Risk Factors For Invasive Fungal Infections Research Articles

Infections of Venetoclax-Based Chemotherapy in Acute Myeloid Leukemia: Rationale for Proper Antimicrobial Prophylaxis.

Simple SummaryVenetoclax (VEN)-based combination chemotherapy has been a promising option for acute myeloid leukemia (AML) treatment. However, the risk of infections and strategies of prophylaxis are not yet established. This study aimed to evaluate the severe infectious complications of VEN-based chemotherapy and to clarify the evidence for antimicrobial prophylaxis. The incidence of invasive fungal infections (IFIs) and bloodstream infections (BSIs) was 6.6/100 cycles and 12.7/100 cycles respectively. Secondary and therapy-related AML was an independent risk factor for IFIs (odds ratio, 3.859; 95% confidence interval, 1.344–11.048, p = 0.012). Patients with IFIs showed significantly poorer outcomes, but there was no statistically significant difference in patients with BSIs. Mold-active antifungal agents as prophylaxis are generally recommended in high-risk patients with AML who are treated with VEN-based combination chemotherapy.Although venetoclax (VEN)-based combination chemotherapy in patients with acute myeloid leukemia (AML) results in prolonged and profound neutropenia, data regarding infectious complications and antimicrobial prophylaxis are lacking. We investigated the infectious complications in 122 adult patients with AML under the same standard of care for prevention. The prophylaxis protocol was fluconazole 400 mg/d without antibacterial agents. The incidence of proven or probable invasive fungal infections (IFIs) was 6.6/100 cycles, and 22 patients (18.0%) were diagnosed (median, second cycle; interquartile range, 1–2). All IFIs were caused by Aspergillus and significantly influenced the overall mortality (odds ratio (OR), 2.737; 95% confidence interval (CI), 1.051–7.128; p = 0.034). In the multivariate analysis, secondary or therapy-related AML was an independent risk factor for IFIs (OR, 3.859; 95% CI, 1.344–11.048, p = 0.012). A total of 39 bloodstream infection (BSIs) episodes occurred in 35 patients (28.7%), with an incidence of 12.7/100 cycles. High-dose steroid administration within 90 days was associated with the occurrence of BSIs (OR, 7.474; 95% CI; 1.661–3.631, p = 0.008), although BSIs themselves did not have an impact on the outcomes. Our findings suggest evidence for the need for mold-active antifungal agents as antifungal prophylaxis, rather than fluconazole, especially in patients with secondary or therapy-related AML.

Incidence of invasive fungal infection in acute lymphoblastic and acute myelogenous leukemia in the era of antimold prophylaxis

The incidence of invasive fungal infection (IFI) in patients with acute myeloid leukemia (AML) has decreased with the introduction of antimold prophylaxis. Although acute lymphoblastic leukemia (ALL) has a lower risk of IFI than does AML, the incidences of IFI in both AML and ALL in the era of antimold prophylaxis should be re-evaluated. We analyzed adults with AML or ALL who had undergone induction, re-induction, or consolidation chemotherapy from January 2017 to December 2019 at Seoul National University Hospital. Their clinical characteristics during each chemotherapy episode were reviewed, and cases with proven or probable diagnoses were regarded as positive for IFI. Of 552 episodes (393 in AML and 159 in ALL), 40 (7.2%) were IFI events. Of the IFI episodes, 8.1% (12/148) and 5.9% (13/220) (P = 0.856) occurred in cases of ALL without antimold prophylaxis and AML with antimold prophylaxis, respectively. After adjusting for clinical factors, a lack of antimold prophylaxis (adjusted odds ratio [aOR], 3.52; 95% confidence interval [CI], 1.35–9.22; P = 0.010) and a longer duration of neutropenia (per one day, aOR, 1.02; 95% CI, 1.01–1.04; P = 0.001) were independently associated with IFI. In conclusion, the incidence of IFI in ALL without antimold prophylaxis was not lower than that in AML. A lack of antimold prophylaxis and prolonged neutropenia were independent risk factors for IFI. Clinicians should be on guard for detecting IFI in patients with ALL, especially those with risk factors.

Risk factors of invasive fungal infections in lung transplant recipients: A systematic review and meta-analysis

Invasive fungal infection (IFI) remains a common complication after lung transplantation, causing significant morbidity and mortality. We have attempted to quantify systematically risk factors of IFI in lung transplant recipients. Studies were retrieved from Ovid MEDLINE, Ovid Embase, Cochrane database of systematic reviews and Cochrane central register of controlled trials. All case-control and cohort studies evaluating the risk factors of IFI in adult lung transplant recipients were screened. Two researchers reviewed and assessed all studies independently. We pooled the estimated effect of each factor associated with IFI by using a random effect model. Eight studies were included in the systematic review and 5 studies were eligible for the meta-analysis. Rates of IFI range from 8% to 33% in lung transplant recipients. Independent risk factors for invasive aspergillosis (IA) in lung transplantation include previous fungal colonization (odds ratio [OR] 2.44; 95% confidence interval [CI] 0.08-0.47), cytomegalovirus infection (OR 1.96; 95% CI 1.08-3.56), and single lung transplantation (OR 1.77; 95% CI 1.08-2.91). Pre-emptive antifungal therapy is a protective factor for IA in lung transplant (OR 0.2; 95% CI 0.08-0.47). Cytomegalovirus infection, previous fungal colonization and single lung transplantation independently increase the risk of IA in lung transplant recipients. Pre-emptive antifungal therapy is a protective factor for IA in the lung transplant population.

Invasive Fungal Diseases in Children with Acute Leukemia and Severe Aplastic Anemia.

Although the outcomes of childhood leukemia and severe aplastic anemia (SAA) have improved, infectious complications are still the major concern. Particularly worrisome are invasive fungal diseases (IFDs), one of the most common causes of infectious-related deaths in patients with prolonged neutropenia. A retrospective study was conducted of IFDs in pediatric patients with newly diagnosed or relapsed acute leukemia, or with SAA, at Siriraj Hospital, Mahidol University, Thailand. There were 241 patients: 150 with acute lymphoblastic leukemia (ALL), 35 with acute myeloid leukemia (AML), 31 with relapsed leukemia, and 25 with SAA. Their median age was 5.4 years (range, 0.3–16.0 years). The overall IFD prevalence was 10.7%, with a breakdown in the ALL, AML, relapsed leukemia, and SAA patients of 8%, 11.4%, 19.3%, and 16%, respectively. Pulmonary IFD caused by invasive aspergillosis was the most common, accounting for 38.5% of all infection sites. Candidemia was present in 34.6% of the IFD patients; Candida tropicalis was the most common organism. The overall case-fatality rate was 38.5%, with the highest rate found in relapsed leukemia (75%). The incidences of IFDs in patients with relapsed leukemia and SAA who received fungal prophylaxis were significantly lower than in those who did not (P = N/A and 0.04, respectively). IFDs in Thai children with hematological diseases appeared to be prevalent, with a high fatality rate. The usage of antifungal prophylaxes should be considered for patients with SAA to prevent IFDs.

Ibrutinib: A Risk Factor for Invasive Fungal Infections?

Background : Invasive fungal infections (IFI) are life threatening infections reported mainly in acute leukemia patients with prolonged deep neutropenia and patients post bone marrow or organ transplants.IFI are an uncommon consequence of CLL and NHL, cranial (brain, sinuses) involvement is distinctly rare. Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. The Italian SEIFEM group reported the frequency of IFI in a retrospective multicenter study of CLL patients as 4 per 1104 patients over 5 years and among patients with NHL 27 per 3457 over 5 years. In a report combining 8 European countries, only 10 cases of CNS aspergillosis were identified in non-neutropenic ICU patients, between the years 2006-2011.Ibrutinib is a kinase inhibitor effective in the treatment of CLL and other NHLs has also been shown to have inhibitory activity against macrophages essential for defense against molds and Cryptococcus species.In 2016 we described 3 non-neutropenic CLL patients who developed invasive cranial aspergillosis while on treatment with ibrutinib (NEJM, 2016). In all three patients this developed shortly after beginning therapy with ibrutinib. All were on steroids before starting therapy and the course was fulminant. In two of the three patients the infection was fatal.Recently Lionakis et al (Cancer Cell, 2017) reported invasive aspergillosis in seven of 18 (39%) PCNSL patients treated with ibrutinib. Sites of involvement were cranial, pulmonary or both. None had prolonged neutropenia. The authors suggest that ibrutinib impairs fungal immune surveillance which may be exacerbated by the combined use of steroids and/or chemotherapy.In order to better understand if these cases were isolated events or connected to therapy with ibrutinib, in this retrospective, investigator initiated international study we summarize the clinical and laboratory parameters of patients who developed invasive fungal infections while being treated with ibrutinib.Methods : Patients with IFI were identified by treating physicians. Clinical and laboratory data were collected and managed using REDCap electronic data capture tools hosted at Shaare-Zedek Medical Center1(doi:10.1016/j.jbi.2008.08.010). The study received an IRB approval.Results : Twenty-eight patients with IFI were enrolled from 15 centers in 6 countries by 18 physicians (Table 1). The median age at the start of ibrutinib treatment was 71, and 71% had CLL. The median number of prior therapies was 3. Six out of 11 (54%) of patients with FISH results had 17pdel/ TP53 mutations. Twenty patients (71%) had at least 1 predisposing factor, 36% were treated with steroids when starting ibrutinib and three patients were post bone marrow transplants. The median lowest neutrophil count in the month before starting ibrutinib was 1.5 x 103/µl. Aspergillus was the main pathogen (64% of the cases), the main site being the lungs (75%) and cranial (brain, sinuses) in 57%. Six patients had multiple sites of involvement. The diagnosis of the pathogen was definite in 25 (89%) and probable in 11%. IFI resolved in only 25% of patients and mortality was 61% from all causes.Discussion : This cohort of 28 patients developed IFI on therapy with ibrutinib in the absence of common risk factors. Other unique features of our cohort are the high prevalence of CNS involvement (almost half of the patients); and the presentation of Aspergillus and Mucor ycosis spp infections at multiple sites, which is not a typical presentation for these pathogens. As the differential diagnosis was wide, most patients went through an invasive diagnostic procedure and therefore a high rate of a definite diagnosis was achieved rapidly in comparison to acute leukemia patients. Our preliminary results suggest that ibrutinib might be a risk factor for IFI resulting in unique patterns of clinical presentations. Subsequent comparative studies are urgently needed to better identify which patients on ibrutinib treatment are at greater risk for IFI. [Display omitted] DisclosuresBrown:Astellas Pharma: Consultancy; Sun BioPharma: Consultancy, Research Funding; Redx: Consultancy; Infinity Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Janssen: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy; Janssen Oncology: Honoraria; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding. Nijland:Novartis Pharmaeuticals Corporation: Honoraria; Kite Pharma: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; MIllennium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria.

Invasive Fungal Infections after Anti-CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy: State of the Evidence and Future Directions.

Studies describing invasive fungal infections (IFIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. Although post-CAR-T-cell IFIs appear to be uncommon, they are associated with significant morbidity and mortality. Specific risk factors for IFIs in CAR-T-cell recipients have not been fully characterized and are often extrapolated from variables contributing to IFIs in patients with other hematologic malignancies or those undergoing hematopoietic cell transplant. Optimal prophylaxis strategies, including the use of yeast versus mold-active azoles, also remain ill-defined. Further research should investigate key risk factors for IFIs and establish an evidence-based approach to antifungal prophylaxis in these patients in order to improve clinical outcomes.

Epidemiology and risk of invasive fungal infections in systemic lupus erythematosus: a nationwide population-based cohort study.

Introduction:Infections are a leading cause of mortality in patients with systemic lupus erythematosus (SLE). Among various infections, invasive fungal infections (IFIs) have a particularly high mortality rate; however, studies examining IFIs in patients with SLE are limited.Methods:Patients diagnosed as having SLE between 1997 and 2012 were enrolled from Taiwan’s National Health Insurance Research Database along with age- and sex-matched non-SLE controls at a ratio of 1:10. IFIs were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification codes and validated by the prescriptions of systemic antifungal agents. The incidence rate (IR), incidence rate ratio (IRR), and all-cause mortality rate of IFIs and its subtypes were analyzed. A Cox multivariate regression model with time-dependent covariates was applied to analyze independent risk factors for IFIs.Results:A total of 24,541 patients with SLE and 245,410 non-SLE controls were included. We observed 445 IFI episodes in the SLE cohort, with an all-cause mortality rate of 26.7%. Candida spp. (52.8%) was the most common pathogen, followed by Cryptococcus spp. (18.2%) and Aspergillus spp. (18.2%). The IR of IFIs in the SLE cohort was 20.83 per 10,000 person-years, with an IRR of 11.1 [95% confidence interval (CI): 9.8–12.6] relative to the non-SLE controls. Juvenile patients with SLE aged ⩽18 years had the highest IRR of 47.2 (95% CI: 26.9–86.8). Intravenous steroid therapy administered within 60 days (hazard ratio: 29.11, 95% CI: 23.30–36.37) was the most critical risk factor for overall IFIs and each of the three major fungal pathogens. Distinct risk factors were found among different IFI subtypes.Conclusion:Patients with SLE had a higher risk of IFIs, especially juvenile patients. Intravenous steroid therapy is the most critical risk factor for IFIs. This study provides crucial information for the risk stratification of IFIs in SLE.Plain Language SummariesPatients with systemic lupus erythematosus and physicians treating this patient group should be aware of the risk of invasive fungal infections.Invasive fungal infections (IFIs) are a severe complication with a high mortality rate among patients with systemic lupus erythematosus (SLE); however, studies on this topic are scant. We performed a nationwide population-based study in Taiwan to estimate the incidence and mortality of and risk factors for IFIs. We found an incidence rate of 20.83 per 10,000 person-years for IFIs, with a mortality rate of 26.7%. Juvenile patients aged ⩽18 years had the highest relative risk of IFIs. Although candidiasis was the most common IFI, cryptococcosis and aspergillosis should be concerned in juvenile patients as well. Intravenous steroid therapy was the most critical risk factor for all IFIs, and different immunosuppressive agents posed different risks in patients for acquiring certain fungal pathogens.Our findings provide pivotal epidemiological information and indicate risk factors for IFIs in patients with SLE. Age and exposure to specific immunosuppressants and steroids might help predict the risk of IFIs. Because the manifestation of these infections is sometimes indistinguishable from a lupus flare, physicians should be aware of this fatal complication, especially when patients are not responsive to immunosuppressive therapy. Early recognition, implication of diagnostic tools, and empirical antimicrobial agents can be the key to treating patients with IFIs. Additional studies are required to develop a risk management program for patients with SLE.

93. A Diagnostic Stewardship Intervention to Improve Utilization of 1,3-β-D-glucan Testing

Background1,3-β-D-glucan (BDG) is a cell wall component of fungi such as Aspergillus spp., Candida spp., and Pneumocystis jirovecii. BDG assay is used as a screening test to aid early diagnosis of invasive fungal infections (IFI) that are associated with significant morbidity and mortality in immunocompromised patients. The diagnostic performance varies depending on IFI risks among study populations, thus it is important to appropriately select patients with risk factors for IFI to optimize utilization of the BDG test.Figure 1. Figure 2. MethodsAn intervention to improve BDG test utilization was initiated at Truman Medical Center on November 28, 2018. The BDG test order was replaced by a BDG test request. The request was sent to the inbox of an on-call pathology team. Patient information was reviewed and the on-call pathology team called the ordering physician to discuss the case based on the approval algorithm chart. The criteria for BDG test approval were 1) immunocompromised or ICU patient, and 2) on empiric antifungal therapy, or inability to perform specific diagnostic tests such as bronchoscopy. If approved, a BDG test order was immediately processed. Retrospective chart review was conducted for 1 year pre- and post- intervention to obtain demographic, clinical, and laboratory data for 4 patient groups. Group 1 included patients who had BDG tests during pre-intervention period. Group 2 was composed of all patients who had BDG test requests during post-intervention period. Group 2a and 2b were the post-intervention patients with approved and rejected BDG test requests, respectively.Figure 3. ResultsThe number of BDG tests performed per year decreased from 156 pre-intervention to 24 post-intervention. The number of test requests was 65 and 41 of them were rejected which led to $7,380 direct cost savings. There was no significant difference in age or the proportion of immunocompromised and ICU patients between Group 1 and 2. The test positivity rate was significantly higher in Group 2-a compared to Group 1 (45.8 % vs. 25.3%, p=0.038). There was no delay in IFI diagnosis or IFI-related mortality in patients for whom BDG test requests were rejected.ConclusionWe successfully and safely implemented a diagnostic stewardship intervention for BDG testing and improved test utilization.Disclosures All Authors: No reported disclosures

1087. Evaluation of Risk Factors for Infection among Patients Receiving Ibrutinib

BackgroundIbrutinib is a small-molecule inhibitor of Bruton tyrosine kinase (BTK) approved for various B-cell malignancies and cGVHD. Rates of serious infection—defined as requiring hospitalization or parenteral antimicrobials— and invasive fungal infection (IFI) in patients on ibrutinib are as high as 11.4% and 4.2% respectively (Varughese T, et al. Clin Infect Dis 2018;67(5):687-92), which may be related to off-target inhibition of interleukin-2-inducible T-cell kinase or macrophage function.MethodsWe retrospectively reviewed infection complications in patients receiving ibrutinib at our institution between 06/01/2014 and 08/31/2019, including patients who received single-agent or combination ibrutinib. In this study, serious infection was defined as above, or a diagnosis of pneumonia regardless of hospitalization or parenteral antimicrobial therapy. Logistic regression was used to identify risk factors.ResultsBaseline characteristics of 134 included patients are in Table 1. Infection and serious infection occurred in 96 (72%) and 48 (36%) patients, respectively. When pneumonia was not included as a criterion for serious infection, the serious infection rate was 22%. Prior allogeneic stem cell transplant (allo-HSCT) (OR 4.50; 95% CI 1.19 – 17.00) and corticosteroid use (OR 5.42; 95% CI 1.49 – 19.82) were significant risk factors for serious infection without pneumonia (Table 2).Of 37 patients (28%) who received primary HSV/VZV prophylaxis with acyclovir, there was one case of suspected herpes zoster infection (3%). IFI developed in 7 patients (5%): 5 with Pneumocystis jirovecii pneumonia (PJP), 1 with invasive aspergillosis, and 1 with a filamentous fungus, species unknown. Other identified organisms are detailed in Figure 1. Classical risk factors for IFI, including diabetes, allo-HSCT, and concurrent corticosteroid use, were not significant predictors in this group.Table 1. Baseline Characteristics Table 2. Risk Factor Analysis Figure 1. Identified Organisms in Serious Infection ConclusionSerious infections developed at a higher rate than previously reported in the literature, with IFI rates similar to those previously described. Prior allo-HSCT and steroid use were found to be risk factors for serious infection without pneumonia. Treating physicians should have a high index of suspicion for pneumonia, IFI, and PJP in this population.Disclosures All Authors: No reported disclosures

The Incidence of Invasive Fungal Infections in Patients With AML Treated With a Hypomethylating Agent

BackgroundNewly diagnosed patients with acute myeloid leukemia (AML) who receive induction with a hypomethylating agent (HMA) are often neutropenic with an increased risk for invasive fungal infections (IFIs). This study analyzed the incidence and risk factors for IFIs in these patients, evaluated clinical patterns in antifungal prophylaxis, and assessed the diagnostic utility of tests in this setting. Patients and MethodsWe studied 117 newly diagnosed patients with AML treated with HMAs at our center, divided into groups based on concern for IFI (cIFI: all possible, probable, and proven IFIs) versus no concern for IFI. The Fisher exact test compared patients with cIFI versus without, and a multivariable logistic regression model estimated odds for cIFI. ResultsSixty-seven (57%) patients had cIFI, with 48 possible IFIs, 17 probable, and 2 proven cases. There was no difference in incidence based on home zip code, but the presence of chronic obstructive pulmonary disease was highly associated with cIFI (P = .001), as was male gender (P = .01). Neutropenia at treatment initiation was borderline in significance (P = .08). In diagnostics, 9% of patients had positive serum fungal markers, and 30 patients underwent bronchoscopy, with only 27% of cases yielding positive results. There was a difference in treatment regimens between patients receiving antifungal prophylaxis with mold coverage versus without mold coverage with respect to cIFI (P = .04). ConclusionscIFI in patients with AML treated with HMAs remains significant, especially in males and those with chronic obstructive pulmonary disease, who were found to be at higher risk. This may prompt clinicians to consider anti-mold prophylaxis in this setting.

Risk of invasive fungal infections in patients with high-risk MDS and AML receiving hypomethylating agents.

Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre-specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold-active prophylaxis can be considered in patients who are neutropenic at the start of therapy.

Low-dose liposomal amphotericin B for antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell transplantation.

Primary antifungal prophylaxis in paediatric allogeneic HSCT recipients is mainly based on azoles, which can have related toxicity and drug interactions. Low-dose liposomal amphotericin B (L-AmB) is an attractive intravenous alternative because of its low toxicity and lower risk of interactions. To evaluate the effectiveness and safety of L-AmB (1 mg/kg/day) for primary antifungal prophylaxis in pre-engraftment paediatric HSCT patients. Retrospective, observational study including all consecutive patients aged ≤18 years who underwent HSCT and received antifungal prophylaxis with intravenous L-AmB (1 mg/kg/day, from day -1 to 48 h before discharge) between January 2012 and December 2016. In total, 125 HSCT procedures in 118 patients were included, median age 7.2 years (IQR 4.2-11.5). Haematological malignancies were the main underlying condition (63.6%), and 109 (87.2%) were considered at high risk for invasive fungal infection (IFI). Ten patients (7.7%), all high risk, developed breakthrough IFI (three Candida spp., seven invasive mould infections) and tended to have higher overall mortality. The only statistically significant risk factor for IFI was cytomegalovirus co-infection. Adverse events, all grade I, occurred in 25 (20%), requiring L-AmB withdrawal in one case. Overall survival at 30 days was 99.2%. At study completion, one patient had died of IFI. The incidence of breakthrough IFI was comparable to that of previous reports, with a very low rate of significant toxicity. Thus, prophylactic L-AmB may be a safe, effective option for antifungal prophylaxis in the pre-engraftment phase for children undergoing HSCT, even those at high risk.

Risk Factors of Invasive Fungal Infections in Heart and Lung Transplantation: Systematic Review and Meta-Analysis

Invasive fungal infection (IFI) remains one of the most common complications after heart and lung transplantation, which relates to high morbidity and mortality rates. However, risk factors associated with this infection have not been well demonstrated. We performed a comprehensive search using Ovid MEDLINE, Ovid Embase, Cochrane database of systematic reviews, and Cochrane central register of a controlled trial. All case-control and cohort studies evaluated the risk factors of IFI in the adult heart, and lung transplantation was screened. Two researchers reviewed, extracted, and assessed all studies independently. We pooled the estimated effect of each independent factor associated with IFI from the multivariate analysis by using the random-effect model. Seventeen studies were included in the systematic review, and nine studies are eligible for meta-analysis. Rates of IFI among all studies range from 8 to 44%. Independent risk factors of IFI in heart and lung transplantation include anti-thymocyte globulin (ATG) therapy (HR 2.87), cytomegalovirus (CMV) infection (HR 2.53), previous fungal colonization (HR 2.43), single lung transplantation (HR 1.79) and rejection (HR 1.54). Antifungal prophylaxis (HR 0.29) and antifungal pre-emptive therapy (HR 0.20) are preventive factors for IFI. CMV infection, previous fungal colonization, rejection, ATG therapy, and single lung transplantation independently increase the risk of IFI in heart and lung transplant recipients. Antifungal prophylaxis and pre-emptive treatment are both practical preventive approaches in this transplant population.

Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents

AbstractThe combination of venetoclax with hypomethylating agents (VEN-HMAs) showed promising activity in newly diagnosed and relapsed/refractory (r/r) acute myeloid leukemia (AML). Treatment with VEN-HMAs results in prolonged cytopenia, thereby exposing patients to invasive fungal infections (IFIs). Here, we retrospectively studied a cohort of 119 AML patients treated with VEN-HMAs and analyzed the occurrence of IFIs, as well as our practice of antifungal prophylaxis, with the aim to identify the nature and risk factors for IFIs and their association with the type of antifungal prophylaxis used. The intended antifungal prophylaxis was micafungin in 38% of patients, azoles in 41% of patients, and none in 21% of patients. Older age was associated with no antifungal prophylaxis or micafungin use and lesser use of azoles (P = .043). We recorded 15 (12.6%) patients who developed probable or proven IFIs, with a median onset of 72 days (range, 35-281) after starting therapy. IFIs were more common among nonresponders compared with responders to VEN-HMA therapy (22% vs 6%, P = .0132) and in r/r compared with newly diagnosed AML (19% vs 5%, P = .0498); however, the antifungal prophylaxis used, patient age, hypomethylating agent schedule, history of prior allogeneic transplant, and initial neutropenia duration did not influence the development of IFIs during therapy. We conclude that the overall risk of IFIs during VEN-HMA therapy is low. The risk of IFIs is higher in nonresponders and in those who were treated in the r/r setting; these patients need reevaluation of their antifungal prophylaxis to minimize the risk of IFIs during therapy.

Risk Factors Associated With Invasive Fungal Infections in Kidney Transplant Patients

BackgroundKidney transplant recipients are at increased risk for developing invasive fungal infections (IFI). We queried the United States Renal Data System (USRDS) for risk factors for IFI in these patients. MethodsPatients who underwent a kidney transplant between 2005 and 2008 were queried for an IFI diagnosis using ICD-9 codes. An IFI was defined as at least one documented diagnosis from one of the following: (1) Candida (candidemia); (2) Histoplasmosis; (3) Aspergillosis; (4) Cryptococcosis; (5) “Other” mycoses. Potential risk factors included demographics, certain comorbidities and immunosuppressive medications. To examine the relative risk (RR), simple bivariate models were used, followed by a comprehensive full model to estimate the adjusted RR (aRR). ResultsOf 57,188 kidney transplant patients, 1,218 had 1,343 IFI diagnoses, with a median time to infection of 495 days. “Other” mycoses accounted for the most IFI diagnoses (37%), followed by aspergillosis (22%). The risk for any IFI was increased with age ≥65 years. Diabetes (aRR = 1.71), bacterial pneumonia (aRR = 1.62) and UTI (aRR = 1.34) were the top 3 clinical risk factors for infection. Each of the IFI groups was also associated with individual risk factors. Therapy with mycophenolate mofetil was associated with a decreased risk of candidemia. ConclusionsRisk factors for IFI in renal transplant patients include demographic, medication-associated and clinical data, as well as organism-specific factors. These results offer an extensive clinical profile of risk for IFI, and may thus help inform the diagnosis and presumptive therapy of invasive fungal infections in renal transplant recipients.

279. Evaluation of β-d-Glucan Utilization in Thailand: Single Academic Center Experience

Backgroundβ-d-glucan (BG) detection was first available in Thailand in 2016 to aid diagnosis of invasive fungal infections (IFIs). Given a paucity of real-world experience of BG use in resource-limited countries, this study was conducted to describe appropriateness of BG testing and sequelae of BG results.MethodsA retrospective study included all patients with at least 1 BG ordered at King Chulalongkorn Memorial Hospital, Bangkok, Thailand during March 2016 to December 2018. Descriptive statistics were used.Results83 patients were tested by BG assay (Fungitell, Associates of Cape Cod, Inc.): 6 with hematopoietic stem cell transplant, 12 with solid-organ transplant, 20 with active cancer receiving chemotherapy, 34 receiving high dose steroids (≥20 mg/day of prednisone for ≥3 weeks) and 11 with other conditions. Seventy-three patients were tested under infectious disease (ID) service’s recommendations. There were 13 and 20 cases of proven and probable IFIs, respectively. Among 13 proven IFIs, there were 11 positive, 1 indeterminate and 1 negative (mucormycosis) BG results. Among 49 cases with positive BG results, 24 were determined to be false-positive results. Median turn-around time for BG results was 16 (IQR: 9–23) days. Due to high turn-around time, only 8 patients were started on antifungal agent(s) and 3 underwent bronchoscopy due to positive BG results. All proven IFI cases were started on antifungal treatment prior to BG availability.ConclusionApproximately 87% of BG use in Thailand was ordered in patients with risk factors for IFIs. This could be due to majority of BG test was recommended by ID specialist. Despite being used in right clinical context, 49% had false-positive BG results. Another barrier of BG use in Thailand was high turn-around time due to small numbers of BG ordered and relative high cost to run the assay. Therefore, the utility of BG for aiding diagnosis or management of fungal infection in our setting is limited.Disclosures All authors: No reported disclosures.

High incidence of invasive fungal infection during acute myeloid leukemia treatment in a resource-limited country: clinical risk factors and treatment outcomes.

Invasive fungal infection (IFI) causes high morbidity and mortality during acute myeloid leukemia (AML) treatment. Interventions to prevent fungal infection, including air filtration systems and antifungal prophylaxis, may improve outcomes in this group of patients. However, they are expensive and therefore inapplicable in resource-limited countries. The benefit of antifungal therapy is also dependent on the local epidemiology. That led us to conduct the study to evaluate the characteristics and impact of IFI in AML patients without prophylaxis in our setting. Clinical data from patients with AML who have been treated with chemotherapy without antifungal prophylaxis were retrieved during a 5-year period at Thailand's hematology referral center. Incidence and risk factors of IFI and outcomes of patients were evaluated. Among 292 chemotherapy courses, there were 65 (22.3%) episodes of IFI. Of those, 10 (15.4%) were proven, 19 (29.2%) were probable, and 36 (55.4%) were categorized as being possible IFI. Molds were the most commonly observed causative pathogens (93.1%). The incidence of probable/proven IFI was highest during first induction (20.5%), followed by second induction (6.1%), and consolidation (2.7%). A long duration of neutropenia, old age, and low serum albumin were the strongest predictors of IFI. Compared with patients who had no IFI, patients with probable/proven IFI had a longer length of hospital stay and higher in-hospital mortality. Patients with proven IFI had a significantly worse outcome at 1 year. These results suggest the change in health policy to implement IFI preventive measures to improve outcomes of AML treatment.

PB2379 INVASIVE FUNGAL INFECTIONS IN PATIENTS UNDERGOING ALLOGENEIC STEM CELL TRANSPLANTATION CONDITIONED WITH REDUCED BUCY2

Background:Invasive fungal infection (IFI) is a major cause of morbidity and mortality in patients undergoing allogeneic stem cell transplantation (allo‐SCT). We previously reported (Ann Hematol 2017) that reduced BUCY2 (rBUCY2) preserves an immunosuppressive and myeloablative effect, achieving an adequate bone marrow engraftment with acceptable toxicity, low graft‐versus‐host disease (GVHD), and low transplant‐related mortality (TRM)Aims:To determine the frequency of IFI in patients undergoing allo‐HSCT using rBUCY2 as the conditioning regimenMethods:We conducted a retrospective study of consecutive patients undergoing allo‐SCT using rBUCY2 between November 1998 and December 2014. The median follow‐up was 90 months. Data was analyzed in March 2018.All the SCT procedure and follow‐up was performed at the National Institute of Medical Sciences and Nutrition “Salvador Zubiran”, a public tertiary/referral center in Mexico City.Patients were conditioned with rBUCY2 (busulfan 12 mg/kg, ORAL and cyclophosphamide 80 mg/kg, IV), using G‐CSF‐primed bone marrow as the stem cell source. Antifungal prophylaxis consisted of low‐dose amphotericin B (0.2 mg/kg/day) administered until neutrophil engraftment.The primary endpoint was 1‐year cumulative incidence of proven or probable IFI and the secondary endpoint was the IFI‐associated mortality. Risk factors of IFI were also assessed.Results:From all the cohort, 57% were male and the median age was 39 years (range, 17‐67). Hematological malignancies were the underlying diseases in most patients (n = 55, 94.8%). Within 100 days post‐SCT, IFI was presented in 4 patients (6.8%) and only 1 patient presented late IFI. The multivariate analysis showed that cytomegalovirus (CMV) viremia was the main risk factor associated with the development of IFI (p = 0.031). IFI‐associated mortality was 5% and showed an association with matched unrelated donors (p = 0.022), parenteral nutrition (p = 0.027), and early IFI (p = 0.004). The TRM was 17%Summary/Conclusion:Our results highlight the low incidence of IFI using our modified conditioning regimen compared to international literature. As other studies have reported, we demonstrated that CMV was associated with the development of IFI. We emphasize the safety of rBUCY2 demonstrated by the low incidence of IFI and the low TRM.

Invasive Fungal Infection After Lung Transplantation: Epidemiology in the Setting of Antifungal Prophylaxis.

Lung transplant recipients commonly develop invasive fungal infections (IFIs), but the most effective strategies to prevent IFIs following lung transplantation are not known. We prospectively collected clinical data on all patients who underwent lung transplantation at a tertiary care academic hospital from January 2007-October 2014. Standard antifungal prophylaxis consisted of aerosolized amphotericin B lipid complex during the transplant hospitalization. For the first 180 days after transplant, we analyzed prevalence rates and timing of IFIs, risk factors for IFIs, and data from IFIs that broke through prophylaxis. In total, 156 of 815 lung transplant recipients developed IFIs (prevalence rate, 19.1 IFIs per 100 surgeries, 95% confidence interval [CI] 16.4-21.8%). The prevalence rate of invasive candidiasis (IC) was 11.4% (95% CI 9.2-13.6%), and the rate of non-Candida IFIs was 8.8% (95% CI 6.9-10.8%). First episodes of IC occurred a median of 31 days (interquartile range [IQR] 16-56 days) after transplant, while non-Candida IFIs occurred later, at a median of 86 days (IQR 40-121 days) after transplant. Of 169 IFI episodes, 121 (72%) occurred in the absence of recent antifungal prophylaxis; however, IC and non-Candida breakthrough IFIs were observed, most often representing failures of micafungin (n = 16) and aerosolized amphotericin B (n = 24) prophylaxis, respectively. Lung transplant recipients at our hospital had high rates of IFIs, despite receiving prophylaxis with aerosolized amphotericin B lipid complex during the transplant hospitalization. These data suggest benefit in providing systemic antifungal prophylaxis targeting Candida for up to 90 days after transplant and extending mold-active prophylaxis for up to 180 days after surgery.

Risk Factors for Invasive Fungal Infection in Children and Adolescents With Hematologic and Malignant Diseases: A 10-year Analysis in a Single Institute in Japan.

Infection, especially invasive fungal infection (IFI), is an important complication of chemotherapy and stem cell transplantation. It is also a well-known risk factor in pediatric hematologic malignancy, acute myelogenous leukemia, recurrent disease and allogeneic stem cell transplantation. We previously revealed that a diagnosis of acute myelogenous leukemia, recurrent disease and >10 years of age were risk factors for IFI in patients with pediatric hematologic malignancies. We examined and compared the incidence, risk factors and mortality rate from IFI between 276 patients from 2007 to 2016 and patients in our past report. The cumulative incidence of IFI was 10.5%; this comprised cases of probable and possible IFI at rates of 5.1% and 5.4%, respectively. Univariate analysis showed that age >9 years at admission, recurrent disease and acute myelogenous leukemia diagnosis were risk factors for IFI. Similar to the results of the previous study, multivariate analysis showed that each of these 3 variables was an independent predictor of IFI. The survival rate was lower in patients with IFI than in those without IFI (38.8% versus 69.9%; P < 0.001). However, IFI was a direct cause of death in only 2 patients. Although 11 patients received stem cell transplantation after IFI treatment, only 2 patients have survived, and the other 9 patients died of other complications.