Case Report: Invasive Sinusitis due to Sporothrix Brasiliensis in a Renal Transplant Recipient

ABSTRACT.

Sporotrichosis is usually a subcutaneous infection caused by thermodimorphic fungi of the genus Sporothrix. The disease occurs worldwide, but endemic areas are located in tropical and subtropical regions. The epidemiology of sporotrichosis in Brazil is peculiar because of the cat’s entry in the chain of transmission of this mycosis, associated with Sporothrix brasiliensis, the most virulent species in the genus. Sinusitis caused by Sporothrix species is unusual and may be underdiagnosed or confused with other fungal etiologies, like mucormycosis. We report a case of sinusitis due to a Sporothrix species in a 6-year renal transplant recipient. Direct examination of smears of exudate of the sinus specimen (aspirate, biopsy) revealed budding yeasts and cigar-shaped cells. Sporothrix was subsequently recovered from the patient’s exudate culture and identified as S. brasiliensis using species-specific polymerase chain reaction, and she was successfully treated with antifungal therapy. Her parents also developed the disease a week later, both only cutaneous involvement. Sporotrichosis sinusitis is a rare disease, even in immunocompromised patients. Diagnosis is crucial, and benefits from good epidemiological history.

CASE PRESENTATION

We report a case of a 38-year-old female type 1 diabetic kidney transplant recipient who presented to the emergency service in November 2019 with acute facial pain, headache, mild cough, and nasal obstruction for 3 days. No fever or skin lesions were related. The patient had undergone a deceased donor renal transplant 6 years prior, and her immunosuppression regimen included tacrolimus, sirolimus, and prednisone. She had a history of several hospitalizations for urinary tract, skin, and soft tissue infections. The patient is a veterinarian but has not exercised her profession for many years. She lives in São Paulo and has several pet cats, with close contact also sharing bed, one of which died of sporotrichosis 2 weeks before the hospitalization.

After an initial evaluation, the patient was admitted for intravenous antibiotics. There was no leukocytosis or increase of C-reactive protein (CRP). Blood cultures later came negative, and symptoms did not improve after 14 days of treatment.

Nasopharyngoscopy evaluation revealed purulent discharge and crusts, with no mass or polyps. A computed tomography (CT) scan showed mucosal thickness and a soft tissue mass filling both maxillary sinuses, mainly at the right. Magnetic resonance imaging (MRI) also showed thickening and enhancement of the paranasal and maxillary sinuses, protruding to the right (Figure 1). As facial pain and mucopurulent discharge worsened, antifungal therapy with 7 mg/kg/day of liposomal amphotericin B was added to treat presumptive mucormycosis, and the patient underwent sinusectomy. Histopathological analysis showed chronic granuloma formation with no yeasts visualized with Grocott’s methenamine silver stain. Because of the worsening of renal function with the need for hemodialysis, liposomal amphotericin was switched to posaconazole, and sirolimus was discontinued. After 10 days of antifungal therapy, we received the sinus culture results, in which grew Sporothrix species. Here, we applied a species-specific PCR assay to identify medically relevant Sporothrix species based on sequence polymorphisms from the calmodulin gene as previously described.¹ The amplification of a single band of 469 bp using the primers Sbra-F and Sbra-R identified both isolates as S. brasiliensis. Additionally, molecular characterization of the mating-type locus revealed that the isolate harbors a MAT 1-2, the same genotype that emerged in the outbreak in Rio de Janeiro.¹

Figure 1.

Magnetic resonance images showing thickening and enhancement of the paranasal and maxillary sinuses, protruding to the right. (A) Coronal section. (B) Axial section.

After 2 months of posaconazole therapy, symptoms improved, and nasopharyngoscopy showed no lesions. She was discharged on oral itraconazole therapy, to be used for 10 more months. One month after discharge, the renal function improved and hemodialysis was stopped. The patient had two hospitalizations for another reason, and after the itraconazole treatment she was seen in the outpatient clinic. No symptoms or relapse have been related.

Two weeks before admission, her cat died of sporotrichosis despite treatment with itraconazole. She also has a dog that developed the disease and was also treated with itraconazole with full recovery. One week after the patient’s hospital admission, her father, a 70-year-old man with a medical history of type 1 diabetes, developed the lymphocutaneous form of sporotrichosis, and her mother, a 64-year-old obese woman, presented the fixed cutaneous form. Both parents had contact with the affected animals and were both treated with itraconazole.

DISCUSSION

To our knowledge, this is the first case of rhinosinusitis caused by a Sporothrix species in a kidney transplant recipient reported in the literature. Moreover, the first case of rhinosinusitis caused by S. brasiliensis, a species responsible for epizooties in domestic cats and consequently massive zoonotic transmission to humans since the 2000s.²

Acute rhinosinusitis is a common infection in adults, accounting for more than 1 in 5 antibiotic prescriptions in the United States. Bacteria and viruses are the most frequent cause of rhinosinusitis, but fungi have been increasingly recognized as emerging agents, especially in tropical areas.³

Fungal rhinosinusitis comprises a spectrum of disease processes, which vary in clinical presentation, histologic appearances, and biological significance, probably depending on the variety of host interactions and mechanism of fungal tissue invasion.⁴ Aspergillus spp. is the most common agent, but other fungal species such as Cryptococcus spp., Candida spp., Mucorales, Fusarium spp., and Scedosporium spp. have been reported, mainly in HIV-AIDS patients.^4,5

Sporotrichosis is caused by the dimorphic fungus of the genus Sporothrix, first isolated in 1898. In Latin America, sporotrichosis is the most frequent subcutaneous mycosis and has emerged as a significant fungal infection over the last two decades.⁶ The estimated prevalence rates of sporotrichosis range from 0.5% to 1% in Brazil.^7,8 Most of the registered cases in Brazil are concentrated in Rio de Janeiro, and it is a significant cause of hospitalization in the state.^9,10

Sporothrix spp. lives saprophytically in nature, usually associated with plants, and can be isolated from soil and plants. It is usually an occupational disease affecting miners, forestry workers, gardeners, and florists. Some animals have been associated with the zoonotic transmission of sporotrichosis.

There are two important disease transmission routes for humans in Brazil, a sapronotic route involving direct contact with the soil and decomposing organic matter; and a zoonotic route, through cats. Feline sporotrichosis is unique among infections caused by endemic dimorphic fungi because it is directly transmitted in the yeast phase. The feline lesions typically harbor a high yeast-like fungal burden that can be acquired via cat scratches and bites, by nontraumatic ways, such as a cat’s cough or sneezing, and direct contact between patients integumental barriers and animal secretions.⁶ Sporothrix brasiliensis, the most virulent species of the genus, is the primary agent of zoonotic sporotrichosis in Brazil.¹⁰

The virulence profiles change depends on the pathogen characteristics and the host defenses. The average incubation time is 3 weeks. It is usually a cutaneous or subcutaneous infection but can progress to lymphatics, fascia, muscles, cartilage, and bones. It is associated with morbidity but rarely associated with mortality. The disease may evolve into different clinical forms, cellular and humoral immune responses, mode of inoculation, and fungal virulence appear to interfere with the clinical form of the disease.¹¹

In this case, the decreased cellular and humoral immune response of the patient due to the use of immunosuppressive agents, diabetes, and the intimal contact with the cat appear to be determinant to the clinical presentation. The transmission route was probably from inhalation of Sporothrix propagules and posterior spread to paranasal sinus mucosa and bone.¹² mTOR (mammalian target of rapamycin) inhibitors, such as sirolimus taken by the patient, and tacrolimus suppress T-cell proliferation.^13,14 Decreased chemotaxis, phagocytic, and killing activities of macrophages and neutrophils were described in uncontrolled diabetic patients.¹⁵

Fungal rhinosinusitis related to Sporothrix spp. is very uncommon and remains anecdotal as only six reports have been published between 1963 and 2016. In these six reports, four involved immunocompetent patients,^12,16–18 while the other, patients that were immunocompromised: diabetes,¹⁹ HIV,²⁰ hematological neoplasias, and use of steroids.¹⁸ Pulmonary involvement seems to be more common, there are several related cases, and it was suggested that the infection occurred through inhalation of the fungal conidia as well, usually in immunocompromised patients.^21,22 What would make the fungus establishes a sinus or pulmonary infection is not known.

Opportunistic infections are common in organ transplant patients, where fungal infections comprise approximately 5% of all infections, mostly by Candida species, Aspergillus species, and Cryptococcus neoformans complex.²³ There are few cases reported of sporotrichosis in transplant recipients.^23–36 Most of them in kidney transplant patients,^{23–25,28,29,33,34} and disseminated, as pulmonary and cerebral involvement, as shown in Table 1. Among solid organ transplant patients, sporotrichosis has been mostly reported in kidney transplantation, probably because it is the most frequent organ transplant carried out worldwide. To our knowledge, no case of sporotrichosis with sinusitis in a kidney transplant patient was described.

Table 1.

Cases of sporotrichosis in renal transplant recipients previously reported

Author/year	Age, years/gender	Clinical manifestation	Time after transplantation	Treatment
Gullberg et al., 1987	50/male	Cutaneous, osteoarticular, neurological	4 years	AMB-d
Agarwal et al., 1994	23/male	Urinary tract	9 months	None
Rao et al., 2002	49/female	Nasal mucosa	6 months	None
Caroti et al., 2010	59/male	Cutaneous, osteoarticular	Unknown	FLZ
Gewehr et al., 2013	48/female	Cutaneous	9 months	AMB-L, ITZ
	53/male	Cutaneous, osteoarticular	1 month	AMB-L, ITZ
Amirali et al., 2020	43/male	Cutaneous	10 years	ITZ
	56/male	Neurological, pulmonary	17 years	AMB-d; ITZ
Fichman et al., 2020	41/female	Cutaneous, oral, and nasal mucosa	Unknown	AMB-d, AMB-L, ITZ, TRB
	34/male	lymphocutaneous	Unknown	TRB+ITZ
	51/male	lymphocutaneous	Unknown	TRB
	43/male	Cutaneous, oral, and nasal mucosa, osteoarticular	Unknown	AMB-L, ITZ
	42/male	lymphocutaneous	Unknown	ITZ
	54/male	lymphocutaneous	Unknown	TRB

AMB-d = amphotericin B; AMB-L = liposomal amphotericin B; FLZ = fluconazole; ITZ = itraconazole; TRB = terbinafine.

Azotemia occurs in 80% of patients who receive amphotericin for deep mycoses, with dose-dependent toxicity, the lipid formulation is less nephrotoxicity and should be preferred in kidney transplant patients.³⁷ Nevertheless, unfortunately, our patient required dialysis even after receiving the lipid formulation.

Because sinusitis sporotrichosis in the immunocompromised patient can have an extended incubation period and may go undiagnosed for a long time before worsening symptoms, its diagnosis remains challenging. The gold standard and the most reliable laboratory tool is the culture since serology is often not available. Moreover, the clinical presentation is atypical for Sporothrix spp., and no clinical distinction from sinusitis caused by other microbial and fungus agents, a broad differential diagnosis. Treatment consists of long-term use of antifungal drugs such as terbinafine, itraconazole, posaconazole, or amphotericin B. There are no clinical trials to guide therapy for disseminated sporotrichosis in immunosuppressed hosts, and some cases need life-long suppressive therapy.³⁸

In conclusion, sinusitis sporotrichosis is a rare condition, and therefore the absence of specific symptoms can lead to possible confusion with other opportunistic agents, mainly in immunocompromised hosts. Therefore, the epidemiological history and biological confirmation are essential for the correct diagnosis.