Challenges in the management of hereditary angioedema in urban and rural settings: Results of a United States survey.

BACKGROUND: Caring for patients with hereditary angioedema (HAE), especially rural patients, has challenges. OBJECTIVE: To confirm experiences of allergy and immunology health professionals in diagnosing and treating patients with HAE, including those living in rural settings. METHODS: An online survey of 2996 members of the American College of Allergy, Asthma, and Immunology was conducted in April 13 to May 3, 2022. Eligible participants were association members (physician, fellow, or allied health professional members) currently practicing allergy or immunology, in the United States, seeing or treating at least 1 patient with HAE yearly. RESULTS: A total of 138 responders saw an average of 9 patients with HAE yearly; 12% of the patients resided in a rural area. They reported that 66% of their patients with HAE had type I, 15% type II, and 19% HAE C1nl-INH. Misdiagnosis was the top diagnostic challenge reported (82%). Inability to afford treatment was the top treatment challenge (76%). Other observations include the sentiment that patients with HAE with government insurance are at a disadvantage because it is not accepted by many specialists who treat HAE (64%) and that better payments for drugs from Medicaid and Medicare (57%) and better payments to providers from Medicaid and Medicare (49%) could better support the treatment of patients in rural settings. Responders expressed a preference for therapies administered at home (72%). Since the coronavirus disease 2019 pandemic, 86% of the respondents used telehealth for appointments occasionally. CONCLUSION: Our findings illustrate the challenge of diagnosing HAE, especially HAE C1nl-INH, and the economic challenges of treatment, which can be compounded for those living in rural areas. We provide a call to action for addressing several of these real challenges.

Optimization of care for patients with hereditary angioedema living in rural areas.

BACKGROUND: People living in rural areas of the United States experience greater health inequality than individuals residing in urban or suburban locations and encounter several barriers to obtaining optimal health care. Health disparities are compounded for patients with rare diseases such as hereditary angioedema (HAE), an autosomal dominant genetic disorder characterized by recurrent, severe abdominal pain and life-threatening oropharyngeal or laryngeal swelling. OBJECTIVE: To explore the challenges of managing patients with HAE in rural areas and suggest possible improvements for optimizing care. DATA SOURCES: PubMed was searched for articles on patient care management, treatment challenges, rural health, and HAE. STUDY SELECTIONS: Relevant articles were selected and reviewed. RESULTS: Challenges in managing HAE in the rural setting were identified, including obtaining a diagnosis of HAE, easy access to a physician with expertise in HAE, continuity of care, availability of telemedicine services, access to approved HAE therapies, patient education, and economic barriers to treatment. Ways to improve HAE patient care in rural areas include health care provider recognition of the patient with undiagnosed HAE, development of individualized management plans, expansion of telemedicine, effective care at the local level, appropriate access to HAE medication, and increased awareness of patient support and advocacy groups. CONCLUSION: For patients with HAE living in rural areas, optimal care is complicated by health disparities. Given the scarcity with which these topics have been covered in the literature to date, it is intended that this article will serve as the impetus for a range of further initiatives focused on improving access to care.

Health-care resource utilization associated with peanut allergy management under allergen avoidance among commercially insured individuals.

Background: Until recently, the standard approach to care for individuals with peanut allergy (PA) was limited to allergen avoidance and treatment of reactions with emergency medicines. Objectives: To assess health-care resource utilization (HRU) and costs associated with PA management under allergen avoidance and to identify risk factors associated with peanut reactions that resulted in inpatient (IP) and/or emergency department (ED) visits. Methods: Privately insured individuals with PA diagnosis codes were identified from a large U.S. administrative claims data base (January 1, 1999, to March 31, 2017). PA-related HRU, indicated by a PA diagnosis and/or diagnostic procedure codes and by epinephrine autoinjectors (EAI) prescription fills in medical and pharmacy claims, respectively, and all-cause costs were described per patient-year (PPY). Risk factors associated with peanut reactions in an IP and/or ED setting were identified by using a multivariable logistic regression model. Results: A total of 86,483 patient-years from 14,136 individuals with PA were included. At the patient-year level, 28.1% were ages 0-3 years, 43.6% were ages 4-11 years, 13.7% were ages 12-17 years, and 14.5% were ages ≥ 18 years; 35.6% had PA-related outpatient visits; 50.6% had EAI fills; and 2.4% had PA-related IP and/or ED visits PPY. Younger individuals had more PA-related outpatient visits and EAI fills, with peak intensive use at ages 4-11 years. The proportion of individuals with PA-related IP and/or ED visits was highest among those aged ≥ 18 years. Mean all-cause costs were $3084 PPY; individuals with PA-related IP and/or ED visits incurred $8902 PPY ($17,451 for those with one or more IP visits). Risk factors associated with peanut reactions that resulted in IP and/or ED visits included young adults (odds ratio [OR] 3.19 [95% confidence interval {CI}, 2.66-3.83]), previous peanut reaction(s) (OR 1.66 [95% CI, 1.23-2.24]), asthma (OR 1.33 [95% CI, 1.18-1.51]), and male sex (OR 1.14 [95% CI, 1.01-1.28]). Conclusion: Individuals with PA and under allergen avoidance had significant HRU that varied across all age groups, with more PA-related outpatient visits during preschool and/or school age and PA-related urgent care among adults. Individuals with previous peanut reaction(s), asthma, and males had a higher risk of peanut reactions that resulted in IP and/or ED visits.

Single-Session Percutaneous Endovascular Mesocaval Shunt Creation and Balloon-Occluded Retrograde Transvenous Obliteration for the Treatment of Gastric Varices.

In the setting of portal hypertension, the body responds by creating portosystemic venous shunts, which may lead to the development of varices. Endoscopic treatment of these varices is often warranted to prevent catastrophic bleeding. During the course of variceal treatment, 1 or more portosystemic shunts may be sacrificed, which may acutely exacerbate portal hypertension and reduce systemic venous return. This report describes percutaneous creation of a mesocaval shunt and balloon-occluded retrograde transvenous obliteration (BRTO) in a patient with cavernous transformation of the portal vein. The patient had previously undergone an unsuccessful attempt at transjugular intrahepatic portosystemic shunt (TIPS) creation with postoperative bleeding requiring splenectomy. As TIPS was not feasible, creation of a percutaneous mesocaval shunt provided an alternate pathway for portosystemic decompression, facilitating safe treatment of gastric varices with BRTO via a gastrorenal shunt. These procedures were performed simultaneously to reduce the risk of variceal bleeding from acute changes in portal venous pressures and redirect blood flow through the shunt to maintain patency. This is the first reported case of combined mesocaval shunt placement and BRTO in a single session.

Endovascular Iliocaval Stent Reconstruction for Inferior Vena Cava Filter-Associated Iliocaval Thrombosis: Approach, Technical Success, Safety, and Two-Year Outcomes in 120 Patients.

PURPOSE: To report technical success, outcomes, and patency of iliocaval stent reconstruction for inferior vena cava (IVC) filter-bearing iliocaval thrombosis. MATERIALS AND METHODS: A total of 120 patients with 123 IVC filters and symptomatic iliocaval thrombosis underwent stent reconstruction. Mean patient age was 55 years (range, 19-88 y). Filters included 70 (57%) retrievable and 53 (43%) permanent filters. Symptoms included lower extremity swelling or pain (n = 93), ulcers (n = 8), phlegmasia (n = 7), back pain (n = 5), shortness of breath (n = 4), worsening renal function (n = 2), and stenosis identified during translumbar catheter placement (n = 1). Clinical success was defined as decrease in clinical, etiology, anatomy, and pathophysiology (CEAP) score of at least 1; resolution of presenting symptoms; or normalization of renal function in patients with juxtarenal or suprarenal thrombosis on presentation. Technical aspects of reconstruction, technical success, complications, 6-month clinical response, and 6-, 12-, and 24-month primary, primary-assisted, and secondary stent patency rates were recorded. RESULTS: Stent reconstruction was technically successful in all 120 patients, 63 of whom (53%) underwent thrombolysis. Thirty filters (24%) were retrieved, and 93 (76%) were excluded with stent placement across the indwelling filter. Six minor and 2 major complications occurred. Clinical success was achieved in 115 patients (96%) at 6 months. Six-, 12-, and 24-month primary iliocaval stent patency rates were 96.4%, 94.8%, and 87.2%, respectively. Twenty-four month primary-assisted and secondary patency rates were 90.3% and 94.2%, respectively. CONCLUSIONS: Iliocaval stent reconstruction is an effective treatment for filter-associated thrombosis with 100% technical success and 96% clinical success at 6 months. Technical and clinical outcomes in patients who underwent filter retrieval versus filter exclusion were similar.

Absolute quantification reveals the stable transmission of a high copy number variant linked to autoinflammatory disease.

BACKGROUND: Dissecting the role copy number variants (CNVs) play in disease pathogenesis is directly reliant on accurate methods for quantification. The Shar-Pei dog breed is predisposed to a complex autoinflammatory disease with numerous clinical manifestations. One such sign, recurrent fever, was previously shown to be significantly associated with a novel, but unstable CNV (CNV_16.1). Droplet digital PCR (ddPCR) offers a new mechanism for CNV detection via absolute quantification with the promise of added precision and reliability. The aim of this study was to evaluate ddPCR in relation to quantitative PCR (qPCR) and to assess the suitability of the favoured method as a genetic test for Shar-Pei Autoinflammatory Disease (SPAID). RESULTS: One hundred and ninety-six individuals were assayed using both PCR methods at two CNV positions (CNV_14.3 and CNV_16.1). The digital method revealed a striking result. The CNVs did not follow a continuum of alleles as previously reported, rather the alleles were stable and pedigree analysis showed they adhered to Mendelian segregation. Subsequent analysis of ddPCR case/control data confirmed that both CNVs remained significantly associated with the subphenotype of fever, but also to the encompassing SPAID complex (p < 0.001). In addition, harbouring CNV_16.1 allele five (CNV_16.1|5) resulted in a four-fold increase in the odds for SPAID (p < 0.001). The inclusion of a genetic marker for CNV_16.1 in a genome-wide association test revealed that this variant explained 9.7 % of genetic variance and 25.8 % of the additive genetic heritability of this autoinflammatory disease. CONCLUSIONS: This data shows the utility of the ddPCR method to resolve cryptic copy number inheritance patterns and so open avenues of genetic testing. In its current form, the ddPCR test presented here could be used in canine breeding to reduce the number of homozygote CNV_16.1|5 individuals and thereby to reduce the prevalence of disease in this breed.

Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease.

BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10-15 , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

Severe left diaphragmatic hernia limits size of fetal left heart more than does right diaphragmatic hernia.

OBJECTIVES: To assess whether severity of congenital diaphragmatic hernia (CDH) correlates with the degree of left heart hypoplasia and left ventricle (LV) output, and to determine if factors leading to abnormal fetal hemodynamics, such as compression and reduced LV preload, contribute to left heart hypoplasia. METHODS: This was a retrospective cross-sectional study of fetuses at 16-37 weeks' gestation that were diagnosed with CDH between 2000 and 2010. Lung-to-head ratio (LHR), liver position and side of the hernia were determined from stored ultrasound images. CDH severity was dichotomized based on LHR and liver position. The dimensions of mitral (MV) and aortic (AV) valves and LV were measured, and right and left ventricular outputs were recorded. RESULTS: In total, 188 fetuses with CDH were included in the study, 171 with left CDH and 17 with right CDH. Fetuses with severe left CDH had a smaller MV (Z = -2.24 ± 1.3 vs -1.33 ± 1.08), AV (Z = -1.39 ± 1.21 vs -0.51 ± 1.05) and LV volume (Z = -4.23 ± -2.71 vs -2.08 ± 3.15) and had lower LV output (26 ± 10% vs 32 ± 10%) than those with mild CDH. MV and AV in fetuses with right CDH (MV, Z = -0.83 ± 1.19 and AV, Z = -0.71 ± 1.07) were larger than those in fetuses with left CDH, but LV outputs were similarly diminished, regardless of hernia side. Severe dextroposition and abnormal liver position were associated independently with smaller left heart, while LHR was not. CONCLUSION: The severity of left heart hypoplasia correlates with the severity of CDH. Altered fetal hemodynamics, leading to decreased LV output, occurs in both right- and left-sided CDH, but the additional compressive effect on the left heart is seen only when the hernia is left-sided. Improved knowledge of the physiology of this disease may lead to advances in therapy and better risk assessment for use in counseling affected families.

Improving Detection of Alpha-1 Antitrypsin Deficiency: Role of the Allergist.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that manifests as lung and/or liver disease. Because symptoms of AATD overlap with those of common pulmonary and hepatic conditions, AATD is often misdiagnosed, which has resulted in substantial underdiagnosis of AATD worldwide. Although screening patients for AATD is recommended, the lack of procedures to facilitate testing remains a barrier to accurate diagnosis of AATD. Delays in AATD diagnosis can worsen outcomes for patients by postponing appropriate disease-modifying treatments. Patients with AATD-related lung disease experience symptoms similar to other obstructive lung disorders and are often misdiagnosed for years. In addition to existing screening guidelines, we recommend that screening for AATD become a standard part of allergists' workups of patients with asthma and fixed obstructive disease, chronic obstructive pulmonary disease, bronchiectasis without known origin, and patients under consideration for treatment with biologics. This Rostrum article reviews screening and diagnostic tests available in the United States and emphasizes evidence-based strategies to increase testing frequency and improve AATD detection rates. We underscore the pivotal role of allergists in managing care for patients with AATD. Finally, we urge health care providers to be aware of potentially poor clinical outcomes among patients with AATD during the coronavirus disease 2019 pandemic.