Chronic Disseminated Candidiasis Research Articles

Chronic Disseminated Candidiasis among Pediatric Cancer Patients: The Hidden Threat

Abstract Background Chronic disseminated Candidiasis (CDC) is a severe invasive fungal infection observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Clinical manifestations include persistent fever under broad-spectrum antibiotics and abdominal discomfort. HSC is characterized by the presence of nodular lesions in the liver, spleen, and other organs (lungs, kidneys, and skin) on radiological imaging. Methods The retrospective study was conducted from 2013 - 2022 including all pediatric hematological patients diagnosed with chronic disseminated candidiasis admitted and treated in Children’s Cancer Hospital Egypt (CCHE). Data included primary diagnosis, clinical presentation, microbiological, radiological, and treatment data. Results Three hundred fifty (350) pediatric cancer patients were diagnosed with candidemia. The median age was four years (4 months- 18 years). Chronic dissemination candidiasis (CDC) was reported in 30(9%) of our patients. The most affected organs were Liver (19 patients), spleen (13), renal (13), cautelous (13), brain (2) and retina (2). Candida tropicalis was the most common isolated spp. from blood/tissue culture (24 patients) followed by C. parapsilosis (3 patients). The primary diagnosis in patients with CDC was ALL (24 Patients) while (4 patients) has AML. CDC was developed on top of antifungal prophylaxis in 7 patients (24%): liposomal-amho B (3 patients), Micafungin (3 patients) and voriconazole (1 patient). Candida tropicalis was the most common isolated spp. from blood/tissue culture (80%). Steroid as treatment for CDC immune reconstitution syndrome done in around 50% of patients (Persistent fever with neutrophil recovery, absent progressive clinical/radiological findings). PET-CT was done in 10 patients with positive uptake in all cases, was helpful in resuming intensive chemotherapy in six patients despite persistent lesions in CT and was used to stop antifungal treatment despite positive radiological lesions in CT in three patients. The first line of treatment was echinocandin (53%) and liposomal ampho-B (46%) with overall mortality among CDC patients were 30%. Conclusion CDC is still a hidden threat among pediatric patients with still high mortality rate. Antifungal stewardship through screening and Rapid diagnosis using non-culture diagnostics are needed. PET scan is a helpful tool for diagnosis and response assessment and can add to treatment decision. Figure 1. Chronic Disseminated Candidiasis among Pediatric Cancer patients.

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.

B-245 Applicability of metagenomic Next-Generation Sequencing (mNGS) in challenging infectious diseases in a tertiary hospital

Abstract Background Infectious diseases caused by rare pathogens or with unusual presentations pose a diagnostic challenge. Traditional microbiologic tests can be time-consuming, labor-intensive and have limited sensitivity for some organisms. Plasma metagenomic Next-Generation Sequencing (mNGS) detects whole microbial genetic material and detects even unsuspected organisms. We present three cases of challenging infectious diseases and discuss the applicability of mNGS in different scenarios. Methods Plasma NGS was performed at Karius, Inc. (Redwood City, CA, USA). Patient data was collected from hospital and laboratory electronic records. Results Case 1: An 8-year-old female with sickle-cell anemia developed a persistent daily fever two weeks after recovery from sepsis due to Streptococcus pyogenes. Clinical exam was normal and investigation was negative (blood cultures, echocardiogram, thoracic and abdominal CT scans and bone scintigraphy). Two weeks later mNGS was performed, which came out positive for Cytomegalovirus. As patient became afebrile in 48 h and the viral burden was low, she could be safely discharged. Case 2: A 43-year-old male with prosthetic aortic valve and an intraluminal aortic ring had a year-long history of fatigue, weight loss and hypoalbuminemia. CT scans showed ground-glass infiltrates and enlarged mediastinal lymph nodes. Empirical treatment for tuberculosis was ineffective. A year later, he developed hepatosplenomegaly, fever and pancytopenia. Blood cultures, bone marrow biopsy and serologies (HIV, hepatitis B/C, syphilis, brucellosis, bartonellosis, leishmaniasis) were negative. Cardiac surgery found no apparent signs of endocarditis and the prosthetic aortic valve biopsy revealed only an inflammatory infiltrate. A new CT scan showed thickened intraluminal aortic ring with aortic pseudoaneurysms and splenomegaly with splenic infarction. A blood sample was then collected for mNGS and liver biopsy and splenectomy were performed. However, surgery complicated with hemodynamic instability, renal and liver failure and the patient died in less than 24 h. Two days later, mNGS came out positive for Coxiella burnetti. Case 3: A 45-year-old female with relapsed AML treating a chronic disseminated candidiasis with micafungin for 3 months had persistent liver and splenic nodules and new pulmonary nodules on the CT scan. In the following three months after chemotherapy (Gilteritinib), she developed multiple episodes of febrile neutropenia, some without microbiological documentation, leading to multiple courses of antibiotic treatment and a shift to liposomal amphotericin B. After clinical improvement and bone marrow recovery, liposomal amphotericin B was replaced by isavuconazole. A negative mNGS result allowed antifungal treatment to be safely discontinued, avoiding six months of unnecessary antifungal treatment. Conclusion We summarize three different scenarios of mNGS applications. In common, patients were submitted to multiple laboratory and image testing and received large doses of empirical antimicrobials due to lack of a precise diagnosis. In two cases, mNGS was diagnostic, shortened hospital stay and reduced overall costs. In case 2, the patient’s death might have been prevented if mNGS had been performed earlier. Vulnerable hospitalized patients with a broad spectrum of diagnostic possibilities, in whom sequential diagnostic tests could delay adequate therapy and cause significant adverse effects, could greatly benefit from mNGS when performed in a timely manner.

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 ± 123days, 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 7.18mg/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.

A Functional Polymorphism in IL-1B Is Associated With Immune Reconstitution Inflammatory Syndrome of Chronic Disseminated Candidiasis.

We investigated single nucleotide polymorphisms (SNPs) possibly involved in immune reconstitution inflammatory syndrome of chronic disseminated candidiasis (IRIS-CDC) through a candidate gene approach and a prospective matched-control study. We found that an SNP located in interleukin-1B at rs1143627 was significantly associated with the risk of developing IRIS-CDC.

Does 18F-FDG PET/CT add value to conventional imaging in clinical assessment of chronic disseminated candidiasis?

Chronic disseminated candidiasis (CDC) classically occurs after profound and prolonged neutropenia. The aim of the CANHPARI study was to assess the clinical value of adding 18F-fluorodeoxyglucose PET/CT to conventional radiology for initial and subsequent evaluations of CDC. A pilot prospective study was conducted in 23 French onco-hematological centers from 2013 to 2017 (NCT01916057). Patients ≥ 18 y.o. suspected for CDC on abdominal conventional imaging (CT or MRI) were included. PET/CT and conventional imaging were performed at baseline and month 3 (M3). Follow-up was assessed until M12. The primary outcome measure was the global response at M3, i.e., apyrexia and complete response to PET/CT. The secondary outcome measure consists in comparison between responses to PET/CT and conventional imaging at diagnosis and M3. Among 52 included patients, 44 were evaluable (20 probable and 24 possible CDC); 86% had acute leukemia, 55% were male (median age 47 years). At diagnosis, 34% had fever and conventional imaging was always abnormal with microabscesses on liver and spleen in 66%, liver in 25%, spleen in 9%. Baseline PET/CT showed metabolic uptake on liver and/or spleen in 84% but did not match with lesion localizations on conventional imaging in 32%. M3 PET/CT showed no metabolic uptake in 13 (34%) patients, 11 still having pathological conventional imaging. Global response at M3 was observed in eight patients. Baseline PET/CT does not replace conventional imaging for initial staging of CDC lesions but should be performed after 3 months of antifungal therapy. [www.clinicaltrials.gov], identifier [NCT01916057].

360. The diagnostic sensitivity of beta-D-glucan assay in patients with chronic disseminated candidiasis

Abstract Background Chronic disseminated candidiasis (CDC) is a specific syndrome in patients with hematologic malignancies which usually occurs after the recovery of neutrophils due to previous chemotherapy. The beta-D-glucan (BDG) assay has been proposed as an adjunct test for diagnosing invasive fungal infection. However, data on BDG assay in patients with CDC are scare. We aimed to investigate the diagnostic sensitivity of BDG assay in patients with CDC. Methods All adult patients who were diagnosed as CDC in a tertiary hospital in Seoul, South Korea, from January 2017 to December 2019 and underwent BDG assay (Gold Mountain River Tech Development, Beijing, China) were retrospectively reviewed. CDC was defined by the demonstration of small, target-like abscesses in liver or spleen (bull’s-eye lesions) or in the brain at the time of neutrophil recovery after a prolonged phase of neutropenia. The values for BDG over 80 pg/mL was classified as positive. Results A total of 20 patients were enrolled. The median age was 51 years (Interquartile range 39 – 64). Of these, 13 patients had acute myeloid leukemia, 3 acute lymphoid leukemia, 2 myelodysplastic syndrome, and 1 aplastic anemia. Candida spp. were isolated in 6 patients; 3 were C. tropicalis, 2 C. glabrata, and 1 C. krusei. Of the 20 patients, 10 (50%) revealed positive BDG results. The median BDG value was 174 pg/dL (IQR 137–402). More CDC patients with previous candidemia had positive BDG assay than those without candidemia, but with no statistical significance (4/5 (80%) vs. 6/15 (40%), P = 0.30). In the 7 patients with BDG assay-positive CDC, for whom follow-up BDG results were available, the BDG remained high in 6 patients (86%) for more than 4 weeks after adequate antifungal therapy. All 4 patients who died had a positive BDG assay, and 3 of them showed an increasing trend of BDG values during treatment. Conclusion Negative BDG assay appears to be not useful to rule out CDC. BDG assay decreased slowly during the adequate treatment of CDC. Disclosures All Authors: No reported disclosures.

A case of chronic disseminated candidiasis in metamizole-induced neutropaenia

Chronic disseminated candidiasis (CDC) is a severe complication of a disseminated yeast infection mainly seen after prolonged chemotherapy-induced neutropaenia in the context of haematological malignancy. We present a case of CDC in a patient with metamizole-induced neutropaenia. To the best of our knowledge, this is the first case described in this context. Furthermore, we highlight the role of steroids in the management of this disease.

Next-generation sequencing assistance in the diagnosis of three cases of acute leukemia complicated with chronic disseminated candidiasis

Next-generation sequencing assistance in the diagnosis of three cases of acute leukemia complicated with chronic disseminated candidiasis

Sub cutaneous micro-abscesses and myositis as part of immune reconstitution inflammatory syndrome (IRIS) due to chronic disseminated candidiasis in a child with acute lymphoblastic leukemia

Sub cutaneous micro-abscesses and myositis as part of immune reconstitution inflammatory syndrome (IRIS) due to chronic disseminated candidiasis in a child with acute lymphoblastic leukemia

Invasive candidiasis in children

The prevalence of invasive candidiasis (IC) in pediatric hospitals is from 4,3 to 15,2 per 10,000 hospitalized, in ICU – from 3,5 to 7 cases per 1,000, with HSCT – 2,9%. The average length of stay of a patient in the hospital before the development of IC varies from 21 to 56 days, in the ICU – more than 15 days. Knowledge of risk factors (ICU stay for ≥15 days, use of antibacterial drugs and parenteral nutrition, active malignant neoplasm, etc.) makes it possible to identify patients with a high (10-46%) risk of developing IC. Candida albicans remains the leading causative agent of IC in children, but infections with non-albicans Candida spp. have increased and an increase in the resistance of IC pathogens to azole antimycotics was noted. The main clinical variant of IC in children is candidemia, other forms include the central nervous system, abdominal organs, eyes, heart, bones and joints, kidneys, skin and subcutaneous tissue involvement, as well as chronic disseminated (hepatolienal) candidiasis. Blood culture, the main method of laboratory diagnostics of IC, is characterized by low sensitivity and requires a long time. Methods of noncultural diagnostics of IC (1,3-β-D-glucan, mannan and antimannan antibodies, T2 Candida etc) in children have not been sufficiently studied. The main drugs for the treatment of IC in children are echinocandins (anidulafungin, etc.), and CVC removal/replacement is necessary. The overall mortality rate in pediatric patients within 30 days after the diagnosis of IC is 37% to 44%.

"Chronic Disseminated Aspergillosis," a Novel Fungal Immune Reconstitution Inflammatory Syndrome.

We report a case of chronic hepatosplenic aspergillosis following immune reconstitution complicating colic aspergillosis in an AIDS patient with multicentric Castleman disease. Symptoms mimicked the clinical presentation of chronic disseminated candidiasis and responded to corticosteroid. This emerging entity enlarges the spectrum of fungal immune reconstitution inflammatory syndrome in the HIV setting.

PET in the diagnostic management of infectious/inflammatory pulmonary pathologies: a revisit in the era of COVID-19.

PET in the diagnostic management of infectious/inflammatory pulmonary pathologies: a revisit in the era of COVID-19.

Mechanisms of Pathogenic Candida Species to Evade the Host Complement Attack.

Candida species are common colonizers of the human skin, vagina, and the gut. As human commensals, Candida species do not cause any notable damage in healthy individuals; however, in certain conditions they can initiate a wide range of diseases such as chronic disseminated candidiasis, endocarditis, vaginitis, meningitis, and endophthalmitis. The incidence of Candida caused infections has increased worldwide, with mortality rates exceeding 70% in certain patient populations. C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei are responsible for more than 90% of Candida-related infections. Interestingly, the host immune response against these closely related fungi varies. As part of the innate immune system, complement proteins play a crucial role in host defense, protecting the host by lysing pathogens or by increasing their phagocytosis by phagocytes through opsonization. This review summarizes interactions of host complement proteins with pathogenic Candida species, including C. albicans and non-albicans Candida species such as C. parapsilosis. We will also highlight the various ways of complement activation, describe the antifungal effects of complement cascades and explore the mechanisms adopted by members of pathogenic Candida species for evading complement attack.

Chronic Disseminated Candidiasis During Hematological Malignancies: An Immune Reconstitution Inflammatory Syndrome With Expansion of Pathogen-Specific T Helper Type 1 Cells.

Chronic disseminated candidiasis (CDC) is a rare disease that mostly occurs after chemotherapy-induced prolonged neutropenia in patients with hematological malignancies. It is believed to ensue from Candida colonization, breach of the intestinal epithelial barrier, and venous translocation to organs. Fungal blood or liver biopsy cultures are generally negative, suggesting the absence of an ongoing invasive fungal disease. To unravel the contribution of the immune system to CDC pathogenesis, we undertook a prospective multicentric exploratory study in 44 CDC patients at diagnosis and 44 matched controls. Analysis of Candida-specific T-cell responses using enzyme-linked immunospot assays revealed higher numbers of interferon (IFN)γ-producing T cells reactive to mp65 or candidin in 27 CDC cases compared with 33 controls. Increased plasma levels of soluble CD25, interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and IL-10 and lower levels of IL-2 were observed in CDC patients versus controls. Neutrophilia and higher levels of CD4 and CD8 T-cell activation were found in CDC patients as well as increased proportions of CXCR3-expressing TCRγδ +Vδ2+ cells. The expansion of Candida-specific IFNγ-producing T cells together with features of T-cell activation and systemic inflammation identified here support the view that CDC belongs to the broad spectrum of fungal-associated immune reconstitution inflammatory syndromes.

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

BackgroundThe outcomes of deep-seated abscesses attributed to chronic disseminated candidiasis (CDC) in patients with hematological malignancies have rarely been reported in recent years.MethodsWe 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.ResultsSixty-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.ConclusionThe 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.

Response of Symptomatic Persistent Chronic Disseminated Candidiasis to Corticosteroid Therapy in Immunosuppressed Pediatric Patients: Case Study and Review of the Literature

Chronic disseminated candidiasis (CDC) is a severe invasive fungal infection principally observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Its pathophysiology remains unclear. We describe the management of 6 children with symptomatic CDC who did not respond to antifungal therapy. The databases of the hematology-oncology departments of 2 tertiary pediatric medical centers were searched for all patients diagnosed with CDC from 2003 to 2015, who responded to corticosteroids after failing antifungal therapy. Clinical, laboratory and radiologic data were collected. Six patients (3 women, 3 men; 9-18 years of age) met the study criteria. Underlying diseases were acute lymphoblastic leukemia (n = 3) and large B-cell lymphoma, acute myeloid leukemia and severe aplastic anemia (n = 1 each). Presenting symptoms/signs of CDC were fever in all cases, with abdominal or chest pain, and/or mucositis. Candida infection was identified in blood cultures in 4 patients and in bronchoalveolar lavage fluid in one. In the absence of response to antifungal agents (4-50 days from CDC diagnosis), prednisone 2 mg/kg/day or equivalent was administered. CDC-attributable clinical symptoms resolved in 4 patients within 6-19 days; one patient required an additional nonsteroidal anti-inflammatory agent. Abnormalities on imaging decreased or disappeared within 5 months to 2 years in 4 patients. In children with persistent symptomatic CDC, despite adequate antifungal therapy, administration of corticosteroids may yield rapid resolution of symptoms and decreased inflammatory markers. In patients who do not respond to steroids, the addition of a nonsteroidal anti-inflammatory drug should be considered.

Usefulness of ß-D-glucan for diagnosis and follow-up of invasive candidiasis in onco-haematological patients

ObjectivesDefinitive diagnosis of invasive candidiasis (IC) may be difficult to achieve in patients with haematological malignancy (PHM). We aimed to evaluate the performance of BDG for the diagnosis and the follow-up of IC in PHM. Patients and methodsWe retrospectively reviewed the serological data of BDG assay in adult and paediatric PHM, who developed candidemia or chronic disseminated candidiasis (CDC) through a 4-year period. Sensitivity and kinetics of BDG were determined for both clinical forms. ResultsIn a panel of 3027 PHM, incidence rates of candidemia and CDC ranged between 0.74 and 0.77 and 0.30 and 0.44 according to the group of patients. At the time of diagnosis, 43.5% and 73% of cases of candidemia and CDC had a positive BDG assay, respectively. We found a significant correlation between the level of BDG at diagnosis and the outcome of candidemia (p = 0.022). In all cases of CDC, BDG negative results were obtained 2 to 6 months before recovery of the CT-scan lesions. ConclusionsBDG exhibits a low sensitivity to detect IC in PHM, but its kinetics correlates the clinical outcome. Additional studies are warranted in patients with CDC to evaluate the interest of monitoring BDG levels to anticipate the discontinuation of antifungal maintenance therapy.

Chronic disseminated candidiasis and acute leukemia: Impact on survival and hematopoietic stem cell transplantation agenda

ObjectivesTo study the management of chronic disseminated candidiasis (CDC) in patients presenting with acute leukemia. Patients and methodsSingle-center retrospective study of acute leukemia patients (2006–2015) to investigate three aspects of CDC: its impact on the time interval between diagnosis and hematopoietic stem cell transplantation, when required (non-parametric Wilcoxon-Mann-Whitney test); its impact on overall survival (Cox proportional hazard regression model); antifungal therapeutic strategies implemented. ResultsA total of 639 patients presenting with acute leukemia were included; 144 were transplanted and 29 developed CDC. CDC did not significantly increase the time interval between diagnosis and transplantation, nor did it impact the overall survival of recipients. An improved overall survival was observed in non-transplanted acute leukemia patients presenting with CDC. ConclusionCDC should not postpone transplantation if antifungal treatment is optimized.

Clinical characteristics and outcomes of patients with chronic disseminated candidiasis who need adjuvant corticosteroid therapy

We performed a retrospective study involving 21 patients with chronic disseminate candidiasis (CDC) and 38 patients with candidemia. Neutropenia of >2 weeks' duration was more common in those with CDC (71%) than in those with candidemia (26%, P < .001), and the azole-resistant rate in patients with CDC (5%) was lower than that in those with candidemia (29%, P = .03). Of the 21 patients with CDC, five (24%) needed adjuvant corticosteroid therapy due to persistent debilitating fever (median, 19 days). Rapid defervescence (median, 5 days) occurred after adjuvant corticosteroid therapy. However, there were no significant differences in 90-day mortality between CDC patients with and without corticosteroid therapy. Further prospective data are needed to define the role of steroids in this setting.