Rhodotorula fungemia in a patient with acute lymphoblastic leukemia

Objectives: Rhodotorula is an environmental yeast that belongs to Basidiomycota Phylum. Rhodotorula species are ubiquitous in nature, can be found in soil and freshwater. Immunocompromised patients can develop Rhodotorulosis due to wide-ranging exposure to Rhodotorula in the hospital environment. Case Discussion: The patient was a 3-year-old male with a diagnosis of Pro B-Acute Lymphoblastic Leukemia (ALL). He was admitted to the hospital with complaints of malaise, fatigue, weight loss, and diarrhea between courses of chemotherapy. Rhodotorula was isolated from the patient’s blood culture obtained during the elevation of temperature. After 14 days of amphotericin B treatment, clinical situation of the patient was improved and he was discharged. Conclusion: Rhodotorula spp. as a rare yet emerging pathogen, often presents as fever of unknown etiology resistant to antibacterial treatment and can be associated with fungemia and other severe complications.


INTRODUCTION
Rhodotorula is an environmental yeast that belongs to Basidiomycota Phylum. Rhodotorula species produce carotenoid pigments usually causing pink or coral mucoid colonies, multilateral budding cells, undistinguished pseudohyphae and infrequently, an indistinct capsule 1 . Rhodotorula species are ubiquitous in nature, can be found in soil and freshwater 1 . Rhodotorula isolation from food such as fruit juice and milk, several medical equipments, such as dialysis equipment, fiberoptic bronchoscopes, and other environmental sources, such as shower curtains, bathtubs, and toothbrushes due to strong affinity with plastic, was also reported. 2 In the last three decades, Rhodotorula species have become an increasing challenge, especially in immunocompromised patients as an opportunistic yeast. 3 Extensive use of central venous catheters (CVC) and intensive treatments may be the potential explanation for the greater number of Rhodotorula infection cases after the first reports in late 1980s. 4 Immunocompromised patients can develop Rhodotorulosis that is usually associated with endocarditis, peritonitis, meningitis, and endophthalmitis due to a wide-ranging exposure to Rhodotorula in the hospital environment. 4

CASE DESCRIPTION
The patient was a 3-year-old male with a diagnosis of Pro B-Acute Lymphoblastic Leukemia (ALL). He was admitted to hospital with complaints of malaise, fatigue, weight loss, and diarrhea between courses of chemotherapy. At hospital admission, the cardiac examination was normal, lymphadenopathy, hepatomegaly, and splenomegaly were not found. At admission, creactive protein (CRP) was found 35.44 mg/L (normal range: 0-5 mg/L), white blood cell count was 4.02 10³/μL (normal range : 3.8-8.76 10³/μL) and hemoglobin was 8.4 g/dL. Rapid immunochromatographic test from stool sample for Rotavirus, Giardia intestinalis, Entamoeba histolityca, and Adenovirus antigens and Clostridium difficile Toxin A was negative. Direct microscopic examination of stool and stool sample culture were also negative. Teicoplanin and amikacin therapy were prescribed as empiric antibiotics. Although antibacterial therapy was administered, the patient had fever episodes. Tuberculosis was excluded with acid-fast stain and PCR tests. Fungal infection was suspected but anti-mannan antibody and galactomannan antigen tests were negative.
After eight days of hospital stay, Rhodotorula was isolated from the patient's blood culture obtained during the elevation of temperature. Standard procedure for blood cultures was followed.
When the patient had a fever, two sets of blood cultures were collected from different peripheral veins. Blood culture sample from the CVC was also collected simultaneously in order to find differential time to positivity. Blood samples were inoculated into aerobic blood culture bottles and administered to the BACTEC FX-400 system (Becton Dickinson, USA). Bottles with the positive signal in BACTEC FX-400 system were inoculated onto Columbia Agar (with 5% Sheep Blood) and Eosin Methylene Blue Agar (BD, USA). The inoculated plates were incubated at 36°C in 5% CO2. After 24h incubation, colonies were identified with BD Phoenix automated system (BD, USA). After the first isolation of Rhodotorula, eight subsequent blood cultures were Rhodotorula positive in ten-day periods, but CVC culture was negative. After the isolation of Rhodotorula spp, amphotericin B was added to the prescription of the patient. After 14 days of amphotericin B treatment, the clinical situation of the patient was improved and he was discharged. The c-reactive protein remained high for a very long time and was high even at patient's discharge.

DISCUSSION
Rhodotorula species are an increasing health problem with their ability to colonise and infect patients with depressed immunity, and account for 0.5%-2.3% of fungemia in the USA. 5 Approximately 90% of patients with Rhodotorula infections have immunodepressant clinical conditions such as AIDS, solid or hematologic malignancy, organ/bone marrow transplant, or immunosuppression due to corticosteroid use, neutropenia, or malnutrition. 6 Rhodotorula infections in patients with hematologic malignancies are usually associated with CVC and result in fungemia, whereas Rhodotorula infections in patients with AIDS usually result in central nervous system infections. 7 In our case, having the negative culture of CVC indicates the difficulty of finding a source for contamination. Therefore, detailed environmental surveillance may be necessary especially in case of outbreaks.
Intestinal colonization is found in up to 5% of healthy children and in up to 12% of young adults. 8 Although one of the patient's complaint at admittance was diarrhea, to our knowledge there is no report for Rhodotorula species causing diarrhea. However, it may be responsible for unsettling gut flora in immunocompromised patients. Furthermore, they often colonise hands of medical staff. 9 Control interventions, including training to reemphasize hand washing for reducing nosocomial transmission risk, were applied in our hospital for the prevention of an outbreak infection.
The isolation of Rhodotorula species from sterile site samples, such as blood, peritoneal fluid or cephalo spinal fluid , is generally suggestive of the infection, especially in patients without indicative symptoms of infection. Morphological and biochemical confirmation of the diagnosis is usually necessary, as yeast cells can usually be seen on microscopic examination. 6 Overall, mortality from Rhodotorula fungemia is 17.3%. 7 Expected mortality may be higher in immunocompromised pediatric patients.
Rhodotorula species are susceptible to amphotericin B and flucytosine in vitro, resistant to fluconazole and caspofungin, and have varying susceptibility to voriconazole. 7 Amphotericin B is the first choice drug for Rhodotorula infections. 10 In our case, Amphotericin B was effective as a treatment.
In conclusion, Rhodotorula spp. as a rare yet emerging pathogen, often presents as fever of unknown etiology resistant to antibacterial treatment and can be associated with fungemia and other severe complications, especially in immunocompromised patients.