Chronic disseminated candidiasis in a patient with acute leukemia - an illustrative case and brief review for clinicians

Candida species are colonizers of the human skin and gastrointestinal (GI) tract, existing as part of the microbiome in up to 60% of healthy individuals [1, 2]. Patients with hematologic malignancies are at increased risk for invasive candidiasis due to iatrogenic immunosuppression as well as chemotherapy- induced injury of the gastrointestinal mucosa that can lead to a translocation of the commensal Candida species and other gastrointestinal pathogens into a bloodstream [1].

There are two forms of invasive candidiasis that include candidemia and deep-seated tissue candidiasis [3, 4]. The latter arises from either hematogenous spread of the infection or from direct inoculation of the organism into a sterile tissue site [1, 3]. Chronic disseminated candidiasis (CDC) is one form of invasive candidiasis that occurs in patients with hematologic malignancies after a period of prolonged neutropenia upon neutrophil count recovery [1, 3]. The diagnosis of CDC is made based on the combination of clinical, radiographic, and laboratory data.

As microbiologic data is often negative, high index of suspicion is needed to make this diagnosis in the appropriate host. Here, we present a case of an 18-year-old patient with B- cell acute lymphoblastic leukemia (B-ALL) undergoing reinduction chemotherapy who developed CDC and describe classic radiographic and histopathologic manifestations of this condition as well as common challenges in diagnosis and treatment.

An 18-year-old female patient with relapsed B-ALL was admitted for re-induction chemotherapy under Children’s Oncology Group protocol AALL1131, a regimen including vincristine, mitoxantrone, dexamethasone and intrathecal methotrexate; pegaspargase was omitted due to prior history of intracranial hemorrhage. Her induction course was complicated by port cellulitis treated with port removal, cefepime, and intravenous vancomycin. For neutropenic prophylaxis, she received intravenous micafungin 100 mg daily and oral acyclovir 400 mg twice daily. During admission, she developed neutropenic fever with repeatedly negative cultures. The chemistry panel revealed mildly elevated AST(aspartate aminotransferase) and ALT (alanine aminotransferase) at 55 units/L and 148 units/L respectively (ALT normal range < 35 units/L, AST normal range 14–36 units/L) for which an abdominal ultrasound was obtained demonstrating hepatomegaly with mild hepatic steatosis. Due to persistent neutropenic fever, prophylactic micafungin was transitioned to voriconazole 6 mg/kg twice daily for 2 loading doses, followed by 4 mg/kg twice daily.

On day 38 of treatment, the patient developed a left lower extremity skin nodule. Laboratory values demonstrated absolute neutrophil count of 400 cells/µL, AST of 67 units/L, ALT of 51 units/L, and alkaline phosphatase of 211 units/L (normal range 38–126 units/L). Repeat abdominal ultrasound demonstrated interval development of multiple hypoechoic splenic foci suspicious for microabscesses. Voriconazole was switched to intravenous liposomal amphotericin B (AmBisome ®) at 5 mg/kg daily. Skin punch biopsy of the left lower extremity was performed and tissue fungal culture revealed Candida tropicalis growth susceptible to fluconazole, caspofungin, and voriconazole; minimal inhibitory concentration values were not available. Diagnosis of CDC was made based on the constellation of the patient’s symptoms, splenic lesions on imaging, and presence of the nodular skin lesion with Candida tropicalis. At that point, antifungal therapy was changed to fluconazole per susceptibility testing. The patient’s fevers resolved, and she was discharged home.

She was admitted again to receive blinatumomab as part of her anti-neoplastic regimen. The course was again complicated by non-neutropenic fevers with negative microbiologic workup. However, an interim abdominal ultrasound performed 4 weeks after initial imaging demonstrated new hepatic target lesions and increased number of splenic lesions. Fluconazole was changed to intravenous micafungin 100 mg daily for suspected progression of CDC.

Shortly after, the patient was referred to our institution for allogeneic stem cell transplantation evaluation (SCT) for the treatment of her underlying hematologic condition. Pre-transplant imaging revealed multiple hepatosplenic lesions (Fig. 1), right kidney lesions, and a nodular appearing opacity in the lateral left lower lobe. Lung nodule biopsy revealed mild interstitial fibrosis and chronic inflammation without granulomas, with cultures negative for bacterial and fungal growth. The hepatic lesion was biopsied and revealed budding yeast consistent with Candida species (Fig. 2), although culture failed to grow this organism. Liver tissue specimen was sent for next generation 16 S rRNA sequencing (University of Washington, USA) and returned positive for C. tropicalis, confirming the diagnosis of persistent CDC. The patient was treated with dual antifungal therapy with intravenous micafungin 150 mg daily, (dose increased from prior) and intravenous liposomal amphotericin B 5 mg/kg daily. Splenectomy was performed 6 months after initial CDC diagnosis to reduce the burden of the disease. Follow up CT scans of the abdomen 1 month after splenectomy demonstrated stable to mildly improved hepatic lesions and stable right kidney lesions. She was continued on amphotericin B and micafungin throughout pre- and post-transplant periods for the total of 6 months following splenectomy. The patient ultimately underwent allogeneic SCT and passed away 32 days later after developing early post-SCT multi-organ failure unrelated to CDC that had been diagnosed 11 months earlier.