):767-71. 2012;87(5 Dermatol. Bras An

©2012 by Anais Brasileiros de Dermatologia de Brasileiros Anais by ©2012

Dermatologist, Member of the Brazilian Society of Dermatology - São Paulo (SP), Brazil. (SP), Paulo São - Dermatology of Society Brazilian the of Member Dermatologist,

5

(PR), Brazil. Brazil. (PR),

do Paraná (HC-UFPR) – Curitiba Curitiba – (HC-UFPR) Paraná do Federal Universidade da Clínicas de (Hospital Paraná of University Federal the of Hospital Teaching the at Biologist/Mycologist

4

Dermatopathologist - Federal University of Paraná (Universidade Federal do Paraná - UFPR) – Curitiba (PR), Brazil. Brazil. (PR), Curitiba – UFPR) - Paraná do Federal (Universidade Paraná of University Federal - Dermatopathologist

3

l. l. Brazi (PR), Curitiba – UFPR) - Paraná do Federal (Universidade Paraná of University Federal Dermatology, of Professor Assistant

2

MD, Resident in Dermatology – Federal University of Paraná (Universidade Federal do Paraná - UFPR) – Curitiba (PR), Brazil. Brazil. (PR), Curitiba – UFPR) - Paraná do Federal (Universidade Paraná of University Federal – Dermatology in Resident MD,

1

Financial funding: None funding: Financial

Conflict of interest: None interest: of Conflict

o Paraná (HC-UFPR) – Curitiba (PR), Brazil. (PR), Curitiba – (HC-UFPR) Paraná o d Federal Universidade da Clínicas de (Hospital Paraná of University Federal the of Hospital Teaching the at out carried Study *

Approved by the Advisory Board and accepted for publication on 09.11.2011. 09.11.2011. on publication for accepted and Board Advisory the by Approved

eevdo 25.08.2011. on Received

soil and in decaying matter), most humans are expo- are humans most matter), decaying in and soil is a chronic disease cau- disease chronic a is Chromoblastomycosis

immunosuppressed conditions. conditions. immunosuppressed in (found fungi these of nature ubiquitous the Given

1

Mucor, Cunninghamella) Mucor, Absidia Rhizomucor, their low virulence, mainly affecting individuals with individuals affecting mainly virulence, low their . ,

Rhizopus, Nonetheless, they rarely cause disease because of because disease cause rarely they Nonetheless, ( by caused infection

sed to these organisms on a daily or weekly basis. weekly or daily a on organisms these to sed life-threatening emerging an is

INTRODUCTION

Palavras-chave: Cromoblastomicose; Hanseníase; Hospedeiro imunocomprometido; Mucormicose imunocomprometido; Hospedeiro Hanseníase; Cromoblastomicose; Palavras-chave:

infecções oportunistas em pacientes imunossuprimidos. pacientes em oportunistas infecções

ruim, neste caso o tratamento foi bem sucedido. Este caso alerta dermatologistas para a possibilidade de possibilidade a para dermatologistas alerta caso Este sucedido. bem foi tratamento o caso neste ruim,

tada por excisão cirúrgica e a mucormicose com anfotericina B. Embora o prognóstico da mucormicose seja mucormicose da prognóstico o Embora B. anfotericina com mucormicose a e cirúrgica excisão por tada

de talidomida e atividades profissionais são alguns fatores de risco neste caso. A cromoblastomicose foi tra- foi cromoblastomicose A caso. neste risco de fatores alguns são profissionais atividades e talidomida de

prednisona e talidomida devido a eritema nodoso (reação hansênica tipo II). Disfunção de neutrófilos, uso neutrófilos, de Disfunção II). tipo hansênica (reação nodoso eritema a devido talidomida e prednisona

micose e cromoblastomicose em um paciente com hanseníase multibacilar, que estava sendo tratado com tratado sendo estava que multibacilar, hanseníase com paciente um em cromoblastomicose e micose

com AIDS. A doença pode apresentar-se em diferentes formas. Este caso ilustra a rara ocorrência de mucor- de ocorrência rara a ilustra caso Este formas. diferentes em apresentar-se pode doença A AIDS. com

em pacientes com neutropenia, diabetes, corticoterapia e condições malignas. Porém, é rara em pacientes em rara é Porém, malignas. condições e corticoterapia diabetes, neutropenia, com pacientes em

Mucormicose é uma infecção fúngica incomum causada por Mucorales. Ocorre frequentemente Ocorre Mucorales. por causada incomum fúngica infecção uma é Mucormicose Resumo:

Keywords: Chromoblastomycosis; Immunocompromised host; Leprosy; Mucormycosis Leprosy; host; Immunocompromised Chromoblastomycosis; Keywords:

This case should alert dermatologists to possible opportunistic infections in immunosuppressed patients. patients. immunosuppressed in infections opportunistic possible to dermatologists alert should case This

the prognosis of mucormycosis is generally poor, in the reported case the patient recovered successfully. recovered patient the case reported the in poor, generally is mucormycosis of prognosis the

Chromoblastomycosis was treated by surgical excision and mucormycosis with . Although B. amphotericin with mucormycosis and excision surgical by treated was Chromoblastomycosis

Neutrophil dysfunction, thalidomide therapy and work activities are some of the risk factors in this case. this in factors risk the of some are activities work and therapy thalidomide dysfunction, Neutrophil

leprosy, under prolonged corticosteroid and thalidomide therapy to control leprosy type 2 reaction. 2 type leprosy control to therapy thalidomide and corticosteroid prolonged under leprosy,

rence of chromoblastomycosis and mucormycosis in an immunosuppressed patient with multibacillary with patient immunosuppressed an in mucormycosis and chromoblastomycosis of rence

with AIDS. Clinical disease can be manifested in several forms. The case reported illustrates the rare occur- rare the illustrates reported case The forms. several in manifested be can disease Clinical AIDS. with

patients with neutropenia, diabetes, malignancy and on corticoid therapy. However, it is rare in patients in rare is it However, therapy. corticoid on and malignancy diabetes, neutropenia, with patients

Mucormycosis is an uncommon fungal infection caused by Mucorales. It frequently occurs in occurs frequently It Mucorales. by caused infection fungal uncommon an is Mucormycosis Abstract:

Sandra Moritz Sandra Pinheiro Lameira Rosângela

5 4

Betina Werner Betina Mukai Mitsue Maira

3 2

Mariana Hammerschmidt Mariana Basílio Alves Machado Flávia

1 1

II sob terapia prolongada com corticosteróide e talidomida e corticosteróide com prolongada terapia sob II

Mucormicose e cromoblastomicose em um paciente com reação hansênica tipo hansênica reação com paciente um em cromoblastomicose e Mucormicose

corticosteroid and thalidomide therapy therapy thalidomide and corticosteroid

*

a patient with leprosy type 2 reaction under prolonged under reaction 2 type leprosy with patient a Mucormycosis and chromoblastomycosis occurring in in occurring chromoblastomycosis and Mucormycosis

▲

R C EPORT ASE 767 768 Basilio FMA, Hammerschmidt M, Mukai MM, Werner B, Pinheiro RL, Moritz S

sed by traumatic inoculation of saprophagous dema- tiaceous fungi, when they enter through an open wound and infect both and subcutaneous tissue. This disease is mostly reported in tropical and subtro- pical areas (higher in rural populations) and is often caused by (F.) pedrosoi. Countries with the highest numbers of cases are Madagascar and Brazil. 2 The case reported illustrates the rare occurren- ce of chromoblastomycosis and mucormycosis in an immunosupressed patient with multibacillary leprosy, under prolonged corticosteroid and thalidomide the- rapy to control leprosy type 2 reaction.

CASE REPORT A 28 year-old white male, rebar setter, born in Itaperuçu-PR and residing in Curitiba-PR/Brazil, was diagnosed with leprosy and neuritis in 2001, confir- FIGURE 1: Skin biopsy - Leprosy diagnosis. Dense infiltrate of med by skin biopsy (Figure 1). He was being treated histiocytes containing large amount of Mycobacterium leprae in the cytoplasm. Fite Faraco x400 (original magnification) with multibacillary chemotherapy and prednisone 1 mg/kg since May 2001. Three months later, he develo- ped flu-like symptoms. Rifampin was discontinued comitant serum glucose control. Surgical drainage and dapsone and clofazimine were maintained. was performed in the larger lesions. Prednisone was Erythema nodosum appeared in May 2002, and thali- tapered during this period. The patient was dischar- domide was added to the treatment. In April 2003, at ged from the hospital with only skin scars in the pre- the end of the multibacillary chemotherapy, dapsone viously involved areas (Figure 5). and clofazimine were suspended. During this time the In February, 2004, the patient returned with patient was kept on prednisone and thalidomide to papular lesions, plaques and fever. A new biopsy of a control neuritis and leprosy type 2 reaction (both thigh lesion revealed virchowian leprosy and Lucio’s drugs were suspended only in 2007). phenomenon (necrotizing erythema). Modified multi- In August 2003, he had a single erythematous, bacillary chemotherapy was started, with dapsone, hyperkeratotic plaque with black dots on his right clofazimine and ofloxacin (due to rifampin intoleran- hand (Figure 2). A skin biopsy demonstrated large pig- ce), and was finished after 24 months of treatment, in mented muriform cells inside multinucleated giant March, 2006. cells and was isolated from the During follow-up, patient had been free from fungi culture (Figure 3). Chromoblastomycosis was lesions or reactional states since July, 2006, and last diagnosed and treated by surgical excision, with total negative bacterioscopy was in December, 2008. resolution. Erythema nodosum and neuritis persisted, Outpatient treatment was finished in January, 2010. and increased doses of both prednisone (80 mg/d) and thalidomide (300 mg/d) were necessary. DISCUSSION In December 2003, six nodular, non-tense, warm Mucormycosis is described in several clinical and erythematous lesions were noticed on his thighs forms, with rhinocerebral disease affecting the parana- and trunk (anterior and posterior). Systemic com- sal sinus orbits and the brain (80% to 90% of cases). 1 plaints were absent and blood analysis was normal, The pulmonary, disseminated, cutaneous, and gas- except for an elevation of serum glucosis (229 mg/dl). trointestinal forms are less common. The major route HIV test (ELISA) was negative. Seven days later, a yel- of infection is via inhalation of fungal spores; other low-greenish fistulization replaced the first lesions and routes include ingestion and traumatic inoculation. 3 new ones appeared. Skin biopsy of a left thigh lesion The cutaneous form (shown in this case) is less showed acute and chronic inflammation with broad common than other clinical forms, but potentially let- dermal necrosis; secondary vasculitis was seen focally hal if early treatment is not started. It is usually related and fungi were not detected. A PAS- stained pus smear to local trauma, with several cases described after the with diastase highlighted broad, pleomorphic, non-sep- use of adhesive bandages and invasive catheters con- tated hyphae with irregular, non-parallel contours taminated by spores. Two different presentations of (Figure 4). Mucor sp was isolated from the culture. primary cutaneous mucormycosis have been descri- Treatment was started with parenteral ampho- bed. The superficial form appears as vesicles or pustu- tericin B 1 mg/kg/d (total dose=1880 mg) with con- les that ulcerate with scar formation, usually in healt-

An Bras Dermatol. 2012;87(5 ):767-71. Mucormycosis and chromoblastomycosis occurring in a patient with leprosy type 2 reaction under... 769

A B

FIGURE 2: A and B. Chromoblatomycosis lesion. Single erythematous , hyperkeratotic plaque with black dots on the right hand hy hosts. Rapidly progressing ulceration and dissemi- be obtained in order to identify the hyphae and cultu- nation in patients with decreased immunity are descri- re can identify the causative organism. Vascular inva- bed in the gangrenous form. After inoculation, the sion is a hallmark of , commonly associa- invades the skin and appears as a small disco- ted with thrombosis of vessels and necrosis of sur- lored area that becomes black and necrotic with sur- rounding tissue.4,6 rounding erythema.4 The mucormycosis treatment approach should The risk factors for mucormycosis (neutrope- begin with primary prevention, including careful use nia, diabetes mellitus with high glucose and metabolic of immunosuppressive therapy in patients whose con- acidosis, prolonged corticoid therapy, history of defe- dition demand the use of such agents. Correction of roxamine therapy in dialysis, hematologic malignan- predisposing factors such as hypoalbuminemia, hypo- cy) suggest that multiple cell types and mechanisms gammaglobulinemia, neutropenia, and hyperglycemia are responsible for the innate immunity against this are also recommended.6 organism. Neutrophils play the major role and indivi- Amphotericin B is the agent of choi- duals with neutropenia or neutrophil dysfunction are ce against mucormycosis. The recommended dose is more susceptible, while cell-mediated immunity has a 1mg/kg/d and the duration of treatment is between 3 minor contribution. Nevertheless, it is uncommon in and 6 weeks.3,5 Lipossomal amphotericin presents patients with AIDS. 3,5 reduced nephrotoxic effect and improved cell pene- The defense mechanisms against mucormycosis tration.5 Besides, recent data suggest that posaconazo- are not well understood. After inhalation, alveolar le may be useful as salvage therapy, and adjunctive macrophages, neutrophils and serum factors, like immune therapy with recombinant granulocyte colo- transferrin, may contribute to the damage of fungal ny-stimulating factor (G-CSF) and GM-CSF, or with spores, and sufficient levels of iron increase the fun- recombinant IFN-γ, has been used successfully in con- gus proliferation and tissue penetration ability.6 junction with lipid formulations of amphotericin B in A skin biopsy and direct mycology exam should treatment of mucormycosis. 5,7 An iron chelator, deferasirox, does not allow iron utilization by the fungus and has been used as an

FIGURE 3: Skin biopsy: Chromoblastomycosis diagnosis. FIGURE 4: Mucormycosis diagnosis. A smear taken from skin lesion Granulomatous inflammation with giant cell containing large secretions showed large irregular and right-angle branched hyphae pigmented muriform cells of Chromoblastomycosis in the with large ovoid conidia of Mucormycosis. PAS with diastase x400 cytoplasm. H.E. x400 (original magnification) (original magnification)

An Bras Dermatol. 2012;87(5 ):767-71. 770 Basilio FMA, Hammerschmidt M, Mukai MM, Werner B, Pinheiro RL, Moritz S

and extremely difficult to eradicate. Chemotherapy (especially ), surgical excision and/or cryosurgery have been used throughout the years, but an effective treatment has not yet been established. Recent studies provide evidence that the HIV PIs (nel- finavir and saquinavir) have multiple effects on crucial biological processes of F. pedrosoi, showing the possi- bility of exploiting HIV PIs as a potential therapeutic agent, alone or in combination with currently used antimycotic drugs, in chromoblastomycosis.10 FIGURE 5: Cutaneous Reported cases of mucormycosis in literature Mucormycosis - skin scars. The patient was include several clinical conditions, but none was des- discharged from the cribed in association with leprosy. hospital with only In this case, the patient had some risk factors to skin scars in pre- development of mucormycosis, such as: prolonged viously involved areas corticosteroid therapy, which has negative effects on neutrophilic granulocytes (although the number of these cells is enhanced), causing impaired margina- agent for infection treatment, unlike deferoxamine tion, reduced chemotactic activity, affecting phagocy- that is a risk factor, since it allows the fungus to utili- tosis and intracellular killing by neutrophils; thalido- ze deferoxamine-bound iron by recognizing it as a mide therapy, leading to diminished TNF alfa produc- siderophore. 8 tion and suppressed Th1 response; his profession, Furthermore, early and repeated surgical rebar setter, includes activities for steel reinforcement debridement of the involved tissues associated with for concrete structures in which there is contact with an antifungal agent is an important part of the treat- sharp edges, iron and wood materials in a damp envi- ment and hyperbaric oxygen may be useful as an ronment, the perfect place for fungi reproduction. auxiliary treatment in cutaneous and rhinocerebral This way, probably traumatic inoculation of fungal mucormycosis.3,5,7 spores was the route of infection for both mucormy- Chromoblastomycosis is primarily a disease of cosis (multiple lesions) and chromoblastomycosis tropical or subtropical regions, mainly in people wor- (single lesion). king outdoors in agricultural occupations. The cha - Patients with leprosy are not susceptible to racteristic lesion is the warty papule or plaque even- infections caused by Mucorales, as the neutrophil tually leaving a fibrotic scar. functions remain intact. However, the immunosup- The disease spreads in the adjacent skin with pressive effects of the therapy used to control reactio- characteristic, satellite lesions surrounding the prima- nal states may increase the prevalence of such infec- ry source. The lesions develop slowly at the site of tions. Probably the patient would not have the two implantation. Over the years, the nodule grows centri- diseases if he were not under prolonged corticoste- fugally. In many instances, the central parts of the roid and thalidomide therapy. In addition, work activi- lesion heals, leaving ivory-colored scars. Mortality due ties may have contributed significantly to mucormyco- to chromoblastomycosis is a rare event. 9 sis and chromoblastomycosis infections in this case. The diagnosis is based on KOH examination, Mucormycosis has a high mortality rate and the identification of organism in histological sections and survival outcome depends on early diagnosis, follo- culture of the organism, which reveal slow growth of wed by an effective and aggressive treatment. green to black colonies, and microscopic analysis of Although the prognosis of mucormycosis is the conidia may identify the agent. A skin biopsy generally poor, in the reported case the patient reco- usually shows hyperkeratotic pseudoepitheliomatous vered successfully. hyperplasia with neutrophilic granulomatous reaction This case alerts dermatologists to possible infec- in the dermis. Pigmented large fungi are easily seen tions occurring in immunosuppressed patients. A high when stained with H & E.1,9 index of suspicion is warranted in order to perform an Chromoblastomycosis lesions are recalcitrant early diagnosis and treatment, and better prognosis. q

An Bras Dermatol. 2012;87(5 ):767-71. Mucormycosis and chromoblastomycosis occurring in a patient with leprosy type 2 reaction under... 771

REFERENCES 1. Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KV. Zygomycosis in the 1990s in 9. Queiroz-Telles F, Esterre P, Perez-Blanco M, Vitale RG, Salgado CG, Bonifaz A. a tertiary-care cancer center. Clin Infect Dis. 2000;30:851-6. Chromoblastomycosis: an overview of clinical manifestations, diagnosis and treat- 2. Kim DM, Hwang SM, Suh MK, Ha GY, Choi GS, Shin J, et al. Chromoblastomycosis ment. Med Mycol. 2009;47:3-15. Caused by Fonsecaea pedrosoi. Ann Dermatol. 2011;23:369-74. 10. Palmeira VF, Kneipp LF, Rozental S, Alviano CS, Santos ALS. Beneficial effects of 3. Yeung CK, Cheng VC, Lie AK, Yuen KY. Invasive disease due to Mucorales: a case HIV peptidase inhibitors on Fonsecaea pedrosoi: promising compounds to arrest report and review of the literature. Hong Kong Med J. 2001;7:180-8. key fungal biological processes and virulence. PLoS ONE. 2008;3:e3382. 4. Oh D, Notrica D. Primary Cutaneous mucormycosis in infants and neonates: case report and review of the literature. J Pediatr Surg. 2002;37:1607-11. 5. Spellberg B, Walsh TJ, Kontoyiannis DP, Edwards J Jr, Ibrahim AS. Recent advan- ces in the management of mucormycosis: from bench to bedside. Clin Infect Dis. 2009;48:1743-51 MAILING ADDRESS: 6. Mok CC, Que TL, Tsui EYK, Lam W. Mucormycosis in systemic lupus erythemato- Flávia Machado Alves Basilio sus. Semin Arthritis Rheum. 2003;33:115-24. 7. Sun HY, Singh N. Mucormycosis: its contemporary face and management strate- Rua General Carneiro, 181 gies. Lancet Infect Dis. 2011;11:301-11. Alto da Glória 8. Lewis RE, Pongas GN, Albert N, Ben-Ami R, Walsh TJ, Kontoyiannis DP. Activity of 80060 -900 Curitiba, PR Deferasirox in Mucorales: Influences of Species and Exogenous Iron. Antimicrob Agents Chemother. 2011;55:411-3. E-mail: [email protected]

How to cite this arti cle: Basilio FMA, Hammerschmidt M, Mukai MM, Werner B, Pinheiro RL, Moritz S. Mucormycosis and Chromoblastomycosis occurring in a patient with leprosy type 2 reaction under prolonged corticosteroid and thalidomide therapy. An Bras Dermatol. 2012;87(5):767-71.

An Bras Dermatol. 2012;87(5 ):767-71.