Diagnosis of HAE delayed a median of 20 years in Latvia: Study

Delays found despite 6 in 10 patients having family history of angioedema

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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People with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) typically experience a significantly delayed diagnosis — even with a family history positive for the disease, according to a nationwide study in Latvia.

Indeed, the median delay in obtaining a diagnosis in the Northern European country is 20.5 years, researchers found, despite 60% of patients having a family history of angioedema.

“Higher awareness and better information and communication between doctors would improve the diagnosis and management of HAE,” the team wrote.

The study, “National survey on clinical and genetic characteristics of patients with hereditary angioedema in Latvia,” was published in the journal Allergy, Asthma & Clinical Immunology.

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Symptoms start at age 15, but delayed diagnosis not until age 45

HAE is chiefly caused by mutations in the SERPING1 gene, which carries the instructions for making the C1-INH protein. C1-INH-HAE, which comprises HAE types 1 and 2, is characterized by lower levels of or a dysfunctional C1 inhibitor (C1-INH) protein.

Patients experience recurrent episodes of swelling in the face, tongue, feet, gastrointestinal tract, genitals, and/or upper airways.

While worldwide estimates suggest that C1-INH-HAE affects one in every 50,000 to 100,000 people, the disease’s prevalence in the Baltic countries of Europe — Estonia, Latvia, and Lithuania — remains unknown, according to researchers.

Now, a team led by scientists at the Riga Stradiņš University, in Latvia, have described the results of the “first ever nationwide survey on HAE” in their country.

The analysis included all 10 C1-INH-HAE patients — from eight families — who had been diagnosed with HAE in Latvia from March 2006 through 2022. These individuals had a median age of 54, and all but one were women.

With a country population of 1,870,400 inhabitants in March 2022, this represents a HAE prevalence of 0.53 per 100,000 inhabitants, “which is lower than estimated in the literature (1 in 50,000−100,000 people worldwide) or other European studies,” the team wrote.

A large majority (70%) were diagnosed with C1-INH-HAE type 1, whereas 30% had type 2. The median age at diagnosis was 45.5 years. Symptom onset, however, was at a median age of 15, with the one male patient first showing symptoms when he was 6.

It took 20.5 years (median) for patients to get a diagnosis, with the male patient waiting 24 years compared with a median of 17 years for the female patients.

During 2021, nine patients experienced a median of 10 attacks, with the women reporting a median of 29 attacks, and the man one attack. Attacks were deemed severe — meaning they occurred 12 or more times a year — in half of the patients. Moderate attacks, or those occurring 4-11 times, occurred in one patient, while mild attacks, or 1-3 per year, happened in four.

Patients were hospitalized a median of two times during their lifetime. Skin (100%), abdominal (80%), and airway (80%) fluid accumulation were the most frequent symptoms. According to data from six patients, stress (four patients) and trauma (two patients) were the most frequent triggering factors for attacks. Early symptoms included tiredness, a burning or prickling sensation, and pain, including in the abdomen.

Lack of awareness of HAE among physicians, the intermittent nature of the symptoms, and non-specific signs of the disorder contribute to underdiagnosis, a delay in proper diagnosis, and thus undertreatment.

The most frequent on-demand treatments included antihistamines — icatibant, marked as Firazyr or as generics — and glucocorticoids. Fresh frozen plasma (FFP), the liquid portion of blood, and non-steroidal anti-inflammatory drugs were administered in three patients each. Icatibant’s treatment effect was deemed very good, while other treatments were deemed poor or with no effect.

Preventive (prophylactic) treatments included FFP (three patients), tranexamic acid, and danazol (sold under the brand name Danocrine), each administered to four patients. Prophylactic treatment efficacy was rated as moderate (tranexamic acid and danazol) and poor (FFP).

Genetic testing identified mutations in the SERPING1 gene in eight patients. Three of the mutations — one confirmed pathogenic (disease-causing) and two likely pathogenic — had never been reported. No mutations were found in two patients.

Overall, these findings suggest a significantly delayed diagnostic in HAE, even in patients with a positive family history of angioedema.

“Lack of awareness of HAE among physicians, the intermittent nature of the symptoms, and non-specific signs of the disorder contribute to underdiagnosis, a delay in proper diagnosis, and thus undertreatment,” the researchers wrote.

Besides better awareness among clinicians, halting the delay in diagnosis requires “screening of family members, patients with recurrent angioedema unresponsive to antihistamines and glucocorticoids, and patients with recurrent episodes of severe, unexplained abdominal pain,” they concluded.