European Journal of Epidemiology 18: 913–915, 2003. Ó 2003 Kluwer Academic Publishers. Printed in the Netherlands.
INFECTIOUS DISEASES
Acute brucellosis presenting with erythema nodosum Elias Mazokopakis1,2, Emilios Christias2 & Diamantis Kofteridis1 1
Division of General Internal Medicine, University Hospital, Heraklion Crete; 2Division of Internal Medicine, Naval Hospital of Athens, Greece Accepted in revised form 7 April 2003
Abstract. Brucellosis is a common world-wide zoonotic disease. Cutaneous manifestations are not specific and affect 1–14% of patients with brucellosis. We describe two cases of young males presenting with skin lesions of erythema nodosum on the anterior
surface of the legs. Histopathology of skin biopsy revealed septal panniculitis, but the positive cultures of blood or bone marrow for Brucella melitensis established the diagnosis of brucellosis.
Key words: Brucellosis, Cutaneous manifestations, Erythema nodosum
Introduction Brucellosis, a world-wide zoonotic disease, is a systemic infection caused by facultative intracellular bacteria of the genus Brucella that can involve many organs and tissues [1]. Cutaneous manifestations are not specific and their prevalence is reported to range between 1 and 14% of patients with brucellosis [2, 3]. This report is of two cases of brucellosis associated with lesions of the erythema nodosum (EN) type with a brief review of the relevant literature.
Case reports Case 1. A 33 year old shepherd was admitted to hospital, because of a 2-week period of intermittent low grade fever, fatigue, and painful subcutaneous erythematous nodules on the anterior surface of the left leg, which had appeared 3 days previous to admission. His personal and family medical history was unremarkable. There was no history of the use of drugs, consumption of unpasteurized dairy products or any type of infection during the preceding months. The physical examination was otherwise unrevealing. Laboratory tests showed the following values: hematocrit, 42%; WBCs, 12,000 cells/mm3 (neutrophils 82%, lymphocytes 17%, monocytes 0.4%); platelet count, 160,000 mm)3; erythrocyte sedimentation rate, 63 mm/hour; C-reactive protein, 73 mg/dl (normal: 0.08–0.8 mg/dl); normal biochemical parameters and urinalysis. An electrocardiogram, chest X-ray and an abdominal ultrasound scan were within normal limits. A tuberculin skin test, rheumatoid factor, serological tests for syphilis, leptospirosis, rickettsiae, chlamydia, mycoplasma, toxoplasma, CMV, EBV, HSV, HIV and hepatitis B and C were
negative. Brucella agglutinin titer was positive at 1:320 and the blood culture had grown Brucella melitensis by the fifth day. Histologic examination of the skin biopsy showed panniculitis involving inflammation of the septa in the subcutaneous fat tissue. After a putative diagnosis of brucellosis, the patient was administered doxycycline 100 mg per os twice daily for 6 weeks plus streptomycin 1 g im for the first 21 days, beginning on the third day of hospitalization, while waiting the serological and cultural confirmation. Ten days after the initiation of treatment, the skin lesions vanished. Case 2. A 32 year old man was admitted to hospital because of a 3-week period of intermittent fever, fatigue, malodorous sweating, headache and painful, subcutaneous erythematous nodules on the anterior surfaces of both legs which had appeared 5 days previous to admission. His medical history included hepatitis C and occasionally smoking marijuana. A record of the consumption of unpasteurized dairy products during the previous months was also reported. The physical examination revealed hepatomegaly which was confirmed by an abdominal ultrasound scan. Laboratory tests showed the following values: hematocrit, 38%; WBCs, 7700 cells/ mm3 (neutrophils 60.1%, lymphocytes 29.9%, monocytes 6.2%, eosinophils 1.4%); platelet count, 129,000 mm)3; erythrocyte sedimentation rate, 35 mm/hour; C-reactive protein, 2.8 mg/dl; alanine aminotransferase, 109 U/l; aspartate aminotransferase, 52 U/l; c-glutamyl transpeptidase, 40 U/l; alkaline phosphatase, 75 U/l; lactate dehydrogenase, 116 U/l; a normal urinalysis and negative rheumatoid factor. An electrocardiogram and a chest X-ray were both within normal limits. A tuberculin skin test, serological tests for syphilis, leptospirosis, rickettsiae, chlamydia, mycoplasma, toxoplasma, CMV, EBV,
914 HSV, HIV and hepatitis B were negative, but a positive hepatitis C antibody was revealed. Blood and urine cultures were negative, however, Brucella agglutinin titer was positive at 1:320, and bone marrow cultures, which had been obtained on admission, were positive for Brucella melitensis. Histopathology of a skin biopsy revealed septal panniculitis in the subcutaneous fat tissue with slight perivascular inflammatory infiltration by neutrophils and lymphocytes. After a putative diagnosis of brucellosis, the patient was administered doxycycline 100 mg per os twice daily for 6 weeks, plus streptomycin 1 g im for the first 21 days, beginning on the third day of hospitalization, while waiting the serological and cultural confirmation. Twelve days after treatment had been initiated the skin lesions vanished.
Discussion The cutaneous manifestations of brucellosis can be multiple and are due to direct inoculation, hypersensitivity phenomena, deposition of immune complexes, and direct invasion by the organism reaching the skin hematogenously [2–5]. Except for the welldefined cutaneous findings of exogenous character (as brucellar dermatitis and primary inoculation abscess) occurring in veterinarians and animal handlers [5, 6], a large variety of cutaneous manifestations of endogenous character have been reported in previous studies [2–5]. Ariza et al. [2] described four different clinical patterns in patients with brucellar skin lesions [disseminated erythematous/violaceous papulonodular eruption (most common), EN like lesions, diffuse maculopapular rash and extensive purpura], but vasculitis, liquefactive panniculitis, livedo reticularis and palmar erythema have also reported in other studies [3]. EN has been associated with many conditions (as bacterial, viral or fungal infections, drugs, sarcoidosis, inflammatory bowel disease, connective tissue diseases, Hodgkin’s disease, idiopathic, etc.) [7], but other forms of panniculitis can be manifested with similar skin lesions; especially nodular vasculitis (also called erythema induratum), Weber–Christian disease, subcutaneous infections due to bacteria or fungi, superficial thrombophlebitis, and cutaneous vasculitides [8, 9]. EN is presumed to represent a delayed hypersensitivity reaction to antigens associated with the various infectious agents, drugs, and other diseases with which it is associated, although the pathogenesis is largely unclear. Although EN has previously been described in patients with brucellosis [2, 3, 5, 10–14], few reports have described skin lesions of the EN type as being the main or only clinical manifestation of the disease. Ariza et al. [2], in a review of 436 patients with brucellosis, identified 27 patients (6%) with skin lesions
appearing during the initial episode of the disease or in relapse, and three of them (11% of patients with skin lesions) had EN-like lesions. Berger et al. [5] described a patient with fever of unknown origin who exhibited disseminated popular lesions, as well as EN-like deep dermal nodules on the legs, with the same granulomatous findings in both, and Ariza et al. [2] suggested that disseminated papulonodular lesions and EN-like lesions in patients with brucellosis share a common pathogenetic mechanism. Metin et al. [3], in a study of 14 patients with brucellar skin lesions (13.59% of patients with brucellosis), identified four patients with EN-like lesions. Diagnosis of brucellosis can be made by the detection or rise of specific antibodies at significant titers in serum specimens, compatible with the clinical findings. However, the isolation of the Brucella species from blood or marrow cultures, establishes the diagnosis of the disease [15, 16]. With acute Brucella melitensis infections, positive blood cultures can be obtained in about 95% of cases when proper culture media are used; bone marrow cultures give an even higher yield [15]. In conclusion, brucellosis is a preventable and readily treatable condition that must be considered in the differential diagnosis of patients with ‘fever and EN’ mainly of endemic areas and positive history of occupational exposure.
Acknowledgements The authors thank Prof. D. Boumpas for his critical comments.
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Address for correspondence: Elias E. Mazokopakis, Division of General Internal Medicine, University Hospital, Heraklion Crete, P.O. Box 1352, Voutes, Greece Phone: þ32-81-392-728; Fax: þ32-81-392-847 E-mail:
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