Serum Galactomannan Research Articles

1291. Safety of Isavuconazole Compared with Voriconazole as Primary Antifungal Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients

BackgroundVoriconazole (VCZ) is used as mold active primary antifungal prophylaxis (AFP) after allogenic hematopoietic cell transplant (HCT) but is frequently discontinued due to adverse events (AE), variable pharmacokinetics and drug-drug interactions. Limited data exists on the safety of Isavuconazole (ICZ) as AFP in HCT patients (pts). The study objectives were to compare 1) rates of AFP premature discontinuation (d/c), 2) changes in transaminases values from start to end of treatment (EOT) and 3) rates of invasive fungal infections (IFI) and all-cause mortality by Day (D) +180 post HCT between VCZ and ICZ AFP.MethodsThis is a matched cohort analysis of 95 pts enrolled in a clinical trial of ICZ AFP from 7/1/2017-10/31/2018 (ICZ-cohort) and 210 pts who received VCZ AFP standard of care between 9/1/2014-12/31/2015 at MSKCC (VCZ-cohort). The cohorts were matched using propensity scores (Table 1). AFP was administered for 75-100 days per institutional guidelines. Premature d/c of AFP was defined as d/c for IFI or AE by D +100 post HCT or interruption of >14 days for any reason. The cumulative incidence function and log rank test were used to compare groups. Mean transaminase values were compared using paired T-tests.Table 1. Baseline characteristics ResultsThe median (Interquartile range) duration of AFP was 94 (87-100) days and 76 (23-94) days in ICZ and VCZ cohorts respectively (p< 0.0001). Premature d/c occurred in 14/95 (14.7%) of ICZ and 92/210 (43.8%) of VCZ cohorts (p< 0.0001) (Figure 1). The most common cause for AFP d/c was hepatotoxicity: ICZ-cohort: 5/95 (5.26%) vs VCZ-cohort: 48/210 (22.8%). Transaminases at EOT and up to 14 days were increased in VCZ but not ICZ cohort (Figure 2). IFI occurred in 3.15% (3/95) in ICZ-cohort and 2.85% (6/210) in VCZ-cohort (p=0.88) (Figure 3). In ICZ-cohort IFI included 3 Candida bloodstream infections (BSI) occurring on ICZ AFP. In VCZ-cohort IFI included one Candida BSI after VCZ d/c, and 5 probable mold infections; 3/5 with serum galactomannan > 0.5 and 2 with beta-D-glucan > 80. IFI occurred on VCZ in 1 pt and after VCZ premature d/c in 5 pts. All-cause mortality was 6.31% (6/95) in ICZ-cohort and 2.85% (6/210) in VCZ-cohort (p=0.089).Figure 1. Cumulative incidence of premature discontinuation of AFP by D+100 Figure 2. Transaminases at baseline,end of treatment (EOT), EOT +7 days and EOT +14 days in ICZ- and VCZ cohorts Figure 3. Cumulative incidence of IFI by day +180 ConclusionThere was less premature discontinuation and hepatotoxicity with ICZ AFP, but no increase in IFI or death compared to VCZ AFP in allogeneic HCT pts.Disclosures Yeon Joo Lee, MD, MPH, Ansun BioPharma (Scientific Research Study Investigator)Astellas Pharma (Scientific Research Study Investigator) Sergio Giralt, MD, Amgen (Advisor or Review Panel member, Research Grant or Support, Served an advisory board for Amgen, Actinuum, Celgene, Johnson & Johnson, JAZZ pharmaceutical, Takeda, Novartis, KITE, and Spectrum pharma and has received research support from Amgen, Actinuum, Celgene, Johnson & Johnson, and Miltenyi, Takeda.) Miguel-Angel Perales, MD, Abbvie (Other Financial or Material Support, Honoraria from Abbvie, Bellicum, Celgene, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda.)ASTCT (Other Financial or Material Support, Volunteer member of the Board of Directors of American Society for Transplantation and Cellular Therapy (ASTCT), Be The Match (National Marrow Donor Program, NMDP), and the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Committee)Cidara Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Serve on DSMBs for Cidara Therapeutics, Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune.)Kite/Gilead (Research Grant or Support, Other Financial or Material Support, Received research support for clinical trials from Incyte, Kite/Gilead and Miltenyi Biotec.) Dionysios Neofytos, MD, Basilea (Advisor or Review Panel member)Gilead (Advisor or Review Panel member)MSD (Advisor or Review Panel member, Research Grant or Support)Pfizer (Advisor or Review Panel member, Research Grant or Support) Genovefa Papanicolaou, MD, Chimerix (Research Grant or Support)Merck&Co (Research Grant or Support, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas)

Aspergillus fumigatus and Its Allergenic Ribotoxin Asp f I: Old Enemies but New Opportunities for Urine-Based Detection of Invasive Pulmonary Aspergillosis Using Lateral-Flow Technology.

Invasive pulmonary aspergillosis (IPA) caused by Aspergillus fumigatus is a life-threatening lung disease of immunocompromised patients. Diagnosis currently relies on non-specific chest CT, culture of the fungus from invasive lung biopsy, and detection of the cell wall carbohydrate galactomannan (GM) in serum or in BAL fluids recovered during invasive bronchoscopy. Urine provides an ideal bodily fluid for the non-invasive detection of pathogen biomarkers, with current urine-based immunodiagnostics for IPA focused on GM. Surrogate protein biomarkers might serve to improve disease detection. Here, we report the development of a monoclonal antibody (mAb), PD7, which is specific to A. fumigatus and related species in the section Fumigati, and which binds to its 18 kDa ribotoxin Asp f I. Using PD7, we show that the protein is secreted during hyphal development, and so represents an ideal candidate for detecting invasive growth. We have developed a lateral-flow device (Afu-LFD®) incorporating the mAb which has a limit of detection of ~15 ng Asp f I/mL urine. Preliminary evidence of the test’s diagnostic potential is demonstrated with urine from a patient with acute lymphoid leukaemia with probable IPA. The Afu-LFD® therefore provides a potential novel opportunity for non-invasive urine-based detection of IPA caused by A. fumigatus.

1175. Pulmonary Aspergillosis in Critically Ill Patients with COVID-19: A Case Series

BackgroundInvasive pulmonary aspergillosis (IPA) has been reported in critically ill patients without pre-existing immunocompromising conditions. However, there are scant data on pulmonary aspergillosis in patients with COVID-19.MethodsWe performed a retrospective review of pharmacy records of antifungal use during 3/21-4/22, 2020, and collect longitudinal clinical data. Cases were then classified by the clinical algorithm for IPA in the ICU (AspICU).Results7 out of 18 (39%) patients who received antifungal therapy had Aspergillus fumigatus in tracheal aspirate specimens while mechanically ventilated in the ICU. None of the patients had EORTC/MSG host factors. Median time from admission to the date of positive respiratory culture was 9 days (range: 2-15). High-dose glucocorticoids were started a mean of 5.6 days (range 3-8) before the positive respiratory culture in 5 and on the day of the culture in 2. Six received 583-1000 mg equivalent of prednisone. Two received Tocilizumab. By AspICU criteria, 4 had putative IPA. Radiographic abnormalities included cavitary pneumonia, opacities with dense consolidation, worsening infiltrates, and diffuse interstitial and patchy hazy opacities. Compatible signs included worsening respiratory failure in 3 and fever after 3 days of antibacterial agents in 1. Associated findings were leukocytosis in 4, > 1 positive cultures in 3, high procalcitonin in 2, and positive serum galactomannan in 1. The remaining three were classified as colonization as they lacked compatible signs. One had concomitant Klebsiella aerogenes pneumonia with bacteremia, and two later developed Candidemia and Stenotrophomonas maltophilia pneumonia, respectively. All 3 had fever with leukocytosis. One had elevated procalcitonin. Six received antifungal therapy; one did not due to goals of care. All 7 patients expired despite ICU care.ConclusionThe critically ill patients with severe COVID-19 in whom respiratory culture grew Aspergillus fumigatus showed very high mortality despite antifungal treatment. By AspICU algorithm, 4 patients had putative IPA. Further data on risk factors and clinical predictors of IPA in COVID-19 are needed.Disclosures All Authors: No reported disclosures

384. Invasive aspergillosis in COVID-19 patients in an intensive care unit in Mexico City

BackgroundAn elevated incidence of invasive pulmonary aspergillosis (IPA) in patients with COVID-19 without traditional risk factors for IPA has been recently reported around the world. This co-infection has been described in patients requiring treatment in an intensive care unit. The risk factors for its development are still unclear.MethodsWe conducted a nested case-control study using the COVID-19 registry of the ARMII study group, based in the Centro Médico ABC, a private hospital in Mexico City. We included all patients that required admission to the intensive care unit (ICU) from March 12 to June 15, 2020, and excluded patients without serum galactomannan measurements or bronchial secretion cultures. We used the modified definition of IPA proposed by Schauwvlieghe et al for IPA in influenza patients. The control group was formed by patients with ruled-out IPA (negative galactomannan and secretion cultures). We compared both groups to identify risk factors for IPA using the chi-squared test or the Mann-Whitney U test as applicable.ResultsOut of a total 239 patients, 54 met the inclusion criteria. We identified 13 patients with IPA (24.07%) that met the definition of IPA (2 with positive cultures and 11 with positive galactomannan) and 41 without IPA. Only three patients with IPA had important comorbidities (COPD, chronic kidney disease, and HIV). Patients with IPA tended to have a higher median age (64.6 vs 53.59, p=0.075) and a higher serum glucose at their arrival (145 vs 119, p=0.028). All patients with IPA presented to the hospital with ARDS (100% vs 72.5%, p=0.034), but ultimately did not have a higher requirement for mechanical ventilation (100% vs 82.93%, p=0.110). There were no statistical significant differences in use of Tocilizumab, use of glucocorticoids, mortality (23.07% vs 17.50%, p=0.563) or length of stay.ConclusionIt has been previously described that patients with acute respiratory disease syndrome triggered by viral infection, like the influenza virus, are prone to invasive aspergillosis even in the absence of underlying immunodeficiency. The use of antifungals to prevent aspergillosis in COVID-19 patients should be assessed because of the gravity presented in the patients with this co-infection.Disclosures All Authors: No reported disclosures

366. Characteristics and Outcomes of COVID-19 Patients with Fungal Infections

BackgroundThere is concern that patients with coronavirus disease 2019 (COVID-19) are at risk of developing secondary bacterial and fungal infections; however, data on the clinical characteristics and outcomes of COVID-19 patients with fungal infections are limited. We evaluated the risk factors and mortality of hospitalized COVID-19 patients with fungal infections.MethodsThis was a retrospective chart review of 51 patients with fungal infections at an 877-bed teaching hospital in Detroit, Michigan from March through May 2020. Demographic data, comorbidities, complications, treatment, and outcomes, including relapse, readmission and mortality were collected. We performed a descriptive analysis.ResultsA total of 51 patients with fungal infections were included, in which 31 (60.8%) had confirmed or suspected COVID-19 infection. Of the COVID-19 patients, the average age was 66 years and the majority (54.9%) were female. The average length of stay (LOS) was 29.3 days. Aspergillus sp. (2 A. fumigatus, 1 A. niger) were isolated in 3 (10%) patients while 23 (74.2%) had candidemia diagnosed via blood culture or T2Candida® Panel. One had a positive serum galactomannan. The average time from admission to diagnosis was 13 days. Significant comorbidities included hypertension (74%), diabetes (51.6%), coronary artery disease (25.8%), congestive heart failure (32.2%), chronic kidney disease (22.6%), and malignancy (16.1%). Most patients received steroids (83.9%) and broad-spectrum antibiotics (80.6%), had a central line (80.6%), and required intensive care unit management (90%). Only 71% were treated with antifungals. One patient with candidemia relapsed due to poor source control; two were readmitted within 30 days. In-hospital mortality rate was 51.6% among COVID-19 patients.ConclusionCOVID-19 patients with fungal infections had multiple comorbidities, prolonged hospitalization and predisposing risk factors for fungal infections with a high in-hospital mortality rate. Prevention of fungal infections in COVID-19 patients is paramount.Disclosures All Authors: No reported disclosures

Invasive pulmonary aspergillosis in the COVID-19 era: An expected new entity.

ObjectivesInformation on the recently COVID‐19‐associated pulmonary aspergillosis (CAPA) entity is scarce. We describe eight CAPA patients, compare them to colonised ICU patients with coronavirus disease 2019 (COVID‐19), and review the published literature from Western countries.MethodsProspective study (March to May, 2020) that included all COVID‐19 patients admitted to a tertiary hospital. Modified AspICU and European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria were used.ResultsCOVID‐19‐associated pulmonary aspergillosis was diagnosed in eight patients (3.3% of 239 ICU patients), mostly affected non‐immunocompromised patients (75%) with severe acute respiratory distress syndrome (ARDS) receiving corticosteroids. Diagnosis was established after a median of 15 days under mechanical ventilation. Bronchoalveolar lavage was performed in two patients with positive Aspergillus fumigatus cultures and galactomannan (GM) index. Serum GM was positive in 4/8 (50%). Thoracic CT scan findings fulfilled EORTC/MSG criteria in one case. Isavuconazole was used in 4/8 cases. CAPA‐related mortality was 100% (8/8). Compared with colonised patients, CAPA subjects were administered tocilizumab more often (100% vs. 40%, p = .04), underwent longer courses of antibacterial therapy (13 vs. 5 days, p = .008), and had a higher all‐cause mortality (100% vs. 40%, p = .04). We reviewed 96 similar cases from recent publications: 59 probable CAPA (also putative according modified AspICU), 56 putative cases and 13 colonisations according AspICU algorithm; according EORTC/MSG six proven and two probable. Overall, mortality in the reviewed series was 56.3%.ConclusionsCOVID‐19‐associated pulmonary aspergillosis must be considered a serious and potentially life‐threatening complication in patients with severe COVID‐19 receiving immunosuppressive treatment.

Diagnostic value of galactomannan in serum and bronchoalveolar lavage fluid for invasive pulmonary aspergillosis in non-neutropenic patients

Objective: To evaluate the diagnostic performance of galactomannan (GM) detection in serum and bronchoalveolar lavage fluid (BALF) for invasive pulmonary aspergillosis (IPA) in non-neutropenic patients. Methods: A total of 291 non-neutropenic patients in the Second Xiangya Hospital of Central South University were included. According to the 2019 EORTC/MSG guidelines, all cases were divided into an IPA group (n = 24) and a non-IPA group (n = 267). Receiver operating characteristic (ROC) curves were drawn to compare the diagnostic efficiency of GM detection in BALF and serum. Results: According to the receiver operating characteristic curves of BALF and serum GM, the areas under the curve were 0.961 and 0.699, respectively. The optimal BALF GM detection was found when the cutoff value was set to 0.87, whereas the sensitivity and specificity were 91.7% and 92.5%, respectively. Conclusions: BALF GM detection is more sensitive than serum GM detection for diagnosing IPA, and the optimal cutoff value for BALF GM is 0.87.

Liquid Biopsy for Invasive Mold Infections in Hematopoietic Cell Transplant Recipients With Pneumonia Through Next-Generation Sequencing of Microbial Cell-Free DNA in Plasma.

Noninvasive diagnostic options are limited for invasive mold infections (IMIs). We evaluated the performance of a plasma microbial cell-free DNA sequencing (mcfDNA-Seq) test for diagnosing pulmonary IMI after hematopoietic cell transplant (HCT). We retrospectively assessed the diagnostic performance of plasma mcfDNA-Seq next-generation sequencing in 114 HCT recipients with pneumonia after HCT who had stored plasma obtained within 14 days of diagnosis of proven/probable Aspergillus IMI (n = 51), proven/probable non-Aspergillus IMI (n = 24), possible IMI (n = 20), and non-IMI controls (n = 19). Sequences were aligned to a database including >400 fungi. Organisms above a fixed significance threshold were reported. Among 75 patients with proven/probable pulmonary IMI, mcfDNA-Seq detected ≥1 pathogenic mold in 38 patients (sensitivity, 51% [95% confidence interval {CI}, 39%-62%]). When restricted to samples obtained within 3 days of diagnosis, sensitivity increased to 61%. McfDNA-Seq had higher sensitivity for proven/probable non-Aspergillus IMI (sensitivity, 79% [95% CI, 56%-93%]) compared with Aspergillus IMI (sensitivity, 31% [95% CI, 19%-46%]). McfDNA-Seq also identified non-Aspergillus molds in an additional 7 patients in the Aspergillus subgroup and Aspergillus in 1 patient with possible IMI. Among 19 non-IMI pneumonia controls, mcfDNA-Seq was negative in all samples, suggesting a high specificity (95% CI, 82%-100%) and up to 100% positive predictive value (PPV) with estimated negative predictive values (NPVs) of 81%-99%. The mcfDNA-Seq assay was complementary to serum galactomannan index testing; in combination, they were positive in 84% of individuals with proven/probable pulmonary IMI. Noninvasive mcfDNA-Seq had moderate sensitivity and high specificity, NPV, and PPV for pulmonary IMI after HCT, particularly for non-Aspergillus species.

Comparison of β-D-Glucan and Galactomannan in Serum for Detection of Invasive Aspergillosis: Retrospective Analysis with Focus on Early Diagnosis.

The early diagnosis of invasive aspergillosis (IA) relies mainly on computed tomography imaging and testing for fungal biomarkers such as galactomannan (GM). We compared an established ELISA for the detection of GM with a turbidimetric assay for detection of the panfungal biomarker β-D-glucan (BDG) for early diagnosis of IA. A total of 226 serum specimens from 47 proven and seven probable IA cases were analysed. Sensitivity was calculated for samples obtained closest to the day of IA-diagnosis (d0). Additional analyses were performed by including samples obtained during the presumed course of disease. Most IA cases involved the respiratory system (63%), and Aspergillus fumigatus was the most frequently isolated species (59%). For proven cases, sensitivity of BDG/GM analysis was 57%/40%. Including all samples dating from –6 to +1 weeks from d0 increased sensitivities to 74%/51%. Sensitivity of BDG testing was as high as or higher than GM testing for all subgroups and time intervals analysed. BDG testing was less specific (90–93%) than GM testing (99–100%). Combining BDG and GM testing resulted in sensitivity/specificity of 70%/91%. Often, BDG testing was positive before GM testing. Our study backs the use of BDG for diagnosis of suspected IA. We suggest combining BDG and GM to improve the overall sensitivity.

PULMONARY CAVITARY TB IN A PATIENT WITH SARS COV 2 PNEUMONIA

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: COVID-19 disease caused by SARS COV 2 can lead to severe disease with pneumonia, respiratory failure, and death. Pathologic mechanisms include a cytokine storm with an elevated IL-6 level. Tocilizumab (TCZ), a monoclonal antibody that inhibits IL-6 receptors, has been used as a potential therapeutic intervention. We report a case of rapidly progressive tuberculosis (TB) following TCZ and steroid use. CASE PRESENTATION: A 44-year-old male was placed on invasive mechanical ventilation for worsening hypoxia due to SARS COV 2 pneumonia. Other interventions included high dose steroids, with a cumulative dose of 675 mg over 8 days, and a single dose of 400 mg of TCZ. The Quantiferon TB (QT TB) test performed on day 2 of steroid administration and prior to TCZ use was negative. His respiratory status improved and he was subsequently extubated. One week later, he developed fever with leukocytosis. Respiratory, blood, urine, and fungal cultures, as well as serum galactomannan were negative. Repeat chest X-ray showed persistent multifocal infiltrates. Chest CT scan showed a 6.6 x 9.4 x 9.5 cm soft tissue density consolidation within the right lower lobe with multiple intralesional airspaces. Despite treatment with broad-spectrum antibacterial and antifungal agents, fever and leukocytosis persisted. A second scan revealed increased size of the cavity, from 6 cm to 8 cm, along with multifocal bronchiectasis and bronchiolectasis throughout the right upper lobe, and increased bronchiolectasis and bronchiectasis in right upper, middle and bilateral lower lobes. Three acid-fast bacillus smears of sputum were found to be positive 3+ and the isolate was subsequently identified as Rifampin-susceptible Mycobacterium tuberculosis (MTB). He improved after initiation of a four drug anti-TB treatment with prompt resolution of fever and leukocytosis. Upon further questioning, the patient reported that he had had a positive PPD test in the past after traveling to and from Haiti multiple times and was treated for 3 months in the last 10 years or so. DISCUSSION: This case illustrates the potential for reactivation of latent TB infection with rapid progression to cavitary disease following the use of corticosteroid and TCZ for severe COVID-19. It is possible that prior administration of corticosteroid could have led to a false negative QT TB test. Dual TCZ and corticosteroid likely contributed to impaired MTB host defenses and to the reactivation of incompletely treated latent MTB infection. CONCLUSIONS: Rapidly progressive cavitary TB can follow the concomitant use of TCZ and high dose steroids for COVID-19. Complete TB history, along with TB screening before use could increase the detection of latent TB infection and trigger appropriate interventions to reduce the risk of reactivation of latent TB infection. Reference #1: Russell B, Moss C, Rigg A, Van Hemelrijck M. COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting?. Ecancermedicalscience 2020;14:1023. Reference #2: Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center experience [published online ahead of print, 2020 Apr 6]. J Med Virol 2020;10.1002. Reference #3: Sotgiu G, Saderi L, Petruccioli E, Aliberti S, Piana A, Petrone L, Goletti D. Quantiferon TB Gold for the diagnosis of tuberculosis: a systematic review and meta-analysis. J Infect 2019;79:444-453. DISCLOSURES: No relevant relationships by Amna Aijaz, source=Web Response No relevant relationships by Svetlana Chernyavsky, source=Web Response Scientific Medical Advisor relationship with Gilead Please note: $1001 - $5000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with VIIV Please note: $1001 - $5000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with Janssen Please note: $1001 - $5000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with Theratechnologies Please note: $1-$1000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Honoraria Stock Owner relationship with TXMD Please note: $5001 - $20000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Ownership interest No relevant relationships by Arielle Sasson, source=Web Response

ASPERGILLUS EMPYEMA IN A LUNG TRANSPLANT PATIENT

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Fungal empyema thoracis is an uncommon entity with reported mortality rates as high as 73% [1]. Here we report a case of aspergillus empyema with associated cutaneous lesion in a lung transplant patient. CASE PRESENTATION: A 70 year old man who had undergone left lung transplant 5 years prior for chronic hypersensitivity pneumonitis, on immune suppressive therapy with tacrolimus, mycophenolate and prednisone presented with 3 months of weight loss, generalized weakness and confusion. He noted a stable chronic cough productive of clear phlegm, without dyspnea, hemoptysis, fever or night sweats. Approximately 3 months prior to presentation, while undergoing treatment for squamous cell carcinoma of the scalp, he had an anterior chest wall mass excised, histopathology notable for severe acute inflammation and narrow septate hyphal elements. Serum and bronchoalveolar lavage fluid galactomannan levels at that time were not detected, and treatment with systemic antifungals was deferred. On hospitalization, he was well-appearing with normal oxyhemoglobin saturation on room air. Limited bedside ultrasound examination demonstrated a large multi-loculated pleural effusion. Computed tomography imaging revealed severe traction bronchiectasis and fibrosis of native right lung and a large right sided pleural effusion. Diagnostic thoracentesis yielded a hazy yellow exudate with a pH 6.99, LDH of 1462 U/L, total protein 2.2 g/dL, and glucose 256 mg/dL. Fluid culture revealed 2+ Aspergillus fumigatus, consistent with a diagnosis of aspergillus fumigatus. He underwent treatment with oral isavuconazole and intrapleural tPA/dornase alpha via a pleural pigtail catheter. Unfortunately, the effusion persisted; surgical options were reviewed with patient, who elected to defer surgery and discharge home with hospice. DISCUSSION: Aspergillus empyema thoracis is an uncommon disease which mostly occurs in patients with established empyema or bronchiectectatic cavities and a bronchopleural or pleurocutaneous fistula [2]. In our case, early manifestations of invasive aspergillosis were subtle, and diagnosis elusive until the disease was advanced. CONCLUSIONS: Fungal empyema thoracis is an important differential consideration for pleural effusion in patients with chronic immune suppression, solid organ or hematologic malignancy. Mortality for this condition is high, particularly if not recognized and treated appropriately. Reference #1: Ko, SC et al. Fungal empyema thoracis: an emerging clinical entity. Chest, 2000; 117(6):1672-8. Reference #2: Zhang, W. et al. Pleural aspergillosis complicated by recurrent pneumothorax: a case report. J Med Case Rep, 2010. 4: p 180. DISCLOSURES: No relevant relationships by Nicholas Braus, source=Web Response No relevant relationships by Timothy Rowe, source=Web Response

Modeling Invasive Aspergillosis: How Close Are Predicted Antifungal Targets?

Animal model systems are a critical component of the process of discovery and development of new antifungal agents for treatment and prevention of invasive aspergillosis. The persistently neutropenic rabbit model of invasive pulmonary aspergillosis (IPA) has been a highly predictive system in identifying new antifungal agents for treatment and prevention of this frequently lethal infection. Since its initial development, the persistently neutropenic rabbit model of IPA has established a strong preclinical foundation for dosages, drug disposition, pharmacokinetics, safety, tolerability, and efficacy for deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B colloidal dispersion, caspofungin, micafungin, anidulafungin, voriconazole, posaconazole, isavuconazole, and ibrexafungerp in treatment of patients with invasive aspergillosis. The findings of combination therapy with a mould-active triazole and an echinocandin in this rabbit model also predicted the outcome of the clinical trial for voriconazole plus anidulafungin for treatment of IPA. The plasma pharmacokinetic parameters and tissue disposition for most antifungal agents approximate those of humans in persistently neutropenic rabbits. Safety, particularly nephrotoxicity, has also been highly predictive in the rabbit model, as exemplified by the differential glomerular filtration rates observed in animals treated with deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion. A panel of validated outcome variables measures therapeutic outcome in the rabbit model: residual fungal burden, markers of organism-mediated pulmonary injury (lung weights and infarct scores), survival, and serum biomarkers. In selected antifungal studies, thoracic computerized tomography (CT) is also used with diagnostic imaging algorithms to measure therapeutic response of pulmonary infiltrates, which exhibit characteristic radiographic patterns, including nodules and halo signs. Further strengthening the predictive properties of the model, therapeutic response to successfully developed antifungal agents for treatment of IPA has been demonstrated over the past two decades by biomarkers of serum galactomannan and (1→3)-β-D-glucan with patterns of resolution, that closely mirror those documented responses in patients with IPA. The decision to move from laboratory to clinical trials should be predicated upon a portfolio of complementary and mutually validating preclinical laboratory animal models studies. Other model systems, including those in mice, rats, and guinea pigs, are also valuable tools in developing clinical protocols. Meticulous preclinical investigation of a candidate antifungal compound in a robust series of complementary laboratory animal models will optimize study design, de-risk clinical trials, and ensure tangible benefit to our most vulnerable immunocompromised patients with invasive aspergillosis.

Effect of an oral probiotic nutraceutical containing Aspergillus-derived ingredients on a serum and urine galactomannan antigen assay in dogs

A commercial Aspergillus galactomannan antigen (GMA) enzyme linked immunosorbent assay (ELISA) is used to support a diagnosis of systemic aspergillosis in dogs. In human patients, false positive results have been associated with administration of medications derived from molds. We sought to determine the effect of administration of a commercially available oral probiotic nutraceutical that contained Aspergillus-derived ingredients on serum and urine Aspergillus GMA levels in dogs by conducting a prospective, cross-over study. Galactomannan index (GMI) was measured on the solubilized probiotic nutraceutical and was positive (GMI ≥ 0.5) with a mean of 7.91. Serum and urine galactomannan indices were measured in 10 healthy dogs before (day 0) and after 1 week (day 7) of probiotic nutraceutical administration, then again 2 weeks after the probiotic nutraceutical was discontinued (day 21).Median (range) serum GMI were 0.19 (0.08–0.62), 0.22 (0.07–1.15) and 0.17 (0.14–0.63) at day 0, 7 and 21, respectively. Two of 10 dogs developed positive GMI (≥0.5) results after probiotic nutraceutical administration; however, no significant changes were noted over the study period. Median (range) urine GMI results were 0.06 (0.04–0.22), 0.07 (0.05–0.41) and 0.06 (0.03–0.16) at day 0, 7 and 21, respectively. A trend towards an increase urine GMI was noted between day 0 and 7 (P = 0.18), and decrease was noted between day 7 and 21 (P = 0.09). Administration of probiotics containing Aspergillus-derived ingredients to dogs did not reliably result in elevated Aspergillus GMA levels.

Role of Serum (1,3)-Β-D-Glucan to Screen for Pneumocystis Pneumonia in Kidney Transplant Recipients

BackgroundPneumocystis pneumonia is a common opportunistic infection in kidney transplant recipients caused by the ascomycetous fungi Pneumocystis jirovecii. Its clinical presentation of a progressive nonproductive cough, shortness of breath, and fever is nonspecific and often delays diagnosis and appropriate treatment. Moreover, the plain radiograph may show a spectrum of findings from normal to bilateral diffuse infiltrates. Detection of serum (1,3)-β-D-glucan along with consistent clinical findings can be used as early screening tools to diagnose and initiate treatment for Pneumocystis pneumonia pending confirmation by bronchoscopy. MethodsThis case series describes 6 kidney transplant recipients who were diagnosed as having Pneumocystis pneumonia. The baseline demographic variables, presenting symptoms, radiographic findings, laboratory findings including lactate dehydrogenase and serum (1,3)-β-D-glucan levels, bronchoscopy findings, and its timing in relation to a positive serum (1,3)-β-D-glucan test, and response to treatment were collected. ResultsAll 6 patients who completed the first 3 months of prophylaxis against Pneumocystis pneumonia with sulfamethoxazole-trimethoprim were diagnosed as having Pneumocystis pneumonia between 2 to 24 years post transplant. They initiated treatment early based on a positive serum (1,3)-β-D-glucan and negative Histoplasma antigen and serum galactomannan test with a presumptive diagnosis of Pneumocystis pneumonia, which was later confirmed with a positive polymerase chain reaction on bronchoalveolar lavage fluid. ConclusionsPneumocystis pneumonia is a common opportunistic fungal infection in immunosuppressed kidney transplant recipients, and use of serum (1,3)-β-D-glucan can be used as an initial screening test for its early diagnosis and treatment.

908P Impact of serum galactomannan assay on diagnosis and outcome of invasive fungal infections in high risk febrile neutropenia: A prospective cohort study

908P Impact of serum galactomannan assay on diagnosis and outcome of invasive fungal infections in high risk febrile neutropenia: A prospective cohort study

Role of Voriconazole in the Management of Invasive Central Nervous System Aspergillosis: A Case Series from a Tertiary Care Centre in India

Invasive central nervous system (CNS) aspergillosis is acquired by either hematogenous dissemination or direct spread from a sinus infection. We describe a series of nine patients with CNS aspergillosis from a tertiary care teaching institute in North India who were treated with voriconazole alone or in combination with surgery. All patients who had clinical and radiological features consistent with fungal CNS infection, showed the presence of septate hyphae on histopathology/microscopy and were either culture positive for Aspergillus spp. or had serum galactomannan positivity were diagnosed as CNS aspergillosis. Clinical features, risk factors, diagnostic modalities, treatment details and outcome at last follow-up were recorded for all patients diagnosed with CNS aspergillosis. A total of nine patients were diagnosed with CNS aspergillosis. The median duration of presentation at our hospital was six months (IQR-2-9 months). Six patients had concomitant sinus involvement, while two patients had skull-base involvement as well. All patients were treated with voriconazole therapy, and three of these patients underwent surgery. All but one patient survived at the last follow-up (median duration was 14 months (IQR- 8-21.5). Two patients had complete resolution, and voriconazole was stopped at the last follow-up, and the rest of the patients were continued on voriconazole. Of the six patients who were continued on voriconazole, all but one had more than 50% radiological resolution on follow-up imaging. Invasive CNS aspergillosis is an important cause of CNS fungal infection that is often diagnosed late and requires long-term voriconazole-based therapy.

Abstract 494: Mitral to Meninges: Aspergillus Endocarditis With Septic Emboli

Introduction: Fungal endocarditis comprises less than 2% of infective endocarditis, with Aspergillus causing less than 28% of fungal endocarditis. Fungal endocarditis should be suspected in immunocompromised patients with persistent fevers, negative blood cultures, and vegetation on echocardiography. Invasive Aspergillus can affect any organ, but typically begins in the respiratory tract. Mortality rates climb to 90% with signs of hematogenous spread, such as cerebral abscesses. Case Presentation: Patient is a 53-year-old female with a past medical history of Sweet syndrome and chronic pancreatitis. Patient was admitted for persistent fevers and confusion. Patient was tachycardic but normotensive with a temperature of 102.5 F. Labs included significantly elevated serum LDH and Beta-D-Glucan. Blood cultures remained negative. Lumbar puncture cultures were negative; CSF cytology revealed pleocytosis with positive Aspergillus galactomannan serum antigen. Head MRI revealed multiple peripherally enhancing supratentorial lesions and intracranial abscesses (largest 8.4 mm) with ventriculitis of lateral ventricles, right greater than left. Transesophageal Echocardiogram (TEE) revealed mitral valve vegetation at A2 segment, no surrounding perivalvular abscess, minimal mitral regurgitation (MR). Management: Antibiotics were discontinued and patient was counseled on avoiding glucocorticoids. Patient was transferred to large tertiary center for Neurosurgery evaluation but was not candidate for biopsy/aspiration of the ring-enhancing lesions per Neurosurgery. Cardiothoracic Surgery was also consulted and patient was not a candidate for mitral valve replacement due to small size of vegetation without abscess and only mild MR. Voriconazole was continued and patient ultimately demonstrated a slow improvement in her strength and mental status over the next 6 months. Discussion: Mitral endocarditis from Aspergillus is rare but has a very high mortality rate. This case illustrates the importance of early recognition of systemic fungal infections in the setting of immunosuppression. Glucocorticoids and broad-spectrum antibiotics placed this patient at elevated risk for invasive Aspergillosis, which led to mitral endocarditis and subsequent cerebral abscesses from septic emboli.

Is the COVID-19 Pandemic a Good Time to Include Aspergillus Molecular Detection to Categorize Aspergillosis in ICU Patients? A Monocentric Experience.

(1) Background: The diagnosis of invasive aspergillosis (IA) in an intensive care unit (ICU) remains a challenge and the COVID-19 epidemic makes it even harder. Here, we evaluated Aspergillus PCR input to help classifying IA in SARS-CoV-2-infected patients. (2) Methods: 45 COVID-19 patients were prospectively monitored twice weekly for Aspergillus markers and anti-Aspergillus serology. We evaluated the concordance between (I) Aspergillus PCR and culture in respiratory samples, and (II) blood PCR and serum galactomannan. Patients were classified as putative/proven/colonized using AspICU algorithm and two other methods. (3) Results: The concordance of techniques applied on respiratory and blood samples was moderate (kappa = 0.58 and kappa = 0.63, respectively), with a higher sensitivity of PCR. According to AspICU, 9/45 patients were classified as putative IA. When incorporating PCR results, 15 were putative IA because they met all criteria, probably with a lack of specificity in the context of COVID-19. Using a modified AspICU algorithm, eight patients were classified as colonized and seven as putative IA. (4) Conclusion: An appreciation of the fungal burden using PCR and Aspergillus serology was added to propose a modified AspICU algorithm. This proof of concept seemed relevant, as it was in agreement with the outcome of patients, but will need validation in larger cohorts.

Low Rate of Invasive Fungal Infections During Induction and Consolidation Chemotherapy for Adults with De Novo Acute Myeloid Leukemia Without Anti-mold Prophylaxis: Single-Center 2002-2018 Empirical/Pre-emptive Approach.

Broad-spectrum antifungal prophylaxis is currently considered the standard of care for adults with de novo AML for the prevention of invasive fungal infections (IFIs), especially invasive pulmonary aspergillosis (IPA). Because fluconazole has been used in our center as anti-yeast prophylaxis, we sought to analyze in detail the incidence of IFIs over a 17-year period, as well as their impact on outcome. A standardized protocol of patient management, including serum galactomannan screening and thoracic CT-guided diagnostic-driven antifungal therapy, was used in all patients. A total of 214 consecutive adults with de novo AML who were treated in 3 CETLAM (Grupo Cooperativo para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias) protocols from 2002 to 2018 were included. The 90-day incidence of any IFI (including possible cases) was 11% (95% CI 4-15%), most cases occurred during induction chemotherapy (8%, 95% CI 4-12%), and most cases were probable/proven IPA (8%, 95% CI 3-13%). Developing an IFI during induction and consolidation had no impact on 1-year survival. A case-control study with 23 cases of IPA and 69 controls identified induction/re-induction chemotherapy, chronic pulmonary disease and age > 60 years/poor baseline performance status as potential pretreatment risk factors. The current study proves that inpatient induction and consolidation chemotherapy for de novo AML can be given in areas with "a priori" high-burden of airborne molds with fluconazole prophylaxis, while the selective use of anti-mold prophylaxis in patients at very high risk may further reduce the incidence of IFI in this specific clinical scenario.

Serum galactomannan level for the diagnosis of invasive pulmonary aspergillosis in hospitalized patients with chronic obstructive pulmonary disease (COPD): Meta-analysis

Background: The serum galactomannan (GM) assay is used to diagnose invasive pulmonary aspergillosis (IPA). We conducted a meta-analysis to assess the overall accuracy of the serum GM test for detecting IPA in critically ill COPD patients. Methods: The web of science, Pubmed, Embase, China National Knowledge Infrastructure, WanFang, Weipu (VIP) Science China databases were searched for all the eligible studies, including randomized controlled trials and prospective studies up to February 2019. We selected and assessed articles that reported diagnostic data related to serum GM for diagnosis of invasive fungal disease in hospitalized COPD patients. Additionally, pooled sensitivity (SEN), specificity (SPE), true positive (TP), false positive (FP), true negative (TN), false negative (FN) were estimated for summarizing overall test performance. Results: Of 1104 articles screened, 14 studies were involved in the meta-analysis with 1127 patients in the COPD serum sample. The pooled serum GM assay results with cutoff value of 0.5 were as follows: DOR: 15 (95% CI, 6–38), sensitivity: 0.57 (95% CI, 0.37–0.75), specificity: 0.92 (95%,CI, 0.85–0.96), and the SROC was 0.89 (95% CI, 0.86–0.91). When the cutoff value was 1, the results were as follows: DOR: 33 (95% CI, 15–70), sensitivity: 0.57 (95% CI, 0.39–0.73), specificity: 0.96 (95% CI, 0.93–0.98), and SROC was 0.95 (95% CI, 0.92–0.96). Conclusion: Serum GM can be used to assist in diagnosis of IPA in critically ill COPD patients. When cutoff value was set as 1, serum GM had better diagnostic value compared to those with cutoff of 0.5.