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

Chronic disseminated candidiasis (CDC) is a severe but rarely seen fungal infection presenting in patients with hematologic malignancies after a prolonged duration of neutropenia. A high index of suspicion is required to diagnose CDC as standard culture workup is often negative. While tissue biopsy is the gold standard of diagnosis, it is frequently avoided in patients with profound cytopenias and increased bleeding risks. A presumptive diagnosis can be made in patients with recent neutropenia, persistent fevers unresponsive to antibiotics, imaging findings of hypoechoic, non-rim enhancing target-like lesions in the spleen and liver, and mycologic evidence. Here, we describe the case of an 18-year-old woman with relapsed B-cell acute lymphoblastic leukemia treated with re-induction chemotherapy who subsequently developed CDC with multi-organ involvement. The diagnosis was made based on clinical and radiologic features with positive tissue culture from a skin nodule and hepatic lesion. The patient was treated for a total course of 11 months with anti-fungal therapy, most notably amphotericin B and micafungin, and splenectomy. After initial diagnosis, the patient was monitored with monthly CT abdomen imaging that showed disease control after 5 months of anti-fungal therapy and splenectomy. The diagnosis, treatment, and common challenges of CDC are outlined here to assist with better understanding, diagnosis, and treatment of this rare condition.

Successful Treatment of Chronic Disseminated Candidiasis Complicated by Immune Reconstitution Inflammatory Syndrome in a Child With Acute Lymphocytic Leukemia.

Chronic disseminated candidiasis (CDC) is a severe form of disseminated fungal infection that commonly affects the liver, spleen, and kidneys. In rare cases, CDC can be further complicated by an excessive immune response known as immune reconstitution inflammatory syndrome (IRIS). This syndrome occurs during the phase of immune recovery and is characterized by a systemic inflammatory response and excessive release of cytokines. We present a case of a two-year-old female with a medical history of acute lymphocytic leukemia on chemotherapy. She was admitted with high fever refractory to conservative management that included broad-spectrum antimicrobials. Additionally, multiple skin lesions and a left-sided limp were noted. Whole-body imaging revealed multiple abscesses in the spleen, kidneys, scalp, and left lower limb. The culture of an aspirate material from skin lesions grew Candida tropicalis. Despite receiving appropriate antifungals, the patient showed no signs of improvement, leading to the diagnosis of CDC-induced IRIS. The patient was started on systemic corticosteroids, which resulted in rapid improvement in the patient's clinical status, resolution of fever, and significant reduction in inflammatory markers.

Muscular and hepatosplenic candidiasis in a patient with acute myeloblastic leukemia: A case report and literature review.

Key Clinical Message: Muscular and subcutaneous candidiasis is a rare entity in immunocompromised patients, but it should be kept in mind when we see multiple cystic soft tissue masses in addition to target-shaped hepatosplenic lesions in neutropenic patients. US and MRI are useful imaging modalities for the diagnosis and follow-up of these patients. Abstract: Soft tissue candidiasis is an opportunistic infection in immunocompromised patients and must always be diagnosed and treated as soon as possible. In this case report, the patient is a 14-year-old boy with acute myeloid leukemia M3-type who presented with numerous soft tissue and hepatosplenic candidal abscesses.

Epidemiology, Clinical Characteristics and Risk Factors for Severity of Chronic Disseminated Candidiasis in Jerusalem, Israel.

Chronic disseminated candidiasis (CDC) occurs mostly in patients with acute hematologic malignancy and its clinical manifestations derive from immune reconstitution following neutrophil recovery. The aim of this study was to describe epidemiological and clinical characteristics of CDC and define risk factors for disease severity. Demographic and clinical data were collected from medical files of patients with CDC hospitalized in two tertiary medical centers in Jerusalem between 2005 and 2020. Associations between different variables and disease severity were evaluated, as well as characterization of Candida species. The study included 35 patients. CDC incidence slightly increased during study years and the average number of involved organs and disease duration was 3 ± 1.26 and 178 ± 123 days, respectively. Candida grew in blood in less than third of cases and the most common isolated pathogen was Candida tropicalis (50%). Histopathological or microbiological workup in patients who underwent an organ biopsy demonstrated Candida in about half of the patients. Nine months after starting antifungals, 43% of the patients still didn't have resolution of organ lesions in imaging modalities. Factors associated with protracted and extensive disease were prolonged fever prior to CDC and absence of candidemia. A C- Reactive Protein (CRP) cutoff level of 7.18 mg/dL was found to predict extensive disease. In conclusion, CDC incidence is increasing and the number of involved organs is higher than previously described. Clinical factors such as fever duration prior to CDC and absence of candidemia can predict severe course of disease and assist in treatment decisions and follow-up planning.

Splenectomy for treating hepatosplenic candidiasis: Two cases and literature review suggesting its feasibility.

Background: Hepatosplenic candidiasis is a rare but severe complication in immunocompromised patients undergoing chemotherapy. Antifungal agents are widely accepted as the first choices for therapy. However, resistance to or side-effect of antifungal agents may comxpromise its efficiency. Splenectomy has also been rarely performed as treatment for this disease. Methods: We present two cases of splenectomy for treating hepatosplenic candidiasis after failure of the initial drug therapy. Literatures on splenectomy as treatment for hepatosplenic candidiasis were searched in Pubmed and summarized. Results: Two leukemia patients developed hepatosplenic candidiasis after received chemotherapy for their primary diseases. Various antifungal agents including amphotericin B were all demonstrated failure to cure fever and the Candida abscesses due to resistance or intractable side-effect. Laparoscopic splenectomy were finally performed and resolved the candidiasis successfully. A total of 12 splenectomy cases for treating hepatosplenic candidiasis had been previously reported in literature. All the cases showed either resistance or unimproved to initial antifungal therapies. Splenectomy provided salvage therapeutic value in all cases. Conclusion: Splenectomy has therapeutic effect and may change the traditional concept in most surgeons. The present study may expand an alternative strategy in clinical practice guideline for the management of hepatosplenic candidiasis.

Hepatosplenic Candidiasis in Patients With Hematological Malignancies: A 13-Year Retrospective Cohort Study.

Background: Hepatosplenic candidiasis (HSC) used to be reported in patients with acute myeloid leukemia (AML) without antifungal prophylaxis. The aim was to describe the clinical features and outcomes of HSC over the last 13 years in a single French hematology center. Methods: All patients diagnosed with HSC between 2008 and 2020 were included in a single-center retrospective cohort study. Data were collected from patient charts, and HSC was classified according to the 2020 European Organisation for Research and Treatment of Cancer/Mycoses Study Group definitions. Results: Sixty patients were included, with 18.3% proven, 3.3% probable, and 78.3% possible HSC according to the 2020 European Organization for Research and Treatment of Cancer Mycoses Study Group classification. Among them, 19 patients were treated for acute myeloid leukemia (AML), 21 for lymphomas, and 14 for acute lymphoblastic leukemia. HSC occurred in 13 patients after autologous stem cell transplantation for lymphoma. At HSC diagnosis, 13 patients were receiving antifungal prophylaxis. Candida colonization was present in 84.2%, with prior candidemia in 36.7% of cases. ß-D-glucans was positive in 55.8%, and 45.8% of tissue biopsies were contributive. First-line antifungal therapy was azoles in 61.7%, and steroids were associated in 45% of cases. At 3 months of follow-up, partial response to antifungal therapy was 94.2%. At last follow-up (mean, 22.6 months), 41 patients (68.3%) presented a complete hematological remission and 22 patients were deceased, none because of HSC. Conclusions: The epidemiology of HSC has changed in the last decade, with fewer cases occurring in the AML setting. A better identification of patients at risk could lead to specific prophylaxis and improved diagnosis.

Clinical feature, image findings and outcome of hepatosplenic candidiasis in patients with acute myeloid leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) are at risk of hepatosplenic candidiasis (HSC). HSC is often associated with prolonged fever and difficulty in definitive clinical diagnosis. We aimed to explore the incidence, clinical features, image findings and outcomes of HSC among patients with AML in a tertiary hospital, Taiwan. METHODS: We did a chart review of patient data in our institute from 2009 to 2012. The diagnosis of HSC was based on risk factors, febrile symptoms and image findings. RESULTS: Two hundred and ninety-two patients with AML were analyzed. In total, 1051 chemotherapy sessions were administered. Eleven patients (4 males and 7 females) experienced HSC (incidence 3.8%, 95% conference interval 2.11-6.72%). Among those with HSC, the median age was 62. Eight patients developed HSC following induction or re-induction chemotherapies. Three developed HSC following consolidation chemotherapies. The median duration of severe neutropenia was 25 days (range 10-142). In all patients with HSC, multiple hypodense lesions were found in the involved organs by computed tomography scans. Lesions consistent with HSC could be identified by ultrasound in 5 out of 6 patients. Other than liver and spleen, lung was frequently (7 cases) and kidney occasionally (3 cases) involved. Four patients died within 90 days. Prolonged neutropenia was associated with mortality. CONCLUSION: HSC occurred more often during induction or re-induction periods. Lungs are commonly involved and pleural effusion was frequently seen in CT scans. Pleural effusion may suggest more serious infections but its clinical relevance should be investigated in large-scale studies. Prolonged neutropenia is the only prognostic factor. Prophylaxis should be considered. In the absence of prophylaxis, we advise early image studies and prompt antifungal treatment in patients at risk for HSC.

Clinical features and outcome of hepatosplenic fungal infections in children with haematological malignancies.

Hepatosplenic fungal infection (HSFI) is a severe invasive fungal infection observed during neutrophil recovery in patients with acute leukaemia treated with intensive chemotherapy. Retrospective analysis including all paediatric haematological malignancies patients with HSC treated in Children Cancer Hospital Egypt (2013-2018). Twenty-five patients with acute leukaemia developed HSFI (19 patients diagnosed as hepatosplenic candidiasis). Most of the cases (92%) occurred during the induction phase. Organs affected were as follows: liver in 18 patients, renal in 13 patients, spleen in 12 patients, skin in four patients and retina in one patient. Five (20%) patients had proven HSC, 14 (56%) probable and six (24%) possible HSFI. Ten patients had a PET-CT for response assessment. Candida tropicalis was the most common isolated spp. from blood/tissue culture. Six (24%) patients developed HSFI on top of antifungal prophylaxis. Steroids were given in 12 (52%) patients with HSFI as immune reconstitution syndrome (IRS). Caspofungin was the first line of treatment in 14 (56%) patients, liposomal amphotericin B in six (24%) patients and azoles in five (20%) patients. HSFI was associated with delayed of intensification phase of chemotherapy (median 42 days). The success rate was reported in 24 patients with complete response (68%) and partial response in (28%) patients, while failure (death) seen in 1(4%) patient. HSC is still a major challenge in paediatric leukaemias patients with impact on treatment delay and survival outcome. PET scan, non-culture diagnostics and steroid role evidence in IRS are growing. Antifungal stewardship for screening, early detection for high-risk patients and better response assessment is challenging.

Chronic disseminated candidiasis manifesting as hepatosplenic abscesses among patients with hematological malignancies.

BACKGROUND: The outcomes of deep-seated abscesses attributed to chronic disseminated candidiasis (CDC) in patients with hematological malignancies have rarely been reported in recent years. METHODS: We retrospectively reviewed and analyzed the data of patients with hematological malignancies who received a diagnosis of CDC at a medical center in Taiwan between 2008 and 2013. RESULTS: Sixty-one patients (32 men and 29 women) were diagnosed with CDC. The median age was 51 years (range: 18-83). The overall incidence of CDC was 1.53 per 100 patient-years in patients with hematological malignancies between 2008 and 2013. The highest incidence of CDC was 4.3 per 100 patient-years for acute lymphoblastic leukemia, followed by 3.6 for acute myeloid leukemia. We detected 3 (4.9%) proven, 13 (21.3%) probable, and 45 (73.8%) possible cases of CDC. A total of 13 patients had positive blood cultures for Candida species: C. tropicalis (8), C. albicans (2), C. glabrata (2), and C. famata (1). The median duration of antifungal treatment was 96 days (range: 7-796 days). Serial imaging studies revealed that the resolution rate of CDC was 30.0% at 3 months and 54.3% at 6 months. Five patients (8.2%) had residual lesions that persisted beyond one year. A multivariate analysis of the 90-day outcome revealed that shock was the only independent prognostic factor of 90-day survival in patients with CDC. CONCLUSION: The incidence of CDC did not decrease between 2008 and 2013. Patients with acute leukemia had a higher risk of CDC than those with other hematological malignancies. Imaging studies conducted at 6 months after diagnosis revealed that only half of the patients showed complete resolution. CDC requires prolonged treatment, and serial imaging at 6 months interval is suggested. Shock is the only independent prognostic factor of 90-day survival in patients with CDC.

Candida-Reactive T Cells for the Diagnosis of Invasive Candida Infection-A Prospective Pilot Study.

Background: Blood or tissue culture or histology prove invasive Candida infection, but long time to result, limited feasibility and sensitivity call for new approaches. In this pilot project, we describe the diagnostic potential of quantitating Candida-reactive, CD4/CD69/CD154 positive lymphocytes in blood of patients with invasive Candida infection. Methods: We used flow cytometry quantitating Candida-reactive, CD4/CD69/CD154 positive lymphocytes from peripheral blood of patients with invasive Candida infection, from patients at risk and healthy volunteers as controls. Results: Elevated levels of Candida-reactive lymphocytes were measured in 13 patients with proven invasive Candida infection and in one patient with probable hepatosplenic candidiasis. Results of three candidemia patients were uninterpretable due to autofluorescence of samples. Twelve of 13 patients had Candida identified to species level by conventional methods, and T cell reactivity correctly identified Candida species in 10 of 12 patients. Nine hematological high-risk patients and 14 healthy donors had no elevated Candida-reactive T cell counts. Conclusions: This Candida-reactive lymphocyte assay correctly identified the majority of patients with invasive Candida infection and the respective species. Our assay has the potential to support diagnosis of invasive Candida infection to species level and to facilitate tailored treatment even when biopsies are contraindicated or cultures remain negative.

Liver fungal infections: an overview of the etiology and epidemiology in patients affected or not affected by oncohematologic malignancies.

Fungal infections of the liver, most commonly caused by Candida spp., often occur in patients with hematologic malignancies treated with chemotherapy. Colonization of the gastrointestinal tract is thought to be the main origin of dissemination of Candida; mucositis and neutropenia facilitate the spread of Candida from the gastrointestinal tract to the liver. Hepatic involvement due to other fungi is a less common infectious complication in this setting. Fungal infections represent a less common cause of hepatic abscesses in non-oncohematologic population and the trend appears to be decreasing in recent years. Understanding of the etiology and epidemiology of fungal infections of the liver is indicated for an appropriate antimicrobial therapy and an overall optimal management of fungal liver infections.

Hepatosplenic Candidiasis Without Prior Documented Candidemia: An Underrecognized Diagnosis?

INTRODUCTION: Patients with a history of chemotherapy or stem cell transplantation (SCT) and prolonged neutropenia are at risk for hepatic and/or splenic seeding of Candida. In our experience, hepatosplenic candidiasis (HSC) without documented candidemia often remains unrecognized. CASE PRESENTATIONS: We describe three cases of HSC without documented candidemia and the challenges in establishing the diagnosis and adequately treating this condition. The first patient had a history of SCT for treatment of breast cancer and was scheduled for hemihepatectomy for suspected liver metastasis. A second opinion at our institute resulted in the diagnosis of hepatic candidiasis without prior documented candidemia, for which she was treated successfully with fluconazole. The second case demonstrates the limitations of (blood and tissue) cultures and the value of molecular methods to confirm the diagnosis. Case 3 illustrates treatment challenges, with ongoing dissemination and insufficient source control despite months of antifungal therapy, eventually resulting in a splenectomy. LITERATURE REVIEW: A structured literature search was performed for articles describing any patient with HSC and documented blood culture results. Thirty articles were available for extraction of data on candidemia and HSC. Seventy percent (131/187) of patients with HSC did not have documented candidemia. The majority of HSC events were described in hematologic patients, although some cases were described in patients with solid tumors treated with SCT (n = 1) or chemotherapy and a history of leukopenia (n = 2). Current guidelines and practices for diagnosis and treatment are described. CONCLUSION: Clinicians should be aware that HSC most often occurs without documented candidemia. In case of persistent or unexplained fever or lesions in the liver and/or spleen, a history of neutropenia should place disseminated candidiasis in the differential diagnosis. HSC is not limited to hematological patients and may occur in patients with solid tumors treated with bone marrow-suppressing chemotherapy or SCT. In the latter group, HSC as alternative diagnosis for hepatic metastasis should be considered when lesions are not typical for metastasis. This might prevent unnecessary surgery or inappropriate treatment. IMPLICATIONS FOR PRACTICE: Timely diagnosis of hepatosplenic candidiasis (HSC) is challenging, but can prevent further complications and dissemination, and may even prevent unnecessary invasive procedures. Clinicians should realize that HSC often occurs without documented candidemia and that sensitivity of blood cultures for candidemia is limited. HSC is not strictly limited to hematologic patients and might also occur in patients with solid tumors treated with intensive chemotherapy or stem cell transplantation. Increased awareness for HSC in patients with any history of neutropenia is of importance to increase detection and prevent serious sequelae.

Hepatosplenic Candidiasis Detected by (18)F-FDG-PET/CT.

Hepatosplenic candidiasis is a fungal infection, which mostly affects patients with hematologic malignancies such as leukemia. The pathogenesis of this infection is not clear yet, and the liver is the most commonly affected organ. Diagnosis of hepatosplenic candidiasis can be only established via biopsy, since computed tomography (CT) scan, ultrasonography, and magnetic resonance imaging (MRI) yield non-specific results. The role of fluorine-18 fluorodeoxyglucose positron emission tomography /computed tomography ((18)F-FDG PET/CT) in diagnosis of hepatosplenic candidiasis remains undetermined, considering a few evidences in the literature. In this case report, we present the case of a 47-year-old patient, affected by acute myeloid leukemia, which was treated with three cycles of chemotherapy, resulting in the development of neutropenia and fever following the last cycle. The (18)F-FDG PET/CT scan showed some foci of intense FDG uptake in the liver and spleen. The subsequent diagnostic investigations (i.e., abdominal CT scan and biopsy) were suggestive of hepatosplenic candidiasis. The patient was started on antifungal treatment with fluconazole. After one month, the clinical conditions were resolved, and the subsequent abdominal CT scan was negative.

Prolonged fever and splenic lesions caused by Malassezia restricta in an immunocompromised patient.

Malassezia species are commonly found on human skin as commensals but can cause invasive infections in premature infants and immunocompromised hosts. Due to their fastidious growth, diagnosis of Malassezia infections can prove challenging. Molecular techniques can aid in diagnosis and treatment of invasive infections. We describe the case of a pediatric oncology patient with splenic lesions secondary to Malassezia restricta.