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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.

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.

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.

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.

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.

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.

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.

Background Timely diagnosis of IM remains a major challenge in clinical mycology. Because of the lack of specific diagnostic methods for IM and the frequently fulminant nature of this infection, IM-associated mortality remains high. Methods We examined breath volatile metabolite profiles in a neutropenic murine model of IM, using the 3 Mucorales species that most commonly cause human IM - Rhizopus arrhizus var. arrhizus, R. arrhizus var. delemar, and R. microsporus - and for comparison, Aspergillus fumigatus. We infected female balb/c mice (N = 4 per group) treated with cyclophosphamide and cortisone followed by intranasal administration of 106 conidia of each species. 3 days post-infection, we collected breath samples from each mouse via tracheostomy using a flexiVent murine ventilator, examining breath volatile metabolites using thermal desorption gas chromatography/tandem mass spectrometry (GC-MS/MS). We also sampled breath prospectively from five patients eventually diagnosed with proven IM caused by R. microsporus, analyzing breath volatile metabolites using thermal desorption GC-MS/MS. Results Each Mucorales species produced a consistent profile of breath sesquiterpene secondary metabolite VOCs in our murine models, which distinguished these species from each other and from murine invasive aspergillosis (Figure A). These fungi shifted their secondary metabolism significantly in vivo, compared with their previously characterized in vitro metabolism. We found overlapping VOC sesquiterpene metabolites between breath samples from the murine model of R. microsporus infection and 5 of 5 patients with R. microsporus IM, with additional sesquiterpene secondary metabolites detected in patient breath, compared with the murine IM model (Figure B). In one patient with serial breath samples, these sesquiterpenes declined in abundance and disappeared with antifungal therapy, in parallel with clinical improvement (Figure C). Conclusion The three Mucorales species that cause most human IM have distinct breath sesquiterpene profiles that can be used to identify these infections in vivo noninvasively. These profiles distinguish these infections from each other and from aspergillosis, and may be useful in monitoring clinical response to treatment. Disclosures F. M. Marty, Astellas Pharma US: Consultant and Grant Investigator, Consulting fee and Grant recipient; Chimerix: Consultant and Grant Investigator, Consulting fee and Grant recipient; Fate Therapeutics: Scientific Advisor, Consulting fee; Gilead Sciences: Consultant and Grant Investigator, Consulting fee and Grant recipient; LFB: Consultant, Consulting fee; Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; Roche Molecular Systems: Consultant, Consulting fee; Shire: Consultant and Grant Investigator, Consulting fee and Grant recipient; D. P. Kontoyiannis, Pfizer: Research Contractor, Research support and Speaker honorarium; Astellas: Research Contractor, Research support and Speaker honorarium; Merck: Honorarium, Speaker honorarium; Cidara: Honorarium, Speaker honorarium; Amplyx: Honorarium, Speaker honorarium; F2G: Honorarium, Speaker honorarium

A 78-year-old man presented with a 4-month history of worsening fatigue, weakness, and anorexia, with an unintentional weight loss of 11.4 kg. He reported fevers, chills, night sweats, dry mouth, nonproductive cough, dyspnea with minimal exertion, nausea, and postural light-headedness.

Background BAL-GM is a mycologic criterion for diagnosis of probable invasive aspergillosis (IA). However, in a contemporary cohort of consecutive patients with BAL-GM measured as part of their workup for potential IA, we previously showed that 42% of positive (≥0.5) BAL-GM values can be falsely positive; positive predictive value was increased by using higher cutoffs and in patient groups with high pre-test probability for IA. In this study from the same cohort, we analyze the prognostic value of BAL-GM and identify predictors of 6-week mortality, the main outcome in most studies of mold-active antifungal drugs. Methods We reviewed clinical and microbiologic data of patients who had ≥1 positive BAL-GM (≥0.5), at Brigham and Women’s Hospital (November 2009–March 2016). We applied EORTC/MSG invasive mold infection (IMI) definitions to classify cases as possible, probable or proven IMI, excluding BAL-GM result as mycologic criterion, and used Cox regression to identify factors associated with 6-week all-cause mortality. Results We studied 134 patients (median age 58 years, 49% women, 55% with hematologic malignancy, 10% solid-organ and 34% hematopoetic stem-cell transplant recipients). APACHE II score, liver disease, acute kidney injury, and shock were independently associated with higher 6-week mortality. ICU stay, mechanical ventilation, corticosteroids, hypertension, EORTC/MSG category, serum-GM and antifungal treatment were associated with higher mortality in univariate, but not multivariate analyses. BAL-GM value was independently associated with 6-week mortality (adjusted HR 1.24(continuous variable), 95% CI 1.1–1.39, P < 0.001). The association of BAL GM strata with 6-week crude mortality was significant in patients with possible, probable or proven IMI, but not in those without IMI (Figure 1). Conclusion Higher BAL-GM values were an independent predictor of 6-week mortality, having prognostic value in patients with possible, probable or proven IMI, but not in patients who did not meet other criteria for IMI. We propose critical reassessment of BAL-GM cutoff values in different patient populations. Figure 1. Kaplan–Meier (KM) curves for different cutoffs of BAL GM. Disclosures All authors: No reported disclosures.

Prognostic features of serum galactomannan (GM) remain poorly defined in patients with GM-positive invasive aspergillosis (GPA). We identified 93 patients with proven or probable invasive aspergillosis (IA) and GM values of ≥0.50 from January 2005 to March 2009. We used Cox modeling of time to 6- and 12-week mortality for the GM level at the time of diagnosis (GM 0 ), GM decay in the week following diagnosis in 72 patients with ≥2 GM values, other predictors of mortality, and antifungal use during the week following diagnosis. Six-week mortality was 55% in the whole cohort and 43% in patients with ≥2 GM determinations. The hazard ratio (HR) of GM 0 per unit increase and 1-week GM decay per unit decline per week were 1.25 (95% confidence interval [CI], 1.01 to 1.54; P = 0.04) and 0.78 (95% CI, 0.63 to 0.96; P = 0.02), respectively, adjusting for other predictors of IA mortality; these values remained stable after adjusting for antifungal use and were predictive of all-cause mortality at 12 weeks with similar adjusted HR values. We conclude that the combination of GM 0 and 1-week GM decay is predictive of all-cause mortality in patients with GPA, independent of other traditional risk factors for mortality and antifungal exposure, supporting GM decay as a potential surrogate endpoint for future antifungal therapeutic trials.

Background Diagnosis of invasive fungal disease (IFD) is challenging, and it remains a significant cause of morbidity and mortality in immunocompromised patients. The (1-->3)-beta-D-glucan (BG) assay may be a useful adjunct, but its diagnostic performance is not well characterized. Methods We retrospectively assessed the diagnostic indices of the BG assay in patients at risk of IFD who had a compatible clinical syndrome for the diagnosis of IFD a week after initial BG testing and at the end of the hospitalization associated with the first BG value. Patients with IFD were classified according to current European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria, independent of BG results. Results A total of 1308 BG assays were performed for 871 patients. One hundred twelve proven or probable IFD cases were diagnosed within 1 week after initial testing, and 116 cases were diagnosed by the end of hospitalization. Sensitivity of an initial BG level 80 pg/mL for IFD at 1 week was 0.64 (95% confidence interval [CI], 0.55-0.73), specificity was 0.84 (95% CI, 0.81-0.86), the positive likelihood ratio was 3.93 (95% CI, 2.94-5.26), and the negative likelihood ratio was 0.43 (95% CI, 0.31-0.59). Albumin, intravenous immunoglobulin, and hemodialysis were associated with elevated BG levels in patients without IFD (odds ratio, 4.78; 95% CI, 2.59-8.80). After excluding patients with these factors, specificity and the positive likelihood ratio of an initial BG level 80 pg/mL increased slightly. Empirical systemic antifungal treatment did not reduce overall BG sensitivity. Sensitivity was slightly lower among patients with hematologic malignancy or stem cell transplantation. Consideration of BG results would have increased the diagnostic certainty to probable in 54% of possible IFD cases. Conclusions BG level appears to be a fair diagnostic adjunct for IFD in patients with appropriate pretest probability and a suggestive clinical syndrome, especially when checked serially in patients not receiving factors associated with an elevated BG level in the absence of IFD.

Background Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients. Methods We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran’s Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates. Results Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27–0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36–1.87) or overall mortality (RR 0.95, 95% CI 0.46–1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing. Conclusions Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals.

Prophylaxis against deep-vein thrombosis in hospitalized patients remains underused. We hypothesized that the use of a computer-alert program to encourage prophylaxis might reduce the frequency of deep-vein thrombosis among high-risk hospitalized patients.We developed a computer program linked to the patient database to identify consecutive hospitalized patients at risk for deep-vein thrombosis in the absence of prophylaxis. The program used medical-record numbers to randomly assign 1255 eligible patients to an intervention group, in which the responsible physician was alerted to a patient's risk of deep-vein thrombosis, and 1251 patients to a control group, in which no alert was issued. The physician was required to acknowledge the alert and could then withhold or order prophylaxis, including graduated compression stockings, pneumatic compression boots, unfractionated heparin, low-molecular-weight heparin, or warfarin. The primary end point was clinically diagnosed, objectively confirmed deep-vein thrombosis or pulmonary embolism at 90 days.More patients in the intervention group than in the control group received mechanical prophylaxis (10.0 percent vs. 1.5 percent, P0.001) or pharmacologic prophylaxis (23.6 percent vs. 13.0 percent, P0.001). The primary end point occurred in 61 patients (4.9 percent) in the intervention group, as compared with 103 (8.2 percent) in the control group; the Kaplan-Meier estimates of the likelihood of freedom from deep-vein thrombosis or pulmonary embolism at 90 days were 94.1 percent (95 percent confidence interval, 92.5 to 95.4 percent) and 90.6 percent (95 percent confidence interval, 88.7 to 92.2 percent), respectively (P0.001). The computer alert reduced the risk of deep-vein thrombosis or pulmonary embolism at 90 days by 41 percent (hazard ratio, 0.59; 95 percent confidence interval, 0.43 to 0.81; P=0.001).The institution of a computer-alert program increased physicians' use of prophylaxis and markedly reduced the rates of deep-vein thrombosis and pulmonary embolism among hospitalized patients at risk.

Purpose This study examined the impact that seminal vesicle invasion (SVI), observed on endorectal magnetic resonance imaging (erMRI), had on prostate-specific antigen (PSA) outcome after external beam radiation therapy (EBRT) for patients with clinically localized prostate cancer. Methods and materials The study cohort was comprised of 250 patients who received 3D conformal radiation therapy without hormones for clinically localized prostate cancer between 1992 and 2001. The primary end point was PSA failure, defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Cox regression multivariable analysis was used to determine the ability of the pretreatment risk group and erMRI SVI to predict for time to PSA failure after EBRT. Results Both risk group ( p Cox = 0.001) and erMRI SVI ( p Cox = 0.003) were independent and significant predictors of time to PSA failure. For patients beyond low risk, 4-year estimates of PSA failure–free survival for erMRI SVI–negative vs. erMRI SVI–positive patients were 68% vs. 33% ( p log-rank = 0.0014), respectively. Conclusion Patients with clinically localized disease and PSA >10 or biopsy Gleason score ≥7 or clinical T category T2b or T2c who also have erMRI evidence of SVI have PSA outcomes similar to patients with locally advanced prostate cancer after EBRT monotherapy. Consideration should be given to combining EBRT with hormonal therapy in these patients.

We assessed the performance of galactomannan and (1→3)-β- d -glucan in 29 serum samples from patients with multiple myeloma and Waldenstrom's macroglobulinemia without invasive fungal disease to address issues of false positivity and uninterpretable results previously reported among patients with these conditions. Galactomannan and (1→3)-β- d -glucan assays were not falsely elevated in any patient. (1→3)-β- d -glucan assay results were uninterpretable in 24% of patients. Patients with IgG levels of >2,000 mg/dl had higher odds of uninterpretable (1→3)-β- d -glucan results.

Background Invasive aspergillosis (IA) is the most common invasive mold infection (IMI) and early diagnosis is critical to improving clinical outcomes. Galactomannan (GM) is a major component of the Aspergillus cell wall. BAL GM is one of the mycologic criteria for diagnosis of probable IA, but it is frequently positive in patients with Aspergillus airway colonization, and its specificity has not been well-studied. Our goal was to estimate the specificity of a positive BAL galactomannan value in a contemporary cohort of consecutive patients with BAL GM checked as part of their workup for potential IA. Methods We reviewed clinical and microbiologic data of patients who had at least one positive BAL GM (≥0.5), at Brigham and Women’s Hospital from November 2009 to March 2016. We applied EORTC/MSG IMI definitions to classify patients as having possible, probable or proven IMI, excluding BAL GM result as mycologic criterion. Results We studied 134 patients. Median age was 58; 49% were women. 54% had hematologic malignancy (HM), 10% were solid organ (SOT) and 34% hematopoetic stem-cell transplant (HSCT) recipients. 60% received mold-active antifungal treatment. 4 patients (3%) had proven, 60 (45%) probable, 15 (11%) possible, and 55 (41%) no IMI. One had proven mucormycosis, making at least 42% of positive BAL GM results falsely positive (specificity 58%, 95% confidence interval 47–69%). 6-week mortality was 35% overall: 75% for proven, 47% probable, 33% possible, and 20% for no IMI (χ2 for trend P = 0.008). In patients with no IMI, 6-week mortality was comparable in those who did not receive mold-active treatment (13%, 5/38) and those who did (38%, 6/16, Fischer’s P = 0.07). Conclusion In this study, at least 42% of positive BAL GM values were falsely positive, potentially exposing these patients to unnecessary antifungals. The number of ‘probable’ IMI cases (which, along with proven IMI are typically included in clinical trials of new antifungals) would be falsely increased by 25%, using a positive BAL GM alone to adjudicate IMI status. Accurate noninvasive tests for diagnosis of IMI are urgently needed. Table: % +BAL GM values in patients with no IMI at various cutoff values. BAL GM ≥ 0.5 BAL GM ≥ 0.8 BAL GM ≥ 1.0 Overall 42 22 17 HM 28 14 7 SOT 100 50 50 HSCT 30 11 7 Disclosures All authors: No reported disclosures.

Background. Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection. Methods. Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples. Results. The monoterpenes camphene, α- and β-pinene, and limonene, and the sesquiterpene compounds αand β-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, β-trans-bergamotene, a β-vatirenene–like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%–98%) and 93% specificity (95% CI, 79%–98%). Conclusions. In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia.

Background Heart transplant (HT) recipients are at risk for invasive fungal disease (IFD), a morbid and potentially fatal complication. Methods We performed a retrospective cohort study to evaluate the incidence and risk factors for IFD in HT recipients from 1995 to 2012 at a single center. IFD cases were classified as proven or probable IFD according to current consensus definitions of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. We calculated IFD incidence rates and used Cox proportional hazards models to determine IFD risk factors. Results Three hundred sixty patients underwent HT during the study period. The most common indications were dilated (39%) and ischemic (37%) cardiomyopathy. There were 23 (6.4%) cases of proven (21) or probable (2) IFD, for a cumulative incidence rate of 1.23 per 100 person-years (95% CI 0.78 to 1.84). Candida (11) and Aspergillus (5) were the most common etiologic fungi. Thirteen cases (56%) occurred within 3 months of HT, with a 3-month incidence of 3.8% (95% CI 2.2 to 6.4). Delayed chest closure (HR 3.3, 95% CI 1.4 to 7.6, p = 0.01) and the addition of OKT3, anti-thymocyte globulin or daclizumab to standard corticosteroid induction therapy (HR 2.7, 95% CI 1.1 to 6.2, p = 0.02) were independently associated with an increased risk of IFD. Conclusions IFD incidence was greatest within the first 3 months post-HT, largely reflecting early surgical-site and nosocomial Candida and Aspergillus infections. Patients receiving additional induction immunosuppression or delayed chest closure were at increased risk for IFD. Peri-transplant anti-fungal prophylaxis should be considered in this subset of HT recipients.

Mucormycosis is a life-threatening fungal disease in patients with hematological malignancies. The diagnosis of pulmonary mucormycosis is particularly challenging. We describe 3 mucormycosis cases with an uncommon presentation in patients whose cavitary lung disease was attributed to well documented bacterial infection, although evolution and reassessment established mucormycosis as the underlying disease.