Repurposing of poly-gamma-glutamic acid, immunotherapeutic drug for cervical intraepithelial neoplasia 1, as covid-19 treatment

Covid-19 virus variants identified so far are due to viral genetic diversity, genetic evolution, and variable infectivity, suggesting that high infection rates and high mortality rates may be contributed by these mutations. And it has been reported that the targeting strategies for innate immunity should be less vulnerable to viral evolution, variant emergence and resistance. Therefore, the most effective solution to Covid-19 infection has been proposed to prevent and treat severe exacerbation of patients with moderate disease by enhancing human immune responses such as NK cell and T cell. In previous studies, we demonstrated for the first time that gamma-PGA induced significant antitumor activity and antiviral activity by modulating NK cell-mediated cytotoxicity. Especially intranasal administration of gamma-PGA was found to effectively induce protective innate and CTL immune responses against viruses and we found out that gamma-PGA can be an effective treatment for cervical intraepithelial neoplasia 1 through phase 2b clinical trial. In this study, the possibility of gamma-PGA as a Covid-19 immune modulating agent was confirmed by animal experiments infected with Covid-19 viruses. After oral administration of gamma-PGA 300mug/mouse once a day for 5 days in a K18-hACE2 TG mouse model infected with SARS-CoV-2 (NCCP 43326;original strain) and SARS-CoV-2 (NCCP 43390;Delta variant), virus titer and clinical symptom improvement were confirmed. In the RjHan:AURA Syrian hamster model infected with SARS-CoV-2 (NCCP 49930;Delta variant), 350 or 550 mug/head of gamma-PGA was administered orally for 10 days once a day. The virus for infection was administered at 5 x 104 TCID50, and the titer of virus and the improvement of pneumonia lesions were measured to confirm the effectiveness in terms of prevention or treatment. In the mouse model infected with original Covid-19 virus stain, the weight loss was significantly reduced and the survival rate was also improved by the administration of gamma-PGA. And gamma-PGA alleviated the pneumonic lesions and reduced the virus titer of lung tissue in mice infected with delta variant. In the deltavariant virus infected hamster model, gamma-PGA showed statistically significant improvement of weight loss and lung inflammation during administration after infection. This is a promising result for possibility of Covid-19 therapeutics along with the efficacy results of mouse model, suggesting gammaPGA can be therapeutic candidate to modulate an innate immune response for Covid-19.

A Case of a Relapsing Remitting Macrophage Activating Syndrome After Covid-19 Vaccine In a Teenager with UNC13D Heterozygous Variant of Uncertain Significance

Introduction: Macrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case Presentation: A 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron;however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. Discussion(s): MAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Formula presented] [Formula presented] [Formula presented]Copyright © 2023 Elsevier Inc.

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.

Preliminary safety of Bcl-2 inhibitor BGB-11417 in relapsed/refractory multiple myeloma Harbouring t(11,14): Phase 1b/2 study

Background: B-cell lymphoma-2 (Bcl-2) proteins play an important role in multiple myeloma (MM) cell survival and represent an attractive therapeutic target. In prior trials, a subgroup analysis of patients with t(11;14)-positive relapsed/refractory (R/R) MM showed the combination of a Bcl-2 inhibitor, a proteasome inhibitor, and dexamethasone improved progression-free survival with no increased mortality. BGB-11417, a Bcl-2 inhibitor, is more potent and selective than venetoclax. BGB-11417- 105 (NCT04973605) is a phase 1b/2 study assessing the safety and efficacy of BGB-11417 monotherapy, in combination with dexamethasone, or with dexamethasone+carfilzomib in patients with t(11;14)-positive R/R MM. Preliminary safety results for the combination of BGB-11417 + dexamethasone are presented. Method(s): Eligible patients had t(11;14)-positive R/R MM and had been exposed to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 therapy. Patients received 80-, 160-, 320-, or 640-mg BGB-11417 daily with 40-mg dexamethasone weekly until death, intolerability, or disease progression. Dose escalation was guided by a mTPI-2 design and overall review by a safety monitoring committee. Pharmacokinetics (PK) were also assessed. Result(s): As of 1 July 2022, 10 patients were enrolled in the 80-, 160-, and 320-mg (3 patients each) and 640-mg (1 patient) dose-escalation cohorts of BGB-11417 + dexamethasone. The median age was 69 years (range, 52-81) and median prior lines of therapy was 3 (range, 1-5). The median treatment duration was 3.2 months (range, 0.5-6.5). No patients experienced dose-limiting toxicity at any dose level. Three patients died whilst on study: 1 due to COVID-19 complications 157 days after treatment discontinuation (day 208), 1 due to progressive disease 50 days after treatment discontinuation (day 89), and 1 due to COVID-19 whilst on study treatment (day 78). No deaths were associated with study treatment. Two patients experienced Grade >= 3 treatment-emergent adverse events (TEAEs). One patient in the 160-mg cohort experienced Grade 3 increase in liver enzymes and lymphopenia. One patient in the 320-mg cohort experienced Grade 3 lymphopenia. The most common TEAEs were insomnia (50%), fatigue (30%), arthralgia (20%), back pain (20%), lymphopenia (20%), and nausea (20%). BGB-11417 exposure increased dose-dependently from 80 mg to 320 mg with high interpatient PK variability. BGB-11417 exposures after single and multiple doses appeared similar, indicating limited accumulation. Conclusion(s): BGB-11417 plus dexamethasone was generally well-tolerated in patients with R/R MM harbouring t(11;14) at doses <=640 mg. Efficacy data are forthcoming. Recruitment is ongoing in the US, Australia, and New Zealand;the BGB-11417, dexamethasone, and carfilzomib combination arm will open in the future.

Renal Toxicity Boxed Warnings of Drugs Marketed in the US

Objectives: To assess the characteristics of FDA renal toxicity boxed warnings (formerly called Black Box Warning) included in the labels of drugs approved by the FDA and marked in the US. Method(s): We extracted the labels of human prescription drugs with renal toxicity boxed warnings from the "FDA Label: Full-Text Search of Drug Product Labeling" database, FDA regulatory information from drugs@FDA as of September 1, 2022. We extracted the therapeutic classification from the WHO ATC system. We conducted a descriptive analysis of the data. Result(s): The FDA listed 86 drugs including 72 active ingredients and 14 combinations with a boxed warning mentioning renal toxicity. Three drugs had emergency use authorizations for COVID-19, and all combinations included metformin. There were 8 (8.7%) drugs with renal toxicity boxed warnings approved before 1970, 6 (6.5%) in the 1970s, 14 (15.2%) in the 1980s, 34 (37.0%) in the 1990s, 17 (18.5%) in the 2000s, 9 (9.8%) in the 2010s, and 4 (4.3%) in 2020-Sep 2022. The therapeutic classes with the largest number of renal toxicity boxed warning included anti-infectives for systemic use 24 (26.1%), antineoplastic and immunomodulating agents 22 (23.9%), and alimentary tract and metabolism 17 (18.5%). The most common boxed warnings included renal impairment (n=21, 22.8%), nephrotoxicity (10, 10.9%), and nephrogenic systemic fibrosis (7, 7.6%). Additionally, 9 (9.8%) boxed warnings referred to the potential problems for patients with kidney transplants. Conclusion(s): Most drugs with a boxed warning were approved in the 1990s and 2000s. The therapeutic classes with the highest number of renal toxicity warnings were anti-infective for systemic use, antineoplastic and immunomodulating agents, and alimentary tract and metabolism. The most common warnings were renal impairment, nephrotoxicity, nephrogenic systemic fibrosis, and issues for patients with kidney transplants. Future research could expand the analysis to renal toxicity warnings, interactions, and precautions.Copyright © 2023

Diarrhea as an Independent Risk Factor for COVID-19 Severity and Inpatient Mortality

Introduction: Multiple meta-analyses have shown that over 15% patients with COVID-19 have at least one gastrointestinal complaint, most commonly diarrhea. The effects on the gastrointestinal system are thought to be mediated by the high expression of angiotensin-converting enzyme 2 (ACE2) and cellular serine proteases (TMPRSS2) in enterocytes, which cause altered intestinal permeability. The purpose of this study was to determine the incidence of diarrhea as it relates to COVID-19 infection and to determine if having concomitant diarrhea had a significant impact on disease course. Method(s): A retrospective chart review of 164,730 patients in a hospital system who were older than 18 years of age and had a positive SARS-CoV-2 test from March 2020 to February 2022 was completed. Diarrhea was determined using ICD code or patient's symptoms. Patients with confounding variables such as IBD, IBS, Celiac, Clostridium difficile, and pancreatic insufficiency were excluded. Demographic clinical characteristics and outcomes, including inpatient admission and mortality, were compared in patients with and without diarrhea. The Mann-Whitney test and Fisher's exact or Chi-square test was used for continuous and categorical variables respectively and multivariate logistic regression was used to evaluate for significant differences in disease outcome between the two groups. (Table) Results: Of the 164,730 patients included, 14,648 (8.89%) had diarrhea at the time of SARS-CoV-2. 6,748/33,464 (20.16%) of inpatient admissions were associated with diarrhea. On multivariate analysis, diarrhea was an independent risk factor for inpatient hospitalization (OR 2.39, CI 95% 2.28-2.51, P, 0.001) and inpatient mortality (OR 1.15, CI 96% 1.06-1.26, P= 0.001) after controlling for age, gender, race, comorbidities that could impact patient outcome, use of immunomodulators and outpatient antibiotics. Conclusion(s): These findings show that, even with controlling for comorbidities with COVID-19, diarrhea was an independent factor for predicting inpatient mortality and inpatient admission in general. Patients who had diarrhea and COVID-19 were sicker, having more comorbid conditions than those without diarrhea in our cohort. Attention should be given to not only respiratory complaints of COVID-19, but also gastrointestinal complaints, as they are an indicator of poor prognosis and mortality.

Prevention of COVID-19 coronavirus infection with aminodihydrophthalazinedione sodium (Galavit) in medical staff of the "red zone": results of the multicenter observational study

COVID-hospital healthcare workers belong to a high-risk SARS-CoV-2 infection. The aminodihydrophthalazinedione sodium (Galavit) belongs to the group of immunomodulatory and anti-inflammatory drugs. It has been shown that aminodihydrophthalazinedione sodium is effective in the prevention of acute respiratory infections, respiratory tract diseases and ENT-organs of bacterial and viral etiology. The purpose of the study. To evaluate the effectiveness and safety of immunoprophylaxis of new coronavirus infection (COVID-19) with aminodihydrophthalazinedione sodium in healthcare workers providing medical care in the "red zone". Material and methods. A multicenter prospective-retrospective observational comparative non-randomized study in healthcare workers providing medical care in the "red zone" was conducted. 428 participants were included in the study: the observation group - healthcare workers who administered aminodihydrophthalazinedione sodium (Galavit) for prophylactic purposes (n=214), and control group (n=214). The observation period of the participants or the period of collecting retrospective data in the study was 30 days. The results of PCR tests and tests for antibodies to the SARS-CoV-2 were analyzed, clinical status (COVID-19 in any form) was assessed. Descriptive statistic methods and Pearson chi2 test were used. The risk ratios, odds ratios and 95% confidence intervals were calculated with them. The influence of potential confounding factors (age, gender, work place in clinical site, the presence or absence of concomitant disease) on the clinical status were analyzed using logistic regression. The analysis of propensity score matching was carried out. The Stata/IC 14.2 for Windows software used for statistical analysis. Results and discussion. Observational study results describe the risk ratios and odds ratios of infection with a new coronavirus (COVID-19) in healthcare workers providing medical care in the "red zone" considering prophylactic administration of aminodihydrophthalazinedione sodium (Galavit). 205 (95.8%) participants in the group of healthcare workers who took aminodihydrophthalazinedione sodium (Galavit) for prophylactic purposes and 194 (90.7%) participants in control group had a negative PCR test during the observation period, chi2=4.48, p=0.034. The risk of a positive status according to the PCR test for 30 days in the preventive group was 0,04, and in the control group 0.09. The risk difference was -0.05 [95% confidence interval (CI) -0.099;-0.004]. The adjusted odds ratio using multiple logistic regression was - 0.41 (95% CI 0.18-0.93). No adverse events were observed during the prophylactic administration of aminodihydrophthalazinedione sodium over 30 days. Conclusion. Galavit preventive administration in a tablet form at a dose of 50-100 mg per day by employees of medical institutions providing medical care to patients with CIVID-19 significantly reduces the risk of SARS-CoV-2 infection and more than 2 times increases the chances not ill of new coronavirus infection. Galavit administration up to 30 days at a dose of 50-100 mg was well tolerated, no adverse events were registered.Copyright © 2022 by the authors.

Clinical features and acute management in adults

COVID-19 is a multisystem disease that requires holistic management. Most patients will experience mild symptoms including cough, fever and mild dyspnoea. A small proportion of patients will have severe manifestations including respiratory failure, ARDS and multiorgan failure. Extrapulmonary features are common and include gastrointestinal, thromboembolic, neurological, cardiac, renal, endocrine and dermatological manifestations. The care of COVID-19 patients requires close attention to these features. This includes respiratory support (such as supplemental oxygen, NIV and awake proning);fluid, electrolyte and nutrition management;prevention, detection and treatment of thrombotic events;management of diabetic complications;review of medications;appropriate use of antibiotics;and evidence-based use of therapeutic agents such as corticosteroids, antivirals such as remdesivir and other emerging therapies such as immunomodulating agents. Early planning for treatment escalation and decision making around the appropriateness of cardiopulmonary resuscitation are crucial as deterioration can be rapid. Prolonged symptoms occur in a minority of patients and longitudinal follow-up is required.Copyright © ERS 2021.

Evaluation of Quality-of-Care Indicators Among Patients With Crohn's Disease and Ulcerative Colitis in the United States: 2019-2020

Introduction: Crohn's disease (CD) and ulcerative colitis (UC) can be difficult to manage and, due to a lack of meaningful quality measures, patient (pt) care may vary by provider. To understand where gaps in care may exist for these pts, this study assessed specific healthcare resource utilization (HRU) and medication metrics that may be potential quality of care (QOC) indicators. Method(s): Using a large commercial US claims database (2019-2020), pts with CD or UC were identified. Potential QOC indicators were selected based on clinical guidelines and recommendations from measures of quality organizations and included CD or UC prevalence;gastroenterologist (GE) and IBD-related non-GE outpatient visits;IBD-related emergency department visits or hospitalizations;excessive steroid use (prednisone equivalent >=10 mg/day for >=60 consecutive days or a single prescription of >=600 mg prednisone);excessive steroid users on corticosteroid (CS)-sparing therapy;excessive steroid users with central dual-energy X-ray absorptiometry (DEXA) or osteoporosis pharmacologic treatment;use of targeted immunomodulators (TIMs) and oral mesalamine (CD only);imaging assessments;and assessment of inflammatory biomarkers. National percentages of pts achieving each metric are reported. Result(s): In total, 41,555 CD and 52,507 UC pts were identified in 2019, resulting in a 0.3% and 0.4% prevalence, respectively (Table). Over a third of CD pts (39.8%) and almost half of UC pts (45.5%) did not visit a GE in 2019. Around 10% CD pts, and up to 6.4% of UC pts, had IBD-related ED visits or hospitalizations. 17.1% CD and 14.5% UC pts were excessive steroid users, yet < 9% CD and UC pts, received DEXA scans and/or bone treatments. A third of excessive steroid users with CD (34.5%), and over half (53.0%) of those with UC, did not receive CS-sparing therapy. The rate of TIM use was over two times higher in CD vs UC pts (CD: 44.3%;UC: 18.9%). Despite evidence that mesalamine is ineffective in CD, 18.7% of pts with CD were prescribed it. Inflammatory biomarker level testing rates were < 50% in both CD and UC. Similar outcomes were reported in 2020, with lower HRU, possibly due to COVID-19. Conclusion(s): This analysis of QOC indicators highlights various areas for improvement that may provide better treatment outcomes and reduce HRU for pts with CD and UC. Future research is needed to assess outcomes in pts that are not being routinely monitored. (Table Presented).

Tocilizumab, a cutting-edge therapeutic resource against SARS-CoV-2 infection: A scoping review.

OBJECTIVE: To explore the medical evidence published until April 20, 2022, about the efficacy and safety of tocilizumab in COVID-19 patients. METHODOLOGY: Scoping review that included PubMed and Scopus, searching for clinical trials and observational studies in English and Spanish. Additionally, records of clinical trials from the International Clinical Trials Registry Platform were analyzed. RESULT(S): Fifty-four documents were included: retrospective cohort studies (n = 20), randomized clinical trials (n = 16), case control studies (n = 7), non-randomized clinical trials (n = 5) and prospective cohort studies (n = 6), with a total study population of 20,007 patients. There were 15 records of clinical trials of which 10 were registered in the US National Library of Medicine. CONCLUSION(S): Tocilizumab could be effective and safe to treat patients with moderate to critical COVID-19, in conjunction with additional immunomodulators and antivirals. A greater number of randomized clinical trials, however, are needed to explore the efficacy and safety of tocilizumab.Copyright © 2023 Comunicaciones Cientificas Mexicanas S.A. de C.V.. All rights reserved.

Cilta-Cel Efficacy and Safety in Patients with Progressive Multiple Myeloma after Exposure to Non-Cellular Anti-BCMA Immunotherapy

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating cilta-cel, an anti-BCMA CAR-T therapy, in several multiple myeloma (MM) patient (pt) populations. Objective(s): To report updated results with longer follow-up on cohort C pts with previous exposure to a non-cellular anti- BCMA immunotherapy. Method(s): Cohort C pts had progressive MM after treatment (tx) with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non-cellular BCMA-targeting agent. A single cilta-cel infusion (target dose 0.75x106 CAR+ viable T cells/kg) was administered 5-7 days post lymphodepletion. Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and adverse events (AEs). Result(s): As of June 1, 2022, 20 pts (13 ADC exposed;7 BsAb exposed) were treated with cilta-cel;4 pts did not receive cilta-cel due to either low cellular yield (n=2, 1 in each group) or death due to progressive disease (PD) prior to dosing (n=2, 1 in each group) and 6 pts received anti-BCMA tx as their last line of therapy (n=4 ADC, n=2 BsAb). During prior anti-BCMA tx, best responses included VGPR (ADC: 2 pts;BsAb: 1 pt), sCR (ADC: 1 pt), and CR (BsAb: 1 pt);the rest had best response of stable disease or PD (1 pt not evaluable). Baseline characteristics are presented in Figure 1A. Median time from last anti- BCMA agent to cilta-cel infusion was 195 d;median administered dose of cilta-cel was 0.65x106 CAR+ viable T cells/kg. At a median follow-up of 18.0 mo, 7/10 evaluable pts (70%) were MRD negative at 10-5 (ADC: 5/7 [71.4%], BsAb: 2/3 [66.7%]). ORR: full cohort, 60%;ADC, 61.5%;BsAb, 57.1% (Figure 1B). Median DOR: full cohort, 12.8 mo;ADC, 12.8 mo;BsAb, 8.2 mo. Median PFS: full cohort, 9.1 mo;ADC, 9.5 mo;BsAb, 5.3 mo. Cilta-cel responders had a shorter median duration of last anti- BCMA agent exposure (29.5 d) compared with non-responders (63.5 d). Responders also had a longer median time from last anti-BCMA tx exposure to apheresis (161.0 d) than non-responders (56.5 d). Most common AEs were hematologic. CRS: n=12 (60%;all Gr1/2), median time to onset 7.5 d, median duration 6.0 d. ICANS: n=4 (20%, 2 Gr3/4), median time to onset 9.0 d, median duration 7.0 d. No patient had movement or neurocognitive tx emergent AE/parkinsonism. There were 12 deaths (PD: 8;COVID-19 pneumonia: 2 [not tx related];subarachnoid hemorrhage: 1 [not tx related];C. difficile colitis: 1 [tx related]). (Figure Presented)(Figure Presented)Conclusions: Pts with heavily pretreated MM and previous exposure to a non-cellular anti-BCMA therapy had favorable responses to cilta-cel. However, depth and DOR appear lower than that seen in anti-BCMA-naive pts treated with cilta-cel (at 27.7 mo, median DOR was not reached in heavily pre-treated but anti-BCMA naive CARTITUDE-1 pts). These data may inform tx plans, including sequencing and washout period between BCMA-targeting agentsCopyright © 2023 American Society for Transplantation and Cellular Therapy

Glucosaminylmuramyl dipeptide efficacy in post-COVID-19 patient rehabilitation treatment.

The COVID-19 pandemic has altered people's lifestyles around the world. Prevention of recurrent episodes of the disease and mitigation of its consequences are especially associated with effective post-COVID-19 rehabilitation in patients. The aim of the study was to evaluate the effects of the drug Likopid (glucosaminylmuramyl dipeptide, GMDP) for post-COVID-19 rehabilitation in patients. Material and methods. Patients who recovered from mild to moderate COVID-19 (n=60, mean age 54+/- 11.7 years) were randomized into the observation group (n=30, 15 men and 15 women) who received 2 courses of Licopid (1 mg twice a day) and the comparison group (n=30, 15 men and 15 women). Analysis of the phenotypic and functional characteristics of the innate immune cellular factors was carried out before the start of immunomodulatory therapy, immediately after the end of the course, and also after 6 months observations. In order to assess the quality of life of all patients, we used the SF-36 Health Status Survey and the Hospital Anxiety and Depression Scale questionnaires. Results. During assessing the effect of immunomodulatory therapy on the parameters of innate immunity of patients at the stage of rehabilitation after COVID-19, an increase in the protective cytolytic activity of CD16+ and CD8+Gr+ cells, as well as a persistent increase in TLR2, TLR4 and TLR9 expression was found, which indicates the antigen recognition recovery and presentation at the level of the monocytic link of the immune system. The use of GMDP as an immunomodulatory agent resulted in an 8-fold reduction in the frequency and severity of respiratory infections due to an increase in the total monocyte count. As a result of assessing patients' quality of life against the background of the therapy, a positive dynamic in role functioning was revealed in patients. In the general assessment of their health status, an increase in physical and mental well-being was noted during 6 months of observation. The comparison group showed no improvement in the psychoemotional state. Discussion. The study demonstrated the effectiveness of GMDP immunomodulatory therapy in correcting immunological parameters for post-COVID-19 rehabilitation in patients. The data obtained are consistent with the previously discovered ability of GMDP to restore impaired functions of phagocytic cells and induce the expression of their surface activation markers, which in turn contributes to an adequate response to pathogens. Conclusion. The study revealed that the correction of immunological parameters with the use of GMDP in COVID-19 convalescents contributed not only to a decrease in the frequency and severity of respiratory infections, but also to an improvement in the psycho-emotional state of patients, and a decrease in anxiety and depression.Copyright © Eco-Vector, 2023. All rights reserved.

Complications Of A Severe Case Of Multisystem Inflammatory Syndrome In Children

Case Presentation: A 10 year old male with prior COVID-19 exposure presented with 7 days of fever, rash, cough, vomiting, and hypotension. Laboratory evaluation was notable for SARS-CoV2 antibodies, elevated cardiac enzymes, BNP, and inflammatory markers. Initial echocardiogram showed normal cardiac function and a small LAD coronary aneurysm. He was diagnosed with Multisystemic Inflammatory Syndrome in Children (MIS-C) and given methylprednisolone and IVIG. Within 24 hours, he developed severe LV dysfunction and progressive cardiorespiratory failure requiring VA-ECMO cannulation and anticoagulation with bivalirudin. Cardiac biopsy demonstrated lymphocytic infiltration consistent with myocarditis. On VA-ECMO, he had transient periods of complete AV block. With immunomodulator treatment (anakinra, infliximab) and 5 days of plasmapheresis, inflammatory symptoms and cardiac function improved. He weaned off ECMO, and anticoagulation was transitioned to enoxaparin. He had left sided weakness 5 days later, and brain MRI revealed an MCA infarct. Ten days later, he had focal right sided weakness and repeat MRI showed multiple hemorrhagic cortical lesions, thought to be thromboembolic with hemorrhagic conversion secondary to an exaggerated inflammatory response to an MSSA bacteremia in the setting of MIS-C. Enoxaparin was discontinued. After continued recovery and a slow anakinra and steroid wean, he has normal coronary arteries, cardiac function, and baseline ECG but requires ongoing neurorehabilitation. Discussion(s): COVID-19 infection in children is often mild, but MIS-C is an evolving entity that can present with a wide range of features and severity. This case highlights two concepts. While first degree AV block is often reported in MIS-C, there is potential for progression to advanced AV block. Close telemetry monitoring is critical, especially if there is evidence of myocarditis. MIS-C shares features with Kawasaki disease, with a notable difference being a higher likelihood of shock and cardiac dysfunction in MIS-C. In MIS-C patients with cardiovascular collapse requiring ECMO, there is a risk for stroke. There should be a low threshold for neuroimaging and multidisciplinary effort to guide anticoagulation in these complex cases.

Impact of COVID-19 in a Cohort of Patients With Inflammatory Intestinal Disease

BACKGROUND: There are few data on the outcome of COVID-19 in patients with IBD, none in the Chilean population. The aim of the study was to describe the demographic and clinical characteristics of patients with IBD who developed COVID-19, the evolution and clinical course of IBD at 1 month follow-up after SARS-CoV-2 infection. METHOD(S): This was an observational, cross-sectional, and analytical study. Patients with positive RT-PCR SARS-Cov-2 who were followed in the IBD Program of Clinica las Condes tertiary referral center (n = 1,493), were studied by spontaneous patient consultation and/or email survey. The clinical IBD data and COVID-19 related symptoms were obtained from the medical record and follow-up telephone interviews. Statistical significance was determined (Fisher's test P < 0.05). RESULT(S): From March 1 to August 31, 2020, 32 patients were reported positive RT-PCR SARSCov- 2, 18 (56%) ulcerative colitis and 14 (44%) Crohn's disease. The median age was 32 years (range 18 - 69), 56% women. Seven patients had an additional comorbidities. At the time of infection, 9 patients and their co-habitants maintained quarantine, isolation and social distancing recommendations. Only 1 patient was clinically active at the time of infection. Ten patients (31%) were on immunomodulator/biologic maintenance treatment, of which 4 were on combination therapy. Sixty percent of patients contacted the IBD clinical team when RT-PCR SARS-Cov-2 resulted positive. The most frequent COVID-19 onset symptoms were headache (66%), myalgia (63%), and fever (50%). Four patients required hospitalization (no 1 in Critical Care Unit), none of them were on immunomodulator nor biologic treatment. Two patients received Azithromycin and 1 received steroids as treatment for COVID-19. In univariate analysis, there were no significant differences in age, diagnosis or IBD treatment in patients who required hospitalization for COVID-19 infection. Seven patients discontinued their IBD treatment during the infection (6 at the direction of the IBD Program and 1 self-discontinued therapy). Two patients had a flare of their IBD during 1 month post-COVID-19 follow-up. CONCLUSION(S): In this cohort of patients, IBD medications, including immunomodulators and biologic therapy, were not associated with a greater severity of COVID-19 infection.

Patients with interstitial lung disease are high-risk of COVID-19 morbidity with implications on access to early oral anti-viral treatments

Introduction/Aim: Patients with interstitial lung disease (ILD) are at higher risk of COVID-19 infection associated morbidity and mortality, and hence may benefit from early anti-viral therapy. The access criteria for early oral anti-viral therapies for COVID-19 varied in early 2022 due to limited supplies nationally. We created a live clinical database of ILD patients in a tertiary hospital setting, stratifying them by measurable risk factors and therefore accessibility by state or national criteria to anti-viral therapy. Method(s): A list of active ILD clinic patients was generated from the WEBPAS clinic database. Data on patient demographics, co-morbidities and immunosuppressive medications relevant to access to anti-viral medications via the PBS criteria and state-based criteria was gathered by medical records review. Demographic information included age, BMI, ethnicity, residential care living and rurality. Co-morbidity risk factors included congestive cardiac failure, neurological disease, diabetes mellitus, chronic kidney disease, liver cirrhosis, chronic lung disease and immunodeficiencies. Medications of relevance included glucocorticoids, steroid-sparing immunomodulators and chemotherapy. Combinations of the above risk factors equate to eligibility to treatment. Result(s): Between the data capture dates of 1 February 2021 and 31 January 2022, 526 patients were identified. Of these 457 fit the inclusion criteria. Median age was 71.4 years (range 20-92), ratio of F:M was 1.09. 11% of patients were on long term oxygen therapy. Commonest conditions were idiopathic pulmonary fibrosis (26.3%), connective-tissue disease ILD (18%) and sarcoidosis (13.4%). 92 (20%) of patients fit into 'moderate or severely immunocompromised' criteria. 346 (75%) of patients fit criteria for early anti-virals by the first iteration of PBS criteria. Using the second iteration of PBS criteria, 374 (82%) of the ILD patients fit criteria for early anti-viral treatment. Notably, some patients qualify for anti-virals on multiple eligibility PBS criteria. Conclusion(s): A large proportion of our ILD cohort is deemed 'high risk' for COVID-19 morbidity and would qualify for early anti-viral therapies (regardless of vaccination status).

Anaplastic extramedullary plasmacytoma resistant to novel therapies: A case report

The treatment of choice for extramedullary plasmacytoma (EMP) is radiotherapy (RT). It is under discussion whether the management of an anaplastic form of EMP requires the addition of systemic therapy. We present a case of a 66-year-old male who was diagnosed with anaplastic plasmacytoma of the maxillary sinus. After the exclusion of multiple myeloma, Dara-VMP (daratumumab, bortezomib, melphalan, and prednisolone) regimen was initiated. During the third cycle of Dara-VMP, a progression of the tumor was observed. RT and BRd (bendamustine, dexamethasone, and lenalidomide) regimen were initiated. After 4 cycles of BRd, disease progression was established. KRd (carfilzomib, lenalidomide, and dexamethasone) regimen was initiated. The first cycle of KRd was not completed, as the patient was diagnosed with COVID-19. After the infection, the progression of EMP was observed. In this case, the anaplastic EMP was resistant to RT and chemotherapy regimens with novel agents, including a monoclonal antibody, an immunomodulatory drug, and proteasome inhibitors. Copyright © 2023 the author(s), published by De Gruyter, Berlin/Boston.

Epidemiologic Characteristics of Multisystem Inflammatory Syndrome in Children (Mis-C) with a Focus on Outcomes

Purpose of Study Treatment outcomes of children diagnosed with MIS-C are unclear and warrant investigation. The purpose of this study is to investigate the characteristics of pediatric patients diagnosed with MIS-C and their treatment outcomes with an emphasis on fatalities associated with MISC. Methods Used A literature review using Google Scholar and Pubmed using keywords such as 'Multisystem Inflammatory Syndrome in Children', 'Pediatric Inflammatory Multisystem Syndrome', and 'Coronavirus Disease 2019' was conducted. We included studies of hospitalized MIS-C patients with a sample size of more than 15. Summary of Results Of ten studies published before August 2020, five reported hospitalized MIS-C cases in the United States and five in Europe. A total of 514 hospitalized patients were reported with a sample size of 15 to 186 in various studies. Of 514 patients, 431 (84%) tested positive for SARS-CoV-2 via RT-PCR or serology. In different studies, 50% to 100% of MIS-C patients required PICU admission, 10% to 54% were intubated, and up to 80% required vasopressors. In studies that reported echocardiogram results, coronary artery dilations or aneurysm were noted in up to 93%, and depressed cardiac function was reported in 51- 100% of MIS-C patients. Treatment of MIS-C patients included intravenous immunoglobulins (IVIG) 388/514 (75%) plus steroids 288/514 (56%), along with anticoagulants and Anakinra 26/514 (5%). In total, 23 patients were put on ECMO, and of those, 16 (70%) survived. The larger studies reported fatality rate of 2% to 3% in hospitalized MIS-C patients. A total of 10 deaths were reported. Of the fatality causes that were described, 3 were associated with cerebral infarction after ECMO, 2 had not received IVIG, systemic glucocorticoids, or immunomodulators, and another 2 had co-morbidities. Conclusions Our review suggests that children with MIS-C who are hospitalized typically have a severe disease course. The outcome in vast majority of patients is favorable but death can occur, most likely as a result of cardiac dysfunction or cerebral infarction. Larger studies are needed to identify clinical features as well as laboratory and diagnostic parameters that predict disease severity and outcome.

A comparison of peripheral blood stem cell collection outcomes for multiple myeloma, mobilization matters in the era of IMiD induction

Collection of peripheral blood stem cells (PBSCs) for autologous stem cell transplant (ASCT) requires mobilization from the bone marrow. There is variation in mobilization choice;during the COVID-19 pandemic BSBMT&CT guidelines recommended using granulocyte-colony stimulating factor (G-CSF) alone to minimize the use of chemotherapy. We report on the impact of mobilization regimen on stem cell collection, and whether IMiD-containing induction therapy impacts on mobilization and consequently transplant engraftment times for 83 patients undergoing ASCT at Leeds Teaching Hospitals. Cyclophosphamide plus G-CSF (cyclo-G) mobilization yielded more CD34+ cells (8.94 vs. 4.88 x106/kg, p = < 0.0001) over fewer days (1.6 vs. 2.4 days, p = 0.007), and required fewer doses of salvage Plerixafor than G-CSF only (13.6% vs. 35%, p = 0.0407). IMiD-containing induction impaired all of these factors. CD34+ doses > 8x106/kg were more frequent with Cyclo-G (62% vs. 11%, p = 0.0001), including for those receiving IMiD 1st line induction (50% vs. 13.3%, p = 0.0381). Note that 92.6% of those receiving IMiD-free inductions were mobilized with Cyclo-G. The novel agents used in modern induction regimens (e.g Daratumumab) have been shown to impair yields, increasing the importance of optimizing mobilization regimens in the first instance. Furthermore, as cellular therapies become established in the management of multiple myeloma emerging data highlights the potential benefits of stem cell top up in the management of the haematological toxicities of these therapies. Our findings support re-adoption of Cyclo-G as the gold standard for mobilization to optimize PBSC harvesting and ensure sufficient cells for subsequent ASCTs.Copyright © 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

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.

Adequacy of Sotrovimab Prescription in Sarscov- 2 Infection in a University Hospital

Background and Importance The Spanish Medicines and Health Products Agency (AEMPS) has developed criteria to adapt the prescription of sotrovimab1, due to the pandemic situation and the limited drug stock. Aim and Objectives To describe the patients' population on treatment with sotrovimab and to assess the adequacy of this prescription according to the criteria established by the AEMPS. Material and Methods Retrospective observational study analysing all sotrovimab prescriptions in patients with SARS-CoV-2 infection from 01/25/2022 to 08/31/2022. Demographic variables and data required by the AEMPS for sotrovimab prescription were collected: Omicron variant infection, SARS-CoV-2 vaccination status, serology [anti-S antibody< 260 BAU (binding antibody units)/mL]. Also, patients had to belong to one of the following groups: * Group 1: Immunocompromised, regardless of vaccination status. * Group 2: >80 years unvaccinated. * Group 3: >65 years (regardless of vaccination status) and >=1 risk factor for progression. Prescriptions for sotrovimab were collected and analysed to determine whether they met the criteria and whether they were accepted. Data collected from electronic medical records and processed using Excel2019. Results Fifty patients were included, 62% male;median age 69 years (IQR=60-76). 100% had the Omicron variant. Vaccination status: 84% complete, 6% incomplete and 10% unvaccinated. Serology: 96% (<260 BAU/mL) and 4% (>260 BAU/ ml). 92% belonged to group 1 (39% solid organ transplantation, 29% active myelotoxic chemotherapy, 13% non-cytotoxic onco-haematological treatments with neutropenia/lymphopenia, 13% treatment with biological immunomodulators, 2% Down's syndrome, 2% haematopoietic stem cell transplantation or CAR-T, 2% HIV infection (with <=200 cells/mL). Two per cent belonged to group 2. The remaining patients (6%) did not belong to any group. Ten per cent of the applications did not meet the criteria: four of them were not accepted (patients did not belong to any risk group);one was accepted, although it was a well-controlled HIV. Conclusion and Relevance The main profile of patients treated with sotrovimab is men with solid organ transplantation, vaccinated and with negative immunity to SARS-CoV-2. Although the appropriateness of the prescription is high, it is necessary to continue protocolising the use of this drug to ensure its rational use.