Invasive Fungal Infection Group Research Articles

Invasive Fungal Infections Among Patients with Hematological Malignancies: A Two-Year Multicentric Study from Tehran, Iran

Background: Invasive fungal infection (IFI) is a life-threatening condition, particularly in individuals with compromised immune systems. Objectives: Our study aims to evaluate IFI in hospitalized patients with hematological malignancies. Methods: In this retrospective cross-sectional study, we evaluated patients with hematological malignancies admitted to two university hospitals in Tehran, Iran, from 2020 to 2021 for IFI. We selected only those patients who had been hospitalized for at least four days for antimicrobial treatment. Data analysis was conducted using SPSS-26 software, employing Mann-Whitney U, chi-square, and Fisher exact tests. Results: During the study period, 60 out of 213 patients with hematological malignancies were admitted for antimicrobial treatment. The average age of the patients was 57.1 years, with fever being the most common symptom, reported in 63.3% of cases. We identified 24 cases of IFI, including three proven cases (Candida spp.) and 21 probable cases. Statistical analysis showed a lower mean neutrophil count in the IFI group compared to the non-IFI group (3862 versus 12881, P = 0.001) and a higher mortality rate (58.3% versus 27.8%, P = 0.031). Conclusions: Our study revealed that severe neutropenia is a significant risk factor for IFI, and the mortality rate associated with IFI remains high despite advances in the treatment of hematological malignancies.

Antifungal susceptibility of clinically isolated invasive Candida tropicalis in East China from 2017 to 2021

Objective: To explore the epidemiological characteristics of sample distribution and antifungal susceptibilities of clinically invasive C. tropicalis isolates from 2017 to 2021 in East China. Methods: Using a retrospective analysis, the East China Invasive Fungal Infection Group (ECIFIG) collected C. tropicalis clinically isolated from 32 hospitals in East China between January 2017 and December 2021. The identification results of the strains were reviewed using mass spectrometry by the central laboratory of the Shanghai East Hospital. The minimum inhibitory concentrations (MICs) of the strains against fluconazole (FLU), voriconazole (VOR), itraconazole (ITR), Posaconazole (POS), isavuconazole (ISA), anidulafungin (ANI), caspofungin (CAS), micafungin (MICA) and 5-fluorocytosine (FCT) were tested by the ThermoFisher CMC1JHY colorimetric microdilution method. The MIC of amphotericin B (AMB) was tested by the broth microdilution method. The MIC results were analyzed based on the clinical breakpoints and epidemiological cutoff values (ECV) published by the Clinical and Laboratory Standards Institute (CLSI) M27 Ed3 and M57 Ed4 documents. Data analysis was conducted using the Kruskal-Wallis test and paired t-test. Results: In total, 305 C. tropicalis isolates were collected. There were 38.0% (116/305) strains isolated from blood, 11.5% (35/305) ascites, 8.9% (27/305) catheter and 8.9% (27/305) drainage fluid. The resistance rate of C. tropicalis to FLU was 32.5%, to VOR was 28.5%, and the cross-resistance rate to FLU and VOR was 28.5%. The wild-type proportions for ITR and POS were 79.3% and 29.2% respectively. There was no significant difference in resistance rates, MIC50, and MIC90 of FLU and VOR, or in the wild-type rates of ITR and POS over five years. More than 95.0% of the isolates were susceptible to echinocandins. However, one strain was identified as being multi-drug resistant. In azole antifungals, voriconazole, itraconazole, posaconazole, and isavuconazole have similar GM MIC values. The GM MIC of fluconazole is significantly higher than that of itraconazole (t=9.95, P<0.05), posaconazole (t=9.99, P<0.05), and voriconazole (t=10.01, P<0.05), Meanwhile, among echinocandins, the GM MIC of ANI was comparable to that of CAS (t=1.17, P>0.05), both of which were significantly higher than MICA (t=11.56, P<0.05; t=4.15, P<0.05). Conclusion: The clinical isolates of C. tropicalis in East China from 2017 to 2021 were relatively susceptible to echinocandins. However, there was consistently high resistance to fluconazole and voriconazole. More intensive efforts should be made on the monitoring of drug resistance in C. tropicalis.

Molecular Epidemiology and Antifungal Resistance of Cryptococcus neoformans From Human Immunodeficiency Virus-Negative and Human Immunodeficiency Virus-Positive Patients in Eastern China

Cryptococcosis is an opportunistic and potentially lethal infection caused by Cryptococcus neoformans and Cryptococcus gattii complex, which affects both immunocompromised and immunocompetent people, and it has become a major public health concern worldwide. In this study, we characterized the molecular epidemiology and antifungal susceptibility of 133 C. neoformans isolates from East China Invasive Fungal Infection Group (ECIFIG), 2017–2020. Isolates were identified to species level by matrix-assisted laser desorption ionization-time of flight mass spectrometry and confirmed by IGS1 sequencing. Whole-genome sequencing (WGS) was conducted on three multidrug-resistant isolates. Among the 133 strains, 61 (45.86%) were isolated from HIV-positive patients and 72 (54.16%) were isolated from HIV-negative patients. In total, C. neoformans var. grubii accounted for 97.74% (130/133), while C. neoformans var. neoformans was rare (2.06%, 3/133). The strains were further classified into nine sequence types (STs) dominated by ST5 (90.23%, 120/133) with low genetic diversity. No association was observed between STs and HIV status. All strains were wild type to voriconazole, while high antifungal minimal inhibitory concentrations (MICs) above the epidemiological cutoff values (ECVs) were observed in C. neoformans strains, and more than half of isolates were non-wild-type to amphotericin B (89.15%, 109/133). Eight isolates were resistant to fluconazole, and eight isolates were non-wild type to 5-fluorocytosine. Furthermore, WGS has verified the novel mutations of FUR1 in 5-fluorocytosine-resistant strains. In one isolate, aneuploidy of chromosome 1 with G484S mutation of ERG11 was observed, inducing high-level resistance (MIC: 32 μg/ml) to fluconazole. In general, our data showed that there was no significant difference between HIV-positive and HIV-negative patients on STs, and we elucidate the resistant mechanisms of C. neoformans from different perspectives. It is important for clinical therapy and drug usage in the future.

Combination of C-Reactive Protein and Procalcitonin in Distinguishing Fungal from Bacterial Infections Early in Immunocompromised Children.

Invasive fungal infection (IFI) is life-threatening in children with cancer and hematology disorders, especially when diagnosis and treatment are delayed. Conventional β-D-glucan and galactomannan tests have poor positive predictive values in the diagnosis of IFI in children with cancer. This study aims to access the diagnostic performance of C-reactive protein (CRP) and procalcitonin (PCT) in differentiating IFI from bacterial bloodstream infections in children with malignant and hematology disorders. CRP and PCT levels were measured in samples taken from patients between 12 and 24 h after fever onset, of which 24 and 102 were in the IFI and bacterial groups, respectively. We found that the CRP levels were much higher in the IFI group than the bacterial group (100.57 versus 40.04 mg/L, median, p < 0.001), while the PCT levels remained significantly lower (0.45 versus 1.29 μg/L, median, p = 0.007). Both CRP and PCT showed significant diagnostic utilities with an area under the curve (AUC) of 0.780 (95% CI, 0.664–0.896, p < 0.001) and 0.731 (95% CI, 0.634–0.828, p < 0.001) when using the cut-off values of 94.93 mg/L and 2.00 μg/L, respectively. However, the combined biomarker of CRP and PCT yielded a better diagnostic performance with an AUC of 0.934 (95% confidential interval (CI), 0.881–0.987, p < 0.001), which was significantly higher than that of CRP or PCT (both p < 0.001), with a sensitivity of 87.5% and a specificity of 87.3%. Our study demonstrates high levels of CRP combined with low PCT could differentiate IFI from bacterial bloodstream infections in immunocompromised children.

Invasive Fungal Infections in Children with Leukemia: Clinical Features and Prognosis

Objective:The incidence of invasive fungal infections (IFIs) has increased due to intensive chemotherapy in childhood leukemia. The aim of this study was to evaluate the incidence, risk factors, causative pathogens, and impact on survival of IFIs among pediatric leukemia patients.Materials and Methods:The hospital records of 307 children with acute lymphoblastic leukemia (ALL, n=238), acute myeloid leukemia (AML, n=51), and relapsed leukemia (n=18) between January 2010 and December 2015 were retrospectively evaluated.Results:A total of 1213 febrile neutropenia episodes were recorded and 127 (10.4%) of them were related to an IFI. Of 307 children, 121 (39.4%) developed IFIs. The mean age was significantly older in the IFI group compared to children without IFIs (p<0.001). IFIs were defined as possible, probable, and proven in 73.2%, 11.9%, and 14.9% of the attacks, respectively. Invasive aspergillosis (81.9%) was the most frequent infection, followed by invasive candidiasis (13.4%) and rare fungal diseases (4.8%). The majority of IFI attacks in both ALL and AML occurred during the induction phase. In total, the death rate was 24% and the IFI-related mortality rate was 18%. The mortality rate among children with IFIs was found to be significantly higher than that of children without IFIs (p<0.001). Overall and event-free survival rates at 5 years were also found to be significantly lower in the IFI group (p<0.001). Relapse (odds ratio: 8.49) was the most effective risk factor for mortality, followed by developing an IFI episode (odds ratio: 3.2) and AML (odds ratio: 2.33) according to multivariate regression analysis.Conclusion:Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode of IFI. Rare fungal diseases were also identified as a major problem. Despite success in treatment, IFIs increased the rate of mortality in children with acute leukemia.

In vitro activities of the tetrazole VT-1161 compared with itraconazole and fluconazole against Cryptococcus and non-albicans Candida species

ABSTRACT Recently, Cryptococcus and non-albicans Candida (NAC) have emerged as health-threatening pathogens for clinical fungal infections. Due to their increased resistance to existing antifungal drugs, novel antifungals are urgently needed. In this study, we evaluated the antifungal effect of VT-1161 and its comparators itraconazole and fluconazole against common fluconazole-sensitive or -resistant Cryptococcus and NAC strains. The tested strains were obtained from Chinese patients by the Invasive Fungal Infection Group within the past 2 years. The minimum inhibitory concentrations (MICs) of VT-1161 and other triazoles were measured according to the Clinical and Laboratory Standards Institute (CLSI) M27-Ed4 guidelines. We found that VT-1161 exhibited strong in vitro activity against Cryptococcus spp.. VT-1161 (geometric mean MIC = 0.024 μg/mL) was 21.7-fold and 104.5-fold more potent than itraconazole and fluconazole, respectively. Against the seven Cryptococcus neoformans isolates with higher fluconazole MICs (≥8 μg/mL based on the MIC90 value of this azole), VT-1161 maintained potent activities, with MICs ranging between 0.031 and 0.5 μg/mL. For NAC spp., VT-1161 (geometric mean MIC = 0.099 μg/mL) was 6.0-fold and 11.4-fold more effective than itraconazole and fluconazole, respectively. There is a positive correlation of the MICs between VT-1161 and itraconazole/fluconazole. The MIC values of VT-1161 against Candida glabrata and Candida tropicalis were significantly lower than those of fluconazole, whereas for Candida parapsilosis the differences in the MIC values between VT-1161 and fluconazole were not statistically significant. The results showed that tetrazole VT-1161 might be a promising candidate for treating Cryptococcus and NAC infections.

The Frequency of Natural Killer Cell Subsets in Patients with Acquired Immune Deficiency Syndrome with Deep Fungal Infections.

ObjectiveThis study aimed to investigate the expression of natural killer (NK) cell subsets in patients with acquired immune deficiency syndrome (AIDS) and deep fungal infections and the significance of such expression.MethodsA total of 829 patients with AIDS, who were treated in People’s Hospital of Deyang City our hospital between January 2011 and March 2019, were enrolled in the study. They were divided into two groups: those with human immunodeficiency virus (HIV) and invasive fungal infection (IFI) (HIV + IFI) (n = 390) and those with HIV and no IFI (HIV + non-IFI) (n = 439). Another 200 healthy volunteers were enrolled as the control group. The numbers of NK cell subsets in each group were compared.ResultsThe level of NK cells, number of NK cells in all lymphocytes, proportions of CD56bright, CD56dim, and CD56dim NK cells in NK cells, and the level of CD56–CD16+ NK cells were significantly lower in the HIV + IFI group than in the HIV + non-IFI group and control group (P < 0.05). Moreover, CD4+ T, CD4+/CD8+, and NK cells were negatively correlated with HIV-RNA expression (P < 0.05).ConclusionA combination of AIDS and deep fungal infection can change the immune status of a patient. This condition can be diagnosed early through the detection of NK cell expression.

PB2041 UTILITY OF INFLAMMATORY MARKERS IN DISTINGUISHING VARIOUS INFECTIVE ETIOLOGIES OF FEVER IN FEBRILE NEUTROPENIC PATIENTS

Background:Febrile neutropenia is a common cause in morbidity and mortality during treatment of hematological neoplasms. This leads to unnecessary use of broad‐spectrum antibiotics adding to the cost of treatment, selection pressure amongst bacteria and side effects of antibiotics.Aims:To study the utility of Procalcitonin and CRP in differentiating various causes of fever in patients with febrile neutropenia.Methods:Subjects included all cases admitted under hematology department with febrile neutropenia from February to June 2018 (age ranged‐1‐60 years). Institutional Ethics Committee clearance was obtained for the conduct of this study.Etiology of febrile episodes classified according to International Immunocompromised Host Society (ICHS) into four groups:• Microbiologically documented infections (MDI)• Clinically documented infections (CDI)• Fever of unexplained origin (FUO)• Invasive fungal infections (IFI)Diagnostic work up for each febrile episode was done including Procalcitonin (PCT) and CRP. PCT and CRP was sent at fever onset 0,24,48hour, day 7 and day 14 or defervescence.Results:A total of 72 patients evaluated out of which 17 patients excluded either due to incomplete data or fever due to non‐ infective causes. Data was analyzed for 52 febrile episodes in 50 patients. At fever onset no significant difference was observed in the PCT &amp; CRP values amongst various etiologies. PCT cut off value at 24 hours of ≤1.2ng/ml had a sensitivity and specificity of 62.5% and 87.5% for discriminating IFI and MDI (p = 0.033). PCT had a negative predictive value of 70% for the diagnosis of IFI as compared to MDI. PCT cut‐off of 0.4ng/ml on day 7 had a sensitivity and specificity of 60.98% and 100% respectively for discriminating IFI and PUO (p = 0.0001). Procalcitonin was significantly higher in the pneumonia group compared to other site infections (median‐11.42; IQR‐6.170 ‐ 13.003; p &lt; 0.05). Patients who developed signs of severe infection like Septic shock, hypoxia were noticed to have significantly high median PCT value at 24 and 48 hours (p value‐ 0.007 for PCT 24 and 0.001 for PCT 48). Patients with only MDI infections had the highest PCT level over the course of febrile episode. CRP cut off &gt;160 mg/dl at 48 hours was suggestive of fever due to fungal infection rather than other causes, with a sensitivity of 100%, specificity of 48%, PPV of 33.3% and NPV of 100%. There was a significant rise from baseline in CRP values at 48 hours in the IFI group when compared to the other groups (median = 33.6; p = 0.045). The CRP values at 24 hours and 48 hours were significantly lower in the PUO (disease fever) group (p = 0.001) when compared to the other groups. There was a significant fall in the level of PCT by day 14(median fall in PCT of 10.8) in the group of patients who had both IFI+ MDI when compared to other groups (p = 0.047).Summary/Conclusion:PCT level at 24 and 48 hours can be a predictor of severity of infection. High PCT level throughout the course of febrile episode were more suggestive of blood culture positive bacterial infection. Regarding CRP, significant rise from baseline at 48 hrs or CRP&gt;160 mg/dl at 48 hrs were significantly indicative of fungal infection rather than bacterial. PCT or CRP may be a useful adjunct to step down or step up antimicrobials.

Clinical value of plasma (1, 3)-β-D-glucan in the detection of invasive fungal infections

Objective To discuss the clinical value of plasma (1, 3)-β-D-glucan detection (G test) for early diagnosis of invasive fungal infections (IFI). Methods A total of 180 cases of IFI were divided into suspected group (84 cases), diagnosed group (49 cases) and clinical diagnosis group (47 cases). At the same period, the other 44 hospitalization patients with bacterial infection and 53 healthy persons were selected.All personnel were participated in the experiment using the MB-80 system for rapid detection of microbial dynamic detection, simultaneous plasma G test was evaluated using ROC curve analysis G optimal threshold test. Results Candida albicans was a common respiratory infections of IFI.Compared with bacterial group (9.4pg/mL) and normal group (7.8pg/mL) plasma glucan content median, IFI group plasma G test (29.3pg/mL) was significantly higher, and the differences were statistically significant(Z=-2.41, P=0.015; Z=-2.19, P=0.028), Compared with the median plasma glucan content of the diagnosis group (105.8pg/mL) and clinical diagnosis group (46.3pg/mL), to be diagnosed group (8.1pg/mL) was significantly lower, and the differences were statistically significant(Z=-2.99, P=0.003; Z=-2.19, P=0.027). ROC curve analysis showed that when the cutoff value was 9.35pg/mL, its specificity (67.2%), sensitivity (70.3%) and negative/positive predictive value (69.3% / 65.8%) were the best, and more consistent with the culture method, the Kappa value was 0.603, the difference was statistically significant (P=0.036). Conclusion In the early diagnosis of IFI, plasma G test has good results and can be widely used. Key words: Mycoses; Infection; Diagnosis

The effect of albumin on (1, 3)-β-D-glucan for diagnosis of invasive fungal infections

To explore the diagnostic value of plasma ( 1, 3 )-β-D-glucan test ( G test ) in diagnosis of invasive fungal infections ( IFI ) and the influence of albumin on G test. A prospective observational study was conducted. 267 patients admitted to medical intensive care unit ( MICU ) of Dalian Municipal Central Hospital from January 21st, 2012 to October 31st, 2014 were enrolled. According to IFI guideline, the patients were divided into without IFI group ( n = 35 ), possible IFI group ( n = 70 ), hypotheticle IFI group ( n = 145 ) and proven IFI group ( n = 17 ). G test was examined routinely using microbiology kinetic rapid reader MB-80.The different threshold values were calculated on G test. The difference among G tests, fungal culture and clinical diagnosis were compared. The results of G test ahead of and post albumin administration in each group were compared, and the value of G test for diagnosis of IFI during albumin infusion was evaluated. When the cut-off value was 20 ng/L for IFI diagnosis, higher sensitivity ( 79.8% ), specificity ( 87.9% ), and Youden index ( 67.7% ) were found. The positive rates of G test, fungal culture and clinical diagnosis of IFI were 57.7% ( 154/267 ), 60.7% ( 162/267 ) and 54.3% ( 145/267 ) respectively, without showing significant differences ( all P > 0.05 ). The result of G test ( ng/L ) was not obviously changed after albumin administration compared with that before in without IFI, possible IFI, hypotheticle IFI, and proven IFI groups ( without IFI group: 11.25±2.33 vs. 10.99±1.07, t = -1.723, P = 0.085; possible IFI group: 53.14±5.53 vs. 49.22±8.11, t = -0.395, P = 0.693; hypotheticle IFI group: 90.30±9.38 vs. 85.41±10.11, t = 710.500, P = 0.860; proven IFI group: 100.98±19.24 vs. 103.21±17.66, t = 653.000, P = 0.449 ). Prior to the administration of albumin, sensitivity, specificity, positive predictive value ( PPV ), negative predictive value ( NPV ) and Youden index were 79.8%, 87.9%, 45.6%, 96.7%, 67.7%, respectively. However, after the administration of albumin, they were 81.5%, 85.7%, 44.8%, 96.5%, and 67.2%, respectively, without significant difference. G test is method for early diagnosis of IFI. The sensitivity and specificity are higher with 20 ng/L as the critical value. The result of G test is not interfered by albumin administration.

Detection of (1,3)-β-D-glucan for diagnosis of invasive fungal infection in premature infants

Objective To evaluate the diagnostic value of (1, 3)-β-D-glucan assay (G test) in the plasma of premature infants with invasive fungal infection (IFI) and determinate the best diagnostic value of G test. Methods The premature infants who were at risk of IFI from NICU were enrolled in Shengjing Hospital of China Medical University from July 2010 to September 2011. The concentration of (1, 3)-β-D-glucan were detected by GKT-5MSet microbial dynamic detection system, and the fungal and bacterial culture were performed in the same samples of blood. We used to perform statistic analysis for sensitivity, specificity, positive predictive value and negative predictive value at different cutoff values, and draw receiver operating characteristic curve for G test. Results Forty-four infants were eligible for the study, of 17 permature infants with IFI, and of 27 ones with non IFI, in whom bacterial culture was positive in 12 cases and culture was negative in 15 cases. The concentration of (1, 3)-β-D-glucan in IFI group[5~3 117 pg/ml, median (Q75-25) 190.60 (501.44) pg/ml] was higher than that in non IFI group[5.0~434.3 pg/ml, median (Q75-25) 5.86 (5.62) pg/ml], the difference was significant (Z=-3.77, P<0.01).15 pg/ml was the best cutoff value, and the area under curve was 0.839, 95%CI (0.697, 0.980). Conclusion G test is useful in the diagnosis of IFI in premature infants with high sensitivity and specificity. G test can be used for the screening of high-risk patients with high risk of fungal infection ratio. Key words: (1, 3)-β-D-glucan; Invasive fungal infection; Premature infant

Invasive fungal infections in Argentine patients with systemic lupus erythematosus

Infections are the leading cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Invasive fungal infections (IFI) comprise a group of diseases caused by Cryptococcus, Histoplasma, Aspergillus and Candida. Few studies of IFI have been published in patients with SLE and associated factors have not been completely defined. The objectives of this paper are to estimate the frequency of IFI in admitted patients with SLE in our hospital, to determine the risk factors associated with IFI in our patients with SLE, and to compare IFI group with a control group (SLE without IFI). The medical charts of patients with IFI (EORTC/MSG, 2008) and SLE (ACR, 1997) admitted to our hospital from June 2001 until June 2012 were reviewed. To identify factors associated with IFI, we developed a case-control study (SLE + IFI vs SLE alone) in a one to three ratio adjusted for sex and age and hospitalization for other reasons. Comparison was made of demographic characteristics, duration of disease and disease activity previous to IFI diagnosis, especially three months before fungal infection. We defined severe activity as SLEDAI ≥ 8. Infection by fungi of the genus Candida was considered only in its disseminated form. Ten cases of IFI were identified in 208 patients with SLE admitted between June 2001 and June 2012. We included 40 patients with SLE (10 with IFI and 30 controls). Of the SLE-IFI patients, eight were women and the average age was 27.5 years (range, 19-42 years). Fungal isolation: eight Cryptococcus neoformans, one Histoplasma capsulatum and one Candida albicans. Sites affected: five in peripheral blood, five in central nervous system (CNS), four in skin/soft tissue and one in pleura. Mortality was 40% (p = 0.002), with Cryptococcus neoformans being the most common fungus. The SLE disease activity was severe in 70% of infected patients and no significant difference with the control group was found (p = 0.195). We also found no association with leukopenia, lymphopenia, hypocomplementemia, hypogammaglobulinemia or anti-DNA positivity; neither with meprednisone doses >20 mg/day or intravenous methylprednisolone pulse therapy before fungal infection. The use of immunosuppressive therapy with azathioprine showed a significant association (p = 0.017). Cyclophosphamide (p = 0.100) or mycophenolate mofetil (p = 0.256) did not show similar results. The frequency of IFI in hospitalized SLE patients in our hospital was 4.8%. Cryptococcus neoformans was the most common etiologic agent and was primarily responsible for the deaths in this cohort. These data are consistent with publications in East Asia rather than North America where Candida spp. is more common. Unlike other publications, previous immunosuppression with azathioprine was the only risk factor associated with the development of the infection. Invasive fungal infection should be suspected in hospitalized patients with SLE and immunosuppression with CNS or atypical cutaneous manifestation of SLE in order to start appropriate treatment early and obtain better outcome.

Perfil epidemiológico y patrón de sensibilidad de aislamientos causantes de infección fúngica invasora frente a aislamientos fúngicos de colonización en pacientes críticos no neutropénicos

BackgroundPatients admitted to critical care units can be infected with a large number of fungal isolates that are occasionally responsible for invasive fungal infections (IFI). AimsTo describe the epidemiological profile and antifungal susceptibility patterns of fungal isolates in our unit, and to identify key risk factors associated with the development of IFI. MethodsA descriptive cohort and retrospective study with patients admitted to a polyvalent Critical Care Unit of a university hospital was carried out. The isolation of at least one fungal species in a culture of biological samples, over a period of 48 months was considered. ResultsTwenty patients out of 232 developed IFI. Patients in the IFI group had a higher mortality and higher Candida score value 48h prior to clinical diagnosis. Risk factors associated with the development of IFI were chronic obstructive pulmonary disease, gastrointestinal surgery, total parenteral nutrition, and prolonged systemic corticosteroid therapy. The predominant fungal species in both groups was Candida albicans, with global resistance to fluconazole and itraconazole of 1.94%. ConclusionsWe found a low incidence of species of Candida non-C. albicans in our unit. The rate of resistance to azoles in C. albicans was similar to that of larger series. Gastrointestinal surgery, COPD, prolonged treatment with corticosteroids, and parenteral nutrition administration are risk factors associated with the development of IFI.

Three major achievements of the Infections Disease Group

The EORTC Infectious Disease Group (IDG) and its forerunners, the International Antimicrobial Therapy Cooperative Group (IATCG) and the Invasive Fungal Infection Group (IFIG), have helped drive and develop clinical practice in the management of bacterial and fungal infectious diseases. Besides undertaking seminal studies, the group in its various forms has played a key role in understanding the nature and management of the infectious complications that arise during the treatment of cancer, particularly hematological malignancies. The IATCG was also instrumental in setting the stage for large randomized controlled trials to address therapies for dealing with infections that developed during neutropenia. The three most important achievements of the group were in finding a rational basis for managing bacterial and fungal infections, the establishment of disease definitions, and the development of the guidelines.

Reduced Incidence of Early Invasive Fungal Infection in Allogeneic Transplant Patients Following Micafungin Prophylaxis

Abstract 4567Reduced incidence of early invasive fungal infection in allogeneic transplant patients following micafungin prophylaxis.D To1, D Warkentin2, R Broady1, J. D. Shepherd1, S.H. Nantel1, T.J. Nevill1,C.M. Toze1, D.E. Hogge1, M.J. Barnett1, K.W. Song1, H.J. Sutherland1, D.L. Forrest1, S. Narayanan1, M. M. Power1 (on behalf of the Leukemia/BMT Program of BC and Department of Pharmacy, Vancouver General Hospital)1Leukemia and Bone Marrow Transplantation Program of BC,2Department of Pharmaceutical Science Vancouver General Hospital and University of British Columbia Introduction:Invasive fungal infection (IFI) is both highly prevalent and highly morbid in the allogeneic transplant (HSCT)patient population. We have previously documented an incidence of IFI in our HSCT patient cohort of 20%(2006–2007). At the time of the initial analysis, low dose amphotercin B (LDAB) (10mg/m2) was the routine prophylaxis given for the neutropenic phase post HSCT. This study was carried out to analyse whether an alteration in prophylaxis strategy for patients during the neutropenic phase post HSCT was effective in reducing the incidence of IFI in this heavily immunocompromised patient group. We also aimed to identify risk factors for IFI which would help to guide prophylactic strategies beyond the neutropenic phase. Methods:A retrospective analysis of all patients undergoing allogeneic stem cell transplant between January 2010 and June 2011 was carried out. 67 patients thus identified were reviewed and the incidence and risk factors for IFI in this group was compared to our historical control group from 2006–2007 (n=69). Patients with a prior history of IFI were excluded. EORTC criteria were used to define possible, probable or proven IFI. Diagnostic criteria guiding treatment of IFI did not change between the two study periods. Micafungin 100mg iv was the prophylaxis given to inpatients undergoing myeloablative or unrelated donor non myeloablative transplantation. For outpatient based non- myeloablative transplants, fluconazole 200 mg orally daily was the prophylaxis of choice. Prophyaxis was started on day +1 and was continued until absolute neutrophil count (ANC) was >0.5× 109/L. Results:The overall incidence of IFI was 10/67 (15%), with 5% proven/probable and 10% possible IFI's. The median time to diagnosis of IFI was 78 days from date of transplant. This represents a decrease in incidence of IFI compared to the earlier cohort (20%). The reduction in IFI seen in our current cohort of patients who received micafungin or fluconazole prophylaxis appears to be largely attributable to a reduction in the rate of early (before day +30) IFI in the group of patients treated with iv micafungin (Table 1). Only one of the 43 patients given micafungin prophylaxis developed an IFI in the first 30 days following transplantion.Table 1Characteristics of IFI and Prophylactic Cohort.HSCT-LDAB N=69HSCT-Mi100 N=43HSCT-fluco N=24IFI %13 (20%)5 (10%)5 (21%)p=0.07Proven/probable IFI4 (6%)2 (4%)1 (4%)nsPossible IFI9 (14%)3 (6%)4 (17%)Median time to IFI from HSCT (days) (range)80 (5-590)139 (56-173)40 (11-184)IFI<30 days38%020%p<0.001IFI 30-100 days17%40%60%IFi>100 days45%60%20%Timing of IFI; median time to diagnosis of IFI was 78 days. Only two patients developed an IFI during the neutropenic phase post chemotherapy (20%), 4 patients developed IFI between days 30 and 100 and 4 patients developed an IFI after day 100. (38%, 17% and 45% in earlier cohort.Risk factors for IFI were assessed(Table 2). Of striking significance is the finding that those patients who developed steroid refractory graft versus host disease (GVHD) had an incidence of IFI of 56% (5 of 9 patients developed an IFI) compared to those patients with GVHD who did not require second line therapy of whom only 7% developed an IFI.50% (5/10) of patients who developed an IFI have died compared to 9% of the patients in the no IFI group (5/57). Mortality attributable to IFI was 30% in the IFI group. Conclusion:We demonstrate a reduction in early IFI in patients prophylaxed with micafungin in this small series of uniformly treated patients. Late IFI remains a problem and we have identified a subgroup of patients for whom further prophylaxis is warranted. Prophylaxis with a mold active azole should be given to all patients who develop steroid refractory GVHD given the unacceptably high incidence of IFI in this patient subset. Disclosures:Sutherland:Centocor Ortho Biotech research & Development: Research Funding.

Diagnostic Accuracy of Serum 1,3-β- d -Glucan for Pneumocystis jiroveci Pneumonia, Invasive Candidiasis, and Invasive Aspergillosis: Systematic Review and Meta-Analysis

Serum 1,3-β-d-glucan (BG) assay may be helpful as a marker for the diagnosis of Pneumocystis jiroveci pneumonia (PJP) and invasive fungal infection (IFI). We conducted a systematic review to assess the diagnostic accuracy of this assay. We searched MEDLINE, Web of Science, Cochrane Collaboration databases, Ichushi-Web, reference lists of retrieved studies, and review articles. Our search included studies of serum BG assay that used (i) positive cytological or direct microscopic examination of sputum or bronchoalveolar lavage fluid for PJP and (ii) European Organization for Research and Treatment of Cancer or similar criteria for IFI as a reference standard and provided data to calculate sensitivity and specificity. Only major fungal infections such as invasive candidiasis and invasive aspergillosis were included in the IFI group. Twelve studies for PJP and 31 studies for IFI were included from January 1966 to November 2010. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC-SROC) for PJP were 96% (95% confidence interval [95% CI], 92% to 98%), 84% (95% CI, 83% to 86%), 102.3 (95% CI, 59.2 to 176.6) and 0.96 (95% CI, 0.94 to 0.99), respectively. No heterogeneity was found. For IFI, the values were 80% (95% CI, 77% to 82%), 82% (95% CI, 81% to 83%), 25.7 (95% CI, 15.0 to 44.1), and 0.88 (95% CI, 0.82 to 0.93). Heterogeneity was significant. The diagnostic accuracy of the BG assay is high for PJP and moderate for IFI. Because the sensitivity for PJP is particularly high, the BG assay can be used as a screening tool for PJP.

Diagnostic value of serum (1-3)-β-D-glucan for invasive fungal infection in neonates

Objective To evaluate the diagnostic value of serum (1-3)-β-D-glucan detection for invasive fungal infection (IFI) in neonates. Methods Eighty-seven neonates who were suspected to be IFI cases in neonatal intensive care unit from May 2008 to January 2010 were enrolled into this study. All subjects had infection symptoms, while did no react to the antibiotics treatment. The diagnosis of IFI was made according to Invasive pulmonary fungal infection diagnostic criteria of children set by Subspecialty Group of Respiratory Diseases, the Society of Pediatrics, Chinese Medical Association and Invasive fungal infection diagnostic criteria for critical patients set by the Society of Critical Care Medicine, Chinese Medical Association. Circulating (1-3)-β-D-glucan levels were determined with GKT-5M set kinetic fungus detection kit. Levels of (1-3)-Β-D-glucan in IFI group and that in the control group were compared; optimal cut-off value was established with receiver operating characteristic (ROC) curve; and the sensitivity and specificity at the cut-off value of 20.0 pg/ml and optimal cut-off value were calculated and compared. Results Among the 87 suspected cases, 59 cases were not diagnosed as IFI and 28 cases were diagnosed as IFI finally. Five patients were confirmed to be IFI; seven cases were clinically diagnosed and 16 cases were still suspected IFI. Among the five confirmed cases, four cases were blood culture positive for Candida parapsilosis, one case Candida albicans positive and two cases both cerebrospinal fluid culture and blood culture positive for Candida albicans. The median levels of (1-3)-β-D-glucan of patients diagnosed as IFI (n=28) was 131.6 pg/ml(18.6-9999.0 pg/ml), which was higher than that of the patients without IFI (8.5 pg/ml, 5.0-34.6 pg/ml)(Z=-5.064, P<0.05). Area under ROC curve was 0.806 (95% CI: 0.725-0.886, P<0.05). The sensitivity (96.43% vs 69.49%) and specificity (72.22% vs 84.21%) for (1-3)-β-D-glucan were different as 20.0 pg/ml and 53.7 pg/ml were used as the cut-off values for diagnosing IFI. Conclusions (1-3)-β-D-glucan level could be used to diagnose IFI of neonates, but further studies are needed to evaluate false-positive rates and its cut-off value in IFI diagnosis. Key words: Mycoses; Infant, newborn; beta-Glucan

Mortality, length of hospitalization, and costs associated with invasive fungal infections in high-risk patients

The mortality, length of hospitalization, and costs associated with invasive fungal infections (IFIs) in hospitalized patients were studied. This retrospective database study used data from the 2004 Healthcare Cost and Utilization Project Nationwide In-patient Sample. Patients were selected for inclusion based on diagnostic codes corresponding to an IFI. A control group was matched to the IFI group based on high-risk conditions (i.e., cancer, infection with human immunodeficiency virus, chronic obstructive pulmonary disease, diabetes mellitus, and solid-organ, hematopoietic stem cell, or bone marrow transplant), age, sex, and hospital region and teaching status. Excess mortality, length of hospital stay, and costs were estimated as the differences between the IFI and control groups. A total of 11,881 patients were identified with a discharge diagnosis of an IFI who could be matched to a control. Frequent infections included candidiasis (40.2%), other mycoses (36.3%), and aspergillosis (16.4%). Patients with IFIs had a significantly higher mortality rate (15% versus 5%), mean +/- S.E. length of stay (18.7 +/- 0.4 days versus 7.3 +/- 0.1 days), and mean +/- S.E. costs ($44,726 +/- $1,255 versus $15,445 +/- $404) (p < 0.001 for all comparisons) than did patients without IFIs. The burden of IFIs varied by high-risk condition (highest for transplant recipients and patients with cancer) and type of infection (highest for candidiasis, zygomycosis, and aspergillosis). Examination of a large database showed that, compared with high-risk patients without IFIs, those with IFIs had higher mortality, a longer hospital stay, and higher costs associated with their hospitalization.

Prospective study of pattern of invasive fungal infections (IFI) and role of latex agglutination (LA) in galactomannan (GM) and candidamannan (CM) antigen detection in patients presenting with high-risk neutropenic fever (FN): Tata Memorial Hospital experience

20534 Background: IFI is a common cause of morbidity & mortality in hematolymphoid malignancy. This study was initiated to document the profile of IFI and to test LA in diagnosis. Methods: Prospective study of IFI in acute leukemia, high grade lymphoma and stem cell transplant with high risk FN. Sample size was calculated to be 270 with an assumed probability of 20% IFI. Consecutive consenting patients, without serious comorbid conditions were included. In a subset of 96 patients serial serum samples were tested for GM,CM. Endpoints were afebrile for 2 days, neutrophil > 1,000/cumm and clearance of infection or death. Episodes were classified as proven, probable, possible IFI and nonIFI based on the EORTC/MSG criteria. Results: From Feb 2006 to Jan 2007, 269 high risk FNs were studied. 85% of the episodes had acute leukemia. 14 (5.2%), 12 (4.5%) and 78 (29%) episodes had proven, probable and possible IFI. Halo sign, nodules and cavity were seen in 22%, 17% and 15% of chest CT scans and liver, spleen or kidney hypodensities in 5, 7 and 3 episodes respectively by abdominal imaging (n-37) in IFI group. Blood culture grew candida in 14 and mold in 4 in IFI. 3/64 respiratory (all IFI) and 7/84 stool samples also cultured candida (3 IFI). 2/3rd of the candida were non albicans. A total of 39 and 57 patients underwent LA assay in IFI and nonIFI group respectively. Sensitivity and specificity were 31%, 88% for GM and 5%,91% for CM detection respectively. The predictive values were 63%–65% for GM and 29%–61% for CM. In multivariate model presence of infectious focus, prolonged neutropenia and fever, poor PS and albumin <3.5gm/dl were associated with increased risk of IFI. Conclusion: IFI is on rise in hematolymphoid malignancy as chemotherapy regimens get more aggressive. LA for GM, CM detection is a simple test but had a low predictive value and sensitivity in our experience. IFI % (n: 104) * Non IFI % (n:165) Focus of infection Any 100 60 Chest 90 28 Abnormal Chest Xray 64 8 Abnormal Chest CT scan 97(n: 69) 40(n:20) Neutropenia > 10days 92 51 Fever > 10days 65 23 Death 33 1 * p value <.001 in all No significant financial relationships to disclose.

Forum report: issues in the evaluation of diagnostic tests, use of historical controls, and merits of the current multicenter collaborative groups.

This forum report contains conclusions about 3 different issues relevant to conducting clinical trials in deep mycoses. (1) Trials of diagnostic tests for deep mycoses must define the population appropriate for testing and the clinical question being asked. The unanswered question for the serum Aspergillus galactomannan assay is whether knowledge of results can change use of empirical therapy to treat febrile patients at high risk of invasive aspergillosis. (2) Use of historical controls is suboptimal but offers a pragmatic solution for studying rare mycoses; use of contemporaneous controls, matched for critical variables and evaluated by a blinded data review committee using detailed criteria, appears optimal. (3) Established groups of independent investigators, such as the European Organization for Research on Treatment of Cancer's Invasive Fungal Infections Group and National Institute of Allergy and Infectious Diseases's Bacteriology and Mycology Study Group, provide a pool of experienced investigators, defined operating rules, impartiality, and specialized expertise. Considering the enormous investment required for adequately powered efficacy trials of antifungal agents and the importance of these trials to guide clinical practice, use of collaborative groups outweighs the extra administrative time that is sometimes required.