Athanasios Tragiannidis

Minireview: Malassezia infections in immunocompromised patients.

Malassezia 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.

Recent Advances in Antifungal Prevention and Treatment

Invasive fungal infections are important causes of morbidity and mortality in patients with bone marrow failure syndromes and hematological malignancies, or who are undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Current epidemiological trends indicate a shift toward infections by Aspergillus spp., non-albicans Candida spp., and previously uncommon fungal pathogens that have decreased susceptibility to the available antifungal agents. The last two decades have seen substantial improvements in the clinical, laboratory, and radiological diagnosis of these infections and the development of new antifungal compounds. Progress has been made in establishing disease definitions and paradigms for antifungal intervention and in the design and conduct of interventional clinical trials. Collectively, these advances have led to major but ongoing changes in the management of patients at risk of or being affected by invasive fungal infections. This article reviews current approaches to prevention and treatment of opportunistic fungal infections in immunocompromised patients with hematological disorders and discusses novel approaches to antifungal chemotherapy and adjunctive treatments.

Clinical hepatotoxicity associated with antifungal agents.

ABSTRACT Introduction: 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.

Invasive Aspergillosis in Children With Acquired Immunodeficiencies

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.

Invasive candidiasis: update on current pharmacotherapy options and future perspectives

Introduction: Invasive candidiasis (IC), mainly candidemia, is a leading cause of morbidity and mortality among immunocompromised patients and those admitted to intensive care units. Despite the recognition of risk factors and advances in disease prevention, Candida-related hospitalizations and mortality continue to rise. For treatment, four classes of older and newer antifungal agents are currently available. Adjunctive immunotherapies and a monoclonal antibody against heat shock protein 90 (efungumab) are promising novel therapeutic approaches. Areas covered: In this article, approaches and therapeutic agents for candidemia and other forms of IC are reviewed. Expert opinion: The thorough understanding of the available antifungal agents in combination with the increasing knowledge of the mechanisms that underlie the pathogenesis of Candida infections and the development of newer approaches such as efungumab and immunotherapy with adjunctive cytokines may improve the prognosis of patients with life-threatening invasive Candida infections.

FcγRIIa and FcγRIIIa polymorphisms in childhood primary immune thrombocytopenia: implications for disease pathogenesis and outcome.

Primary immune thrombocytopenia (ITP) is the commonest acquired cause of bleeding in childhood. The aim of the present study was to evaluate the role of Fc&ggr;RIIa and Fc&ggr;RIIIa polymorphisms in the pathogenesis and therapeutic result of childhood ITP. The genotypic frequencies for two Fc&ggr; receptor single-nucleotide polymorphisms, Fc&ggr;RIIa-131 arginine (R) versus histidine (H) and Fc&ggr;RIIIa-158 valine (V) versus phenylalanine (F) were examined in 53 children diagnosed with ITP. The genotype frequencies were compared with those of 45 healthy controls. The association between the above frequencies and disease natural course as well as therapeutic result following intravenous immunoglobulin (IVIG) administration was investigated. Fc&ggr;RIIIa-158V was significantly overrepresented in children with ITP versus controls (P = 0.029), whereas no statistically significant difference was noted in Fc&ggr;RIIa polymorphism distribution. No statistically significant difference was noted in the above genotype frequencies’ distribution between children with newly diagnosed and chronic ITP, as well as with regards to the therapeutic result following IVIG administration. High-affinity Fc&ggr;RIIIa variant (158 V) is possibly implicated in disease susceptibility, but neither of the two Fc&ggr; receptor single-nucleotide polymorphisms seem to have any impact on chronicity or therapeutic effect of IVIG.

Standard-dose intravenous anti-D immunoglobulin versus intravenous immunoglobulin in the treatment of newly diagnosed childhood primary immune thrombocytopenia.

Background We conducted a study to evaluate the efficacy of intravenous (IV) anti-D against IV immunoglobulin (IVIG) in newly diagnosed immune thrombocytopenia (ITP) in children and to identify the clinical characteristics of the children most likely to benefit from one or the other treatment. Procedure Children (6 mo to 14 y) with newly diagnosed ITP and a platelet count <20,000/&mgr;L were treated either with a single bolus dose of 50 &mgr;g/kg IV anti-D or with 0.8 to 1 g/kg IVIG in a randomized manner. Results Twenty-five patients, mean age of 6.8 years, were treated either with IV anti-D (n=10) or with IVIG (n=15). Both drugs were equally efficient in raising the platelet count above 20,000/&mgr;L at 24 hours posttreatment. Children who presented with bleeding stage 1 or 2 (no mucosal bleeding) responded better to IVIG treatment, in terms of an increase in platelet count at 24 hours posttreatment (P=0.04). Hemoglobin drop was greater in the anti-D group (P=0.002). Conclusions A single bolus dose of 50 &mgr;g/kg of IV anti-D is a safe and effective first-line treatment in newly diagnosed ITP in childhood and mucosal bleeding is a poor prognostic factor for treatment with IVIG.

Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors

Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFα) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohns disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid‐refractory graft‐vs‐host disease and other immune‐mediated conditions. Currently, five anti‐TNFα agents are approved by the European Medicines Agency (EMA), including the monoclonal anti‐TNF antibodies infliximab, adalimumab, golimumab and certolizumab pegol along with etanercept, a TNFα‐receptor/IgG‐Fc fusion protein. Theoretical considerations related to their mode of action and clinical observations suggest that opportunistic infectious complications should be seriously considered as possible adverse events of macromolecular immunosuppressants. The purpose of this review is to critically analyze the literature on invasive fungal infections (IFIs) occurring in association with TNFα inhibitors alone or in combination with other immunosuppressive agents, with a focus on pediatric patients, and to provide a framework of evaluating the risk for IFIs in this population.

Invasive candidiasis and candidaemia in neonates and children: update on current guidelines

Invasive candidiasis (IC) and candidaemia are leading causes of infectious morbidity and mortality among immunocompromised paediatric patients and those admitted to intensive care units. Despite improvements in diagnosis, prevention and treatment, both mortality rates and the economic burden of disease still remain high. To address this issue, several international societies and organisations have proposed guidelines for the management of IC/candidaemia in both neonates and children. In this article, we review current recommendations of the Infectious Diseases Society of America, the European Conference on Infection in Leukaemia, the European Society of Clinical Microbiology and Infectious Diseases and the German Speaking Mycological Society/Paul‐Ehrlich Society for Chemotherapy for the management and prevention of IC/candidaemia in children and neonates.

Invasive aspergillosis in children and adolescents.

Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised children. Disease control depends on prevention, early diagnosis, predictive microbiological information, prompt and appropriate treatment and restoration of host defenses. Relative to adults, invasive aspergillosis in children and adolescents is unique in its clinical presentation, epidemiology, and in particular, the utility of newer diagnostic tools and the pharmacokinetics of active antifungal agents. Here we review the presentation and epidemiology of invasive aspergillosis in children and adolescents and discuss the value of current diagnostic tools and strategies and options for treatment and prevention in this special population.