Mansour, Razan

Abstract We conducted this systematic review to evaluate outcomes of thrombolysis followed by anticoagulation vs anticoagulation alone in pediatric patients with venous thromboembolism (VTE). This systematic review addresses mortality, VTE resolution, recurrence, bleeding, and organ-specific outcomes in 5 PICO (population, intervention, comparison, outcomes) questions on thrombolysis across pulmonary embolism (PE), extremity deep vein thrombosis (DVT), right atrial thrombosis (RAT), cerebral sinus venous thrombosis (CSVT), and renal vein thrombosis (RVT). Meta-analysis reported risk ratios or differences (95% confidence intervals [CIs]), and absolute effects per 1000 patients. Certainty of evidence was assessed using GRADE (Grading of recommendation, assessment, Development, and Evaluation) guidelines. Thirteen nonrandomized studies were included and no randomized clinical trials addressed these questions. Thrombolysis might be associated with a higher risk of major bleeding, clinically relevant nonmajor bleeding, or unspecified bleeding with risk differences of 0.09 (95% CI, −0.06 to 0.23), 0.06 (95% CI, −0.11 to 0.22), and 0.09 (95% CI, −0.04 to 0.23), respectively. In PE with hemodynamic compromise, thrombolysis might be associated with a lower risk of mortality but conclusions on PE progression were uncertain in submassive PE. In DVT, thrombolysis may have little to no effect on mortality or thrombus resolution but might be associated with lower risk of postthrombotic syndrome. In RAT, thrombolysis might have little to no effect on thrombus resolution but a higher risk of major bleeding and mortality. For CSVT and RVT, the evidence was very limited. These findings were based on very-low-certainty evidence because of confounding and imprecision from small sample sizes. This systematic review highlights key challenges in developing recommendations for thrombolysis in children with VTE.

Abstract Accurate molecular diagnostic tests are necessary for confirming a diagnosis of coronavirus disease 2019 (COVID-19) and for identifying asymptomatic carriage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The number of available SARS-CoV-2 nucleic acid detection tests continues to increase as does the COVID-19 diagnostic literature. Thus, the Infectious Diseases Society of America (IDSA) developed an evidence-based diagnostic guideline to assist clinicians, clinical laboratorians, patients, and policymakers in decisions related to the optimal use of SARS-CoV-2 nucleic acid amplification tests. In addition, we provide a conceptual framework for understanding molecular diagnostic test performance, discuss nuances of test result interpretation in a variety of practice settings, and highlight important unmet research needs related to COVID-19 diagnostic testing. IDSA convened a multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review to identify and prioritize clinical questions and outcomes related to the use of SARS-CoV-2 molecular diagnostics. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. The panel agreed on 12 diagnostic recommendations. Access to accurate SARS-CoV-2 nucleic acid testing is critical for patient care, hospital infection prevention, and the public health response to COVID-19 infection. Information on the clinical performance of available tests continues to grow, but the quality of evidence of the current literature to support this updated molecular diagnostic guideline remains moderate to very low. Recognizing these limitations, the IDSA panel weighed available diagnostic evidence and recommends nucleic acid testing for all symptomatic individuals suspected of having COVID-19. In addition, testing is suggested for asymptomatic individuals with known or suspected contact with a COVID-19 case when the results will impact isolation/quarantine/personal protective equipment (PPE) usage decisions. Evidence in support of rapid testing and testing of upper respiratory specimens other than nasopharyngeal swabs, which offer logistical advantages, is sufficient to warrant conditional recommendations in favor of these approaches.

Background: Daratumumab-based combination with proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) have revolutionized the treatment outcomes of relapsed/refractory multiple myeloma (RRMM). Several daratumumab-based triplet combinations have been approved for the management of RRMM, but outcomes of daratumumab-based triplets in patients with high-risk cytogenetics RRMM (HC-RRMM) are not well described in the literature. This study aimed to evaluate the clinical outcome of daratumumab-based regimens in patients with HC-RRMM who are daratumumab-naïve. Methods: A retrospective review of 110 patients with HC-RRMM who received daratumumab-containing regimens from 6/2016 through 2/2023 at the University of Kansas Medical Center, in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC) was conducted. Daratumumab was combined with bortezomib/dexamethasone (DVd), carfilzomib/dexamethasone (DKd), and pomalidomide/dexamethasone (DPd) for treatment of RRMM. HC-RRMM was defined as patients with one or more cytogenetic abnormalities (on FISH panel) including -17/del(17p), t(4;14), t(14;16), t(14;20), or amplification of 1q. Responses to therapy including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Descriptive statistics were used to summarize patient and disease characteristics, along with efficacy outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier methods. Results: Of the 110 patients with HC-RRMM, the median age was 66 years (range 43-84), 83 (75%) were Caucasian, 60 (54%) had IgG isotype, 41 (37%) had revised international staging system (R-ISS) stage III disease, 35 (32%) had extramedullary disease (EMD), 57 (52%) patients had one high-risk cytogenetic (HC) abnormality, 49 (44%) had 2 HC abnormalities, while four (4%) had 3 HC abnormalities. The median number of previous lines of therapy was 2 (1-4). Eighty-eight patients (80%) were lenalidomide refractory, while 53 patients (48%) had double refractory disease to both a PI and IMiD treatment. A total of 19 (17%), 27 (25%), and 64 (58%) patients received DVd, DKd, and DPd, respectively. The overall response rate (ORR) for the entire patient population was 73%, 45% had VGPR or better, and 35% achieved ≥CR. Median follow-up was 28 months (12.07-53.57), the median OS was 28 months (95% CI 23.2 - 43.9) and PFS was 8.03 months (95% CI 5.8 - 12.2) for all treatment groups. The median PFS for 1 HC vs ³ 2 HC was 14.8 vs 4.57 months (HR 1.72, 95%CI 1.17-2.72 p = 0.006), respectively. Similarly, median OS for 1 HC vs ³ 2 HC was 43.93 vs 22.47 months (HR 1.87, 95%CI 1.15-3.05, p = 0.011), respectively. (Figure 1). On multivariate analysis, R-ISS stage III, -17/del(17p), and the presence of more than one HC abnormality were associated with poor OS. The most common cause for treatment discontinuation was progressive disease, accounting for 73% of patients in the whole cohort. As for each daratumumab-based triplet, discontinuation due progression occurred in 78%, 48%, and 83% in DVd, DKd, and DPd, respectively. Other causes of discontinuation included > grade 3 neuropathy, which occurred in 16% of patients receiving DVd, and cardiac events, which occurred in 11% of patients receiving DKd. Treatment-related mortality occurred in 2% of patients in the whole cohort. At the time of evaluation, 14 patients remain on treatment. Conclusion: Advanced stage R-ISS disease at diagnosis, presence of -17/del(17p), and 2 or more HC abnormalities were associated with poor prognosis reflected by worse PFS and OS in HC-RRMM treated with daratumumab-based therapies. A larger cohort or a prospective study in patients with HC-RRMM is needed to compare long-term outcomes between daratumumab-based therapies (DKd, DVd, and DPd).

Abstract Immunoassays designed to detect SARS-CoV-2 protein antigens (Ag) are commonly used to diagnose COVID-19. The most widely used tests are lateral flow assays that generate results in approximately 15 minutes for diagnosis at the point-of-care. Higher throughput, laboratory-based SARS-CoV-2 Ag assays have also been developed. The number of commercially available SARS-CoV-2 Ag detection tests has increased rapidly, as has the COVID-19 diagnostic literature. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the literature and develop best-practice guidance related to SARS-CoV-2 Ag testing. This guideline is an update to the third in a series of frequently updated COVID-19 diagnostic guidelines developed by the IDSA. IDSA's goal was to develop evidence-based recommendations or suggestions that assist clinicians, clinical laboratories, patients, public health authorities, administrators, and policymakers in decisions related to the optimal use of SARS-CoV-2 Ag tests in both medical and nonmedical settings. A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review identified and prioritized clinical questions related to the use of SARS-CoV-2 Ag tests. A review of relevant, peer-reviewed published literature was conducted through 1 April 2022. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. The panel made 10 diagnostic recommendations that address Ag testing in symptomatic and asymptomatic individuals and assess single versus repeat testing strategies. US Food and Drug Administration (FDA) SARS-CoV-2 Ag tests with Emergency Use Authorization (EUA) have high specificity and low to moderate sensitivity compared with nucleic acid amplification testing (NAAT). Ag test sensitivity is dependent on the presence or absence of symptoms and, in symptomatic patients, on timing of testing after symptom onset. In most cases, positive Ag results can be acted upon without confirmation. Results of point-of-care testing are comparable to those of laboratory-based testing, and observed or unobserved self-collection of specimens for testing yields similar results. Modeling suggests that repeat Ag testing increases sensitivity compared with testing once, but no empirical data were available to inform this question. Based on these observations, rapid RT-PCR or laboratory-based NAAT remain the testing methods of choice for diagnosing SARS-CoV-2 infection. However, when timely molecular testing is not readily available or is logistically infeasible, Ag testing helps identify individuals with SARS-CoV-2 infection. Data were insufficient to make a recommendation about the utility of Ag testing to guide release of patients with COVID-19 from isolation. The overall quality of available evidence supporting use of Ag testing was graded as very low to moderate.

Abstract Immunoassays designed to detect SARS-CoV-2 protein antigens are now commercially available. The most widely used tests are rapid lateral flow assays that generate results in ~15 minutes for diagnosis at the point-of-care. Higher throughput, laboratory-based SARS-CoV-2 antigen (Ag) assays have also been developed. The overall accuracy of SARS-CoV-2 Ag tests, however, is not well defined. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the literature and develop best-practice guidance related to SARS-CoV-2 Ag testing. This guideline is the third in a series of rapid, frequently updated COVID-19 diagnostic guidelines developed by IDSA. IDSA’s goal was to develop evidence-based recommendations or suggestions that assist clinicians, clinical laboratories, patients, public health authorities, administrators, and policymakers in decisions related to the optimal use of SARS-CoV-2 Ag tests in both medical and nonmedical settings. A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review identified and prioritized clinical questions related to the use of SARS-CoV-2 Ag tests. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. The panel agreed on 5 diagnostic recommendations. These recommendations address Ag testing in symptomatic and asymptomatic individuals as well as assess single versus repeat testing strategies. Data on the clinical performance of US Food and Drug Administration SARS-CoV-2 Ag tests with Emergency Use Authorization are mostly limited to single, one-time testing versus standard nucleic acid amplification testing (NAAT) as the reference standard. Rapid Ag tests have high specificity and low to modest sensitivity compared with reference NAAT methods. Antigen test sensitivity is heavily dependent on viral load, with differences observed between symptomatic compared with asymptomatic individuals and the time of testing post-onset of symptoms. Based on these observations, rapid reverse transcriptase–polymerase chain reaction (RT-PCR) or laboratory-based NAAT remain the diagnostic methods of choice for diagnosing SARS-CoV-2 infection. However, when molecular testing is not readily available or is logistically infeasible, Ag testing can help identify some individuals with SARS-CoV-2 infection. The overall quality of available evidence supporting use of Ag testing was graded as very low to moderate.