A first-level customization study of SAPS II with Norwegian Intensive Care and Pandemic Registry (NIPaR) data.

BACKGROUND: Severity scores and mortality prediction models (MPMs) are important tools for benchmarking and stratification in the intensive care unit (ICU) and need to be regularly updated using data from a local and contextual cohort. Simplified acute physiology score II (SAPS II) is widely used in European ICUs. METHODS: A first-level customization was performed on the SAPS II model using data from the Norwegian Intensive Care and Pandemic Registry (NIPaR). Two previous SAPS II models (Model A: the original SAPS II model and Model B: a SAPS II model based on NIPaR data from 2008 to 2010) were compared to the new Model C. Model C was based on patients from 2018 to 2020 (corona virus disease 2019 patients omitted; n = 43,891), and its performances (calibration, discrimination, and uniformity of fit) compared to the previous models (Model A and Model B). RESULTS: Model C was better calibrated than Model A with a Brier score 0.132 (95% confidence interval 0.130-0.135) versus 0.143 (95% confidence interval 0.141-0.146). The Brier score for Model B was 0.133 (95% confidence interval 0.130-0.135). In the Cox's calibration regression α ≈ 0 and ß ≈ 1 for both Model C and Model B but not for Model A. Uniformity of fit was similar for Model B and for Model C, both better than for Model A, across age groups, sex, length of stay, type of admission, hospital category, and days on respirator. The area under the receiver operating characteristic curve was 0.79 (95% confidence interval 0.79-0.80), showing acceptable discrimination. CONCLUSIONS: The observed mortality and corresponding SAPS II scores have significantly changed during the last decades and an updated MPM is superior to the original SAPS II. However, proper external validation is required to confirm our findings. Prediction models need to be regularly customized using local datasets in order to optimize their performances.

Patients over 75 years admitted to the National Burn Centre, Haukeland University Hospital, 2000-19. / Pasienter over 75 år innlagt ved Brannskadeavdelinga, Haukeland universitetssjukehus 2000­19.

BACKGROUND: The number of burn patients over the age of 75 receiving advanced treatment, including extensive surgery and intensive care, is increasing. We aimed to describe the treatment and outcomes for burn patients over the age of 75 admitted to the National Burn Centre at Haukeland University Hospital. We also wanted to investigate whether frailty scores can be a predictor of the treatment outcome. MATERIAL AND METHOD: All patients ≥ 75 years admitted to the National Burn Centre at Haukeland University Hospital in the period 2000-19 were included in the study. Frailty scores were calculated retrospectively based on patients' medical records. RESULTS: Our study included 101 patients (50 women and 51 men). The number of admissions of older burn patients increased from an average of 3.3 per year in 2000-14 to 10.2 in the period 2015-19. The median total body surface area with burns was 11 % (range 0.9-80 %). Seventeen patients received palliative care, and 12 patients receiving active treatment died in hospital. In 68 of 84 (81 %) actively treated patients, tangential excision and split-thickness skin grafting were performed. The remainder received conservative treatment (non-surgical) with wound care and application of a silver dressing. Patients who died in hospital had a significantly higher total body surface area with burns (p < 0.0001) and higher frailty scores (p = 0.003) than patients who survived. INTERPRETATION: The yearly number of patients over the age of 75 treated at the National Burn Centre tripled during the period. More than two-thirds of the patients were discharged alive. Extent of burn injury and frailty score are associated with mortality and may be useful for adjusting therapy.

Epiglottitis. / Epiglottitt.

BACKGROUND: Acute epiglottitis in adults is a rare, potentially life-threatening condition caused by a bacterial infection in the epiglottis. Typical symptoms are fever, sore throat, and respiratory distress caused by upper airway obstruction. Proper treatment is needed for a good outcome. CASE PRESENTATION: We here present a 54-year-old female patient with acute epiglottitis. Her airway was secured by endotracheal intubation and she received antimicrobial therapy. She developed an abscess around the epiglottis that needed surgical drainage and tracheotomy. However, she fully recovered after nine days in hospital. INTERPRETATION: Acute epiglottitis in adults is a potentially life-threatening condition. The prognosis is good with proper treatment including selective airway intervention, antimicrobial therapy, and close monitoring.

Bidirectional crosstalk between platelets and monocytes initiated by Toll-like receptor: an important step in the early defense against fungal infections?

Monocytes are important in the defense against fungal infections due to their phagocytic and immunoregulatory functions. Platelets also contribute in such immune responses through their release of soluble mediators, including chemokines as well as several other soluble mediators. Both monocytes and platelets express several Toll-like receptors (TLRs) that can recognize fungal molecules and thus initiate intracellular signaling events. TLR ligation on monocytes and platelets may thereby be an early immunological event and function as an initiator of a local proinflammatory crosstalk between platelets and monocytes resulting in (i) monocyte-induced increase of platelet activation and (ii) platelet-associated enhancement of the monocyte activation/function. These effects may have clinical implications both for the efficiency of antifungal treatment and for the predisposition to fungal infections, for example, increased predisposition in patients with thrombocytopenia/monocytopenia due to chemotherapy- or disease-induced bone marrow failure.

The Regulation of Neutrophil Migration in Patients with Sepsis: The Complexity of the Molecular Mechanisms and Their Modulation in Sepsis and the Heterogeneity of Sepsis Patients.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Common causes include gram-negative and gram-positive bacteria as well as fungi. Neutrophils are among the first cells to arrive at an infection site where they function as important effector cells of the innate immune system and as regulators of the host immune response. The regulation of neutrophil migration is therefore important both for the infection-directed host response and for the development of organ dysfunctions in sepsis. Downregulation of CXCR4/CXCL12 stimulates neutrophil migration from the bone marrow. This is followed by transmigration/extravasation across the endothelial cell barrier at the infection site; this process is directed by adhesion molecules and various chemotactic gradients created by chemotactic cytokines, lipid mediators, bacterial peptides, and peptides from damaged cells. These mechanisms of neutrophil migration are modulated by sepsis, leading to reduced neutrophil migration and even reversed migration that contributes to distant organ failure. The sepsis-induced modulation seems to differ between neutrophil subsets. Furthermore, sepsis patients should be regarded as heterogeneous because neutrophil migration will possibly be further modulated by the infecting microorganisms, antimicrobial treatment, patient age/frailty/sex, other diseases (e.g., hematological malignancies and stem cell transplantation), and the metabolic status. The present review describes molecular mechanisms involved in the regulation of neutrophil migration; how these mechanisms are altered during sepsis; and how bacteria/fungi, antimicrobial treatment, and aging/frailty/comorbidity influence the regulation of neutrophil migration.

Systemic Metabolomic Profiles in Adult Patients with Bacterial Sepsis: Characterization of Patient Heterogeneity at the Time of Diagnosis.

Sepsis is a dysregulated host response to infection that causes potentially life-threatening organ dysfunction. We investigated the serum metabolomic profile at hospital admission for patients with bacterial sepsis. The study included 60 patients; 35 patients fulfilled the most recent 2016 Sepsis-3 criteria whereas the remaining 25 patients only fulfilled the previous Sepsis-2 criteria and could therefore be classified as having systemic inflammatory response syndrome (SIRS). A total of 1011 identified metabolites were detected in our serum samples. Ninety-seven metabolites differed significantly when comparing Sepsis-3 and Sepsis-2/SIRS patients; 40 of these metabolites constituted a heterogeneous group of amino acid metabolites/peptides. When comparing patients with and without bacteremia, we identified 51 metabolites that differed significantly, including 16 lipid metabolites and 11 amino acid metabolites. Furthermore, 42 metabolites showed a highly significant association with the maximal total Sequential Organ Failure Assessment (SOFA )score during the course of the disease (i.e., Pearson's correlation test, p-value < 0.005, and correlation factor > 0.6); these top-ranked metabolites included 23 amino acid metabolites and a subset of pregnenolone/progestin metabolites. Unsupervised hierarchical clustering analyses based on all 42 top-ranked SOFA correlated metabolites or the subset of 23 top-ranked amino acid metabolites showed that most Sepsis-3 patients differed from Sepsis-2/SIRS patients in their systemic metabolic profile at the time of hospital admission. However, a minority of Sepsis-3 patients showed similarities with the Sepsis-2/SIRS metabolic profile even though several of them showed a high total SOFA score. To conclude, Sepsis-3 patients are heterogeneous with regard to their metabolic profile at the time of hospitalization.

Adult presentation of ornithine transcarbamylase deficiency: a possible cause of hyperammonemia after high-dose chemotherapy and stem cell transplantation.

Hyperammonemia is a rare and often fatal complication following the conditioning therapy in autologous and allogeneic stem cell transplant recipients. It is characterized by anorexia, vomiting, lethargy and coma without any other apparent cause. The diagnosis is often delayed because symptoms can be subtle and ammonia is usually not included among the routine analyzes. Previous reports have not identified the molecular mechanisms behind hyperammonemia in stem cell transplant recipients. Urea cycle disorders (UCDs) are inborn errors of metabolism leading to hyperammonemia that usually presents in early childhood, whereas first presentation in adults is less common. Here we describe an adult woman with hyperammonemia following autologous stem cell transplantation for multiple myeloma. No apparent cause of hyperammonemia was identified, including portosystemic shunting, liver dysfunction or recent hyperammonemia-inducing chemotherapy. Hyperammonemia, normal blood glucose as well as anion gap and a previous history of two male newborns that died early after birth, prompted biochemical and genetic investigations for a UCD. A heterozygous variant in the X-linked gene encoding ornithine transcarbamylase (OTC) was identified and was regarded as a cause of UCD. The patient improved after treatment with nitrogen scavengers and high caloric intake according to a UCD protocol. This case report suggests that UCD should be considered as a possible cause of hyperammonemia following stem cell transplantation.

A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7-/-) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7-/- mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X-/- mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.

Implementation of a low-titre whole blood transfusion program in a civilian helicopter emergency medical service.

BACKGROUND: Early balanced transfusion is associated with improved outcome in haemorrhagic shock patients. This study describes the implementation and evaluates the safety of a whole blood transfusion program in a civilian helicopter emergency medical service (HEMS). METHODS: This prospective observational study was performed over a 5-year period at HEMS-Bergen, Norway. Patients in haemorrhagic shock receiving out of hospital transfusion of low-titre Group O whole blood (LTOWB) or other blood components were included. Two LTOWB units were produced weekly and rotated to the HEMS for forward storage. The primary endpoints were the number of patients transfused, mechanisms of injury/illness, adverse events and survival rates. Informed consent covered patient pathway from time of emergency interventions to last endpoint and subsequent data handling/storage. RESULTS: The HEMS responded to 5124 patients. Seventy-two (1.4%) patients received transfusions. Twenty patients (28%) were excluded due to lack of consent (16) or not meeting the inclusion criteria (4). Of the 52 (100%) patients, 48 (92%) received LTOWB, nine (17%) received packed red blood cells (PRBC), and nine (17%) received freeze-dried plasma. Of the forty-six (88%) patients admitted alive to hospital, 35 (76%) received additional blood transfusions during the first 24 h. Categories were blunt trauma 30 (58%), penetrating trauma 7 (13%), and nontrauma 15 (29%). The majority (79%) were male, with a median age of 49 (IQR 27-70) years. No transfusion reactions, serious complications or logistical challenges were reported. Overall, 36 (69%) patients survived 24 h, and 28 (54%) survived 30 days. CONCLUSIONS: Implementing a whole blood transfusion program in civilian HEMS is feasible and safe and the logistics around out of hospital whole blood transfusions are manageable. Trial registration The study is registered in the ClinicalTrials.gov registry (NCT02784951).

Patients with Bacterial Sepsis Are Heterogeneous with Regard to Their Systemic Lipidomic Profiles.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. In the present study, we investigated the systemic/serum lipidomic profile at the time of hospital admission for patients with bacterial sepsis. The study included 60 patients; 35 patients fulfilled the most recent 2016 Sepsis-3 criteria (referred to as Sepsis-3) whereas the remaining 25 patients had sepsis only according to the previous Sepsis-2 definition and could be classified as having Systemic Inflammatory Response Syndrome (SIRS). A total of 966 lipid metabolites were identified. Patients fulfilling the Sepsis-3 criteria differed from the Sepsis-2 patients with regard to only 15 lipid metabolites, and especially sphingolipids metabolism differed between these patient subsets. A total of only 43 metabolites differed between patients with and without bacteremia, including 12 lysophosphatidylcholines and 18 triacylglycerols (15 C18/C20 fatty acid metabolites decreased and three C14 myristate acid metabolites that were increased in bacteremia). Unsupervised hierarchical clustering analyses based on the identified sphingolipids, phosphatidylcholine and triacylglycerols showed that (i) the majority of Sepsis-3 patients differed from SIRS patients especially with regard to lysophosphatidylcholine levels; (ii) the minority of Sepsis-3 patients that clustered together with the majority of SIRS patients showed lower Sequential Organ Failure Assessment (SOFA) scores than the other Sepsis-3 patients; and (iii) the variation between the patients in the identified/altered sphingolipid and triacylglycerol metabolites further increased the heterogeneity of Sepsis-3 patients with regard to their systemic lipidomic profile at the time of diagnosis. To conclude, patients fulfilling the Sepsis-3 criteria differ with regard to their metabolic profile, and this variation depends on disease severity.

Spontaneous Splenic Artery Rupture as the First Symptom of Systemic Amyloidosis.

Spontaneous splenic rupture is a life-threatening condition leading to a rapidly progressing hypovolemic shock due to intra-abdominal blood loss, with a mortality rate of about 10%. Spontaneous splenic rupture can be caused by widely different disorders including acute and chronic infections, neoplastic disorders, and inflammatory noninfectious disorders. In this case report, we present a 67-year-old male patient with hemorrhagic shock caused by an acute bleeding from the splenic artery. The patient was massively transfused with blood products and fluids and underwent laparotomy for hemostatic control and clinical stabilization. Multiorgan involvement by amyloid light-chain amyloidosis (AL-amyloidosis) caused by plasma cell dyscrasia, specifically with infiltration of the spleen artery, was found to be the underlying cause of his life-threatening bleeding. Based on this case, we discuss the features of serious spleen bleeding, massive transfusion therapy in the intensive care setting, and AL-amyloidosis pathophysiology and treatment.

21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison's Disease Are Restricted by HLA-A2 and HLA-C7 Molecules.

Objectives: CD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison's disease (AAD). Earlier reports have suggested two immunodominant CD8+ T cell epitopes within 21OH: LLNATIAEV (21OH342-350), restricted by HLA-A2, and EPLARLEL (21OH431-438), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD. Methods: Recombinant fluorescent HLA-peptide multimer reagents were used to quantify antigen-specific CD8+ T cells by flow cytometry. Interferon-gamma (IFNγ) Elispot and biochemical assays were used to functionally investigate the 21OH-specific T cells, and to map the exactly defined epitopes of 21OH. Results: We found a significantly higher frequency of HLA-A2 restricted LLNATIAEV-specific cells in patients with AAD than in controls. These cells could also be expanded in vitro in an antigen specific manner and displayed a robust antigen-specific IFNγ production. In contrast, only negligible frequencies of EPLARLEL-specific T cells were detected in both patients and controls with limited IFNγ response. However, significant IFNγ production was observed in response to a longer peptide encompassing EPLARLEL, 21OH430-447, suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH434-442) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated. Conclusion: We have identified two dominant 21OH epitopes targeted by CD8+ T cells in AAD, restricted by HLA-A2 and HLA-C7, respectively. To our knowledge, this is the first HLA-C7 restricted epitope described for an autoimmune disease.

Transcriptional Changes in Regulatory T Cells From Patients With Autoimmune Polyendocrine Syndrome Type 1 Suggest Functional Impairment of Lipid Metabolism and Gut Homing.

Autoimmune polyendocrine syndrome type I (APS-1) is a monogenic model disorder of organ-specific autoimmunity caused by mutations in the Autoimmune regulator (AIRE) gene. AIRE facilitates the expression of organ-specific transcripts in the thymus, which is essential for efficient removal of dangerous self-reacting T cells and for inducing regulatory T cells (Tregs). Although reduced numbers and function of Tregs have been reported in APS-I patients, the impact of AIRE deficiency on gene expression in these cells is unknown. Here, we report for the first time on global transcriptional patterns of isolated Tregs from APS-1 patients compared to healthy subjects. Overall, we found few differences between the groups, although deviant expression was observed for the genes TMEM39B, SKIDA1, TLN2, GPR15, FASN, BCAR1, HLA-DQA1, HLA-DQB1, HLA-DRA, GPSM3 and AKR1C3. Of significant interest, the consistent downregulation of GPR15 may indicate failure of Treg gut homing which could be of relevance for the gastrointestinal manifestations commonly seen in APS-1. Upregulated FASN expression in APS-1 Tregs points to increased metabolic activity suggesting a putative link to faulty Treg function. Functional studies are needed to determine the significance of these findings for the immunopathogenesis of APS-1 and for Treg immunobiology in general.