Painless swelling of the forefoot and recurrent subcutaneous abscesses of the lower leg – two distinct presentations of eumycetoma Adrian Schibli 1, Daniel Goldenberger 2, Andreas Krieg 6, Anna Hirschmann 3, Elisabeth Bruder 4, Michael Osthoff 5 1 Triemli Hospital, Division of Infectious Diseases & Hospital Epidemiology, Zürich, Switzerland; 2 Division of Clinical Microbiology, 3 Clinic of Radiology and Nuclear Medicine, 4 Pathology and 5 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland; 6 Division of Orthopedics, University Children’s Hospital Basel, Basel, Switzerland.

Introduction Case 2

• Eumycetoma is a neglected tropical disease that is characterized by chronic progressive local • 21-year old Eritrean migrant with progressive pain and swelling of his left ankle, who left Eritrea 4 inflammation of subcutaneous tissues with sinus formation and purulent discharge. months before presentation in Switzerland with stopovers in Sudan, Libya and Italy. • Although the infection evolves from a small subcutaneous nodule, patients often present late with • He reported recurrent local infections on his left foot since the age of 10 treated with dressings only. advanced disease. • On examination, a painful fluctuation was noted below his medial ankle (Fig 3A) in addition to multiple • Eumycetoma is endemic in tropical and subtropical countries, in particular in Sudan and the Indian scars. Subsequently the abscess was drained and sent for culture. subcontinent, whereas it is diagnosed infrequently in temperate climate zones. * * • Abscess cultures flagged positive with a mold (Fig. 4), which was identified as Madurella mycetomatis by • We report two cases of eumycetoma, one early and one late presentation , both diagnosed in a non- panfungal PCR and sequence analysis. endemic country (Switzerland). • Resistence testing indicated susceptibility to amphotericin B, itraconazole, posaconazole and voriconazole. • MR imaging demonstrated residual infection with a pathognomonic appearance (Fig. 3B). • Treatment was initiated with itraconazole 100mg bid which resulted in marked pain reduction after 4 Case 1 weeks. • Unfortunately, the patient was transferred back to Italy and lost to follow-up. • 41-year old Indian man with a painless, slowly progressive (3 months) swelling on his left forefoot (Fig 1A); no constitutional symptoms; last visit to the Indian subcontinent in 2008. • MRI showed an interdigital mass (25 x 27 x 43 mm) with marked capsular contrast enhancement (Fig 2A) and no evidence of osteomyelitis. • Surgical resection was performed owing to a preliminary diagnosis of a soft tissue tumor, and purulent liquid and particles of black granular texture were evacuated. • Histological examination showed fragments of black grain (Fig 2B) with an inflammatory reaction characterised by focal necrosis and giant cells surrounding fungal hyphae (Fig 2C-E) • Panfungal polymerase chain reaction (PCR) of the formalin-fixed paraffin-embedded tissue and Figure 2 . Case 1. (A) Large polycyclic cystic intermetatarsal mass surrounded by a thick wall (MRI). (B) Macroscopic sequence analysis (ITS1 and ITS2) was consistent with Madurella mycetomatis as the causative agent. aspect of a paraffin block revealing multiple black granules in an oval zone of necrosis (arrow), surrounded by a wall of granulation tissue (asterisk). (C) Wall of fibrous tissue (asterisik , H&E stain). (D) Necrotizing inflammation with • Treatment consisted of itraconazole 100mg bid for 6 months with regular therapeutic drug monitoring. epitheloid-giant cells (arrow, H&E stain) (E) Fungal hyphae (double arrow; Grocott's Methenamine Silver stain). • The patient showed no evidence of relapse 30 months after cessation of antifungal treatment (Fig 1B)

Fig 4: Case 2. Agar plate of the Madurella Fig 5: Map of the global distribuation of mycetoma in 2013. mycetomatis isolate producing a brownish Zijlstra EE et al., Lancet Infect Dis 2015. diffusible pigment in the agar.

Conclusion

• This presentation is a useful reminder for clinicians to consider epidemiological clues for eumycetoma in the differential diagnosis of painless soft tissue swellings or recurrent subcutaneous abscesses, in particular of the lower leg. • Clinicians in countries currently hosting refugees from tropical areas of Africa and Asia need a high index of suspicion for this uncommon infection (Fig. 5). • Panfungal polymerase chain reaction may serve as a powerful tool to identify the causative agent of eumycetoma, in particular if culture is not available. • Treatment of eumycetoma necessitates an interdisciplinary approach with surgeons, radiologists and infectious diseases physicians being involved.

Figure 1 . Case 1 . Clinical presentation (A) before surgery: soft tissue swelling of the left forefoot. Figure 3 . Case 2 . (A) Clinical presentation after drainage of the subcutaneous abscess (arrow). (B) Diffuse inflammation of the soft tissue Conflict of interest: none (B) after surgical and antifungal treatment. and a pathognomonic central hypointense dot (arrow) surrounded by hyperintensities reflecting the grain (T2 fat-saturated MR image). Contact details: Michael Osthoff, M.D., University Hospital Basel, Basel, Switzerland, email: [email protected]