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Background Patients with rare diseases (RD) may present to the emergency department (ED) with an acute manifestation of an undiagnosed RD. If not identified, some of these patients may suffer from increased morbidity, mortality and worse outcomes compared to patients with more common diseases. Unfortunately, patients with RD often present with common symptoms, e.g. abdominal pain, making it even more difficult for ED physicians to identify those patients. Thus, strategies are needed to determine when certain RD should be suspected in the ED. We aimed to identify common features of RD through a systematised literature review of a predefined set of RD. Methods Embase and MEDLINE were searched for eligible studies published in all years up to November 2023. Studies reporting clinical characteristics of patients who presented to the ED with one out of a predefined set of eight RD were included: acute hepatic porphyria, Fabry disease, familial Mediterranean fever, hereditary angioedema, hereditary hemorrhagic telangiectasia, myasthenia gravis, paroxysmal nocturnal hemoglobinuria and thrombotic thrombocytopenic purpura. Clinical characteristics, symptoms and family history were extracted to explore potential common features. Database searches, title, abstract and full-text screening and data extraction were conducted by a single reviewer. Results Of the 4 732 articles identified, 18 were included in the review. For two RD no articles and for three RD only one article could be included. All but two prospective studies were retrospective chart reviews or case series reporting on small patient cohorts ( n  = 3 - 75 patients). The common features of patients were: age under 65 years, recurrent symptoms affecting multiple organ systems, normal or nonspecific findings in routine laboratory tests and imaging, presence of trigger factors and a positive family history of similar symptoms or RD. Conclusion This review highlights the limited knowledge about RD in the ED setting. Some common features of RD patients were identified that could aid future research in developing risk stratification algorithms to facilitate early detection and treatment of RD in the ED. To our knowledge, this is the first literature review to explore the common features of patients with RD in the ED.

Background Early in the host-response to infection, neutrophils release calprotectin, triggering several immune signalling cascades. In acute infection management, identifying infected patients and stratifying these by risk of deterioration into sepsis, are crucial tasks. Recruiting a heterogenous population of patients with suspected infections from the emergency department, early in the care-path, the CASCADE trial aimed to evaluate the accuracy of blood calprotectin for detecting bacterial infections, estimating disease severity, and predicting clinical deterioration. Methods In a prospective, observational trial from February 2021 to August 2022, 395 patients ( n  = 194 clinically suspected infection; n  = 201 controls) were enrolled. Blood samples were collected at enrolment. The accuracy of calprotectin to identify bacterial infections, and to predict and identify sepsis and mortality was analysed. These endpoints were determined by a panel of experts. Results The Area Under the Receiver Operating Characteristic (AUROC) of calprotectin for detecting bacterial infections was 0.90. For sepsis within 72 h, calprotectin’s AUROC was 0.83. For 30-day mortality it was 0.78. In patients with diabetes, calprotectin had an AUROC of 0.94 for identifying bacterial infection. Conclusions Calprotectin showed notable accuracy for all endpoints. Using calprotectin in the emergency department could improve diagnosis and management of severe infections, in combination with current biomarkers. Clinical trial registration number DRKS00020521

Background Providing individualised healthcare in line with patient wishes is a particular challenge for emergency healthcare professionals. Documentation of patient wishes (DPW), e.g. as advance directives, can guide clinicians in making end-of-life decisions that respect the patient’s wishes and autonomy. However, patient centered decisions are hindered by limited availability of DPWs in emergency settings. Objective This systematic review aims to congregate present data on recorded rates for DPW existence and availability in the emergency department (ED) as well as contributing factors for these rates. Methods We searched MEDLINE, Google Scholar, Embase and Web of Science databases in September 2023. Publications providing primary quantitative data on DPW in the ED were assessed. Publications referring only to a subset of ED patients (other than geriatric) and investigating DPW issued after admission were excluded. Results A total of 22 studies from 1996 to 2021 were included in the analysis. Most were from the US ( n  = 12), followed by Australia ( n  = 4), Canada ( n  = 2), South Korea, Germany, the United Kingdom and Switzerland ( n  = 1 each). In the general adult population presenting to the ED, 19.9–27.8% of patients reported having some form of DPW, but only in 6.8% or less it was available on presentation. In the geriatric population, DPW rates (2.6–79%) as well as their availability (1.1–48.8%) varied widely. The following variables were identified as positive predictors of having DPW, among others: higher age, poorer overall health, as well as sociodemographic factors, such as female gender, having children, being in a relationship, higher level of education or a recent previous presentation to hospital. Conclusions Existence and availability of a recorded DPW among ED patients was low in general and even in geriatric populations mostly well below 50%. While we were able to gather data on prevalence and predictors, this was limited by heterogeneous data. We believe further research is needed to explore the quality of DPW and measures to increase both rates of existence and availability of DPW in the ED.

Background Acute porphyrias (APs) are a group of rare metabolic diseases related to a disturbed heme biosynthesis. Symptoms may first occur as life threatening attacks, comprising abdominal pain and/or variable neuro-psychiatric symptoms, thus leading to presentation in emergency departments (ED) first. Due to the low prevalence, diagnosis of AP is often missed, even after readmission to the ED. Therefore, strategies are needed to consider APs in ED patients with unexplained abdominal pain, especially since early and adequate treatment will avoid an unfavorable clinical course. Aim of this prospective study was to investigate the prevalence of APs in ED patients and thus, addressing feasibility of screening for rare diseases, such as APs in the real life setting. Methods From September 2019 to March 2021, patients presenting to the ED of three German tertiary care hospitals with moderate to severe prolonged abdominal pain (Visual Analog Scale, VAS > 4 out of 10 points) not otherwise explained were screened and prospectively enrolled. In addition to standard of care (SOC) diagnostics a blood and urine sample for plasma fluorescence scan and biochemical porphyrin analysis were sent to a certified German porphyria laboratory. Results Overall, of 653 screened patients, 68 patients (36 females; mean age 36 years) were included for biochemical porphyrin analysis. No patient with AP was detected. The most frequent discharge diagnoses included “abdominal and digestive symptoms” (n = 22, 32%), “gastrooesophageal diseases” (n = 18, 27%), “infectious bowel disease” (n = 6, 9%) and “biliopancreatic diseases” (n = 6, 9%). Although not primarily addressed, we observed an increase in knowledge of the ED staffs at all study sites regarding our screening algorithm and thus, awareness for APs. Conclusions To the best of our knowledge, we performed the first prospective screening project for APs in the ED. Although we detected no patient with AP in this study, we demonstrated the feasibility of a multicenter screening process for APs by building up a well-working infrastructure comprising laboratory testing as well as data management. This enables the set-up of a larger scale revised follow-up study with a central focus on structured education, thus, possibly acting as blueprint for other rare diseases.

Background: We evaluated how plasma proteomic signatures in patients with suspected COVID-19 can unravel the pathophysiology, and determine kinetics and clinical outcome of the infection. Methods: Plasma samples from patients presenting to the emergency department (ED) with symptoms of COVID-19 were stratified into: (1) patients with suspected COVID-19 that was not confirmed (n = 44); (2) non-hospitalized patients with confirmed COVID-19 (n = 44); (3) hospitalized patients with confirmed COVID-19 (n = 53) with variable outcome; and (4) patients presenting to the ED with minor diseases unrelated to SARS-CoV-2 infection (n = 20). Besides standard of care diagnostics, 177 circulating proteins related to inflammation and cardiovascular disease were analyzed using proximity extension assay (PEA, Olink) technology. Results: Comparative proteome analysis revealed 14 distinct proteins as highly associated with SARS-CoV-2 infection and 12 proteins with subsequent hospitalization (p < 0.001). ADM, IL-6, MCP-3, TRAIL-R2, and PD-L1 were each predictive for death (AUROC curve 0.80–0.87). The consistent increase of these markers, from hospital admission to intensive care and fatality, supported the concept that these proteins are of major clinical relevance. Conclusions: We identified distinct plasma proteins linked to the presence and course of COVID-19. These plasma proteomic findings may translate to a protein fingerprint, helping to assist clinical management decisions.

Porphyrias are predominantly genetic metabolic disorders caused by dysregulation of specific enzymes in porphyrin-heme biosynthesis. The enzymatic dysfunction leads to formation and excretion of intermediate metabolic products in the form of porphyrins and/or their precursors δ‑aminolevulinic acid and porphobilinogen, which have cyto- and tissue-toxic properties. Clinically, porphyrias are extremely diverse, with symptoms ranging from skin changes on light-exposed areas of the body to potentially life-threatening neurovisceral attacks. Biochemical tests in urine, blood and stool are used for diagnosis, which can be supplemented by molecular genetic analyses. Treatment of the various forms of porphyria is complex and often requires close interdisciplinary cooperation between different medical specialties.

Aims, Objectives and BackgroundReliable risk assessment in patients presenting to emergency departments (ED) with suspected infection is of utmost importance to support clinical decisions. Vital sign-based scoring systems such as NEWS2 or qSOFA enable a rapid first assessment of patient urgency at triage. However, their inherent high sensitivity might drive over-utilization of healthcare resources. Our aim was to evaluate if adding the result of a transcriptomic severity classifier can synergistically improve current score-based risk assessment in the ED.Method and DesignWe performed a secondary analysis of a patient cohort (n=312) enrolled in the Charité University hospital ED (Berlin, Germany) with suspected infection and at least one vital sign alteration. The expression of 29-host mRNAs in PAXgene-stabilized whole blood was quantified using NanoString nCounter® SPRINT. The proprietary machine learning classifier IMX-SEV-3 was applied to calculate a score that falls into pre-defined interpretation bands: low/moderate/high severity. NEWS2 and qSOFA were documented on admission and combined with the classifier results to analyze the incidence of two clinical endpoints: ‘need for critical care’ (composite of need for ventilation, dialysis, and/or vasopressors) within 7d and ‘28d mortality’.Results and ConclusionAmong enrolled patients, 22 (7.1%) died and 66 (21.1%) required ICU-level care. Of patients with a high NEWS2 (≥5 points; n=184), there was a stepwise increase in mortality among the low (0%; n=0/47), medium (10.1%; n=12/119) and high (44.4% n=8/18) IMX-SEV-3 severity subgroups. A similar stratification was achieved across the low (17%), moderate (31%), and high (61%) IMX-SEV-3 subgroups for prediction of critical care. More granular risk stratification could also be confirmed when using IMX-SEV-3 in combination with high qSOFA (≥2 points; n=76): 0/10.6/50% mortality and 23.5/40.4/66% need for critical care in the low/moderate/high subgroups, respectively.In summary, the combined use of immune-based IMX-SEV-3 results for ED patients with high clinical scores allows improved prediction of mortality and the need for critical care.

BackgroundRare diseases (RD) like akute porphyrias (APs) present a particular challenge for emergency physicians (EP), as their acute symptoms are usually nonspecific and resemble common clinical presentations. This is compounded by low awareness and limited training of EP regarding RD, often leading to patients with RD being discharged without an accurate diagnosis. Consequently, despite the availability and necessity of targeted diagnostic and treatment options, RD patients may experience further complications and fatal outcomes. This study aimed to characterise patients with RD, such as APs, in the ED and to raise awareness of the problem of unrecognised rare but treatable diseases in the ED.MethodsThe BEAWARE study conducted from July 2023 to June 2024 surveyed patients with RD throughout the German-speaking area, focusing on acute symptoms and presentations in the ED. A select group of RD, including AHP, was chosen to meet the following criteria: (a) causing acute symptoms, (b) diagnosable in the ED for adolescents or adults and (c) availability of therapeutic options. In addition, Embase and MEDLINE were searched up to November 2023 in a systematized literature review of articles on the clinical characteristics of patients with AHP in the ED.ResultsA total of 147 RD patients (15 with APs) participated in the survey. Except for one patient, all AP patients (93.3%) reported that they did present to the ED prior to diagnosis. 8/14 of AP patients presented to the ED 1–2 times, 4/15 3–5 times, 1/15 11–20 times and 1/15 more than 20 times with symptoms of their later diagnosed AP.Of 327 identified articles, 3 could be included that described the clinical presentation of 59 AP patients in the ED. The most common symptoms were abdominal pain (53/59) and neurological symptoms (confusion, paresis, numbness of the extremities, and seizures). The main reported trigger factors included menstrual cycle (28/36) and medication (8/49). Imaging typically yielded unremarkable results. Vital signs were within normal ranges for most patients and hyponatremia was observed in 32/46 patients. The patients‘ outcomes ranged from hospital release after two days to respiratory paralysis (in 3/59 patients) followed by three months of recovery and death in one patient due to a delay in diagnosis for a month.Discussion and ConclusionPatients with APs frequently present to the ED prior to diagnosis and remain often undiagnosed for several visits. The sometimes serious and even fatal consequences emphasize the need for immediate diagnosis and treatment of APs in the ED.Awareness and knowledge of rare diseases such as APs should be increased in the emergency department. So far, little is known in the literature about the presentation of AP patients in the emergency department. Perhaps AI-supported algorithms can support rapid diagnosis in the future.

One third of patients with APs suffer from menstrual cycle-dependent lower abdominal pain, which can also become a more severe relapsing symptom. Therefore, menstrual cycle-dependent pain also marks an initial symptom to think of porphyria before diagnosis. Strategies for the short- and long-term management of this special patient population will be developed in the course of this project.

Background/Objectives: Acute intermittent porphyria (AIP) is a metabolic disease characterised by neurovisceral crises with episodes of acute abdominal pain alongside life-altering, and often hidden, chronic symptoms. The elimination of precipitating factors, hemin therapy, and pain relief are strategies used to treat porphyria symptoms, but are often reserved for patients suffering recurrent, acute attacks. Givosiran (siRNA) is an emerging AIP therapy capable of silencing delta-aminolevulinic acid synthase-1 (ALAS1) and, in turn, reducing the accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) that precede porphyria symptoms. The aim of this study was to investigate the efficacy and safety of givosiran administration in patients with both acute and chronic AIP burden, who were poorly responsive to current therapies, using a personalised medicine approach. Methods: Real-world data were collected in consecutive patients treated with givosiran at an accredited German Porphyria Clinical Center. Biochemical, clinical, and HR-QoL outcomes were monitored alongside adverse events (AEs). Results: Twenty-eight patients treated between 2018 and 2024 were sub-categorised into groups corresponding to Ipnet terms 13 ‘Sporadic Attacks, 5 ‘Symptomatic High Excretors’, 5 ‘Prophylactic Heme’, and 5 “Recurrent Attacks’. The mean time from diagnosis to treatment was 9.2 years (range in months 1–324), and the mean duration of treatment was 30 months (range 3–68). After 6 months of monthly givosiran injection (2.5 mg/kg), all patients’ ALA levels reached <2ULN, and 60% of patients attained PBG levels < 2ULN (p < 0.001). These biochemical responses were not different between sub-groups (p > 0.05). Clinically, 75% of patients’ chronic and acute porphyria symptoms improved. The total patient populations’ annualised attack ratio (AAR) improved; Historical AAR: 2.9 (0–12.0) vs. Givo AAR: 0.45 (0–3.0) (p < 0.01). During follow-up, nine patients experienced minor breakthrough episodes. Of these, three patients required hemin infusion. An association between clinical success and a shorter interim period between diagnosis and treatment was evident (r = −0.522, p = 0.0061). All patients’ indices of HR-QoL improved under givosiran, including mental health (38%, p < 0.0001) and pain (38%, p < 0.0001). Patient-reported health (givosiran 77.9% vs. baseline 37.1%, p < 0.0001) and clinical outcome scores (86.9%: good–very good) were also positive. Two patients withdrew from treatment <6 months, citing fatigue, which was a common side effect. A mild elevation in liver enzymes (AST and/or ALT < 1.5ULN, 15.4%) and reduced glomerular filtration rates (GFR, 11.5%) were also evident, but no life-threatening adverse events (AEs) were attributed to givosiran treatment. Conclusions: Givosiran is effective in preventing severe acute attacks and reducing the chronic health burden in patients with acute intermittent porphyria. Importantly, HR-QoL improved in patients suffering chronic AIP burden with few incidences of historical attacks. All patients experienced substantially improved mental health, ease of living, and self-perceived health.