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Prolonged coronavirus disease 2019 may generate new viral variants. We report an immunocompromised patient treated with monoclonal antibodies who experienced rebound of viral RNA and emergence of an antibody-resistant (>1000-fold) variant containing 5 mutations in the spike gene. The mutant virus was isolated from respiratory secretions, suggesting the potential for secondary transmission.

We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study.

Background Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. Methods Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. Results No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. Conclusions Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

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.

Enterococcus faeciumis a member of the human gastrointestinal (GI) tract microbiota but can also cause invasive infections, especially in immunocompromised hosts. Enterococci display intrinsic resistance to many antibiotics, and most clinicalE. faeciumisolates have acquired vancomycin resistance, leaving clinicians with a limited repertoire of effective antibiotics. As such, vancomycin-resistantE. faecium(VREfm) has become an increasingly difficult to treat nosocomial pathogen that is often associated with treatment failure and recurrent infections. We followed a patient with recurrentE. faeciumbloodstream infections (BSIs) of increasing severity that ultimately became unresponsive to antibiotic combination therapy over the course of 7 years. Whole genome sequencing (WGS) showed that the patient was colonized with closely relatedE. faeciumstrains for at least two years, and that invasive isolates likely emerged from a largeE. faeciumpopulation in the patient’s GI tract. The addition of bacteriophage (phage) therapy to the patient’s antimicrobial regimen was associated with several months of clinical improvement and reduced intestinal burden of VRE andE. faecium. Eventual recurrence ofE. faeciumBSI was not associated with the development of antibiotic or phage resistance in post-treatment isolates. However, an anti-phage neutralizing antibody response occurred simultaneously with an increased relative abundance of VRE in the GI tract, both of which may have contributed to clinical failure. Taken together, these findings highlight the potential utility and limitations of phage therapy to treat antibiotic-resistant enterococcal infections.ImportancePhage therapy is an emerging therapeutic approach for treating bacterial infections that do not respond to traditional antibiotics. The addition of phage therapy to systemic antibiotics to treat a patient with recurrentE. faeciuminfections that were non-responsive to antibiotics alone resulted in fewer hospitalizations and improved the patient’s quality of life. Combination phage and antibiotic therapy reducedE. faeciumand VRE abundance in the patient’s stool. Eventually an anti-phage antibody response emerged that was able to neutralize phage activity, which may have limited clinical efficacy. This study demonstrates the potential of phages as an additional option in the antimicrobial toolbox for treating invasive enterococcal infections and highlights the need for further investigation to ensure phage therapy can be deployed for maximum clinical benefit.

Background Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. Methods We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. Results Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 livers). Each year the number of donors increased. The prevalence of hepatitis B (16% vs 0%), syphilis (16% vs 0%), and cytomegalovirus (CMV; 91% vs 58%) was higher in HIV-positive versus FP donors; the prevalences of hepatitis C viremia were similar (2% vs 6%). Most HIV-positive donors (71%) had a known HIV diagnosis, of whom 90% were prescribed ART and 68% had a VL Conclusion The use of HIV-positive donor organs is increasing. HIV DRMs are common, yet resistance that would compromise integrase strand transfer inhibitor–based regimens is rare, which is reassuring regarding safety.

[Purpose of Review] Certain immunocompromised individuals are at risk for protracted COVID-19, in which SARS-CoV-2 leads to a chronic viral infection. However, the pathogenesis, diagnosis, and management of this phenomenon remain ill-defined., [Recent Findings] Herein, we review key aspects of protracted SARS-CoV-2 infection in immunocompromised individuals, or the so-called long persisters, and describe the clinical presentation, risk factors, diagnosis, and treatment modalities of this condition, as well as intra-host viral evolution. Based on the available data, we also propose a framework of criteria with which to approach this syndrome., [Summary] Protracted COVID-19 is an uncharacterized syndrome affecting patients with B-cell depletion; our proposed diagnostic approach and definitions will inform much needed future research.

BackgroundSecondary infection (SI) diagnosis in COVID-19 is challenging, due to overlapping clinical presentations, practical limitations in obtaining samples from the lower respiratory tract (LRT), and low sensitivity of microbiologic cultures.Research QuestionCan metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) help diagnose SIs complicating COVID-19?Study Design and MethodsWe enrolled 42 inpatients with COVID-19 classified as microbiologically-confirmed SI (Micro-SI, n=8), clinically-diagnosed SI (Clinical-SI, n=13, i.e. empiric antimicrobials), or no clinical suspicion for SI (No-Suspected-SI, n=21) at time of enrollment. From baseline and follow-up plasma samples (days 5 and 10 post-enrollment), we quantified mcfDNA for all detected microbes by mcfDNA sequencing and measured nine host-response biomarkers. From LRT samples among intubated subjects, we quantified bacterial burden with 16S rRNA gene quantitative PCR.ResultsWe performed mcfDNA-Seq in 82 plasma samples. Sequencing was successful in 60/82 (73.2%) samples, which had significantly lower levels of human cfDNA than failed samples (p10 mcfDNA, p=0.03).InterpretationHigh circulating levels of mcfDNA in a substantial proportion of patients with COVID-19 without clinical suspicion for SI suggest that SIs may often remain undiagnosed. McfDNA-Seq, when clinically available, can offer a non-invasive diagnostic tool for pathogen identification, with prognostic value on host inflammatory response and clinical outcomes.

Treatment with latency-reversing agents (LRAs) alone has been ineffective in reducing HIV-1 reservoirs in persons with HIV-1 (PWH) on antiretroviral therapy (ART), due to inefficiencies in reservoir reactivation and adaptive immune responses. However, NK cells that are activated with cytokines may be able to target HIV-1 reservoirs more efficiently. To study the therapeutic potential of NK cells, we expanded blood NK cells from multiple donorsex vivointo CD56brightCD16+“eNK” cells using artificial antigen presenting cells (aAPCs) expressing membrane-bound IL21. eNK cells express multiple activating receptors and are highly cytotoxic against specific target cells. eNK cells can also kill HIV-infected CD4 T cells via antibody dependent cell-mediated cytotoxicity (ADCC) using broadly neutralizing antibodies against HIV-1 Env gp120/gp41. Importantly, eNK cells from PWH on ART efficiently killed autologous HIV-1+T cells reactivated by a combination of vorinostat (SAHA) and IL-15 or an IL-15 superagonist (N-803), as detected by declines in proviral load, inducible HIV-1 mRNA, and virus release. Adoptive immunotherapy with eNK cells is therefore a promising approach to reduce the latent HIV-1 reservoir in PWH when combined with LRA treatment.Author SummarySuccessful antiretroviral therapy (ART) eliminates progression to AIDS by reducing HIV to nearly indetectable levels by routine clinical measurements of blood samples. However, more sensitive DNA and RNA measurements show that most persons on ART retain a reservoir of long lived latently infected cells, which remain undetected by the immune system while no HIV is being produced. In nearly all cases, ART interruption results in a rebound of HIV production and spread, requiring an immediate return to ART. Currently the goal of HIV eradication is to achieve a “functional cure”, where HIV reservoirs are reduced to the point where ART can be interrupted indefinitely, and low levels of infected cells remaining can be controlled by the immune system. Our eradication strategy combines HIV latency-reversing agents (LRAs), ex vivo expansion of natural killer (NK) cells, and enhancement of specificity and killing of infected cells with broadly neutralizing antibodies against HIV. In this study, we have demonstrated that NK cells from person living with HIV can be isolated and expanded ex vivo into “eNK” cells that kill HIV-infected cells without killing uninfected cells, especially when broadly neutralizing antibodies are present, and can significantly reduce HIV reservoirs after LRA treatment.

The COVID-19 pandemic has been accompanied by SARS-CoV-2 evolution and emergence of viral variants that have far exceeded initial expectations. Five major variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) have emerged, each having both unique and overlapping amino acid substitutions that have affected transmissibility, disease severity, and susceptibility to natural or vaccine-induced immune responses and monoclonal antibodies. Several of the more recent variants appear to have evolved properties of immune evasion, particularly in cases of prolonged infection. Tracking of existing variants and surveillance for new variants are critical for an effective pandemic response. Expected final online publication date for the

This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy. Prophylaxis effectively prevents CMV infection after solid organ transplantation (SOT) but is associated with high rates of neutropenia and delayed-onset postprophylaxis disease. In contrast, preemptive therapy has the advantage of leading to lower rates of CMV disease and robust humoral and T-cell responses. It is widely used in hematopoietic cell transplant recipients but is infrequently utilized after SOT due to logistical considerations, though these may be overcome by novel methods to monitor CMV viremia using self-testing platforms. We review recent developments in CMV immune monitoring, vaccination, and monoclonal antibodies, all of which have the potential to become part of integrated strategies that rely on viral load monitoring and immune responses. We discuss novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer. We also explore the role of donor factors in transmitting CMV after SOT. Finally, we propose a framework with which to approach CMV prevention in the foreseeable future.

Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab.A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound.Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab.Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb.This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.

Background Risk factors for acquisition of vancomycin-resistant Enterococcus (VRE) include immunosuppression, antibiotic exposure, indwelling catheters, and manipulation of the gastrointestinal tract, all of which occur in liver transplant recipients. VRE infections are documented in liver transplantation (LT); however, only one single center study has assessed the impact of daptomycin-resistant Enterococcus (DRE) in this patient population. Methods We conducted a retrospective multicenter cohort study comparing liver transplant recipients with either VRE or DRE bacteremia. The primary outcome was death within 1 year of transplantation. Multivariable logistic regression analyses were performed to calculate adjusted odds ratios for outcomes of interest. Results We identified 139 cases of Enterococcus bacteremia following LT, of which 78% were VRE and 22% were DRE. When adjusted for total intensive care unit days in the first transplant year, liver-kidney transplantation, and calcineurin inhibitor use, patients with DRE bacteremia were 2.65 times more likely to die within 1 year of transplantation (adjusted odds ratio [aOR], 2.648; 95% CI, 1.025–6.840; P = .044). Prior daptomycin exposure was found to be an independent predictor of DRE bacteremia (aOR, 30.62; 95% CI, 10.087–92.955; P Conclusions In this multicenter study of LT recipients with Enterococcus bacteremia, DRE bacteremia was associated with higher 1-year mortality rates when compared with VRE bacteremia. Our data provide strong support for dedicated infection prevention and antimicrobial stewardship efforts for transplant patients. Further research is needed to support the development of better antibiotics for DRE and practical guidance focusing on identification and prevention of colonization and subsequent infection in liver transplant recipients at high risk for DRE bacteremia.

IMPORTANCEThe effectiveness of monoclonal antibodies (mAbs), casirivimab and imdevimab, and sotrovimab, for patients with mild to moderate COVID-19 from the Delta variant is unknown.OBJECTIVETo evaluate the effectiveness of mAbs for the Delta variant compared to no treatment, and the comparative effectiveness between mAbs.DESIGN, SETTING, AND PARTICIPANTSTwo parallel studies among patients who met Emergency Use Authorization criteria for mAbs from July 14, 2021 to September 29, 2021: i.) prospective observational cohort study comparing mAb treatment to no mAb treatment and, ii.) Bayesian adaptive randomized trial comparing the effectiveness of casirivimab-imdevimab versus sotrovimab. In the observational study, we compared eligible patients who received mAb at an outpatient infusion center at UPMC, to nontreated patients with a positive SARS-CoV-2 test. In the comparative effectiveness trial, we randomly allocated casirivimab-imdevimab or sotrovimab to patients presenting to infusion centers and emergency departments, per system therapeutic interchange policy.EXPOSUREIntravenous mAb per their EUA criteria.MAIN OUTCOMES AND MEASURESFor the observational study, risk ratio estimates for hospitalization or death by 28 days were compared between mAb treatment to no mAb treatment using propensity matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day) in a Bayesian cumulative logistic model, adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio RESULTSAmong 3,558 patients receiving mAb, the mean age was 54 (SD 18 years), 1,511 (43%) were treated in an infusion center, and 450 (13%) were hospitalized or died by day 28. In propensity matched models, mAb treatment was associated with reduced risk of hospitalization or death compared to no treatment (risk ratio (RR)=0.40, 95% CI: 0.28–0.57). Both casirivimab and imdevimab (RR=0.31, 95% CI: 0.20–0.50), and sotrovimab (RR=0.60, 95% CI: 0.37–1.00) reduced hospitalization or death compared to no mAb treatment. Among patients allocated randomly to casirivimab and imdevimab (n=2,454) or sotrovimab (n=1,104), the median hospital-free days were 28 (IQR 28–28) for both groups, 28-day mortality was 0.5% (n=12) and 0.6% (n=7), and hospitalization by day 28 was 12% (n=291) and 12% (n=140), respectively. Compared to casirivimab and imdevimab, the median adjusted odds ratio for hospital-free days was 0.88 (95% credible interval, 0.70–1.11) for sotrovimab. This odds ratio yielded 86% probability of inferiority of sotrovimab versus casirivimab and imdevimab, and 79% probability of equivalence.CONCLUSIONS AND RELEVANCEIn non-hospitalized patients with mild to moderate COVID-19 due to the Delta variant, casirivimab and imdevimab and sotrovimab were both associated with a reduced risk of hospitalization or death. The comparative effectiveness of mAbs appeared similar, though prespecified criteria for statistical inferiority or equivalence were not met.TRIAL REGISTRATIONClinicalTrials.gov: NCT04790786Key PointsQuestionIn non-hospitalized patients with mild to moderate COVID-19 due to the Delta variant, what is the effectiveness of monoclonal antibodies (mAb) compared to no treatment, and what is the comparative effectiveness between mAb?FindingsAmong 3,069 patients, mAb treatment (casirivimab and imdevimab or sotrovimab) was associated with reduced risk of hospitalization or death by 28 days compared to no treatment (risk ratio=0.40, 95% CI: 0.28–0.57). In a Bayesian randomized comparative effectiveness trial of casirivimab and imdevimab vs. sotrovimab in 3,558 patients, the median hospital–free days were 28 days for both groups. Compared to casirivimab-imdevimab, the median adjusted odds ratio for hospital-free days was 0.88 (95% credible interval, 0.70–1.11) for sotrovimab, an 86% probability of inferiority of sotrovimab versus casirivimab and imdevimab, and 79% probability of equivalence.MeaningIn non-hospitalized patients with mild to moderate COVID-19 due to the Delta variant, casirivimab and imdevimab and sotrovimab were associated with reduced risk of hospitalization or death compared to no treatment. The comparative effectiveness of mAbs appeared similar, though prespecified criteria for statistical inferiority or equivalence were not met.

Background We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency. Methods Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. Results A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P Conclusions Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.

Risk factors for acquisition of vancomycin-resistantWe conducted a retrospective multicenter cohort study comparing liver transplant recipients with either VRE or DRE bacteremia. The primary outcome was death within 1 year of transplantation. Multivariable logistic regression analyses were performed to calculate adjusted odds ratios for outcomes of interest.We identified 139 cases ofIn this multicenter study of LT recipients with

BackgroundNeutralizing monoclonal antibodies (mAb) targeting SARS-CoV-2 decrease hospitalization and death in patients with mild to moderate Covid-19. Yet, their clinical use is limited, and comparative effectiveness is unknown.MethodsWe present the first results of an ongoing, learning health system adaptive platform trial to expand mAb treatment to all eligible patients and evaluate the comparative effectiveness of available mAbs. The trial launched March 10, 2021. Results are reported as of June 25, 2021 due to the U.S. federal decision to pause distribution of bamlanivimab-etesevimab; patient follow-up concluded on July 23, 2021. Patients referred for mAb who met Emergency Use Authorization criteria were provided a random mAb allocation of bamlanivimab, bamlanivimab-etesevimab, or casirivimab-imdevimab with a therapeutic interchange policy. The primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day. The primary analysis was a Bayesian cumulative logistic model of all patients treated at an infusion center or emergency department, adjusting for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio < 1. Equivalence was defined as a 95% posterior probability that the odds ratio is within a given bound.ResultsPrior to trial launch, 3.1% (502) of 16,345 patients who were potentially eligible by an automated electronic health record (EHR) screen received mAb. During the trial period, 23.2% (1,201) of 5,173 EHR-screen eligible patients were treated, a 7.5-fold increase. After including additional referred patients from outside the health system, a total of 1,935 study patients received mAb therapy (128 bamlanivimab, 885 bamlanivimab-etesevimab, 922 casirivimab-imdevimab). Mean age ranged from 55 to 57 years, half were female (range, 53% to 54%), and 17% were Black (range, 12% to 19%). Median hospital–free days were 28 (IQR, 28 to 28) for each mAb group. Hospitalization varied between groups (bamlanivimab, 12.5%; bamlanivimab-etesevimab, 14.7%, casirivimab-imdevimab, 14.3%). Relative to casirivimab-imdevimab, the median adjusted odds ratios were 0.58 (95% credible interval (CI), 0.30 to 1.16) and 0.94 (95% CI, 0.72 to 1.24) for the bamlanivimab and bamlanivimab-etesevimab groups, respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab respectively, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab, at the prespecified odds ratio bound of 0.25. Twenty-one infusion-related adverse events occurred in 0% (0/128), 1.4% (12/885), and 1.0% (9/922) of patients treated with bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively.ConclusionIn non-hospitalized patients with mild to moderate Covid-19, bamlanivimab, compared to bamlanivimab-etesevimab and casirivimab-imdevimab, resulted in 91% and 94% probabilities of inferiority with regards to odds of improvement in hospital-free days within 28 days. There was an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab at an odds ratio bound of 0.25. However, the trial was unblinded early due to federal distribution decisions, and no mAb met prespecified criteria for statistical inferiority or equivalence. (ClinicalTrials.gov, NCT04790786).

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA) is detected in the bloodstream of some patients with coronavirus disease 2019 (COVID-19), but it is not clear whether this RNAemia reflects viremia (ie, virus particles) and how it relates to host immune responses and outcomes. Methods SARS-CoV-2 vRNA was quantified in plasma samples from observational cohorts of 51 COVID-19 patients including 9 outpatients, 19 hospitalized (non–intensive care unit [ICU]), and 23 ICU patients. vRNA levels were compared with cross-sectional indices of COVID-19 severity and prospective clinical outcomes. We used multiple imaging methods to visualize virions in plasma. Results SARS-CoV-2 vRNA was detected in plasma of 100%, 52.6%, and 11.1% of ICU, non-ICU, and outpatients, respectively. Virions were detected in plasma pellets using electron tomography and immunostaining. Plasma vRNA levels were significantly higher in ICU > non-ICU > outpatients (P 6000 copies/mL was strongly associated with mortality (hazard ratio, 10.7). Levels of vRNA were significantly associated with several inflammatory biomarkers (P Conclusions Visualization of virus particles in plasma indicates that SARS-CoV-2 RNAemia is due, at least in part, to viremia. The levels of SARS-CoV-2 RNAemia correlate strongly with disease severity, patient outcome, and specific inflammatory biomarkers but not with neutralizing antibody titers.

A chimeric antigen receptor-modified T-cell therapy recipient developed severe coronavirus disease 2019, intractable RNAemia, and viral replication lasting >2 months. Premortem endotracheal aspirate contained >2 × 1010 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copies/mL and infectious virus. Deep sequencing revealed multiple sequence variants consistent with intrahost virus evolution. SARS-CoV-2 humoral and cell-mediated immunity were minimal. Prolonged transmission from immunosuppressed patients is possible.

We represent a group of investigators funded by the National Institutes of Health (R01AI120938, U01AI134591, U01AI138897) to conduct a prospective multicenter study of the landscape of HIV-infected (HIV+) donors and two prospective multicenter trials comparing outcomes between HIV+ recipients of HIV+ and non-HIV+ donor kidneys and livers. These clinical trials are ongoing (NCT02602262, NCT03500315, NCT03734393).

Data on invasive mold infections (IMIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. We describe 2 patients with post–CAR-T-cell IMI (Fusarium, Mucorales) and review the published literature. We propose strategies to prevent IMIs in patients, based on the IMI rate and presence of neutropenia or steroid use.

Chronic granulomatous disease (CGD) is a heterogeneous condition due to defects in NADPH oxidase characterized by granuloma formation and increased susceptibility to invasive infections, in particular moulds. The use of broad-spectrum, mould-active antifungal prophylaxis has improved mortality. However rare resistant moulds have emerged as important pathogens. Diagnosis of these rare fungi requires molecular techniques, and treatment data are limited. Herein, we present a case of with disseminated Rasamsonia infection involving the heart. Keywords: Chronic granulomatous disease, Filamentous fungi, Invasive fungal infections

ObjectivesImmunocompromised patients were excluded from COVID-19 vaccine clinical trials. The objectives of the study were to measure antibody responses, levels, and neutralization capability after COVID-19 vaccination among immunocompromised patients and compare these variables to those of immunocompetent healthcare workers.MethodsThis is an interim analysis of an ongoing observational, prospective cohort study which launched on April 14, 2021 across Western Pennsylvania. Participants were healthy healthcare workers (HCW) and immunocompromised patients who had completed their COVID-19 vaccination series. Individuals with a history of COVID-19 were not eligible. Serum was collected to measure for the presence of IgG against the SARS-CoV-2 Spike protein using a semi-quantitative assay; antibody levels were available for comparisons. A quasi-random subset of patients was selected for pseudovirus neutralization assays. Seropositivity with 95% Clopper-Pearson exact confidence intervals and distribution of antibody levels were measured. To identify risk factors for seronegativity, clinical characteristics were univariately compared between antibody reactive and non-reactive individuals within the immunocompromised group.Results107 HCW and 489 immunocompromised patients were enrolled. Compared to HCWs, seropositivity was significantly lower (pConclusionOur findings demonstrate the heterogeneity of the humoral immune response to COVID-19 vaccines based on underlying immunosuppressive condition and highlight an urgent need to optimize and individualize COVID-19 prevention in these patients. These findings also have implications on public health guidance, particularly given revised Centers for Disease Control and Prevention recommendations permitting vaccinated individuals to abandon masking and social distancing in most settings. Future studies are warranted to determine assessment of cellular immunity, longitudinal measurement of immune responses, and the safety and efficacy of revaccination.

Studies describing SARS-CoV-2 immune responses following mRNA vaccination in hematology malignancy (HM) patients are virtually non-existent. We measured SARS-CoV-2 IgG production in 67 HM patients who received 2 mRNA vaccine doses. We found that 46% of HM patients did not produce antibodies and were therefore vaccine non-responders. Patients with B-cell CLL were at a particularly high risk, as only 23% had detectable antibodies despite the fact that nearly 70% of these patients were not undergoing cancer therapy. HM patients should be counseled about the ongoing risk of COVID-19 despite vaccination. Routine measurement of post-vaccine antibodies in HM patients should be considered. Novel strategies are needed to prevent COVID-19 in these individuals.

Objectives The primary objective is to evaluate the comparative effectiveness of COVID-19 specific monoclonal antibodies (mABs) with US Food and Drug Administration (FDA) Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs. Trial design Open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization Participants We will evaluate patients who meet the eligibility criteria stipulated by the COVID-19 mAB EUAs who receive mABs within the UPMC Health System, including infusion centers and emergency departments. EUA eligibility criteria include patients with mild to moderate COVID-19, <10 days of symptoms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization (elderly, obese, and/or with specific comorbidities). The EUA criteria exclude patients who require oxygen for the treatment of COVID-19 and patients already hospitalized for the treatment of COVID-19. We will use data collected for routine clinical care, including data entered into the electronic medical record and from follow-up calls. Intervention and comparator The interventions are the COVID-19 specific mABs authorized by the EUAs. All aspects of mAB treatment, including eligibility criteria, dosing, and post-infusion monitoring, are as per the EUAs. As a comparative effectiveness trial, all patients receive mAB treatment, and the interventions are compared against each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mAB interventions will accordingly change. From November 2020 to February 2021, FDA issued EUAs for three mAB treatments (bamlanivimab; bamlanivimab and etesevimab; and casirivimab and imdevimab), and at trial launch on March 10, 2021 we evaluated all three. Due to a sustained increase in SARS-CoV-2 variants in the United States resistant to bamlanivimab administered alone, on March 24, 2021 the U.S. Government halted distribution of bamlanivimab alone, and UPMC accordingly halted bamlanivimab monotherapy on March 31, 2021. On April 16, 2021, FDA revoked the EUA for bamlanivimab monotherapy. At the time of manuscript submission, we are therefore evaluating the two mAB treatments authorized by EUAs (bamlanivimab and etesevimab; and casirivimab and imdevimab). Main outcomes The primary outcome is total hospital free days (HFD) at 28 days after mAB administration, calculated as 28 minus the number of days during the index stay (if applicable – e.g., for patients admitted to hospital after mAB administration in the emergency department) minus the number of days readmitted during the 28 days after treatment. This composite endpoint captures the number of days from the day of mAB administration to the 28 days thereafter, during which the patient is alive and free of hospitalization. Death within 28 days is recorded as -1 HFD, as the worst outcome. Randomisation We will start with equal allocation. Due to uncertainty in sample size, we will use a Bayesian adaptive design and response adaptive randomization to ensure ability to provide statistical inference despite variable sample size. When mABs are ordered by UPMC physicians as a generic referral order, the order is filled by UPMC pharmacy via therapeutic interchange. OPTIMISE-C19 provides the therapeutic interchange via random allocation. Infusion center operations teams and pharmacists use a mAB assignment application embedded in the electronic medical record to determine the random allocation. Blinding (masking) This trial is open-label. However, outcome assessors conducting follow-up calls at day 28 are blinded to mAB assignment, and investigators are blinded to by-mAB aggregate outcome data until a statistical platform trial conclusion is reached. Numbers to be randomised (sample size) Sample size will be determined by case volume throughout the course of the pandemic, supply of FDA authorized mABs, and by that needed to reach a platform trial conclusion of inferiority, superiority, or futility of a given mAB. The trial will continue as long as more than one mAB type is available under EUA, and their comparative effectiveness is uncertain. Trial Status Protocol Version 1.0, February 24, 2021. Recruitment began March 10, 2021 and is ongoing at the time of manuscript submission. The estimated recruitment end date is February 22, 2022, though the final end date is dependent on how the pandemic evolves, mAB availability, and when final platform trial conclusions are reached. As noted above, due to U.S. Government decisions, UPMC Health System halted bamlanivimab monotherapy on March 31, 2021. Trial registration ClinicalTrials.gov Identifier: NCT04790786. Registered March 10, 2021 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Background: Multidrug-resistant (MDR) Pseudomonas aeruginosa is a major public health threat. Treatment with ceftolozane-tazobactam improves patient outcomes compared to salvage therapy; however, resistance has emerged in ~15% of patients following courses ranging from 7 to 53 days. Understanding the development and mechanisms of resistance in these difficult to treat MDR P. aeruginosa has public health importance. Our objective was to study the in vitro activity of alternative β-lactams in the setting of ceftolozane-tazobactam resistance. Methods: Isolates from 23 patients in whom ceftolozane-tazobactam resistance emerged were selected for analysis. Minimum inhibitory concentrations (MICs) were determined by standard broth microdilution in triplicate and interpreted by CLSI breakpoints. Mechanisms of resistance and relatedness of isolates were explored through whole-genome sequence (WGS) analysis in 15 patients from whom baseline and post-treatment isolates were available. Results: 23 baseline and 32 post-treatment isolates were included. The median baseline ceftolozane-tazobactam MIC was 2 µg/mL (range: 0.5 – 8 µg/mL). 75%, 25%, 82.6%, and 83.3% of baseline isolates were non-susceptible to ceftazidime, ceftazidime-avibactam, imipenem, and piperacillin-tazobactam respectively. Following a median 16 (range: 3- 60) days of therapy, the median post-exposure ceftolozane-tazobactam MIC was 64 µg/mL (range: 8 – >256 µg/mL). 100%, 72.7%, 69.6%, and 79.2% of post-treatment isolates were resistant to ceftazidime, ceftazidime-avibactam, imipenem, and piperacillin-tazobactam. The corresponding MIC foldchanges were 4, 8, -2, and 0, respectively. Median imipenem-relebactam MICs did not change before or after treatment with ceftolozane-tazobactam (median= 2 µg/mL for both) and 16.7% were classified as resistant. WGS data revealed several mutations in ampC and ampR sequences. Discussion: Our findings show that resistance to ceftolozane-tazobactam impacts the susceptibility of alternative β-lactams. Cross resistance occurs with ceftazidime and ceftazidimeavibactam (median 4 and 8 fold MIC increase, respectively). Imipenem MICs are decreased 2fold potentially demonstrating collateral sensitivity. Piperacillin-tazobactam MICs were unchanged and isolates remained resistant. Importantly, imipenem-relebactam MICs were unchanged suggesting the mechanism of ceftolozane-tazobactam resistance may be due to structural changes in ampC. WGS data showed a number of different mutations in both ampC and ampR. Certain mutations, such as F147L and mutations found in positions 234-244, were found to promote resistance to ceftolozane-tazobactam.

Host inflammatory responses predict worse outcome in severe pneumonia, yet little is known about what drives dysregulated inflammation. We performed metagenomic sequencing of microbial cell-free DNA (mcfDNA) in 83 mechanically ventilated patients (26 culture-positive, 41 culture-negative pneumonia, 16 uninfected controls). Culture-positive patients had higher levels of mcfDNA than those with culture-negative pneumonia and uninfected controls (p

BackgroundMonoclonal antibody (mAb) treatment may prevent complications of COVID-19. We sought to quantify the impact of bamlanivimab monotherapy on hospitalizations and mortality, as well as Emergency Department (ED) visits without hospitalization, among outpatients at high risk of COVID-19 complications.MethodsWe compared patients receiving mAb to patients who met criteria but did not receive mAb from December 2020 through March 2021. The study population selection used propensity scores to match 1:1 by likelihood to receive mAb. The primary outcome was hospitalization or all-cause mortality within 28 days; the secondary outcome was hospitalization or ED visit without hospitalization within 28 days. Odds ratios (OR) calculation used logistic regression modeling including propensity score and mAb receipt predictors.ResultsThe study population included 234 patients receiving mAb and 234 matched comparator patients not receiving mAb. Patients receiving mAb were less likely to experience hospitalization or mortality (OR 0.31, 95% confidence interval [95%CI] 0.17-0.56, p=0.00001) and hospitalization or ED visit without hospitalization (OR 0.50, 95%CI 0.43-0.83, p=0.007). The impact of mAb was more pronounced in prevention of hospitalization (among all age groups, OR 0.35, 95%CI 0.19-0.66, p=0.001) than mortality or ED visit without hospitalization, and most strongly associated with patients age 65 years and older (primary outcome OR 0.28, 95%CI 0.14-0.56, p=0.0003).ConclusionsBamlanivimab monotherapy was associated with reduction in the composite outcome of hospitalizations and mortality in patients with mild-moderate COVID-19. The benefit may be strongest in preventing hospitalization in patients ages 65 years or older.

Recent case studies have highlighted the fact that certain immunocompromised individuals are at risk for prolonged SARS-CoV-2 replication, intrahost viral evolution of multiply-mutated variants, and poor clinical outcomes. The immunologic determinants of this risk, the duration of infectiousness, and optimal treatment and prevention strategies in immunocompromised hosts are ill defined. Of additional concern is the widespread use of immunosuppressive medications to treat COVID-19, which may enhance and prolong viral replication in the context of immunodeficiency. We outline the rationale for 4 interrelated approaches to usher in an era of evidence-based medicine for optimal management of immunocompromised patients with COVID-19: multicenter pathogenesis and outcomes studies to relate the risk of severe disease to the type and degree of immunodeficiency, studies to evaluate immunologic responses to SARS-CoV-2 vaccines, studies to evaluate the efficacy of monoclonal antibodies for primary prophylaxis, and clinical trials of novel antiviral agents for the treatment of COVID-19.

The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant.To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab.This study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria.For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy.For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned -1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound.A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence.In this propensity score-matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant.ClinicalTrials.gov Identifier: NCT04790786.

Background We implemented a preprocedural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening initiative designed to sustain health care during a time when the extent of SARS-CoV-2 infection was unknown. Methods This was a prospective study of patients undergoing procedures at 3 academic hospitals in Pittsburgh, Pennsylvania (April 21–June 11), and 19 community hospitals across Middle/Western Pennsylvania and Southwestern New York (May 1–June 11). Patients at academic hospitals underwent symptom screening ≤7 days preprocedure, then SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) testing 1–4 days preprocedure. A subset also underwent day-of-procedure testing. Community hospital patients underwent testing per local protocols. We report SARS-CoV-2 PCR positivity rates, impact, and barriers to testing encountered through June 11. PCR positivity rates of optional preprocedural SARS-CoV-2 testing for 2 consecutive periods following the screening initiative are also reported. Results Of 5881 eligible academic hospital patients, 2415 (41.1%) were tested (April 21–June 11). Lack of interest, distance, self-isolation, and nursing home/incarceration status were barriers. There were 11 PCR-positive patients (10 asymptomatic) among 10 539 patients tested (0.10%; 95% CI, 0.05%–0.19%): 3/2415 (0.12%; 95% CI, 0.02%–0.36%) and 8/8124 (0.10%; 95% CI, 0.04%–0.19%) at academic and community hospitals, respectively. Procedures were performed as scheduled in 40% (4/10) of asymptomatic PCR-positive patients. Positivity increased during subsequent coronavirus disease 2019 (COVID-19) surges: 54/34 948 (0.15%; 95% CI, 0.12%–0.20%) and 101/24 741 (0.41%; 95% CI, 0.33%–0.50%) PCR-positive patients from June 12–September 10 and September 11–December 15, respectively (P Conclusions Implementing preprocedural PCR testing was complex and revealed low infection rates (0.24% overall), which increased during COVID-19 surges. Additional studies are needed to define the COVID-19 prevalence threshold at which universal preprocedural screening is warranted.

Background: Patients with B-cell aplasia, such as recipients of CAR-T-cell therapy forhematological malignancies, may be at risk for protracted SARS-CoV-2 replication and chronicshedding of infectious virus.Methods: A man in his 70’s who had undergone CAR-T-cell therapy presented with COVID-19pneumonia and improved after receipt of convalescent plasma and remdesivir. He wasdischarged on room air but returned on day 41 after COVID-19 diagnosis with progressiveradiographic abnormalities and persistent detection of SARS-CoV-2 RNA from nasopharyngealswabs. He died due to progressive respiratory failure on day 74 of illness. Plasma andendotracheal aspirate (ETA) samples were collected for viral quantification, viral titration andculture, and immunological assays.Findings: The patient had high-grade SARS-CoV-2 RNAemia in plasma collected on days 4, 9,13, 16, and 71. RNAemia peaked at >105 copies/ml, declined after administration of remdesivirand convalescent plasma (104 copies/ml), but subsequently rebounded to >105 copies/ml beforedeath. On day 72, ETA showed 2.78x1010 copies/mL of SARS-CoV-2 RNA, high-titer infectiousvirus (1.125x106 plaque-forming units/mL) that was successfully cultured, and numerous virusparticles by electron microscopy. Serologic assays showed minimal to no antibody to SARSCoV-2, and B-cells were not detected by immunophenotyping or by single-cell RNAseq.Interpretation: This case provides new insights into the potential prolonged duration and extentof viral replication without appropriate humoral immune responses. This case also challengesthe belief that persistent detection of SARS-CoV-2 RNA in respiratory secretions representsshedding of non-infectious RNA, which should prompt re-evaluation of infection preventionguidelines in immunosuppressed hosts.

Purpose of review Data on the infectious complications of anti-CD19 chimeric antigen receptor-modified T-cell (CAR-T-cell) therapies are scant. The approaches to preventing and managing infections among CAR-T-cell recipients are extrapolated from those of patients with other hematological malignancies. Understanding the incidence and risk factors of infections in these patients will improve clinical outcomes. Recent findings Infections occur in 23-42% of CAR-T-cell recipients and are most frequent in the first month after infusion, declining sharply thereafter. Risk factors include preinfusion (e.g., prior hematopoietic cell transplant, underlying malignancy) and postinfusion variables (e.g., cytokine release syndrome [CRS], neutropenia). Neutropenic fever after CAR-T-cell therapy is nearly universal but is confounded by CRS. The timeline of infections can be divided into preinfusion (because of the preparative regimen); 0-30 days after infusion, when bacterial infections predominate; and 30 days onwards, when respiratory viral infections predominate. Fungal and herpesviridae infections are uncommon. Summary Recent studies have shed light on the epidemiology of infections after CAR-T-cell therapy. Future efforts should focus on identifying modifiable risk factors for infection, defining neutropenic fever in the setting of CRS, determining the benefit of antimold prophylaxis, and identifying the optimal approach to viral monitoring, vaccination, and immunoglobulin replacement.

BACKGROUND HIV-infected (HIV+) donor to HIV+ recipient (HIV D+/R+) transplantation might improve access to transplantation for people living with HIV. However, it remains unknown whether transplant candidates living with HIV will accept the currently unknown risks of HIV D+/R+ transplantation. METHODS We surveyed transplant candidates living with HIV from 9 US transplant centers regarding willingness to accept HIV+ donor organs. RESULTS Among 116 participants, the median age was 55 years, 68% were men, and 78% were African American. Most were willing to accept HIV+ living donor organs (87%), HIV+ deceased donor organs (84%), and increased infectious risk donor organs (70%). Some (30%) were concerned about HIV superinfection; even among these respondents, 71% were willing to accept an HIV D+ organ. Respondents from centers that had already performed a transplant under an HIV D+/R+ transplantation research protocol were more willing to accept HIV+ deceased donor organs (89% vs. 71%, P = 0.04). Respondents who chose not to enroll in an HIV D+/R+ transplantation research protocol were less likely to believe that HIV D+/R+ transplantation was safe (45% vs. 77%, P = 0.02), and that HIV D+ organs would work similar to HIV D- organs (55% vs. 77%, P = 0.04), but more likely to believe they would receive an infection other than HIV from an HIV D+ organ (64% vs. 13%, P < 0.01). CONCLUSIONS Willingness to accept HIV D+ organs among transplant candidates living with HIV does not seem to be a major barrier to HIV D+/R+ transplantation and may increase with growing HIV D+/R+ transplantation experience.

Invasive aspergillosis and mucormycosis are life-threatening infections in solid organ and hematopoietic cell transplant recipients. Despite medical advancements in the care of these patients and the availability of new mold-active drugs, the outcomes remain suboptimal. Therefore, there has been increased interest in the use of combination antifungal therapy, in hopes that leveraging the possible in vitro synergy of these agents will improve the prognosis of invasive mold disease. However, there has been a large disconnect between the results of experimental and clinical investigations, as clinical studies have not unequivocally demonstrated the superiority of combination therapy over monotherapy. This is particularly true for mucormycosis, where the rarity of the condition has made it nearly impossible to prospectively study novel therapeutic strategies. We review the current standard of antifungal therapy and the preclinical and clinical data addressing the merit of combination therapy, and we provide guidance to optimize the management of these mycoses.