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OBJECTIVE Vertebral osteomyelitis is a rare complication of coccidioidomycosis infection. Surgical intervention is indicated when there is failure of medical management or presence of neurological deficit, epidural abscess, or spinal instability. The relationship between timing of surgical intervention and recovery of neurological function has not been previously described. The purpose of this study was to investigate if the duration of neurological deficits at presentation affects neurological recovery after surgical intervention. METHODS This was a retrospective study of all patients diagnosed with coccidioidomycosis involving the spine at a single tertiary care center between 2012 and 2021. Data collected included patient demographics, clinical presentation, radiographic information, and surgical intervention. The primary outcome was change in neurological examination after surgical intervention, quantified according to the American Spinal Injury Association Impairment Scale. The secondary outcome was the complication rate. Logistic regression was used to test if the duration of neurological deficits was associated with improvement in the neurological examination after surgery. RESULTS Twenty-seven patients presented with spinal coccidioidomycosis between 2012 and 2021; 20 of these patients had vertebral involvement on spinal imaging with a median follow-up of 8.7 months (IQR 1.7–71.2 months). Of the 20 patients with vertebral involvement, 12 (60.0%) presented with a neurological deficit with a median duration of 20 days (range 1–61 days). Most patients presenting with neurological deficit (11/12, 91.7%) underwent surgical intervention. Nine (81.2%) of these 11 patients had an improved neurological examination after surgery and the other 2 had stable deficits. Seven patients had improved recovery sufficient to improve by 1 grade according to the AIS. The duration of neurological deficits on presentation was not significantly associated with neurological improvement after surgery (p = 0.49, Fisher’s exact test). CONCLUSIONS The duration of neurological deficits on presentation should not deter surgeons from operative intervention in cases of spinal coccidioidomycosis.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

The effect of vaccination on severity of subsequent COVID-19 in patients with hematologic malignancies (HMs) is unknown. In this single-center retrospective cohort study, we found no difference in severity of COVID-19 disease in vaccinated (n=16) versus unvaccinated (n=54) HM patients using an adjusted multiple logistic regression model. Recent anti-B-cell therapy was associated with more severe illness.

Background Pneumonia is the most common infectious cause of morbidity and excess mortality complicating hematopoietic cell transplantation (HCT) and treatment of hematologic malignancy. Standard bronchoscopic and noninvasive microbiologic testing identify causative pathogens in less than half of cases. The Karius Test, a plasma next-generation sequencing assay of microbial cell-free DNA, may improve diagnostic yield in these patients. Methods Patients with active hematologic malignancy or recent HCT undergoing bronchoscopy for suspected pneumonia were prospectively enrolled in this observational study conducted at 10 United States medical centers. A panel of expert clinicians blinded to Karius Test results reviewed a standardized panel of microbiologic and molecular testing from bronchoalveolar lavage and blood samples for bacterial and fungal testing, nasopharyngeal swab for respiratory viral testing, imaging results, clinical documentation, and any additional microbiologic or molecular testing collected per usual standard of care to adjudicate a probable cause of pneumonia. The panel then adjudicated whether a probable cause of pneumonia or other clinically relevant infection was identified by the Karius Test. Results Between January 3, 2020 and February 4, 2022, 257 patients were enrolled. A planned interim analysis of the first 69 sequentially enrolled patients in the per protocol population was conducted. An adjudicated probable cause of pneumonia was identified by standard care in 18/69 (26%) patients. The Karius Test identified an adjudicated probable cause of pneumonia in 10/51 (20%) patients when no cause of pneumonia was identified by standard care testing. The combination of standard care and the Karius Test together identified a probable cause of pneumonia in 28/69 (41%) patients. At least one additional pathogen adjudicated as a probable cause of pneumonia was identified by the Karius Test in 6/18 (33%) of patients with positive standard care testing. Conclusion The Karius Test notably increased the probability of identifying a pathogenic cause of pneumonia among immunocompromised patients undergoing bronchoscopy. The additive diagnostic value of the Karius Test may significantly enhance management of this common condition. Disclosures Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support Radha Duttagupta, PhD, Karius Inc: Stocks/Bonds Sanjeet S. Dadwal, MD, FACP, FIDSA, AlloVir: Advisor/Consultant|AlloVir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope: Advisor/Consultant|Aseptiscope: Stocks/Bonds|Astellas: Speaker's Bureau|Cidara: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Speaker's Bureau|Takeda: Speaker's Bureau Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Ghady Haidar, MD, Karius, Allovir, and AstraZeneca: Grant/Research Support Alfred Luk, MD, Karius: Grant/Research Support Jamie Todd, MD, Altavant Sciences: Advisor/Consultant|AstraZeneca: Grant/Research Support|Boehringer Ingelheim: Grant/Research Support|CareDx: Grant/Research Support|Cellarity: Advisor/Consultant|Natera: Advisor/Consultant Genovefa Papanicolaou, MD, AlloVir: Board Member|AlloVir: Serve as member of DSMC|Amplyx: Board Member|Amplyx: Serve as member of DSMC|Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|CSL Behring: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Investigator for Merck|MSD: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Board Member|Octapharma: Serve as EAC member|Partners RX: Advisor/Consultant|SymBio: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Takeda: Investigator for Takeda|Vera: Board Member|Vera: Serve as member of DSMC Elena Nemirovich-Danchenko, MD PhD, Karius: Stocks/Bonds Mona Mughar, BS, Karius: Stocks/Bonds Sudeb Dalai, MD, Karius: Stocks/Bonds Sudeb Dalai, MD, Karius: Stocks/Bonds Yuen Cho, MS, CLS(CA-DPH), Karius: Stocks/Bonds Asim A. Ahmed, MD, Karius: Employee|Karius: Stocks/Bonds Desiree Hollemon, MSN, MPH, Karius: Stocks/Bonds David K. Hong, MD, Janssen Pharmaceutical Companies of Johnson & Johnson: Employee|Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Marla Lay Vaughn, BS, MT(ASCP), Karius: Employee|Karius: Stocks/Bonds Tim Blauwkamp, PhD, Karius: Board Member|Karius: Ownership Interest Zivjena Vucetic, MD, Karius: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds Thomas L. Holland, MD, Aridis: Advisor/Consultant|Lysovant: Advisor/Consultant.

Background Antimicrobial resistance (AMR) is rising at an alarming rate and complicating the management of infectious diseases including lower respiratory tract infections (LRTI). Metagenomic next-generation sequencing (mNGS) is a recently established method for culture-independent LRTI diagnosis, but its utility for predicting AMR has remained unclear. We aimed to assess the performance of mNGS for AMR prediction in bacterial LRTI and demonstrate proof of concept for epidemiological AMR surveillance and rapid AMR gene detection using Cas9 enrichment and nanopore sequencing. Methods We studied 88 patients with acute respiratory failure between 07/2013 and 9/2018, enrolled through a previous observational study of LRTI. Inclusion criteria were age ≥ 18, need for mechanical ventilation, and respiratory specimen collection within 72 h of intubation. Exclusion criteria were decline of study participation, unclear LRTI status, or no matched RNA and DNA mNGS data from a respiratory specimen. Patients with LRTI were identified by clinical adjudication. mNGS was performed on lower respiratory tract specimens. The primary outcome was mNGS performance for predicting phenotypic antimicrobial susceptibility and was assessed in patients with LRTI from culture-confirmed bacterial pathogens with clinical antimicrobial susceptibility testing (n = 27 patients, n = 32 pathogens). Secondary outcomes included the association between hospital exposure and AMR gene burden in the respiratory microbiome (n = 88 patients), and AMR gene detection using Cas9 targeted enrichment and nanopore sequencing (n = 10 patients). Results Compared to clinical antimicrobial susceptibility testing, the performance of respiratory mNGS for predicting AMR varied by pathogen, antimicrobial, and nucleic acid type sequenced. For gram-positive bacteria, a combination of RNA + DNA mNGS achieved a sensitivity of 70% (95% confidence interval (CI) 47–87%) and specificity of 95% (CI 85–99%). For gram-negative bacteria, sensitivity was 100% (CI 87–100%) and specificity 64% (CI 48–78%). Patients with hospital-onset LRTI had a greater AMR gene burden in their respiratory microbiome versus those with community-onset LRTI (p = 0.00030), or those without LRTI (p = 0.0024). We found that Cas9 targeted sequencing could enrich for low abundance AMR genes by > 2500-fold and enabled their rapid detection using a nanopore platform. Conclusions mNGS has utility for the detection and surveillance of resistant bacterial LRTI pathogens.

Passive reporting to the Centers for Disease Control and Prevention has identified carbapenemase-producing organisms (CPOs) among solid organ transplant (SOT) recipients, potentially representing an emerging source of spread. We analyzed CPO prevalence in wards where SOT recipients receive inpatient care to inform public health action to prevent transmission.From September 2019 to June 2020, five US hospitals conducted consecutive point prevalence surveys (PPS) of all consenting patients admitted to transplant units, regardless of transplant status. We used the Cepheid Xpert Carba-R assay to identify carbapenemase genes (blaIn total, 154 patients were screened and 92 (60%) were SOT recipients. CPOs were detected among 7 (8%) SOT recipients, from two of five screened hospitals: four blaLongitudinal surveillance in transplant units, as well as PPS in areas with diverse CPO epidemiology, may inform the utility of routine screening in SOT units to prevent the spread of CPOs.

A 60 year-old well-travelled botanist with a history of chronic sinusitis and treated stage IV follicular lymphoma presented to an outside facility with two weeks of progressive headache and nausea.

We characterized the antibody composition of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) and the immunologic responses of hospitalized COVID-19 patients after receiving CCP or nonimmune fresh frozen plasma. Despite selection of CCP with significantly higher total immunoglobulin G than recipients, neutralizing antibody levels did not differ between donor plasma and CCP recipients.

Key Clinical Message Local and systemic complications of Bacillus Calmette‐Guérin therapy are important to recognize as they require prolonged antimicrobial therapy; molecular genomic testing may be key to diagnosis when culture data are inconclusive., Local and systemic complications of Bacillus Calmette‐Guérin therapy are important to recognize as they require prolonged antimicrobial therapy; molecular genomic testing may be key to diagnosis when culture data are inconclusive.

OBJECTIVE: To review the virology, immunology, epidemiology, clinical manifestations, and treatment of the three major zoonotic coronavirus epidemics: severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19). DATA SOURCES: Published literature obtained through PubMed database searches and reports from national and international public health agencies. STUDY SELECTIONS: Studies relevant to the basic science, epidemiology, clinical characteristics, and treatment of SARS, MERS, and COVID-19 with a focus on patients with asthma, allergy, and primary immunodeficiency. RESULTS: Whereas SARS and MERS each caused less than a thousand deaths, COVID-19 has caused a worldwide pandemic with nearly 1 million deaths. Diagnosing COVID-19 relies of nucleic acid amplification tests, and infection has broad clinical manifestations that can affect almost every organ system. Asthma and atopy do not appear to predispose patients to COVID-19 infection, but their effects on COVID-19 clinical outcomes remain mixed and inconclusive. It is recommended that effective therapies, including inhaled corticosteroids and biologic therapy, be continued to maintain disease control. There are no reports of COVID-19 among patients with primary innate and T-cell deficiencies. The presentation of COVID-19 among patients with primary antibody deficiencies is variable, with some experiencing mild clinical courses while others experiencing fatal. The landscape of treatment for COVID-19 is rapidly evolving, with both antivirals and immunomodulators currently with demonstrated efficacy. CONCLUSION: Further data is needed to better understand the role of asthma, allergy, and primary immunodeficiency on COVID-19 infection and outcomes.

We report a liver transplant patient with disseminated Legionella micdadei infection with pulmonary, laryngeal, and suspected muscle involvement. This organism, which stains weakly acid-fast, primarily affects immunocompromised patients. The diagnosis is difficult to make; in this case, the organism was identified via molecular diagnostics on laryngeal and pulmonary biopsy tissue.

Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n =24) versus non-CLAD (n=21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1β as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.

Summary: Lung transplantation can be lifesaving in end-stage cystic fibrosis (CF), but long-term survival is limited by chronic lung allograft dysfunction (CLAD). Persistent upper airway Pseudomonas aeruginosa (PsA) colonization can seed the allograft. While de novo PsA infection is associated with CLAD in non-CF recipients, this association is less clear for CF recipients experiencing PsA recolonization. Here, we evaluate host and pathogen contributions to this phenomenon. In the context of PsA infection, brushings from the airways of CF recipients demonstrate type 1 interferon gene suppression. Airway epithelial cell (AEC) cultures demonstrate similar findings in the absence of pathogens or immune cells, contrasting with the pre-transplant CF AEC phenotype. Type 1 interferon promoters are relatively hypermethylated in CF AECs. CF subjects in this cohort have more mucoid PsA, while non-CF PsA subjects have decreased microbiome α diversity. Peri-transplant protocols may benefit from consideration of this host and microbiome equilibrium.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality for patients and stressed healthcare systems worldwide. The clinical features and outcomes of COVID-19 among immunosuppressed patients, who are at presumed risk of more severe disease but who may also have decreased detrimental inflammatory responses, are not well characterized. We review the existing literature on COVID-19 among immunocompromised populations ranging from patients with cancer and solid-organ transplant recipients to patients with HIV and those receiving immunomodulatory therapy for autoimmune disease. Patients with malignancy and solid-organ transplant recipients may be at increased risk of severe COVID-19 disease and death, whereas for those with other types of immunocompromise, current evidence is less clear. Overall, further prospective controlled studies are needed to determine the attributable risk of immunocompromising conditions and therapies on COVID-19 disease prognosis.

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (P = 0.002) and improved prediction of graft failure (P = 0.02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (P ≤0.04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.

The coronavirus disease 2019 (COVID‐19) pandemic caused by SARS coronavirus 2 (SARS‐CoV‐2) has caused significant morbidity and mortality for patients and stressed healthcare systems worldwide. The clinical features, disease course, and serologic response of COVID‐19 among immunosuppressed patients such as solid organ transplant (SOT) recipients, who are at presumed risk for more severe disease, are not well characterized. We describe our institutional experience with COVID‐19 among ten SOT patients, including the clinical presentation, treatment modalities, and outcomes of seven renal transplant recipients, one liver transplant recipient, one heart transplant recipient, and one lung transplant recipient. In addition, we report the serologic response in SOT recipients, documenting a positive IgG response in all seven hospitalized patients. We also review the existing literature on COVID‐19 in SOT recipients to consolidate the current knowledge on COVID‐19 in the SOT population for the transplant community.

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.

Background Carbapenemase gene-positive organisms (CPOs) are associated with infections with high mortality rates and have the potential to facilitate epidemic spread of carbapenem resistance. Passive reporting to CDC identified CPOs among organ transplant recipients, potentially representing an emerging reservoir for spread. We aimed to determine the prevalence of CPOs in hospital units where solid organ transplant (SOT) recipients receive care in order to inform public health action to prevent transmission. Methods All healthcare facilities identified one medical unit where SOT recipients received inpatient care and conducted point prevalence surveys (PPS) of all consenting patients on 1-2 designated calendar days. We used the Cepheid Xpert® Carba-R assay to identify carbapenemase genes (blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-48) from rectal swabs; carbapenemase-positive swabs were cultured for organisms. All laboratory testing was conducted at the Wadsworth Center, part of CDC’s Antibiotic Resistance Laboratory Network. Results Five participating hospitals performed nine PPS from September 2019 through June 2020. In total, 154 patients were screened and 92 (60%) were SOT recipients (Table). The most common transplanted organs were kidney (44, 48%) and liver (39, 42%). Carbapenemase genes were detected among 5 (5%) SOT recipients, all from a single healthcare facility; 4 (80%) were blaKPC and 1 (20%) was blaNDM. Of the positive specimens cultured, blaKPC was carried by Enterobacter cloacae complex (ECC), Klebsiella pneumoniae, and Klebsiella oxytoca and blaNDM was carried by K. oxytoca; blaKPC was carried by both ECC and K. pneumoniae in a single individual. For SOT patients with CPOs, the median interval from transplantation to swab collection was 108 days (range: 12 to 323). CPOs were only detected in 1 (2%) of 62 non-transplant patients. TABLE Characteristics of Carbapenemase Gene-positive Organism (CPO) Pilot Surveillance Participants Conclusion Among participating facilities, most did not identify CPOs among patients admitted to transplant units. These findings represent a small number of patients and facilities; additional PPS in areas with varied CPO epidemiology are needed to understand whether SOT recipients should be routinely screened for CPOs. Disclosures All Authors: No reported disclosures

Purpose End-stage cystic fibrosis (CF) can be managed by lung transplantation (LT), but chronic allograft dysfunction (CLAD) limits long-term survival. While Pseudomonas aeruginosa airway infection (PsA) is a risk factor for CLAD for most lung allograft recipients, this association does not hold for CF recipients. We hypothesized that differences in host epithelial immune responses and the composition of airway microbial communities could contribute to protection from CLAD in CF recipients with PsA. Methods We compared transcriptomes from clinical airway brushes following LT for 28 subjects, grouped by CF status and PsA culture result (CF+PsA+, n=8; CF+PsA-, n=6; CF-PsA+, n=5; and CF-PsA-, n=9) using DEseq2. For in vitro analysis of immune responses, airway epithelial cells (AEC) were isolated from lung explants (pre-LT) or surveillance airway brushes (post-LT) and grown at air-liquid interface until polarized and differentiated. Gene expression differences and DNA methylation were compared by CF status using quantitative PCR and DNA methylation array. Results For subjects with a positive PsA culture following LT, there were 193 differentially expressed genes between CF and non-CF airways. Pathway analysis demonstrated suppression of interferon response in CF airways. Relative to non-CF referents, CF AEC in vitro transitioned from increased expression of neutrophil-associated genes (Cxcl8 and Lcn2) pre-LT, to decreased expression of interferon-associated genes (Mx1 and Oas1) post-LT. DNA methylation analysis showed hypermethylation of promoters in type I interferon responsive genes (p = 0.002). All CF+PsA+ subjects had mucoid PsA strains while 72% of non-CF subjects had non-mucoid PsA (p Conclusion The combination of attenuated interferon responses and prevalence of mucoid strains may explain the differential outcomes in CF LT recipients with PsA.

Modern advances in oncologic and end-organ therapies have led to an increase in immunocompromised patients and a corresponding rise in acute invasive fungal sinusitis (AIFS). Here, we present a comprehensive medical and surgical approach to the diagnosis and management of immunocompromised cancer and transplant patients with AIFS. Aspergillus and Mucorales are the most common fungi to cause AIFS, though atypical fungal pathogens have been implicated particularly among patients on azole prophylaxis. Symptoms present in the majority of AIFS cases include fever, nasal congestion, and facial swelling. Nasal endoscopy and radiology are adjuncts to clinical exam with the gold standard diagnostic test still being histopathology, though molecular testing such as panfungal PCR is playing a larger role. The treatment of AIFS requires surgery, antifungal therapy, and reversal of immunosuppression. We recommend initiation of liposomal amphotericin B as an empiric therapy for AIFS, transitioned to targeted therapy when/if a fungal pathogen is identified. Goals of surgery include diagnostic sampling and debridement of necrotic tissue. Equally, if not more important, is reversal of underlying immune suppression. Immune-stimulating therapies hold promise for reducing mortality, but require additional study. Despite improvements in medical and surgical management of AIFS, mortality continues to approach 50%. Early diagnosis of this disease entity followed by aggressive surgical and medical management are important, including reversal of the underlying immunosuppression.

Culture-confirmed bacteremia occurs in only a fraction of pneumonia cases. The degree to which microbial DNA circulates in blood of patients with pneumonia, however, is unknown. Detection of cell-free microbial DNA from plasma is a promising new tool for infectious disease diagnosis. We conducted unbiased metagenomic next-generation sequencing (mNGS) of paired plasma and respiratory fluid from 25 subjects, 18 with pneumonia (four with concurrent bloodstream infections) and seven with non-infectious respiratory illnesses. Cell-free plasma mNGS identified one or more culture-confirmed bacterial or fungal pathogens in 67% of patients with pneumonia, compared to 100% for respiratory mNGS. In two patients who developed probable ventilator-associated pneumonia (VAP), plasma mNGS afforded early detection of the eventual culture-confirmed VAP pathogens. Our findings suggest that in a majority of patients with severe pneumonia, circulating microbial DNA from confirmed respiratory pathogens can be detected in the bloodstream, even in the setting of negative blood cultures.

Culture-confirmed bacteremia occurs in only a fraction of pneumonia cases. The degree to which microbial DNA circulates in blood of patients with pneumonia, however, is unknown. Detection of cell-free microbial DNA from plasma is a promising new tool for infectious disease diagnosis. We conducted unbiased metagenomic next-generation sequencing (mNGS) of paired plasma and respiratory fluid from 25 subjects, 18 with pneumonia (four with concurrent bloodstream infections) and seven with non-infectious respiratory illnesses. Cell-free plasma mNGS identified one or more culture-confirmed bacterial or fungal pathogens in 72% of patients with pneumonia, compared to 100% for respiratory mNGS. In two patients who developed probable ventilator-associated pneumonia (VAP), plasma mNGS afforded early detection of the eventual culture-confirmed VAP pathogens. Our findings suggest that in a majority of patients with severe pneumonia, circulating microbial DNA from confirmed respiratory pathogens can be detected in the bloodstream, even in the setting of negative blood cultures.

Lower respiratory tract infections (LRTIs) lead to more deaths each year than any other infectious disease category. Despite this, etiologic LRTI pathogens are infrequently identified due to limitations of existing microbiologic tests. In critically ill patients, noninfectious inflammatory syndromes resembling LRTIs further complicate diagnosis. To address the need for improved LRTI diagnostics, we performed metagenomic next-generation sequencing (mNGS) on tracheal aspirates from 92 adults with acute respiratory failure and simultaneously assessed pathogens, the airway microbiome, and the host transcriptome. To differentiate pathogens from respiratory commensals, we developed a rules-based model (RBM) and logistic regression model (LRM) in a derivation cohort of 20 patients with LRTIs or noninfectious acute respiratory illnesses. When tested in an independent validation cohort of 24 patients, both models achieved accuracies of 95.5%. We next developed pathogen, microbiome diversity, and host gene expression metrics to identify LRTI-positive patients and differentiate them from critically ill controls with noninfectious acute respiratory illnesses. When tested in the validation cohort, the pathogen metric performed with an area under the receiver-operating curve (AUC) of 0.96 (95% CI, 0.86–1.00), the diversity metric with an AUC of 0.80 (95% CI, 0.63–0.98), and the host transcriptional classifier with an AUC of 0.88 (95% CI, 0.75–1.00). Combining these achieved a negative predictive value of 100%. This study suggests that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome, and host transcriptome may hold promise as a tool for LRTI diagnosis.

Allogeneic hematopoietic stem cell transplant patients are at risk for common and atypical infections. Superior diagnostics can decrease infection-related morbidity and mortality. A novel plasma cell–free DNA next-generation sequencing test detected an uncommon presentation of Chlamydia trachomatis and recurrent and metastatic complications of Staphylococcus aureus bacteremia before standard microbiology.

Lower respiratory tract infections (LRTI) lead to more deaths each year than any other infectious disease category(1). Despite this, etiologic LRTI pathogens are infrequently identified due to limitations of existing microbiologic tests(2). In critically ill patients, non-infectious inflammatory syndromes resembling LRTI further complicate diagnosis. To address the need for improved LRTI diagnostics, we performed metagenomic next-generation sequencing (mNGS) on tracheal aspirates from 92 adults with acute respiratory failure and simultaneously assessed pathogens, the lung microbiome and the host transcriptome. To differentiate pathogens from respiratory commensals, we developed rules-based and logistic regression models (RBM, LRM) in a derivation cohort of 20 patients with LRTI or non-infectious acute respiratory illnesses. When tested in an independent validation cohort of 24 patients, both models achieved accuracies of 95.5%. We next developed pathogen, microbiome diversity, and host gene expression metrics to identify LRTI-positive patients and differentiate them from critically ill controls with non-infectious acute respiratory illnesses. When tested in the validation cohort, the pathogen metric performed with an AUC of 0.96 (95% CI = 0.86 - 1.00), the diversity metric with an AUC of 0.80 (95% CI = 0.63 – 0.98), and the host transcriptional classifier with an AUC of 0.91 (95% CI = 0.80 – 1.00). Combining all three achieved an AUC of 0.99 (95% CI = 0.97 – 1.00) and negative predictive value of 100%. This study suggests that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome and host transcriptome may hold promise as a novel tool for LRTI diagnosis.SIGNIFICANCE STATEMENTLower respiratory tract infections (LRTI) are the leading cause of infectious disease-related death worldwide yet remain challenging to diagnose because of limitations in existing microbiologic tests. In critically ill patients, non-infectious respiratory syndromes that resemble LRTI further complicate diagnosis and confound targeted treatment. To address this, we developed a novel metagenomic sequencing-based approach that simultaneously interrogates three core elements of acute airway infections: the pathogen, lung microbiome and host response. We studied this approach in a prospective cohort of critically ill patients with acute respiratory failure and found that combining pathogen, microbiome and host gene expression metrics achieved accurate LRTI diagnosis and identified etiologic pathogens in patients with clinically identified infections but otherwise negative testing.FundingNHLBI K12HL119997 (Langelier C), NHLBI K23HL123778 (Christensen S), NIAID P01AI091575 and the Chan Zuckerberg Biohub (DeRisi JL), NHLBI K23 HL136844 (Moazed F), NHLBI R01HL110969, K24HL133390, R35HL140026 (Calfee C), Gladstone Institutes (Pollard KS).

Background Allogeneic stem-cell transplant (allo-SCT) recipients are at risk of developing severe CMV infection. The pre-emptive approach to CMV prevention, weekly monitoring with CMV PCR with treatment for positive viral load (VL), is standard of care. The quantitative Karius plasma Next Generation Sequencing test (KT) can identify DNA from >1,000 human pathogens. We report on the clinical validation and utility of KT for detecting and monitoring CMV viremia in allo-SCT patients. Methods Plasma samples negative or positive by CMV PCR (COBAS® AmpliPrep/COBAS® TaqMan® CMV Test [CAP/CTM] or cobas 6800/8800 [cobas® CMV]) were tested with KT for analytical comparison. For KT, after cell-free DNA (cfDNA) was sequenced, human-derived reads were excluded bioinformatically, and remaining DNA sequences were aligned to a curated microbial pathogen database. KT results were reported as molecules per microliter (MPM). Linear regression was used to correlate log10 transformed CMV VL results within the overlapping quantifiable range of comparison assays. Using the regression equation to convert KT results from MPM to IU/mL, percent agreement was calculated and assay result agreement was analyzed with Bland-Altman plots. Allo-SCT recipients with CMV viremia were selected from the prospective observational DISCOVER trial (NCT02804464), and their plasma specimens were tested with KT. Mean differences in MPM between ≥7 days before start of antiviral treatment (D-7) and start of treatment (D0), and between D0 and ≥14 days after start of treatment (≥D14) were examined with Wilcoxon rank-sum tests. Results Among 125 residual samples tested by all 3 assays, 1 sample failed KT sequencing and was excluded from the analysis. Percent agreement between KT and cobas CMV (n = 124) was 94% using the cobas cut-off for negative samples (VL Conclusions High correlation was observed between KT and two FDA-approved CMV VL assays. KT identified significant increases in CMV VL at start of treatment and significant decreases at ≥14 post-treatment in allo-SCT recipients, showing potential clinical utility of KT as a monitoring assay, with the added value of detecting >1,000 pathogens in the same blood draw.

Background Isavuconazole (ISA) is a novel triazole antifungal approved for treating invasive aspergillosis and mucormycosis. While ISA is increasingly used for prophylaxis in hematologic malignancy patients when other azoles are contraindicated, there are currently limited data on breakthrough invasive fungal infection (IFI) rates in this context. Methods We retrospectively reviewed inpatient and outpatient pharmacy records from March 2015 to April 2018 to identify adult patients with hematologic malignancy who received at least 7 days of ISA for prophylaxis. Breakthrough IFI was defined by EORTC-MSG criteria. Results We identified 73 hematologic malignancy patients who received ISA; 29 received at least 7 days ISA for prophylaxis in 33 separate episodes. Of these patients, 52% had acute myeloid leukemia, 14% had acute promyelocytic leukemia, 10% had myelodysplastic syndrome, and 21% had another malignancy. Eighty-six percent of patients were neutropenic (median duration 24 days; range 2–213). Median duration of ISA prophylaxis was 61 days (range 8–635). The most common reason for choosing ISA over other antifungal agents was QTc prolongation (45%), followed by intolerance of other antifungals (27%) and drug-drug interactions with other azoles (21%). Four patients (12%) developed proven or probable breakthrough IFI (Table 1). Among patients with breakthrough IFI, mortality was 50% at 12 weeks. Table 1. Characteristics of Breakthrough IFI Among Hematologic Malignancy Patients Receiving ISA Prophylaxis Age/Gender Disease IFI site Organism Diagnostic Test ANCNadir Neutropenia Duration (days) Duration ISA (days) Outcome (12 weeks) 32M AML Lung Aspergillus fumigatus BAL: fungal culture

The use of surgical antibiotic prophylaxis (AP) in children is poorly characterized. The aims of this study were to examine (1) trends in the use of AP for commonly performed operations, (2) appropriateness in the context of available guidelines, and (3) adverse events potentially attributable to AP.We conducted a 5-year retrospective analysis of 22 children's hospitals (January 2005-March 2009) for all patients younger than 18 years who underwent 1 of the 40 commonly performed general and urological procedures. Indications for AP were defined by published specialty-specific guidelines. Clostridium difficile infection and surrogate events for drug allergy (diphenhydramine and epinephrine administrations) were examined as potential antibiotic-associated adverse events.Procedures of 246,316 were identified, of which 25% met criteria for AP. Eighty-two percent of the children received antibiotics during procedures when AP was indicated (range, 60%-96% by hospital), and 40% of the patients received antibiotics when there was no indication (range, 10%-83%). The likelihood of receiving AP was significantly different between hospitals for all procedures examined (P.0001 for each procedure). Adverse events were significantly more frequent in children receiving AP than in those who did not (odds ratio [95% confidence interval] C difficile: 18.8 [6.9-51.5], P.0001; epinephrine: 1.8 [1.7-2.0], P.0001; diphenhydramine: 6.0 [5.6-6.5], P.0001).Significant variation exists in the use of AP in the pediatric surgical population. Many children do not receive AP when indicated, and an even greater proportion may receive antibiotics when there is no indication. These findings may have profound implications from a public health perspective when extrapolated to all children undergoing surgical procedures.

This study aimed to systematically review and describe the evidence on chlamydia and gonorrhoea reinfection among men, and to evaluate the need for retesting recommendations in men. PubMed and STI conference abstract books from January 1995 to October 2006 were searched to identify studies on chlamydia and gonorrhoea reinfection among men using chlamydia and gonorrhoea nucleic acid amplification tests or gonorrhoea culture. Studies were categorised as using either active or passive follow‐up methods. The proportions of chlamydial and gonococcal reinfection among men were calculated for each study and summary medians were reported. Repeat chlamydia infection among men had a median reinfection probability of 11.3%. Repeat gonorrhoea infection among men had a median reinfection probability of 7.0%. Studies with active follow‐up had moderate rates of chlamydia and gonorrhoea reinfection among men, with respective medians of 10.9% and 7.0%. Studies with passive follow‐up had higher proportions of both chlamydia and gonorrhoea reinfections among men, with respective medians of 17.4% and 8.5%. Proportions of chlamydia and gonorrhoea reinfection among men were comparable with those among women. Reinfection among men was strongly associated with previous history of sexually transmitted diseases and younger age, and inconsistently associated with risky sexual behaviour. Substantial repeat chlamydia and gonorrhoea infection rates were found in men comparable with those in women. Retesting recommendations in men are appropriate, given the high rate of reinfection. To optimise retesting guidelines, further research to determine effective retesting methods and establish factors associated with reinfection among men is suggested.

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.

Background The diagnosis of infections in stem-cell transplant (SCT) patients is challenging. There is a need for improved diagnostics that can quickly and accurately detect a broad range of viruses, bacteria, and fungi that can infect these patients to guide targeted therapy. Methods We enrolled 20 patients in a prospective study evaluating the Karius plasma next-generation sequencing (plasma NGS) test to detect infections in SCT patients. Patients had baseline plasma samples drawn prior to transplant followed by weekly collections during engraftment and at onset of febrile episodes. Samples were transferred to the Karius CLIA/CAP laboratory (Redwood City, CA) where cell-free DNA was extracted from plasma and NGS performed. Human sequences were removed and remaining reads were aligned against a curated pathogen database. Organisms present at a significance level above a predefined threshold were reported. Results Cytomegalovirus (CMV) was identified in 12/20 patients. Using a nearest-neighbor method, 61 pairs of observations were identified for a comparison of plasma NGS and CMV qPCR collected within 1 day of each other. Positive agreement (PPA) between plasma NGS and CMV qPCR was 84.1% (37/44). PPA was 100% (20/20) when values below the lower limit of quantitation (

Importance Appropriate use of surgical antibiotic prophylaxis (AP) reduces surgical site infection rates, but prior data suggest variability in use patterns. Objective To assess national variability and appropriateness of AP in pediatric surgical patients. Design, Setting, and Participants Retrospective cohort study of 31 freestanding children’s hospitals in the United States using administrative data from 2010-2013. The study included 603 734 children younger than 18 years who underwent one of the 45 most commonly performed operations. Exposures Receipt of surgical AP. Main Outcomes and Measures Primary outcomes included procedure- and hospital-specific rates of AP use and appropriateness of use based on clinical guidelines and consensus statements. We also assessed rates of Clostridium difficile infection and potential allergic reactions (using epinephrine administration as a surrogate event) after AP receipt. Results Of the 603 734 eligible patients, the mean (SD) patient age was 4.8 (4.4) years and 384 571 (63.7%) were boys. For the 671 255 operations evaluated, AP was administered for 348 119 (52%) of procedures. Intrahospital variation in AP use by procedure ranged from 11.5% to 100% (median, 78.1%). Overall, AP use was considered appropriate for 64.6% of cases. Appropriate use of AP by hospital varied from 47.3% to 84.4% with large variability by procedure within each hospital. For procedures for which AP was indicated, the median rate of appropriate use by hospital was 93.8%; however, for procedures for which AP was not indicated, the median rate of appropriate use by hospital was 52.0%. The odds of C difficile infection and epinephrine administration were significantly higher among children who received AP (odds ratio, 3.34; 95% CI, 1.66-6.73 and odds ratio 1.97; 95% CI, 1.92-2.02; respectively). Conclusions and Relevance There is substantial national variability in the overall and appropriate use of AP for the most commonly performed operations in children both at a procedure and hospital level. A high proportion of AP use is inappropriate, potentially exposing many children to avoidable adverse events. Urgent attention should be directed to efforts to standardize the use of surgical AP in pediatrics.