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CASE REPORT
Year : 2021  |  Volume : 22  |  Issue : 4  |  Page : 352-355

Conundrum of recurrent erythema nodosum leprosum and dapsone hypersensitivity syndrome complicating pediatric leprosy


1 Department of Dermatology, Military Hospital Kirkee, Pune, Maharashtra, India
2 Department of Pathology, Military Hospital Kirkee, Pune, Maharashtra, India
3 Department of Paediatrics, Military Hospital Kirkee, Pune, Maharashtra, India
4 Department of Medicine, Armed Forces Medical College, Pune, Maharashtra, India
5 Department of Dermatology, Command Hospital, Lucknow, UttarPradesh, India

Date of Submission16-May-2020
Date of Decision19-May-2020
Date of Acceptance30-Mar-2021
Date of Web Publication01-Oct-2021

Correspondence Address:
Anwita Sinha
Military Hospital Kirkee, Pune
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_81_20

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  Abstract 


Introduction: Leprosy, a chronic infectious disease affecting the skin and peripheral nerves, has been considered a disease of adults due to its long incubation period, but in endemic regions like the Indian subcontinent, pediatric leprosy cases continue to rise reflecting active disease transmission in the community. Case report: We describe a case of bordeline lepromatous leprosy in a child complicated by severe type 2 lepra reaction and dapsone hypersensitivity syndrome. Conclusion: Pediatric leprosy cases though commonly paucibacillary, can also present with a high bacillary burden. Complicated leprosy cases need nuanced care and highlight the importance of adequate clinical exposure to leprosy cases, so that such cases can be confidently managed.

Keywords: Leprosy, Dapsone, Mycobacterium leprae, Child, Thalidomide


How to cite this article:
Sinha A, Dangwal V, R. Mallick AK, Singh AR, Sinha A. Conundrum of recurrent erythema nodosum leprosum and dapsone hypersensitivity syndrome complicating pediatric leprosy. Indian J Paediatr Dermatol 2021;22:352-5

How to cite this URL:
Sinha A, Dangwal V, R. Mallick AK, Singh AR, Sinha A. Conundrum of recurrent erythema nodosum leprosum and dapsone hypersensitivity syndrome complicating pediatric leprosy. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Dec 6];22:352-5. Available from: https://www.ijpd.in/text.asp?2021/22/4/352/327460




  Introduction Top


Leprosy is a chronic infectious disease caused by  Mycobacterium leprae Scientific Name Search bacterium lepromatis which predominantly affects the skin and peripheral nerves, resulting in neuropathy and associated long-term consequences such as deformities and disabilities. Children are a vulnerable group to this infection due to their nascent or immature immunity and exposure to intrafamilial contacts.[1] Pediatric leprosy commonly presents as a paucibacillary disease with multibacillary (MB) cases and reactional episodes less commonly encountered.[2] Reactions in leprosy can occur as the presenting feature of the disease or can manifest post introduction of multidrug therapy (MDT) and pose a unique problem in children due to the potential toxicity of drugs used such as steroids, and thalidomide. Majority of reactions encountered in pediatric leprosy are Type 1 reactions with scarce reports of Type 2 reactions and erythema nodosum leprosum (ENL).[3] Children generally tolerate MDT well, but rarely instances of failure of first-line MDT or idiosyncratic reactions to first-line agents have been reported.[4] Dapsone hypersensitivity syndrome (DHS), first described by Aldday and Barnes (1951), is an idiosyncratic severe adverse drug reaction to dapsone, which is characterized by fever, rash, lymphadenopathy, and multiorgan involvement.[5] DHS precludes the use of dapsone. We herein present the case of a child presenting with ENL as a presenting feature of borderline lepromatous (BL) leprosy and subsequently developing DHS and hemolysis necessitating the use of thalidomide and second-line MDT.


  Case Report Top


An 11-year-old girl presented with complaints of high-grade fever, swelling of both hands and legs, and multiple painful red raised lesions over the body since seven days. Systemic examination was unremarkable. Dermatological examination revealed bilateral supraciliary madarosis along with multiple hypopigmented, hypotrichic, hypoesthetic patches over the body [Figure 1]a with bilaterally thickened and tender ulnar and common peroneal nerves. Multiple tender erythematous nodular lesions were present on the trunk and extremities [Figure 1]b and [Figure 1]c. The patient was diagnosed as a case of BL leprosy with Type 2 reaction and was started on MDT at standard child dosages for MB leprosy for the age group of 10–14 years: rifampicin 450 mg once a month, clofazimine 150 mg once a month and 50 mg every other day, and dapsone 50 mg daily. The child's weight was 38 kg, and she was started on 40 mg prednisolone for Type 2 reaction and neuritis. Slit-skin smear from the ear lobes returned a bacteriological index of 4 plus. Skin biopsy from a hypoesthetic patch on back showed a grenz zone with a dense collection of macrophages, histiocytes, and mononuclear cells in the dermis suggesting BL leprosy along with acid-fast bacilli seen on modified Ziehl–Neelsen stain [Figure 2]a and [Figure 2]b. Histopathology from an erythematous nodule showed lobular panniculitis with neutrophilic infiltration [Figure 2]c and [Figure 2]d.
Figure 1: (a) Multiple hypopigmented hypoesthetic patches over back. (b and c) Multiple tender erythematous subcutaneous nodules over upper and lower extremities

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Figure 2: (a) Histopathology of borderline lepromatous lesion: flattening of rete ridges with dermal infiltration of lymphocytes and foamy histiocytes (H and E, ×40). (b) Multiple acid-fast bacilli seen (modified Ziehl–Neelsen, ×40). (c) Lobular panniculitis with foamy histiocytes and neutrophilic infiltration (H and E, ×40). (d) Lobular panniculitis with neutrophilic infiltration (H and E, ×40 [zoomed in view])

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The patient responded well to steroids with resolution of fever, ENL lesions, and ulnar neuritis within a week. She was on tapering doses of prednisolone and was tolerating MDT well till the ninth week, when she developed recurrence of ENL. At this point, the patient was started on thalidomide 50 mg thrice a day with resolution of ENL lesions within three days of starting thalidomide. However, 1 week later, the patient again became febrile with generalized redness and flaking of skin. General examination revealed bilateral cervical lymphadenopathy and pitting pedal edema along with hepatosplenomegaly. Dermatological examination revealed generalized exfoliative dermatitis [Figure 3]a and [Figure 3]b. Hematological investigations revealed hemoglobin (Hb) of 4 g/dL, eosinophilia of 20% along with schistocytes and eosinophilia on peripheral blood smear [Figure 3]c. Biochemical parameters showed a raised bilirubin of 3 g along with aspartate transaminase/alanine aminotransferase of 150/230. The patient was diagnosed as a case of DHS along with dapsone-induced hemolysis. MDT was stopped, and the patient was started on oral prednisolone at a dose of 40 mg. In view of Hb of 4 g/dL, she was transfused two-packed red blood cells with a rise in Hb to 8 g/dL. Fever and exfoliative dermatitis resolved within 10 days of starting steroids with return of hematological and biochemical parameters to normal. The patient was continued on tapering doses of steroids for the next 10 weeks, after which she was started on dapsone-sparing modified MDT in the form of monthly doses of rifampicin – 450 mg, ofloxacin – 400 mg, and minocycline – 100 mg (ROM) along with alternate day clofazimine – 50 mg. The patient is tolerating modified MDT well and is on tapering doses of thalidomide for ENL with regular follow-up.
Figure 3: (a and b) Generalized exfoliative dermatitis over body. (c) Peripheral blood smear showing eosinophilia and schistocytes

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  Discussion Top


Pediatric leprosy comprises approximately 9% of total leprosy cases in India[6] with the lepromatous variants of disease being rare in childhood. The disease reflects a higher frequency in 10–14-year age group as was seen in our case, possibly due to the long incubation period of leprosy, delay in diagnosis of early lesions, and difficulty in assessing sensory loss in younger children.[4] An important source of infection in childhood is familial leprosy contacts with the risk of developing leprosy being nine times when the contact is intrafamilial and further increasing to 14 times if the contact has lepromatous disease.[2] In our case, the contact was found to be child's father with lepromatous leprosy who was subsequently started on MDT.

Leprosy reactions which are acute/subacute inflammatory processes mediated by T-lymphocytes or antibodies are rare in pediatric age group. The frequency of reactions in children varies from 3.1% to 33.9% as compared to adults where more than 50% of the patients develop reactions.[4] Type 1 lepra reaction is common, given that majority of pediatric leprosy is in the paucibacillary spectrum. ENL which is a manifestation of Type 2 lepra reaction mediated by immune complexes and proinflammatory cytokines has been reported in 0%–3.1% of pediatric leprosy cases, which is much less than the reported incidence of 35% among all the age groups.[7] ENL is clinically characterized by the occurrence of crops of tender skin lesions and can be associated with neuritis, arthritis, dactylitis, eye inflammation, osteitis, orchitis, lymphadenitis, and nephritis. The onset of ENL is acute, but it may pass into a chronic phase and can be recurrent. Please add as next sentence same para-Of note, when type 2 lepra reactions have associated neuritis steroids are needed as thalidomide works only on the cutaneous component (ENL).

The management of reactional episodes involves long-term use of corticosteroids which can have adverse effects in children such as hypothalamic–pituitary–adrenal axis suppression, growth failure, and retarded bone formation. Thalidomide with immunomodulatory properties is the first-line drug for ENL. However, due to a lack of safety information, thalidomide is not recommended for children below 12 years.[8] Our patient was initially given a trial of steroids due to associated neuritis along with ENL but had to be started on thalidomide in view of recurrence of ENL on tapering steroids. Another important consideration when choosing thalidomide therapy is its significant adverse events such as somnolence, dizziness, orthostatic hypotension, neutropenia, constipation, hypersensitivity, allergic reactions, teratogenicity, and potentially irreversible peripheral neuropathy.[8] Our patient had recurrence of ENL on tapering steroids and thalidomide, where dose of thalidomide had to be titrated to optimal response. She is presently on tapering doses of thalidomide and is on regular follow-up for any neuropathic side effects. The patient was also supplemented with Vitamin D and calcium to avoid side effects of steroids.

MDT is the mainstay of leprosy treatment. The formation of toxic intermediate metabolites of dapsone through N-hydroxylation pathway are thought to be responsible for dapsone related adverse effects.[9] DHS which is in the spectrum of reactions termed “drug reactions with eosinophilia and systemic symptoms” is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release. The incidence of DHS ranges from 0.5% to 3%.[9]

DHS is treated with oral corticosteroids in dose of 1–1.5 mg/kg/day. Since, dapsone persists up to 35 days in organs through protein binding and enterohepatic recirculation, slow tapering of the corticosteroid therapy with close monitoring of organ function is required, as abrupt discontinuation may cause a relapse. Our patient was treated with prednisolone 40 mg with slow tapering over 10 weeks with close monitoring of hematological and biochemical parameters and any autoimmune sequelae post-DHS.

Children with DHS are usually offered a modified World Health Organization MDT regimen consisting of rifampicin monthly and clofazimine daily at the usual doses and same duration. Alternative regimens use bactericidal drugs such as ofloxacin (quinolone) and minocycline (tetracycline), which are contraindicated in children under 10 years of age due to the risk of the early closure of the epiphysis and degenerative changes in weight-bearing joints with ofloxacin along with dental and bone alterations with minocycline.[4] Monthly ROM is found to be as safe and effective as MDT in adults conferring similar clinical, bacteriologic, and histologic improvements, without increased rates of lepra reaction.[10] In view of high bacillary load in our patient with recurrent reactions and DHS, we decided to include monthly ROM in treatment regimen of child along with alternate day clofazimine. The patient has tolerated modified MDT well with partial resolution of leprosy patches on 8-month follow-up.


  Conclusion Top


Cases of childhood leprosy need nuanced care. Our case was especially challenging because of a high bacillary burden and severe ENLs which needed thalidomide and steroids. Furthermore, dapsone hypersensitivity syndrome necessitated use of second-line drugs.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child 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

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Dogra S, Narang T, Khullar G, Kumar R, Saikia UN. Childhood leprosy through the post-leprosy-elimination era: A retrospective analysis of epidemiological and clinical characteristics of disease over eleven years from a tertiary care hospital in North India. Lepr Rev 2014;85:296-310.  Back to cited text no. 1
    
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Oliveira MB, Diniz LM. Leprosy among children under 15 years of age: Literature review. An Bras Dermatol 2016;91:196-203.  Back to cited text no. 2
    
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Chaitra P, Bhat RM. Postelimination status of childhood leprosy: Report from a tertiary-care hospital in South India. Biomed Res Int 2013;2013:328673.  Back to cited text no. 3
    
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Narang T, Kumar B. Leprosy in children. Indian J Paediatr Dermatol 2019;20:12.  Back to cited text no. 4
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Bucaretchi F, Vicente DC, Pereira RM, Tresoldi AT. Dapsone hypersensitivity syndrome in an adolescent during treatment during of leprosy. Rev Inst Med Trop Sao Paulo 2004;46:331-4.  Back to cited text no. 5
    
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Rao PN, Suneetha S. Current situation of leprosy in India and its future implications. Indian Dermatol Online J 2018;9:83-9.  Back to cited text no. 6
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Pandhi D, Mehta S, Agrawal S, Singal A. Erythema nodosum leprosum necroticans in a child – An unusual manifestation. Int J Lepr Other Mycobact Dis 2005;73:122-6.  Back to cited text no. 7
    
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Yang CS, Kim C, Antaya RJ. Review of thalidomide use in the pediatric population. J Am Acad Dermatol 2015;72:703-11.  Back to cited text no. 8
    
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Craig J, MacRae C, Melvin RG, Boggild AK. Case report: A case of Type 1 leprosy reaction and dapsone hypersensitivity syndrome complicating the clinical course of multibacillary leprosy. Am J Trop Med Hyg 2019;100:1145-8.  Back to cited text no. 9
    
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