Inhibitor eradication and treatment for acquired hemophilia A.

INTRODUCTION: Acquired hemophilia A (AHA) is a rare hemorrhagic autoimmune disorder characterized by autoantibodies against coagulation factor VIII (FVIII). In approximately half of the cases AHA does not recognize any cause (idiopathic form), while in the other cases it may be triggered by autoimmune disorders, cancers, drugs, infections, or pregnancy. Besides treating the underlying disorder, specific AHA treatment includes management of bleeding, if necessary, and inhibitor eradication. AREAS COVERED: This narrative review summarizes the main epidemiological, clinical, laboratory, and therapeutic characteristics of AHA. In particular, it is focused on the current therapeutic options for the inhibitor eradication, also showing the latest findings on the innovative therapies. A literature search strategy was performed, without temporal limits, through Medline and PubMed electronic databases. EXPERT OPINION: Various first-line and second-line immunosuppressive agents are currently available for the management of AHA. Among the latter, the anti-CD20 monoclonal antibody rituximab has been the object of intense research during the last years from investigators as innovative promising eradicating therapy for AHA. Preliminary data from the studies support the use of this drug as a first-line option for newly diagnosed AHA cases.

COVID-19 therapeutics.

SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range of therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy of those approaches often remains controversial or compromised by viral evolution. Uncertainties still persist regarding the best therapies for high-risk patients, and the drug pipeline is suffering fatigue and shortage of funding. In this article, we review the antiviral activity, mechanism of action, pharmacokinetics, and safety of COVID-19 antiviral therapies. Additionally, we summarize the evidence from randomized controlled trials on efficacy and safety of the various COVID-19 antivirals and discuss unmet needs which should be addressed.

Response to the Comment: "Advocating prudent D-dimer testing: constructive perspectives and comments on "How we manage a high D-dimer".

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Passive immunotherapies for the next influenza pandemic.

Influenzavirus is among the most relevant candidates for a next pandemic. We review here the phylogeny of former influenza pandemics, and discuss candidate lineages. After briefly reviewing the other existing antiviral options, we discuss in detail the evidences supporting the efficacy of passive immunotherapies against influenzavirus, with a focus on convalescent plasma.

An update on the anti-spike monoclonal antibody pipeline for SARS-CoV-2.

BACKGROUND: Anti-spike monoclonal antibodies represent one of the most tolerable prophylaxis and therapies for COVID-19 in frail and immunocompromised patients. Unfortunately, viral evolution in Omicron has led all of them to failure. OBJECTIVES: We review here the current pipeline of anti-spike mAb's, discussing in detail the most promising candidates. SOURCES: We scanned PubMed, ClinicalTrials.gov and manufacturers' press releases for clinical studies on anti-spike monoclonal antibodies. CONTENT: We present state-of-art data clinical progress for AstraZeneca's AZD3152, Invivyd's VYD222, Regeneron's REGN-17092 and Aerium Therapeutics' AER-800. IMPLICATIONS: The anti-spike monoclonal antibody clinical pipeline is currently limited to few agents (most being single antibodies) with unknown efficacy against the dominant JN.1 sublineage. The field of antibody-based therapies requires boosting by both manufacturers and institutions.

Safety and Efficacy of Convalescent Plasma Combined with Other Pharmaceutical Agents for Treatment of COVID-19 in Hospitalized Patients: A Systematic Review and Meta-Analysis.

Plasma collected from people recovered from COVID-19 (COVID-19 convalescent plasma, CCP) was the first antibody-based therapy employed to fight the pandemic. CCP was, however, often employed in combination with other drugs, such as the antiviral remdesivir and glucocorticoids. The possible effect of such interaction has never been investigated systematically. To assess the safety and efficacy of CCP combined with other agents for treatment of patients hospitalized for COVID-19, a systematic literature search using appropriate Medical Subject Heading (MeSH) terms was performed through PubMed, EMBASE, Cochrane central, medRxiv and bioRxiv. The main outcomes considered were mortality and safety of CCP combined with other treatments versus CCP alone. This review was carried out in accordance with Cochrane methodology including risk of bias assessment and grading of the quality of evidence. Measure of treatment effect was the risk ratio (RR) together with 95% confidence intervals (CIs). A total of 11 studies (8 randomized controlled trials [RCTs] and 3 observational) were included in the systematic review, 4 studies with CCP combined with remdesivir and 6 studies with CCP combined with corticosteroids, all involving hospitalized patients. One RCT reported information on both remdesivir and steroids use with CCP. The use of CCP combined with remdesivir was associated with a significantly reduced risk of death (RR 0.74; 95% CI 0.56-0.97; p = 0.03; moderate certainty of evidence), while the use of steroids with CCP did not modify the mortality risk (RR 0.72; 95% CI 0.34-1.51; p = 0.38; very low certainty of evidence). Not enough safety data were retrieved form the systematic literature analysis. The current evidence from the literature suggests a potential beneficial effect on mortality of combined CCP plus remdesivir compared to CCP alone in hospitalized COVID-19 patients. No significant clinical interaction was found between CCP and steroids.

Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants.

Among the anti-Spike monoclonal antibodies (mAbs), the S-309 derivative sotrovimab was the most successful in having the longest temporal window of clinical use, showing a high degree of resiliency to SARS-CoV-2 evolution interrupted only by the appearance of the BA.2.86* variant of interest (VOI). This success undoubtedly reflects rational selection to target a highly conserved epitope in coronavirus Spike proteins. We review here the efficacy of sotrovimab against different SARS-CoV-2 variants in outpatients and inpatients, discussing both randomized controlled trials and real-world evidence. Although it could not be anticipated at the time of its development and introduction, sotrovimab's use in immunocompromised individuals who harbor large populations of variant viruses created the conditions for its eventual demise, as antibody selection and viral evolution led to its eventual withdrawal due to inefficacy against later variant lineages. Despite this, based on observational and real-world data, some authorities have continued to promote the use of sotrovimab, but the lack of binding to newer variants strongly argues for the futility of continued use. The story of sotrovimab highlights the power of modern biomedical science to generate novel therapeutics while also providing a cautionary tale for the need to devise strategies to minimize the emergence of resistance to antibody-based therapeutics.

Tranexamic Acid: An Evergreen Hemostatic Agent.

Tranexamic acid (TXA) is an important antifibrinolytic agent, which inhibits plasminogen activation and fibrinolysis. Several controlled randomized trials have investigated the role of TXA in preventing or decreasing blood loss across different surgical interventions or medical conditions characterized by excessive bleeding, consistently documenting its effectiveness and safety. Although the first clinical use of TXA dates back to more than 60 years ago, TXA remains the focus of intense research. This narrative review summarizes the more recent results and indications on the clinical use of TXA.

Innovative Therapies for Acquired Hemophilia A.

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder which can be life-threatening. AHA is due to autoantibodies against coagulation factor VIII. Disease onset may be idiopathic (approximately half of the cases) or triggered by autoimmune disorders, cancers, drugs, infections, or pregnancy. Besides treating the underlying disorder, specific AHA treatments include management of bleeding and inhibitor eradication. Various first-line and second-line hemostatic and immunosuppressive agents are currently available for the management of AHA. Recently, the hemostatic drug emicizumab and the immunosuppressive drug rituximab have been the object of intense research from investigators as innovative promising therapies for AHA. This narrative review will be focused on the current status of the clinical use of these two off-label therapeutic agents in AHA.

Hyperimmune Plasma and Immunoglobulins against COVID-19: A Narrative Review.

Since late 2019, the new SARS-CoV-2 virus belonging to the Coronaviridae family has been responsible for COVID-19 pandemic, a severe acute respiratory syndrome. Several antiviral therapies, mostly derived from previous epidemics, were initially repurposed to fight this not rarely life-threatening respiratory illness. Among them, however, the only specific antibody-based therapy available against SARS-CoV-2 infection during the first year of the pandemic was represented by COVID-19 convalescent plasma (CCP). CCP, collected from recovered individuals, contains high levels of polyclonal antibodies of different subclasses able to neutralize SARS-CoV-2 infection. Tens of randomized controlled trials have been conducted during the last three years of the pandemic to evaluate the safety and the clinical efficacy of CCP in both hospitalized and ambulatory COVID-19 patients, whose main results will be summarized in this narrative review. In addition, we will present the current knowledge on the development of anti-SARS-CoV-2 hyperimmune polyclonal immunoglobulins.

ABO blood group-related mechanism of infection of SARS-CoV-2: an overview of systematic reviews.

Among the host genetic factors playing a role in the susceptibility to infectious diseases, the ABO blood group system is of utmost importance. Following the first reports in early 2020, the association between ABO blood groups and SARS-CoV-2 infection or COVID-19 severity has been thoroughly investigated. The aim of this narrative review is to provide an overview of systematic reviews regarding the link between ABO blood groups and such risks. The possible molecular mechanisms underlying these associations will also be discussed. ABO blood group has a robust association with susceptibility to infection but not with disease severity, and studies on long COVID anre still missing.Prov.

How we manage a high D-dimer.

D-dimer, a soluble fibrin degradation product that originates from plasmin-induced degradation of cross-linked fibrin, is an important biomarker of coagulation activation and secondary fibrinolysis that is routinely used to rule out venous thromboembolism (VTE), and to evaluate the risk of VTE recurrence, as well as the optimal duration of anticoagulant therapy. Besides VTE, D-dimer may be high due to physiologic conditions, including aging, pregnancy, and strenuous physical activity. In addition, several disorders have been associated with increased D-dimer levels, ranging from disseminated intravascular coagulation to infectious diseases and cancers. Thus, it is far from unusual for hematologists to have to deal with ambulatory individuals with increased D-dimer without signs or symptoms of thrombus formation. This narrative review is dedicated to the management of these cases by the hematologist.

The Role of Convalescent Plasma in COVID-19: A Conclusive Post-Pandemic Review.

COVID-19 convalescent plasma (CCP) has represented the frontline response to the COVID-19 pandemic, largely because of encouraging historical evidences in previous pandemics, biological plausibility, and the initial unavailability of targeted antivirals. Unfortunately, investigator-initiated randomized clinical trials in 2020, launched during a stressful pandemic peak, were designed mostly at addressing the main unmet need, i.e., treating critically ill hospitalized patients who were unlikely to benefit from any antiviral therapy. The failure of most of these drugs, in combination with the lack of any sponsor, led to the false belief that convalescent plasma was useless. With the relaxing pandemic stages, evidences have instead mounted that, when administered properly (i.e., within 5 days from onset of symptoms and at high titers of neutralizing antibodies), CCP is as effective as other antivirals at preventing disease progression in outpatients, and also reduces mortality in hospitalized patients. Recently, the focus of clinical use has been on immunosuppressed patients with persistent seronegativity and infection, where a randomized clinical trial has shown a reduction in mortality. Lessons learnt during the COVID-19 pandemic will be of utmost importance for future pandemics.

Outpatient randomized controlled trials to reduce COVID-19 hospitalization: Systematic review and meta-analysis.

This COVID-19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants, and vaccine status. Outpatient RCTs with hospitalization endpoint were identified in Pubmed searches through May 2023, excluding RCTs <30 participants (PROSPERO-CRD42022369181). Risk of bias was extracted from COVID-19-NMA, with odds ratio utilized for pooled comparison. Searches identified 281 studies with 61 published RCTs for 33 diverse interventions analyzed. RCTs were largely unvaccinated cohorts with at least one COVID-19 hospitalization risk factor. Grouping by class, monoclonal antibodies (mAbs) (OR = 0.31 [95% CI = 0.24-0.40]) had highest hospital reduction efficacy, followed by COVID-19 convalescent plasma (CCP) (OR = 0.69 [95% CI = 0.53-0.90]), small molecule antivirals (OR = 0.78 [95% CI = 0.48-1.33]), and repurposed drugs (OR = 0.82 [95% CI: 0.72-0.93]). Earlier in disease onset interventions performed better than later. This meta-analysis allows approximate head-to-head comparisons of diverse outpatient interventions. Omicron sublineages (XBB and BQ.1.1) are resistant to mAbs Despite trial heterogeneity, this pooled comparison by intervention class indicated oral antivirals are the preferred outpatient treatment where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.

Rates Among Hospitalized Patients With COVID-19 Treated With Convalescent Plasma: A Systematic Review and Meta-Analysis.

Objective: To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. Patients and Methods: On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature from January 1, 2020, to October 26, 2022. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of 5 reviewers. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using an inverse-variance random effects model. The prespecified end point was all-cause mortality during hospitalization. Results: Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses reported that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio [OR], 0.87; 95% CI, 0.76-1.00) and matched cohort studies (OR, 0.76; 95% CI, 0.66-0.88). The meta-analysis of subgroups revealed 2 important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared with convalescent plasma containing low antibody levels (OR, 0.85; 95% CI, 0.73 to 0.99). Second, earlier treatment with COVID-19 convalescent plasma was associated with a decrease in mortality compared with the later treatment cohort (OR, 0.63; 95% CI, 0.48 to 0.82). Conclusion: During COVID-19 convalescent plasma use was associated with a 13% reduced risk of mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.