Acute quadruple extremity compartment syndrome due to angio-oedema after polypharmacy overdose including olmesartan medoxomil, telmisartan and vildagliptin.

This case report describes a rare manifestation of acute compartment syndrome (ACS) involving all four extremities, precipitated by angio-oedema in a middle-aged woman who consumed an overdose of multiple medications: nifedipine, azelnidipine, amlodipine besylate, olmesartan medoxomil, telmisartan, esaxerenone and vildagliptin. She presented with haemodynamic instability, necessitating intubation. Despite stabilising haemodynamic parameters within 24 hours, she manifested escalating extremity oedema. At 52 hours after ingestion, mottled skin was observed, along with necrotic alterations in the swollen hands and compartment pressures exceeding 30 mm Hg in all extremities. ACS was diagnosed, leading to fasciotomies. The aetiology is postulated to be drug-induced angio-oedema, possibly intensified by the concurrent overdose of olmesartan medoxomil, telmisartan and vildagliptin, each of which has a risk of angio-oedema even at standard dosages. This scenario is a very rare case caused by drug-induced angio-oedema, which underscores the importance of vigilant monitoring to detect ACS in patients with progressing limb oedema.

Kallikrein inhibitors for angioedema: the progress of preclinical and early phase studies.

INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent edema and predominantly caused by the dysregulation of the kinin-kallikrein system. AREAS COVERED: This manuscript presents the results of preclinical and early clinical trials of newer drugs targeting the dysregulated kinin-kallikrein system. ATN-249 is an oral drug that has shown promising results in preclinical and Phase I studies, and good tolerability in the prophylactic treatment of attacks. KVD900 is also an oral agent developed for the on-demand treatment of HAE attacks. It has shown positive results in Phase I/II studies, with rapid absorption. The third drug, IONIS-PKKRx, is an antisense oligonucleotide targeting plasma prekallikrein mRNA. It has shown a dose-dependent reduction of plasma prekallikrein levels and proenzyme activation in Phase I/II studies, and has shown promising results. STAR-0215 is a long acting anti-activated kallikrein monoclonal antibody. A Phase 1a single ascending dose trial evaluated its safety, pharmacokinetics, and pharmacodynamics. Lastly, NTLA-2002 is an investigational gene-editing therapy. EXPERT OPINION: The targeted treatment of the dysregulated kinin-kallikrein system with specific inhibitors is promising for the prevention of angioedema attacks. Ongoing phase III studies will provide further insight into the efficacy and long-term safety of these novel therapies, potentially expanding treatment options for HAE treatment.

Tranexamic acid for angiotensin converting enzyme inhibitor induced angioedema: A retrospective multicenter study.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-Is) prevent the breakdown of bradykinin and can lead to life threatening angioedema. Tranexamic acid is an antifibrinolytic that inhibits formation of precursors involved in bradykinin synthesis and, in case reports, has been described as a potential treatment for ACE-I angioedema. METHODS: This retrospective study included patients who presented to the emergency department (ED) from January 2018 to August 2021 with angioedema while taking an ACE-I. Patients who received tranexamic acid (treatment group) were compared with patients who did not receive tranexamic acid (control group). Primary outcome was length of stay (LOS). Secondary outcomes evaluated included ICU admissions, intubations, and safety events. RESULTS: A total of 262 patients were included in this study (73 treatment; 189 control). Overall, the median ED LOS was longer in the treatment group than controls (20.9 h vs 4.8 h, p < 0.001). ICU admission rates were higher in the treatment group (45% vs 16%, p < 0.001). More patients were intubated in the treatment group (12% vs 3%, p = 0.018). No difference was seen between the treatment group and the controls for return within 7 days, complications related to thrombosis, and death. In patients presenting with severe angioedema symptoms who were admitted to the hospital, median LOS was not different between the two groups (58.7 h vs 55.7 h, p = 0.61). CONCLUSIONS: Patients who received tranexamic acid had increased ED LOS, rates of ICU admission, and need for intubation. This finding may be related to the severity of presentation. Administration of tranexamic acid appears safe to use in ACE-I angioedema. Prospective randomized controlled studies should be considered to determine whether tranexamic acid is an effective treatment for ACE-I angioedema.

Comorbidities in Angioedema Due to C1-Inhibitor Deficiency: An Italian Survey.

BACKGROUND: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is characterized by unpredictable recurrent episodes of swelling affecting the skin and the mucosa tissues, including gastrointestinal tract and/or oropharyngeal-laryngeal mucosae. Long-term prophylaxis (LTP) is used to prevent attacks. OBJECTIVE: Because C1-INH plays a pivotal role in several biological pathways, we investigated the possible association of comorbidities with C1-INH deficiency and the use of LTP with attenuated androgens (AA) or tranexamic acid (TXA). METHODS: This retrospective cohort study involved adult patients with HAE referred to Milan and Padua angioedema centers in the period 1979-2021. A qualitative comparison was performed to analyze comorbidities versus general population. The incidence of comorbidities was evaluated during LTP with AA or TXA versus patients without LTP. RESULTS: A total of 446 patients were studied. A greater prevalence among patients was found for heart diseases (9.6% vs 4.8%), acute myocardial infarction (5.6% vs 1.4%), hepatitis C virus infection (10.5% vs 2.5%), and appendectomy (15.9% vs 4.3%). In patients taking AA, a greater incidence was found for hypertension (22.8% vs 10.8%; odds ratio [OR]: 2.02), hypercholesterolemia (19.5% vs 5.3%; OR: 3.97), diabetes mellitus (5% vs 1.4%; OR: 3.21), hepatic angioma (4.4% vs 0.7%; OR: 8.35), and focal nodular hyperplasia (2.5% vs 0.4%; OR: 6.9). No association between TXA and comorbidities was found. CONCLUSION: In this large patient population with a rare disease followed for up to a 43-year period, we found a greater prevalence of comorbidities hitherto unreported in the literature and an association between comorbidities and LTP with AA.

Tenecteplase-associated orolingual angioedema: A case report and literature review.

PURPOSE: Orolingual angioedema (OA) secondary to administration of thrombolytic therapy is a rare, but serious, known adverse effect. Despite the lack of robust evidence for their use, C1 esterase inhibitors are recommended by guidelines for the treatment of refractory thrombolytic-associated OA. This report highlights the use of a C1 esterase inhibitor in a patient with tenecteplase-associated OA unresolved by antihistamine and corticosteroid therapy. SUMMARY: A 67-year-old white male with a history of hypertension managed with lisinopril presented to the emergency department with acute onset of slurred speech and left-sided hemiparesis. Following workup, an outside hospital's neurology stroke team suspected an acute infarct and determined the patient to be a candidate for tenecteplase. Approximately 1 hour after tenecteplase administration, the patient began complaining of dyspnea and mild oral angioedema. Immediate interventions for OA management included intravenous therapy with dexamethasone 10 mg, diphenhydramine 25 mg, and famotidine 20 mg. After an additional 30 minutes, the patient's OA symptoms continued to progress and a C1 esterase inhibitor (Berinert) was administered. Shortly after administration of the C1 esterase inhibitor, the patient's symptoms continued to worsen, ultimately leading to endotracheal intubation. Following intubation, symptom improvement was noted, and the patient was safely extubated after 30 hours. CONCLUSION: Although rare, OA is a potentially life-threatening complication of tenecteplase therapy and requires prompt pharmacological intervention to optimize patient outcomes. Currently, no single agent or treatment algorithm exists that has shown significant efficacy or safety in the setting of thrombolytic-associated OA. Until data are available for C1 esterase inhibitors in this application, these inhibitors should only be considered if there is continued symptom progression after intravenous administration of corticosteroids and antihistamines.

Ipsilateral orolingual angioedema following rhTNK-tPA administration for acute ischemic stroke.

Recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA), a genetically modified variant of conventional alteplase with longer half-life and higher fibrin specificity, has now emerged as a reasonable choice for thrombolytic treatment of acute ischemic stroke (AIS) in China. Orolingual angioedema is a rare but potentially life-threatening complication of intravenous thrombolysis. Currently, there is no documented evidence of orolingual angioedema occurring after thrombolysis with rhTNK-tPA. In this report, we present a unique case of a 75-year-old Chinese man who developed ipsilateral orolingual angioedema following the administration of rhTNK-tPA for AIS. Our case emphasizes the need for caution when using rhTNK-tPA due to its potential to induce ipsilateral orolingual angioedema.

COVID-19 infection and vaccination in patients with hereditary angioedema: a multicentric study.

Summary: Background. Due to similarities between the pathophysiological mechanisms of hereditary angioedema (HAE) and COVID-19, it has been hypothesized that SARS-CoV-2 infection may trigger HAE attacks or, alternatively, that HAE patients may experience different of COVID-19 disease severity. Furthermore, the potential for COVID-19 vaccination to trigger angioedema attacks in patients with HAE is still not completely defined. The objective is to characterize the exacerbations and clinical manifestations associated with COVID-19 infection and describe the adverse effects of COVID-19 vaccination in patients with HAE.Methods. Retrospective observational, descriptive, non-interventional, multicenter study conducted in four Allergy Units and Departments in Central Portugal between March 2020 and July 2022. HAE patient data were obtained from electronic medical records. Results. The study included 34 patients (67.6% female): 26 with HAE type 1, 5 with HAE type 2, and 3 with HAE with normal C1 inhibitor. Most patients with HAE type 1 and 2 were receiving long-term prophylaxis. Among the 32 patients who received COVID-19 vaccination, 86 doses, were administered with one angioedema attack (1.2%) associated with vaccination. A small increase in the average number of attacks was observed in the year following COVID vaccination (7.1 versus 6.2 in the previous year, p = 0.029), however, this difference is unlikely to be clinically significant, as the context of the COVID-19 pandemic likely introduced numerous confounders. During the study period, 16 HAE patients had COVID-19, all presenting with mild disease. Four out of 16 patients (25%) reported angioedema attacks during COVID-19, and 43.8% during the convalescence period (3 months after infection). Conclusions. Patients with HAE can safely receive COVID-19 vaccination. The severity of COVID-19 infection does not appear to be increased in HAE patients.

Efficacy and Safety of Rituximab-Based Treatments in Angioedema With Acquired C1-Inhibitor Deficiency.

BACKGROUND: Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce. OBJECTIVE: To evaluate efficacy of rituximab in AAE-C1-INH. METHODS: A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July 2019. RESULTS: Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014). CONCLUSIONS: Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies.

Icatibant averting mechanical ventilation in acute ischemic stroke patient with alteplase-induced orolingual angioedema.

BACKGROUND AND PURPOSE: Orolingual angioedema (OA) represents a rare but life-threatening complication among patients with acute ischemic stroke treated with intravenous thrombolysis with alteplase. Novel agents, including icatibant, are recommended in resistant patients with alteplase-induced OA who have failed to respond to first-line therapies including corticosteroids, antihistamines, and/or adrenaline. METHODS: We present a patient with alteplase-induced OA who showed substantial clinical improvement following the administration of icatibant. RESULTS: We describe a 71-year-old woman with known arterial hypertension under treatment with angiotensin-converting enzyme inhibitor, who presented with acute ischemic stroke in the territory of the right middle cerebral artery and received intravenous alteplase. During intravenous thrombolysis, the case was complicated with OA without any response to standard anaphylactic treatment including corticosteroids, dimetindene, and adrenaline. Thirty minutes after symptom onset, icatibant, a synthetic selective bradykinin B2-receptor antagonist, was administered subcutaneously. Substantial symptomatic resolution was observed only following the icatibant administration. CONCLUSIONS: This case highlights the effectiveness of icatibant in the acute management of alteplase-induced OA. In particular, icatibant administration, following first-line therapies including corticosteroids, antihistamines, and/or adrenaline, may avert tracheostomy and intubation in resistant and refractory cases with OA following intravenous thrombolysis for acute ischemic stroke.

Losartan-Induced Angioedema with Acute Hypoxemic Respiratory Failure (Anaphylaxis): A Case Report.

Angioedema is a condition characterized by swelling of the skin or mucosa resulting from loss of vascular integrity that leads to swelling of mucosal tissues and can lead to life-threatening respiratory compromise. Drug-induced angioedema is not a frequent side effect seen with angiotensin receptor blockers (ARBs), particularly when there are no other contributing risk factors like a prior episode. Few studies reported subsequent angioedema episodes after ARB use in patients who had a prior episode with angiotensin converting enzyme inhibitors; however, there are very few cases that documented non-fatal angioedema after ARB as the only therapy. We report a rare case of life-threatening anaphylaxis after losartan use. We hope that our case will bring awareness to this rare but fatal side effect in order to quickly recognize it and encourage further research.

Acquired Angioedema Due to C1-Inhibitor Deficiency (AAE-C1-INH)-A Bicenter Retrospective Study on Diagnosis, Course, and Therapy.

BACKGROUND: Acquired angioedema with C1-inhibitor deficiency (AAE-C1-INH) is a rare condition resembling hereditary angioedema (HAE), but with late onset and low C1-inhibitor (C1-INH) due to consumption potentially caused by autoimmune diseases and mainly lymphatic malignancies. Being about 10-fold rarer than HAE, there is limited knowledge and no licensed therapy. OBJECTIVE: To report clinical and biological data from a newly described population of 20 patients with AAE-C1-INH assessing diagnostic delay, AAE-C1-INH:HAE-ratio, underlying conditions, and therapeutic management in Germany. METHODS: Retrospective data analysis of 20 patients from 2 angioedema centers in southern Germany. RESULTS: Median age at symptoms' onset was 64 years (60% females), with predominant swellings of the face (85%) and low levels for C1-INH in almost all patients. The ratio AAE-C1-INH:HAE was 1:9.7. From symptoms' onset to diagnosis of AAE-C1-INH, the median delay was 7.5 months, and between AAE-C1-INH symptoms' onset and diagnosis of the underlying hematological condition (n = 9) it was 4 months (median). Four patients had a history of solid neoplasm, 1 had a papillary thyroid carcinoma as the only potential cause for AAE-C1-INH, with treatment of the malignancy resulting in resolution of AAE-C1-INH. All the symptomatic patients were treated with off-label on-demand icatibant subcutaneously or C1-INH concentrate intravenously, and 6 severely affected patients needed off-label long-term prophylaxis with good symptom control. CONCLUSIONS: AAE-C1-INH is characterized by late-onset swellings mainly involving the face and low C1-INH levels. Diagnostic delay for AAE-C1-INH is further decreasing despite being about 10-fold rarer than HAE. Patients severely affected without underlying condition or no indication for treatment could benefit from off-label therapy.

Patients With Chronic Spontaneous Urticaria Who Have Wheals, Angioedema, or Both, Differ Demographically, Clinically, and in Response to Treatment-Results From CURE.

BACKGROUND: Patients with chronic spontaneous urticaria (CSU) have spontaneous wheals (W), angioedema (AE), or both, for longer than 6 weeks. Clinical differences between patients with standalone W, standalone AE, and W and AE (W+AE) remain incompletely understood. OBJECTIVE: To compare W, AE, and W+AE CSU patients regarding demographics, disease characteristics, comorbidities, disease burden, and treatment response. METHODS: Baseline data from 3,698 CSU patients in the ongoing, prospective, international, multicenter, observational Chronic Urticaria REgistry (CURE) were analyzed (data cut: September 2022). RESULTS: Across all CSU patients, 59%, 36%, and 5% had W+AE, W, and AE, respectively. The W+AE patients, compared with W and AE patients, showed the lowest male-to-female ratio (0.33), higher rates of concomitant psychiatric disease (17% vs 11% vs 6%, respectively), autoimmune disease (13% vs 7% vs 9%, respectively), and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (9% vs 5% vs 2%, respectively) and the highest disease impact. The W patients, compared with W+AE and AE patients, showed the lowest rates of concomitant hypertension (15% vs 21% vs 40%, respectively) and obesity (11% vs 16% vs 17%, respectively), the highest rate of concomitant inducible urticaria (24% vs 22% vs 6%, respectively), and shorter W duration. The AE patients, compared with W+AE and W patients, were older at disease onset, showed longer AE duration, and the best response to increased doses of H1-antihistamines (58% vs 24% vs 31%, respectively) and omalizumab (92% vs 67% vs 60%, respectively). CONCLUSIONS: Our findings provide a better understanding of CSU phenotypes and may guide patient care and research efforts that aim to link them to pathogenic drivers.

How Infection and Vaccination Are Linked to Acute and Chronic Urticaria: A Special Focus on COVID-19.

Since more than a century ago, there has been awareness of the connection between viral infections and the onset and exacerbation of urticaria. Our knowledge about the role of viral infection and vaccination in acute and chronic urticaria improved as a result of the COVID-19 pandemic but it has also highlighted knowledge gaps. Viral infections, especially respiratory tract infections like COVID-19, can trigger the onset of acute urticaria (AU) and the exacerbation of chronic urticaria (CU). Less frequently, vaccination against viruses including SARS-CoV-2 can also lead to new onset urticaria as well as worsening of CU in minority. Here, with a particular focus on COVID-19, we review what is known about the role of viral infections and vaccinations as triggers and causes of acute and chronic urticaria. We also discuss possible mechanistic pathways and outline the unmet needs in our knowledge. Although the underlying mechanisms are not clearly understood, it is believed that viral signals, medications, and stress can activate skin mast cells (MCs). Further studies are needed to fully understand the relevance of viral infections and vaccinations in acute and chronic urticaria and to better clarify causal pathways.

Chronic Urticaria and Angioedema: Masqueraders and Misdiagnoses.

Chronic urticaria is a common condition presenting with intensely pruritic wheals. Although individual lesions resolve within 24 hours, by definition, chronic urticaria lasts for a duration of at least 6 weeks. Both spontaneous and inducible forms exist. In the spontaneous variant, chronic urticaria occurs in the absence of clearly identifiable triggers. In chronic inducible urticaria, specific triggers may include dermatographism, cholinergic (heat), cold, exercise, delayed pressure, and solar. Extensive laboratory evaluation for chronic spontaneous urticaria is not required unless indicated by clinical history or physical examination. Angioedema describes sudden onset of localized edema involving the deep layers of the skin and submucosal tissues. It can be seen in isolation or in conjunction with chronic urticaria. Angioedema typically resolves slower than wheals, taking up to 72 hours or longer. Histamine- and bradykinin-mediated forms exist. Both chronic urticaria and angioedema have many mimics, and a broad range of differential diagnoses should be considered. Importantly, an incorrect diagnosis may have significant implications for the additional investigation, treatment, and prognosis of the affected patient. The aim of this article is to discuss the characteristics of chronic urticaria and angioedema, and an approach to the investigation and diagnosis of their mimics.

Angioedema With Normal Complement Studies: What Do We Know?

Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue caused by increased vascular permeability and extravasation of intravascular fluid. It can occur via a variety of mechanisms. A number of clinical conditions (masqueraders) are occasionally mistaken for angioedema. Clinical classification of the various angioedema forms begins with noting the presence or absence of concurrent urticaria or wheals. Pathogenesis can be considered through two broad categories: mast cell-mediated with release of vasoactive mediators causing angioedema usually associated with urticaria or in the context of an anaphylactic reaction; and bradykinin (BK)-driven, in which increased vascular permeability is mediated by BK. BK-mediated angioedema does not occur with urticaria, nor does it respond to antiallergic medications. The various forms of hereditary angioedema are included in this category, requiring specific tests of C4 and C1 inhibitor level and function to confirm the diagnosis. Angiotensin converting enzyme inhibitors, which impair the degradation of BK, account for up to a third of all patients with angioedema presenting to the emergency department. Finally, angioedema may occur by yet unknown mechanisms; under this circumstance, it is difficult to manage.