Hereditary angioedema (HAE) is a condition characterized by increased blood vessel permeability, predisposing an individual to localized tissue swelling. It is driven by bradykinin or mast cell mediators and is caused by C1 inhibitor deficiency, which is the result of mutations in the SERPING1 gene.

The typical presentation of a patient with HAE is intermittent recurrent vascular edema, occurring in the mucosal/submucosal tissue or in the dermis or subcutis. Depending on the area of swelling, patients who have not received a formal diagnosis may turn to specialists whose disciplines match the anatomical location of the swelling, which can often lead to misdiagnosis. The condition is most often misdiagnosed as allergy or appendicitis. 

The main concern regarding undiagnosed HAE is swelling in the upper respiratory tract, especially the larynx. This is typically the point at which the disease becomes acutely life-threatening, since it obstructs breathing. Studies indicate that around half of the patients diagnosed with this disease experience laryngeal swelling at least once in their lifetime. 


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“Immediate effective treatment is essential to prevent death as a result of asphyxiation or permanent brain damage as a result of a lack of oxygen,” Greve and colleagues wrote in Allergo Journal International. 

Dangers of Undiagnosed Disease 

Unsurprisingly, studies have indicated that the risk of mortality from asphyxiation is much higher among undiagnosed patients compared to patients with a known HAE diagnosis. A study examining 70 cases of mortality arising from asphyxiation found that 63 cases were from undiagnosed HAE (while the remaining 7 were from known cases of the disease). 

This means that the cost of delayed action is inexorably high. The obvious answer to this problem is to diagnose the condition early so that appropriate treatment can be initiated. However, this rarely happens in clinical practice; studies reveal that the mean time of diagnosis from the start of symptoms is a staggering 8-12 years. In other words, a significant proportion of patients do not get adequate answers to their episodes of unexplained swelling until a decade later. 

Read more about hereditary angioedema etiology 

“This period is very tough for those affected: with numerous doctors’ appointments in various specialist clinics and emergency admissions they can over time lose trust in the medical system and its ability to provide them with a correct diagnosis or effective treatment,” Greve et al wrote. 

In addition to an increasing distrust in the healthcare system, patients with undiagnosed HAE continue to experience challenges in school, work, and social life — both for them and their parents/caregivers. The lack of a proper diagnosis may hinder their ability to present medical paperwork accounting for absenteeism or the need for a reduced workload. 

Another danger of a missed diagnosis is that the chronic complement consumption between attacks increases patients’ risk of developing autoimmune and cardiovascular diseases, as well as malignant tumors. 

The Patient Journey 

The typical patient journey to diagnosis usually starts with the patient experiencing initial signs and symptoms of the disease. Patients usually then reflect on possible triggers for their symptoms and carefully evaluate whether they need to see a doctor.

When they do see a doctor, it is usually in primary care. Depending on the quality of history-taking and the degree to which the attending doctor is familiar with HAE, the doctor may either refer the patient to an HAE expert or misdiagnose the patient, leading to unnecessary and ineffective treatment. 

Among the more helpful indicators that a patient may be suffering from HAE are the frequency and location of the swellings, and whether the patient has any family history of HAE. In addition, questions should also be directed at whether the patient experiences any prodromal symptoms. 

“Prior to HAE attacks, prodromal symptoms such as fatigue, a general feeling of being unwell, malaise, debility (asthenia) can occur, but also inner unease, restlessness, and reddening of the skin (erythema marginatum) or localized unpleasant sensations such as wheals,” Greve et al wrote. They explained that attacks usually begin slowly and peak after 12 to 24 hours; if untreated, they generally last 48 to 72 hours.

Read more about hereditary angioedema treatment

The key role of a primary doctor is to correctly refer the patient to an HAE expert, who will be able to conduct specific tests and administer effective treatment. Any treatment initiated has a 3-prong strategy: controlling attacks, preventing future attacks, and preventing future attacks in risky situations. The goal, ultimately, is to increase the quality of life and reduce morbidity and mortality. 

In addition, new experimental therapies such as gene therapy can potentially modify patients’ genes to restore the body’s own ability to produce C1 inhibitors. Other drugs target the biological pathways that lead to localized swelling. 

There are a number of ongoing clinical trials that show tremendous promise; however, one of the biggest hurdles remains the early and correct diagnosis of HAE. A sharpened focus on the key features of HAE during history-taking and physical examination can help arouse clinical suspicion and increase the chances that a patient receives the specialized care they need. 

References

Caballero T. Treatment of hereditary angioedemaJ Investig Allergol Clin Immunol. 2021;31(1):1-16. doi:10.18176/jiaci.0653

Greve J, Kinaciyan T, Maurer M, et al. Expert consensus on prophylactic treatment of hereditary angioedemaAllergo J Int. Published online September 2, 2022. doi:10.1007/s40629-022-00223-8