Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from "higher-risk" units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. "Higher-risk" CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with "lower-risk" units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex-activated coagulopathy.

The Association for the Advancement of Blood and Biotherapies guidelines recommend the use of high-titer COVID-19 convalescent plasma (CCP) for patients with SARS-CoV-2 at high risk of disease progression, including those who are immunocompromised. We hypothesized that conventional plasma units have comparable neutralizing antibody levels to CCP.

Conventional plasma and CCP units were obtained from blood suppliers. Quantitatively measured antibodies to SARS-CoV-2 were assessed using the MesoScale Discovery multiplex electrochemiluminescence immunoassay. Binding antibody distributions were compared with Wilcoxon rank-sum tests. SARS-CoV-2 neutralizing antibodies were analyzed using the GeneScript ELISA-based neutralization assay. The proportion of conventional and CCP units with a percent signal inhibition of ≥80% (as defined by the United States Food and Drug Administration for CCP in 2021) and exact binomial confidence intervals (CIs) were calculated.

Among 218 conventional plasma units and 74 CCP units collected between September 2023 and July 2024, the distribution of total antibody binding levels largely overlapped between conventional plasma and CCP, though statistically significant differences in median nucleocapsid and spike Omicron variant concentrations were observed. Median percent signal neutralization was 97.5% (range 3.4%-98.6%) among conventional plasma units and 97.7% (range 95.4%-98.6%) among CCP units. For conventional plasma, 95.0% (95% CI = 91.2%-97.5%) met the neutralization antibody threshold for high-titer CCP. For CCP, 100% (95% CI = 95.1%-100.0%) met the neutralization threshold for high-titer CCP.

Conventional plasma units demonstrate similar median antibody concentration to CCP units. In countries or regions where licensed CCP is unavailable and titers are unknown, transfusion of multiple conventional plasma units may be of clinical utility.

Despite concerns about potential side effects, based both on historical experience with plasma products and more recent concerns about contemporary use of plasma, COVID-19 convalescent plasma has been shown to be a very safe product. Research early in the COVID-19 pandemic documented-among the very large population of convalescent plasma recipients in the US Convalescent Plasma Study component of the FDA-authorized Expanded Access Program-that the overall risk profile was no different than that seen for fresh frozen plasma, a product used routinely in medical practice. The safety of CCP was further demonstrated using real-world evidence, pragmatic trials, and formal randomized trials. The rates of all serious adverse events were very low, an especially impressive finding in light of the fact that nearly all safety data came from the use of COVID-19 convalescent plasma in patients who were hospitalized, were older, and/or had significant co-morbid cardiopulmonary and metabolic disorders. The well-known complications of blood and plasma transfusions-transfusion-associated circulatory overload and transfusion-related acute lung injury-were found with no higher incidence than with standard use of blood and plasma, nor was there evidence for antibody-dependent enhancement or increased incidence of thromboembolic events. The comprehensive safety profile derived from studies enrolling hundreds of thousands of recipients of COVID-19 convalescent plasma across the world should allay safety fears about the rapid deployment of convalescent plasma in future pandemics.

Sepsis, characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection, remains a significant challenge in clinical practice. Despite advancements in understanding host-bacterial interactions, molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standard evaluations typically exclude viral panels. Moreover, these viruses not only activate conventional pattern recognition receptors (PRRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) but also initiate primary antiviral pathways such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling and interferon response mechanisms. Such activations lead to cellular stress, metabolic disturbances, and extensive cell damage that exacerbate tissue injury while leading to a spectrum of clinical manifestations. This complexity poses substantial challenges for the clinical management of affected cases. In this review, we elucidate the definition and diagnosis criteria for viral sepsis while synthesizing current knowledge regarding its etiology, epidemiology, and pathophysiology, molecular mechanisms involved therein as well as their impact on immune-mediated organ damage. Additionally, we discuss clinical considerations related to both existing therapies and advanced treatment interventions, aiming to enhance the comprehensive understanding surrounding viral sepsis.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies.

When Coronavirus Disease-19 (COVID-19) struck the world in December 2019, initiatives started to investigate the efficacy of convalescent plasma, a readily available source of passive antibodies, collected from recovered patients as a therapeutic option. This was based on historical observational data from previous virus outbreaks.

A scoping review was conducted on the efficacy and safety of convalescent plasma and hyperimmune immunoglobulins for COVID-19 treatment. This review included the latest Cochrane systematic review update on 30-day mortality and safety. We also covered use in pediatric and immunocompromised patients, as well as the logistic challenges faced in donor recruitment and plasma collection in general. Challenges for low resource countries were specifically highlighted.

A major challenge is the high donation frequency required from first-time donors to ensure a safe product, which minimizes the risk of transfusion-transmitted infectious. This is particularly difficult in low- and middle- income countries due to inadequate infrastructure and insufficient blood product supplies. High-certainty evidence indicates that convalescent plasma does not reduce mortality or significantly improve clinical outcomes in patients with moderate to severe COVID-19 infection. However, CCP may provide a viable treatment for patients unable to mount an endogenous immune response to SARS-CoV-2, based on mostly observational studies and subgroup data of published and ongoing randomized trials. Convalescent plasma has been shown to be safe in adults and children with COVID-19 infection. However, the efficacy in pediatric patients remains unclear.

Data on efficacy and safety of CCP are still underway in ongoing (randomized) studies and by reporting the challenges, limitations and successes encountered to-date, research gaps were identified to be addressed for the future.

This experience serves as a valuable example for future pandemic preparedness, particularly when therapeutic options are limited, and vaccines are either being developed or ineffective due to underlying immunosuppression.

Antiviral passive antibody therapy includes convalescent plasma, hyperimmune globulin, and monoclonal antibodies. Passive antibodies have proven effective in reducing morbidity and mortality for SARS-CoV-2 and other infectious diseases when given early in the disease course with sufficiently high specific total and neutralizing antibody levels. Convalescent plasma can be delivered to patients before vaccination implementation or novel drug production. Carefully designed and executed randomized controlled trials near the pandemic outset are important for regulatory bodies, healthcare workers, guideline committees, the public, and the government. Unfortunately, many otherwise well-designed antibody-based clinical trials in COVID-19 were futile, either because they intervened too late in the disease or provided plasma with insufficient antibodies. The need for early treatment mandates outpatient clinical trials in parallel with inpatient trials. Early outpatient COVID-19 convalescent plasma transfusion with high antibody content within 9 days of symptom onset has proven effective in blunting disease progression and reducing hospitalization, thus reducing hospital overcrowding in a pandemic. Convalescent plasma offers the opportunity for hope by enabling community participation in outpatient curative therapy while monoclonal therapies, vaccines, and drugs are being developed. Maintaining the appropriate infrastructure for antibody infusion in both outpatient and inpatient facilities is critical for future pandemic readiness.

Donor-recipient proximity emerged as an important factor influencing the efficacy of COVID-19 convalescent plasma (CCP) treatment during the early stages of the COVID-19 pandemic. This relationship was uncovered while analyzing data collected in the collaborative Expanded Access Program (EAP) for CCP at Mayo Clinic, a project aimed to establish protocols for CCP use amid the uncertainty of the novel disease. Analysis of data from nearly 28,000 patients revealed a significant reduction in risk of 30-day mortality for those receiving near-sourced plasma when compared to those receiving distantly sourced plasma [pooled relative risk, 0.73 (95% CI 0.67-0.80)], prompting adjustments in treatment protocols at selected institutions, and highlighting the importance of proximity in optimizing CCP outcomes. Despite its significance, subsequent studies of CCP effectiveness in COVID-19 have often overlooked donor-recipient proximity. Our findings emphasize the importance of donor-recipient proximity in CCP treatment in the current pandemic, and we discuss potential methods for improving CCP efficacy in future pandemics. Our recommendations include prioritizing virus genotyping for vulnerable patients, establishing a robust testing infrastructure, and collecting additional donor data to enhance plasma selection. This chapter underscores the importance of comprehensive data collection and sharing to navigate the evolving landscape of newly emerging infectious diseases.

There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19), with rapidly changing efficacy and safety evidence from trials. The objective was to develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19. In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Based on the most recent search conducted on 31 May 2022, the IDSA guideline panel has made 32 recommendations for the treatment and management of the following groups/populations: pre- and postexposure prophylaxis, ambulatory with mild-to-moderate disease, and hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at: https://idsociety.org/COVID19guidelines. At the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials. Since then, many trials were conducted that provided much-needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved, which we hope future trials can answer.

Between early April 2020 and late August 2020, nearly 100,000 patients hospitalized with SARS-CoV2 infections were treated with COVID-19 convalescent plasma (CCP) in the US under the auspices of an FDA-authorized Expanded Access Program (EAP) housed at the Mayo Clinic. Clinicians wishing to provide CCP to their patients during that 5-month period early in the COVID pandemic had to register their patients and provide clinical information to the EAP program. This program was utilized by some 2,200 US hospitals located in every state ranging from academic medical centers to small rural hospitals and facilitated the treatment of an ethnically and socio-economically diverse cross section of patients. Within 6 weeks of program initiation, the first signals of safety were found in 5,000 recipients of CCP, supported by a later analysis of 20,000 recipients (Joyner et al. in J Clin Invest 130:4791-4797, 2020a; Joyner et al. in Mayo Clin Proc 95:1888-1897, 2020b). By mid-summer of 2020, strong evidence was produced showing that high-titer CCP given early in the course of hospitalization could lower mortality by as much as a third (Joyner et al. in N Engl J Med 384:1015-1027, 2021; Senefeld et al. in PLoS Med 18, 2021a). These data were used by the FDA in its August decision to grant Emergency Use Authorization for CCP use in hospitals. This chapter provides a personal narrative by the principal investigator of the EAP that describes the events leading up to the program, some of its key outcomes, and some lessons learned that may be applicable to the next pandemic. This vast effort was a complete team response to a crisis and included an exceptional level of collaboration both inside and outside of the Mayo Clinic. Writing just 4 years after the initiation of the EAP, this intense professional effort, comprising many moving parts, remains hard to completely understand or fully explain in this brief narrative. As Nelson Mandela said of the perception of time during his decades in prison, "the days seemed like years, and the years seemed like days."

Convalescent plasma (CP) emerged as potential treatment for COVID-19 early in the pandemic. While efficacy in hospitalised patients has been lacklustre, CP may be beneficial at the first stages of disease. Despite multiple new variants emerging, no trials have involved analyses on variant-specific antibody titres of CP.

We recruited hospitalised COVID-19 patients within 10 days of symptom onset and, employing a double-blinded approach, randomised them to receive 200 ml convalescent plasma with high (HCP) or low (LCP) neutralising antibody (NAb) titre against the ancestral strain (Wuhan-like variant) or placebo in 1:1:1 ratio. Primary endpoints comprised intubation, corticosteroids for symptom aggravation, and safety assessed as serious adverse events. For a preplanned ad hoc analysis, the patients were regrouped by infused CP's NAb titers to variants infecting the recipients i.e. by titres of homologous HCP (hHCP) or LCP (hLCP).

Of the 57 patients, 18 received HCP, 19 LCP and 20 placebo, all groups smaller than planned. No significant differences were found for primary endpoints. In ad hoc analysis, hHCPrecipients needed significantly less respiratory support, and appeared to be given corticosteroids less frequently (1/14; 7.1%) than those receiving hLCP (9/23; 39.1%) or placebo (8/20; 40%), (p = 0.077).

Our double-blinded, placebo-controlled CP therapy trial remained underpowered and does not allow any firm conclusions for early-stage hospitalised COVID-19 patients. Interestingly, however, regrouping by homologous - recipients' variant-specific - CP titres suggested benefits for hHCP. We encourage similar re-analysis of ongoing/previous larger CP studies.

ClinTrials.gov identifier: NCT0473040.

Coronavirus disease 2019 (COVID-19) is still causing hospitalization and death, and vaccination appears to become less effective with each emerging variant. Spike, non-spike, and other possible unrecognized mutations have reduced the efficacy of recommended therapeutic approaches, including monoclonal antibodies, plasma transfusion, and antivirals. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) and probably dipeptidyl peptidase 4 (DPP-4) to initiate the process of endocytosis by employing host proteases such as transmembrane serine protease-2 (TMPRSS-2) and ADAM metallopeptidase domain 17 (ADAM17). Spironolactone reduces the amount of soluble ACE2 and antagonizes TMPRSS-2 and ADAM17. DPP-4 inhibitors play immunomodulatory roles and may block viral entry. The efficacy of treatment with a combination of spironolactone and DPP-4 inhibitors does not appear to be affected by viral mutations. Therefore, the combination of spironolactone and DPP-4 inhibitors might improve the clinical outcome for COVID-19 patients by decreasing the efficiency of SARS-CoV-2 entry into cells and providing better anti-inflammatory, antiproliferative, and antifibrotic effects than those achieved using current therapeutic approaches such as antivirals and monoclonal antibodies.

This study aims to assess the safety, virological, and clinical outcomes of convalescent plasma transfusion (CPT) in immunocompromised patients hospitalized for coronavirus disease 2019 (COVID-19). We conducted a retrospective multicenter cohort study that included all immunosuppressed patients with COVID-19 and RNAemia from May 2020 to March 2023 treated with CPT. We included 81 patients with hematological malignancies (HM), transplants, or autoimmune diseases (69% treated with anti-CD20). Sixty patients (74%) were vaccinated, and 14 had pre-CPT serology >264 BAU/mL. The median delay between symptom onset and CPT was 23 days [13-31]. At D7 post-CPT, plasma PCR was negative in 43/64 patients (67.2%), and serology became positive in 25/30 patients (82%). Post-CPT positive serology was associated with RNAemia negativity (p < 0.001). The overall mortality rate at D28 was 26%, being higher in patients with non-B-cell HM (62%) than with B-cell HM (25%) or with no HM (11%) (p = 0.02). Patients receiving anti-CD20 without chemotherapy had the lowest mortality rate (8%). Positive RNAemia at D7 was associated with mortality at D28 in univariate analysis (HR: 3.05 [1.14-8.19]). Eight patients had adverse events, two of which were severe but transient. Our findings suggest that CPT can abolish RNAemia and ameliorate the clinical course in immunocompromised patients with COVID-19.

The COVID-19 pandemic has resulted in many therapies, of which many are repurposed and used for other diseases in the last decade such in Influenza and Ebola. We intend to provide a robust foundation for cardiovascular outcomes of the therapies to better understand the rationale for the clinical trials that were conducted during the COVID-19 pandemic, and to gain more clarity on the steps moving forward should the repurposing provide clinical benefit in pandemic situations. With this state-of-the-art review, we aim to improve the understanding of the cardiovascular involvement of the therapies prior to, during, and after the COVID-19 pandemic to provide meaningful findings to the cardiovascular specialists and clinical trials for therapies, moving on from the period of pandemic urgency.

To update the recommendations to support decisions regarding the pharmacological treatment of patients hospitalized with COVID-19 in Brazil.

Experts, including representatives of the Ministry of Health and methodologists, created this guideline. The method used for the rapid development of guidelines was based on the adoption and/or adaptation of existing international guidelines (GRADE ADOLOPMENT) and supported by the e-COVID-19 RecMap platform. The quality of the evidence and the preparation of the recommendations followed the GRADE method.

Twenty-one recommendations were generated, including strong recommendations for the use of corticosteroids in patients using supplemental oxygen and conditional recommendations for the use of tocilizumab and baricitinib for patients on supplemental oxygen or on noninvasive ventilation and anticoagulants to prevent thromboembolism. Due to suspension of use authorization, it was not possible to make recommendations regarding the use of casirivimab + imdevimab. Strong recommendations against the use of azithromycin in patients without suspected bacterial infection, hydroxychloroquine, convalescent plasma, colchicine, and lopinavir + ritonavir and conditional recommendations against the use of ivermectin and remdesivir were made.

New recommendations for the treatment of hospitalized patients with COVID-19 were generated, such as those for tocilizumab and baricitinib. Corticosteroids and prophylaxis for thromboembolism are still recommended, the latter with conditional recommendation. Several drugs were considered ineffective and should not be used to provide the best treatment according to the principles of evidence-based medicine and to promote resource economy.

This pivotal study reveals that high neutralizing titer COVID-19 convalescent plasma therapy (CPT) combined with favipiravir (FPV) is non-inferior to sotrovimab in preventing hospitalization and severe outcomes in outpatients with mild-to-moderate COVID-19 and high-risk comorbidities. It underscores the potential of CPT-FPV as a viable alternative to neutralizing monoclonal antibodies like sotrovimab, especially amid emerging variants with spike protein mutations. The study's unique approach, comparing a monoclonal antibody with CPT, demonstrates the efficacy of early intervention using high neutralizing antibody titer CPT, even in populations with a significant proportion of elderly patients. These findings are crucial, considering the alternative treatment challenges, especially in resource-limited countries, posed by the rapidly mutating SARS-CoV-2 virus and the need for adaptable therapeutic strategies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is capable of large-scale transmission and has caused the coronavirus disease 2019 (COVID-19) pandemic. Patients with COVID-19 may experience persistent long-term health issues, known as long COVID. Both acute SARS-CoV-2 infection and long COVID have resulted in persistent negative impacts on global public health. The effective application and development of blood-derived products are important strategies to combat the serious damage caused by COVID-19. Since the emergence of COVID-19, various blood-derived products that target or do not target SARS-CoV-2 have been investigated for therapeutic applications. SARS-CoV-2-targeting blood-derived products, including COVID-19 convalescent plasma, COVID-19 hyperimmune globulin, and recombinant anti-SARS-CoV-2 neutralizing immunoglobulin G, are virus-targeting and can provide immediate control of viral infection in the short term. Non-SARS-CoV-2-targeting blood-derived products, including intravenous immunoglobulin and human serum albumin exhibit anti-inflammatory, immunomodulatory, antioxidant, and anticoagulatory properties. Rational use of these products can be beneficial to patients with SARS-CoV-2 infection or long COVID. With evidence accumulated since the pandemic began, we here summarize the progress of blood-derived product therapies for COVID-19, discuss the effective methods and scenarios regarding these therapies, and provide guidance and suggestions for clinical treatment.

Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7-9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome Coronavirus 2 and its variants of concern (VOCs) has been ongoing for over 3 years. Antibody therapies encompassing convalescent plasma, hyperimmunoglobulin, and neutralizing monoclonal antibodies (mAbs) applied in passive immunotherapy have yielded positive outcomes and played a crucial role in the early COVID-19 treatment. In this review, the development path, action mechanism, clinical research results, challenges, and safety profile associated with the use of COVID-19 convalescent plasma, hyperimmunoglobulin, and mAbs were summarized. In addition, the prospects of applying antibody therapy against VOCs was assessed, offering insights into the coping strategies for facing new infectious disease outbreaks.

Convalescent plasma (CP) became a prominent treatment in the early stages of the SARS-CoV-2 pandemic. In Argentina, a randomized clinical trial was executed to compare the use of CP in inpatients with severe COVID-19 pneumonia versus placebo. No differences in clinical outcomes or overall mortality between groups were observed. We conducted a cohort study in outpatients enrolled in the trial to describe long-term antibody titer variations between CP and placebo recipients.

Patients' total SARS-CoV-2 IgG antibodies against spike protein were collected 3, 6 and 12 months after hospital discharge from August 2020 to December 2021. In addition, reinfections, deaths and vaccination status were retrieved. Statistical analysis was performed using antibody geometric mean titers (GMT). All estimations were made considering the date of the trial infusion (placebo or CP) as time 0.

From the 93 patients included in the follow-up, 64 had received CP and 29 placebo. We excluded all 12-month measurements because they were collected after the patients' vaccination date. At 90 days post-infusion, patients had an antibody GMT of 8.1 (IQR 7.4-8.1) in the CP group and 8.8 (IQR 8.1-9.1) in the placebo group. At 180 days, both groups had a GMT of 8.1 (IQR 7.4-8.1). No statistical differences in GMT were found between CP and placebo groups at 90 days (p = 0.12) and 180 days (p = 0.25). No patients registered a new COVID-19 infection; one died in the CP group from an ischemic stroke.

No differences were observed in long-term antibody titers in unvaccinated patients that received CP or placebo after severe COVID-19 pneumonia.

As part of the non-clinical safety package characterizing bamlanivimab (SARS-CoV-2 neutralizing monoclonal antibody), the risk profile for antibody-dependent enhancement of infection (ADE) was evaluated in vitro and in an African green monkey (AGM) model of COVID-19. In vitro ADE assays in primary human macrophage, Raji, or THP-1 cells were used to evaluate enhancement of viral infection. Bamlanivimab binding to C1q, FcR, and cell-based effector activity was also assessed. In AGMs, the impact of bamlanivimab pretreatment on viral loads and clinical and histological pathology was assessed to evaluate enhanced SARS-CoV-2 replication or pathology. Bamlanivimab did not increase viral replication in vitro, despite a demonstrated effector function. In vivo, no significant differences were found among the AGM groups for weight, temperature, or food intake. Treatment with bamlanivimab reduced viral loads in nasal and oral swabs and BAL fluid relative to control groups. Viral antigen was not detected in lung tissue from animals treated with the highest dose of bamlanivimab. Bamlanivimab did not induce ADE of SARS-CoV-2 infection in vitro or in an AGM model of infection at any dose evaluated. The findings suggest that high-affinity monoclonal antibodies pose a low risk of mediating ADE in patients and support their safety profile as a treatment of COVID-19 disease.

The coronavirus disease (COVID)-19 has turned into a pandemic causing a global public health crisis. While acute COVID-19 mainly affects the respiratory system and can cause acute respiratory distress syndrome, an association with persistent inflammatory stress affecting different organ systems has been elucidated in long COVID syndrome (LCS). Increased severity and mortality rates have been reported due to cardiophysiological and metabolic systemic disorders as well as multiorgan failure in COVID-19, additionally accompanied by chronic dyspnea and fatigue in LCS. Hence, novel therapies have been tested to improve the outcomes of LCS of which one potential candidate might be sodium-glucose cotransporter 2 (SGLT2) inhibitors. The aim of this narrative review was to discuss rationales for investigating SGLT2 inhibitor therapy in people suffering from LCS. In this regard, we discuss their potential positive effects-next to the well described "cardio-renal-metabolic" conditions-with a focus on potential anti-inflammatory and beneficial systemic effects in LCS. However, potential beneficial as well as potential disadvantageous effects of SGLT2 inhibitors on the prevalence and long-term outcomes of COVID-19 will need to be established in ongoing research.

Convalescent plasma therapy, which involves administering plasma from recovered coronavirus disease 2019 (COVID-19) patients to infected individuals, is being explored as a potential treatment for severe cases of COVID-19. This study aims to evaluate the efficacy and safety of convalescent plasma therapy in COVID-19 patients with moderate to severe illness. An open-label, single-arm intervention study was conducted without a control group. Plasma collected from recovered COVID-19 patients was administered to eligible participants. The primary endpoint was the proportion of patients who were placed on artificial ventilation or died within 14 days of transfusion. Secondary endpoints included clinical improvement, viral load measurements, and adverse event monitoring. A total of 59 cases were included in the study. The primary endpoint was evaluated by comparing the rate obtained in the study to an existing rate of 25%. The study also assessed clinical improvement, viral load changes, and safety endpoints through adverse event monitoring. Convalescent plasma therapy shows potential as a treatment option for COVID-19. This study aimed to provide evidence for the efficacy and safety of this therapy and may contribute to its future use in treating severe cases of COVID-19.

Passive immunization with plasma collected from convalescent patients has been regularly used to treat coronavirus disease 2019 (Covid-19). Minimal data are available regarding the use of convalescent plasma in patients with Covid-19-induced acute respiratory distress syndrome (ARDS).

In this open-label trial, we randomly assigned adult patients with Covid-19-induced ARDS who had been receiving invasive mechanical ventilation for less than 5 days in a 1:1 ratio to receive either convalescent plasma with a neutralizing antibody titer of at least 1:320 or standard care alone. Randomization was stratified according to the time from tracheal intubation to inclusion. The primary outcome was death by day 28.

A total of 475 patients underwent randomization from September 2020 through March 2022. Overall, 237 patients were assigned to receive convalescent plasma and 238 to receive standard care. Owing to a shortage of convalescent plasma, a neutralizing antibody titer of 1:160 was administered to 17.7% of the patients in the convalescent-plasma group. Glucocorticoids were administered to 466 patients (98.1%). At day 28, mortality was 35.4% in the convalescent-plasma group and 45.0% in the standard-care group (P = 0.03). In a prespecified analysis, this effect was observed mainly in patients who underwent randomization 48 hours or less after the initiation of invasive mechanical ventilation. Serious adverse events did not differ substantially between the two groups.

The administration of plasma collected from convalescent donors with a neutralizing antibody titer of at least 1:160 to patients with Covid-19-induced ARDS within 5 days after the initiation of invasive mechanical ventilation significantly reduced mortality at day 28. This effect was mainly observed in patients who underwent randomization 48 hours or less after ventilation initiation. (Funded by the Belgian Health Care Knowledge Center; ClinicalTrials.gov number, NCT04558476.).

Boarding of critically ill patients in the emergency department (ED) has long been known to compromise patient care and affect outcomes. During the COVID-19 pandemic, multiple hospitals worldwide experienced overcrowded emergency rooms. Large influx of patients outnumbered hospital beds and required prolonged length of stay (LOS) in the ED. Our aim was to assess the ED LOS effect on mortality and morbidity, in addition to the predictors of in-hospital mortality, intubation, and complications of critically ill COVID-19 ED boarder patients.

This was a retrospective cohort study, investigating 145 COVID-19-positive adult patients who were critically ill, required intensive care unit (ICU), and boarded in the ED of a tertiary care center in Lebanon. Data on patients who boarded in the emergency from January 1, 2020, till January 31, 2021, was gathered and studied.

Overall, 66% of patients died, 60% required intubation, and 88% developed complications. Multiple risk factors were associated with mortality naming age above 65 years, vasopressor use, severe COVID pneumonia findings on CT chest, chemotherapy treatment in the previous year, cardiovascular diseases, chronic kidney diseases, prolonged ED LOS, and low SaO2 < 95% on triage. In addition, our study showed that staying long hours in the ED increased the risk of developing complications.

To conclude, all efforts need to be drawn to re-establish mitigation strategies and models of critical care delivery in the ED to alleviate the burden of critical boarders during pandemics, thus decreasing morbidity and mortality rates. Lessons from this pandemic should raise concern for complications seen in ED ICU boarders and allow the promotion of health measures optimizing resource allocation in future pandemic crises.

COVID-19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to enormous morbidity and mortality worldwide. After gaining entry into the human host, the virus initially infects the upper and lower respiratory tract, subsequently invading multiple organs, including the pancreas. While on one hand, diabetes mellitus (DM) is a significant risk factor for severe COVID-19 infection and associated death, recent reports have shown the onset of DM in COVID-19-recovered patients. SARS-CoV-2 infiltrates the pancreatic islets and activates stress response and inflammatory signaling pathways, impairs glucose metabolism, and consequently leads to their death. Indeed, the pancreatic autopsy samples of COVID-19 patients reveal the presence of SARS-CoV-2 particles in β-cells. The current review describes how the virus enters the host cells and activates an immunological response. Further, it takes a closer look into the interrelationship between COVID-19 and DM with the aim to provide mechanistic insights into the process by which SARS-CoV-2 infects the pancreas and mediates dysfunction and death of endocrine islets. The effects of known anti-diabetic interventions for COVID-19 management are also discussed. The application of mesenchymal stem cells (MSCs) as a future therapy for pancreatic β-cells damage to reverse COVID-19-induced DM is also emphasized.

Antibody-dependent enhancement (ADE) is a phenomenon where virus-specific antibodies paradoxically cause enhanced viral replication and/or excessive immune responses, leading to infection exacerbation, tissue damage, and multiple organ failure. ADE has been observed in many viral infections and is supposed to complicate the course of COVID-19. However, the evidence is insufficient. Since no specific laboratory markers have been described, the prediction and confirmation of ADE are very challenging. The only possible predictor is the presence of already existing (after previous infection) antibodies that can bind to viral epitopes and promote the disease enhancement. At the same time, the virus-specific antibodies are also a part of immune response against a pathogen. These opposite effects of antibodies make ADE research controversial. The assignment of immunoglobulins to ADE-associated or virus neutralizing is based on their affinity, avidity, and content in blood. However, these criteria are not clearly defined. Another debatable issue (rather terminological, but no less important) is that in most publications about ADE, all immunoglobulins produced by the immune system against pathogens are qualified as pre-existing antibodies, thus ignoring the conventional use of this term for natural antibodies produced without any stimulation by pathogens. Anti-glycan antibodies (AGA) make up a significant part of the natural immunoglobulins pool, and there is some evidence of their antiviral effect, particularly in COVID-19. AGA have been shown to be involved in ADE in bacterial infections, but their role in the development of ADE in viral infections has not been studied. This review focuses on pros and cons for AGA as an ADE trigger. We also present the results of our pilot studies, suggesting that AGAs, which bind to complex epitopes (glycan plus something else in tight proximity), may be involved in the development of the ADE phenomenon.

Since December 2019, many drugs have been evaluated or advocated as potential treatments of SARS-CoV-2 induced disease (COVID-19), including many repositioned drugs and some others specifically developed for these diseases. They can be roughly classified into three categories according to their main mechanism of action (passive immunization, direct antivirals, and anti-inflammatory treatments), and their use depends on the stage of the disease. Despite often promising preclinical data, most of the treatments evaluated failed to show a significant clinical benefit. In addition, a few others have seen their effectiveness affected by the occurrence of SARS-CoV-2 variants and sub-variants. Herein, the aim of this article is to take stock of the data available as of the 14th of July 2022, concerning the specific healing options evaluated for patients suffering from COVID-19. We focus particularly on healing treatments of COVID-19 and do not deal with preventive treatments such as vaccine. Associated therapies such as venous thromboembolism prophylaxis are not detailed since they are covered in a specific chapter of this issue. Passive immunization, especially through monoclonal antibodies, showed a positive impact on the clinical evolution, whether in outpatients or inpatients without oxygen supply. However, their effectiveness strongly depends on the type of SARS-CoV-2 variant, and often decreases or even vanishes with the most recent variants. Among direct antiviral treatments, ritonavir-boosted nirmatrelvir appears to currently be the cornerstone in the management of early infections, but its use may be limited by drug interactions. Remdesivir remains as an alternative in this situation, even though it is potentially less convenient. Anti-inflammatory treatments have often been shown to be the most effective in inpatients with oxygen supply. Dexamethasone is now a cornerstone of management of these patients. Added tocilizumab seems beneficial in the case of hyper inflammation. JAK inhibitors and anakinra have also gained an interest in some studies. As a conclusion of this narrative review, the best treatment strategy has yet to be defined and is likely to evolve in the future, not only because many other drugs are still under development and evaluation, but also because of the viral epidemics and epidemiology evolution.

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.

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.

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.

In this article, we highlight the contributions of passive experiments that address important exercise-related questions in integrative physiology and medicine. Passive experiments differ from active experiments in that passive experiments involve limited or no active intervention to generate observations and test hypotheses. Experiments of nature and natural experiments are two types of passive experiments. Experiments of nature include research participants with rare genetic or acquired conditions that facilitate exploration of specific physiological mechanisms. In this way, experiments of nature are parallel to classical "knockout" animal models among human research participants. Natural experiments are gleaned from data sets that allow population-based questions to be addressed. An advantage of both types of passive experiments is that more extreme and/or prolonged exposures to physiological and behavioral stimuli are possible in humans. In this article, we discuss a number of key passive experiments that have generated foundational medical knowledge or mechanistic physiological insights related to exercise. Both natural experiments and experiments of nature will be essential to generate and test hypotheses about the limits of human adaptability to stressors like exercise. © 2023 American Physiological Society. Compr Physiol 13:4879-4907, 2023.

The COVID-19 pandemic posed a significant challenge for clinicians in managing pregnant women, who were at high risk of virus transmission and severe illness. While the WHO declared in May 2023 that COVID-19 is no longer a public health emergency, it emphasized that it remains a global health threat. Despite the success of vaccines, the possibility of new pandemic waves due to viral mutations should be considered. Ongoing assessment of the safety and effectiveness of pharmacological therapies is crucial in clinical practice. This narrative review summarizes the evidence-based therapeutic strategies for pregnant women with COVID-19, considering over three years of pandemic experience. The review discusses the safety and effectiveness of various drug regimens (antivirals, anticoagulants, corticosteroids, immunoglobulins, monoclonal antibodies, and therapeutic gases) and procedures (prone positioning and extracorporeal membrane oxygenation). Drugs with contraindications, inefficacy during pregnancy, or unknown adverse effects were excluded from our evaluation. The aim is to provide healthcare professionals with a comprehensive guide for managing pregnant women with COVID-19 based on lessons learned from the pandemic outbreak.