Invasive Fungal Infections In Children Research Articles

Invasive fungal infections in the pediatric population

Expert Rev. Anti Infect. Ther. 9(3), 275-278 (2011) Invasive fungal infections (IFIs) are increasing in incidence and constitute an important cause of morbidity and mortality in immunocompromised pediatric patient populations, including, but not limited to, preterm neonates, children and adolescents with hematologic malignancies, and those undergoing hematopoietic stem cell trans- plantation (HSCT) (1-3). Although chil- dren and adults are similarly vulnerable to IFIs, important differences between these two patient groups have to be considered. These include epidemiology, diagnostic approaches, as well as pharmaco kinetics (PK) and adverse effects of antifungal agents, all of which have an impact on anti- fungal management strategies. In order to optimize prevention and treatment of IFIs in children, all specialists involved in the care of pediatric patients have to be familiar with these specifics of pediatric care . Populations at risk & epidemiology

Invasive fungal infections in pediatric oncology

Data on the epidemiology and outcome of invasive fungal infections in children with cancer are limited. The aim of the study was to delineate the epidemiologic, clinical features, risk factors, and outcome of invasive fungal infections in this population. The medical records of all children with malignancies diagnosed with an invasive fungal infection in 1998-2006 at a tertiary pediatric medical center were reviewed for demographic, clinical, and laboratory data. Invasive fungal infection was diagnosed according to the latest EORTC/MSG criteria. Of the 1,047 children hospitalized in the hematology/oncology department during the study period, 75 (7.2%) were diagnosed with a proven (n = 16, 21.3%), probable (n = 18, 24%), or possible (n= 41, 54.7%) invasive fungal infection. Fifteen (20%) had candidemia (non-albicans in 60%), and 60 (80%) had a mold infection (non-Aspergillus in 55%). Crude mortality was 21.7%. The most common underlying diseases were myeloid leukemia (n = 26, 34.7%) and acute lymphoblastic leukemia (n = 24, 32%). Compared to other malignancies, acute myeloid leukemia was significantly associated with the development of invasive fungal infections. Profound neutropenia and high treatment intensity were present in 89% and 73% of patients with IFI respectively. The current mortality rates of invasive fungal infection in children with cancer are lower than previously reported in children and adults. However, the proportion of non-albicans candidemia is increasing, and non-Aspergillus molds are emerging as important pathogens, which may have important implications for prophylaxis and empiric therapy. Improved prevention, early detection, and advanced treatment strategies are needed to improve the outcome.

Invasive Fungal Infections in Pediatric Hematopoietic Stem Cell Transplant Patients, a Retrospective Analysis

Invasive fungal infections (IFI) remain a major cause of morbidity and mortality in patients (pts) undergoing HCT. The epidemiology of IFI has changed, with a higher proportion of mould infections reported compared to earlier reports (Marr et al. Clin Infect Dis. 2002). The incidence of IFI in children undergoing HCT has been reported at a range of 1.6-25%. The changes in epidemiology of IFI are attributed to multiple factors, including corticosteroid treatment, graft-versus-host disease (GVHD), increase in transplants from alternative donors, and emergence of resistance with use of azoles for IFI prevention.

The advances of epidemiology and earlier laboratory diagnosis for invasive fungal infection in children

Invasive fungal infection(IFI) is becoming increasingly important issue in pediatrics and pediatric intensive care unit. IFI often occurs in newborns and children with immune dysfunction. Candida and Aspergillus spp. are the most commonly isolated organisms. Early diagnosis can improve the prognosis of IFI. The 1,3-β-D-glucan(G)test,galatomannan antigen(GM)test and PCR test can aid earlier dignosis for IFI in high-risk children. Key words: Invasive fungal infection; Epidemiology; Laboratory diagnosis; Children

Invasive fungal infections in pediatric patients: a review focusing on antifungal therapy

Invasive fungal infections in children appear to have increased over the past few decades. Substantial differences compared with adult patients in risk factors, pathogen epidemiology, pathophysiology and, most notably, pharmacokinetics of antifungal agents require age-adapted management and treatment approaches. The present article reviews these aspects for invasive aspergillosis and invasive candidiasis, the two most common life-threatening fungal infections.

Incidence of Viral and Fungal Infections following Busulfan-Based Reduced-Intensity versus Myeloablative Conditioning in Pediatric Allogeneic Stem Cell Transplantation Recipients

Reductions in the duration and nadir of neutropenia have translated into a significant decrease in bacteremia in adult recipients of allogeneic stem cell transplantation (allo-SCT) with reduced-intensity conditioning (RIC) during the first 30 days after transplantation. It remains to be determined whether RIC allo-SCT also will result in a decrease in systemic viral infections (SVIs) and invasive fungal infections (IFIs), which are more dependent on alterations in cellular immunity. We compared the incidence of SVIs and IFIs in children receiving busulfan-based RIC allo-SCT and in children receiving myeloablative conditioning (MAC) allo-SCT for various malignant and nonmalignant diseases. Allo-SCT recipients at risk for cytomegalovirus (CMV) received ganciclovir/foscarnet, and most of the patients received antifungal prophylaxis with liposomal amphotericin B until day +100. Eighty-six patients (median age, 7.5 years; 70% with malignant disease, 30% with nonmalignant disease; 80% average risk, 20% poor risk) were evaluated. The probability of developing grade II-IV acute graft-versus-host disease (aGVHD) was 29.1% (95% confidence interval [CI]=16.7%-41.6%) in RIC allo-SCT versus 40.3% (95% CI=23.9%-56.6%) in MAC allo-SCT (P=.23), and that of chronic GVHD (cGVHD) was 28.9% (95% CI=14.7%-43.0%) in RIC allo-SCT versus 28.4% (95% CI=10.5%-46.3%) in MAC allo-SCT (P=.73). The overall probability of developing an SVI was 58%, and that of developing an IFI was 15%. These probabilities did not differ significantly by conditioning intensity. In a multivariate Cox regression model, the following were identified as independent risk factors for invasive fungal infection: older age (hazard ratio [HR]=1.3; 95% CI=1.1-1.6; P=< .01), poor risk status (HR=6.5; 95% CI =1.1-37.4; P=.03), and CMV-positive recipient (high vs low CMV risk group, HR=26.7; 95% CI=3.4-210.8; P=< .01). Overall infection-related mortality was only 1.1% (1/86) for SVIs and 2.3% (2/86) for IFIs. Our data indicate that RIC allo-SCT does not carry a lower risk of SVIs and IFIs than MAC allo-SCT in pediatric recipients.

Invasive Fungal Infections in Children

Invasive Fungal Infections in Children

Invasive fungal infections in the paediatric and neonatal population: diagnostics and management issues

Invasive fungal infections in children appear to have increased over the past few decades. Especially neonates and children with primary and secondary immunodeficiencies are at risk. Candida and Aspergillus spp. are the most commonly isolated organisms. In addition, Malassezia may cause systemic infections in newborns and zygomycosis is important because of its rising incidence and high case fatality rate. Timely diagnosis and initiation of appropriate antifungal therapy is imperative for improving outcomes. However, traditional techniques are time-consuming and representative sample material, using invasive procedures, may be difficult to obtain in the paediatric setting. This review provides an overview of the advances in detection and rapid species identification, with a focus on issues relevant in these settings. Subsequently, the current antifungal treatment options for neonates and children are discussed in light of the antifungal spectrum of the available agents and the specific pharmacokinetic properties in different age groups. Although a multitude of newer antifungal compounds have become available within the last decade, further studies are necessary to clearly establish the role for each of these agents among neonates and children.

Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis

Children with acute leukemia have increased risk for invasive fungal infections (IFI) but the role of long term antifungal prophylaxis (AFP) in morbidity and mortality of IFI is not well-known. Medical records of 154 children with acute leukemia who received AFP with fluconazole during intensive chemotherapy were retrospectively reviewed to determine risk factors, clinical characteristics and outcome of IFI. The overall incidence of IFI was 13.6%. Frequencies of proven, probable and possible infections were 7.2%, 2.6%, and 3.8%, respectively. The causative agent was Candida in 12 (57.2%) and Aspergillus in 9 (42.8%) children. There were 10 children with candidemia (47.6%), 7 with pulmonary aspergillosis (33.4%), 2 with hepatosplenic candidiasis (10.0%), one with sinopulmonary aspergillosis (4.5%) and one with sinus aspergillosis (4.5%). IFI was twice as common in acute myeloid leukemia (AML) (20.7%) than in acute lymphoblastic leukemia (ALL) (10.2%). Duration of profound neutropenia (P = 0.01) and steroid medications (P = 0.001) were significantly associated with IFI in univariate but not in multivariate analysis. Liposomal amphotericin B (L-AMB) was successful in 15 of 21 children as a single agent. Voriconazole produced complete response in four children with invasive aspergillosis and two with hepatosplenic candidiasis, who were unresponsive to L-AMB. The rate of IFI attributable death was 5%. Our results indicate that AFP with fluconazole and early empirical antifungal therapy may be effective in reducing the incidence and mortality of IFI in children with acute leukemia.

The Clinical Feature of Invasive Fungal Infection in Pediatric Patients With Hematologic and Malignant Diseases

Invasive fungal infections (IFI) are an important complication in hematologic malignancies and stem-cell transplantation (SCT). However, there are limited data characterizing IFI in children. The clinical feature of IFI after chemotherapy and SCT were analyzed in 334 pediatric patients treated at Hokkaido University Hospital from 1997 to 2006. The cumulative incidence of IFI was 6.9%; this comprised cases of proven, probable and possible IFI at rates of 1.2%, 3.0%, and 2.7%, respectively. The infected lesions were lung in 14 patients, liver in 5 patients, brain in 3 patients, fungemia in 2 patients, kidney in 1 patient, and endophthalmitis in 1 patient. The mortality of IFI was 48.2%, excluding patients who died due to relapse and interstitial pneumonitis; in particular, 71.4% patients with a lung lesion (10/14) died due to IFI. Fifty-nine pediatric patients died in our institution over the 10-year period of the study and IFI was the direct cause of death in 18.6% (11/59) of the patients. Risk factors for IFI with chemotherapy and SCT were also analyzed. Univariate analysis showed that age at diagnosis older than 10 years, relapse of original disease, long-term administration of broad-spectrum antibiotics, and acute myelogenous leukemia (AML) were the risk factors for IFI. All patients with IFI received long-term antibiotic therapy. AML was most strongly associated using a multivariate analysis. The prognosis of IFI has been expected poor; therefore, prevention of this condition, especially for older patients with AML, would be important.

260: Comparison of Incidence of Systemic Viral Infection (SVI) and Invasive Fungal Infection (IFI) in Children Receiving Busulfan Based Reduced Intensity Allogeneic Stem Cell Transplant (RIAlloSCT) vs. Myeloablative AlloSCT (MA-AlloSCT) for Malignant and Non-Malignant Diseases

We have previously demonstrated the safety and efficacy of RIAlloSCT in pediatric recipients (DelToro/Cairo et al, BMT, 2004; Bradley/Cairo et al, BMT, 2007). RIAlloSCT in adults is associated with a significant decrease in early bactermia (Junghanns et al, BBMT, 2002), but not in incidence of IFI or CMV (Fukuda et al, Blood 2003; Junghanns et al, Blood 2002). Date is lacking on incidence and timing of SVI and IFI in children undergoing RIAlloSCT. We compared the incidence of SVI and IFI in children receiving busulfan (BU)-based RIAlloSCT (group-A) vs.

Invasive fungal infection in children undergoing chemotherapy for cancer

In children with cancer, invasive fungal infection is a serious complication of anticancer therapy. Successful treatment is a major challenge for clinical oncologists. The records of all episodes of invasive fungal infection occurring in children with cancer undergoing chemotherapy at Mackay Memorial Hospital, Taipei between January 1987 and October 2005 were reviewed. The following were documented: general characteristics, clinical presentation, predisposing factors, pathogens, antifungal treatment, association with anticancer therapy and outcome. We endeavoured to preserve renal function by administration of new antifungal agents. Anticancer therapy was given as soon as possible after diagnosis and the dose of chemotherapeutic agents was adjusted as required to prevent unduly prolonged interruption of chemotherapy and minimise the risk of leukaemia relapse. Twenty-six patients with 29 episodes of invasive fungal infection were reviewed. Candida species were the leading pathogens (14/29) followed by Aspergillus species (11/29). In six episodes there was both visceral dissemination and fungaemia. In 23/29 patients, antibiotic therapy preceded fungal infection with a median of 11 days. Three children died from extensive fungal infection and four from progression of malignancy; the remainder survived with a median follow-up of 40 months (range 12-233). The actuarial 12-month survival rate was 87%; in patients with invasive candidiasis and aspergillosis the rates were 75% and 100%, respectively. In children with cancer, most invasive fungal infections can be treated successfully. Current antifungal prophylaxis should protect patients from fungal infection.

Voriconazole

Voriconazole (VFEND), a synthetic second-generation, broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the cell membrane and halting fungal growth. In the US, intravenous and/or oral voriconazole is recommended in adults for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, disseminated infections caused by Candida spp., oesophageal candidiasis, and in patients with scedosporiosis and fusariosis who are refractory to or intolerant of other antifungal therapy. In Europe, intravenous and/or oral voriconazole is recommended in adults and paediatric patients of at least 2 years of age for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, fluconazole-resistant serious invasive Candida spp. infections, scedosporiosis and fusariosis. In large randomised trials, voriconazole was an effective and generally well tolerated primary treatment for candidiasis and invasive aspergillosis in adults and adolescents. More limited data also support the use of voriconazole for the treatment of invasive fungal infections in children, in those with rare fungal infections, such as Fusarium spp. or Scedosporium spp., and in those refractory to or intolerant of other standard antifungal therapies. The availability of both parenteral and oral formulations and the almost complete absorption of the drug after oral administration provide for ease of use and potential cost savings, and ensure that therapeutic plasma concentrations are maintained when switching from intravenous to oral therapy. On the other hand, the numerous drug interactions associated with voriconazole may limit its usefulness in some patients. Further clinical experience will help to more fully determine the position of voriconazole in relation to other licensed antifungal agents. In the meantime, voriconazole is a valuable emerging option for the treatment of invasive aspergillosis and rare fungal infections, including Fusarium spp. and Scedosporium spp. infections, and provides an alternative option for the treatment of candidiasis, particularly where the causative organism is inherently resistant to other licensed antifungal agents.

Antifungal treatment in pediatric patients

Invasive fungal infections have increased in frequency and severity over the past two decades as a result of an increasing number of immunocompromised patients. This new age of opportunistic fungal infections extends to pediatric patients. The last decade has seen the development of several new antifungal agents for the treatment of these infections. However, there is a paucity of data on the treatment of invasive fungal infections in children. This review provides a brief overview of the current state of antifungal therapy for children, discussing the important antifungal classes and the differences in mechanisms of action and resistance, pharmacology, and efficacy and safety data in pediatric patients outside the neonatal period.

Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation

Invasive fungal infections (IFI) are the leading cause of infectious mortality in adult patients undergoing hematopoietic cell transplantation (HCT) after myeloablative conditioning, but the extent of this problem in the pediatric population is unclear. We retrospectively examined risk factors for IFI among 120 consecutive pediatric patients undergoing allogeneic HCT at a single center. The incidence of proven or probable IFI in pediatric patients during the first year after allogeneic HCT was 13%, comparable to the rate reported in adult patients; however, unlike IFI in adult patients, the majority of IFI in children occurred within the first month after transplantation. The primary risk factors for IFI were duration of neutropenia, age greater than 10 years, transplant for severe aplastic anemia or Fanconi anemia, and high-dose corticosteroid administration for 10 days or longer. IFI were more likely to be successfully treated (42%, 5/12 patients) in pediatric HCT recipients when compared to previous reports of adult recipients. Nonrelapse mortality was estimated at 17% (20/120 patients) after allogeneic HCT, of which 35% (seven patients) were directly attributed to IFI. Thus, IFI is a significant cause of nonrelapse mortality in children undergoing allogeneic HCT and more effective strategies are needed to prevent and treat IFI.

Invasive fungal infection in children with persistent febrile neutropenia.

Children with persistent febrile neutropenia (fever > 96 hours) refractory to antibacterial therapy carry a high risk of invasive fungal infection (IFI). However, epidemiologic data in such patient populations is lacking in Taiwan. A retrospective study was conducted to identify risk factors and outcome of IFI in children with persistent febrile neutropenia (> 96 hours) hospitalized at National Taiwan University Hospital from January 1, 1999 through December 31, 1999. They were categorized into proven, probable, possible, or no IFI according to host, microbiologic and clinical criteria. A total of 29 episodes (35.4%) of IFI occurred in 82 episodes of persistent febrile neutropenia and included 1 proven, 12 probable and 16 possible cases. Pneumonia was most common (69.0%), followed by disseminated infection (17.2%), paranasal sinusitis (6.9%), and hepatosplenic abscess (6.9%). Multivariate analysis revealed 4 risk factors independently associated with IFI: prolonged neutropenia (> 30 days; odds ratio [OR], 10.4; 95% confidence interval [CI], 1.8-60.5), prolonged steroid therapy (OR 2.0, 95% CI 1.0-10.8), allogeneic bone marrow transplantation (OR 5.3, 95% CI 1.0-28.0), and relapsed malignancy (OR 3.5, 95% CI 1.1-11.1). Patients with IFI carried higher in-hospital mortality than those without (51.7% vs 3.8%, p < 0.001). Among those with IFI, delayed antifungal therapy (persistent fever > 7 days) was associated with higher mortality rate than earlier treatment (73.3% vs 28.6%, p = 0.024) and was an independent adverse prognostic factor. IFI was common in patients with persistent febrile neutropenia and delayed antifungal therapy was an independent adverse prognostic factor.

P0253 TARGETING HIGH RISK PATIENTS BY ANTIFUNGAL PROPHYLAXIS COULD PREVENT FUNGAL INFECTIONS AFTER LIVER TRANSPLANTATION IN CHILDREN

Introduction: Fungal infection (FI) causes significant morbidity and mortality after liver transplantation (LTx) in children. The aims of this study were to establish the incidence of, and risk factors for, FI, and the value of antifungal prophylaxis in high risk patients Methods: A comparison was made of the incidence of FI between a group of children (n = 79) transplanted between 1997 and 1998 (Group 1) and those transplanted between 1999 and 2000 (n = 93) following the introduction of an anti-fungal prophylaxis protocol (Group 2). Fluconazole was given immediately after and for 2 weeks post-LTx to those with risk factors identified from the data from Group 1, or amphotericin B to those also colonised by Aspergillus spp. or non-C. albicans yeasts. Results: The incidence of FI in Group 1 was 40% (32/79): half of these were invasive. Candida spp. were recovered in 73% of patients; 55% were Candida albicans. The following were risk factors for FI: pre LTx colonisation with fungus; ICU stay >2 weeks; antibacterials for >3 weeks within 2 months of LTx; steroids; re-transplantation, and hepatic artery thrombosis. 48% (38/79) of children were colonised by fungus pre-LTx: C. albicans in 71.5%, and Aspergillus spp. in 3%. Post-LTx the same number were colonised, but C. albicans and Aspergillus spp. were more frequent. The incidence of FI pre-LTx in Group 2 was 44% (41/93): 68% by C. albicans and 5% by Aspergillus spp.; post-LTx the incidence of detectable colonisation was 16% (15/93). The incidence of FI and invasive FI in Group 2 was 10% and 2%, respectively. Conclusion: Although this is not a controlled study, this targeted approach to antifungal prophylaxis appears to have been effective in reducing the incidence of both non-invasive and invasive FIs in children after LTx. However, the influence of changes in antibacterial policy - that may have affected both fungal colonisation and FI – are acknowledged and will be discussed.

Caspofungin associated with liposomal amphotericin B or voriconazole for treatment of refractory fungal pneumonia in children with acute leukaemia or undergoing allogeneic bone marrow transplant

Caspofungin, in association with other antifungal drugs, was administered as rescue therapy in two cases of documented and one case of possible invasive fungal infection in children with acute leukaemia or undergoing allogeneic bone marrow transplant. The combined therapy was well-tolerated and seemed to be effective in all three patients. A combination antifungal therapy including caspofungin could represent an effective therapy for children with invasive mycoses refractory to single-agent antifungal therapy.

Efficacy of amphotericin B lipid complex in the treatment of invasive fungal infections in immunosuppressed paediatric patients.

The safety and efficacy of amphotericin B lipid complex (ABLC) were evaluated in a retrospective study of 46 paediatric patients with invasive infections. The study included a large proportion of patients who were refractory to or intolerant of conventional antifungal therapy. The mean age of the children was 9.7 +/- 4.8 years. Primary underlying conditions included mainly haematopoietic stem cell transplantation, leukaemia and lung transplantation. The mean daily dose given was 4.11 mg/kg for a mean duration of 38.7 days. At the end of therapy, 38 of 46 (83%) patients responded successfully to treatment with ABLC, including 18 of 23 (78%) with aspergillosis and 17 of 19 (89%) with candidiasis. ABLC was well tolerated, with a low incidence of adverse events. The mean creatinine value was 74.5 microl/mol/l at baseline and 78.2 micromol/l at the end of therapy. These results support the use of ABLC in the treatment of invasive fungal infections in children, including patients who have previously failed, or are intolerant of, traditional antifungal regimens.

Current approaches to diagnosis and treatment of fungal infections in children infected with human immuno deficiency virus.

The prolonged survival of profoundly immunocompromised patients has revealed mucosal and invasive fungal infections to be major causes of morbidity and mortality in advanced HIV disease in children of all age groups. Antifungal resistance has become a clinically relevant problem. Paediatricians caring for HIV-infected children need to be aware of these increasingly frequent and often life-threatening infectious complications. This article reviews what is currently known about epidemiology, clinical presentation, diagnosis and treatment of mucosal and invasive fungal infections in children and adolescents with HIV disease. Candida spp. have become a leading bloodstream isolate in hospitalised patients; mucosal candidiasis is the most prevalent opportunistic infection in HIV-infected patients, and in both invasive and superficial infections, non Candida albicans spp. are on the increase. Invasive pulmonary aspergillosis has surfaced as an HIV-associated complication and previously uncommon fungi are more frequently encountered. HIV-infected individuals are particularly susceptible to Peumocystis carinii, Cryptococcus neoformans and infections by endemic fungi, such as Histoplasma capsulatum, Coccidioides immitis, Penicillium marneffei, and others. Newer immunological and molecular-based methods provide early and rapid diagnosis and monitoring. Potent and broad-spectrum third generation triazoles and novel fungicidal lipopeptides of the echinocandin class of antifungal antibiotics have entered clinical trials. Immunmodulation by recombinant cytokines and antifungal vaccines are very actively pursued inroads to adjunctive and preventive immunotherapy. Mucosal and invasive fungal infections will remain important complications in HIV-infected children of all age groups. Interventional studies and well documented case series are needed to improve the molecular diagnosis, treatment and prevention of invasive fungal infections in the paediatric HIV-infected population.