Development and validation of a US quality of life instrument for hereditary angioedema due to C1 inhibitor deficiency.

BACKGROUND: Hereditary angioedema (HAE) attacks are unpredictable, cause a substantial and enduring burden of illness, and are potentially fatal. Because of issues unique to the US health care system, there is a need for a US-validated, HAE-specific quality of life (QoL) instrument. OBJECTIVE: To develop and validate a US HAE-specific QoL instrument according to US Food and Drug Administration guidelines and established methodologies. METHODS: We generated 41 QoL-related items likely relevant to US patients with HAE due to C1 inhibitor (C1INH) deficiency (HAE-C1INH) and performed a 10-patient pilot study to refine the question wording. A total of 415 US patients with HAE-C1INH completed the initial 41-item instrument online, thereby providing data for item reduction, factor analysis, and the assessment of validity and reliability. We used a multiple linear regression to identify the drivers of the total and domain scores. Convergent validity analysis was used to assess the extent to which the HAE-C1INH QoL instrument (HAE-C1INH-QoL) is theoretically related to the angioedema-QoL instrument (AE-QoL). RESULTS: Item reduction and factor analysis yielded a final instrument of 31 items across 5 domains, and the assessment analysis showed that the HAE-C1INH-QoL is valid and reliable. Attack frequency and severity were statistically significant factors that influenced the total and domain scores. Correlation analysis of the 2 instruments indicated that 8 items of the HAE-C1INH-QoL were not included or well-described in the AE-QoL. CONCLUSION: The HAE-C1INH-QoL is the first HAE-specific QoL tool validated in the United States. When compared with the AE-QoL, the items in our instrument are more relevant to US patients with HAE.

Contact System Activation and Bradykinin Generation in Angioedema: Laboratory Assessment and Biomarker Utilization.

The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1INH, plasma kallikrein activation, and cleavage of high-molecular-weight kininogen have each been associated with disease activity. More recently, HAE with normal levels of C1INH (HAE-nl-C1INH) has been recognized. Six genetic mutations have been identified which are linked to HAE-nl-C1INH phenotypes. The majority of individuals with HAE-nl-C1INH fall into the unknown category. There is substantial evidence that bradykinin generation underlies the recurrent attacks of swelling in some of these cohorts.

Classification, Diagnosis, and Pathology of Angioedema Without Hives.

A clear disease classification schema coupled with an understanding of the specific mechanisms involved in the different types of angioedema without hives informs the diagnostic assessment. The recommended approach involves several key steps. Foremost is the recognizing of the clinical clues which allow for the differentiation of mast cell-mediated disorders from bradykinin-mediated angioedema. Enhanced vascular permeability related to bradykinin is of critical importance to identify given the implications for disease morbidity and risk of mortality. The ability to efficiently categorize and diagnose all forms of angioedema results in improved patient outcomes.

Lower serum 15-HETE level predicts nasal ILC2 accumulation during COX-1 inhibition in AERD.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D2, and low levels of prostaglandin E2. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown. OBJECTIVE: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD. METHODS: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis. RESULTS: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081). CONCLUSION: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

The US Hereditary Angioedema Association Scientific Registry: hereditary angioedema demographics, disease severity, and comorbidities.

BACKGROUND: Hereditary angioedema (HAE) and idiopathic nonhistaminergic angioedema (INHA) are ultra-rare diseases whose natural histories and comorbidities are incompletely understood. OBJECTIVE: To develop a national patient-centric registry to address these deficiencies in our knowledge and improve our ability to assess the real-world impact of therapeutic interventions. METHODS: Data from members of the US HAE Association were collected into an online registry between 2009 and April 7, 2021. Cohorts were categorized by reported physician diagnosis. Patient reported data were collected using a series of questionnaires. Demographic, natural history, and family history outcomes of the HAE due to C1 inhibitor deficiency (HAE-C1INH) participants were compared with those of the combined HAE with normal C1 inhibitor (HAE-nl-C1INH) plus INHA group. The prevalence of comorbid conditions in the HAE-C1INH group was compared with the general US population. RESULTS: A total of 485 HAE-C1INH, 26 HAE-nl-C1INH, and 70 INHA participants were included in the analysis. Delay to diagnosis was shorter in HAE-C1INH (5 vs 11 years), but both had decreasing delays over time. Differences in attack frequency and location were found between the groups. Morbidity surrogates including emergency department visits, hospitalizations, unnecessary abdominal surgeries, and intubations were strikingly high as was mortality with 36.9% of HAE-C1INH and 15.4% of HAE-nl-C1INH participants reporting family members who died from a HAE attack. Females with HAE-C1INH had a significant increase in the prevalence of depression, sleep disorders, kidney disease, anemia, and hepatitis. Cardiovascular comorbidities were significantly reduced in the HAE-C1INH group. CONCLUSION: The US HAEA Scientific Registry provides a mechanism to enhance our knowledge of HAE and INHA.

Hereditary Angioedema: Impact of COVID-19 pandemic stress upon disease related morbidity and well-being.

Background: Individuals with hereditary angioedema (HAE) experience stress-related sequelae, including enhanced disease morbidity and reduced quality of life. The pervasive societal strain that surround the coronavirus disease 2019 (COVID-19) pandemic may theoretically pose a disproportionate risk for patients with HAE. Objective: To dissect the interrelationship(s) among the COVID-19 pandemic, stress, and HAE disease-related morbidity and overall well-being. Methods: Subjects with HAE (either due to C1-inhibitor deficiency or with normal C1 inhibitor) as well as non-HAE household members (normal controls) completed online questionnaires that covered the impact of the COVID-19 pandemic on attack frequency, observed effectiveness of HAE medications, stress, and perceived quality of life and/or well-being. The subjects scored each of the questions to reflect their current status as well as their status before being aware of the pandemic. Results: Disease morbidity and psychologic stress outcomes were significantly worse in patients with HAE during the pandemic compared with before they were aware of the pandemic. A COVID-19 infection further increased attack frequency. Control subjects also experienced deterioration of well-being and optimism. A comorbid diagnosis of anxiety, depression, or posttraumatic stress disorder (PTSD) was generally associated with worse outcomes. Women consistently showed greater decrements in wellness during the pandemic compared with men. Women also reported higher levels of comorbid anxiety, depression, or PTSD than men and experienced a higher rate of job loss during the pandemic. Conclusion: The results implicated a deleterious impact of stress in the aftermath of COVID-19 awareness on HAE morbidity. The female subjects were universally more severely affected then were the male subjects. Overall well-being and/or quality of life, and optimism for the future deteriorated after awareness of the COVID-19 pandemic for the subjects with HAE and non-HAE household controls.

COVID-19 and hereditary angioedema: Incidence, outcomes, and mechanistic implications.

Background: Patients with hereditary angioedema (HAE) have been postulated to be at increased risk for coronavirus disease 2019 (COVID-19) infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data have been available to explore this hypothesis. Objective: To assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity, and mortality were surveyed by using an online questionnaire. The participants included subjects with HAE with C1 inhibitor (C1INH) deficiency (HAE-C1INH) and subjects with HAE with normal C1-inhibitor (HAE-nl-C1INH), and household controls (normal controls). The impact of HAE medications was examined. Results: A total of 1162 participants who completed the survey were analyzed, including: 695 subjects with HAE-C1INH, 175 subjects with HAE-nl-C1INH, and 292 normal controls. The incidence of reported COVID-19 was not significantly different between the normal controls (9%) and the subjects with HAE-C1INH (11%) but was greater in the subjects with HAE-nl-C1INH (19%; p = 0.006). Obesity was positively correlated with COVID-19 across the overall population (p = 0.012), with a similar but nonsignificant trend in the subjects with HAE-C1INH. Comorbid autoimmune disease was a risk factor for COVID-19 in the subjects with HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all the groups. Reported COVID-19 was reduced in the subjects with HAE-C1INH who received prophylactic subcutaneous C1INH (5.6%; p = 0.0371) or on-demand icatibant (7.8%; p = 0.0016). The subjects with HAE-C1INH and not on any HAE medications had an increased risk of COVID-19 compared with the normal controls (24.5%; p = 0.006). Conclusion: The subjects with HAE-C1INH who were not taking HAE medications had a significantly higher rate of reported COVID-19 infection. Subcutaneous C1INH and icatibant use were associated with a significantly reduced rate of reported COVID-19. The results implicated potential roles for the complement cascade and tissue kallikrein-kinin pathways in the pathogenesis of COVID-19 in patients with HAE-C1INH.

Consensus on treatment goals in hereditary angioedema: A global Delphi initiative.

BACKGROUND: Hereditary angioedema (HAE) is a rare, life-threatening genetic disorder characterized by recurrent episodes of subcutaneous or submucosal angioedema. The ultimate goals of treatment for HAE remain ill-defined. OBJECTIVES: The aim of this Delphi process was to define the goals of HAE treatment and to examine which factors should be considered when assessing disease control and normalization of the patient's life. METHODS: The Delphi panel comprised 23 participants who were selected based on involvement with scientific research on HAE or coauthorship of the most recent update and revision of the World Allergy Organization/European Academy of Allergy and Clinical Immunology guideline on HAE. The process comprised 3 rounds of voting. The final round aimed to aggregate the opinions of the expert panel and to achieve consensus. RESULTS: Two direct consensus questions were posed in round 2, based on the responses received in round 1, and the panel agreed that the goals of treatment are to achieve total control of the disease and to normalize the patient's life. For the third round of voting, 21 statements were considered, with the participants reaching consensus on 18. It is clear from the wide-ranging consensus statements that the burdens of disease and treatment should be considered when assessing disease control and normalization of patients' lives. CONCLUSIONS: The ultimate goal for HAE treatment is to achieve no angioedema attacks. The availability of improved treatments and disease management over the last decade now makes complete control of HAE a realistic possibility for most patients.

Assessing the cost and quality-of-life impact of on-demand-only medications for adults with hereditary angioedema.

Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.

Intranasal ketorolac, diagnosis, and desensitization for aspirin-exacerbated respiratory disease.

BACKGROUND: Intranasal ketorolac has been proposed as a diagnostic test for aspirin-exacerbated respiratory disease (AERD) and a faster, safer, and reliable addition to facilitating aspirin (ASA) desensitization. OBJECTIVE: We conducted the first prospective study to dissect the impact of intranasal ketorolac incorporation during ASA desensitization vs standard oral protocols in concert with evaluating its diagnostic use for AERD. METHODS: Patients with AERD were enrolled in a prospective open-label observational study between November 2006 and August 2013. Participants selected either one of the following desensitization protocols: intranasal ketorolac 1 day before oral ASA (group 1, combined) or ketorolac challenge with greater than 2 weeks elapsing until oral ASA (group 2, washout). All patients were on a leukotriene-modifying drug (montelukast) for at least 1 week before the challenge. RESULTS: A total of 20 patients were enrolled: 13 in group 1 and 7 in group 2. No significant differences were seen for baseline symptom scores or forced expiratory volume in 1 second. Group 1 exhibited significant increases for the threshold dose of ASA (P = .009), the likelihood of having silent ASA desensitization (P = .01), and decreased reaction severity to oral ASA (P = .04). There were no significant differences in reaction forced expiratory volume in 1 second, the incidence of extrapulmonary symptoms, limited nasoocular reactions, rescue treatment requirements, or time to symptom resolution. There was 100% concordance between reactions to intranasal ketorolac and oral ASA for group 2, supporting its use as a diagnostic test for AERD. CONCLUSION: Intranasal ketorolac is a useful diagnostic test and adjunct within the combined ketorolac/ASA protocol to achieve effective, efficient, and perhaps safer desensitization to ASA for patients with AERD.

US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema.

Scientific and clinical progress together with the development of effective novel therapeutic options has engendered multiple important changes in the diagnosis and management of hereditary angioedema (HAE). We now update and extend the 2013 United States Hereditary Angioedema Association Medical Advisory Board guidelines for the treatment and management of HAE. The guidelines are based on a comprehensive literature review with recommendations indicating both the strength of our recommendation and the quality of the underlying evidence. Guidelines are provided regarding the classification, diagnosis, on-demand treatment, prophylactic treatment, special considerations for women and children, development of a comprehensive management and monitoring plan, and assessment of burden of illness for both HAE due to C1 inhibitor deficiency and HAE with normal C1 inhibitor. Advances in HAE treatment now allow the development of management plans that can help many patients with HAE lead a normal life. Achieving this goal requires that physicians be familiar with the diagnostic and therapeutic transformations that have occurred in recent years.

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.

Hereditary angioedema: On-demand treatment of angioedema attacks.

The availability of effective acute treatment for angioedema has been fundamental in reducing the burden of illness for patients with hereditary angioedema (HAE). In building on the foundation of scientific advances that elucidate the pathomechanism(s) of attacks related to vascular permeability, novel targeted on-demand treatments have been developed and approved. These therapies have provided the means to arrest episodes of swelling, which, in the past, had the potential to inexorably lead to morbidity, and even mortality, for patients with HAE. Access to these medications, along with an emphasis on early administration and guidance that all attacks are candidates for treatment, has shifted the management paradigm for HAE. Although unmet needs remain, these acute therapies, coupled with advances in prophylactic treatment, have furthered the goal for all patients with HAE to live a normal life.

What is in your pantry? Entomologic anaphylaxis.

Background: The booklouse, Liposcelis bostrychophila, is a potent environmental allergen clinically associated with rhinoconjunctivitis and asthma. Despite its known infestation of grain products, anaphylaxis from ingestion of this organism has, to our knowledge, not been previously reported. We present the case of a 44-year-old woman who developed anaphylaxis to ingested oats and rice shown to be contaminated with L. bostrychophila. Objective: The objective was to isolate a distinct antigen from L. bostrychophila implicated in a case of unexplained anaphylaxis. Methods: In vitro studies were obtained for relevant ingested materials and aeroallergens. Skin-prick testing (SPT) was performed with standard extracts, contaminated oats, fresh oats, and crushed L. bostrychophila. Western blots were conducted using subject and control serum to detect specific immunoglobulin E (IgE) against the grains and L. bostrychophila extract. Competitive inhibition immunoblotting was used to assess specificity of IgE binding. Results: In vitro studies and SPT were notable for positive responses to dust mite and flour contaminated by L. bostrychophila, along with contaminated oats. Testing results for fresh oat and rice were negative. Immunoblots that used the subject's serum revealed a strongly positive band in the contaminated oat and rice extracts at 24 kD, whereas dust-mite extract yielded a single 14-kD band. Isolated L. bostrychophila extract also yielded a 24-kD band. Competitive inhibition experiments demonstrated that the 24-kD band in the contaminated oat extract was immunologically distinct from the 14-kD dust-mite band. Conclusion: Our case highlights the importance of considering L. bostrychophila as a potential culprit for unexplained anaphylaxis due to ingested grain products. Given the ubiquitous presence of this insect, we suspect that this may be a more common problem than previously recognized.

Association Between Self-Reported Dental Hygiene Practices and Dental Procedure-Related Recurrent Angioedema Attacks in HAE Subjects: A Multicenter Survey.

BACKGROUND: Hereditary angioedema (HAE) symptoms may be triggered by dental procedures, thereby complicating dental care in individuals affected by the condition. OBJECTIVE: This study investigated the self-perceived dental care needs, perceived susceptibility to acute angioedema (AE) attacks after dental procedures, and dental care behavior of patients with HAE. METHODS: A self-administered semistructured web-based questionnaire was distributed to 250 adult patients with HAE (type 1 or 2; 88% type 1) and 256 matched non-HAE controls. Data were analyzed using stratified χ2 tests, logistic regression, and classification trees. RESULTS: A total of 46.4% of HAE versus 55.5% of control patients had dental visits within 6 months (P = .04). Dental insurance was a barrier to seeking routine dental visits among both groups. However, significantly fewer patients with HAE had routine dental visits within 6 months despite having dental insurance compared with control patients (48% vs 60%, P = .01). Within the HAE group, a significantly greater number of patients with dental visits at intervals greater than 6 months had a history of recurrent postprocedural AE attacks (odds ratio [OR]: 3.9 [1.7, 8.8], P = .0005) and used antibacterial toothpaste more frequently than those without recurrent AE attacks (OR: 4.7 [1.5, 15.4], P = .005). CONCLUSIONS: These data support the hypothesis that patients with HAE who are predisposed to having AE episodes in response to medical or physical trauma visit the dentist less and engage in specific oral hygiene practices more frequently than matched control patients and patients with HAE who reported that they were less likely to swell after a dental procedure.