Repeated episodes of excruciating abdominal pain and swelling that occurs suddenly without warning and results in a disfiguring swelling of the face, lips and tongue that persists for several days. Life-threatening laryngeal edema often requiring repeated intubation given the concern for asphyxiation that is unresponsive to allergy medications including anti-histamines, steroids and epinephrine.
These are symptoms of hereditary angioedema (HAE). Patients suffering with HAE, but not yet diagnosed, are often frequently seen in the emergency department for their acute complaints yet their diagnosis is often missed, leading to substantial delays in care and appropriate treatment.
This missed diagnosis is particularly unfortunate as evaluation for HAE can be initiated in the emergency department with collection of common lab tests assessing the complement system whose dysfunction is the cause of recurrent swelling: analysis of C4 and C1 esterase inhibitor. Referral to an allergist/immunologist is also warranted to help uncover the underlying cause of these recurrent and painful edema episodes and initiation of appropriate preventative treatment.
Unfortunately, there is often a delay in referral and diagnosis given these non-specific symptoms and inappropriate association of these episodes with other etiologies including food or medication allergy, appendicitis or drug-seeking behavior.
Investigators at Emory University School of Medicine in the Departments of Human Genetics and Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine have teamed up in a study funded by the ThinkGenetic Foundation to identify patients at risk of HAE.
HAE is a genetic condition with 7 current FDA-approved therapies for both prevention and acute treatment of these attacks. These medications inhibit or block the dysfunctional pathway triggering these recurrent swelling episodes. Current medications are administered through intravenous infusion, subcutaneous infusion or injection. However, a new oral therapy called berotralstat was approved for use in December 2020 with others are on the horizon.
The partnership between genetics and allergy makes for a perfect team as they partner to develop a scoring system that can be applied to data in the medical chart and identify patients at risk, theoretically reducing the frequent several years of delay in diagnosis.
Once at-risk patients are identified, the multi-disciplinary team will work with primary care physicians to discuss next steps for testing, referral and treatment. As HAE is inherited in an autosomal dominant manner, each individual found to be affected by HAE has a 50% chance of passing it on to their children. Yet approximately 25% of patients have a de novo mutation and thus no affected family members, making identification of at-risk patients even more important.
By taking a detailed family history, the team can identify other family members at risk who need testing and treatment. Identification of one individual can save another family member the painful, frustrating and life-threatening symptoms of untreated HAE. At Emory, after received his diagnosis of HAE, one patient with frequent abdominal edema diagnosed after a long medical odyssey reports that getting a diagnosis of HAE and starting target therapy was ‘life changing’ and ‘he feels great.”
Other causes of angioedema, including medication reaction, should be excluded prior to making an official diagnosis of HAE. A recent study from Austria published in The Journal of Allergy and Clinical Immunology In Practice identified that up to 0.1% of patients diagnosed with angiotension inhibitor (ACEI) induced edema had underlying HAE that has not yet been diagnosed, raising further concern that HAE patients are often missed.
The combined team at Emory is very interested to see if that number holds true in Atlanta. The team will also see if efforts to more readily diagnose patients early in disease onset will prevent associated morbidity and mortality of these recurrent swelling events, optimize patient health and improve their quality of life.
