Chapter 186

Leprosy
Delphine J. Lee, Thomas H. Rea, & Robert L.
Modlin

HISTORICAL ASPECTS
Leprosy is an ancient disease; sacred writings from
India in the sixth century bc give a good description of a similar or identical illness. By the second
century ad, Greek physicians in Europe wrote descriptions of the disease, evidently well established
by that time. Stigmatization of patients with leprosy
remains an unfortunate but enduring legacy
of the European pandemic that occurred from
1,0001,500 ad Hansens attribution of Mycobacterium leprae as its etiologic agent in 1873 marks the
beginning of scientific leprology.1
Effective chemotherapy began with the introduction of sulfones in 1943. In 1961, the limited growth
of M. leprae in the mouse footpad provided a way
to screen for therapeutic agents and to identify
drug resistance.2 In 1970, rifampin was the first drug
to be identified as bactericidal for M. leprae and is
now the cornerstone of most therapeutic regimens.
Ridley and his associates3 provided a detailed account of the granulomatous spectrum of leprosy
that is useful to clinicians and pathologists and essential to subsequent immunologic studies. Jopling
clearly defined and separated the two common
reactional states.
In 1919, the lepromin skin test inaugurated
systematic study of host resistance as the source
of disease diversity,4 with lymphocyte transformation tests being established in the 1960s as an in
vitro correlate. The recognition of leprosy in the
nine-banded armadillo, in 1971, provided a source
of large quantities of highly purified M. leprae for a
wide variety of investigations,5 culminating in the
sequencing of the entire genome of M. leprae in
2001.6

EPIDEMIOLOGY
Now primarily a disease of developing countries,
leprosy is endemic in all continents, except Antarctica. In the Americas, only Canada and Chile are not
endemic countries, with Texas and Louisiana having
endemic foci in the United States. The southernmost nations of Europe have a very low incidence,

while leprosy is endemic in many Pacific islands.

The Indian subcontinent has two-thirds of the
worlds leprosy burden. The highest case detection
rates are in Angola, Brazil, Central African Republic,
Democratic Republic of the Congo, India, Madagascar, Nepal, and Tanzania.7,8 During the decade
of the 1990s, the prevalence of leprosy fell by 90%,
because patients completing a course of multipledrug therapy have been considered cured, but
the incidence of the disease, which varies in direct
proportion to case finding efforts, has not been
convincingly reduced.
In all populations studied, lepromatous disease
is more common in men than in women by a 2:1
ratio.9 If leprosy is common, the high resistance
forms (tuberculoidTT and borderline tuberculoidBT) dominate. If leprosy is uncommon, the
low resistance forms (borderline lepromatousBL
and lepromatousLL) dominate. Leprosy is said to
be a disease of rural incidence but of urban prevalence. The median age of onset is less in tuberculoid
than in lepromatous patients, but in both groups,
leprosy is predominantly a young persons disease,
the medial age of onset being less than 35 years.
However, age is not protective; new cases of each
type occur in the eighth and ninth decades of life.
The incubation time for tuberculoid leprosy (TT) is
up to 5 years and for lepromatous may be 20 years
or longer.
The preponderance of opinion supports the
traditional view that M. leprae is transmitted from
human-to-human, but the presence of a lepromatous-like illness caused by M. leprae in wild armadillos,10 evidence of armadillo exposure as a risk factor
for leprosy in people,11 and the presence of an M.
leprae-like organism on sphagnum moss,12 suggest
that nonhuman sources for M. leprae may be important. The route of infection is unproven, but current
evidence favors respiratory transmission; evidence
for congenital and percutaneous transmission
has been presented, but these are probably rare.13
In leprosy endemic areas, subclinical infection is
common, as judged by serologic studies identifying
M. leprae-specific antibodies,14 but the incidence
of overt disease is by comparison very small, most
individuals apparently making a curative immunological response.

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284 Chapter 186: Leprosy

CLINICAL FINDINGS
Reactional States
LUCIOS PHENOMENON HISTOLOGY.
Lucio lesions feature ischemic necrosis in the epidermis and its appendages, vessel occlusion in the
deep dermis by thrombosis or endothelial proliferation, and also a feature of normal-appearing skin in
patients with Latapis lepromatosis heavy bacillary
parasitization of endothelial cells.38 When an early
infarct is sampled (eFigs. 186-8.12 and 186-8.13),
necrotic nuclei in the epidermis and upper dermis failed to stain normally, but early reparative
changes are found at the junction of the infarcted
and noninfarcted tissues. When an older lesion
is sampled, this necrotic epidermis, recognizable
because of ghost cells and residual melanin, can be
recognized above a new stratum corneum, and epidermis (eFig. 186-8.14). When a still older lesion is
sampled, the necrotic epidermis that is so conspicuous clinically may be lost during tissue processing. Passive congestion of superficial vessels with
extravasation of erythrocytes and necrosis of skin
appendages may be well developed in early lesions,
but diminishes with the passage of time. In the
early lesions, proliferation of endothelial cells with
heavy parasitization by bacilli and/or thrombus formation in the deep dermal vessels is conspicuous,
affording a tempting explanation for the infarct.
These changes also diminish with time. There is
little inflammatory change in the infarct, with what
there is entering from the adjacent viable tissue,
supporting the idea that Lucios phenomenon is
best described as a vasculosis, not as a vasculitis.
This having been said, in a minority of specimens,
a lepromatous-granulates vasculitis of unknown
significance has been described at the dermalsubcutaneous interface.39

Immunopathology and
Immunology
Investigation into the immunology of leprosy
offers three promises: (1) a better understanding of
the disease itself; in particular, the immunopathogenesis of the granulomatous spectrum and the
reactional states; (2) eradication or control of the
disease by vaccination; and (3) development of a
probe of cell-mediated immunity (CMI) in humans
that, when understood in the model of leprosy,
will illuminate other disease processes. The immunopathogenesis of the granulomatous spectrum

of leprosy is widely accepted as being mediated

by a type IV immunologic reaction, that is, CMI or
delayed-type hypersensitivity (DTH).
CELLULAR IMMUNITY.
At one end of the disease spectrum, patients with
TT typify the resistant response that restricts the
growth of the pathogen. The number of lesions
is few and bacilli rare, although tissue and nerve
damage are frequent. At the opposite end of this
spectrum, patients with lepromatous leprosy (LL)
represent susceptibility to disseminated infection. Skin lesions are numerous and growth of the
pathogen is unabated. These clinical presentations
correlate with the level of CMI against M. leprae. The
standard measure of CMI to the pathogen is the
Mitsuda reaction or lepromin skin test, a 3-week response to intradermal challenge with M. leprae. The
test is positive in TT patients but negative in lepromatous patients. Interestingly, antibody responses
are greater in LL patients, suggesting that humoral
immunity does not contribute to host defense.
The inverse correlation between CMI and humoral
immunity correlates with distinct T-cell subset responses to M. leprae including CD4 and CD8 T cells40
and the T cell cytokine patterns they produce.4143
CD4+ T cells that produce the type 1 or Th1 cytokine
pattern including IFN- predominate in TT lesions;
whereas, CD8+ T cells that produce the type 2 or
Th2 cytokine pattern including IL-4 predominate
in LL lesions. In addition, cells of the innate immune system equipped with germ line encoded
pattern recognition receptors (PRRs) recognizing
pathogen-associated molecular patterns (PAMPs)
play an important contribution to CMI. For example,
M. leprae lipopeptides are recognized by the Tolllike receptor (TLR) 2/1 heterodimer, triggering the
production of cytokines such as TNF-, as part of
the acute inflammatory response44 and IL-12, which
mediates the instructive role of the innate immune
response in instructing the adaptive type 1 or Th1
cytokine response.44 In addition, deficiency of dendritic cells, key instructors of the adaptive response,
in LL lesions may be due to inhibitory receptors as
well as host-derived oxidized phospholipids found
in LL lesions.4547
ANTIBODY IMMUNITY.
ENL is widely regarded as mediated by immune
complexes. There are large amounts of anti-M. leprae antibodies in both LL and BL patients, but these
antibodies do not confer disease protection. Also,
the blood of BL and LL patients contains abundant

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Chapter 186:

antigens including intact bacilli, up to 105/mL.

Therefore, it is readily conceivable that BL and LL
patients are subject to immune complex-mediated
tissue injury. The best direct support for the hypothesis that ENL is immune complex mediated is the
presence of split complement products in serum,
which is consistent with extravascular complement
activation within tissues.48 Inferential evidence is
that of neutrophil infiltration, suggesting an Arthus
phenomenon, and an excess of glomerulonephritis
in ENL patients. Also, the cytokine profile in ENL
is type 2, despite a preponderance of the CD4+
subset.43 However, evidence for immune complex
mediation has been difficult to reproduce, and it is
confounded by a number of observations, including Major Histocompatibility Complex class II (MHC
class II) antigen expression in lesional epidermis,49
an increase in IFN- containing cells by hybridization studies,41 an excess of IL-2-positive cells as
compared with LL tissue,50 and the precipitation of
ENL by the administration of recombinant rIFN-.51
Study of ENL and LL lesions has suggested a
thalidomide-susceptible pathway in which immune
complexes may activate Fc receptors, leading to IL-1
secretion and subsequent e-selectin expression
on endothelium, and neutrophil recruitment.52 Also,
other thalidomide responsive syndromes, such
as multiple myeloma and Behets syndrome, are
not directly immune complex mediated. Perhaps
both immune complexes and cellular immunity are
important in the pathogenesis of ENL.
Little is known concerning the immunopathogenesis of the Lucio reaction. Evidence favors immune
complex mediation. The abundant acid-fast bacilli
(AFB) in endothelial cells could be the optimum
location for presentation of antigen to antibody. Its
mechanism does appear to differ from that of ENL,
there being little in the way of epidermal expression of HLA-DR framework antigen.49
Concerning the reactional states of leprosy, type
1 reactions (reversal reactions or DTH reactions) are
mediated by DTH, and type 2 reactions (ENL) are
widely regarded as being mediated by immune
complexes.

TREATMENT
Medical management is directed at the infection
itself (Box 186-2), and if present, at a reactional
state (Box 186-3).54 A patient is considered to be
paucibacillary if no AFB are found in tissue or
smears, and to be multibacillary if one or more
AFB are found. The rationale for the three drug

Leprosy 285

regimens is that rifampin (bactericidal) will kill all

susceptible organisms, including those resistant to
dapsone (bacteriostatic), and dapsone will eventually eliminate all susceptible organisms, including
those resistant to rifampin. Clofazimine (weakly
bactericidal) is added to obviate the risk of primary
dapsone resistance. The absence of routine follow
up in the World Health Organization WHO recommendations perhaps reflects expectations of a low
relapse rate, as well as a low rate of posttreatment
reactional states. They also implicitly recognize very
limited financial resources in many endemic areas.
The presence of semiannual follow up visits for up
to 10 years in the United States National Hansens
Disease Program (US-NHDP) recommendations reflects a differing opinion as to the frequency of and
tolerance for both bacterial relapse and posttreatment reactional states. In most patients who have
relapsed following use of triple drug regimens, the
organisms have remained susceptible to the agents
used. After finishing treatment, it is desirable that
patients should be educated regarding signs of
relapse, reaction, and nerve damage, and followed
annually.
The rate of relapse after completion of a triple
drug regimen is controversial. It is not known why
the reported rate of relapse is so variable, ranging
from virtually no relapses, to as high as 10%20%
within 10 years of stopping treatment,5558 but may
reflect differences in patient compliance, reexposure, and/or general health and immune competence. One group reported relapses beginning 6
years after completing treatment and continuing
for 10 years or more.56 Also relapse may occur after
the patient has become smear negative more.56,58
Among the reports of significant relapse rates,
there is good agreement that patients with a high
biopsy index (3 or greater) appear to be particularly
vulnerable. Also, a 1-year course of treatment had
a higher relapse rate than did a 2-year course.57
The possible reasons for such conflicting findings
have been reviewed by Shetty et al,58 who did not
consider the reported relapses to be reinfection.
However, the ability to discern differences between
relapse and reinfection are difficult since M. leprae
cannot be grown for genomic studies. Opinion
varies as to how to cope with this problem. The
WHO plan depends upon the patients self-referral,
while the US-NHDP recommendations would allow
resumption of treatment based upon a physicians
periodic follow-up evaluations. Some recommend
continuing the patient on dapsone alone, after
completing a course of multiple drug therapy, but

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286 Chapter 186: Leprosy

for how long is not certain.

A number of antibiotics, in addition to rifampin,
have potent bactericidal activity, including minocycline, clarithromycin, and, several fluoroquinolones,
including ofloxacin and levofloxacin. Because of
their expense, the use of the above agents on a
daily basis may be prohibitive. Also, it is not known
if combinations of these potent bactericidal agents,
would have any advantage over the WHO and USNHDP recommendations, although some were well
tolerated in a small trial.59
In reversal reactions (Box 186-3), because of the
risk of permanent nerve damage, prompt institution of prednisone therapy (0.51 mg/kg/day) is
recommended. The dose of prednisone is titrated
against overt nerve tenderness, the patients symptoms, and careful motor and sensory evaluation of
hands and feet, the latter, for example, with graded
SemmesWeinstein filaments. Once instituted,
therapy should be tapered slowly, over 6 months
or more in many cases. If the response to prednisone 40 mg/day has no effect after 1 week, then
rest, enforced with splinting of affected extremities, is also recommended in addition to increase
the prednisone dose. For patients who respond to
prednisone, taper by 2.5 mg every 2 weeks. When
the dose has been decreased to 20 mg daily, switch
to every other day dosing (40 mg every other day)
and reduce doses in 2.5 mg increments every 24
weeks. Patients on average will require prednisone
for approximately 6 months.
In ENL (Box 186-3), thalidomide use is very often
dramatically effective but may not be available or
may be interdicted by its teratogenic effects. Thalidomide is available in the United States through
the Celgene Corporationss System for Thalidomide
Education and Prescribing Safety (S.T.E.P.S.) program. In the United States, only physicians who are
registered with the S.T.E.P.S. program can prescribe
thalidomide. It is teratogenic, causing phocomelia,
and should not be given to women of childbearing
potential unless they are enrolled in the S.T.E.P.S.
program and on several forms of birth control. The
effective dose ranges over one order of magnitude,
50500 mg at bedtime. When introducing therapy
we follow patients closely and make changes in
doses or add prednisone every 2 weeks. We usually
start with 100200 mg nightly of thalidomide and,
if it is only partially effective, we may add prednisone 0.51.0 mg/kg, tapering the prednisone over
the subsequent 68 weeks. If that combination of
low-dose thalidomide and prednisone is not effec-

tive within 2 weeks), we increase the dose of thalidomide until obtaining a therapeutic or toxic effect,
having gone as high as 600 mg at bedtime. Toxic
effects include drowsiness, dizziness, orthostatic
hypotension, constipation, neutropenia, and hypersensitivity reactions, and neuropathy. Some recommend daily baby aspirin when starting thalidomide
because of potential thromboembolic events.
Thalidomide is slowly tapered over months once
a patient has been stable with no skin lesions for
approximately 6 months. The goal of treatment is
the abolition of systemic symptoms and morbidity
from skin lesions, not the elimination of skin lesions.
Patients who still have some active skin lesions but
no systemic symptoms, should be maintained on
their current dose, and patients often worsen if the
dose is reduced. In our experience patients requiring thalidomide for the treatment of ENL require
an approximate median duration of 5 years on this
drug. If thalidomide cannot be used then corticosteroids may well be needed. Clofazimine, acting as
a steroid-sparing agent, is recommended by some
at a dose of 300 mg daily. (To lessen gastrointestinal
intolerance, increasing the daily dose in 100 mg
increments at weekly intervals is recommended.)
Management with nonsteroidal anti-inflammatory
agents or pentoxifylline has been found useful by
some, but has been disappointing in our hands.
Adverse reactions to dapsone seen in the near
term include the dapsone syndrome, a rare, potentially fatal infectious mononucleosis-like condition and three kinds of hemolytic anemia, almost
universally from a direct erythrocyte membrane
effect, uncommonly from a glucose-6-phosphate
deficiency. In the long term, dapsone is associated
with peripheral neuropathy, usually motor with a
sensory component, and, rarely, bone marrow suppression, especially agranulocytosis.
The serious problem with rifampin is hepatotoxicity. Red urine is alarming but not indicative
of pathology. As a P450 inducer, rifampin may
lessen the effect of other drugs, for example, oral
contraceptives resulting in pregnancy, or reduced
anti-inflammatory activity of corticosteroids. Once
monthly use of rifampin is rarely associated with
severe hemolysis and acute renal failure.
Clofazimine produces skin darkening from the
clofazimine itself in the near term and from a
ceroid-lipofuscin pigment in the long term (eFig.
186-8.15).60 At usual doses of 50100 mg a day,
gastrointestinal intolerance, dry skin, and acquired
ichthyosis are common. Prolonged administration

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Chapter 186:

of large doses may produce a novel enteropathy

secondary to mucosal and enteric lymph node drug
accumulation. Accumulation in the spleen may
predispose to splenic rupture.
Thalidomide, infamous for teratogenicity, may
also produce constipation and dizziness. Neuritis, a
common side effect in nonleprosy patients, appears to be rare in ENL patients. An idiosyncratic
intolerance manifested as prohibitive drowsiness or
general flu-like symptoms is uncommon.
Long-term use of minocycline may be limited by
hyperpigmentation,59 much more common in patients with leprosy than in acne, perhaps related to
the large accumulation of macrophages in leprosy
(eFig. 186-8.16). We have seen both diffuse hyperpigmentation and intense hyperpigmentation at
the site of lesions, usually on the legs or feet.
Corticosteroids, in addition to their well-known
side effects, may also exacerbate coexisting diseases, for example, tuberculosis, hepatitis B, and
some gastrointestinal parasites.

PREVENTION
Protocols endeavoring to control leprosy by vaccination usually consist of BCG alone, viable BCG
in combination with killed M. leprae, or killed M.
leprae alone.61 Most studies support a reduction in
leprosy incidence, roughly one-third in tuberculoid
cases, considerably less in lepromatous. The recent
observation that lipid and lipoglycan antigens are
presented to T cells (CD4, CD8, CD3+) by CD1+ cells
opens the door to entirely new vaccination protocols.62 Other preventive measures, such as isolation
of patients or prophylactic treatment of patient
contacts with antimicrobials, have been disappointing.

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Leprosy 287