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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.

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.

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.

Background: Since August 2021, multiple vaccines have been approved 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 an exceptionally high risk of infection and more severe illness than non-immunocompromised hosts. Sotrovimab (VIR-7831) is an engineered monoclonal antibody that targets a highly conserved epitope on the SARS-CoV-2 spike glycoprotein. It is neither renally excreted nor metabolized by P450 (CYP) enzymes; therefore, interactions with concomitant medications are unlikely, which is an important consideration for patients receiving multiple immunosuppressive medications. In this Phase II open-label safety and tolerability study protocol, we propose to evaluate the safety and tolerability of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals.Methods: We will enroll a total of 93 eligible immunocompromised adults with a negative or low-positive (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 to study the safety and tolerability of sotrovimab (VIR-7831) prophylaxis against COVID-19 infection and evaluate its PK in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity. We also aim to determine COVID-19 infections over the study period and self-reported quality of life measures over the course of the study.Trial registration: ClinicalTrials.gov Identifier: NCT05210101

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.

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.

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.

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.

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.

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.

Background Histoplasmosis is a common endemic fungal infection in the Americas, causing significant morbidity and mortality, particularly in immunocompromised patients. Existing diagnostic methods are limited in their sensitivity (especially in pulmonary histoplasmosis) and turnaround time. Methods We examined prospectively collected breath samples from 84 patients with suspected histoplasmosis 3/2019 - 2/2020 at Hospital Roosevelt (HR; Guatemala City, Guatemala, n = 56) and suspected invasive fungal disease 1/2018 - 10/2019 at Brigham and Women’s Hospital (BWH; Boston, MA, USA, n = 28) using thermal desorption gas chromatography-tandem mass spectrometry (TDU-GC-MS/MS). Patients were evaluated for histoplasmosis and other infections according to the local standard of care – of note, 18/56 patients at HR did not have Histoplasma urine antigen testing. Results Median age was 44 years, 60 (71%) were male, 23 (27%) had HIV, 15 (18%) had hematologic malignancy. 7 patients were diagnosed with histoplasmosis over the study period (4 at HR, 5 at BWH), with a clinical syndrome + positive Histoplasma urine or serum antigen test, with some patients also having yeast forms on tissue biopsy. 3 patients had disseminated and 4 pulmonary histoplasmosis. 4 patients with histoplasmosis had co-infections – 2 tuberculosis (TB), 1 influenza, and 1 Pneumocystis jirovecii (PJP) pneumonia. 4 patients were receiving antifungal therapy active against Histoplasma at the time of their first breath sample. We found 3 sesquiterpenes: (A) cyperene, (B) 1R,4aR,8aR)-2,5,5,8a-Tetramethyl-4,5,6,7,8,8a-hexahydro-1H-1,4a-methanonaphthalene, and (C) viridiflorol in patients with histoplasmosis, that distinguished these patients from those with other pneumonia (TB, coccidioidomycosis, invasive aspergillosis, mucormycosis, PJP, bacterial pneumonia) with 100% sensitivity and 70% (95% CI 59, 80) specificity. Figure 1. TDU GC-MS/MS spectral comparison in histoplasmosis vs. the other invasive mycoses aspergillosis or mucormycosis. A: Cyperene; B: (1R,4aR,8aR)-2,5,5,8a Tetramethyl-4,5,6,7,8,8a-hexahydro-1H-1,4a-methanonaphthalene; C: viridiflorol; D: 1H-Indene, 2,3,3a,4-tetrahydro-3,3a,6-trimethyl-1-(1-methylethyl)-; E: β-funebrene; F: trans-α-bergamotene; G: eremophilene; H: spathulenol; I: cedrene; J: cedranoxide, 8,14- Conclusion Conclusion: Patients with histoplasmosis have a unique secondary metabolite breath signature that can be used for the noninvasive diagnosis of pulmonary and disseminated histoplasmosis. Many patients in this cohort did not undergo urine antigen testing or other diagnostic workup for histoplasmosis, which may have affected our specificity estimates. Disclosures Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator)

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.

Respiratory tract infections (RTIs) drive many outpatient encounters and, despite being predominantly viral, are associated with high rates of antibiotic prescriptions. With rising antibacterial resistance, optimization of prescribing of antibiotics in outpatients with RTIs is a critical need. Fortunately, this challenge arises at a time of increasing availability of novel RTI diagnostics to help discern which patients have bacterial infections warranting treatment. Effective implementation of antibiotic stewardship is needed, but optimal approaches for ambulatory settings are unknown. Future research needs are reviewed in this summary of a research summit convened by the Infectious Diseases Society of America in the fall of 2019.

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.

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., Molecular assays have revolutionized the diagnosis of acute respiratory tract infections. However, many unanswered questions about the optimal use and cost-effectiveness of these tests remain. Additional prospective diagnostic studies are needed to measure impact on medical decision making and clinical outcomes.

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.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.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%).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.

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 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.

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, Waldenstrom 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.

Infectious, wound and soft tissue events contribute to the morbidity of radical cystectomy but the association between these events and antibiotic prophylaxis is not clear. We sought to describe the contemporary use of antibiotic prophylaxis in radical cystectomy and adherence to published guidelines, and identify regimens with the lowest rates of infectious events.We identified the intraoperative antibiotic prophylaxis regimen in a population based, retrospective cohort study of patients who underwent radical cystectomy across the United States between 2003 and 2013. Multivariable regression was done to evaluate 90-day infectious events and length of stay.In a weighted cohort of 52,349 patients there were 579 unique antibiotic prophylaxis regimens. Cefazolin was the most commonly used antibiotic (16% of cases). The overall infectious event rate was 25%. Only 15% of patients received antibiotic prophylaxis based on guidelines. Of guideline based antibiotic prophylaxis ampicillin/sulbactam had the lowest odds of infectious events (OR 0.34, p0.001). In 2.7% of patients a penicillin based regimen with a β-lactamase inhibitor was associated with a prominent reduction in the odds of infectious events (OR 0.45, p = 0.001) and decreased length of stay (-1.3 days, p = 0.016).Antibiotic prophylaxis practices are highly heterogeneous in radical cystectomy. There is a lack of adherence to published guidelines. We observed decreased infectious event rates and shorter length of stay with regimens that included broad coverage of common skin, genitourinary and gastrointestinal flora. The ideal antibiotic regimen requires further study to optimize perioperative outcomes.

Encephalitozoon cuniculi was transmitted from an infected donor to 3 solid organ recipients, 1 of whom died., In April 2014, a kidney transplant recipient in the United States experienced headache, diplopia, and confusion, followed by neurologic decline and death. An investigation to evaluate the possibility of donor-derived infection determined that 3 patients had received 4 organs (kidney, liver, heart/kidney) from the same donor. The liver recipient experienced tremor and gait instability; the heart/kidney and contralateral kidney recipients were hospitalized with encephalitis. None experienced gastrointestinal symptoms. Encephalitozoon cuniculi was detected by tissue PCR in the central nervous system of the deceased kidney recipient and in renal allograft tissue from both kidney recipients. Urine PCR was positive for E. cuniculi in the 2 surviving recipients. Donor serum was positive for E. cuniculi antibodies. E. cuniculi was transmitted to 3 recipients from 1 donor. This rare presentation of disseminated disease resulted in diagnostic delays. Clinicians should consider donor-derived microsporidial infection in organ recipients with unexplained encephalitis, even when gastrointestinal manifestations are absent.

Objectives We sought to determine the rate of incident neutropenia and identify potential clinical factors associated with incident neutropenia among patients treated with long courses of ceftaroline. Methods We retrospectively identified adult patients who received ceftaroline for ≥7 days consecutively at two large academic medical centres in Boston, USA between November 2010 and March 2015. Clinical characteristics (age, gender, medication allergies, baseline renal function, duration of ceftaroline exposure, total daily ceftaroline dose, body mass-adjusted ceftaroline dose and development of rash and neutropenia) were recorded and the rate of incident neutropenia was calculated. The Naranjo probability scale was used to assess whether ceftaroline exposure was associated with neutropenia. We assessed whether clinical factors were associated with neutropenia. Results The overall rate of incident neutropenia was 10%-14% with ≥2 weeks and 21% with ≥3 weeks of ceftaroline exposure. The median duration of ceftaroline exposure [26 days (IQR 22-44; range 13-68) in patients who developed neutropenia and 15 days (IQR 9-29; range 7-64) in patients without neutropenia] was associated with incident neutropenia (P = 0.048). The median total number of ceftaroline doses received [63 (IQR 44-126; range 36-198) by neutropenic patients and 32 (IQR 22-63; range 14-180) by non-neutropenic patients] was also associated with incident neutropenia (P = 0.023). Conclusions The overall rate of neutropenia was high and associated with duration of ceftaroline exposure and total number of doses received. Close laboratory monitoring is warranted with long-term ceftaroline use.

Among 302 first candidemia episodes, 210 (69.6%) were initially treated with an echinocandin or polyene (E/P) antifungal drug. In 137 (72.5%) patients with fluconazole-susceptible isolates, treatment was changed to fluconazole based on disk diffusion susceptibility testing. Clinical outcomes were not compromised in patients receiving E/P who were de-escalated to fluconazole for treatment of candidemia based on disk diffusion results.

OBJECTIVES Bronchoalveolar lavage galactomannan (BAL-GM) is a mycological criterion for diagnosis of probable invasive aspergillosis (IA) per European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORT-MSG) consensus criteria, but its real-world positive predictive value (PPV) has not been well-studied. Our aim was to estimate the PPV of BAL-GM in a contemporary cohort of patients with positive BAL-GM. METHODS We identified consecutive patients with ≥1 positive BAL-GM value (index ≥ 0.5) at Brigham and Women's Hospital from 11/2009 to 3/2016. We classified patients as having no, possible, probable, or proven IA, excluding BAL-GM as mycological criterion. RESULTS We studied 134 patients: 54% had hematologic malignancy (HM), and 10% were solid organ transplant (SOT) recipients. A total of 42% of positive (≥0.5) BAL-GM results were falsely positive (PPV 58%). The number of probable IA cases was increased by 23% using positive BAL-GM as mycologic criterion alone. PPV was higher in patients with HM or SOT (P

IMPORTANCE: Powassan virus is a rare but increasingly recognized cause of severe neurological disease. OBJECTIVE: To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis. DESIGN, SETTING, AND PARTICIPANTS: Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center. EXPOSURE: Infection with Powassan virus. MAIN OUTCOMES AND MEASURES: Results of individual assays compared retrospectively. RESULTS: In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid. CONCLUSIONS AND RELEVANCE: Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.

Volatile organic compounds (VOCs) produced by microbes through their primary and secondary metabolism can be used to identify infections caused by these organisms. The detection of microbial VOCs in human breath allows noninvasive, rapid, species-specific diagnosis of these infections. However, the detection and identification of these microbe-specific breath VOC signatures are still quite challenging due to the very low abundance of microbial VOCs in human breath. Pre-concentration of these VOCs, which are highly diluted in human breath, is important for the evaluation of these metabolites. In this chapter, we discuss methods for pre-concentration of VOCs using sorbent materials, solid-phase microextraction, and headspace sorptive extraction, and review common analytical techniques used to analyze breath VOCs, such as gas chromatography-mass spectrometry, soft ionization mass spectrometry techniques, ion mobility spectrometry, differential mobility spectrometry, and electronic nose sensors.

Background CRE infections cause significant mortality, in large part because rapid identification of these infections is challenging. We tested the hypothesis that CRE and their isogenic carbapenem-susceptible counterparts have differential metabolic responses to carbapenem therapy. Methods We generated isogenic pairs of E. coli, E. cloacae, and K. pneumoniae by inserting a blaNDM-1-containing plasmid into carbapenem-susceptible E. coli, E. cloacae, and K. pneumoniae. We confirmed phenotypic meropenem (MPM) resistance per CLSI breakpoints for Enterobacteriaceae (MIC ≥4) in the NDM-1+ member and susceptibility (MIC≤1) in the NDM-1- member of each pair. We administered 2 × 108 CFU of each isolate intranasally to 23–28 g male C57BL/6J mice, infecting 6 mice with the NDM-1+ member and 6 with the NDM-1− member of each species pair (12 mice per bacterial species). 24 hours after infection, we treated 3 mice in each NDM-1+ and NDM-1− bacterial species cohort with MPM over 4 hours, and the other 3 mice in each cohort with saline over 4 hours as controls, confirming adequate infection (a target of 106 CFU/g of lung tissue) in quantitative lung homogenate cultures. We then collected breath samples from each mouse via tracheostomy using a murine ventilator, identifying all volatile metabolites in each sample using thermal desorption-gas chromatography/tandem mass spectrometry. We used Wilcoxon tests to examine differences in metabolite abundance between MPM and saline-treated control mice in the NDM-1+ and NDM-1− a member of each species pair, with a two-sided P-value threshold of < 0.1. Results Several breath volatile metabolites changed differentially within each NDM-1+/NDM-1- pair, outlined in Table 1 (E. coli), Table 2 (E. cloacae), and Table 3 (K. pneumoniae). Each listed metabolite that changed with MPM did not change with MPM in mice infected with each isogenic counterpart Conclusion There are differential in vivo metabolic responses with effective vs. ineffective treatment of mice with pneumonia caused by E. coli, E. cloacae, and K. pneumoniae pairs that are genetically identical other than blaNDM-1; this differential treatment response can potentially be used to identify these infections. Disclosures All authors: No reported disclosures.

Invasive aspergillosis and other invasive fungal infections are associated with significant morbidity and mortality in immunocompromised patients, in large part due to limitations of existing diagnostic methods for these infections. Detection of species-specific volatile sesquiterpene metabolites of fungal origin in the breath of patients with invasive fungal infections allows the diagnosis and monitoring of these infections in vivo, non-invasively and more rapidly than possible with current diagnostic methods. While detection of exogenous microbial volatile metabolites in the breath has opened up a new and exciting dimension of diagnostic research and development in infectious diseases, we discuss the daunting challenges to volatile diagnostic biomarker discovery and clinical development.

Infections following kidney transplantation are an important cause of morbidity and mortality throughout the entire posttransplantation period. Patients become more susceptible to an assortment of diverse infections following transplantation due to ongoing immunosuppression and may present with atypical clinical manifestations. An expeditious microbiologic workup and appropriate management are essential to ensure timely diagnosis and prompt initiation of specific therapy.

Objectives Ethanol is bactericidal against most pathogens implicated in central line-associated bloodstream infections (CLABSIs) and biofilms. Current Infectious Diseases Society of America guidelines cite insufficient evidence to support adjunctive ethanol-lock therapy (ELT) for central venous catheter (CVC) salvage in patients with CLABSI in combination with systemic antimicrobial treatment. We evaluated the safety and potential efficacy of 70% ELT for CLABSI at our institution after implementation of a hospital ELT protocol. Methods We collected data on all patients treated with adjunctive 70% ELT for catheter salvage from September 2009 to September 2011 and assessed clinical outcomes and adverse events associated with ELT. Results Sixty-eight hospitalized patients received 70% ELT for CVC salvage: 45 (66%) met the criteria for CLABSI. Five (11%) had persistent or recurrent bacteraemia triggering CVC removal; 28 (62%) preserved their CVC long term. There were no documented adverse events associated with ELT. Discussion Adjunctive 70% ELT is an inexpensive, well-tolerated option for CVC salvage in patients with CLABSI and warrants further investigation.

Background While VORI is recommend as first-line therapy for patients with IA, ISAV, and POSA have been approved for the treatment and prophylaxis of IA, respectively. We evaluated treatment responses among patients with IA receiving triazole antifungals. Methods We performed a retrospective cohort study at our center in patients diagnosed with probable or proven IA between March 2015 and January 2018 who were initially treated with VORI, ISAV, or POSA. Patients were followed until April 2018. Baseline characteristics, laboratory parameters, and clinical evolution were documented. We captured changes in antifungal therapy due to lack of drug efficacy (clinical, radiographic, or mycological progression) and changes in response to drug toxicities. Results A total of 73 patients were diagnosed with IA (55 probable, 18 proven) during the study period. Median age was 61 years (range, 19–80) and 37 (50.7%) were male. At IA diagnosis, 57 (78.1%) had an active hematological malignancy, 27 (37%) had undergone hematopoietic-cell transplantation, and 10 (13.7%) had undergone solid organ transplantation. Sixty-two patients (84.9%) were neutropenic, 42 (57.5%) were on glucocorticoids > 0.3 mg/kg/day prednisone-equivalents in the 3 weeks preceding diagnosis, and 43 (58.9%) were on other T-cell immunosuppressants. Thirty-six patients were initially treated with VORI for a median of 20 days (range, 1–453), 29 with ISAV for a median of 35 days (range, 1–714), and 8 with POSA for a median of 15 days (range, 2–399). Pulmonary-only IA was treated initially with POSA in 87.5%, VORI in 86.1% and ISAV in 65.5% of patients. ISAV was more commonly used in patients with extrapulmonary involvement (44.5%) compared with VORI (13.9%) or POSA (12.5%). Antifungal changes due to lack of efficacy or drug toxicities were: 2.8% and 22.2% for VORI, 24.1% and 3.4% for ISAV, and 37.5% and 25.0% for POSA. In an analysis based on initial treatment not accounting for later changes, the EORTC/MSG clinical success rate at 6 weeks was 33.3%, 31.0%, and 12.5% for VORI, ISAV, and POSA, respectively. Conclusion While the drug efficacy and toxicity rates varied among agents, the 42-day clinical success rate did not. Further research is warranted to determine the optimal antifungal agent for patients with IA. Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium. Astellas: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Fate Therapeutics: Consultant, Consulting fee. GlaxoSmithKline: Consultant, Consulting fee. LFB: Consultant, Consulting fee. Roche Molecular Diagnostics: Consultant, Consulting fee. Shire: Consultant and Investigator, Consulting fee and Research support. S. Hammond, Merck: Investigator, Research support.

Background Data on the incidence, timing, and risk factors for herpes zoster (HZ) in heart transplant (HT) recipients are limited. Methods We determined HZ incidence rates and actuarial estimates of time to first HZ episode in 314 HT recipients at our institution from 1995 to 2010. We developed Cox models to assess potential risk factors for HZ in HT. Results Median age at HT was 54 (range, 17–71) years; 237 (76%) were male. There were 60 episodes of HZ in 51 patients, with an overall incidence rate of 31.6 cases (95% confidence interval [CI], 23.5–41.6)/1000 person-years. Although most cases occurred during the first post-HT year, cumulative HZ incidence was 0.078 at 1, 0.15 at 5, and 0.20 at 10 years. Many patients had substantial HZ morbidity, including 14% with HZ ophthalmicus and 45% with post-herpetic neuralgia. Adjusting for age, gender, and acute cellular rejection episodes, exposure to mycophenolate mofetil (MMF) was an independent risk factor for HZ (adjusted hazard ratio [HR] 2.18; 95% CI, 1.20–3.96; P = 0.01), while ganciclovir-based cytomegalovirus prophylaxis reduced HZ risk (adjusted HR 0.09; 95% CI, 0.01–0.71; P = 0.02). Although age and female gender increased HZ risk, the magnitude of their effect was not statistically significant in Cox models. Conclusions HZ is common and morbid after HT, particularly with MMF exposure. Ganciclovir prophylaxis is effective in reducing the short-term risk of HZ, but the steady incidence of cases for years post HT makes long-term HZ prevention challenging. Augmenting varicella zoster virus immunity post HT with vaccines warrants further exploration.

Viral infections have been reported with dasatinib use, but its cytomegalovirus risk after hematopoietic-cell transplantation (HCT) is not known. We found that post-HCT dasatinib use increased the risk of cytomegalovirus reactivation (adjusted hazard ratio, 7.65; 95% confidence interval, 1.84-31.7), controlling for acute graft-versus-host disease, in 109 patients with Philadelphia-chromosome-positive malignancies.

Background Survival after lung transplantation is limited by chronic lung allograft dysfunction (CLAD). Immunomodulatory therapies such as extracorporeal photopheresis (ECP) and alemtuzumab (AL) have been described for refractory CLAD, but comparative outcomes are not well defined. Methods We retrospectively reviewed spirometric values and clinical outcomes after therapy with ECP, AL, or no treatment (NT) in patients with CLAD who underwent transplant between January 2005 and December 2014. We used inverse probability-weighted regression adjustment (IPWRA) to adjust for potential confounders affecting treatment choice. Results Of 267 patients, 31 received immunomodulatory therapies for CLAD, and 78 received NT. The slope of forced expiratory volume in 1 second (FEV 1 ) decline significantly improved after treatment with AL and with ECP compared with pre-treatment FEV 1 slope; however, there was no significant change in slope of forced vital capacity (FVC). Comparison with NT was limited because of clinical differences in treatment groups. After IPWRA, we found no significant difference in mean difference of FEV 1 slope (ml/month) when comparing treatment with NT, suggesting stabilization of lung function in the treatment group. We found no difference between the 2 immunomodulatory therapies 1, 3, and 6 months post-treatment (−49.9 [95% CI −581.8, +482.0], p = 0.85; +27.7 [95% CI −167.6, +223.0], p = 0.78; −9.6 [95% CI −167.5, +148.2], p = 0.91). We found no difference in mean FVC slope or differences between ECP and AL in infection rates or survival after treatment. Conclusions Immunomodulatory therapy for CLAD with ECP or AL was associated with a significant change in FEV 1 slope post-treatment compared with pre-treatment slope, with minimal effect on FVC. There was no difference between the 2 therapies in their effect on pulmonary function.