University of Alabama at Birmingham

Gorgas Case 2014-06

Universidad Peruana Cayetano Heredia
The following patient was seen by Course participants in the outpatient clinic of the Tropical Medicine Institute in Lima.
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History: 39-year-old male with a 5-year history of multiple sinus tracts in the left foot. An initial small painless ulcer on the sole of the left foot drained yellowish grains up to twice per week. No history of trauma. Two years before admission more sinus tracts developed on the dorsal, medial, and lateral aspects of the foot. The foot was painful with progressive inability to weight bear or walk. Sporadic episodes of fever predominantly at night but no weight loss were reported. 15 months earlier, after a biopsy at an outside hospital that was unavailable for review, a presumptive diagnosis of tuberculosis was made and the patient was treated with anti-TB drugs for 8 months with no improvement. More recently, he noticed more pain and extension of the sinus tracts to the upper part of the foot.

Epidemiology: Born and lives in Huánuco in the Andean highlands where he is a farmer. No alcohol, tobacco or illicit drug use. No risk factors for STDs. No known TB exposure.

Physical Examination: Afebrile; no lymphadenopathy or splenomegaly; otherwise unremarkable except for the findings in the left foot. Foot was non-tender and was not warm. Lateral [Image A], medial [Image B], and plantar [Image C] views of the foot are shown.

Laboratory Results: Hb: 13; WBC 7500 (N: 70%, L: 28%, E: 1%, M: 1%, Baso: 0%); Cr: 0.8; BUN 40. Chest x-ray normal. Left foot x-ray [Image D] and grains from sinus tracts [Image E] are shown.
Diagnosis: Botryomycosis due to Staphylococcus aureus.
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Discussion: The foot x-rays were reviewed with a bone radiologist and were normal. A culture of one of the yellow grains grew S. aureus, methicillin-sensitive. Fungal, and mycobacterial cultures were negative. Grossly the granules of botryomycosis are yellowish-white and 1-3 mm in diameter. A low power view of the biopsy [Image F] shows many blue stained granules in the center that are aggregates of cocciform bacteria together with scattered micro-abscesses with pus and sinuses (because of pus moving between micro-abscesses). A higher magnification of one of the granules [Image G] shows intense eosinophilic reaction between the granules (so-called Splendore-Hoeppli phenomenon). Ziehl-Neelsen, Grocott and gram stain of the biopsy were negative for Nocardia and fungus. Splendore-Hoeppli phenomenon (asteroid bodies) is the in vivo formation of intensely eosinophilic material (radiate, star-like, asteroid or club-shaped configurations) around microorganisms (may be fungi, bacteria and parasites) or biologically inert substances. The fungal infections include sporotrichosis, pityrosporum folliculitis, zygomycosis, candidiasis, aspergillosis and blastomycosis. The bacterial infections include botryomycosi and nocardiosis. The Splendore-Hoeppli reaction material comprises antigen-antibody complex, tissue debris and fibrin. If this were a mycetoma in Perú, one would expect to see distinct hyphae inside the black granules characteristic of Madurella mycetomatis or a related fungus. In actinomycetoma a silver stain would demonstrate very thin filamentous bacteria and a gram stain of the grains would show gram-positive bacteria.

Botryomycosis is an uncommon chronic bacterial infection with a global distribution in the tropics and non-tropics that is characterized by a granulomatous inflammatory response to bacterial pathogens [recent review Clin Dermatol. 2012 Jul-Aug;30(4):397-402]. The disease is characterized by the presence of granules containing a central mass of bacteria within an area of pus. In the tropics, clinically and histologically, botryomycosis can mimic both eumycetoma (Madura foot) [see Gorgas Case 2002-04] due to fungal etiologies (black grains) as well as actinomycetoma due to bacteria (Nocardia, Actinomadura [red grains], or Streptomyces [white/yellow grains]). Had the purulent lesion presented to us without the granule formation, other possible diagnoses would have included TB, sporotrichosis, malignancy or chronic osteomyelitis. Other uncommon subcutaneous mycoses include chromomycosis and lobomycosis. Up to one-third of cases of botryomycosis present with only deep visceral involvement, usually in debilitated patients.

Until Staphylococcus aureus was cultured from lesions in 1919, botryomycosis was believed to be fungal in nature, hence the name. The infection is uncommon but no specific incidence data is available. The literature consists of about 200 case reports and no large case series, but we have seen at least 5 cases in recent years suggesting it is not as rare as the numbers in the published literature. Staphylococcus aureus causes the majority of infections, followed by Pseudomonas aeruginosa and then a long list of other bacteria including Propionibacterium. Pathogenesis is not clear but limited animal work suggests that it is related to bacterial strain, inoculum of bacteria, and perhaps host immune response. The frequent findings of intracellular bacteria suggest a host immune defect. Most of the individual case reports have been in individuals with impaired T-cell immunity of one sort or another, including HIV infection as well as those with diabetes as well as liver disease, but again there are no systematic incidence studies. One of the cases we have seen was HTLV-1 positive. Visceral cases have been reported.

Our patient has responded well over several weeks to a combination of clindamycin and cotrimoxazole with decreased pain and cessation of drainage and granules from the sinus tract. There are no clinical trials to guide therapy or duration, so we will follow the clinical response but treat for at least a year. Debridement is sometimes necessary in non-responders.