Hereditary angioedema (HAE) is a rare genetic condition that results in recurrent severe swelling. Episodes of severe swelling, typically labeled as “attacks,” can occur with alarming frequency, as often as every few days. If left untreated, these attacks have the potential to severely disrupt the lives of patients.
Angioedema occurs when there is increased endothelial permeability, which raises susceptibility to subcutaneous fluid accumulation. When swelling occurs, papules may also be present, which constitutes either acute or chronic urticaria, depending on how long they last.
Swelling may manifest in different parts of the body, causing varying degrees of discomfort. For example, edema underneath the skin is often described as painless. However, swelling that results in an acute abdomen can be very painful. In the setting of an acute abdomen, there is a tendency to perform exploratory laparotomies, which are unnecessary if a diagnosis of HAE has already been established.
“Intestinal loop edema is the second most common site of HAE involvement in children, and, in addition to colic, abdominal distension, nausea, vomiting, watery diarrhea, prostration, and dehydration may occur, in some cases progressing to intestinal intussusception,” Campos and colleagues wrote in Jornal de Pediatria.
A Difficult Diagnosis to Reach
The difficulty in diagnosing HAE lies in the variability of its phenotype. An initial misdiagnosis is not uncommon. For example, the swelling associated with HAE can be mistaken for an allergic reaction. Gastrointestinal symptoms can be mistaken for purely gastrointestinal disease (gastroenteritis or intestinal obstruction, for example).
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Studies indicate that the mean time from symptom onset to diagnosis is between 11 to 20 years, with every year representing another missed opportunity for early and effective intervention. Currently, the main way to diagnose this disease is to conduct laboratory tests that analyze the complement system.
Responding to Attacks
Once a patient is diagnosed, what should physicians do when an acute attack occurs? One of the first steps that must be taken is to assess whether the patient’s airway remains patent. This means a careful assessment of the airway, tongue, and uvula. If the patient is at a high risk of suffocation, physicians should initiate orotracheal intubation without delay.
“The cornerstones for management of acute attacks of HAE include the following: availability of effective on-demand acute therapy for all patients, early administration to prevent attack progression, and treatment of attacks, irrespective of the site of swelling,” Christiansen and colleagues wrote in Allergy & Asthma Proceedings.
Once the patient’s airway has been secured, it is important that on-demand treatment is administered as soon as possible. On-demand therapy is meant to stop the progression of swelling during an attack; hence, time is of the essence. Among the medications often used in an acute setting are icatibant (a synthetic analog of bradykinin), plasma-derived C1-inhibitor concentrate, recombinant C1 inhibitor, and ecallantide (a kallikrein inhibitor).
After the resolution of an acute attack, physicians should refocus their attention to prophylaxis and ensuring quality of life. In Allergy & Asthma Proceedings, Settipane and colleagues proposed a model of “shared decision-making.”
“[Shared decision making] is a process in which clinicians and patients work together to make decisions and select tests, treatment, and care plans based on clinical evidence that balances risks and expected outcomes with patient preferences and values,” Settipane et al wrote.
In the context of HAE, this means educating patients on how to prevent future attacks. In between episodes of attack, it is vital that patients are armed with the information they need to decrease the likelihood of future attacks. They should also be trained to recognize signs of an attack and to seek immediate medical attention should one occur in the future.
What are some of the risk factors for attacks? Current guidelines suggest that patients should avoid physical activities in which mechanical trauma is likely to occur. In addition, infections should be treated with urgency, and appropriate vaccines should be taken. In the case of patients who report mental stress as a predisposing factor for attacks, psychotherapy and appropriate prescription medications should be recommended.
In the case of diseases such as HAE, it is vital that physicians and patients work closely together. This is because physicians can only understand the cocktail of risk factors that are unique to each patient based on a personal account of the patient’s medical history. In addition, the prevention of risk factors and the early recognition of the signs of an attack rely heavily on the patient.
As with any rare/chronic disease, it is important that physicians maintain focus on what is achievable: ensuring the best possible quality of life while reducing acute episodes that require hospital care. In this sense, the management of HAE shares many characteristics with the management of sickle cell disease.
“The lives of patients with HAE have been transformed by the development, approval, and availability of effective targeted on-demand therapy,” Christiansen et al wrote. “Emphasis on early administration to prevent attack progression, coupled with the understanding that all sites are candidates for care, should inform treatment decisions.”
Campos RA, Valle SOR, Toledo EC. Hereditary angioedema: a disease seldom diagnosed by pediatricians. J Pediatr (Rio J). 2021;97 Suppl 1:S10-S16. doi:10.1016/j.jped.2020.10.011
Settipane RA, Bukstein DA, Riedl MA. Hereditary angioedema and shared decision making. Allergy Asthma Proc. 2020;41(Suppl 1):S55-S60. doi:10.2500/aap.2020.41.200057
Christiansen SC, Zuraw BL. Hereditary angioedema: on-demand treatment of angioedema attacks. Allergy Asthma Proc. 2020;41(Suppl 1):S26-S29. doi:10.2500/aap.2020.41.200066