Delayed HAE diagnosis carries substantial burden, review finds
For patients, getting correct diagnosis took from 3 to 26 years
People with hereditary angioedema (HAE) typically experience a markedly delayed diagnosis — from three to 26 years following the onset of symptoms — that results in a greater disease burden for patients, with growing HAE-related expenses from hospitalizations, medications, potentially unnecessary surgeries, and a plethora of doctor visits, according to an analysis of published studies.
Indeed, the researchers noted that misdiagnoses, along with “a lack of awareness among health care professionals, limited availability of diagnostic tests, and incorrect treatment restrict the timely and optimal management of HAE.”
Delays also lead to increased costs, per the researchers. The total direct costs of HAE in the U.S., once diagnosed, were estimated at more than $25,000 per patient annually in one study.
With studies suggesting a link between a delayed diagnosis and worse physical function, a higher risk of death, and steeper medical costs, these findings highlight “the importance of early diagnosis and the need for improving awareness among health care professionals to reduce the burden of HAE on patients and society,” the researchers wrote.
The review study, “Epidemiology, economic, and humanistic burden of hereditary angioedema: a systematic review,” was published in the Orphanet Journal of Rare Diseases.
Delayed diagnosis linked to ‘widespread misdiagnosis of HAE globally’
A genetic disorder, HAE is marked by swelling in the deeper layers of the skin. Swelling episodes can occur in the lining of the respiratory and digestive systems, leading to breathing difficulties, vomiting, and intense pain.
HAE types 1 and 2 are caused by mutations in the SERPING1 gene, which encodes a protein called C1 inhibitor, or C1-INH. The deficiency in C1-INH (type 1), or its malfunction (type 2) results in the overproduction of a pro-inflammatory molecule called bradykinin, which triggers the swelling attacks.
According to the researchers, the economic, epidemiological, and social burden of HAE remains poorly characterized. To get a better understanding, the team, from China, reviewed studies published in English or Chinese databases through May 2022.
A total of 65 studies involving 10,310 people with HAE were included in the analysis. In these studies, slightly more than half of the patients — 57% or 5,861 individuals — were female.
Altogether, the studies spanned more than two decades, from 1997 to 2022, and were conducted in 25 countries or regions, with 11 from the U.S. The vast majority of patients (81%) had HAE type 1, whereas 9% had HAE type 2, and 8% had HAE with normal C1-INH. The type of angioedema was not identifiable in 2% of the patients.
The overall prevalence of HAE, which was one of the epidemiology measures assessed, ranged from 0.13 to 1.6 cases per 100,000 people.
A delayed diagnosis was common. According to data reported in 34 studies, the diagnosis was confirmed with a mean or median delay ranging from 3.9 to 26 years from the first HAE symptoms. In 25 studies, the delay was longer than 10 years, which supports a “widespread misdiagnosis of HAE globally,” the investigators wrote.
After adjusting for age, the mortality risk in the U.S. was low — 0.17 cases per million persons per year — according to a single study. Nine studies reported 124 deaths by asphyxiation, a consequence of swelling of the larynx, or voice box, representing an estimated risk of 8.6%.
Direct medical costs of HAE more than $25K per patient per year
The economic burden associated with HAE was assessed in six studies and included hospitalization costs, outpatient visits expenses, treatment costs, the costs of potentially unnecessary surgeries, specialist services fees, and nursing costs.
According to data from three studies, the estimated hospitalization costs in the U.S. reached $17,335 per year and $4,000 for a single hospitalization. The annual costs associated with acute attacks were $235, whereas chronic management of HAE cost $2,013 per year. According to two studies, emergency department visits in the U.S. reached $2,603 per year, and in one study the direct medical costs totaled $25,884 a year.
There is considerable evidence indicating that delayed diagnosis of HAE is associated with decreased physical function, increased risk of mortality, negative psychological impact, and higher direct and indirect costs.
A dozen studies reported on the indirect costs linked to HAE. Attacks accounted for 5.9% to 31.1% of job absenteeism, or times patients missed work, with one study reporting a loss of $5,750 due to decreased productivity in the workplace. The loss in wages for a single attack was $525, or $3,402 in income annually.
The average number of missed days per year varied between 1.7 and 19.9, causing an indirect cost of $16,108 annually.
Patient-reported outcomes, mainly the 36-item Short Form health survey, revealed an impairment in quality of life, both at the physical and mental level. The most common symptoms were depression, anxiety, and stress, as reported by both adults and children.
“To the best of our knowledge, this systematic review is the first to provide a comprehensive understanding of the epidemiologic, economic, and humanistic burden of HAE,” the investigators wrote.
“There is considerable evidence indicating that delayed diagnosis of HAE is associated with decreased physical function, increased risk of mortality, negative psychological impact, and higher direct and indirect costs,” the team added, noting the “substantial burden” linked to HAE not only for patients but for society as a whole.
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