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BACKGROUND: During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection. METHODS: We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants. RESULTS: Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects. CONCLUSION: Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flows origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of Americas aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

ABSTRACT Background Methods Results Conclusion The 2015 International Society for Heart and Lung Transplant (ISHLT) fungal guidelines recommend the use of bronchoalveolar lavage (BAL) galactomannan over serum galactomannan for the diagnosis of invasive aspergillosis (IA) in lung transplant (LTx) recipients, based on limited evidence. Galactomannan testing is costly.A single‐center, retrospective cohort study reviewing all 814 serum and BAL galactomannan samples received from 184 LTx recipients in our center between 2021 and 2022 and assessing their diagnostic performance in the diagnosis of IA.Over the study period, 394 serum galactomannan samples were received from 144 patients and 420 BAL galactomannan samples from 143 patients. Using a cut‐off of ≥ 1.0 for BAL galactomannan, the sensitivity and specificity were 65.9% and 98.4%, respectively. In total, 30 patients had positive BAL galactomannan. Antifungal therapy was commenced or continued in 29 of these patients either as targeted or pre‐emptive treatment. Using a cut‐off of ≥ 0.5 for serum galactomannan, the sensitivity and specificity were 9.7% and 99.7%, respectively. In total, four patients had a positive serum galactomannan. All four patients were either already on antifungal treatment for IA or were started before the serum galactomannan result was available, supported by laboratory, clinical, and radiological findings. A positive serum galactomannan was used to monitor treatment response in one patient.Serum galactomannan is not a valuable test in the diagnosis of IA in our LTx recipients, is costly, and does not remove the need for bronchoscopy and BAL galactomannan. This supports the ISHLT recommendation. [ABSTRACT FROM AUTHOR]

Background Cerebral aspergillosis (CA) is associated with high mortality. According to the European Conference on Infections in Leukemia and the European Society of Clinical Microbiology and Infectious Diseases guidelines, the recommended first-line treatment for all forms of aspergillosis is voriconazole or isavuconazole. However, little is known about the efficacy and safety of isavuconazole in CA. Methods We conducted a European multicenter retrospective study of patients treated with isavuconazole for proven or probable CA between 2014 and 2022 and compared the outcomes with those of weighted control groups from the previously published French national cohort of CA, the Cerebral Aspergillosis Lesional Study (CEREALS). Results Forty patients from 10 countries were included. The main underlying conditions were hematological malignancies (53%) and solid-organ transplantation (20%). Isavuconazole was administered as a first-line treatment to 10 patients, primarily in combination therapy, resulting in control of CA in 70% of these cases. Thirty patients received isavuconazole after a median of 65 days on another therapy, mostly because of side effects (50%) or therapeutic failure (23%) of the previous treatment. Predominantly given as monotherapy, it achieved control of CA in 73% of the patients. Seventeen patients (43%) underwent neurosurgery. When measured, isavuconazole levels were low in cerebrospinal fluid but adequate in serum and brain tissue. Isavuconazole toxicity led to treatment interruption in 7.5% of the patients. Twelve-week mortality was 18%. Comparison with the CEREALS cohort showed comparable survival in patients receiving isavuconazole or voriconazole as a first-line treatment. Conclusions Isavuconazole appears to be a well-tolerated treatment. Mortality of CA treated with isavuconazole is similar to that reported with voriconazole. [ABSTRACT FROM AUTHOR]

Introduction: Although the progression of invasive Aspergillosis (IA) shares some risk factors in the development of active Pulmonary Tuberculosis (PTB), however, the prevalence of IA in PTB remains unclear. Material and methods: 100 consecutive sputum samples with proven PTB between 12.7.203 and 7.12.23 were collected during the study period. All sample were processed for KOH mount followed by culture on SDA, if growth appeared colony were processed by slide culture followed by LPCB. Result: out of 100 sputum samples positive for Pulmonary Tuberculosis, 8 samples were found positive for pulmonary Aspergillosis of which A. fumagatus, A.flavus and A.niger were 4, 3 and 1 respectively. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to report the emergence of azole-resistant invasive aspergillosis in hematologic patients admitted to a tertiary hospital in Spain during the last 4 months. Methods: Prospective, descriptive study was performed to describe and follow all consecutive proven and probable invasive aspergillosis resistant to azoles from hematological cohort during the last 4 months. All patients had fungal cultures and antifungal susceptibility or real-time PCR detection for Aspergillus species and real-time PCR detection for azole-resistant mutation. Results: Four cases of invasive aspergillosis were diagnosed in 4 months. Three of them had azole-resistant aspergillosis. Microbiological diagnosis was achieved in three cases by means of fungal culture isolation and subsequent antifungal susceptibility whereas one case was diagnosed by PCR-based aspergillus and azole resistance detection. All the azole-resistant aspergillosis presented TR34/L98H mutation. Patients with azole-resistant aspergillosis had different hematologic diseases: multiple myeloma, lymphoblastic acute leukemia, and angioimmunoblastic T lymphoma. Regarding risk factors, one had prolonged neutropenia, two had corticosteroids, and two had viral co-infection. Two of the patients developed aspergillosis under treatment with azoles. Conclusion: We have observed a heightened risk of azole-resistant aspergillosis caused by A. fumigatus harboring the TR34/L98H mutation in patients with hematologic malignancies. The emergence of azole-resistant aspergillosis raises concerns for the community, highlighting the urgent need for increased surveillance and the importance of susceptibility testing and new drugs development. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Invasive aspergillosis (IA) can lead to life‐threatening respiratory failure necessitating extracorporeal membrane oxygenation (ECMO) support. However, data on ECMO experience in the management of IA patients are scarce.The purpose of this systematic review was to evaluate the potential benefits and risks of ECMO as a supportive intervention for critically ill patients with IA.We conducted a systematic review of the literature using the search terms ECMO, extracorporeal membrane oxygenation, Aspergillus and Aspergillosis in two databases (Medline and Scopus). Clinical data were extracted by two independent investigators. Clinical parameters, such as mode of ECMO support, duration of treatment and clinical outcomes, were assessed.Overall, 32 patients were included in the analysis. The age ranged from 5 to 69 years, 59% were male, and 38% were female. The majority of patients suffered from ARDS (82%). 82% received VV‐ECMO, and 18% received VA‐ECMO. Aspergillus fumigatus was the most frequent cause of IA, coinfections were frequently observed (51%). The overall mortality was 78%. Complications during ECMO support were observed in 21 of the 39 cases (53.8%).IA poses significant management challenges for critically ill ICU patients, even with ECMO support. Although ECMO appears to improve survival of patients at high risk of AI, potential risks such as bacterial superinfection and altered pharmacokinetics of antifungal drugs must be carefully considered. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) is a potentially life-threatening complication of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We conducted a systematic review and meta-analyses of studies on acute leukemia in children aged 0–17 years since 2000. Findings were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We included 24 studies with 3661 ALL patients and 1728 AML patients. IA cumulative incidence varied (0%–10% for ALL and 0%–18% for AML) across the studies. Pooled cumulative IA incidences were estimated at 3.2% (95% CI: 1.8%–5.8%) in ALL and 5.2% (95% CI: 3.1%–8.6%) in AML, with corresponding case fatality rates of 13.3% (95% CI: 6.3%–25.9%), and 7.8% (95% CI: 0.7%–51.2%), respectively. Our analysis highlights the impact of IA in childhood leukemia, underscoring the need to address strategies for prevention, early detection, and treatment of IA in pediatric leukemia. [ABSTRACT FROM AUTHOR]

Background: Invasive aspergillosis (IA) is a significant cause of morbidity and mortality in patients with haematological malignancies. Accurate diagnosis of IA is challenging due to non-specific symptoms and the impact of antifungal prophylaxis on biomarker sensitivity. Methods: This retrospective study evaluated the diagnostic performance of three serum biomarkers: Aspergillus Galactomannan Ag VirClia Monotest® (VirClia), Wako β-D-Glucan Test® (Wako BDG), and MycoGENIE Real-Time PCR® (MycoGENIE PCR). True positives were defined as patients with proven or probable IA (n = 14), with a positive Platelia Aspergillus Antigen® (Platelia) serving as a mycological criterion. True negatives were identified as patients with a positive Platelia assay but classified as non-probable IA (n = 10) and outpatients who consistently tested negative with the Platelia test throughout the study period (n = 20). Results: Most patients diagnosed with proven or probable IA were acute myeloid leukaemia or myelodysplastic syndrome patients receiving mould-active antifungal prophylaxis or treatment (71%). VirClia demonstrated high sensitivity (100%) for detecting IA, with a specificity of 83%. Wako BDG and MycoGENIE PCR showed lower sensitivities for IA (57% and 64%, respectively). MycoGENIE PCR detected Aspergillus spp. and Mucorales in two patients. Conclusions: Accurate diagnosis of IA remains challenging, especially in patients who have received mould-active antifungal treatment. VirClia showed comparable performance to Platelia, suggesting its potential for routine use. However, Wako BDG and MycoGENIE PCR results were less favourable in our study cohort. Nevertheless, MycoGENIE PCR detected two probable co-infections with Aspergillus spp. and Mucorales. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the outcomes of voriconazole in terms of functional recovery and response on imaging in the management of invasive aspergillosis of orbit. This was a prospective non-comparative interventional study. Diagnosed cases of invasive orbital aspergillosis were studied in a tertiary care hospital. Intravenous voriconazole followed by oral treatment was given. Sinus debridement was done, where needed. The response to treatment was assessed clinically and on radiology. A total of 10 diagnosed cases of invasive orbital aspergillosis were studied. Nine cases (90%) occurred in immunocompetent patients. Predisposing sinus infection was seen in 8 patients (80%). The most common presenting complaint was the protrusion of eye. On voriconazole treatment, there was a statistically significant improvement in vision and extraocular movements from first week onwards (p = 0.01 and p = 0.02, respectively) and reduction in proptosis from second week onwards (p = 0.003). Imaging was done at three months follow-up which revealed a good response to treatment in 90% of patients. All patients tolerated the drug well except one who had transient hepatic dysfunction. The mean follow-up was 5.8 months (range: 3–12 months). There was no recurrence of disease till the last follow-up. Invasive orbital aspergillosis commonly presents as sino-orbital disease, mostly in immunocompetent adult patients. Voriconazole is a safe and effective drug with good short-term clinical outcome. [ABSTRACT FROM AUTHOR]

Diverse pathogenic fungi can produce severe infections in immunocompromised patients, thereby justifying intensive care unit (ICU) admissions. In some cases, the infections can develop in immunocompromised patients who were previously admitted to the ICU. Aspergillus spp., Pneumocystis jirovecii, Candida spp., and Mucorales are the fungi that are most frequently involved in these infections. Diagnosis continues to be challenging because symptoms and signs are unspecific. Herein, we provide an in-depth review about the diagnosis, with emphasis on recent advances, and treatment of these invasive fungal infections in the ICU setting.

Background: Invasive fungal infections (IFIs) are important infectious complications amongst critically ill children. The most common fungal infections are due to Candida species. Aspergillus, Zygomycetes and Fusarium are also emerging because of the empirical use of antifungal drugs. This updated review discusses the epidemiology of IFIs as well as antifungal drugs, dosing and potential adverse effects in critically ill children. Methods: A PubMed search was conducted with Clinical Queries using the key terms “antifungal”, “children”, “critical care” AND “paediatric intensive care unit” OR “PICU”. The search strategy included clinical trials, randomized controlled trials, meta-analyses, observational studies and reviews and was limited to the English literature in paediatrics. Results: Candida and Aspergillus spp. are the most prevalent fungi in paediatric IFIs, causing invasive candidiasis infections (ICIs) and invasive aspergillosis infections (IAIs), respectively. These IFIs are associated with high morbidity, mortality and healthcare costs. Candida albicans is the principal Candida spp. associated with paediatric ICIs. The risks and epidemiology for IFIs vary if considering previously healthy children treated in the paediatric intensive care unit or children with leukaemia, malignancy or a severe haematological disease. The mortality rate for IAIs in children is 2.5–3.5-fold higher than for ICIs. Four major classes of antifungals for critically ill children are azoles, polyenes, antifungal antimetabolites and echinocandins. Conclusions: Antifungal agents are highly efficacious. For successful treatment outcomes, it is crucial to determine the optimal dosage, monitor pharmacokinetics parameters and adverse effects, and individualized therapeutic monitoring. Despite potent antifungal medications, ICIs and IAIs continue to be serious infections with high mortality rates. Pre-emptive therapy has been used for IAIs. Most guidelines recommend voriconazole as initial therapy of invasive aspergillosis in most patients, with consideration of combination therapy with voriconazole plus an echinocandin in selected patients with severe disease. The challenge is to identify critically ill patients at high risks of ICIs for targeted prophylaxis. Intravenous/per os fluconazole is first-line pre-emptive treatment for Candida spp. whereas intravenous micafungin or intravenous liposomal amphotericin B is alternative pre-emptive treatment. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections

Abstract Background Several antifungal agents are available for primary therapy in patients with invasive aspergillosis (IA). Although a few studies have compared the effectiveness of different antifungal agents in treating IA, there has yet to be a definitive agreement on the best choice. Herein, we perform a network meta-analysis comparing the efficacy of different antifungal agents in IA. Methods We searched PubMed, Embase, and the Cochrane Central Register of Controlled Clinical Trials databases to find studies (both randomized controlled trials [RCTs] and observational) that reported on treatment outcomes with antifungal agents for patients with IA. The study quality was assessed using the revised tool for risk of bias and the Newcastle Ottawa scale, respectively. We performed a network meta-analysis (NMA) to summarize the evidence on antifungal agents’ efficacy (favourable response and mortality). Results We found 12 studies (2428 patients) investigating 11 antifungal agents in the primary therapy of IA. There were 5 RCTs and 7 observational studies. When treated with monotherapy, isavuconazole was associated with the best probability of favourable response (SUCRA, 77.9%; mean rank, 3.2) and the best reduction mortality against IA (SUCRA, 69.1%; mean rank, 4.1), followed by voriconazole and posaconazole. When treated with combination therapy, Liposomal amphotericin B plus caspofungin was the therapy associated with the best probability of favourable response (SUCRA, 84.1%; mean rank, 2.6) and the best reduction mortality (SUCRA, 88.2%; mean rank, 2.2) against IA. Conclusion These findings suggest that isavuconazole, voriconazole, and posaconazole may be the best antifungal agents as the primary therapy for IA. Liposomal amphotericin B plus caspofungin could be an alternative option.

Invasive Aspergillosis (IA) is a severe and fatal infection, especially in immunocompromised patients. Galactomannan is a polysaccharide antigen present in the cell wall of Aspergillus species, which is secreted into the blood and other body fluids during hyphal growth. Therefore, detecting galactomannan antigen is very useful in diagnosing IA, along with clinical features and radiological findings. The study period was one year (January 2022 to December 2022). The data was collected retrospectively from the medical records and case sheets of all clinically suspected invasive aspergillosis patients. Galactomannan antigen assay was performed using an FDA-approved Platelia Aspergillus EIA test kit, and results were interpreted according to the manufacturer’s instructions (Cut off > 0.5). A total of 236 clinically suspected Invasive Aspergillosis cases were enrolled in the study. Galactomannan positivity was predominantly seen in patients aged 40 – 60 years, with male preponderance. Of 236 patients, 14.40% were immunocompromised, and 85.59% were immunocompetent. According to EORTC/MSG definitions, we got one proven IA case, 21 probable cases (8.89%), and nine (3.81%) possible cases. In immunocompetent individuals also, we observed 48.72% (115/236) galactomannan positivity, especially in old Pulmonary Tuberculosis (PTB) patients. Galactomannan positivity was higher in Broncho alveolar lavage (BAL) samples (n=70, 85.36%) than in serum samples (n=77, 46.67%). We found culture positivity of 14.06%, with Aspergillus fumigatus being the commonest isolate, followed by Aspergillus flavus. There is increased positivity of galactomannan in BAL samples compared to serum; hence BAL is a better specimen for diagnosis of Invasive Pulmonary Aspergillosis (IPA).

In the realm of aspergillosis, a critical concern for immunocompromised patients facing Aspergillus fumigatus, effective management hinges on understanding fungal growth, stress resistance, and response to antifungal treatments. Our study investigates the crucial role of fungal plasma membrane proton ATPase (PMA) in nutrient absorption, intertwined with growth and antifungal susceptibility. We employed a high-throughput knockout method to create the PMA gene knockout mutant, ΔAfu-PMA1, in A. fumigatus, alongside a complementation strain. Antifungal susceptibility to triazoles was assessed by micro-dilution method and E-test, revealing decreased sensitivity to voriconazole in ΔAfu-PMA1. Comparative analysis demonstrated significant growth differences, with wild-type strain surpassing ΔAfu-PMA1 by 3.2-fold. Under oxidative stress and heightened osmotic pressure, ΔAfu-PMA1 showed notable growth defects. Loss of PMA led to increased ergosterol and decreased ATP content, alongside pH changes in the culture medium. Transcriptome sequencing unveiled revealed a reduced expression of genes associated with ribosome function, the MAPK pathway, endoplasmic reticulum, and the transport and metabolism of fats, sugars, and proteins in ΔAfu-PMA1, highlighting PMA’s regulatory role in growth and adaptation. These findings emphasise PMA as a potential target for future antifungal drugs, offering hope in combating aspergillosis.

We investigated a cohort of 370 patients in Austria with hantavirus infections (7.8% ICU admission rate) and detected 2 cases (cumulative incidence 7%) of invasive pulmonary aspergillosis; 1 patient died. Hantavirus-associated pulmonary aspergillosis may complicate the course of critically ill patients who have hemorrhagic fever with renal syndrome.

The clinical spectrum of invasive pulmonary aspergillosis (IPA) has expanded in recent decades. A large group of patients admitted to intensive care units (ICU) is indeed susceptible to the development of IPA. Although timely diagnosis and antifungal therapy of IPA in this expanding population is crucial to prevent IPA-related deaths, the magnitude of the favorable prognostic impact of antifungal therapy is difficult to measure precisely. In our opinion, the development of standardized research definitions could have favorable implications for further improving our ability both to measure the favorable effect of antifungal treatment and to prevent IPA-related death in ICU patients. [ABSTRACT FROM AUTHOR]

Introduction: Invasive fungal diseases (IFD) constitute a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT) recipients. Areas covered: We describe epidemiology, causes and risk factors of IFD in allogeneic HSCT discussing prophylaxis and treatment in various HSCT phases. We present the most recent studies on this thematic area, including novel data on currently available antifungals, i.e. formulations, dosing, safety, efficacy and therapeutic drug monitoring. Finally, we present the most recent relevant recommendations published. Literature search included PubMed, Scopus, and clinicaltrials.gov between January 2014 and April 2024. Expert opinion: The antifungal agents employed for prophylaxis and therapy should be predicated on local epidemiology of IFD. Fluconazole prophylaxis remains a first-line choice before engraftment when the main pathogen is Candida spp. After engraftment, prophylaxis should be with mold-active agents (i.e. triazoles). For candidiasis, echinocandins are suggested as first-line treatment, whereas aspergillosis responds well to mold-active azoles and liposomal amphotericin B (L-AmB). For mucormycosis, treatment of choice includes L-AmB and isavuconazole. Choice between fever-driven and diagnostics-driven strategies remains equivocal. Open research topics remain: 1) optimization of tools to ensure prompt and accurate IFD diagnosis to avoid unnecessary exposure to antifungals, drug interactions and cost; 2) refinement of treatment for resistant/refractory strains. [ABSTRACT FROM AUTHOR]

Background: The performance of serum galactomannan (GM) for the diagnosis of invasive aspergillosis (IA) has been studied mainly in adults. Paediatric data are scarce and based on small and heterogeneous cohorts. Objective: To evaluate the performance of serum GM for the diagnosis of IA in a paediatric oncologic population at high risk of IA and to clarify the impact of antifungal prophylaxis on this test. Methods: We performed a retrospective study from January 2014 to December 2020 in the paediatric oncologic haematologic department of the University Hospital of Bordeaux. The diagnosis of IA was made using the recommendations of the EORTC and the MSGERC. Results: Among the 329 periods at high risk of IA in 222 patients, the prevalence of IA was 1.8% (3 proven and 3 probable IA). In the total population, the sensitivity, and the positive predictive value (PPV) were respectively 50% and 17.6%. Under antifungal prophylaxis, the sensitivity and PPV dropped, respectively, to 33.3% and 14.3%. In this group, the post‐test probability of IA was 2% for a negative serum GM and only 14%. Conclusion: In this large cohort of children at high risk of IA, the incidence of IA is low and the diagnostic performance of GM is poor, especially in the case of mould‐active prophylaxis. Screening should be targeted rather than systematic and should be reserved for patients at highest risk for IA without mould‐active prophylaxis. Combination with other tests such as Aspergillus PCR would increase the accuracy of GM in screening setting. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) represents a common form of fungal infection caused by various species of Aspergillus that most frequently affect immunocompromised patients. Typically, this disease occurs preferentially in high-risk groups including patients infected with the human immunodeficiency virus (HIV), patients with leukemia, patients with autoimmune diseases, and organ transplant patients undergoing medical immunosuppression. Considered the second most common cause of opportunistic fungal infection in humans after Candida albicans, this pathogen predominantly affects the lungs, but it may also spread by a hematogenous route to various organs and have a heterogeneous presentation. Owing to its high iodine levels, high perfusion, and enclosed capsule, the thyroid gland is considered to have a lower susceptibility to microbial invasion, and it is fairly uncommon to find associated infectious nodules. In metabolic imaging, 18F-FDG-PET/CT has become increasingly useful for detecting a wide range of infectious and inflammatory diseases and is already the gold standard for certain indications. According to the literature, no studies of hypermetabolic nodular thyroid aspergillosis on 18F-FDG-PET/CT confirmed on histology have yet been reported. Here, we report the first case of a patient with a heterogeneous presentation of IA and the presence of a hypermetabolic nodule in the thyroid with a surprising result. [ABSTRACT FROM AUTHOR]

In the realm of aspergillosis, a critical concern for immunocompromised patients facing Aspergillus fumigatus, effective management hinges on understanding fungal growth, stress resistance, and response to antifungal treatments. Our study investigates the crucial role of fungal plasma membrane proton ATPase (PMA) in nutrient absorption, intertwined with growth and antifungal susceptibility. We employed a high-throughput knockout method to create the PMA gene knockout mutant, ΔAfu-PMA1, in A. fumigatus, alongside a complementation strain. Antifungal susceptibility to triazoles was assessed by micro-dilution method and E-test, revealing decreased sensitivity to voriconazole in ΔAfu-PMA1. Comparative analysis demonstrated significant growth differences, with wild-type strain surpassing ΔAfu-PMA1 by 3.2-fold. Under oxidative stress and heightened osmotic pressure, ΔAfu-PMA1 showed notable growth defects. Loss of PMA led to increased ergosterol and decreased ATP content, alongside pH changes in the culture medium. Transcriptome sequencing unveiled revealed a reduced expression of genes associated with ribosome function, the MAPK pathway, endoplasmic reticulum, and the transport and metabolism of fats, sugars, and proteins in ΔAfu-PMA1, highlighting PMA’s regulatory role in growth and adaptation. These findings emphasise PMA as a potential target for future antifungal drugs, offering hope in combating aspergillosis. [ABSTRACT FROM AUTHOR]

Background: Serum galactomannan (GM) testing is essential for diagnosing invasive aspergillosis (IA), particularly in immunocompromised individuals. The global lack of on‐site GM testing capacities necessitates cost‐effective alternatives, such as.the clarus Aspergillus GM enzyme immunoassay prototype (clarus AGM prototype). Methods: This single‐centre, cross‐sectional study compared the diagnostic performance of the clarus AGM prototype (IMMY, Norman, Oklahoma) with the serological gold standard (=Platelia AGM assay; Bio‐Rad, Marnes‐la‐Cocquette, France). IA was classified according to modified 2020 EORTC/MSG consensus and 2024 FUNDICU criteria. In total, 300 prospectively (May‐Dec 2023) and retrospectively (2012–2015) collected samples were included. Results: Among 300 samples from 232 patients, 49 (16%) were classified as proven (n = 1) or probable IA (n = 48). In non‐IA cases (n = 250), one patient was classified as possible IA. With the manufacturer recommended cut‐off of ≥0.2, sensitivity and specificity of the clarus AGM prototype were 27% (13/49; 95% confidence interval [CI]: 15%–41%) and 99% (248/250; 95% CI: 97%–100%), respectively, while sensitivity and specificity were 78% and 79% when using the optimised Youden's cut‐off of 0.0045 ODI. ROC curve analysis demonstrated an area under the curve (AUC) of 0.829 (95% CI: 0.760–0.898) for the clarus AGM prototype in distinguishing between proven/probable IA and non‐IA. The AUC for the Platelia AGM was 0.951 (95% CI: 0.909–994). Spearman's correlation analysis showed a weak correlation between the two assays (0.382; p <.001). Conclusions: The weak correlation between the clarus AGM prototype and Platelia AGM highlights the need for further investigation into the clinical performance of the clarus AGM prototype, giving the different antigen epitopes addressed. [ABSTRACT FROM AUTHOR]

Purpose: Cancer patients are at heightened risk for invasive aspergillosis (IA), a condition associated with elevated mortality risk. The JF5-based Aspergillus Galactomannoprotein Lateral Flow Device (AspLFD) offers rapid point-of-care testing (POCT) for IA. This study evaluated the diagnostic performance of AspLFD in cancer populations. Methods: This retrospective study examined cancer patient bronchoalveolar lavage fluid (BALF) and serum samples collected between September 2021 and January 2023. Both AspLFD and galactomannan (GM) assays were conducted, and the results were analysed by two independent researchers. Results: This study included 242 samples from 218 cancer patients, with 58 BALF and 184 serum samples. The overall agreement between AspLFD and GM assay results was 92.1%, with a kappa value of 0.552. AspLFD diagnosed proven/probable IA with a sensitivity and specificity of 91.7% and 95.3%, respectively, whereas GM exhibited sensitivity and specificity values of 83.3% and 93.7%, respectively. There were no statistical differences in the sensitivity and specificity between the two methods (P > 0.05). For serum analyses, AspLFD and GM exhibited similar sensitivity (66.7% vs. 66.7%, P > 0.05) and specificity (98.6% vs. 96.6%, P > 0.05) values. However, the sensitivity of the AspLFD was superior to the GM assay (100% vs. 88.9%) in BALF analyses but the difference was not statistically significant (P > 0.05), with no difference in specificity (83.7% vs. 83.7%, P > 0.05). In the solid-tumour cohort, both the AspLFD and GM assay exhibited high sensitivity (100% for both) and specificity (94.2% vs. 92.8%, P > 0.05). Conclusion: The AspLFD demonstrated good performance in diagnosing IA in cancer patients, especially those with solid tumours. The AspLFD is thus an alternative POCT, particularly when GM evaluations are not readily available. [ABSTRACT FROM AUTHOR]

Invasive fungal infections are uncommon in an immunocompetent host and pose a real diagnostic dilemma. As they have a propensity for locoregional destruction, clinic-radiological findings can mislead to a faulty diagnosis of a malignancy. Here we present a case of Primary Aspergillus dacryocystitis in an immunocompetent individual initially thought to be an orbital malignancy until the histopathological examination. [ABSTRACT FROM AUTHOR]

Invasive Aspergillosis (IA) is a severe and fatal infection, especially in immunocompromised patients. Galactomannan is a polysaccharide antigen present in the cell wall of Aspergillus species, which is secreted into the blood and other body fluids during hyphal growth. Therefore, detecting galactomannan antigen is very useful in diagnosing IA, along with clinical features and radiological findings. The study period was one year (January 2022 to December 2022). The data was collected retrospectively from the medical records and case sheets of all clinically suspected invasive aspergillosis patients. Galactomannan antigen assay was performed using an FDA-approved Platelia Aspergillus EIA test kit, and results were interpreted according to the manufacturer’s instructions (Cut off > 0.5). A total of 236 clinically suspected Invasive Aspergillosis cases were enrolled in the study. Galactomannan positivity was predominantly seen in patients aged 40 – 60 years, with male preponderance. Of 236 patients, 14.40% were immunocompromised, and 85.59% were immunocompetent. According to EORTC/MSG definitions, we got one proven IA case, 21 probable cases (8.89%), and nine (3.81%) possible cases. In immunocompetent individuals also, we observed 48.72% (115/236) galactomannan positivity, especially in old Pulmonary Tuberculosis (PTB) patients. Galactomannan positivity was higher in Broncho alveolar lavage (BAL) samples (n=70, 85.36%) than in serum samples (n=77, 46.67%). We found culture positivity of 14.06%, with Aspergillus fumigatus being the commonest isolate, followed by Aspergillus flavus. There is increased positivity of galactomannan in BAL samples compared to serum; hence BAL is a better specimen for diagnosis of Invasive Pulmonary Aspergillosis (IPA). [ABSTRACT FROM AUTHOR]

The development of invasive fungal infections (IFIs) is a serious complication in acute myeloid leukemia (AML) patients who undergo an induction to remission chemotherapy. Given the increased mortality in AML patients with IFI despite prophylaxis, we need to address this problem. Statins have traditionally been employed in clinical settings as agents for reducing lipid levels. Nonetheless, recent investigations have brought to light their antifungal properties in animals, as well as in vitro studies. The objective of this study was to assess the effectiveness of atorvastatin when added to the routine IFI prophylaxis regimen in patients diagnosed with AML. A randomized, multicenter, triple-blind study was conducted on 76 AML patients aged 18–70, who received either placebo or atorvastatin in addition to fluconazole. Patients were followed for 30 days in case of developing IFIs, patient survival, and atorvastatin- related adverse drug reactions. Data were analyzed with SPSS version 26.0. A level of significance of 0.05 was utilized as the threshold for all statistical tests. The data were analyzed by adjusting for the effect of age, regarding that there was a significant difference between the two groups, and showed that atorvastatin reduced the development of both probable and proven IFI (based on EORTC/MSGERC criteria) compared to placebo. IFI-free survival was also significantly better in the atorvastatin group. The incidence of developing aspergillosis did not differ between the two groups. No serious adverse events related to atorvastatin were observed. The present investigation has substantiated the antecedent in vitro and animal research on the fungicidal impact of statins and has suggested the need for additional research involving larger sample sizes and an extended duration of follow-up. Trial registration: This study was registered on the Iranian registry of clinical trials as IRCT20210503051166N1 (Date of confirmation 2021.05.03). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) significantly increases mortality in critically ill patients in the ICU and its occurrence is closely related to immunocompromise. Dissemination of IA is easily misdiagnosed and mistreated due to its ability to invade multiple systems throughout the body and lack of typical clinical manifestations. In this case, a 25-year-old previously healthy woman was hospitalized with fulminant myocarditis and treated with veno-arterial extracorporeal membrane pulmonary oxygenation (VA-ECMO) support and intravenous acyclovir, high-dose methylprednisolone, and immunoglobulin. 6 days later, she was successfully weaned from VA-ECMO and underwent cardiac rehabilitation. On day 10, she developed a fever (Tmax 38.3°C) and an irritating cough and began to experience reduced vision over the right eye with eye pain, redness, photophobia, and tearing 2 days later. Administration of levofloxacin eye drops and tobramycin/dexamethasone eye ointment was ineffective. The patient was positive for serum Aspergillus galactomannan antigen. Positron emission tomography/computed tomography (PET/CT) scan showed multiple hypermetabolic cavitary nodules in both lungs (SUVmax3.6) and thickening of the ocular ring wall with hypermetabolism in the right eye (SUVmax3.2). Ophthalmologic examination revealed that her best-corrected visual acuity in the right eye was reduced to light perception with an intraocular pressure of 21 mmHg, and B-scan ultrasonography showed vitreous opacity and retinal edema with mild detachment in the right eye. Metagenomic next-generation sequencing (mNGS) identified a large number of Aspergillus fumigatus sequences in bronchoalveolar lavage fluid, blood, and aqueous humor from the right eye, supporting the diagnosis of pulmonary and ocular involvement due to disseminated IA. Vitrectomy, anterior chamber irrigation, combined with intravenous and intravitreal injections of voriconazole and liposomal amphotericin B eventually cured the patient. This case highlights the importance of early identification and intervention regarding disseminated IA in immunocompromised critically ill patients, especially in the presence of multiple organ involvement.

Immunocompromised patients in the hematology department are usually hospitalized in areas protected by the high-efficiency particulate air (HEPA) filtration system. Renovations may require moving these patients at risk for invasive fungal infection to areas without HEPA. Mobile air handling units may be a solution in these cases. For renovation purposes, we evaluated the efficiency of mobile air handling units called Plasmair® as well as their optimization, by comparing two generations of devices.Particle counts were performed to determine a particle cleanliness classification according to the ISO 14644–1 standard (high ISO classes correspond to a degraded particulate cleanliness). Mycological air samples were also taken to determine the percentage of positive samples and the median number of filamentous fungi colonies.Without air treatment, only 18 % (38/216) of particle counts were classified as ISO 6. With the use of mobile air treatment units, this proportion increased to 71 % (205/288). The positivity rate of mycological samples without air treatment was 86 % (31/36) with a median number of fungal colonies of 3 (1–5)/0.5m3. A significant decrease in fungal pressure was observed when using Plasmair®. Percentages of positive air samples and the median number of colonies found between the old generation Plasmair® (T2006) and the new generation Plasmair® (Guardian) were significantly different, respectively 55.6 % (20/36) versus 22.2 % (8/36) and 1(0–1) versus 0 (0–0).Finally, we confirm Plasmair® were effective in reducing airborne fungal pressure, the new generation especially. However, they were not effective enough to obtain negative mycological air samples as usually observed with the HEPA system, whatever the generation.

Xue Ting Tan, Nurin Nazirah Binti Mokhtar, Shirley Yi Fen Hii, Fairuz Amran Bacteriology Unit, Infectious Diseases Research Centre, Institute for Medical Research, National Institute of Health, Ministry of Health Malaysia, Setia Alam, Selangor, MalaysiaCorrespondence: Xue Ting Tan, Bacteriology unit, Infectious Diseases Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, No. 1, Jalan Setia Murni U13/52 Seksyen U13, Setia Alam, 40170, Selangor, Malaysia, Email tanxt@moh.gov.myPurpose: Azole resistance in Aspergillus fumigatus poses a significant challenge in the management of invasive aspergillosis. This study aimed to investigate the antifungal susceptibility and cyp51A mutation profiles of A. fumigatus isolates in Malaysia.Patients and Methods: Sixty clinical A. fumigatus isolates were collected and subjected to antifungal susceptibility testing (AFST) and molecular analysis. The antifungal susceptibility testing was performed according to CLSI M38 guideline. The geometric mean (GM) minimum inhibitory concentration (MIC), MIC50/MIC90 for voriconazole, itraconazole, posaconazole, amphotericin B, and isavuconazole against A. fumigatus in non-invasive cases and invasive cases were calculated. In addition, the presence of cyp51A mutations was also identified.Results: The present study revealed an overall resistance rate of 6.7% among the isolates. In non-invasive cases, isavuconazole and posaconazole demonstrated the lowest GM MIC of 0.08 μg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.15μg/mL, 0.16μg/mL and 0.90μg/mL, respectively. Similarly, in invasive cases, isavuconazole and posaconazole exhibited the lowest GM MIC of 0.09μg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.14μg/mL, 0.17μg/mL and 0.80μg/mL, respectively. Genotypic analysis revealed various cyp51A mutations, including F46Y, M172V, N248K, R34L, V244A, V244S, and E427K. However, not all mutations corresponded to antifungal resistance.Conclusion: The majority of clinical Aspergillus fumigatus isolates demonstrated susceptibility to the antifungal agents tested, with isavuconazole and posaconazole demonstrating the lowest MIC values. However, cyp51A mutations were discovered without a consistent correlation to antifungal resistance, emphasising the need for additional research.Keywords: invasive aspergillosis, minimum inhibitory concentration, voriconazole, isavuconazole, posaconazole

Background Limited data exist on when and how to stop antifungal treatment (AFT) in patients with invasive mold infections (IMIs) who are immunocompromised. Methods This retrospective multicenter study included adult patients with acute myelogenous leukemia and proven/probable IMI (1 January 2010–31 December 2022) in 3 university hospitals. The primary objective was to describe AFT duration and adaptation. Secondary objectives were to investigate the reasons for AFT adjustments and prolongation. Results In total 71 patients with 73 IMIs were identified; 51 (71.8%) had an allogeneic hematopoietic cell transplant. Most infections were invasive aspergillosis (IA; 49/71, 69%), followed by mucormycosis (12, 16.9%) and other (12, 16.9%); there were 2 mixed infections. Median treatment duration was 227 days (IQR, 115.5–348.5). There was no difference in AFT duration between patients with IA and non-IA IMI (P =.85) or by center (P =.92). Treatment was longer in patients with an allogeneic hematopoietic cell transplant vs not (P =.004). Sixteen patients (22.5%) had no therapy modifications. In 55 patients (77.5%), a median 2 changes (IQR, 1–3; range, 1–8) were observed. There were 182 reasons leading to 165 changes, associated with clinical efficacy (82/182, 44.5%), toxicity (47, 25.8%), and logistical reasons (22, 12.1%); no reason was documented in 32 changes (18.8%). AFT was continued beyond days 90 and 180 in 59 (83%) and 39 (54.9%) patients, respectively, mostly due to persistence of immunosuppression. Conclusions AFT in patients with acute myelogenous leukemia and IMI is longer than that recommended by guidelines and is frequently associated with treatment adjustments due to variable reasons. More data and better guidance are required to optimize AFT duration and secondary prophylaxis administration according to immunosuppression. [ABSTRACT FROM AUTHOR]

Aspergillosis is a fungal infection caused by various species of Aspergillus, most notably A. fumigatus. This fungus causes a spectrum of diseases, including allergic bronchopulmonary aspergillosis, aspergilloma, chronic pulmonary aspergillosis, and invasive aspergillosis. The clinical manifestations and severity of aspergillosis can vary depending on individual immune status and the specific species of Aspergillus involved. The recognition of Aspergillus involves pathogen-associated molecular patterns (PAMPs) such as glucan, galactomannan, mannose, and conidial surface proteins. These are recognized by the pathogen recognition receptors present on immune cells such as Toll-like receptors (TLR-1,2,3,4, etc.) and C-type lectins (Dectin-1 and Dectin-2). We discuss the roles of cytokines and pathogen recognition in aspergillosis from both the perspective of human and experimental infection. Several cytokines and chemokines have been implicated in the immune response to Aspergillus infection, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), CCR4, CCR17, and other interleukins. For example, allergic bronchopulmonary aspergillosis (ABPA) is characterized by Th2 and Th9 cell-type immunity and involves interleukin (IL)-4, IL-5, IL-13, and IL-10. In contrast, it has been observed that invasive aspergillosis involves Th1 and Th17 cell-type immunity via IFN-γ, IL-1, IL-6, and IL-17. These cytokines activate various immune cells and stimulate the production of other immune molecules, such as antimicrobial peptides and reactive oxygen species, which aid in the clearance of the fungal pathogen. Moreover, they help to initiate and coordinate the immune response, recruit immune cells to the site of infection, and promote clearance of the fungus. Insight into the host response from both human and animal studies may aid in understanding the immune response in aspergillosis, possibly leading to harnessing the power of cytokines or cytokine (receptor) antagonists and transforming them into precise immunotherapeutic strategies. This could advance personalized medicine. [ABSTRACT FROM AUTHOR]

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Invasive fungal diseases pose a significant threat to non-neutropenic ICU patients, with Candida and Aspergillus infections being the most common. However, diagnosing these infections in the ICU population remains challenging due to overlapping clinical features, poor sensitivity of blood cultures, and invasive sampling requirements. The classical host criteria for defining invasive fungal disease do not fully apply to ICU patients, leading to missed or delayed diagnoses. Recent advancements have improved our understanding of invasive fungal diseases, leading to revised definitions and diagnostic criteria. However, the diagnostic difficulties in ICU patients remain unresolved, highlighting the need for further research and evidence generation. Invasive candidiasis is themost prevalent form of invasive fungal disease in non-neutropenic ICU patients, presenting as candidemia and deep-seated candidiasis. Diagnosis relies on positive blood cultures or histopathology, while non-culture-based techniques such as beta-D-glucan assay and PCR-based tests show promise. Invasive aspergillosis predominantly manifests as invasive pulmonary aspergillosis in ICU patients, often associated with comorbidities and respiratory deterioration in viral pneumonia. Diagnosis remains challenging due to poor sensitivity of blood cultures and difficulties in performing lung biopsies. Various diagnostic criteria have been proposed, including mycological evidence, clinical/radiological factors and expanded list of host factors. Non-culture-based techniques such as galactomannan assay and PCRbased tests can aid in diagnosis. Antifungal management involves tailored therapy based on guidelines and individual patient factors. The complexity of diagnosing and managing invasive fungal diseases in ICU patients underscore the importance of ongoing research and the need for updated diagnostic criteria and treatment approaches. Invasive fungal disease, Invasive fungal infection, Invasive candidiasis, Invasive aspergillosis, Antifungal drugs. [ABSTRACT FROM AUTHOR]

The challenge of discriminating closely related species persists, notably within clinical diagnostic laboratories for invasive aspergillosis (IA)-related species and food contamination microorganisms with toxin-producing potential. We employed Analysis of the whole-GEnome (AGE) to address the challenges of closely related species within the genus Aspergillus and developed a rapid detection method. First, reliable whole genome data for 77 Aspergillus species were downloaded from the database, and through bioinformatic analysis, specific targets for each species were identified. Subsequently, sequencing was employed to validate these specific targets. Additionally, we developed an on-site detectionmethod targeting a specific target using a genome editing system. Our results indicate that AGE has successfully achieved reliable identification of all IA-related species (Aspergillus fumigatus, Aspergillus niger, Aspergillus nidulans, Aspergillus flavus, and Aspergillus terreus) and three well-known species (A. flavus, Aspergillus parasiticus, and Aspergillus oryzae) within the Aspergillus section. Flavi and AGE have provided species-level-specific targets for 77 species within the genus Aspergillus. Based on these reference targets, the sequencing results targeting specific targets substantiate the efficacy of distinguishing the focal species from its closely related species. Notably, the amalgamation of room-temperature amplification and genome editing techniques demonstrates the capacity for rapid and accurate identification of genomic DNA samples at a concentration as low as 0.1 ng/µl within a concise 30-min timeframe. Importantly, this methodology circumvents the reliance on large specialized instrumentation by presenting a singular tube operational modality and allowing for visualized result assessment. These advancements aptly meet the exigencies of on-site detection requirements for the specified species, facilitating prompt diagnosis and food quality monitoring. Moreover, as an identification method based on species-specific genomic sequences, AGE shows promising potential as an effective tool for epidemiological research and species classification. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) is the most severe type of Aspergillus infection. Yunnan has developed agriculture, and the proportion of triazole-resistant A. fumigatus induced by triazole fungicides is much higher than that in other regions of China. Inhalation of triazole-resistant A. fumigatus is one of the main factors inducing IA. We gathered five strains of A. fumigatus from the sputum or bronchoalveolar lavage fluid (BALF) of patients with IA in Yunnan. Subsequent testing showed that all of these strains were resistant to triazoles and harboured mutations in the tandem repeat sequence of the cyp51A promoter region, suggesting that they may be triazole-resistant A. fumigatus present in the environment. [ABSTRACT FROM AUTHOR]

Background: Efficient diagnosis of patients at high risk for invasive aspergillosis (IA) improves the outcome of the disease. Lateral flow assay (LFA) is a novel technology and assessing its diagnostic accuracy is of great significance in the clinical management of IA. Methods: A meta-analysis using case-control studies was performed to assess the diagnostic performance of LFA alone or galactomannan (GM) combined with LFA (GM-LFA) as screening tests for IA. The sensitivity, specificity, and summary receiver operating characteristic curves were constructed. Results: Nineteen studies with 2838 patients were included. The pooled effect sizes for different indicators included: sensitivity (77 % for LFA and 75 % for GM-LFA), specificity (88 % for LFA and 87 % for GM-LFA), positive likelihood ratio (6.65 for LFA and 12.02 for GM-LFA), negative likelihood ratio (0.26 for LFA and 0.27 for GM-LFA), and the diagnostic odds ratio (25.81 for LFA and 44.87 for GM-LFA). The area under the curve was 0.91 for LFA and 0.94 for GM-LFA with a cut-off value ≥ 0.5. Conclusion: The present meta-analysis suggested that LFA or GM-LFA at an optical density index (ODI) cutoff of ≥0.5 was a useful diagnostic tool for IA in patients. The results showed no significant differences in the accuracy of LFA alone and GM-LFA in diagnosing IA. In the clinical diagnosis and treatment of IA, LFA can be recommended if timely results are needed.

Background: During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection. Methods: We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants. Results: Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects. Conclusion: Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections.

Anna Basok,1 Elvira Romanjuk,1 Boris Rogachev,1 Yosef Shmuel Haviv,1 Ruth Shaco Halevy,2 Marina Vorobiov1 1Nephrology Department, Ben Gurion University Medical Center, Beer Sheva, Israel; 2Pathology Department, Ben Gurion University Medical Center, Beer Sheva, IsraelCorrespondence: Anna Basok, Nephrology Department, Ben Gurion University Medical Center, Uchmanit 13, Beer-Sheva, 8485283, Israel, Email basok@bgu.ac.ilAbstract: We described an extraordinary case of invasive aspergillosis (IA) after commercial kidney transplantation. Massive infestation by angiotrophic fungi with morphological features of Aspergillus caused fungal arteritis of renal blood vessels with detachment of the kidney graft from the iliac artery with ipsilateral leg ischemia, necessitating graft removal and recurrent vascular surgery to restore the blood supply to the leg. A literature review comprising various features of invasive aspergillosis and ethical aspects of commercial kidney transplantations is elucidated in this paper.Keywords: invasive aspergillosis, IA, transplant tourism, TT, galactomannan

Invasive fungal infections (IFIs) are a serious threat to patients with hematological diseases. These infections are characterized by high mortality and lead to significant financial costs for treatment. The most common pathogens of IFIs are Aspergillus spp. and Candida spp., but in recent years, cases of infections caused by rare pathogens have become more frequent. Diagnosis of IFIs and choice of treatment remain challenging due to the nonspecificity of symptoms and the diversity of clinical cases. In this regard, the problem of start time and choice of antifungal therapy remains of current interest. This review briefly describes diagnostic criteria, challenges associated with IFIs diagnosing, provides evidence for empiric and preventive strategies as two early treatment approaches, and examines the impact of therapy initiation on patient outcomes. Treatment of IFIs in hematologic patients should be individualized. At the same time, early administration of therapy with broad-spectrum drugs for febrile neutropenia and parallel diagnostic measures can improve treatment outcomes. There is a lack of current data on the benefits of specific treatment strategies, highlighting the need for further research.

Invasive aspergillosis (IA) is the most severe type of Aspergillus infection. Yunnan has developed agriculture, and the proportion of triazole-resistant A. fumigatus induced by triazole fungicides is much higher than that in other regions of China. Inhalation of triazole-resistant A. fumigatus is one of the main factors inducing IA. We gathered five strains of A. fumigatus from the sputum or bronchoalveolar lavage fluid (BALF) of patients with IA in Yunnan. Subsequent testing showed that all of these strains were resistant to triazoles and harboured mutations in the tandem repeat sequence of the cyp51A promoter region, suggesting that they may be triazole-resistant A. fumigatus present in the environment.

Background: Invasive aspergillosis (IA) is a significant cause of morbidity and mortality in patients with haematological malignancies. Accurate diagnosis of IA is challenging due to non-specific symptoms and the impact of antifungal prophylaxis on biomarker sensitivity. Methods: This retrospective study evaluated the diagnostic performance of three serum biomarkers: Aspergillus Galactomannan Ag VirClia Monotest® (VirClia), Wako β-D-Glucan Test® (Wako BDG), and MycoGENIE Real-Time PCR® (MycoGENIE PCR). True positives were defined as patients with proven or probable IA (n = 14), with a positive Platelia Aspergillus Antigen® (Platelia) serving as a mycological criterion. True negatives were identified as patients with a positive Platelia assay but classified as non-probable IA (n = 10) and outpatients who consistently tested negative with the Platelia test throughout the study period (n = 20). Results: Most patients diagnosed with proven or probable IA were acute myeloid leukaemia or myelodysplastic syndrome patients receiving mould-active antifungal prophylaxis or treatment (71%). VirClia demonstrated high sensitivity (100%) for detecting IA, with a specificity of 83%. Wako BDG and MycoGENIE PCR showed lower sensitivities for IA (57% and 64%, respectively). MycoGENIE PCR detected Aspergillus spp. and Mucorales in two patients. Conclusions: Accurate diagnosis of IA remains challenging, especially in patients who have received mould-active antifungal treatment. VirClia showed comparable performance to Platelia, suggesting its potential for routine use. However, Wako BDG and MycoGENIE PCR results were less favourable in our study cohort. Nevertheless, MycoGENIE PCR detected two probable co-infections with Aspergillus spp. and Mucorales.

As microbiological tests play an important role in our diagnostic algorithms and clinical approach towards patients at-risk for pulmonary aspergillosis, a good knowledge of the diagnostic possibilities and especially their limitations is extremely important. In this review, we aim to reflect critically on the available microbiological diagnostic modalities for diagnosis of pulmonary aspergillosis and formulate some future prospects. Timely start of adequate antifungal treatment leads to a better patient outcome, but overuse of antifungals should be avoided. Current diagnostic possibilities are expanding, and are mainly driven by enzyme immunoassays and lateral flow device tests for the detection of Aspergillus antigens. Most of these tests are directed towards similar antigens, but new antibodies towards different targets are under development. For chronic forms of pulmonary aspergillosis, anti- Aspergillus IgG antibodies and precipitins remain the cornerstone. More studies on the possibilities and limitations of molecular testing including targeting resistance markers are ongoing. Also, metagenomic next-generation sequencing is expanding our future possibilities. It remains important to combine different test results and interpret them in the appropriate clinical context to improve performance. Test performances may differ according to the patient population and test results may be influenced by timing, the tested matrix, and prophylactic and empiric antifungal therapy. Despite the increasing armamentarium, a simple blood or urine test for the diagnosis of aspergillosis in all patient populations at-risk is still lacking. Research on diagnostic tools is broadening from a pathogen focus on biomarkers related to the patient and its immune system. [ABSTRACT FROM AUTHOR]

The purpose of this study was to prospectively investigate the incidence of influenza-associated pulmonary aspergillosis (IAPA) in influenza patients admitted to intensive care units in Sweden. The study included consecutive adult patients with PCR-verified influenza A or B in 12 Swedish intensive care units (ICUs) over four influenza seasons (2019-2023). Patients were screened using serum galactomannan and β-d-glucan tests and fungal culture of a respiratory sample at inclusion and weekly during the ICU stay. Bronchoalveolar lavage was performed if clinically feasible. IAPA was classified according to recently proposed case definitions. The cohort included 55 patients; 42% were female, and the median age was 59 (IQR 48-71) years. All patients had at least one galactomannan test, β-d-glucan test and respiratory culture performed. Bronchoalveolar lavage was performed in 24 (44%) of the patients. Five (9%, 95% CI 3.8% − 20.4%) patients were classified as probable IAPA, of which four lacked classical risk factors. The overall ICU mortality was significantly higher among IAPA patients than non-IAPA patients (60% vs 8%, p = 0.01). The study represents the first prospective investigation of IAPA incidence. The 9% incidence of IAPA confirms the increased risk of invasive pulmonary aspergillosis among influenza patients admitted to the ICU. Therefore, it appears reasonable to implement a screening protocol for the early diagnosis and treatment of IAPA in influenza patients receiving intensive care. ClinicalTrials.gov NCT04172610, registered November 21, 2019 [ABSTRACT FROM AUTHOR]

Aspergillus fumigatus can cause different clinical manifestations/phenotypes in lung transplant (LTx) recipients and patients with chronic respiratory diseases. It can also precipitate chronic lung allograft dysfunction (CLAD) in LTx recipients. Many host factors have been linked with the severity of A. fumigatus infection, but little is known about the contribution of different A. fumigatus strains to the development of different phenotypes and CLAD. We used multi-locus microsatellite typing (MLMT) to determine if there is a relationship between strain (i.e., genotype) and phenotype in 60 patients post LTx or with chronic respiratory disease across two time periods (1 November 2006–31 March 2009 and 1 November 2015–30 June 2017). The MLMT (STRAf) assay was highly discriminatory (Simpson's diversity index of 0.9819–0.9942) with no dominant strain detected. No specific genotype–phenotype link was detected, but several clusters and related strains were associated with invasive aspergillosis (IA) and colonisation in the absence of CLAD. Host factors were linked to clinical phenotypes, with prior lymphopenia significantly more common in IA cases as compared with A. fumigatus-colonised patients (12/16 [75%] vs. 13/36 [36.1%]; p = 0.01), and prior Staphylococcus aureus infection was a significant risk factor for the development of IA (odds ratio 13.8; 95% confidence interval [2.01–279.23]). A trend toward a greater incidence of CMV reactivation post-A. fumigatus isolation was observed (0 vs. 5; p = 0.06) in LTx recipients. Further research is required to determine the pathogenicity and immunogenicity of specific A. fumigatus strains. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this multicenter study was to compare the diagnostic performance of lateral flow assay (LFA) and enzyme-linked immunosorbent assay (ELISA) to detect the Dynamiker Aspergillus Galactomannan levels in serum and bronchoalveolar lavage fluid (BALF) samples for I. Methods: We registered 310 clinically suspected Aspergillus infection patients from December 2021 to February 2023 and classified them into subgroups as the "IA group" and "non-IA group" based on the latest EORTC/MSG guidelines. The immunoassays were analyzed by LFA and ELISA respectively. Results: Galactomannan was examined using LFA, and serum and BALF samples demonstrated sensitivities of 82.57% and 89.47%, specificities of 90.76% and 92.00%, PPVs of 89.11% and 96.23%, and NPVs of 85.04% and 79.31%, respectively. Galactomannan was observed using two assays in serum and BALF samples and showed PPAs of 95.11% and 93.33%, NPAs of 89.19% and 96.30%, and TPAs of 92.47% and 94.25%, respectively. The ROC curve demonstrated that LFA had optimum diagnostic value when the index value (I value) = 0.5, the sensitivity was 84.94%, and the specificity was 90.97%. Conclusion: Compared to the ELISA method, the LFA has shown excellent performance for the diagnosis of IA in serum and BALF sample and can be used as an assay for the early diagnosis of patients with IA. The dynamic change in galactomannan levels may be useful for assessing treatment response. [ABSTRACT FROM AUTHOR]

Background Immunocompromised patients now represent the population most at risk for severe coronavirus disease 2019. Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral shedding was reported in these patients ranging from several weeks up to 9 months. We conducted a bicentric retrospective case-control study to identify risk and prognostic factors associated with persistent viral shedding in immunocompromised patients. Material and Methods Symptomatic immunocompromised adults with persistent SARS-CoV-2 viral shedding >8 weeks were retrospectively included between 1 March 2020 and 24 April 2022 at 2 university hospitals in Paris, France, and matched with a control group consisting of symptomatic immunocompromised patients without persistent viral shedding. Results Twenty-nine immunocompromised patients with persistent viral shedding were compared with 40 controls. In multivariate analysis, fever and lymphocytopenia (<0.5 G/L) were associated with an increased risk of persistent viral shedding (odds ratio [OR]: 3.3; 95% confidence interval [CI], 1.01–11.09) P =.048 and OR: 4.3; 95% CI, 1.2–14.7; P =.019, respectively). Unvaccinated patients had a 6-fold increased risk of persistent viral shedding (OR, 6.6; 95% CI, 1.7–25.1; P =.006). Patients with persistent viral shedding were at risk of hospitalization (OR: 4.8; 95 CI, 1.5–15.6; P =.008), invasive aspergillosis (OR: 10.17; 95 CI, 1.15–89.8; P =.037) and death (log-rank test <0.01). Conclusions Vaccine coverage was protective against SARS-CoV-2 persistent viral shedding in immunocompromised patients. This new group of immunocompromised patients with SARS-CoV-2 persistent viral shedding is at risk of developing invasive aspergillosis and death and should therefore be systematically screened for this fungal infection for as long as the viral shedding persists. [ABSTRACT FROM AUTHOR]

There is increasing recognition that respiratory viral infections such as influenza, respiratory syncytial virus, parainfluenza virus, adenovirus, and SARS‐CoV‐2 can promote the development of invasive fungal pulmonary coinfections, particularly invasive aspergillosis, both in immunocompetent and immunocompromised patients. To date, there are no case reports exploring the role of human metapneumovirus as a risk factor for fungal coinfection. Below, we describe the case of a 63‐year‐old woman who received a kidney transplant and developed invasive pulmonary aspergillosis after a human metapneumovirus infection and discuss the possible phenomena that could favor this association [ABSTRACT FROM AUTHOR]