Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.

Dynamics and prognostic value of plasma cell-free DNA PCR in patients with invasive aspergillosis and mucormycosis.

Aspergillus species and Mucorales agents are the primary etiologies of invasive fungal disease (IFD). Biomarkers that predict outcomes are needed to improve care. Patients diagnosed with invasive aspergillosis and mucormycosis using plasma cell-free DNA (cfDNA) PCR were retested weekly for 4 weeks. The primary outcome included all-cause mortality at 6 weeks and 6 months based on baseline cycle threshold (CT) values and results of follow-up cfDNA PCR testing. Forty-five patients with Aspergillus and 30 with invasive Mucorales infection were retested weekly for a total of 197 tests. Using the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, 30.7% (23/75), 25.3% (19/75), and 38.7% (29/75) had proven, probable, and possible IFD, respectively. In addition, 97.3% (73/75) were immunocompromised. Baseline CT increased significantly starting at week 1 for Mucorales and week 2 for Aspergillus. Aspergillosis and mucormycosis patients with higher baseline CT (CT >40 and >35, respectively) had a nonsignificantly higher survival rate at 6 weeks, compared with patients with lower baseline CT. Mucormycosis patients with higher baseline CT had a significantly higher survival rate at 6 months. Mucormycosis, but not aspergillosis patients, with repeat positive cfDNA PCR results had a nonsignificantly lower survival rate at 6 weeks and 6 months compared with patients who reverted to negative. Aspergillosis patients with baseline serum Aspergillus galactomannan index <0.5 and <1.0 had significantly higher survival rates at 6 weeks when compared with those with index ≥0.5 and ≥1.0, respectively. Baseline plasma cfDNA PCR CT can potentially be used to prognosticate survival in patients with invasive Aspergillus and Mucorales infections. IMPORTANCE: We show that Aspergillus and Mucorales plasma cell-free DNA PCR can be used not only to noninvasively diagnose patients with invasive fungal disease but also to correlate the baseline cycle threshold with survival outcomes, thus potentially allowing the identification of patients at risk for poor outcomes, who may benefit from more targeted therapies.

Factors associated with coinfections in invasive aspergillosis: a retrospective cohort study.

OBJECTIVES: To describe the coinfections in invasive aspergillosis (IA), to identify factors associated with coinfections, and to evaluate the impact of coinfection on mortality. PATIENTS AND METHODS: We conducted a monocentric retrospective study of consecutive putative, probable, or proven IA that occurred between 1997 and 2017. All coinfections, with an onset within 7 days before or after the first sign of aspergillosis, were identified. Factors associated with coinfections and mortality were analysed by multivariable analysis. RESULTS: Among the 690 patients with IA included in the study, the median age was 57 years (range 7 days to 90 years). A coinfection was diagnosed in 272/690 patients (39.4%, 95%CI 35.8-43.2). The location of this coinfection was pulmonary only in 131/272 patients (48%), bloodstream only in 66/272 patients (24%) and other/multiple sites in 75/272 patients (28%). Coinfections were bacterial (110/272 patients, 40%), viral (58/272, 21%), fungal (57/272, 21%), parasitic (5/272, 2%) or due to multiple types of pathogens (42/272, 15%). Factors associated with a coinfection in adjusted analysis were: allogeneic haematopoietic stem-cell transplantation (OR 2.3 (1.2-4.4)), other haematological malignancies (OR 2.1 (1.2-3.8)), other underlying diseases (OR 4.3 (1.4-13.6)), lymphopenia (OR 1.7 (1.1-2.5)), C-reactive protein >180 mg/L (OR 1.9 (1.2-3.0)), fever (OR 2.4 (1.5-4.1)), tracheal intubation (OR 2.6 (1.5-4.7)), isolation of two or more different Aspergillus species (OR 2.7 (1.1-6.3)), and the presence of non-nodular lesions on chest computed tomography (OR 2.2 (1.3-3.7) and OR 2.2 (1.2-4.0)). Coinfections were independently associated with a higher mortality at week 12 (adjusted HR 1.5 (1.1-1.9), p < 0.01). CONCLUSIONS: Coinfections are frequent in IA patients and are associated with higher mortality.

Influenza-Associated Aspergillosis: Nationwide Trends, Predictors and Outcomes From 2005 to 2014.

BACKGROUND: Influenza-associated aspergillosis (IAA) has been increasingly reported in the literature in recent years, but contemporary large-scale data on the morbidity and mortality burden of IAA are lacking. RESEARCH QUESTION: The goal of this study was to estimate the predictors, associations, and outcomes of IAA in the United States. STUDY DESIGN AND METHODS: This retrospective cohort study was performed by using the National (Nationwide) Inpatient Sample database from 2005 to 2014 to identify influenza and IAA hospitalizations. Baseline variables and outcomes were compared between influenza hospitalizations without IAA and those with IAA. These variables were then used to perform an adjusted analysis for obtaining predictors and associations of the diagnosis and in-hospital mortality of IAA. RESULTS: Of the 477,556 hospitalizations identified with the principal diagnosis of influenza, IAA was identified in 823 (0.17%) hospitalizations. The IAA cohort consisted more commonly of 45- to 65-year-olds in urban teaching hospitals with substance abuse. Yearly trends revealed that both influenza and IAA hospitalizations have increased over time, with a peak observed in 2009, the year of the influenza A(H1N1) pandemic. Mortality was higher (20.58% vs 1.36%), average length of stay was longer (17.94 vs 4.05 days), and mean cost per hospitalization was higher ($194,932 vs $24,286) in the IAA cohort compared with the influenza cohort without IAA (P < .005). Solid-organ transplantation, hematologic malignancies, and use of invasive mechanical ventilation were associated with higher odds of IAA, among other factors. Use of invasive mechanical ventilation (adjusted OR, 13.43; P < .005), longer length of stay (adjusted OR, 5.47; P < .005), utilization of extracorporeal membrane oxygenation (adjusted OR, 4.99; P = .014), and the group aged 45 to 64 years (adjusted OR, 3.03; P = .012) were associated with higher in-hospital mortality in the IAA cohort. INTERPRETATION: Although IAA is a rare complication of influenza hospitalizations, it is associated with increased all-cause mortality, more extended hospital stays, and higher hospital charges compared with influenza without IAA.

Intracranial aspergillosis amongst immunocompetent patients: An experience with combined surgical and medical management of 18 patients.

OBJECTIVE: Fungal infections of central nervous system (CNS) commonly affect immunocompromised patients, however, recently such cases have been reported even amongst immunocompetent patients. PATIENTS & METHODS: In this study, we retrospectively analyzed outcome of 18 immunocompetent patients with histopathologically proven intracranial Aspergillosis undergoing combined surgical and medical management. RESULTS: The age of patients ranged from 5-65 years. Fourteen out of 18 patients had well defined lesions while 4 had diffuse disease. Paranasal sinuses were involved in 8 & cavernous sinus in 3 patients. Six patients had hydrocephalus. Four patients developed infarcts during their clinical course. Surgical interventions included gross (n = 4) or subtotal excision (n = 8), decompressive craniectomy & biopsy of lesion (n = 4), biopsy only (n = 2) and ventriculoperitoneal shunt placement (n = 6). All patients received postoperative antifungal therapy. The duration of follow up ranged from 10-60 months. Overall mortality was 44.4%. Mortality amongst patients undergoing gross total and subtotal excision was 25% & 50% respectively. Patients undergoing DC had a mortality of 25%. Both patients undergoing only biopsy died. Hydrocephalus was associated with a very high mortality (83.3%). Amongst surviving patients (n = 10), 6 patients became disease free & rest 4 had stable disease at last follow up. CONCLUSIONS: Intracranial aspergillosis is associated with high morbidity & mortality even amongst immunocompetent patients. An aggressive multidisciplinary management is thus needed to improve outcome. Our study shows that a combination of surgical excision or decompressive craniectomy and antifungal therapy can be helpful in improving prognosis of these patients.

Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients.

BACKGROUND: Increasing resistance of Aspergillus fumigatus to triazoles in high-risk populations is a concern. Its impact on mortality is not well understood, but rates from 50% to 100% have been reported. OBJECTIVES: To determine the prevalence of voriconazole-resistant A. fumigatus invasive aspergillosis (IA) and its associated mortality in a large multicentre cohort of haematology patients with culture-positive IA. METHODS: We performed a multicentre retrospective study, in which outcomes of culture-positive haematology patients with proven/probable IA were analysed. Patients were stratified based on the voriconazole susceptibility of their isolates (EUCAST broth microdilution test). Mycological and clinical data were compared, along with survival at 6 and 12 weeks. RESULTS: We identified 129 A. fumigatus culture-positive proven or probable IA cases; 103 were voriconazole susceptible (79.8%) and 26 were voriconazole resistant (20.2%). All but one resistant case harboured environment-associated resistance mutations in the cyp51A gene: TR34/L98H (13 cases) and TR46/Y121F/T289A (12 cases). Triazole monotherapy was started in 75.0% (97/129) of patients. Mortality at 6 and 12 weeks was higher in voriconazole-resistant cases in all patients (42.3% versus 28.2%, P = 0.20; and 57.7% versus 36.9%, P = 0.064) and in non-ICU patients (36.4% versus 21.6%, P = 0.16; and 54.4% versus 30.7%; P = 0.035), compared with susceptible ones. ICU patient mortality at 6 and 12 weeks was very high regardless of triazole susceptibility (75.0% versus 66.7%, P = 0.99; and 75.0% versus 73.3%, P = 0.99). CONCLUSIONS: A very high prevalence of voriconazole resistance among culture-positive IA haematology patients was observed. The overall mortality at 12 weeks was significantly higher in non-ICU patients with voriconazole-resistant IA compared with voriconazole-susceptible IA.

Contrasts between mucormycosis and aspergillosis in oncohematological patients.

In retrospective multicenter study from years 2007-2017, we evaluated 59 oncohematological patients with mucormycosis and 541 with invasive aspergillosis (IA). Mucormycosis developed more often in children and adolescents (P = .001), as well as after the emergence of graft versus host disease (P = .0001). Patients with mucormycosis had more severe neutropenia (88% vs 82%), the median duration was 30 versus 14 days (P = .0001) and lymphocytopenia (77% vs 65%), with a median duration (25 vs 14 days, P = .001) as compared to patients with IA. The lung infection was less frequent in patients with mucormycosis than in IA patients (73% vs 97%, P = .02), but more frequent was involvement of 2 or more organs (42% vs 8%, P = .001) and involvement of paranasal sinuses (15% vs 6%, P = .04). Typical clinical features of mucormycosis were localized pain syndrome (53% vs 5%, P = .0001), hemoptysis (32% vs 6%, P = .001), pleural effusion on lung CT scan (53% vs 7%, P = .003), lesions with destruction (38% vs 8%, P = .0001), and a "reverse halo" sign (17% vs 3%). The overall 12-week survival was significantly lower in patients with mucormycosis than for IA patients (49% vs 81%, P = .0001). In both groups unfavorable prognosis factors were ≥2 organs involvement (P = .0009), and concomitant bacterial or viral infection (P = .001, P = .008, respectively). In mucormycosis patients favorable prognosis factor was remission of underlying disease (P = .006).

Inpatient Mortality After Endoscopic Sinus Surgery for Invasive Fungal Rhinosinusitis.

OBJECTIVES:: Invasive fungal rhinosinusitis is a rare, life-threatening condition that affects the paranasal sinuses. The standard of care after diagnosis includes surgical debridement and aggressive medical management. Despite treatment, mortality remains unacceptably high. Most data are derived from small cohort experiences, with limited identification of mortality risk factors in the acute setting. The authors used a large national database to better understand clinical factors associated with inpatient mortality for this challenging condition. METHODS:: Using the 2000-2014 National (Nationwide) Inpatient Sample database, the authors identified 979 adult patients with an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of mucormycosis or aspergillosis and a procedure code of sinus surgery. Multivariate imputation by chained equation was performed to account for missing data, followed by multivariate logistic regression to identify predictors of inpatient mortality. RESULTS:: In total, 979 adult patients were identified, with a median age of 57 years. The inpatient mortality rate was 15.8%. The most prevalent comorbidity was hematologic disorders (42.9%). Mucormycosis versus aspergillosis was associated with increased odds of inpatient mortality (odds ratio, 2.95; 95% confidence interval, 2.00-4.34; P < .001). The odds of inpatient mortality were significantly increased between patients with hematologic disorders and those without (odds ratio, 1.92; 95% confidence interval, 1.08-3.39; P = .024). Diabetes (odds ratio, 0.53; 95% confidence interval, 0.34 - 0.80; P = .003) was associated with the lowest odds of inpatient mortality. CONCLUSIONS:: This represents the first population-based study evaluating the factors associated with inpatient mortality. These findings support prior observations demonstrating that the underlying immune dysfunction and type of fungal infection are important predictors of early mortality.

Treating invasive aspergillosis in patients with hematologic malignancy: diagnostic-driven approach versus empiric therapies.

BACKGROUND: Early antifungal therapy for invasive aspergillosis (IA) has been associated with improved outcome. Traditionally, of empiric antifungal therapy has been used for clinically suspected IA. We compared outcomes of patients with hematologic malignancy and IA who were treated with voriconazole using the diagnostic driven DDA (DDA-Vori) that includes galactomannan testing vs. empiric therapy with a non-voriconazole-containing regimen (EMP-non-Vori) or empiric therapy with voriconazole (EMP-Vori). METHODS: We retrospectively reviewed the medical records of 342 hematologic malignancy patients diagnosed with proven, or probable IA between July 1993 and February 2016 at our medical center who received at least 7 days of DDA-Vori, EMP-Vori, or EMP-non-Vori. Outcome assessment included response to therapy (clinical and radiographic), all-cause mortality, and IA-attributable mortality. RESULTS: By multivariate analysis, factors predictive of a favorable response included localized/sinus IA vs. disseminated/pulmonary IA (p <  0.0001), not receiving white blood cell transfusion (p <  0.01), and DDA-Vori vs. EMP-non-Vori (p < 0.0001). In contrast, predictors of mortality within 6 weeks of initiating IA therapy included disseminated/pulmonary infection vs. localized/sinus IA (p < 0.01), not undergoing stem cell transplantation within 1 year before IA (p = 0.01), and EMP-non-Vori vs. DDA-Vori (p < 0.001). CONCLUSIONS: DDA-Vori was associated with better outcome (response and survival) compared with EMP-non-Vori and with equivalent outcome to EMP-Vori in hematologic malignancy patients. These outcomes associated with the implementation of DDA could lead to a reduction in the unnecessary costs and adverse events associated with the widespread use of empiric therapy.

The burden of Invasive Aspergillosis in patients with haematological malignancy: A meta-analysis and systematic review.

INTRODUCTION: Successful treatment of haematological malignancies is frequently complicated by Invasive Aspergillosis (IA), a life-threatening fungal infection that occurs in at least 10% of haemato-oncological patients. Case fatality rates (CFR) may fluctuate over time, depending on host pathogen interactions as well as on treatment and quality of patient care. We conducted a systematic review and metaanalysis of current - i.e. 2008-revised EORTC-MSG criteria era - incidence and case fatality rates (CFR) of IA in patients with haematological malignancy. METHODS: A systematic search according to PRISMA guidelines was performed to identify all literature reporting populations with a haematological malignancy and the incidence of IA, defined according to the EORTC/MSG 2008 criteria. Pooled cumulative incidences and CFR within 100 days were estimated using a random effects model for predefined patient populations and stratified by use of prophylaxis. RESULTS: The systematic literature search yielded 1285 publications of which n = 49 met the inclusion criteria. Overall, 16.815 patients were involved of which 1056 (6.3%) developed IA. IA risk ranged from 4% (during remission-induction, with prophylaxis) to 11% (during remission-induction, without prophylaxis). Antifungal prophylaxis was associated with a lower rate of IA, especially in the pre-HSCT population. The pooled CFR within 100 days was 29% (95% CI: 20-38%). DISCUSSION: This study confirms that IA is a relevant threat in the treatment of haematological cancer despite the universal use of antifungal prophylaxis. These outcomes inform scientists and other stakeholders about the current burden of IA and may be used to direct, implement and improve antifungal stewardship programs.

Epidemiology and Outcomes of Hospitalizations With Invasive Aspergillosis in the United States, 2009-2013.

Background: Though invasive aspergillosis (IA) complicates care of up to 13% of patients with immunocompromise, little is known about its morbidity and mortality burden in the United States. Methods: We analyzed the Health Care Utilization Project's data from the Agency for Healthcare Research and Quality for 2009-2013. Among subjects with high-risk conditions for IA, IA was identified via International Classification of Diseases, Ninth Revision, Clinical Modification codes 117.3, 117.9, and 484.6. We compared characteristics and outcomes between those with (IA) and without IA (non-IA). Using propensity score matching, we calculated the IA-associated excess mortality and 30-day readmission rates, length of stay, and costs. Results: Of the 66634683 discharged patients meeting study inclusion criteria, 154888 (0.2%) had a diagnosis of IA. The most common high-risk conditions were major surgery (50.1%) in the non-IA and critical illness (41.0%) in the IA group. After propensity score matching, both mortality (odds ratio, 1.43; 95% confidence interval, 1.36-1.51) and 30-day readmission (1.39; 1.34-1.45) rates were higher in the IA group. IA was associated with 6.0 (95% confidence interval, 5.7-6.4) excess days in the hospital and $15542 ($13869-$17215) in excess costs per hospitalization. Conclusions: Although rare even among high-risk groups, IA is associated with increased hospital mortality and 30-day readmission rates, excess duration of hospitalization, and costs. Given nearly 40000 annual admissions for IA in the United States, the aggregate IA-attributable excess costs may reach $600 million annually.

Antifungal prophylaxis with fluconazole in allogeneic stem cell transplantation recipients who had prior invasive aspergillosis with subsequent complete resolution by computed tomography.

BACKGROUND: Consensus has yet to be reached regarding secondary prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT) with a complete resolution of invasive aspergillosis (IA) confirmed by chest computed tomography (CT). METHODS: We retrospectively evaluated the feasibility of antifungal prophylaxis with fluconazole in allogeneic HSCT recipients who had previously developed IA which showed complete resolution as confirmed by chest CT before HSCT. Consecutive adult patients who underwent allogeneic HSCT at our institution and who had received fluconazole as systemic antifungal prophylaxis from June 2007 to January 2015 were included. We compared the clinical outcomes between patients with a past history of IA who showed a complete resolution of chest CT abnormalities (n = 13) and those without a previous history of IA (n = 137). RESULTS: The cumulative incidence of proven or probable IA was 8.8% in the group without a past history of IA and 0.0% in the group with a past history of IA (p = .268). The cumulative incidence of proven or probable invasive fungal disease (IFD) within 100 days after allogeneic HSCT was 10.9% in the group without a past history of IA and 15.4% in the group with a past history of IA (p = .647). Fluconazole was switched to anti-mould agents in two-thirds of the patients in each group by day 100 after HSCT. CONCLUSIONS: Fluconazole was confirmed to be an acceptable prophylactic agent early after allogeneic HSCT in appropriately selected patients.

Host immune status-specific production of gliotoxin and bis-methyl-gliotoxin during invasive aspergillosis in mice.

Delayed diagnosis in invasive aspergillosis (IA) contributes to its high mortality. Gliotoxin (GT) and bis-methyl-gliotoxin (bmGT) are secondary metabolites produced by Aspergillus during invasive, hyphal growth and may prove diagnostically useful. Because IA pathophysiology and GT's role in virulence vary depending on the underlying host immune status, we hypothesized that GT and bmGT production in vivo may differ in three mouse models of IA that mimic human disease. We defined temporal kinetics of GT and bmGT in serum, bronchoalveolar lavage fluid (BALF) and lungs of A. fumigatus-infected chronic granulomatous disease (CGD), hydrocortisone-treated, and neutropenic mice. We harvested lungs for assessment of fungal burden, histology and GT/bmGT biosynthetic genes' mRNA induction. GT levels were higher in neutropenic versus CGD or steroid-treated lungs. bmGT was persistently detected only in CGD lungs. GT, but not bmGT, was detected in 71% of sera and 50% of BALF of neutropenic mice; neither was detected in serum/BALF of CGD or steroid-treated mice. Enrichment of GT in Aspergillus-infected neutropenic lung correlated with fungal burden and hyphal length but not induction of GT biosynthetic genes. In summary, GT is detectable in mouse lungs, serum and BALF during neutropenic IA, suggesting that GT may be useful to diagnose IA in neutropenic patients.

Utility of the Aspergillus galactomannan antigen testing for neutropenic paediatric patients.

Invasive aspergillosis (IA) is an increasingly important cause of morbidity and mortality particularly in paediatric patients. Early diagnosis and the initiation of efficacious antifungal treatments could affect the prognosis of these patients. The aim of this study was to determine the clinical contribution of Galactomannan (GM) screening in paediatric patients. We reviewed the records of all in-patients, and followed up, in the various units at the Medical Faculty Children's Hospital of Erciyes University (Kayseri, Turkey), those who had at least one GM assay result from August 2009 to April 2012. Paediatric patients were classified as proven, probable or possible, according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG). Twenty-five patients, with proven IA (n=3), probable IA (n=9) and possible IA (n=13) were included in the study. The GM antigen assay results were analysed in 158 blood samples from 47 patients. At the cut-off value of 0.5 ng/ml, the sensitivity was 68% [95% confidence interval (CI); 47-85]; specificity, 77% (95% CI; 55-92). To obtain more accurate results with GM testing, the diagnosis of IA should be confirmed by clinical investigation and the factors causing false positivity of the test should also be considered.

Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole.

Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUCave]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate.

Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Cost-Effectiveness Analysis of Isavuconazole vs. Voriconazole as First-Line Treatment for Invasive Aspergillosis.

INTRODUCTION: Invasive aspergillosis (IA) is associated with a significant clinical and economic burden. The phase III SECURE trial demonstrated non-inferiority in clinical efficacy between isavuconazole and voriconazole. No studies have evaluated the cost-effectiveness of isavuconazole compared to voriconazole. The objective of this study was to evaluate the costs and cost-effectiveness of isavuconazole vs. voriconazole for the first-line treatment of IA from the US hospital perspective. METHODS: An economic model was developed to assess the costs and cost-effectiveness of isavuconazole vs. voriconazole in hospitalized patients with IA. The time horizon was the duration of hospitalization. Length of stay for the initial admission, incidence of readmission, clinical response, overall survival rates, and experience of adverse events (AEs) came from the SECURE trial. Unit costs were from the literature. Total costs per patient were estimated, composed of drug costs, costs of AEs, and costs of hospitalizations. Incremental costs per death avoided and per additional clinical responders were reported. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted. RESULTS: Base case analysis showed that isavuconazole was associated with a $7418 lower total cost per patient than voriconazole. In both incremental costs per death avoided and incremental costs per additional clinical responder, isavuconazole dominated voriconazole. Results were robust in sensitivity analysis. Isavuconazole was cost saving and dominant vs. voriconazole in most DSA. In PSA, isavuconazole was cost saving in 80.2% of the simulations and cost-effective in 82.0% of the simulations at the $50,000 willingness to pay threshold per additional outcome. CONCLUSION: Isavuconazole is a cost-effective option for the treatment of IA among hospitalized patients. FUNDING: Astellas Pharma Global Development, Inc.

Invasive fungal sinusitis in the pediatric population: Systematic review with quantitative synthesis of the literature.

BACKGROUND: Invasive fungal sinusitis (IFS) represents an often fatal condition within the pediatric population. In an effort to characterize demographics, treatment modalities, and prognostic factors, we performed a systematic review. METHODS: We systematically reviewed EMBASE, Medline, TRIPdatabase, SCOPUS and the Cochrane database for invasive fungal nasal and sinus infections limited to individuals <18 years of age. Case series including 3 or more patients were included. Demographics, treatment and outcomes were analyzed using R Gui statistical software. RESULTS: Twelve studies met inclusion criteria (103 patients). There was male preponderance of 48.5% with median age of 11 years old. Majority of patients had underlying leukemia (44.6%). Aspergillus was the predominant organism (47%). Isolated nasal findings occurred in 14% of patients and nasal findings occurred in 49% overall. Absolute neutrophil count (ANC) of immunocompromised patients was below 600 in most patients (99%). Average and median length of neutropenia was 2 weeks. All patients were prescribed amphoterocin with 50% as single medicinal therapy. Surgery occurred in 82.8% of cases. The mortality rate was 46%. Univariate analysis identified presenting with facial pain as a negative predictor of overall mortality (OR 0.296, 95% CI: 0.104-0.843, p < 0.05). CONCLUSION: Mortality remains high in pediatric patients with IFS. An ANC of <600 occurred in the majority of immunocompromised patients at a duration of 2 weeks. Presenting with facial pain was a negative predictor of mortality. Many studies label this condition as invasive fungal sinusitis; however, approximately one seventh presented with only nasal findings and half overall had nasal involvement.

Clinical Features and Survival Outcomes of Invasive Aspergillosis in Pediatric Patients at a Medical School in Thailand.

BACKGROUND: Invasive aspergillosis (IA) is a severe infection in immunocompromised patients. Recently, serum galactomannan has been widely used for diagnosis and voriconazole as an antifungal agent. The objective of this study is to describe clinical features and survival outcomes of IA. MATERIAL AND METHOD: A retrospective chart review of IA in patients younger than 18 years old at King Chulalongkorn Memorial Hospital, Thailand, was conducted. Clinical definitions were based on criteria oft he European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) 2008. RESULTS: Between January 2006 and December 2012, 40 cases of invasive aspergillosis were identified, classified as proven (8 patients, 20%), probable (28, 70%), and possible IA (4, 10%). Median age of patients was 10 years (range, 42 days-17 years). The most common underlying disease was hematologic malignancy (60%). The major risk factor was neutropenia (65%) with median duration of 21 days (range, 4-58 days). The most common site of infection was in the lungs (80%). The most common computed tomography chest finding was nodules (71%). An air crescent sign was seen only in 11% and a halo sign was found only in 7% of patients. Serum galactomannan was positive in 78% of patients with median value of 1.34 (range 0.5-5.6). Only seven patients (17%) had microbiological confirmation, of which were Aspergillus flavus (4 cases) and Aspergillus fumigates (3 cases). Antifungal therapy included voriconazole (23 patients, 58%), amphotericin B (12, 30%), liposomal amphotericin B (3, 8%), caspofungin (1, 2%) and itraconazole (1, 2%). Two deaths related to angioinvasive complications of aspergillosis (pulmonary hemorrhage and rupture mycotic aneurysm) were reported The 3-month and 12- month survival rates after diagnosed IA were 73.7% and 56.7%, respectively. The major cause of death was new episode of sepsis found in 11 cases (52%). CONCLUSION: The 1-year survival rate was poor; however, cause of death is related to complications of the immunocompromised state not from IA.