23 Chapter 159 :: Leprosy

:: Claudio Guedes Salgado, Arival Cardoso

de Brito, Ubirajara Imbiriba Salgado, &
John Stewart Spencer

sensation on the skin—with or without dermatologic

AT A GLANCE lesions—and the development of incapacities during
the progression of the disease. WHO states that any
■ Definition: A chronic granulomatous disease individual in endemic countries presenting skin lesions
Part 23

affecting mainly the skin and nerves caused by with definite sensory loss or positive skin smears may
the obligate intracellular pathogen Mycobacterium be diagnosed with leprosy.1
leprae.
::

■ Involvement: Primarily the skin and nerves, but

Bacterial Diseases

causing sequelae to a wide range of tissues and

systems including eyes, upper respiratory tract, HISTORICAL PERSPECTIVE
lymphoid tissue, testicles, muscles, and bones.
■ Diagnosis: Based on clinical signs and Leprosy is one of the oldest diseases known to afflict
symptoms, hallmarks include loss of sensation mankind. Gerhard Armauer Hansen, a Norwegian
within skin lesions, nerve swelling or pain, or physician, was the first to describe the M. leprae bacil-
demonstration of acid-fast bacilli in skin smears lus in 1873, identifying the first bacterial pathogen
or biopsies. associated with human disease. The name Hansen
■ Incidence: 214,783 new cases detected worldwide disease is used in some countries, like Brazil, to lessen
in 2016, essentially unchanged for the last 4 years. the stigma associated with the common name. The
More than 80% of all new cases are detected in only characteristic destructive changes that lead to disfig-
3 countries—India, Brazil, and Indonesia. urement, deformity, and disability were among the
hallmarks of the disease that allowed it to become
■ Long-term morbidity: Despite the global use of
stigmatized in ancient times.2 Speculations about
multidrug therapy in use since the mid-1980s,
the existence of leprosy in ancient India, Egypt, and
up to 30% to 50% of all leprosy patients will
China have been proposed, with the earliest paleo-
experience some type of reactional episode that
pathological evidence found in 4000-year-old bones
may result in a permanent neurologic deficit or
from the Balathal burial site in Rajasthan, western
disability.
India.3 The first use of molecular techniques using
■ A clinical challenge: The long incubation time polymerase chain reaction (PCR) to detect M. leprae
prior to the slow development of diverse DNA specific sequences in ancient bones dated to ad
symptoms (3-7 years postinfection), the very 600 was described in 1994.4 PCR was used to iden-
low rate of disease progression in infected tify M. leprae DNA in 1st century ce bones from the
individuals, and issues with misdiagnosis all Tomb of the Shroud burial site in Israel, the earliest
create challenges to the development of ways to known date of existence of leprosy in this region.5
interrupt transmission. Using paleopathological and molecular methods to
■ An immunologic spectrum of disease: analyze ancient bones from archeological sites, burial
Understanding what genetic factors and the grounds, and cemeteries, evidence of the spread of
interplay of innate and adaptive immune leprosy has emerged, indicating the spread of the
responses of the host that leads to resistance or disease from Western and Central Asia from the 4th
susceptibility to disease are critical in developing century ad into Eastern and Central Europe occurred
novel treatment approaches. mainly due to human migrations associated with mil-
itary campaigns, expansion of territories, or migra-
tions to effect colonization.6 Houses were established
to quarantine those with leprosy and other communi-

INTRODUCTION cable diseases, called lazarets, in 7th-century France,

but it was not until the return of the Crusaders from
ad 1100 coming back from countries of the Ottoman
DEFINITION Empire where leprosy was endemic that the disease
became an increasing problem.
Leprosy is a chronic granulomatous infection caused Leprosy in Europe and the United Kingdom peaked
by Mycobacterium leprae, that infects mucous cutane- in the 13th and 14th centuries and then began a slow
ous tissues and peripheral nerves, leading to loss of decline. Comparison of the M. leprae whole genome

Kang_CH159_p2892-2924.indd 2892 04/12/18 2:41 pm

 obtained from ancient European, UK, and Scandina-
vian gravesites show only a few dozen single nucleo- EPIDEMIOLOGY 23
tide polymorphism (SNP) changes over the last 1000 Leprosy is still a serious neglected disease. WHO refers
years, with no mutations in any genes related to the number of new cases is gradually decreasing in the
increased virulence or pathogenesis.7 The essentially last 10 years, from 265,661 in 2006 to 210,758 in 2015,13
clonal nature of M. leprae from the ancient to modern but different groups of researchers have demonstrated
times suggests that the precipitous decrease in lep- that the hidden endemics may be high,14,15 the number
rosy prevalence was independent of features of the of cases in children is increasing16 or stable,17 whereas
pathogen and were more likely related to changes the proportion of multibacillary patients is increasing18
in host resistance or environment. Since people with and cases with grade 2 disability seem to be stable,19
lepromatous leprosy likely had a weakened immune but high,20 indicating late diagnosis. Altogether, these
status, they were more likely to succumb to other factors demonstrate that instead of a true decline of
infections. Events thought to have contributed to a new cases, delay21 and absence of diagnosis seem to be
higher death rate in those with leprosy included a the main problems.15,22,23 In fact, mathematical model-

Chapter 159 :: Leprosy

serious famine in 1325, followed by the outbreak of ing shows that in 2020 we may have 4 million cases
plague, or Black Death, in 1349 that killed between of undiagnosed leprosy worldwide, that is, almost
one-third and two-thirds of the population in Europe 20 times more than the present number of cases diag-
and the United Kingdom. Such massive death would nosed annually.24
have severely curtailed the support networks of hos- The definition of leprosy has changed with time.
pices and leprosaria whose religious clergy, patrons There is currently no laboratory test to diagnose lep-
and physicians had cared for patients, but were likely rosy. Once a patient completes multidrug therapy, the
decimated. There is also suggestive evidence that individual is usually removed from the registry and
increases in population density, overcrowded living is no longer considered a case, even if disability and
conditions, and the rise of tuberculosis after the 15th reactional episodes continue long after treatment. For
century contributed to death by coinfections with decades, treatment of leprosy was done continuously
multiple diseases.8 As those susceptible individuals with dapsone alone (monotherapy), and all cases that
succumbed to disease, the innate resistance of the received dapsone monotherapy were registered in the
surviving population to mycobacterial infection and system. Because of this practice, the prevalence of lep-
other diseases common during that period likely rosy remained high, with more than 10 million patients
improved, and coupled with improved socioeco- on the registry during the 1980s. With the implemen-
nomic conditions, sanitation, and hygiene, the lines tation of multidrug therapy in 1982, treatment was
of transmission of infection were broken. Currently, shortened to, at most, 2 years. The active registry then
endemic cases of leprosy in Europe and the United changed to only those being treated, while those who
Kingdom are extremely rare. completed their therapy were subsequently “cleared.”
Comparative genomic studies of M. leprae isolates all Thus, over the course of a decade, millions of patients
over the world revealed a remarkable conservation of who completed multidrug therapy and did not have
the genome (99.995% identity among all strain types), symptoms were purged from registries.25 The net
showing the existence of 215 polymorphic sites consist- effect was that within 20 years after the introduction
ing mainly of SNPs. Four of these SNPs represented 4 of multidrug therapy, leprosy prevalence was mark-
main strain types that showed very strong geographical edly reduced by more than 85%13 although the new
associations that were used to trace the evolution and case detection rate has remained relatively stable
distribution of M. leprae based on human migration pat- at more than 200,000 worldwide for almost 10 years
terns throughout history.9 SNP Type 1 was found pri- (Fig. 159-1).
marily in Southeast Asia; SNP Type 2 was found mainly Currently, the most important epidemiologic indica-
in East Africa; SNP Type 3 was associated with the tors of leprosy burden are the new case detection rate
European/North African region, whereas SNP Type 4 by country, and the proportion of cases in children,
was found mainly in West Africa. Leprosy did not those with multibacillary disease and those with grade
exist in North or South America until its introduction 2 disability, indicating a late diagnosis.13 Although
via colonialism from Europe (SNP Type 3) and from India has the highest number of leprosy cases in the
the importation of slaves from Africa (SNP Type 4). world, Brazil has the highest new case detection rate
These four main types were subdivided into 16 sub- among all countries (Fig. 159-2). However, when we
types based on further characterization of SNPs and look at the other 2 most significant parameters, the per-
insertion/deletion events from modern and ancient centage of cases in children (Fig. 159-3) and those with
M. leprae genomes from a total of 400 samples from grade 2 disability (Fig. 159-4), there is a clear shift, with
28 different regions of the world, namely SNP Type 1 most of the reporting countries considered as high or
(A-D), Type 2 (E-H), Type 3 (I-M), and Type 4 (N-P).10 very high, whereas Brazil, India, and Indonesia have
Besides humans, M. leprae is also found as a zoonotic medium or low percentages. Although these 3 coun-
infection in armadillos in the Southern United States,11 tries collectively account for >80% of the global leprosy
and recently in red squirrels in the British Isles.12 Inter- burden, the large number of cases reported dilutes the
estingly, both armadillo and squirrel M. leprae have the percentage of both children with leprosy and those
same SNP subtype, 3I, indicating a common European with grade 2 disability, while countries who report 2893
ancestry.

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23 Global prevalence and new case detection of leprosy

12 12

11 11

10 10

9 9

8 8
Prevalence (millions)

NCD (millions)
7 7
Prevalence
6 6
New cases detection
5 5
Part 23

4 4

3 3
::

2 2
Bacterial Diseases

1 1

0 0
1966 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015
Year

Figure 159-1 Historic evolution of global prevalence and new case detection of leprosy. The first formal attempt to esti-
mate the global leprosy burden was made by WHO in 1966, when the case load was estimated to be 10,786,000, of whom
60% were not registered for treatment. Global detection was first reported in 1991, with 584,000 new cases detected
worldwide in 1990. Currently, the new case detection is one of the most important epidemiologic indicators of leprosy
burden, together with the proportion of children and proportions of grade 2 disability. (Used with permission from Prof.
Josafá Barreto, Pará Federal University, Brazil.)

Leprosy new case detection rate, world 2015

Figure 159-2 Leprosy new case detection rate per 100,000 population in the world, 2015. More than 210,000 new cases
were reported in 136 countries or territories in 2015. India, Brazil, and Indonesia accounted for 81% of the global bur-
2894 den of leprosy. The global new case detection rate was 3.2. (Used with permission from Prof. Josafá Barreto, Pará Federal
University, Brazil.)

Kang_CH159_p2892-2924.indd 2894 04/12/18 2:42 pm

 Proportion of cases among children
23

Chapter 159 :: Leprosy

Figure 159-3 Proportion of leprosy cases among children below 15 years old, 2015. Although there is no specific classifica-
tion from “low” to “high” for this indicator, it is a robust indicative of active source of infection in the community where they
live. (Used with permission from Prof. Josafá Barreto, Pará Federal University, Brazil.)

Proportion of new cases with grade-2 disability, world 2015

Arctic Ocean

Figure 159-4 Proportion of new leprosy cases with grade 2 disability at diagnosis, 2015. It reflects long delays in the diag-
nosis of leprosy, highlighting a failure of the health services system and gaps in the approach to control the disease. (Used
with permission from Prof. Josafá Barreto, Pará Federal University, Brazil.)
2895

Kang_CH159_p2892-2924.indd 2895 04/12/18 2:42 pm

23 less than 1000 new cases per year generally have much
higher rates in both categories. A high or very high
with more than 90% of people having a natural immu-
nity, with cell-mediated immunity being most impor-
percentage of these 2 parameters likely means that tant in preventing disease progression.
children and adults are diagnosed only when present- All patients, except those with primary neural
ing classical pathognomonic lesions of leprosy and/or leprosy,27 first present 1 or a few hypopigmented mac-
disabilities, indicating late diagnosis.15,21 ules on the skin. Indeterminate leprosy (Fig. 159-6) may
last for months or years before moving to spontaneous
cure or toward one of the poles or borderline forms of

CLINICAL FEATURES the clinical spectrum, depending mainly on the cell-

mediated immunity of the host against the bacilli.
At one end of the spectrum with a better cell-
CUTANEOUS FINDINGS mediated immunity, there is polar tuberculoid leprosy,
where well-defined plaques, usually a few in just one
During the IV International Leprosy Congress in segment of the body, hypochromic and/or erythema-
Part 23

Madrid, 1953, leprosy was classified in 2 stable forms, tous, sometimes atrophic, present with papules or
tuberculoid leprosy and lepromatous leprosy, and tubercles that are mainly circinate on the periphery of
a borderline group between these 2 polar forms. In the lesions (Fig. 159-7). A special self-healing type of
1966, Ridley and Jopling proposed a 5-group classifi- tuberculoid leprosy, infantile nodular leprosy, can be
::

cation system based on clinical, histopathologic, and found as a single nodular lesion, but also as papules or
Bacterial Diseases

immunologic criteria26 that is still in use for classify- plaques, usually on the face of the child (Fig. 159-8).28
ing leprosy. The colonization of skin and invasion of At the other end of the spectrum lies polar leproma-
peripheral nerves by the bacilli, followed by innate tous leprosy, which is established by a complete lack
and adaptive immune responses by the host, results in of cell-mediated immunity, usually presenting with
the clinical spectrum of leprosy (Fig. 159-5). There is an plentiful nodular lesions disseminated throughout the
overall genetic resistance toward developing leprosy, body, associated with diffuse infiltration (Fig. 159-9),

Leprosy clinical spectrum

M. leprae Person Cure

Primary Indeterminate
Neural leprosy leprosy

TT BT BB BL LL

Cell-, Borderline Antibody-,

mediated unstable forms mediated
immune IL-2 IL-4 immune
response IFN- γ IL-10 response

AFB
anti-PGL- I IgM

Reversal Reaction

ENL

Chronic Neuritis/Neuropathy

Figure 159-5 Leprosy clinical spectrum. Up to 80% of people exposed to M. leprae may solve the problem and get rid of
the bacilli before appearance of symptoms or after subclinical leprosy. Some patients will develop primary neural leprosy,
with no skin lesions. All those with skin lesions pass through an indeterminate form, and then evolve to a polar tuberculoid
leprosy (TT) or lepromatous leprosy (LL) disease or to an unstable borderline form of leprosy. The paucibacillary (PB) pole
toward TT has a good cellular immune response (CIR), with the presence of Th1 cytokines, while multibacillary pole toward
LL present an impaired CIR and a high antibody response, with Th2 cytokines. Acid-fast bacilli and anti-PGL-I IgM are, both,
low or negative on PB and increase through multibacillary pole. Reversal reaction may happen especially in borderline
2896 leprosy, whereas erythema nodosum leprosum occurs in borderline-lepromatous leprosy (BL) and LL patients. Chronic
neuritis or neuropathy may happen in primary neural leprosy and in all but the indeterminate leprosy clinical form.

Kang_CH159_p2892-2924.indd 2896 04/12/18 2:42 pm

 23

Chapter 159 :: Leprosy

Figure 159-6 Indeterminate leprosy. Macular hypochro-
mic lesion on the lower back.

including the ears (Fig. 159-10) and face, that may

have facial features so marked that it gives the
appearance of a lion’s face, known as leonine facies
(Fig. 159-11).29 A special type of lepromatous leprosy
is histoid leprosy, that has an even higher bacillary
load than the usual lepromatous leprosy, with rafts of
bacilli called globi, presenting diffuse shiny nodules
and papules, and a variable degree of skin infiltration Figure 159-8 Infantile nodular leprosy. Presence of
(Fig. 159-12).30 Some cases of lepromatous leprosy are 2 tuberous lesions on the face of a child from a family
a challenge for less experienced health professionals where 2 adults were diagnosed with multibacillary leprosy.
to diagnose when the main skin manifestation is infil-
tration (Fig. 159-13). This special type is called Lucio
leprosy, first described by Lucio and Alvarado in in between are all immunologically unstable. All bor-
Mexico in 1852.31 Isolation and characterization of this derline patients have skin infiltration, varying from
new species from Lucio patients, called Mycobacterium a few to many lesions, in one or many areas of the
lepromatosis,32 and whole genome sequencing33 have body. Although tuberculoid leprosy patients have just
now firmly established that this closely related myco- papules or tubercles with no infiltration, borderline-
bacterium causes this form of leprosy found mainly in tuberculoid leprosy presents a clear infiltrative band
Mexico and the Caribbean. around the periphery of the lesions, changing from a
The 3 borderline forms (borderline-tuberculoid, very sharp border in tuberculoid leprosy to a more dif-
borderline-borderline, and borderline-lepromatous) fuse infiltrated outer layer in borderline-tuberculoid
leprosy (Fig. 159-14). As the forms progress toward the

Figure 159-7 Tuberculoid leprosy. A well-circumscribed

lesion, with a central macular hypochromic and atrophic Figure 159-9 Lepromatous leprosy. Multiples nodules
appearance, and a peripheric group of papules distributed (hansenomes or lepromes) disseminated throughout the 2897
in annular pattern. skin, associated to diffuse infiltration.

Kang_CH159_p2892-2924.indd 2897 04/12/18 2:42 pm

23
Part 23

Figure 159-10 Lepromatous leprosy. Papules, nodules, Figure 159-12 Lepromatous leprosy histoid or Wade lep-
and infiltration on the ear of a child. He had also many rosy. Presence of nodules, which may be disseminated
lesions on other parts of the skin. or scattered, some resembling molluscum contagiosum
::

lesions, as in the picture, but note the presence of a nodule

Bacterial Diseases

on the right nipple, and also some infiltration with a claw

lepromatous end in borderline-borderline (Fig. 159-15) formation on the left hand.
with its classical foveolar lesions, and borderline-
lepromatous leprosy (Fig. 159-16), effective cell-
mediated immunity decreases, allowing a progressive
spread and increase in the number of bacilli, an increase
in infiltration of the lesions, with the evolution to form
more nodular lesions, often involving the face and ears.
The diagnosis of leprosy is based on the detection
of hypo- or total anesthesia in the lesions that may
be associated with hypohidrosis and alopecia. Tuber-
culoid leprosy patients can present both dryness of
the skin and alopecia restricted to the territory of the
lesions. In contrast, lepromatous leprosy patients may
show extensive areas of dryness, especially on the
legs, and in advanced cases may result in madarosis
and hair loss in different parts of the skin. Borderline
patients follow the same pattern, with more restricted
features in borderline-tuberculoid leprosy and more
diffuse in borderline-lepromatous leprosy. Figure 159-13 Lepromatous leprosy. Diffuse infiltration of
Paresthesia is a frequent symptom associated with the skin.
leprosy cases. Burning, numbness, tickling, and other

Figure 159-14 Borderline-tuberculoid leprosy. Presence

Figure 159-11 Leonine facies. Lepromatous patient with of various hypochromic annular lesions, with papules and
2898 diffuse nodules and infiltration on the face, resulting in a infiltration on the periphery, located on the buttocks and
lion’s face appearance. thighs of a child.

Kang_CH159_p2892-2924.indd 2898 04/12/18 2:42 pm

 Iodine-starch or alizarin red34 may be used to assess
sweating function of leprosy lesions. After iodine
23
painting followed by starch, or after alizarin red, exer-
cise may be required to induce sweating. When auto-
nomic nerve function is affected sweating is impaired
or completely absent and the skin remains dry. On
normal skin, a bluish or dark brown (iodine-starch)
or violet (alizarin red) color will appear, while there
will be no reaction (anhidrosis) or irregular sweating
(hypohidrosis) on leprosy lesions.
Thermal, pain and tactile, and Semmes-Weinstein
Monofilaments tests are all directly dependent on cor-
rect verbal responses from the patient. Therefore, it
is crucial to explain what each test is for, how to give

Chapter 159 :: Leprosy

proper feedback for the sensation elicited, and to per-
form the test on normal non-lesional skin sites to famil-
Figure 159-15 Borderline-borderline leprosy. Two foveolar
lesions on the upper dorsal thorax. iarize the individual with the sensation before testing
lesion areas to measure any changes.
The thermal test is based on the capacity to discrimi-
nate between hot and cold sensitivity on touching
sensations may be present within the lesions or fol-
the skin with 2 tubes containing hot (±45°C [113°F])
lowing the territory innervated by the nerve trunks
or cold water. The tube surface is touched on lesional
in the affected area. Patients may feel these sensations
and normal skin randomly, followed by recording the
in acute crisis, especially at night in cold weather, that
patients’ answers. The professional must be careful to
may recur frequently, becoming increasingly common
avoid touching lesional and normal skin at the same
with the progression of the disease. All types of lep-
time, especially for smaller lesions.
rosy lesions must be submitted to a thorough sensitiv-
Pain sensitivity is based on the ability to distinguish
ity evaluation, including vasomotor reflex, sweating
between the tip or the base of a needle, since one pro-
function, thermal, pain, and tactile sensitivity.
duces pain whereas the other does not. Also, randomly,
Dilation of blood capillaries as a secondary axon
lesional and nonlesional skin must be touched with the
reflex erythema, which is dependent on nerve integ-
tip or the base of the needle, followed by recording the
rity, may be tested using a 1:1000 histamine solution,
answers. A clear limitation of this method is the use of
injected intradermally in normal and lesional skin.
a perforating instrument, that may cause fear to some
Within 5 to 10 seconds, erythema will result from the
patients, especially children.
direct action of histamine on the capillaries, caus-
Tactile sensitivity is tested using a cotton wad, and
ing vasodilation in both areas, normal and lesional.
the patient should answer if he/she senses the light
Two minutes after this a secondary erythema caused
touch of the cotton touching the skin, both normal or
by capillary dilation will occur only on normal skin.
lesional. Semmes-Weinstein Monofilaments or esthe-
The last phase of triple Lewis response is exudation
siometer kits are monofilament lines graded in thick-
of liquid to the dermis, resulting in wheal formation
ness with different colors that are attached to plastic
in both areas. Therefore, the triple Lewis response is
posts to apply different amounts of target pressure
incomplete only on lesional skin, with the absence of
to the skin. The color and range of target force varies
secondary erythema.
from green (range 0.008-0.07 g, normal skin sensa-
tion), the thinnest of which is like the sensation of a
mosquito landing on skin, to the thickest, red (up to
300 g).35 These devices are simple and cheap and can
easily measure diminished or loss of protective sensa-
tion cause by diabetic neuropathy or neuropathy cause
by leprosy nerve damage. Loss of sensation using
the blue Semmes-Weinstein monofilaments indicates
diminished sensation of light touch (0.16-0.4 g), purple
indicates diminished protective sensation (0.6-2 g), and
red indicates more profound loss of protective sensation
(4-300 g). More recently, the simplicity and ease of use
of Semmes-Weinstein monofilaments have supplanted
all of the other tactile, thermal, and pain tests.36 After
showing the patient how the monofilament works and
getting a “yes” response if he or she feels the touch,
various thicknesses of Semmes-Weinstein monofila-
ments can test areas of skin randomly inside and out-
Figure 159-16 Borderline-lepromatous leprosy. Foveolar side the suspect lesion, as depicted in Video 159-1 at 2899
and nodular infiltrated lesions. mhprofessional.com/fitzderm9evideos. Even children

Kang_CH159_p2892-2924.indd 2899 04/12/18 2:42 pm

23 as young as 6 to 7 years old can respond very well to
this kind of test, and those children who are not able
to communicate well can still point to the place on the
skin if they feel the device touching it (see Video 159-1
at mhprofessional.com/fitzderm9evideos).
In conclusion, the “classic” cases as defined by
Ridley-Jopling classification have well-defined lesions,
associated with a range of signs and symptoms, which
facilitate the diagnosis of leprosy. After 35 years of
multidrug therapy, the challenge now is to diagnose
cases early, with the goal to eliminate disabilities.

NONCUTANEOUS FINDINGS
Part 23

Figure 159-17 Lagophthalmos on the right eye.

Although leprosy diagnosis is based primarily on the
presence of skin lesions, usually when dermatologic
::

signs are detected, at this point the peripheral nerves functional deficit without any skin lesions, in which
Bacterial Diseases

have been already invaded and damaged by M. leprae case the diagnosis may be pure neuritic, or the more
itself and/or by the response of our immune system. common term primary neural leprosy,37 because up to
In fact, nerves may be the first target of M. leprae, and 35% of such cases may develop skin lesions after the
the infection itself together with immune cell infiltra- diagnosis of primary neural leprosy.38
tion and inflammation that can be clinically detected Primary neural leprosy accounts for about 4% to
by palpation. 8% of all leprosy cases, although in India it may be
Palpation of the peripheral nerve trunks can estab- as high as 17%.37 A positive acid-fast bacilli result on
lish nerve thickness and tenderness. However, even slit-skin smear eliminates primary neural leprosy, but
for highly trained health professionals, it is not a a nerve biopsy can demonstrate the presence of acid-
simple task to detect differences in thickness from one fast bacilli in 16% of these cases, whereas PCR is posi-
side to the other, or to decide if the nerve is soft, and tive in almost half of them.39 Definitive diagnosis of
therefore normal, or fibrotic. Furthermore, those dif- primary neural leprosy is not a simple task and may
ferences should be considered only when it is associ- require clinical signs, nerve histopathology, electro-
ated to some functional harm, as (1) loss of sensation physiology, and ultrasonography,37 although most of
defined by hypo- or total anesthesia on the territory of those techniques are not available in highly endemic
the nerve; (2) motor dysfunction, as in the case of inter- countries.
osseous muscle hypotrophy; or (3) autonomic altera- Endocrine dysfunctions, after nerve and skin
tion, as with skin sweating deficit. lesions, are most prominent in patients, but are not
Although tuberculoid leprosy patients may have readily detected, reaching up to 25% of cases40 leading
conspicuous alterations in just one specific peripheral to, among other problems, hypothyroidism, euthy-
nerve trunk, usually in the same segment of the skin roid sick syndrome, hypogonadism, sterility and
lesion, lepromatous leprosy patients often present osteoporosis.41 Levels of testosterone were inversely
thickness and tenderness variations in many nerves, correlated with the number of skin lesions,40 and the
accompanied or not with functional alterations in dif- level of adrenal androgen dehydroepiandrosterone
ferent segments of the body. Borderline-tuberculoid, sulphate had an inverse correlation with interleukin
borderline-borderline, and borderline-lepromatous (IL)-6 and tumor necrosis factor (TNF)-α, whereas
leprosy patients usually present nerve changes, vary- gonadotropins—luteinizing hormone and follicle-
ing from a few nerve trunks affected in borderline- stimulating hormone—were positively correlated with
tuberculoid leprosy to many in borderline-lepromatous proinflammatory cytokines,42 suggesting a possible
leprosy. In many cases, there is some degree of pain, neuro-immune-endocrine correlation in leprosy.
spontaneously reported by the patient, or mentioned
during palpation.
Besides upper and lower limbs, the face also may be
affected when facial or trigeminal nerves are damaged, COMPLICATIONS
which can result in hypo- or anesthesia, including on
the cornea, and muscle hypotrophy, especially when The natural history of leprosy is the evolution to
palpebral muscles are involved, resulting in lagoph- impairment, especially with the eyes, hands, and feet,
thalmos (Fig. 159-17). in both soft tissues and bones, leading to disfigure-
The presence of any of these changes in peripheral ment and deformity, the origin of all leprosy-related
nerve trunks detected by palpation or functional loss stigma. Even with bacteriological cure after multidrug
eliminates the diagnosis of indeterminate leprosy. On therapy implementation, and assistance from social
2900 the other hand, between 5% and 17% of all leprosy networks involved in education, training, and reinte-
patients only have signs of nerve inflammation or gration of those with disabilities into society, estimates

Kang_CH159_p2892-2924.indd 2900 04/12/18 2:42 pm

 of the numbers of people living with varying levels
of disability, including Grade 1 (partially disabled)
23
to Grade 2 (can be completely disabled and unable
to work) caused by M. leprae are likely between 1 and
4 million worldwide.43
With the eyes, loss of corneal sensation can result in
wounds, followed by infection and blindness, whereas
hypotrophy of palpebral muscles may result in lagoph-
thalmos, which can also contribute to corneal infection.
Advanced cases, especially in multibacillary leprosy,
mostly toward the lepromatous leprosy pole, may pres-
ent characteristic facial bone malformations, resorption,
and pitting, particularly involving destruction of the
anterior nasal spine, resorption of the alveolar process

Chapter 159 :: Leprosy

of the maxilla, sometimes with loss of teeth, collectively
characterized as rhinomaxillary syndrome.44
Figure 159-19 Fixed claws and bone resorption associated
For hands and feet, complications start with a with anhidrosis and atrophy as sequels on the hands of a
loss of sensation that may lead to wound formation borderline-lepromatous leprosy patient.
(Fig. 159-18) after burns, trauma, or repetitive mod-
erate pressure–induced skin disruption not detected

ETIOLOGY AND
by the patient, with possible evolution to fissures
and ulcers, soft tissue inflammatory autolysis, muscle
atrophy, bone decalcification, osteitis and resorption
(Fig. 159-19), fusion and joint dislocation, osteoarthri- PATHOGENESIS
tis, and destruction.45 At the same time, interosseous
hypotrophy or amyotrophy may result in paresis or RISK FACTORS
paralysis, leading to formation of claw and/or drop
hand or foot (see Video 159-2 at mhprofessional.com/ Mycobacterium leprae, a noncultivable obligate intracel-
fitzderm9evideos), that may be mobile at first, and lular pathogen that mainly damages skin and periph-
constitute severe impairments to leprosy patients,46 eral nerves, is the causative agent of leprosy, resulting
like walking (see Video 159-3 at mhprofessional.com/ in a broad range of skin lesions with anesthesia, periph-
fitzderm9evideos). eral neuropathy through nerve damage, and muscle
weakness and atrophy leading to bone loss by resorp-
tion, with related deformity, disfigurement, and dis-
ability along with the social stigmatization associated
with this disease afflicting mankind for thousands of
years. Although M. leprae shares roughly 1,439 gene
orthologs and homologs with M. tuberculosis, a reduc-
tive evolutionary event that occurred between 10 and
20 million years ago resulted in massive gene deletion
and decay, resulting in the transformation of nearly half
of all coding genes into nonfunctional truncated gene
remnants or pseudogenes.47 This process of reductive
evolution has occurred in several obligate intracellu-
lar pathogens, including Rickettsia and Chlamydia,
and is thought to be a survival response to dramatic
changes in ecological niche or lifestyle. The streamlin-
ing and elimination of many genes and pathways once
required for survival as a free-living species would be
superfluous in an intracellular habitat, resulting in
deletion or inactivation of large parts of the genome.
Thus, M. tuberculosis has 4.41 Mb, where >90% of
the genome encodes 3,998 protein coding sequences,
whereas M. leprae has 3.27 Mb, where just under 50%
of the genome codes for 1614 functional genes, with
the remainder coding for 1306 pseudogenes and gene
remnants whose complete counterparts can be found
in M. tuberculosis. The combined effect of gene reduc-
tion has created a minimal gene set, reducing the
number of genes involved in all functional metabolic
Figure 159-18 Ulcers in a hypotrophic and anhidrotic pathways, including critical pathways involved in 2901
hand of a LL patient. gene regulation, detoxification, DNA repair, transport

Kang_CH159_p2892-2924.indd 2901 04/12/18 2:42 pm

23 or efflux of metabolites and small molecules, while
generally decreasing the frequency of genes in degra-
Epidemiologic studies, including twin studies, com-
plex segregation analyses, and genomewide analyses
dative pathways versus synthetic ones and a paucity in various genetically diverse populations from differ-
of respiratory enzymes. Because of these deficiencies, ent leprosy endemic countries have indicated the prob-
M. leprae has one of the longest doubling times of able importance of host genetics in the susceptibility
any bacteria, around 13 days, possibly explaining the or resistance to this disease. Twin studies conducted
exceptionally long incubation time between infection in India in the 1960s and 1970s showed that there was
and development of clinical disease, usually between an overwhelming concordance (60%-80%) for mono-
3 and 7 years, although in some cases up to 20 years. zygotic twin pairs to develop leprosy.51,52 Genomewide
The failure to grow M. leprae in axenic medium despite analysis studies examining linkage and association of
decades of attempts is probably the result of the com- multiple gene candidates suggest that there is genetic
bined effects of gene reduction and mutations in key control involved in the susceptibility of developing
metabolic pathways. leprosy and a predilection to develop a particular form
One of the hallmarks of the leprosy bacillus is the of disease. Evidence for the latter is seen in Mexico
Part 23

ability to attach and invade Schwann cells associated and the Philippines, where 90% of cases develop the
with the peripheral nervous system, which leads to lepromatous form of the disease, whereas about equal
colonization and inflammation within nerves, caus- numbers of patients develop tuberculoid or leproma-
ing nerve damage, demyelination, and neuropa- tous disease in many African countries and in Brazil.
::

thy. Binding to the laminin-2 molecule in the basal Extensive studies have implicated associations with
Bacterial Diseases

lamina of Schwann cells is mediated by 2 bacterial human leukocyte antigen (HLA) complex genes (class I
cell wall components, the laminin-binding protein and class II) because of their primary role in the adap-
(encoded by ML1683c) and the terminal trisaccha- tive host immune response, and a number of alleles
ride of the M. leprae–specific phenolic glycolipid I are overrepresented for leprosy susceptibility or the
(PGL-I).48 Transmission is thought to occur through development of either the tuberculoid or lepromatous
the aerosol route, with the bacillus gaining entry and subtype when particular ethnic populations in differ-
colonizing resident macrophages within the nasal ent countries were examined. There is also a shared
mucosa and turbinate,49 then disseminating to tissues genetic background between leprosy and a number
and nerves through the bloodstream. Early events of inflammatory diseases, including Crohn disease
involved in host–pathogen interaction at the cellu- (nucleotide-binding oligomerization domain contain-
lar level is likely mediated by host genes involved ing 2 [NOD2]), myocardial infarction (lymphotoxin
in pattern recognition receptors and mycobacterial α [LTA]), Type 1 diabetes and psoriasis (vitamin D
uptake (Toll-like receptors [TLR], nucleotide-binding receptor [VDR]), and Parkinson disease (E3 ubiquitin-
oligomerization domain containing 2 [NOD2], and protein ligase [PARK2]).50 More recently, genomewide
mannose receptor C-Type 1 lectin [MRC1]), which association studies examining SNP differences between
modulate autophagy. For example, bacterial cell wall leprosy cases and controls in China have increased the
lipoproteins that recognize and bind TLR 1/2 het- list of genes that may be involved in regulating innate
erodimer ligands on the host cell surface trigger an and adaptive immune response pathways associated
innate immune response, the outcome of which will with susceptibility or resistance to leprosy.53 Fifteen
determine whether the bacillus is contained or killed SNPs detected among 6 genes were associated with
within a granuloma or grows uncontrollably. There leprosy (HLA-DR-DQ, RIPK2, TNFSF15, CCDC122,
is an overall genetic resistance toward developing C13orf31, and NOD2), whereas pathway analysis iden-
leprosy, with more than 90% of people worldwide tified a total of 35 genes involved in a single network
having a natural immunity.50 Early innate immune involved in leprosy susceptibility or resistance.
responses to mycobacteria binding to these pattern Besides genetic risk factors, many studies have
recognition receptors and entry into the cell regulates shown that there are a number of other factors, oper-
cellular metabolism to activate NF-κB and vitamin D ational or socioeconomic, that increase the risk or
receptor pathways to upregulate cytokine produc- predispose individuals toward developing disease.
tion and genes that are critical to form and maintain Household contacts living within a dwelling with an
granulomas required to contain the bacilli, includ- untreated multibacillary leprosy index case have the
ing TNF, interferon gamma (IFN-γ) and lymphotoxin highest risk of eventually coming down with disease,
alpha. What occurs next is likely determined by the particularly if the household contact is a blood rela-
complex interplay of the adaptive immune response tive to the index case.54 Individuals who have a posi-
involving cell-mediated and humoral immune tive anti-PGL-I titer have up to an 8-fold higher risk
responses, with T helper 1 (Th1) cytokines and a of developing leprosy. Other risk factors include liv-
pro-inflammatory response leading to heightened ing in an endemic or hyperendemic area for leprosy,
cell-mediated responses controlling bacterial growth poverty, living in high-density households with >2
and preventing dissemination, and a shift to T helper persons sleeping together in a room, poor nutritional
2 (Th2) cytokine production downregulating the status, poor sanitation or lack of clean water, and lack
inflammatory response and leading to uncontrolled of health care availability.55 Improving these underly-
growth, high levels of ineffective antibody responses ing problems would greatly decrease the likelihood
2902 to bacterial antigens, and progressively worsening of those at risk of leprosy from ever developing this
disease symptoms. disease.

Kang_CH159_p2892-2924.indd 2902 04/12/18 2:42 pm

 DIAGNOSIS (α-DG) might be necessary for the adherence of
M. leprae to Schwann cells.60 The matrix cytoskeleton
23
link (α-DG, α2-laminin, β -DG) may be the route used
SUPPORTIVE STUDIES by M. leprae to enter the host cell (Fig. 159-20).
M. leprae bypass neuregulin receptor (an epidermal
PATHOLOGY growth factor family component) and does a direct bac-
terial ligation to ErbB2, signaling with no ErbB3 het-
Physiopathology of Leprosy: The routes erodimerization and amplifying Erk1/2 signaling that
used by M. leprae to gain access to the target cells, may induce myelin sheath degradation.61 In addition,
mainly Schwann cells, have always been a matter of using a nonclassical pathway and MEK-independent
discussion. Basically, 4 different pathways have been signaling, M. leprae can activate Erk1/2 directly by
proposed: (1) naked nerve filaments in the epider- lymphoid cell kinase (p56LcK), inducing cell prolif-
mis; (2) entrance of M. leprae in the epidermis, and eration and maintaining its niche of proliferation.62 On
from there to other Schwann cells; (3) phagocytosis of infection, there is an increased expression of 9-O-acetyl

Chapter 159 :: Leprosy

M. leprae by dermal macrophages, which then invade the GD3 ganglioside, a molecule involved in anti-apoptotic
perineurium, liberating bacilli to enter Schwann cells; signaling and nerve regeneration (Fig. 159-20). Immu-
and (4) through the blood, that is, M. leprae could gain noblocking of 9-O-acetyl GD3 ganglioside on Schwann
access to the nerve by intraneural capillaries. Enlarged cells reduces Erk1/2 and cell proliferation.63
endothelial cells could facilitate bacilli entrance to the M. leprae can dedifferentiate and reprogram adult
nerve system, and finally to Schwann cells.56 Schwann cells to stem cell–like cells, possibly using
M. leprae interaction with and engulfment by endo- this to promote dissemination of infection.64 Bacilli
thelial cells was identified long ago.57 Armadillo stud- survival may be maintained by different mechanisms.
ies showed epineural thickening following M. leprae After invasion (Fig. 159-20), M. leprae interferes with
infection of macrophages of lymphatic and vascular (1) endocytic maturation inhibiting vesicle acidification
endothelial cells.58 Although this model of infection is of phagosomes65; (2) host-cell lipid homeostasis, induc-
well known, it is still not clear how M. leprae is then ing and accumulating lipid droplets through cytoskel-
transferred from those cells to Schwann cells. eton reorganization and PI3K signaling, independently
Once M. leprae reaches the extracellular matrix, PGL-I48 of TLR-266; and (3) oxidative pathways, by an intensifi-
or a histonelike 21-kDa laminin-binding protein59 cation of glucose uptake and augmentation of glucose-
binds to the laminin α2 chain to invade Schwann 6-phosphate dehydrogenase, that once inhibited can
cells. The presence of the G domain of α-dystroglycan decrease M. leprae viability by up to 70%.67

Mechanisms of adhesion, survival, and

growth of Mycobacterium leprae cell on interaction

Extracellular matrix
PGL-I
Schwann cell
Glucose α-DG
uptake Antiapoptotic 9-o-acetyl GD3 α2-Laminin
pathway and ganglioside
β -DG
nerve regeneration
MEK-independent
signaling (p56LcL)

PI3K ERBB2

Inhibiting
Accumulation of vesicle
of lipid droplets ERK1/2
acidification Phagosome
Neuregulin
of phagosome
ErbB3 receptor
heterodimerization
Myelin sheath
degradation

Myelin Axon

Figure 159-20 Host cell interaction of M. leprae. The figure shows the main mechanisms of entrance and maintenance of 2903
the bacteria inside a Schwann cell.

Kang_CH159_p2892-2924.indd 2903 04/12/18 2:42 pm

23 The immune response may initiate at any phase of
the host–bacteria interaction. Epidemiologic surveys
thalidomide.78 Moreover, metalloproteinases 2 and 9
and TNF-α are upregulated in Schwann cells, mac-
in hyperendemic areas in Brazil show a high percent- rophages and endothelial cells in primary neural
age (up to 50% or more) of anti-PGL-I IgM antibodies leprosy nerves,79 that result in a prominent endoneu-
circulating among schoolchildren, indicating infection rial infiltrate, with perineurial fibrosis and enlarge-
with M. leprae followed by an early antibody response ment in comparison to non-leprosy peripheral
against the bacilli.68 Although nerve demyelination neuropathy.80
may occur in T and B lymphocyte–depleted mice,69 Besides the Th1/Th2 cytokine profile, other fac-
diverse immune reactions occur during infection. tors, such as IL-17, cathelicidin LL-37, and insulinlike
There is a well-characterized dichotomy in the growth factor I also seem to be important in lep-
human immune response in leprosy, with those at rosy physiopathology. VCAM-1 is augmented in the
the tuberculoid end of the spectrum having a strong serum of leprosy patients,81 whereas vascular endo-
Th1 cell–mediated response whereas those at the thelial growth factor and thromboplastin expression
lepromatous end have a skewed Th2 response with is increased by endothelial cells of leprosy patients.82
Part 23

T-cell anergy present. Tuberculoid leprosy cases have IL-17 is low in all leprosy patients in comparison to
a strong Th1 response, with IL-2, TNF-α, IFN-γ, and nonleprosy controls, but even lower in lepromatous
IL-12 cytokine production, whereas lepromatous lep- leprosy.83 Although IL-17-producing CD4+CD45RO+
rosy patients have a Th2 response, with IL-4, IL-5, Th17 cells were increased in peripheral blood mono-
::

IL-10 and high levels of antibody production. Those nuclear cells of tuberculoid leprosy patients, IL-
Bacterial Diseases

characteristics are found also in the skin, where gener- 10-producing Foxp3+ Treg cells were 5 times more
ally the 2 situations may appear as demonstrated by prevalent in lepromatous leprosy than in tuberculoid
the progressive disorganization of the immune cells leprosy patients, indicating a role for Tregs in multi-
that infiltrate the skin70 in histochemical stained tissue bacillary leprosy development.84 Cathelicidin LL-37,
sections of lesions. Tuberculoid leprosy patients pres- a unique cathelicidin family member of host defense
ent a well-organized granuloma containing epithelioid peptides found in humans that is known to modulate
cells, CD4+ T cells, a good cell–mediated immunity, the immune response against M. tuberculosis, is low in
almost no antibody production, and no bacilli found all leprosy patients85 (Fig. 159-21). Insulinlike growth
by slit-skin smear bacilloscopy. On the other hand, factor I, known to decrease macrophage antimicrobial
lepromatous leprosy patients demonstrate a massive capacity, inhibiting M. leprae killing,86 was also found
infiltration of foamy macrophages filled with large to be low in lepromatous leprosy patients, mostly
numbers of bacilli, with few lymphocytes, mostly among those who did not develop Type 2 reaction or
CD8+ T cells, and a defective cell-mediated immunity erythema nodosum leprosum (ENL).87
with high titers of antibodies to M. leprae antigens, ENL, an immunologic Type III hypersensitivity
including to PGL-I.71 response, occurs with immune complex deposition88
Toll-like receptors, such as TLR-1, TLR-2, and TLR-4, with anti-PGL-I and anti-monocyte chemoattractant
along with DC-SIGN (CD209) and CD163 may be protein-I antibodies,89 upregulation of Th17, IL-6, IL-1β ,
involved in macrophage/dendritic cell interac- sIL2R, and sIL6R; a decrease of the Treg response; and
tions with M. leprae. TLR-1 and TLR-2 have a higher an influx of neutrophils in the lesions90 (Fig. 159-21).
expression in tuberculoid leprosy in comparison with In addition, ENL can be initiated on IFN-γ intradermal
lepromatous leprosy lesions, and TLR-1/TLR-2 het- injection in lepromatous leprosy patients,91 there is an
erodimers mediate monocyte and dendritic cell acti- increase in the CD4+/CD8+ ratio, high serum levels of
vation, stimulating TNF-α and IL-12 production72 TNF-α are found,92 and the use of TLR-9 agonists aug-
(Fig. 159-19). M. leprae can also stimulate TNF-α, ments TNF-α, IL-6, and IL-1β .93 E-selectin is expressed
IL-6, and CXCL10 (IP-10) production through TLR-4 in a vascular pattern, higher in ENL than in nonre-
signaling in macrophages.73 On the other hand, TLR-2 actional lepromatous leprosy patients,94 and FcγRI
signaling in Schwann cells is related to apoptosis.74 increases in circulating neutrophils of ENL patients95
M. leprae increases IL-10 expression in dendritic (Fig. 159-21).
cells through DC-SIGN signaling, activating Raf-1, Gene expression analysis showed an increased
resulting in acetylation of the NFκB p65 subunit after expression of a “cell movement” biologic group,
TLR-induced activation of NFκB.75 IL-10 induces including P-selectin, E-selectin, and neutrophil adhe-
phagocytosis by macrophages through DC-SIGN and sion to endothelial cells, with migration and inflam-
differentiates monocytes into foamy macrophages by mation. In vitro stimulation of TLR-2 induced IL-1β
upregulation of oxidized low-density lipoprotein and FcR expression, that together with IFN-γ and
uptake, whereas IL-15 induces the vitamin D anti- granulocyte macrophage colony–stimulating factor,
microbial pathway, exhibiting less phagocytosis.76 augmented E-selectin expression, and increased neu-
Together with upregulation of DC-SIGN and indole- trophil adhesion to endothelial cells.94 Thalidomide
amine 2,3-dioxygenase, CD163 is also increased and inhibited this neutrophil recruitment pathway,
contributes to iron uptake and to the creation of an decreases neutrophil influx, FcγRI expression, and
advantageous environment for M. leprae entry and TNF-α production. C1qA, B, and C components of
survival in lepromatous leprosy macrophages77 the classical complement pathway, and the receptors
2904 (Fig. 159-20). M. leprae can modulate NFκB activation C3AR1 and C5AR1, were also increased in leproma-
in Schwann cells, a function that can be inhibited by tous leprosy patients.59

Kang_CH159_p2892-2924.indd 2904 04/12/18 2:42 pm

 Immunology highlights on PB and MB sides of the leprosy spectrum
23
DC TT
TT LL TLR-4
CD163 DC

TLR-1 Fe+ P65/NFκB

TLR-2 IDO Raf-1
IL-12 IL-10
Monocyte
oxLDL DC-SIGN
TNF-α

IL-5 LB
IL-4
Th2
IL-2 Th1

Chapter 159 :: Leprosy

INF-γ
Ab

Reversal Reaction Erythema Nodosum

CD4 + VEGF Leprosum
IL-1β IL-10 IL-17 IL-17 Th17 IL-1β
IGF-I IL-6 sIL2r
IL-2 CXCL-9
Well-organized Massive infiltration sIL6R Neutrophils
TNF-α IL-17A
granuloma of foamy macrophages
IFN-γ G-CSF TNF-α FcγRi
IL-10 Treg E-selectin CD4 +/CD8+
Increase of VCAM-1, VEGF, and tromboplastine
Decrease of cathelicidin LL-37 Treg

Figure 159-21 Immunology of leprosy. The main differences of tuberculoid leprosy and lepromatous leprosy poles are
demonstrated, together with the key variations between reversal reaction and erythema nodosum leprosum.

Type 1 reaction or reversal reaction, a Type IV beginning treatment. When there are doubts about the
hypersensitivity immune response, is caused by a clinical diagnosis, laboratory tests can be used to assist
specific increase in cell-mediated immunity against or confirm a presumptive case of leprosy.
M. leprae, and may rapidly evolve to nerve damage. The clinical spectrum of leprosy shows a range of
Together with an increase of CD4+ T cell infiltra- pathologic manifestations in skin lesions and nerve
tion associated with IL-1β , IL-2, TNF-α, and IFN-γ damage that is aligned with the competence of the
upregulation96 (Fig. 159-21), an augmentation of CC host’s immune response, and is dependent on the
chemokines monocyte chemoattractant protein-I and strength and interaction of both cell-mediated and
RANTES97 is observed. antibody responses.100 The standard for laboratory
Also, vascular endothelial growth factor, IL-10, diagnosis in a skin biopsy is the detection of acid-fast
CXCL-9, and IL-17A were demonstrated to be upreg- bacilli by the Fite-Faraco modification of the carbol
ulated on the reversal reaction onset, together with fuchsin technique and characteristic cellular histo-
downregulation of IL-10 and granulocyte colony- logic patterns that make up the immunopathologic
stimulating factor. This profile was related to a decrease types of leprosy as detected by hematoxylin–eosin
of CD39+CCL4+CD25++ regulatory T-cell subsets and staining. The widely used Ridley-Jopling classifica-
an increase of GNLY, GZMA/B, and PRF1 genes associ- tion system26 divides the disease into 5 forms based on
ated with cytotoxic T cell.98 the number of acid-fast bacilli and the degree of lym-
phocytic infiltration and organization, as described
in pathology (above). Bacilloscopy of multiple skin
LABORATORY TESTING biopsies or slit-skin smear can establish the bacillary
index on a logarithmic scale, which can range from 0
Further reduction in leprosy would require the diag- (no acid-fast bacilli detected in tuberculoid leprosy
nosis of those in the early stages of disease to allow lesions) to 6+ (>1000 acid-fast bacilli per field in lep-
treatment to prevent nerve damage and impairment, romatous leprosy) (Fig. 159-22). For treatment pur-
but it is estimated that most patients experience up to poses, detection of acid-fast bacilli in skin lesions or
2 years delay in diagnosis.99 Reasons for this are com- slit-skin smear automatically places the patient in the
plicated, but include a reduction in the numbers of multibacillary category to receive 12 months of mul-
trained leprosy clinicians and laboratory technicians tidrug therapy.
worldwide and the incorporation of leprosy diagnosis There is currently no laboratory test capable of
into the general family health delivery system, result- diagnosing leprosy or identifying asymptomatic 2905
ing in increased levels of misdiagnosis or delays in individuals who are progressing toward developing

Kang_CH159_p2892-2924.indd 2905 04/12/18 2:42 pm

23 of the RLEP sequence in the genome, this enables
the detection of as few as 3 bacterial genomes in a
sample. Recent evidence indicates that individuals
who are RLEP PCR positive in biopsies of skin lesion
sites, earlobe slit-skin smear, or the nasal turbinate as
well as having a positive anti-PGL-I titer likely have
asymptomatic infection and are at the highest risk
of developing disease.49 Our own household contact
studies in hyperendemic areas in Pará, Brazil, support
these findings. Initial results of multiple families liv-
ing in “hot zones” indicated that in many instances
>80% of household contacts had a positive anti-PGL-I
titer, >70% were positive for RLEP by PCR in slit-skin
smear, with up to 65% being positive for both bio-
Part 23

markers, demonstrating extreme rates of infection,

with 1 or more individuals in each household diag-
Figure 159-22 Acid-fast bacilli of a slit-skin smear of a
lepromatous leprosy patient. The cells are in blue and the nosed with leprosy based on clinical signs (Salgado
bacteria are in red, forming globi. et al, unpublished observations). Finally, metabolo-
::

mics has been used to identify molecular features

Bacterial Diseases

found in the serum of leprosy patients, indicating that

early symptoms, so the development of a simple and there was an increase of circulating polyunsaturated
cheap test that could assist health professionals to cor- fatty acids and phospholipids in individuals with lep-
rectly diagnose the disease based on immunologic romatous disease.107 A recent report has even shown
or metabolomic biomarkers of infection is desirable. that molecular features of infection can be identi-
A number of research groups have developed a vari- fied by mass spectrometry simply by pressing silica
ety of tests that partially achieve this goal, measuring plates against patient skin lesions.108 Moreover, the
antibody titers to mycobacterial antigens by rapid leprosy miRNome sequencing has been recently pub-
lateral flow devices; cell-mediated cytokine release lished, and revealed new markers involved on leprosy
assays (such as the detection of IFN-γ, similar to com- physiopathology109
mercial whole blood assays used to detect infection Although advances have been made in identify-
by M. tuberculosis); amplification of mycobacterial ing biomarkers of infection by many research groups,
DNA by PCR; or the use of metabolomics to detect translating this to a rapid, cheap, point-of-care test
molecular features specific to M. leprae infection in the that will aid in diagnosing all patients throughout the
blood or urine. Laboratory assays adapted to assess leprosy clinical spectrum, including asymptomatic
leprosy patient antibody titers to the M. leprae– individuals, has a long way to go. Currently, leprosy
specific antigen, PGL-I, have been in use for more than diagnosis must remain in the competent hands of well-
30 years101,102 and include enzyme-linked immunosor- trained leprosy clinicians and health care workers.
bent assays and lateral flow devices that use the solu- We have shown the importance of targeting school-
ble synthetic disaccharide of PGL-I coupled to either children in school-based surveillance and followup
bovine or human albumin, called ND-O-BSA or ND- of household contacts of those diagnosed children
O-HSA, respectively. Another is the protein antigen to detect cases early in the disease process. The use
LID-1, composed of the fusion of 2 well-recognized of a Geographic Information System, spatial analysis
M. leprae proteins, ML0405 and ML2331, that is rec- tools, and laboratory tests (anti-PGL-I enzyme-linked
ognized by >95% of lepromatous patients.103 Cou- immunosorbent assay and RLEP PCR) has enhanced
pling the synthetic disaccharide of PGL-I to LID-1 and the ability to identify “hot zones” within hyperen-
incorporating this NDO-LID glycoprotein in a lateral demic cities,110,111 which can then allow focused tar-
flow test resulted in enhanced sensitivity to detect lep- geting of foci of infection by community health care
rosy patients, even those at the paucibacillary end of agents working in local areas. Nevertheless, given the
the spectrum.104 Another group has combined lateral complexities of examining, diagnosing, and ensur-
flow assays with up-converting phosphor reporter ing treatment to individuals living in hyperendemic
technology to assess both anti-PGL-I titers along with areas,15 developing a simple laboratory test to diag-
T cell–mediated cytokine responses (IFN-γ, IL-10, and nose leprosy early is highly desirable and would facil-
others) in a single sample. The ability to quantitate itate breaking the lines of transmission to eventually
the ratio of inflammatory Th1 cytokines versus down- reach the goal of leprosy elimination.
regulating Th2 responses provides more information
about the complex interplay of cellular and humoral
immunity within individuals that can be used to HISTOPATHOLOGY
better predict those with asymptomatic infection or
who are progressing to disease.105,106 Another method Skin biopsies should include the dermis and, if pos-
that has been used to diagnose difficult cases is the sible, subcutis of a lesion. Hematoxylin–eosin stain-
2906 molecular detection of the M. leprae–specific repetitive ing is complemented using the Fite-Faraco staining
RLEP sequence by PCR. Because there are 37 copies method or another method to detect acid-fast bacilli.

Kang_CH159_p2892-2924.indd 2906 04/12/18 2:43 pm

 23

Chapter 159 :: Leprosy

A C

Figure 159-23 Indeterminate leprosy histopathology. Up to 70% of the indeterminate cases may have an unspecific his-
topathology. In 30% it is possible to observe a perineural infiltrate with nerve delamination (A and B, arrows), as dem-
onstrated here, and if extensively searched, sometimes it is possible to find an acid-fast bacilli (C, arrow). (Used with
permission from Dr. Jaison Barreto, Lauro de Souza Lima Institute, Brazil.)

Histopathologic findings are graded according to In borderline-borderline, there are aggregates of epithe-
the Ridley and Jopling scale.26 The tissue response in lioid cells, scarce dispersed lymphocytes, no Langhans
Indeterminate leprosy is nonspecific. The normal epi- multinucleated giant cells, and increasing numbers of
dermis or basal layer of the skin show melanin reduc- acid-fast bacilli (Fig. 159-26).
tion. Perivascular or perineural, superficial and deep Borderline-lepromatous leprosy shows a subepidermal
dermal infiltration by few macrophages and lympho- grenz zone, aggregates of macrophages, occasional
cytes are common findings. Sometimes the infiltrate epithelioid cells with abundant cytoplasm, and some
surrounds skin appendages and rarely there are bacilli foamy cells, with few lymphocytes. A great number of
in nerves (Fig. 159-23). bacilli and some globi can be found (Fig. 159-27).114
Tuberculoid leprosy shows an epidermis that is In lepromatous leprosy there is a normal to flattened
usually normal and the subepidermal clear zone is epidermis, subepidermal grenz zone, aggregates and
absent. There is a noncaseating dermal granuloma- sheets of foamy macrophages admixed with predomi-
tous process composed chiefly of activated macro- nantly CD8+ lymphocytes and plasma cells through-
phages (epithelioid cells) with CD4+ T cells in the out the dermis and into the subcutaneous fat. Huge
center of the epithelioid cells, CD8+ T cells in the numbers of acid-fast bacilli and globi are found within
mantle surrounding the granuloma, and giant cells foamy macrophages (Virchow cells), nerves, arrecto-
of the Langhans type. Granulomas may contact the res pilorum muscle, follicular epithelium, and sweat
epidermis and are often arranged around nerves and glands (Fig. 159-28).
vessels. Peripheral nerve involvement, cellular infil- Histoid leprosy is characterized by epidermal atro-
tration of sweat glands, and invasion of the arrecto- phy, a subepidermal grenz zone, and a dermis show-
res pilorum muscle by a granulomatous infiltrate is ing sheets of predominantly spindle-shaped cells with
common. There are no acid-fast bacilli or when they nuclear pyknosis and foamy cytoplasm, vacuolated,
are present are found more frequently within periph- and arranged in a storiform pattern. Some polygonal-
eral nerves, arrectores pilorum muscle, or even shaped cells, macrophages, and inflammatory cells are
granulomas112,113 (Fig. 159-24). present. Some cases may show a pseudocapsule. The
The histopathology of the borderline-tuberculoid form lesion resembles a fibrohistiocytic tumor (Fig. 159-29).
can be distinguished from tuberculoid leprosy by the The Fite-Faraco stain reveals a large number of acid-
presence of a subepidermal grenz zone. In general, fast bacilli, mostly as rafts or globi (Fig. 159-30). Bacilli
there is no well-defined granuloma with organized can be located in nerves, Schwann cells, eccrine glands,
collections of epithelioid cells, and there is a reduction and in the vascular endothelium. CD68-positive mac-
in the frequency of lymphocytes and scarce Langhans rophages and spindle cells are present in histoid 2907
cells with rare acid-fast bacilli (Fig. 159-25). leprosy.115

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23

B
Part 23
::
Bacterial Diseases

A C

Figure 159-24 Tuberculoid leprosy histopathology. Presence of deep and superficial well-developed granuloma, that
touch the epidermis (A), associated with lymphocyte infiltration surrounding or invading and destroying skin append-
ages, like nerves, erector pili muscle (B), or sweat gland (C).

In leprosy reversal reaction, the histopathologic fea- granuloma. Fibrinoid necrosis is present in severe
tures are edema both extracellular as in epithelioid cases of reversal reaction. Bacilli are found in macro-
cell granulomas, increased number of lymphocytes phages and nerves (Fig. 159-31). The downgrading
and Langhans giant cells in the infiltrate, small collec- reaction reveals aggregates of foamy macrophages,
tions of epithelioid cells, as well as a poorly organized a remarkable reduction or complete absence in the

A C D

Figure 159-25 Borderline-tuberculoid leprosy histopathology. Deep and superficial tuberculoid granuloma (A) that does
2908 not touch the epidermis (B). The tuberculoid granuloma may be seen invading the nerves (C), and acid-fast bacilli can be
found (D, 100×). (Used with permission from Dr. Jaison Barreto, Lauro de Souza Lima Institute, Brazil.)

Kang_CH159_p2892-2924.indd 2908 04/12/18 2:43 pm

 23

Chapter 159 :: Leprosy

A C

Figure 159-26 Borderline-borderline leprosy histopathology. Deep and superficial tuberculoid granuloma that does not
touch the epidermis, starting to form a grenz zone (A). Inflammatory cells are invading cutaneous annexes and nerves,
that are degenerated (B), and acid-fast bacilli can be found more easily, some forming globi (C). (Used with permission
from Dr. Cleverson Soares, Lauro de Souza Lima Institute, Brazil.)

number of lymphocytes, and acid-fast bacilli in greater in the dermis and in the subcutis, predominantly neu-
numbers.116,117 trophils with eosinophils, lymphocytes, aggregates
ENL or Type 2 reaction. The characteristic histologic of foamy macrophages, plasma cells, and mast cells.
features are edema and a mixed inflammatory infiltrate Vasculitis and a mixed lobular and septal panniculitis

A C

Figure 159-27 Borderline-lepromatous leprosy histopathology. There is a mixed macrophage lymphocytic inflammatory
infiltrate (macrophage granuloma) on superficial and deep dermis (A). The mixed infiltrate does not touch the epidermis 2909
and may be seen surrounding or invading nerve bundles (B). A large number of acid-fast bacilli is seen (C).

Kang_CH159_p2892-2924.indd 2909 04/12/18 2:43 pm

23

B
Part 23
::
Bacterial Diseases

A C

Figure 159-28 Lepromatous leprosy histopathology. An inflammatory infiltrate composed mostly by foamy macrophages
is observed on the dermis. The epidermis is flattened, and there is a clear grenz zone on the dermal–epidermal interface
(A). Fite-Faraco demonstrate acid-fast bacilli globi inside macrophages (B) and on sweat glands cells (C).

are present in most cases (Fig. 159-32). Bacilli in large Lucio phenomenon or erythema necrotisans. The main
numbers, usually granular in appearance, are easily microscopic features are that of a cutaneous or subcu-
found. The predominant lymphocyte present in ENL is tis necrotizing vasculitis. There is fibrinoid necrosis of
the T-helper cell, whereas T-suppressor cells predomi- small and medium-sized vessels. The other histologic
nate in the lepromatous leprosy.117,118 picture reported in Lucio phenomenon are necrosis of

A C

Figure 159-29 Lepromatous leprosy histoid Wade leprosy histopathology. A flattened epidermis is observed over a dense
2910 inflammatory infiltrate (A) of spindle and epithelioid cells arranged in a storiform or fasciculated pattern (B), which may
have a foamy aspect on closer view (C).

Kang_CH159_p2892-2924.indd 2910 04/12/18 2:43 pm

 23

Chapter 159 :: Leprosy

A B

Figure 159-30 Globi. Aggregates of bacilli (globi) inside the host cells, as seen here inside macrophages (A and B), is a
characteristic of M. leprae.

epidermis and superficial dermis, micro-abscess for- infiltrate of neutrophils, eosinophils, lymphocytes,
mation, angiogenesis, endothelial swelling, vascular and nuclear dust. Bacilli are found in endothelial cells,
occlusion caused by luminal thrombi, and deposits in blood vessels, nerves, arrectores pilorum muscle,
of fibrin in small blood vessel walls of the dermis and follicular epithelium, sebaceous glands, and sweat
the subcutis. There is a mixed dermal and/or subcutis glands.119-122

A C

Figure 159-31 Histopathology reversal reaction. Presence of an inflammatory infiltrate, associated to epithelial hyper-
plasia (A) and foci of epidermal aggression with dermal edema (B) and fibrin deposit (C). (Used with permission from
Dr. Jaison Barreto, Lauro de Souza Lima Institute, Brazil.) 2911

Kang_CH159_p2892-2924.indd 2911 04/12/18 2:43 pm

23

A
Part 23
::
Bacterial Diseases

B C

Figure 159-32 Histopathology erythema nodosum leprosum. A mixed inflammatory infiltrate, composed of foamy macro-
phages with large vacuoles and neutrophils (A) is shown. Foamy macrophages are also seen surrounding a vessel under-
going fibrinoid necrosis and presenting aggregates of inflammatory cells in its lumen and wall (B), where Fite-Faraco
reveals the presence of large amounts of globi, and single bacilli inside a vessel and in its wall (C, arrows).

NERVE CONDUCTION STUDY— recently has it seen more use in the evaluation of nerve
function impairment in leprosy neuropathy. Clinical
ELECTRONEUROMYOGRAPHY examination of nerve enlargement may be difficult
to measure, even for experienced leprologists, and
Leprosy neuropathy manifests as asymmetric focal or
there are no robust parameters to be recorded to fol-
multifocal lesions, mononeuropathy or mononeuritis
lowup the leprosy patient during and after multidrug
multiplex, caused by the direct damage of nerves by
therapy.
M. leprae and by an inflammatory immune response
High-resolution ultrasound can be used for evalu-
of the host. There is chronic neuropathy, with acute
ation of echogenicity, vascularity, and nerve thicken-
exacerbations resulting from reversal reaction or ENL.
ing, using objective parameters and values for several
Besides focal lesions, entrapment of the enlarged nerves
neuropathies, including leprosy.124 In addition, nerve
is also a concern, that may require surgical intervention
abscesses and entrapment also can be detected early
to decompress the nerve. Evaluation includes nerve
and evaluated.123 Its utilization for leprosy neuropa-
palpation, pain evaluation, sensory assessment, muscle
thy evaluation is still evolving, but very promising.
power measurement and autonomic examination.
Echogenicity abnormalities, intraneural Doppler and
Electroneuromyography is a refined tool for nerve
post-multidrug therapy cross-sectional areas above
function assessment at diagnosis, and for patient fol-
normal limits, with less than 30% reduction, have
lowup to detect and characterize new lesions, espe-
been linked to poor outcomes. Worsening of nerve
cially during reversal reaction or ENL, or to evaluate
abnormalities after multidrug therapy were found
entrapment syndromes and neuropathic pain. Leprosy
independent of leprosy classification or presence of
neuropathy starts with Schwann cell demyelination
reactions.125
that may evolve to axon loss. Commonly affected
sites include the elbow for the ulnar nerve, the carpal
tunnel for the median nerve, the fibula head for the
fibular nerve, and the tarsal tunnel for the posterior
tibial nerve, all which are key areas for evaluating DIAGNOSTIC ALGORITHM
neuropathy.123
See Fig. 159-33.

IMAGING
High-resolution ultrasound use for peripheral nerve
DIFFERENTIAL DIAGNOSIS
2912
evaluation is an established procedure. However, only See Table 159-1.

Kang_CH159_p2892-2924.indd 2912 04/12/18 2:43 pm

 Leprosy diagnosis algorithm

Kang_CH159_p2892-2924.indd 2913
Hypo or Tingling,
Autonomic
anesthetic prickly or pain Skin lesions Paresthesia
dysfunctions
area sensation

Ask patient to remove clothes,

examine all skin surface and
palpate nerve trunks

Not leprosy No

Autonomic alterations?
or
Thickened nerves with sensitivity
Normal or motor function impairment?
or
Skin lesions with altered
1. Test sensitivity on sensitivity?
the nerve territory Only
thickened
2. Test motor nerves?
function Yes

Altered
1 or 2
One or a few Diffuse infiltration,
One or many Many infiltrated
hypochromic lesions One or a few One or a few nodules and
infiltrated lesions, lesions, associated
tuberculoid lesions infiltrated lesions autonomic
No autonomic that may be foveolar or not to nodules
Primary Neural No more than one One or more dysfunctions
alteration Usually, more than Many thickened
Leprosy thickened nerve thickened nerves Many thickened
No thickened nerves one thickened nerve nerves
nerves

Indeterminate TT BT BB BL LL
Leprosy Leprosy Leprosy Leprosy Leprosy Leprosy

Figure 159-33 Leprosy diagnosis. At any time, it is possible to ask for laboratory examinations: slit-skin smear for acid-fast bacilli or for PCR, biopsy for histopathology, and anti-PGL-I
serology.

Chapter 159 :: Leprosy

2913
23

04/12/18 2:43 pm
23 TABLE 159-1
extent of the disease, and the presence of lesions over-
lying peripheral nerve trunks are factors that increase
Differential Diagnosis the risk of reactions and nerve function impairment.126
Reversal reaction and ENL may happen together in
Primary Lesions some patients (Table 159-2).
■ Macules and patches. The hypopigmentation of pityriasis alba and
Reversal reaction can occur in up to 30% of
indeterminate leprosy mimic each other. If the patient was born in,
patients, whereas tuberculoid leprosy cases are
or had resided in, an endemic area, then the distinction between
the two may be made by neurologic or histologic examination.
seldom affected,127 the majority of the reactional
Hypopigmented BL plaques can be so faintly indurated as to mimic episodes occur in borderline forms, mainly borderline-
patches. Telangiectasias may be eruptive or present as mats on the lepromatous and borderline-borderline, followed by
face and upper trunk. lepromatous leprosy.128 It starts as a sudden worsening
■ Papular to nodular lesions. In the dermis, leprosy may mimic, or of skin lesions and nerve function impairment, with no
be mimicked, by dermatofibromas, histiocytomas, lymphomas, apparent systemic involvement. Besides prereactional
sarcoidosis, neurofibromatosis, syphilis, anergic leishmaniasis, lesions presenting more infiltration and desquamation,
paracoccidioidomycosis, chromoblastomycosis, sporotrichosis, lobo-
Part 23

previous and newly developing lesions may be bright

mycosis, tuberculosis, and other granulomas. Eruptive and recurrent
red, hot, and sensitive to the touch (Fig. 159-34), some-
inflammatory subcutaneous nodules may be ENL, erythema nodo-
times ulcerated, frequently associated with peripheral
sum, erythema induratum, and vasculitis. Palpable, but not visible,
subcutaneous nodules in Lucio leprosy may mimic lipomas.
nerve enlargement, and usually accompanied by pain.
::

■ Plaques. Erythematous plaques may mimic mycosis fungoides. Reversal reaction requires immediate intervention,
Bacterial Diseases

Plaques without pigmentary change may be wheal like in appear- because it can result in nerve impairment and perma-
ance, causing confusion with urticaria. Hypopigmented plaques nent disabilities.
may mimic papulosquamous eruptions. Islands of normal skin ENL is an aggressive vasculitis with immune com-
within a plaque may suggest psoriasis. plex deposition affecting different organs, resulting
■ Polymorphous vesiculobullous eruption/Dermoepidermal sep- in, among other sequelae, neuritis, panniculitis, glo-
aration. They may occur in ENL. IgM is deposited not uncommonly merulonephritis, arthralgia, epididymitis, orchitis, eye
at the epidermal basement membrane in LL. These antibodies are
inflammation, osteitis and lymphadenitis with sys-
not necessarily pathogenic but may confuse diagnosis.
temic symptoms such as fever, edema and malaise.129
■ Annular lesions. Leprosy may mimic, or be mimicked by, annular
erythemas, sarcoidosis, syphilis, or tinea.
Secondary Lesions
■ Infarcts. Lucio phenomenon lesions and necrotic ENL mimic septic
infarcts.
TABLE 159-2
■ Ulcers. Ulcers occur in Lucio phenomenon and ENL secondary to Lepra Reactions and Management
vascular occlusion. In patients with nerve destruction, neurotrophic
ulcers occur on the plantar surface, patients with Leg ulcers sec- REVERSAL REACTION ERYTHEMA NODOSUM
ondary to venous insufficiency are seen in Lucio leprosy. (TYPE I) LEPROSUM (TYPE II)

Clinical Constellations Predominant Borderline-tuberculoid Lepromatous leprosy

■ Systemic lupus erythematosus–like changes. Fusiform fingers, leprosy Borderline-borderline
swan neck deformity,yy, false positive syphilis
syphilis tests, antiphospholipid subtype Borderline lepromatous
antibodies, lupus anticoagulant, hyperglobulinemia, and anemia. Lepromatous leprosy
■ Vasculitis. A true vasculitis may occur in ENL, Lucio phenomenon, Signs and Acute worsening of Erythema nodosum
and Lucio leprosy. Clinically,
yy, leprosy
leprosy lesions of a nodular character symptoms skin lesions Erythema
may be misdiagnosed as “vasculitis.” Acute worsening polymorphous
of nerve function Severe cutaneous
impairment necrotizing vasculitis

CLINICAL COURSE
No apparent systemic Fever, edema, malaise
symptoms

AND PROGNOSIS Extracutaneous

involvement
Neuritis Neuritis
Panniculitis
Glomerulonephritis
One of the most important problems during the lep-
Arthralgia
rosy clinical course is the appearance of acute or sub-
Epididymitis
acute episodes of inflammation, defined as reactions. Orchitis
Leprosy reactions, caused by immune response against Eye inflammation
M. leprae antigens, are divided into Type 1 or reversal Osteitis
reaction, involving mainly peripheral nerves and skin, Lymphadenitis
and Type 2 or ENL, that may have localized or sys- Treatment Prednisone (1-2 mg/ Thalidomide
temic symptoms. Acute neuritis also may be consid- kg/d with slow taper 100-400 mg/d
ered as a type of reaction. ∼ 3 mo) AND
Reactions never occur in Indeterminate patients. prednisone
Up to 50% of all patients on multidrug therapy may (1-2 mg/kg/d)
present reactions during treatment, but these reactions OR
can also occur before and after therapy. Neuropathy Pentoxif lline 400 mg
Pentoxify
Pentoxifylline
2914 thrice a day
present at the time of diagnosis, multibacillary leprosy,

Kang_CH159_p2892-2924.indd 2914 04/12/18 2:43 pm

 23

Chapter 159 :: Leprosy

A C

Figure 159-34 Reversal reaction. Reappearance or worsening of pre-multidrug therapy lesions, during or after treatment
(A), usually presenting severe infiltrated lesions, that may coalesce in small, foveolar (B) or large scaly (C) plaques.

A high bacillary index and diffuse skin infiltration are to antiviral therapy in AIDS patients is now well recog-
important risk factors130 and 65% of the cases have nized in IRIS,133 and the percentage of HIV and other
more than one episode of ENL.131 The main skin mani- viral infections in leprosy patients is high, indicating
festation is erythema nodosum, more palpable than that all leprosy patients should be tested for HIV, HBV,
visible (Fig. 159-35), and may be accompanied by ery- HCV and HTLV-1.134 Viral coinfection decreases the
thema polymorphous or severe cutaneous necrotizing
vasculitis (Lucio phenomenon) (Fig. 159-36).
Immunologic disorders, like HIV and HTLV infec-
tions, immunosuppressive drugs, or immunobiological
medications can interfere with the resolution of leprosy.
The first case of leprosy occurring as a result of immune
reconstitution inflammatory syndrome (IRIS) in an
HIV-infected individual was described in 2003.132 The
upgrading of the cell-mediated immune response due

Figure 159-35 Erythema nodosum leprosum. Presence of Figure 159-36 Lucio phenomenon. Small and large ulcers
fever and malaise with painful subcutaneous nodules that with infiltration in lepromatous leprosy patients. Slit-skin
are easy to palpate, but much less apparent then reversal smear of those patients is loaded heavily with acid-fast 2915
reactions lesions. bacilli.

Kang_CH159_p2892-2924.indd 2915 04/12/18 2:44 pm

23 survival of leprosy patients,135 whereas increasing rates
of neuritis, nerve function impairment, and leprosy
used treatment for leprosy, although its efficacy was
questionable, as it generally induced only a localized
relapses.134 Anti-TNF therapy can result in the develop- inflammatory response in the skin.
ment of clinical leprosy in infected individuals follow- Dapsone is a simple, low-cost, highly effective
ing cessation of the immunobiological medication136-138 drug for leprosy, used in a daily dose of 100 mg or
regardless of whether reactional episodes are involved. 1 to 2 mg/kg. The drug is absorbed by the GI tract and
It is important to distinguish reactions from relapses. eliminated through the kidneys. It is usually well tol-
Reactions may occur before, during, and a few years erated, although it is dependent on the presence of the
after multidrug therapy. Usually, they are acute, with a enzyme glucose 6-phosphate dehydrogenase (G6PD),
rapid appearance of new lesions and infiltration of the an X-chromosomally transmitted enzyme, that is lack-
old ones, deterioration of neural function, and/or sys- ing in 400 million people worldwide, mostly in tropi-
temic involvement, responding well to treatment with cal areas where malaria is present143 and also where
antiinflammatory drugs. On the other hand, relapses leprosy is prevalent. G6PD deficiency leads to serious
in general are slowly progressing, almost always with hemolytic events by oxidative stress, including the for-
Part 23

resurgence of primary lesions followed by the grad- mation of methemoglobin that is clinically detected as
ual appearance of new lesions, together with nerve a violet color on sclera, lips, and the extremities of fin-
involvement, and, in contrast, there is no response to gers together with malaise, headache, and dyspnea. In
antiinflammatory drugs. A true relapse must be defined addition to a high level of hemolysis, G6PD-deficient
::

after confirmation of completion of the first treatment patients using dapsone are at a greater risk of devel-
Bacterial Diseases

by the patient. If the full course of treatment is con- oping severe life-threatening hemolytic anemia, and
firmed, it becomes necessary to test for drug resistance, must change their medication.144 Dapsone hypersen-
although reinfection cannot be ruled out. If the patient sitivity syndrome, a rare but potentially fatal event,
was wrongly classified, then an insufficient length of presents with fever and cutaneous rash, eventually
therapy may be the case. Histopathology can be useful involving internal organs, especially the lungs, with
to distinguish a reaction from a case of relapse.139 eosinophilic infiltrates and pneumonitis. It may occur
Although leprosy is well known for loss of skin at any time during treatment, and it may be related to
sensation, neuropathic pain may arise during or after drug rash with eosinophilia and systemic symptoms
multidrug therapy, due to tissue inflammation or dys- (DRESS syndrome).145
function of the nervous system.140 Nerve trunk pain Clofazimine is a pigment that, in addition to its
onset may be spontaneous or appear after palpation, unknown antibiotic mechanism, also has antiin-
either abrupt or insidious, but many patients experi- flammatory properties. The main objection as far as
ence recurrent episodes. More than half of the patients patients are concerned is its affinity to fat tissue and
have some pain episode during or after multidrug macrophage deposits leading to skin hyperpigmenta-
therapy, with a higher prevalence in lepromatous lep- tion, especially in the lesions. An additional side effect
rosy, decreasing toward the borderline and tuberculoid is skin dryness that together with pigmentation, gives
forms. The most affected nerves are ulnar and tibial.140 the skin a highly xerodermic appearance (Fig. 159-37).
If the pain persists during treatment, or becomes long- It is used in a dose of 300 mg once a month, and 50 mg
lasting after completing multidrug therapy, it may be per day, only in multibacillary patients. Clofazimine is
defined as chronic neuritis or neuropathy.141 well-tolerated by leprosy patients.146
Rifampicin is highly bactericidal, and unlike the
daily administration of dapsone and clofazimine, it is
MANAGEMENT
INTERVENTIONS
MEDICATIONS
There are, basically, 3 groups of medications used
for treating leprosy: antibiotics, antiinflammatory or
immunosuppressants and analgesic drugs. The first
group, antibiotics, has a well-defined standard for
treatment, the WHO Multidrug Therapy drug regi-
men, that contains rifampicin and dapsone, with or
without clofazimine, in monthly blister packs. Anti-
inflammatory drugs, usually prednisone and thalido-
mide, are prescribed to control leprosy reactions by
reducing inflammation, whereas analgesics are used to
control neuropathic pain.
Before the discovery of sulfones’ power to improve Figure 159-37. Clofazimine pigmentation. Brownish color
2916 leprosy signs by Guy Faget in 1941,142 chaulmoogra oil, and dry skin in a patient on multibacillary multidrug
drug used in India for decades, was the only commonly therapy.

Kang_CH159_p2892-2924.indd 2916 04/12/18 2:44 pm

 only administered once per month with supervision,
450 mg to children and 600 mg to adults. Adverse
methylprednisolone pulse therapy,155 WHO recom-
mends leprosy reactions must be immediately treated
23
effects include face and neck redness, pruritus and with antiinflammatory or immunosuppressant drugs.144
cutaneous rash, loss of appetite, nausea, vomiting, The most widely used are corticosteroids and tha-
and diarrhea, malaise (which may require cessation of lidomide. Reversal reaction can be treated with pred-
the drug), purpura, and epistaxis. Flulike syndrome, nisone at doses of 1 to 2 mg/kg/d in a regressive
a not well-understood immunologic side effect occur- scheme, diminishing 10% to 15% of the dose every
ring with the use of intermittent doses of rifampicin, 15 days, with a complete cycle of treatment lasting up
is characterized by fever, asthenia, myalgia, and head- to 3 months. If there is a worsening of the clinical situ-
ache, sometimes accompanied by bone pain. Eosino- ation, it may be necessary to go back to the previous
philia, nephritis, thrombocytopenia, and shock may higher dose, extending this level of corticosteroid treat-
eventually develop. Although considered rare, it was ment for 30 to 45 days, followed by tapering off again.
the major side effect reported in a Brazilian study with Glucose levels and blood pressure must be con-
20,667 leprosy patients on multidrug therapy.147 trolled during the use of corticosteroids. Glaucoma,

Chapter 159 :: Leprosy

Multidrug therapy schemes used today are the cataracts, moon face, striae, adrenal gland atrophy,
same as 1982 when they were first implemented and osteoporosis may occur with long term usage, and
(Table 159-3), with dapsone, clofazimine, and rifam- as with other immunosuppressive agents, other infec-
picin prescribed for multibacillary cases for up to tious diseases, such as systemic fungal infections and
24 months, or dapsone and rifampicin for 6 months for tuberculosis may arise. In addition, Strongiloydes ster-
paucibacillary patients. Pregnancy and breastfeeding coralis hyperinfection is a concern. Ivermectin 200 µg/
do not contraindicate the use of multidrug therapy.144 kg/d for 2 days, repeated after 2 weeks, can be used in
In the 1960s, together with the confirmation of clofazi- prevention.156 After an equivalence conversion calcu-
mine and rifampicin148 efficacy against M. leprae, the lation, prednisone may be replaced by other steroids,
first cases of dapsone-resistant leprosy appeared.149 In including its metabolite prednisolone, dexamethasone,
the 1970s, WHO decided to replace dapsone mono- or deflazacort. Calcium intake of 1200 to 1500 mg/d
therapy in favor of a 3-drug strategy with dapsone, and vitamin D supplements are recommended for any
rifampicin, and clofazimine combined in a new drug patient using glucocorticoids, independent of dose
regimen to treat leprosy called multidrug therapy. and duration of therapy.157
Although drug resistance in leprosy appears to remain ENL may be treated with 100 to 400 mg/d of tha-
low,150 reports of MDR-leprosy are increasing in the lidomide. As thalidomide is a teratogenic drug, it
literature,151-153 and it may be a concern for leprosy is mandatory to test for pregnancy and prescribe 2
treatment in the near future.154 The substitute drugs contraceptive methods before starting therapy in
available, either to resistant strains or to patients with women of childbearing age. Usually, ENL appears
side effects on multidrug therapy, ofloxacin, minocy- with nerve damage, and concomitant treatment with
cline, or clarithromycin (Table 159-3), appear to be safe steroids is required. Higher doses of prednisone, up
and effective for leprosy treatment,146 but new alterna- to 2 mg/kg/d, are linked to improved nerve function
tive drugs are necessary. outcome, but if therapy is initiated immediately after
Although there are a few well-structured clinical tri- the first signs of reaction, lower doses of 1 mg/kg/d
als for treating nerve damage in leprosy, with moder- may have the same effect.158 If ENL is associated with
ate-quality evidence, including one with intravenous any other tissue inflammation, like orchitis or iritis, or

TABLE 159-3
Antibacterial Treatment of Leprosy Recommendations
RECOMMENDING ORGANIZATION DISEASE TYPE RIFAMPICIN DAPSONE CLOFAZIMINE DURATION FOLLOWUP

World Health Organization PB 600 mg/mo 100 mg/d — 6 mo No mandated followup.

  To return as needed
  MB 600 mg/mo 100 mg/d 50 mg/d 1y No mandated followup
 
300 mg/mo
          To return as needed
US Public Health Service PB 600 mg/d 100 mg/d — 1y At 6-mo intervals for 5 y
  MB 600 mg/d 100 mg/d 50 mg/d 2y At 6-mo intervals for 10 y
Other Microbicidal Agents Dose
Clarithromycin 500 mg/d          
Minocycline (substitute for dapsone 100 mg/d          
or clofazimine)
Ofloxacin 400 mg/d          
2917
PB, paucibacillary; MB, multibacillary.

Kang_CH159_p2892-2924.indd 2917 04/12/18 2:44 pm

23 with reactions of the hands and feet, as with osteoar-
thritis and soft tissue inflammation, steroids are also
is nowadays rare,163 or the interosseous and first web
space atrophy of the hands.164
necessary. In cases where the use of thalidomide must
be avoided, pentoxifylline 400 mg, 3 times a day, is
an alternative drug, quite useful for controlling limb COUNSELING
edema and systemic symptoms.159
Steroids and thalidomide may help patients with Counseling is a key process involved in leprosy patient
neuropathic pain by reducing edema and immuno- management. Nerve damage and its management
logic reactions targeting the nerve, especially in acute include counseling and harm reduction.165 Although
episodes. However, its treatment continues to be a there was improvement in the last decades by the
challenge, especially for those with chronic neuritis/ presence of active social movements fighting against
neuropathy. Central nerve system drugs, such as the discrimination, helping to reintegrate people into soci-
tricyclic antidepressants amitriptyline and imipramine ety, and banning discriminatory laws, stigma is still
or the anticonvulsants carbamazepine and gabapentin present in modern society. Although curable, leprosy
is still a disease resulting in serious disabilities, and
Part 23

have been used in an attempt to control chronic neu-

ritis/neuropathy in those patients, but these drugs do even patients diagnosed at the first stages of disease
not interfere with the nerve damage process, and there- fear evolution through incapacities. Therefore, coun-
fore do not protect leprosy patients from nerve dete- seling should be available for every person diagnosed
::

rioration. Although some anecdotal reports show that with leprosy, and their families.166 Self-care groups
are necessary, but they should not be exclusive. Lep-
Bacterial Diseases

immunosuppressive agents, like cyclosporine and aza-

thioprine, may be useful for treating chronic neuritis/ rosy-related disability care and management must be
neuropathy patients, a recent trial with azathioprine included with care for disabilities caused by other dis-
did not show improvement in patients with reversal eases in the general health services.167
reaction.160 More research is necessary in physiopathol-
ogy and with new drugs for treating neuropathic pain.

TREATMENT ALGORITHM
PROCEDURES See Fig. 159-38.
Simple preventive techniques may be used by patients
to prevent the progression of damage. Massage and
hydration of the skin of hands and feet are necessary
to avoid fissures, ulcers, and fixed claw formation. In PREVENTION/SCREENING
addition to the use of special boot soles or customized
shoes for feet with loss of sensation and with disabili- There is one fundament requirement for leprosy pre-
ties, self-examination is mandatory for early detec- vention, that being contact examination. It should be
tion and immediate treatment of trauma. For hands, a mandatory part of any leprosy program in endemic
adduction, abduction, and opposition movements are countries to examine all household contacts, and some
necessary to keep trophic muscles and healthy joints. programs expand this concept to social contacts, those
Adaptation of working instruments and household who work or have closer proximity with the index case.
items help to prevent trauma and burns. For eyes, the A household contact has a 5- to 8-fold higher risk of
use of lubricating eye drops may prevent keratitis in contracting leprosy than a person without contact with
cases of lagophthalmos. In more complex cases, the a case (Fig. 159-39). However, even if there is constant
patients may be referred to specialized centers for more vigilance, only up to 30% of the cases in a community
complex treatments with a multiprofessional team for will be detected among the household contacts; there-
physical, psychological, and social rehabilitation. fore, other genetic or environmental factors may be
In different stages of leprosy, surgery may be neces- involved in the maintenance of the infection.168
sary. Nerve abscess is infrequent, appearing more in Early detection of cases is another tool for the effi-
primary neural leprosy and tuberculoid leprosy and cient prevention of leprosy. Besides contact examina-
less toward the lepromatous leprosy pole, but it may tion, leprosy campaigns in the general population or
be the first clinical manifestation161 of disease. In such in special communities, such as schoolchildren,110 may
cases, abscess drainage is mandatory, and the content be used to raise awareness, to diminish stigma, and to
must be sent to the laboratory for investigation. Nerve increase detection of early cases of leprosy. Although
decompression may be used to improve leprosy neu- chemoprophylaxis with rifampicin has shown some
ropathy and muscular function, albeit there are no reli- degree of protection (57%) in the first 2 years, after
able clinical trials to definitely prove its usefulness.162 4 years no difference was observed in comparison
Finally, reconstructive surgery may recover some func- between rifampicin and placebo groups169; therefore
tional aspects in the hands and feet, such as the ability there is no current official recommendation to use
to hold a glass or the capacity to raise the feet; correct chemoprophylaxis in leprosy contacts. For immuno-
eye problems, like lagophthalmos, preventing kerati- prophylaxis, Brazil has been using Bacillus Calmette-
2918 tis, infection, and blindness; and improve aesthetics Guerin (BCG) revaccination in contacts for a long time.
as in the surgical correction of nose collapse, which An 18-year followup study found 56% protection for

Kang_CH159_p2892-2924.indd 2918 04/12/18 2:44 pm

 Leprosy treatment algorithm
23
Primary
Indeterminate TT BT BB BL LL
Neural
Leprosy Leprosy Leprosy Leprosy Leprosy Leprosy
Leprosy

Paucibacillary (PB) Multibacillary (MB)

PB MDT MB MDT
Erythema Nodosum
Leprosum (ENL)

Reversal Reaction (RR)

Chapter 159 :: Leprosy

Test pregnancy
Contraceptive
Check Glucose Calcium
ENL + RR If pregnant or
ENL + Neuritis can't use
Blood Pressure Vitamin D contraceptive
ENL + Organ
inflammation * #
lvermectin Thalido Pentoxy
mide filine
Prednisone oral daily or Associate
methylprednisolone pulse IV

or

Chronic Neuritis or Neuropathy (CN)

Tricyclic antidepressants
or anticonvuIsants

Figure 159-38 Leprosy treatment. Multidrug therapy is the choice for leprosy treatment. However, when there is intoler-
ance to any of the drugs, available alternatives may be used, as ofloxacin, minocycline, or clarithromycin. Also, if there is
no answer to multidrug therapy, drug resistance may be tested, and the same alternative drugs used in place of 1 or more
multidrug therapy drugs. For reactions, thalidomide is not available in all countries, and may even be prohibited. *It is not
permitted to prescribe thalidomide to pregnant women or to women of childbearing age. If it is necessary to use it, some
countries have strict rules or laws that may require a pregnancy test and the use of contraceptives to prescribe thalido-
mide. #Pentoxyfiline is a “category C” drug for pregnancy and, therefore, it should be used only if the potential benefits
justify the potential risk to the fetus.

BCG-vaccinated contacts,170 compared those who were

not vaccinated; hence, Brazil guidelines for leprosy
continue to include BCG vaccination for all household
contacts.

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