A Pathology-based Case Series of Influenza- and COVID-19-associated Pulmonary Aspergillosis: The Proof Is in the Tissue.

RATIONALE: Invasive pulmonary aspergillosis has emerged as a frequent coinfection in severe COVID-19, similarly to influenza; yet the clinical invasiveness is more debated. OBJECTIVES: We investigated the invasive nature of pulmonary aspergillosis in histology specimens of influenza and COVID-19 intensive care unit (ICU) fatalities in a tertiary care center. METHODS: In this monocentric, descriptive, retrospective case series we included adult ICU patients with PCR-proven influenza/COVID-19 respiratory failure that underwent postmortem examination and/or tracheobronchial biopsy during ICU admission from September 2009 until June 2021. Diagnosis of probable/proven viral-associated pulmonary aspergillosis (VAPA) was made based on the ICM-IAPA and ECMM/ISHAM-CAPA consensus criteria. All respiratory tissues were independently reviewed by two experienced pathologists. MEASUREMENTS AND MAIN RESULTS: In the 44 patients of the autopsy-verified cohort, 6 proven influenza-associated and 6 proven COVID-19-associated pulmonary aspergillosis diagnoses were identified. Fungal disease was identified as missed-diagnosis upon autopsy in 8% of proven cases (n=1/12), yet most frequently found as confirmation of probable antemortem diagnosis (n=11/21, 52%) despite receiving antifungal treatment. Bronchoalveolar lavage galactomannan testing showed highest sensitivity for VAPA diagnosis. Among both viral entities, an impeded fungal growth was the predominant histologic pattern of pulmonary aspergillosis. Fungal tracheobronchitis was histologically indistinguishable in influenza (n=3) and COVID-19 (n=3) cases, yet macroscopically more extensive at bronchoscopy in influenza setting. CONCLUSIONS: Proven invasive pulmonary aspergillosis diagnosis was found regularly and with a similar histological pattern in influenza and in COVID-19 ICU case-fatalities. Our findings highlight an important need for VAPA awareness with an emphasis on mycological bronchoscopic work-up. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

COVID-19-associated pulmonary aspergillosis (CAPA): identification of Aspergillus species and determination of antifungal susceptibility profiles.

Among the co-infectious agents in COVID-19 patients, Aspergillus species cause invasive pulmonary aspergillosis (IPA). IPA is difficult to diagnose and is associated with high morbidity and mortality. This study is aimed at identifying Aspergillus spp. from sputum and tracheal aspirate (TA) samples of COVID-19 patients and at determining their antifungal susceptibility profiles. A total of 50 patients with COVID-19 hospitalized in their intensive care units (ICU) were included in the study. Identification of Aspergillus isolates was performed by phenotypic and molecular methods. ECMM/ISHAM consensus criteria were used for IPA case definitions. The antifungal susceptibility profiles of isolates were determined by the microdilution method. Aspergillus spp. was detected in 35 (70%) of the clinical samples. Among the Aspergillus spp., 20 (57.1%) A. fumigatus, six (17.1%) A. flavus, four (11.4%) A. niger, three (8.6%) A. terreus, and two (5.7%) A. welwitschiae were identified. In general, Aspergillus isolates were susceptible to the tested antifungal agents. In the study, nine patients were diagnosed with possible IPA, 11 patients were diagnosed with probable IPA, and 15 patients were diagnosed with Aspergillus colonization according to the used algorithms. Serum galactomannan antigen positivity was found in 11 of the patients diagnosed with IPA. Our results provide data on the incidence of IPA, identification of Aspergillus spp., and its susceptibility profiles in critically ill COVID-19 patients. Prospective studies are needed for a faster diagnosis or antifungal prophylaxis to manage the poor prognosis of IPA and reduce the risk of mortality.

Assessing the safety profile of voriconazole use in suspected COVID-19-associated pulmonary aspergillosis-a two-centre observational study.

The decision to use voriconazole for suspected COVID-19-associated pulmonary aspergillosis (CAPA) is based on clinical judgement weighed against concerns about its potential toxicity. We assessed the safety profile of voriconazole for patients with suspected CAPA by conducting a retrospective study of patients across two intensive care units. We compared changes in any liver enzymes or bilirubin and any new or increasing corrected QT interval (QTc) prolongation following voriconazole use to patient baseline to indicate possible drug effect. In total, 48 patients with presumed CAPA treated with voriconazole were identified. Voriconazole therapy was administered for a median of 8 days (interquartile range [IQR] 5-22) and the median level was 1.86 mg/L (IQR 1.22-2.94). At baseline, 2% of patients had a hepatocellular injury profile, 54% had a cholestatic injury profile, and 21% had a mixed injury profile. There were no statistically significant changes in liver function tests over the first 7 days after voriconazole initiation. At day 28, there was a significant increase in alkaline phospahte only (81-122 U/L, P = 0.006), driven by changes in patients with baseline cholestatic injury. In contrast, patients with baseline hepatocellular or mixed injury had a significant decrease in alanine transaminase and aspartate transaminase. Baseline QTc was 437 ms and remained unchanged after 7 days of voriconazole therapy even after sensitivity analysis for concomitantly administered QT prolonging agents. Therefore, at the doses used in this study, we did not detect evidence of significant liver or cardiac toxicity related to voriconazole use. Such information can be used to assist clinicians in the decision to initiate such treatment.

Our study did not show significant voriconazole-related liver or cardiac side effects in a critically ill cohort of patients with suspected COVID-19-associated pulmonary aspergillosis. These findings may allay specific clinician concerns when commencing therapy for such patients.

Invasive Pulmonary Aspergillosis in Coronavirus Disease 2019 Patients Lights and Shadows in the Current Landscape.

Invasive pulmonary aspergillosis (IPA) presents a known risk to critically ill patients with SARS-CoV-2; quantifying the global burden of IPA in SARS-CoV-2 is extremely challenging. The true incidence of COVID-19-associated pulmonary aspergillosis (CAPA) and the impact on mortality is difficult to define because of indiscriminate clinical signs, low culture sensitivity and specificity and variability in clinical practice between centers. While positive cultures of upper airway samples are considered indicative for the diagnosis of probable CAPA, conventional microscopic examination and qualitative culture of respiratory tract samples have quite low sensitivity and specificity. Thus, the diagnosis should be confirmed with serum and BAL GM test or positive BAL culture to mitigate the risk of overdiagnosis and over-treatment. Bronchoscopy has a limited role in these patients and should only be considered when diagnosis confirmation would significantly change clinical management. Varying diagnostic performance, availability, and time-to-results turnaround time are important limitations of currently approved biomarkers and molecular assays for the diagnosis of IA. The use of CT scans for diagnostic purposes is controversial due to practical concerns and the complex character of lesions presented in SARS-CoV-2 patients. The key objective of management is to improve survival by avoiding misdiagnosis and by initiating early, targeted antifungal treatment. The main factors that should be considered upon selection of treatment options include the severity of the infection, concomitant renal or hepatic injury, possible drug interactions, requirement for therapeutic drug monitoring, and cost of therapy. The optimal duration of antifungal therapy for CAPA is still under debate.

Galactomannan-Antigen Testing from Non-Directed Bronchial Lavage for Rapid Detection of Invasive Pulmonary Aspergillosis in Critically Ill Patients: A Proof-of-Concept Study.

Invasive pulmonary aspergillosis is associated with high mortality. For diagnosis, galactomannan-antigen in serum and bronchoalveolar lavage fluid is recommended, with higher sensitivity in bronchoalveolar lavage fluid. Because of invasiveness, bronchoalveolar lavage might be withheld due to patients' or technical limitations, leading to a delay in diagnosis while early diagnosis is crucial for patient outcome. To address this problem, we performed an analysis of patient characteristics of intubated patients with invasive pulmonary aspergillosis with comparison of galactomannan-antigen testing between non-directed bronchial lavage (NBL) and bronchoalveolar lavage fluid. A total of 32 intubated ICU patients with suspected invasive pulmonary aspergillosis could be identified. Mycological cultures were positive in 37.5% for A. fumigatus. Galactomannan-antigen in NBL (ODI 4.3 ± 2.4) and bronchoalveolar lavage fluid (ODI 3.6 ± 2.2) showed consistent results (p-value 0.697). Galactomannan-antigen testing for detection of invasive pulmonary aspergillosis using deep tracheal secretion showed comparable results to bronchoalveolar lavage fluid. Because of widespread availability in intubated patients, galactomannan-antigen from NBL can be used as a screening parameter in critical risk groups with high pretest probability for invasive aspergillosis to accelerate diagnosis and initiation of treatment. Bronchoalveolar lavage remains the gold standard for diagnosis of invasive aspergillosis to be completed to confirm diagnosis, but results from NBL remove time sensitivity.

Aspergillus overlap syndromes: From allergic bronchopulmonary aspergillosis to invasive pulmonary aspergillosis

Case report Background: Aspergillus is a saprophytic mold that can cause a broad variety of pulmonary syndromes, categorized in three branches: allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA) and invasive pulmonary aspergillosis (IPA). Although these three pathologies involve damaged lung tissue and presence of Aspergillus, it is uncommon to find more than one of them in the same patient. In recent years, overlap of these syndromes is being recognized in some patients, primarily in those treated with immunosuppressive agents, such as long term use of corticosteroids. Case report: We report a case of a 54 year old woman diagnosed with ABPA in 2014, that, following treatment for her pathology with steroids and benralizumab (monoclonal antibody against interleukin- 5), developed IPA, that required hospital admission and treatment with antifungal agents. Since the diagnosis of ABPA, she had been treated with oral corticosteroids and antifungal agents in 2 occasions (2014 and 2017) and omalizumab (monoclonal antibody against IgE) in 2016. Omalizumab had to be discontinued after second administration due to flu-like symptoms, headache, joint and neck pain. In February 2020 due to lack of control of her illness with 15 mg oral prednisone daily, she initiated treatment with benralizumab, being hospitalized after the onset of this new medication as a result of an asthmatic exacerbation. Due to COVID pandemic, she reinitiated benralizumab in June 2020, and continued ever since the administration at home every 2 months in association with 7.5 mg oral Prednisone daily. Following clinical worsening of the patient, a thorax CT scan was performed in September 2021, where a nodule accompanied by a "halo" sign was visualized. The patient was admitted to hospital to start new treatment with higher dose of corticosteroids, antifungal therapy, supplementary oxygen and benralizumab was discontinued. Conclusion(s): To our knowledge, this is the first case of IPA secondary to ABPA in a patient treated with a monoclonal antibody and long term oral corticosteroids. Physicians should be aware of this possible overlap syndromes so that appropriate therapy can be instituted.

Comparison of clinical features, risk factors and outcome of invasive pulmonary aspergillosis in critically ill COVID19, influenza and community acquired pneumonia patients

Objective: To determine the frequency and outcomes of invasive pulmonary aspergillosis (IPA) in patients with influenza, COVID-19 and community acquired pneumonia (CAP) admitted in critical care units of a tertiary care hospital in Pakistan. Method(s): A prospective cross sectional study was conducted at the Aga Khan University from Nov 2019-June 2020. Adult patients admitted in critical care units with CAP, influenza and COVID-19 pneumonia were included. IPA was diagnosed as per EORTC/MSG criteria. Clinical information and outcome were collected on predesigned performa. Result(s): A total of 140 patients [70 Influenza, 35 COVID-19 and 35 CAP] were included. Of total, 20(14.2%) patients were found to have invasive aspergillosis with 10/35(28.5%), 9/75(12.8%) and 1/35(2.8%) patients in COVID-19, influenza and CAP groups, respectively. Duration of symptoms was 12.5+/-12.13 days in CAPA and 7.56+/-4.0 days in IAPA patients (p=0.24). Mean APCHE II score was 17.4+/-8.42 and 16.6+/-6.27 in patients with CAPA and IAPA respectively (p=0.85). 9(90%) CAPA patients required vasopressor support compared to 3(33%) patients in IAPA (p=0.020). 7(70%) CAPA patients required invasive mechanical ventilation compared to 4(44%) IAPA patients (p=0.37). Length of stay in hospital was highest in CAPA patients (18.3+/-7.28 days) compared to IAPA patients (11.7+/-5.33 days) (p=0.036). The number of deaths in IAPA patients and CAPA patients was 3(33.3%) and 5(50%), respectively (p=0.526). Conclusion(s): A higher proportion of patients with COVID-19 developed IPA compared to influenza and CAP. CAPA patients had a significantly longer stay in hospital and mortality.

Incidence, risk factors and pre-emptive screening for COVID-19 associated pulmonary aspergillosis in an era of immunomodulant therapy.

PURPOSE: COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential benefit of a pre-emptive screening strategy for CAPA in ICUs in the Netherlands/Belgium during immunosuppressive COVID-19 treatment. MATERIALS AND METHODS: A retrospective, observational, multicentre study was performed from September 2020-April 2021 including patients admitted to the ICU who had undergone diagnostics for CAPA. Patients were classified based on 2020 ECMM/ISHAM consensus criteria. RESULTS: CAPA was diagnosed in 295/1977 (14.9%) patients. Corticosteroids were administered to 97.1% of patients and interleukin-6 inhibitors (anti-IL-6) to 23.5%. EORTC/MSGERC host factors or treatment with anti-IL-6 with or without corticosteroids were not risk factors for CAPA. Ninety-day mortality was 65.3% (145/222) in patients with CAPA compared to 53.7% (176/328) without CAPA (p = 0.008). Median time from ICU admission to CAPA diagnosis was 12 days. Pre-emptive screening for CAPA was not associated with earlier diagnosis or reduced mortality compared to a reactive diagnostic strategy. CONCLUSIONS: CAPA is an indicator of a protracted course of a COVID-19 infection. No benefit of pre-emptive screening was observed, but prospective studies comparing pre-defined strategies would be required to confirm this observation.

COVID-19-Associated Pulmonary Aspergillosis (CAPA) in Northern Greece during 2020-2022: A Comparative Study According to the Main Consensus Criteria and Definitions.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has emerged as an important complication among patients with acute respiratory failure due to SARS-CoV-2 infection. Almost 2.5 years since the start of the COVID-19 pandemic, it continues to raise concerns as an extra factor that contributes to increased mortality, which is mostly because its diagnosis and management remain challenging. The present study utilises the cases of forty-three patients hospitalised between August 2020 and February 2022 whose information was gathered from ten ICUs and special care units based in northern Greece. The main aim was to describe the gained experience in diagnosing CAPA, according to the implementation of the main existing diagnostic consensus criteria and definitions, and present the different classification of the clinical cases due to the alternative algorithms.

Aspergillus-specific IgM/IgG antibody serostatus of patients hospitalized with moderate-critical COVID-19 in Uganda.

Invasive pulmonary aspergillosis is known to complicate the coronavirus diseases-2019 (COVID-19), especially those with critical illness. We investigated the baseline anti-Aspergillus antibody serostatus of patients with moderate-critical COVID-19 hospitalized at 3 COVID-19 Treatment Units in Uganda. All 46 tested patients, mean age 30, and 11% with underlying respiratory disease had a negative serum anti-Aspergillus IgM/IgG antibody immunochromatographic test on day 3 (mean) of symptom onset (range 1-26), but follow up specimens to assess seroconversion were not available.

THE PANDEMIC'S FUNGAL REVENGE: COVID-19 ASSOCIATED PULMONARY ASPERGILLOSIS (CAPA)

SESSION TITLE: Pathologies of the Post-COVID-19 World SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Since the start of the COVID-19 pandemic, COVID-19 Associated Pulmonary Aspergillosis (CAPA) has been on the rise. This superinfection, if not properly identified and treated, has shown to increase mortality up to 67% in COVID-19 patients. We are presenting a late presentation of CAPA after 4-month of COVID-19 infection and treated successfully. CASE PRESENTATION: A 57-year-old female patient with past medical history type 2 diabetes mellitus, hypertension and cardiomyopathy in addition to COVID-19 pneumonia treated for months ago with azithromycin, Bamlanivimab/Etesevimab, and Dexamethasone who presents to the hospital with massive hemoptysis and shortness of breath requiring intubation and mechanical ventilation. There was no reported history of recent travel, smoking, alcohol, or illicit drug use. Physical exam showed diminished lung sounds at the right lower lobe. Her labs showed mild leukocytosis, lactic acidosis and negative COVID-19 PCR. CT scan showed dense consolidation on right lower lobe consistent with lobar pneumonia and centrilobular ground glass opacities in the right upper lobe. Bronchoscopy showed complete obstruction of right bronchus intermedius and minimal blood clots in LLL. BAL respiratory culture, fungal smear, acid fast bacilli were non-diagnostic and negative for malignancy. Patient continued to have hemoptysis and bronchoscopy was repeated with negative cytology and cultures. The patient continued to have hemoptysis and she was transferred to tertiary center were bronchoscopy was repeated and confirmed right bronchus intermedius stenosis, blood clots, and suspicious right mainstem nodules with mucosal lesion. Biopsy results from bronchoscopy came back positive for the morphologic features of Aspergillus species. The patient was started on voriconazole with significant improvement in her symptoms. DISCUSSION: The recent literature of COVID-19 suggest association between COVID infection and invasive pulmonary Aspergillosis. COVID-19 virus causes damage in the airway epithelium and enable aspergillus to invade the pulmonary tract leading to serious infections with Aspergillus. It has also been known that Aspergillus infections are associated with diabetes mellitus and immune suppression which can be precipitated by steroid use and other treatments for COVID-19 infection like IL-6 inhibitors. Here in our patient with help of tissue biopsy we diagnosed CAPA, started treatment early and treated successfully. CONCLUSIONS: CAPA can be difficult to diagnose and needs high index of suspicion in the appropriate clinical scenario when dealing with post COVID respiratory complaints like hemoptysis. Bronchoalveolar lavage alone without tissue biopsy might miss the diagnosis in the context of invasive aspergillosis like the scenario we observed in our case. Doing tissue biopsy through bronchoscopy might add more clinical benefit when Aspergillus infections are suspected. Reference #1: Chih-Cheng Lai, Weng-Liang Yu, COVID-19 associated with pulmonary aspergillosis: A literature review, https://doi.org/10.1016/j.jmii.2020.09.004 DISCLOSURES: No relevant relationships by Haytham Adada No relevant relationships by Mahmoud Amarna No relevant relationships by Rishika Bajaj No relevant relationships by Camelia Chirculescu No relevant relationships by Sonia Dogra No relevant relationships by Azad Patel

INVASIVE PULMONARY ASPERGILLOSIS ASSOCIATED WITH NONSPECIFIC INTERSTITIAL PNEUMONIA CAUSING RECURRENT RESPIRATORY FAILURE

SESSION TITLE: Unusual Pneumonias SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Invasive pulmonary aspergillosis (IPA) commonly occurs in the setting of immunosuppression. Underlying lung disease is a well-known risk factor for IPA;however, interstitial lung disease (ILD) has not been recognized as a risk factor for IPA[1]. CASE PRESENTATION: A 40-year-old male with a history of a failed kidney transplant now on hemodialysis (HD), Juvenile Rheumatoid Arthritis, Mixed Connective Tissue Disease, Aspergilloma led to right lower lobectomy a year ago, COVID-19 infection three months ago, chronic lung disease (CLD) thought to be due to Nonspecific interstitial pneumonia (NSIP) presented with dyspnea. He had several hospitalizations for respiratory failure needing intubation or NIPPV, broad-spectrum antibiotics, steroids, and HD with improved respiratory status, eventually discharged. Bronchoalveolar lavage fluid culture grew aspergillus terreus but was negative for Pneumocystis (PCP), bacteria, acid-fast bacilli, and Nocardia. The transbronchial biopsies showed mixed inflammatory type and fungal forms in one specimen. Additionally, the initially negative galactomannan converted into a serial rise in galactomannan (>3.75 Index) along with a rise in beta d-glucan (>500 pg/ml). Unfortunately, he had gaps in antifungals and was readmitted similarly. Micafungin was added for dual fungal coverage and was planned for surgical lung biopsy to characterize ILD further once his respiratory status allows. DISCUSSION: He has multiple risk factors for developing IPA, such as high-dose steroids for ILD and recent COVID infection. Initially, respiratory failure was thought to be due to exacerbation of ILD, and suspicion for IPA was low because of lack of neutropenia, negative fungal biomarkers, lack of classic findings on lung imaging, and in-hospital clinical improvement with steroids. However, the eventual course of recurrent respiratory failure while on high-dose steroids, along with gaps in antifungal therapy and continued growth of Aspergillus, made IPA the most likely diagnosis. For IPA, the mainstay of treatment is both adequate antifungal therapy and reduction in immunosuppression to the extent possible[2];however, it is unclear if his underlying ILD can tolerate steroid taper. He will need a lung transplant after adequately treating IPA. CONCLUSIONS: There are no current guidelines on simultaneously treating IPA and NSIP. It is challenging to balance reduction in immunosuppression as tolerated for ILD and concurrently maintain antifungal therapy. During this patient's hospitalization, there have been considerations of using a steroid-sparing agent for his suspected NSIP, however, in the setting of active infection, its benefit is debatable.[3] Reference #1: Matsuyama H, Miyoshi S, Sugino K, et al. Fatal Invasive Pulmonary Aspergillosis Associated with Nonspecific Interstitial Pneumonia: An Autopsy Case Report. Intern Med. 2018;57(24):3619-3624. doi:10.2169/internalmedicine.1144-18 Reference #2: Thomas F. Patterson, George R. Thompson, III, David W. Denning, Jay A. Fishman, Susan Hadley, Raoul Herbrecht, Dimitrios P. Kontoyiannis, Kieren A. Marr, Vicki A. Morrison, M. Hong Nguyen, Brahm H. Segal, William J. Steinbach, David A. Stevens, Thomas J. Walsh, John R. Wingard, Jo-Anne H. Young, John E. Bennett, Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America, Clinical Infectious Diseases, Volume 63, Issue 4, 15 August 2016, Pages e1–e60, https://doi.org/10.1093/cid/ciw326 Reference #3: Mezger, M., Wozniok, I., Blockhaus, C., Kurzai, O., Hebart, H., Einsele, H., & Loeffler, J. (2008). Impact of mycophenolic acid on the functionality of human polymorphonuclear neutrophils and dendritic cells during interaction with Aspergillus fumigatus. Antimicrobial agents and chemotherapy, 52(7), 2644–2646. https://doi.org/10.1128/AAC.01618-07 DISCLOSURES: No relevant relationships by Nasir Alhamdan No relevant relati nships by Parth Jamindar No relevant relationships by Harshitha Mergey Devender No relevant relationships by Abira Usman No relevant relationships by Vishruth Vyata

WELL, THAT ESCALATED RATHER QUICKLY: A CASE OF RAPIDLY PROGRESSIVE SUBACUTE INVASIVE PULMONARY ASPERGILLOSIS

SESSION TITLE: TB and TB-Involved Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Pulmonary Aspergillus infection has a wide array of manifestations. Chronic Pulmonary Aspergillosis is an uncommon progressive respiratory disease, with the Subacute Invasive Pulmonary Aspergillosis form, one of the most challenging to manage. Typically it presents with rapidly progressive infection (of less than 3 months) in mild to moderately immunocompromised patients with underlying structural lung disease. We herein report the case of a 69-year old female with post-tuberculous cavity with disease progression, in approximately 6 weeks, associated with Aspergillus infection. CASE PRESENTATION: Patient is a 69-year old African American female, never smoker, with known history of Type 2 Diabetes Mellitus and previously treated mycobacterium tuberculosis with residual small right upper lobe cavity (measuring approximately 35 x 40 mm). She was being followed in our outpatient thoracic oncology clinic with serial imaging for surveillance, CT Chest initially every 3 - 6 months then annually thereafter with PET scan as clinically indicated. The cavity remained relatively unchanged for approximately 5 years. In October 2021, her CT Chest had revealed a stable cavity, even despite SARS-CoV-2 Pneumonia infection the previous year. The following month she was admitted to an outside hospital for hyperglycemia with notable significant increase in size of the right upper lobe cavity to 69 x 72 mm with surrounding nodularity. She completed a course of antibiotics and was seen in our clinic 3 months post discharge with a repeat CT Chest which now revealed a mass like area of consolidation with large area of lucency and superimposed fungus ball (now measuring 80 mm x 70mm). She underwent Electromagnetic Navigational Bronchoscopy with transbronchial biopsy and right upper lobe bronchoalveolar lavage. BAL culture identified Aspergillus niger, with no other pathogens (including acid fast bacilli isolated) or malignant cells observed. Biopsy revealed marked mixed inflammation and fungal hyphae. Patient is currently undergoing long-term oral antifungal therapy with plan for close surgical follow-up. DISCUSSION: The diagnosis of Chronic Pulmonary Aspergillosis requires a combination of clinical, radiological and histopathological characteristics present for atleast 3 months for diagnosis. This includes the presence of one or more cavities on thoracic imaging, evidence of aspergillus infection or an immunological response to aspergillus as well as excluding alternative diagnoses. Advances in diagnostic tools have improved early diagnosis and subsequent management as noted in our case. Surgical resection is recommended for simple aspergilloma, however rapidly progressive disease processes are recommended to be managed as invasive aspergillosis. CONCLUSIONS: Post-tuberculosis chronic pulmonary aspergillosis is an emerging disease with significant associated morbidity and likely health burden. Reference #1: Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management David W. Denning, Jacques Cadranel, Catherine Beigelman-Aubry, Florence Ader, Arunaloke Chakrabarti, Stijn Blot, Andrew J. Ullmann, George Dimopoulos, Christoph Lange European Respiratory Journal Jan 2016, 47 (1) 45-68;DOI: 10.1183/13993003.00583-2015 Reference #2: Bongomin F. Post-tuberculosis chronic pulmonary aspergillosis: An emerging public health concern. PLoS Pathog. 2020;16(8):e1008742. Published 2020 Aug 20. doi:10.1371/journal.ppat.1008742 DISCLOSURES: No relevant relationships by Omotooke Babalola No relevant relationships by Mark Bowling, value=Consulting fee Removed 04/02/2022 by Mark Bowling No relevant relationships by Mark Bowling, value=Consulting fee Removed 04/02/2022 by Mark Bowling No relevant relationships by Mark Bowling, value=Consulting fee Removed 04/02/2022 by Mark Bowling No relevant relationships by Sulaiman Tijani

A CASE OF COVID-19-ASSOCIATED PULMONARY ASPERGILLOSIS

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: COVID-19 patients requiring admission to an ICU have a higher risk of invasive pulmonary aspergillosis (IPA) with a reported incidence of 19.6%-33.3%. CASE PRESENTATION: A 63-year-old male presented with progressively worsening dyspnea for one week. He has a past medical history of atrial fibrillation, hypertension, and obesity. He was tested positive for COVID about two weeks prior. He did receive a single dose of Moderna vaccine. Initial chest x-ray(CXR) showed diffuse ground-glass opacities. He was initiated on Remdesivir and decadron, and later received a dose of tocilizumab. He was intubated on hospital day 3 for worsened hypoxemia. Repeat CXR suggested some improvement but a new left lower lobe airspace haziness. He also had new-onset leukocytosis with elevated procalcitonin level. He was started on cefepime for concern of superimposed hospital-acquired pneumonia. A second dose of tocilizumab was administered. No clinical improvement was seen, and additional workups were obtained. Serial CXRs revealed increasing diffuse airspace opacities concerning for ARDS. Tracheal aspirate culture grew coagulase-negative staphylococcus and Aspergillosis Fumigatus. Cefepime was changed to vancomycin, and voriconazole and caspofungin were added. Unfortunately, the patient's respiratory status worsened with increasing ventilation requirement. He also developed septic shock and acute renal failure requiring CVVH. He became even more hypotensive after CVVH initiation, and multiple vasopressors were required to maintain his hemodynamics. Unfortunately, he continued to deteriorate and he also developed profound respiratory acidosis. He died shortly afterwards after family decided to withdraw care. DISCUSSION: In this case, in addition to superimposed bacterial pneumonia, pulmonary aspergillosis likely also contributed to his clinical deterioration. The mechanism by which fungal infections develop in COVID-19 infection is not well-understood. Severe COVID-related immune dysregulation, ARDS, and high-dose steroids use are potential culprits for the increased risk of IPA. Tocilizumab, an IL-6 receptor monoclonal antibody used in patients with severe COVID-19 infection, may also predispose the patient to IPA according to post-marketing data. The mortality rate from current case reports is as high as 64.7%. Diagnosis and treatment in such a scenario remain a challenge. Sputum culture, serum Beta-galactomannan, Beta-D glucan, and aspergillosis PCR have low sensitivity. Tissue biopsy and CT scan in critically ill patients are often not feasible. Voriconazole is usually considered the first-line treatment in IPA. CYP3A4-mediated drug interactions between azoles and antiviral agents require further investigation. CONCLUSIONS: Clinicians should be aware that severe COVID-19 patients are at higher risk of IPA. The prognosis is poor. Early detection and treatment in clinically deteriorated patients are warranted. Reference #1: Borman, A.M., Palmer, M.D., Fraser, M., Patterson, Z., Mann, C., Oliver, D., Linton, C.J., Gough, M., Brown, P., Dzietczyk, A. and Hedley, M., 2020. COVID-19-associated invasive aspergillosis: data from the UK National Mycology Reference Laboratory. Journal of clinical microbiology, 59(1), pp.e02136-20. Reference #2: Lai CC, Yu WL. COVID-19 associated with pulmonary aspergillosis: A literature review. J Microbiol Immunol Infect. 2021;54(1):46-53. doi:10.1016/j.jmii.2020.09.004 Reference #3: Thompson Iii GR, Cornely OA, Pappas PG, et al. Invasive Aspergillosis as an Under-recognized Superinfection in COVID-19. Open Forum Infect Dis. 2020;7(7):ofaa242. Published 2020 Jun 19. doi:10.1093/ofid/ofaa242 DISCLOSURES: No relevant relationships by Jason Chang No relevant relationships by Jason Chang No relevant relationships by kaiqing Lin No relevant relationships by Guangchen Zou

IMPORTANCE OF HIGH CLINICAL SUSPICION FOR COVID-19-ASSOCIATED PULMONARY ASPERGILLOSIS IN PATIENTS WITH EQUIVOCAL BIOMARKERS

SESSION TITLE: Pathologies of the Post-COVID-19 World SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Pulmonary aspergillosis is a recognized complication of COVID-19. Options for diagnostic evaluation in patients with suspected pulmonary aspergillosis include serum galactomannan, beta-D-glucan, Aspergillus PCR, fungal cultures and tissue biopsy. Diagnosis is challenging due to the risks and logistical barriers associated with procedural/surgical tissue biopsy and the variable reliability of serum biomarkers. We present a case of a 76-year-old male who developed invasive pulmonary aspergillosis after a COVID-19 respiratory infection. CASE PRESENTATION: 76-year-old male with a past medical history that includes emphysematous COPD, history of chronic lymphocytic leukemia in remission, on ibrutinib, who contracted SARS-CoV-2 resulting in hypoxemic respiratory failure and requiring hospital admission and was treated with dexamethasone and remdesivir. He was discharged home and due to his worsening respiratory condition, he was readmitted to the hospital next month. Ct chest performed revealed pulmonary embolism and diffuse multifocal opacification with interspersed scattered dense opacities and nodules with cavitary lesions in the right upper lobe. A bronchoscopy was performed and the Aspergillus antibody test, beta D glucan and galactomannan antigens resulted as negative. Due to this, voriconzaole was discontinued. Subsequently CT-guided lung biopsy demonstrated Aspergillus. Eventually, fungal cultures from BAL began growing fungus. DISCUSSION: Our patient initially presented with a Covid infection in January 2022 he was initially treated with remdesivir, 14 days of baricitinib and 10 days of Decadron followed by a steroid taper (due to his underlying COPD). He did not receive tocilizumab. He was found to have progression of the cavitary lesions during a third admission. We suspect that the main contributing factors for the development of invasive pulmonary aspergillosis are related to interleukin production, distorted architecture from COVID-19 infection and multiple courses of steroids. This case report demonstrates the importance of having a high clinical suspicion for invasive pulmonary aspergillosis in all patients with COVID-19 infection. It also demonstrates that serum biomarkers are not reliable indicators of infection and cannot be used to definitively rule out infection or to exclude treatment with antifungal therapy. It should be noted that positive serum biomarkers in patients with true invasive aspergillosis have a higher mortality rate as compared to those without positive serum biomarkers. This case also underscores the importance of obtaining tissue diagnosis in patients where there is a high suspicion for fungal infection when all other studies are equivocal. CONCLUSIONS: We believe that this case underscores the importance of maintaining a high clinical suspicion for opportunistic and fungal infections in patients with COVID-19, regardless of the serum biomarkers. Reference #1: Arastehfar A, Carvalho A, van de Veerdonk FL, et al. Covid-19 associated Pulmonary Aspergillosis (capa)—from immunology to treatment. Journal of Fungi. 2020;6(2):91. doi:10.3390/jof6020091 Reference #2: Machado M, Valerio M, Álvarez-Uría A, et al. Invasive Pulmonary Aspergillosis in the COVID-19 ERA: An expected new entity. Mycoses. 2020;64(2):132-143. doi:10.1111/myc.13213 Reference #3: Maschmeyer G, Haas A, Cornely OA. Invasive aspergillosis. Drugs. 2007;67(11):1567-1601. doi:10.2165/00003495-200767110-00004 DISCLOSURES: No relevant relationships by Hira Bakhtiar No relevant relationships by Amanda Lindo No relevant relationships by Carlos Merino No relevant relationships by Joanna Moore

POST-COVID-19 ASPERGILLOSIS

SESSION TITLE: Post-COVID-19 Infection Complications SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Since the start of Covid-19 pandemic, several respiratory microorganisms have been identified that cause coinfection with Sars-Cov-2. Bacteria like Staphylococcus aureus and viruses like influenza are some of the identified pathogens. Rarely, fungal infections from Aspergillus are also being reported. CASE PRESENTATION: 59-year-old male with past medical history of hypertension and hyperlipidemia was admitted for shortness of breath and was found to be positive for Covid-19. He received Remdesivir, dexamethasone & tocilizumab. He required non-invasive ventilation via continuous positive airway pressure but continued to remain hypoxemic with elevated procalcitonin, he was treated with cefepime for bacterial pneumonia. Patient required emergent intubation and eventually underwent tracheostomy. He developed methicillin-resistant Staphylococcus aureus pneumonia for which he received vancomycin. He was eventually discharged to long term acute care facility. Patient was readmitted after 2 months due to worsening respiratory status. Computed Tomography Angiography of chest was negative for pulmonary embolism but showed pleural effusion. He underwent thoracentesis which showed exudative effusion with negative cultures. Echocardiogram showed right heart failure. Patient's symptoms were believed to be due to Covid-19 fibrosis. He required home oxygen and also received pulmonary rehabilitation. One year after the initial Covid-19 infection, he developed pulmonary hypertension and was referred for lung transplant consultation. However, he developed severe hemoptysis requiring intubation and vasopressors. Galactomannan was positive, Karius digital culture revealed Aspergillus Niger for which he received voriconazole. He was not deemed a suitable candidate for lobectomy. Patient developed arrhythmia and had prolonged QT interval so voriconazole was switched to Isavuconazole. He continued to have hemoptysis and his condition did not improve so family requested to transition care and patient passed away. DISCUSSION: Several studies have proven co-infection of Aspergillus with Covid-19. This case highlights Aspergillus infection approximately 1 year after initial Covid-19 infection. Sars-Cov-2 causes damage to airway lining which can result in Aspergillus invading tissues. IL-6 is increased in severe Covid-19 infection. Tocilizumab is an anti-IL-6 receptor antibody that has been approved for treatment of Covid-19 pneumonia. However, IL-6 provides immunity against Aspergillus so use of tocilizumab decreases protection against Aspergillosis which is usually the reason for co-infection. However, in this case patient developed fungal infection later during Covid-19 fibrosis stage. CONCLUSIONS: Recognizing fungal etiology early on is important in Covid-19 patients as mortality is high and appropriate intervention can reduce morbidity and mortality. Some patient may eventually require lung resection. Reference #1: Kakamad FH, Mahmood SO, Rahim HM, Abdulla BA, Abdullah HO, Othman S, Mohammed SH, Kakamad SH, Mustafa SM, Salih AM. Post covid-19 invasive pulmonary Aspergillosis: a case report. International journal of surgery case reports. 2021 May 1;82:105865. Reference #2: Nasrullah A, Javed A, Malik K. Coronavirus Disease-Associated Pulmonary Aspergillosis: A Devastating Complication of COVID-19. Cureus. 2021 Jan 30;13(1). Reference #3: Dimopoulos G, Almyroudi MP, Myrianthefs P, Rello J. COVID-19-associated pulmonary aspergillosis (CAPA). Journal of Intensive Medicine. 2021 Oct 25;1(02):71-80. DISCLOSURES: No relevant relationships by Maria Haider Baig

CALCIUM OXALATE DEPOSITION IN PULMONARY ASPERGILLOSIS

SESSION TITLE: Infectious Complications with Obstructions and Connections SESSION TYPE: Case Reports PRESENTED ON: 10/17/2022 03:15 pm - 04:15 pm INTRODUCTION: Invasive pulmonary fungal infections are a challenge for diagnosis. One of the most common types is Invasive pulmonary aspergillosis. It occurs usually among immunocompromised patients [1], so an early diagnosis is warranted for potential better outcome. Evidence of calcium oxalate can be an early diagnostic tool for such an infection. The presence of calcium oxalate crystals can be detected within 24 hours under polarized light in the microbiology labs. We present this case to highlight the potential importance of pulmonary oxalosis in diagnosing pulmonary aspergillosis. CASE PRESENTATION: A 62-year-old-woman with limited breast cancer was admitted to the hospital seven days after her last cycle of docetaxel and cyclophosphamide with COVID-19 pneumonia and hypoxemic respiratory failure. She was not neutropenic. She received a full course of dexamethasone and remdesivir. Sputum cultures subsequently grew Klebsiella aerogenes for which she was treated with antibiotics but failed to significantly improve over four weeks. Repeat chest computed tomography (CT) showed progressive multifocal airspace opacities with new areas of cavitation. Patient underwent bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy. Transbronchial biopsy specimen from the right upper lobe showed bronchial mucosa and lung parenchyma with calcium oxalate crystals and no organisms. Biopsy specimen from the right middle lobe showed fungal organisms consistent with Aspergillus invading bronchial mucosa and lung parenchyma. Several days later, serum beta-D-glucan returned within normal limits, serum galactomannan was significantly elevated, and BAL culture grew Aspergillus niger. Patient improved with antifungal therapy. DISCUSSION: Fungal pneumonia has high morbidity and mortality. It is essential to start antifungal therapy as soon as possible. Pulmonary oxalosis or calcium oxalate has been seen among Aspergillus Fumigatus and Aspergillus Niger [2-3]. It is a combination of oxalic acid which is produced by Aspergillus spp. and calcium from blood supply of an invaded tissue. Further progression of lesions can be due to calcium oxalate toxicity itself [4-5]. In our case, clinical suspicion for pulmonary aspergillosis was high and we were able to document fungal invasion of lung parenchyma on one of the lung specimens. Though fungal culture is very sensitive and specific, it can take several days to result. Tissue staining for crystals can be performed quickly and provide more timely information when deciding about starting anti-fungal therapy. CONCLUSIONS: Pulmonary oxalosis, calcium oxalate deposition, can be seen in aspergillus infection and should be considered as an early diagnostic tool for invasive pulmonary aspergillosis. Reference #1: Kousha M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011;20(121): 156–174, doi: 10.1183/09059180.00001011 Reference #2: U. Pabuccuoglu, Aspects of oxalosis associated with aspergillosis in pathology specimens, Pathol. Res. Pract. 201 (2005) 363–368 Reference #3: Osholowu OS, Kak V, Singh H. Pulmonary oxalosis in pulmonary aspergillosis syndrome. Adv Respir Med. 2020;88(2):153-156. doi: 10.5603/ARM.2020.0090. PMID: 32383468. DISCLOSURES: No relevant relationships by Mohammed Alsaggaf No relevant relationships by Daniel Baram No relevant relationships by Ivana Milojevic

PULMONARY ASPERGILLOSIS POST-TOCILIZUMAB TREATMENT IN A PATIENT WITH COVID-19 PNEUMONIA

SESSION TITLE: Global Pulmonary Cases SESSION TYPE: Global Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: COVID 19 is associated with hyper- inflammation with levels of IL 6 correlating with the severity of COVID 19. IL6 causes increased vascular permeability and endothelial dysfunction and plays a major role in the development of ARDS.[1] Tocilizumab is a monoclonal antibody against the IL6 receptor which is being used for COVID pneumonia. Large randomized controlled trials including REMAP-CAP and RECOVERY reported a mortality benefit of tocilizumab in certain patients [3]. Aspergillus is a mold that causes variety of pulmonary infections depending on host's immune status. In immunocompromised hosts, it causes invasive pulmonary aspergillosis [2]. Symptoms initially are similar to bronchopneumonia: cough with sputum, dyspnea, fever not responsive to antibiotics. With disease progression, patients experience pleuritic chest pain and hemoptysis. CASE PRESENTATION: 69 y/o female came to ER with complaint of dyspnea and cough. PMH significant for Diabetes. She had a recent admission for COVID 3 weeks ago during which she received tocilizumab. This time, her vitals were HR- 96 RR- 24 Temp- 99.6 BP- 124/72, Sat- 88% on 2L NC. Labs WBC 31.1 D dimer- 2.17 ABG PO2- 61. CT pulmonary angiogram was consistent with left mid lung zone cavitary mass with an air-fluid level measuring 5 x 8 cm in transverse and AP dimension. Patient was started on broad-spectrum antibiotics (vancomycin, cefepime, metronidazole). Sputum cultures, Beta glucan assay, AFB and fungal immunodiffusion panel was ordered. Beta D Glucan assay came positive. Fungal immunodiffusion panel was negative. Bronchoscopy was done and AFB, aspergillus antigen and cultures were collected. BAL aspergillus antigen came positive and KOH fungal culture grew Aspergillus Fumigatus. Voriconazole was started. She was discharged on voriconazole for 12 weeks, ceftriaxone and clindamycin for 6 weeks for antibacterial coverage with plan to repeat CT chest in 3 weeks. DISCUSSION: We use tocilizumab for COVID 19 patients requiring invasive or non invasive mechanical ventilation and CRP ≥7.5 and exclude patients with ANC <2000, platelet <50,000 and history of serious bacterial, fungal or viral infection. This patient did not have any exclusion criteria but developed invasive fungal infection 3-4 weeks later. Due to worsening hypoxia and high D dimer, initial consideration was pulmonary embolism for which CT angiogram was done and a cavitary lesion was found. Differentials were bacterial abscess, tuberculosis or fungal infection. BAL played a crucial role in diagnosing aspergillosis. CONCLUSIONS: In patients presenting with worsening respiratory symptoms post tocilizumab administration we must keep a low index of suspicion for superimposed opportunistic infections including aspergillosis. Appropriate workup including CT chest, sputum or bronchoalveolar lavage for cultures (bacterial, fungal), Beta D Glucan and fungal panel is essential for diagnosis. Reference #1: Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia Ivan O Rosas;Norbert Bräu;Michael Waters;et al. New England Journal of Medicine, v384 n16 (20210422): 1503-1516 Reference #2: Pulmonary aspergillosis: a clinical review M. Kousha, R. Tadi, A.O. Soubani European Respiratory Review 2011 20: 156-174;DOI: 10.1183/09059180.00001011 Reference #3: Interleukin-6 Inhibitors. Available at: https://www.covid19treatmentguidelines.nih.gov. DISCLOSURES: No relevant relationships by Shaylika Chauhan No relevant relationships by Vipul Gidwani

Effectiveness of Eculizumab Treatment for Generalized Myasthenia Gravis in Us Clinical Practice: GMG Registry Data

INTRODUCTION: Clinical trial data have demonstrated that eculizumab improves clinical outcomes in individuals with refractory generalized myasthenia gravis (gMG). Data from clinical practice on treatment patterns and effectiveness of eculizumab in gMG are being collected by the Alexion-sponsored gMG Registry. OBJECTIVE: To describe treatment outcomes and safety (serious adverse events [SAEs]) in current gMG Registry participants during eculizumab therapy in clinical practice in the USA. METHODS: Starting in December 2019, adults with gMG who had ever received eculizumab enrolled in the gMG Registry (NCT04202341). After obtaining consent, demographic data, myasthenia gravis activities of daily living (MG-ADL) total score and Myasthenia Gravis Foundation of America (MGFA) classification were collected from medical records at two time points: In the 6 months before eculizumab initiation and at first gMG Registry assessment after eculizumab treatment initiation (at Registry enrollment). SAEs in patients receiving eculizumab during Registry participation were recorded. RESULTS: As of November 29, 2021, in total, 111 adults with gMG had enrolled in the gMG Registry (male, 52.3%;mean [range] age at MG diagnosis, 56.1 [16.0-92.0] years). The mean (range) time from eculizumab initiation to gMG Registry enrollment was 2.0 (0.0-6.7) years. Mean (standard deviation) MG-ADL total score decreased from 8.3 (3.6) before eculizumab initiation to 3.1 (3.6) after eculizumab treatment. MGFA classification improved with eculizumab treatment: Class I, 0.0% of patients before eculizumab initiation versus 28.9% after eculizumab treatment;class II, 36.8% versus 55.3%;class III, 52.6% versus 15.8%;class IV, 10.5% versus 0.0%. The median MGFA class was III before eculizumab initiation and II after eculizumab treatment. One SAE (invasive pulmonary aspergillosis) considered by the investigator to be related to eculizumab was reported in a patient who died, and two serious infections considered unrelated to eculizumab were reported (COVID-19/pneumonia and urinary tract infection);there were no meningococcal infections. Two patients died of causes considered to be unrelated to eculizumab (lung adenocarcinoma and acute congestive heart failure/myocardial infarction). CONCLUSION: These data from the gMG Registry provide evidence of the effectiveness of eculizumab for the treatment of gMG in clinical practice across the USA, demonstrating a benefit/risk profile consistent with that observed in clinical trials.

Potential Original Drug for Aspergillosis: In Vitro and In Vivo Effects of 1-N,N-Dimethylamino-5-Isocyanonaphthalene (DIMICAN) on Aspergillus fumigatus.

As the recent outbreak of coronavirus disease 2019 (COVID-19) has shown, viral infections are prone to secondary complications like invasive aspergillosis with a high mortality rate, and therefore the development of novel, effective antifungals is of paramount importance. We have previously demonstrated that 1-amino-5-isocyanonaphthalene (ICAN) derivatives are promising original drug candidates against Candida strains (Patent pending), even against fluconazole resistant C. albicans. Consequently, in this study ICANs were tested on Aspergillus fumigatus, an opportunistic pathogen, which is the leading cause of invasive and systematic pulmonary aspergillosis in immunosuppressed, transplanted and cancer- or COVID-19 treated patients. We have tested several N-alkylated ICANs, a well as 1,5-naphthalene-diisocyanide (DIN) with the microdilution method against Aspergillus fumigatus strains. The results revealed that the diisocyanide (DIN) was the most effective with a minimum inhibitory concentration (MIC) value as low as 0.6 µg mL-1 (3.4 µM); however, its practical applicability is limited by its poor water solubility, which needs to be overcome by proper formulation. The other alkylated derivatives also have in vitro and in vivo anti-Aspergillus fumigatus effects. For animal experiments the second most effective derivative 1-N, N-dimethylamino-5-isocyanonaphthalene (DIMICAN, MIC: 7-8 µg mL-1, 36-41 µM) was selected, toxicity tests were made with mice, and then the antifungal effect of DIMICAN was tested in a neutropenic aspergillosis murine model. Compared to amphotericin B (AMB), a well-known antifungal, the antifungal effect of DIMICAN in vivo turned out to be much better (40% vs. 90% survival after eight days), indicating its potential as a clinical drug candidate.