ABSTRACT
Background. The FilmArray Pneumonia Panel (bioMerieux) is a rapid multiplex PCR aiming to increase speed and sensitivity in the microbiological diagnosis of pneumonia. This offers potential for improved antimicrobial stewardship and evidencebased antibiotic prescribing. Whether such gains can be realised in practise is uncertain, thus, we conducted a randomized controlled trial to examine this. Methods. Adults and children in ICU with suspected hospital-acquired or ventilator-associated pneumonia were randomized to standard care or a FilmArray Pneumonia Panel PCR test at the point of care supported by an optional prescribing algorithm. Participants were followed for 28 days. FilmArray tests were run retrospectively in the control-arm but results were not provided to treating clinicians. Antimicrobial therapy was adjudged by a committee of blinded, independent microbiologists for 'activity? and 'proportionality? vs. pathogens detected in each arm regardless of the time and method by which they were found. Clinical cure was not blinded and judged by site PI according to defined clinical parameters. Results. Between July 2019 and August 2021, 556 participants were randomized at 13 hospitals;545 met eligibility criteria;92 were children and 183 had COVID-19 at enrolment. Baseline characteristics were well balanced between study arms. In the intervention arm 76.5% of participants were judged to have received active and proportionate antibiotics at 24h vs. 55.9% in the control arm (p< 0.001);proportions at 72h were 73.4% and 58.8%, respectively p< 0.001). Site-reported clinical cure of pneumonia at 14 days was 56.7% in the intervention arm and 64.7% in the control arm (95% CI -0.15 to 0.02), with exploratory analyses suggesting site heterogeneity. 28-day mortality was 31.3% in the intervention arm and 28.2% in the control arm (p = 0.098). Median ventilator-free days by Day 21 were 2 days in both study arms. Median ICU length of stay was 14 days in both arms. Conclusion. Use of the FilmArray Pneumonia Panel PCR led to a significant increase in the proportion of patients receiving 'active and proportionate? antibiotic therapy at 24h. Reasons for lower reported clinical cure, despite better tailored antibiotic use, remain under active analysis.
ABSTRACT
Background: Tisagenlecleucel (Tisagen) and Axicabtagene Ciloleucel (Axicel) CD19 CAR T-cell products are licensed in the UK for adults with relapsed/refractory high-grade B-cell Non-Hodgkin's lymphoma (B-NHL). Infection rates for the first 30 days post CAR T range from 23% (Hill et al, Blood 2018) to 42% (Park et al, Clin Infect Dis 2018) with a predominance of early bacterial infections. Infection etiology is multifactorial, including pre-existing immunosuppression, poor marrow reserve, concomitant disease, delayed cytopenias and lymphodepletion. CRS has been shown to be an independent risk factor and associated treatment (Tocilizumab, steroids) may contribute. Risk assessment is limited by heterogenous cohorts in published reports and practice variations in use of prophylactic antibiotics and intravenous immunoglobulin (IVIG). To determine incidence and outcome of infection with licensed CAR T-cell products, we conducted a retrospective review at UCLH, London, UK. Methods: Electronic medical records were used to collect data on patients treated with Tisagen/Axicel from May 2019 to July 2020. Infections at ≤28 days and >28days following infusion were recorded. Infections were defined as a positive microbiological/virology result in conjunction with clinical symptoms. Invasive fungal infections were classified according to revised EORTC criteria. Infections were graded as severe (requiring systemic treatment) or life threatening (hypotension/organ support). Results: Sixty adults with B-NHL received Tisagen (n=19) or Axicel (n=41). Patients did not receive prophylactic antibiotics. IVIG was given for hypogammaglobulinaemia with recurrent infections (n=4). Within 28 days of infusion, 44 episodes of infection occurred in 28 patients (47%). Post day 28 (range 29-452), 19 episodes occurred in 9 patients (15%). Severe (n=9) and life-threatening (n=7) infection occurred in 15% and 12% of patients respectively, with two infections resulting or contributing to death (3.3%). Infections were bacterial (56%), respiratory viral (24%), other viral (14%) and fungal (6%). Six (10%) developed viral reactivations;CMV (n=1), BK virus in blood or urine (n=2), HHV6 (n=1) or AdV (n=2). PCR proven JC virus causing progressive multifocal leukoencephalopathy was reported in 1 patient at day 116. Only one late COVID-19 infection occurred despite the program remaining operational throughout lockdown. There was no association between early infection and CRS severity (p=0.43), or use (p=0.94) and dose of Tocilizumab (p=0.54). With regard to pre-treatment variables, advanced disease at time of infusion (≥stage 3) was associated with higher risk of any infection (OR 4.2, 95% CI 1.3- 13.4, p=0.016) and lines of prior therapy (≥3) with higher risk of early infection (OR 3.0, 95% CI 1.0-8.9, p=0.048). Steroid treatment was associated with a higher risk of early (and overall) infection (OR 3.0. 95% CI 1.0-8.6, p=0.048). A diagnosis of ICANS was associated with infection beyond day 30 (p=0.021). In multivariate analyses, steroid use (p=0.03) and ≥3 lines of prior therapy (p=0.021) were associated with infection ≤28 days of infusion. Steroid use (p= 0.049) and stage pre infusion (p=0.023) were associated with higher risk of any infection. Conclusion: In this real world analysis of B-NHL patients treated with Tisagen or Axicel, 47% developed early infection at ≤28 days. Severe or life-threatening infection occurred in 27% of patients. Multivariate analysis confirms significant association with (1) steroid exposure (2) ≥stage 3 disease and (3) ≥3 lines of previous therapy. There was no overt association with Tocilizumab use or CRS severity. Unlike other centers, our cohort did not receive prophylactic antibiotics or IVIG. Patients with advanced disease are high risk for CRS, ICANS and infectious complications. Risk modification strategies include bridging optimization to reduce disease burden pre CAR T with infectious prophylaxis from referral until at least 3-6 months post-infusion. In this analysis, steroids represent a significant ri k and efforts should be made to wean doses swiftly. The use of steroid sparing agents such as Anakinra may be important (clinical trial results awaited). In ≥ stage 3 disease or heavily pre-treated patients, there may be a role for prophylactic antibiotics but this should be explored within a clinical study with consideration of local antimicrobial resistance patterns. Disclosures: Neill: Novartis: Other: Funded attendance at academic conferences;Celgene: Other: Funded attendance at academic conferences. Townsend: Roche, Gilead: Consultancy, Honoraria. Ardeshna: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees;Beigene: Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi, Genzyme, AstraZeneca: Speakers Bureau;University College London (UCL)/UCL Hospitals (UCLH) Biomedical Research Unit: Other: Supported by this organisation. Cwynarski: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau;Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees;Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau;Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Peggs: Autolus: Consultancy. Roddie: Celgene: Honoraria;Gilead: Honoraria;Novartis: Honoraria. O'Reilly: Gilead: Honoraria;Novartis: Honoraria, Other: Travel support.
ABSTRACT
Background: The objective of this study was to evaluate the performance characteristics of early commercial SARS-CoV-2 antibody assays in mild and asymptomatic subjects to enable the selection of suitable immunoassays for routine diagnostic use.Methods: We used serum samples from a pre-COVID era patient cohort (n = 50, pre-December 2019), designated SARS-CoV-2 negative, and serum samples from a SARS-CoV-2 RT-PCR-positive cohort (n = 90) taken > 14 days post-symptom onset (April-May 2020). Six ELISA assays were evaluated, including one confirmation assay to investigate antibody specificity. We also evaluated one point-of-care lateral flow device (LFIA) and one high throughput electrochemiluminescence immunoassay (CLIA).Results: The ELISA specificities ranged from 84% to 100%, with sensitivities ranging from 75.3% to 90.0%. The LFIA showed 100% specificity and 80% sensitivity using smaller sample numbers. The Roche CLIA immunoassay showed 100% specificity and 90.7% sensitivity. When used in conjunction, the Euroimmun nucleocapsid (NC) and spike-1 (S1) IgG ELISA assays had a sensitivity of 95.6%. The confirmation Dia.Pro IgG assay showed 92.6% of samples tested contained both NC and S1 antibodies, 32.7% had NC, S1 and S2 and 0% had either S1 or S2 only.Conclusions: The Roche assay and the Euroimmun NC and S1 assays had the best sensitivity overall. Combining the assays detecting NC and S1/S2 antibody increased diagnostic yield. These first-generation assays were not calibrated against reference material and the results were reported qualitatively. A portfolio of next-generation SARS-CoV-2 immunoassays will be necessary to investigate herd and vaccine-induced immunity.