Blood derivative therapy

There are three main components manufactured from whole blood: red blood cells (RBCs), plasma, and platelets. Plasma contains a multitude of different proteins, peptides, and biologic substances. Approximately 53 million liters of plasma was collected in the United States in 2019. Following collection, plasma is frozen and manufactured into plasma-derived medicinal products (PDMPs). During the manufacture process, several thousand plasma units are pooled for Cohn fractionation, which is based upon cold ethanol precipitation of proteins. The PDMPs are further prepared using ion exchange or affinity chromatography and additional steps to inactivate and remove infectious diseases such as viruses. Almost 20 different therapeutic plasma proteins are purified from plasma via these multi-step manufacturing processes. Interestingly, the demand for pharmaceutical plasma products, particularly intravenous immunoglobulin (IVIG) products, has been increasing. The manufacture and therapeutic role of blood derivatives particularly immunoglobulin therapy, Rh immunoglobulin (RhIG), COVID-19 convalescent plasma (CCP) and hyperimmune globulins, albumin, clotting factors, fibrin sealants, and platelet rich plasma will be described.Copyright © 2022 AME Publishing Company. All Rights Reserved.

Safety of Pharmacotherapy in COVID-19 Patients: A Literature Review.

The safety of COVID-19 pharmacotherapy is a relevant issue, first of all, because of the current lack of experience with using particular medicinal products and with off-label prescribing. The aim of the study was to analyse information on potential adverse drug reactions (ADRs) and their predictors in etiology- and pathogenesis-oriented COVID-19 therapy. According to literature data, the main clinically significant risk factors for COVID-19 patients to develop an ADR are the duration of their hospital stay, combined use of antivirals, polypharmacy, and their history of drug allergies. The most common adverse reactions to antivirals, to virus-neutralising antibodies, and to human anti-COVID-19 immunoglobulin and convalescent plasma are, respectively, gastrointestinal and hepatobiliary disorders;gastrointestinal disorders, neurological disorders, and allergic reactions;and transfusion reactions (fever, chills, etc.). For pathogenesis-oriented therapy with systemic glucocorticosteroids, the most characteristic ADR is hyperglycaemia. Janus kinase inhibitors and interleukin inhibitors are most often associated with gastrointestinal disorders and hypertransaminasemia;neutropenia is also characteristic of a number of interleukin inhibitors. Haemostatic adverse reactions to anticoagulants depend on the patient's dosing regimen and condition. Drug-drug interactions are a common problem in COVID-19 treatment, with the combination of nirmatrelvir and ritonavir showing the largest number of significant interactions attributed to their pharmacokinetics. Currently, there is data on the role of pharmacogenetic biomarkers in the safety and clinical outcomes of COVID-19 therapy. Thus, to improve the safety of COVID-19 therapy, an integrated approach is needed that will take into account both the clinical, demographic, and pharmacogenetic predictors of ADRs and the risk of drug-drug interactions.Copyright © 2023 Safety and Risk of Pharmacotherapy. All rights reserved.

SARS-CoV-2 infection in patients with multiple myeloma: survey in 23 centers across Europe and USA

Introduction: Despite several studies, the impact of coronavirus disease 2019 on patients with multiple myeloma remains uncertain. Material(s) and Method(s): We performed a survey that covered the period of the first and second waves of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 23 centers inseven countries. Out of 352 patients with myeloma and SARS-CoV-2, 23% died. Results/Conclusions: Logistic regression showed a lower risk of death among patients treated with proteasome inhibitor and a higher risk of death for those who had a severe or a very severe course of disease.Copyright © 2023 Sciendo. All rights reserved.

The Future of COVID-19: What Is Next in the Drug Pipeline

Objectives: Development of new and repurposed medicines in response to the COVID-19 pandemic has occurred at an unprecedented rate, resulting in a dynamic pipeline marked by significant challenges and successes. This analysis provides an overview of the vaccines and therapies undergoing clinical evaluation or with recent approval for the treatment and prevention of COVID-19 in global markets. Method(s): For this analysis, COVID-19 pipeline medicines are defined in three categories: vaccines, new treatments and repurposed medicines. GlobalData is the primary data source for this study, in addition to online databases from Health Canada, the US FDA, and the EMA. International markets examined include the US and geographic Europe (excluding Russia and Turkey). Result(s): As of November 2022, the global pipeline contained over 600 therapies and vaccines undergoing Phase I, II, III clinical trials or pre-registration for the prevention and treatment of COVID-19. Preventive and repurposed medicines include antivirals, immunoglobulins, monoclonal antibodies, cellular therapies, and convalescent plasma. In Canada, twelve medicines, including six vaccines, have been approved for COVID-19. The number of global approvals is greater, with approximately 9 vaccines on the market in OECD countries. In addition to pre-exposure preventative therapies, manufacturers are also developing COVID-19 drugs to be used as prophylactic therapy. The analysis identifies new oral antiviral treatments and preventative therapies in the pipeline and under review in various jurisdictions globally. Conclusion(s): This research provides a clearer picture of the characteristics and evolution of the market for new and emerging COVID-19 medicines, which will help policy-makers and other stakeholders understand and anticipate the unique pressures of the COVID-19 pandemic.Copyright © 2023

A systematic approach for COVID-19 predictions and parameter estimation.

The world is currently facing a pandemic called COVID-19 which has drastically changed our human lifestyle, affecting it badly. The lifestyle and the thought processes of every individual have changed with the current situation. This situation was unpredictable, and it contains a lot of uncertainties. In this paper, the authors have attempted to predict and analyze the disease along with its related issues to determine the maximum number of infected people, the speed of spread, and most importantly, its evaluation using a model-based parameter estimation method. In this research the Susceptible-Infectious-Recovered model with different conditions has been used for the analysis of COVID-19. The effects of lockdown, the light switch method, and parameter variations like contact ratio and reproduction number are also analyzed. The authors have attempted to study and predict the lockdown effect, particularly in India in terms of infected and recovered numbers, which show substantial improvement. A disease-free endemic stability analysis using Lyapunov and LaSalle's method is presented, and novel methods such as the convalescent plasma method and the Who Acquires Infection From Whom method are also discussed, as they are considered to be useful in flattening the curve of COVID-19.

Diminished Neutralization Capacity of SARS-CoV-2 Omicron BA.1 in Donor Plasma Collected from January to March 2021.

The 50% plaque reduction neutralization assay (PRNT50) has been previously used to assess the neutralization capacity of donor plasma against wild-type and variant of concern (VOC) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging data suggest that plasma with an anti-SARS-CoV-2 level of ≥2 × 104 binding antibody units/mL (BAU/mL) protects against SARS-CoV-2 Omicron BA.1 infection. Specimens were collected using a cross-sectional random sampling approach. For PRNT50 studies, 63 previously analyzed specimens by PRNT50 versus SARS-CoV-2 wild-type, Alpha, Beta, Gamma, and Delta were analyzed by PRNT50 versus Omicron BA.1. The 63 specimens plus 4,390 specimens (randomly sampled regardless of serological evidence of infection) were also tested using the Abbott SARS-CoV-2 IgG II Quant assay (anti-spike [S]; Abbott, Chicago, IL, USA; Abbott Quant assay). In the vaccinated group, the percentages of specimens with any measurable PRNT50 versus wild-type or VOC were wild type (21/25 [84%]), Alpha (19/25 [76%]), Beta (18/25 [72%]), Gamma (13/25 [52%]), Delta (19/25 [76%]), and Omicron BA.1 (9/25 [36%]). In the unvaccinated group, the percentages of specimens with any measurable PRNT50 versus wild type or VOC were wild-type SARS-CoV-2 (16/39 [41%]), Alpha (16/39 [41%]), Beta (10/39 [26%]), Gamma (9/39 [23%]), Delta (16/39 [41%]), and Omicron BA.1 (0/39) (Fisher's exact tests, vaccinated versus unvaccinated for each variant, P < 0.05). None of the 4,453 specimens tested by the Abbott Quant assay had a binding capacity of ≥2 × 104 BAU/mL. Vaccinated donors were more likely than unvaccinated donors to neutralize Omicron when assessed by a PRNT50 assay. IMPORTANCE SARS-CoV-2 Omicron emergence occurred in Canada during the period from November 2021 to January 2022. This study assessed the ability of donor plasma collected earlier (January to March 2021) to generate any neutralizing capacity against Omicron BA.1 SARS-CoV-2. Vaccinated individuals, regardless of infection status, were more likely to neutralize Omicron BA.1 than unvaccinated individuals. This study then used a semiquantitative binding antibody assay to screen a larger number of specimens (4,453) for individual specimens that might have high-titer neutralizing capacity against Omicron BA.1. None of the 4,453 specimens tested by the semiquantitative SARS-CoV-2 assay had a binding capacity suggestive of a high-titer neutralizing capacity against Omicron BA.1. These data do not imply that Canadians lacked immunity to Omicron BA.1 during the study period. Immunity to SARS-CoV-2 is complex, and there is still no wide consensus on correlation of protection to SARS-CoV-2.

Antiviral Therapy of COVID-19.

Since the beginning of the COVID-19 pandemic, the scientific community has focused on prophylactic vaccine development. In parallel, the experience of the pharmacotherapy of this disease has increased. Due to the declining protective capacity of vaccines against new strains, as well as increased knowledge about the structure and biology of the pathogen, control of the disease has shifted to the focus of antiviral drug development over the past year. Clinical data on safety and efficacy of antivirals acting at various stages of the virus life cycle has been published. In this review, we summarize mechanisms and clinical efficacy of antiviral therapy of COVID-19 with drugs based on plasma of convalescents, monoclonal antibodies, interferons, fusion inhibitors, nucleoside analogs, and protease inhibitors. The current status of the drugs described is also summarized in relation to the official clinical guidelines for the treatment of COVID-19. In addition, here we describe innovative drugs whose antiviral effect is provided by antisense oligonucleotides targeting the SARS-CoV-2 genome. Analysis of laboratory and clinical data suggests that current antivirals successfully combat broad spectra of emerging strains of SARS-CoV-2 providing reliable defense against COVID-19.

COVID-19 IN A PATIENT WITH GRANULOMATOSIS WITH POLYANGIITIS: MANAGEMENT TACTICS

Patients with ANCA-associated vasculitis (AAV) cause extreme alertness during the coronavirus disease 2019 (COVID-19) pandemic, associated with many factors: the initial damage to the respiratory system (upper respiratory tract, lungs) and kidneys, immunosuppressive treatments, difficult prognosis of COVID-19 with the risk of AAV exacerbation. We present a clinical case of a moderate COVID-19 in a patient with granulomatosis with polyangiitis, who received anti-B cell therapy with rituximab (RTX) for a long time. Coronavirus pneumonia developed one year after RTX, while B-lymphocyte depletion persisted. In order to achieve an adequate antiviral immune response and prevent hyperinflammation, treatment was carried out with antiviral drugs, anticoagulants, convalescent plasma, human normal immunoglobulin, and interleukin-6 antagonist tocilizumab. Possible predictors of severe COVID-19 in patients with AAV are discussed.Copyright © 2023 Ima-Press Publishing House. All rights reserved.

The therapeutics, based on virus specific antibodies, for special prophylactic and current of COVID-19

The analyses of effectiveness of medical means of protection based on virus specific antibodies, intended for special prophylactic and current of COVID-19 is conducted. The plasma of patients, obtained from the blood takes the leading part among these prepares. It is concluded, that convalescents plasma, containing virus neutralizing antibodies, may be used for emergency prevention or in the early stages of the disease. A risk group, that primarily needs in such drugs for special prophylactics, is medical workers. The other prepares, based on virus specific antibodies, including purified prepares of monoclonal antibodies, that may have certain advantages to convalescent's plasma due to their safety and high activity, due to complexity of their production and presumably high cost are unlikely to be available in the near future for mass use in the practice of medicine. The use of convalescents plasma for the prevention and treatment of COVID-19.can be based on the experience of their application in specialized medical centers and summarizing data from randomized clinical trials.Copyright © 2021 Moscow State University of Psychology and Education. All right reserved.

A Descriptive, Retrospective Analysis of Covid-19 Antibody Therapy and Its Effects on Morbidity and Mortality in Patients Receiving B-Lymphocyte Depleting Therapies

Intro: Patients receiving B-cell depleting or inhibiting therapies (BCDT), such as anti-CD20 monoclonal antibodies (CD20-MAB), are at risk for severe COVID-19. BCDT decreases production of neutralizing antibodies, causing delayed viral clearance and prolonged viral shedding. Passive antibody therapy (PAT), including COVID-19 convalescent plasma (CCP) and monoclonal antibodies (MAB), is hypothesized to be an effective Findings: * At the time of treatment, all patients (19/19) receiving CCP were hospitalized compared with10/53 patients treated with MAB. 2/10(20%) hospitalized patients treated with MAB died, compared with 3/19(15%) treated with CCP. **5/43 patients treated outpatient with MAB were hospitalized for COVID following CCP/MAB treatment with no COVID related deaths. Conclusion(s): Our data suggest that patients with COVID-19 who received BCDT within the last year may have improved outcomes after treatment with MAB or CCP. Elderly patients with >3 comorbidities and underlying hematological malignancy who contracted COVID-19 within 30 days of last BCDT had increased morbidity and mortality. To improve clinical outcomes, passive antibody therapy should be administered prior to the development of severe disease requiring hospitalization. Further prospective studies and comparisons to COVID-19 patients that did not receive MAB or CCP are needed to help confirm this association.Copyright © 2023

Inflammatory profile of convalescent plasma to treat COVID: Impact of amotosalen/UVA pathogen reduction technology.

Blood products in therapeutic transfusion are now commonly acknowledged to contain biologically active constituents during the processes of preparation. In the midst of a worldwide COVID-19 pandemic, preliminary evidence suggests that convalescent plasma may lessen the severity of COVID-19 if administered early in the disease, particularly in patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms. This study examined the influence of photochemical Pathogen Reduction Treatment (PRT) using amotosalen-HCl and UVA light in comparison with untreated control convalescent plasma (n= 72 - paired samples) - cFFP, regarding soluble inflammatory factors: sCD40L, IFN-alpha, IFN-beta, IFN-gamma, IL-1 beta, IL-6, IL-8, IL-10, IL-18, TNF-alpha and ex-vivo inflammatory bioactivity on endothelial cells. We didn't observe significant modulation of the majority of inflammatory soluble factors (8 of 10 molecules tested) pre- or post-PRT. We noted that IL-8 concentrations were significantly decreased in cFFP with PRT, whereas the IL-18 concentration was increased by PRT. In contrast, endothelial cell release of IL-6 was similar whether cFFP was pre-treated with or without PRT. Expression of CD54 and CD31 in the presence of cFFP were similar to control levels, and both were significant decreased in when cFFP had been pre-treated by PRT. It will be interesting to continue investigations of IL-18 and IL-8, and the physiopathological effect of PRT- treated convalescent plasma and in clinical trials. But overall, it appears that cFFP post-PRT were not excessively pro-inflammatory. Further research, including a careful clinical evaluation of CCP-treated patients, will be required to thoroughly define the clinical relevance of these findings.

Convalescent Plasma Treatment of Severe Covid-19 Cases in the Bronx, Ny

Junior Physician Investigator Award Recipient Purpose of study Severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Convalescent plasma obtained from recovered persons was used for previous respiratory pandemics. Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) was proposed as an option that may hold promise as treatment for COVID-19. Our aim was to retrospectively evaluate the efficacy of CCP treatment of patients with severe to life-threatening COVID-19 hospitalized at Montefiore Medical Center (MMC) in the Bronx, NY between April 13 to May 4, 2020. Methods used We administered CCP as part of the Mayo Clinic expanded access investigational new drug (IND) program for hospitalized patients. We compared the mortality and clinical outcome of 73 patients with COVID-19 who received 200 mL of CCP with a Spike protein IgG titer >=1:2,430 (median 1:47,385) within 72 hours of admission to 1:1 propensity score-matched controls. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroids, and anticoagulation use (figure 1). We additionally measured Spike protein IgG and neutralizing antibody titer in CCP and pre- and post-transfusion Spike protein IgG, IgM and IgA titer in CCP recipients. The primary outcome was all-cause mortality at day 28 post-CCP. The secondary outcomes were improvement in oxygenation status or mortality at day 28 post-CCP. Exploratory outcomes were associations between pre-CCP SARS-CoV-2 antibody titers and mortality at day 28. Summary of results There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared to matched controls, CCP recipients < 65 years had 4-fold lower mortality and 4-fold lower deterioration in oxygenation or mortality at day 28 (figure 2, 3). There was no association between CCP IgG or neutralizing antibody titer and clinical outcome. For CCP recipients, pre-transfusion Spike protein IgG, IgM and IgA titers were associated with mortality at day 28 in univariate analyses but not in multivariable analyses. Pre-transfusion Spike protein IgG titer was significantly correlated with Ddimer and detected viral load measured by cycle threshold (Ct) value of nasopharyngeal SARS-CoV-2 reverse-transcriptase- polymerase-chain-reaction (figure 4). No adverse effects of CCP were observed. Conclusions We report that CCP administration within 72 hours of hospitalization demonstrated a possible signal of reduced mortality in patients < 65 years. Pre-transfusion IgG titer may be a proxy for disease severity that may be useful in identifying those who are more likely to respond to CCP. Data from controlled trials is needed to validate this finding and establish the effect of ageing on CCP efficacy. (Figure Presented).

Hospital Protection Correlates in Outpatient Covid-19 Convalescent Plasma Recipients

Background: High titer COVID-19 convalescent plasma (CCP) reduces hospitalizations among immunocompetent outpatients. This study evaluated recipient post-transfusion S receptor binding domain (S-RBD) IgG antibody levels and the association of progressing to hospitalization among unvaccinated outpatients with COVID-19 treated with CCP or control plasma. Method(s): This analysis focused on participants from a multicenter doubleblind, randomized, controlled trial comparing treatment of outpatients with COVID-19 convalescent plasma (CCP) or control plasma without SARS-CoV-2 antibodies. Participants with confirmed SARS-CoV-2 infection were transfused within 9-days of symptom onset between June 2020 and October 2021 (n=110 vaccinated control;n=105 vaccinated CCP;n=464 unvaccinated control;n=472 unvaccinated CCP;total n=574 control and n=577 CCP recipients). All subjects had specimens collected the day prior to transfusion (D-1), within 30 minutes after transfusion (D0), 14 (D14), 28 (D28), and 90 (D90) days post-transfusion. Ancestral SARS-CoV-2 S-RBD was measured by an in-house validated ELISA. All 54 COVID-19-related hospitalizations occurred within 2 weeks of transfusion. Result(s): Post-transfusion anti-S-RBD IgG levels on D0 were significantly greater for CCP (median=4 titer,log3) compared to control (median=2 titer,log3;p< 0.001) recipients. Neither sex nor age impacted antibody levels following CCP treatment at D14, D28, and D90. Vaccinated recipients had greater titers than unvaccinated recipients prior to transfusion with little change in titers post-transfusion. Unvaccinated recipients had low antibody titers on D-1 with CCP recipients exhibiting a significant increase in titer from D-1 to D0 compared to controls (mean fold change=1.89;p< 0.001). Among unvaccinated recipients, those who received CCP transfusion late ( >5 days after symptom onset) and had low D0 antibody levels (< 4.24 titer, log3) had the greatest proportion of hospitalizations (5.5%). In contrast, those who received CCP transfusion early (< 5 days after symptom onset) with high D0 antibody levels ( >4.24 titer, log3) had no hospitalizations. Unvaccinated CCP recipient anti-S-RBD IgG antibody levels on D0 correlated with donor anti-S-RBD IgG antibody levels (r=0.30, p< 0.001). Conclusion(s): Among unvaccinated outpatients with COVID-19, CCP recipient antibody dilutional titers after transfusion over 540 titer correlated with protection against hospitalization when transfusion occurred within 5 days of symptom onset. (Figure Presented).

An analysis of convalescent plasma unit cost calculation using time-driven activity-based costing (TDABC) method

Introduction: The viral pneumonia disease covid-19 is currently becoming a pandemic throughout the world due to SARS-CoV-2. With a lack of therapy choices for covid-19, convalescent plasma therapy was considered an emergency intervention in some countries. Convalescent plasma was, by unit cost, the most expensive service at the laboratory of Dolopo Hospital, thus easy, practical, and efficient calculation of unit cost was needed. This research aims to analyze the unit cost of convalescent plasma as calculated using the Time-Driven Activity-Based Costing (TDABC) method and to examine the difference between the unit cost of convalescent plasma calculated using the TDABC with the real cost at Dolopo Hospital. Methods: This qualitative research used a case study approach. The primary data were obtained through observation of convalescent plasma activity, and the secondary data were obtained through interviews related to the data of convalescent plasma cost. Results: The convalescent plasma unit cost calculated based on the TDABC method was IDR2,287,675 and on real cost was IDR2,250,000. The result of the calculation using the TDABC method was higher than the real cost calculation by IDR36.765. Conclusion: The research results showed that cost analysis using the TDABC method resulted in a more detailed and accurate calculation that the calculation was activity and time-based. © 2023, Sanglah General Hospital. All rights reserved.

COVID-19 IN A PATIENT WITH GRANULOMATOSIS WITH POLYANGIITIS: MANAGEMENT TACTICS.

Patients with ANCA-associated vasculitis (AAV) cause extreme alertness during the coronavirus disease 2019 (COVID-19) pandemic, associated with many factors: the initial damage to the respiratory system (upper respiratory tract, lungs) and kidneys, immunosuppressive treatments, difficult prognosis of COVID-19 with the risk of AAV exacerbation. We present a clinical case of a moderate COVID-19 in a patient with granulomatosis with polyangiitis, who received anti-B cell therapy with rituximab (RTX) for a long time. Coronavirus pneumonia developed one year after RTX, while B-lymphocyte depletion persisted. In order to achieve an adequate antiviral immune response and prevent hyperinflammation, treatment was carried out with antiviral drugs, anticoagulants, convalescent plasma, human normal immunoglobulin, and interleukin-6 antagonist tocilizumab. Possible predictors of severe COVID-19 in patients with AAV are discussed.Copyright © 2023 Ima-Press Publishing House. All rights reserved.

Convalescent plasma therapy for managing infectious diseases: A narrative review

The coronavirus disease 2019 (COVID-19) pandemic in 2020 is one of the worst catastrophic events in human history. A number of therapeutic modalities have been utilized in order to fight the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although the majority of them failed to demonstrate a beneficial clinical effect. Among the anti-COVID-19 agents being investigated, the convalescent plasma collected from recovered donors has gained a growing interest. Convalescent plasma has been employed for over a hundred years to treat severe acute viral infections when a vaccine or a specific antiviral treatment was not yet available. In this narrative review, we summarize the literature data on the use of convalescent plasma during previous viral outbreaks and pandemics, including influenza viruses, coronaviruses other than SARS-CoV-2 and Ebola virus. A literature search, using the Medline and PubMed electronic database, was performed to retrieve publications on the use of convalescent plasma in previous viral epidemics. In conclusion, the available literature data suggest the safety profile of convalescent plasma and its potential benefit in treating emerging viral infectious diseases. In addition, these data retrieved from previous viral epidemics provide a solid rationale for the employment of plasma from convalescent donors also in COVID-19 patients.Copyright © 2021 AME Publishing Company. All rights reserved.

Anaphylaxis to Cyclophosphamide Metabolites during Lymphodepletion for CAR-T Therapy

Background: Cyclophosphamide (Cy) is used in hematopoietic stem cell transplant (HSCT) preparative regimens and lymphodepletion for chimeric antigen receptor T-cell (CAR-T) therapy. We describe a case of cyclophosphamide hypersensitivity in a pediatric patient during CAR-T therapy. Case description: A 13 year old boy was diagnosed with very high risk ALL in 2015 and had 2 isolated CNS relapses treated with intensified chemotherapy (chemo) and cranial radiation (1st relapse) and Blinatumomab with intrathecal (IT) chemo followed by sibling donor HSCT (2nd relapse). At age 19, and 18 months after HSCT, he had a 3rd CNS relapse treated with IT chemo and referral for CAR-T therapy. At our center, leukapheresis and CAR-T production (Novartis) were performed. Later, during lymphodepletion with fludarabine (Flu) and Cy, physiologic replacement hydrocortisone (HC) was briefly held to prevent interference with CAR-T function. After 3 days of Flu/Cy, he developed fever and hypotension requiring inotropic support. Hypotension and fever resolved with stress dose HC and antibiotics and was attributed to culture-negative sepsis and adrenal crisis. CAR-T infusion was subsequently delayed by skin GVHD requiring glucocorticoids and COVID-19 infection treated with convalescent plasma and nirmatrelvir/ritonavir. Physiologic HC replacement was continued when he was re-admitted for CAR-T therapy, but he again developed fever, diffuse erythema and shock in hours following the first dose of Cy necessitating stress dose HC, antibiotics, inotropes, and mechanical ventilation. Negative blood cultures and ongoing physiologic HC replacement suggested an alternative explanation for shock. Case reports of anaphylaxis to Cy metabolites implicated Cy as the causative agent so it was discontinued. After recovery, CAR-T cells were infused without complications. In the following weeks, he had no evidence of recurrent leukemia but was persistently pancytopenic. A sibling donor stem cell boost was proposed but the patient accepted only palliative care. He had several opportunistic infections before succumbing to E. coli sepsis. Discussion(s): The first episode of shock was initially attributed to adrenal crisis and sepsis, although no organism was identified. The second episode appeared anaphylactic in timing and clinical presentation with adequate HC replacement and negative cultures, suggesting Type I hypersensitivity. The patient previously received Cy uneventfully before HSCT, suggesting that the donor-derived immune system was the source of new Cy hypersensitivity. Onset of anaphylaxis within hours rather than minutes after Cy administration supports hypersensitivity to Cy metabolites rather than to the drug itself. This case highlights the importance of consideration of sensitivity to Cy metabolites as well as acquired donor-specific allergy even when alternative explanations are likely.Copyright © 2023 American Society for Transplantation and Cellular Therapy

A Multicenter Study of Covid-19 Infection in Pediatric Intensive Care Units in the Us

Background: To describe characteristics of COVID-19 infection among patients requiring admission to pediatric intensive care units (PICU) in the USA. Method(s): Observational surveillance study of COVID-19 infected patients admitted to PICUs in 27 US states between April 1, 2020 - May 1, 2021. Result(s): Four hundred fifty-three patients were included;the majority were from institutions in the South and Midwest regions (40% and 34%). The population was mainly male (57%) and Hispanic (36%), with a median age of 10 years (IQR 4-15). 76% had 1 or more comorbidity. Patient's or caregiver's reported sources for COVID-19 infection were household and community contacts (31% and 24%). One hundred sixty-seven (40%) individuals were diagnosed with the multisystem inflammatory syndrome in children (MISC) within 7 days of PICU admission. Compared to COVID-19 cases without MISC, gastrointestinal, mucocutaneous, and neurological signs and symptoms were more frequent at PICU admission. Nasal cannula (20%) and high-flow oxygen (12.4%) were the most common respiratory support strategies at day 1 of admission, and mechanical ventilation by day 7. Overall, 104 (23%) and 8 (1.8%) individuals were placed on mechanical ventilation and extracorporeal membrane oxygenation (ECMO) within the interval of observation. Steroids and remdesivir were the most delivered COVID-19 targeted therapies (60% and 33%), and only 3% of the patients received convalescent plasma;IVIG (86.8%) and anakinra (61%) were commonly used among individuals with MISC. The overall mortality proportion (MP) was 2.65 (n= 12), and mortality was more frequent among individuals > 2 years old. Of the 167 children with MISC, only 1 died, MP (0.6). Conclusion(s): Mortality associated with pediatric COVID-19 infection is less frequent than in critically ill COVID-19-infected adults. Among pediatric/ adolescent patients, children > 2 years are the most vulnerable to adverse COVID-19-associated outcomes. MISC cases were frequent, yet mortality was low.

Clinical trials during the pandemic: research design and lessons

The COVID-19 pandemic has required a substantial coordinated international effort to develop effective treatments and vaccines, which has led to an acceleration in innovation in clinical research with the rapid adoption of pragmatic, open, adaptive platform trials for new therapeutics. Large platform trials such as RECOVERY, SOLIDARITY and REMAP-CAP have demonstrated the ability to recruit thousands of patients across multiple sites in a short period of time, resulting in therapies that have now been adopted into clinical practice. Therapies tested for COVID-19 include repurposed antivirals, immunomodulatory drugs, convalescent plasma and, more recently, novel therapeutics developed specifically to target SARS-CoV-2. Challenges have included ethical and practical issues of delivering clinical research during a pandemic, some duplication of effort and the testing of some therapies with a low likelihood of success. COVID-19 has required acceleration of the process of clinical trial conduct, from grant funding to approvals and simplification of trial processes. Many of the innovations and simplifications to clinical trial conduct that have featured so prominently during the COVID-19 pandemic are likely to be just as valuable in a post-pandemic world. An important legacy of the pandemic may be a more efficient and effective way of delivering clinical research in the future.Copyright © ERS 2021.