Convalescent plasma transfusion for immunocompromised viremic patients with COVID-19: A retrospective multicenter study.

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

Expert Revision of Key Elements for Clinical-Grade Production and Qualification of Perinatal Derivatives.

Perinatal derivatives have been proposed as adjunct therapeutic strategies or innovative treatments. Undoubtedly, perinatal derivatives can offer the opportunity and source material to isolate multipotent stem cells, but both maternal- and fetal-derived tissues can be processed and transformed into engineered tissues or advanced biomedical devices, whose potential remains to be fully elucidated. Promising preclinical and clinical results collected so far clearly foresee an escalation of such novel treatments. Market forecasts predict exponential growth in such advanced medicinal products during the next decade, with a pragmatic innovation for medicine into a more advanced biomedical version, enlarging the portfolio for treating a wide range of congenital and acute conditions. However, all these promising and fascinating therapeutic possibilities cannot gain a solid and recognized role in established medical practice without rigid and harmonized manufacturing strategies. The implementation of strategies according to guidelines and directives compiled by Regulatory Agencies, in conformity to (European) Pharmacopoeia and for Good Manufacturing Practice -conforming production of such products, represent critical steps required to translate perinatal technologies into effective therapeutic approaches. During the past 5 years, a panel of European experts and developers, gathered under the umbrella of the COST Sprint Action, supported by the European Cooperation in Science and Technology action, had the opportunity to revise and summarize experience and recommendations for a fruitful and proficient generation of perinatal biomedical products. In order to facilitate the creation and potential commercialization of perinatal bioengineered and advanced pharmaceutical products and technologies, such a collection of data and recommendations is described and discussed here.

Effect of microorganisms isolated by preoperative osseous sampling on surgical site infection after autologous cranioplasty: A single-center experience.

PURPOSE: The most frequent postoperative complication in autologous cranioplasty (AC) is infection. European recommendations include osseous sampling before cryogenic storage of a bone flap. We evaluated the clinical impact of this sampling. METHODS: All patients who underwent decompressive craniectomy (DC) and AC in our center between November 2010 and September 2021 were reviewed. The main outcome was the rate of reoperation for infection of the cranioplasty. We evaluated risk factors for bone flap infection, rate of reoperation for any reason (hematoma, skin erosion, cosmetic request, or bone resorption), and radiological evidence of bone flap resorption. RESULTS: A total of 195 patients with a median age of 50 (interquartile range: 38.0-57.0) years underwent DC and AC between 2010 and 2021. Of the 195 bone flaps, 54 (27.7%) had a positive culture, including 48 (88.9%) with Cutibacterium acnes. Of the 14 patients who underwent reoperation for bone flap re-removal for infection, 5 and 9 had positive and negative bacteriological cultures, respectively. Of patients who did not have bone flap infection, 49 and 132 had positive and negative bacteriological cultures, respectively. There were no significant differences between patients with and without positive bacteriological culture of bone flaps in the rates of late bone necrosis and reoperation for bone flap infection. CONCLUSIONS: A positive culture of intraoperative osseous sampling during DC is not associated with a higher risk of re-intervention after AC.

Expert Consideration on Regulatory Aspects for Perinatal Derivatives in Clinical Settings.

Perinatal derivatives (PnD) are drawing growing interest among the scientific community as an unrestricted source of multipotent stem cells, secretome, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options, but they require the development of regenerative approaches. With this development, the question of regulation of donation, processing, and distribution has therefore become more important. Within the European Cooperation in Science and Technology (COST) community, we compiled a group of international experts on PnD technologies, who revised and compared existing EU national regulations. Notably, despite clear European directives, each EU Country has developed their own implementation and standard levels for cell- and tissue-based therapies. To enable extended applications of PnD treatments within the EU community and worldwide, harmonization is highly recommended. This paper aims to provide an overview of the various options available to introduce PnD into clinical practice. For this purpose, the different aspects resulting from (1) the type of PnD, (2) the amount of available data, (3) the degree of manipulation, and (4) the intended application and the process toward a possible commercialization will be presented. In the future, it will be important to find a balance between regulatory requirements and the best medical quality of the PnD product.

De novo natural anti-M alloantibody emergence in severe Coronavirus Disease 2019.

The immune response is a key player in the course of SARS-CoV-2 infection, and is often seriously dysfunctional in severe Coronavirus Disease 2019. The hyperinflammatory status has been described to be accompanied by the appearance of autoantibodies. In a lethal COVID-19 infection, we observed the emergence of a de novo natural alloantibody which targeted the M antigen from the MNS blood group on red blood cells (RBC) without evidence of any cross-reaction with SARS-CoV-2 antigens. This IgM lambda alloantibody was unmutated and unswitched. Here, we describe for the first time the emergence of a bystander de novo natural alloantibody against RBCs in a severe COVID-19 patient, highlighting the extra-follicular humoral response reported in these cases.

Perinatal derivatives application: Identifying possibilities for clinical use.

Perinatal derivatives are drawing growing interest among the scientific community as an unrestricted source of multipotent stromal cells, stem cells, cellular soluble mediators, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options by means of developing regenerative approaches. In this paper, to generate a complete view of the state of the art, a comprehensive 10-years compilation of clinical-trial data with the common denominator of PnD usage has been discussed, including commercialized products. A set of criteria was delineated to challenge the 10-years compilation of clinical trials data. We focused our attention on several aspects including, but not limited to, treated disorders, minimal or substantial manipulation, route of administration, dosage, and frequency of application. Interestingly, a clear correlation of PnD products was observed within conditions, way of administration or dosage, suggesting there is a consolidated clinical practice approach for the use of PnD in medicine. No regulatory aspects could be read from the database since this information is not mandatory for registration. The database will be publicly available for consultation. In summary, the main aims of this position paper are to show possibilities for clinical application of PnD and propose an approach for clinical trial preparation and registration in a uniform and standardized way. For this purpose, a questionnaire was created compiling different sections that are relevant when starting a new clinical trial using PnD. More importantly, we want to bring the attention of the medical community to the perinatal products as a consolidated and efficient alternative for their use as a new standard of care in the clinical practice.

Tips and Tricks and Clinical Outcome of Cryopreserved Human Amniotic Membrane Application for the Management of Medication-Related Osteonecrosis of the Jaw (MRONJ): A Pilot Study.

Medication-related osteonecrosis of the jaw (MRONJ) is a complication of certain pharmacological treatments such as bisphosphonates, denosumab, and angiogenesis inhibitors. There are currently no guidelines on its management, particularly in advanced stages. The human amniotic membrane (hAM) has low immunogenicity and exerts anti-inflammatory, antifibrotic, antimicrobial, antiviral, and analgesic effects. It is a source of stem cells and growth factors promoting tissue regeneration. hAM acts as an anatomical barrier with suitable mechanical properties (permeability, stability, elasticity, flexibility, and resorbability) to prevent the proliferation of fibrous tissue and promote early neovascularization at the surgical site. In oral surgery, hAM stimulates healing and facilitates the proliferation and differentiation of epithelial cells in the oral mucosa and therefore its regeneration. We proposed using cryopreserved hAM to eight patients suffering from cancer (11 lesions) with stage 2-3 MRONJ on a compassionate use basis. A collagen sponge was added in some cases to facilitate hAM grafting. One or three hAMs were applied and one patient had a reapplication. Three patients had complete closure of the surgical site with proper epithelialization at 2 weeks, and two of them maintained it until the last follow-up. At 1 week after surgery, three patients had partial wound dehiscence with partial healing 3 months later and two patients had complete wound dehiscence. hAM reapplication led to complete healing. All patients remained asymptomatic with excellent immediate significant pain relief, no infections, and a truly positive impact on the patients' quality of life. No adverse events occurred. At 6 months of follow-up, 80% of lesions had complete or partial wound healing (30 and 50%, respectively), while 62.5% of patients were in stage 3. Radiological evaluations found that 85.7% of patients had stable bone lesions (n = 5) or new bone formation (n = 1). One patient had a worsening MRONJ but remained asymptomatic. One patient did not attend his follow-up radiological examination. For the first time, this prospective pilot study extensively illustrates both the handling and surgical application of hAM in MRONJ, its possible association with a collagen sponge scaffold, its outcome at the site, the application of multiple hAM patches at the same time, and its reapplication.

Surgical Application of Human Amniotic Membrane and Amnion-Chorion Membrane in the Oral Cavity and Efficacy Evaluation: Corollary With Ophthalmological and Wound Healing Experiences.

Due to its intrinsic properties, there has been growing interest in human amniotic membrane (hAM) in recent years particularly for the treatment of ocular surface disorders and for wound healing. Herein, we investigate the potential use of hAM and amnion-chorion membrane (ACM) in oral surgery. Based on our analysis of the literature, it appears that their applications are very poorly defined. There are two options: implantation or use as a cover material graft. The oral cavity is submitted to various mechanical and biological stimulations that impair membrane stability and maintenance. Thus, some devices have been combined with the graft to secure its positioning and protect it in this location. This current opinion paper addresses in detail suitable procedures for hAM and ACM utilization in soft and hard tissue reconstruction in the oral cavity. We address their implantation and/or use as a covering, storage format, application side, size and number, multilayer use or folding, suture or use of additional protective covers, re-application and resorption/fate. We gathered evidence on pre- and post-surgical care and evaluation tools. Finally, we integrated ophthalmological and wound healing practices into the collected information. This review aims to help practitioners and researchers better understand the application of hAM and ACM in the oral cavity, a place less easily accessible than ocular or cutaneous surfaces. Additionally, it could be a useful reference in the generation of new ideas for the development of innovative protective covering, suturing or handling devices in this specific indication. Finally, this overview could be considered as a position paper to guide investigators to fulfill all the identified criteria in the future.

Feasibility of convalescent plasma therapy in severe COVID-19 patients with persistent SARS-CoV-2 viremia.

This study aims to assess the efficacy and safety of convalescent plasma therapy (CPT) in COVID-19 critically ill patients with protracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia. A retrospective cohort study was conducted in intensive care unit (ICU). All patients with severe COVID-19 pneumonia for whom RNAemia remained positive more than 14 days after onset of the infection were included and given CPT. The primary objective was to evaluate SARS-CoV-2 RNAemia 7 days (D7) after CPT. A total of 14 patients were included and they received a median CPT volume of 828 ml (range: 817-960). CPT was administered in a median time of 14 days after ICU admission. At D7, 13/14 patients had negative SARS-CoV-2 blood PCR and one patient had negative blood PCR 11 days after CPT. At D7 and at D14, the clinical status was improved in 7/14 and 11/14 patients, respectively. The 28-day mortality rate was 14%. No CPT-related adverse effects had been reported. CPT is safe and may be efficient in patients with protracted RNAemia admitted in ICU for severe COVID-19 pneumonia. Randomized controlled trials are needed to confirm these results.

Discarded plasma obtained after cord blood volume reduction as an alternative for fetal calf serum in mesenchymal stromal cells cultures.

BACKGROUND: Utilization of the fetal calf serum (FCS) carries a potential health risk and raises growing economic and ethical problems. Umbilical cord blood volume reduction, required for banking, provides clinical-grade umbilical cord blood plasma (UCBP) discarded as a waste. The aim of this study was to test whether serum derived from UCBP could replace FCS for the amplification of mesenchymal stromal cells (MSCs). STUDY DESIGN AND METHODS: To this end, the amplification of the MSCs and mesenchymal progenitors was estimated in the presence of serum derived from UCBP and its cytokine content was determined by cytometric bead array and enzyme-linked immunosorbent assay techniques. As a comparison, other sources of clinical-grade human serum were tested in parallel: serum derived from solvent/detergent-treated fresh-frozen plasma (S/D-FFP) and from platelet (PLT)-rich and PLT-poor umbilical plasma. RESULTS: Serum derived from UCBP-supplemented culture sustains identical amplification of MSCs and their progenitors as in the case of FCS addition. Furthermore, the assays reveal the presence in the serum derived from UCBP of cytokines influencing the properties of MSCs (basic fibroblast growth factor, transforming growth factor-ß, vascular endothelial growth factor, and interleukin-8) or involved in the development of the myeloid lineage (thrombopoietin, erythropoietin, granulocyte-colony-stimulating factor, and granulocyte-macrophage-colony-stimulating factor). Also, our study indicates important differences between neonatal and adult-derived serum. Poor cytokine content in the S/D-FFP makes a less efficient replacement of FCS comparing to other human blood-derived supplements. CONCLUSION: Our work shows that the discarded human cord blood plasma from volume reduction is an easily obtainable and greatly available, xeno-free source of serum that is a highly efficient replacement of FCS in sustaining MSC growth.

Killer immunoglobulin-like receptor genotypes and chronic myeloid leukemia outcomes after imatinib cessation for treatment-free remission.

BACKGROUND: Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin-like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells. METHODS: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2. RESULTS: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B-positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32-0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment-free remission rates. CONCLUSION: These results suggest that KIR2DL5B could carry a role in lymphocyte-mediated control of leukemic residual disease control in patient with CML relapse.

HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation.

Matching for HLA-A, -B, -C, and -DRB1 loci (8/8 match) is currently the gold standard for unrelated donor hematopoietic cell transplantation (HCT). In Europe, patients are also matched at the HLA-DQB1 loci (10/10 match). However, there is increasing evidence that matching at HLA-DRB3/4/5 loci may help to lower transplant-related morbidity and mortality. We therefore investigated the impact of HLA-DRB3/4/5 mismatches on outcomes in 1975 patients who received a first 10/10 matched unrelated donor (MUD) HCT in France from 2000 to 2012 for a hematological malignancy. High-resolution typing was performed at HLA-A, -B, -C, -DRB1, -DQB1, -DPB1, and -DRB3/4/5 loci for all donor/recipient pairs. Compared with DRB3/4/5-matched pairs, patients who received a MUD HCT from a DRB3/4/5 mismatched donor had a significantly increased risk of grade II-IV acute graft-versus-host disease (aGVHD) (Adjusted Hazard Ratio (HR) 1.43 (1.07 to 1.90)) associated with lower graft-versus-host disease-free and relapse-free survival (GRFS) (Adjusted HR 1.20 (1.02 to 1.42)). Conversely, we observed no differences in terms of chronic GVHD, nonrelapse mortality, relapse and overall survival. However, we believe that patients stand to benefit from DRB3/4/5 loci being considered for unrelated donor selection to improve GRFS and then quality of life after unrelated HCT.

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD.

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

Risk Factors for Steroid-Refractory Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation from Matched Related or Unrelated Donors.

We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients.

Neonatal sex and weight influence CD34(+) cell concentration in umbilical cord blood but not stromal cell-derived factor 1-3'A polymorphism.

BACKGROUND: Umbilical cord blood (UCB) has been used as an alternative source of donor hematopoietic stem cells for hematologic transplant setting over the past decade. This study attempted to evaluate potential predictors of cord blood quality. METHODS: A total of 750 UCB samples were studied (male, n = 365; female, n = 385). The impact of neonatal sex, weight and stromal cell-derived factor-1α polymorphism on the quality of these UCB samples was investigated. RESULTS: Male neonatal UCB was significantly richer in CD34(+) cells than was female UCB (P < 0.001), whereas female UCB was richer in total nucleated cells (P = 0.01). There was a slight correlation between CD34(+) cells concentration and UCB sample weight (P < 0.01) that could be attributed to the higher weight of male neonates. The use of tetra-polymerase chain reaction to detect stromal cell-derived factor-1α polymorphisms in 180 neonates revealed no differences between A/A, G/G and A/G allelic combinations. CONCLUSIONS: These data emphasize the lack of predictive factors for CD34(+) cells and total nucleated cell concentrations in UCB samples before processing.

Hypoxia/hypercapnia-induced adaptation maintains functional capacity of cord blood stem and progenitor cells at 4°C.

We analyzed the effect of exposure to hypoxic/hypercapnic (HH) gas mixture (5% O2 /9% CO2 ) on the maintenance of functional cord blood CD34(+) hematopoietic stem and progenitor cells in severe hypothermia (4°C) employing the physiological and proteomic approaches. Ten-day exposure to HH maintained the Day 0 (D-0) level of hematopoietic stem cells as detected in vivo on the basis of hematopoietic repopulation of immunodeficient mice-short-term scid repopulating cells (SRC). Conversely, in the atmospheric air (20% O2 /0.05% CO2 ), usual condition used for cell storage at 4°C, stem cell activity was significantly decreased. Also, HH doubled the survival of CD34(+) cells and committed progenitors (CFCs) with respect to the atmospheric air (60% vs. 30%, respectively). Improved cell maintenance in HH was associated with higher proportion of aldehyde dehydrogenase (ALDH) positive cells. Cell-protective effects are associated with an improved maintenance of the plasma and mitochondrial membrane potential and with a conversion to the glycolytic energetic state. We also showed that HH decreased apoptosis, despite a sustained ROS production and a drop of ATP amount per viable cell. The proteomic study revealed that the global protein content was better preserved in HH. This analysis identified: (i) proteins sensitive or insensitive to hypothermia irrespective of the gas phase, and (ii) proteins related to the HH cell-protective effect. Among them are some protein families known to be implicated in the prolonged survival of hibernating animals in hypothermia. These findings suggest a way to optimize short-term cell conservation without freezing.

Preliminary pharmaceutical development of antimalarial-antibiotic cotherapy as a pre-referral paediatric treatment of fever in malaria endemic areas.

Artemether (AM) plus azithromycin (AZ) rectal co-formulations were studied to provide pre-referral treatment for children with severe febrile illnesses in malaria-endemic areas. The target profile required that such product should be cheap, easy to administer by non-medically qualified persons, rapidly effective against both malaria and bacterial infections. Analytical and pharmacotechnical development, followed by in vitro and in vivo evaluation, were conducted for various AMAZ coformulations. Of the formulations tested, stability was highest for dry solid forms and bioavailability for hard gelatin capsules; AM release from AMAZ rectodispersible tablet was suboptimal due to a modification of its micro-crystalline structure.