Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies.

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

Oral Antibiotics for Treatment of Gram-Negative Bacteremia in Solid Organ Transplant Recipients: A Propensity Score Weighted Retrospective Observational Study.

BACKGROUND: We assessed the safety and efficacy of oral antibiotic step-down therapy for uncomplicated gram-negative blood stream infections in solid organ transplant recipients. METHODS: We identified all solid organ transplant recipients within the Massachusetts General and Brigham and Women's Hospital systems from 2016-2021 with uncomplicated gram-negative bacteremia involving an organism susceptible to an acceptably bioavailable oral antibiotic agent. Using inverse probability of treatment-weighted models based on propensity scores adjusting for potential clinical confounders, we compared outcomes of those transitioned to oral antibiotics vs those who continued IV therapy for the duration of treatment. Primary endpoints were mortality, bacteremia recurrence and re-initiation of IV antibiotics. Secondary endpoints included length of stay, C. difficile infection, treatment associated complications and tunneled central venous catheter placement. RESULTS: 120 bacteremia events from 107 patients met inclusion criteria in the oral group and 42 events from 40 patients in the IV group. There were no significant differences in mortality, bacteremia recurrence, or re-initiation of IV antibiotics between groups. Patients transitioned to oral antibiotics had an average length of stay that was 1.97 days shorter (95% CI -0.39, 3.56 days. p = 0.005). Odds of developing C. difficile and other treatment associated complications were 8.4 times higher (95% CI 1.5, 46.6, p = 0.015) and 6.4 times higher (95% CI 1.9-20.9, p = 0.002), respectively, in the IV group. 55% of patients in the IV group required tunneled catheter placement. There was no difference in treatment duration between groups. CONCLUSIONS: Oral step-down therapy was effective and associated with fewer treatment-related adverse events.

Safety and tolerability study of sotrovimab (VIR-7831) prophylaxis against COVID-19 infection in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity.

BACKGROUND: Multiple vaccines have been approved since August 2021 to prevent infection with SARS-CoV-2; however, 20-40% of immunocompromised people fail to develop SARS-CoV-2 spike antibodies after COVID-19 vaccination and remain at high risk of infection and more severe illness than non-immunocompromised hosts. Sotrovimab (VIR-7831) is a monoclonal neutralizing antibody that binds a conserved epitope on the SARS-CoV-2 spike protein. It is neither renally excreted nor metabolized by P450 enzymes and therefore unlikely to interact with concomitant medications (e.g., immunosuppressive medications). In this open-label feasibility study protocol, we will define the optimal dose and dosing interval of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals as well as its safety and tolerability in this population specifically. METHODS: We will enroll 93 eligible immunocompromised adults with a negative or low-positive (< 50 U/mL) SARS-CoV-2 spike antibody. In phase 1, the first 10 patients will participate in a lead-in pharmacokinetics (PK) cohort study to determine the optimal dosing interval. Phase 2 will expand this population to 50 participants to examine rates of infusion-related reactions (IRR) with a 30-min 500 mg sotrovimab IV infusion. Phase 3 will be an expansion cohort for further assessment of the safety and tolerability of sotrovimab. In phase 4, the first 10 patients receiving 2000 mg IV of sotrovimab on the second sotrovimab infusion day will comprise a lead-in safety cohort that will inform the duration of observation following administration of the drug. The patients will be followed for safety and COVID-19 events for 36 weeks after the second dose. DISCUSSION: In a previous phase III randomized, placebo-controlled pivotal trial, there were no significant differences in the prevalence of adverse events in patients receiving sotrovimab vs. placebo. Thus, we propose an open-label feasibility study protocol of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals to evaluate its PK in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity and define optimal dosing intervals. We also aim to determine COVID-19 infections over the study period and self-reported quality of life measures throughout the study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05210101.

Blastomycosis in New England: 5 Cases and a Review.

The geographic range of blastomycosis is thought to include New England, but documentation is sparse. We report 5 cases of infection with Blastomyces dermatitidis that were likely acquired in New England between 2011 and 2021. Our experience suggests that chart coding for the diagnosis of blastomycosis is imprecise and that mandatory reporting might help resolve uncertainties about the prevalence and extent of blastomycosis.

Modulation of Tumor-Treating Fields by Cerebral Edema from Brain Tumors.

Purpose: Cerebral edema is an important component of brain metastasis, and its presence may alter the distribution of tumor-treating fields (TTFields). We therefore performed a computational study to model the extent of this alteration according to various edema conditions associated with the metastasis. Methods and Materials: Postacquisition magnetic resonance imaging data sets were obtained from 2 patients with solitary brain metastases from non-small cell lung cancer. After delineation of various anatomies, a 3-dimensional finite element mesh model was generated and then solved for the distribution of applied electric fields, rate of energy deposition, and current density at the gross tumor volume (GTV), edema, and other cranial structures. Electric field-volume histograms, specific absorption rate-volume histograms, and current density-volume histograms were generated, by which plan quality metrics were derived from and used to evaluate relative differences in field coverage between models under various conditions. Results: Changes in the conductivity of cerebral edema altered the electric fields, rate of energy deposition, and current density at the GTV region. At the cerebral edema region, increasing electric conductivity of the edema only decreased the electric fields and rate of energy deposition while the current density increased. The ratio of edema-to-tumor is also important because the plan quality metrics increased linearly when the edema-to-GTV ratio decreased, and increased vice versa. Furthermore, a conductive necrotic core additionally altered the distribution of TTFields according to the plan quality metrics. Conclusions: Our modeling study demonstrated that cerebral edema alters the distribution of applied TTFields in patients. Personalized treatment planning will need to take into account the modulating effects of cerebral edema on TTFields as well as additional effects from a necrotic core inside the GTV.

A consensus conference to define the utility of advanced infectious disease diagnostics in solid organ transplant recipients.

The last decade has seen an explosion of advanced assays for the diagnosis of infectious diseases, yet evidence-based recommendations to inform their optimal use in the care of transplant recipients are lacking. A consensus conference sponsored by the American Society of Transplantation (AST) was convened on December 7, 2021, to define the utility of novel infectious disease diagnostics in organ transplant recipients. The conference represented a collaborative effort by experts in transplant infectious diseases, diagnostic stewardship, and clinical microbiology from centers across North America to evaluate current uses, unmet needs, and future directions for assays in 5 categories including (1) multiplex molecular assays, (2) rapid antimicrobial resistance detection methods, (3) pathogen-specific T-cell reactivity assays, (4) next-generation sequencing assays, and (5) mass spectrometry-based assays. Participants reviewed and appraised available literature, determined assay advantages and limitations, developed best practice guidance largely based on expert opinion for clinical use, and identified areas of future investigation in the setting of transplantation. In addition, attendees emphasized the need for well-designed studies to generate high-quality evidence needed to guide care, identified regulatory and financial barriers, and discussed the role of regulatory agencies in facilitating research and implementation of these assays. Findings and consensus statements are presented.

Low incidence of invasive fungal disease following CD19 chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma.

CAR T-cell therapy has revolutionized the treatment of hematologic malignancies, although its use may be complicated by toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. Invasive fungal disease (IFD) has been reported after CAR T-cell therapy, but the incidence in the absence of antifungal prophylaxis is unknown. Optimal prophylaxis strategies are widely debated. We performed a single-center retrospective study of 280 adults receiving CD19 CAR T-cell therapy for non-Hodgkin lymphoma (NHL) from December 2017 through September 2021. Patients did not receive routine antiyeast or antimold prophylaxis. IFD was identified between day of cell infusion and last follow-up. Cumulative incidence functions were calculated at 100 days and 18 months based on time to IFD, using dates of IFD-free death, initiation of salvage treatment, and hematopoietic cell transplantation as competing risks. Eight patients (2.9%) developed IFD, including 3 Pneumocystis jirovecii pneumonia, 3 invasive mold infections (IMIs), and 2 invasive yeast infections (IYIs). The 100-day cumulative incidence of IFD accounting for competing risks was 1.8% (95% confidence interval [CI], 0.8% to 4.4%). Among the 280 patients, early toxicities including CRS (85%) and ICANS (55%) and late toxicities after day 30 including grades 3 and 4 neutropenia (41%) and low CD4 T-cell count (20%) were common. IFD was rare among patients who received CD19 CAR T-cell therapy for NHL in the absence of routine antifungal prophylaxis, despite frequent toxicities. These results suggest that, in settings with low institutional rates of IFD, routine antifungal prophylaxis may not be indicated.

Safety evaluation of Fy Protein™ (Nutritional Fungi Protein), a macroingredient for human consumption.

Fy Protein™ (Nutritional Fungi Protein) is a macro-ingredient produced from the fermentation of the fungal microorganism Fusarium strain flavolapis, isolated from springs in Yellowstone National Park. Fy Protein contains all of the essential amino acids plus fiber, fat, carbohydrates, vitamins, and minerals and is developed as an alternative to animal-based protein foods such as meat and dairy. Fy Protein's nutritional, digestibility, genotoxicity, allergenicity, toxicity, secondary metabolites, and pathogenicity were evaluated. Fy Protein did not show mutagenic or genotoxic potential in in vitro tests. In an allergenicity review, Fy Protein was found to be of low allergenic potential. In a 90-day sub chronic dietary study in rats, administration of Fy Protein did not produce any significant toxicologic manifestations, and the no observed effect level (NOAEL) was the highest-level fed of 150,000 ppm (15% in the diet). Regulated secondary metabolites from fungi (termed mycotoxins) were non-detectable and below regulated levels using quantitative analytical techniques. A literature review was completed to identify the potential human pathogenicity of Fusarium sp., showing that Fusarium rarely infects humans, with infections seldom developing even in immunocompromised individuals. The results of these studies confirm that Fy Protein from fermented F. str. flavolapis has low toxicological, genotoxic, pathogenic, and allergenic potential under the conditions tested and anticipated use.

Clarithromycin-Rifampin-Based Treatment for Nontuberculous Mycobacteria Infections in Immunocompromised Patients who Require Concomitant CYP-Metabolized Medications.

Clarithromycin (CYP inhibitor) can be used instead of azithromycin for nontuberculous mycobacteria therapy in patients requiring CYP substrates to mitigate rifampin's CYP induction. We found no differences in adverse events (10/13 vs 14/17; P = .73), drug intolerability (1/5 vs 4/11; P = 1), or 90-day mortality (0/13 vs 1/17; P = 1) in patients receiving clarithromycin vs azithromycin.

Breath-Based Diagnosis of Infectious Diseases: A Review of the Current Landscape.

Various analytical methods can be applied to concentrate, separate, and examine trace volatile organic metabolites in the breath, with the potential for noninvasive, rapid, real-time identification of various disease processes, including an array of microbial infections. Although biomarker discovery and validation in microbial infections can be technically challenging, it is an approach that has shown great promise, especially for infections that are particularly difficult to identify with standard culture and molecular amplification-based approaches. This article discusses the current state of breath analysis for the diagnosis of infectious diseases.

A eulogy for Dr Francisco Miguel Marty Forero.

As some of those who were lucky enough to have been mentored by Dr Francisco Marty in transplant infectious diseases, we stand with the larger medical community in mourning his untimely death and in commemorating him as a uniquely exceptional and talented physician, investigator, teacher, mentor, friend, artist, and human being.

The Evolving Landscape of Fungal Diagnostics, Current and Emerging Microbiological Approaches.

Invasive fungal infections are increasingly recognized in immunocompromised hosts. Current diagnostic techniques are limited by low sensitivity and prolonged turnaround times. We review emerging diagnostic technologies and platforms for diagnosing the clinically invasive disease caused by Candida, Aspergillus, and Mucorales.

Somatic GATA2 mutations define a subgroup of myeloid malignancy patients at high risk for invasive fungal disease.

Invasive fungal disease (IFD) can be a severe treatment complication in patients with myeloid malignancies, but current risk models do not incorporate disease-specific factors, such as somatic gene mutations. Germline GATA2 deficiency is associated with a susceptibility to IFD. To determine whether myeloid gene mutations were associated with IFD risk, we identified 2 complementary cohorts of patients with myeloid malignancy, based on (1) the diagnosis of invasive aspergillosis (IA), or (2) the presence of GATA2 mutations identified during standard clinical sequencing. We found somatic GATA2 mutations in 5 of 27 consecutive patients who had myeloid malignancy and developed IA. Among 51 consecutive patients with GATA2 mutations identified in the evaluation of myeloid malignancy, we found that IFD was diagnosed and treated in 21 (41%), all of whom had received chemotherapy or had undergone an allogeneic stem cell transplant. Pulmonary infections and disseminated candidiasis were most common. The 90-day mortality was 52% among patients with IFD. Our results indicate that patients with somatic GATA2 mutations are a vulnerable subgroup of patients with myeloid malignancy who have high risk for treatment-associated IFD and suggest that a focused approach to antifungal prophylaxis be considered.

Neuroimaging Markers for Studying Gulf-War Illness: Single-Subject Level Analytical Method Based on Machine Learning.

Gulf War illness (GWI) refers to the multitude of chronic health symptoms, spanning from fatigue, musculoskeletal pain, and neurological complaints to respiratory, gastrointestinal, and dermatologic symptoms experienced by about 250,000 GW veterans who served in the 1991 Gulf War (GW). Longitudinal studies showed that the severity of these symptoms often remain unchanged even years after the GW, and these veterans with GWI continue to have poorer general health and increased chronic medical conditions than their non-deployed counterparts. For better management and treatment of this condition, there is an urgent need for developing objective biomarkers that can help with simple and accurate diagnosis of GWI. In this study, we applied multiple neuroimaging techniques, including T1-weighted magnetic resonance imaging (T1W-MRI), diffusion tensor imaging (DTI), and novel neurite density imaging (NDI) to perform both a group-level statistical comparison and a single-subject level machine learning (ML) analysis to identify diagnostic imaging features of GWI. Our results supported NDI as the most sensitive in defining GWI characteristics. In particular, our classifier trained with white matter NDI features achieved an accuracy of 90% and F-score of 0.941 for classifying GWI cases from controls after the cross-validation. These results are consistent with our previous study which suggests that NDI measures are sensitive to the microstructural and macrostructural changes in the brain of veterans with GWI, which can be valuable for designing better diagnosis method and treatment efficacy studies.

Molecular Testing for Acute Respiratory Tract Infections: Clinical and Diagnostic Recommendations From the IDSA's Diagnostics Committee.

The clinical signs and symptoms of acute respiratory tract infections (RTIs) are not pathogen specific. Highly sensitive and specific nucleic acid amplification tests have become the diagnostic reference standard for viruses, and translation of bacterial assays from basic research to routine clinical practice represents an exciting advance in respiratory medicine. Most recently, molecular diagnostics have played an essential role in the global health response to the novel coronavirus pandemic. How best to use newer molecular tests for RTI in combination with clinical judgment and traditional methods can be bewildering given the plethora of available assays and rapidly evolving technologies. Here, we summarize the current state of the art with respect to the diagnosis of viral and bacterial RTIs, provide a practical framework for diagnostic decision making using selected patient-centered vignettes, and make recommendations for future studies to advance the field.

Correction to: Clinical experience with a novel assay measuring cytomegalovirus (CMV)-specific CD4+ and CD8+ T-cell immunity by flow cytometry and intracellular cytokine staining to predict clinically significant CMV events.

After publication of the original article [1], we were notified that an author's family name has been erroneously spelled. Aditya Chandrokar should be replaced with Aditya Chandorkar.

Clinical experience with a novel assay measuring cytomegalovirus (CMV)-specific CD4+ and CD8+ T-cell immunity by flow cytometry and intracellular cytokine staining to predict clinically significant CMV events.

BACKGROUND: Cytomegalovirus (CMV) infection is one of the most common opportunistic infections following organ transplantation, despite administration of CMV prophylaxis. CMV-specific T-cell immunity (TCI) has been associated with reduced rates of CMV infection. We describe for the first time clinical experience using the CMV T-Cell Immunity Panel (CMV-TCIP), a commercially available assay which measures CMV-specific CD4+ and CD8+ T-cell responses, to predict clinically significant CMV events. METHODS: Adult (> 18-year-old) patients with CMV-TCIP results and ≥ 1 subsequent assessment for CMV DNAemia were included at Brown University and the University of Maryland Medical Center-affiliated hospitals between 4/2017 and 5/2019. A clinically significant CMV event was defined as CMV DNAemia prompting initiation of treatment. We excluded indeterminate results, mostly due to background positivity, allogeneic hematopoetic cell transplant (HCT) recipients, or patients who were continued on antiviral therapy against CMV irrespective of the CMV-TCIP result, because ongoing antiviral therapy could prevent a CMV event. RESULTS: We analyzed 44 samples from 37 patients: 31 were solid organ transplant recipients, 4 had hematologic malignancies, 2 had autoimmune disorders. The CMV-protection receiver operating characteristic (ROC) area under the curve (AUC) was significant for %CMV-specific CD4+ (AUC: 0.78, P < 0.001) and borderline for CD8+ (AUC: 0.66, P = 0.064) T-cells. At a cut-off value of 0.22% CMV-specific CD4+ T-cells, positive predictive value (PPV) for protection against CMV was 85% (95%CI 65-96%), and negative predictive value (NPV) was 67% (95%CI 41-87%). CONCLUSIONS: The CMV-TCIP, in particular %CMV-specific CD4+ T-cells, showed good diagnostic performance to predict CMV events. The CMV-TCIP may be a useful test in clinical practice, and merits further validation in larger prospective studies.

Use of triazoles for the treatment of invasive aspergillosis: A three-year cohort analysis.

In a 3-year cohort study of adult patients with proven or probable IA, fewer patients initially treated with isavuconazole experienced adverse events compared with voriconazole, but more patients required a change in therapy due to lack of clinical efficacy.

Increased Risk of Infectious Complications in Older Patients With Indolent Non-Hodgkin Lymphoma Exposed to Bendamustine.

Background: Bendamustine is a potent chemotherapy agent increasingly used to treat indolent non-Hodgkin lymphoma (iNHL). While effective, it causes significant T-cell lymphopenia, which may increase risk of infection. We examined infectious complications associated with bendamustine-containing regimens among older patients with iNHL. Methods: For this Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort study, we identified 9395 patients with iNHL (follicular, marginal zone, Waldenström macroglobulinemia) treated with chemotherapy from 2006 to 2013. Thirteen percent received bendamustine-containing regimens. We compared baseline characteristics and infection incidence rates between patients treated with and without bendamustine. We conducted multivariate Cox proportional hazards regression (adjusting for demographics, comorbidities, disease and treatment characteristics, risk factors for infection, and antimicrobial prophylaxis) to determine infectious risks associated with bendamustine. Results: Bendamustine was associated with an increased risk of both common infections such as bacterial pneumonia (hazard ratio [HR], 1.50 [95% confidence interval {CI}, 1.21-4.85]) and opportunistic infections such as cytomegalovirus (HR, 3.98 [95% CI, 1.40-11.26]), varicella zoster virus (HR, 1.49 [95% CI, 1.18-1.89]), histoplasmosis (HR, 3.55 [95% CI, 1.10-11.42]), and Pneumocystis jirovecii pneumonia (when administered as third-line therapy: HR, 3.32 [95% CI, 1.00-11.11]). Risk of infections was more prominent in patients receiving bendamustine as part of later (third-line and above) regimens, and independently associated with well-established factors such as neutropenia and corticosteroid exposure. Conclusions: Bendamustine is associated with an increased risk of common and opportunistic infections in patients with iNHL. Further prospective investigation into the potential role of antimicrobial prophylaxis is needed in these patients.