. Between 1856 and 1920, case detection
rates in Norway declined from 36.9 per 100,000
person-years to 0.3 per 100,000 person-years.
Some researchers theorize that improvement in
living conditions and an isolation policy led to
decrease in transmission (30).
HD is a reportable disease in the United States. It
has been endemic in Louisiana, Texas, and Hawaii.
Puerto Rico, American Samoa, and some US Trust
Territories also have endemic areas. In 2006, a total
of nine HD cases were reported from Hawaii, and
one from Puerto Rico. The 2006 reports from
Hawaii were almost entirely among immigrants
from Micronesia or the Trust Territories where HD
is endemic (31). FIG. 3 shows the annual number of
new HD cases reported in the United States (31,32).
A total of 7166 HD cases were registered in the
United States from 1976 through the end of 2006. In
2006, there were 137 new cases from 30 states with
an age range of 783 years. Nationwide in 2006,
116 (85%) of the 137 newly registered patients had
been born outside the United States. Others were
US-born individuals who have lived for extended
periods in endemic areas, both within the United
States and also ex-United States. As FIG. 4 shows,
the states with the highest numbers of cases (92/137
or 67%) were California, Florida, Louisiana, New
York, Massachusetts, and Texas. A total of 20 pa-

522

United States, 2006 (31).

tients were reported from Texas (11) and Louisiana

(9) of whom half were US-born individuals with no
history of living outside the United States (31).

Genetic factors
Although only about 5% of exposed individuals
develop clinical disease, subclinical infection is
probably common: there is no test for detecting
exposure to the bacillus and subsequently mounting a protective immune response (13,14). Leprosy
sometimes clusters in families, and twin studies
have shown higher concordance rates for disease
susceptibility among monozygotic twins (6085%)
than in dizygotic twins (520%) (33,34). The human
Nramp1 gene (now designated SLC11A1) on chromosome region 2 q35 has been linked to leprosy
susceptibility among Vietnamese families, but may
be only one of several genes contributing to disease
susceptibility (35).
A locus in the promoter gene of PARK2 and a
coregulated gene PACRG, has been associated in
a Vietnamese patient population and a second
analysis of Brazilian patients with overall susceptibility to M. leprae infection (36). This was the first
report of a positional cloning being used to identify
genes with susceptibility to an infectious disease
in two unrelated populations. These two genes
also have a close linkage to early onset Parkinsons
disease susceptibility genes (37) and are expressed
in both Schwann cells and macrophages.
Two genetic studies have linked HLA-DR2 and
DR3 with the development of tuberculoid HD, and
in one study, with both lepromatous and tuberculoid HD. HLA DQ1 has been linked to development
of lepromatous leprosy. Other studies have looked

Leprosy/Hansens disease treatment

at microsatellite markers on chromosome 10p13,

the TAP2 gene, tumor necrosis factor alpha
(TNF-a) gene alleles and human Toll-like receptors, and the human vitamin D receptor gene
(VDR) alleles and their associations with development of leprosy (13). Polymorphisms in Toll-like
receptor 4 (TLR4) have been associated with protection against leprosy among Ethiopians (38).

Diagnosis and classification of HD

The HD incubation period varies from 3 months
(39) to 40 years, although 57 years is typical. All
age groups are susceptible, with the median age of
onset around 35 years of age. Leprosy in infants
is extremely rare (40). Individual host resistance
determines whether an individual will develop
paucibacillary or multibacillary disease (1). For
paucibacillary disease, the incubation period is up
to 5 years, and for multibacillary disease is 20 years
or longer (15). Men are generally diagnosed about
twice as often as women, but not always. For
example, 2007 statistics from Brazil showed almost
an equal gender distribution with women constituting 20,437 of 44,436 (46%) newly diagnosed HD
patients (41).
The first step in diagnosis is awareness of the
possibility of HD in patients who present with skin
lesions and sensory loss and who have lived in
endemic areas or who have relatives/household
members with the disease. Diagnosis is based on
finding consistent skin lesions with associated
sensory loss, with or without associated thickened
nerves. In the developed world and elsewhere, at
medical centers, the gold standard for diagnosis
is histological confirmation with both H&E and
Fite stains being done to recognize granulomatous
disease and the presence of M. leprae. Slit skin
smears to examine for presence of acid fast bacteria (AFB), if expertise to do them is available, help
evaluate extent of disease burden.
The earliest clinically apparent lesion is that of
indeterminate leprosy which may be self-healing
(FIG. 5). The RidleyJopling Classification (1)
divides determinate HD along a continuum
according to polar tuberculoid, borderline tuberculoid, borderline, borderline lepromatous, and
polar lepromatous stages (FIG. 6). The tuberculoid
pole is marked by a strong Th 1 cytokine response;
and the lepromatous pole, by a Th 2 response. This
classification system, introduced in 1966, is useful
for precise diagnosis and follow-up of clinical
disease over long periods of time. It depends on
having histological confirmation of clinical find-

ings and reflects the individual patients immune

status in fighting the disease. It guides the choice
and length of antimicrobial therapy and predicts
the probability and type of reactions.
The average number of bacteria seen using an
oil immersion objective are quantified on Ridleys
logarithmic scale, called the Bacterial Index (BI)
which varies from 6+ to 1+ as follows:
6+
Many clumps of bacilli (over 1000) in an
average field
5+
1001000 bacilli in average field
4+
10100 bacilli in average field
3+
110 bacilli in average field
2+
110 bacilli in 10 fields
1+
110 bacilli in 100 fields
Organisms which stain solidly are considered
viable and nonviable organisms stain in a granular,
beaded, or irregular pattern. This observation, that
granular staining bacteria are nonviable, was first
proposed by Hansen in 1895 (1). The morphological index (MI) is the % of solid staining bacteria,
based on examining 200 red-staining bacteria lying
singly, not in globi, and the MI is used to monitor
whether a patients disease is active, and response
to treatment. An increased MI indicates worsening
and a decreased MI indicates improvement.
Unavailable in the United States, and not Food
and Drug Administration (FDA)-approved for skin
testing, lepromin is a heat-killed M. leprae sonicate preparation, which on skin testing causes a
strong reaction in patients at the tuberculoid pole
with a strong cell-mediated immunity (CMI) TH1
response, but causes no response in patients
at the lepromatous pole with specific anergy to
M. leprae. Lepromin testing provided the first
confirmation that specific host immunity was responsible for determining polarity on the Ridley
Jopling classification system (15,42). However, the
lepromin test is not diagnostic of leprosy because
many people who have never been exposed to M.
leprae will have a positive reaction. Read at 4
weeks (unlike the Day 2 or 3 readings of tuberculin tests), it essentially measures a persons ability
to mount a granulomatous response to mycobacterial antigens (13,15).

Indeterminate leprosy
One or several (1) hypopigmented or faintly
erythematous patches (FIG. 7) are found in
persons who are susceptible to infection and
whose immunological status is still to be elucidated. There may be sensory loss of temperature

523

Worobec

FIG. 5. Stages in leprosy infection (42,43).

High resistance
Borderline
Tuberculoid tuberculoid
(TT)
(BT)
Number of
lesions
Bacillary
load
Lepromin
test
reactivity
Histology

1-3

Few

1+

2+

3+

4+

3+

2+

Epitheliod cell granulomata

ringed by lymphocytes.
Nerve infiltration, destruction.

FIG. 6. RidleyJopling classification (42).

524

Little or no
Unstable resistance
resistance
Borderline
Borderline
Lepromatous Lepromatous
(BB)
(BL)
(LLsp and LLp)
Few or many
Numerous and
Many
asymmetrical
symmetrical

Increasing histiocytes, foamy

xanthoma-like granulomata, globi.

Leprosy/Hansens disease treatment

FIG. 7. Indeterminate Hansens disease facial hypopigmented patch.

discrimination, or ability to feel light touch, and it

should be in the differential diagnosis of an individual who lives or has lived in an endemic area or
is a family/household member of an index case.
The differential diagnosis includes pityriasis alba,
pityriasis versicolor, postinflammatory hypopigmentation, and hypopigmented vitiligo (44). Pfaltzgraff and Bryceson cautioned that especially in
children, the diagnosis should not be made unless
there is a confirmatory biopsy (45).
For suspected indeterminate HD, the optimal
biopsy site is the center of the lesion (46), unlike
defined cases, where the optimal biopsy site is
within the active lesional border. In the United
States, some HD specialists will biopsy both a
central and a border lesional area. There is no
reason to include adjacent normal skin. Usual
biopsy size is 4 mm, but Ridley and Jopling preferred a 5-mm biopsy. The biopsy should include
the entire depth of the dermis and be into the
upper subcutaneous fat (1).
Skin histological findings may show a histiocytic
or lymphocytic infiltrate, with reaction around or
within a dermal nerve or in the subepidermal zone
or around arrector pilaris muscles. AFB are absent
or scanty according to the histologic description
given by Ridley and Jopling (42). However, Scollard
et al. have cautioned that an indeterminate diagnosis should only be applied if both nerve involvement and AFB are seen because a diagnosis of HD

FIG. 8. Polar tuberculoid (TT) Hansens disease. Facial patch

with partial slightly elevated erythematous border and loss of
temperature discrimination.

can have significant impact on a patient and his/

her family (13).

RidleyJopling classification: clinical

and histopathological findings
Polar tuberculoid (TT)
This occurs in individuals with high, but not complete resistance. Symptoms may be neural or cutaneous or both. The neural symptoms may include:
numbness, pain, tingling, muscle weakness (e.g.,
foot drop, weakness of 4th and 5th fingers along
ulnar enervation) and/or paralysis. The skin lesions
are usually single, or rarely two to three asymmetrically distributed well-demarcated plaques or flat
patches (see FIG. 8). These occur on cooler areas of
the body, not on warmer areas such as the scalp,
axillae, groin, or perineum. The TT skin lesions have
been described as having a right side up saucer
appearance (1): raised well-demarcated borders
which slope inwards toward the center, but considerable variation can occur. The lesions are hypopigmented or less commonly erythematous, or have a
coppery or orange tint in darker skin (1). The lesions
are dry and tend to be hairless and have an insensi-

525

Worobec

tive surface, except on the face where the rich

dermal nerve supply may result in preservation of
sensation. About 30% of nerves have to be destroyed
before sensory impairment can be detected, therefore pain may be the first neurological symptom
(1). Temperature discrimination may be the first
sensory modality lost within facial lesions. Often an
enlarged nerve is palpable nearby, e.g., an ulnar
nerve if the skin lesion is near the elbow.
Skin histology consists of small tuberculoid
granulomas, sometimes with Langhans giant cells
present, with well-organized lymphocytic mantles
consisting of mostly CD4 positive cells, around
neurovascular bundles. The Grenz zone may be
involved, unlike the Grenz zone sparing seen in
multibacillary disease. Few or no AFB may be seen.
Dermal nerves can be swollen by epithelioid granulomas, or completely destroyed, or sometimes
contain AFB and/or areas of caseation necrosis.
Borderline tuberculoid (BT)
Skin findings. Clinical findings are similar to that of
TT HD but with more numerous skin lesions and
smaller satellite lesions around the larger lesion;
however, solitary lesions can occur but are larger
(FIG. 9), often over 10 cm in diameter (15,47). Skin
histology shows a narrow Grenz zone, with more
diffuse granulomas with less frequent or absent
foreign body giant cells; dermal nerves show moderate infiltration or only Schwann cell proliferation. A few AFB may be found in the nerves, but not
lying freely in the dermis.

Hypopigmented skin lesion

with palpable enlarged great
auricular nerve (marked by
arrows)

FIG. 9. Borderline tuberculoid Hansens disease.

526

Enlarged superficial nerves may be found, the

most common ones being the ulnar, median and
radial cutaneous, common peroneal, posterior
tibial and sural, and the great auricular and zygomatic arch of the facial nerves. It is wise to remember that even in normal, very lean muscular
individuals, the ulnar and the great auricular
nerves can be palpable (48). It is important to
become familiar with normal nerve size by practicing on many disease-free individuals and to
palpate the nerve on the opposite side of the body
for comparison (49). A diagnosis of HD cannot be
based solely on finding an enlarged nerve as these
findings are consistent but not diagnostic, and
need confirmatory evaluation.
Borderline (BB)
Skin findings. Lesions are more numerous, generalized but still asymmetrically distributed but less
well defined and smaller satellite lesions are
common (FIG. 10). Histology differs from BT in
that AFB can be found in the dermis as well as in
nerves, there is a defined Grenz zone, and granulomas are mostly epithelioid with few lymphocytes
and no giant cells. Nerves show slight swelling and
cellular infiltration.
Borderline lepromatous (BL)
Skin findings. There may be a single original or first
appearing lesion, or symmetrical lesions that are
too numerous to count which consist of macules,

Hypopigmented skin lesion >10 cm in

diameter on lower back

Leprosy/Hansens disease treatment

FIG. 10. BB Hansens disease. Treated irregular annular

lesion on elbow with smaller satellite lesions and redbrown
clofazimine hyperpigmentation.

papules, plaques, and nodules. The classic dimorphic lesion: annular with diffuse outer border and
sharply demarcated inner border is seen in 1/3 of
patients. But many variations are seen, ranging
from annular lesions with sharply demarcated
inner and outer margins or poorly defined plaques
with well-demarcated Swiss cheese type islands
of clearing within the plaques (15) (FIG. 11).
If multiple lesions are present, the smaller
lesions predominate and there is no sensory loss
over the lesions. Nerve involvement appears later
and tends to be symmetrical. Classic findings of
polar lepromatous disease such as saddle nose,
madarosis, and leonine facies are usually not
present (47). Dermal histology shows macrophage
granulomas with slight foamy change and lymphocytes in clumps or widely distributed among the
granulomas. Dermal nerves can show an onion
skin lamination, and have a cellular infiltrate.
There is a clear Grenz zone and many AFB are
present in clumps, globi (clumped within a distended macrophage) or singly.
Polar lepromatous (LL)
This stage starts from indeterminate HD in those
with little resistance, or as a downgrading progression of BL HD (15). Diffuse dermal infiltration is
always present and can be nodular or non-nodular.
Findings can include small hypopigmented
macules similar to that seen in pityriasis versicolor
but symmetrically distributed all over the body, or
consist of lepromatous infiltrates that can be

FIG. 11. Borderline lepromatous Hansens disease with

widespread erythematous plaques containing islands of clear
skin within the plaques (image courtesy of Dr. Thomas H. Rea,
Los Angeles).

diffuse, plaque-like, or nodular. Macules are ill

defined and show no sensory loss or loss of sweating. Sweating is eventually lost with compensatory
hyperhidrosis in areas of sparing. Hair loss starts
over the lateral third of the eyebrows, then may
involve the eyelashes (madarosis) and the body but
scalp hair is preserved (FIG. 12). Nodular infiltration can be seen on acral parts: the earlobes, nose,
chin, elbows, hands, buttocks, and knees. These
nodules can enlarge and destroy underlying structures such as the nasal cartilage causing a saddle
nose deformity and erode the alveolar ridge
leading to loss of teeth. Epistaxis is a common early
finding; leonine facial nodular infiltration can be
seen in advanced disease.
Skin histology shows flattening of the epidermis
with a clear Grenz zone, with a deeper diffuse
foamy histiocytic infiltrate with few lymphocytes
and plasma cells. The foamy appearance is a result
of lipids in the M. leprae cell walls and a Fite stain
shows numerous AFB in globi or lying freely within
the dermis.
Sensory loss tends to be symmetrical over the
distal limbs (starts in a glove and stocking distribution). Peripheral neuropathy can occur in diabetes
mellitus, vitamin B12, and/or folate deficiency and
alcoholism. These other diseases can coexist and
should be screened for and treated if present, but
they do not cause the nerve enlargement seen in

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Worobec

Nodular earlobe
infiltration

Madarosis in diffuse
non-nodular disease

Diffuse hypopigmented
plaques on back and arm

FIG. 12. Polar lepromatous Hansens disease.

leprosy. Bone involvement can contribute to

osteoporosis and fractures. Testicular involvement
can result in gynecomastia and testicular atrophy
with complaints of impotence and infertility.
LL has been subdivided into polar (LLp) and
subpolar (LLs) types. In LLp, reactional states do
not occur as there is no upgrading toward greater
immune resistance. Patients with LLs are prone to
severe reactional states because of their bacterial
burden.

Variant clinical presentations

Histoid HD is a rare form of multibacillary HD in
which 0.11.5-cm papules and nodules are found,
mostly on the midsection of the body. It can appear
de novo (15) and also when dapsone monotherapy
was used in the past with the development of drug
resistance, or if there has been irregular dosing
of multidrug therapy because of lack of drug
availability or noncompliance, and in relapse after
treatment. Histology shows spindle-shaped cells
and many AFB.
Pure neuritic leprosy presents with multiple
asymmetrical peripheral nerve trunk involvement
showing sensory loss and possible motor deficit
but without any characteristic skin lesions. It
occurs most often in India and Nepal and in parts
of Africa. Diagnosis in the absence of characteristic
skin findings can be difficult and requires nerve
biopsy. Biopsy of an involved nerve, e.g., sural
nerve, will reveal granulomatous infiltration and
AFB.
Other organ involvement may include the eyes,
due to 7th nerve involvement or direct involvement of ocular structures, even leading to blindness in advanced cases. In advanced multibacillary
disease, there can be bacteremia with lymph

528

nodes, bone marrow, liver, and spleen being

heavily infected. Secondary amyloidosis with renal
impairment and glomerulonephritis (1) was more
common prior to the multidrug therapy (MDT)
era. Glomerulonephritis may be seen in patients
undergoing ENL reactions.
The diffuse lepromatous leprosy (1,15) variant
has been called beautiful leprosy, (Spanish:
bonita lepra) because in its early stages it causes
skin smoothening and a younger appearance and
is not associated with nodules. Later, telangiectasia, madarosis, hoarseness, arthritic symptoms,
and glove stocking sensory loss have been noted. It
is most common in Western Mexico, Costa Rica,
and along the Caribbean and rarely seen elsewhere, although recently two fatal cases were
reported from Singapore and rare cases have been
reported throughout the world (17). Slit skin
smears can be positive for AFB and dermal blood
vessels can show numerous AFB bacilli within
vascular endothelial cells. These patients are at risk
for a very dangerous vasculitic reactional state
called Lucio phenomenon which causes stellate
necrotic ulcers especially on the lower extremities
and a bluish discoloration of hands and feet. The
condition is often complicated by secondary infection and sepsis, and can be fatal.

WHO classification: paucibacillary

and multibacillary
The WHO posits that leprosy can be diagnosed
under field conditions, by health workers on clinical signs alone, allowing early treatment and thus
averting disability (22). In many endemic countries, using WHO guidelines, trained field workers
used to make the diagnosis and confirm it by slit
skin smears taken from lesions and from cooler

Leprosy/Hansens disease treatment

Table 1. Current WHO therapy guidelines for leprosy treatment (53)

Classification

Adult (5070 kg)

Child (1014 years)

Paucibacillary
(single lesion)
Paucibacillary

Rifampin (600 mg) and Ofloxacin (400 mg)

and Minocycline (100 mg), once
Dapsone (100 mg), daily (self-administered)
and Rifampin (600 mg) once per month
(supervised) 6-month regimen
Dapsone (100 mg), daily (self-administered)
and Clofazimine (50 mg), daily
(self-administered); plus Rifampin
(600 mg) and Clofazimine (300 mg) once
per month (supervised) 12-month
regimen

Rifampin (300 mg) and Ofloxacin (200 mg)

and Minocycline (50 mg), once
Dapsonea (50 mg), daily and Rifampin
(450 mg) once per month
6-month regimen
Dapsoneb (50 mg), daily and Clofazimine
(50 mg), every other day; plus Rifampin
(450 mg) and Clofazimine (150 mg) once
per month (supervised) 12-month
regimen

Multibacillary

Adjust dose for child less than 10 years on basis of body weight: rifampin 10 mg/kg monthly and dapsone 2 mg/kg daily (26).
Adjust dose for child less than 10 years on the basis of body weight: rifampin 10 mg/kg monthly, clofazimine 1 mg/kg daily and
6 mg/kg monthly, dapsone 2 mg/kg daily (26).
Note: The standard child blister pack may be broken up so that the appropriate dose is given to children under 10 years of age.
Clofazimine can be spaced out as required. The WHO states that, A patient with a high BI may rarely need to be treated for longer
than 12 months. Only specialists at referral centers should make this decision.
b

areas of the body (earlobes, elbows, and knees).

These smears were examined for AFB and the
patients were considered paucibacillary if the
smears are negative and the patient had five or
fewer skin lesions, and multibacillary if the smears
are positive for AFB. In 1998, the WHO eliminated
requiring slit smear examinations for AFB and any
neurological assessment (24), and adopted the following simplified, but controversial, classification
system for field programs:
Paucibacillary single lesion leprosy (one skin lesion
present), Paucibacillary leprosy (two to five skin lesions),
and Multibacillary leprosy (more than five skin lesions).

Treatment
WHO treatment recommendations
A WHO Study Group recommended MDT in 1982
because of increasing resistance to dapsone, which
is weakly bacteriocidal against M. leprae. MDT
consists of three drugs: dapsone, rifampin, and
clofazimine. Rifampin is the most effective bactericidal drug against M. leprae, with patients considered noninfectious within several days of
rifampin therapy. Clofazimine is weakly bactericidal and has some anti-inflammatory action. In
combination, dapsone and clofazimine potentiate
each other and the use of triple combination
therapy hinders the possible development of
rifampin drug resistance.
Other drugs with strong bactericidal effects
include: minocycline, clarithromycin, ofloxacin,
and levofloxin (12,15).

The WHO posits that MDT is safe, effective, and

easily administered under field conditions. Table 1
shows the MDT currently recommended by the
WHO (50). The WHO has shortened the treatment
period for multibacillary disease to 1 year, a
change that remains controversial (12,14,27). Currently, ex-United States, the WHO has provided
free MDT in convenient monthly calendar blister
packs to all patients who qualify for treatment.
Since 1995, drug funding was provided by the
Nippon Foundation and since 2000, through
Novartis and the Novartis Foundation for Sustainable Development.
The WHO recently recommended a single-dose
treatment, consisting of rifampin, ofloxacin, and
minocycline (ROM) for paucibacillary patients who
have a single skin lesion (51). This recommendation
assumes that the host response will eliminate any
residual viable bacteria. However, longer therapy
whenever possible is also recommended. The rationale for more extended treatment is as follows: not
all single lesions are paucibacillary, and not all bacterial organisms in a lesion are metabolically active,
in which state they are susceptible to these drugs,
over a single time interval. Leprosy lesions are not
a synchronous culture of bacteria which can be
instantaneously killed (52). The half lives for these
drugs are 35 hours for rifampin, 78 hours for
ofloxacin, and 1218 hours for minocycline, and
any dormant bacteria will not be affected by this
drug combination (52). Therefore, especially if this
treatment approach is used under field conditions,
in which slit skin smears (which would have a negative BI in paucibacillary disease) or skin biopsies are
not done as part of initial evaluation to confirm

529

Worobec

Table 2. US NHDP leprosy treatment guidelines

Classification

Adult

Children

Tuberculoid (TT & BT)

(WHO Pauci-bacillary, PB)

Dapsone (100 mg) daily, and Rifampicin

(Rifampin, Rifadin) (600 mg) daily for
12 months, and then therapy
discontinued
Dapsone (100 mg) daily, and Rifampicin
(Rifampin, Rifadin) (600 mg) daily,
plus Clofazimine (Lamprene)a (50 mg)
daily, for 24 months, and then therapy
discontinued

Dapsone (1 mg/kg) daily, and

Rifampicin (12 mg/kg) daily, for 12
months, and then therapy
discontinued
Dapsone (1 mg/kg) daily, and
Rifampicin (12 mg/kg) daily, plus
Clarithromycinb (7.5 mg/kg) daily, for
24 months, and then therapy
discontinued

Lepromatous (LL, BL, BB)

(WHO Multibacillary, MB)

a
Only available as an investigational new drug (IND) through the NHDP, which holds the IND for its use in the United States for
treating Hansens disease (HD). In order for physicians to obtain the drug for treating HD, they have to be registered as an investigator
under the NHDP IND.
b
This drug is recommended in place of clofazimine, as clofazimine cannot be used in children in the United States.

paucibacillary disease, it is essential that long-term

follow-up be carried out.
A reason for relapse posttreatment is initial
mistaken diagnosis of multibacillary disease as
paucibacillary when resources for bacteriological
assessment are lacking. Worldwide, including in
developed countries, treatment failure may result
from: noncompliance, drug resistance, relapse
after apparent cure, and persistence. Persisters are
viable M. leprae that in mouse foot pad resistance
studies are sensitive to all anti-mycobacterial
agents given, but persist in the patients macrophages and nerves despite bactericidal tissue levels.
The finding of persisters correlates with relapse 69
years after finishing MDT. Therefore, patients
should be followed at least annually after finishing
treatment whenever possible for signs of relapse,
reaction, and nerve damage (47).
The WHO recommends screening of household
members and family at time of patient diagnosis,
along with education about possible clinical signs
of leprosy.
Treatment of leprosy includes not only antimycobacterial chemotherapy, but also patient education about the disease, treatment of reactions,
monitoring for and care of nerve damage, care of
any disability, social support, physical and occupational therapy, and rehabilitation.

US National Hansen Disease

Program (NHDP) treatment
recommendations
The US NHDP recommends daily rifampin and
treatment times longer than those recommended
by the WHO.

530

Table 2 gives general NHDP medication treatment guidelines for immunologically competent
patients (54,55).
The NHDP also recommends the following alternative anti-microbial agents:
Minocycline, 100 mg daily, can be used as a substitute for
dapsone in individuals who do not tolerate this drug. It
can also be used instead of clofazimine, although evidence
of the efficacy of its anti-inflammatory activity against
Type 2 reactions is not as substantial as the evidence for
clofazimine.
Clarithromycin, 500 mg daily, is also effective against M.
leprae, and can be used as a substitute for any of the other
drugs in a multiple drug regimen. In children, this drug is
recommended in place of clofazimine, as clofazimine
cannot be used in children in the United States.
Ofloxacin, 400 mg daily, may also be used in place of clofazimine, for adults. This is not recommended for children.

For immunologically compromised patients,

these protocols may be modified, and consultation
with the NHDP is recommended. In the United
States, the occurrence of leprosy in children is rare.
The NHDP strongly recommends contacting the
NHDP for management of leprosy in children.
Five-year follow-up every 6 months is recommended in the United States for paucibacillary
cases and 10-year follow-up at 6-month intervals
for multibacillary patients. Examination of household and family contacts at time of diagnosis and
annually is also recommended.
Patient and accompanying person(s) education
about the disease and reactional states is vital.
Adjunctive therapies are targeted at prevention
of ocular, neurological, orthopedic impairments
along with cosmetic surgery as needed (e.g., for
nasal reconstruction, replacement of hair at lateral
eyebrows) as well as provision of occupational and
physical therapy.

Leprosy/Hansens disease treatment

Side effects of main

antimycobacterial
therapeutic agents
(This listing is not exhaustive and idiosyncratic
side effects can occur.)
1. Dapsone
Systemic: anemia, hemolysis (need to check
G6PD prior to start of therapy but two other
mechanisms exist: idiosyncratic, and much
more commonly from a direct membrane effect),
methemglobinemia, agranulocytosis (rare, potentially fatal), hepatotoxicity, sulfone/dapsone
syndrome (rare, potentially fatal), peripheral
neuropathy.
Cutaneous: fixed drug eruption, exanthems,
erythema multiforme, photosensitivity (56).
2. Rifampin
Systemic: nausea, hepatotoxicity (rarely fatal; preexisting liver disease and co-administration of
other hepatotoxic drugs increase toxicity), red coloration of urine, feces, saliva, sputum, sweat and
tears; thrombocytopenia, eosinophilia.
With intermittent use: shock, marrow suppression, flu-like syndrome with chills, headache,
muscle and none pain, intravascular hemolysis
and acute renal failure (rare but potentially fatal)
(57).
Strong inducer of CYP34a; can decrease levels of
corticosteroids (CS), estrogens (render birth
control pills ineffective), protease inhibitors, carbamazepine, macrolides, methadone, etc.
Cutaneous: rare reports of pemphigus, exfoliative dermatitis, acneiform lesions, urticaria, pruritus with or without rash; fixed drug eruptions;
urticarial and classic with hyperpigmentation,
maculopapular eruption, contact dermatitis,
anaphylactoid reactions, anaphylaxis, Stevens
Johnson syndrome (58).
3. Clofazimine
Systemic: anticholinergic action with decreased
sweating and tearing; red tears, urine and stools;
nausea, enteric lymph node and mucosal deposition, possible gastrointestinal obstruction, reports
of death following severe abdominal symptoms.
Accumulation in spleen may result in infarction
and rupture (15).
Cutaneous: red sweat, skin hyperpigmentation
which is worse in lesional skin and ranges from
pink to red blue or brownish black (56) (FIGS. 10
and 14) and clears slowly over 612 months after
drug discontinuation but traces can remain even
longer than 4 years (59); xerosis, acquired ichthyosis, phototoxicity.

Reactional states and their treatment

Several reactional states can occur as a result of
altered immune responsiveness. At least 50% and
possibly a much higher percentage of HD patients
will experience reactional states after initiating
therapy. Intercurrent infections, vaccinations,
pregnancy, and the postpartum state, stem cell
transplants, use of immunosuppressive medications, Vitamin A, halogens such as bromides and
iodides can increase the severity of or trigger these
reactions (1). Reactions can be abrupt and represent true medical emergencies.
There are two main types of reaction:
Type 1 reaction (T1R), or Reversal Reaction is the
result of increasing (upgrading) cell-mediated
immune response or decreasing (downgrading)
cell-mediated immune response to M. leprae.
Type 2 reaction (T2R), also known as erythema
nodosum leprosum (ENL), is mediated by circulating immune complexes. There is evidence that ENL
reactions are accompanied by very high releases of
TNF-a by peripheral blood monocytes.
Patients in all borderline stages can develop T1R,
but only BL and LLs patients develop ENL reactions. All patients need to continue their antimicrobial MDT while receiving immunosuppressive
therapy for these reactional states. All need to be
monitored for risk of M. tuberculosis and fungal
infections as well as side effects of therapy.
T1Rs present with inflammation (erythema,
edema, and even possible necrosis) of preexisting
skin lesions and neuritis of affected nerves. Associated signs include: erythema and edema of hands
and feet and face, silent neuritis, pain or tenderness of nerves and new erythematous and edematous papules, plaques and nodules (see FIG. 13). All
newly diagnosed HD patients should have a baseline neurological exam, so that a neurologist who
already is familiar with the patient can help assess
nerve involvement if and when a T1R occurs and
help guide immunosuppressive drug dosing. T1Rs
of the upgrading type usually appear soon after
chemotherapy is started. In early stages of T1R,
subclinical skin lesions may become apparent as
new lesions because of increased T helper Type 1
inflammatory attack on the M. leprae antigens.
Whereas conservative therapy, e.g., aspirin and/or
hydroxychloroquine, has been advocated for mild
lesions, it may be counterproductive as there is no
evidence that it is effective or prevents progression
to nerve damage. CS, in conjunction with CS
sparing drugs, adequate analgesia, and physical
support and maintenance of anti-mycobacterial
drugs are essential (26).

531

Worobec

Elevated edematous plaque in BT

disease developing after start of
anti-microbial regimen.

Same patient one year after T1R

treatment & continued antimicrobial regimen.

FIG. 13. Reversal reaction.

T1R with neuritis should be treated immediately

as an emergency as there is risk of permanent
nerve damage and loss of function even within the
first 24 hours. Skin necrosis can cause permanent
scarring, color change, or atrophy. Prednisone at
4060 g (0.51 mg/kg) daily is the treatment of
choice and should be started immediately and
dosage adjusted downwards or upwards as response is achieved/not achieved. Treatment may
be needed for 46 months and tapered very slowly;
alternate day dosage may be tolerated. If a nerve
continues to be painful whereas others improve,
neurosurgical evaluation for decompression of a
nerve abscess has been recommended; however,
the efficacy of this surgical intervention has not
been demonstrated conclusively (10). Cyclosporin
in doses of 510 mg/kg can be used if prednisone
fails to control the reaction or as a steroid sparing
agent. Azathioprine acts slowly and has no effect
on intraneuronal edema and should only be used
as a long-term CS sparing agent (60). Mycophenolate mofetil (MM) is more expensive than azathioprine and its use was reported in three patients
with different reactional states with one (a BL
patient with T1R) benefiting and the MM had to be
stopped after 3 months as a result of severe gastrointestinal side effects (61). Methotrexate (MTX)
has been used very successfully as a CS sparing
agent (62).
HIV-1 and M. leprae co-infected patients have
developed T1Rs leading to their being diagnosed
with HD, as part of immune reconstitution inflammatory syndrome (IRIS) after effective chemotherapy of their HIV disease (63). T1R reaction
occurs as part of IRIS, in co-infected patients, as
the CD4 T helper cell count increases, at time
intervals of 6 weeks to 6 months poststart of
highly active antiretroviral therapy (HAART). In
BT disease, this T1R can be as subtle as a single

532

erythematous edematous plaque with skin biopsy

confirmation need to establish diagnosis (64). If
neuritis occurs in these co-infected HD-HIV
patients suffering from T1R reactions, CS therapy
is indicated with close monitoring for accelerated
development of Kaposis sarcoma, avascular bone
necrosis, and activation of cytomegalovirus and
Mycobacterium avium infections (65).
Type 2/ENL reactions (FIG. 14) occur within 2
years of starting antibacterial therapy and present
clinically with eruptive painful erythematous
nodules and plaques over the entire body along
with fever, anemia and joint swelling, and pain. The
nodules, in severe reaction, may develop bullae,
pustules, or necrosis. Severe ENL has systemic
symptoms of fever and malaise, and can manifest
arthritis, dactylitis, uveitis, iridocyclitis and episcleritis, neuritis, lymphadenitis, myositis, and
orchitis (1,15,66). In the absence of an awareness
of HD, ENL may be initially misdiagnosed as
lupus erythematosus or seronegative rheumatoid
arthritis.
ENL reactions are very responsive to thalidomide, which is available in the United States
through the Celgene Corporationss System for
Thalidomide Education and Prescribing Safety
(S.T.E.P.S.) program. In the United States, only
physicians who are registered with the S.T.E.P.S.
program can prescribe thalidomide. It is teratogenic, causing phocomelia, and should not be given
to women of childbearing potential unless they are
enrolled in the S.T.E.P.S. program and on several
forms of birth control. The initial recommended
dosage is up to 400 mg daily for those weighing
over 50 kg. It is sedating and preferably given at
bedtime. Lower doses of 100200 mg can be tried
in less severe ENL, or in combination with prednisone for more severe ENL. Thalidomide can also
cause a sensory neuropathy, which is rare in HD

Leprosy/Hansens disease treatment

Erythematous
nodules and hand
swelling with redblue clofazimine
pigmentation

Scattered erythematous nodules and papules on

arms and hands

FIG. 14. Erythema nodosum leprosum nodular lesions.

patients but has been reported and can limit its

long-term use. Other adverse effects include but
are not limited to: dizziness and orthostatic
hypotension, neutropenia, and hypersensitivity
reactions. Male patients using it can excrete it in
semen and must use a latex condom when having
sexual contact with a woman of childbearing
potential, and should not donate sperm. Patients
who have received thalidomide for the treatment of
multiple myeloma have had an increased risk for
venous thrombolic events, therefore all patients
receiving this drug should be advised to seek
immediate medical help if they develop signs and
symptoms of thromboembolism.
Prednisone is also effective and provides rapid
relief when thalidomide is unavailable or cannot
be used. High doses exceeding 60 mg daily
(0.5 mg1 mg/kg) may be needed. Clofazimine in
high doses of 300 mg daily has also been used (15),
but is not uniformly successful (14). Many patients intensely dislike the skin pigmentation it
produces.
There is a report of a 52-year-old woman with
persistent severe ENL despite the use of prednisolone 40 mg daily, thalidomide 300 mg daily starting
dose, and pentoxifyline 400 mg TID; being treated
with infliximab. Infliximab 5 mg/kg was infused IV
over 4 hours after premedication with intravenous
prednisolone 25 mg, and 1 gram acetaminophen
and 10 mg cetirizine orally with improvement
noticed within several hours; the infusions were
repeated at Weeks 2 and 6 with no further treatment and no signs of ENL for 1 year after the last
infusion (67). Another patient with severe ENL had
MTX added to corticosteroid therapy, as thalidomide was not available, with excellent control of

ENL (68). Because of high bacterial loads in BL and

LL disease, ENL may persist for several years. A
strong family support system and caring staff is
essential to help a patient through this.
LP is a rare, poorly understood vasculitic reaction, which occurs in DLL. Most patients who
develop it have had undiagnosed DLL and not
been previously treated for HD. Its cause is
unknown and it is often accompanied by profound anemia (69). Early signs may include irregularly shaped erythematous patches that darken
and heal or progress to bullae with underlying
necrosis, leaving deep irregularly shaped stellate
ulcers, most commonly below the knees, that are
painful and slow to heal. LP is treated by intensive
wound care and watchfulness for complications of
secondary infection and sepsis. CS and thalidomide are ineffective (14). Rea and Modlin have
reported that new lesions of LP cease once
rifampin therapy is started (15). Both cryoglobulinemia and antiphospholipid antibodies have
been reported in this reaction and plasmapheresis
therapy may be helpful (14). In the United States,
consultation with the NHDP is recommended
(69).

Special treatment considerations

Pregnancy and lactation
Ideally, pregnancies should be planned for when
leprosy is well controlled (70).
The WHO recommends continued treatment
with standard MDT during pregnancy and lactation, but recommends deferring single dose ROM

533

Worobec

treatment for single lesion paucibacillary treatment until after delivery (71). Clofazimine can
cause pigmentation of the infants skin during lactation (69). Dapsone in the mothers milk can
induce hemolysis in the infant (15).
Dapsone, rifampin, clofazimine, clarithromycin,
ofloxacin, and levofloxacin are Food and Drug
Administration (FDA) Category C, which means
that fetal risk cannot be ruled out, but the potential
benefits may outweigh the risk. Minocycline (FDA
Category D: Positive evidence of risk) should not
be used during pregnancy. Consultation with the
NHDP physicians is appropriate for patients in the
United States.
CMI is suppressed during pregnancy and
restored after parturition. ENL reactions occur
throughout pregnancy and lactation and can be
severe. For 70 years, retrospective reports have
documented the first diagnosis of leprosy, or
worsening symptoms during pregnancy. This
may be partly a result of increased medical care
contact during pregnancy. In 1981 prior to the
uniform use of MDT, Duncan et al. showed in an
prospective study that reversal reactions (T1R)
and neuritis were more frequent in the immediate
postpartum period (72). There is a lack of prospective case-controlled studies on the course of
MDT-treated leprosy during pregnancy and the
effect on mothers and the subsequent development of children (73). In 2007, Duncan et al.
published a follow-up prospective, open-ended
cohort study which started in 1975 with follow-up
of mothers and their children until 2003, about
the development of children of mothers with
leprosy: they had lower birth weights, smaller placentae, grew more slowly, and had higher infant
mortality with delay of the pubertal growth spurt
and menarche for the girls, with catch-up by the
late teens. The changes were most marked in children of mothers with lepromatous, especially LL
disease (74).
A very complex treatment management case has
been described of a 31-year-old woman, with no
prior diagnosis of leprosy, being diagnosed postpartum with BT disease and neuritis with T1R, and
treated with the WHO regimen for paucibacillary
disease and prednisone 40 mg daily who then
developed a perforated duodenal ulcer which was
successfully treated, followed by flu-like symptoms
and rifampin-induced hemolysis complicated by
acute renal failure; rifampin was stopped and her
prednisone dose was increased along with supportive care followed by recovery of renal function
and continued treatment of her HD and neuritis
(75).

534

HD and tuberculosis (TB)

Newly diagnosed HD patients should be screened
for TB prior to initiating treatment. Rifampin
should be adjusted upwards to doses appropriate
for TB treatment.
HD and HIV disease
No change in standard treatment of HD. Rifampin,
especially if given daily, can decrease levels of antiprotease inhibitors.
Drug intolerance because of side effects or
comorbidities, e.g, allergy, G96PD deficiency,
or hepatitis
Consultation with the US NHDP is recommended
for alternate therapeutic regimens.
HD unmasked after treatment with biologicals
for arthritic symptoms
Recently, a Louisiana man with diffuse polyarthritis
and a Texan woman with rheumatoid arthritis after
receiving infliximab, were diagnosed with leprosy.
The diagnosis in both was established clinically
and histologically, and confirmed by molecular
identification of M. leprae DNA in the biopsy specimens. The man had no significant contact with
armadillos, and no known prior HD nor contact
with humans with HD. The second patients
husband, who had died the prior year, had hunted
and handled armadillos; had a rash and numbness
of his hands and feet but had avoided doctors; and
had no medical diagnosis for these problems.
Neither patient had traveled outside the United
States. Their cases illustrate two important points:
1. M. leprae infection progressed more rapidly in
both of these patients than is typical. They were
diagnosed with BL HD within 12 years after
receiving infliximab, which is shorter than the
typical incubation time for multibacillary HD.
Both patients probably had preexisting, subclinical HD, and this disease progression is
comparable with the activation of latent tuberculosis after infliximab treatment.
2. After the infliximab was stopped, both patients
developed Type I lepra reactions which happens
in about 40% of BL patients (76). One of them,
who had also been treated with MTX, had
re-occurrence of the T1R, after the MTX was
stopped, indicating a protective effect of the
MTX on suppressing T1R. Scollard et al. have
theorized that, The reactions in our patients

Leprosy/Hansens disease treatment

may have been the result of rapid restoration of

preexisting immunity that had been transiently
impaired by infliximab treatment, which is
similar to the T1Rs that occur as an immune
reconstitution phenomenon in persons with HD
and AIDS after receiving HAART (77).
A 47-year-old Brazilian man presenting with
joint pain and swelling, and no known family nor
personal history of leprosy, was treated in Florida
for seronegative rheumatoid arthritis with prednisone 10 mg/day, MTX 20 mg /week for 5 months
without improvement, followed by adalimumab
40 mg, two doses subcutaneously 2 weeks apart.
Five weeks after his last adalimumab dose, he
developed erythema and edema of his ears, hands
and feet, and over 50 erythematous and edematous
papules and plaques on his trunk. His neurosensory examination was normal. Skin biopsy and
slit skin smears showed granulomas and were positive for AFB with BIs of +1 to +4, with globi, and
he was diagnosed with BT HD with T1R. Antimycobacterial MDT was initiated with dapsone
100 mg/day, minocycline 100 mg/day, and
rifampin 600 mg monthly. Prednisone was increased to 60 mg daily and then tapered to 30 mg
daily over 2 months with resolution of skin lesions.
His initial joint pain and swelling may have been
his first sign of T1R which then worsened after
stopping adalimumab, a TNF-a antagonist (78).

Role of US states in HD
Public health services of each state provide background information on infectious diseases, including HD. Several states (e.g., New York, Georgia) do
not require reporting new cases of HD. The State of
Louisiana Office of Public Health has an Infectious
Disease Epidemiology Section website with an
exceptionally lucid, well-written manual on HD
(79). The NHDP collects HD incidence in the states
and provides annual statistical summaries.

History and services of the NHDP

The United States has been a leader in both the
fight for the human rights of HD patients and also
in the search for effective therapies (80,81).
In 1894, the Louisiana State Legislature, with Dr.
Isadore Dyer, a dermatologist from Tulane University Medical School, established the Louisiana
Leper Home at Carville, as a place of refuge, not
reproach; a place of treatment and research, not
detention. In 1921, it came under operational

control of the US Public Health Service as the

National Leprosarium. In 1933, Sister Hilary Ross
and Dr. George Fite started a laboratory for drug
testing. From 1940 to 1947, Dr. Faget proved the
efficacy of sulfone medications for the treatment of
leprosy at Carville.
From 1970s into the 1990s, while working at
Carville, Dr. Robert Hastings made thalidomide
available under an investigational new drug (IND)
protocol for the treatment of ENL in the United
States at a time when it was otherwise banned in
the United States. Dr. Robert Jacobson headed
research into drug resistance and the development
of MDT leading to the United States Public Health
Service (USPHS) recommending it in 1981, followed by WHO adoption of MDT in 1982.
In 1981, Regional Hansens Disease Clinics were
established by the USPHS to provide outpatient
care throughout the United States for HD patients.
Eleven community health programs were established in: Boston, Chicago, Los Angeles, Miami,
New York, Puerto Rico, San Diego, San Francisco/
Martinez, Seattle, Texas, and Hawaii. Later, another
center was added in Arizona. At present (2009), the
NHDP maintains a network of Outpatient Hansens Disease Clinics and a Private Physician
Program.
Thalidomide is now available through the
S.T.E.P.S. program and clofazimine is available
through an IND held by the NHDP. The NHDP
website www.hrsa.gov/hansens has information
about its programs. The US Department of Health
and Human Services also has toll free phone
service at 1-800-642-2477, weekdays 9 am to 5:30
pm EST for consultation and/or referral to physicians nationwide who have expertise in treating
HD (Hawaii: 1-808-733-9831).

Concluding remarks
Leprosy is a treatable disease that can be managed
mostly on an outpatient basis. Severe reactions
may require hospitalization. To eradicate any
infectious disease, a highly effective vaccine is
needed (13). Hopefully, the tremendous progress
seen in the past decades in controlling this disease
and defining the causative organisms will lead to
further advances and prevention of infection.

References
1. Jopling WH, McDougall AC. Handbook of Leprosy, 4th ed.
Oxford: Hainemann Medical Books, 1988.

535

Worobec
2. Shepard CC. The first decade in experimental leprosy. Bull
W H O 1971: 44: 821827.
3. Levy L, Ji B. The mouse foot-pad technique for cultivation
of Mycobacterium leprae. Lepr Rev 2006: 77: 524.
4. Desikan KV, Sreevatsa. Extended studies on the viability of
Mycobacterium Leprae outside the human body. Lepr Rev
1995: 66 (4): 287295.
5. Davis WB, Schmidly DJ. The Mammals of Texas OnLine
edition, 1994.
6. Lumpkin LR, Fox GF, Wolf JE. Leprosy in five armadillo
handlers. J Am Acad Dermatol 1983: 9: 899903.
7. Clark BM, Murray CK, Horvath LL, Deye GA, Rasnake MS,
Longfield RN. Case-control study of armadillo contact
and Hansens disease. Am J Trop Med Hyg 2008: 78: 962
967.
8. Monot M, Honor N, Garnier T, et al. On the origin of
leprosy. Science 2005: 308: 10401042.
9. Truman, R. Leprosy in wild armadillos. Lepr Rev 2005: 76:
198208.
10. Wilder-Smith EP, Van Brakel WH. Nerve damage in leprosy
and its management. Nat Clin Pract Neurol 2008: 4 (12):
656663.
11. Cole ST, Eiglmeier K, Parkhill J, et al. Massive gene decay in
the leprosy bacillus. Nature 2001: 409: 10071011.
12. Gelber RH. Ch 159 Leprosy (Hansens Disease) In: Fauci AS,
Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson L,
Loscalzo J, eds. Harrisons principles of internal medicine,
17th ed. New York: McGrawHill, 2008: 10211027.
13. Scollard DM, Adams LB, Gillis TP, et al. The continuing
challenges of leprosy. Clin Microbiol Rev 2006: 19 (2): 367
368.
14. Lockwood DNJ. Ch 29 Leprosy. In: Burns DA, Breathnach
SM, Cox N, Griffiths CE, eds. Rooks textbook of dermatology Vol 2, 7th eds. Oxford: Blackwell Publishing, 2004: 21.1
21.21.
15. Rea TH, Modlin RL. Ch 186 Leprosy. In: Wolff K, Goldsmith
LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds. Fitzpatricks dermatology in general medicine, 7th ed. New
York: McGrawHill Professional, 2008: 17861796.
16. Han XY, Seo Y-H, Sizer KC, et al. A new mycobacterium
species causing diffuse lepromatous leprosy. Am J Clin
Pathol 2008: 130: 856864.
17. Ang P, Tay Y-K, Ng S-K, et al. Fatal Lucios phenomenon in
2 patients with previously undiagnosed leprosy. J Am Acad
Dermatol 2003: 48: 958961.
18. Duncan ME, Melsom R, Pearson JMH, et al. A clinical and
immunological study of four babies of mothers with lepromatous leprosy, two of whom developed leprosy in infancy.
Int J Lepr 1983; 51: 717.
19. Porrit RJ, Olsen RS. Two simultaneous cases of leprosy
developing in tattoos. Am J Pathol 1947; 23: 805817.
20. Cree IA, Smith WC. Leprosy transmission and mucosal
immunity: towards eradication? Lepr Rev 1998; 69: 112121.
21. Kerr-Pontes LRS, Barreto ML, Evangelista CMN, et al.
Socioeconomic, environmental, and behavioural risk
factors for leprosy in North-east Brazil: results of a casecontrol study. Int J Epidemiol 2006: 35: 9941000.
22. World Health Organization. WHO factsheet. http://www.
who.int/lep/strategy/wha/en/. Accessed June 16, 2009.
23. World Health Organization. WHO weekly epidemiological
record. 2008: 83 (33): 293300.
24. Lockwood DNJ. Leprosy elimination- a virtual phenomenon or a reality? BMJ 2002: 324: 15161518
25. http://www.who.int/lep/situation/en/. Accessed June 2,
2009.

536

26. Kumar B, Dogra SL. Leprosy. In: Rakel RE, Bope ET, eds.
Conns current therapy 2009. Philadelphia: Elsevier Health
Sciences, 2008: 97103.
27. Moschella SL. An update on the diagnosis and treatment of
leprosy. J Am Acad Dermatol 2004: 51: 417426.
28. Meima A, Smith WC, van Oortmarssen GJ, et al. The future
incidence of leprosy: a scenario analysis. Bull World Health
Organ 2004: 82: 373380.
29. Smith C , Richardus JH. Leprosy strategy is about control,
not eradication. Lancet 2008: 371: 969970.
30. Meima A, Irgens LM, van Oortmarssen GJ, et al. Disappearance of leprosy from Norway: an exploration of critical
factors using an epidemiological modelling approach. Int J
Epidemiol 2002: 31: 9911000.
31. A summary of Hansens disease in the United States
2006. U.S. Department of Health and Human Services
Health Resources and Services Administration National
Hansens Disease Program. http://www.hrsa.gov/hansens/
data2006/. Accessed June 2, 2009.
32. World Health Organization. WHO weekly epidemiological
record. 2008: 83 (50): 449460.
33. Chakravartti MR, Vogel FA. A twin study on leprosy. In:
Becker PE, ed. Topics in human genetics Vol 1. Stuttgart:
Georg Thieme, 1973: 1123.
34. Mohammed AP, Ramanujam K. Leprosy in twins. Int J Lepr
1966: 34: 405406.
35. Abel L, Sanchez FO, Oberti J, et al. Susceptibility to leprosy
is linked to the human NRAMP1 Gene. J Infect Dis 1998:
177: 133145.
36. Mira MT, Alcais A, Nguyen VT, et al. Susceptibility to
leprosy is associated with PARK2 and PACRG. Nature 2004:
427: 636640.
37. Buschman E, Skameme E. Linkage of leprosy susceptibility
to Parkinsons disease genes. Int J Lepr Other Mycobact
Infect 2004: 72: 169170.
38. Bochud P-Y, Sinsimer D, Aderem A, et al. Polymorphisms
in Toll-like receptor 4 (TLR4) are associated with protection against leprosy. Eur J Clin Microbiol and Infect
Dis 2009: 28: 10551065.
39. Girdhar A, Mishra B, Lavania RK, et al. Leprosy in infantsreport of two cases. Int J Lepr 1989: 57 (2): 472475.
40. Krishna Moorthy KV, Desikan KV. Indeterminate leprosy in
an infant. Lepr Rev 2006: 77: 377380.
41. http://www.who.int/lep/situation/americas/en/
index.html. Accessed May 30, 2009.
42. Ridley DS, Jopling WH. Classification of leprosy according
to immunity. A five-group system. Int J Lepr Other Mycobact Dis 1966: 34: 255273.
43. Boggild AK, Keystone JS, Kain KC. Leprosy: a primer
for Canadian physicians. Can Med Assoc J 170 (1): 71
78.
44. Walker SL, Lockwood DNJ. The clinical and immunological
features of leprosy. Br Med Bull 2006: 119.
45. Pfaltzgraff RE, Bryceson A. Clinical leprosy. In: Hastings RC,
ed. Leprosy, 1st ed. Edinburgh: Churchill Livingstone, 1985:
134176.
46. Ridley D. Skin biopsy in leprosy. Histologic interpretation
and clinical application. Documenta Geigy. Basel, Switzerland: Ciba-Geigy Limited, 1977: 13.
47. James WD, Berger TG, Elston DM. Chapter 17 Hansens
disease. In Andrews diseases of the skin: clinical dermatology, 10th ed. Saunders W B Co., 2005: 343352.
48. Barton RPE. Ear, nose and throat involvement in leprosy.
In: Hastings RC, ed. Leprosy. Edinburgh: Churchill Livingstone, 1985: 243252.

Leprosy/Hansens disease treatment

49. Lynch P. Greater auricular nerve in diagnosis of leprosy. Br
Med J 1978: iv: 1340.
50. http://www.who.int/lep/mdt/regimens/en/index.html.
Accessed June 14, 2009.
51. Ramu G. Single-dose rifampicin, oflaxicin and minocycline
(ROM) therapy for single leprosy lesions. Lepr Rev 1998; 69
(1): 7882.
52. Katoch VM. Is there a microbiological rationale for singledose treatment of leprosy? Lepr Rev 1998: 69: 25.
53. World Health Organization. Global strategy for further
reducing the leprosy burden and sustaining leprosy control
activities 20062010; Operational Guidelines. Regional
Office for South-East Asia, New Delhi, 2006.
54. King K, Browning JC, Metry DW, et al. Leprosy and international adoption. Pediatr Infect Dis J 2009: 28 (4): 322325.
55. http://www.hrsa.gov/hansens/clinical/regimens.htm.
Accessed June 12, 2009.
56. Litt JZ. Litts drug eruption reference manual, 15th ed. New
York: Informa Healthcare, 2009: 182183.
57. Gupta A, Sakhuja V, Gupta KL, et al. Intravascular hemolysis and acute renal failure following intermittent rifampin
therapy. Int J Lepr Other Mycobact Dis 1992: 60: 185
188.
58. John SS. Fixed drug eruption due to rifampin. Lepr Rev
1998: 69: 397399.
59. Jacobsen, RR. Treatment of leprosy. In: Hastings RC, ed.
Leprosy, 2nd ed. Edinburgh: Churchill Livingstone, 1994:
317349.
60. Britton W. The management of leprosy reversal reactions.
Lepr Rev 1998: 69: 225234.
61. Burdick AE, Ramirez CC. The role of mycophenolate
mofetil in the treatment of leprosy reactions. Int J Lepr
Other Mycobact Dis 2005: 73: 127128.
62. Biosca G, Casallo S, Lopez-Velez R. Methotrexate treatment
for type 1 (reversal) leprosy reactions. Clin Infect Dis 2007:
45: e7e9.
63. Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and
leprosy. Arch Dermatol 2004: 140: 9971000.
64. Kar HK, Sharma P, Bhardwaj M. Borderline tuberculoid
leprosy with upgrading Type 1 reaction in a HIV seropositive patient, after antiretroviral therapy: an Immune Reconstitution Inflammatory Syndrome. Lepr Rev 2009: 80:
8588.
65. Dolev J, Reyter I, Maurer T. Treatment of recurring cutaneous drug reactions in patients with human immunodeficiency virus 1 infection: a series of 3 cases. Arch Dermatol
2004: 140: 10511053.

66. Ling TC, Prescott RJ, Daly M. Painful skin nodules and
epididymo-orchitis. Arch Dermatol 2002: 138: 16071612.
67. Faber WR, Jensema AJ, Goldschmidt WFM. Treatment of
recurrent erythema nodosum leprosum with infliximab. N
Engl J Med 2006: 355 (7): 739.
68. Kar BR, Babu R. Methotrexate in resistant ENL. Int J Lepr
Other Mycobact Dis 2004: 72: 480482.
69. Scollard DM, Joyce MP. Leprosy (Hansens Disease). In:
Rakel RE, Bope ET, eds. Conns current therapy, 55th ed. St.
Louis: Saunders Elsevier, 2003: 101105.
70. Lockwood D. Ch. 18 Leprosy. In Gill G, Beeching N, eds.
Lecture notes: tropical medicine, 6th ed. Oxford: Blackwell
Publishing, 2009: 171182.
71. World Health Organization. WHO model prescribing information: drugs used in Leprosy. 2008. http://apps.who.int/
medicinedocs/en/d/Jh2988e/10.html. Accessed June 20,
2009.
72. Duncan ME, Melson R, Pearson JMH, Ridley DS. The association of pregnancy and leprosy.1. New cases, relapse of
cured patients and deterioration of patients on treatment
during pregnancy and lactation-results of a prospective
study of 154 pregnacies in 147 Ethiopian women. Lepr Rev
1981: 52: 245262.
73. Lockwood DNJ, Sinha HH. Pregnancy and leprosy. Int J
Lepr Other Mycobact Dis 1999: 67: 612.
74. Duncan ME, Miko T, Howe R, et al. Growth and development of children of mothers with leprosy and healthy controls. Ethiop Med J 2007: 45 (Suppl. 1): 923.
75. Dawe S, Lockwood DNJ, Creamer D. A case of post-partum
borderline tuberculoid leprosy complicated by a median
nerve abscess, peptic ulceration and rifampicin-induced
haemolytic renal failure. Lepr Rev 2004: 75: 181187.
76. Scollard DM, Smith T, Bhoopat L, et al. Epidemiologic characteristics of leprosy reactions. Int J Lepr Other Mycobact
Dis 1994: 62: 559567.
77. Scollard DM, Joyce MP, Gillis TP. Development of leprosy
and Type 1 leprosy reactions after treatment with infliximab:
a report of two cases. Clin Infect Dis 2006: 43: e19e22.
78. Camacho ID, Valencia I, Rivas MP, et al. Type 1 leprosy
reaction manifesting after discontinuation of adalimumab
therapy. Arch Dermatol 2009: 145 (3): 349351.
79. Office of Public Health, Louisiana Dept. of Health & Hospitals; Infectious Disease Epidemiology Section. Hansens
Disease (Leprosy), Oct. 8, 2004.
80. http://www.hrsa.gov/hansens/history.htm. Accessed June
9, 2009.
81. http://www.fortyandeight.org/star.htm. Accessed April 29,
2009.

537