
Cornelia Lass-Flörl- Innsbruck Medical University
Cornelia Lass-Flörl
- Innsbruck Medical University
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Publications (731)
The rise in antifungal resistance and changing epidemiology underscores the need to improve antifungal susceptibility testing. This study tested the standard medium RPMI 1640 and healthy lung and sinus media against Aspergillus, Mucor, and Candida species. Candida showed greater variability in minimum inhibitory concentra tions (MICs) compared with...
We analyzed mucormycosis data from the Zygomyco.net registry (2009–2022), encompassing cases from 16 countries. India, Russia and the Czech Republic provided the largest contributions. India reported the highest case number, consistent with its substantially higher incidence compared to that of high-income countries. Among the 382 patients with muc...
Aspergillus terreus is an opportunistic fungal pathogen and a major cause of aspergillosis. Its clinical significance is heightened by high mortality rates, dissemination, and resistance to amphotericin B, complicating treatment. The present study investigates the distribution of A. terreus in Tyrolean (Austria) soils and explores potential environ...
SF001, a next-generation polyene drug, offers broad-spectrum fungicidal activity with less potential for toxicity than classic polyene amphotericin B (AmB). This study compared the in vitro activity of SF001 and amphotericin B against Candida and Aspergillus species. SF001 demonstrated activity comparable to AmB against Candida isolates (MIC50/90 o...
The Aspergillus genus encompasses a diverse array of species, some of which are opportunistic pathogens. Traditionally, human aspergillosis has primarily been linked to a few Aspergillus species, predominantly A. fumigatus. Changes in epidemiology and advancements in molecular techniques have brought attention to less common and previously unrecogn...
Prolonged cultivation of certain filamentous fungi, including Aspergillus terreus, on drug-free medium leads to degeneration and morphological heterogeneity, marked by the emergence of fluffy mycelium-type sectors. This phenomenon may indicate alterations in antifungal susceptibility profiles (particularly to amphotericin B (AmB) in A. terreus), as...
Febrile Neutropenia is an emergency in the treatment of cancer patients. It requires prompt and evidence-based clinical and antimicrobial management. The implementation of standard operating procedures (SOP) across hospitals and outpatient cancer departments can improve the outcome of FN patients by reducing FN-related morbidity and mortality and b...
Background
Despite advances in antifungals, Candida infections still have a high mortality rate of up to 40%. The ECMM Candida III study in Europe investigated the changing epidemiology and outcomes, highlighting the need to understand and manage these infections.
Methods
In this observational cohort study, participating hospitals enrolled the fir...
Objectives
Worldwide emergence of clonal outbreaks caused by fluconazole‐resistant (FLCR) and the recent emergence of echinocandin‐ and multidrug‐resistant (ECR and MDR) Candida parapsilosis isolates pose serious threats to modern clinics. Conducting large‐scale epidemiological studies aimed at determining the genetic composition and antifungal res...
In 2021, an ultra-rapid rollout vaccination campaign in the Schwaz district, Tyrol, Austria, delivered the COVID-19 vaccine BNT162b2 to 66.9% of eligible residents (dose 1: March 11–16, dose 2: April 8–13). Alongside the campaign, we recruited 11,955 residents into the prospective study REDUCE, of whom 3,859 participated in a booster vaccination in...
Although water-based paint is increasingly being advocated as environmentally friendly, it is more susceptible to biodeterioration during processing, preparation, and storage. Therefore, sufficient proactive measures are urgently needed to control and prevent microbial contamination along the production chain. The experimental setup comprised the i...
Invasive candidiasis and candidemia remain a significant public health concern. The European Confederation of Medical Mycology (ECMM) conducted three pan-European multicentre studies from 1997 to 2022 to investigate various aspects of invasive Candida infections. These studies revealed shifting trends in Candida species distribution, with an increa...
Introduction
Despite antifungal advancements, candidaemia still has a high mortality rate of up to 40%. The ECMM Candida III study in Europe investigated the changing epidemiology and outcomes of candidaemia for better understanding and management of these infections.
Methods
In this observational cohort study, participating hospitals enrolled the...
Candidemia is a major cause of morbidity and mortality in health care settings, and its epidemiology is changing. In the last two decades, the proportion of non-albicans Candida (NAC) yeasts in candidemia has increased. These yeasts more often display resistance to common antifungals. In many western countries, candidemia is mainly caused by suscep...
This case involves a 53‐year‐old female with concurrent acute myeloid leukemia (AML) and multiple myeloma. She underwent cytarabine and daunorubicin (7+3) induction chemotherapy followed by cytarabine (HiDAC) consolidation, with an early AML relapse requiring azacitidine and venetoclax therapy. She achieved complete remission and incomplete count r...
Invasive fungal infections are a significant cause of morbidity and mortality in immunocompromised patients. The primary and most frequent pathogens in Europe are Aspergillus and Candida species. However, other representatives such as Mucorales, Trichosporon, and Fusarium species are increasingly being identified. Confirming the diagnosis of an inv...
Our understanding of fungal epidemiology and the burden of antifungal drug resistance in COVID-19-associated candidemia (CAC) patients is limited. Therefore, we conducted a retrospective multicenter study in Iran to explore clinical and microbiological profiles of CAC patients. Yeast isolated from blood, were identified by matrix-assisted laser des...
The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs).
After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions a...
Invasive candidiasis is an important fungal disease caused by Candida albicans and, increasingly, non-albicans Candida pathogens. Invasive Candida infections originate most frequently from endogenous human reservoirs and are triggered by impaired host defences. Signs and symptoms of invasive candidiasis are non-specific; candidaemia is the most dia...
Antimicrobial resistance (AMR) is a major public health threat, reducing treatment options for infected patients. AMR is promoted by a lack of access to rapid antibiotic susceptibility tests (ASTs). Accelerated ASTs can identify effective antibiotics for treatment in a timely and informed manner. We describe a rapid growth-independent phenotypic AS...
Introduction: The BIOFIRE Joint Infection (JI) Panel is a diagnostic tool that uses multiplex-PCR testing to detect microorganisms in synovial fluid specimens from patients suspected of having septic arthritis (SA) on native joints or prosthetic joint infections (PJIs). Methods: A study was conducted across 34 clinical sites in 19 European and Midd...
Candida parapsilosis is known to cause severe and persistent outbreaks in clinical settings. Patients infected with multidrug-resistant C. parapsilosis (MDR Cp) isolates were identified in a large Turkish hospital from 2017–2020. We subsequently identified three additional patients infected with MDR Cp isolates in 2022 from the same hospital and tw...
The work addresses the use of bio-based and –degradable materials for the production of a moist, adaptive and anti-microbial wound dressing. The dressing is targeted to exhibit a pH-dependent active agent release. Xanthan hydrogel structures are coated on cellulose fabrics via stencil printing and subsequently cross-linked using glyoxal. By alterat...
Introduction
To explore whether the reported lower pathogenicity in infected individuals of variant of concern (VoC) Omicron and its current subvariants compared to VoC Delta may be related to fundamental differences in the initial virus-tissue interaction, we assessed their ability to penetrate, replicate and cause damage in a human 3D respiratory...
The rare, but emerging mold Aspergillus terreus is an important pathogen in some geographical areas, like Tyrol (Austria) and Houston (Texas). The reason for this high prevalence is unknown. The present serosurveillance study aimed to evaluate the trends in levels of A. terreus-specific IgG antibodies in various regions of Tyrol and to compare the...
There is an ongoing effort to optimize and revise antifungal susceptibility testing (AFST) methods due to the rising number of fungal infections and drug-resistant fungi. The rising antifungal resistance within Candida and Aspergillus species, which are common contributors to invasive fungal infections (IFIs), is a cause for concern, prompting an e...
The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream metabolites of each pathways in intestinal homeostasis, their role in lung immune homeostasis is underappreciated. Here we have examined the role played by the Trp hydroxylase/5-hydroxy...
Representatives of the Candida parapsilosis complex are important yeast species causing human infections, including candidaemia as one of the leading diseases. This complex comprises C. parapsilosis, Candida orthopsilosis and Candida metapsilosis, and causes a wide range of clinical presentations from colonization to superficial and disseminated in...
Introduction
Immunosuppression after chemotherapy, stem cell transplantation or solid organ transplantation are the main risk factors for invasive fungal infections in Austria. Here, we aim to describe the status of laboratory mycology and the access to antifungal treatment in Austria.
Methods
Between October and November 2021, hospitals were cont...
Currently, SARS-CoV-2 Omicron BA.5 subvariants BF.7 and BQ.1.1 are rapidly emerging worldwide. To evaluate the SARS-CoV-2-neutralizing capacity of sera and saliva from triple vaccinated individuals, either boosted with an adapted bivalent COVID-19 vaccine or recovered from BA.4/BA.5 infection, we analyzed the sensitivity of replication-competent SA...
The objectives of this study were to assess Candida spp. distribution and antifungal resistance of candidaemia across Europe. Isolates were collected as part of the third ECMM Candida European multicentre observational study, conducted from 01-07-2018 to 31-03-2022. Each centre (maximum number/country determined by population size) included ~10 con...
Small colony variants (SCVs) are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata – a major intracellular fungal pathogen – produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C . glabrata str...
Background:
HCC is the leading cause of cancer in chronic liver disease. A growing body of experimental mouse models supports the notion that gut-resident and liver-resident microbes control hepatic immune responses and, thereby, crucially contribute to liver tumorigenesis. However, a comprehensive characterization of the intestinal microbiome in...
Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendat...
The epidemiology of invasive fungal infections (IFIs) is currently changing, driven by aggressive immunosuppressive therapy, leading to an expanded spectrum of patients at risk of IFIs. Aspergillosis is a leading cause of IFIs, which usually affects immunocompromised patients. There are a limited number of antifungal medications available for treat...
The epidemiology of invasive fungal infections (IFIs) is currently changing, driven by aggressive immunosuppressive therapy, leading to an expanded spectrum of patients at risk of IFIs. Aspergillosis is a leading cause of IFIs, which usually affects immunocompromised patients. There is a limited number of antifungal medications available for treati...
Background
The role of respiratory viruses in chronic otitis media with effusion (COME) in children is not clearly defined. In our study we aimed to investigate the detection of respiratory viruses in middle ear effusions (MEE) as well as the association with local bacteria, respiratory viruses in the nasopharynx and cellular immune response of chi...
Background:
Invasive fungal infections are an important cause of morbidity and mortality in a broad range of patients. Adequate and early diagnosis is a challenge, and of importance for improved survival. New molecular-based diagnostic methods are trend-setting yet with the drawback that conventional tests receive less attention, in the lab as wel...
Rising breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4/5 led to the performance of various studies investigating systemic immunity and neutralizing antibodies in sera, but mucosal immunity remains understudied. In this cohort study, the humoral immune responses, including immunoglobulin levels...
With increasing frequency, clinical and laboratory-based mycologists are consulted on invasive fungal diseases caused by rare fungal species. This review aims to give an overview of the management of invasive aspergillosis (IA) caused by non-fumigatus Aspergillus spp.—namely A. flavus, A. terreus, A. niger and A. nidulans—including diagnostic and t...
Candida parapsilosis is one of the significant causes of candidemia worldwide. Although rare, echinocandin-resistant (ECR) and echinocandin-tolerant (ECT) C. parapsilosis isolates have been reported from various countries. Resistance and tolerance are predominantly caused by mutations related to the hotspot (HS) regions of the FKS1 gene. Some studi...
Although perceived as a rare clinical entity, recent studies have noted the emergence of multidrug-resistant C. parapsilosis (MDR-Cp) isolates from single patients (resistant to both azole and echinocandins). We previously reported a case series of MDR-Cp isolates carrying a novel FKS1R658G mutation. Herein, we identified an echinocandin-naïve pati...
were more similar to the A. fumigatus A1160 reference strain than to the Af293 strain when grown in infection-relevant stresses, except for interactions with human immune cells wherein macrophage responses were similar to those induced by the Af293 reference strain. Collectively, our data indicate that CAPA isolates are genomically diverse but are...
Background:
The emerged SARS-CoV-2 Omicron variants BA.1, BA.2 and BA.4/5 demonstrate higher transmission and infection compared to previous variants of concern. To evaluate effectiveness of heterologous and homologous booster vaccination, we directly compared cellular and humoral immune responses as well as neutralizing capacity against replicati...
The identification of the SARS-CoV-2 Omicron variants BA.4/BA.5, BF.7 and BQ.1.1 immediately raised concerns regarding the efficacy of currently used monoclonal antibody therapies. Here we examined the activity of monoclonal antibody therapies and antiviral drugs against clinical specimens for SARS-CoV-2 Omicron BA.4/BA.5, BF.7 and BQ.1.1 employing...
Providing timely antifungal treatment to patients suffering from life-threatening invasive fungal infections (IFIs) is essential. Due to the changing epidemiology and the emergence of antifungal resistance in Aspergillus, the most commonly responsible mold of IFIs, antifungal susceptibility testing (AFST) has become increasingly important to guide...
Background:
UV light emitting diodes (UV-LEDs) are energy efficient and of special interest for the inactivation of microorganisms. In context of the current pandemic, novel UV technologies can offer a powerful alternative of effective infection prevention and control (IPC).
Methods:
We here assessed the antimicrobial efficacy of UV-C LEDs on Es...
Background:
Various assay methods have been developed to study antimicrobial activity based on contamination of surfaces with different amounts of liquid bacterial suspensions. Since surfaces with frequent hand contact are typically touched in a dry state in clinical settings, these tests may be inappropriate at assessing effectiveness to reduce p...
Background:
The European Confederation of Medical Mycology (ECMM) collected data on epidemiology, risk factors, treatment, and outcomes of patients with culture-proven candidaemia across Europe to assess how adherence to guideline recommendations is associated with outcomes.
Methods:
In this observational cohort study, 64 participating hospitals...
Background: Mucormycetes, a heterogeneous group of fungi, induce a life-threatening disease called mucormycosis. Immune deficiencies represent a major risk factor; hence, we wanted to illuminate the role of complement and platelets in the defense against mucormycetes. Methods: Rhizopus arrhizus (Ra), Rhizopus microsporus (Rm), Lichtheimia ramosa (L...
(1) Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) raises concerns to contribute to an increased mortality. The incidence of CAPA varies widely within hospitals and countries, partly because of difficulties in obtaining a reliable diagnosis. (2) Methods: Here, we assessed Aspergillus culture-positive and c...
Background
Amphotericin B is an antifungal drug whose main limitation is toxicity. To reduce these side effects, liposomal formulations have been developed, being AmBisome (L-AmB, Gilead Science Inc) the most commonly used. We describe the in vitro antifungal activity of L-AmB component used in the AmBisome formulation
Methods
We performed a multi...
Pancreatic ductal adenocarcinoma (PDAC) is still hampered by a dismal prognosis. A better understanding of the tumor microenvironment within the pancreas and of the factors affecting its composition is of utmost importance for developing new diagnostic and treatment tools. In this context, the complement system plays a prominent role. Not only has...
The discovery of amphotericin B, a polyene antifungal compound, in the 1950s, and the formulation of this compound in a liposomal drug delivery system, has resulted in decades of use in systemic fungal infections. The use of liposomal amphotericin B formulation is referenced in many international guidelines for the treatment of fungal infections su...
Omicron variants are still the dominant SARS-CoV-2 viruses worldwide, therefore determining the level of protection from infection and severe disease is essential. Here, we investigated humoral and cellular immunity of individuals immunized by ChAdOx1, BNT162b2 and mRNA-1273 and our results show that IgG and neutralization titers wane over time. Ho...
This study aimed to determine the impact of ultra-rapid rollout vaccination on incidence of SARS-CoV-2 infection. Vaccination with BNT162b2 was provided to 66.9% of eligible residents of the Schwaz district in Tyrol, Austria, within six days per dose (first dose: 11–16 March 2021, second dose: 8–13 April 2021). Of 11,955 individuals enrolled at nin...
Hypoxia contributes to the exaggerated yet ineffective airway inflammation that fails to oppose infections in cystic fibrosis (CF). However, the potential for impairment of essential immune functions by the hypoxia-inducible factor (HIF)-1α inhibition demands for a better comprehension of downstream hypoxia-dependent pathways that are amenable for...
Platelets are currently thought to harbor antimicrobial functions and might therefore play a crucial role in infections, e.g., those caused by Aspergillus or mucormycetes. The incidence of invasive fungal infections is increasing, particularly during the coronavirus disease 2019 (COVID-19) pandemic, and such infections continue to be life-threateni...
Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM
Objectives
Species belonging to the genus of Aspergillus are among the most common causative agents of human and animal infections. Less than 40 species among all Aspergillus species are known to be associated with human infections, including allergic bronchopulmonary aspergillosis, chronic...
Background
Trichoderma spp. are filamentous fungi causing invasive fungal diseases in patients with haematological malignancies and in peritoneal dialysis patients.
Objectives
To analyse clinical presentation, predisposing factors, treatment and outcome of Trichoderma infections.
Methods
A systematic literature review was conducted for published...
Background
Invasive Fungal Diseases (IFD), account for high morbidity and mortality in immunocompromised and seriously ill patients worldwide. Early, faster and accurate diagnosis with timely and appropriate patient management is critical for improved patient outcome and antifungal stewardship. Clinical/radiological presentations in IFD are non-spe...
The influence of inoculum preparation in EUCAST broth dilution and Etest to detect the coexistence of resistant and susceptible Candida subpopulations (defined as polyresistance [PR]) was evaluated. Cocultures of two echinocandin-resistant and susceptible clinical C. glabrata strains were used to simulate the occurrence of mixed populations in clin...
Background
Hospital-acquired infections (HAI) represent increasing problems in health-care facilities worldwide. Adequate infection control measures are key elements in preventing those infections. Expert societies have published recommendations that help to reduce HAI.
Methods
In November 2019, a questionnaire-based point-prevalence survey, elici...
Background
Residents of nursing homes are one of the most vulnerable groups during the severe acute syndrome coronavirus 2 (SARS-CoV-2) pandemic. The aim of this study was to characterize cellular and humoral immune responses in >70-year-old participants before vaccination, after first and second vaccination with BNT162b2, in contrast to second-dos...
This book brings together cutting-edge studies and reviews on the water-related health aspects of SARS-CoV-2, contributed by our research community. The contributions are related to the potential risk of waterborne COVID-19 transmission, household water uses, and hygiene during the pandemic, and surveillance of SARS-CoV-2 RNA in wastewater.
In Focu...
Introduction:
The epidemiology of invasive Candida infections is evolving. Infections caused by non-albicans Candida spp. are increasing; however, the antifungal pipeline is more promising than ever and is enriched with repurposed drugs and agents that have new mechanisms of action. Despite progress, unmet needs in the treatment of invasive candid...
Invasive fungal infections (IFIs) are commonly observed in patients, who are at high risk of severe infections during the neutropenic phase. The aim of this retrospective single-center study was to evaluate the efficacy and safety of voriconazole as a fungal prophylaxis after induction chemotherapy for acute myeloid leukemia (AML) in adult patients...
Objectives
Many factors influence the outcome of in vitro antifungal susceptibility testing (AFST), including endpoint definition, inoculum sizes, time and temperature of incubation, and growth medium used. This European Confederation of Medical Mycology (ECMM) Excellence center driven study investigated multiple colony testing (MCT) of five separa...
Aspergillus terreus is an opportunistic causative agent of invasive aspergillosis and, in most cases, it is refractory to amphotericin B (AMB) therapy. Notably, AMB-susceptible Aspergillus terreus sensu stricto (s.s.) representatives exist which are also associated with poor clinical outcomes. Such findings may be attributable to drug tolerance, wh...
Objectives
We evaluated the epidemiology of candidemia among COVID-19 patients admitted to intensive care units (ICUs).
Methods
We conducted a retrospective multicenter study in Turkey between April- December 2020.
Results
Twenty-eight of 148 enrolled patients developed candidemia, yielding an incidence of 19% and incidence rate of 14/1,000 patie...
Background
Only a few studies directly compared virus-specific antibodies and their neutralizing capacity against SARS-CoV-2 wild type and circulating variants of concern, despite the reported high efficacy of mRNA- and vector-based vaccines.
Objective
Here we assessed SARS-CoV-2-S1-specific antibodies of BNT162b2, mRNA-1273 and ChAdOx1 vaccinated...
In 2020, we published a multicentre study validating a new EUCAST method for the antifungal susceptibility testing of microconidia-forming dermatophytes.¹ We included molecularly confirmed terbinafine-resistant and -susceptible Trichophyton rubrum and Trichophyton interdigitale isolates and established wild-type upper MIC limits (WT-UL) for both sp...
Wastewater-based epidemiology (WBE) is an effective approach for tracking information on spatial distribution and temporal trends of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the community level. Herein, the development, implementation, and operation of the wastewater monitoring program serving Tyrol – a federal province of Au...
Africa, although not unique in this context, is a favourable environment for fungal infections, given the high burden of risk factors. An online survey was developed asking about laboratory infrastructure and antifungal drug availability. We received 40 responses (24·4% response rate) of 164 researchers contacted from 21 African countries. Only fiv...
Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) raises concerns as to whether it contributes to an increased mortality. The incidence of CAPA varies widely within hospitals and countries, partly because of difficulties in obtaining a reliable diagnosis. We implemented a routine screening of respiratory specimens in COV...
Background
Optimizing antifungal therapy is important to improve outcomes in severely immunocompromised patients.
Objectives
We analysed the in vitro interaction between pulmonary surfactant and antifungal agents used for management of invasive pulmonary aspergillosis.
Methods
Amphotericin B formulations, mould-active triazoles and echinocandins...
Susceptibility testing is an important tool in the clinical setting; its utility is based on the availability of categorical endpoints, breakpoints (BPs) or epidemiological cutoff values (ECVs/ECOFFs). CLSI and EUCAST have developed antifungal susceptibility testing, BPs and ECVs for some fungal species. Although the Concentration Gradient Strip Bi...
Complement-opsonized HIV-1 triggers efficient antiviral type I interferon (IFN) responses in dendritic cells (DCs), which play an important role in protective responses at the earliest stages in retroviral infection. In contrast, HIV-1 suppresses or escapes sensing by STING- and MAVS-associated sensors. Here, we identified a complement receptor-med...
The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and c...
IntroductionGender plays an active role in the incidence and outcome of many infectious and malignant diseases. However, there is still no study examining sex differences for developing bloodstream infections (BSIs) in pediatric patients with cancer. We sought to identify potential gender-specific risk factors for BSIs.Methods
Data were retrospecti...
Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Sacch...
Objectives
Coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. The objectives of this multinational study were to determine the prevalence of CAPA in patients with COVID-19 in intensive care units (ICU) and to investigate risk factors for CAPA as well as ou...
Members of the order Mucorales may cause severe invasive fungal infections (mucormycosis) in immune-compromised and otherwise ill patients. Diagnosis of Mucorales infections and discrimination from other filamentous fungi are crucial for correct management. Here, we present an overview of current state-of-the-art mucormycosis diagnoses, with a focu...