Research
Angioedema
We manage the largest cohort of hereditary angioedema patients on the African continent and have published on the unique biological and treatment aspects relevant to this condition. We contribute ongoingly with our unique African data to several international efforts on the more uncommon urticarial and angioedema diseases. We are active contributors to the international guidelines for hereditary angioedema management(1, 2).
(2) Potter P, Peter J. Life-threatening hereditary angio-oedema: Challenges of care in South Africa. South African Medical Journal. 2018;108(4):254.
HAE guidelines:
Acute Angioedema in the South African Emergency Room
Angioedema (AE) is the commonest acute allergic presentation to emergency rooms (ER) with hospitalization rates increasing in high income countries. AE can complicate with life-threatening laryngeal obstruction. There is no local data; thus, we aimed to characterize acute AE cases presenting to ERs.
We conducted a retrospective folder review of all patients admitted to Groote Schuur Hospital and Mitchel’s Plain District Hospital ERs from 1st June 2018 to 30th June 2020. Patients ≥18 years that were coded T78.3/T78.4 by the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD10) were included in this cohort. The authors then reviewed each event and collected information regarding patient demographics, medical history, management, and outcomes.
A total of 231 events were T78.3/4 by ICD10 coding. Of these there were 149 (64.5%) events of acute AE. AE events had a median (IQR) age of 42 (27-58) years and 63% were female. Drug induced AE was the most common cause with 63/149 (42%) of the events linked to an offending drug; ACE-Inhibitors were the likely culprit in 41/63 (65%). Ten patients were known with Hereditary Angioedema (HAE). Twenty-two (14.8%) of cases reported recurrent AE, with none known or referred to allergy services for investigation. The median (IQR) number of hours from onset to presentation was delayed at 12 (5-24 hours). The majority of acute AE involved swelling above the shoulders (60%, 90/149), and there was airway involvement in 22 patients with 2 needing intubation. Twenty-one patients were admitted with 6/21 (28.6%) requiring ICU, with no deaths. Guideline acute management occurred in 83.2% of cases, with only 2 cases of HAE treated incorrectly with antihistamines and corticosteroids.
AE is the commonest allergy presentation to ERs in Cape Town, South Africa with 1-3 cases per week. Bradykinin-mediated AE secondary to ACE-I therapy is the single commonest offender. Ongoing awareness and system-strengthening is required to ensure accurate diagnosis of less common causes of AE (particularly bradykinin-mediated AE) and linkage to allergy specialist services for recurrent AE.
ABA Project
This project draws on existing infrastructure, and interdisciplinary networks of clinicians, genomics, proteomics and bioinformatics scientists at the Universities of Cape Town and the Witwatersrand to tackle this research question through Afrocentric GWAS and urine proteomic approaches. The project will utilize the DIPLOMICS laboratory – Centre for Proteomics and Genomics Research (CPGR) to generate raw genomics and proteomic data
HAE and FFP
In South Africa, and other developing country settings, most HAE patients cannot access international standard of care treatment, although we are now making substantial progress through collaborations with industry and patient advocacy groups. Despite this progress, many of our patients are cared for with the use of older, more affordable medications, such as the use of Fresh Frozen Plasma for acute attacks. Our publication of the largest number of acute attacks treated with Fresh Frozen Plasma had a major impact on local treatment guidelines, demonstrating that although FFP was effective the cost-effectiveness of targeted therapies was better given the auxiliary health care costs associated with FFP therapy. Based on this HAE patients in the public health system now have access to either recombinant C1-INH or Bradykinin-2 receptor blockade(3).
Wentzel et al. World Allergy Organization Journal (2019) 12:100049:
ACE2 in COVID-19
ACE2 is the entry receptor for SARS-CoV-2 leading to the COVID-19 pandemic. Physiologically, ACE2 is an integral regulator of the renin-angiotensin system (RAS) and involved in the metabolism of bradykinin, which is the key peptide of the kallikrein-kinin system (KKS). Virus-related perturbations of the RAS and the connected KKS are leading hypotheses associated with COVID-19 disease severity and manifestations, yet there is a paucity of experimental data available. Through the use of whole genome sequencing (WGS), coupled with high-quality longitudinal clinical data & biochemical assays, we aim to address a) what happens to systemic or tissue ACE2 and related proteins/enzymes during the course of COVID-19 disease, b) how RAS and KKS derangements impact COVID-19 disease severity and duration, and c) how cardiovascular disease and drugs such as ACE-Is/ARBs aggravate or mitigate these RAS system changes. Our purpose is for this to lead to the development of locally relevant biomarkers to predict who is at risk for severe COVID-19 compared to asymptomatic/mild disease.
We focus on meeting this need by studying the response of the human body to COVID-19 infection at multiple levels, including by examining both physiological and genetic factors leading to severe disease. Our aim is for this to lead to the development of locally relevant biomarkers to predict who is at risk for severe COVID-19.
Clinical Trials
Berotralstat study
This is an open-label study to provide berotralstat access to subjects with type 1 and 2 hereditary angioedema who were previously enrolled in berotralstat studies. The primary objective of the study is to monitor the long-term safety of berotralstat. There are currently 12 patients on this study.
Berotralstat is a potent, synthetic, second-generation small molecule inhibitor of plasma kallikrein. The benefit of berotralstat is that, in contrast to other commercially available treatment options which are administered parenterally, it can be administered orally. Berotralstat is expected to have significant benefits for patients by reducing the duration and/or severity of HAE attacks. Berotralstat has been approved in the US, EU, UK, and UAE for prevention of HAE attacks in adults and pediatric patients at least 12 years of age. Berotralstat has also been approved in Japan for suppression of the onset of acute hereditary angioedema attacks in adults and children aged 12 years and older
Kalvista study
This is an Open-label Extension Trial to Evaluate the Long-term Safety of KVD900, an Oral Plasma Kallikrein Inhibitor, for On-demand Treatment of Angioedema Attacks in Adolescent and Adult Patients with Hereditary Angioedema Type I or II.
The recurrent swelling experienced in HAE is predominantly due to excessive generation of bradykinin because of dysregulated plasma kallikrein activity. Bradykinin is responsible for increased vascular permeability, vasodilation and smooth muscle contraction which leads to the tissue swelling that characterizes a typical angioedema attack. The inhibition of plasma kallikrein activity has emerged as a target for the treatment of HAE. KVD900 has been shown to be a selective inhibitor of plasma kallikrein, maintaining mean inhibition of plasma kallikrein activity in the plasma above 95% for 3 to 4 hours. It is therefore thought that treatment with a single dose of KVD900 600 mg may be effective to treat HAE attacks.
For more information about trials and participation please contact Noejfah Jardien noejfah.jardien@uct.ac.za
