Development Of Invasive Fungal Disease Research Articles

2714. Invasive Fungal Disease in Lung Transplant Recipients: Incidence, Risk Factors, and Outcomes

Abstract Background Invasive fungal disease (IFD) is common after lung transplant and is associated with increased morbidity and mortality. Antifungal prophylaxis is a common preventative strategy against IFD in lung transplant recipients (LTRs). We assessed the incidence of IFD in the first 3-years post-transplant, diagnosed by EORTC/MSG criteria, risk factors for developing IFD, and outcomes of LTRs stratified by development of IFD at a single center that does not use universal antifungal prophylaxis post-lung transplant. Table 1 Preoperative and perioperative characteristics and clinical outcomes of lung transplant recipients stratified by invasive fungal disease (IFD) status Methods A single-center, retrospective study of lung transplant recipients between January 2017 and December 2019 was performed with 3-year follow-up. Donor and recipient preoperative characteristics, microbiologic and radiographic data, perioperative characteristics, and 1- and 3-year outcomes were adjudicated and analyzed. Results In this 3-year study period, 168 patients underwent lung transplant. 26 (15%) developed IFD; 23 (14%) were proven or probable, and 3 (1%) were possible [Table 1]. 21 (81%) had evidence of pulmonary infection and 17 (65%) were mold infections with Aspergillus being the predominant pathogen. 4 (15%) were Candida. 81% (21/26) of patients who developed IFD were recipients of bilateral lung transplants compared to 95% (135/142) of patients who did not develop IFD (p = 0.022). Other donor/recipient characteristics and 12-month outcomes between patients who did vs did not develop IFD were similar. 21% of patients (4/19) who developed IFD had developed antibody-mediated rejection (AMR) by three years post-transplant compared to only 4% of patients without IFD (5/112) (p = 0.025). The incidence of acute cellular rejection, chronic allograft rejection, and overall survival at three years were similar. Conclusion Despite the lack of universal antifungal prophylaxis in the first 90 days post-transplant, we observed a low incidence of IFD in LTRs at our center in this 3-year cohort. Other than receipt of a single vs bilateral lung transplant, there were no significant differences in preoperative or perioperative recipient characteristics. Other than an increased proportion of patients who had AMR, patients who developed IFD had similar overall outcomes to those who did not have IFD, including overall survival at 1, 2, and 3 years. Disclosures Nicolas C. Issa, MD, AiCuris: Grant/Research Support|Astellas: Grant/Research Support|Boehringer Ingelheim: Advisor/Consultant|Fujifilm: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Moderna: Grant/Research Support

Current challenges in the diagnosis and treatment of filamentous mycosis in critically ill patients

Influenza and coronavirus disease 2019 are independent risk factors for the development of invasive fungal disease (IFD) in critically ill patients in the intensive care unit. IFD, particularly mold infections, have a high mortality rate. The diagnosis and treatment of mold infections is challenging, and early detection and timely treatment are crucial in reducing the mortality of IFD. This review will summarize the latest epidemiology and risk factors for the development of mold infections in critically ill patients, current diagnostic criteria and challenges, as well as the treatment strategies recommended by the international clinical guidelines, aiming to provide some references for the diagnosis and treatment of mold infections in critically ill patients in clinical practice.

Defective antifungal immunity in patients with COVID-19.

The COVID-19 pandemic has placed a huge strain on global healthcare and been a significant cause of increased morbidity and mortality, particularly in at-risk populations. This disease attacks the respiratory systems and causes significant immune dysregulation in affected patients creating a perfect opportunity for the development of invasive fungal disease (IFD). COVID-19 infection can instill a significant, poorly regulated pro-inflammatory response. Clinically induced immunosuppression or pro-inflammatory damage to mucosa facilitate the development of IFD and Aspergillus, Mucorales, and Candida infections have been regularly reported throughout the COVID-19 pandemic. Corticosteroids and immune modulators are used in the treatment of COVID-19. Corticosteroid use is also a risk factor for IFD, but not the only reason for IFD in COVID -19 patients. Specific dysregulation of the immune system through functional exhaustion of Natural killer (NK) cells and T cells has been observed in COVID-19 through the expression of the exhaustion markers NK-G2A and PD-1. Reduced fungicidal activity of neutrophils from COVID-19 patients indicates that immune dysfunction/imbalance are important risk factors for IFD. The COVID-19 pandemic has significantly increased the at-risk population for IFD. Even if the incidence of IFD is relatively low, the size of this new at-risk population will result in a substantial increase in the overall, annual number of IFD cases. It is important to understand how and why certain patients with COVID-19 developed increased susceptibility to IFD, as this will improve our understanding of risk of IFD in the face of future pandemics but also in a clinical era of increased clinical immuno-suppression/modulation.

Antibiotic-induced depletion of Clostridium species increases the risk of secondary fungal infections in preterm infants.

Preterm infants or those with low birth weight are highly susceptible to invasive fungal disease (IFD) and other microbial or viral infection due to immaturity of their immune system. Antibiotics are routinely administered in these vulnerable infants in treatment of sepsis and other infectious diseases, which might cause perturbation of gut microbiome and hence development of IFD. In this study, we compared clinical characteristics of fungal infection after antibiotic treatment in preterm infants. As determined by 16S rRNA sequencing, compared with non-IFD patients with or without antibiotics treatment, Clostridium species in the intestinal tracts of patients with IFD were almost completely eliminated, and Enterococcus were increased. We established a rat model of IFD by intraperitoneal inoculation of C. albicans in rats pretreated with meropenem and vancomycin. After pretreatment with antibiotics, the intestinal microbiomes of rats infected with C. albicans were disordered, as characterized by an increase of proinflammatory conditional pathogens and a sharp decrease of Clostridium species and Bacteroides. Immunofluorescence analysis showed that C. albicans-infected rats pretreated with antibiotics were deficient in IgA and IL10, while the number of Pro-inflammatory CD11c+ macrophages was increased. In conclusion, excessive use of antibiotics promoted the imbalance of intestinal microbiome, especially sharp decreases of short-chain fatty acids (SCFA)-producing Clostridium species, which exacerbated the symptoms of IFD, potentially through decreased mucosal immunomodulatory molecules. Our results suggest that inappropriate use of broad-spectrum antibiotics may promote the colonization of invasive fungi. The results of this study provide new insights into the prevention of IFD in preterm infants.

SARS-CoV-2 related ARDS and invasive fungal infections in intensive care patients.

SARS-CoV-2 infection can potentially necessitate intensive care management. An increasing number of case reports are found in the literature indicating patients admitted in an intensive care setting with COVID-19 pneumonitis being complicated with invasive fungal infections.In a retrospective assessment of a three-month period at the national hospital of Malta, examining patients who were suffering from SARS-CoV-2 acute respiratory distress syndrome, 6 out of 63 patients (9.5%) were found to have confirmation or high probability of invasive fungal infection. The consensus definition for invasive fungal disease developed by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium was utilised to aid in the identification of these patients.In total, 15 patients received treatment with an anti-fungal agent in this three-month period, the decision being led by both clinical suspicion and the use of fungal markers obtained from the serum and bronchoalveolar lavage. Although several risk factors are attributed for the development of invasive fungal disease, the main factors identified in our cohort of patients is the SARS-CoV-2 ARDS in itself, along with the use of high dose corticosteroids. The average period of time between admission in intensive care and diagnosis of invasive fungal infection was noted to be 10.5 days.This high incidence of invasive fungal disease in mechanically ventilated patients suffering from SARS-CoV-2 ARDS, relatively early in their course of disease, should guide the clinician to investigate further with fungal biomarkers and cultures in those patients who are clinically deteriorating despite optimal medical treatment, as well as possibly considering empirical anti-fungal treatment if suspicion remains high.

Invasive Fungal Disease in Patients with Newly Diagnosed Acute Myeloid Leukemia.

This single-center retrospective study of invasive fungal disease (IFD) enrolled 251 adult patients undergoing induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) from 2014–2019. Patients had primary AML (n = 148, 59%); antecedent myelodysplastic syndrome (n = 76, 30%), or secondary AML (n = 27, 11%). Seventy-five patients (30%) received an allogeneic hematopoietic cell transplant within the first year after induction chemotherapy. Proven/probable IFD occurred in 17 patients (7%). Twelve of the 17 (71%) were mold infections, including aspergillosis (n = 6), fusariosis (n = 3), and mucomycosis (n = 3). Eight breakthrough IFD (B-IFD), seven of which were due to molds, occurred in patients taking antifungal prophylaxis. Patients with proven/probable IFD had a significantly greater number of cumulative neutropenic days than those without an IFD, HR = 1.038 (95% CI 1.018–1.059), p = 0.0001. By cause-specific proportional hazards regression, the risk for IFD increased by 3.8% for each day of neutropenia per 100 days of follow up. Relapsed/refractory AML significantly increased the risk for IFD, HR = 7.562 (2.585–22.123), p = 0.0002, and Kaplan-Meier analysis showed significantly higher mortality at 1 year in patients who developed a proven/probable IFD, p = 0.02. IFD remains an important problem among patients with AML despite the use of antifungal prophylaxis, and development of IFD is associated with increased mortality in these patients.

1150. Breakthrough Invasive Fungal Disease (IFD) in Patients with Acute Myeloid Leukemia (AML)

BackgroundDespite the use of antifungal prophylaxis, IFD remains a serious complication of AML causing extensive morbidity and mortality. This study seeks to clarify our experience with breakthrough infections in patients with AML.MethodsThis retrospective study included all adult patients undergoing induction chemotherapy for a new diagnosis of AML from June 2014 – Dec 2019 at the University of Michigan Hospital. Chart review determined co-morbidities, chemotherapy regimens, allogeneic hematopoietic cell transplant (HCT), antifungal prophylaxis, development of IFD, and outcomes. Patients were followed for 1 year from first induction chemotherapy. EORTC-MSGERC definitions for proven, probable, and possible IFD were used, as were MSGERC-ECMM definitions for breakthrough IFD.ResultsOf 251 patients, mean age was 61.8±14 years, 55% were men, and 73 (29%) underwent allogeneic HCT, 52 of whom developed GVHD. Thirty-one patients developed 33 IFD (12.3%): 4 proven, 12 probable, and 17 possible IFD. Four IFD occurred in patients with GVHD post-HCT; all were treated with high dose steroids and one received an anti-TNF agent. Of the 16 proven and probable IFD, 8 were breakthrough IFD. Mucormycosis occurred in 2 patients on voriconazole; fusariosis occurred in 3 patients taking fluconazole (2), or posaconazole (1). Aspergillosis occurred in 2 patients taking isavuconazole (1) or fluconazole (1), and pneumocystosis occurred in a patient receiving inhaled pentamidine. There were 8 non-breakthrough IFD, including 2 pneumocystosis, 4 aspergillosis, and 2 candidiasis. Risk for IFD increased with subsequent episodes of induction chemotherapy, p=.04.Six of 8 patients with breakthrough IFD and 5 of 8 without breakthrough IFD died within 12 weeks of IFD diagnosis. Excluding the 15 patients who had only possible IFD, 69% (11/16) patients with proven/probable IFD died compared with 35% (77/220) patients without IFD, p=.01.ConclusionPatients with AML remain at risk for fatal IFD despite the use of antifungal prophylaxis. Failure of prophylaxis in our patients who developed breakthrough IFD was associated with a shift towards less common fungi.Disclosures All Authors: No reported disclosures

1158. D-index as a Novel Index to Predict Invasive Fungal Disease in High-Risk Neutropenic Pediatric Cancer Patients and Hematopoietic Stem Cell Transplantation

BackgroundProlonged and profound neutropenia are risk factors for invasive fungal disease (IFD) during febrile neutropenia (FN) episodes. The D-index combines both depth and duration of neutropenia in a single assessment and has been proposed as a useful tool to exclude or predict IFD in high-risk adult patients. We assessed the D-index as a predictor of IFD in pediatric cancer patients.MethodsWe conducted a retrospective study of pediatric oncology patients with FN at UCM Comer Children’s Hospitals. IFD was stratified as possible, probable, and proven according EORTC/MSG criteria. Patients considered high risk of IFD were receiving intensive chemotherapy with expected prolonged neutropenia >7 days, including, but not limited to, AML, high-risk acute ALL, and hematopoietic stem cell transplantation (HSCT). The D1-index was equal to 2t1 + 3t2, where t1, and t2 are the number of days from the first day of neutropenia < 500mm3 and < 100/ mm3 respectively, until the development of IFD. The D2-index approximates the area over the neutrophil curve during neutropenia. A cumulative D-index (c-D-index) was also calculated using the first day of neutropenia until the date of the first clinical manifestation of IFD. We compared duration of neutropenia vs D-index vs c-D-index as a predictor of IFD using receiver operating characteristic curve (ROC)/AUC analysis.Figure 1 Figure 2 ResultsWe identified 455 FN episodes in 203 high-risk patients. 53/455 (11.6%) had IFD, 12 (2.6%) proven, 23 (5%) probable, and 18 (4%) possible. The median of D1, D2 indexes and c-D-index were significantly higher in patients developing IFD (38, 5225, 7352) compared to the non-IFD group (26, 3857, 5169) (P=.001, P=.001, and P=.01) respectively. The ROC curve of D-index and c-D-index (figure 1,2,3) showed better performance (AUC of 0.85,0.89, 0.81) respectively compared to the duration of neutropenia alone. The ROC was highest when D-index was combined with prolonged fever >5 days (AUC 0.94)Figure 3 Figure 4 ConclusionThe D-index may be a useful tool to stratify high-risk pediatric patients according to risk of IFD. The c-D-index, particularly, may be a useful tool to guide for empiric antifungal therapy and diagnostic testing. Prospective multi-center studies using these tools are required to refine the clinical approach to IFD.Disclosures All Authors: No reported disclosures

Invasive fungal infection before and after liver transplantation.

Invasive infections are a major complication before liver transplantation (LT) and in the early phase after surgery. There has been an increasing prevalence of invasive fungal disease (IFD), especially among the sickest patients with decompensated cirrhosis and acute-on-chronic liver failure, who suffer from a profound state of immune dysfunction and receive intensive care management. In such patients, who are listed for LT, development of an IFD often worsens hepatic and extra-hepatic organ dysfunction, requiring a careful evaluation before surgery. In the post-transplant setting, the burden of IFD has been reduced after the clinical advent of antifungal prophylaxis, even if several major issues still remain, such as duration, target population and drug type(s). Nevertheless, the development of IFD in the early phase after surgery significantly impairs graft and patient survival. This review outlines presentation, prophylactic and therapeutic strategies, and outcomes of IFD in LT candidates and recipients, providing specific considerations for clinical practice.

Invasive Fungal Infections in Pediatric Patients with High-Risk Acute Lymphoblastic Leukemia during Initial Phases of Therapy: A Retrospective Evaluation

BACKGROUND Patients with newly diagnosed acute lymphoblastic leukemia (ALL) are at increased risk of infection. While previously published guidelines recommend primary antifungal prophylaxis in patients with T-cell ALL, we sought to determine the pattern of invasive fungal disease (IFI) at our center so as to assess risk factors for IFI, beyond the diagnosis of T-ALL, with the administration of dexamethasone and an anthracycline during induction. The current practice at Children's Health Children's Medical Center Dallas is to provide primary antifungal prophylaxis with micafungin during induction therapy for hospitalized patients with T-cell ALL and those with Down Syndrome. Additionally, we recently decided to provide primary antifungal prophylaxis to patients with HR B-ALL with hyperglycemia who remain hospitalized during induction. The primary objective of this study was to capture the institution-specific five-year incidence of IFI prior to the start of delayed intensification (DI) phase chemotherapy among pediatric patients with ALL. Secondary objectives were to identify potential IFI risk factors specifically amongst pediatric patients with HR ALL. METHODS This retrospective chart review included patients younger than 21 years with newly diagnosed ALL between July 1, 2014 and June 30, 2019. Patients with secondary leukemia, infantile leukemia, or those receiving treatment for a fungal infection at presentation were excluded. The primary outcome was the development of probable or proven IFI, as defined by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria, prior to the start of the DI phase of therapy. Statistical methods included Chi-square test, t-test, and Wilcoxon Rank Sum test, as appropriate to the variable's level of measurement and distribution. Time series analyses were used to assess overall and seasonal trends of IFI incidence over the study period. RESULTS Of 220 included patients, there were 13 cases of IFI diagnosed during the induction and consolidation phases of therapy during the five-year period. IFI occurred in 15.3% of the HR group (11/72), 5.9% of the T-cell ALL group (1/17), and 0.8% of the standard risk (SR) group (1/131). Among individuals with HR ALL, the majority of cases occurred in the absence of primary antifungal prophylaxis (90.9%). The most common sites of IFI included the lungs (n=6) and sinuses (n=4). Implicated fungal pathogens included Aspergillus, Candida, Curvularia, Exserohilum, and Bipolaris. Univariate analysis of the potential IFI risk factors in HR ALL patients did not identify any significant differences between those patients that did or did not develop IFI, with respect to pre-existing comorbidities, body mass index, laboratory results at diagnosis, or hospital exposures during induction including length of stay, intensive care admissions, and receipt of systemic antibiotics (Table). Race and ethnicity was significantly different likely due to the skewed distribution of IFI among patients who identified as Asian (p = 0.03; 8/8 identified as Asian and did not develop IFI). With respect to seasonality of ALL diagnosis, the percent of patients in each group (winter, spring, summer, and fall) that developed IFI were 7.4%, 18.2%, 20%, and 31.2%, respectively. However, time series analysis did not show an association between seasonality of diagnosis and development of IFI (p=0.89). During the induction phase of therapy, hyperglycemia, defined as blood glucose 140-200 mg/dL for ≥ 2 days or &amp;gt;200 mg/dL for 1 day, was present in 100% of the HR patients that developed IFI and 74% of the HR patients that did not develop IFI (p=0.12). CONCLUSION In this pediatric population, patients with HR B-ALL developed more fungal infections during the early phases of therapy then those with SR disease (15.6% versus 0.8%). In analysis of potential risk factors, there were no significant differences between HR ALL groups that did or did not develop IFI. Larger-scale studies are needed in order to identify potential risk factors that will guide decisions on the routine use of primary antifungal prophylaxis in patients with HR ALL during induction therapy. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Micafungin use for primary antifungal prophylaxis during induction phase of therapy.

Association between the kinetics of cytomegalovirus reactivation evaluated in terms of the area under the curve of cytomegalovirus antigenemia and invasive mold infection during the post-engraftment phase after allogeneic hematopoietic stem cell transplantation.

We evaluated the clinical impact of cytomegalovirus (CMV) reactivation calculated in terms of the area under the curve of CMV antigenemia (CMV-AUC) on the development of invasive mold infection (IMI) in the post-engraftment phase after allogeneic hematopoietic stem cell transplantation (HSCT). Among 394 consecutive patients who underwent their first allogeneic HSCT at our center between 2007 and 2018, 335 were included after excluding patients with a past history of invasive fungal disease (IFD), the development of IFD before engraftment, engraftment failure, or early death within 30days. CMV antigenemia (CMV-AG) was monitored weekly after engraftment and 3 or more cells/2 slides were regarded as positive. CMV-AUC was calculated by the trapezoidal method using the number of CMV-AG after logarithmic transformation and the duration in weeks and was added until negative conversion. Patients with CMV reactivation were divided into low and high CMV-AUC groups using the median value of CMV-AUC as a threshold. There were 17 proven/probable IMIs including one mucormycosis and 16 probable invasive aspergillosis, and the 2-year cumulative incidence was 1.0% in the negative CMV-AUC group (n=136), 3.3% in the low CMV-AUC group (n=98) and 13.8% in the high CMV-AUC group (n=101) (P=.001). In a multivariate analysis, grade II-IV acute GVHD (HR 3.74) and CMV-AUC (HR low 1.25, high 5.91) were identified as independent significant factors associated with a higher incidence of IMI. Cytomegalovirus kinetics evaluated in terms of CMV-AUC were significantly associated with the development of IMI in the post-engraftment phase after allogeneic HSCT.

PS1285 INVASIVE FUNGAL DISEASES IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION RECIPIENTS WITH HODGKIN'S LYMPHOMA

Background:Data on invasive fungal disease (IFD) in allogeneic hematopoietic stem cell transplantation (allo‐HSCT) recipients with relapsed/refractory Hodgkin's lymphoma (r/r HL) are limited. Outcome of allo‐HSCT in patients with prior IFD is still a subject of controversy.Aims:The aim is to study the epidemiology of IFD in allo‐HSCT recipients with r/r HL.Methods:Single center prospective observational study included 86 patients with classical r/r HL who underwent allo‐HSCT from 2002 to 2018. The median age was 27 (13–49) y.o., children (&lt;18 yo) – 13% (n = 11). Allo‐HSCT from MUD was performed in 45,4% (n = 39), MRD – 24,4% (n = 21), MMUD – 15,1% (n = 13), haplo – 15,1% (n = 13), with RIC (100%) and predominantly PTCY‐based GvHD prophylaxis (71%). Primary antifungal prophylaxis was fluconazole in 85%, secondary – voriconazole (100%). EORTC/MSG 2008 criteria for diagnosis and response to therapy were used. In pts with CT‐scan lung lesions before allo‐HSCT bronchoscopy with BAL was used. “Active IFD” means IFD diagnosed just before HSCT. Median follow‐up time was 12 months [1–71].Results:Incidence of pre‐existing IFD in allo‐HSCT recipients with r/r HL was 12,8% (n = 11). All cases of IFD prior to HSCT were invasive aspergillosis (IA) with lungs involvement. Antifungal therapy before allo‐HSCT was used in 81,8% pts with median duration – 2 months. Complete response to antifungal therapy was in 45,4% pts, partial response or stabilization – 36,4%, and 18,2% pts had an “active IFD”. After allo‐HSCT all pts received voriconazole as an antifungal therapy or secondary prophylaxis. Cumulative incidence of relapse or progression of IA after allo‐HSCT was 18,2% with the median 49 day [19–79] of onset after HSCT, which were successfully treated with voriconazole. Incidence of IFD after allo‐HSCT for naïve patients was 17,6% (n = 13/74). Etiology of IFD after allo‐HSCT was IA – 69%, invasive candidiasis (IC) – 15%, mucormycosis – 8%, and combined IFD caused by Aspergillus fumigatus + Rhizopus stolonifer ‐ 8%. The median day of onset of IFD after allo‐HSCT was day+ 114 [1–489]. The main site of infection were lungs (88%), the main clinical symptom – febrile fever (100%). Antifungal therapy was following: voriconazole – 59%, micafungin – 17%, posaconazole – 8%, lipid amphotericin B – 8% and combination lipid amphotericin B with caspofungin – 8%. Overall survival (OS) at 12 weeks from the IFD diagnosis after allo‐HSCT was 80%. The 2‐year OS in children and adult with r/r HL after allo‐HSCT was 73,3%. Development of IFD after allo‐HSCT do not decrease the 2‐year OS rate (69,2% vs 74%, p = 0,77). The impact of prior IFD on 2‐year OS in allo‐HSCT recipients was not statistically significant in all group (63,6% vs 74,7%, p = 0,47), and separately in children and adults.Summary/Conclusion:Incidence of pre‐existing IFD in children and adults with r/r Hodgkin's lymphoma allo‐HSCT recipients was 12,8%. Incidence of IFD after allo‐HSCT in naïve patients with Hodgkin's lymphoma was 17,6%. The major etiology agent as before as after allo‐HSCT were Aspergillus spp. IFD was a late complication after allo‐HSCT. Despite the high incidence of IFD before or after allo‐HSCT didn’t influence the outcome in children and adults with r/r Hodgkin lymphoma.

Cytomegalovirus Reactivation Is Associated with Increased Risk of Late-Onset Invasive Fungal Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter Study in the Current Era of Viral Load Monitoring

Opportunistic infections such as cytomegalovirus (CMV) reactivation and invasive fungal disease (IFD) cause significant morbidity and mortality to recipients of hematopoietic stem cell transplant (HSCT). We aimed to characterize the risk and relationship of CMV reactivation post-HSCT to IFD in the current era of CMV viral load monitoring using highly sensitive plasma DNA. A multicenter, retrospective, cohort study was conducted of consecutive patients undergoing allogeneic HSCT from January 2006 to December 2010 in Melbourne, Australia. CMV reactivation was defined as detection of plasma CMV DNA ≥ 546 IU/mL or development of CMV disease. IFD was classified in accordance with current international consensus guidelines. Of the 419 study participants, the median age was 44 years (IQR, 34 to 54), and CMV reactivation occurred in 106 participants (25%) at a median time of 56 days (IQR, 45 to 79). Thirty-eight participants (9.1%) were identified with 41 cases of IFD (n = 22 proven, n = 8 probable, n = 11 possible) at a median time of 76 days (IQR, 24 to 344). The incidence of IFD was higher in participants with CMV reactivation compared with no CMV reactivation (15% versus 7%, P = .012). In a multivariate analysis CMV reactivation remained an independent risk factor for IFD (hazard ratio, 3.7; 95% CI, 1.6 to 8.5; P = .002). The cumulative incidence of all IFD in patients with and without CMV reactivation using a competing risk regression was a hazard ratio of 2.2 (95% CI, 1.2 to 4.1; P = .017) and for late-onset IFD was a hazard ratio of 3.95 (95% CI, 1.7 to 9; P = .001). The median time to IFD onset was longer in participants with than without CMV reactivation (184 versus 37 days, P = .03). The peak viral load, detection of any level of viremia, and experiencing more than 1 episode of CMV reactivation were not associated with development of IFD. CMV reactivation in HSCT recipients in the post-transplant period is associated with an increased risk of developing late-onset IFD. Further research is warranted to understand the interaction between these 2 important infectious complications.

Consensus guidelines for the use of empiric and diagnostic-driven antifungal treatment strategies in haematological malignancy, 2014.

Invasive fungal disease (IFD) causes significant morbidity and mortality in patients undergoing allogeneic haemopoietic stem cell transplantation or chemotherapy for haematological malignancy. Much of these adverse outcomes are due to the limited ability of traditional diagnostic tests (i.e. culture and histology) to make an early and accurate diagnosis. As persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients despite broad-spectrum antibiotics have been associated with the development of IFD, most centres have traditionally administered empiric antifungal therapy (EAFT) to patients with PFUO. However, use of an EAFT strategy has not been shown to have an overall survival benefit and is associated with excessive antifungal therapy use. As a result, the focus has shifted to developing more sensitive and specific diagnostic tests for early and more targeted antifungal treatment. These tests, including the galactomannan enzyme-linked immunosorbent assay and Aspergillus polymerase chain reaction (PCR), have enabled the development of diagnostic-driven antifungal treatment (DDAT) strategies, which have been shown to be safe and feasible, reducing antifungal usage. In addition, the development of effective antifungal prophylactic strategies has changed the landscape in terms of the incidence and types of IFD that clinicians have encountered. In this review, we examine the current role of EAFT and provide up-to-date data on the newer diagnostic tests and algorithms available for use in EAFT and DDAT strategies, within the context of patient risk and type of antifungal prophylaxis used.

Positive tip culture with Candida and negative blood culture: to treat or not to treat? A systematic review with meta-analysis.

Invasive candidiasis is a major invasive fungal infection. It has high lethality, and even higher if not treated early. There is no consensus on antifungal treatment in patients with positive catheter tip culture for Candida spp. The objective of this study was to evaluate the impact of antifungal therapy and mortality of patients with positive culture for Candida spp. in catheter tip that have negative blood culture. The PubMed database was searched to identify articles related to Candida and catheter. Articles with adequate data were included. Of 1208 studies initially screened, 5 met the selection criteria. All were retrospective studies. In all, 265 patients were evaluated for outcomes 'candidemia' and 'invasive candidiasis' and 158 for the outcome 'mortality.' Antifungal therapy had no impact on the development of invasive fungal disease (Odds ratio (OR) = 1.41; 95% confidence interval (CI) = 0.56-3.52). Also there was no benefit of therapy on mortality (OR = 1.02; 95% CI = 0.54-1.95). Due to the poor quality of the studies no conclusion can be made. Randomized prospective studies are needed to better evaluate this therapeutic strategy.

Yield of Fungal Surveillance Cultures in Pediatric Hematopoietic Stem Cell Transplant Patients: A Retrospective Analysis and Survey of Current Practice

Fungal surveillance cultures (FSCs) have been proposed as predictors for development of invasive fungal disease (IFD) and identifiers of the causative organism, although data supporting these are limited and predate universal initiation of antifungal prophylaxis. We aimed to define the epidemiology of fungal colonization and investigate the utility of FSCs for predicting IFD in recipients of pediatric hematopoietic stem cell transplantation (HSCT). FSCs performed from 2007 to 2011 on HSCT patients and laboratory and clinical data were reviewed, and incidence of IFD was determined. Descriptive analyses of culture results were performed to determine the yield of FSCs and their utility. A Web-based survey of national pediatric HSCT providers was undertaken to evaluate current practice and the relevance of our results. Five thousand six hundred eighteen FSCs from nares, throat, and stool from 360 patients were processed. Of these, 14.8% were positive: 30.3% from stool, 13.2% from throat, and 0.9% from nares; 64.4% of patients had >1 positive FSCs. Thirty (8.3%) patients had IFD. IFD occurred in 7.9% and 10.1% of patients with positive and negative FSCs, respectively (P = .25). Antifungal coverage was changed in 69 patients (29.9%) after positive FSC; 8.6% developed IFD (n = 2 of 6 pathogen concordance with FSC) compared with 6.7% (P = .59) who had no treatment change (n = 3 of 11 concordance). The response rate to the survey was 70.8%; 40% of institutions reported performing routine FSC. Twenty-five percent of providers would not change management based on FSC results; overall rating of usefulness of FSCs was low. Although FSCs are commonly performed for pediatric HSCT patients, they have limited utility for predicting IFD.

Patogenia de la infección fúngica invasora

Invasive fungal infections remain a life-threatening disease. The development of invasive fungal disease is dependent on multiple factors, such us colonization and efficient host immune response. We aimed to review the pathogenesis of invasive fungal infections, in particular, those caused by Candida and Aspergillus. For this we propose, to describe the fungal characteristics, to detail the host defence mechanisms against fungus and to analyse the host risk factors for invasive fungal infection.

Risk factors for invasive fungal disease in critically ill adult patients: a systematic review

IntroductionOver 5,000 cases of invasive Candida species infections occur in the United Kingdom each year, and around 40% of these cases occur in critical care units. Invasive fungal disease (IFD) in critically ill patients is associated with increased morbidity and mortality at a cost to both the individual and the National Health Service. In this paper, we report the results of a systematic review performed to identify and summarise the important risk factors derived from published multivariable analyses, risk prediction models and clinical decision rules for IFD in critically ill adult patients to inform the primary data collection for the Fungal Infection Risk Evaluation Study.MethodsAn internet search was performed to identify articles which investigated risk factors, risk prediction models or clinical decisions rules for IFD in critically ill adult patients. Eligible articles were identified in a staged process and were assessed by two investigators independently. The methodological quality of the reporting of the eligible articles was assessed using a set of questions addressing both general and statistical methodologies.ResultsThirteen articles met the inclusion criteria, of which eight articles examined risk factors, four developed a risk prediction model or clinical decision rule and one evaluated a clinical decision rule. Studies varied in terms of objectives, risk factors, definitions and outcomes. The following risk factors were found in multiple studies to be significantly associated with IFD: surgery, total parenteral nutrition, fungal colonisation, renal replacement therapy, infection and/or sepsis, mechanical ventilation, diabetes, and Acute Physiology and Chronic Health Evaluation II (APACHE II) or APACHE III score. Several other risk factors were also found to be statistically significant in single studies only. Risk factor selection process and modelling strategy also varied across studies, and sample sizes were inadequate for obtaining reliable estimates.ConclusionsThis review shows a number of risk factors to be significantly associated with the development of IFD in critically ill adults. Methodological limitations were identified in the design and conduct of studies in this area, and caution should be used in their interpretation.

Platelets enhance activity of antimycotic substances against non-Aspergillus fumigatus Aspergillusspeciesin vitro

Platelets are known to be part of haemostasis but they are also players in innate host defense. Recently, we observed that platelets attenuate the virulence of Aspergillus spp. in vitro. However, little is known about the antifungal effects of platelets in the presence of antimycotics against non-A. fumigatus Aspergillus species. We therefore investigated whether platelets increase the in vitro activity of amphotericin B, voriconazole, posaconazole and caspofungin against two clinical isolates each of Aspergillus flavus, Aspergillus terreus and Aspergillus niger. The antifungal activity was evaluated by assessing germination percentages, hyphal elongation and hyphal damage by use of XTT. The combination of platelets plus amphotericin B significantly (P < 0.05) enhanced the reduction of germination percentage compared to either substance alone. Among triazoles, voriconazole exhibited significant effects with platelets for all tested aspergilli. Overall, these findings suggest that among the tested antimycotic substances, amphotericin B in combination with platelets has enhancing effects in reducing germination and hyphal elongation in the tested non-A. fumigatus Aspergillus species. These data indicate that platelets act beneficially with antimycotics in an early stage of fungal growth by blocking and/or delaying fungal germination and hyphal elongation; both crucial mechanisms in the development of invasive fungal disease.

Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients

Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients