Treatments for emerging and rare invasive fungal diseases (IFDs) represent a critical unmet medical need. For IFDs that occur less frequently than invasive aspergillosis, such as mucormycosis, hyalohyphomycosis, and phaeohyphomycosis, randomized controlled clinical trials are impractical and unlikely to meet urgent public health needs. Understanding regulatory approaches for approval of drugs for rare cancers and rare metabolic diseases could help meet the challenges of studying drugs for rare IFDs. A single-arm, controlled clinical trial with a high-quality external control(s), with confirmatory evidence from nonclinical studies, including pharmacokinetic/pharmacodynamic data in predictive animal models of the disease may support findings of effectiveness of new drugs and biologics. Control populations may include historical controls from published literature, patient registries, and/or contemporaneous external control groups. Continuous engagement among clinicians, industrial sponsors, and regulatory agencies to develop consensus on trial design and innovative development pathways for emergent and rare invasive fungal diseases is important.

BACKGROUND: Limited reports exist regarding invasive fungal diseases (IFDs) in inflammatory bowel disease (IBD) patients.
OBJECTIVE: This study aims to investigate the incidence and risk factors of IFDs, specifically invasive candidiasis, aspergillosis and pneumocystosis, in IBD patients in South Korea using nationwide data.
METHODS: A population-based retrospective cohort of 42,913 IBD patients between January 2010 and December 2018 was evaluated using the Health Insurance Review and Assessment database. The primary outcome was the incidence of IFDs, including invasive candidiasis, aspergillosis and pneumocystosis, while the secondary outcome involved analysing the risk factors associated with each specific infection.
RESULTS: The study included a total of 42,913 IBD patients, with 29,909 (69.7%) diagnosed with ulcerative colitis (UC) and 13,004 (30.3%) diagnosed with Crohn\'s disease (CD). IFDs occurred in 166 IBD patients (0.4%), with 93 cases in UC patients and 73 cases in CD patients. The incidence rates of invasive candidiasis, aspergillosis and pneumocystosis in IBD patients were 0.71 per 1000 person-years (PYs), 0.15 per 1000 PYs and 0.12 per 1000 PYs, respectively. The cumulative incidence of invasive candidiasis (adjusted p-value <.001) and Pneumocystosis (adjusted p-value = .012) was found to be higher in CD patients than in UC patients. Each IFD had different risk factors, including IBD subtypes, age at diagnosis, anti-tumour necrotic factor agents or the Charlson comorbidity index.
CONCLUSIONS: Based on nationwide data in South Korea, this study shows that IFDs occur consistently in patients with IBD, albeit with a low frequency.

To have a comprehensive understanding of epidemiology and antifungal susceptibilities in pathogenic yeasts, the China Antifungal Resistance Surveillance Trial (CARST-fungi) study was conducted. All yeast isolates were identified by ribosomal DNA sequencing. Antifungal susceptibilities were performed using CLSI M27-A4 broth microdilution method. Sequence and expression level of resistant-related genes in resistant/non-wide-type (NWT) Candida isolates were analyzed. Totally 269 nonduplicate yeast isolates from 261 patients were collected. About half of the yeast isolates (127, 47.2%) were recovered from blood, followed by ascetic fluid (46, 17.1%). C. albicans remained the most prevalent (120, 44.6%), followed by C. parapsilosis complex (50, 18.6%), C. tropicalis (40, 14.9%), and C. glabrata (36, 13.4%). Fourteen (11.7%) C. albicans isolates and 1 (2.0%) C. parapsilosis isolate were resistant/NWT to triazoles. Only 42.5% (17/40) C. tropicalis were susceptible/WT to all the triazoles, with 19 (47.5%) isolates NWT to posaconazole and 8 (20%) cross-resistant to triazoles. Among C. glabrata, 20 (55.6%) and 8 (22.2%) isolates were resistant/NWT to voriconazole and posaconazole, respectively, and 4 (10.3%) isolates were cross-resistant to triazoles. Isavuconazole was the most active triazole against common Candida isolates. Except for 2 isolates of C. glabrata cross-resistant to echinocandins which were also NWT to POS and defined as multidrug-resistant, echinocandins exhibit good activity against common Candida species. All isolates were WT to AMB. For less common species, Rhodotorula mucilaginosa exhibited high MICs to echinocandins and FLC, and 1 isolate of Trichosporon asahii showed high MICs to all the antifungals except AMB. Among triazole-resistant Candida isolates, ERG11 mutations were detected in 10/14 C. albicans and 6/23 C. tropicalis, while 21/23 C. tropicalis showed MDR1 overexpression. Overexpression of CDR1, CDR2, and SNQ2 exhibited in 14, 13, and 8 of 25 triazole-resistant C. glabrata isolates, with 5 isolates harboring PDR1 mutations and 2 echinocandins-resistant isolates harboring S663P mutation in FKS2. Overall, the CARST-fungi study demonstrated that although C. albicans remain the most predominant species, non-C. albicans species accounted for a high proportion. Triazole-resistance is notable among C. tropicalis and C. glabrata. Multidrug-resistant isolates of C. glabrata and less common yeast have been emerging.

BACKGROUND: There is no consensus on the optimal secondary antifungal prophylaxis (SAP) regimen in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the efficacy and safety of posaconazole oral suspension as secondary prophylaxis of invasive fungal disease (IFD) for allo-HSCT patients.
METHODS: We retrospectively reviewed clinical data from prior IFD patients who received posaconazole oral suspension as systemic antifungal prophylaxis between June 2016 and January 2021 and have a follow-up period of 1 year after HSCT. The clinical outcomes of patients with a prior history of IFD (n = 30) and those without (n = 93) were compared.
RESULTS: The 1-year cumulative incidence of prophylaxis failure was 58.3% in the group with prior history of IFD and 41.6% in the group without a prior history of IFD (p = 0.459). The cumulative incidence of proven, probable or possible IFD within 1 year after allo-HSCT was 23.1% in the group with prior history of IFD and 14.1% in the group without prior history of IFD (p = 0.230). There was no significant difference between the cumulative incidence of proven or probable IFD within 1-year after allo-HSCT in the group with a prior history of IFD and the group without (p = 0.807). Multivariate logistic regression revealed cytomegalovirus disease as risk factor for post-transplantation IFD occurrence in posaconazole oral suspension prophylaxis. There was not a significant difference in overall survival between the patients with IFD history and those without (P = 0.559).
CONCLUSIONS: Our study support that allo-HSCT recipients with a prior history of IFD and normal GI absorption can choose posaconazole oral suspension as a safe and effective SAP option.

BACKGROUND: Invasive fungal diseases (IFD) remain a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) and are associated with high mortality rates in patients receiving alloHSCT. Antifungal prophylaxis is increasingly being used in the management of IFDs in patients receiving alloHSCT.
METHODS: A post-hoc analysis of the cross-sectional observational AFHEM study was carried out to describe the use of antifungal drugs in real-life clinical practice in alloHSCT recipients hospitalized in French hematological units.
RESULTS: A total of 147 alloHSCT recipients were enrolled; most were adults (n = 135; 92%) and had received alloHSCT < 6 months prior to enrollment (n = 123; 84%). Overall, 119 (81%) patients received a systemic antifungal therapy; of these, 95 (80%) patients received antifungal prophylaxis. Rates of patients receiving systemic antifungal treatment were similar irrespective of transplant time, neutropenic, and graft-versus-host disease status. Among patients on systemic antifungal treatment, 83 (70%) received an azole, 22 (18%) received an echinocandin, and 16 (13%) received a polyene.
CONCLUSIONS: This work provides evidence of the antifungal strategies used in alloHSCT recipients hospitalized in French hematological units. Unlike earlier studies, the AFHEM study showed that prophylaxis appears to be the leading antifungal strategy used in alloHSCT recipients in France.

UNASSIGNED: Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials.
UNASSIGNED: In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria.
UNASSIGNED: Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1-105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially.
UNASSIGNED: The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies.

Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.
To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups\' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.
There is no change in the classifications of \"proven,\" \"probable,\" and \"possible\" IFD, although the definition of \"probable\" has been expanded and the scope of the category \"possible\" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.
These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

BACKGROUND: Invasive fungal diseases (IFD) are life-threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases.
OBJECTIVE: Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment.
METHODS: Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non-Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software.
RESULTS: Thirty-five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1-540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD.
CONCLUSIONS: The prevalence of IFD among chronic lymphocytic leukaemia/non-Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib-associated IFD.

Invasive fungal disease (IFD) is a major infectious complication in patients with hematological malignancies. In this study, we examined 4889 courses of chemotherapy in patients with hematological diseases to establish a training dataset (n = 3500) by simple random sampling to develop a weighted risk score for proven or probable IFD through multivariate regression, which included the following variables: male patients, induction chemotherapy for newly diagnosed or relapsed disease, neutropenia, neutropenia longer than 10 days, hypoalbuminemia, central-venous catheter, and history of IFD. The patients were classified into three groups, which had low (0-10, ~1.2%), intermediate (11-15, 6.4%), and high risk ( > 15, 17.5%) of IFD. In the validation set (n = 1389), the IFD incidences of the groups were ~1.4%, 5.0%, and 21.4%. In addition, we demonstrated that antifungal prophylaxis offered no benefits in low-risk patients, whereas benefits were documented in intermediate (2.1% vs. 6.6%, P = 0.007) and high-risk patients (8.4% vs. 23.3%, P = 0.007). To make the risk score applicable for clinical settings, a pre-chemo risk score that deleted all unpredictable factors before chemotherapy was established, and it confirmed that anti-fungal prophylaxis was beneficial in patients with intermediate and high risk of IFD. In conclusion, an objective, weighted risk score for IFD was developed, and it may be useful in guiding antifungal prophylaxis.

Contemporary, comprehensive data on epidemiology and outcomes of invasive fungal disease (IFD) including breakthrough IFD among allogeneic hematopoietic stem cell transplantation (HSCT) recipients are scarce. We included 479 allogeneic HSCT recipients with 10 invasive candidiasis (IC) and 31 probable/proven invasive mold disease (IMD) from the Swiss Transplant Cohort Study from 01.2009 to 08.2013. Overall cumulative incidence was 2.3% for IC and 8.5% for probable/proven IMI: 6% for invasive aspergillosis (IA) and 2.5% for non-AspergillusIMI. Among 41 IFD, 46% IFD were breakthrough, with an overall incidence of 4.6%, more frequently caused by other-than-Aspergillus fumigatus molds than primary IFD (47.6% (10/21) vs 13% (3/23), P = 0.04). Twelve-week mortality among patients with IC was 20% and 58.6% for probable/proven IMD (60% IA and 54.6% non-Aspergillus). Our results reveal that breakthrough IFD represent a marked burden of probable/proven IFD postallogeneic HSCT and mortality remains above 50% in patients with probable/proven IMD, underscoring the ongoing challenges to prevent and treat IFD in these patients.