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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.79 no.4 Rio de Janeiro July/Aug. 2004
Localized eosinophilic panniculitis following intramuscular injection of pentavalent antimonium for treatment of american tegumentary leishmaniasis*
Manoel P Oliveira-NetoI; Marise MattosI; Tulia Cuzzi-MayaI; Claude PirmezII
IOswaldo Cruz Foundation - Evandro
IIOswaldo Cruz Foundation - Department of Biochemistry and Molecular Biology
Eosinophilic panniculitis may be induced by several
triggering factors and this syndrome is described here following the intramuscular
injection of antimonial compounds for treatment of American muco-cutaneous leishmaniasis.
Three patients, treated with intramuscular injections of pentavalent antimony (Glucantime®) were studied through clinical examination, histopathology and immunologic methods.
The three patients developed deep infiltrated plaques at the site of antimony injection. Histopathology disclosed a prominent inflammatory infiltrate of the subcutaneous fat with numerous eosinophils. Immunologic studies could not detect immunoglobulins or complement fractions in the lesions.
The final diagnosis was eosinophilic panniculitis occurring as a side-effect of antimonial therapy. The pathogenesis was not clear and it is suggested that the disease could be induced by a physical factor such as pressure or an immunological reaction to antimony.
Key words: antimony/adverse effects; leishmaniasis, cutaneous/therapy; panniculitis
Pentavalent antimony is the therapy of choice for leishmaniasis. Among the several side effects of this therapy, local phenomena of pain, swelling and discomfort following intramuscular administration are common.1,2 We describe three cases that developed erythematous and infiltrated plaques at the site of the pentavalent antimony injection employed for therapy of New World mucocutaneous leishmaniasis. The clinical picture was consistent with an acute cellulitis and histopathology showed an important eosinophilic infiltration of the subcutis. The relations with Wells' syndrome and eosinophilic panniculitis of Burket &Burket are discussed. To the best of our knowledge, this particular side effect of antimonial therapy was not previously described in the literature.
This 47-year-old woman was first seen in our hospital in 1997 complaining of an ulcerative lesion of left hand that was diagnosed as cutaneous leishmaniasis. Pathologic history disclosed arterial hypertension and toxoplasmosis (19 years ago during pregnancy). Leishmaniasis was treated with intramuscular injections of pentavalent antimonium at the dosage of 5mg of antimonium per kg of body weight and per day. The total amount of solution injected was 6ml per day. Therapy was scheduled for 30 days. In the eighth day of treatment she noted red plaques at the site of injections. The patient also complained of a faintness sensation appearing two to three hours after injections and lasting for about 20 minutes. The lesions were painless and slightly itchy. On clinical examination two lesions were noted on the left buttock: deeply infiltrated, edematous plaques, red-pink in color and with an orange peel surface (Figure 1). Therapy was stopped and the lesions cleared in two weeks leaving no trace. EKG, blood biochemistry and urinalysis were normal. The white blood cell count was 4,900 per mm3, with 71 neutrophils, 26% lymphocytes and 3% eosinophils. When plaque lesions appeared, a slight elevation - 7% - in eosinophil count was noted.
A 40-year-old woman with a history of cutaneous leishmaniasis and treatment with intramuscular injections of pentavalent antimonium at the dose of two ampoules (10 ml) per day. In the 18th day of treatment, erythematous plaques were noted at the site of injections. Patient complained of moderate pain and itching. Her doctor suggested a change in the site of injections and she began to apply the injections at the anterior region of the thighs. Similar lesions developed at the new location and the patient came to our attention. Clinical examination disclosed several infiltrated red plaques on buttocks and thighs. More recent lesions were red in color while older lesions showed a brownish hue. Medication was discontinued and the lesions gradually faded away. The patient refused a biopsy. The patient referred to allergic rhinitis of many years duration. EKG, blood biochemistry and urinalysis were normal. White blood cell count was 6,300 per mm3, 60% neutrophils, 32% lymphocytes and 4% eosinophils.
A 45-year-old man with mucosal leishmaniasis affecting the nasal mucosa and cavum was submitted to antimonial treatment at the dose of 5 mg/kg/day of antimony. Treatment was scheduled for 30 days. Total amount injected was 5 ml per day during 30 days. At the 10th day of treatment he noted erythematous lesions at the site of the injections. Patient was examined at the 16th day and presented a low-grade fever (37° C). At the right deltoid and left gluteal regions, erythematous and deeply infiltrated plaques were noted. The lesions were painless but highly pruritic. Intramuscular treatment was suspended and the intravenous route was used. The plaques gradually faded away and the patient had no further complaints. Pathologic history was not significant. EKG, blood biochemistry and urinalysis were normal. White blood cell count was 8,000 per mm3 with 41% neutrophils, 55% lymphocytes, 2% eosinophils. The eosinophil count showed a discrete elevation - 4% - during the active phase of the panniculitis reaction.
Biopsies, histopathology and immunohistochemistry studies
Punch biopsies were obtained from cases 1 and 3, fixed in formalin and paraffin embedded for histopathological examination. slides were stained with H&E. For better demonstration of eosinophils the picrosirius stain3 was performed. Direct immunofluorescence was performed in frozen skin fragments using anti-human IgA, IgE, IgG and IgM and the complement fractions C3 and C3b (Sigma, St. Louis, USA).
Histopathological examination of cases 1 and 3 disclosed a mixed, perivascular inflammatory infiltrate of lymphocytes, macrophages and eosinophils located in upper and deep dermis. In the subcutaneous fat the infiltrate had mainly a septal distribution and eosinophils were particularly numerous around blood vessels. Necrosis of vessel walls or fat necrosis was not detected. Epidermal changes were represented by focal parakeratosis, acanthosis and spongiosis, the latter particularly evident in case 1 where intraepidermal vesicles were noted (Figures. 2, 3 and 4). Immunofluorescence studies were negative for all antibodies employed.
The panniculitis were recently reviewed by Peters and Su, 1992.4 Among the various types described by these authors, three of our cases should be considered: (i) traumatic, (ii) drug induced and (iii) eosinophilic panniculitis.
Traumatic panniculitis may be caused by a variety of exogenous factors like trauma with blunt objects5,6 or injection of foreign substances such mineral oils, silicone and drugs. Factitial lesions induced by self-injection of drugs, e.g. meperidine hydrochloride7 or intentional hits inflicted on the skin surface3 could also be considered as belonging to this group.
Drug injection induced-panniculitis include povidone, pentazocine, vitamin K15,6 and the well-known cases following insulin or steroid injections. Korting12 described a case following injection of a streptococcal vaccin, and Förström and Winkelmann6 a case of panniculitis developing at the site of a tetanus toxoid injection. In all these cases (traumatic, factitial or drug-induced) histopathology showed inflammatory infiltrate with many polymorphonuclear leukocytes and no, or only occasional, eosinophils.
Eosinophilic panniculitis is a septal panniculitis according to the classification of Black and Cunliffe13 ccharacterized by a significant infiltration of subcutaneous fat with eosinophils. It has been associated with a great variety of clinical conditions, such as: streptococcal infection,14 olyarteritis nodosa, arthropod bites, gnasthostomiasis,15 datopic dermatitis,16 diabetes mellitus,17 oral administration of non steroid anti-inflammatory drugs,18 infiltration of subcutaneous tissue with gabexate mesilate19 and injection of a tetanus vaccine.20 Among the 18 patients studied by Winkelmann and Frigas,21 three cases were classified as "injection granuloma" associated with narcotic dependency. These authors support the viewpoint that eosinophilic panniculitis is a non-specific finding that can signify either a localized disease, such as insect bites and injection lipophagic granuloma, or systemic diseases like systemic lymphoma or immune reactive disease, as many patients in their series have a past history of atopy and/or contact dermatitis.
Eosinophilic cellulitis or Wells' syndrome is an idiopathic skin disorder first described by Wells in 197122 cas a recurrent dermatosis. Clinically the disease resembles infectious cellulitis but not responding to antibiotic therapy and with the pathologic findings of eosinophilic panniculitis, characteristic dermal flame figures and granulomas. Wells and Smith in 197923 speculated that different antigens might trigger the syndrome. Nowadays, many authors support the viewpoint that eosinophilic cellulitis appears to be a hypersensitive response to various antigens.24-27 Therefore, a typical Well's syndrome can be excluded here since the disease is not recurrent and dermal flame figures and granulomas are lacking. The condition showed by our patients may be considered as a drug-induced panniculitis through a direct, local effect of the drug, in the present cases the pentavalent antimony solution. A pressure panniculitis should also be considered, since the volume of the solution injected is usually high. The subcutaneous fat is vulnerable to a great number of noxious insults: despite the fact that fat cells have a rich capillary blood supply, there are no lymphatics and a small amount of connective tissue. Also, the vessels have a slow flowing. The sequence of events following an injury to subcutis is initiated by infiltration of neutrophils and/or eosinophils.13 The reaction is initiated by tissue-resident mast cells, releasing inflammatory mediators such as histamine and others. The stimulus may be immunologic (IgE dependent) or nonimmunologic such as degranulation substances in the case of insect bites or physical factors as rubbing and/or pressure.25 Since the immunologic studies carried out in our cases failed to demonstrate immunoglobulins or complement fractions, the latter mechanism is more likely to be involved in the pathogenesis of our cases. Nevertheless, an immunological reaction to the drug could not be entirely discarded. Antimony, as a trioxide, has been reported to be a sensitizer causing allergic contact dermatitiss and urticaria was described during pentavalent antimony therapy.29 In cases 1 and 2, the interruption of therapy was followed by clinical cure, but in case 3 the patient had continued the therapy by intravenous route and this procedure also leads to the cure. This is not surprising since the site to which an antigen is delivered may be the determining factor of an antigenic response or not.30 Clinically our cases resemble those described following phytonadione injection.31 Two types of reaction to phytonadione have been described: an eczematous, pruritic, erythematous, indurated, or urticarial plaque developing at the site of injection about 14 days after the injection and a sclerodermoid plaque, the so called Texier disease,32-34 that may appear long after the injection and occasionally persists.
In conclusion, the intramuscular injection of pentavalent antimony may be one of the triggering factors for the development of eosinophilic pannicullitis. These lesions represents the response of a fragile tissue as the subcutaneous fat to the presence of a heavy metal and, although the pathogenesis is not clear, probably result either from a non-specific stimulus such as pressure or an antigenic reaction.
This paper was supported by a grant from FAPERJ (Fundaç&aatilde;o de Amparo a Pesquisa do Estado do Rio de Janeiro) grant number E-26/170.825/95
We are grateful to the technicians Marcelo B. Meuser, Luzia F.G. Caputo, and Ester M. Mota (Oswaldo Cruz Institute) for histological and immunological preparations.
Pictures were provided by the Laboratory of Image Processing (Oswaldo Cruz Institute) - technicians Genilton José Vieira and Heloisa Diniz.
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Manoel Paes Oliveira-Neto
Fundação Oswaldo Cruz
Av. Brasil, 4365
21045-900 Rio de Janeiro RJ
Tel./Fax: (21) 2590-9988
Received on October 19, 2001.
Approved by the Consultive Council and accepted for publication on August 07, 2002.
* Work done at Oswaldo Cruz Foundation - Evandro Chagas' Hospital.