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 Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 9  |  Issue : 2  |  Page : 226-228

Late leprosy reaction presenting as erythema multiforme-like erythema nodosum leprosum with underlying rifampicin resistance and its potential implications


1 Department of Dermatology and STDs, Dr. RML Hospital and PGIMER, New Delhi, India
2 Department of Dermatology and STDs, Dr. RML Hospital and ABVIMS, New Delhi, India
3 Department of Pathology, Dr. RML Hospital and ABVIMS, New Delhi, India
4 Research Scientist, Stanley Browne Laboratory, The Leprosy Mission Community Hospital, New Delhi, India

Date of Web Publication29-May-2020

Correspondence Address:
Anita Kulhari
Department of Dermatology and STDs, Dr. RML Hospital and ABVIMS, New Delhi - 110 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_26_20

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  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


How to cite this article:
Sardana K, Kulhari A, Mathachan SR, Khurana A, Bansal P, Ahuja A, Lavania M, Ahuja M. 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

How to cite this URL:
Sardana K, Kulhari A, Mathachan SR, Khurana A, Bansal P, Ahuja A, Lavania M, Ahuja M. Late leprosy reaction presenting as erythema multiforme-like erythema nodosum leprosum with underlying rifampicin resistance and its potential implications. Int J Mycobacteriol [serial online] 2020 [cited 2020 Jul 5];9:226-8. Available from: http://www.ijmyco.org/text.asp?2020/9/2/226/285223




  Introduction Top


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 Top


A 40-year-old male, a known case of lepromatous leprosy treated with MB-MDT for 2 years, presented to us after an asymptomatic period of 1 year with the acute eruption of crops 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]. 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.
Figure 1: Multiple erythematous plaques with well-defined raised outer margins and central dusky hue giving a targetoid appearance

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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 [Figure 2] and [Figure 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 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+).
Figure 2: Pandermal perivascular, periadnexal, periappendageal, and perineural lymphohistiocytic infiltrate, with many foam cells (H and E, ×400)

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Figure 3: Vessel walls showing neutrophilic infiltration suggestive of vasculitis (H and E, ×400)

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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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  Discussion Top


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 in 3% of patients, which is generally mild.[9],[10],[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].{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 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.



 
  References Top

1.
Balagon MV, Gelber RH, Abalos RM, Cellona RV. Reactions following completion of 1 and 2 year multidrug therapy (MDT). Am J Trop Med Hyg 2010;83:637-44.  Back to cited text no. 1
    
2.
Saunderson P, Gebre S, Byass P. Reversal reactions in the skin lesions of AMFES patients: Incidence and risk factors. Lepr Rev 2000;71:309-317.  Back to cited text no. 2
    
3.
Sauderson P, Gebre S, Byass P. ENL reactions in the multi-bacillary cases of the AMFES cohort in central Ethiopia: Incidence and risk factors. Lepr Rev 2000;71:318-24.  Back to cited text no. 3
    
4.
Taverne J, Reichlin M, Turk JL, Rees RJ. Detection of immune complexes in mice infected with Mycobacterium leprae murium. Clin Exp Immunol 1976;24:157-67.  Back to cited text no. 4
    
5.
Sinha S, Sardana K, Agrawal D, Malhotra P, Lavania M, Ahuja M. Multidrug resistance as a cause of steroid-nonresponsive downgrading type I reaction in Hansen's disease. Int J Mycobacteriol. 2019;8:305-8.  Back to cited text no. 5
    
6.
Arora P, Sardana K, Agarwal A, Lavania M. Resistance as a cause for chronic steroid dependent ENL-A novel paradigm with potential implications in management. Lepr Rev 2019:19;201-5.  Back to cited text no. 6
    
7.
World Health Organization. WHO Expert Committee onleprosy: Eighth Report. Geneva: World Health Organization; 2012.  Back to cited text no. 7
    
8.
Pocaterra L, Jain S, Reddy R, Muzaffarullah S, Torres O, Suneetha S, et al. Clinical course of erythema nodosum leprosum; An 11 year cohort study in Hyderabad, India. Am J Trop Med Hyg 2006;74:868-79.  Back to cited text no. 8
    
9.
Kumar B, Dogra S, Kaur I. Epidemiological characteristics of leprosy reactions: 15 years experience from North India. Int J Lepr Other Mycobact Dis 2004;72:125-30.  Back to cited text no. 9
    
10.
Van Brakel WH, Khawas IB, Lucas S. Reactions in leprosy: An epidemiological study of 386 patients in West Nepal. Lepr Rev 1994;65:190-203.  Back to cited text no. 10
    
11.
Vijaykumaran V, Manimozhi N, Jesudasan K. Incidence of late lepra reaction among multibacillary leprosy after MDT. Int J Lepr Other Mycobact Dis 1995;63:18-22.  Back to cited text no. 11
    
12.
Yan W, Xing Y, Yuan LC, De Yang R, Tan FY, Zhang Y, et al. Application of RLEP real-time PCR for detection of M. leprae DNA in paraffin-embedded skin biopsy specimens for diagnosis of paucibacillary leprosy. Am J trop Med Hyg 2014;90:524-9.  Back to cited text no. 12
    
13.
World Health Organization. A Guide for Surveillance of Antimicrobial Resistance in Leprosy (An Update). World Health Organization; 2017.  Back to cited text no. 13
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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