Common features of rare disease patients in the emergency department: a systematised literature review.

In the first step, a set of diseases was defined to represent RD most relevant for identification in the ED because a) patients experience acute symptoms in adolescence or adulthood and are relevant for ED physicians beyond paediatrics, b) initial diagnostic tools in the ED can rule out or include a rare differential diagnosis and c) treatment options for the initial management in the ED or prognostic relevant long-term therapies exist, making the diagnosis in the ED urgent. PubMed and Orphanet were searched on the basis of these criteria to identify candidate RD. The final set, agreed upon by all the authors, encompassed eight RD: acute hepatic porphyria (AHP), Fabry disease (FD), familial Mediterranean fever (FMF), hereditary angioedema (HAE), hereditary hemorrhagic telangiectasia (HHT), myasthenia gravis (MG), paroxysmal nocturnal hemoglobinuria (PNH) and thrombotic thrombocytopenic purpura (TTP). A brief description of each RD and its emergency specifics is provided in Table 1 . The set is not exhaustive and many more RD fall within these criteria. Table 1 Selected set of rare diseases in adults that may be seen in the ed and for which a treatment option exists Epidemiology: typical age of onset, gender distribution and estimated prevalence Pathophysiology and clinical manifestation Emergency Department (ED) management, treatment options AHP Manifestation : after puberty W > M Prevalence : ~1/100.000 [ 29 – 31 ] Inborn error of metabolism (IEM): Inherited enzyme dysfunction in hepatic heme biosynthesis pathway leads to accumulation of porphyrin precursors (aminolevulinic acid and porphobilinogen). Described trigger: medication, menstrual cycle, fasting, stress, infection. Acute attack(s): neuropsychiatric (neuropathic limb, back or chest pain, paresis, confusion), gastrointestinal (severe abdominal pain, constipation, nausea) and cardiovascular (hypertension, tachycardia) symptoms to severe complications (hyponatremia, seizures, tetraplegia, respiratory paralysis). Chronic symptoms may occur between attacks. [ 32 , 33 ] Diagnostic approach in ED: Aminolevulinic acid and/or Porphobilinogen increased fourfold or higher in spot urine (sample must be stored light protected). Therapy: ED management: elimination of aggravating factors, pain medication (often opioids necessary), antiemetics, glucose, hemin. Approved since 2019 (FDA)/2020 (EMA): small interfering RNA (siRNA) Givosiran for reduction of acute attacks and chronic symptoms. [ 34 , 35 ] [ 32 ] FD Manifestation: Mainly affects males (between 3 and 10 years), but females too (6–15 years) First event (TIA, stroke, cardiac event, CKD stage 5) in classical FD at age of 41–50 years [ 36 , 37 ] Prevalence : 1/40.000 to 1/117.000 live births [ 38 – 40 ] IEM: X-Chromosomal inherited lysosomal storage disease. Defect in GLA-gene causes inactivity (classic form) or reduced activity (late-onset form) of lysosomal enzyme alpha-Galactose A (AGLA). Affected organs and related symptoms vary widely between patients, e.g.: heart (left ventricular hypertrophy, arrythmias, infarct), kidney (proteinuria, CKD), peripheral and central nervous system (neuropathic pain, fatigue, stroke, TIA), gastrointestinal tract (pain, constipation, diarrhea, nausea), ears (tinnitus, sensorineural hearing loss), skin (angiokeratoma, reduced or excessive sweating). [ 41 , 42 ] Diagnostic approach in ED : Dried blood spot card to determine AGLA-activity (men). In women a pathologic variant in GLA-gene needs to be examined. Therapy: ED management : Treatment of stroke, heart failure, pain, myocardial infarct, arrhythmias. [ 43 ] Enzyme replacement therapy (Agalsidase alfa, Agalsidase beta), oral chaperone therapy (Migalastat). [ 42 ] FMF Manifestation: in first decade, ~5% onset after age of 30. [ 44 , 45 ] W = M up to M > W (3:2) [ 46 ] Prevalence : Common in Mediterranean and middle eastern region (e.g. Turkey 1:400 to 1:1000, Israel 1:1000, Armenia 1:500, Jordan, Lebanon, Syria), rare in non-Mediterranean regions. [ 47 ] Autoinflammatory disease, most common periodic fever syndrome. Recurrent acute attacks (lasting 1–3 days) of fever with possible manifestations of serous membranes (abdominal pain, chest pain), skin (erysipelas-like erythema) and joints (arthralgia, arthritis) due to dysregulation of innate immune system caused by defect in MEFV gene (mostly autosomal recessive inherited). [ 46 , 48 , 49 ] Diagnostic approach in ED: clinical criteria (Tel Hashomer, Livneh, Eurofever/PRINTO), raised CRP [ 50 ] Therapy: ED management : determine CRP, supportive care consisting of sufficient pain management (NSAID, paracetamol, metamizole; opioids can be necessary) and intravenous hydration, consider/refer to specialist care for consideration of Glucocorticoids, IL-1 blockers [ 51 – 53 ] Colchicin, Biologicals (IL-1 blocker, TNF inhibitors) to prevent/reduce attacks and prevent long term complications (e.g. AA-amyloidosis) [ 54 ] HAE Manifestation : in childhood or adolescence (first or second decade of life) W = M Prevalence : 1.1–1.6/100.000 [ 55 , 56 ] Bradykinin-mediated angioedema: due to inherited enzyme defect. In most cases, a quantitative or functional deficiency of the C1-esterase inhibitor (C1-INH) leads to oversupply of bradykinin causing angioedema attacks. HAE – attack: painful recurrent swelling of the face, tongue, throat, larynx, extremities and/or genitals; visceral angioedema can cause abdominal pain with nausea and vomiting. No urticaria. [ 22 , 56 ] Diagnostic approach in ED : Activity and concentration of C1-INH and concentration of C4 complement in serum or plasma. Therapy: ED management : evaluation for airway involvement and airway management if necessary, C1-INH concentrate (intravenous or subcutaneous), Bradykinin receptor antagonist; solvent detergent plasma or fresh frozen plasma if specific treatment is not available. Long term prophylaxis (C1-INH, lanadelumab, Berotralstat), short term prophylaxis before potential HAE inducing events (e.g. surgical or dental procedures) and on-demand treatment with C1-INH or bradykinin receptor antagonist (or kallikrein inhibitor). [ 57 ] HHT Manifestation : of epistaxis by about half of patients < 20 years of age. [ 58 ] W = M Prevalence : 1–2/10 000 [ 59 ] Vascular disease: autosomal dominant inherited disorder of the connective tissue of the blood vessels causing mucocutaneous telangiectasia (located on: lips, oral cavity, fingers, nose) and visceral arteriovenous malformations (gastrointestinal telangiectasia (with or without bleeding), pulmonary AVM, hepatic AVM, cerebral AVM, spinal AVM). [ 60 ] Recurrent spontaneous Epistaxis is the most common symptom. [ 58 ] Diagnostic approach in ED : clinical criteria (Curaçao Criteria) [ 60 ] Therapy: ED management : Epistaxis management (consider complications due to recurrent/severe epistaxis such as anemia, hemodynamic instability/shock, chronic cardiac failure), management of complications of pulmonary or cerebral AVMs (stroke, brain abscess, haemorrhage). [ 61 – 63 ] Epistaxis management (topical saline, oral tranexamic acid, ablative therapies, bevacicumab), management of iron deficiency and anemia, screening for and treatment of relevant AVMs to avoid unnecessary stroke and life-threatening hemorrhage. [ 64 ] MG Manifestation : incidence increases with age in both sexes with a peak between the 6th and 8th decade of life. [ 65 ] Bimodal incidence peak in women (20–40 years and > 70 years), Men > Women in late onset MG ( > 50 years) [ 65 ] Prevalence : 5.35–46.5/100,000 [ 66 – 68 ] Autoimmune disease: autoantibody-caused impaired transmission at neuromuscular junction resulting in use related weakness of affected muscles. Typical symptoms include (asymmetric) diplopia, ptosis, bulbar muscle involvement (e.g. difficulties swallowing), weakness of proximal muscles and respiratory weakness. [ 69 ] In approximately 50% of patients MG manifests with ocular symptoms (diplopia, ptosis) and progresses to generalised MG in up to 80% mostly within the next two years. [ 70 , 71 ] Life-threatening complication of MG is myasthenic crisis. Patients with myasthenic crisis are at risk of respiratory failure and therefore need to be closely monitored (rapid progression with need for intubation possible). [ 72 ] Red flags suggesting possible myasthenic crisis are: history of febrile infection treated with antibiotics in the last two weeks, difficulties in swallowing and speech, dropping of head or chin. [ 73 ] Diagnostic approach in ED : Anamnesis and physical examination: use related muscle weakness. Ice-pack test as bedside test option in the ED (76% sensitivity, 98% specificity). [ 74 ] Therapy: ED management of myasthenic crisis : close monitoring of respiratory function, admission to IMC or ICU, intravenous immunoglobulin/plasma exchange therapy. Acetylcholinesterase inhibitors (e.g. pyridostigmine), glucocorticoids and immunosuppressants (e.g. azathioprine), thymectomy, complement inhibitors (eculizumab, ravulizumab), rituximab based on patients age, thymic pathology, antibody status and disease activity. [ 75 ] PNH Manifestation : median age 30–40 years W = M up to W > M [ 76 – 78 ] Prevalence : ~ 5–16/Mio [ 77 , 79 ] Hematopoetic disease: acquired defect of hematopoetic stem cells (somatic mutation in PIGA gene causing GPI anchor defect with changes in surface proteins) causing chronic complement-mediated hemolysis, (pan-)cytopenia and increased risk for thrombosis. [ 80 ] Variable unspecific signs and symptoms: signs of anemia (e.g. fatigue, headache, shortness of breath), thrombosis (main cause of death), hemoglobinuria, abdominal pain, chest pain, dyspnoea, dysphagia, erectile dysfunction, impaired renal function. PNH patients may have a history of bone marrow disease (e.g. aplastic anemia). [ 76 , 78 , 81 ] Diagnostic approach in ED : Coombs-negative hemolytic anemia, (pan-)cytopenia, thrombosis (typical or atypical location, in combination with cytopenia and/or hemolytic anemia, unprovoked/no risk factors present). (PNH clone cells in flow cytometry.) [ 82 ] Therapy: ED management : Treatment of PNH-related emergencies: - thrombosis (life-time risk of 50%): can occur in typical (extremities) or atypical (e.g. Budd-Chiari syndrome, mesenteric or portal veins, cerebral veins, dermal veins) locations; tendency for thrombosis in abdominal or/and intracranial veins; can even occur under adequate anticoagulative therapy - severe pancytopenia - severe haemolytic crisis - abdominal pain crisis [ 83 , 84 ] Long-term treatment can increase to normalise life expectancy: Eculizumab (C5 inhibitor), Ravulizumab (long-acting C5 inhibitor), Pegcetacoplan (C3 inhibitor). Patients treated with complement inhibitors have an increased risk for infections with capsule forming bacteria (e.g. meningococci, pneumococci). [ 77 ] TTP congenital TTP: hereditary, W = M, manifestation in early childhood or adulthood immune mediated TTP: acquired, adults in 3rd-5th decade, W > M (2.5:1 to 3.5:1) annual incidence of iTTP in Europe: 1.5 - 6.0/1 Mio. [ 85 – 87 ] Thrombotic microangiopathy: inherited or acquired deficiency of ADAMTS-13 leading to platelet rich thrombi causing thrombocytopenia, microangiopathic haemolysis and ischaemic organ dysfunction up to organ failure presenting with neurological symptoms (headaches, confusion, delirium, coma, paresis, visual disturbances, seizures, speech or language disorders), signs of thrombocytopenia/anemia, sometimes acute kidney damage or fever. Further end organ damage, e.g. to heart (troponinaemia), lungs, pancreas or GI tract can occur. Primary iTTP where no underlying factor (disease, trigger) is evident accounts for the majority of TTP cases. [ 88 – 91 ] Diagnostic approach in ED : Thrombocytopenia + hemolytic anemia. Fragmentocytes in blood smear. ADAMTS13 antibodies and determination of ADAMTS13 activity (TTP < 10%). PLASMIC score and French score. Therapy: ED management : Therapeutic plasma exchange, glucocorticoids, caplacizumab, rituximab. Regular ambulatory monitoring of ADAMTS13 activity/antibody and blood count/hemolysis parameters. Prophylaxis with recombinant ADAMTS13 in patients with cTTP. [ 92 – 94 ] AHP – acute hepatic porphyria, FD – Fabry disease, FMF – familial Mediterranean fever, HAE - hereditary angioedema, HHT - hereditary hemorrhagic telangiectasia, MG - myasthenia gravis, PNH - paroxysmal nocturnal hemoglobinuria, TTP - thrombotic thrombocytopenic purpura, w – women, m – men, IEM – inborn error of metabolism, EMA - European Medicines Agency, FDA - U.S. Food and Drug Administration, siRNA – small interfering RNA, TIA - Transient ischemic attack, CKD - Chronic kidney disease, NSAID - non steroidal anti-inflammatory drug, AVM - arteriovenous malformations Selected set of rare diseases in adults that may be seen in the ed and for which a treatment option exists Manifestation : after puberty W > M Prevalence : ~1/100.000 [ 29 – 31 ] Inborn error of metabolism (IEM): Inherited enzyme dysfunction in hepatic heme biosynthesis pathway leads to accumulation of porphyrin precursors (aminolevulinic acid and porphobilinogen). Described trigger: medication, menstrual cycle, fasting, stress, infection. Acute attack(s): neuropsychiatric (neuropathic limb, back or chest pain, paresis, confusion), gastrointestinal (severe abdominal pain, constipation, nausea) and cardiovascular (hypertension, tachycardia) symptoms to severe complications (hyponatremia, seizures, tetraplegia, respiratory paralysis). Chronic symptoms may occur between attacks. [ 32 , 33 ] Diagnostic approach in ED: Aminolevulinic acid and/or Porphobilinogen increased fourfold or higher in spot urine (sample must be stored light protected). Therapy: ED management: elimination of aggravating factors, pain medication (often opioids necessary), antiemetics, glucose, hemin. Approved since 2019 (FDA)/2020 (EMA): small interfering RNA (siRNA) Givosiran for reduction of acute attacks and chronic symptoms. [ 34 , 35 ] [ 32 ] Manifestation: Mainly affects males (between 3 and 10 years), but females too (6–15 years) First event (TIA, stroke, cardiac event, CKD stage 5) in classical FD at age of 41–50 years [ 36 , 37 ] Prevalence : 1/40.000 to 1/117.000 live births [ 38 – 40 ] IEM: X-Chromosomal inherited lysosomal storage disease. Defect in GLA-gene causes inactivity (classic form) or reduced activity (late-onset form) of lysosomal enzyme alpha-Galactose A (AGLA). Affected organs and related symptoms vary widely between patients, e.g.: heart (left ventricular hypertrophy, arrythmias, infarct), kidney (proteinuria, CKD), peripheral and central nervous system (neuropathic pain, fatigue, stroke, TIA), gastrointestinal tract (pain, constipation, diarrhea, nausea), ears (tinnitus, sensorineural hearing loss), skin (angiokeratoma, reduced or excessive sweating). [ 41 , 42 ] Diagnostic approach in ED : Dried blood spot card to determine AGLA-activity (men). In women a pathologic variant in GLA-gene needs to be examined. Therapy: ED management : Treatment of stroke, heart failure, pain, myocardial infarct, arrhythmias. [ 43 ] Enzyme replacement therapy (Agalsidase alfa, Agalsidase beta), oral chaperone therapy (Migalastat). [ 42 ] Manifestation: in first decade, ~5% onset after age of 30. [ 44 , 45 ] W = M up to M > W (3:2) [ 46 ] Prevalence : Common in Mediterranean and middle eastern region (e.g. Turkey 1:400 to 1:1000, Israel 1:1000, Armenia 1:500, Jordan, Lebanon, Syria), rare in non-Mediterranean regions. [ 47 ] Autoinflammatory disease, most common periodic fever syndrome. Recurrent acute attacks (lasting 1–3 days) of fever with possible manifestations of serous membranes (abdominal pain, chest pain), skin (erysipelas-like erythema) and joints (arthralgia, arthritis) due to dysregulation of innate immune system caused by defect in MEFV gene (mostly autosomal recessive inherited). [ 46 , 48 , 49 ] Diagnostic approach in ED: clinical criteria (Tel Hashomer, Livneh, Eurofever/PRINTO), raised CRP [ 50 ] Therapy: ED management : determine CRP, supportive care consisting of sufficient pain management (NSAID, paracetamol, metamizole; opioids can be necessary) and intravenous hydration, consider/refer to specialist care for consideration of Glucocorticoids, IL-1 blockers [ 51 – 53 ] Colchicin, Biologicals (IL-1 blocker, TNF inhibitors) to prevent/reduce attacks and prevent long term complications (e.g. AA-amyloidosis) [ 54 ] Manifestation : in childhood or adolescence (first or second decade of life) W = M Prevalence : 1.1–1.6/100.000 [ 55 , 56 ] Bradykinin-mediated angioedema: due to inherited enzyme defect. In most cases, a quantitative or functional deficiency of the C1-esterase inhibitor (C1-INH) leads to oversupply of bradykinin causing angioedema attacks. HAE – attack: painful recurrent swelling of the face, tongue, throat, larynx, extremities and/or genitals; visceral angioedema can cause abdominal pain with nausea and vomiting. No urticaria. [ 22 , 56 ] Diagnostic approach in ED : Activity and concentration of C1-INH and concentration of C4 complement in serum or plasma. Therapy: ED management : evaluation for airway involvement and airway management if necessary, C1-INH concentrate (intravenous or subcutaneous), Bradykinin receptor antagonist; solvent detergent plasma or fresh frozen plasma if specific treatment is not available. Long term prophylaxis (C1-INH, lanadelumab, Berotralstat), short term prophylaxis before potential HAE inducing events (e.g. surgical or dental procedures) and on-demand treatment with C1-INH or bradykinin receptor antagonist (or kallikrein inhibitor). [ 57 ] Manifestation : of epistaxis by about half of patients < 20 years of age. [ 58 ] W = M Prevalence : 1–2/10 000 [ 59 ] Vascular disease: autosomal dominant inherited disorder of the connective tissue of the blood vessels causing mucocutaneous telangiectasia (located on: lips, oral cavity, fingers, nose) and visceral arteriovenous malformations (gastrointestinal telangiectasia (with or without bleeding), pulmonary AVM, hepatic AVM, cerebral AVM, spinal AVM). [ 60 ] Recurrent spontaneous Epistaxis is the most common symptom. [ 58 ] Diagnostic approach in ED : clinical criteria (Curaçao Criteria) [ 60 ] Therapy: ED management : Epistaxis management (consider complications due to recurrent/severe epistaxis such as anemia, hemodynamic instability/shock, chronic cardiac failure), management of complications of pulmonary or cerebral AVMs (stroke, brain abscess, haemorrhage). [ 61 – 63 ] Epistaxis management (topical saline, oral tranexamic acid, ablative therapies, bevacicumab), management of iron deficiency and anemia, screening for and treatment of relevant AVMs to avoid unnecessary stroke and life-threatening hemorrhage. [ 64 ] Manifestation : incidence increases with age in both sexes with a peak between the 6th and 8th decade of life. [ 65 ] Bimodal incidence peak in women (20–40 years and > 70 years), Men > Women in late onset MG ( > 50 years) [ 65 ] Prevalence : 5.35–46.5/100,000 [ 66 – 68 ] Autoimmune disease: autoantibody-caused impaired transmission at neuromuscular junction resulting in use related weakness of affected muscles. Typical symptoms include (asymmetric) diplopia, ptosis, bulbar muscle involvement (e.g. difficulties swallowing), weakness of proximal muscles and respiratory weakness. [ 69 ] In approximately 50% of patients MG manifests with ocular symptoms (diplopia, ptosis) and progresses to generalised MG in up to 80% mostly within the next two years. [ 70 , 71 ] Life-threatening complication of MG is myasthenic crisis. Patients with myasthenic crisis are at risk of respiratory failure and therefore need to be closely monitored (rapid progression with need for intubation possible). [ 72 ] Red flags suggesting possible myasthenic crisis are: history of febrile infection treated with antibiotics in the last two weeks, difficulties in swallowing and speech, dropping of head or chin. [ 73 ] Diagnostic approach in ED : Anamnesis and physical examination: use related muscle weakness. Ice-pack test as bedside test option in the ED (76% sensitivity, 98% specificity). [ 74 ] Therapy: ED management of myasthenic crisis : close monitoring of respiratory function, admission to IMC or ICU, intravenous immunoglobulin/plasma exchange therapy. Acetylcholinesterase inhibitors (e.g. pyridostigmine), glucocorticoids and immunosuppressants (e.g. azathioprine), thymectomy, complement inhibitors (eculizumab, ravulizumab), rituximab based on patients age, thymic pathology, antibody status and disease activity. [ 75 ] Manifestation : median age 30–40 years W = M up to W > M [ 76 – 78 ] Prevalence : ~ 5–16/Mio [ 77 , 79 ] Hematopoetic disease: acquired defect of hematopoetic stem cells (somatic mutation in PIGA gene causing GPI anchor defect with changes in surface proteins) causing chronic complement-mediated hemolysis, (pan-)cytopenia and increased risk for thrombosis. [ 80 ] Variable unspecific signs and symptoms: signs of anemia (e.g. fatigue, headache, shortness of breath), thrombosis (main cause of death), hemoglobinuria, abdominal pain, chest pain, dyspnoea, dysphagia, erectile dysfunction, impaired renal function. PNH patients may have a history of bone marrow disease (e.g. aplastic anemia). [ 76 , 78 , 81 ] Diagnostic approach in ED : Coombs-negative hemolytic anemia, (pan-)cytopenia, thrombosis (typical or atypical location, in combination with cytopenia and/or hemolytic anemia, unprovoked/no risk factors present). (PNH clone cells in flow cytometry.) [ 82 ] Therapy: ED management : Treatment of PNH-related emergencies: - thrombosis (life-time risk of 50%): can occur in typical (extremities) or atypical (e.g. Budd-Chiari syndrome, mesenteric or portal veins, cerebral veins, dermal veins) locations; tendency for thrombosis in abdominal or/and intracranial veins; can even occur under adequate anticoagulative therapy - severe pancytopenia - severe haemolytic crisis - abdominal pain crisis [ 83 , 84 ] Long-term treatment can increase to normalise life expectancy: Eculizumab (C5 inhibitor), Ravulizumab (long-acting C5 inhibitor), Pegcetacoplan (C3 inhibitor). Patients treated with complement inhibitors have an increased risk for infections with capsule forming bacteria (e.g. meningococci, pneumococci). [ 77 ] congenital TTP: hereditary, W = M, manifestation in early childhood or adulthood immune mediated TTP: acquired, adults in 3rd-5th decade, W > M (2.5:1 to 3.5:1) annual incidence of iTTP in Europe: 1.5 - 6.0/1 Mio. [ 85 – 87 ] Diagnostic approach in ED : Thrombocytopenia + hemolytic anemia. Fragmentocytes in blood smear. ADAMTS13 antibodies and determination of ADAMTS13 activity (TTP < 10%). PLASMIC score and French score. Therapy: ED management : Therapeutic plasma exchange, glucocorticoids, caplacizumab, rituximab. Regular ambulatory monitoring of ADAMTS13 activity/antibody and blood count/hemolysis parameters. Prophylaxis with recombinant ADAMTS13 in patients with cTTP. [ 92 – 94 ] AHP – acute hepatic porphyria, FD – Fabry disease, FMF – familial Mediterranean fever, HAE - hereditary angioedema, HHT - hereditary hemorrhagic telangiectasia, MG - myasthenia gravis, PNH - paroxysmal nocturnal hemoglobinuria, TTP - thrombotic thrombocytopenic purpura, w – women, m – men, IEM – inborn error of metabolism, EMA - European Medicines Agency, FDA - U.S. Food and Drug Administration, siRNA – small interfering RNA, TIA - Transient ischemic attack, CKD - Chronic kidney disease, NSAID - non steroidal anti-inflammatory drug, AVM - arteriovenous malformations In the second step a systematised literature review [ 95 ] was conducted to investigate the common and distinct features of the predefined set of RD in the ED. The search strategy was developed and discussed collectively by all the authors. Title and abstract screening, full-text evaluation and data synthesis were performed by a single reviewer. In cases of uncertainty of eligibility of a study, two additional reviewers assessed the full text and resolved the inclusion decision by discussion and consensus. The review adhered to the principles outlined in the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis Chap. 5 and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. The selection of the eight RD was made by a panel of three experienced emergency physicians based on their professional judgment. Given that a comprehensive literature review across the entire spectrum of RD was not feasible, these eight conditions were selected as illustrative examples. This approach enabled a focused literature review, while acknowledging that the list is neither systematic nor exhaustive. Rather, it was intended to highlight a diverse range of presentations and to facilitate the identification of recurring features across different disease entities. The defined set should therefore be understood as exemplary of a wider group of RD meeting the above criteria. Embase and MEDLINE were searched in November 2023 without restrictions on the publication period. The search string comprised a combination of various synonyms for the ED and each RD within the described set, connected by Boolean operators (OR and AND). The complete search strategy is presented in Supplement 1 . The research question and inclusion criteria were defined according to the CoCoPop strategy [ 96 ]: Condition: AHP, FD, FMF, HAE, HHT, MG, TTP, PNH. Context: All types of emergency departments (e.g. urban, rural, academic, community). Population: Patients 16 years or older. Condition: AHP, FD, FMF, HAE, HHT, MG, TTP, PNH. Context: All types of emergency departments (e.g. urban, rural, academic, community). Population: Patients 16 years or older. We included all studies reporting primary data, including case series, published up to November 2023. No restriction on publication date range was applied. Outcomes of interest were patient characteristics (demographics, clinical status, medical history), disease presentation (symptoms, affected organ systems, presenting symptom in ED), risk factors (trigger factors, recent new medication, recent pregnancy), clinical assessment (vital signs, laboratory results, physical examination findings, imaging results) and clinical course in the ED (diagnostic process, ICU admission, total ED visits, death). The following exclusion criteria were applied: setting other than the ED, age < 16 years, RD other than the defined set, inappropriate publication type (case report, review, letter to the editor, conference abstracts, conference reviews). Only studies in English and German were included, as the team is proficient in these languages. If no setting was specified, the study was excluded. All studies were included regardless of sample size, ensuring a comprehensive review of available evidence. Studies that did not mention any of the patient characteristics according to the outcomes of interest described above were excluded from the review. All eligible articles from MEDLINE were exported, whereas for EMBASE, a filter was applied to exclude unsuitable publication types (conference abstracts, conference reviews, conference papers, notes, errata, letters to the editor). Case reports and reviews were not automatically excluded. For deduplication and title and abstract screening the free version of the Rayyan.ai web application was used. Rayyan.ai is an AI-powered tool registered in Qatar designed to support the process of systematic literature reviews by facilitating the screening and management of research articles [ 97 , 98 ]. Full texts whose title and abstract appeared suitable or whose suitability could not be adequately assessed on the basis of the abstract (e.g. no abstract available) were retrieved and evaluated on the basis of the defined inclusion and exclusion criteria. The reasons for exclusion were documented for each publication. The initial screening and selection of studies was conducted by a single reviewer. In cases of uncertainty regarding the eligibility of a study, two additional reviewers were consulted. These reviewers assessed the full text of the respective publication and reached a consensus on inclusion or exclusion through discussion and consensus. An adapted version of the JBI data extraction form for prevalence studies was used to gather patient and RD characteristics in the ED, including age, sex, age of manifestation of RD, disease history, all reported symptoms, presenting symptoms in the ED, family history, vital signs, laboratory, physical examination, (incorrect) differential diagnoses made, number of visits to the ED, trigger factors, pregnancy, admission to the ICU, death and other findings of interest. Missing data were documented as N/A. A single reviewer extracted data from all included studies. The extracted data was then presented to two additional reviewers for verification and discussion. Throughout the extraction process, regular team meetings were held to discuss any challenges or ambiguities encountered and to maintain consistency in data interpretation. This review focused on reported symptoms, clinical features, family history and patient characteristics of adult and adolescent patients presenting to the ED. Therefore, all studies that reported patients diagnosed with one disease of the defined set of RD in the ED context were included if the study met the inclusion and exclusion criteria, even if the study sample size was small or if the description of the study subjects was inconclusive. No further systematic quality assessment was performed. Owing to the expected heterogeneity and limited number of publications, the findings were synthesised in a narrative form. For each RD, separate tables were created, collecting and summarising all information that could be extracted from the studies using the data extraction form. The findings were thematically grouped and structured in comparative tables to make key features for each RD clearly visible. Data were first condensed and analysed separately for each RD and then across all RD, to identify recurrent patterns. The tables were compared to detect common features. In addition to the outcomes, study characteristics, including number, age and gender of participants, number of studies for each RD, study design and extractable outcomes, were compiled in a comparative table to facilitate assessment of the robustness of results.

In total, 4.732 records were identified in Embase and MEDLINE (Fig. 1 ). Ineligible report types were automatically excluded by filtering (letter to the editor, conference abstract, conference paper, conference review, erratum, note). After deduplication, 2 214 records were assessed for title and abstract screening. The title and abstract were considered ineligible ( n  = 1 999) if they obviously did not intend to describe the characteristics of patients aged 16 years or older with one of the eight defined RD, if the study population did not present to an ED, if it was a case report or review or if the language was other than English or German. The remaining 215 reports were considered for the full-text screening. All full texts were evaluated on the basis of the predefined inclusion and exclusion criteria. Most of the assessed reports ( n  = 116) were excluded because they either did not describe patient characteristics or the assessed patients had not presented to an ED or both [ 100 – 102 ]. For studies reporting on both ED patients and patients who presented elsewhere [ 103 ], only ED patients’ outcomes were retrieved. The publication type was considered inapplicable, if it was a case report or review ( n  = 72). Two full texts were excluded for assessing patients aged < 16 years and another seven were excluded for being in a language other than English or German. Excluded full texts and the reasons for exclusion are listed in Supplement 2 . Thus, 18 articles were left for inclusion [ 25 , 72 , 103 – 118 ]. No studies could be included for PNH and FD, despite the low-threshold inclusion and exclusion criteria. Fig. 1 Prisma (preferred reporting items for systematic reviews and meta-analyses) flow diagram [ 99 ] Prisma (preferred reporting items for systematic reviews and meta-analyses) flow diagram [ 99 ] The study’s characteristics are presented in Table 2 . Among the 18 included studies, 11 were retrospective chart reviews with small sample sizes, ranging from 4 to 36 patients. One study [ 109 ] included patients with HAE only as a subgroup and did not report their size. Four studies [ 72 , 111 , 112 , 114 ] were case series, each describing only three patients, for MG and HHT being the only identified articles reporting on clinical patient characteristics in the ED. Three prospective observational studies were included for HAE and FMF (3 to 75 described patients) [ 25 , 107 , 110 ]. Table 2 Study characteristics RD Authors (year), country Study design, No. of described patients Patient Age (years) Patient gender (female) RD already known Study objective Outcome (described patient/disease characteristics) AHP Kumar et al. (2010), India RCR, n  = 13 mean 25.7 ± 14.9 5/13 Yes 7/13 Characterisation of acute intermittent porphyria presentation in the ED. patient age (years), patient gender, age of disease onset, history of RD, all reported symptoms, family history, vital signs (initial), laboratory, imaging, trigger factors, death Liu et al. (2005), Taiwan RCR, n  = 10 N/A 7/10 No Characterisation of AHP presentation in the ED. patient age (years), patient gender, age at disease onset, history of RD, presenting symptom in ED, family history, laboratory, physical examination, total ED visits Yang et al. (2016), China RCR, n  = 36 Median 25.3 (range 18–45) 33/36 N/A Characterisation of AHP presentation in the ED. patient age (years), patient gender, all reported symptoms, vital signs (initial), laboratory, differential diagnosis/other applied diagnosis in ED, trigger factors, recent new medication, death FMF Huseyin et al. (2014), Turkey prospective two-site observational study, n = 75 mean: 38.7 ± 12.6 and 33.1 ± 12.1 (2 groups) 41/75 Yes Investigation of regional and ethnic differences in trigger factors of FMF. patient age (years), patient gender, history of RD, presenting symptom in ED, family history, trigger factors HAE Day et al. (2023), Southafrica RCR, n  = 11 Study population: median 57 (IQR 43 - 67) HAE-Subgroup: NA 10/11 Yes Characterisation and outcome of acute angioedema in ED. patient age (years), patient gender, history of RD, all reported symptoms (regarding ED visit), presenting symptom in ED, trigger factors Felder et al. (2014), Canada RCR, n  = 455, HAE-subgroup NA Study population: mean 37.8 (SD 22.8) HAE-Subgroup: NA Study population: 60.6%, HAE-subgroup: NA Yes Characterisation of undifferentiated angioedema in ED. history of RD, all reported symptoms (regarding ED visit), presenting symptom in ED Moldovan et al. (2018), Romania Case series, n = 3 42, 52, 59 1/3 Yes 2/3 Case series to demonstrate fatal outcome in missed or mismanaged laryngeal angioedema in HAE patients. patient age (years), patient gender, age at disease onset, history of RD, all reported symptoms (regarding ED visit), family history, death Hirose et al. (2017), Japan prospective multicentre observational screening study, n  = 3 median 52 (IQR 38–85) 2/3 No Determine incidence of HAE patients in ED. patient age (years), patient gender, age at disease onset, history of RD, all reported symptoms (regarding ED visit), presenting symptom in ED, family history, laboratory, Imaging, differential diagnosis/other applied diagnosis in ED, total ED visits/history of ED visits, ICU admission, death Javaud et al. (2015), France prospective multicentre observational study, n  = 29 median 29 (IQR 26–36) 19/29 Yes Identify factors associated with hospital admission in HAE patients presenting to ED with acute attack. patient age (years), patient gender, history of RD, presenting symptom in ED, trigger factors, ICU admission Pekdemir et al. (2007), Turkey Case series, n = 3 21, 33, 35 all Yes 2/3, NA 1/3 Presentation of HAE patients treated with fresh frozen plasma. patient age (years), patient gender, age at disease onset, history of RD, presenting symptom in ED, family history, Vital signs (initial), total ED visits/history of ED visits, trigger factors, death Songur Kodik et al. (2023), Turkey RCR, n  = 35 mean 36.4 (SD 13) 54.3% Yes and no, exact number N/A Calculate LACE index and identify factors to predict recurrent admission in HAE patients. patient age (years), patient gender, age at disease onset, history of RD, presenting symptom in ED, family history, Vital signs (initial), total ED visits/history of ED visits, trigger factors, death HHT Kuwayama et al. (2003), Japan Case series, n = 3 23, 32, 62 1/3 No Presentation of three HHT cases with neurological emergency. patient age (years), patient gender, history of RD, presenting symptom in ED, family history, laboratory, physical examination, Imaging, differential diagnosis/other applied diagnosis in ED MG Smulowitz et al. (2005), USA Case series, n = 3 48, 78, 65 all Yes 1/3 Characterisation of MG presentation in the ED. patient age (years), patient gender, age of disease onset, history of RD, all reported symptoms, presenting symptom in ED, Vital signs (initial), physical examination, Imaging, death TTP Boisriou et al. (2023), France Multicentre RCR, n  = 40, TTP - subgroup = 29 Median 44 (IQR 28–57) 27 (67.5%) No Misdiagnosis of Thrombotic microangiopathy in the ED. patient age (years), patient gender, age of disease onset, history of RD, all reported symptoms, presenting symptom in ED, laboratory, differential diagnosis/other applied diagnosis in ED, Recent pregnancy, death Li et al. (2021), China RCR, n  = 19 Median 56 (Range 19 - 75) 10/19 No Characterisation of TTP presentation in ED. patient age (years), patient gender, age of disease onset, history of RD, all reported symptoms, presenting symptom in ED, laboratory, trigger factors/aetiology, death Noel et al. (2013), France RCR, n  = 12, TTP-subgroup = 6 Median 35.2 (range 23.4–74) 4/6 N/A Discriminate TTP and pseudothrombotic microangiopathies related to vitamin B12 deficiency (pseudo- TMA). patient age (years), patient gender, all reported symptoms, laboratory, death Pieralli et al. (2011), Italy RCR, n  = 12 mean 59 (range 37—85) 58% No Factors to predict in-hospital death of TTP. patient age (years), patient gender, age of disease onset, history of RD, all reported symptoms, presenting symptom in ED, vital signs (initial), laboratory, trigger factors/aetiology, recent pregnancy, death Stella et al. (2009), USA Multicenter RCR, n  = 12, ED - subgroup = 4 range 20–40 all Yes 1/12 Characterisation of acute presentation of TTP in ED and obstetric triage in pregnancy. patient age (years), patient gender, age of disease onset, history of RD, all reported symptoms, presenting symptom in ED, vital signs (initial), laboratory, differential diagnosis/other applied diagnosis in ED, total ED visits, recent pregnancy, death RCR = retrospective chart review, N/A – not known/no information Study characteristics mean 25.7 ± 14.9 prospective two-site observational study, n = 75 Study population: median 57 (IQR 43 - 67) HAE-Subgroup: NA Study population: mean 37.8 (SD 22.8) HAE-Subgroup: NA Case series, n = 3 prospective multicentre observational study, n  = 29 Case series, n = 3 Kuwayama et al. (2003), Japan Case series, n = 3 Case series, n = 3 Multicentre RCR, n  = 40, TTP - subgroup = 29 RCR, n  = 12, TTP-subgroup = 6 Discriminate TTP and pseudothrombotic microangiopathies related to vitamin B12 deficiency (pseudo- TMA). Multicenter RCR, n  = 12, ED - subgroup = 4 RCR = retrospective chart review, N/A – not known/no information Half of the studies were conducted in East Asia ( n  = 5) (China, Taiwan, Japan), India ( n  = 1) and Turkey ( n  = 3), the other half in Europe ( n  = 5) (France, Italy, Romania), North America ( n  = 3) (USA, Canada) and one study in South Africa. Although there were no restrictions on the study period, the included studies were published between 2003 and 2023. Only half of the study objectives were designed to characterise patients and their RD in the ED. The deviating focus limited the characterisation. As expected, studies reported very different on patient characteristics and to varying extents. Four of the 18 studies were case series selectively reporting on patients individually selected by the authors. Therefore, very selective and mostly small patient cohorts formed the basis of this review. Three studies [ 104 – 106 ] described the clinical presentation of 59 patients with AHP aged 16 years or older in the ED (Table 3 ). Table 3 Characteristics of ahp patients in the ed Kumar et al. 2010 Liu et al. 2005 Yang et al. 2016 Patients (female, male) n = 13 (f: 5, m: 8) only patients with AIP n = 10 (f: 7, m: 3) n = 36 (f:33, m:3) Age (years) mean 25.7 ± 14.9 N/A Median 25.3 (range: 18–45) AHP known Yes 7/13 No N/A Age of AHP onset 17–37 (12/13 patients with manifestation before age of 30 years) 17–55 (mean age: 32) N/A Symptoms (No. of patients) Gastrointestinal: - abdominal pain (11/13) - vomiting (8/13) Gastrointestinal: - abdominal pain (10/10) Gastrointestinal: - abdominal pain(32/36) - constipation (26/36) Neurological: - seizure (7/13) - acute quadriparesis or quadriplegia (7/13) - peripheral neuropathy (4/13) - respiratory paralysis (1/13) Neurological - muscle weakness (1/10) - seizure (2/10, only after inpatient admission) Neurological - confusion 16/36 - seizure 12/36 - paresis 5/36 - numbness of extremities 3/36 - respiratory paralysis 2/36 Other: temporary red urine in history (3/13) Other: dark urine (1/10) cyclic attacks 28/36 Reason for ED visit N/A abdominal pain (10/10) N/A Vital signs hypertension 4/13 N/A tachycardia 10/36 hypertension 3/36 family history of AHP 0/13 2/10 N/A trigger factors medication (7/13), infections N/A 28/36 cyclic attacks linked to menstruation cycle 2/36 history of alcohol consumption 3/36 history of severe dieting 1/36 valproat Additional findings Ultrasound (abdomen), MRI or CT (head) were either normal or not performed (except in one patient: bilateral parietoocipital infarct area). hyponatremia 3/10 normal: WBC, CRP, liver enzymes, lipase, amylase patients required at least 2 different painkillers (mean: 2.6) mean 4 (range 1–8) visits to ED, other hospital, outpatient department before diagnosis hyponatremia 29/36 severe hyponatremia ( < 125mEq/L) 14/36 transaminases (21/36) (ALT (U/L) 69.5 ± 56.3) anemia 10/36 (haemoglobin (g/L) 117.6 ± 17.9) Misdiagnosis: intestinal obstruction, epilepsy AHP – acute hepatic porphyria, AIP – acute intermittent porphyria, m – male, f – female, ED – emergency department, N/A – not specified, WBC – white blood cell count Characteristics of ahp patients in the ed n = 13 (f: 5, m: 8) only patients with AIP Symptoms (No. of patients) Gastrointestinal: - abdominal pain (11/13) - vomiting (8/13) Gastrointestinal: - abdominal pain (10/10) Gastrointestinal: - abdominal pain(32/36) - constipation (26/36) Neurological: - seizure (7/13) - acute quadriparesis or quadriplegia (7/13) - peripheral neuropathy (4/13) - respiratory paralysis (1/13) Neurological - muscle weakness (1/10) - seizure (2/10, only after inpatient admission) Neurological - confusion 16/36 - seizure 12/36 - paresis 5/36 - numbness of extremities 3/36 - respiratory paralysis 2/36 Other: temporary red urine in history (3/13) Other: dark urine (1/10) tachycardia 10/36 hypertension 3/36 28/36 cyclic attacks linked to menstruation cycle 2/36 history of alcohol consumption 3/36 history of severe dieting 1/36 valproat hyponatremia 3/10 normal: WBC, CRP, liver enzymes, lipase, amylase patients required at least 2 different painkillers (mean: 2.6) mean 4 (range 1–8) visits to ED, other hospital, outpatient department before diagnosis hyponatremia 29/36 severe hyponatremia ( < 125mEq/L) 14/36 transaminases (21/36) (ALT (U/L) 69.5 ± 56.3) anemia 10/36 (haemoglobin (g/L) 117.6 ± 17.9) Misdiagnosis: intestinal obstruction, epilepsy AHP – acute hepatic porphyria, AIP – acute intermittent porphyria, m – male, f – female, ED – emergency department, N/A – not specified, WBC – white blood cell count The typical presentation of AHP, characterised by neurovisceral symptoms, was consistent across all three studies. Abdominal pain was the most common symptom, affecting nearly all patients (53/59). Although pain intensity was not assessed, one study [ 105 ] noted that patients with AHP typically required at least two painkillers (mean 2.6). Only one study [ 105 ] examined patients with undiagnosed AHP who presented to the ED. Their findings suggested that AHP presentations in the ED can be inconclusive and may evolve further over time. Life-threatening progression of respiratory paralysis was reported for 3/59 patients and death occurred in one patient due to delayed diagnosis. [ 104 ] One study exploring trigger factors in 75 FMF patients presenting to an ED [ 107 ] reported the patient characteristics shown in Table 4 . Table 4 Characteristics of FMF patients in the ed Huseyin et al. 2014 Patients (female, male) N  = 75 (f: 41, m: 34) Age (mean ± SD) per cohort 38.7 ± 12.6 and 33.1 ± 12.1 FMF known Yes, 7.4–8 (1–24) attacks per year (70/75 patients received treatment with colchicine) Reason for ED admission Abdominal pain family history of FMF Yes 41/75 trigger factors Yes 75/75  - Emotional stress (54/75)  - Physical activity (40/75)  - Menstruation cycle (22/75)  - Cold (20/75) SD – standard deviation, ED – emergency department, FMF – familial Mediterranean fever, m – male, f – female Characteristics of FMF patients in the ed Yes 75/75 - Emotional stress (54/75) - Physical activity (40/75) - Menstruation cycle (22/75) - Cold (20/75) SD – standard deviation, ED – emergency department, FMF – familial Mediterranean fever, m – male, f – female Five retrospective [ 108 , 109 , 111 – 113 ] and two prospective [ 25 , 110 ] studies investigated HAE presentation in at least 84 patients presenting to the ED. In two studies [ 108 , 109 ], HAE only formed a subgroup of patients with unspecified angioedema in the ED. The extracted characteristics are listed in Table 5 . Table 5 Characteristics of patients with HAE in the ED Author, Year Patients HAE known Presentation in ED Symptoms Family history of HAE Trigger factors Additional findings Day et al. 2023 n = 11 (f: 10, m: 1) Yes Abdominal angioedema, no additional sites affected (36.4%) Swelling above the shoulder (54.5%) N/A N/A Spontaneous: 8/11 Possible trigger reported: 3/11 Time from angioedema onset to presentation was longer in HAE-patients (median time: 24 (IQR 15 - 48) hours). Age (median): Study population: 57 (IQR 43 - 67) years HAE-subgroup: N/A Manifestation age: N/A Felder et al. 2014 n = 455, HAE-subgroup NA Yes Localisation of angioedema per patient visit to the ED: - Periorbital (10%) - Lips (10%) - Tongue (26%) - Face/cheeks (20%) - Pharynx (38%) - Extremities (52%) - multiple localisations (44%) N/A N/A N/A Significant association between cause and localisation of angioedema: angioedema of the extremities associated with HAE Age (mean): All 37.8 (SD 22.8) years HAE-subgroup: N/A Manifestation age: N/A Moldovan et al. 2018 n = 3 (f: 2, m: 1) Presentation of 3 patients with fatal laryngeal oedema Yes 2 No 1 Manifestation of laryngeal oedema with: - Dysphagia, dysphonia and dyspnoea (1/3) - Dysphonia (1/3) - Feeling of a lump in the throat, in the course of dysphagia and dysphonia (1/3) Frequency of HAE attacks: - weekly (1/3) − 2 ×per month (1/3) - annually (1/3) Yes (3/3) 3–6 also affected family members N/A misdiagnosis led to surgical removal of gall bladder, appendix, ovary Time from onset of laryngeal oedema to asphyxia: 20 min − 11 h Diagnostic latency: 30–49 years Age: 42, 52, 59 years Manifestation age: 8, 20, 22 years Hirose et al. 2017 n = 3 (f: 2, m: 1) No Facial oedema that does not respond to antihistamines or steroids (1/3) Abdominal pain + vomiting (1/3) Out-of-hospital cardiac arrest - onset of facial oedema 20 hours earlier (1/3) N/A Yes 2/3 No 1/3 N/A Routine laboratory: WBC count higher (13 820 [IQR: 10 400–23 200] vs 7750 [IQR: 6167.5–11 057.5]/mL, p  = 0.04)) Other routine laboratory parameters normal. Imaging: CT- face and neck: laryngeal oedema(1/3) CT-abdomen: intestinales oedema + ascites(1/3) Misdiagnosis: Gastroenteritis, Endometriosis Age (median): 52 (IQR 38–85) years Manifestation age: 13, 25, N/A years Javaud et al. 2015 n = 29 (f: 19, m: 10) 57 HAE.attacks in 29 patients Yes Angioedema localisation: - face (49%) - abdomen (40%) - larynx (32%) - tongue (16%) - extremities (14%) - multiple sites (18/57) N/A N/A Trigger identified for 31/57 attacks: - stress (35%) - trauma (23%) - estrogen (contraception, pregnancy) (23%) - infection (13%) - Discontinuing HAE-Prophylaxis (6%) management required: - ICU: 6 (21%) - Intubation: 2 (7%) - Tracheotomy: 1 Age (median): 29 (IQR 26–36) years Manifestation age: N/A Pekdemir et al. 2007 n = 3 (f: 3) Yes 2 N/A. 1 - Shortness of breath, oedema on left arm and rash (since 24 h) (1/3) - Angioedema since 12 h: swelling of the face, especially periorbital; mild abdominal cramps (1/3) - Bilateral oedema of the hand since 12 h N/A Yes 1/3 N/A 2/3 Menstruation, infection of the upper airways Vital signs normal (3/3) Presentation to 2 other medical centres without improvement after treatment with steroids, antihistamines and epinephrine. Age: 21, 33, 35 years Manifestation age: 4, 29, N/A Songur Kodik et al. 2023 n = 35 (f: 19, m: 16) Yes and No, not further specified Most frequent: abdominal pain Localisation of HAE attack: - Abdomen 13 (37.2%) - Uvula 15 (42.9%) - Face 10 (28.6%) - Lips 2 (5.8%) - Trunk/trunk 3 (8.6%) GI symptoms: Abdominal pain 13/35 (37%), Nausea/vomiting 3/35 (8.6%) Cardiovascular: Chest pain 1/35 (2.9%), Syncope/presyncope 2/35 (5.7%) Respiratory: dyspnoea 7/35 (20%) Skin: Facial swelling 11/35 (31.4%), Body swelling 9/35 (25.7%), Urticaria 0/35 ENT: Sore throat 9/35 (25.7%) Dysphonia 3/35 (8.6%), Dysphagia 1/35 (2.9%) Yes 32/35 (91.4%) Trauma (1/35) Mean vital signs normal. Age (mean): 36.4 (SD 13) years N/A – not specified, ICU – intensive care unit, SD – standard deviation, IQR – interquartile range, m – male, f – female, ED – emergency department, WBC – white blood cell count, GI – Gastrointestinal, ENT - Ear, nose and throat, ICU – intensive care unit Characteristics of patients with HAE in the ED Abdominal angioedema, no additional sites affected (36.4%) Swelling above the shoulder (54.5%) Spontaneous: 8/11 Possible trigger reported: 3/11 Age (median): Study population: 57 (IQR 43 - 67) years HAE-subgroup: N/A Localisation of angioedema per patient visit to the ED: - Periorbital (10%) - Lips (10%) - Tongue (26%) - Face/cheeks (20%) - Pharynx (38%) - Extremities (52%) - multiple localisations (44%) Age (mean): All 37.8 (SD 22.8) years HAE-subgroup: N/A n = 3 (f: 2, m: 1) Presentation of 3 patients with fatal laryngeal oedema Yes 2 No 1 Manifestation of laryngeal oedema with: - Dysphagia, dysphonia and dyspnoea (1/3) - Dysphonia (1/3) - Feeling of a lump in the throat, in the course of dysphagia and dysphonia (1/3) Frequency of HAE attacks: - weekly (1/3) − 2 ×per month (1/3) - annually (1/3) misdiagnosis led to surgical removal of gall bladder, appendix, ovary Time from onset of laryngeal oedema to asphyxia: 20 min − 11 h Diagnostic latency: 30–49 years n = 3 (f: 2, m: 1) Facial oedema that does not respond to antihistamines or steroids (1/3) Abdominal pain + vomiting (1/3) Out-of-hospital cardiac arrest - onset of facial oedema 20 hours earlier (1/3) Yes 2/3 No 1/3 Routine laboratory: WBC count higher (13 820 [IQR: 10 400–23 200] vs 7750 [IQR: 6167.5–11 057.5]/mL, p  = 0.04)) Other routine laboratory parameters normal. Imaging: CT- face and neck: laryngeal oedema(1/3) CT-abdomen: intestinales oedema + ascites(1/3) Misdiagnosis: Gastroenteritis, Endometriosis n = 29 (f: 19, m: 10) 57 HAE.attacks in 29 patients Angioedema localisation: - face (49%) - abdomen (40%) - larynx (32%) - tongue (16%) - extremities (14%) - multiple sites (18/57) Trigger identified for 31/57 attacks: - stress (35%) - trauma (23%) - estrogen (contraception, pregnancy) (23%) - infection (13%) - Discontinuing HAE-Prophylaxis (6%) management required: - ICU: 6 (21%) - Intubation: 2 (7%) - Tracheotomy: 1 Yes 2 N/A. 1 - Shortness of breath, oedema on left arm and rash (since 24 h) (1/3) - Angioedema since 12 h: swelling of the face, especially periorbital; mild abdominal cramps (1/3) - Bilateral oedema of the hand since 12 h Yes 1/3 N/A 2/3 Vital signs normal (3/3) Presentation to 2 other medical centres without improvement after treatment with steroids, antihistamines and epinephrine. Most frequent: abdominal pain Localisation of HAE attack: - Abdomen 13 (37.2%) - Uvula 15 (42.9%) - Face 10 (28.6%) - Lips 2 (5.8%) - Trunk/trunk 3 (8.6%) GI symptoms: Abdominal pain 13/35 (37%), Nausea/vomiting 3/35 (8.6%) Cardiovascular: Chest pain 1/35 (2.9%), Syncope/presyncope 2/35 (5.7%) Respiratory: dyspnoea 7/35 (20%) Skin: Facial swelling 11/35 (31.4%), Body swelling 9/35 (25.7%), Urticaria 0/35 ENT: Sore throat 9/35 (25.7%) Dysphonia 3/35 (8.6%), Dysphagia 1/35 (2.9%) N/A – not specified, ICU – intensive care unit, SD – standard deviation, IQR – interquartile range, m – male, f – female, ED – emergency department, WBC – white blood cell count, GI – Gastrointestinal, ENT - Ear, nose and throat, ICU – intensive care unit The most common presentation of HAE patients in the ED was “swelling above the shoulder” [ 108 ], indicating angioedema of the face (lips, periorbital and cheeks), tongue, uvula and/or pharynx. The leading symptoms were abdominal pain and swelling of the face and/or body. Most of the included studies had a primary study objective other than characterising patients with HAE in the ED. Swelling of the extremities plus the absence of urticaria should suggest HAE in the ED [ 109 ]. HAE patients often had a history of similar previous ED visits and therapy attempts with steroids, epinephrine and antihistamines did not result in any improvement [ 112 ]. One study [ 111 ] evaluated what went wrong in the ED and proposed lessons learned [ 111 ]: misjudgement/insufficient assessment of severity and type of angioedema by the emergency physician and insufficient awareness of rapid HAE progression led to Misdiagnosis and ineffective treatment. Airway not secured and emergency measures not prepared. Delay in providing life-saving treatment resulting in patients’ death. Misdiagnosis and ineffective treatment. Airway not secured and emergency measures not prepared. Delay in providing life-saving treatment resulting in patients’ death. Therefore, the authors concluded that emergency physicians need to be aware of the possible rapid progression of angioedema in patients with HAE and need to have measures in place to secure the airway and even be prepared for cricothyrotomy. For HHT, a case series [ 114 ] describing the initial presentation of three patients with HHT and CNS lesions in the ED was identified. The extracted characteristics are listed in Table 6 . Table 6 Characteristics of HHT patients in the ed Kuwayama et al. 2003 Patients (female, male) n = 3 (f: 1, m:2) Age (years) 23, 32, 62 Age of manifestation N/A Epistaxis since childhood: 3/3 HHT known No ED presentation Hemiparesis right + loss of consciousness (1/3) Loss of consciousness for a few minutes after drinking alcohol (1/3) Sudden onset and worsening of left arm paresis for 1 day (1/3) family history of recurrent epistaxis Yes 2/3 (1/3 N/A) 1 st degree family member with HHT – Yes 1/3 Additional findings Patient 1 (23 years)  Normal CT on admission  DSA: occlusion of cerebral artery  Chest radiography: shadow in left lung  Polycythemia (Hemoglobin 17.6 g/dl)  Blood coagulation analysis normal Patient 2 (62 years)  MRI: ring enhanced lesion temporal lobe  Chest radiography: perihilar consolidation  laboratory: mild infection Patient 3 (32 years)  CT: subcortical hemorrhage  MRI: no further findings  laboratory: normal  Chest-CT/pulmonary arteriography: Pulmonary arteriovenous malformations 3/3 N/A – not specified, DSA – digital subtraction angiography, ED – emergency department, HHT – hereditary haemorrhagic telangiectasia, m – male, f – female Characteristics of HHT patients in the ed N/A Epistaxis since childhood: 3/3 Hemiparesis right + loss of consciousness (1/3) Loss of consciousness for a few minutes after drinking alcohol (1/3) Sudden onset and worsening of left arm paresis for 1 day (1/3) Yes 2/3 (1/3 N/A) 1 st degree family member with HHT – Yes 1/3 Patient 1 (23 years) Normal CT on admission DSA: occlusion of cerebral artery Chest radiography: shadow in left lung Polycythemia (Hemoglobin 17.6 g/dl) Blood coagulation analysis normal Patient 2 (62 years) MRI: ring enhanced lesion temporal lobe Chest radiography: perihilar consolidation laboratory: mild infection Patient 3 (32 years) CT: subcortical hemorrhage MRI: no further findings laboratory: normal Chest-CT/pulmonary arteriography: Pulmonary arteriovenous malformations 3/3 N/A – not specified, DSA – digital subtraction angiography, ED – emergency department, HHT – hereditary haemorrhagic telangiectasia, m – male, f – female All three patients presented with mucocutaneous telangiectasia (nose, tongue, oesophagus, stomach) and reported recurring epistaxis since childhood. Two patients had either a family history of recurrent epistaxis, telangiectasias or HHT diagnosis itself. Pulmonary AVMs were diagnosed in all three patients. The authors concluded that earlier diagnosis of HHT and screening for AVMs could have prevented the occurrence of complications such as ischemic stroke and brain abscess. They stressed the importance of paying attention to patients’ history (nosebleeds since childhood) and their family history in the ED. One US publication from 2005 [ 72 ] presented a case series of three patients (Table 7 ). The primary presenting feature in the ED was ptosis. Table 7 Characteristics of patients with mg in the ED Smulowitz et al. 2005 Patients (female, male) n = 3 (f: 3) Age (years) 48–78 Manifestation age of MG (years) 48, 65, N/A MG diagnosis known Yes 1/3 No 2/3 Symptoms Ptosis (3/3)  - one sided (2/3)  - both sides (1/3) Diplopia (2/3)  - fluctuating (1/3)  - constantly (1/3) Dyspnoea (1/3) Other (1/3)  - Difficulty swallowing (including own saliva)  - symmetric mild paresis of extremities ED presentation Diplopia (2/3) Increased dyspnea and dysphagia after initial improvement after treatment for pre-existing pneumonia (1/3) trigger factors Patient with myasthenic crisis: pneumonia and surgery (1/3) N/A 2/3 Additional findings MRI (head) und CT (thorax): normal (2/3, 1 N/A) Vital signs: normal (1/3), respiratory rate 20 and SaO2 98% under 2 L oxygen (1/3), (1 N/A) Patient with myasthenic crisis: FVC 1.2 L (normal 4.5–5 L) One patient reported a previous episode of diplopia one month prior to ED presentation. N/A – not specified, FVC – forced vital capacity Characteristics of patients with mg in the ED Ptosis (3/3) - one sided (2/3) - both sides (1/3) Diplopia (2/3) - fluctuating (1/3) - constantly (1/3) Dyspnoea (1/3) Other (1/3) - Difficulty swallowing (including own saliva) - symmetric mild paresis of extremities Diplopia (2/3) Increased dyspnea and dysphagia after initial improvement after treatment for pre-existing pneumonia (1/3) Patient with myasthenic crisis: pneumonia and surgery (1/3) N/A 2/3 MRI (head) und CT (thorax): normal (2/3, 1 N/A) Vital signs: normal (1/3), respiratory rate 20 and SaO2 98% under 2 L oxygen (1/3), (1 N/A) Patient with myasthenic crisis: FVC 1.2 L (normal 4.5–5 L) One patient reported a previous episode of diplopia one month prior to ED presentation. N/A – not specified, FVC – forced vital capacity The authors recommended considering MG in all patients exhibiting muscle weakness and myasthenic crisis in those with known MG plus dyspnoea. Although two publications [ 119 , 120 ] described patients with myasthenic crisis, the setting and presentation in the ED were unclear. Additionally, four publications [ 121 – 124 ] detailed MG patients with specific key symptoms in the ED and provided guidance for distinguishing them from other differential diagnoses. However, none of these publications characterised the presentation of MG specifically in the ED and therefore could not be included. Five studies [ 103 , 115 – 118 ] characterised 70 adult patients with TTP who presented to the ED (Table 8 ). Most patients (64/70) presented with their first episode of TTP. Table 8 Characteristics of patients with TTP in the ED Author, Year Patients TTP known Presentation in ED Symptoms Laboratory Additional findings Boisriou et al. 2023 n = 40 (with TMA) 29/40 TTP (72.5%) 2/40 HUS (5%) 9/40 other TMA (22.5%) (f: 27 (67.5%), m: 13 (32.5%)) No Symptoms of patients with TMA at arrival at ED: Neurological 10 (25%) Headache 4 (10%) Aphasia 6 (15%) Confusion 4 (10%) Paraesthesia 2 (5%) Ataxia 1 Paralysis 1 Seizure 2 Loss of vision 1 GI symptoms 12 (30%) Vomiting 4 (10%) Abdominal pain 9 (22.5%) Cardiovascular 4 (10%) Dyspnoea 2 (5%) Hypertension 3 (7.5%) Chest pain 1 Haemorrhage 20 (50%) Cutaneous and mucosal 17 (42.5%) Acute renal failure 9 (22.5%) Other Jaundice/pallor 7 (17.5%) Symptoms of patients with TMA prior to arrival at ED: Neurological 20 (50%) Headache 13 (32.5%) Aphasia 6 (15%) Confusion 4 (10%) Paraesthesia 3 (7.5%) Ataxia 2 (5%) Paralysis 1 Seizure 1 Loss of vision 1 GI symptoms 17 (42.5%) Vomiting 11 (27.5%) Diarrhoea 8 (20%) Abdominal pain 7 (17.5%) Cardiovascular 11 (27.5%) Dyspnoea 6 (15%) Hypertension 4 (10%) Chest pain 1 Haemorrhage 16 (40%) Cutaneous and mucosal 11 (27.5%), Gynaecological 4 (10%), GI 2 (5%), Urological 2 (5%) Urological 9 (22.5%) Brown urine 8 (20%), Anuria 1 Other Fatigue 14 (35%), Fever 13 (32.5%), Yellow colouration 1, Diffuse pain 3 (7.5%) Median platelet count (/mm3) 17,000 (IQR 10,000– 39,250) Median haemoglobin (g/dL) 9.5 (IQR 7.4 - 10.5) Schistocytes present 28/34 (82.4%) (6 N/A) Elevated hsTroponin I ( > 14 ng/L) 15/24 (62.5%) (16 N/A) Pregnancy/Postpartum 1/40 Duration of symptoms before arrival in the emergency department: median 4 days (IQR 3–7) Death 4/40 Misdiagnosis: Infection, immune thrombocytopenia, autoimmune haemolytic anaemia, stroke In 16/40 (40%) of patients, the diagnosis of TMA, TTP or HUS was not mentioned, despite the presence of thrombocytopenia, anaemia and schistocytes in 6 of these cases (37.5%) Age (Median): 44 (IQR 28–57) years Li et al. 2021 n = 19 (f:10, m:9) No Impaired consciousness (9/19) and: - Purpura (3/19) - Skin ecchymoses (1/19) - Fatigue, fever (1/19) - Dizziness, fatigue, subcutaneous ecchymoses (1/19) Vomiting (3/19) and: - Palpitations (1/19) - Ecchymoses on extremities, fever (1/19) - Nausea, jaundice (1/19) Haemorrhage (2/19): - bleeding wounds (1/19) - Blood in sputum and stool, headache (1/19) Other (5/19): - Dizziness, fatigue, slurred speech (1/19) - Skin ecchymoses, difficulty opening mouth (1/19) - Chest tightness and sore throat (1/19) - Oedema, joint pain, cough, sputum, shortness of breath (1/19) - Loss of appetite (1/19) Neurological symptoms 11 (58%) Symptoms of thrombocytopenia* 8 (42%) Fever 2 (11%) Renal function impairment 6 (32%) Classical pentad 4 (21%) *Symptoms of thrombocytopenia: petechiae, haematomas, melena, haematuria, haematemesis Platelet count: median 12 × 10^9/L (3–99 ×10^9/L) Haemoglobin: 71 g/L (44–108 g/L) Schistocytes (9/19): 5.7% (0.3–40%) Discussed trigger: Idiopathic 10/19 (53%) Surgery 1/19 Pregnancy/Postpartum: 2/19 Connective tissue disease: 6/19 Median time between symptom onset and diagnosis: 7 days (2 days to 3 month) Death 4/19 Age (median): 56 (range 19–75) years Noel et al. 2013 n = 6 (f:4, m:2) N/A N/A Neurological symptoms 4/6 (66.6%) Acute renal failure 2/6 (33.3%) Haemoglobin (g/l) 69 [ 48 – 94 , 96 – 98 , 100 – 111 ] Schistocytes, n (%) 6 [ 101 ] Platelet count (10^9/L) 12.5 (8–41) Median (min-max) Death 0/6 Age (median): 35 (range 23 - 74) years Pieralli et al. 2011 n = 12 (f:58%, m:42%) No Fluctuating neurological symptoms 9/12 (83%) Fever 9/12 (83%) Weakness 10/12 (91%) Renal failure 4/12 (36%) Purpura 2/12 Haematuria 2/12 Abdominal pain 1/12 Most frequent: fluctuating neurological symptoms (e.g. focal deficits, coma, seizure) and fever Platelet count 24,300 (9000 - 63,000) (cell/L) Haemoglobin (g/dL) 7.2 (4.5–11.7) Mean schistocyte count per field of view 3 (2 - 6) Creatinine (mg/dL) 1.5 (0.8–2.1) (mean) Discussed trigger/etiology: Pregnancy/Postpartum: 1/12 Ticlopidin 2/12 Unknown 9/12 Timed between symptom onset and diagnosis (mean): 6 days (range 3–36) Death 5/12 (42%) Misdiagnosis: Depression, anxiety, thyroid disease (misdiagnoses, especially in younger patients) Age (mean): 59 (range 37–85) years Women were significantly younger than men (50.5 vs. 67 years) Stella et al. 2009 n = 12, ED - subgroup = 4, all female and pregnant No 11/12 Yes 1/12 Diagnosis not known in ED-subgroup. Anxiety (1/4) Nausea, vomiting (1/4) Loss of consciousness (1/4) Loss of consciousness, confused (1/4) 2/4 were discharged home 2–3 times before being hospitalised Nausea, vomiting, abdominal pain and changes in the state of consciousness were the most common symptoms. Fever: 0/4. Platelet count 3–13 ×(10 3 /mm 3 ) Hematocrite: 20.6 - 24.2% (range) Duration between symptom onset and diagnosis 1–6 days Maternal Death: 0/4 (ED presentation), 3/12 (total, n  = 12) Fetal Death: 1/4, 2/12 Misdiagnosis: Panic attack, domestic violence, gastroenteritis Age (range): 20–40 years Gestational age: 12, 21, 24, 30 weeks ED – emergency department, HUS - hemolytic uremic syndrome, TMA – thrombotic microangiopathy, TTP – thrombotic thrombocytopenic purpura, f – female, m – male, GI – Gastrointestinal, N/A – not specified Characteristics of patients with TTP in the ED n = 40 (with TMA) 29/40 TTP (72.5%) 2/40 HUS (5%) 9/40 other TMA (22.5%) (f: 27 (67.5%), m: 13 (32.5%)) Symptoms of patients with TMA at arrival at ED: Neurological 10 (25%) Headache 4 (10%) Aphasia 6 (15%) Confusion 4 (10%) Paraesthesia 2 (5%) Ataxia 1 Paralysis 1 Seizure 2 Loss of vision 1 GI symptoms 12 (30%) Vomiting 4 (10%) Abdominal pain 9 (22.5%) Cardiovascular 4 (10%) Dyspnoea 2 (5%) Hypertension 3 (7.5%) Chest pain 1 Haemorrhage 20 (50%) Cutaneous and mucosal 17 (42.5%) Acute renal failure 9 (22.5%) Other Jaundice/pallor 7 (17.5%) Symptoms of patients with TMA prior to arrival at ED: Neurological 20 (50%) Headache 13 (32.5%) Aphasia 6 (15%) Confusion 4 (10%) Paraesthesia 3 (7.5%) Ataxia 2 (5%) Paralysis 1 Seizure 1 Loss of vision 1 GI symptoms 17 (42.5%) Vomiting 11 (27.5%) Diarrhoea 8 (20%) Abdominal pain 7 (17.5%) Cardiovascular 11 (27.5%) Dyspnoea 6 (15%) Hypertension 4 (10%) Chest pain 1 Haemorrhage 16 (40%) Cutaneous and mucosal 11 (27.5%), Gynaecological 4 (10%), GI 2 (5%), Urological 2 (5%) Urological 9 (22.5%) Brown urine 8 (20%), Anuria 1 Other Fatigue 14 (35%), Fever 13 (32.5%), Yellow colouration 1, Diffuse pain 3 (7.5%) Median platelet count (/mm3) 17,000 (IQR 10,000– 39,250) Median haemoglobin (g/dL) 9.5 (IQR 7.4 - 10.5) Schistocytes present 28/34 (82.4%) (6 N/A) Elevated hsTroponin I ( > 14 ng/L) 15/24 (62.5%) (16 N/A) Pregnancy/Postpartum 1/40 Duration of symptoms before arrival in the emergency department: median 4 days (IQR 3–7) Death 4/40 Misdiagnosis: Infection, immune thrombocytopenia, autoimmune haemolytic anaemia, stroke In 16/40 (40%) of patients, the diagnosis of TMA, TTP or HUS was not mentioned, despite the presence of thrombocytopenia, anaemia and schistocytes in 6 of these cases (37.5%) Age (Median): 44 (IQR 28–57) years n = 19 (f:10, m:9) Impaired consciousness (9/19) and: - Purpura (3/19) - Skin ecchymoses (1/19) - Fatigue, fever (1/19) - Dizziness, fatigue, subcutaneous ecchymoses (1/19) Vomiting (3/19) and: - Palpitations (1/19) - Ecchymoses on extremities, fever (1/19) - Nausea, jaundice (1/19) Haemorrhage (2/19): - bleeding wounds (1/19) - Blood in sputum and stool, headache (1/19) Other (5/19): - Dizziness, fatigue, slurred speech (1/19) - Skin ecchymoses, difficulty opening mouth (1/19) - Chest tightness and sore throat (1/19) - Oedema, joint pain, cough, sputum, shortness of breath (1/19) - Loss of appetite (1/19) Neurological symptoms 11 (58%) Symptoms of thrombocytopenia* 8 (42%) Fever 2 (11%) Renal function impairment 6 (32%) Classical pentad 4 (21%) *Symptoms of thrombocytopenia: petechiae, haematomas, melena, haematuria, haematemesis Platelet count: median 12 × 10^9/L (3–99 ×10^9/L) Haemoglobin: 71 g/L (44–108 g/L) Schistocytes (9/19): 5.7% (0.3–40%) Discussed trigger: Idiopathic 10/19 (53%) Surgery 1/19 Pregnancy/Postpartum: 2/19 Connective tissue disease: 6/19 Median time between symptom onset and diagnosis: 7 days (2 days to 3 month) Death 4/19 Age (median): 56 (range 19–75) years n = 6 (f:4, m:2) Neurological symptoms 4/6 (66.6%) Acute renal failure 2/6 (33.3%) Haemoglobin (g/l) 69 [ 48 – 94 , 96 – 98 , 100 – 111 ] Schistocytes, n (%) 6 [ 101 ] Platelet count (10^9/L) 12.5 (8–41) Median (min-max) Age (median): 35 (range 23 - 74) years n = 12 (f:58%, m:42%) Fluctuating neurological symptoms 9/12 (83%) Fever 9/12 (83%) Weakness 10/12 (91%) Renal failure 4/12 (36%) Purpura 2/12 Haematuria 2/12 Abdominal pain 1/12 Platelet count 24,300 (9000 - 63,000) (cell/L) Haemoglobin (g/dL) 7.2 (4.5–11.7) Mean schistocyte count per field of view 3 (2 - 6) Creatinine (mg/dL) 1.5 (0.8–2.1) (mean) Discussed trigger/etiology: Pregnancy/Postpartum: 1/12 Ticlopidin 2/12 Unknown 9/12 Timed between symptom onset and diagnosis (mean): 6 days (range 3–36) Death 5/12 (42%) Misdiagnosis: Depression, anxiety, thyroid disease (misdiagnoses, especially in younger patients) Age (mean): 59 (range 37–85) years Women were significantly younger than men (50.5 vs. 67 years) n = 12, ED - subgroup = 4, all female and pregnant No 11/12 Yes 1/12 Diagnosis not known in ED-subgroup. Anxiety (1/4) Nausea, vomiting (1/4) Loss of consciousness (1/4) Loss of consciousness, confused (1/4) 2/4 were discharged home 2–3 times before being hospitalised Platelet count 3–13 ×(10 3 /mm 3 ) Hematocrite: 20.6 - 24.2% (range) Duration between symptom onset and diagnosis 1–6 days Maternal Death: 0/4 (ED presentation), 3/12 (total, n  = 12) Fetal Death: 1/4, 2/12 Misdiagnosis: Panic attack, domestic violence, gastroenteritis Age (range): 20–40 years Gestational age: 12, 21, 24, 30 weeks ED – emergency department, HUS - hemolytic uremic syndrome, TMA – thrombotic microangiopathy, TTP – thrombotic thrombocytopenic purpura, f – female, m – male, GI – Gastrointestinal, N/A – not specified The most common presentations in the ED were neurological and/or gastrointestinal symptoms and weakness; in one patient, anxiety was noted as the ED presentation. Misdiagnosis was reported specifically in younger patients [ 118 ]. The median duration of symptoms before presentation to the ED ranged from 4 to 7 days. One study [ 103 ] specifically investigated TTP in pregnant patients. Among the four included patients, two were sent home two to three times from the ED before hospitalisation. All four women survived; however, one of the four unborn children died. The overall mortality rate reported in all the studies ranged from 0% to 42% [ 117 ]. On the basis of the findings for each individual investigated RD, common features identified at the time of presentation to the ED are shown in Table 9 . In case a common feature was not applicable for all patients evaluated for an RD, it was distinguished between described for at least two third of patients included in the review (= ✓) and described for less than two third of patients (= (✓)). To assess the robustness of results, a comparative overview of study design, patient numbers and extracted outcomes across all RD is provided in Table 2 . Table 9 Characteristics of RD presentation in the ED RD (No. of patients included in this review) Age < 65 years Organ systems affected Recurrent episodes Vital signs Routine laboratory Imaging Trigger factor present Family history AHP (n = 59) ✓ Gastrointestinal, Neurologic, Urologic, Cardiovascular mean 4 (range 1-8) visits to ED, other hospital or outpatient department before diagnosis † cyclic attacks † Hypertensive 7/49 Tachycardic 10/36 N/A: 10/59 Hyponatremia▽ Abdominal ultrasound, head-CT/MRI normal † ✓* (✓)* FMF † (n = 75) ✓ — ✓ — — — ✓ ✓ HAE (n >84) ✓° Gastrointestinal, Cardiovascular, Respiratory, Skin, ENT † Weekly (1/3), two per month (1/3), annually (1/3) † Normal* WBC↑ † CT face and neck: laryngeal oedema (1/3), CT abdomen: intestinal oedema + ascites (1/3) † (✓)* ✓* HHT † (n = 3) ✓ Neurological, ENT, Skin, Respiratory ✓ — Polycythaemia, mild infection Chest radiography: shadow in left lung/perihilar consolidation Chest-CT/pulmonary arteriography: Pulmonary arteriovenous malformations CNS lesion in DSA, MRI, CT — ✓ MG † (n = 3) (✓) Ophthalmologic, Neurologic, ENT, Respiratory (✓) Normal Patient with myasthenic crisis had normal vital signs except for a respiratory rate of 20 and O 2 saturation of 98% under 2L of oxygen. — Normal MRI (head) und CT (thorax) (✓) — TTP (n = 70) ✓° Neurologic, Gastrointestinal, Cardiovascular, Urologic, Gynaecologic, ENT, Orthopaedic, Skin, Psychiatric, General (Fatigue, Fever) 2/4 patients had been sent home 2–3 times before being hospitalized* — Thrombocytopenia ▽ Schistocytes ▽ Anaemia ▽ Signs of end organ damage (Troponin ↑, Creatinin ↑)▽ — (✓)* — ✓= described for at least two third of patients included in the review (✓)= described for less than two third of patients (—)= not assessed * = not assessed by all studies † = assessed by only one study ° = based on mean and median ▽ = disease specific characteristic WBC — white blood cell count, DSA — digital subtraction angiography Characteristics of RD presentation in the ED AHP (n = 59) mean 4 (range 1-8) visits to ED, other hospital or outpatient department before diagnosis † cyclic attacks † Hypertensive 7/49 Tachycardic 10/36 N/A: 10/59 FMF † (n = 75) HAE (n >84) HHT † (n = 3) Chest radiography: shadow in left lung/perihilar consolidation Chest-CT/pulmonary arteriography: Pulmonary arteriovenous malformations CNS lesion in DSA, MRI, CT MG † (n = 3) Normal Patient with myasthenic crisis had normal vital signs except for a respiratory rate of 20 and O 2 saturation of 98% under 2L of oxygen. TTP (n = 70) Thrombocytopenia ▽ Schistocytes ▽ Anaemia ▽ Signs of end organ damage (Troponin ↑, Creatinin ↑)▽ ✓= described for at least two third of patients included in the review (✓)= described for less than two third of patients (—)= not assessed * = not assessed by all studies † = assessed by only one study ° = based on mean and median ▽ = disease specific characteristic WBC — white blood cell count, DSA — digital subtraction angiography The listed organ systems were not affected in all patients at the same time. Basic imaging (ultrasound, CT, MRI, chest radiography) was normal (AHP, MG), showed nonspecific findings (oedema or ascites in HAE, shadow or consolidation in chest radiography in HHT) or was not assessed (FMF, TTP). Normal or nonspecific findings (including disease specific findings e.g. hyponatremia in AHP) in standard imaging and laboratory results were therefore a common feature among patients with AHP, HAE, MG and HHT. Two additional characteristics were observed in patients with RD who presented to the ED. The first is the presence of trigger factors reported for patients with AHP, FMF, HAE, MG and TTP and the second is a family history of similar symptoms or even RD itself (AHP, FMF, HAE, HHT).

Emergency departments (ED), and thus, emergency medicine, provide care for patients requiring diagnosis and management of urgent and emergency aspects of illness and injury with a full spectrum of undifferentiated physical and behavioral disorders [ 1 ]. Therefore, ED are often the first place for patients with acute symptoms, including patients with certain (unknown) rare diseases (RD). There is no global definition for RD [ 2 ]. A disease is considered rare, if it affects no more than five out of 10 000 people in the EU [ 3 ], less than 200 000 in the US [ 4 ] or less than 50 000 in Japan [ 5 ]. Given that more than 7 000 RD have been described [ 6 ], RD may affect up to 36 million people in the EU [ 7 ] and up to 446 million people worldwide [ 8 ]. Since a huge number of patients (140 million in the US [ 9 ], 19 million in Germany [ 10 ] or 21 million in France [ 11 ], respectively) visit ED annually, it might be reasonable for ED physicians to consider RD during clinical decision making, particularly in ED patients with otherwise unexplained symptoms. Patients with RD face problems, inside and outside the ED, regarding diagnosis and treatment resulting in diagnostic latency, misdiagnosis and multiple healthcare contacts before diagnosis [ 12 , 13 ]. On average, RD patients wait 4.7 years [ 14 ] to receive a correct diagnosis. Compared with patients with more common diseases, they experience increased morbidity and mortality, both overall and in the ED [ 15 – 17 ] and worse inpatient outcomes [ 18 ]. Strategies are needed to determine when to suspect an RD, as a lack of suspicion seems to be a major factor in diagnostic delay [ 19 ]. Unfortunately, patients with RD present with common symptoms, e.g. abdominal pain, making it even more difficult for ED physicians to identify those patients. Recent studies have indicated the need for emergency specific education on RD [ 17 , 20 ] and have started to provide strategies for RD in the ED [ 21 – 23 ]. The feasibility of screening for RD in the ED setting has been demonstrated [ 24 – 26 ] and the number of therapies (“orphan drugs”) available is increasing [ 27 ]. Therefore, the prognosis of patients with RD depends crucially on early diagnosis and initiation of treatment. “Red flags” could help to identify RD patients [ 28 ]. To explore potential common features among patients with RD in the ED that could serve as such, we conducted a systematised literature review.

In this systematised review of primary data, 18 studies were assessed for common features among patients with rare but treatable diseases presenting to the ED. The studies were all published after 2003. The ED presentation included both diagnosed and undiagnosed RD patients. Some studies did not provide information on whether the diagnosis was already established or not. The common features identified in this review were patient age < 65 years; symptoms affecting multiple organ systems contributing to a nonspecific presentation; recurrence of symptoms reflected by previous presentation to other health institutions with similar symptoms or a history of similar previous episodes; the presence of trigger factors; nonindicative or normal findings in routine laboratory, imaging and vital signs; and a positive family history. Deviations from these common features can occur especially in vital signs, laboratory tests, imaging and family history. For example disease specific and therefore non-common features were hyponatremia, tachycardia and hypertension in AHP patients, signs of oedema on CT scans of HAE patients and severe thrombocytopenia and haemolytic anaemia in TTP patients and a negative family history in patients with MG. Nevertheless, a positive family history was a common feature among other RD and can serve as a strong red flag indicating an RD in the ED if present. RD represents a highly heterogeneous group of conditions that can manifest in very individual ways, making it challenging to derive common features and red flags across them. This list should not be viewed as a checklist to rule out an RD in the ED. Instead, it serves as an initial attempt to describe patients with RD in the ED, providing a starting point for further research aimed at enhancing care for RD patients, potentially by utilising these common features. Previous studies have described general characteristics of RD patients outside the ED setting. A recent study derived seven biopsychosocial red flags in patients with RD from reports of RD patient groups [ 125 ]. In line with some findings in our review, they also identified the involvement of multiple organ systems (at least three) and a positive family history as sign of a genetic inheritance as common features. They also reported a continuance of presentation from child- to adulthood, which was also mentioned in the studies included in this review on HHT (epistaxis since childhood) and HAE (recurrent angioedema since childhood), referrals to multiple specialists, which were reported in the included studies in our review as multiple health care or ED visits described for AHP, HAE and TTP patients and misdiagnosis. In addition to our characteristics, they reported difficulties in school (absence, problems participating in physical activities, bullying and social isolation) and prolonged unexplained symptoms. Another study defined characteristics for patients that should prompt further testing to exclude an RD [ 126 ]. These consisted of physical changes without sufficient explanation affecting multiple organ systems that began in childhood or adolescence and may similarly be encountered in the patient’s family, with no improvement despite therapy, a duration of complaints of more than six months to one year without a diagnosis and avoidance of generally welcomed activities. All three sets of potential warning signs of the underlying RD are summarised in Table 10 . Table 10 Potential red flags of patients with RD Potential red flags derived from this review Grigull 2021 [ 126 ] Al-Attar et al. 2024 [ 125 ] - Multiple organ systems affected, nonspecific presentation - Recurrent symptoms, previous presentation to health institutions - Patient age < 65 years - Positive family history - Nonspecific or normal findings in: routine laboratory, standard imaging (chest radiography, CT, MRI, ultrasound), vital signs - Trigger factor present - Several organ systems are affected - > 6–12 months of complaints and search for a diagnosis (in adults) - Specific features go back to childhood/adolescence, possibly also similar features in the family environment - Irritating physical changes without explanation - No improvement despite adequate therapy - Deliberate avoidance of certain, generally welcome activities (e.g. holidays, meetings with friends) - Multi-system involvement (3 or more) - Multiple specialist referrals - Presentation in both childhood and adulthood - Genetic inheritance pattern - Delayed diagnosis (no diagnosis after one year of seeking medical help) - Misdiagnosis - Difficulties at school e.g. especially absences, difficulty participating in physical education and bullying/social isolation Potential red flags of patients with RD - Multiple organ systems affected, nonspecific presentation - Recurrent symptoms, previous presentation to health institutions - Patient age < 65 years - Positive family history - Nonspecific or normal findings in: routine laboratory, standard imaging (chest radiography, CT, MRI, ultrasound), vital signs - Trigger factor present - Several organ systems are affected - > 6–12 months of complaints and search for a diagnosis (in adults) - Specific features go back to childhood/adolescence, possibly also similar features in the family environment - Irritating physical changes without explanation - No improvement despite adequate therapy - Deliberate avoidance of certain, generally welcome activities (e.g. holidays, meetings with friends) - Multi-system involvement (3 or more) - Multiple specialist referrals - Presentation in both childhood and adulthood - Genetic inheritance pattern - Delayed diagnosis (no diagnosis after one year of seeking medical help) - Misdiagnosis - Difficulties at school e.g. especially absences, difficulty participating in physical education and bullying/social isolation The identified common features of RD patients in the ED and the validity for RD outside of the predefined set of RD need to be assessed in further studies, particularly with respect to their applicability beyond the predefined set of RD. Several studies have emphasised the need for immediate diagnosis and treatment of RD in the ED to prevent possible fatal outcomes [ 25 , 104 , 111 ]. In the high-pressure setting of the ED, where time and resources are limited and the primary focus is on stabilising immediate life-threatening conditions, it is crucial to develop criteria that help patients who may benefit from additional diagnostic workup. The identified common features may serve as red flags for RD in the ED, but their effectiveness in this context needs further careful evaluation. Integrating such red flags into triage protocols and decision support systems may strengthen the ability of ED teams to recognise and manage patients with RD. Beyond individual patient care, the implementation of such a system could enhance the overall awareness of RD among emergency staff. There are several limitations to this review and the thereby identified common features. First, this was a systematised and not fully systematic literature review, mainly performed by a single reviewer. Although the whole search process based on methodological standards (JBI Manual PRISMA), the search strategy was non-exhaustive. While a comprehensive search of additional databases (done exemplarily for AHP) did not yield further eligible studies, the risk of missing relevant studies cannot be fully ruled out. The languages of the included studies were limited to English and German, -although only n  = 7 studies were ruled out due to language reasons, a language bias remains possible. The included studies were mostly retrospective chart reviews considering small patient cohorts. Only a few prospective cohort studies could be identified. This reliance on mainly retrospective data may introduce selection bias, as for these studies available medical records may not represent the entire patient population. Excluding case reports may also have led to the omission of valuable information, particularly for RD with limited published research. However, since the review aimed to identify broader trends relevant to larger patient populations, case reports were considered not to contribute significantly to the overall understanding, as they describe specific isolated cases. Patient characteristics were reported very heterogeneously throughout the studies, only 33% ( n  = 6) were designed to characterise patients with RD in the ED. Such limited data may lead to inconsistencies in disease classification and symptom interpretation. The limited number of studies for specific RD (e.g., only one case series each for MG and HHT and none for PNH and FD) increases the risk of misclassification due to insufficient data. Studies were not limited to patients presenting to the ED with undiagnosed RD, which may bias the findings of symptoms and presenting features in the ED in terms of potential overestimation of diagnostic clarity in the ED. Taken together, these limitations highlight the need for caution when interpreting the results and emphasise the importance of further research. Nevertheless, as mentioned before methodological specifications (JBI Manual, PRISMA) informed the whole review process to ensure the scientific robustness of the results. Further research is necessary to identify ED specific features of RD that could support risk stratification to identify patients with RD in the ED. To the best of our knowledge, this is the first literature review exploring the common features of patients with RD specifically in the ED context.

Information available on RD in the emergency care setting remain limited and descriptions of RD presentation in the ED are scarce. This review proposes some common features among patients with RD in the ED that could be used to develop risk stratification algorithms and early warning systems. In practice, these findings could be integrated into structured triage checklists or serve as input for clinical decision support tools including AI based approaches, helping emergency physicians to recognise early signs of RD and initiate prompt treatment, potentially improving patient outcomes and reducing the overall burden on healthcare resources. Further studies should focus on prospectively enrolling patients in the specific ED setting and thus testing and validating these identified common features to determine their applicability and effectiveness in clinical practice. As emphasised before, this is a first approach to identify ED specific findings in patients with RD. We were only able to explore a small and exemplary group of RD, but with rising awareness of RD in the emergency care setting, there will be more diagnoses and therefore more usable data. It is important to address RD in the ED - not least since they are individually rare but collectively common.

Below is the link to the electronic supplementary material. Supplementary Material 1 Supplementary Material 1 Supplementary Material 2 Supplementary Material 2