Managing blood supplies during natural disasters, humanitarian emergencies, and pandemics: lessons learned from COVID-19.

INTRODUCTION: The COVID-19 pandemic has resulted in a historic public health crisis with widespread social and economic ramifications. The pandemic has also affected the blood supply, resulting in unprecedented and sustained blood shortages. AREAS COVERED: This review describes the challenges of maintaining a safe and sufficient blood supply in the wake of natural disasters, humanitarian emergencies, and pandemics. The challenges, which are accentuated in low- and high-income countries, span the impact on human capacity (affecting blood donors and blood collections personnel alike), disruption to supply chains, and economic sustainability. COVID-19 imparted lessons on how to offset these challenges, which may be applied to future pandemics and public health crises. EXPERT OPINION: Pandemic emergency preparedness plans should be implemented or revised by blood centers and hospitals to lessen the impact to the blood supply. Comprehensive planning should address the timely assessment of risk to the blood supply, rapid donor recruitment, and communication of need, measures to preserve safety for donors and operational staff, careful blood management, and resource sharing.

Convalescent plasma for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma may reduce mortality in patients with viral respiratory diseases, and is being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of this intervention is required. OBJECTIVES: To assess the effectiveness and safety of convalescent plasma transfusion in the treatment of people with COVID-19; and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, and the Epistemonikos COVID-19 L*OVE Platform. We searched monthly until 03 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating convalescent plasma for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies we used RoB 2. We used the GRADE approach to rate the certainty of evidence for the following outcomes: all-cause mortality at up to day 28, worsening and improvement of clinical status (for individuals with moderate to severe disease), hospital admission or death, COVID-19 symptoms resolution (for individuals with mild disease), quality of life, grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS: In this fourth review update version, we included 33 RCTs with 24,861 participants, of whom 11,432 received convalescent plasma. Of these, nine studies are single-centre studies and 24 are multi-centre studies. Fourteen studies took place in America, eight in Europe, three in South-East Asia, two in Africa, two in western Pacific and three in eastern Mediterranean regions and one in multiple regions. We identified a further 49 ongoing studies evaluating convalescent plasma, and 33 studies reporting as being completed. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease 29 RCTs investigated the use of convalescent plasma for 22,728 participants with moderate to severe disease. 23 RCTs with 22,020 participants compared convalescent plasma to placebo or standard care alone, five compared to standard plasma and one compared to human immunoglobulin. We evaluate subgroups on detection of antibodies detection, symptom onset, country income groups and several co-morbidities in the full text. Convalescent plasma versus placebo or standard care alone Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.03; 220 per 1000; 21 RCTs, 19,021 participants; high-certainty evidence). It has little to no impact on need for invasive mechanical ventilation, or death (RR 1.03, 95% CI 0.97 to 1.11; 296 per 1000; 6 RCTs, 14,477 participants; high-certainty evidence) and has no impact on whether participants are discharged from hospital (RR 1.00, 95% CI 0.97 to 1.02; 665 per 1000; 6 RCTs, 12,721 participants; high-certainty evidence). Convalescent plasma may have little to no impact on quality of life (MD 1.00, 95% CI -2.14 to 4.14; 1 RCT, 483 participants; low-certainty evidence). Convalescent plasma may have little to no impact on the risk of grades 3 and 4 adverse events (RR 1.17, 95% CI 0.96 to 1.42; 212 per 1000; 6 RCTs, 2392 participants; low-certainty evidence). It has probably little to no effect on the risk of serious adverse events (RR 1.14, 95% CI 0.91 to 1.44; 135 per 1000; 6 RCTs, 3901 participants; moderate-certainty evidence). Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces or increases all-cause mortality at up to day 28 (RR 0.73, 95% CI 0.45 to 1.19; 129 per 1000; 4 RCTs, 484 participants; very low-certainty evidence). We are uncertain whether convalescent plasma reduces or increases the need for invasive mechanical ventilation, or death (RR 5.59, 95% CI 0.29 to 108.38; 311 per 1000; 1 study, 34 participants; very low-certainty evidence) and whether it reduces or increases the risk of serious adverse events (RR 0.80, 95% CI 0.55 to 1.15; 236 per 1000; 3 RCTs, 327 participants; very low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus human immunoglobulin Convalescent plasma may have little to no effect on all-cause mortality at up to day 28 (RR 1.07, 95% CI 0.76 to 1.50; 464 per 1000; 1 study, 190 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and mild disease We identified two RCTs reporting on 536 participants, comparing convalescent plasma to placebo or standard care alone, and two RCTs reporting on 1597 participants with mild disease, comparing convalescent plasma to standard plasma. Convalescent plasma versus placebo or standard care alone We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (odds ratio (OR) 0.36, 95% CI 0.09 to 1.46; 8 per 1000; 2 RCTs, 536 participants; very low-certainty evidence). It may have little to no effect on admission to hospital or death within 28 days (RR 1.05, 95% CI 0.60 to 1.84; 117 per 1000; 1 RCT, 376 participants; low-certainty evidence), on time to COVID-19 symptom resolution (hazard ratio (HR) 1.05, 95% CI 0.85 to 1.30; 483 per 1000; 1 RCT, 376 participants; low-certainty evidence), on the risk of grades 3 and 4 adverse events (RR 1.29, 95% CI 0.75 to 2.19; 144 per 1000; 1 RCT, 376 participants; low-certainty evidence) and the risk of serious adverse events (RR 1.14, 95% CI 0.66 to 1.94; 133 per 1000; 1 RCT, 376 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (OR 0.30, 95% CI 0.05 to 1.75; 2 per 1000; 2 RCTs, 1597 participants; very low-certainty evidence). It probably reduces admission to hospital or death within 28 days (RR 0.49, 95% CI 0.31 to 0.75; 36 per 1000; 2 RCTs, 1595 participants; moderate-certainty evidence). Convalescent plasma may have little to no effect on initial symptom resolution at up to day 28 (RR 1.12, 95% CI 0.98 to 1.27; 1 RCT, 416 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence. AUTHORS' CONCLUSIONS: For the comparison of convalescent plasma versus placebo or standard care alone, our certainty in the evidence that convalescent plasma for individuals with moderate to severe disease does not reduce mortality and has little to no impact on clinical improvement or worsening is high. It probably has little to no effect on SAEs. For individuals with mild disease, we have very-low to low certainty evidence for most primary outcomes and moderate certainty for hospital admission or death. There are 49 ongoing studies, and 33 studies reported as complete in a trials registry. Publication of ongoing studies might resolve some of the uncertainties around convalescent plasma therapy for people with asymptomatic or mild disease.

Hyperimmune immunoglobulin for people with COVID-19.

BACKGROUND: Hyperimmune immunoglobulin (hIVIG) contains polyclonal antibodies, which can be prepared from large amounts of pooled convalescent plasma or prepared from animal sources through immunisation. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). This review was previously part of a parent review addressing convalescent plasma and hIVIG for people with COVID-19 and was split to address hIVIG and convalescent plasma separately. OBJECTIVES: To assess the benefits and harms of hIVIG therapy for the treatment of people with COVID-19, and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Research Database, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform and Medline and Embase from 1 January 2019 onwards. We carried out searches on 31 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated hIVIG for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies that evaluated standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used RoB 2. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), quality of life, adverse events, and serious adverse events. MAIN RESULTS: We included five RCTs with 947 participants, of whom 688 received hIVIG prepared from humans, 18 received heterologous swine glyco-humanised polyclonal antibody, and 241 received equine-derived processed and purified F(ab')2 fragments. All participants were hospitalised with moderate-to-severe disease, most participants were not vaccinated (only 12 participants were vaccinated). The studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern. There are no data for people with COVID-19 with no symptoms (asymptomatic) or people with mild COVID-19. We identified a further 10 ongoing studies evaluating hIVIG. Benefits of hIVIG prepared from humans We included data on one RCT (579 participants) that assessed the benefits and harms of hIVIG 0.4 g/kg compared to saline placebo. hIVIG may have little to no impact on all-cause mortality at 28 days (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.43 to 1.44; absolute effect 77 per 1000 with placebo versus 61 per 1000 (33 to 111) with hIVIG; low-certainty evidence). The evidence is very uncertain about the effect on worsening of clinical status at day 7 (RR 0.85, 95% CI 0.58 to 1.23; very low-certainty evidence). It probably has little to no impact on improvement of clinical status on day 28 (RR 1.02, 95% CI 0.97 to 1.08; moderate-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if hIVIG has any impact on quality of life. Harms of hIVIG prepared from humans hIVIG may have little to no impact on adverse events at any grade on day 1 (RR 0.98, 95% CI 0.81 to 1.18; 431 per 1000; 1 study 579 participants; low-certainty evidence). Patients receiving hIVIG probably experience more adverse events at grade 3-4 severity than patients who receive placebo (RR 4.09, 95% CI 1.39 to 12.01; moderate-certainty evidence). hIVIG may have little to no impact on the composite outcome of serious adverse events or death up to day 28 (RR 0.72, 95% CI 0.45 to 1.14; moderate-certainty evidence). We also identified additional results on the benefits and harms of other dose ranges of hIVIG, not included in the summary of findings table, but summarised in additional tables. Benefits of animal-derived polyclonal antibodies We included data on one RCT (241 participants) to assess the benefits and harms of receptor-binding domain-specific polyclonal F(ab´)2 fragments of equine antibodies (EpAbs) compared to saline placebo. EpAbs may reduce all-cause mortality at 28 days (RR 0.60, 95% CI 0.26 to 1.37; absolute effect 114 per 1000 with placebo versus 68 per 1000 (30 to 156) ; low-certainty evidence). EpAbs may reduce worsening of clinical status up to day 28 (RR 0.67, 95% CI 0.38 to 1.18; absolute effect 203 per 1000 with placebo versus 136 per 1000 (77 to 240); low-certainty evidence). It may have some effect on improvement of clinical status on day 28 (RR 1.06, 95% CI 0.96 to 1.17; low-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if EpAbs have any impact on quality of life. Harms of animal-derived polyclonal antibodies EpAbs may have little to no impact on the number of adverse events at any grade up to 28 days (RR 0.99, 95% CI 0.74 to 1.31; low-certainty evidence). Adverse events at grade 3-4 severity were not reported. Individuals receiving EpAbs may experience fewer serious adverse events than patients receiving placebo (RR 0.67, 95% CI 0.38 to 1.19; low-certainty evidence). We also identified additional results on the benefits and harms of other animal-derived polyclonal antibody doses, not included in the summary of findings table, but summarised in additional tables. AUTHORS' CONCLUSIONS: We included data from five RCTs that evaluated hIVIG compared to standard therapy, with participants with moderate-to-severe disease. As the studies evaluated different preparations (from humans or from various animals) and doses, we could not pool them. hIVIG prepared from humans may have little to no impact on mortality, and clinical improvement and worsening. hIVIG may increase grade 3-4 adverse events. Studies did not evaluate quality of life. RBD-specific polyclonal F(ab´)2 fragments of equine antibodies may reduce mortality and serious adverse events, and may reduce clinical worsening. However, the studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern and prior to widespread vaccine rollout. As no studies evaluated hIVIG for participants with asymptomatic infection or mild disease, benefits for these individuals remains uncertain. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence.

Convalescent plasma for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma may reduce mortality in patients with viral respiratory diseases, and is being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of this intervention is required. OBJECTIVES: To assess the effectiveness and safety of convalescent plasma transfusion in the treatment of people with COVID-19; and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, and the Epistemonikos COVID-19 L*OVE Platform. We searched monthly until 03 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating convalescent plasma for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies we used RoB 2. We used the GRADE approach to rate the certainty of evidence for the following outcomes: all-cause mortality at up to day 28, worsening and improvement of clinical status (for individuals with moderate to severe disease), hospital admission or death, COVID-19 symptoms resolution (for individuals with mild disease), quality of life, grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS: In this fourth review update version, we included 33 RCTs with 24,861 participants, of whom 11,432 received convalescent plasma. Of these, nine studies are single-centre studies and 24 are multi-centre studies. Fourteen studies took place in America, eight in Europe, three in South-East Asia, two in Africa, two in western Pacific and three in eastern Mediterranean regions and one in multiple regions. We identified a further 49 ongoing studies evaluating convalescent plasma, and 33 studies reporting as being completed. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease 29 RCTs investigated the use of convalescent plasma for 22,728 participants with moderate to severe disease. 23 RCTs with 22,020 participants compared convalescent plasma to placebo or standard care alone, five compared to standard plasma and one compared to human immunoglobulin. We evaluate subgroups on detection of antibodies detection, symptom onset, country income groups and several co-morbidities in the full text. Convalescent plasma versus placebo or standard care alone Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.03; 220 per 1000; 21 RCTs, 19,021 participants; high-certainty evidence). It has little to no impact on need for invasive mechanical ventilation, or death (RR 1.03, 95% CI 0.97 to 1.11; 296 per 1000; 6 RCTs, 14,477 participants; high-certainty evidence) and has no impact on whether participants are discharged from hospital (RR 1.00, 95% CI 0.97 to 1.02; 665 per 1000; 6 RCTs, 12,721 participants; high-certainty evidence). Convalescent plasma may have little to no impact on quality of life (MD 1.00, 95% CI -2.14 to 4.14; 1 RCT, 483 participants; low-certainty evidence). Convalescent plasma may have little to no impact on the risk of grades 3 and 4 adverse events (RR 1.17, 95% CI 0.96 to 1.42; 212 per 1000; 6 RCTs, 2392 participants; low-certainty evidence). It has probably little to no effect on the risk of serious adverse events (RR 1.14, 95% CI 0.91 to 1.44; 135 per 1000; 6 RCTs, 3901 participants; moderate-certainty evidence). Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces or increases all-cause mortality at up to day 28 (RR 0.73, 95% CI 0.45 to 1.19; 129 per 1000; 4 RCTs, 484 participants; very low-certainty evidence). We are uncertain whether convalescent plasma reduces or increases the need for invasive mechanical ventilation, or death (RR 5.59, 95% CI 0.29 to 108.38; 311 per 1000; 1 study, 34 participants; very low-certainty evidence) and whether it reduces or increases the risk of serious adverse events (RR 0.80, 95% CI 0.55 to 1.15; 236 per 1000; 3 RCTs, 327 participants; very low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus human immunoglobulin Convalescent plasma may have little to no effect on all-cause mortality at up to day 28 (RR 1.07, 95% CI 0.76 to 1.50; 464 per 1000; 1 study, 190 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and mild disease We identified two RCTs reporting on 536 participants, comparing convalescent plasma to placebo or standard care alone, and two RCTs reporting on 1597 participants with mild disease, comparing convalescent plasma to standard plasma. Convalescent plasma versus placebo or standard care alone We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (odds ratio (OR) 0.36, 95% CI 0.09 to 1.46; 8 per 1000; 2 RCTs, 536 participants; very low-certainty evidence). It may have little to no effect on admission to hospital or death within 28 days (RR 1.05, 95% CI 0.60 to 1.84; 117 per 1000; 1 RCT, 376 participants; low-certainty evidence), on time to COVID-19 symptom resolution (hazard ratio (HR) 1.05, 95% CI 0.85 to 1.30; 483 per 1000; 1 RCT, 376 participants; low-certainty evidence), on the risk of grades 3 and 4 adverse events (RR 1.29, 95% CI 0.75 to 2.19; 144 per 1000; 1 RCT, 376 participants; low-certainty evidence) and the risk of serious adverse events (RR 1.14, 95% CI 0.66 to 1.94; 133 per 1000; 1 RCT, 376 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (OR 0.30, 95% CI 0.05 to 1.75; 2 per 1000; 2 RCTs, 1597 participants; very low-certainty evidence). It probably reduces admission to hospital or death within 28 days (RR 0.49, 95% CI 0.31 to 0.75; 36 per 1000; 2 RCTs, 1595 participants; moderate-certainty evidence). Convalescent plasma may have little to no effect on initial symptom resolution at up to day 28 (RR 1.12, 95% CI 0.98 to 1.27; 1 RCT, 416 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence. AUTHORS' CONCLUSIONS: For the comparison of convalescent plasma versus placebo or standard care alone, our certainty in the evidence that convalescent plasma for individuals with moderate to severe disease does not reduce mortality and has little to no impact on clinical improvement or worsening is high. It probably has little to no effect on SAEs. For individuals with mild disease, we have low certainty evidence for our primary outcomes. There are 49 ongoing studies, and 33 studies reported as complete in a trials registry. Publication of ongoing studies might resolve some of the uncertainties around convalescent plasma therapy for people with asymptomatic or mild disease.

ANTECEDENTES: El plasma de convaleciente podría reducir la mortalidad en pacientes con enfermedades respiratorias víricas, y se está investigando como posible tratamiento para la enfermedad por coronavirus 2019 (covid­19). Se requiere un profundo conocimiento del conjunto de evidencia actual sobre los beneficios y riesgos de esta intervención. OBJETIVOS: Evaluar la efectividad y seguridad de la transfusión de plasma de convaleciente en el tratamiento de las personas con covid­19; y mantener la vigencia de la evidencia con un enfoque de revisión sistemática continua. MÉTODOS DE BÚSQUEDA: Para identificar estudios en curso y completados, se realizaron búsquedas en la base de datos COVID­19 de la OMS: literatura global sobre la enfermedad por coronavirus, MEDLINE, Embase, el Registro Cochrane de Estudios de covid­19 y la Plataforma COVID­19 L*OVE de Epistemonikos. Se realizaron búsquedas mensuales hasta el 3 de marzo de 2022. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados (ECA) que evaluaron el plasma de convaleciente para la covid­19, independientemente de la gravedad de la enfermedad, la edad, el sexo o el origen étnico. Se excluyeron los estudios que incluyeron poblaciones con otras enfermedades por coronavirus, como el síndrome respiratorio agudo grave (SARS) o el síndrome respiratorio de Oriente Medio (MERS), así como los estudios que evaluaron la inmunoglobulina estándar. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se siguió la metodología estándar de Cochrane. Para evaluar el sesgo en los estudios incluidos se utilizó la herramienta RoB 2. Se utilizó el método GRADE para evaluar la certeza de la evidencia para los siguientes desenlaces: mortalidad por todas las causas hasta el día 28, empeoramiento y mejoría del estado clínico (para personas con enfermedad moderada a grave), ingreso hospitalario o muerte, resolución de los síntomas de covid­19 (para personas con enfermedad leve), calidad de vida, eventos adversos de grado 3 o 4 y eventos adversos graves. RESULTADOS PRINCIPALES: En esta cuarta versión actualizada de la revisión se incluyeron 33 ECA con 24 861 participantes, de los cuales 11 432 recibieron plasma de convaleciente. De ellos, 9 estudios son unicéntricos y 24 multicéntricos. Se realizaron 14 estudios en América, 8 en Europa, 3 en el Sudeste Asiático, 2 en África, 2 en el Pacífico occidental, 3 en el Mediterráneo oriental y 1 en varias regiones. Se identificaron otros 49 estudios en curso que evaluaron el plasma de convaleciente, y 33 estudios que informaban de que se habían completado. Personas con un diagnóstico confirmado de covid­19 y enfermedad de moderada a grave El uso de plasma de convaleciente se investigó en 29 ECA con 22 728 participantes con enfermedad moderada a grave. En 23 ECA con 22 020 participantes se comparó el plasma de convaleciente con el placebo o la atención habitual sola, en 5 se comparó con plasma estándar y en 1, con inmunoglobulina humana. Se evalúan subgrupos sobre detección de anticuerpos, aparición de síntomas, grupos de ingresos de países y varias comorbilidades en el texto completo. Plasma de convaleciente versus placebo o atención habitual sola El plasma de convaleciente no reduce la mortalidad por todas las causas hasta el día 28 (razón de riesgos [RR] 0,98; intervalo de confianza [IC] del 95%: 0,92 a 1,03; 220 por cada 1000; 21 ECA, 19 021 participantes; evidencia de certeza alta). Tiene poca o ninguna repercusión en la necesidad de ventilación mecánica invasiva o la muerte (RR 1,03; IC del 95%: 0,97 a 1,11; 296 por cada 1000; seis ECA, 14 477 participantes; evidencia de certeza alta) y no tiene ningún efecto en si los participantes reciben el alta hospitalaria (RR 1,00; IC de 95%: 0,97 a 1,02; 665 por cada 1000; seis ECA, 12 721 participantes; evidencia de certeza alta). El plasma de convaleciente podría tener poca o ninguna repercusión en la calidad de vida (DM 1,00; IC del 95%: ­2,14 a 4,14; un ECA, 483 participantes; evidencia de certeza baja). El plasma de convaleciente podría tener poco o ningún efecto en el riesgo de eventos adversos de grado 3 y 4 (RR 1,17; IC del 95%: 0,96 a 1,42; 212 por cada 1000; seis ECA, 2392 participantes; evidencia de certeza baja). Es probable que tenga poco o ningún efecto sobre el riesgo de eventos adversos graves (RR 1,14; IC del 95%: 0,91 a 1,44; 135 por cada 1000; seis ECA, 3901 participantes; evidencia de certeza moderada). Plasma de convaleciente versus plasma estándar No se sabe si el plasma de convaleciente reduce o aumenta la mortalidad por cualquier causa hasta el día 28 (RR 0,73; IC del 95%: 0,45 a 1,19; 129 por cada 1000; cuatro ECA, 484 participantes; evidencia de certeza muy baja). No se sabe si el plasma de convaleciente reduce o aumenta la necesidad de ventilación mecánica invasiva o la muerte (RR 5,59; IC del 95%: 0,29 a 108,38; 311 por cada 1000; un estudio, 34 participantes; evidencia de certeza muy baja) ni si reduce o aumenta el riesgo de eventos adversos graves (RR 0,80; IC 95%: 0,55 a 1,15; 236 por cada 1000; tres ECA, 327 participantes; evidencia de certeza muy baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Plasma de convaleciente versus inmunoglobulina humana El plasma de convaleciente podría tener poco o ningún efecto sobre la mortalidad por cualquier causa hasta el día 28 (RR 1,07; IC del 95%: 0,76 a 1,50; 464 por cada 1000; un estudio, 190 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Personas con un diagnóstico confirmado de infección por SARS­CoV­2 y enfermedad leve Se identificaron dos ECA, con 536 participantes, que compararon el plasma de convaleciente con placebo o atención habitual sola y dos ECA, con 1597 participantes con enfermedad leve, que compararon el plasma de convaleciente con plasma estándar. Plasma de convaleciente versus placebo o atención habitual sola No se sabe si el plasma de convaleciente reduce la mortalidad por cualquier causa hasta el día 28 (odds ratio [OR] 0,36; IC del 95%: 0,09 a 1,46; 8 por cada 1000; dos ECA, 536 participantes; evidencia de certeza muy baja). Podría tener poco o ningún efecto en el ingreso hospitalario o la muerte a los 28 días (RR 1,05; IC del 95%: 0,60 a 1,84; 117 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja), en el tiempo hasta la resolución de los síntomas de covid­19 (cociente de riesgos instantáneos [CRI] 1,05; IC del 95%: 0,85 a 1,30; 483 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja), en el riesgo de eventos adversos de grados 3 y 4 (RR 1,29; IC del 95%: 0,75 a 2,19; 144 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja) y en el riesgo de eventos adversos graves (RR 1,14; IC del 95%: 0,66 a 1,94; 133 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Plasma de convaleciente versus plasma estándar No se sabe si el plasma de convaleciente reduce la mortalidad por cualquier causa hasta el día 28 (OR 0,30; IC del 95%: 0,05 a 1,75; 2 por cada 1000; dos ECA, 1597 participantes; evidencia de certeza muy baja). Es probable que reduzca el ingreso hospitalario o la muerte a los 28 días (RR 0,49; IC del 95%: 0,31 a 0,75; 36 por cada 1000; dos ECA, 1595 participantes; evidencia de certeza moderada). El plasma de convaleciente podría tener poco o ningún efecto sobre la resolución inicial de los síntomas hasta el día 28 (RR 1,12; IC del 95%: 0,98 a 1,27; un ECA, 416 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Esta es una revisión sistemática continua. Cada mes se busca nueva evidencia y se actualiza la revisión cuando se identifica evidencia nueva relevante. CONCLUSIONES DE LOS AUTORES: Para la comparación del plasma de convaleciente versus placebo o la atención habitual sola, existe evidencia de certeza alta de que el plasma de convaleciente para personas con enfermedad moderada a grave no reduce la mortalidad y tiene poco o ningún efecto en la mejoría o el empeoramiento clínico. Es probable que tenga poco o ningún efecto en los eventos adversos graves. Para las personas con enfermedad leve, existe evidencia de certeza baja para los desenlaces principales. Hay 49 estudios en curso y 33 estudios que declaran estar completados en un registro de ensayos. La publicación de los estudios en curso podría resolver algunas de las incertidumbres en torno al tratamiento con plasma de convaleciente para personas con enfermedad asintomática o leve.

Guidance on the Use of Convalescent Plasma to Treat Immunocompromised Patients With Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immunocompromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease, and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.

Hyperimmune immunoglobulin for people with COVID‐19

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Using a living systematic review approach, to assess whether hyperimmune immunoglobulin therapy is effective and safe in the treatment of people with COVID‐19; and to maintain the currency of the evidence.

E-learning/online education in transfusion medicine: A cross-sectional international survey.

OBJECTIVES: This survey aims to assess the scope of transfusion e-learning courses in blood establishments and transfusion services internationally. BACKGROUND: E-learning/online education is increasingly used in the education of medical professionals. There is limited published data on the use of e-learning for transfusion medicine. MATERIAL AND METHODS: An International survey was designed and distributed to all members of the International Society of Blood Transfusion to assess utilisation of e-learning in their institutions. Descriptive statistics were used to summarise the results. RESULTS: A total of 177 respondents participated, 68 of which had e-learning modules in their institutions. Approximately two-thirds of the courses were developed in-house (66%), and 63% are available to learners from outside the host institutions. In one-third of institutions, these courses were established during the COVID-19 pandemic, while 15% had used e-learning courses for more than 10 years. The courses target different audiences and topics ranging from blood donation to hemovigilance. The most common audiences were physicians (71%), laboratory scientists/technologists (69%) and transfusion practitioners (63%). Formal assessment of learning outcomes is used in 70% of the programs. CONCLUSIONS: The survey demonstrates the widespread use of e-learning courses in transfusion education, with a substantial proportion being developed during the COVID-19 pandemic.

SARS-CoV-2-neutralising monoclonal antibodies to prevent COVID-19.

BACKGROUND: Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as potential prophylaxis to prevent coronavirus disease 2019 (COVID-19). OBJECTIVES: To assess the effects of SARS-CoV-2-neutralising mAbs, including mAb fragments, to prevent infection with SARS-CoV-2 causing COVID-19; and to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, and three other databases on 27 April 2022. We checked references, searched citations, and contacted study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated SARS-CoV-2-neutralising mAbs, including mAb fragments, alone or combined, versus an active comparator, placebo, or no intervention, for pre-exposure prophylaxis (PrEP) and postexposure prophylaxis (PEP) of COVID-19. We excluded studies of SARS-CoV-2-neutralising mAbs to treat COVID-19, as these are part of another review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results, extracted data, and assessed risk of bias using Cochrane RoB 2. Prioritised outcomes were infection with SARS-CoV-2, development of clinical COVID-19 symptoms, all-cause mortality, admission to hospital, quality of life, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE. MAIN RESULTS: We included four RCTs of 9749 participants who were previously uninfected and unvaccinated at baseline. Median age was 42 to 76 years. Around 20% to 77.5% of participants in the PrEP studies and 35% to 100% in the PEP studies had at least one risk factor for severe COVID-19. At baseline, 72.8% to 82.2% were SARS-CoV-2 antibody seronegative. We identified four ongoing studies, and two studies awaiting classification. Pre-exposure prophylaxis Tixagevimab/cilgavimab versus placebo One study evaluated tixagevimab/cilgavimab versus placebo in participants exposed to SARS-CoV-2 wild-type, Alpha, Beta, and Delta variant. About 39.3% of participants were censored for efficacy due to unblinding and 13.8% due to vaccination. Within six months, tixagevimab/cilgavimab probably decreases infection with SARS-CoV-2 (risk ratio (RR) 0.45, 95% confidence interval (CI) 0.29 to 0.70; 4685 participants; moderate-certainty evidence), decreases development of clinical COVID-19 symptoms (RR 0.18, 95% CI 0.09 to 0.35; 5172 participants; high-certainty evidence), and may decrease admission to hospital (RR 0.03, 95% CI 0 to 0.59; 5197 participants; low-certainty evidence). Tixagevimab/cilgavimab may result in little to no difference on mortality within six months, all-grade AEs, and SAEs (low-certainty evidence). Quality of life was not reported. Casirivimab/imdevimab versus placebo One study evaluated casirivimab/imdevimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type, Alpha, and Delta variant. About 36.5% of participants opted for SARS-CoV-2 vaccination and had a mean of 66.1 days between last dose of intervention and vaccination. Within six months, casirivimab/imdevimab may decrease infection with SARS-CoV-2 (RR 0.01, 95% CI 0 to 0.14; 825 seronegative participants; low-certainty evidence) and may decrease development of clinical COVID-19 symptoms (RR 0.02, 95% CI 0 to 0.27; 969 participants; low-certainty evidence). We are uncertain whether casirivimab/imdevimab affects mortality regardless of the SARS-CoV-2 antibody serostatus. Casirivimab/imdevimab may increase all-grade AEs slightly (RR 1.14, 95% CI 0.98 to 1.31; 969 participants; low-certainty evidence). The evidence is very uncertain about the effects on grade 3 to 4 AEs and SAEs within six months. Admission to hospital and quality of life were not reported. Postexposure prophylaxis Bamlanivimab versus placebo One study evaluated bamlanivimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type. Bamlanivimab probably decreases infection with SARS-CoV-2 versus placebo by day 29 (RR 0.76, 95% CI 0.59 to 0.98; 966 participants; moderate-certainty evidence), may result in little to no difference on all-cause mortality by day 60 (R 0.83, 95% CI 0.25 to 2.70; 966 participants; low-certainty evidence), may increase all-grade AEs by week eight (RR 1.12, 95% CI 0.86 to 1.46; 966 participants; low-certainty evidence), and may increase slightly SAEs (RR 1.46, 95% CI 0.73 to 2.91; 966 participants; low-certainty evidence). Development of clinical COVID-19 symptoms, admission to hospital within 30 days, and quality of life were not reported. Casirivimab/imdevimab versus placebo One study evaluated casirivimab/imdevimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type, Alpha, and potentially, but less likely to Delta variant. Within 30 days, casirivimab/imdevimab decreases infection with SARS-CoV-2 (RR 0.34, 95% CI 0.23 to 0.48; 1505 participants; high-certainty evidence), development of clinical COVID-19 symptoms (broad-term definition) (RR 0.19, 95% CI 0.10 to 0.35; 1505 participants; high-certainty evidence), may result in little to no difference on mortality (RR 3.00, 95% CI 0.12 to 73.43; 1505 participants; low-certainty evidence), and may result in little to no difference in admission to hospital. Casirivimab/imdevimab may slightly decrease grade 3 to 4 AEs (RR 0.50, 95% CI 0.24 to 1.02; 2617 participants; low-certainty evidence), decreases all-grade AEs (RR 0.70, 95% CI 0.61 to 0.80; 2617 participants; high-certainty evidence), and may result in little to no difference on SAEs in participants regardless of SARS-CoV-2 antibody serostatus. Quality of life was not reported. AUTHORS' CONCLUSIONS: For PrEP, there is a decrease in development of clinical COVID-19 symptoms (high certainty), infection with SARS-CoV-2 (moderate certainty), and admission to hospital (low certainty) with tixagevimab/cilgavimab. There is low certainty of a decrease in infection with SARS-CoV-2, and development of clinical COVID-19 symptoms; and a higher rate for all-grade AEs with casirivimab/imdevimab. For PEP, there is moderate certainty of a decrease in infection with SARS-CoV-2 and low certainty for a higher rate for all-grade AEs with bamlanivimab. There is high certainty of a decrease in infection with SARS-CoV-2, development of clinical COVID-19 symptoms, and a higher rate for all-grade AEs with casirivimab/imdevimab.   Although there is high-to-moderate certainty evidence for some outcomes, it is insufficient to draw meaningful conclusions. These findings only apply to people unvaccinated against COVID-19. They are only applicable to the variants prevailing during the study and not other variants (e.g. Omicron). In vitro, tixagevimab/cilgavimab is effective against Omicron, but there are no clinical data. Bamlanivimab and casirivimab/imdevimab are ineffective against Omicron in vitro. Further studies are needed and publication of four ongoing studies may resolve the uncertainties.

International Society of Blood Transfusion survey of experiences of blood banks and transfusion services during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has impacted blood systems worldwide. Challenges included maintaining blood supplies and initiating the collection and use of COVID-19 convalescent plasma (CCP). Sharing information on the challenges can help improve blood collection and utilization. MATERIALS AND METHODS: A survey questionnaire was distributed to International Society of Blood Transfusion members in 95 countries. We recorded respondents' demographic information, impacts on the blood supply, CCP collection and use, transfusion demands and operational challenges. RESULTS: Eighty-two responses from 42 countries, including 24 low- and middle-income countries, were analysed. Participants worked in national (26.8%) and regional (26.8%) blood establishments and hospital-based (42.7%) institutions. CCP collection and transfusion were reported by 63% and 36.6% of respondents, respectively. Decreases in blood donations occurred in 70.6% of collecting facilities. Despite safety measures and recruitment strategies, donor fear and refusal of institutions to host blood drives were major contributing factors. Almost half of respondents working at transfusion medicine services were from large hospitals with over 10,000 red cell transfusions per year, and 76.8% of those hospitals experienced blood shortages. Practices varied in accepting donors for blood or CCP donations after a history of COVID-19 infection, CCP transfusion, or vaccination. Operational challenges included loss of staff, increased workloads and delays in reagent supplies. Almost half of the institutions modified their disaster plans during the pandemic. CONCLUSION: The challenges faced by blood systems during the COVID-19 pandemic highlight the need for guidance, harmonization, and strengthening of the preparedness and the capacity of blood systems against future infectious threats.

Production and Quality Assurance of Human Polyclonal Hyperimmune Immunoglobulins Against SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the potential therapeutic value of early passive polyclonal immunotherapy using high-titer convalescent plasma (CCP). Human polyclonal hyperimmune immunoglobulin (HIG) has several advantages over CCP. Unlike CCP, HIG can provide standardized and controlled antibody content. It is also subjected to robust pathogen reduction rendering it virally safe and is purified by technologies demonstrated to preserve immunoglobulin neutralization capacity and Fc fragment integrity. This document provides an overview of current practices and guidance for the collection and testing of plasma rich in antibodies against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) and its industrial fractionation for the manufacture of quality-assured and safe HIG. Considerations are also given to the production of HIG preparations in low- and middle-income countries.

SARS‐CoV‐2‐neutralising monoclonal antibodies to prevent COVID‐19

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effectiveness and safety of SARS‐CoV‐2‐neutralising mAbs, including mAb fragments, to prevent infection with SARS‐CoV‐2 causing COVID‐19;and to maintain the currency of the evidence, using a living systematic review approach.

SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19.

BACKGROUND: Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). OBJECTIVES: To assess the effectiveness and safety of SARS-CoV-2-neutralising mAbs for treating patients with COVID-19, compared to an active comparator, placebo, or no intervention. To maintain the currency of the evidence, we will use a living systematic review approach. A secondary objective is to track newly developed SARS-CoV-2-targeting mAbs from first tests in humans onwards.  SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane COVID-19 Study Register, and three other databases on 17 June 2021. We also checked references, searched citations, and contacted study authors to identify additional studies. Between submission and publication, we conducted a shortened randomised controlled trial (RCT)-only search on 30 July 2021. SELECTION CRITERIA: We included studies that evaluated SARS-CoV-2-neutralising mAbs, alone or combined, compared to an active comparator, placebo, or no intervention, to treat people with COVID-19. We excluded studies on prophylactic use of SARS-CoV-2-neutralising mAbs. DATA COLLECTION AND ANALYSIS: Two authors independently assessed search results, extracted data, and assessed risk of bias using the Cochrane risk of bias tool (RoB2). Prioritised outcomes were all-cause mortality by days 30 and 60, clinical progression, quality of life, admission to hospital, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE. MAIN RESULTS: We identified six RCTs that provided results from 17,495 participants with planned completion dates between July 2021 and December 2031. Target sample sizes varied from 1020 to 10,000 participants. Average age was 42 to 53 years across four studies of non-hospitalised participants, and 61 years in two studies of hospitalised participants. Non-hospitalised individuals with COVID-19 Four studies evaluated single agents bamlanivimab (N = 465), sotrovimab (N = 868), regdanvimab (N = 307), and combinations of bamlanivimab/etesevimab (N = 1035), and casirivimab/imdevimab (N = 799). We did not identify data for mortality at 60 days or quality of life. Our certainty of the evidence is low for all outcomes due to too few events (very serious imprecision).  Bamlanivimab compared to placebo No deaths occurred in the study by day 29. There were nine people admitted to hospital by day 29 out of 156 in the placebo group compared with one out of 101 in the group treated with 0.7 g bamlanivimab (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.02 to 1.33), 2 from 107 in the group treated with 2.8 g (RR 0.32, 95% CI 0.07 to 1.47) and 2 from 101 in the group treated with 7.0 g (RR 0.34, 95% CI 0.08 to 1.56). Treatment with 0.7 g, 2.8 g and 7.0 g bamlanivimab may have similar rates of AEs as placebo (RR 0.99, 95% CI 0.66 to 1.50; RR 0.90, 95% CI 0.59 to 1.38; RR 0.81, 95% CI 0.52 to 1.27). The effect on SAEs is uncertain. Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Bamlanivimab/etesevimab compared to placebo There were 10 deaths in the placebo group and none in bamlanivimab/etesevimab group by day 30 (RR 0.05, 95% CI 0.00 to 0.81). Bamlanivimab/etesevimab may decrease hospital admission by day 29 (RR 0.30, 95% CI 0.16 to 0.59), may result in a slight increase in any grade AEs (RR 1.15, 95% CI 0.83 to 1.59) and may increase SAEs (RR 1.40, 95% CI 0.45 to 4.37). Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Casirivimab/imdevimab compared to placebo Casirivimab/imdevimab may reduce hospital admissions or death (2.4 g: RR 0.43, 95% CI 0.08 to 2.19; 8.0 g: RR 0.21, 95% CI 0.02 to 1.79). We are uncertain of the effect on grades 3-4 AEs (2.4 g: RR 0.76, 95% CI 0.17 to 3.37; 8.0 g: RR 0.50, 95% CI 0.09 to 2.73) and SAEs (2.4 g: RR 0.68, 95% CI 0.19 to 2.37; 8.0 g: RR 0.34, 95% CI 0.07 to 1.65). Mortality by day 30 and clinical progression/improvement of symptoms or development of severe symptoms were not reported. Sotrovimab compared to placebo We are uncertain whether sotrovimab has an effect on mortality (RR 0.33, 95% CI 0.01 to 8.18) and invasive mechanical ventilation (IMV) requirement or death (RR 0.14, 95% CI 0.01 to 2.76). Treatment with sotrovimab may reduce the number of participants with oxygen requirement (RR 0.11, 95 % CI 0.02 to 0.45), hospital admission or death by day 30 (RR 0.14, 95% CI 0.04 to 0.48), grades 3-4 AEs (RR 0.26, 95% CI 0.12 to 0.60), SAEs (RR 0.27, 95% CI 0.12 to 0.63) and may have little or no effect on any grade AEs (RR 0.87, 95% CI 0.66 to 1.16).  Regdanvimab compared to placebo Treatment with either dose (40 or 80 mg/kg) compared with placebo may decrease hospital admissions or death (RR 0.45, 95% CI 0.14 to 1.42; RR 0.56, 95% CI 0.19 to 1.60, 206 participants), but may increase grades 3-4 AEs (RR 2.62, 95% CI 0.52 to 13.12; RR 2.00, 95% CI 0.37 to 10.70). 80 mg/kg may reduce any grade AEs (RR 0.79, 95% CI 0.52 to 1.22) but 40 mg/kg may have little to no effect (RR 0.96, 95% CI 0.64 to 1.43). There were too few events to allow meaningful judgment for the outcomes mortality by 30 days, IMV requirement, and SAEs.  Hospitalised individuals with COVID-19 Two studies evaluating bamlanivimab as a single agent (N = 314) and casirivimab/imdevimab as a combination therapy (N = 9785) were included.   Bamlanivimab compared to placebo  We are uncertain whether bamlanivimab has an effect on mortality by day 30 (RR 1.39, 95% CI 0.40 to 4.83) and SAEs by day 28 (RR 0.93, 95% CI 0.27 to 3.14). Bamlanivimab may have little to no effect on time to hospital discharge (HR 0.97, 95% CI 0.78 to 1.20) and mortality by day 90 (HR 1.09, 95% CI 0.49 to 2.43). The effect of bamlanivimab on the development of severe symptoms at day 5 (RR 1.17, 95% CI 0.75 to 1.85) is uncertain. Bamlanivimab may increase grades 3-4 AEs at day 28 (RR 1.27, 95% CI 0.81 to 1.98). We assessed the evidence as low certainty for all outcomes due to serious imprecision, and very low certainty for severe symptoms because of additional concerns about indirectness. Casirivimab/imdevimab with usual care compared to usual care alone Treatment with casirivimab/imdevimab compared to usual care probably has little or no effect on mortality by day 30 (RR 0.94, 95% CI 0.87 to 1.02), IMV requirement or death (RR 0.96, 95% CI 0.90 to 1.04), nor alive at hospital discharge by day 30 (RR 1.01, 95% CI 0.98 to 1.04). We assessed the evidence as moderate certainty due to study limitations (lack of blinding). AEs and SAEs were not reported.  AUTHORS' CONCLUSIONS: The evidence for each comparison is based on single studies. None of these measured quality of life. Our certainty in the evidence for all non-hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS-CoV-2-neutralising mAbs. Further studies and long-term data from the existing studies are needed to confirm or refute these initial findings, and to understand how the emergence of SARS-CoV-2 variants may impact the effectiveness of SARS-CoV-2-neutralising mAbs. Publication of the 36 ongoing studies may resolve uncertainties about the effectiveness and safety of SARS-CoV-2-neutralising mAbs for the treatment of COVID-19 and possible subgroup differences.

Lessons learned in the collection of convalescent plasma during the COVID-19 pandemic.

BACKGROUND: The lack of definitive treatment or preventative options for COVID-19 led many clinicians early on to consider convalescent plasma (CCP) as potentially therapeutic. Regulators, blood centres and hospitals worldwide worked quickly to get CCP to the bedside. Although response was admirable, several areas have been identified to help improve future pandemic management. MATERIALS AND METHODS: A multidisciplinary, multinational subgroup from the ISBT Working Group on COVID-19 was tasked with drafting a manuscript that describes the lessons learned pertaining to procurement and administration of CCP, derived from a comprehensive questionnaire within the subgroup. RESULTS: While each country's responses and preparedness for the pandemic varied, there were shared challenges, spanning supply chain disruptions, staffing, impact of social distancing on the collection of regular blood and CCP products, and the availability of screening and confirmatory SARS-CoV-2 testing for donors and patients. The lack of a general framework to organize data gathering across clinical trials and the desire to provide a potentially life-saving therapeutic through compassionate use hampered the collection of much-needed safety and outcome data worldwide. Communication across all stakeholders was identified as being central to reducing confusion. CONCLUSION: The need for flexibility and adaptability remains paramount when dealing with a pandemic. As the world approaches the first anniversary of the COVID-19 pandemic with rising rates worldwide and over 115 million cases and 2·55 million deaths, respectively, it is important to reflect on how to better prepare for future pandemics as we continue to combat the current one.

ABO blood group and COVID-19: a review on behalf of the ISBT COVID-19 Working Group.

Growing evidence suggests that ABO blood group may play a role in the immunopathogenesis of SARS-CoV-2 infection, with group O individuals less likely to test positive and group A conferring a higher susceptibility to infection and propensity to severe disease. The level of evidence supporting an association between ABO type and SARS-CoV-2/COVID-19 ranges from small observational studies, to genome-wide-association-analyses and country-level meta-regression analyses. ABO blood group antigens are oligosaccharides expressed on red cells and other tissues (notably endothelium). There are several hypotheses to explain the differences in SARS-CoV-2 infection by ABO type. For example, anti-A and/or anti-B antibodies (e.g. present in group O individuals) could bind to corresponding antigens on the viral envelope and contribute to viral neutralization, thereby preventing target cell infection. The SARS-CoV-2 virus and SARS-CoV spike (S) proteins may be bound by anti-A isoagglutinins (e.g. present in group O and group B individuals), which may block interactions between virus and angiotensin-converting-enzyme-2-receptor, thereby preventing entry into lung epithelial cells. ABO type-associated variations in angiotensin-converting enzyme-1 activity and levels of von Willebrand factor (VWF) and factor VIII could also influence adverse outcomes, notably in group A individuals who express high VWF levels. In conclusion, group O may be associated with a lower risk of SARS-CoV-2 infection and group A may be associated with a higher risk of SARS-CoV-2 infection along with severe disease. However, prospective and mechanistic studies are needed to verify several of the proposed associations. Based on the strength of available studies, there are insufficient data for guiding policy in this regard.

Understanding the role of therapeutic plasma exchange in COVID-19: preliminary guidance and practices.

BACKGROUND AND OBJECTIVES: Cytokine release syndrome in COVID-19 is due to a pathological inflammatory response of raised cytokines. Removal of these cytokines by therapeutic plasma exchange (TPE) prior to end-organ damage may improve clinical outcomes. This manuscript is intended to serve as a preliminary guidance document for application of TPE in patients with severe COVID-19. MATERIAL AND METHODS: The available literature pertaining to the role of TPE for treatment of COVID-19 patients was reviewed to guide optimal management. It included indication, contraindication, optimal timing of initiation and termination of TPE, vascular access and anticoagulants, numbers and mode of procedures, outcome measures and adverse events. RESULTS: Out of a total of 78 articles, only 65 were directly related to the topic. From these 65, only 32 were acceptable as primary source, while 33 were used as supporting references. TPE in critically ill COVID-19 patients may be classified under ASFA category III grade 2B. The early initiation of TPE for 1-1·5 patient's plasma volume with fresh frozen plasma, or 4-5% albumin or COVID-19 convalescent plasma as replacement fluids before multiorgan failure, has better chances of recovery. The number of procedures can vary from three to nine depending on patient response. CONCLUSION: TPE in COVID-19 patients may help by removing toxic cytokines, viral particles and/or by correcting coagulopathy or restoring endothelial membrane. Severity score (SOFA & APACHE II) and cytokine levels (IL-6, C-reactive protein) can be used to execute TPE therapy and to monitor response in COVID-19 patients.

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are being investigated as potential therapies for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of these interventions is required.  OBJECTIVES: Using a living systematic review approach, to assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19; and to maintain the currency of the evidence. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform, and trial registries. Searches were done on 17 March 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating convalescent plasma or hyperimmune immunoglobulin for COVID-19, irrespective of disease severity, age, gender or ethnicity. For safety assessments, we also included non-controlled non-randomised studies of interventions (NRSIs) if 500 or more participants were included. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of Bias 2' tool for RCTs, and for NRSIs, the assessment criteria for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), development of severe clinical COVID-19 symptoms (for individuals with asymptomatic or mild disease), quality of life (including fatigue and functional independence), grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS: We included 13 studies (12 RCTs, 1 NRSI) with 48,509 participants, of whom 41,880 received convalescent plasma. We did not identify any completed studies evaluating hyperimmune immunoglobulin. We identified a further 100 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, and 33 studies reporting as being completed or terminated. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease Eleven RCTs and one NRSI investigated the use of convalescent plasma for 48,349 participants with moderate to severe disease. Nine RCTs compared convalescent plasma to placebo treatment or standard care alone, and two compared convalescent plasma to standard plasma (results not included in abstract). Effectiveness of convalescent plasma We included data on nine RCTs (12,875 participants) to assess the effectiveness of convalescent plasma compared to placebo or standard care alone.  Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.05; 7 RCTs, 12,646 participants; high-certainty evidence). It has little to no impact on clinical improvement for all participants when assessed by liberation from respiratory support (RR not estimable; 8 RCTs, 12,682 participants; high-certainty evidence). It has little to no impact on the chance of being weaned or liberated from invasive mechanical ventilation for the subgroup of participants requiring invasive mechanical ventilation at baseline (RR 1.04, 95% CI 0.57 to 1.93; 2 RCTs, 630 participants; low-certainty evidence). It does not reduce the need for invasive mechanical ventilation (RR 0.98, 95% CI 0.89 to 1.08; 4 RCTs, 11,765 participants; high-certainty evidence). We did not identify any subgroup differences.  We did not identify any studies reporting quality of life, and therefore, do not know whether convalescent plasma has any impact on quality of life. One RCT assessed resolution of fatigue on day 7, but we are very uncertain about the effect (RR 1.21, 95% CI 1.02 to 1.42; 309 participants; very low-certainty evidence).  Safety of convalescent plasma We included results from eight RCTs, and one NRSI, to assess the safety of convalescent plasma. Some of the RCTs reported on safety data only for the convalescent plasma group.  We are uncertain whether convalescent plasma increases or reduces the risk of grade 3 and 4 adverse events (RR 0.90, 95% CI 0.58 to 1.41; 4 RCTs, 905 participants; low-certainty evidence), and serious adverse events (RR 1.24, 95% CI 0.81 to 1.90; 2 RCTs, 414 participants; low-certainty evidence).  A summary of reported events of the NRSI (reporting safety data for 20,000 of 35,322 transfused participants), and four RCTs reporting safety data only for transfused participants (6125 participants) are included in the full text. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and asymptomatic or mild disease We identified one RCT reporting on 160 participants, comparing convalescent plasma to placebo treatment (saline).  Effectiveness of convalescent plasma We are very uncertain about the effect of convalescent plasma on all-cause mortality (RR 0.50, 95% CI 0.09 to 2.65; very low-certainty evidence). We are uncertain about the effect of convalescent plasma on developing severe clinical COVID-19 symptoms (RR not estimable; low-certainty evidence).  We identified no study reporting quality of life.  Safety of convalescent plasma We do not know whether convalescent plasma is associated with a higher risk of grade 3 or 4 adverse events (very low-certainty evidence), or serious adverse events (very low-certainty evidence). This is a living systematic review. We search weekly for new evidence and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. AUTHORS' CONCLUSIONS: We have high certainty in the evidence that convalescent plasma for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement. We are uncertain about the adverse effects of convalescent plasma. While major efforts to conduct research on COVID-19 are being made, heterogeneous reporting of outcomes is still problematic. There are 100 ongoing studies and 33 studies reporting in a study registry as being completed or terminated. Publication of ongoing studies might resolve some of the uncertainties around hyperimmune immunoglobulin therapy for people with any disease severity, and convalescent plasma therapy for people with asymptomatic or mild disease.

Clinical use of Convalescent Plasma in the COVID-19 pandemic: a transfusion-focussed gap analysis with recommendations for future research priorities.

BACKGROUND AND OBJECTIVES: Use of convalescent plasma for coronavirus disease 2019 (COVID-19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID-19 convalescent plasma (CCP). MATERIALS AND METHODS: The International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature. RESULTS: Gaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long-term outcome, adverse events and CCP application in less-resourced countries as well as in paediatrics and neonates. CONCLUSION: This paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.