Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological malignancies, hematopoietic stem cell transplantation (HSCT), those admitted in intensive care units (ICUs) and those with prolonged febrile neutropenia. IFDs occur in a setting of multiple morbidities and are associated with case fatality rates between 30 and 70%. Along with the development of classes and compounds, the last two decades have seen substantial improvements in the prevention and management of these infections and an overall increased use of antifungal agents. Areas covered: All antifungal agents, including amphotericin B formulations, echinocandins and the triazoles, may cause hepatic toxicity that ranges from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure. Expert opinion: The present article reviews incidence and severity of hepatotoxicity associated with different classes and agents to provide a better understanding of this specific end organ toxicity and safer use of antifungal agents A thorough understanding of the distribution, metabolism, elimination and drug-drug interactions of antifungal agents used for management of IFDs in combination with safety data from clinical trials, pharmacokinetic and pharmacodynamic studies may guide the use of antifungal treatment in patients at high risk for the development of hepatic dysfunction and in those with underlying liver damage due to cytotoxic therapy.

In this retrospective observational study covering 1998 to 2008, 32 patients (mean age: 7.50 years) were identified that had 35 episodes of candidaemia (0.47 cases/1000 hospital discharges). Cancer/allogeneic haematopoietic stem cell transplantation (43%) and congenital malformations/syndromes (21%) were the predominant underlying conditions. Central venous catheterization (90%), a history of antibacterial therapy (69%) and previous bacteraemia (54%) were frequent comorbidities. Candida albicans (46%) was most common, followed by Candida parapsilosis (17%) and Candida glabrata (14%). Resistance was infrequent and limited to non-albicans Candida spp. The 30-day and 100-day mortality rates were 11.4%.

SummaryMalassezia spp. form part of the normal human cutaneous flora and are implicated in several mild, but recurrent cutaneous diseases, such as pityriasis versicolor, Malassezia folliculitis, seborrhoeic dermatitis, and, with lesser frequency, a range of other dermatological disorders. Malassezia spp. have also been associated with cutaneous and systemic diseases in immunocompromised patients including folliculitis, seborrhoeic dermatitis, catheter-related fungaemia and a variety of deeply invasive infections. In this review, we provide an overview of the epidemiology, risk factors, pathogenesis, clinical manifestations, diagnosis, treatment and outcome of cutaneous and invasive Malassezia infections in immunocompromised patients.

The metabolic syndrome is a cluster of potent risk factors for cardiovascular diseases. To provide information on the late complications of chemotherapy for acute lymphoblastic leukemia (ALL), the authors prospectively studied the frequency of overweight, obesity, and metabolic syndrome in survivors of ALL in the initial years after the completion of therapy. Children and adolescents were classified as having the metabolic syndrome if they met three or more of the following criteria: hypertriglyceridemia, low levels of high-density lipoprotein (HDL), high fasting glucose, obesity, and hypertension. Obesity was defined on the basis of Body Mass Index (BMI) (kg/m2) standard deviation scores or z-scores. Cutoff points for triglycerides and HDL were taken from equivalent pediatric percentiles with the cutoff points proposed by the Adult Treatment Panel III (ATPIII). Hyperglycemia was defined using the ATPIII cutoff points. Elevated systolic or diastolic blood pressure was defined as a value greater than the 95th percentile for age, gender, and height. Fifty-two subjects (29 male and 23 female) with a median age of 15.2 years (range 6.1-22.6 years) were evaluated. Median interval since completion of therapy was 37 months (range 13-121 months). All of them had been treated according to the ALL-BFM 90 chemotherapy protocol and none had received cranial radiotherapy. Of the 52 subjects, 25 (48%) were overweight (BMI z-score >1.5) and 3 (5.76%) were obese (BMI z-score >2); among them, 1 was severely obese (BMI z-score >2.5). Three criteria for the metabolic syndrome (high triglyceride levels, glucose intolerance, and obesity) were fulfilled by three subjects (5.76%). Twenty-nine subjects (55.7%) had at least one risk factor for metabolic syndrome. Hyperglycemia and hypertension were infrequent. Prompt recognition of the risk factors for metabolic syndrome and intervention seem mandatory to ensure early prevention of cardiovascular disease in survivors of ALL.

Zygomycetes are increasingly reported as a cause of life-threatening invasive fungal infections in profoundly immunocompromised patients and in those with diabetic ketoacidosis. Zygomycosis, typically presents as soft tissue, rhino-orbitocerebral, pulmonary or disseminated disease and is characterized by rapid clinical progression and high mortality rates. Treatment with amphotericin B lipid formulations in combination with surgery and, perhaps, the addition of caspofungin offers the best chance for survival; posaconazole, a new antifungal triazole, is increasingly used for consolidation or maintenance therapy. Because of the poor prognosis of zygomycosis, particularly in immunocompromised cancer patients, adjunctive treatments such as hyperbaric oxygen therapy, use of immunomodulatory cytokines, and in vivo iron starvation continue to be explored. However, although each of these modalities is based on a plausible scientific rationale and has been helpful in the management of individual patients, there is no clinical evidence for their general effectiveness as adjunctive treatments in patients with zygomycosis. Further experimental and clinical investigations are necessary to determine whether and how these treatments can impact on outcome and to determine which patients and which types of infection may benefit from them.

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Invasive aspergillosis has emerged as an important cause of morbidity and mortality in immunocompromised children. It remains difficult to diagnose, and outcome depends on early diagnosis, appropriate treatment, and restoration of host defenses. Pediatric patients represent a unique population in their clinical presentation and epidemiology, particularly in respect to the utility of newer diagnostic tools and the pharmacokinetics of antifungal agents. This article reviews the presentation and epidemiology of invasive aspergillosis in children and adolescents with acquired immunodeficiencies and discusses the value of current diagnostic tools and the options for treatment and prevention in this population.

Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children with hematologic malignancies. A detailed literature review until January 2021 was conducted regarding pediatric patient populations treated with agents that target CD2 (alefacept), CD3 (bispecific T-cell engager [BiTE] blinatumomab), CD19 (denintuzumab mafodotin, B43, BiTEs blinatumomab and DT2219ARL, the immunotoxin combotox, and chimeric antigen receptor [CAR] T-cell therapies tisagenlecleucel and axicabtagene ciloleucel), CD20 (rituximab and biosimilars, 90Y-ibritumomab tiuxetan, ofatumumab, and obinutuzumab), CD22 (epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, BiTE DT2219ARL, and the immunotoxin combotox), CD25 (basiliximab and inolimomab), CD30 (brentuximab vedotin and iratumumab), CD33 (gemtuzumab ozogamicin), CD38 (daratumumab and isatuximab), CD52 (alemtuzumab), CD66b (90Y-labelled BW 250/183), CD248 (ontuxizumab) and immune checkpoint inhibitors against CTLA-4 (CD152; abatacept, ipilimumab and tremelimumab) or with PD-1/PD-L1 blockade (CD279/CD274; atezolizumab, avelumab, camrelizumab, durvalumab, nivolumab and pembrolizumab). The aim of this narrative review is to describe treatment-related invasive fungal diseases (IFDs) of each category of agents. IFDs are very common in patients under blinatumomab, inotuzumab ozogamicin, basiliximab, gemtuzumab ozogamicin, alemtuzumab, and tisagenlecleucel and uncommon in patients treated with moxetumomab pasudotox, brentuximab vedotin, abatacept, ipilimumab, pembrolizumab and avelumab. Although this new era of precision medicine shows promising outcomes of targeted therapies in children with leukemia or lymphoma, the results of this review stress the necessity for ongoing surveillance and suggest the need for antifungal prophylaxis in cases where IFDs are very common complications.