REVIEW

Recognizing and managing the immunologic

reactions in leprosy
Sonia Kamath, BA, Seth A. Vaccaro, MD, Thomas H. Rea, MD, and Maria T. Ochoa, MD
Los Angeles, California

Immunologic reactions are an important aspect of leprosy that significantly impacts the course of the
disease and the associated disability. Reversal reaction (type 1), erythema nodosum leprosum (type 2), and
Lucio phenomenon are the 3 leprosy reactions, and they are most commonly seen in patients with the
lepromatous and borderline categories of the disease. Because these forms of leprosy are the most
common types seen in the United States, it is particularly important for physicians to be able to recognize
and treat them. The reactions may occur before, during, or after treatment with multidrug therapy. Reversal
reactions are the most common cause of nerve damage in leprosy, and erythema nodosum leprosum may
also lead to neuritis. Although there have not been enough studies to confirm the most effective
management regimens, treatment of reversal reaction and Lucio phenomenon with prednisone and of
erythema nodosum leprosum with thalidomide and/or prednisone may help improve symptoms and
prevent further disability. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.03.034.)

Key words: erythema nodosum leprosum; Hansen disease; leprosy; Lucio phenomenon; reversal reaction;
type 1 reaction; type 2 reaction.

L eprosy remains an important global disease,

and dermatologists should be able to identify
it. Despite highly effective antibiotic therapy
reducing leprosy prevalence, case detection rates
have not declined.1 Caused by the acid-fast bacteria
Mycobacterium leprae, which primarily affects the
skin and peripheral nerves, leprosy may result in
debilitating physical deformity.2 Impairment of
nerve function occurs throughout the disease course,
and immunologic reactions often rapidly accelerate
the nerve damage.1
Two types of reactions affect 30% to 50% of
patients: type 1 reaction (reversal reaction) and
type 2 reaction (erythema nodosum leprosum
[ENL]).3-5 The third reactioneLucio phenomenoneis
relatively rare, occurring only in diffuse nonnodular
lepromatous leprosy (lepra bonita). However, the
manifestations can be dramatic with patients deve-
loping widespread skin necrosis.6 These 3 reactions
are often incorrectly viewed as complications of
multidrug therapy (MDT). In reality, they may
interrupt the course of leprosy both before initiation
of treatment and after completion.2,7,8 Regardless of
Abbreviations used:
ENL:
IL:
MDT:
erythema nodosum leprosum
interleukin
multidrug therapy
TLR: Toll-like receptor
TNF: tumor necrosis factor
when they occur, reactions are medical emergencies,
greatly increasing leprosy-related morbidity. It
is important to specifically recognize and treat re-
actions, to reduce the burden of disability in leprosy.
In the United States, approximately 200 leprosy
cases are detected annually, mostly in California,
Florida, Hawaii, Louisiana, New York, and Texas.9,10
The majority of cases cite a location outside the
United States as place of birth, most commonly
Mexico, Brazil, the Philippines, and India. Still,
autochthonous cases are documented in Hawaii,
Puerto Rico, Louisiana, and Texas.10 Recent evidence
suggests that armadillos in the southern United States
are infected with the same strain of M leprae as many
patients and act as a reservoir.11 Nearly half of

From the Department of Dermatology, Keck School of Medicine,
University of Southern California.
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication March 18, 2014.
Reprint requests: Maria T. Ochoa, MD, Department of
Dermatology, Keck School of Medicine, University of Southern
California, 1441 Eastlake Ave, Topping Tower, Suite 3405, Los
Angeles, CA 90033. E-mail: Maria.ochoa@med.usc.edu.
Published online April 23, 2014.
0190-9622/$36.00
Ó 2014 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2014.03.034

1
2 Kamath et al J AM ACAD DERMATOL

leprosy cases identified in the United States are after the initiation of highly active antiretroviral
categorized as lepromatous leprosy, with the vast therapy.23-28 Although epidemiologic studies show
majority of other cases falling into borderline cate- that co-infection with HIV does not change the
gories of disease.10 Reactional states most commonly incidence or clinical presentation of leprosy, it has
occur in patients with lepromatous and borderline been observed that development of immune recon-
forms of leprosy.12 Consequently, it is particularly stitution inflammatory syndrome is associated with
important for US dermatologists to recognize them. higher CD4 counts and lower viral load.27,28 Reversal
The purpose of this review is reaction may result from an
to describe the clinical man- enhanced immune response
ifestations of the 3 leprosy CAPSULE SUMMARY to M leprae as highly active
reactions and highlight cur- antiretroviral therapy sud-
d Immunologic reactions occur at any time
rent concepts in their patho- denly reverses immune
during the course of leprosy and
genesis and treatment. suppression.28,29 Similarly,
dramatically worsen the associated nerve
reversal reaction has also
damage and/or disability.
TYPE I: REVERSAL been described in patients
REACTION d Reversal reaction can be associated with with rheumatoid arthritis
Clinical manifestations HIV and immune reconstitution after discontinuing tumor
Reversal reactions most inflammatory syndrome. necrosis factor (TNF)-alfa
commonly occur in border- d Early recognition and treatment of inhibitors and in patients
line and lepromatous forms reactions by the dermatologist can undergoing stem-cell trans-
of leprosy (borderline tuber- prevent disability, especially when plantation.30-32
culoid, borderline border- associated with neuritis.
line, borderline lepromatous, Diagnosis
lepromatous leprosy).7,12 Reversal reaction is a clin-
Clinically, patients display abrupt inflammatory ical diagnosis. Patients may experience silent
changes of the skin, nerves, or both.13 Existing skin neuropathy: impairment of nerve function without
lesions become erythematous and edematous and obvious skin signs or symptoms.33 It is therefore
14
may display ulcerative changes. Accompanying important to use an objective clinical examination to
edema of the hands and feet is common, whereas assess nerve function in each patient. Palpation of
systemic symptoms are unusual (Fig 1).4,14 nerves may reveal enlargement and tenderness, and
Reversal reaction is the leading cause of nerve monofilament testing is a valid screening test of
damage in leprosy and may lead to permanent sensory function.15 Lastly, voluntary motor testing is
1
disability. Spontaneous nerve pain, tenderness, or a widely accepted method of testing gross
paresthesia signals neuritis, whereas nerve function motor function.34,35 Newer measures for checking
impairment is defined as clinically detectable motor function, such as dynamometry and nerve
reduced motor or sensory function.3,15 The ulnar, conduction studies, are under investigation.15,35,36
median, common peroneal, facial, and posterior Although biopsy is not essential to reversal
tibial nerves are most commonly involved, leading reaction diagnosis, key histologic features, such as
to foot drop, wrist drop, and facial palsy.16,17 granuloma formation and dermal edema, can help
Involvement of the facial nerve is particularly with the diagnosis. Tuberculoid granulomas may
worrisome, given the possibility of lagophthalmos, display central fibrinoid necrosis or coalesce in
keratitis, and blindness.18-20 Eventually, patients the dermis, giving rise to diffuse granulomatous
can lose protective pain sensation, increasing dermatitis instead of multiple nodules.37 Other
vulnerability to injury (Table I). features include epithelioid differentiation of
Reversal reaction is known to occur even years macrophages, increased numbers of lymphocytes,
after MDT. The exact events that trigger reversal epidermal thickening, and destruction of nerves
reaction are unknown. Risk factors for reversal by granulomatous infiltrate.37,38
reaction include increasing age and the postpartum
period.12,21 Patients with World Health Organization Pathogenesis
disability grade 1 (anesthesia without visible Reversal reactions are delayed-type hyper-
deformity) or grade 2 (visible deformity of hands or sensitivity reactions, resulting from increased
feet) are also at increased risk.22 In addition, case cell-mediated immunity to M leprae antigens;
reports suggest that in patients with leprosy however, the mechanisms are not understood.39,40
co-infected with HIV, reversal reaction may surface M leprae antigens localize to Schwann cells and
as immune reconstitution inflammatory syndrome macrophages, and patients with M leprae DNA
J AM ACAD DERMATOL Kamath et al 3

Fig 1. Reversal reaction in leprosy. A, Patient with borderline lepromatous leprosy with
sharply demarcated erythema and edema of the right hand. B, Patient with borderline
lepromatous leprosy with existing plaques that have become erythematous as a result of
reversal reaction. C, Biopsy specimen typical of reversal reaction showing multiple
multinucleated giant cells (black arrows) along with lymphocytic infiltrate surrounding existing
granulomas. (Hematoxylin-eosin stain; original magnification: 3100.)

detectable in the skin by polymerase chain reaction
are more likely to experience reversal reaction.41
Reversal reaction lesions demonstrate an influx of
CD41 T cells and strong type 1 T helper (Th1)
response with high levels of interferon-gamma,
interleukin (IL)-2-induced nitric oxide synthase,
TNF-alfa, and C-X-C motif chemokine 10
(CXCL10).42-46 Increased expression of TNF-alfa,
transforming growth factor-beta, and CXCL10 in
skin biopsy specimens has also been observed.44,45
Recent studies also suggest a role for innate
immunity. Schwann cells express toll-like receptor
(TLR)2. Activation of TLR2 by M leprae antigens
results in Schwann cell death, providing a possible
explanation for nerve damage in these reactions.47 A
single nucleotide polymorphism in TLR1 has been
found to regulate the innate immune response in a
way that protects from reversal reaction.48 Lastly, up-
regulation of human beta defensin 3 in keratinocytes
supports a further role for innate immunity.49
Treatment
Goals of managing reversal reaction include
providing pain relief, controlling inflammation,
and preventing nerve function impairment.2
High-dose prednisone (1 mg/kg/d) provides rapid
symptomatic relief and helps reverse nerve function
impairment.50-52 The regimen must be tailored
individually based on whether nerve tenderness
and motor or sensory deficits are present.
Symptoms should be reassessed every 2 weeks. If
nerve function improves, the dose can be reduced by
2.5 to 5 mg; if there is no improvement or worsening
of nerve function, the dose should be increased.
Treatment may last up to 6 months or even years for
those with neuritis.53
Long-term corticosteroid use carries risk of
adverse effects, prompting exploration of other
therapies. Azathioprine (3 mg/kg/d) combined
with lower doses of prednisolone, cyclosporine
(5 mg/kg/d), methotrexate, and topical tacrolimus
have all been used, but better clinical trials are
needed to improve the treatment.54-59 The National
Hansen’s Disease Program provides helpful re-
sources on managing leprosy reactions (Table II).53
TYPE II: ENL
Clinical manifestations
ENL can happen any time during the course of
leprosy but is most common within 1 year of
starting MDT. Risk factors for ENL include
lepromatous leprosy or borderline lepromatous
disease with high bacterial load and the use
of intralesional injection of interferon-gamma.8,60
4 Kamath et al J AM ACAD DERMATOL

Table I. Characteristics of leprosy reactions

Reversal reaction
Leprosy category d Borderline (borderline
tuberculoid, borderline
borderline, borderline
lepromatous)
Skin lesions d Existing lesions become
tumid and erythematous
d Distribution: locations of
existing lesions
Associated clinical d Edema of hands and feet
features d Neuritis: nerve tenderness,
new anesthesia, and/or
motor loss
d Sudden loss of nerve
function: claw hand,
foot drop, facial palsy
Histopathological d Edema of existing
features granulomas
d Increase in lymphocytes
d Central fibrinoid necrosis
in some tuberculoid
granulomas
d Coalescence of tuberculoid
granulomas in the dermis
ENL
d Lepromatous leprosy,
borderline lepromatous
d New erythematous dermal
and/or subcutaneous
nodules
d Painful and tender
d Distribution: upper and
lower extremities, trunk,
face
d Fever, anorexia, malaise
d Arthralgias, myalgias
d Neuritis
d Epididymitis, orchitis
d Lymphadenitis
d Hepatosplenomegaly
d Glomerulonephritis
d Iridocyclitis
d Lobular panniculitis
d Edema of dermis and
subcutis
Lucio phenomenon
d Diffuse nonnodular
lepromatous leprosy
d Crops of hemorrhagic
infarcts, plaques or blisters,
which become necrotic
ulcers
d Atrophic scars left behind
d Painful but nontender
d Distribution: lower extremities,
forearms, buttocks
d Nasal septal perforation
d Epistaxis
d Intermittent fever
d Anemia
d Lymphadenopathy
d Splenomegaly
d Vasculitis
d Epidermal necrosis
d Dermal vessel thrombosis

ENL, Erythema nodosum leprosum.

Table II. Management of leprosy reactions

Reversal reaction ENL Lucio phenomenon
Recommended Prednisone (start 0.5-1.0 mg/kg) Thalidomide (start 100-200 mg daily) Prednisone (start 1 mg/kg)
medication
Other medications NSAIDs Clofazimine
Azathioprine Prednisone
Cyclosporine Pentoxifylline
TNF-alfa inhibitors
Other aspects of Physical therapy Physical therapy Plasmapheresis
treatment Supportive care

ENL, Erythema nodosum leprosum; NSAID, nonsteroidal anti-inflammatory drug; TNF, tumor necrosis factor.

Other less well-defined risk factors include
pregnancy, lactation, puberty, intercurrent infection,
vaccination, and stress.12,17,61 The reaction is marked
by the rapid appearance of crops of painful, erythem-
atous subcutaneous nodules that may ulcerate.
Unlike erythema nodosum, which has a predilection
for the shins, ENL may surface on extensor surfaces
of both upper and lower extremities and on the
face (Fig 2). Eventually, fibrosis, scarring, and post-
inflammatory hyperpigmentation develop.5,12,13,61
Systemic signs and symptoms such as fever,
anorexia, and malaise distinctively signal ENL.
On presentation, patients may have anemia, neutro-
philic leukocytosis, and albuminuria. Painful lymph-
adenopathy, hepatosplenomegaly, and neuritis may
also occur. Arthralgias and dactylitis may result in
confusion with rheumatologic disease. In addition,
patients may experience glomerulonephritis, iritis,
orchitis, epididymitis, and adenitis. Periostitis,
especially over the tibia, may be detected on bone
J AM ACAD DERMATOL
Fig 2. Erythema nodosum leprosum (ENL). A, Patient
with lepromatous leprosy undergoing ENL reaction with
bright-pink papules, plaques, and nodules occurring on
bilateral upper extremities. B, High-power view of the
lobular panniculitis and characteristic polymorphonuclear
cell infiltrate ( yellow arrows) seen in ENL biopsy speci-
mens. (Hematoxylin-eosin stain; original magnification:
3400.)
scan as the ‘‘double stripe sign.’’7,12,13,62 ENL usually
lasts a few days to weeks. However, as with reversal
reaction, some patients may develop recurrent
lesions, appearing for months at a time (Table I).12
Diagnosis
Like reversal reaction, ENL is a clinical diagnosis.
Serum markers of inflammation, including C-reactive
protein, amyloid A protein, and alpha-1-antitrypsin,
are often elevated.63,64 Histology demonstrates
lobular panniculitis with inflammatory infiltrate
concentrated in the dermis and subcutis, composed
of neutrophils in acute lesions. Foamy macrophages
containing large numbers of acid-fast bacilli, known
as Virchow cells, are present.65 Biopsy specimens
after 72 hours demonstrate more lymphocytes and
plasma cells. Edema of the dermis or vasculitis may
also be observed.61
Pathogenesis
ENL is commonly explained as immune complex-
mediated disease. Patients with lepromatous leprosy
Kamath et al 5
and borderline lepromatous leprosy have high levels
of anti-M leprae antibodies and M leprae antigens.63
In addition, ENL lesions are characterized by neutro-
phil infiltration. TLR2 and fragment crystallizable
(Fc) receptor activation induces IL-1 beta, which
up-regulates expression of E-selectin and neutrophil
binding of endothelial cells.66 M leprae also
stimulates neutrophils to secrete TNF-alfa and IL-8,
increasing inflammation.63
Cell-mediated immunity is also involved in ENL
pathogenesis. CD41 T cells outnumber CD81 T cells
2 to 1.67 Several studies support a type 1 T helper
(Th1) response with high levels of interferon-gamma
and IL-12.68 On the other hand, others suggest a
dominant type 2 T helper (Th2) response with high
levels of TNF-alfa and IL-6 detected in the serum and
in skin lesions.69 More recently, single nucleotide
polymorphisms in the IL-6 gene were found to be
associated with ENL.70
Treatment
The current treatment of choice, thalidomide, is
extremely effective at improving ENL symptoms.
Several mechanisms for thalidomide’s efficacy in
ENL have been proposed, including inhibition of
TNF-alfa production, stimulation of IL-2 production
by T cells, and inhibition of neutrophil recruit-
ment.66,71,72 Given its teratogenicity, thalidomide is
avoided in women of childbearing potential. In the
United States, the THALOMID Risk Evaluation and
Mitigation Strategy, formerly known as the System for
Thalidomide Education and Prescribing Safety, has
been very effective at reducing thalidomide-
associated teratogenicity.73 Treatment of this partic-
ular population remains a challenge, and quality trials
are desperately needed to provide better options.74
For patients with partial thalidomide response or
neuritis, high-dose prednisone should be added.
However, coadministration of thalidomide with
prednisone may increase risk of deep venous
thrombosis.75-77 Clofazimine given along with
prednisone is an option for those who cannot
receive thalidomide, but its full effect is not
observed until 4 to 6 weeks from initiation.1,78,79
Also, clofazimine causes skin discoloration, which
can be additionally stigmatizing.52
Other treatments include nonsteroidal anti-
inflammatory drugs for mild ENL, pentoxifylline,
TNF-alfa inhibitors, methotrexate, and azathio-
prine.5,80-82 Although TNF-alfa inhibitors have been
effective at treating refractory ENL, not all studies
support a central role for TNF-alfa in the pathogen-
esis of ENL, and as discussed previously, discontin-
uation of therapy with TNF-alfa inhibitors has been
associated with reversal reaction (Table II).72,83
6 Kamath et al J AM ACAD DERMATOL

LUCIO PHENOMENON
Clinical manifestations
Lucio phenomenon is most common in Central
America, particularly in Mexico, although cases
have also been reported in Europe and Asia.84,85
Precipitating factors include pregnancy, stress, or
infection.13,84 The occurrence of Lucio phenomenon
is limited to patients with diffuse nonnodular leproma-
tous leprosy. These patients exhibit little immunologic
resistance to the infection and have high antigen
load.86 Diffuse infiltration of skin by bacteria gives a
waxy appearance.87 Other findings include alopecia of
eyebrows and eyelashes, destructive rhinitis with nasal
septal perforation, and eruptive telangiectases.84,87,88
Lucio phenomenon begins with sudden appear-
ance of painful, bluish, or violaceous macules or
plaques surrounded by erythema. They can progress
to hemorrhagic infarcts and bullae, which rupture to
form necrotic ulcers. They are characteristically Fig 3. Lucio phenomenon. A, Patient with lepromatous
painful but nontender. Other distinguishing leprosy and multiple ulcerations with serrated margins at
features include firm, subcutaneous nodules that various stages of resolution on the left lower extremity. B,
are palpable but not visible. Eventually, irregular Biopsy specimen typical of Lucio phenomenon demon-
atrophic scars are left behind. Lesions most strating granulomatous infiltrate in the vessel walls and
commonly surface on the lower extremities, swelling of the endothelium (black arrows). (Hematoxy-
followed by the forearms and buttocks (Fig 3).6 lin-eosin stain; original magnification: 3400.)
Hepatosplenomegaly and lymphadenopathy may
be associated with Lucio phenomenon. Normocytic walls, suggesting that the reaction is immune
normochromic anemia, elevated erythrocyte sedi- complexemediated. Some view Lucio phenomenon
mentation rate, and leukocytosis with neutrophilia as a clinical variant of ENL.88 Direct invasion of the
have also been described.84 If not treated endothelium of dermal vessels by bacteria may
immediately, Lucio phenomenon can be fatal, often contribute to vascular damage.39,87 Most recently,
because of superinfection and sepsis (Table I).89 research using polymerase chain reaction implicates
a new bacterial species M lepromatosis, which has
been shown to cause both diffuse nonnodular
Diagnosis leprosy and Lucio phenomenon.92
Clinical diagnosis should be confirmed by biopsy
specimen, because Lucio phenomenon can be
Treatment
confused with the usual ulcerative lesions of
If not already on MDT, patients experiencing
lepromatous leprosy. Diagnostic hallmarks are
Lucio phenomenon should be started on medica-
epidermal necrosis, involvement of the subpapillary
tions for lepromatous leprosy, including rifampicin,
blood vessels, and abundant aggregates of acid-fast
dapsone, and clofazimine. In addition, high-dose
bacilli in endothelial cells. Other notable histologic
corticosteroids should be initiated and tapered over
features include fibrinoid necrosis of vessels and
months.84 Supportive care plays an important role
occlusion of vessels in the dermis by endothelial
in management of these patients, to prevent fatal
proliferation and thrombosis.88,90,91 Large accumu-
complications associated with superimposed infec-
lations of macrophages are also visible on biopsy
tion. Although thalidomide has been suggested as a
specimen and may explain why Lucio phenomenon
possible treatment, it has been shown that patients
is associated with high levels of angiotensin-
with Lucio phenomenon often do not improve with
converting enzyme and lysozyme.6,91
its administration. For those who have persistence of
the reaction despite these treatments, plasmaphe-
Pathogenesis resis may be an option (Table II).93
Lucio phenomenon is a necrotizing vasculitis, and
medium-sized vessels may be primarily involved.91 Conclusion
Immunofluorescence microscopy has demonstrated Immunologic reactions dramatically worsen the
complexes of IgM, C3, and C1q in dermal vessel clinical course of leprosy. They can occur before
J AM ACAD DERMATOL
initiation of MDT and are not necessarily a
consequence of therapy as is often assumed.
Clinicians should educate patients with newly
diagnosed leprosy on signs and symptoms of these
reactions, so they may seek immediate medical care.
The National Hansen’s Disease Program provides
medication, diagnostic services, and physician
visits at its clinics across the United States. Prompt
recognition of leprosy reactions is imperative;
ensuring rapid initiation of treatment may help
reduce the likelihood of complications, such as
nerve function impairment and the associated
deformity and disability.
We thank Helen Mora, RN, and Robert Jerskey, OTR, for
their dedication to the patients at the Los Angeles County 1
University of Southern California Medical Center Hansen’s
disease clinic.
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