Histamine-mediated Angioedema Research Articles

Angiotensin-Converting Enzyme Inhibitors and Other Medications Associated With Angioedema.

Angioedema is a localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid extravasation into these tissues. Angioedema is associated with certain vasoactive molecules and is typically mediated by histamine or bradykinin. It manifests clinically as facial edema, swelling of the extremities and urogenital area, and potential involvement of the larynx, leading to dyspnea and inspiratory stridor, which can become life-threatening. Histamine-mediated angioedema is associated with urticaria and pruritus and will show classic signs of allergic (type 1 hypersensitivity) reactions. Bradykinin-mediated angioedema is often familial (hereditary angioedema) and is more often associated with gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), edema of the extremities and trunk, and a lack of urticaria and pruritus. Angiotensin-converting enzyme inhibitors (ACEIs) are a class of medications commonly prescribed for hypertension, heart failure, and diabetic nephropathy. ACEIs are associated with an increased risk of angioedema, which can range from a mild reaction to severe and life-threatening. ACEI-induced angioedema is a bradykinin-mediated reaction that can occur in individuals with a genetic predisposition. Other medications, such as angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics, most notably those in the beta-lactam class, can also cause drug-induced angioedema. The present investigation describes current knowledge of the pathophysiology, epidemiology, clinical manifestations, predisposing factors, and management of drug-induced angioedema.

Pseudo-Allergies in the Emergency Department: A Common Misdiagnosis of Hypersensitivity Type 1 Allergic Reaction.

Type-1 hypersensitivity reaction represents an acute IgE-mediated reaction that can cause life-threatening conditions, such as anaphylactic shock, angioedema, and airway obstruction. Other reactions that can mimic type-1 hypersensitivity reactions include IgE-independentmast cell degranulation, bradykinin-mediated reactions, leukotrienes-mediated reactions, and pseudo-allergies. We use the term pseudo-allergy in this article for histamine-mediated reactions that are mast cell-independent. We did not discuss pseudo-allergic reactions that are not acute or life-threatening, such as celiac disease, Heiner's syndrome, eosinophilic esophagitis, and food protein-induced enterocolitis in our article because the emergency department is not the primary location to diagnose or treat these reactions. Herein, we present some allergic-like reactions that can be life-threatening, such as scombroid food poisoning (SFP), bradykinin-induced angioedema, IgE-independent angioedema, opioid-induced angioedema, and non-steroidal anti-inflammatory drug (NSAID)-induced hypersensitivity and angioedema. These reactions may have different treatments based on their mechanism of reaction. Histamine-mediated reactions, such as SFP, histamine-mediated angioedema, and mast cell degranulation induced by NSAIDs, and opioids can be treated with antihistamines, epinephrine, and corticosteroids. Bradykinin-induced angioedema, including hereditary angioedema and acquired angioedema, can be treated with fresh frozen plasma. Hereditary angioedema can be treated withmany FDA-approved targeted medications, such asplasma-derived C1-INH,plasma kallikrein inhibitor (Ecallantide), and selective bradykinin-2 receptor antagonist (Icatibant).However, these targeted agents are not well-studied enough to be used for acquired angioedema.It is crucial for emergency medicine physicians to be familiar with and predict these reactions to prevent misdiagnosis, be prepared to treat these life-threatening conditions appropriately without delay and eliminate patients' exposure to any unnecessary investigations or treatments.

A Comprehensive Review of Bradykinin-Induced Angioedema Versus Histamine-Induced Angioedema in the Emergency Department.

Angioedema (AE) is a condition that is frequently encountered in the emergency department (ED). It is a rare condition with localized, asymmetrical swelling of the skin and/or mucosa that is frequently nonpruritic and primarily affects locations with loose connective tissue. Physicians must have a thorough understanding of this condition since it can cause fatal airway compromise, which might be the presenting symptom. Histamine-mediated AE is the most common type of AE seen in EDs. However, ED physicians must be on the lookout for the less common bradykinin-mediated types of AEas these do not respond to the same therapy as histamine-mediated AE. Hospitals may lack specialized drugs or protocols, and many ED staff may be unable to identify or treat bradykinin-mediated AE. It is crucial to understand the pathophysiology of the various kinds of AE in order to optimize treatment. The goal of this review paper is to provide an overview of the pathophysiology, clinical manifestations, and treatment options for bradykinin and histamine-induced AE in the ED.

Angioedema severity and impact on quality of life: Chronic histaminergic angioedema versus chronic spontaneous urticaria

Histamine-mediated angioedema is the most frequent form of angioedema. It is classified as idiopathic histaminergic acquired angioedema (IH-AAE)1 when allergies and other causes have been excluded and a positive treatment response to antihistamines, corticosteroids, or omalizumab has been reported. Idiopathic histaminergic acquired angioedema may occur in isolation, when it is termed chronic histaminergic angioedema (CHA), or it may be associated with wheals in chronic spontaneous urticaria angioedema (CSU-AE).

Angioedema and Fatty Acids.

Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently has specific therapeutic options, angioedema is sometimes intractable with current treatments, especially histamine-mediated angioedema, suggesting that some other mediators might contribute to the development of angioedema. Fatty acids are an essential fuel and cell component, and act as a mediator in physiological and pathological human diseases. Recent updates of studies revealed that these fatty acids are involved in vascular permeability and vasodilation, in addition to bradykinin and histamine-mediated reactions. This review summarizes each fatty acid’s function and the specific receptor signaling responses in blood vessels, and focuses on the possible pathogenetic role of fatty acids in angioedema.

Identification of novel biomarkers to distinguish bradykinin-mediated angioedema from mast cell-/histamine-mediated angioedema.

The pathophysiology of the underlying paroxysmal permeability disturbances in angioedema (AE) is not well understood. To identify clinical and laboratory parameters specific for a certain AE subtype, 40 AE patients were prospectively enrolled: 15 hereditary (HAE), 13 ACE-inhibitor induced (ACE-AE), and 12 mast cell-mediated without wheals in chronic spontaneous urticaria (CSU-AE). Ten healthy subjects served as controls. Serum levels of markers indicating activation of the ficolin-lectin pathway, of endothelial cells, or those indicating impairment of vascular integrity or inflammation were assessed by enzyme-linked immunosorbent assay. New routine clinical diagnostic criteria could not be identified, not even for distinguishing bradykinin-mediated (BK-) AE (ie, HAE and ACE-AE) from mast cell-/histamine-mediated CSU-AE. However, FAP-α and tPA were significantly increased in all AE compared to controls. In HAE, FAP- α, tPA, uPAR, pentraxin-3, Tie-2, sE-selectin, and VE-cadherin were significantly increased compared to controls. In HAE compared to CSU-AE and ACE-AE, sE-Selectin, Tie-2, and VE-Cadherin were significantly increased, whereas for Ang-2 the difference was significant compared to CSU-AE only. Tie-2 correlated strongly negatively with C4, C1-INH activity, and C1-INH function. This study is the first to compare HAE, ACE-AE, and CSU-AE. Although significance is limited by small sample size, Tie-2 was identified as a new promising biomarker candidate for HAE. FAP- α and tPA might serve as a marker for AE in general, whereas sE-selectin and Ang-2 were increased in BK-AE only. Our results add information to the role of endothelial dysfunction and serine proteases in different AE subtypes.

Identification of Human Kinin-Forming Enzyme Inhibitors from Medicinal Herbs.

The goal of this study was to assess the pharmacological effects of black tea (Camellia sinensis var. assamica) water extract on human kinin-forming enzymes in vitro. Tea is a highly consumed beverage in the world. Factor XII (FXII, Hageman factor)-independent- and -dependent activation of prekallikrein to kallikrein leads to the liberation of bradykinin (BK) from high-molecular-weight kininogen (HK). The excessive BK production causes vascular endothelial and nonvascular smooth muscle cell permeability, leading to angioedema. The prevalence of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema appears to be through BK. Both histamine and BK are potent inflammatory mediators. However, the treatments for histamine-mediated angioedema are unsuitable for BK-mediated angioedema. We hypothesized that long-term consumption of tea would reduce bradykinin-dependent processes within the systemic and pulmonary vasculature, independent of the anti-inflammatory actions of polyphenols. A purified fraction of the black tea water extract inhibited both kallikrein and activated FXII. The black tea water extracts inhibited factor XII-induced cell migration and inhibited the production of kallikrein on the endothelial cell line. We compared the inhibitory effects of the black tea water extract and twenty-three well-known anti-inflammatory medicinal herbs, in inhibiting both kallikrein and FXII. Surprisingly, arjunglucoside II specifically inhibited the activated factor XII (FXIIa), but not the kallikrein and the activated factor XI. Taken together, the black tea water extract exerts its anti-inflammatory effects, in part, by inhibiting kallikrein and activated FXII, which are part of the plasma kallikrein–kinin system (KKS), and by decreasing BK production. The inhibition of kallikrein and activated FXII represents a unique polyphenol-independent anti-inflammatory mechanism of action for the black tea.

When the Red Tide Rolls In: A Red Tide Associated Angioedema Case Report.

IntroductionHistamine-mediated angioedema is a potentially life-threatening reaction following exposures that incite mast cell activation. In Florida, red tides are a frequent phenomenon caused by overgrowth of the harmful algae species Karenia brevis, which contain environmentally detrimental brevetoxins. Even in low concentrations, brevetoxins can cause disease in humans through inducing histamine release. We report the first documented case of angioedema associated with red tide exposure.Case ReportA 52-year-old-male presented with severe angioedema encompassing both lips within a few hours after exposure to red tide algae. Other symptoms included voice changes and difficulty swallowing. Laboratory findings revealed complement factors that were within reference range, which ruled out a bradykinin-mediated pathology and supported the diagnosis of histaminergic angioedema. Symptoms resolved after 24 hours in the intensive care unit under management with epinephrine, diphenhydramine, methylprednisolone, and famotidine.ConclusionIn coastal regions, red tide algae should be recognized as a rare cause of acute angioedema. Emergency management of histamine-mediated angioedema should focus on preventing respiratory compromise with frequent airway monitoring and treatment with steroids, antihistamines, and epinephrine.

Recognition, Evaluation, and Management of Pediatric Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare, often underrecognized genetic disorder caused by either a C1 esterase inhibitor deficiency (type 1) or mutation (type 2). This leads to overproduction of bradykinin resulting in vasodilation, vascular leakage, and transient nonpitting angioedema occurring most frequently in the face, neck, upper airway, abdomen, and/or extremities. Involvement of the tongue and laryngopharynx has been associated with asphyxiation and death. Hereditary angioedema is an autosomal-dominant condition; therefore, there is a 50% chance an offspring will inherit this disorder. Any patient presenting with isolated angioedema should be screened with a C4 measurement, as 25% of cases have no family history of HAE. All patients with HAE will have a functional deficiency of C1 esterase inhibitor. Contributors that delay the diagnosis of HAE include recognition delay by clinicians who confuse this condition with histaminergic angioedema, the disease's varied presentations, and limitations to timely testing. Pediatric emergency clinicians should be knowledgeable about how to distinguish between bradykinin- and histamine-mediated angioedema, as there are significant differences in the diagnostic testing, treatment, and clinical response between these 2 different conditions. Evidence indicates that early diagnosis and treatment of HAE reduces morbidity and mortality. Clinician recognition of the mechanistically different problems will ensure patients are appropriately referred to an expert for outpatient management.

Hereditary angioedema: how to approach it at the emergency department?

ABSTRACTAngioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

Allergic reaction with angioedema after exposure to e-cigarette liquid: a case report

Background: The use of electronic cigarettes (e-cigarettes) is increasing worldwide. Allergic reactions have been reported from the metal used, and a few cases have been reported of angioedema of the lip, but none were related to the e-cigarette liquid. Case Presentation: We report a case of allergic reaction with angioedema from e-cigarette liquid, most likely histamine-mediated angioedema, in a healthy 24-year-old Saudi man, who did not have a history of any allergy or atopy. The subject presented complaining of left lower lip swelling 1 hour after smoking an e-cigarette and spilling liquid into the mouth. The case reported no shortness of breath, skin rash, or tongue swelling. On examination, vital signs were normal. The patient had left lower lip swelling and gingival erythema. The patient reported having experienced a similar episode in the past with a different type of e-cigarette liquid on the right lower lip, but it was less severe. The patient was diagnosed with allergic reaction with angioedema from the e-cigarette liquid and was managed with hydrocortisone 200 mg Intravenous and chlorphenamine 10 mg Intramuscular, and was discharged after 3 hours with full recovery. Conclusion: E-cigarettes are still relatively new and could cause harm. Further studies and reports should be conducted concerning the health effects of e-cigarettes.

Angioedème isolé récurrent : pensez à l’urticaire chronique

Isolated histamine-mediated angioedema is an uncommon form of chronic urticaria. Herein we report a case of recurrent isolated angioedema in a setting of chronic urticaria. A 33-year-old male patient presented with isolated and recurrent angioedema of the lips, external genitalia and palmoplantar regions that had been present for two years. The occurrence of recurrent isolated angioedema may in itself be sufficient to establish a diagnosis of chronic urticaria.

Update on bradykinin-mediated angioedema in 2020

Bradykinin-mediated angioedema is a rare disease, due to vasodilation and increased vascular permeability resulting from bradykinin. This kind of angioedema affects abdominal and/or upper airways. It differs clinically from histamine-mediated angioedema by the absence of urticaria or skin rash. Antihistamines and corticosteroids are not effective. Delayed diagnosis can lead to inadequate and potentially fatal management by asphyxiation. Bradykinin-mediated angioedema results from either overproduction of bradykinin or inhibition of its degradation. Etiology can be hereditary or acquired. Deficiency of C1 inhibitor and drug induced are the main causes of bradykinin-mediated angioedema. Its diagnosis is clinical (presentation, family history, seriousness, frequency, etc.) and biological (dosage of C1-INH level, C1-INH activity, and complement protein 4 level). Acute attack treatment is based on C1-inhibitor concentrates and icatibant, a bradykinin receptor antagonist. Long-term prophylaxis can be necessary, especially before surgical and dental procedures. New drugs, including gene therapy, are being tested.

Evaluation and Management of Angioedema in the Emergency Department.

Angioedema is defined by non-dependent, non-pitting edema that affects several different sites and is potentially life-threatening due to laryngeal edema. This narrative review provides emergency physicians with a focused overview of the evaluation and management of angioedema. Two primary forms include histamine-mediated and bradykinin-mediated angioedema. Histamine-mediated forms present similarly to anaphylaxis, while bradykinin-mediated angioedema presents with greater face and oropharyngeal involvement and higher risk of progression. Initial evaluation and management should focus on evaluation of the airway, followed by obtaining relevant historical features, including family history, medications, and prior episodes. Histamine-mediated angioedema should be treated with epinephrine intramuscularly, antihistaminergic medications, and steroids. These medications are not effective for bradykinin-mediated forms. Other medications include C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists. Evidence is controversial concerning the efficacy of these medications in an acute episode, and airway management is the most important intervention when indicated. Airway intervention may require fiberoptic or video laryngoscopy, with preparation for cricothyrotomy. Disposition is dependent on patient’s airway and respiratory status, as well as the sites involved.

Prodromal Symptoms In Bradykinin Vs. Histamine-Mediated Angioedema

Prodromal symptoms (PS) in bradykinin-mediated angioedema (B) have been well described however data regarding prodromes in histamine-mediated angioedema (H) is lacking. We assessed the prevalence, types and reliability of prodromes in spontaneous histaminergic angioedema. 73 patients (men and non-pregnant women between the ages of 18-70) receiving care at the US HAEA Angioedema Center were recruited for an anonymous 11 question survey. 30 patients had spontaneous histamine-mediated angioedema and 43 patients had either of the following bradykinin-mediated forms of angioedema: hereditary angioedema (HAE) with C1 inhibitor deficiency/dysfunction or HAE with normal C1 inhibitor. Frequencies were summarized and statistical analyses were calculated using Fisher’s exact, Mann-Whitney U or Independent t-tests. 95.3% of B and 66.7% of H patients reported PS prior to their last angioedema (AE) attack (p=0.002) and 97.6% of B and 80% of H patients reported PS associated with any previous AE attacks. The average number of PS before the last AE attack was 6.17 in B and 2.35 in H (p<0.005). The most frequent PS in B was upset stomach/nausea (63.4%) and in H was cutaneous numbness/tingling (40%). 71% of B and 63% of H patients reported being able to predict AE attacks based on PS at least 75% of the time. PS were followed by AE attacks at least 75% of the time in 80.5% of B and 45% of H patients. Prodomal symptoms occur in a majority of patients with histamine-mediated angioedema though appear more prevalent and predictive in bradykinin-mediated conditions.

Gender aspects in angioedema

Angioedema can be triggered by mediators bradykinin or histamine. Gender-specific differences and potential biomarkers for follow-up/therapy monitoring are mostly unknown. To what extent are gender-related defects, prodromes, trigger factors, clinical parameters such as number of attacks, frequency, localization, laboratory values, hormones and response to therapy different for the variant types of angioedema. A literature search was performed in PubMed with the keywords "angioedema" and "sex" or "gender" as well as targeted screening of reviews, guidelines and registration studies with angioedema-relevant drugs. In histamine-mediated angioedema, there are few gender-specific differences. In bradykinin-mediated hereditary angioedema, especially with factor XII mutation, but also in angiotensin-converting enzyme inhibitor-induced angioedema, women are more frequent, more affected and hormonal influences are documented. The localization of bradykinin-mediated hereditary angioedema (HAE) is also gender specific. The proportion of women in clinical trials for HAE therapies is about two-thirds. Principally, differentiating between estrogen-dependent, estrogen-sensitive and estrogen-insensitive angioedema seems reasonable. The characterization of these subgroups may lead to abetter understanding of the pathomechanism of the hormone effects on angioedema. This could lead to the development of urgently needed biomarkers for faster and more targeted diagnosis and prediction of attacks, to significantly improve the health and quality of life of angioedema patients by means of individualized gender-specific therapy.

Threshold-stimulated kallikrein activity distinguishes bradykinin- from histamine-mediated angioedema.

The lack of specific biomarkers makes the diagnosis of hereditary angioedema (HAE) with normal levels of C1-inhibitor (C1INH) protein (HAE-nl-C1INH) and idiopathic non-histaminergic angioedema (INHA) difficult. Confirming or excluding these diagnoses is a significant challenge for clinicians evaluating patients with angioedema. To develop a reliable biomarker that would aid the diagnosis of HAE-nl-C1INH and INHA. A total of 154 consecutive patients referred for angioedema at a single centre were enrolled and evaluated. Subjects were clinically phenotyped based on clinical history and response to treatment by clinicians blinded to laboratory assay results. Plasma kallikrein activity was measured by the cleavage of the fluorometric substrate Z-Phe-Arg-AMC-HCL in plasma samples stimulated exvivo with submaximal doses of dextran sulphate. Stimulated plasma kallikrein activity (mean relative fluorescence units/min±SD) was significantly increased in both HAE-nl-C1INH (1804±600) and INHA (1579±371) subjects compared to non-swelling controls (171±46) and histaminergic angioedema (133±30) subjects. Using a threshold cut-off based on the normal controls, HAE-nl-C1INH and INHA subjects could be differentiated from histaminergic angioedema subjects with high sensitivity (negative predictive value 86%-89%) and specificity (positive predictive value 80%-100%). The stimulated kallikrein activity assay allows differentiation of bradykinin- from histamine-mediated angioedema. The assay could feasibly be considered as a potential clinical tool for the diagnosis of bradykinin-mediated angioedema.

Hereditary Angioedema: Implications of Management

Hereditary angioedema (HAE) is a genetic condition that is characterized by frequent episodes of localized angioedema. It is a rare disorder that a primary care provider, otolaryngologist, dermatologist, or rheumatologist may encounter only occasionally. This disease is being reviewed because of the significant advances in further understanding the genetics, biology, and therapeutic management surrounding the condition. Histamine-mediated angioedema responds to steroids, antihistamines, and epinephrine, whereas bradykinin-mediated angioedema is resistant to those interventions and requires specialized therapy. Previously used medications have significant adverse effects. Approved medications for HAE have been effective in decreasing morbidity and mortality in patients with this condition. We review the presentation, diagnosis, and available pharmaceutical options for HAE and explore the limitations of implementing recommended therapy.

Angioedema and the role of bradykinins: new treatments and implications in patients with heart failure

The definition of angioedema is an edema of subcutaneous and submucosal tissues due to increased vascular permeability and fluid extravasation. It can affect different areas, including extremities, genitals, upper airways and intestinal mucosa. The symptoms are disabling and this condition can be fatal if it involves the larynx. We can distinguish different forms of angioedema (hereditary and acquired) with different pathogenetic mechanisms, therefore responding to different treatments. Bradykinin-mediated angioedema (such as hereditary angioedema due to C1-inhibitor deficiency) does not respond to the standard therapy used for histamine-mediated angioedema. These forms should be immediately recognized and specific treatment should be used. In addition, when a patient manifests hypotension not responding to fluid replacement and associated with diffuse edema, hypoalbuminemia and hemoconcentration, we should consider the diagnosis of idiopathic systemic capillary leak syndrome, a very rare but fatal condition.

Novel usage of fresh frozen plasma in hereditary angioedema.

Hereditary angioedema (HAE) is a rare and potentially life threatening autosomal dominant disease characterized by recurrent episodes of cutaneous and mucosal oedema. It results from reduced expression or loss of function of CI-esterase inhibitors (C1-INH). As opposed to the more common histamine-mediated angioedema, HAE does not respond well to conventional treatments with anti-histamines, steroids and adrenaline. Early recognition and timely intervention with the correct treatment are crucial particularly preventing airway obstruction. New disease specific treatment including plasma derived or recombinant C1-INH, ecallantide and icatibant have recently emerged and its appropriate use can reduce HAE-associated mortality and morbidity. However due to its costs, these disease specific treatments have yet to reach Malaysia. Despite that no randomized clinical trial on FFP has been performed, its efficacy in treating acute attacks of HAE is only demonstrated in case studies. This case report illustrates the successful treatment of acute HAE episode with FFP in a Malaysian government hospital setting.