Case Report: Osteomyelitis Due to Sporothrix brasiliensis in Two Immunocompetent Patients Requiring Surgical Amputation

ABSTRACT.

Sporotrichosis is the most frequent subcutaneous mycosis in Latin America. Sporothrix brasiliensis is the most virulent species, responsible for the majority of human and animal cases in Brazil. Osteomyelitis was described as a potential comorbidity of S. brasiliensis infection; however, surgical amputation resulting from an extracutaneous form is a rare outcome. In such cases, immunodeficiency and alcoholism must be investigated. We present two unusual cases of surgical amputation as a severe morbidity resulting from osteomyelitis by S. brasiliensis in immunocompetent nonalcoholic patients.

INTRODUCTION

Lymphocutaneous and fixed cutaneous forms represent the commonest clinical presentations of sporotrichosis,¹ whereas extracutaneous forms often affect immunocompromised individuals such as HIV-infected persons and alcohol abusers.² However, after the Brazilian outbreak in the mid-1990s, an increase in the number of non-immunocompromised patients with atypical and severe forms has been reported.^3–9 Osteomyelitis was previously described as a potential comorbidity of Sporothrix brasiliensis infection; on the other hand, surgical amputation as a morbidity resulting from an extracutaneous form is a rare outcome.^10,11 We describe two patients with fast-evolving osteomyelitis by S. brasiliensis who underwent surgical amputation of the left chirodactyl first phalanx secondary to lymphocutaneous forms: one 55 days after rescuing a stray diseased cat and the other after 52 days of trauma caused by wood matter during gardening.

Case 1.

A 78-year-old Caucasian woman presented to the Human Sporotrichosis Reference Clinic – Hospital Universitário Antônio Pedro (HSRC-HUAP), Niterói, Rio de Janeiro, Brazil, on February 26, 2016 (Day 0; Supplemental File 1), complaining of an erythematous and painful lesion on the left thumb (Figure 1). She was bitten by a diseased cat 30 days before, referring to it as the cause of the trauma. The patient had previously received cephalexin 2 g/day therapy for 10 days, with progressive worsening of the wound. Comorbidities were high blood pressure and dyslipidemia. Skin examination revealed an extensive ulcerous lesion with significant necrotic content in the left thumb accompanied by slightly erythematous small nodules ascending the regional lymphatic pathway on the ipsilateral forearm (Figure 1). An empiric treatment based on itraconazole 200 mg/day was prescribed, and a skin biopsy and mycological culture were performed (Day 0). The isolate was later genotyped as S. brasiliensis.

Figure 1.

Patient’s lesions as presented at Day 0 in the Human Sporotrichosis Reference Clinic, Niterói, Rio de Janeiro, Brazil. Left fingers and ipsilateral lymph nodes fistulas on the forearms of Case 2 (A and C) and Case 1 (B and D), respectively.

Patient admission to the Infectology Service of HUAP occurred on March 3 (Day 5). Routine laboratory exams showed anemia and increased serum C-reactive protein. Serology testing was nonreactive for HIV-1 and HIV-2. An SsCBF ELISA diagnostic test provided an IgG titer of 12,800 (reagent). Monitoring of white blood cell counts (WBCs) showed no abnormalities (WBC mean count of 8,390/mm³). Serial tests of blood glucose after 12 hours of fasting showed values inferior to 100 mg/dL. No current or previous use of insulin or hypoglycemiants was registered. Radiography of the left hand showed an ostial lesion on the medulla region in the thumb distal phalanx (Figure 2). A treatment regimen based on intravenous amoxicillin and potassium clavulanate was prescribed to treat secondary bacterial infection.

Figure 2.

Image diagnosis. (A) Scintigraphy using (99m) Tc-labeled methylene diphosphonate attested to bone involvement at Day 11 in Case 1 (Left panel: Phase I of the three-phase Bone Scintigraphy - Front Up Member. The thin black arrow indicates the radioactive tracer access point. Right panel: Phase III where the green arrow points to the distribution of the radioactive tracer in the affected bone area by increased radio-label uptake. Blue arrows mark the infectious/inflammatory process of the ascending lesions in soft tissues). (B) X-rays of left hands show an ostial lesion on the medulla region in the thumb distal phalanx of Case 1 on Day 5 (left panel, red arrow) and Case 2 on Day 7 (right panel, green arrow).

On March 8 (Day 11), because of the unsatisfactory clinical response, the patient underwent surgical debridement, and the antibacterial protocol was changed to intravenous cefepime and vancomycin. Also, the Nuclear Medicine Department (HUAP) attested to bone involvement of the left thumb distal phalanx and extensive damage to soft parts in the left hand and forearm by means of bone scintigraphy (Figure 2). Treatment with liposomal amphotericin B 350 mg/day was added to the azole in the antifungal therapeutic regimen.

Later, her signs and symptoms became aggravated with severe pain, expansion of tissue damage, acute renal dysfunction, and risk of progression of the bone lesion. Cefepime and vancomycin were replaced by meropenem and linezolid. To prevent the spread of osteomyelitis, on March 17 (Day 20) the surgery department decided to perform the amputation of the left thumb. The surgical intervention was performed without complications (Day 25). The patient was discharged on Day 33 with a prescription for itraconazole 400 mg/day. Almost 4 months later (Day 102), a new bone scintigraphy supported the decision for oral treatment interruption. After 3-year follow-up, the patient was discharged without recurrence.

Because of an unsatisfactory clinical response to antifungal treatment, we investigated an S. brasiliensis in vitro susceptibility profile, and the minimum inhibitory concentrations (MICs) were determined. A suggestive susceptible phenotype to terbinafine and to all azoles and echinocandins was detected, whereas the amphotericin B MIC (8 µg/mL) was compatible with a resistant phenotype, as previously proposed¹² (Supplemental File 2).

Case 2.

A 37-year-old saleswoman from Rio de Janeiro presented to the HSRC-HUAP on November 4, 2016 (Day 0; Supplemental File 1), complaining about numerous “lumps” in her left forearm and an painful lesion on her ipsilateral thumb. These symptoms had begun 30 days earlier as a result of a wood-spine injury during gardening. Also, the patient noted previous contact with a diseased feline, denying trauma. Oral cephalexin (10 days), ciprofloxacin (6 days), and nonsteroidal anti-inflammatory drugs were administered without clinical response. Fibromyalgia was a comorbidity.

The skin examination revealed erythematous-exudative vegetation in the distal phalanx region of the left thumb, with clear tissue loss and ipsilateral ascending noduloulcerative lesions (Figure 1). Empiric treatment with itraconazole 200 mg daily was initiated (Day 0), and a radiography of the left hand was requested followed by a skin biopsy of the lesion. Histopathology and mycological culture analyses confirmed sporotrichosis with the isolation and later genotyping of S. brasiliensis (Supplemental File 2).

On November 11 (Day 7), a radiographic image (Figure 2) suggesting a medullary lesion on the left thumb’s distal phalanx required hospitalization to institute intravenous antifungal treatment. Histopathologic evaluation was compatible with sporotrichosis. On November 17 (Day 13), the patient was admitted to the Infectology Ward of Hospital Universitário Pedro Ernesto, Rio de Janeiro. Initial and subsequent monitoring of red and white cell counts showed no abnormalities (WBC mean count of 10,175/mm³). Serial tests of blood glucose after 12 hours of fasting showed values inferior to 100 mg/dL. The patient was not receiving treatment with insulin or hypoglycemiants. Serology testing was nonreactive for HIV, toxoplasmosis, and cytomegalovirus. The SsCBF ELISA diagnostic test provided an IgG titer > 51,200 (reagent). Treatment with amphotericin B 350 mg lipid complex was added to the itraconazole antifungal regimen.

On November 22 (Day 18), computed tomography revealed ostial rarefaction and lytic areas in the left thumb distal phalanx, compatible with osteomyelitis. An evaluation via general surgery was requested, and 4 days later (Day 22) the patient underwent partial amputation of the distal phalanx, including the nail bed, to prevent ascending infection and sepsis. On December 13 (Day 43), the patient was discharged with recommendations to continue the itraconazole 400 mg/day treatment and monthly follow-up. After a year, itraconazole was discontinued, although follow-up continued bimonthly for another 12 months, when she was discharged without recurrence.

As a possible explanation for the patient’s poor clinical response to treatment, MICs to antifungal drugs were determined to investigate this isolate susceptibility profile. A suggestive susceptible phenotype to terbinafine, to all azoles, and to echinocandins was verified. In contrast, an MIC of 8 µg/mL was indicative of “resistance” to amphotericin B, as proposed¹² (Supplemental File 2).

DISCUSSION

One hundred sixty-two bone infection cases caused by Sporothrix were reported between 1924 and 2022, but this is the first study to describe surgical amputation as a morbidity resulting from an extracutaneous form of sporotrichosis in immunocompetent hosts.^13–19 We report two cases of S. brasiliensis osteomyelitis from a Brazilian hyperendemic area of very serious manifestation to the point of demanding extreme measures in a short time, assisted by two different teams that did not communicate during clinical management. Bone tissue can be infected primarily by contiguity with other nearby tissues or through blood flow. Fungi and bacteria can invade the bone, leading to an inflammatory process and resulting in damage of varying severity.^20,21

Osteomyelitis is best managed by a multidisciplinary team.²¹ In the present cases, both lesions started in the extremities of the fingers as cutaneous forms of sporotrichosis that, possibly owing to the scarcity of subcutaneous tissue in the region, evolved to a contiguous bone presentation. In all, 162 cases of osteomyelitis caused by Sporothrix spp. have been reported since 1902, with manifestations ranging from mild aggression within the osteoarticular system to severe bone destruction and chronic disease. However, to the best of our knowledge, severe morbidity demanding amputation of the affected bone is infrequent. Also, the previous reports focused on complications in the United States, where sapronosis by Sporothrix schenckii and occupational transmission prevailed.^{11,14,15,17,22–25} In Brazil, sporotrichosis by S. brasiliensis, considered the most virulent species of the genus, is eminently a cat-transmitted zoonotic hyperendemic.²⁶ Although sporotrichosis represents a unique mycosis of compulsory notification in Brazil,²⁷ the scarcity of reports of osteomyelitis by Sporothrix spp. in this country of continental proportions suggests underreporting and diagnostic difficulties that can aggravate this neglected mycosis.²⁸ In a recent paper, 41 cases of osteomyelitis were investigated at a referential hospital in a Brazilian hyperendemic area¹¹ in which three patients for whom amputation was a resulting morbidity were described. However, unlike the two female patients from the present report, the three amputations after osteomyelitis due to Sporothrix occurred in one HIV-positive and two diabetes mellitus individuals. The cases we report draw attention to the speed in which S. brasiliensis can cause such severe damage in immunocompetent hosts. In these two cases, the need for amputation, a last resort for osteomyelitis resolution, suggests that this species may present distinct behavior of S. schenckii in bone tissue infections, causing serious morbidities that were not properly diagnosed. The patients’ proximity suggests a potential common factor, which could be inherent to the virulence of the isolated strains or even to sharing of the same genetic traits of individual susceptibility.^28,29 Neither patient showed evidence of clinical response to the usual treatment with amphotericin B; for this reason, the surgical team opted for amputation.

More studies are needed to identify cases of severe sporotrichosis caused by resistant strains. Nevertheless, this will be challenging as there are no consensus protocols for dimorphic fungi antifungal susceptibility testing. There is also a pressing need for further investigation regarding the interaction between S. brasiliensis and its hosts, which could clarify the severity we observed. In addition, it is noteworthy that the Brazilian hyperendemic scenario favored the higher frequency of clinical atypia,^7,8 hindering early diagnosis and appropriate therapy. Under these circumstances, it is essential that primary care health teams be prepared to investigate sporotrichosis in cases of unusual clinical presentation, using clinical and epidemiological history as guiding lights to formulate clinical hypotheses.

Financial Disclosure

This work was supported by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ - E-26/010.001882/2014), Rede Micologia RJ, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES Finance Code 001), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (W. M. D. and I. G. C. S. were granted PIBIC/CNPq scholarships; A. R. S. B. and R. L. D. M. are research fellows of CNPq, Brazil).

Note: Supplemental material appears at www.ajtmh.org.