Risk Of Invasive Fungal Disease Research Articles

Urban Pigeons as Reservoirs of Critical Pathogens: Improved protocol for sequencing pigeon faeces in disease monitoring

The spread of pathogens by animals is a serious issue around the world that causes a severe threat to human health. Feral pigeons (Columba livia forma domestica) that live in urban areas are zoonotic carriers of various pathogens that can be transmitted to humans by faecal contamination. This study aimed to detect the presence of bacterial, viral, and specifically fungal pathogens in pigeon faeces based on the World Health Organization's (WHO) priority pathogen list published in 2022. Fresh faecal samples were collected at Uppsala, Central Station, and Svandammen, the pigeons' most relevant gathering spots and feeding sites. Genomic DNA was directly extracted from these samples, and ScilifeLab performed High throughput sequencing through Oxford Nanopore Technologies(ONT) (PromethION). Metagenomic analysis revealed that most of the critically prioritized viral and bacterial pathogens listed by WHO were present in pigeon faeces. Regarding fungal pathogens, which were the main objective of this study, samples from both studied locations contained all critical, high and, medium-important fungal pathogens published in the WHO list, such as Aspergillus fumigatus, Candida albicans, Candida auris, Cryptococcus neoformans, Nakaseomyces glabratus, Candida tropicalis, and Cryptococcus gattii. These fungal pathogens pose the risk of invasive fungal diseases and severe infections in low-immunity individuals and vulnerable populations. The findings indicate the importance of conducting further research to comprehensively understand potential exposure to feral pigeons. Furthermore, keeping pigeons away from sensitive areas, such as hospitals, and implementing measures to control pigeon populations can significantly decrease the spread of pathogens.

Epidemiological changes of invasive fungal disease in children with cancer: Prospective study of the National Child Program of Antineoplastic Drugs network, Chile.

Invasive fungal diseases (IFD) are high morbidity and mortality infections in children with cancer suffering episodes of high-risk febrile neutropenia (HRFN). IFD epidemiology has changed in the last two decades, with an increasing incidence in recent years due to the growing number of immunocompromised children at risk for IFD. The aim of this study was to evaluate the incidence of IFD in children with cancer in the period 2016-2020 compared to 2004-2006 in six hospitals in Chile. Prospective, multicentre study, carried out between 2016 and 2020 in six hospitals in Chile. The defined cohort corresponds to a dynamic group of HRFN episodes in patients <18 years old with cancer, who at the fourth day of evolution still presented fever and neutropenia (persistent HRFN). Each episode was followed until resolution of FN. The incidence of IFD was calculated between 2016 and 2020 and compared with data obtained in the period 2004-2006. The incidence rate was estimated. A total of 777 episodes of HRFN were analysed; 257 (33.1%) were considered as persistent-HRFN occurring in 174 patients. The median age was 7 years (IQR: 3-12 years) and 52.3% (N = 91) were male. Fifty-three episodes of IFD were detected: 21 proven, 14 probable and 18 possible. Possible IFD were excluded, leaving 239 episodes of persistent-HRFN with an IFD incidence of 14.6% (95% CI 10.5-19.9) and an incidence rate of 13.6 IFD cases per 1000 days of neutropenia (95% CI 9.5-20.0). Compared to 2004-2006 cohort (incidence: 8.5% (95% CI 5.2-13.5)), a significant increase in incidence of 6.1% (95% CI 0.2-12.1, p = .047) was detected in cohorts between 2016 and 2020. We observed a significant increase in IFD in 2016-2020, compared to 2004-2006 period.

Impact of dexamethasone on transplant-related mortality in pediatric patients: a multi-site, propensity score-weighted, retrospective assessment.

Dexamethasone use during hematopoietic cell transplant (HCT) conditioning varies between pediatric centers. This study aimed to estimate the difference in 1-year treatment-related mortality (TRM) between patients who did or did not receive dexamethasone during HCT conditioning. Secondary objectives were to estimate the difference between dexamethasone-exposed and dexamethasone-unexposed groups in 1-year event-free survival (EFS), time to neutrophil engraftment, acute graft-versus-host disease (aGVHD), and invasive fungal disease (IFD) at day + 100. This was a seven-site, international, retrospective cohort study. Patients < 18years old undergoing their first allogeneic or autologous myeloablative HCT for hematologic malignancy or aplastic anemia between January 1, 2012, and July 31, 2017, were included. To control for potential confounders, propensity score weighting was used to calculate the standardized mean difference for all endpoints. Among 242 patients, 140 received dexamethasone during HCT conditioning and 102 did not. TRM was unaffected by dexamethasone exposure (1.7%; 95% CI - 7.4, 10.2%). Between-group differences in secondary outcomes were small. However, dexamethasone exposure significantly increased possible, probable, and proven IFD incidence (9.0%, 95% CI 0.8, 17.3%). TRM is not increased in pediatric patients who receive dexamethasone during HCT conditioning. Clinicians should consider potential IFD risk when selecting chemotherapy-induced vomiting prophylaxis for pediatric HCT patients.

Epidemiology of Invasive Fungal Diseases: A 10-Year Experience in a Tertiary Pediatric Hematology-Oncology Department in Greece.

Although advances in the management of pediatric neoplasms have profoundly improved infectious disease outcomes, invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in children and adolescents with high-risk hematological malignancies. A retrospective study was conducted in the Pediatric Hematology-Oncology Department of the University General Hospital of Heraklion for 2013-2022 to estimate the prevalence and describe the clinical and epidemiological characteristics of IFDs for pediatric and adolescent patients with neoplasia. Demographic, clinical, and laboratory parameters were analyzed to identify risk factors for the development of IFD. The overall prevalence of IFDs was estimated to be 7.8% (12/154 patients) throughout the study. The mean age at IFD diagnosis was 9.8 years (SD 6.4 years). The most common IFD was possible/probable invasive pulmonary aspergillosis (IPA; in ≈50%), followed by candidemia/invasive candidiasis (in 44%). Candida parapsilosis was the most prevalent Candida species (4/6 events). Of interest, the majority (75%) of IFDs were breakthrough infections. Patients with increased risk for IFDs were those who were colonized by fungi in sites other than the oral cavity, hospitalized in the intensive care unit for >7 days, received >7 different antimicrobials in the last 3 months, or had severe neutropenia for >44 days. Two children out of a total of 12 with IFD died due to refractory disease or relapse (16.7%). More detailed and prospective epidemiological studies on fungal infections in pediatric patients with hematological or solid neoplasms can contribute to the optimization of prevention and treatment.

Clinical performance of metagenomic next-generation sequencing for diagnosis of invasive fungal disease after hematopoietic cell transplant.

Timely diagnosis and appropriate antifungal therapy are critical for improving the prognosis of patients with invasive fungal disease (IFD) after hematopoietic stem cell transplantation (HSCT). We evaluated the performance of metagenomic next-generation sequencing (mNGS) and conventional microbiological testing (CMT), as well as the diagnosis, therapeutic management, and outcomes of IFD after HSCT. We retrospectively studied 189 patients who underwent HSCT and were considered at risk for IFD. In total, 46 patients with IFD were enrolled in this study. The IFD consensus was followed for classifying IFD incidents. Forty-six patients were diagnosed with proven/probable (n = 12), possible (n = 27), and undefined (n = 7) IFD. Aspergillus was the most commonly detected fungal genus. Mucormycosis was found in 15 patients; two had Aspergillus, and one had Candida infections. Compared to CMT, mNGS significantly reduced the time required to identify pathogens (P = 0.0016). mNGS had a much higher sensitivity than CMT (84.78% vs. 36.96%; P < 0.0001). A total of 76.09% of patients received antifungal prophylaxis during fungal infections. All Pneumocystis infections occurred later than 100 days after transplantation. Among patients with Pneumocystis infection, 71.43% occurred following sulfonamide withdrawal, and subsequent treatment with sulfonamide alone or in combination with other drugs was effective. Based on the empirical antifungal treatment, the dosages, modes of administration, frequency of administration, or antifungal of 55.26% of the patients were changed according to the mNGS results. The 4-year overall survival rate of patients diagnosed with IFD after transplantation was 71.55% (95% CI, 55.18%-85.82%). Hypoproteinemia and corticosteroid use are independent risk factors for IFD. mNGS, which has a high sensitivity and a short detection time, aids in the diagnosis and prognosis of pathogenic fungi. As a powerful technology, mNGS can influence treatment decisions in patients with IFD following HSCT.

The Burden of Invasive Fungal Disease Following Chimeric Antigen Receptor T-Cell Therapy and Strategies for Prevention.

Chimeric antigen receptor (CAR) T-cell therapy is a novel immunotherapy approved for the treatment of hematologic malignancies. This therapy leads to a variety of immunologic deficits that could place patients at risk for invasive fungal disease (IFD). Studies assessing IFD in this setting are limited by inconsistent definitions and heterogeneity in prophylaxis use, although the incidence of IFD after CAR T-cell therapy, particularly for lymphoma and myeloma, appears to be low. This review evaluates the incidence of IFD after CAR T-cell therapy, and discusses optimal approaches to prevention, highlighting areas that require further study as well as future applications of cellular therapy that may impact IFD risk. As the use of CAR T-cell therapy continues to expand for hematologic malignancies, solid tumors, and most recently to include non-oncologic diseases, understanding the risk for IFD in this uniquely immunosuppressed population is imperative to prevent morbidity and mortality.

The indirect effects of CMV reactivation on patients following allogeneic hematopoietic stem cell transplantation: an evidence mapping

Cytomegalovirus (CMV) reactivation following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a challenging problem, and the impact on the risk of overall mortality (OM) and non-relapse mortality (NRM) in patients following allo-HSCT is still controversial. Utilizing the evidence mapping method, we aimed to assess the effect of CMV infection on outcomes of patients post-transplantation and identify research gaps through systematic reviews (SRs) and clinical studies. PubMed, EMBASE, Web of Science, and Cochrane library databases were searched from inception until 5 July 2022 to identify relevant literature. After systematic literature screening and data extraction, evidence mapping of the effects of CMV reactivation on patients post-allo-HSCT was conducted. Three SRs and 22 clinical studies were included. In one SR, CMV reactivation was associated with an increased risk of mortality (HR 1.46; 95% CI, 1.24–1.72; P ≤ 0.001). In two SRs, CMV reactivation was associated with NRM. One SR reported CMV reactivation was potentially associated with significant protection against relapse in patients with acute myelocytic leukemia (AML), but no significant correlation with graft-versus-host disease (GVHD) was found. Lastly, in one SR CMV reactivation significantly increased the risk of invasive fungal disease (IFD). Most clinical articles reported that CMV reactivation increased the risk of renal dysfunction, poor graft function, re-hospitalization, and bacterial infections. CMV reactivation following allo-HSCT is associated with an increased risk of OM, NRM, IFD, and renal dysfunction, as well as a reduced risk of relapse in patients with AML.

Evaluation of the Effectiveness of Antifungal Prophylaxis in Adult Acute Lymphoblastic Leukemia during Induction Chemotherapy

Background and Objectives: Due to immune suppression, patients with hematological malignancies are at a high risk of invasive fungal disease (IFD) during chemotherapy. For patients with myeloid tumors, antifungal prophylaxis is generally recognized. However, there are evident interactions between agents used in acute lymphoblastic leukemia (ALL) remission-induction and antifungal agents, resulting in most clinical trials excluding ALL patients. The need for primary antifungal prophylaxis in ALL patients during chemotherapy is still under debate. This study analyzed the efficacy of primary antifungal prophylaxis (PAP) and the incidence of IFD during the first remission induction in the PDT-ALL-2016 cohort, as well as evaluated the impact of PAP on the outcomes of ALL patients. Methods: The PDT-ALL-2016 cohort consists of 408 newly diagnosed ALL patients aged ≥ 14 years, treated between January 2016 and December 2021. All patients were treated using the GRAALL-2003 backbone, a pediatric-like regimen. This study included 280 patients, with a total of 128 exclusions. Excluded patients consisted of 103 individuals who received initial induction treatment in other hospitals, 12 individuals who died without IFD during the induction period, 9 individuals who experienced fungal infection before induction treatment, 2 individuals who did not complete induction remission treatment and were discharged, and 2 individuals who had lost their cases. PAP was defined as the administration of any systemic antifungal agent for two or more consecutive days to a patient without any evidence or history of IFD during the neutropenic period. The diagnosis of IFD was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria. Results: Among the 280 patients, 232 received PAP, with caspofungin (n=104), voriconazole (n=59), micafungin (n=44), and others being used as prophylaxis. The baseline characteristics of patients who did or did not receive PAP were similar, except for the age difference (prophylaxis group median age 28.7 versus without prophylaxis group 23.0, P&amp;lt;0.01). In the cohort, 11 proven/probable and 21 possible IFD cases were identified. The incidence of IFD in patients who did or did not receive PAP was 8.6% and 25.0%, respectively. The cumulative incidence of IFD was significantly lower in patients receiving PAP compared to those who did not (HR 0.3, 95% CI 0.1-0.6; P=0.001). In the cohort, the infections of IFD negatively affected overall survival (HR 1.6, 95% CI 0.9-2.7, P=0.093). Conclusions: Our study demonstrates, in a real-life setting, that IFD is a poor prognostic factor for adult ALL and that PAP significantly reduces the incidence of IFD during induction chemotherapy, thereby improving patient survival. Furthermore, compared to published studies (4.3%-18.3%), the incidence of IFD in the prophylaxis group within our cohort is relatively lower. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

Tocilizumab Is Associated with Increased Risk of Fungal Infections among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study.

Does treatment with tocilizumab increase the risk of a fungal infection in critically ill patients with coronavirus-19? Numerous therapies have been evaluated as possible treatments for coronavirus-2019 caused by severe acute respiratory syndrome coronavirus-2. Tocilizumab is a humanized monoclonal antibody directed against the interleukin-6 receptor that has found a role as a therapy for patients with severe coronavirus-19 pneumonia. The immunomodulatory effects of tocilizumab may have the unintended consequence of predisposing recipients to secondary infections. We sought to assess the risk of invasive fungal disease and the therapeutic impact of tocilizumab on the hospital length of stay, duration of mechanical ventilation, and intensive-care-unit length of stay in critically ill patients with severe coronavirus-19 pneumonia. Records of critically ill patients with coronavirus-2019 admitted from March to September 2020 at our institution were reviewed. The risk for fungal infections, intensive-care-unit length of stay, hospital length of stay, and duration of mechanical ventilation in those that received tocilizumab in addition to standard coronavirus-2019 treatments was assessed. Fifty-six critically ill patients treated with dexamethasone and remdesivir for coronavirus-2019 were included, of which 16 patients also received tocilizumab. The majority of the cohort was African American, Asian, or of other ethnic minorities (53.6%). Invasive fungal infections occurred in 10.7% of all patients, and infection rates were significantly higher in the tocilizumab group than in the control group (31.2% vs. 2.5%, risk difference [RD] = 28.8%, p < 0.01). The increased risk in the tocilizumab group was strongly associated with renal replacement therapy. There was a dose-response relationship between the risk of fungal infection and number of tocilizumab doses received, with 2.5% of infections occurring with zero doses, 20% with a single dose (RD = 17.5%), and 50% with two doses (RD = 47.5%) (trend test p < 0.001). In addition, ICU LOS (23.4 days vs. 9.0 days, p < 0.01), the duration of mechanical ventilation (18.9 vs. 3.5 days, p = 0.01), and hospital length of stay (LOS) (29.1 vs. 15.5, p < 0.01) were increased in patients that received tocilizumab. Repurposed immunomodulator therapies, such as tocilizumab, are now recommended treatments for severe coronavirus-2019 pneumonia, but safety concerns remain. In this early pandemic cohort, the addition of tocilizumab to dexamethasone was associated with an increased risk of fungal infection in those that were critically ill and received renal replacement therapy. Tocilizumab use was also associated with increased ICU and hospital LOSs and duration of mechanical ventilation.

Invasive fungal infections after CLAG-M/CLAG chemotherapy for acute myeloid leukemia and high-grade myeloid neoplasms.

CLAG-M (cladribine, high-dose cytarabine [HiDAC], G-CSF, mitoxantrone)/CLAG are contemporary intensive chemotherapy regimens associated with higher and deeper complete remission rates than 7+3 (cytarabine, anthracycline)/HiDAC, but with greater myelosuppression and potential infection risks. Here, we compared the cumulative incidence (CI) and patterns of invasive fungal disease (IFD) between these regimens by identifying proven/probable and possible cases of IFD following CLAG-M (n=332) and 7+3 (n=115) chemotherapy and subsequent treatment cycles in adults ≥18 years old with newly diagnosed (ND) or relapsed/refractory (R/R) AML or other high-grade myeloid neoplasms between 2006 and 2018. By 90 days (D90) after initiating treatment, the CI of proven/probable IFD was 20% with CLAG-M and 12% with 7+3 (p=0.17). There was no significant difference in the CI of IFD between ND CLAG-M and R/R CLAG-M. Without mold-active prophylaxis, the D90 CI of proven/probable IFD was significantly higher in the CLAG-M than the 7+3 cohort (28% versus 11%; p=0.007), but this difference was mitigated with mold-active prophylaxis (CLAG-M, 7.5%; 7+3, 0%; p=0.65). After each chemotherapy treatment cycle, the CI of newly diagnosed IFD was similar, ranging from 15-20%. Use of mold-active prophylaxis was the only factor associated with reduced IFD risk in adjusted models (HR, 0.32; 95% confidence interval, 0.18-0.56). Together, these data indicate that the IFD risk with CLAG-M is higher than with 7+3 in the absence of mold-active prophylaxis; use of mold-active prophylaxis mitigates this risk.

Mold-Active Antifungal Prophylaxis in Pediatric Patients with Cancer or Undergoing Hematopoietic Cell Transplantation.

Invasive fungal diseases (IFDs), in particular invasive mold infections, still pose considerable problems in the care of children and adolescents treated for cancer or undergoing hematopoietic cell transplantation. As these infections are difficult to diagnose, and the outcomes for IFDs are still unsatisfactory, antifungal prophylaxis has become an important strategy in the clinical setting. Antifungal prophylaxis is indicated in patients at high risk for IFD, which is commonly defined as a natural incidence of at least 10%. As there is a growing interest in pediatric-specific clinical trials and pediatric-specific guidelines, this review focuses on the available data of mold-active antifungal prophylaxis in children and adolescents. The data demonstrate that a major effort is needed to characterize the pediatric patient population in which the net effect of prophylactic antifungals will be beneficial as well as to find the optimal prophylactic antifungal compound and dosage.

The Use of Host Biomarkers for the Management of Invasive Fungal Disease.

Invasive fungal disease (IFD) causes severe morbidity and mortality, and the number of IFD cases is increasing. Exposure to opportunistic fungal pathogens is inevitable, but not all patients with underlying diseases increasing susceptibility to IFD, develop it. IFD diagnosis currently uses fungal biomarkers and clinical risk/presentation to stratify high-risk patients and classifies them into possible, probable, and proven IFD. However, the fungal species responsible for IFD are highly diverse and present numerous diagnostic challenges, which culminates in the empirical anti-fungal treatment of patients at risk of IFD. Recent studies have focussed on host-derived biomarkers that may mediate IFD risk and can be used to predict, and even identify IFD. The identification of novel host genetic variants, host gene expression changes, and host protein expression (cytokines and chemokines) associated with increased risk of IFD has enhanced our understanding of why only some patients at risk of IFD actually develop disease. Furthermore, these host biomarkers when incorporated into predictive models alongside conventional diagnostic techniques enhance predictive and diagnostic results. Once validated in larger studies, host biomarkers associated with IFD may optimize the clinical management of populations at risk of IFD. This review will summarise the latest developments in the identification of host biomarkers for IFD, their use in predictive modelling and their potential application/usefulness for informing clinical decisions.

Invasive fungal diseases impact on outcome of childhood ALL – an analysis of the international trial AIEOP-BFM ALL 2009

In children with acute lymphoblastic leukemia (ALL), risk groups for invasive fungal disease (IFD) with need for antifungal prophylaxis are not well characterized, and with the advent of new antifungal compounds, current data on outcome are scarce. Prospectively captured serious adverse event reports of children enrolled in the international, multi-center clinical trial AIEOP-BFM ALL2009 were screened for proven/probable IFD, defined according to the updated EORTC/MSG consensus definitions. In a total of 6136 children (median age 5.2 years), 224 proven/probable IFDs (65 yeast and 159 mold) were reported. By logistic regression, the risk for proven/probable IFDs was significantly increased in children ≥12 years and those with a blast count ≥10% in the bone marrow on day 15 (P < 0.0001 each). Proven/probable IFDs had a 6-week and 12-week mortality of 10.7% and 11.2%, respectively. In the multivariate analysis, the hazard ratio for event-free and overall survival was significantly increased for proven/probable IFD, age ≥12 years, and insufficient response to therapy (P < 0.001, each). Our data define older children with ALL and those with insufficient treatment-response at high risk for IFD. As we show that IFD is an independent risk factor for event-free and overall survival, these patients may benefit from targeted antifungal prophylaxis.

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.

Epidemiology of invasive fungal diseases in adults with newly diagnosed acute myeloid leukemia

Invasive fungal diseases (IFDs) are common in patients with acute myeloid leukemia (AML), but no recent data on incidence without antifungal prophylaxis are available. We evaluated the incidence of IFDs in patients with AML undergoing induction chemotherapy at Stanford University Hospital from 2012 to 2017, for up to 12 weeks after induction. We also analyzed factors associated with IFD development. Thirty-six of 240 patients (13%) developed at least one proven or probable IFD. Seventy-eight percent of the proven or probable IFDs were due to Candida or Aspergillus species. Infection due to Fusarium and Mucorales was uncommon. Absolute neutrophil count (ANC) of <500 µL/L at the start of induction was associated with an increased risk of IFD. One hundred and eighty-seven patients (78%) were started on systemic antifungal drugs, even without microbiologic evidence of an IFD. IFDs remain frequent in AML patients undergoing induction chemotherapy without antifungal prophylaxis.

Invasive Aspergillosis Resistant to Double-Coverage of Antifungal Therapy in a Very Immunosuppressed Lung Transplant Recipient

<h3>Introduction</h3> Lung transplant (LT) recipients require intensive immunosuppressive regimens, which raises the risk of invasive fungal disease that can be challenging to clear. <h3>Case Report</h3> The patient is an 18-year-old male, bilateral LT (04/2021) recipient for cystic fibrosis, complicated by immediate posttransplant <i>de novo</i> DSA requiring plasma exchange and IVIG. At his 1-month post-discharge visit, significant DSA to multiple class I and class II alleles was found requiring augmented immunosuppression and admission for repeat inpatient plasma exchange and IVIG. Lavage cultures were remarkable for MDR-<i>Pseudomonas</i> with multiple subtypes, sensitive only to cefiderocol. Pulmonary function had not completely recovered since LT as FEV₁ had peaked at 1.5 L (47%) before dropping to 1.1 L (35%) in the current admission. Due to the ongoing DSA burden, we began treatment with antithymocyte globulin (ATG) to prevent the sequalae of antibody-mediated rejection. Additional imaging was remarkable for multiple, confluent, mass-like structures concerning for post-LT lymphoproliferative disorder, prompting biopsies that revealed angioinvasive <i>Aspergillus</i> (<b>Figure 1</b>). We started IV isavuconazole and continued cefiderocol, linezolid, and micafungin given his infectious history. The patient was symptomatic for dyspnea, which did not resolve despite the above antimicrobial coverage, prompting us to substitute voriconazole with some subjective improvement. Serial chest imaging showed worsening markings with new cavitation. Repeat lavage cultures were now significant for <i>Aspergillus terreus</i> and <i>Pseudomonas spp</i> superinfection. After nearly 2 months of ongoing IV antimicrobial therapy, we observed radiographic and symptomatic resolution. <h3>Summary</h3> Early DSA burden with decreasing pulmonary function justified treatment with ATG, but increased the risk of severe fungal infections, which required lengthy double-coverage antifungal therapy.

Assessing the Impact of Prophylactic Anidulafungin during Remission Induction of Acute Myeloid Leukemia - a Propensity-Score Matching Analysis

Introduction: Invasive fungal disease (IFD) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole has recently emerged as a drug of choice for this purpose. In our setting, alternative strategies such as no upfront prophylaxis, fluconazole, or echinocandins have been used during the remission induction, as posaconazole is not available. While few reports have pointed to micafungin as an option for this aim, studies addressing the use of anidulafungin in AML are lacking. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction.Methods: This retrospective cohort encompassing newly diagnosed AML adult patients (pts) treated at Instituto do Cancer do Estado de Sao Paulo, Brazil, between June 2011 and June 2020. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). Over these years, local policies regarding AP changed. All patients received the “7+3” regimen and were divided into three groups: pts who did not receive any AP and pts who received fluconazole (15-400 mg/day) or anidulafungin (100 mg/day) as AP. Local recommendations for IFD treatment were followed, and they also changed over time. The primary endpoint was IFD rate during the first 60 days from the beginning of chemotherapy, following the recommendation of EORTC/MSG. Multivariable analysis (MVA) was performed by logistic regression. Aiming to equalize subgroups for IFD risk factors, a propensity-score matching was performed using the nearest neighbor method.Results: Overall, 204 pts were included, with a median age of 54 years (range,17-74). The main baseline features of this cohort are summarized in Table 1. Regarding AP, 108 pts received anidulafungin, 82 pts did not receive AP, and 14 pts received fluconazole. The incidence of IFI was 26.6% (95% CI 20.8-33.3), classified as possible, probable, and proven in 65.5%, 1.8%, and 32.7%, respectively. Regarding the fungus specimen, Aspergillus sp. responded for most cases (60%), followed by Fusarium sp. (23%), Candida sp. (11%), and Zygomycetes (4%). Complete response was documented at the end of induction in 49%, with the remaining patients being either refractory (27%) or not available (24%). The 60-day mortality was 25.8%. MVA showed that lower neutrophil counts at the AML diagnosis are associated with IFD during induction (OR=2.8, 95% CI 1.3-6.2), whereas age, genetic classification, and lymphocyte counts were not. Comparing the three abovementioned groups (AP: none, anidulafungin, or fluconazole), significant differences could be seen in AGR and anthracycline doses (Table 2). To analyze the impact of anidulafungin in comparison with ‘no AP’, a post-matched cohort with 164 subjects was created, matching for neutrophil and lymphocyte counts and AGR. The use of anidulafungin was not significantly related to less IFD during induction (OR=0.7, 95% CI 0.3-1.6), while neutrophil counts remained significant. Few subjects received fluconazole as AP, and it also was not related to less IFD (p=0.35). At the end of induction, complete response status did not relate to IFD during this period (p=1). Treatment for IFD with amphotericin B and voriconazole was given for 60.2% and 13.1% during induction, respectively. Patients under prophylactic anidulafungin received less amphotericin B (p<0.001) but not voriconazole (p=0.49). Fusarium sp. cases that occurred during induction (n=12) received mostly prophylactic fluconazole (42%), which was statistically relevant in comparison to other AP (p<0.001). Among these 12 cases, no favorable genetic risk was found. The occurrence of IFD during induction did not correlate with early mortality (HR=0.97, 95% CI 0.5-1.8) in our cohort.Conclusion: To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the use of AP did not decrease IFD incidence within this phase. Our results point to the fact that the fungistatic activity of echinocandins in molds might be suboptimal for immunocompromised pts. Furthermore, these results strengthen the role of posaconazole in this setting, especially for baseline neutropenic patients or higher risk subsets, such as primary refractory cases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High risk of invasive fungal disease in children undergoing hematopoietic cell transplantation or complex anticancer therapy: the adverse role of post-transplant CMV replication

Introduction: We analyzed the epidemiology and outcomes of treatment of invasive fungal disease (IFD) in children during anticancer therapy (PHO, pediatric hematology and oncology) or after hematopoietic cell transplantation (HCT) over a period of eight consecutive years in a single-center study. Material and methods: Overall, a total of 254 HCTs were performed, and 415 children were newly diagnosed for malignancy. Incidence, epidemiology and outcome of IFD were analyzed. Results: The cumulative incidence of any IFD was 32.6% in allo-HCT, 22.2% in PHO, and 6.0% in auto-HCT patients. The incidence of proven +probable IFD was 12.6%, 10.4%, and 6.0%, respectively. As many as 77.0% HCT and 67.4% PHO of fungal episodes occurred in acute leukemia patients: the highest incidence of any IFD was observed for acute lymphoblastic leukemia (29.3% in HCT; 40.5% in PHO) and for acute myeloblastic leukemia (51.1% in HCT; 65.0% in PHO) patients. There were no significant differences in the incidence of fungal infections in both allo-HCT and PHO patients between the 2-year periods. Factors contributing to an increased risk of IFD in allo-HCT patients were: CMV replication, and acute and chronic graft-versus-host disease (GvHD). Survival from IFD was 91.9% in PHO, and 78.1% in HCT patients. Fungal pneumonia in HCT patients resolved in 62.9%, while in PHO patients it resolved in 93.5%. Conclusions: The risk of IFD in allo-HCT patients is much higher than in auto-HSCT and PHO patients. The outcome of IFD is better in PHO and auto-HCT than in allo-HCT settings.

High Clinical Impact of Broad-Range Fungal PCR in Suspected Fungal Sinusitis.

Broad-range fungal PCR is a powerful tool for identifying pathogens directly from patient specimens; however, reported estimates of clinical utility vary and costs discourage universal testing. We investigated the diagnostic and clinical utility of broad-range fungal PCR by examining 9 years of results from sinonasal specimens, hypothesizing that this anatomic location would identify immunocompromised patients at high risk for invasive fungal disease. We retrospectively identified 644 PCRs and 1,446 fungal cultures from sinus sites. To determine the relative performance of each testing modality, we performed chart review on 52 patients having specimens submitted for culture and PCR on the same day. Positivity rates were significantly higher for PCR (37.1%) than culture (13.7%) but similar for formalin-fixed and fresh tissues (42.3% versus 34.6%). Relative to culture, PCR had significantly faster turnaround time to both preliminary (94.5 versus 108.8 h) and final positive (137.9 versus 278.5 h) results. Among chart-reviewed patients, 88% were immunocompromised, 65% had proven or probable fungal disease, and testing sensitivities for culture and PCR (67.5% and 85.0%) were not statistically different. Nevertheless, PCR identified pathogens not recovered by culture in 14.9% of cases and informed clinical decision-making in 16.7% of all reviewed cases, and sensitivity of PCR combined with culture (90.0%) was higher than that of culture alone. We conclude that broad-range fungal PCR is frequently informative for patients at risk of serious fungal disease and is complementary to and has faster turnaround time than culture. Formalin-fixed tissue does not adversely affect diagnostic yield, but anatomic site may impact assay positivity rates.

Community Airborne Mold Spore Counts and Invasive Fungal Disease Risk Among Pediatric Hematological Malignancy and Stem Cell Transplant Patients

BackgroundPatients with hematological malignancies and hematopoietic stem cell transplantation (HSCT) recipients are at risk of developing invasive fungal infections, but the quantitative risk posed by exposure to airborne mold spores in the community has not been well characterized.MethodsA single-institution, retrospective cohort study was conducted of pediatric patients treated for hematological malignancies and HSCT recipients between 2014 and 2018. Patients with invasive fungal disease (IFD) due to molds or endemic fungi were identified using published case definitions. Daily airborne mold spore counts were obtained from a local National Allergy Bureau monitoring station and tested for association with IFD cases by 0-inflated Poisson regression. Patients residing outside the region or with symptom onset more than 2 weeks after admission were excluded from the primary analysis.ResultsSixty cases of proven or probable IFD were identified, of whom 47 cases had symptom onset within 2 weeks of admission and were therefore classified as possible ambulatory onset. The incidence of ambulatory-onset IFD was 1.2 cases per 10000 patient-days (95% CI, 0.9–1.7). A small excess of ambulatory-onset IFD was seen from July through September, during which period spore counts were highest, but this seasonal pattern did not reach statistical significance (P = .09). No significant association was found between IFD cases and community mold spore counts over intervals from 1 to 6 weeks before symptom onset.ConclusionsThere was no significant association between IFD cases and community airborne mold spore counts among pediatric hematological malignancy and HSCT patients in this region.