Occurrence Of Invasive Fungal Infections Research Articles

2716. Epidemiology of invasive fungal infection in pediatric liver transplant recipients: A retrospective, single-center study, 2012-2022

Abstract Background Studies on liver transplant (LT) recipients have reported an incidence of invasive fungal infection (IFI) ranging from 2.5 to 5%; however, antifungal prophylaxis has not yet been approved by the Ministry of Food and Drug Safety in Korea. We investigated the incidence of early-onset IFI and its characteristics in pediatric LT recipients in Korea, and also explored the risk factors for IFIs. Methods This is a retrospective, single-center study on children (< 19 years of age) who have undergone LT from 2012 to 2022 at Severance Hospital, Korea. IFI was defined as the detection of fungus in sterile fluid, tissue, and/or blood with symptoms of a fungal infection. Superficial fungal infection and colonization on the skin or urine were excluded. The primary outcome is the occurrence of IFI within 90 days of LT. The logistic regression method was used to analyze the risk factors for IFI. Results A total of 104 LT children were included, among whom 6 received multiple transplantations, resulting in 111 LT cases. 42% (n = 44) were male, and the median age at LT was 4.0 years of age (IQR 1.0–11.0). Two thirds of the patients received LT due to biliary atresia (n = 69, 66%), and the remaining were diagnosed with acute liver failure (n = 17, 16%), miscellaneous causes (n = 11, 11%), and so on (n = 7, 7%). Antifungal prophylaxis, except nystatin gargle, was done in 12.8% of recipients. IFI was identified in 19 patients (18%), and due to five multiple IFI events per patient, a total of 23 IFI events were noted at a median time of 16.5 days after LT (IQR 10-38). 87% of the pathogens detected were Candida species (C. albicans 40%, C. parapsilosis 35%, C. auris 15%), and Aspergillus fumigatus (13%). Antifungal susceptibility patterns are described in Table 1. The risk of IFI was significantly increased in those who underwent acute re-transplantation, postoperative intervention, or surgery due to bleeding, vascular, and bile duct complications (OR = 4.6; 95% CI, 1.5–13.6; P = 0.006) 8) and renal replacement therapy (OR=3.2; 95% CI, 1.1-8.8; P=0.028).Table.Antifungal susceptibility patterns of identified pathogens according to Clinical and Laboratory Standards Institute (CLSI). a Number of cases identified with the fungal pathogen b Antifungal susceptibility testing has to be additionally requested, so it was not performed in all cases. c 1 case had a fluconazole-resistant C.parapsilosis strain with intermediate resistance to other antifungal agents (MIC: fluconazole 32, micafungin 2, caspofungin 2, voriconazole 0.12, amphotericin B 0.5). d CLSI does not provide a tentative MIC breakpoint for voriconazole and other second generation azoles, but that of fluconazole may be considered as a surrogate. Conclusion The incidence of early IFI after LT in Korean children is considerable; therefore, universal antifungal prophylaxis is necessary. High-risk IFI patients, such as those undergoing reoperation, intervention, or renal replacement therapy, require attention and close monitoring. Disclosures All Authors: No reported disclosures

D-index as a Risk Factor for Invasive Fungal Infections in Patients With Acute Lymphoblastic Leukemia From a Reference Hematology Center in Bogota.

Introduction Patients with hematologic malignancies are susceptible hosts for the development of invasive fungal infection (IFI), one of the main life-threatening infectious complications faced by these patients. Currently, we have antifungal prophylaxis strategiesand antifungal treatment schemes and we recognize that the main risk factor involved is profound and prolonged neutropenia. D-index and cumulative D-index are quantitative parameters, which determine the magnitude of neutropenia, as a function of duration and depth and their value correlates with the occurrence of IFI. Materialand methods A case-control study in patients older than 18 years with acute lymphoblastic leukemia (ALL) was admitted between 2009 and 2019 at the National Cancer Institute for induction, consolidationand salvage chemotherapy. Results A total of 167 patients were included, who received 288 cycles of chemotherapy, the latter were considered the unit of analysis. A generalized estimating equations (GEE) model was designed to analyze correlated data; three quantitative and continuous variables of interest were included in this model: age (years), D-index and deep neutropenia (days). For the population D-index, an odds ratio (OR) = 1.000227 (95% CI 1.0002-1.0004); p < 0.001 was obtained. Conclusion D-index is associated with the development of IFI in patients with ALL, with an exponential increase in OR as the absolute value of the D-index increases.

New Perspectives on Primary Prophylaxis of Invasive Fungal Infection in Children Undergoing Hematopoietic Stem Cell Transplantation: A 10-Year Retrospective Cohort Study

Allogenic hematopoietic stem cell transplantation (a-HCT) remains a therapeutic treatment for many pediatric hematological diseases. The occurrence of invasive fungal infections (IFIs) is a complication for which ECIL-8 recommends primary antifungal prophylaxis. In this study, we evaluated the impact of our local strategy of not systematically administering primary antifungal prophylaxis in children undergoing a-HCT on the occurrence and mortality of IFIs. We performed a retrospective monocentric study from 2010 to 2020. We retained all proven and probable IFIs diagnosed during the first year post a-HCT. 308 patients were included. Eighteen patients developed twenty IFIs (thirteen proven, seven probable) (6.5%) among which aspergillosis (n = 10, 50%) and candidosis (n = 7, 35%) were the most frequently diagnosed infections. Only 2% of children died because of an IFI, which represents 14% of all deaths. Multivariate analysis found that age > 10 years (OR: 0.29), the use of a therapeutic antiviral treatment (OR: 2.71) and a low neutrophil count reconstitution (OR: 0.93) were significantly associated with the risk of IFI occurrence. There was also a trend of malignant underlying disease and status ≥ CR2 but it was not retained in multivariate analysis. IFI occurrence was not higher in our cohort than what is reported in the literature with the use of systematic antifungal prophylaxis, with a good survival rate nonetheless. Thus, a prophylaxis could be considered for children with a high risk of IFI such as those aged over 10 years.

Risk of infection in patients with hematological malignancies receiving CAR T-cell therapy: systematic review and meta-analysis

Background Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment option for relapsed or refractory B-cell malignancies and multiple myeloma. Various factors —underlying immune dysfunction, prior chemotherapy, lymphodepletion, prolonged cytopenias, hypogammaglobulinemia and use of corticosteroids and tocilizumab— may contribute to the development of infectious complications. Research design and methods We conducted a systematic review and meta-analysis on the incidence of overall and severe (grade ≥3) infection in patients with hematological malignancies receiving CAR T-cells. Secondary outcomes included the specific rates of bacterial, viral and invasive fungal infection (IFI), and infection-related mortality. PubMed, Embase and Web of Science databases were searched from inception to May 27, 2022. Sensitivity analysis were performed according to the type of malignancy and study design (randomized clinical trials [RCTs] or observational studies). Results Forty-five studies (34 RCTs) comprising 3,591 patients were included. The pooled incidence rates of overall and severe infection were 33.8% (I2 = 96.31%) and 16.2% (I2 = 74.41%). The respiratory tract was the most common site of infection. Most events were bacterial or viral, whereas the occurrence of IFI was rare. The pooled attributable mortality was 1.8% (I2 = 43.44%). Conclusions Infection is a frequent adverse event in patients receiving CAR T-cell therapy. Further research should address specific risk factors in this population.

T-lymphocytes Expression of Toll-like Receptors 2 and 4 in Acute Myeloid Leukemia Patients with Invasive Fungal Infections.

BackgroundInvasive fungal infections (IFIs) are important cause of mortality in acute myeloid leukemia (AML) patients on treatment with intensive induction chemotherapy. Toll-like receptors, mainly Toll-like receptors 2 and 4 (TLR2 and TLR4), play a considerable role in the host defense against microorganisms. The involvement of TLR signaling in modulation of innate immune response is extensively discussed, but the TLR expressions profiling on adaptive immune cells are not specified. Also, the expressions of TLRs and their association with the occurrence of IFIs in patients with AML are not studied. So, the novel aim of this study was to investigate the associations between the T-lymphocyte expression of TLR2 and TLR4 and the occurrence of IFIs in AML patients treated with intensive induction chemotherapy.Materials and MethodsOne hundred twenty two newly diagnosed AML patients were evaluated. The laboratory diagnostic techniques for IFIs include culture, microscopic examination, histopathology, galactomannan assay and PCR. The expressions of TLR2 and TLR4 were analyzed by flow cytometry. The Control group included 20 age and sex-matched individuals.ResultsThere was a significant increase in the expression of TLR4 in AML patients with IFI compared to healthy controls (p = 0.001). TLR2 and TLR4 expressions increased significantly in AML patients with mixed fungal and bacterial infection compared to healthy controls (p= 0.002 and p=0.001, respectively).ConclusionTLRs expressions could be important biological markers for the occurrence of IFI in non-M3 AML patients after intensive induction chemotherapy.

The rising burden of invasive fungal infections in COVID-19, can structured CT thorax change the game

BackgroundThe occurrence of invasive fungal infections in COVID-19 patients is on surge in countries like India. Several reports related to rhino-nasal-sinus mucormycosis in COVID patients have been published in recent times; however, very less has been reported about invasive pulmonary fungal infections caused mainly by mucor, aspergillus or invasive candida species. We aimed to present 6 sputum culture proved cases of invasive pulmonary fungal infection (four mucormycosis and two invasive candidiasis) in COVID patients, the clues for the diagnosis of fungal invasion as well as difficulties in diagnosing it due to superimposed COVID imaging features.Case presentationThe HRCT imaging features of the all 6 patients showed signs of fungal invasion in the form of cavities formation in the pre-existing reverse halo lesions or development of new irregular margined soft tissue attenuating growth within the pre-existing or in newly formed cavities. Five out of six patients were diabetics. Cavities in cases 1, 2, 3 and 4 of mucormycosis were aggressive and relatively larger and showed relatively faster progression into cavities in comparison with cases 5 and 6 of invasive candidiasis.ConclusionIn poorly managed diabetics or with other immunosuppressed conditions, invasive fungal infection (mucormycosis, invasive aspergillosis and invasive candidiasis) should be considered in the differential diagnosis of cavitary lung lesions.

Incidence of Breakthrough Fungal Infections in Acute Myeloid Leukemia Patients Receiving Low Intensity Therapy in the Upfront and Relapsed/Refractory Setting

Introduction: New treatment strategies with low intensity therapy have emerged for acute myeloid leukemia (AML) patients who are not candidates for intensive therapy. To date, there is limited data on the frequency of invasive fungal infections (IFIs) in patients treated with low intensity regimens, and there is no consensus on the most appropriate prophylactic antifungal agent to use in either the newly diagnosed or relapsed/refractory setting. At our institution, fluconazole is the prophylactic antifungal agent of choice for neutropenic patients receiving low intensity therapy, however the appropriateness of fluconazole is being questioned due to the depth and duration of neutropenia observed in these patients. Rates of breakthrough IFIs need to be better characterized to optimize antifungal prophylaxis in this patient population.Methods: This is a retrospective review of AML patients treated with low intensity therapy from January 2017 through May 2020 for both newly diagnosed and relapsed/refractory disease. Patients were included if they received fluconazole as prophylaxis during periods of neutropenia and received at least two cycles of low intensity treatment. Low intensity regimens included hypomethylating agent (HMA) monotherapy or a combination of venetoclax with either a HMA or low dose cytarabine (LDAC). Any patient with a contraindication to fluconazole or those who received prophylaxis with an alternative antifungal agent (i.e. posaconazole, voriconazole, isavuconazole, and micafungin), history of previous IFI, or history of a stem cell transplant were excluded. The primary objective was to determine the incidence of breakthrough IFIs. The secondary objective was to further characterize IFI occurrences as possible, probable or proven using criteria defined by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC). An occurrence of IFI was defined as receipt of any systemic antifungal agent, aside from fluconazole, for four or more days for suspected IFI. Patients were evaluated for antifungal escalation from the time of low intensity treatment initiation through 30 days after treatment discontinuation.Results: Eighty encounters were included for analysis. The median age of the cohort was 73 years (interquartile range [IQR] 67 - 80) and 70% of patients were newly diagnosed (n = 56). HMA/venetoclax was the most commonly utilized regimen (66%, n = 53) followed by HMA monotherapy (29%, n = 23) and LDAC/venetoclax (5%, n = 4). The median number of treatment cycles was 5 (IQR 3 - 9). Nineteen IFI occurrences (24%) were documented, with ten in the newly diagnosed population (18%, n = 10/56) and nine in relapsed/refractory patients (38%, n = 9/24). There were no proven, four probable and fourteen possible IFIs. Of the four probable infections, three were in relapsed/refractory patients. Median times to IFI onset from low intensity treatment initiation were 82 and 80 days for the newly diagnosed and relapsed/refractory populations, respectively. Of the patients with an IFI, 15/19 (79%) were neutropenic at IFI onset.Conclusions: IFIs are a serious complication of AML as these infections are associated with significant morbidity and mortality. With 24% of patients requiring antifungal escalation, our study demonstrates that breakthrough IFIs remain a concern for patients receiving low intensity therapy and fluconazole prophylaxis. Incidence of IFI was higher in the relapsed/refractory setting, which is an expected finding as these patients are typically subjected to multiple lines of therapy, leading to poor hematopoietic reserves and more prolonged periods of profound neutropenia. Additional analysis is needed for determination of risk factors, beyond relapsed/refractory disease, to potentially identify subsets of patients at highest risk of developing IFIs as these patients may benefit from closer monitoring and longer durations of prophylaxis. Given these findings, it is reasonable to consider prophylaxis with an extended spectrum antifungal agent against molds for patients receiving low intensity therapy. [Display omitted] DisclosuresEllis: Rafael Pharmaceuticals: Consultancy. Pardee: Karyopharm Pharmaceuticals: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rafael Pharmaceuticals: Consultancy, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Pharmacyclics: Speakers Bureau.

COVID 19 ASSOCIATED INVASIVE FUNGAL INFECTIONS IN CHURU REGION OF RAJASTHAN

Background: COVID 19 or severe acute respiratory syndrome (SARS-CoV-2) evolved as global pandemic since December 2019 when it was first reported in Wuhan, China. Coinfection in patients with COVID-19 has been reported in multiple studies, being bacterial in origin the most frequent; and fungal infection being reported only in severe cases.&#x0D; Methods: This study was conducted at the department of E.N.T. at PanditDeenDayalUpadhyay Medical College, Churu. Cases presented to E.N.T. OPD with clinical features of invasive rhino-orbital fungal infection for the period of two month from 1st June 2021 were included in the study. Patients were clinically evaluated, HRCT, MRI scans and with KOH mount and culture of involved tissue ere done. Patient’s COVID-19 status was ascertained. The clinicopathological association of occurrence of invasive fungal infections in post covid and non-covid patients along with other risk factors like diabetes mellitus, immune compromised state and long-term steroid use was done using statistical methods&#x0D; Results: We studied 21 patients who attended our OPD with features of invasive fungal infection. Most common presentation was swelling and pain in the cheek region and red eye and swelling around the eye, three patients presented with maxillary swelling with blackish discoloration of teeth. Radiological findings were suggestive of fungal etiology in all patients. KOH mount showed fungal hyphae in 20 cases. Total 20 cases were post COVID status. Old DM was there in 12 patients whereas 9 patients showed new onset hyperglycemia.&#x0D; Conclusions: COVID-19 is associated with a significant incidence of secondary infections, both bacterial and fungal probably due to immune dysregulation. The widespread use of steroids/monoclonal antibodies/broad-spectrum antibiotics as part of the management protocols against COVID-19 may lead to the exacerbation of preexisting fungal diseases or development of new infection. Treating Physicians should make themselves aware and prepare for the possibility of invasive secondary fungal infections in patients with COVID-19 infection especially in patients with preexisting risk factors and should enable early diagnosis and treatment with the subsequent reduction of mortality and morbidity.&#x0D; Keywords: Coronavirus, COVID-19, mucormycosis, invasive fungal infections

Risk of invasive fungal infections among patients treated with disease modifying treatments for multiple sclerosis: a comprehensive review

ABSTRACT Introduction: Disease modifying treatments are commonly used in the treatment of multiple sclerosis. As different opportunistic infections have been reported, concerns are also raised regarding the risk of invasive fungal infections. Areas covered: Both clinical trials and observational studies on safety and efficacy of diseases modifying treatment for multiple sclerosis were reviewed and data regarding the occurrence of invasive fungal infections were reported. Papers evaluating the following drugs were reviewed: rituximab, ocrelizumab, alemtuzumab, fingolimod, natalizumab, dimethyl fumarate, interferon, glatiramer acetate, cladribine, teriflunomide. Expert opinion: Overall, the occurrence of invasive fungal infections was low, with most infective events reported among patients treated with monoclonal antibodies and fingolimod. Aspergillosis and cryptococcal meningitidis were the most representative fungal infections. Although not common, these infections may be difficult to diagnose and their fatality rate is often high. For this reason, screening protocols for fungal infections must be implemented in the clinical practice when managing patients with MS.

Characterisation of CandidaColonisation in Neonates

Introduction: The occurrence of invasive fungal infections has increased significantly worldwide, premature infants in Neonatal Intensive Care Unit (NICU) along with other risk factors are at particular risk of these invasive fungal infections which lead to fungal septicaemia in newborns. Candidaemia is the most common form of invasive candidiasis associated with an unacceptably high mortality rates. Candida colonisation in neonates is considered the first step towards developing neonatal sepsis. Aim: To determine the prevalence of Candida colonisation and its characterisation among neonates admitted in NICU. Materials and Methods: The present study was a prospective cross-sectional study with 150 neonates included in the study. Swabs were taken from four different sites of each neonate and inoculated on Chocolate agar and Sabouraud’s Dextrose Agar (SDA) and incubated at 37°C for seven days. Candida species isolated were confirmed by gram stain, germ tube test, growth on Chromogenic (CHROM) agar and cornmeal agar. Statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 11.0. Results: A total of 32 (21.3%) neonates had Candida colonisation. Twenty two (68.7%) were low birth weight and 24 (75%) were born premature. Perineum was the most common (56%) site of colonisation. Among Candida isolates, Candida tropicalis(63%) was the commonest followed by Candida parapsilosis(25%) and Candida glabrata and Candida albicans (6%). The risk factors identified were low birth weight, premature birth, use of antibiotics. Conclusion: Colonisation of preterm and low birth weight neonates by Candida species is a major risk factor and needs attention to avoid dissemination and life threatening infection.

Effectiveness and Cost-Effectiveness of Prophylactic Voriconazole and Fluconazole Regarding Prevention of Post-hematopoietic Stem Cell Transplantation Invasive Fungal Infection and Its Related Death: A Single Center Experience.

Analyzing effectiveness and cost-effectiveness of voriconazole versus fluconazole prophylaxis in hematopoietic stem cell transplantation (HSCT). The research included 70 patients; 34 undergoing allogeneic HSCT and 36 undergoing autologous stem cell transplantation (ASCT), alternated to receive either voriconazole or fluconazole prophylaxis for 180days on a 1:1 basis. Patients were monitored for occurrence of invasive fungal infections (IFI), IFI-related death (IRD) and total death events. Cost-effectiveness of both agents in both groups was also assessed. Antifungal prophylactic drug had no impact on incidence of IFI and IRD in both allogeneic HSCT and ASCT (P = .452 and P = 1.000; P = .457 and P = .146 respectively). An insignificant difference occurred among patients receiving voriconazole or fluconazole regarding overall survival (OS) and fungal infection-free survival (FFS) in both groups (P = .705 and P = .879; P = .713 and P = .681 respectively). Regarding cost-effectiveness, voriconazole dominated fluconazole regarding prevention of IFI and IRD but was less costly/less effective regarding prevention of total death events and gaining life years in the allogeneic HSCT setting. In the ASCT setting, voriconazole was not cost-effective regarding avoidance of IFI and IRD and was dominated by fluconazole regarding avoidance of total death events and gaining life years. Voriconazole does not differ from fluconazole regarding its efficacy in prevention of IFI and IRD and does not improve OS and FFS in both allogeneic HSCT and ASCT settings. Voriconazole is cost-effective regarding protection from IFI and IRD in allogeneic HSCT but not cost-effective in ASCT.

Ibrutinib induces multiple functional defects in the neutrophil response against Aspergillus fumigatus.

The Bruton tyrosine kinase inhibitor ibrutinib has become a leading therapy against chronic lymphoid leukemia. Recently, ibrutinib has been associated with the occurrence of invasive fungal infections, in particular invasive aspergillosis. The mechanisms underlying the increased susceptibility to fungal infections associated with exposure to ibrutinib are currently unknown. Innate immunity, in particular polymer-phonuclear neutrophils, represents the cornerstone of anti-Aspergillus immunity; however, the potential impact of ibrutinib on neutrophils has been little studied. Our study investigated the response to Aspergillus fumigatus and neutrophil function in patients with chronic lymphoid leukemia or lymphoma, who were undergoing ibrutinib therapy. We studied the consequences of ibrutinib exposure on the functions and anti-Aspergillus responses of neutrophils obtained from healthy donors and 63 blood samples collected at different time points from 32 patients receiving ibrutinib for lymphoid malignancies. We used both flow cytometry and video-microscopy approaches to analyze neutrophils’ cell surface molecule expression, cytokine production, oxidative burst, chemotaxis and killing activity against Aspergillus. Ibrutinib is associated, both in vitro and in patients under treatment, with multiple functional defects in neutrophils, including decreased production of reactive oxygen species, impairment of their capacity to engulf Aspergillus and inability to efficiently kill germinating conidia. Our results demonstrate that ibrutinib-exposed neutrophils develop significant functional defects that impair their response against Aspergillus fumigatus, providing a plausible explanation for the emergence of invasive aspergillosis in ibrutinib-treated patients.

Functionalization of the Chalcone Scaffold for the Discovery of Novel Lead Compounds Targeting Fungal Infections.

The occurrence of invasive fungal infections represents a substantial threat to human health that is particularly serious in immunocompromised patients. The limited number of antifungal agents, devoid of unwanted toxic effects, has resulted in an increased demand for new drugs. Herein, the chalcone framework was functionalized to develop new antifungal agents able to interfere with cell growth and with the infection process. Thus, a small library of chalcone-based analogues was evaluated in vitro against C. albicans ATCC 10231 and a number of compounds strongly inhibited yeast growth at non-cytotoxic concentrations. Among these, 5 and 7 interfered with the expression of two key virulence factors in C. albicans pathogenesis, namely, hyphae and biofilm formation, while 28 emerged as a potent and broad spectrum antifungal agent, enabling the inhibition of the tested Candida spp. and non-Candida species. Indeed, these compounds combine two modes of action by selectively interfering with growth and, as an added value, weakening microbial virulence. Overall, these compounds could be regarded as promising antifungal candidates worthy of deeper investigation. They also provide a chemical platform through which to perform an optimization process, addressed at improving potency and correcting liabilities.

Risk-Adapted Anti-Mould Prophylaxis Improves Supportive Care in Childhood Leukemia Patients

BACKGROUND: Prophylaxis of invasive fungal infections in children treated for malignant hematologic disease has traditionally been based on the widespread use of fluconazole. With the awareness of increasing rates of invasive mould infections, new agents have been developed and offered to patients at highest risk.METHODS: We compared the tolerance and outcome of different antifungal prophylaxis in 198 childhood patients treated for acute myeloid and lymphoblastic leukemia in a pediatric cancer center. Until 2011 antifungal prophylaxis with fluconazole was offered to all patients, resulting in 15.2-19.4% of invasive mould infections. As the burden of fungal infections was restricted to high risk patients only (i.e. acute myeloid leukemia, leukemia relapse, high risk acute lymphoblastic leukemia and patients after stem cell transplant) and no infection with candida was registered, antifungal prophylaxis was replaced with liposomal amphotericin and offered to this particular patient group.RESULTS: Liposomal amphotericin was well tolerated; there was no occurrence of infusion-related reaction and/or glomerular-associated nephrotoxicity. The development of vincristine-induced neurotoxicity was significantly reduced, as stool frequency was increased up to 38% in patients treated with liposomal amphotericin (p = 0.024). Importantly, there was a marked shift in the percentage of patients with severe constipation (15.5% versus 4.2%, fluconazole versus liposomal amphotericin respectively, p = 0.010). Notably, with limitation of prophylactic treatment to high risk patients a major group of patients did not receive any antifungal prophylaxis (48.81%) and most importantly, the occurrence of invasive fungal infection was completely prevented (p = 0.021). In comparison, 10 patients in the fluconazole group developed proven invasive pulmonary infections. Of these, 6 patients developed disseminated disease, and 4 patients died. Aspergillus was isolated in 40% and rhizopus in 30% of biopsy specimens.CONCLUSION: Polyene prophylaxis offers effective antifungal activity with improved tolerability compared to older agents. The potential impact of this treatment should be included in current prophylaxis guidelines of antileukemic treatment. DisclosuresNo relevant conflicts of interest to declare.

971. Breakthrough Invasive Fungal Infections (IFI) in Acute Leukemia (AL) Patients Receiving Antifungal Prophylaxis

BackgroundA major challenge in patients with AL receiving chemotherapy is to decrease the risk of IFI during the prolonged neutropenic period. Even with antifungal prophylaxis, the incidence of breakthrough IFI can be as high as 14%. Our objectives were to determine the incidence of all IFI and breakthrough IFI, to define risk factors associated with IFI, and to assess outcomes.MethodsSingle-center retrospective cohort analysis of all adult patients admitted to the University of Michigan for AL from January 1, 2010 to December 31, 2013. Chart review determined co-morbidities, chemotherapy regimens, antifungal prophylaxis, occurrence of IFI as determined by EORTC/MSG criteria, and outcomes. Chi-square, Fischer’s, ANOVA, and binary logistic regression tests were performed when appropriate.ResultsOf 363 patients, all but 4 had acute myeloid leukemia (AML); 124 had a stem cell transplant (SCT). A total of 103 (28%) had proven (n = 13), probable (n = 22), or possible (n = 68) IFI. Considering only those 35 patients who had proven or probable IFI, the only risk factor for development of IFI by logistic regression analysis was IFLAG chemotherapy (P = .006). Mold infections occurred in 27 patients: Aspergillus (19), Mucorales (5), both Aspergillus and Mucorales (1), Alternaria (1), and Scedosporium (1). Additionally, 5 patients had invasive candidiasis and 3 had Pneumocystis. Eighteen of 35 patients (51%) had breakthrough IFI while on posaconazole suspension (6), fluconazole (5), micafungin (5) or voriconazole (2). Factors significantly associated with breakthrough IFI were SCT (P = .04), neutrophils <500, ≥10 days at diagnosis (P = .002) and prophylaxis with posaconazole suspension (P = .003). Twelve-week mortality in proven and probable IFI was 31% (11/35). Nine of 11 deceased patients had breakthrough IFI; 8 of whom (5 with mold IFI and 3 with invasive candidiasis) died of the fungal infection.ConclusionPatients receiving chemotherapy for AL remain at risk for IFI despite the the use of antifungal prophylaxis. In our study, prophylaxis with posaconazole suspension was found to be an independent risk factor for breakthrough IFI. Mortality was high among patients with breakthrough IFI.Disclosures All authors: No reported disclosures.

Treatment of Invasive Fungal Infection in Childhood Acute Lymphoblastic Leukemia with Amphotericin B and Voriconazole

To study the clinical efficacy of amphotericin B and voriconazole in the treatment of invasive fungal infection in children with acute lymphoblastic leukemia(ALL) during chemotherapy. The clinical data of 214 patients with acute lymphoblastic leukemia admitted in our hospital from March 2014 to February 2017 was retrospectively analyzed. Among them 65 patients had invasive fungal infection (IFI) during the chemotherapy period, out of them 35 patients treated with voriconazole were enrolled in group A; anather 30 patients treated with amphotericin B were enrolled in group B. The clinical factors that affected the incidence of IFI was statistically analyzed. And the efficacy and adverse reactions in children with ALL were compared after treatment for 8 weeks. The incidence of IFI in children with ALL in this study was 30.37%, and was related with the duration of hospitalization and the level of neutrophil deficiency (P<0.05). The total effective rates of group A and group B were 72.28% and 43.33%, respectively, their difference was statistically significant between 2 group (P<0.05). The incidence of renal function impairment, digestive dysfunction and neurotoxicity were 8.57%, 5.71% and 5.71% in children with ALL treated with voriconazole respectively, which were lower than those in children treated with amphotericin B (P<0.05). The score index of Physical health, energy state, emotion control and overall health in group A were significantly higher than those in B group, and the difference was statistically significant (P<0.05). The occurrence of IFI in children with ALL relats with the time of hospitalization and the level of neutrophils. The clinical effect of voriconazole is better, and the incidence of adverse reactions can be reduced, suggesting important clinical significance.

Clinical investigation of sequential therapy with micafungin and reduced-dose voriconazole in prevention of fungal in patients after allogeneic hematopoietic stem cell transplantation

Objective To observe the clinical effect of sequential therapy with micafungin and reduced-dose voriconazole in prevention of invasive fungal infections in patients received allogeneic hematopoietic stem cell transplantion (Allo-HSCT). Methods 28 patients received the treatments for prevention of fungal infection with micafungin 50 mg per day from pretreatment to 30 days, then oral voriconazole at a dose of 100 mg two times per day until 90 days after Allo-HSCT.The occurrence of invasive fungal infection and the side effects of both medicine were observed during 180 days after Allo-HSCT. Results 8 patients(28.6%) developed above grade 2 acute graft verse host disease(GVHD), 2 patients developed grade 3 GVHD among the 8 patients.Two case with GVHD were cured by voriconazole with the therapeutic dose who occurred probably pulmonary invasive fungal infection at two months after Allo-HSCT.There were no other patients diagnosed fungal infection.No toxic efect were observed during the clinical observation during treatment with micafungin.5 patients appeared mild liver function abnormalities during treatment with voriconazole, and liver dysfunction were improved by symptomatic treatment.2 cases developed transient auditory hallucination and visual impairment induced by voriconazole. Conclusion Micafungin and reduced-dose voriconazole are effective and safe prophylaxis in prevention early invasive fungal infection after HSCT. Key words: Micafungin; Voriconazole; Hematopoietic stem cell transplantation; Fungal infection

Incidence and Risk Factors of Invasive Fungal Infection in Adult Patients Receiving Allogeneic Hematopoietic SCT Recipients

▪To investigate the incidence and risk factors for the occurrence of proven or probable invasive fungal infection (IFI) in adult patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), 421 patients undergoing HSCT between 2002 and 2013 in our hospital were retrospectively analyzed. Thirty-one patients with the median age of 42 years (range: 19-60) developed IFI after HSCT. The post-HSCT IFI incidence was 7.4% and median time from HSCT to the diagnosis of IFI was 139 days (range: 2-1809). The risk factors for the occurrence of IFI were analyzed using Cox regression models.Of the pretransplant factors, European Group for Blood and Marrow Transplantation (EMBT) risk>2 (P=0.001) and prior history of IFI (P=0.006) or DM (P=0.042) were the significant predictors for post-HSCT IFI by univariate analyses. In multivariate analysis, EMBT risk>2 (P=0.015) and prior history of IFI (P=0.006) retained significance. Of the post-transplant factors, acute graft-versus-disease (aGVHD) overall grade III-IV (P<0.001), extensive chronic GVHD (cGVHD) (P=0.002), post-transplant lymphoproliferative disorders (PTLD) (P=0.005) and the use of high-dose steroids (P<0.001) were statistically significant in univariate analyses. After multivariate analysis, high-dose steroids (P<0.001) and aGVHD overall grade III-IV (P=0.045) retained significance. These results suggest that risk group stratification prior HSCT and monitoring of IFI in patients with severe GVHD and receiving high-dose steroids is mandatory to decrease the risk of post-HSCT IFI, especially in those with prior history of IFI. Abstract 2476. Table 1Possible factors for the occurrence of invasive fungal infection (IFI) after adult allogeneic HSCTIFIUnivariate analysisMultivariate analysisFactorsNo. of patientsN%HR95%CIP-valueHR95%CIP-valueEMBT risk=<216952.9>22522610.35.0381.930-13.1510.0013.3901.273-9.0290.015Prior history IFINo406276.6Yes15426.64.4571.551-12.8060.0065.8071.675-20.1290.006Prior history DMNo402286.9Yes19315.73.4901.045-11.6530.042aGVHDNo or Overall Gr. I-II379236.0Gr. III-IV42819.06.9363.046-15.796<0.0012.6271.023-6.7480.045High steroids*No367123.2Yes541935.111.1485.401-23.008<0.00111.1853.875-32.289<0.001cGVHDNo or limited364195.2Extensive571221.03.1311.518-6.4590.002PTLDNo405276.6Yes164254.6271.607-13.3200.005Abbreviations: CI = confidence interval; HR = hazard ratio; EBMT = European Group for Blood and Marrow Transplantation; HSCT = hematopoietic stem cell transplantation; GVHD = graft-versus-host disease; aGVHD = acute GVHD; cGVHD = chronic GVHD; Gr.= grade; PTLD = Post-transplant lymphoproliferative disorders. DM = Diabetes mellitus. High steroids* = post-HSCT high-dose steroid; Significant values (P<0.05) are given in bold. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Antifungal prophylaxis following allogeneic haematopoietic stem cell transplantation: what is the role of voriconazole?

Voriconazole is given a provisional A1 rating in the European Conference on Infections in Leukaemia (ECIL)3 guidelines as primary prophylaxis of invasive fungal infections (IFIs) in haematopoietic stem cell transplantation (HSCT) recipients. The rationale for this rating is outlined in a recent review by Hicheri et al. [1]. Interestingly, the main argument supporting the new role of voriconazole in primary prophylaxis is based on the results of one recently published study [2]. In this study, Marks and colleagues demonstrated that voriconazole was superior to itraconazole as antifungal prophylaxis after allogeneic HSCT based on differences in the primary composite endpoint [115/234 (49.1 %) vs. 88/256 (34.5 %), respectively] [2]. However, three considerations should be taken into account when interpreting these results. First, the composite endpoint of the study included not only survival at day 180 post-transplant as well as proven or probable IFI during that same period, but also discontinuation of the study drug for [14 days during the 100-day prophylactic period. No differences were found between the treatment arms in terms of general survival and occurrence of IFI. The only part of the composite endpoint where voriconazole proved to be superior to itraconazole was discontinuation of the study drug—and the results and conclusions were driven by that difference only. In this context it is of interest that even in the voriconazole arm the number of patients who reached sufficient duration of prophylaxis was low (54.3 %; 127/234), but still significantly higher than that in the itraconazole arm (40 %; 102/255). Interestingly, both antifungals were similar for side effect scores. When taking into account both (1) the open label design of the study (i.e., investigators who discontinued antifungals were not blinded to the study drugs) and (2) the fact that discontinuation of study drugs was completely up to the discretion of the treating physician and no reasons for discontinuation were given in the Results section of the paper, we suggest that the conclusion drawn by the authors regarding the superiority of voriconazole compared to itraconazole can, based on these results, not be drawn. Second, the incidence of IFI was very low—1.3 % (3/ 234) in the voriconazole arm and 2.1 % (5/255) in the itraconazole arm. All but two cases of IFIs did not meet the criteria of breakthrough infection as they occurred[40 days after discontinuation of the study drug. In a previous comparable study [3], occurrence of breakthrough IFI in patients receiving itraconazole prophylaxis was consistently [6 % which is threefold higher than that reported by Marks and colleagues. One reason for the low incidence may have been that galactomannan monitoring, which has shown to have a significant impact on the prevalence of invasive mould infection (IMI), was not part of the study design [4]. It may be argued that with a higher IFI incidence significant differences might have been found between voriconazole and itraconazole with respect to the rates of IMI. Third, therapeutic drug monitoring was performed only in a subset of the study cohort. Not surprisingly, the standard oral 200 mg twice-daily voriconazole dosage used in the study led to insufficient trough concentrations in the vast majority of patients; 62 % even had trough levels of \1.0 mg/L. Systematic therapeutic drug monitoring may M. Hoenigl (&) K. Seeber R. Krause Section of Infectious Diseases and Tropical Medicine, Medical University of Graz, Graz, Austria e-mail: martin.hoenigl@medunigraz.at

Assessment of microbiological air quality in hemato-oncology units and its relationship with the occurrence of invasive fungal infections: an integrative review

Worldwide aging of the human population has promoted an increase in the incidence of neoplasia, including hematological cancers, which render patients particularly vulnerable to invasive fungal infections. For this reason, air filtration in hematooncology units has been recommended. However, scarce literature has assessed the impact of microbiological air quality on the occurrence of fungal infections in this population. We performed an integrative review of studies in the MEDLINE database that were published between January 1980 and October 2012, using the following combinations of keywords: air × quality × HEPA, air × quality × hematology, and airborne fungal infections. The search yielded only 13 articles, suggesting that high-efficiency filtering of the ambient air in hemato-oncology units can prevent the incidence of invasive fungal infections. However, no randomized clinical trial was found to confirm this suggestion. Currently, there is no consensus about the maximum allowable count of fungi in the air, which complicates filtration monitoring, including filter maintenance and replacement, and needs to be addressed in future studies.