Our nationwide study revealed an overall point prevalence of 0.53 per 100,000 inhabitants, which is significantly lower than estimated in the literature (1 in 50,000 − 100,000 people worldwide) or other European studies (e.g., 1.54/100,000 in Sweden; 1.09/100,000 in Spain; 1.41/100,000 in Denmark; 1.54/100,000 in Italy; 1.55/100,000 in Austria) (1, 6, 10, 23–25). Current data shows clear underdiagnosis of HAE in Latvia. Lack of awareness of HAE among physicians in Latvia, the intermittent nature of the symptoms, and non-specific signs of the disorder contribute to underdiagnosis (1). The limited availability of C1-INH level and function assays in Latvia before 2021 may explain the low incidence of HAE, as well.
The percentage distribution of the data is only approximate due to the small study group.
In the study, we found that hereditary angioedema was significantly more common in females than males (90% vs. 10%). Accordingly, we confirmed that females have more frequent HAE attacks and more total sick days per year, which is similar to other reports (26, 27). This might be explained by the fact that women are more likely to be symptomatic than men (27). Perhaps women in Latvia also visit specialists more often, more persistently, and more patiently to clarify the diagnosis of HAE.
HAE type I was more prevalent than type II (70% vs. 30%, respectively), which is slightly different from the literature data (85% vs. 15%, respectively), but still comparable because type I significantly dominates type II (3).
In our study, a total of 10 patients were identified in eight unrelated families. In six families, diagnoses were confirmed molecularly in two cases with one or more symptomatic relatives available for genetic investigation. In four cases there were no data about other symptomatic relatives and healthy relatives were not available for the study to confirm de novo inheritance. Hereditary angioedema has an autosomal dominant pattern of inheritance, although it is estimated that 20–25% of cases are the result of spontaneous mutations in persons with no positive family history of the disease (28). A family history of swelling is an important part of the diagnostic evaluation of HAE, but not an absolute requirement. In Latvia, no routine screening tests are performed on family members, including grandparents, parents, siblings, children, and grandchildren of HAE patients, as recommended in guidelines (15). Therefore, it is possible that several HAE patients are not identified, especially asymptomatic patients or those with mild attacks of hereditary angioedema during their lifetime. This is likely also due to limited availability of C1-INH level and function assays in Latvia before 2021. Family members of a patients with hereditary angioedema should be screened more widely and more actively, especially when there is no longer limited availability for examinations of hereditary angioedema in Latvia.
The median diagnostic time in our study was 20.5 years. Zanichelli et al. studied HAE patients from 11 European countries (Austria, Brazil, Czech Republic, Denmark, France, Germany, Greece, Israel, Italy, Spain, and the United Kingdom) and found an overall median diagnostic delay of 2.6 years, ranging from 0.13 to 17.3 years (29). Diagnostic delay in Latvia is not acceptable and is longer than the rest of Europe. Diagnostic delay can be due to the rareness of HAE or to symptoms are being mistaken for other diseases, such as histaminergic angioedema and other causes of abdominal pain, such as acute appendicitis. The determination of diagnostic delay is important because patients who are symptomatic but have not yet been correctly diagnosed with the condition will be given inappropriate treatment or no treatment. Furthermore, delayed diagnosis leads to unnecessary investigations and procedures with significant economic, social, and psychological burden. Patients with a positive family history of HAE, if HAE had already been diagnosed in a family member, are less likely to experience diagnostic delay than patients without family history. Negative values in delay result from pre-symptomatic testing in some family members, as well as a shorter path to a correct diagnosis if symptoms have developed and are similar to those in a family member with HAE (23).
Forty percent of our patients reported more than 24 attacks in the previous year. There is no plasma-derived C1-INH in Latvia, which is currently the preferred long-term prophylaxis for the prevention of HAE attacks (15). Only attenuated androgen (danazol and antifibrinolytic agent (tranexamic acid) are available in Latvia for long-term prophylaxis, which can be used as alternatives (15, 30). Only one of these patients had used tranexamic acid for long-term prophylaxis, and one had used tranexamic acid and danazol for long-term prophylaxis during their lifetime, with moderate effect.
During the previous year, 40% of patients had severe HAE attacks, similar to other studies (23, 31). According to the international WAO/EAACI guideline, long-term prophylaxis should also be considered for these patients to reduce their attack frequency and severity (15).
During their lifetime, all patients have been hospitalised up to 20 times, resulting in significant social and economic hardship to the patient, patient’s family, health care system, and to society—just as elsewhere in the world (32, 33).
Subcutaneous oedema, lips, tongue, abdominal, and laryngeal oedema were the most frequent swelling locations, described in the other studies as the most common symptoms in hereditary angioedema (23, 31).
Prodromes were reported by 90% of patients, which is slightly more than in other studies that reported prodromes between 68% and 82.5% (23, 34–36). Our patients experienced prodromal symptoms such as tiredness, paraesthesia and/or pain, abdominal sensations, nausea, and typical rash of HAE (erythema marginatum), also described in the literature as the most common prodromal symptoms in hereditary angioedema (34, 36).
Factors that triggered attacks were mostly trauma, mental stress, surgical or dental manipulations, infections, and menstruation in females, as were reported in other studies (31, 37, 38). Before known triggers, short-term prophylaxis should be considered to avoid predictable HAE attacks (37).
None of our patients had an HAE attack at the time of SARS-CoV-2 infection, though it could trigger angioedema attacks without influencing the prognosis of the disease in HAE patients, as recently reported by Olivares et al. (39).
Bradykinin B2 receptor-antagonist (icatibant) was effective treatment for HAE attacks and used by 90% of patients. Plasma-derived (pdC1-INH) was no longer available in Latvia at the time of the study. Fresh frozen plasma, tranexamic acid, opioids, and NSAIDs had poor effect during an HAE attack. Glucocorticoids and antihistamines (used by 80% and 100% of patients, respectively) before establishing the diagnosis had no effect during an HAE attack. These drugs are ineffective and are not beneficial for HAE (13). Tranexamic acid and danazol, currently available for long-term prophylaxis in Latvia, had moderate effect. Fresh frozen plasma had poor effect for short-term prophylaxis. Even when a new, specific, and effective treatment for HAE has been registered and is available, governmental regulatory authorities and economic aspects of the health care system in Latvia have limited or delayed access. Unfortunately, the choice of maintenance treatment and prophylaxis drugs are currently limited in Latvia, reducing the opportunities for our patients to receive first-line therapy, as recommended in the guidelines (15). Although effective medicines are available in the world, in Latvia alternatives are often used in the treatment of hereditary angioedema, especially for long-term prevention, thus worsening the effectiveness of treatment in preventing HAE attacks. For this reason, there are still many patients with frequent and severe HAE attacks in Latvia. Use of drugs not specific for HAE is associated with significant and detrimental adverse effects (1).
Pathogenic variations of SERPING1 gene were identified in 80% of all C1-INH-HAE patients. In 20% of patients with C1-INH-HAE, no pathogenic variations in SERPING1 were found. Although pathogenic variations in SERPING1 are the only known cause of the development of HAE types I and II, there are reported 5 − 10% symptomatic HAE patients with reduced C1-INH levels and/or functional activity in whom pathogenic variations cannot be found, even after carrying out a thorough genetic examination (including the entire SERPING1 gene sequencing of the coding and non-coding parts of the gene and analysis of copy number variants) (40, 41). In our study, we have even performed genome sequencing and genetic causes were still not identified in 20% of patients. From identified pathogenic variants, one was reported in ClinVar, two were reported in the literature, but three were reported for the first time in the HAE patients, according to available literature. Similarly, as in other reports, causative variants are mainly localised in the exons 7 and 8. Although we describe a small group of HAE type I and II patients, we did not observe differences in clinical symptoms between patients, similar to other authors who cannot give any clues about genotype/phenotype correlation (42, 43).