A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings

BackgroundCytokine release triggered by a hyperactive immune response is thought to contribute to severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2)–related respiratory failure. Bruton tyrosine kinase (BTK) is involved in innate immunity, and BTK inhibitors block cytokine release. We assessed the next-generation BTK inhibitor zanubrutinib in SARS-CoV-2–infected patients with respiratory distress.MethodCohort 1 had a prospective, randomized, double-blind, placebo-controlled design; cohort 2 had a single-arm design. Adults with SARS-CoV-2 requiring hospitalization (without mechanical ventilation) were randomized in cohort 1. Those on mechanical ventilation ≤24 hours were enrolled in cohort 2. Patients were randomized 1:1 to zanubrutinib 320 mg once daily or placebo (cohort 1), or received zanubrutinib 320 mg once daily (cohort 2). Co-primary endpoints were respiratory failure-free survival rate and time to return to breathing room air at 28 days. Corollary studies to assess zanubrutinib’s impact on immune response were performed.ResultsSixty-three patients in cohort 1 received zanubrutinib (n=30) or placebo (n=33), with median treatment duration of 8.5 and 7.0 days, respectively. The median treatment duration in cohort 2 (n=4) was 13 days; all discontinued treatment early. In cohort 1, respiratory failure-free survival and the estimated rates of not returning to breathing room air by day 28 were not significantly different between treatments. Importantly, serological response to coronavirus disease 2019 (COVID-19) was not impacted by zanubrutinib. Lower levels of granulocyte colony-stimulating factor, interleukin (IL)-10, monocyte chemoattractant protein-1, IL-4, and IL-13 were observed in zanubrutinib-treated patients. Moreover, single-cell transcriptome analysis showed significant downregulation of inflammatory mediators (IL-6, IL-8, macrophage colony-stimulating factor, macrophage inflammatory protein-1α, IL-1β) and signaling pathways (JAK1, STAT3, TYK2), and activation of gamma-delta T cells in zanubrutinib-treated patients.ConclusionsMarked reduction in inflammatory signaling with preserved SARS-CoV-2 serological response was observed in hospitalized patients with COVID-19 respiratory distress receiving zanubrutinib. Despite these immunological findings, zanubrutinib did not show improvement over placebo in clinical recovery from respiratory distress. Concurrent administration of steroids and antiviral therapy to most patients may have contributed to these results. Investigation of zanubrutinib may be warranted in other settings where cytokine release and immune cell exhaustion are important.Clinical Trial Registrationhttps://www.clinicaltrials.gov/study/NCT04382586, identifier NCT04382586

1379. Vaccination Rates among Liver Transplant Recipients at a Tertiary Care Hospital in Newark, NJ

Abstract Background Transplant candidates and recipients are at increased risk of infectious complications of vaccine-preventable diseases due to their longstanding immunosuppressive regimens. We assessed the rates of vaccination in our liver transplant patients at University Hospital (UH) in Newark, NJ. Methods Retrospective chart-review including patients &amp;gt; 18 years old who underwent liver transplantation at UH for a 3-year period from 01/01/2017 to 07/20/2020. Data collected included demographics, clinical outcomes, eligibility and receipt of vaccinations before and after transplantation, protection titers after administration of hepatitis vaccinations and presence of an ID outpatient consultation. We looked at the following receipt of vaccinations: Prevnar-13, Pneumovax-23, Influenza, TDaP, Shingrix, Varivax, Havrix and Engerix/Heplisav. Characteristics of study participants was analyzed using descriptive statistics and Chi-Square/Fisher’s Exact tests were used to test associations. Results 119 unique medical charts were reviewed and no patients were excluded. Of those patients who were eligible to receive Hepatitis A vaccination, only 44.8% were documented to receive vaccination and of those eligible to receive Hepatitis B vaccination, only 47.8% received it. Influenza vaccination pre-transplantation was 46% and 66.1% in post-transplant recipients. For the other vaccinations, during the pre-transplant period, 17.6 % of patients received Prevnar-13, 36.1% Pneumovax-23 and 20.2% TDaP and 26.1% received Shingrix. Patients who had ID consultation were significantly more likely to receive appropriate Hepatitis A and Hepatitis B vaccinations (p values 0.026 and 0.005). Conclusion We are not meeting national vaccination standards set by the American Society of Transplantation (AST) for optimal vaccination in this population. Our study can inform of possible solutions to increase vaccination rates in this population such as the simple addition of a smartphrase within EMR notes to remind providers to order appropriate vaccinations and eventually, a more long term solution of creation of a dedicated vaccination clinic and/or routine ID pre-transplant evaluations for all transplant candidates. Disclosures All Authors: No reported disclosures </jats:sec

1443. Seroprevalence of HTLV-I/II in a Tertiary-Level Hospital in Newark, NJ

Abstract Background Human T-cell lymphotropic virus type I (HTLV-I) remains amongst the most neglected tropical diseases in the medical field due to its low prevalence in developed countries and the low incidence of its associated diseases, Adult T-cell lymphoma/leukemia (ATLL) and tropical spastic paraparesis (TSP). We proposed a higher prevalence of infections with this virus in Newark given its significant percentage of foreign-born residents of HTLV-endemic countries such as Jamaica, the Dominican Republic, Peru, and Brazil. Methods Descriptive study from secondary data. We obtained the total number of HTLV-I/II tests performed at University Hospital in the last 2 years (05/2018-10/2020). Subsequently, medical charts were reviewed to obtain epidemiological and clinical data. Results A total of 89 patients underwent screening for HTLV-I/II, of whom 4 (4%) were positive. The test was more frequently ordered in male (61%) and foreign-born (84%) individuals. The main reasons for testing were positive Strongyloides antibody in transplant candidates (20%), neurological symptoms (20%) and hematological symptoms (20%). In most cases, the test was ordered by Infectious Diseases (58%) and Neurology (18%). Being foreign-born was significantly associated with being tested in the case of non-transplant candidates (93% vs 56%, p&amp;lt; 0.001). Amongst the patients with positive serology, there were 2 cases of ATLL and 2 of TSP. Three of them had their country of origin registered (Ecuador, Barbados and Ghana). Family testing was only offered to one of the positive HTLV-I/II participants. Interestingly, this was the only case referred to Infectious Diseases. Conclusion There is low but significant seroprevalence of HTLV-I/II in our screened population. Most of the seropositive patients were lost to follow up and their relatives were not offered testing, demonstrating the need to raise awareness for this disease in health care workers. Disclosures All Authors: No reported disclosures </jats:sec

1386. Seroprevalence of Strongyloidiasis in Liver Transplant Candidates at a Tertiary-Level Hospital in Newark, NJ

Abstract Background The liver transplant center at University Hospital (Newark, NJ) is one of the busiest in northern NJ. Current guidelines for Strongyloides stercoralis (Ss) screening in solid transplant recipients recommend targeted testing. We propose a high seroprevalence of this infection in our facility given its significant percentage of foreign-born patients from Ss endemic areas such as Latin America, the Caribbean, and Africa. Methods Descriptive study from secondary data. We obtained the total number of Strongyloides antibody tests performed at University Hospital in the last two years (08/2018-10/2020). Subsequently, medical charts were reviewed to obtain epidemiological and clinical data. Results A total of 388 patients underwent screening for Strongyloides antibody, of whom 71 (18%) were positive. The test was mainly performed in male (58%) and foreign-born (55%) patients. More than half (55%) of the US-born individuals had history of travel overseas. The main reasons for testing were transplant evaluation (65%), immunosuppression (14%) and eosinophilia (9%). There was no association between transplant evaluation and seropositivity (81% vs 81%, p = 0.994). Being foreign-born was not associated with a positive test (19% vs 20%, p = 0.834), but for US-born patients, having a history of travel was associated with a positive test (33% vs 14%, p = 0.039). For the Ss positive patients, 34% had a HTLV-I/II test, 48% had at least one stool test, and 76% were given treatment. Conclusion There is a significant seroprevalence of Ss in our transplant candidate population, both non-foreign and foreign-born, prompting the indication for universal screening at our facility. Disclosures All Authors: No reported disclosures </jats:sec

Do Positive Anaerobic Culture Results Affect Physicians\u27 Clinical Management Decisions?

BACKGROUND: Aerobic and anaerobic cultures from body fluids, abscesses, and wounds are ordered routinely. Prior studies have shown that the results of anaerobic blood cultures do not frequently lead to changes in patient management. METHODS: We performed a retrospective chart review to determine whether positive results of anaerobic tissue and fluid cultures (excluding blood) affect physicians\u27 treatment approaches. Of 3234 anaerobic cultures, 174 unique patient admissions had positive cultures and met inclusion criteria. RESULTS: Only 18% (n = 31) of patient charts with positive cultures had documented physician acknowledgment (90.3% of acknowledgments by infectious diseases physicians), with 9% (n = 15) leading to change in antibiotic regimens based on results. Seventy percent of all patients received initial empiric antibiotics active against anaerobes. Of the remaining 30% (inappropriate, unknown, or no empiric coverage), 1 regimen change was documented after culture results were known. CONCLUSIONS: Given the lack of management change based on results of anaerobic wound cultures, the value of routine anaerobic culturing is of questionable utility

Risk Factors and Clinical Outcomes of Candidemia Associated with Severe COVID-19

COVID-19 can cause serious illness requiring multimodal treatment and is associated with secondary infections. Studies have suggested an increased risk of fungal infections, including candidemia following severe COVID-19 though understanding of risk factors and clinical outcomes remains unclear. OBJECTIVES: To describe clinical characteristics, outcomes and risk factors of candidemia among patients hospitalized with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, case-control study of patients with severe COVID-19 was conducted to evaluate risk factors and clinical outcomes in patients who developed candidemia between August 2020 and August 2021. MAIN OUTCOMES AND MEASURES: Chart review evaluating institutional and patient demographics, clinical and mycological characteristics, concomitant interventions (antibiotics, immunosuppressive agents, parenteral nutrition, degree of oxygen support, mechanical ventilation, surgery), treatment regimens, and outcomes (length of stay and discharge disposition) RESULTS: A total of 275 patients were enrolled in the study, including 91 patients with severe COVID-19 and subsequent candidemia and 184 with severe COVID-19 without candidemia. Most patients received antibiotics prior to candidemia episode (93%), while approximately one-quarter of patients received biologic for COVID-19. In-hospital mortality was significantly higher in the cases compared with the controls (68% vs 40%; p < 0.01). Candida albicans was the most common (53%), followed by C. glabrata (19%). Use of central lines, biologic, and paralytics were independent risk factors for candidemia. CONCLUSIONS AND RELEVANCE: Candidemia following COVID-19 infection is a concern that requires clinical consideration and patient monitoring. Risk factors for the development of candidemia in the setting of COVID-19 infection are largely consistent with traditional risk factors for candidemia in hospitalized patients