Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review.

BACKGROUND: Primary antifungal prophylaxis with mold-active azoles is used to prevent invasive fungal infections in patients with high-risk hematological disorders; however, breakthrough infections occur, and the reasons for treatment failure are still not fully understood. To help inform clinical decisions, we sought to define microbiological, clinical, and pharmacological characteristics of proven and probable breakthrough invasive fungal infections (bIFIs) in patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis. METHODS: We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was last conducted on 19 April 2023. RESULTS: We assessed 5293 studies for eligibility, and 300 were selected for data extraction. These studies described 1076 cases of bIFIs occurring under voriconazole (42.5%) or posaconazole (57.5%). The most commonly found pathogens were Aspergillus (40%), Mucorales (20%), Candida (18%), and Fusarium (9%) species. Mucorales were more frequent among voriconazole-emerging cases, whereas Aspergillus and Fusarium were more prevalent among posaconazole-emerging cases. Definitive, putative, or probable antifungal resistance was found in 31% of cases. Therapeutic drug monitoring showed subtherapeutic azole concentration in 32 of 90 (36%) cases. Infection-related mortality was reported in 117 cases and reached 35%. CONCLUSIONS: In our systemic review, the most common bIFIs were aspergillosis, mucormycosis, candidiasis, and fusariosis. Antifungal resistance explains only a minority of cases. Subtherapeutic prophylaxis was frequent but rarely reported. Prospective studies are needed to better understand these infections and to establish optimal management.

Rhizopus arrhizus infection in mice causes brain histopathological alterations and exacerbates neuronal apoptosis.

Rhizopus arrhizus is a fungus that can cause central nervous system infections in animals, resulting in high morbidity and mortality, but the mechanism of injury is rarely reported. In this study, we investigated the mechanism of Rhizopus arrhizus damage to the central nervous system of mice by observing the clinical neurological symptoms and resolving the pathological changes in the ultrastructure of brain tissues, combined with the alteration of apoptosis-related genes and immunohistochemistry (IHC). The results showed that all the mice in the treated group died, the brain pyknosis of neurons, there were black mycelium aggregates around the blood vessels, and apoptotic vesicles were produced. The RT-qPCR results showed that, compared with the control group, the relative transcriptome levels of Caspase 8 and BcL-2 genes were significantly increased (P < 0.05), the relative transcriptome level of Caspase 9 gene was highly significant (P < 0.01), the relative transcriptome level of Caspase 3 and Bax gene was significantly decreased (P < 0.05), and the ratio of Bcl-2/Bax was significantly increased (P < 0.05) in the brains of the treated group. TUNEL staining showed that the rate of neuronal apoptosis in the treated group of mice was extremely significantly higher than that in the control group (P < 0.01). This study shows that Rhizopus arrhizus strain XMLO1 causes brain damage by triggering neuronal apoptosis. This study provided a theoretical basis for revealing the mechanism of Rhizopus arrhizus infection.

Longitudinally extensive posterolateral myelitis revealing invasive CNS aspergillosis in an immunocompetent patient.

BACKGROUND: Fungal infections of the central nervous system usually affect immunocompromised patients. Primary Aspergillus myelitis has never been described. REPORT: A 45-year-old immunocompetent male with subacute paraplegia was treated for inflammatory myelitis before clinical deterioration requiring mechanical ventilation. Purulent meningitis preceded the formation of a paraspinal nodule biopsied by neurosurgery. Histopathological analysis revealed the presence of fungal hyphae, and polymerase chain reaction was positive for Aspergillus fumigatus. No cause of immunodeficiency was identified in this patient. DISCUSSION: Primary Aspergillus myelitis may be confused with inflammatory myelitis and should be considered even in the absence of apparent immunosuppression.

Surgical treatment of invasive fungal infection in pediatric oncology.

BACKGROUND: Invasive fungal disease (IFD) is typically aggressive and related with high mortality in children with a hematological malignancy. The association of medical and surgical treatment may ameliorate the outcome. The aim of this study was to analyze the surgical treatment of fungal infections in pediatric oncological populations. METHODS: Retrospective study (2000-2022) of a single-center experience. We reviewed the medical record of all patients with hematologic malignancies and IFD, analyzing the outcome. RESULTS: From the 70 pediatric cases of hematologic malignancies with the diagnosis IFD over 22 years, we included in the present study 44 cases who required surgical approaches for either diagnosis or treatment. Twenty-one patients were males and the mean age was 11 (range 1-23) years. The main indications for surgery were lack of improvement following medical treatment and/or progression of fungal infection (80%) and diagnosis confirmation (20%). Only five patients needed an emergency operation for rapid worsening of symptoms. The most common site of infection was the lung (80%) and the most frequently identified pathogen was Aspergillus (75%). The most common surgical procedures were lobectomy (performed in 17 patients) and atypical lung resection (10). Complications of surgery were mostly treated by medical approach. The mean time of resumption of oncological treatment was 40 (range 0-150) days. CONCLUSIONS: Surgery is an important step in the multimodal treatment of invasive fungal infection with excellent resolution rate. Overall mortality depends on the underlying malignancy.

Increase in the incidence of invasive fungal infections due to Volvariella Volvacea.

PURPOSE: We aimed to show the increasing incidence of invasive fungal infections due to Volvariella Volvacea in patients with immunosuppression. METHODS: We present a case of an invasive fungal infection caused by Volvariella volvacea, and summarize the clinical and pathological features based on this case and a review of the literature. RESULTS: A total of seven patients with IFIs due to Volvariella Volvacea have been reported in the literature. The majority of cases have been obtained between 2019 and 2022. Including our case, they all had acquired immunosuppression. The lung and brain were the most commonly affected organs. All eight of these patients received antifungal therapy, but five still died one to seven months after occurrences of IFIs. CONCLUSION: The incidence of invasive fungal infections due to Volvariella Volvacea is increasing in recent years. It mainly occurred in patients with immunosuppression, especially in patients with malignant hematological cancers, and increased mortality.

Revealing the hidden interplay: The unexplored relationship between fungi and viruses beyond HIV, SARS-CoV-2, and influenza.

The complex interaction between viruses and fungi has profound implications, especially given the significant impact of these microorganisms on human health. While well-known examples such as HIV, influenza, and SARS-CoV-2 are recognized as risk factors for invasive fungal diseases, the relationship between viruses and fungi remains largely underexplored outside of these cases. Fungi and viruses can engage in symbiotic or synergistic interactions. Remarkably, some viruses, known as mycoviruses, can directly infect fungi, may influencing their phenotype and potentially their virulence. In addition, viruses and fungi can coexist within the human microbiome, a complex ecosystem of microorganisms. Under certain conditions, viral infection might predispose the host to an invasive fungal infection, as observed with influenza-associated pulmonary aspergillosis or COVID-19 associated pulmonary aspergillosis. We aim in this review to highlight potential connections between fungi and viruses (CMV and other herpesviruses, HTLV-1 and respiratory viruses), excluding SARS-CoV-2 and influenza.

The link between invasive fungal diseases and certain viruses (HIV, SARS-CoV-2 and influenza) is now well established. For other viruses, however, the relationship remains uncertain. In this review, we aim to highlight associations between fungi and viruses, except HIV, SARS-CoV-2 and influenza.

Candida auris: Understanding the dynamics of C. auris infection versus colonization.

Candida auris is a pathogen of growing public health concern worldwide. However, risk factors contributing to C. auris infection in patients colonized with C. auris remain unclear. Understanding these risk factors is crucial to prevent colonization-to-infection transition and devise effective preventive strategies. This study aimed to investigate risk factors associated with C. auris infection compared to colonization. The study included 97 patients who acquired laboratory-confirmed C. auris in either matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry or VITEK 2 system from October 2019 to June 2023. Baseline demographics and known risk factors associated with C. auris infection were collected from electronic medical records. The infection group had C. auris from a sterile site, or non-sterile site with evidence of infection. The colonization group were followed up for a median of 30 days for any signs of infection. Associations between relevant variables and C. auris infection were assessed using multivariable logistic regression. The infection group (n=31) was more likely to be bedbound, with longer hospital stays and more arterial catheters. Chronic kidney disease (odds ratio [OR] 45.070), carriage of multidrug-resistant organisms (OR 64.612), and vasopressor use more than 20 days (OR 68.994) were associated with C. auris infection, after adjusting for sex, age, and prior colonization with C. auris. Chronic kidney disease, carriage of multidrug-resistant organisms, and prolonged vasopressor use emerged as significant risk factors for C. auris infection compared to colonization. They could be used to predict C. auris infection early in patients colonized with C. auris.

Identifying risk factors for Candida auris infection should be an essential component of care in patients colonized with C. auris. Chronic kidney disease, carriage of multidrug-resistant organisms, and prolonged vasopressor use emerged as significant risk factors for C. auris infection.

Mycology laboratory diagnostic capacity for invasive fungal diseases in public hospitals in Vietnam.

This was a cross-sectional study on the availability of laboratory infrastructure and capacity for the diagnosis of invasive fungal diseases in 24 public hospitals in Vietnam in 2023. Among the hospitals surveyed, 66.7% (14/21) had specialized personnel assigned for mycology testing, and 95.8% (23/24) had a separate microbiology laboratory space. Microscopy and culture methods are available in nearly all laboratories for isolate identification. Antifungal susceptibility testing is only performed for yeasts in 16/24 (66.7%) laboratories. Non-culture methods are hardly used in laboratories. Strengthening local laboratory capacities is essential to meeting health needs in these endemic regions.

There was a need for investment in fungal diagnostics to improve health services in the settings with a burden of endemic fungal infections.

Diagnostic performance of the (1-3)-ß-d-glucan assay in patients with different risks for invasive fungal diseases.

We evaluated the diagnostic performance of the ß-d-glucan (BDG) test (Beijing Gold Mountain River Tech) in diagnosing invasive fungal disease (IFD) and its variations among patients with different risks. Patients ≥18 years old who underwent a serum BDG test (positive cutoff value >80 pg/ml) from April 2017 through May 2018 were collected consecutively. Patients were classified into three groups: group 1, patients with host factors as defined by the prior 2008 European Organization for Research and Treatment (EORTC) criteria; group 2, those with extended host factors in 2020 EORTC criteria; and group 3, those without any risk factor mentioned in the criteria. IFD was defined by 2020 EORTC criteria, but BDG was not considered. Diagnostic performance of the serum BDG test was measured by the area under the curve (AUC) of the receiver-operating characteristic curve. Among 469 patients, 15.4% (72/469) were diagnosed with IFD (48/191 [25.1%], 14/144 [9.7%], and 10/134 [7.5%] in groups 1, 2, and 3, respectively). The BDG assay showed fair performance (AUC 0.748 [95% CI: 0.688-0.810]). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 77.8%, 60.7%, 26.4%, and 93.8%, respectively. PPV was higher in group 1, and NPV was higher in group 3. Additionally, diagnostic odds ratios were 6.73, 2.88, and 5.92 in groups 1, 2, and 3. Immunosuppressant use, non-IFD/Candida colonization, and central venous catheter were associated with false positivity. Clinicians should cautiously interpret the BDG assay, considering the various diagnostic performances depending on the different levels of risk.

We evaluated the diagnostic performance of the serum ß-d-glucan test in patients with varying risks for invasive fungal diseases. The test showed acceptable performance, but its predictive values differed among risk groups, highlighting the need for tailored interpretation.

Application of cell-free DNA fungal polymerase chain reaction for invasive fungal disease evaluation in pediatric oncology and stem cell transplant patients.

BACKGROUND: Molecular diagnostics may enable early, noninvasive detection of invasive fungal disease (IFD) in immunocompromised patients. Cell-free deoxyribonucleic acid (cfDNA) fungal polymerase chain reaction (PCR) assays were recently incorporated into institutional prolonged febrile neutropenia pathways. We aimed to evaluate the performance of plasma cfDNA PCR panels (mold and Candida panels) in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients with clinical concern for IFD. METHODS: This single-center, observational study assessed plasma cfDNA fungal PCR performance for noninvasive IFD detection in hospitalized pediatric oncology and HSCT patients. The primary outcome was IFD diagnosis per published consensus definitions within 1 month. Positive and negative agreement between plasma cfDNA fungal PCR and consensus definitions were calculated. We also described test turnaround time and patient survival. RESULTS: From October 2021 to 2022, 54 patients underwent 60 evaluations with 11 proven/probable IFD cases. Comparing plasma cfDNA fungal PCRs to consensus definitions for proven/probable IFD, there was 73% positive agreement and 96% negative agreement. Two proven/probable cases with negative PCRs were caused by organisms not included on either panel. Median time to cfDNA fungal PCR result was 35 hours (interquartile range: 19-69) in eight proven/probable cases detected by cfDNA fungal PCR. There were 17 deaths among 54 patients, and IFD contributed to 45% of deaths in patients with proven/probable IFD. CONCLUSIONS: Plasma cfDNA fungal PCRs detected relevant molds or yeast in most cases classified as proven/probable IFD. However, this targeted approach missed some cases. More studies are required to determine optimal utilization of molecular diagnostics in pediatric patients.

Fatal co-infection by multiple pathogens in an indigenous woman with autoimmune hemolytic anemia and tuberculosis: a case report.

BACKGROUND: Tuberculosis (TB), one of the leading causes of death worldwide, has a higher incidence among indigenous people. Albeit uncommon, autoimmune hemolytic anemia (AIHA) has been deemed a risk condition to develop mycobacterial infection, as a result of the immunosuppressive treatments. TB, in turn, can be a predisposing factor for secondary infections. CASE PRESENTATION: Here we present a case of a 28-year-old indigenous woman from Colombia, previously diagnosed with AIHA and pulmonary TB. Despite various treatments, therapies and medical interventions, the patient died after severe medullary aplasia of multiple causes, including secondary myelotoxicity by immunosuppressive therapy and secondary disseminated infections, underlining infection by Staphylococcus aureus, Klebsiella pneumoniae and Candida glabrata, which were identified as drug-resistant microorganisms. Together, this led to significant clinical complications. Invasive aspergillosis was diagnosed at autopsy. CONCLUSIONS: This report presents a rarely finding of AIHA followed by TB, and highlights the great challenges of dealing with co-infections, particularly by drug resistant pathogens. It also aims to spur governments and public health authorities to focus attention in the prevention, screening and management of TB, especially among vulnerable communities, such as indigenous people.

Revision of antifungal strategies definitions for invasive fungal infections (proven/probable/possible) in 461 patients with haematological malignancies (REDEFI-SEIFEM).

BACKGROUND: Invasive fungal infections (IFI) are a relevant cause of morbidity and mortality among patients with haematological neoplasms (HMs). Since 2002, a classification of IFI based on host factors, clinical and radiological features and mycological tests was published for research purpose. OBJECTIVES: These criteria are widely used in clinical practice to identify patients at risk for IFI. The aim of the study was to evaluate the clinical applicability of EORTC/MSG 2008 criteria for the diagnosis of IFI in daily practice. PATIENTS/METHODS: This multicentre, non-interventional, observational, prospective study gathered all consecutive inpatients with HMs in which an intravenous antifungal treatment was started. Exclusion criteria were a previous or concomitant transplant procedure, outpatient status and oral antifungal therapy. EORTC/MSG 2008 criteria were used to classify patients at the beginning of antifungal therapy and at 30 days. An independent board reviewed the classification of IFI given by local clinicians at T0 and T30. RESULTS: The highest percentage of agreement was found for possible IFI (96%), while a lower agreement was reported for proven IFI (74%), and the highest variability was observed for probable IFI (56%). At T30, the board re-evaluation confirmed a strict agreement for possible IFI only (98%). Among 306 patients classified as possible, 156 (51%) patients showed non-typical radiological findings and 45 (15%) patients presented host factors only. CONCLUSIONS: In real life, the EORTC/MSG criteria can be applicable only for possible IFI. As non-typical radiological findings are reported in possible IFI, introducing a new IFI category should be considered.

A retrospective Italian analysis on the characteristics of invasive fungal infections in the intensive care unit setting: CHARTER-IFI study.

BACKGROUND: Invasive fungal infections (IFI), prevalent in critically ill ICU patients, have gained attention due to post-COVID-19 epidemiological shifts. Notably, COVID-19-associated aspergillosis and candidiasis pose significant risks. WHO recognises key fungal pathogens, emphasising the need for enhanced research and interventions. METHODS: The CHARTER-IFI study retrospectively examines 186,310 individuals admitted to ICUs in Italy from 01/01/2012-01/09/2023, utilising administrative databases covering around 10 million inhabitants. Adult patients were included having at least one ICU discharge diagnosis of IFI at their first IFI-related hospitalisation and having at least 12 months of available data prior to this hospitalisation. RESULTS: A total of 746 IFI patients discharged from ICU (incidence of 4.0 per 1000 ICU-hospitalised patients), were included. Median age was 68 years, 63% were males, and the overall Charlson Comorbidity Index was 2.2. The top three diagnoses were candidiasis (N = 501, 2.7/1000 ICU-hospitalised patients), aspergillosis (N = 71, 0.4/1000), and pneumocystosis (N = 55, 0.3/1000). The evaluation of the comorbidity profile in IFI patients revealed the presence of hypertension (60.5%), use of systemic GC/antibacterials (45.3% during 12 months before and 18.6% during 3 months before hospital admission), cancer (23.1%), diabetes (24.3%) and cardiovascular diseases (23.9%). The mean (±SD) length of hospitalisation in ICU was 19.9 ± 24.1 days (median 11 days), and deaths occurred in 36.1% of IFI patients (within 30 days from discharge). CONCLUSIONS: This retrospective analysis among ICU-hospitalised patients described the burden of IFI in ICU, and its understanding could be crucial to strengthen surveillance, investments in research, and public health interventions as required by WHO.

Circulatory Inflammatory Proteins as Early Diagnostic Biomarkers for Invasive Aspergillosis in Patients with Hematologic Malignancies-an Exploratory Study.

OBJECTIVES: Invasive aspergillosis (IA) is a major cause of mortality in immunocompromised patients and it is difficult to diagnose because of the lack of reliable highly sensitive diagnostics. We aimed to identify circulating immunological markers that could be useful for an early diagnosis of IA. METHODS: We collected longitudinally serum samples from 33 cases with probable/proven IA and two matched control cohorts without IA (one with microbiological and clinical evidence of bacterial or viral non-fungal pneumonia and one without evidence of infection, all matched for neutropenia, primary underlying disease, and receipt of corticosteroids/other immunosuppressants) at a tertiary university hospital. In addition, samples from an independent cohort (n = 20 cases of proven/probable IA and 20 matched controls without infection) were obtained. A panel of 92 circulating proteins involved in inflammation was measured by proximity extension assay. A random forest model was used to predict the development of IA using biomarkers measured before diagnosis. RESULTS: While no significant differences were observed between IA cases and infected controls, concentrations of 30 inflammatory biomarkers were different between cases and non-infected controls, of which nine were independently replicated: PD-L1, MMP-10, Interleukin(IL)-10, IL-15RA, IL-18, IL-18R1, CDCP1, CCL19 and IL-17C. From the differential abundance analysis of serum samples collected more than 10 days before diagnosis and at diagnosis, increased IL-17C concentrations in IA patients were replicated in the independent cohort. CONCLUSIONS: An increased circulating concentration of IL-17C was detected both in the discovery and independent cohort, both at the time of diagnosis and in samples 10 days before the diagnosis of IA, suggesting it should be evaluated further as potential (early) biomarker of infection.

Exploring European Consensus About the Remaining Treatment Challenges and Subsequent Opportunities to Improve the Management of Invasive Fungal Infection (IFI) in the Intensive Care Unit.

BACKGROUND: The global prevalence of invasive fungal infections (IFI) is increasing, particularly within Intensive Care Units (ICU), where Candida spp. and Aspergillus spp. represent the most important pathogens. Diagnosis and management of IFIs becomes progressively challenging, with increasing antifungal resistance and the emergence of rare fungal species. Through a consensus survey focused on assessing current views on how IFI should be managed, the aim of this project was to identify challenges around diagnosing and managing IFIs in the ICU. The current status in different countries and perceived challenges to date amongst a multidisciplinary cohort of healthcare professionals involved in the care of IFI in the ICU was assessed. METHODS: Using a modified Delphi approach, an expert panel developed 44 Likert-scale statements across 6 key domains concerning patient screening and minimal standards for diagnosis of IFIs in ICU; initiation and termination of antifungal treatments and how to minimise their side effects and insights for future research on this topic. These were used to develop an online survey which was distributed on a convenience sampling basis utilising the subscriber list held by an independent provider (M3 Global). This survey was distributed to intensivists, infectious disease specialists, microbiologists and antimicrobial/ICU pharmacists within the UK, Germany, Spain, France and Italy. The threshold for consensus was set at 75%. RESULTS: A total of 335 responses were received during the five-month collection period. From these, 29/44 (66%) statements attained very high agreement (≥ 90%), 11/44 (25%) high agreement (< 90% and ≥ 75%), and 4/44 (9%) did not meet threshold for consensus (< 75%). CONCLUSION: The results outline the need for physicians to be aware of the local incidence of IFI and the associated rate of azole resistance in their ICUs. Where high clinical suspicion exists, treatment should start immediately and prior to receiving the results from any diagnostic test. Beta-D-glucan testing should be available to all ICU centres, with results available within 48 h to inform the cessation of empirical antifungal therapy. These consensus statements and proposed measures may guide future areas for further research to optimise the management of IFIs in the ICU.

Broad Protection against Invasive Fungal Disease from a Nanobody Targeting the Active Site of Fungal ß-1,3-Glucanosyltransferases.

Invasive fungal disease accounts for about 3.8 million deaths annually, an unacceptable rate that urgently prompts the discovery of new knowledge-driven treatments. We report the use of camelid single-domain nanobodies (Nbs) against fungal ß-1,3-glucanosyltransferases (Gel) involved in ß-1,3-glucan transglycosylation. Crystal structures of two Nbs with Gel4 from Aspergillus fumigatus revealed binding to a dissimilar CBM43 domain and a highly conserved catalytic domain across fungal species, respectively. Anti-Gel4 active site Nb3 showed significant antifungal efficacy in vitro and in vivo prophylactically and therapeutically against different A. fumigatus and Cryptococcus neoformans isolates, reducing the fungal burden and disease severity, thus significantly improving immunocompromised animal survival. Notably, C. deneoformans (serotype D) strains were more susceptible to Nb3 and genetic Gel deletion than C. neoformans (serotype A) strains, indicating a key role for ß-1,3-glucan remodelling in C. deneoformans survival. These findings add new insight about the role of ß-1,3-glucan in fungal biology and demonstrate the potential of nanobodies in targeting fungal enzymes to combat invasive fungal diseases.

Isavuconazole for Treating Invasive Mould Disease in Solid Organ Transplant Recipients.

Solid organ transplant (SOT) recipients have a higher risk of developing invasive mould diseases (IMD). Isavuconazole is a novel broad-spectrum azole active against Aspergillus spp. and Mucor, well tolerated, with an excellent bioavailability and predictable pharmacokinetics, that penetrates in most tissues rapidly, and has few serious adverse effects, including hepatic toxicity. Contrary to other broad-spectrum azoles, such as voriconazole and posaconazole, isavuconazole appears to show significant smaller drug-drug interactions with anticalcineurin drugs. We have performed an extensive literature review of the experience with the use of isavuconazole in SOT, which included the SOTIS and the ISASOT studies, and published case reports. More than 140 SOT recipients treated with isavuconazole for IMD were included. Most patients were lung and kidney recipients treated for an Aspergillus infection. Isavuconazole was well tolerated (less than 10% of patients required treatment discontinuation). The clinical responses appeared comparable to that found in other high-risk patient populations. Drug-drug interactions with immunosuppressive agents were manageable after the reduction of tacrolimus and the adjustment of mTOR inhibitors at the beginning of treatment. In conclusion, isavuconazole appears to be a reasonable option for the treatment of IMD in SOT. More clinical studies are warranted.

Incidence and Mortality of COVID-19-Associated Invasive Fungal Infections Among Critically Ill Intubated Patients: A Multicenter Retrospective Cohort Analysis.

Background: An association between coronavirus disease 2019 (COVID-19)-associated invasive fungal infections (CAIFIs) and high mortality among intubated patients has been suggested in previous research. However, some of the current evidence was derived from small case series and multicenter studies conducted during different waves of the COVID-19 pandemic. We examined the incidence of CAIFIs and their associated mortality using a large, multicenter COVID-19 database built throughout the pandemic. Methods: We conducted a retrospective analysis of the National COVID Cohort Collaborative (N3C) database collected from 76 medical centers in the United States between January 2020 and August 2022. Patients were 18 years or older and intubated after severe acute respiratory syndrome coronavirus 2 infection. The primary outcomes were incidence and all-cause mortality at 90 days. To assess all-cause mortality, we fitted Cox proportional hazard models after adjusting for confounders via inverse probability weighting. Results: Out of the 4 916 229 patients with COVID-19 diagnosed during the study period, 68 383 (1.4%) met our cohort definition. The overall incidence of CAIFI was 2.80% (n = 1934/68 383). Aspergillus (48.2%; n = 933/1934) and Candida (41.0%; n = 793/1934) were the most common causative organisms. The incidence of CAIFIs associated with Aspergillus among patients who underwent BAL was 6.2% (n = 83/1328). Following inverse probability weighting, CAIFIs caused by Aspergillus (hazard ratio [HR], 2.0; 95% CI, 1.8-2.2) and Candida (HR, 1.7; 95% CI, 1.5-1.9) were associated with increased all-cause mortality. Systemic antifungals reduced mortality in 17% of patients with CAIFI with Aspergillus and 24% of patients with CAIFI with Candida. Conclusions: The incidence of CAIFI was modest but associated with higher 90-day all-cause mortality among intubated patients. Systemic antifungals modified mortality.