ABSTRACT
Background. Invasive aspergillosis (IA) is a great threat to the severely immunocompromised and patients with coronavirus disease (COVID-19). However, diagnosis of IA is often difficult due to need for invasive biopsy and low sensitivity of other diagnostic tests. Next-generation sequencing (NGS) of plasma cell free DNA (cfDNA) can be a novel non-invasive diagnostic modality. We evaluated the clinical accuracy and utility of microbial cfDNA NGS for the diagnosis of IA in patients with hematologic malignancy (HM) and COVID-19. Methods. A single-center prospective study of plasma microbial cfDNA NGS was conducted in a tertiary-care hospital in South Korea. We enrolled adult patients with HM and COVID-19, who suspected IA and performed conventional diagnostic tests for IA. The results of NGS were compared with the diagnosis of IA through conventional methods. IA cases were diagnosed according to EORTC/MSG definitions in patients with HM, and modified AspICU criteria in patients with COVID-19. (Figure 1). Figure 1. Flow chart for the participant selection method used in this study Results. Between March 2021 and January 2022, a total of 33 participants (22 [64.7%] male, median age 66.0 [50.5, 72.0]) were enrolled;19 participants with HM and 15 with COVID-19 were analyzed (Figure1 and Table1). In participants with HM, aspergillus cfDNA was detected in 100% of both proven (1/1) and probable (12/12) IA cases, and 33.3% of both possible (1/3) and no IA (1/3) cases. In participants with COVID-19, 46.2% of probable IA (6/13) showed positive aspergillus cfDNA. Detection rate of aspergillus cfDNA was significantly higher in proven/probable IA cases in participants with HM compared to participants with COVID-19. (100% vs 46.2%, p=0.005) (Figure 2). As shown in Table 2, among proven/probable IA cases, participants with positive aspergillus cfDNA showed significantly higher rate of having uncontrolled hematologic disease, receiving stem cell transplantation and recent chemotherapy. In three participants with HM, non-aspergillus strains confirmed by cfDNA NGS were in accordance with pathogens identified through conventional culture methods. Conclusion. Detection of aspergillus cfDNA showed high concordance in the results of conventional diagnostic methods in proven/probable IA of patients with HM and could be a helpful non-invasive approach to IA diagnosis in those populations.
ABSTRACT
Introduction: Patients with hematologic malignancies are at an increased risk of morbidity and mortality from COVID-19 disease (Vijenthira, Blood 2020). This is likely a result of combination of immunodeficiency conferred by the disease and the therapeutics. The immunogenicity of the COVID-19 vaccines in patients with exposure to CD19 directed Chimeric Antigen Receptor (CAR)-T cell therapy is not established. CD19 CAR-T cell therapies cause B-cell aplasia, which in turn can affect humoral immune response against novel antigens. Herein, we present results from our prospectively conducted clinical study to evaluate immune responses against mRNA based COVID-19 vaccines in patients with lymphoma who have received CD19 directed CAR-T cell therapy. Methods: All patients and healthy controls were enrolled in a prospective clinical study evaluating immune responses against commercial COVID-19 RNA vaccines in patients with hematologic malignancies. Plasma samples were generated from heparinized peripheral blood of 4 heathy controls (HCs) receiving the same vaccines and 19 B cell lymphoma patients treated with CD19 CAR- T cells. Samples from ~4 weeks post second dose of the vaccine (d56) were available for 14 CAR-T patients, for 5 CAR-T patients samples were available from ~4 weeks after the first dose (d28). Plasma samples were analyzed in an enzyme-linked immunosorbent assay (ELISA) using different full-length recombinant SARS-CoV-2 proteins and control proteins. Neutralizing activity was measured using the cPass Neutralization Antibody Detection Kit (GenScript Biotech). Results: Results from 4 healthy controls and 19 patients (12 males and 7 females) with lymphoma are reported. Median age for the lymphoma patients is 65 years. Eleven patients had large B cell lymphoma, 5 had follicular lymphoma and 3 had mantle cell lymphoma as primary diagnoses. Seventeen patients had advance stage disease (III/IV stage) and had received a median of 3 prior lines of therapy. All patients received CD19 directed CAR-T cell therapy. Ten patients received Moderna vaccine and 9 received Pfizer vaccine. Median time between CAR-T infusion and first COVID-19 vaccine was 258 days. While the peripheral blood plasma from 3/4 HCs already showed substantial SARS-CoV-2 neutralizing activity at ~4 weeks after the first dose of COVID-19 mRNA vaccine, none of the 5 CD19 CAR-T patients analyzed evidenced any antibody-mediated neutralizing activity in their blood at the same point in time (Figure 1A). Around 4 weeks after receiving the second dose of the vaccine, all 4 HCs tested evidenced complete or almost complete neutralizing activity (Figure 1B). In marked contrast, only 1 out of 14 CAR-T patients analyzed evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity in their blood (Figure 1B). Interestingly, when we asked whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CAR-T patients, we found that that was clearly not the case since anti-Flu, -TT, and -EBV responses were equivalent to the ones observed in HCs (Figure 2A). However, while at ~4 weeks post second dose of the vaccine the HCs showed marked antibody titers against all the viral spike proteins including their “delta” variants (Figure 2B), that was not the case for our CAR-T patients. The vast majority of our CAR-T patients did not evidence IgG antibody responses against any of the SARS-CoV-2 proteins analyzed such as S1, S1 delta, RBD, RBD delta, or S2 (Figure 2B). Conclusion: In this prospectively conducted clinical study, 18 of 19 patients with lymphoma who have received CD19 CAR-T therapy had poor immunogenicity against mRNA based COVID-19 vaccines as measured by neutralization assays and antibody titers. The antibody titers against B.1.617.2 (delta variant, S1 and RBD protein) were also demonstrably poor. The antibody response to common pathogens (flu, EBV, TT) were preserved, suggesting impaired immune response against novel antigens. Long-term follow-up of this study is ongoin . APR and DJ contributed equally [Formula presented] Disclosures: Dahiya: Kite, a Gilead Company: Consultancy;Atara Biotherapeutics: Consultancy;BMS: Consultancy;Jazz Pharmaceuticals: Research Funding;Miltenyi Biotech: Research Funding. Hardy: American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees;InCyte: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees.
ABSTRACT
In a global pandemic, public health outcomes are not the only variables at stake. Also at stake are countries’ nation brands and influence, which hinge on how a country responded to the crisis. Based on a case study of a middle power, South Korea, one of the more successful COVID-19 national responses so far, we offer an exploratory conceptual explication of pandemic public diplomacy that is grounded in a normative framework of substance, information, trust, collaboration, and mutual benefit. Sentiment analyses of social media and international news media suggest that the country is perceived as a model on how to cope with the pandemic by international audiences. Unlike other public diplomacy contexts, pandemic public diplomacy challenge conventional assumptions about public diplomacy and nation branding. As nation-states confront a common enemy, how public diplomacy and nation branding play out in COVID-19—arguably the most socially disruptive event in modern history—helps to shed light on the dynamics of mutual interdependence in an interconnected yet competitive world fraught with fear, uncertainty, and information deficiency. © 2020, Springer Nature Limited.