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Case Report

Late Leprosy Reaction Presenting as Erythema Multiforme‑Like

Erythema Nodosum Leprosum with Underlying Rifampicin
Resistance and its Potential Implications
Kabir Sardana1, Anita Kulhari2, Sinu Rose Mathachan2, Ananta Khurana2, Prekshi Bansal2, Arvind Ahuja3, Mallika Lavania4, Madhvi Ahuja4
1
Department of Dermatology and STDs, Dr. RML Hospital and PGIMER, Departments of 2Dermatology and STDs and 3Pathology, Dr. RML Hospital and ABVIMS,
4
Research Scientist, Stanley Browne Laboratory, The Leprosy Mission Community Hospital, New Delhi, India

Abstract
Erythema multiforme (EM)‑like erythema nodosum leprosum (ENL) is a rare atypical presentation, and its late appearance after the completion
of multidrug therapy (MDT) is unusual. We describe the case of a lepromatous leprosy patient who after the completion of MDT presented
to us with late EM‑like ENL and was found to be resistant to rifampicin. We discuss the implications of this finding and the potential role of
resistant bacilli in causing reactions with atypical presentations.

Keywords: Erythema multiforme like, erythema nodosum leprosum, leprosy, multibacillary, multidrug therapy, real‑time PCR, resistance,
steroids

Submitted: 11-Feb-2020 Revised: 04-Apr-2020 Accepted: 14-Apr-2020 Published: 29-May-2020

Introduction asymptomatic period of 1 year with the acute eruption of crops

While Type 2 reactions have been reported routinely during
multidrug therapy (MDT), late leprosy reactions, especially
late Type 2 reactions (erythema nodosum leprosum [ENL]), are
uncommon. In fact, the published literature on reactional states
in multibacillary (MB) patients consequent to the completion
of MDT are uncommon.[1] The few studies on this topic have
found that the majority of cases are of Type 1 reaction.[1,2] While
various theories have been propounded for the occurrence of
ENL, it is pertinent to note that it generally occurs during the
rapid killing of bacilli from effective chemotherapy, and like
other antigen‑antibody complex diseases, it occurs particularly
in a state of antigen excess.[1,3,4] Our patient presented to us with
atypical “erythema multiforme (EM)‑like” ENL 1 year after the
completion of MDT, and based on two previous cases,[5,6] we
evaluated the patient for resistance. We detail our observations and
the implications of our findings in the prevalent treatment of ENL.
Case Report
A   40‑year‑old  male, a known case of lepromatous leprosy
treated with MB‑MDT for 2 years, presented to us after an
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DOI:
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of multiple painful evanescent red‑raised targetoid lesions
associated with fever, myalgias, and conjunctival congestion.
The lesions appeared initially on the upper limbs and progressed
to lower limbs, trunk, back, face, and ears. While smaller lesions
coalesced to form larger ones, few subsided on their own leaving
behind pigmentation. Subsequently, vesicles started developing
over the newly appearing lesions on the upper limb and back.
There was no history of recent illness, trauma, surgery, or
drug intake. Cutaneous examination revealed multiple tender
erythematous plaques with well‑defined raised outer margins
and central dusky hue giving a targetoid appearance, present
over the neck, trunk, all four limbs, and buttocks [Figure 1].
Address for correspondence: Dr. Anita Kulhari,
Department of Dermatology and STDs, Dr. RML Hospital and ABVIMS,
New Delhi ‑ 110 001, India.
E‑mail: anitakulhari2008@gmail.com
ORCID:
Anita Kulhari: https://orcid.org/0000-0001-6229-7194
This is an open access journal, and articles are distributed under the terms of the Creative
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For reprints contact: reprints@medknow.com
How to cite this article: Sardana K, Kulhari A, Mathachan SR,
Khurana A, Bansal P, Ahuja A, et al. Late leprosy reaction presenting as
erythema multiforme‑like erythema nodosum leprosum with underlying
rifampicin resistance and its potential implications. Int J Mycobacteriol
2020;9:226-8.

226 © 2020 International Journal of Mycobacteriology | Published by Wolters Kluwer - Medknow

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Sardana, et al.: Erythema multiforme‑like erythema nodosum leprosum
Few plaques on the left flank showed vesiculation. Bilateral
radial, ulnar, radial cutaneous, and lateral popliteal nerves were
enlarged, firm, and nontender. Bilateral posterior tibial nerves
were enlarged and firm with Grade 2 tenderness. Deep tendon
reflexes were normal.
On investigation, slit‑skin smear from the left ear, left eyebrow,
and a plaque showed bacteriological index (BI) of 1+, 0, and
1+, respectively, with presence of granular bacilli. Skin biopsy
taken from an early lesion showed an unremarkable epidermis
with pandermal perivascular, periadnexal, periappendageal, and
perineural lymphohistiocytic infiltrate, with many foam cells,
extending to superficial subcutis with vessel walls showing
neutrophilic infiltration suggestive of vasculitis [Figures 2 and
3]. Fite stain was negative. Based on the clinical appearance,
systemic symptoms, and classical histopathological picture, a
diagnosis of EM‑like ENL was made. Treatment was initiated
with prednisolone 60 mg/day. While the existing lesions began
to heal with decreasing erythema, edema, and tenderness,
the patient continued to develop 6–7 new evanescent painful
Figure 1: Multiple erythematous plaques with well‑defined raised outer
margins and central dusky hue giving a targetoid appearance
Figure 3: Vessel walls showing neutrophilic infiltration suggestive of
vasculitis (H and E, ×400)
International Journal of Mycobacteriology  ¦  Volume 9  ¦  Issue 2  ¦  April-June 2020
papules and nodules every day initially. Gradually, over the
course of his hospital stay, however, the lesions subsided.
He was discharged on prednisolone 40 mg with clofazimine
50 mg daily.[7] The resistance testing revealed a mutation in the
rpoB gene with a change in amino acid threonine to isoleucine
at codon position 433 (Thre433Ile) and 441 (Asp441Tyr)
indicating rifampicin resistance [Figure 4]. A viability‑based
assay targeting the 16 S rRNA gene region using real‑time
Polymerase chain reaction (PCR) showed amplification after
33 cycles possibly due to the low BI (BI = 0.66+).
Discussion
ENL is a Type 3 hypersensitivity reaction caused by
antigen‑antibody complex deposition and can have rare
atypical presentations. Conventional teaching has been that
a high BI is a risk factor for the development of ENL which
strongly suggests that the process is antigen driven. In most
cases, no definite cause can be found, and the reaction is
believed to be seen when the bacilli are granular and thus is
a consequence of antigenic excess due to the bacillary load.[8]
Late reactions have been reported after 2 years of MDT, with
reversal reactions occurring in 1%–9% of patients and ENL
Figure 2: Pandermal perivascular, periadnexal, periappendageal, and
perineural lymphohistiocytic infiltrate, with many foam cells (H and E,
×400)
Figure 4: Graph showing mutation in the rpoB gene with a change in
amino acid threonine to isoleucine at codon position 433 (Thre433Ile)
and 441 (Asp441Tyr) indicating rifampicin resistance
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Sardana, et al.: Erythema multiforme‑like erythema nodosum leprosum
in 3% of patients, which is generally mild.[9‑11] In our case,
the ENL was atypical with an “EM‑like” morphology. In our
case, the patient had a low BI, and no trigger factor could be
elicited. Thus, based on a previous case of chronic ENL,[6]
who tested positive for rifampicin resistance gene mutation,
we replicated this test in our case and discovered rifampicin
resistance [Figure 2].
What is alarming is that in an era where reactions, neuritis,
and disability are the primary concerns, the reduction of the
duration of regimen of MDT to 1 year has been suggested by
the World Health Organization (WHO), but there are instances
where reactions can occur after this fixed duration therapy.
A more pertinent issue is that the treatment of reactions is
primarily corticosteroids with occasional use of adjuvant
immunosuppressive drugs. We feel that cases of chronic and
persistent severe reactions are an emergent indication for
resistance testing,[5,6] as this can enable a logical intervention
of second‑line drugs, instead of steroids, which can predispose
to both reactivation of the disease, spread of resistant strains,
and relapses. Herein, we may emphasize that in our case due
to the low concentration of cDNA, the threshold cycle (Ct)
value was 33 cycles which is due to the low bacterial load
(BI of 0.77), and this corresponds to an approximate 515 copies
of Mycobacterium leprae specific repetitive element gene and
62fg M. leprae DNA.[12]
The patient was subsequently administered second‑line therapy
as proposed by the WHO,[13] our case, in conjunction with
previous reports,[5,6] suggests that resistance can explain some
cases of reactions and can also explain the lack of control of
chronic ENL cases with conventional treatments. To arrive at a
firm conclusion of this hypothesis, a larger study from leprosy
endemic countries is needed to highlight the role of resistance
as a potential cause for leprosy reactions.
Declaration of patient consent
The authors certify that they have obtained all appropriate
patient consent forms. In the form the patient(s) has/have
given his/her/their consent for his/her/their images and other
clinical information to be reported in the journal. The patients
understand that their names and initials will not be published
228 International Journal of Mycobacteriology  ¦  Volume 9  ¦  Issue 2  ¦  April-June 2020
and due efforts will be made to conceal their identity, but
anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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