Isolated angioedema: A review of classification and update on management.

OBJECTIVE: To review the various types of angioedema including diagnosis and treatment. DATA SOURCES: PubMed search of articles in the English language of various types of angioedema. STUDY SELECTIONS: Articles on the subject matter were selected and reviewed. RESULTS: Herein, a case-based approach is presented for discussing the major types of angioedema, including the following: hereditary angioedema types I and II and normal complement, acquired angioedema, angiotensin-converting enzyme-induced angioedema, and histaminergic and nonhistaminergic angioedema. Emerging treatments of hereditary angioedema including targets of prekallikrein, DNA vector technology replacing C1-INH protein, and CRIPSR technology targeting prekallikrein among many others are explored. In addition, other causes and mimickers of angioedema are briefly reviewed. Finally, a novel algorithm is proposed to help guide the treating physician through the workup and management of patients with suspected idiopathic angioedema unresponsive to conventional therapy with antihistamines. CONCLUSION: Over the years, many strides have been made in both understanding the pathophysiology of various types of angioedema and expansion of treatment options. It is important for clinicians to be aware of current and emerging treatment options. We provide a novel practical algorithm to guide clinicians in challenging cases of idiopathic angioedema refractory to antihistamines.

Acquired complement C1 esterase inhibitor deficiency in a patient with a rare SERPING1 variant with unknown significance.

Angioedema (AE) is caused by a wide range of diseases and pharmaceuticals; it can become life-threatening when located to the airways. Patients with deficiency or malfunction of complement C1 esterase inhibitor (hereditary or acquired) experience recurrent AE due to an accumulation of the vasoactive mediator bradykinin (BK). Complement C1 inhibitor normally decreases BK production, so a reduced function hereof causes increased levels. The diagnosis of hereditary or acquired AE can be difficult due to similarities to allergic reactions (swelling, abdominal pain, rash). We describe a 35-year-old man presenting with upper-airway AE progressing rapidly and promptly required cricothyroidotomy. Complement and autoantibody screening together with sequencing of SERPING1 were performed and gave the diagnosis of acquired complement C1 esterase inhibitor deficiency. The patient is unusual to have this disease before the age of 40 years. No associated comorbidities were found. It is important to know that antiallergic medication is not effective in BK-mediated AE.

Splenic marginal zone lymphomas in acquired C1-inhibitor deficiency: clinical and molecular characterization.

Angioedema due to acquired deficiency of the inhibitor of the first component of complement (C1-INH) is a rare disease known as acquired angioedema (AAE). About 70% of patients with AEE display autoantibodies to C1-INH, the remaining patients have no antibodies to C1-INH. The clinical features of C1-INH deficiency include recurrent, self-limiting local swellings involving the skin, the gastrointestinal tract, and the upper respiratory tract. Swelling is due to accumulation of bradykinin released from high molecular weight kininogen. Patients with angioedema due to acquired C1 inhibitor deficiency (AEE) often have an associated lymphoproliferative disease including Non-Hodgkin Lymphomas (NHL). Among AAE patients with NHL, splenic marginal zone lymphoma (SMZL) has a higher prevalence (66%) compared to general population (2%) In the present study, we focused on patients with SMZL in AAE. We found 24 AAE patients with NHL and, among them 15 SMZL (62.5% of all NHL). We found NOTCH 2 activation in 4 /15 patients (26.6%) with SMZL, while no patients carried MYD 88 or BIRC3 mutations. Restricted immunoglobulin gene repertoire analysis showed that the IGHV1-2*04 allele was found to be over-represented in the group of patients with or without lymphoproliferative disease presenting with autoantibodies to C1-INH (41 of 55 (75%) of patients; p value 0.011) when compared to the control group of patients with AEE without antibodies to C1-INH, (7 of 27 (26%) of patients). Immunophenotyping failed to demonstrate the presence of autoreactive clones against C1-inhibitor. Taken together, these findings suggest a role for antigenic stimulation in the pathogenesis of lymphomas associated with AEE.

Extremely Delayed Diagnosis of Type II Hereditary Angioedema: Case Report and Review of the Literature.

We present a case with extremely late diagnosis of type II hereditary angioedema (HAE). Given recent advances in HAE treatment, we want to bring physician awareness to this condition and aid in earlier detection. HAE is a disorder associated with episodes of angioedema of the face, larynx, lips, abdomen, or extremities. Late diagnosis of HAE can lead to significant morbidity and is severely impairing due to recurring attacks. The diagnosis of HAE is ordinarily made during childhood and adolescence. Delayed diagnoses in early and middle adulthood have been documented in the literature. Gastrointestinal symptoms are common features of HAE and can be misdiagnosed as disease of primary gastrointestinal pathology, such as irritable bowel syndrome, recurrent pancreatitis, or appendicitis. These attacks are characterized by recurrent attacks of subcutaneous and submucosal edema without the presence of urticaria.We present a case of an elderly veteran whose diagnoses was extremely delayed into the eighth decade of life subsequent to unexplained abdominal symptoms. After diagnosis, the patient's symptoms were well controlled with medication due to advances in HAE treatment. To prevent further atypically delayed diagnoses, physicians should consider HAE in patients with recurrent attacks of unexplained abdominal pain.

Comparison of the Frequency of Angioedema Attack, before and during Pregnancy, in a Patient with Type I Hereditary Angioedema.

The patient was a 38-year-old Japanese woman who had been diagnosed with hereditary angioedema type I at 7 years of age based on her family history. She had undergone four pregnancies. She gave birth to a healthy baby girl after her first pregnancy and had reported few episodes of angioedema. However, she subsequently required abortions due to frequent angioedema episodes that occurred during her three subsequent pregnancies. Thus, our patient showed two clinical pregnancy courses. After treating her with C1-inhibitor concentrate, her symptoms of angioedema disappeared. The preventive use of C1 inhibitor concentrates should be considered in hereditary angioedema (HAE) patients with frequent angioedema attacks during pregnancy.

Pregnancy and postpartum in hereditary angioedema with C1 inhibitor deficit in women who have no access to therapy

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Hereditary angioedema (HAE): a cause for recurrent abdominal pain.

A 44-year-old Hispanic woman presented to the emergency room with a 2-day history of sudden onset of severe cramping left lower quadrant abdominal pain associated with ∼20 episodes diarrhoea. Abdominal CT scan exhibited bowel wall oedema and acute extensive colitis. On the basis of the preliminary diagnosis of acute abdomen, the patient was admitted under the surgical team and treated for acute colitis. Since her family history was significant for hereditary angioedema (HAE), complement studies were performed which revealed low complement C4 levels and abnormally low values of C1q esterase inhibitor. Thus, the diagnosis of HAE type I was established. This case report summarises that the symptoms of HAE are often non-specific, hence making the underlying cause difficult to diagnose.

Bacteriuria increases the risk of edematous attacks in hereditary angioedema with C1-inhibitor deficiency.

Urinary tract infections are considered among the most common infectious disorders in humans. Various infections may have a role in inducing HAE attacks. Our study intended to evaluate bacteriuria in the urinalysis of patients with C1-INH-HAE. Urine specimens contributed by 139 patients with C1-INH-HAE at the annual control visits were studied retrospectively for microorganisms. We analyzed the presence of bacteriuria in relation to the clinical symptoms. Taking into account three randomly selected urine specimens, we found that the cumulative number of edematous attacks was higher in patients with bacteriuria than in those without (P = 0.019, P = 0.022, P = 0.014). Considering the same patients, attack number was significantly higher (14.51 vs 8.63) in patients with bacteriuria than in those without (P < 0.0001). In patients with bacteriuria, we found a higher incidence of edema formation during the year before evaluation, which may suggest the triggering role of bacteriuria in the occurrence of edematous episodes.

Erythema Marginatum as an Early Symptom of Hereditary Angioedema: Case Report of 2 Newborns.

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare genetic disease that causes recurrent swelling attacks that may affect various body tissues. Angioedematous attacks can be fatal in the case of upper airway edema and are often preceded by prodromal symptoms like erythema marginatum. Initial symptoms usually occur in the first decade of life. We report on manifestation of profound and recurrent erythema marginatum in 2 newborns. In both cases, prodromal symptoms could help determine the diagnosis of C1-INH-HAE such that, at a later time, angioedematous attacks could be treated promptly and effectively. Awareness of C1-INH-HAE is low among physicians and even lower among the general public. This report aims at raising the level of awareness and shows that initial symptoms of the potentially life-threatening condition can manifest in newborns and that erythema marginatum can even be present at birth. Recognition of early symptoms and timely diagnosis of the disease along with adequate education of the pediatrician and parents are a prerequisite for prompt and effective treatment of attacks and the successful management of the disease.

Electroconvulsive therapy in patients with C1 inhibitor deficiency: a major or minor procedure?

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Death due to obstruction of the upper airways caused by edema of the laryngeal mucosa in the course of hereditary angioedema.

A rare case of death of a young man due to airway obstruction in the course of angioedema (Quincke's edema). Type I hereditary angioedema due to C1 esterase inhibitor deficiency had been diagnosed in the man while he was alive. The information concerning the man's health state was given in the Public Prosecutor's decision ordering medico legal autopsy, which was extremely helpful in recognizing the cause of death.

Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk.

BACKGROUND: Recommended management of attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) includes therapy with exogenous C1INH. Thrombotic/thromboembolic events (TEE) have been reported with plasma-derived C1INH, but so far none with recombinant human C1INH (rhC1INH). This phase III, randomized, placebo (saline)-controlled study evaluated the safety of rhC1INH 50 IU/kg for the treatment of acute attacks in 74 patients with C1-INH-HAE. METHODS: Monitoring for TEE and assessment of risk of deep vein thrombosis (DVT) by the Wells prediction rule were performed, and levels of fibrin degradation products (plasma D-dimers) were assessed before study drug administration (baseline), 2 h, and 7 days posttreatment. RESULTS: Plasma D-dimer levels were elevated in 80% of the patients (median [25th-75th percentiles]: 2149 [480-5105] µg/l; normal ≤250 µg/l) and were higher in patients with submucosal (abdominal, oropharyngeal-laryngeal) attacks (3095 [890-10000] µg/l; n = 29) compared with subcutaneous (peripheral, facial) attacks (960 [450-4060] µg/l; n = 35). Median plasma D-dimer levels were comparable across treatment groups at baseline (1874 [475-4568] µg/l rhC1INH; 2259 [586-7533] µg/l saline) and 2 h postinfusion (2389 [760-4974] µg/l rhC1INH; 2550 [310-8410] µg/l saline); median plasma D-dimer levels were decreased by Day 7 in both groups (425 [232-3240] µg/l rhC1INH; 418 [246-2318] µg/l saline). No increased risk of DVT was identified, nor any TEE reported in rhC1INH treated or controls. CONCLUSION: Elevated plasma D-dimer levels were associated with acute C1-INH-HAE attacks, particularly with submucosal involvement. However, rhC1INH therapy was not associated with thrombotic events.

Distinct conditions support a novel classification for bradykinin-mediated angio-oedema.

BACKGROUND: Angio-oedema (AO) can be attributable to bradykinin (BK) accumulation, as is the case for prototypical hereditary AO (HAO) due to C1 inhibitor (C1-INH) deficiency. However, our clinical experience in a reference centre has shown that some patients display a clinical history suggestive of HAO, but exhibit normal C1-INH function, have no mutation in the causative genes associated with HAO (SERPING1, F12), and report no intake of drugs known to promote AO. OBJECTIVE: We sought to determine the frequency and distribution of different AO subtypes suspected to be BK-mediated AO (BK-AO) and defined by clinical, history and biological criteria (enzyme activities implicated in BK formation and catabolism). METHODS: The files of all patients referred to our centre for suspected BK-AO were retrospectively analysed. RESULTS: The distribution of patients (n = 162) was 16 and 4% with a hereditary deficiency of C1-INH or a gain of factor XII function, respectively, 29% with iatrogenic BK-AO, 21% with non-iatrogenic defective kininase activity and 30% with idiopathic increased kinin formation. CONCLUSION: BK-AO may be caused by multiple inherited or acquired factors triggering BK accumulation. Therefore, we propose a novel typology for BK-AO based on the imbalance of production/catabolism of BK.