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The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

Hyperammonemia syndrome is an increasingly recognized and often fatal condition that occurs in immunosuppressed individuals, most commonly lung transplant recipients. Growing evidence suggests hyperammonemia syndrome is associated with systemic infections caused by urease-producing organisms, namely Ureaplasma spp., an organism unable to grow with routine culturing techniques. This review will summarize the epidemiology and clinical manifestations of hyperammonemia syndrome, as well as diagnostic and management strategies once hyperammonemia syndrome is suspected.Hyperammonemia syndrome is being described in increasing frequency in the solid organ transplant population. Morbidity and mortality, even with treatment, is high once hyperammonemia syndrome occurs. Surveillance studies indicate the prevalence of lung donor colonization with Ureaplasma spp. is high, suggesting screening and treatment may be of benefit. Antibiotic resistance is common, and rapid diagnostics can facilitate appropriate antimicrobial therapy in the peri-transplant period.Hyperammonemia syndrome is most commonly seen in lung transplant recipients and has a high mortality rate once it occurs. Screening for Ureaplasma spp. should be considered in all lung transplant donors.

Background Chronic lymphocytic leukemia (CLL) and other non-Hodgkin’s lymphomas (NHLs) lead to broad immunosuppression, conferring a greater risk for morbidity and mortality from SARS-CoV-2. Our study analyzed antibody (Ab) seropositivity from SARS-CoV-2 vaccination in patients with these cancers. Methods In the final analysis, 240 patients were involved, and seropositivity was defined as a positive total or spike protein Ab. Results Seropositivity was 50% in CLL, 68% in WM, and 70% in the remaining NHLs. Moderna vaccination led to higher seropositivity compared to Pfizer vaccination across all cancers (64% vs. 49%; P = .022) and specifically CLL patients (59% vs. 43%; P = .029). This difference was not explainable by differences in treatment status or prior anti-CD20 monoclonal Ab therapy. In CLL patients, current or prior cancer therapy led to lower seropositivity compared to treatment-naïve patients (36% vs. 68%; P = .000019). CLL patients treated with Bruton’s tyrosine kinase (BTK) inhibitors had better seropositivity after receiving the Moderna vaccination compared to Pfizer (50% vs. 23%; P = .015). Across all cancers, anti-CD20 agents within 1 year led to a lower Ab response compared to greater than one year (13% vs. 40%; P = .022), a difference which persisted after booster vaccination. Conclusion Antibody response is lower in patients with indolent lymphomas compared to the general population. Lower Ab seropositivity was found in patients with a history of anti-leukemic agent therapy or those immunized with Pfizer vaccine. This data suggests that Moderna vaccination may confer a greater degree of immunity against SARS-CoV-2 in patients with indolent lymphomas.

Background Lung transplantation is one of the only options for patients with severe coronavirus disease 2019 (COVID-19)–associated lung injury (CALI). Studies on patients who received a lung transplant for CALI have, to date, not looked at the infectious outcomes. Methods After institutional review board approval, a retrospective case-control cohort study, matched 1:1, collected data on patients who underwent lung transplantation for CALI (case) and for non–COVID-19 end-stage lung disease (control) between 1 June 2020 and 1 April 2022 at a large academic hospital in Chicago. We assessed infectious complications and other key outcomes pre-transplant and for 1 year post-transplant. Results Among 78 patients (39 CALI and 39 matched control lung transplant patients), those in the CALI cohort were less likely to be vaccinated pre-transplant and were more likely to have diabetes, to be obese, to not be ambulatory, and to require pre-transplant extracorporeal membrane oxygenation and mechanical ventilation. Patients transplanted for CALI had higher rates of infection pre-transplant (66.7% vs 15.4% of patients in the control) and in the first 30 days post-transplant (43.6% vs 20.5%). Numbers and types of infection were similar in both groups at other time points. One-year mortality was similar for CALI and control groups (12.8% vs 10.3%, respectively). Conclusions Patients who received a lung transplant for CALI are more deconditioned with prolonged hospital stays and experience more infectious complications immediately pre- and post-transplant. Infections due to multidrug-resistant organisms are important contributors to morbidity and mortality in this population. Antimicrobial stewardship is urgently needed.

Human respiratory syncytial virus (RSV) is a negative sense single-stranded RNA virus that can result in epidemics of seasonal respiratory infections. Generally, one of the two genotypes (A and B) predominates in a single season and alternate annually with regional variation. RSV is a known cause of disease and death at both extremes of ages in the pediatric and elderly, as well as immunocompromised populations. The clinical impact of RSV on the hospitalized adults has been recently clarified with the expanded use of multiplex molecular assays. Among adults, RSV can produce a wide range of clinical symptoms due to upper respiratory tract infections potentially leading to severe lower respiratory tract infections, as well as exacerbations of underlying cardiac and lung diseases. While supportive care is the mainstay of therapy, there are currently multiple therapeutic and preventative options under development.

Background Nontuberculous mycobacteria (NTM) are environmental organisms that can form biofilms in municipal water systems and as such are difficult to eliminate. Mycobacterium abscessus is a rapid-growing NTM that can cause skin and soft tissue, disseminated, and pulmonary infections. M. abscessus is difficult to treat, often requiring prolonged therapy with several antibiotics due to its intrinsic drug resistance. In 2021, our institution identified a significant increase in pulmonary infections caused by M. abscessus in the cardiothoracic transplant population. Methods All M. abscessus cases among inpatients at our institution were extracted from the electronic medical record (EMR) between January 2019 and September 2021. Clinical characteristics were determined through EMR review and included demographics, transplant status, specimen type, COVID-19 history, and patient care practices involving water. A multidisciplinary team conducted an investigation to identify possible variations in practice related to the source of water used for clinical care activities in this identified population. Results Between January 2021 and September 2021, there were 12 cases of M. abscessus among inpatients at our institution compared to 6 cases in 2019 and 5 in 2020 (Figure 1). Between 2019 and 2020, post-heart and pre-/post-lung transplant patients comprised 9% of cases, 55% of cases were pulmonary infections, and none had a history of COVID-19 infection. In 2021, post-heart and pre-/post-lung transplant patients comprised 58% of cases, 83% of cases were pulmonary infections, and 33% of cases had a history of COVID-19 infection. There were varying sources of water utilized for the clinical care activities in this identified population (Table 1). Figure 1Mycobacterium abscessus epidemic curveTable 1Patient Care Practices Involving Water Conclusion To investigate the potential outbreak, we are actively collecting water samples and swabs from water fixtures in both patient and nourishment rooms for water culturing. To mitigate a potential water-borne source, we will use sterile water for all clinical care practices involving water and for all patient water drinking needs in the post-heart and pre-/post-lung transplant population impacted by the outbreak. The only use of tap water is hand hygiene and patient bathing. Disclosures Asra Salim, MPH, CPH, FAPIC, IRhythym Technologies Inc: Stocks/Bonds Valentina Stosor, MD, DiaSorin: Advisor/Consultant|Eli Lilly and Company: Grant/Research Support|Med Learning Group: Honoraria Michael P. Angarone, DO, Abbvie: Advisor/Consultant Michael G. Ison, MD MS, GlaxoSmithKlein: Grant/Research Support|Pulmocide: Grant/Research Support|Viracor Eurfins: Advisor/Consultant Janna L. Williams, MD, Abbvie: COVID19 Infection Prevention Consultant.

Background Cefiderocol (FDC) is a novel antimicrobial agent used for multi-drug resistant Gram-negative pathogens. To date, reports of mutations in β-lactamase and siderophore complex genes have been described and may contribute to FDC resistance. This case describes a New Dehli metallo-β-lactamase (NDM)-producing strain of Enterobacter hormaechei that developed FDC resistance following antibiotic exposure. Methods Serial respiratory and blood cultures were collected from a lung transplant recipient throughout 72 days of hospitalization. Confirmatory susceptibility and combination minimal inhibitory concentration (MIC) testing were performed using broth dilution and E-test assays. Short-read sequencing libraries were prepared using a seqWell plexWell 96 kit, and whole-genome sequencing was performed using the Illumina NovaSeq platform. Reads from the sample genomes were aligned to the chromosome and three plasmid sequences of reference genome ENCL48880. Results Four serial respiratory E. hormaechei isolates and one blood isolate were evaluated. Although initial isolates were susceptible to FDC (MICs 1-2 µg/mL), two respiratory isolates cultured after 41 days of FDC therapy had MICs of 128 µg/mL. The blood isolate remained FDC susceptible despite respiratory resistance. The combination of ceftazidime/avibactam and aztreonam was determined to be active via synergy MIC testing in all isolates, and aztreonam therapeutic drug monitoring confirmed an adequate dosing strategy. Whole-genome sequencing revealed no nonsynonymous single nucleotide variants (SNVs) within the chromosomes but identified a deletion of a large urease island in the resistant isolates. In four of the five isolates, a plasmid (p48880_mcr) was identified and analyzed for possible contributions to FDC resistance. Enterobacter Isolate Assemblies This figure demonstrates genomic assemblies from the five Enterobacter clinical isolates, noting an absence of sequence from ECResp2. Conclusion This case demonstrates development of FDC resistance in E. hormaechei isolates during a 41 day course of FDC therapy. Possible causes of resistance include a large chromosomal deletion and plasmid alleles, demonstrating a potential novel mechanism for FDC resistance. Partnering molecular testing and enhanced antimicrobial stewardship should be encouraged to optimize selection of regimens and durations to prevent resistance to FDC. Disclosures Michael G. Ison, MD MS, GlaxoSmithKlein: Grant/Research Support|Pulmocide: Grant/Research Support|Viracor Eurfins: Advisor/Consultant Nathaniel J. Rhodes, PharmD, MSc, American Academy of Colleges of Pharmacy: Grant/Research Support|Paratek: Grant/Research Support|Third Pole Therapeutics: Advisor/Consultant.

Background SARS-CoV-2 can result in a range of infections from asymptomatic disease to progressive COVID-19 and death. In some pts with CALI, lung transplantation (LTx) may be lifesaving. Up to 10% of LTx in the US is currently for pts with CALI. Understanding the characteristics and outcomes of these pts is critical. Methods A open-access electronic registry was established to collect de-identified data from pts who have undergone LTx for CALI from centers globally. The study was IRB approved at Northwestern with a wavier for consent (no PHI is collected sites could submit data about pre-Tx, peri-Tx and post-Tx course). Follow-up for 1-yr post-LTx was collected. Results To date, 89 pts with complete day 30 post-LTx data have been entered into the registry. Pt demographics and pre-Tx status are shown in Table 1. 3 pts required oxygen prior to COVID-19. Most sites required neg PCR tests prior to listing (11 (12.4%) required no - PCRs, 11 (12.4%) required 1 and 61 (68.5%) required 2). LTx occurred 137 days post-infection and none developed COVID-19 in the first 30 d; 4 were given monoclonal antibodies post-tx. Post-tx ICU LOS averaged 24.5 d with total post-tx hospitalization of 37.6 d (See Table 2). Most experienced infectious and non-infectious morbidity. Most (47.8%) required an additional 30 days of rehab. 2 pts died within 30 days due to sepsis and anoxia. 5 died between day 30 and 90 and an additional 12 died between day 90 and 365. Conclusion The contribution of cases to this international registry is ongoing. While outcomes of LTx for CALI are generally good, patients experience prolonged post-transplant hospitalization, rehabilitation and significant morbidity and infections are common. Disclosures Michael G. Ison, MD MS, GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support Saima Aslam, MD, Armata: Grant/Research Support|BioMx: Advisor/Consultant|Contrafect: Grant/Research Support|Gilead: Honoraria|Merck: Honoraria|Phico: Advisor/Consultant.

Background RSV-associated acute respiratory infections (ARI), particularly lower respiratory tract diseases (LRTD), present a significant disease burden in older adults. Currently, there are no approved vaccines against RSV. We present results from an ongoing study designed to demonstrate the vaccine efficacy (VE) of the AS01E-adjuvanted RSVPreF3 OA in adults ≥ 60 YOA. Methods This ongoing, phase 3, observer-blind, placebo-controlled, multi-country study (NCT04886596) enrolled adults ≥ 60 YOA from the northern and southern hemispheres. Participants were randomized (1:1) to receive a single dose of RSVPreF3 OA or placebo before the RSV season. The primary objective was to demonstrate VE of a single dose of RSVPreF3 OA in preventing RSV-confirmed LRTD during one RSV season (criterion: lower limit of VE confidence interval [CI] > 20%). VE is reported also against severe RSV-confirmed LRTD, RSV-confirmed ARI, RSV-confirmed LRTD and RSV-confirmed ARI by RSV subtype (RSV-A and RSV-B), and RSV-confirmed LRTD by age, baseline comorbidity and frailty status. RSV-A/B was confirmed by quantitative RT-PCR. Results A total of 26,664 participants were enrolled, of whom 24,966 (RSVPreF3 OA: 12,467; placebo: 12,499) were included in the exposed set and 24,960 (RSVPreF3 OA: 12,466; placebo: 12,494) in the efficacy analysis. The mean age was 69.5 (±6.5) years and 51.7% were women. Over a median follow-up of 6.7 months (maximum 10.1 months), 47 RSV-confirmed LRTD episodes were reported (RSVPreF3 OA: 7; placebo: 40), resulting in a VE of 82.6% (96.95% CI: 57.9–94.1), thus the primary objective was met. Consistently high VE across the clinical spectrum of RSV disease, from RSV-confirmed ARI (71.7% [95% CI: 56.2–82.3]) to severe RSV-confirmed LRTD (94.1% [95% CI: 62.4–99.9]) was observed. High VE was seen in different age groups and regardless of RSV subtype, baseline comorbidity or pre-frail status (Figure 1). Cumulative incidence curves for RSV-confirmed LRTD and RSV-confirmed ARI showed persistent efficacy throughout the follow-up (Figure 2). Conclusion A single RSVPreF3 OA dose is highly efficacious against RSV-confirmed LRTD and RSV-confirmed ARI in adults ≥ 60 YOA, regardless of RSV disease severity, RSV subtype, baseline comorbidity and pre-frail status. Funding: GlaxoSmithKline Biologicals SA. Abstract and information is also available at the following link : Efficacy results for GSK's older adult RSV vaccine (investis.com). Disclosures Michael G. Ison, MD MS, GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support Alberto Papi, MD, CHIESI, ASTRAZENECA, GSK, BI, MENARINI, NOVARTIS, ZAMBON, MUNDIPHARMA, SANOFI, AVILLION: Honoraria|CHIESI, ASTRAZENECA, GSK, NOVARTIS, SANOFI, IQVIA, AVILLION, ELPEN PHARMACEUTICALS: Advisor/Consultant|CHIESI, ASTRAZENECA, GSK, NOVARTIS, SANOFI, IQVIA, AVILLION, ELPEN PHARMACEUTICALS: Board Member|CHIESI, ASTRAZENECA, GSK, SANOFI: Grant/Research Support Joanne M. Langley, MD, GSK, Merck, Medicago, Sanofi, VBI, VIDO, Entos, Pfizer: Grant/Research Support Isabel Leroux-Roels, PhD MD, Curevac: payment to my institution for the conduct of clinical trials|GSK: payment to my institution for the conduct of clinical trials|ICON Genetics: payment to my institution for the conduct of clinical trials|Janssen Vaccines (J&J): Board Member|Janssen Vaccines (J&J): payment to my institution for the conduct of clinical trials|Osivax: payment to my institution for the conduct of clinical trials Federico Martinon-Torres, MD, PhD, Assoc. Prof, GlaxoSmithKline, Pfizer, Sanofi, Merck, Moderna, Astra Zeneca, Biofabri, Janssen, Novavax: Advisor/Consultant|GlaxoSmithKline, Pfizer, Sanofi, Merck, Moderna, Astra Zeneca, Biofabri, Janssen, Novavax: Grant/Research Support|GlaxoSmithKline, Pfizer, Sanofi, Merck, Moderna, Astra Zeneca, Biofabri, Janssen, Novavax: Honoraria|GlaxoSmithKline, Pfizer, Sanofi, Merck, Moderna, Astra Zeneca, Biofabri, Janssen, Novavax: Clínical trials fees paid to my institution Tino F. Schwarz, Prof. Dr. MD, GlaxoSmithKline: Advisor/Consultant Richard N. Van Zyl-Smit, PhD MD, MSD, Pfizer, GSK, Astra Zeneca, Roche, Novartis, Boehringer Ingelheim, Cipla, J&J, Glenmark: Advisor/Consultant|MSD, Pfizer, GSK, Astra Zeneca, Roche, Novartis, Boehringer Ingelheim, Cipla, J&J, Glenmark: Honoraria Nancy Dezutter, PhD, PharmD, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Nathalie De Schrevel, PhD, GlaxoSmithKline: GSK employee Laurence Fissette, Master in Statistics, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Marie-Pierre David, Master in Statistics, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Marie Van Der Wielen, MD, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Lusine Kostanyan, MD, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Veronica Hulstrøm, PhD MD, GlaxoSmithKline: GSK employee.

Background Nosocomial respiratory viral infections (NRVI), transmitted from infected visitors or healthcare providers to patients, lead to significant morbidity and mortality. This study describes the epidemiology of nosocomial Influenza (flu) and Respiratory Syncytial Virus (RSV) at an academic medical center from 2009 to 2018. Methods After institutional review board (IRB) approval, data on NRVI was collected from our Enterprise Data Warehouse and primary chart review. A nosocomial infection was defined as a positive result of flu or RSV collected ≥ 72 hours after admission between April 2009 and March 2018. Results There were 93/1,317 (7.1%) nosocomial flu cases and 76/617 (12.3%) nosocomial RSV cases detected during the study period (see Table 1). Flu and RSV were first detected at a median of 6.8 and 8.4 days, respectively, after admission. Patients with nosocomial flu and RSV were more likely to have a cancer diagnosis, be a stem cell transplant recipient within one year, and have undergone chemotherapy in the past 30 days (see Table 2). Few nosocomial transmissions (15%) occurred outside the usual winter respiratory viral season (December through March, see Figure 1). Table 1Distribution of Nosocomial RVIsTable 2Underlying Medical Conditions Among Patients with Nosocomial and Community-Acquired RVIFigure 1Distribution of nosocomial RVIs over time assessing for transmission seasonality Conclusion Nosocomial infections account for 7% of hospitalized flu cases and 12% of hospitalized RSV cases. Infection is more common among patients at high risk of complications. Effort needs to be directed at approaches to reduce the risk of nosocomial transmission of RVI. Future studies are needed to assess the impact of interventions, such as universal masking, on the rate of nosocomial infections. Disclosures Michael G. Ison, MD MS, GlaxoSmithKlein: Grant/Research Support|Pulmocide: Grant/Research Support|Viracor Eurfins: Advisor/Consultant.

Background More than 200 orthotopic lung transplants (OLT) have been performed in the United States for patients (pts) with severe CALI. While some outcomes have been reported to generally be good, we conducted this study to describe the infectious outcomes. Methods After IRB approval, a retrospective case review was conducted of pts at Northwestern Memorial Hospital who had undergone OLT for CALI between June 1, 2020 and January 31, 2022. Data was collected from our Enterprise Data Warehouse and primary chart review to describe pts demographics and epidemiology of infectious complications. Results 35 OLTs were included (33 bilateral, 2 single lung; see Table 1). In the two weeks prior to transplant, 65.7% of pts were treated for bacterial, fungal, or mycobacterial infections (Table 2). Post-transplant, 32 (91.4%) of OLTs developed infections (Table 2), with most (28, 80%) developing pneumonia within 30 days of transplant. Five (14.3%) pts had airway complications, 7 (20%) pts required hemodialysis, and 3 (8.6%) pts died within one year of follow-up. Conclusion Infections remain a significant cause of morbidity post-OLT for CALI. Enhanced immunosuppression, long ICU stays post-tx, high rates of primary graft dysfunction and deconditioning likely contributed to this high rate of infection. A matched control group is being collected to compare these outcomes to other OLT pts. Disclosures Michael G. Ison, MD MS, GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support.

Background Cytomegalovirus infection (CMV) is the most common opportunistic infection in solid organ transplant recipients (SOTR). Predicting recurrent disease and appropriate use of secondary antiviral prophylaxis is currently poorly defined. CMV-specific T-cell assays have been shown to be promising tools in determining presence of CMV immunity and helping guide primary and secondary antiviral prophylaxis. The goal of this study was to evaluate the ability of commercially available CMV-TCIP in predicting the risk of CMV relapse. Methods After IRB approval, clinical and laboratory data was retrospectively collected from our Enterprise Data Warehouse and primary chart review on 74 SOTR. As part of routine clinical care, the CMV T-Cell Immunity Panel (CMV-TCIP, Viracor Eurofins, Lenexa, KS) were collected by the TID provider managing the infection; generally this was done around the time of first negative test to inform choice of 2° prophylaxis. Analysis was completed for the total patient population and a subgroup of patients with CMV-TCIP tests completed ± 21 days of the first negative CMV VL. Descriptive statistics and Cohen’s Kappa statistics were used to assess association of relapse with assay results. Results Patient demographics are shown in Table 1. 2° prophylaxis was given to 60 (81.1%) of total patients for a mean of 86 days (0-614 days) after the first negative CMV VL. 26 (35.1%) SOTRs had relapse – 9 with positive CD4 and 20 with positive CD8 CMV-TCIP values. There was no association between specific test results and risk of relapse in the overall study population (see table 2). Similarly, no significance was found in the subgroup analysis of patients with CMV-TCIP results ± 21 days after first negative CMV VL. Conclusion In this study, CMV-TCIP did not predict CMV relapse after initial infection and treatment. While prior studies have shown a potential role for assessment of CMV-specific immunity to guide need for secondary prophylaxis, more studies of the CMV-TCIP are needed to assess the utility of this assay for this indication. Disclosures Michael P. Angarone, DO, Abbvie: Advisor/Consultant Valentina Stosor, MD, DiaSorin: Advisor/Consultant|Eli Lilly and Company: Grant/Research Support|Med Learning Group: Honoraria Michael G. Ison, MD MS, GlaxoSmithKlein: Grant/Research Support|Pulmocide: Grant/Research Support|Viracor Eurfins: Advisor/Consultant.

Reduction of immunosuppression (IS) upon detection of Polyomavirus (BK) viremia is widely used to prevent BK virus nephropathy. This retrospective case-control study assesses the frequency of de novo donor-specific antibodies (dnDSA) in renal transplant recipients with IS modulation due to BK viremia and the associated risk of antibody mediated rejection.Our cohort included recipients of kidney transplantation between 2007 and 2017 with clinical, HLA antibody, and biopsy data. BK positivity was defined as viremia10 000 c/ml or biopsy proven BK nephropathy. A total of 190 BK cases matched our inclusion criteria, each case was matched with two controls based on gender, donor type, and transplant within 1 year (N = 396).Despite lower number of HLA antigen mismatches (mean = 3.5 vs. 4.4, p.001), dnDSA rates were higher in BK cases than in control group (22.1% vs. 13.9%, p = .02), with the majority detected following IS reduction for BK infection, and arising earlier posttransplant compared with no BK infection (294d vs. 434d, p.001). Antibody mediated rejection rates were similar between cases and controls (8.9% and 8.3%, respectively), but rejection was more likely to occur earlier posttransplant in the BK cases (354d vs. 602d, p = .03).Our data suggest a link between IS reduction and the generation of dnDSA and/or rejection, supporting close monitoring for DSA in patients with reduced IS due to BK infection given their increased risk to develop dnDSA.

Organ utilization from donors infected or colonized with multidrug-resistant organisms (MDROs) remains inconsistent, and hesitancy to accept organs from these donors may relate to poor outcomes among solid organ transplant recipients with MDRO donor-derived infections (DDIs). An improved understanding of the risk factors for donor MDRO colonization or infection and the risk of MDRO DDI is needed to safely expand the donor pool while minimizing unnecessary organ discard.Recent studies have begun to delineate risk factors for MDRO acquisition among deceased donors and the epidemiology of MDRO DDIs, but additional efforts are warranted to inform optimal approaches to donor evaluation, risk stratification, management, interfacility and interagency data sharing, and approaches to recipient management.This review summaries recent data regarding risk factors for MDRO colonization and infection in deceased donors, epidemiology of MDRO DDIs, and current approaches to donors harboring MDROs and provides a framework for future research and collaboration.

A novel coronavirus has had global impact on individual health and health care delivery. In this C4 article, contributors discuss various aspects of transplantation including donor and recipient screening, management of infected patients, and prevention of coronavirus disease (COVID). Donor screening with SARS-CoV-2 nucleic acid testing (NAT) close to the time of procurement is recommended. Many programs are also screening all potential recipients at the time of admission. The management of COVID has evolved with remdesivir emerging as a new potential option for transplant recipients. Dexamethasone has also shown promise and convalescent plasma is under study. Prevention strategies for transplant candidates and recipients are paramount. Pediatric-specific issues are also discussed. Strategies for the psychological well-being of patients and providers are also imperative, in addition to future research priorities for transplantation.

Organ procurement organizations (OPO) test potential deceased organ donors for infectious diseases required by policy, but many also perform testing for additional infections. The current state of donor testing in the United States is unknown. We sent an IRB approved survey to all 57 U.S. OPOs using REDCap. Descriptive statistics were performed. From the 57 OPOs, we received 46 (80.7%) unique responses with all 11 United Network of Organ Sharing regions represented. Forty of 46 (87%) OPO respondents consulted an Infectious Diseases physician when needed. Eighteen of 46 (39%) tested for West Nile virus (WNV) and 17 of 18 (94%) tested year-round. Eleven of 46 (23.9%) tested for Strongyloides infection while 17 of 46 (37%) tested for Chagas disease. All OPOs performed prospective nucleic acid testing (NAT) for HIV, hepatitis B and hepatitis C on all donors. OPO testing of additional infections has increased since prior surveys but remains variable. Standardization of organ donor infectious diseases evaluation should be considered.

The continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with decreased susceptibility to neutralizing antibodies is of clinical importance. Several spike mutations associated with immune escape have evolved independently in association with different variants of concern (VOCs). How and when these mutations arise is still unclear. We hypothesized that such mutations might arise in the context of persistent viral replication in immunosuppressed hosts.Nasopharyngeal specimens were collected longitudinally from two immunosuppressed patients with persistent SARS-CoV-2 infection. Plasma was collected from these same patients late in disease course. SARS-CoV-2 whole genome sequencing was performed to assess the emergence and frequency of mutations over time. Select Spike mutations were assessed for their impact on viral entry and antibody neutralization in vitro.Our sequencing results revealed the intrahost emergence of spike mutations that are associated with circulating VOCs in both immunosuppressed patients (del241-243 and E484Q in one patient, and E484K in the other). These mutations decreased antibody-mediated neutralization of pseudotyped virus particles in cell culture, but also decreased efficiency of spike-mediated cell entry.These observations demonstrate the de novo emergence of SARS-CoV-2 spike mutations with enhanced immune evasion in immunosuppressed patients with persistent infection. These data suggest one potential mechanism for the evolution of VOCs and emphasize the importance of continued efforts to develop antiviral drugs for suppression of viral replication in hospitalized settings.

Background Cache Valley virus (CVV) is a mosquito-borne virus that is a rare cause of disease in humans. In the fall of 2020, a patient developed encephalitis 6 weeks following kidney transplantation and receipt of multiple blood transfusions. Methods After ruling out more common etiologies, metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) was performed. We reviewed the medical histories of the index kidney recipient, organ donor, and recipients of other organs from the same donor and conducted a blood traceback investigation to evaluate blood transfusion as a possible source of infection in the kidney recipient. We tested patient specimens using reverse-transcription polymerase chain reaction (RT-PCR), the plaque reduction neutralization test, cell culture, and whole-genome sequencing. Results CVV was detected in CSF from the index patient by mNGS, and this result was confirmed by RT-PCR, viral culture, and additional whole-genome sequencing. The organ donor and other organ recipients had no evidence of infection with CVV by molecular or serologic testing. Neutralizing antibodies against CVV were detected in serum from a donor of red blood cells received by the index patient immediately prior to transplant. CVV neutralizing antibodies were also detected in serum from a patient who received the co-component plasma from the same blood donation. Conclusions Our investigation demonstrates probable CVV transmission through blood transfusion. Clinicians should consider arboviral infections in unexplained meningoencephalitis after blood transfusion or organ transplantation. The use of mNGS might facilitate detection of rare, unexpected infections, particularly in immunocompromised patients.

Ibrutinib ist ein bekannter Inhibitor der Bruton-Tyrosinkinase (BTK) und der Interleukin-2-induzierbaren T-Zell-Kinase (ITK), der zur Behandlung von B-Zell-Erkrankungen (chronische lymphatische Leukämie [CLL] und verschiedene andere Lymphome) und der chronischen Graft-versus-Host-Erkrankung nach allogener Transplantation von hämatopoetischen Zellen eingesetzt wird. Da es als immunsuppressiv gilt, stellt sich bei Patienten mit einer aktiven Infektion häufig die Frage nach einer Fortführung der Ibrutinib-Therapie, und im Zusammenhang mit der Coronavirus-Erkrankung 2019 (COVID-19) ist diese Entscheidung besonders schwierig. In der vorliegenden Arbeit beschreiben wir einen Patienten mit CLL, der mit Ibrutinib behandelt wurde und im weiteren Verlauf eine schwere COVID-19-Infektion entwickelte, die eine mechanische Beatmung erforderlich machte. Wir beschlossen, die Gabe von Ibrutinib noch am Tag der Intubation fortzusetzen, mit der Argumentation, dass die BTK-Inhibition in myeloischen Immunzellen nachgewiesenermaßen die influenza-vermittelte akute Lungenschädigung verringert oder sogar umkehrt und dass die ITK-Inhibition in T-Zellen mit einer Reduzierung der Virusreplikation korreliert und daher in diesem Setting von Nutzen sein könnte. Darüber hinaus hat sich gezeigt, dass Ibrutinib auch Kinasen der Src-Familie blockiert, was möglicherweise ein verringertes Eindringen der Viren zur Folge hat und zu einer verminderten inflammatorischen Zytokinreaktion in der Lunge führt. Der Patient wurde nach 9 Tagen und einem komplizierten stationären Verlauf extubiert und schließlich unter Raumluftatmung entlassen. Die einzige Möglichkeit, solche Entscheidungen rational zu untermauern und ähnliche potenziell vielversprechende Hinweise in dieser Pandemie zu untersuchen, sind sorgfältig durchgeführte klinische Studien.

Background Infection with Ureaplasma species (spp) has been linked to fatal hyperammonemia syndrome (HS) in lung transplant recipients. We sought to characterize the epidemiology of Ureaplasma spp in candidates and donors and describe outcomes of antimicrobial therapy in preventing and treating HS. Methods Candidate testing for Ureaplasma spp was performed with urine culture and polymerase chain reaction (PCR) pretransplant. Positive candidates were treated with levofloxacin. Donor testing was performed with bronchoalveolar lavage (BAL) culture and PCR intraoperatively. From 7/2014 to 2/2017 patients were treated according to results; from 2/2017 to 10/2018 recipients received empiric levofloxacin and azithromycin at transplant until testing returned negative. HS was defined as new onset altered mental status after transplant with ammonia > 200 µmol/L. Results In total, 60 patients who underwent lung transplant were included. And 80% (n = 48) of patients had negative screening tests in donor and candidate pre-lung transplant, 8.3% (n = 5) of recipients had positive Ureaplasma spp testing in urine pre-transplant, and 13.3% (n = 8) had positive donor BAL testing at the time of lung transplant. Three patients developed HS a median of 7 days posttransplant; 2 died of HS. Recipients of organs with Ureaplasma spp who received empiric therapy did not develop HS. Donors with Ureaplasma spp were younger and more sexually active. Conclusions Donor-derived Ureaplasma spp in lung transplant was associated with HS. Screening lung donors for Ureaplasma spp might allow for targeted therapy to reduce risk for development of HS, but future confirmatory studies are needed.

Ibrutinib, a known Burton's tyrosine kinase (BTK) and interleukin‐2 inducible T‐cell kinase (ITK) inhibitor, is used for the treatment of B‐cell disorders (chronic lymphocytic leukemia [CLL] and various other lymphomas) and chronic graft versus host disease following allogeneic hematopoietic cell transplantation. Because it is considered an immunosuppressant, continuation of ibrutinib is often debated when patients have an active infection, and this becomes an especially difficult decision in the setting of coronavirus disease 2019 (COVID‐19). Here, we describe a patient with CLL who was on ibrutinib then developed severe COVID‐19 infection requiring mechanical ventilation. We elected to continue ibrutinib the same day he was intubated, reasoning that BTK inhibition in myeloid immune cells has been shown to reduce or even reverse influenza‐mediated acute lung injury and that ITK inhibition in T cells has correlated with reduction in viral replication, and therefore may have an advantage in this setting. Ibrutinib also has been shown to block Src family kinases, which potentially could result in reduction of viral entry and the inflammatory cytokine response in the lungs. The patient was extubated after 9 days with a complex hospital course and eventually discharged on room air. The only way to rationally inform these decisions and explore similar potentially promising leads in this pandemic is to conduct carefully done clinical trials.

Clinical outcomes in solid organ transplant (SOT) recipients with breakthrough COVID (BTCo) after two doses of mRNA vaccination compared to the non-immunocompromised/immunosuppressed (ISC) general population, are not well described. In a cohort of adult patients testing positive for COVID-19 between December 10, 2020 and April 4, 2022, we compared the cumulative incidence of BTCo in a non-ISC population to SOT recipients (overall and by organ type) using the National COVID Cohort Collaborative (N3C) including data from 36 sites across the United States. We assessed the risk of complications post-BTCo in vaccinated SOT recipients versus SOT with unconfirmed vaccination status (UVS) using multivariable Cox proportional hazards and logistic regression. BTCo occurred in 4776 vaccinated SOT recipients over a median of 149 days (IQR 99-233), with the highest cumulative incidence in heart recipients. The relative risk of BTCo was greatest in SOT recipients (relative to non-ISC) during the pre-Delta period (HR 2.35, 95% CI 1.80-3.08). The greatest relative benefit with vaccination for both non-ISC and SOT cohorts was in BTCo mortality (HR 0.37, 95% CI 0.36-0.39 for non-ISC; HR 0.67, 95% 0.57-0.78 for SOT relative to UVS). While the relative benefit of vaccine was less in SOT than non-ISC, SOT patients still exhibited significant benefit with vaccination.

Allogeneic hematopoietic cell transplant (allo-HCT) recipients are at increased risk for respiratory viral infections (RVIs), which invoke substantial morbidity and mortality. Limited effective antiviral options and drug resistance often hamper successful RVI treatment, creating additional burden for patients and the health care system.Using an open-source health care claims database, we examined differences in clinical outcomes, health resource utilization, and total reimbursements during the 1-year period following allo-HCT in patients with and without any RVI infection (respiratory syncytial virus, influenza, parainfluenza virus, and human metapneumovirus). RVIs were diagnosed at any time ≤1 year after allo-HCT and identified by International Classification of Disease codes. Analyses were stratified by the presence or absence of acute or chronic graft-versus-host disease (GVHD).The study included 13 363 allo-HCT patients, 1368 (10.2%) of whom had a diagnostic code for any RVI. A higher proportion of patients with any RVI had pneumonia ≤1 year after allo-HCT compared to patients without any RVI, with or without GVHD. Patients with any RVI had higher all-cause mortality risk, longer length of post-allo-HCT hospital stay, higher readmission rate, and higher number of hospital days after allo-HCT compared to patients without the infection (all p .05). Total unadjusted median reimbursements were higher for those with any RVI and each specific RVI assessed than those without the specific infection, with or without GVHD.Allo-HCT patients with RVIs had significantly worse clinical outcomes and increased health resource utilization and reimbursements during the year following allo-HCT, with or without GVHD.

Over two years into the COVID-19 pandemic, the human immune response to SARS-CoV-2 during the active disease phase has been extensively studied. However, the long-term impact after recovery, which is critical to advance our understanding SARS-CoV-2 and COVID-19-associated long-term complications, remains largely unknown. Herein, we characterized multi-omic single-cell profiles of circulating immune cells in the peripheral blood of 100 patients, including covenlesent COVID-19 and sero-negative controls. The reduced frequencies of both short-lived monocytes and long-lived regulatory T (Treg) cells are significantly associated with the patients recovered from severe COVID-19. Consistently, sc-RNA seq analysis reveals seven heterogeneous clusters of monocytes (M0-M6) and ten Treg clusters (T0-T9) featuring distinct molecular signatures and associated with COVID-19 severity. Asymptomatic patients contain the most abundant clusters of monocyte and Treg expressing high CD74 or IFN-responsive genes. In contrast, the patients recovered from a severe disease have shown two dominant inflammatory monocyte clusters with S100 family genes: S100A8 & A9 with high HLA-I whereas S100A4 & A6 with high HLA-II genes, a specific non-classical monocyte cluster with distinct IFITM family genes, and a unique TGF-β high Treg Cluster. The outpatients and seronegative controls share most of the monocyte and Treg clusters patterns with high expression of HLA genes. Surprisingly, while presumably short-ived monocytes appear to have sustained alterations over 4 months, the decreased frequencies of long-lived Tregs (high HLA-DRA and S100A6) in the outpatients restore over the tested convalescent time (>= 4 months). Collectively, our study identifies sustained and dynamically altered monocytes and Treg clusters with distinct molecular signatures after recovery, associated with COVID-19 severity.

In preparation of a clinical trial of norovirus treatment, there were concerns raised by FDA about risk of self-storage of stool from patients infected with norovirus affecting quantitative assessments of norovirus RNA. Specifically, most home freezers are frost-free and may expose the samples to multiple rounds of freeze-thaw. Stool samples collected by the study team were stored at different lengths in a frost-free freezer and at -80°C. Quantitative PCRs of norovirus were performed on all samples using the same assay. By all measures, there was no significant change in measured viral load with home storage.

Introduction Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. Methods We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90. Results Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p = Conclusions In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment

Patients with a history of malignancy have been shown to be at an increased risk of COVID-19-related morbidity and mortality. Poorer clinical outcomes in that patient population are likely due to the underlying systemic illness, comorbidities, and the cytotoxic and immunosuppressive anti-tumor treatments they are subjected to. We identified 416 cancer patients with SARS-CoV-2 infection being managed for their malignancy at Northwestern Medicine in Chicago, Illinois, between March and July of 2020. Seventy-five (18.0%) patients died due to COVID-related complications. Older age (>60), male gender, and current treatment with immunotherapy were associated with shorter overall survival. Laboratory findings showed that higher platelet counts, ALC, and hemoglobin were protective against critical illness and death from COVID-19. Conversely, elevated inflammatory markers such as ferritin, d-dimer, procalcitonin, CRP, and LDH led to worse clinical outcomes. Our findings suggest that a thorough clinical and laboratory assessment of infected patients with cancer might help identify a more vulnerable population and implement more aggressive proactive strategies.

Infections remain a common complication of solid-organ transplantation. Most infections in the first month after transplant are typically health care-associated infections, whereas late infections, beyond 6-12 months, are community-acquired infections. Opportunistic infections most frequently present in the first 12 months post-transplant and can be modulated on prior exposures and use of prophylaxis. In this review, we summarize the current epidemiology of postkidney transplant infections with a focus on key viral (BK polyomavirus, cytomegalovirus, Epstein-Barr virus, and norovirus), bacterial (urinary tract infections and Clostridioides difficile colitis), and fungal infections. Current guidelines for safe living post-transplant are also summarized. Literature supporting prophylaxis and vaccination is also provided.

Transplant centers seeking to increase coronavirus disease 2019 (COVID-19) vaccine coverage may consider requiring vaccination for healthcare workers or for candidates. The authors summarize current data to inform an ethical analysis of the harms, benefits, and individual and societal impact of mandatory vaccination, concluding that vaccine requirements for healthcare workers and transplant candidates are ethically justified by beneficence, net utility, and fiduciary duty to patients and public health. Implementation strategies should mitigate concerns about respect for autonomy and transparency for both groups. We clarify how the same arguments might be applied to related questions of caregiver vaccination, allocation of other healthcare resources, and mandates for non-COVID-19 vaccines. Finally, we call for effort to achieve global equity in vaccination as soon as possible.

Adenoviruses result in a wide array of clinical presentations, including primarily respiratory, gastrointestinal, genitourinary, or systemic infections. Although adenovirus causes mild disease limited to a single organ system in immunocompetent individuals, severe and life-threatening infections do rarely occur. Disseminated disease and severe localized disease resulting in significant morbidity and mortality have been well described in the immunocompromised populations. Although asymptomatic viremia, respiratory tract, and gastrointestinal infections are the most common disease in most transplant patients, renal transplant patients more commonly experience urinary tract infections, including hemorrhagic cystitis or nephritis. Diagnosis requires astute clinical awareness of the patient's clinical presentation that would be compatible with adenovirus combined with cultures, molecular testing, polymerase chain reaction, and tissue sampling. There is no Food and Drug Administration-approved treatment for adenovirus; however, several studies have evaluated therapeutic options including cidofovir, brincidofovir, and immunotherapy. This article will summarize our current understanding of adenovirus in the transplant population.

Background While several demographic and clinical correlates of coronavirus disease 2019 (COVID-19) outcome have been identified, their relationship to virological and immunological parameters remains poorly defined. Methods To address this, we performed longitudinal collection of nasopharyngeal swabs and blood samples from a cohort of 58 hospitalized adults with COVID-19. Samples were assessed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load, viral genotype, viral diversity, and antibody titer. Demographic and clinical information, including patient blood tests and several composite measures of disease severity, was extracted from electronic health records. Results Several factors, including male sex, higher age, higher body mass index, higher 4C Mortality score, and elevated lactate dehydrogenase levels, were associated with intensive care unit admission. Of all measured parameters, only the retrospectively calculated median Deterioration Index score was significantly associated with death. While quantitative polymerase chain reaction cycle threshold (Ct) values and genotype of SARS-CoV-2 were not significantly associated with outcome, Ct value did correlate positively with C-reactive protein levels and negatively with D-dimer, lymphocyte count, and antibody titer. Intrahost viral genetic diversity remained constant through the disease course and resulted in changes in viral genotype in some participants. Conclusions Ultimately, these results suggest that worse outcomes are driven by immune dysfunction rather than by viral load and that SARS-CoV-2 evolution in hospital settings is relatively constant over time.

Disparities in access to anti-SARS-CoV-2 monoclonal antibodies have not been well characterized.We sought to explore the impact of race/ethnicity as a social construct on monoclonal antibody delivery.Following implementation of a centralized infusion program at a large academic healthcare system, we reviewed a random sample of high-risk ambulatory adult patients with COVID-19 referred for monoclonal antibody therapy.We examined the relationship between treatment delivery, race/ethnicity, and other demographics using descriptive statistics, binary logistic regression, and spatial analysis.There was no significant difference in racial composition between patients who did (n = 25) and patients who did not (n = 378) decline treatment (p = 0.638). Of patients who did not decline treatment, 64.8% identified as White, 14.8% as Hispanic/Latinx, and 11.1% as Black. Only 44.6% of Hispanic/Latinx and 31.0% of Black patients received treatment compared to 64.1% of White patients (OR 0.45, 95% CI 0.25-0.81, p = 0.008, and OR 0.25, 95% CI 0.12-0.50, p0.001, respectively). In multivariable analysis including age, race, insurance status, non-English primary language, county Social Vulnerability Index, illness severity, and total number of comorbidities, associations between receiving treatment and Hispanic/Latinx or Black race were no longer statistically significant (AOR 1.32, 95% CI 0.69-2.53, p = 0.400, and AOR 1.34, 95% CI 0.64-2.80, p = 0.439, respectively). However, patients who were uninsured or whose primary language was not English were less likely to receive treatment (AOR 0.16, 95% CI 0.03-0.88, p = 0.035, and AOR 0.37, 95% CI 0.15-0.90, p = 0.028, respectively). Spatial analysis suggested decreased monoclonal antibody delivery to Cook County patients residing in socially vulnerable communities.High-risk ambulatory patients with COVID-19 who identified as Hispanic/Latinx or Black were less likely to receive monoclonal antibody therapy in univariate analysis, a finding not explained by patient refusal. Multivariable and spatial analyses suggested insurance status, language, and social vulnerability contributed to racial disparities.