The immunology of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; what can the tonsils reveal. A literature review.

Under embargo until: 25.11.2020Objectives: Tonsillectomy (TE) or adenotonsillectomy (ATE) may have a beneficial effect on the clinical course in children with the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. However, an immunological reason for this effect remains unknown. This literature review summarizes the current knowledge regarding the immunological role of the tonsils in the PFAPA syndrome. Methods: We searched PubMed, Medline, EMBASE and Cochrane for papers written in English dated from 1 January 1987 to 30 April 2019. The search included all studies reporting histological, immunological or microbiological workup of tonsil specimens from children aged 0–18 years with PFAPA. Results: Thirteen articles reported histological, immunological or microbiological workup of tonsil specimens in children with PFAPA. The histology of tonsil specimens from children with PFAPA displayed chronic tonsillar inflammation with lymphoid hyperplasia. No uniform immunological pattern was identified, but some studies found fewer B-lymphocytes and smaller germinal centers in PFAPA compared to controls. A difference in tonsillar microbiota between PFAPA and controls was found in one study. Conclusion: A uniform immunological or microbiological pattern explaining the clinical effect of TE in children with PFAPA has not been revealed. Future targeted immunological studies of tonsils in PFAPA patients could possibly illuminate the understanding of the immunology in this disease.acceptedVersio

Novel Nanoparticulate and Ionic Titanium Antigens for Hypersensitivity Testing

Titanium is used in a wide variety of materials ranging from medical devices to materials used in everyday life. Adverse biological reactions that could occur in patients, consumers, and workers should be monitored and prevented. There is a lack of available agents to test and predict titanium-related hypersensitivity. The aim of this study was to develop two bioavailable titanium substances in ionic and nanoparticulate form to serve as antigens for hypersensitivity testing in vitro. Peripheral blood mononuclear cells from 20 test subjects were stimulated with the antigens and secretion of monocytic and lymphatic cytokines and chemokines were measured by a multiplex bead assay. Lymphocyte stimulation indices were also determined in a subset of test subjects by measuring CD69 and HLA-DR expression by flow cytometry. Cytokine profiling revealed that both antigens increased production of typical monocyte and macrophage secreted cytokines after 24 h, with significant increases in IL-1β, IL-7, IL-10, IL-12, IL-2R, IL-6, GM-CSF, TNF-α, IL-1RA, MIP-1α, MIP-1β, IFN-α, and IL-15. Lymphatic cytokines and chemokines were not significantly induced by activation. After seven days of stimulation, ionic-Ti (2.5 μg/mL) caused proliferation (stimulation index > 2) of CD4+ cells and CD8+ cells in all persons tested (N = 6), while titanium dioxide nanoparticles (50 μg/mL) only caused significant proliferation of CD4+ cells. Our preliminary results show that the experimental titanium antigens, especially the ionic form, induce a general inflammatory response in vitro. A relevant cohort of test subjects is required to further elucidate their potential for predictive hypersensitivity testing.publishedVersio

Training of medical students in the use of emergency whole blood collection and transfusion in the framework of a civilian walking blood

Introduction: In this report, we describe a training program in emergency whole blood collection and transfusion for medical students at the University of Bergen. The overall aim of the program is to improve the availability of early balanced blood transfusion for the treatment of patients with life-threatening bleeding in rural health care services. Study Design and Methods: The voluntary training program provides the knowledge needed to practice emergency whole blood transfusions and understand the system for emergency whole blood collection in the framework of a civilian walking blood bank (WBB). It includes theoretical and practical sessions. In-person teaching and web-based learning resources are provided. An anonymous survey of the students attending the training course in the autumn of 2022 and spring 2023 was performed. Results: 128 of 178 students participated in the practical training. 88 of 128 (69%) responded to the survey. 82 (93%) performed blood typing, 71 (81%) performed donor interviews, 61 (69%) partially performed whole blood collection (up to blood in bag) and 27 (30%) participated in complete whole blood collection and performed autologous reinfusion. No complications occurred during training. The students reported that the training course increased their understanding of how to ensure access to emergency blood transfusion by the use of a WBB. Discussion: Structured theoretical and practical training in emergency whole blood collection and emergency transfusion is feasible and of interest to medical students. A multidisciplinary approach to student training in emergency whole blood collection and transfusion should be considered.publishedVersio

Thrombocytopaenia in the critically ill

publishedVersio

Implementation of a dual platelet inventory in a tertiary hospital during the COVID-19 pandemic enabling cold-stored apheresis platelets for treatment of actively bleeding patients

Background: To increase preparedness and mitigate the risk of platelet shortage without increasing the number of collections, we introduced a dual platelet inventory with cold-stored platelets (CSP) with 14-days shelf life for actively bleeding patients during the COVID-19 pandemic. Study design and methods: We collected apheresis platelet concentrates with blood type O or A. All patients receiving CSP units were included in a quality registry. Efficacy was evaluated by total blood usage and laboratory analysis of platelet count, hemoglobin, and TEG 6s global hemostasis assay. Feasibility was evaluated by monitoring inventory and a survey among laboratory staff. Results: From 17 March, 2020, to 31 December, 2021, we produced 276 CSP units and transfused 186 units to 92 patients. Main indication for transfusion was surgical bleeding (88%). No transfusion reactions were reported. 24-h post-transfusion patient survival was 96%. Total outdate in the study period was 33%. The majority (75%) of survey respondents answered that they had received sufficient information and training before CSP was implemented. Lack of information about bleeding status while issuing platelets, high workload, and separate storage location was described as main reasons for outdates. Discussion: CSP with 14-days shelf life is a feasible alternative for the treatment of patients with bleeding. Implementation of a dual platelet inventory requires thorough planning, including information and training of clinical and laboratory staff, continuous follow-up of practice and patients, and an easy-to-follow algorithm for use of CSP units. A dual platelet inventory may mitigate the risk of platelet shortage during a pandemic situation.publishedVersio

In vitro quality of cold and delayed cold-stored platelet concentrates from interim platelet units during storage for 21 days

Background and Objectives: Based on previous success using apheresis platelets, we wanted to investigate the in vitro quality and platelet function in continuously cold-stored and delayed cold-stored platelet concentrates (PCs) from interim platelet units (IPUs) produced by the Reveos system. Materials and Methods: We used a pool-and-split design to prepare 18 identical pairs of PCs. One unit was stored unagitated and refrigerated after production on day 1 (cold-stored). The other unit was stored agitated at room temperature until day 5 and then refrigerated (delayed cold-stored). Samples were taken after pool-and-split on day 1 and on days 5, 7, 14 and 21. Swirling was observed and haematology parameters, metabolism, blood gas, platelet activation and platelet aggregation were analysed for each sample point. Results: All PCs complied with European recommendations (EDQM 20th edition). Both groups had mean platelet content >200 × 109/unit on day 21. The pH remained above 6.4 for all sample points. Glucose concentration was detectable in every cold-stored unit on day 21 and in every delayed cold-stored unit on day 14. The cold-stored group showed a higher activation level before stimulation as measured by flow cytometry. The activation levels were similar in the two groups after stimulation. Both groups had the ability to form aggregates after cold storage and until day 21. Conclusion: Our findings suggest that PCs from IPUs are suitable for cold storage from day 1 until day 21 and delayed cold storage from day 5 until day 14.publishedVersio

A phase I prospective, non-randomized trial of autologous dendritic cell-based cryoimmunotherapy in patients with metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is an immunologically cold disease with dismal outcomes. Cryoablation destroys cancer tissue, releases tumor-associated antigens and creates a pro-inflammatory microenvironment, while dendritic cells (DCs) activate immune responses through processing of antigens. Immunotherapy combinations could enhance the anti-tumor efficacy. This open-label, single-arm, single-center phase I trial determined the safety and tolerability of combining cryoablation and autologous immature DC, without and with checkpoint inhibitors. Immune responses and clinical outcomes were evaluated. Patients with mCRPC, confirmed metastases and intact prostate gland were included. The first participants underwent prostate cryoablation with intratumoral injection of autologous DCs in a 3 + 3 design. In the second part, patients received cryoablation, the highest acceptable DC dose, and checkpoint inhibition with either ipilimumab or pembrolizumab. Sequentially collected information on adverse events, quality of life, blood values and images were analyzed by standard descriptive statistics. Neither dose-limiting toxicities nor adverse events > grade 3 were observed in the 18 participants. Results indicate antitumor activity through altered T cell receptor repertoires, and 33% durable (> 46 weeks) clinical benefit with median 40.7 months overall survival. Post-treatment pain and fatigue were associated with circulating tumor cell (CTC) presence at inclusion, while CTC responses correlated with clinical outcomes. This trial demonstrates that cryoimmunotherapy in mCRPC is safe and well tolerated, also for the highest DC dose (2.0 × 108) combined with checkpoint inhibitors. Further studies focusing on the biologic indications of antitumor activity and immune system activation could be considered through a phase II trial focusing on treatment responses and immunologic biomarkers.publishedVersio

Platelet functionality in cold-stored whole blood

Whole blood is currently being reintroduced as a blood product to be used in massive bleeding situations because it affords plasma, red cells and platelets in a balanced ratio and in a logistical advantageous way. Questions concerning the haemostatic potential of the platelets have arisen, especially in cold‐stored whole blood, as this is the major whole blood product in use. When reviewing current knowledge on this, there is an abundance of publications demonstrating that in vitro, platelets in cold‐stored whole blood have a haemostatic capacity up to 14 days, and even after 21 and 35 days of storage depending on type of additive solution. There is a paucity of data on clinical trials of cold‐stored platelets, whereas there is an abundance of previous clinical experience with whole blood, both cold‐stored and fresh, as an efficacious and safe product for use in pre‐ and in‐hospital patients with life‐threatening bleeding

The immunology of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; what can the tonsils reveal. A literature review.

Objectives: Tonsillectomy (TE) or adenotonsillectomy (ATE) may have a beneficial effect on the clinical course in children with the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. However, an immunological reason for this effect remains unknown. This literature review summarizes the current knowledge regarding the immunological role of the tonsils in the PFAPA syndrome. Methods: We searched PubMed, Medline, EMBASE and Cochrane for papers written in English dated from 1 January 1987 to 30 April 2019. The search included all studies reporting histological, immunological or microbiological workup of tonsil specimens from children aged 0–18 years with PFAPA. Results: Thirteen articles reported histological, immunological or microbiological workup of tonsil specimens in children with PFAPA. The histology of tonsil specimens from children with PFAPA displayed chronic tonsillar inflammation with lymphoid hyperplasia. No uniform immunological pattern was identified, but some studies found fewer B-lymphocytes and smaller germinal centers in PFAPA compared to controls. A difference in tonsillar microbiota between PFAPA and controls was found in one study. Conclusion: A uniform immunological or microbiological pattern explaining the clinical effect of TE in children with PFAPA has not been revealed. Future targeted immunological studies of tonsils in PFAPA patients could possibly illuminate the understanding of the immunology in this disease

Novel Nanoparticulate and Ionic Titanium Antigens for Hypersensitivity Testing

Titanium is used in a wide variety of materials ranging from medical devices to materials used in everyday life. Adverse biological reactions that could occur in patients, consumers, and workers should be monitored and prevented. There is a lack of available agents to test and predict titanium-related hypersensitivity. The aim of this study was to develop two bioavailable titanium substances in ionic and nanoparticulate form to serve as antigens for hypersensitivity testing in vitro. Peripheral blood mononuclear cells from 20 test subjects were stimulated with the antigens and secretion of monocytic and lymphatic cytokines and chemokines were measured by a multiplex bead assay. Lymphocyte stimulation indices were also determined in a subset of test subjects by measuring CD69 and HLA-DR expression by flow cytometry. Cytokine profiling revealed that both antigens increased production of typical monocyte and macrophage secreted cytokines after 24 h, with significant increases in IL-1β, IL-7, IL-10, IL-12, IL-2R, IL-6, GM-CSF, TNF-α, IL-1RA, MIP-1α, MIP-1β, IFN-α, and IL-15. Lymphatic cytokines and chemokines were not significantly induced by activation. After seven days of stimulation, ionic-Ti (2.5 μg/mL) caused proliferation (stimulation index > 2) of CD4+ cells and CD8+ cells in all persons tested (N = 6), while titanium dioxide nanoparticles (50 μg/mL) only caused significant proliferation of CD4+ cells. Our preliminary results show that the experimental titanium antigens, especially the ionic form, induce a general inflammatory response in vitro. A relevant cohort of test subjects is required to further elucidate their potential for predictive hypersensitivity testing