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In this IDSA policy paper, we review the current diagnostic landscape, including unmet needs and emerging technologies, and assess the challenges to the development and clinical integration of improved tests. To fulfill the promise of emerging diagnostics, IDSA presents recommendations that address a host of identified barriers. Achieving these goals will require the engagement and coordination of a number of stakeholders, including Congress, funding and regulatory bodies, public health agencies, the diagnostics industry, healthcare systems, professional societies, and individual clinicians.

People with persistently asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience no symptoms throughout the course of infection, and pre-symptomatic individuals become infectious days before they report symptoms. Transmission of SARS-CoV-2 from individuals without symptoms contributes to pandemic spread, but the extent of transmission from persistently asymptomatic individuals remains unknown. We describe three methodological issues that hinder attempts to estimate this proportion. First, incomplete symptom assessment probably overestimates the asymptomatic fraction. Second, studies with inadequate follow-up misclassify pre-symptomatic individuals. Third, serological studies might identify people with previously unrecognised infection, but reliance on poorly defined antibody responses and retrospective symptom assessment might result in misclassification. We provide recommendations regarding definitions, detection, documentation, and follow-up to improve the identification and evaluation of people with persistently asymptomatic SARS-CoV-2 infection and their contacts. Accurate characterisation of the persistently asymptomatic fraction of infected individuals might shed light on COVID-19 pathogenesis and transmission dynamics, and inform public health responses.

Abstract Background There has been a surge in coronavirus disease 2019 admissions to intensive care units (ICUs) in Asia-Pacific countries. Because ICU healthcare workers are exposed to aerosol-generating procedures, ensuring optimal personal protective equipment (PPE) preparedness is important. Objective The aim of the study was to evaluate PPE preparedness across ICUs in six Asia-Pacific countries during the initial phase of the coronavirus disease 2019 pandemic, which is defined by the World Health Organization as guideline adherence, training healthcare workers, procuring stocks, and responding appropriately to suspected cases. Methods A cross-sectional Web-based survey was circulated to 633 level II/III ICUs of Australia, New Zealand (NZ), Singapore, Hong Kong (HK), India, and the Philippines. Findings Two hundred sixty-three intensivists responded, representing 231 individual ICUs eligible for analysis. Response rates were 68–100% in all countries except India, where it was 24%. Ninety-seven percent of ICUs either conformed to or exceeded World Health Organization recommendations for PPE practice. Fifty-nine percent ICUs used airborne precautions irrespective of aerosol generation procedures. There were variations in negative-pressure room use (highest in HK/Singapore), training (best in NZ), and PPE stock awareness (best in HK/Singapore/NZ). High-flow nasal oxygenation and noninvasive ventilation were not options in most HK (66.7% and 83.3%, respectively) and Singapore ICUs (50% and 80%, respectively), but were considered in other countries to a greater extent. Thirty-eight percent ICUs reported not having specialised airway teams. Showering and “buddy systems” were underused. Clinical waste disposal training was suboptimal (38%). Conclusions Many ICUs in the Asia-Pacific reported suboptimal PPE preparedness in several domains, particularly related to PPE training, practice, and stock awareness, which requires remediation. Adoption of low-cost approaches such as buddy systems should be encouraged. The complete avoidance of high-flow nasal oxygenation reported by several intensivists needs reconsideration. Consideration must be given to standardise PPE guidelines to minimise practice variations. Urgent research to evaluate PPE preparedness and severe acute respiratory syndrome coronavirus 2 transmission is required.

Summary Healthcare workers involved in aerosol‐generating procedures, such as tracheal intubation, may be at elevated risk of acquiring COVID‐19. However, the magnitude of this risk is unknown. We conducted a prospective international multicentre cohort study recruiting healthcare workers participating in tracheal intubation of patients with suspected or confirmed COVID‐19. Information on tracheal intubation episodes, personal protective equipment use, and subsequent provider health status was collected via self‐reporting. The primary endpoint was the incidence of laboratory‐confirmed COVID‐19 diagnosis or new symptoms requiring self‐isolation or hospitalisation after a tracheal intubation episode. Cox regression analysis examined associations between the primary endpoint and healthcare worker characteristics, procedure‐related factors, and personal protective equipment use. Between 23 March and 2 June 2020, 1718 healthcare workers from 503 hospitals in 17 countries reported 5148 tracheal intubation episodes. The overall incidence of the primary endpoint was 10.7% over a median (IQR [range]) follow‐up of 32 (18–48 [0–116]) days. The cumulative incidence within 7, 14 and 21 days of the first tracheal intubation episode was 3.6%, 6.1%, and 8.5%, respectively. The risk of the primary endpoint varied by country and was higher in females, but was not associated with other factors. Around 1 in 10 healthcare workers involved in tracheal intubation of patients with suspected or confirmed COVID‐19 subsequently reported a COVID‐19 outcome. This has human resource implications for institutional capacity to deliver essential healthcare services, and wider societal implications for COVID‐19 transmission.

Ebola virus infections cause a deadly hemorrhagic disease for which no vaccines or therapeutics has received regulatory approval. Here we show isolation of three (Q206, Q314 and Q411) neutralizing monoclonal antibodies (mAbs) against the surface glycoprotein (GP) of Ebola virus identified in West Africa in 2014 through sequential immunization of Chinese rhesus macaques and antigen-specific single B cell sorting. These mAbs demonstrated potent neutralizing activities against both pseudo and live Ebola virus independent of complement. Biochemical, single particle EM, and mutagenesis analysis suggested Q206 and Q411 recognized novel epitopes in the head while Q314 targeted the glycan cap in the GP1 subunit. Q206 and Q411 appeared to influence GP binding to its receptor NPC1. Treatment with these mAbs provided partial but significant protection against disease in a mouse model of Ebola virus infection. These novel mAbs could serve as promising candidates for prophylactic and therapeutic interventions against Ebola virus infection.

The genome segment B sequence of infectious pancreatic necrosis virus was determined for both the Jasper and Sp serotypes. The sequences are 2784 and 2630 by long, respectively, and contain a single large open reading frame encoding the VP1 protein, the putative RNA-dependent RNA polymerase (RdRp) of IPNV. The proteins exhibit an 88% homology with each other, but only 41% with infectious bursal disease virus (IBDV) VP1, another member of the Birnaviridae. Despite the low overall homology between the IPNV and IBDV VP1 proteins, homologous regions were detected within the central portion of the proteins. The carboxy-proximal regions of the VP1, which contain very low amino acid homology, displayed evidence of conservation in structural features such as a hydrophilic, highly basic domain. Consensus sequences associated with GTP-binding proteins and RdRps were also detected in VP1. However, unlike the RdRps associated with single-stranded plus RNA viruses, the birnavirus RdRp lacks the Gly-Asp-Asp motif characteristic of this enzyme family.

Renal infarction is a rare finding in children. Associations between SARS-CoV-2 infections and thromboembolic events including renal infarcts have been described in adults. Although a similar association in children has not yet been described with this pandemic, the pediatric literature is still evolving with the recognition of new manifestations including the post-infectious Multisystem Inflammatory Syndrome in Children (MIS-C). We report the rare event of multiple renal infarcts in a 6-year-old boy manifesting several features of MIS-C 9 weeks following a self-limiting febrile illness characteristic of COVID-19. An underlying Factor V Leiden mutation was identified in this child but felt to be insufficient on its own to explain his clinical presentation. As SARS-CoV-2 testing was delayed, the failure to identify viral RNA or antibodies may not exclude the virus' potential role in precipitating the infarct in this host. Given that renal infarcts have been described in adult patients with COVID-19, reporting this perplexing case where SARS-CoV-2 may have played a role, may help identify this potential complication.

Abstract Background Best practice for prevention, diagnosis, and management of venous thromboembolism (VTE) in patients with coronavirus disease 2019 (COVID‐19) is unknown due to limited published data in this population. Objectives We aimed to assess current global practice and experience in management of COVID‐19–associated coagulopathy to identify information to guide prospective and randomized studies. Methods Physicians were queried about their current approach to prophylaxis, diagnosis, and treatment of VTE in patients with COVID‐19 using an online survey tool distributed through multiple international organizations between April 10 and 14, 2020. Results Five hundred fifteen physicians from 41 countries responded. The majority of respondents (78%) recommended prophylactic anticoagulation for all hospitalized patients with COVID‐19, with most recommending use of low‐molecular‐weight heparin or unfractionated heparin. Significant practice variation was found regarding the need for dose escalation of anticoagulation outside the setting of confirmed or suspected VTE. Respondents reported the use of bedside testing when unable to perform standard diagnostic imaging for diagnosis of VTE. Two hundred ninety‐one respondents reported observing thrombotic complications in their patients, with 64% noting that the complication was pulmonary embolism. Of the 44% of respondents who estimated incidence of thrombosis in patients with COVID‐19 in their hospital, estimates ranged widely from 1% to 50%. One hundred seventy‐four respondents noted bleeding complications (34% minor bleeding, 14% clinically relevant nonmajor bleeding, and 12% major bleeding). Conclusion Well‐designed epidemiologic studies are urgently needed to understand the incidence and risk factors of VTE and bleeding complications in patients with COVID‐19. Randomized clinical trials addressing use of anticoagulation are also needed.

Abstract Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas associated with poor outcomes following anthracycline-based chemotherapy, even when consolidative autologous stem cell transplantation (ASCT) is used. CD30 expression is universal in anaplastic large cell lymphoma (ALCL) and is frequently expressed in other PTCL subtypes. Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate that prolongs progression-free survival (PFS) and overall survival (OS) when combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as compared to CHOP chemotherapy (Horwitz, 2020). Although a majority of pts treated with BV-CHP remained in durable remission (5y PFS 51%), there is room for improvement. Based on retrospective studies that demonstrated improved outcomes in younger pts, the addition of etoposide to CHOP (CHOEP) is commonly used as initial therapy for PTCL. We performed a multicenter phase 2 trial to evaluate the safety and efficacy of adding etoposide to BV-CHP (CHEP-BV) followed by BV consolidation in pts with newly diagnosed CD30-expressing PTCL. Methods: Adults with newly diagnosed CD30+ (≥ 1% of tumor cells by local pathology) PTCL were eligible, including pts with ALK+ ALCL and IPI score ≥ 2, ALK-negative ALCL, PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma (ATLL), among others. After accrual of 28 pts, the protocol was amended to allow enrollment of 20 additional pts with CD30+ non-ALCL PTCL (with ALCL allowed in Canada). Pts could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to study entry. 6 pts were treated in a safety lead-in cohort and all pts received CHEP-BV at the recommended phase 2 dose: 6 x 21-day cycles of CHP+BV (1.8mg/kg) on d1 and etoposide 100mg/m2 on d1-3. G-CSF prophylaxis was mandatory. Pts in response after CHEP-BV could receive BV consolidation (1.8mg/kg q3w) for up to 10 additional cycles (16 total BV cycles) either after ASCT or CHEP-BV if no ASCT was performed. The co-primary endpoints were safety and the CR rate (Deauville score 1-3) by PET-CT after CHEP-BV assessed by investigators according to the 2014 Lugano classification. Secondary endpoints were PFS and OS. Results: Accrual has completed and 48 pts were enrolled; all were evaluable for toxicity, 46 were evaluable for efficacy. 16 pts had ALCL (13 ALK+, 3 ALK-) and 32 had non-ALCL PTCL subtypes, including 18 with AITL, 11 with PTCL NOS, 2 with T-follicular helper PTCL, and 1 with ATLL. Baseline characteristics are shown in Table. 43 pts completed CHEP-BV, 2 had progressive disease (PD) prior to completion, 1 pt discontinued CHEP-BV early (MD discretion), 1 pt died due to COVID-19, and 1 remains on CHEP-BV. Of 43 pts who completed CHEP-BV, 24 proceeded to ASCT and 19 did not. 33 (74%) pts received BV consolidation (20 after ASCT, 13 directly after CHEP-BV) and completed a median 8 of the planned 10 cycles (range, 1-10). 13 pts completed all cycles of consolidation; 19 pts discontinued early - 12 due to adverse events (AE), 5 due to PD, and 2 due to patient/physician choice. The most frequent CHEP-BV related AEs (all grades, G) include fatigue (73%), peripheral sensory neuropathy (67%), anemia (62.5%), nausea (56%), neutropenia (50%), lymphopenia (44%), leukopenia (42%), thrombocytopenia (40%), elevated transaminases (33%). The most common G3+ AEs were neutropenia (37.5%), febrile neutropenia (23%), lymphopenia (21%), anemia (19%), thrombocytopenia (19%). There were 5 deaths, 4 due to PD and 1 due to COVID-19 infection during C3 of CHEP-BV. The interim (n=46) ORR and CR rates (after 3 CHEP-BV cycles, except 1 pt after 2) were 96% and 59% (27 CR, 17 PR), respectively. At completion of CHEP-BV (n=46), the ORR was 91% with 80% CR (37 CR, 5 PR, 4 PD). The ORR/CR rates in ALCL (n=16) vs non-ALCL (n=30) pts were 94%/94% vs 90%/73%, respectively. The ORR/CR rates in pts with CD30 expression 1-9% (n=15) vs 10+% (n=31) were 93%/67% and 90%/87%, respectively. The median follow-up in surviving pts is 16.1 months (range, 0.9-32.5). The overall 18mo PFS and OS were 61% and 89%; 18mo PFS by subgroup: ALCL 81%, non-ALCL 49%, CD30 1-9% 48%, CD30 10+% 67%. Landmark 1y PFS from end of CHEP-BV in responding pts (n=41) was 82% in pts who underwent ASCT vs 48% in pts who did not. Conclusions: In a cohort of pts with mostly non-ALCL CD30-expressing PTCL, CHEP-BV (+/- ASCT) followed by BV consolidation was tolerable and effective. Figure 1 Figure 1. Disclosures Herrera: Genentech: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Tubulis: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy, Research Funding. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy. Savage: Astra-Zeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Roche: Research Funding; Servier: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brammer: Celgene: Research Funding; Kymera Therapeutics: Consultancy; Seattle Genetics: Speakers Bureau. Popplewell: Hoffman La Roche: Other: Food; Novartis: Other: Travel; Pfizer: Other: Travel. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Mei: Morphosys: Research Funding; Janssen: Honoraria; TG Therapeutics: Research Funding; EUSA: Honoraria; BMS: Research Funding; Epizyme: Research Funding; Beigene: Research Funding. Leslie: Merck: Consultancy; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company.

ABSTRACTImportanceRemote clinical trials may reduce barriers to research engagement resulting in more representative samples. A critical evaluation of this approach is imperative to optimize this paradigm shift in research.ObjectiveTo assess design and implementation factors required to maximize enrollment and retention in a fully remote, longitudinal COVID-19 testing study.DesignFully remote longitudinal study launched in October 2020 and ongoing; Study data reported through July 2021.SettingBrigham and Women’s Hospital, Boston MAParticipantsAdults, 18 years or older, within 45 miles of Boston, MA.InterventionMonthly and “on-demand” at-home SARS-CoV-2 RT-PCR and antibody testing using nasal swab and dried blood spot self-collection kits and electronic surveys to assess symptoms and risk factors for COVID-19.Main OutcomesEnrollment, retention, and lessons learned.ResultsBetween October 2020 and January 2021, we enrolled 10,289 participants reflective of Massachusetts census data. Mean age was 47 years (range 18-93), 5855 (56.9%) were assigned female sex at birth, 7181(69.8%) reported being White non-Hispanic, 952 (9.3%) Hispanic/Latinx, 925 (9.0%) Black, 889 (8.6%) Asian, and 342 (3.3%) other and/or more than one race. Lower initial enrollment among Black and Hispanic/Latinx individuals required an adaptive approach, leveraging connections to the medical system, coupled with community partnerships to ensure a representative cohort. Longitudinal retention was higher among participants who were White non-Hispanic, older, working remotely, and with lower socioeconomic vulnerability. Considerable infrastructure, including a dedicated participant support team and robust technology platforms was required to reduce barriers to enrollment, promote retention, ensure scientific rigor, improve data quality, and enable an adaptive study design to increase real-world accessibility.ConclusionsThe decentralization of clinical trials through remote models offers tremendous potential to engage representative cohorts, scale biomedical research, and promote accessibility by reducing barriers common in traditional trial design. Our model highlights the critical role that hospital-community partnerships play in remote recruitment, and the work still needed to ensure representative enrollment. Barriers and burdens within remote trials may be experienced disproportionately across demographic groups. To maximize engagement and retention, researchers should prioritize intensive participant support, investment in technologic infrastructure and an adaptive approach to maximize engagement and retention.Trial RegistrationN/AKey PointsQuestionLongitudinal clinical studies typically rely on in-person interactions to support recruitment, retention, and implementation. We define factors that promote demographically representative recruitment and retention through implementation of a fully remote COVID-19 study.FindingsRemote trial models can reduce barriers to research participation and engage representative cohorts. Recruitment was strengthened by leveraging the medical system. Implementation highlighted participant burdens unique to this model, underscoring the need for a significant participant support team, robust technological infrastructure, and an adaptive, iterative approach.MeaningAs remote trials become more common following the COVID-19 pandemic, methodologies to ensure accessibility, representation, and efficiency are crucial.