The future of therapeutic options for hereditary angioedema.

Hereditary angioedema (HAE) is a rare genetic condition causing unpredictable and severe episodes of angioedema that are debilitating and life-threatening. Moreover, HAE can be classified into HAE due to C1-esterase inhibitor deficiency (HAE-C1INH) or HAE with normal C1INH. Moreover, HAE-C1INH is subcategorized as types I and II based on deficient or dysfunctional circulating C1INH protein resulting from inherited or spontaneous mutations in the SERPING1 gene leading to uncontrolled factor XII/plasma kallikrein activation and excessive bradykinin production. Bradykinin-2 receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in subcutaneous or submucosal fluid extravasation that can affect the face, extremities, airway, and gastrointestinal and genitourinary systems. Furthermore, HAE with normal C1INH is caused by either a known or unknown genetic mutation, and the mechanisms are less well-established but most forms are thought to be related to bradykinin signaling with a similar presentation as HAE-C1INH despite normal levels of C1INH protein and function. Current HAE management strategies include on-demand and prophylactic treatments which replace C1INH, reduce kallikrein activity, or block bradykinin binding to the bradykinin B2 receptor. With the advent of additional small molecule inhibitors, monoclonal antibodies, RNA-targeted therapies, gene therapies, and gene modification approaches, preclinical studies and human clinical trials are underway to further expand therapeutic options in HAE. This review article will briefly summarize current HAE treatments and provide an overview of potential future therapies for HAE.

Genetic Variants Leading to Urticaria and Angioedema and Associated Biomarkers.

Advances in next generation sequencing technologies, as well as their expanded accessibility and clinical use over the past 2 decades, have led to an exponential increase in the number of identified single gene disorders. Among these are primary atopic disorders-inborn errors of immunity resulting in severe allergic phenotypes as a primary presenting feature. Two cardinal aspects of type I immediate hypersensitivity allergic reactions are hives and angioedema. Mast cells (MCs) are frequent primary drivers of these symptoms, but other cells have also been implicated. Even where MC degranulation is believed to be the cause, mediator-induced symptoms may greatly vary among individuals. Angioedema-particularly in the absence of hives-may also be caused by hereditary angioedema conditions resulting from aberrant regulation of contact system activation and excessive bradykinin generation or impairment of vascular integrity. In these patients, swelling can affect unpredictable locations and fail to respond to MC-directed therapies. Genetic variants have helped delineate key pathways in the etiology of urticaria and nonatopic angioedema and led to the development of targeted therapies. Herein, we describe the currently known inherited and acquired genetic causes for these conditions, highlight specific features in their clinical presentations, and discuss the benefits and limitations of biomarkers that can help distinguish them.

Learning while treating: Gain-of-function STAT6 variants in severe allergic disease.

In an era of rapid identification of inborn errors of immunity, Sharma et al.1 report novel heterozygous gain-of-function variants in the signal transducer and activator of transcription 6 (STAT6) gene in individuals with severe and early onset multi-systemic allergic disease.

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.

Lymphoid malignancy in common variable immunodeficiency in a single-center cohort.

One of the complications of common variable immunodeficiency (CVID) is the development of lymphoid malignancy. In this retrospective, single-center study of 647 CVID subjects followed over 4 decades, we present immunologic and clinical phenotypes, pathology, treatment, and outcomes of 45 patients (15 males and 30 females, 7%) who developed 49 lymphoid malignancies. The mean age at CVID diagnosis was 42.6 years) and at lymphoma diagnosis was 48.8 years. Of the 41 with known follow up, 29 (70%) have died, 27 of these due to this diagnosis. Twelve are alive, in remission or have achieved cure; four others were alive at last encounter. Some patients had a history of only recurrent infections (36.3%); others had autoimmunity (33%), enteropathy (20%), and/or granulomatous disease (11%). Six had previously been treated for another cancer. This report also includes 6 additional living CVID patients who had been diagnosed with NHL; 4 were given treatment for this. However, on pathology review, the initial diagnosis was reversed, as the findings were more consistent with a benign lymphoproliferative process. This study outlines the high incidence of lymphoma in this single CVID cohort, and some of the diagnostic challenges presented due to immune dysregulation characteristic of this immune defect.

Primary B-cell immunodeficiencies.

Primary B-cell immunodeficiencies refer to diseases resulting from impaired antibody production due to either molecular defects intrinsic to B-cells or a failure of interaction between B-cells and T-cells. Patients typically have recurrent infections and can vary with presentation and complications depending upon where the defect has occurred in B-cell development or the degree of functional impairment. In this review, we describe B-cell specific immune defects categorized by presence or absence of peripheral B-cells, immunoglobulins isotypes and evidence of antibody impairment.

Histaminergic Angioedema.

Angioedema is frequently categorized into histamine- or bradykinin-mediated disease. It is critical to determine the underlying mediator of symptoms as it directs treatment. Histaminergic angioedema is the most frequent cause of angioedema. It is classified as either acute (lasting <6 weeks) or chronic (symptoms >6 weeks). It is further classified into angioedema presenting with or without urticaria. Some patients with acute angioedema may have disease that becomes chronic. Mast cells and basophils are central to the underlying pathophysiology of histamine-mediated angioedema. The underlying treatments of histamine-mediated angioedema are antihistamines, corticosteroids, and epinephrine.

Hemoptysis in a Patient with Elevated Immunoglobulin E.

Recurrent pneumonia with cavitation leading to pneumatoceles, secondary fungal infections, and hemoptysis are major causes of mortality and morbidity in patients with hyper-IgE syndrome. Prevention and aggressive treatment of pneumonia in these patients are essential to prevent further lung damage, but treatment may be delayed because the classic signs/symptoms of infection such as fever, chills, or rigors may be lacking. Early imaging to identify infection is essential for diagnosis and treatment. The mainstay of therapy is continuous, full-dose daily trimethoprim-sulfamethoxazole and commonly fungal coverage. Because hyper-IgE syndrome is a progressive disease, patients' condition may worsen despite compliance with prophylactic therapy.

Intractable hiccups due to herpetic esophagitis in an immunocompromised patient.

INTRODUCTION: Herpes virus family's association with visceral lesions is well established. Herpes simplex virus presentations vary based on immune status. Intractable hiccups due to herpes simplex esophagitis, to the best of our knowledge have been described twice in the literature. We present a 68 year-old immunocompromised male with intractable hiccups for 10 months. CASE: 68 year-old male with end-stage renal disease and multiple myeloma presented with coffee ground emesis and hiccups of ten months duration. A year earlier, he received cycles of bortezomib and dexamethasone, remaining on lenalidomide. During chemotherapy, he developed pneumococcal meningitis and subsequently intractable hiccups. Preceding admission, endoscopy showed duodenitis and esophagitis. Proton-pump inhibitor therapy was initiated; however, biopsy was not performed. During admission, hiccups often occurred every few seconds while off anti-emetics, persisting despite therapy. Exam showed cachexia/temporal wasting, aphthous stomatitis and abdominal tenderness. MRI of brain/spine, CT of neck, chest, abdomen and neurological evaluation were unremarkable. Endoscopy revealed gastritis and esophagitis with mucosal tears. Biopsy revealed intra-nuclear inclusions with multi-nucleated cells, consistent with herpes virus, later confirmed as herpes simplex by immunostaining. Hiccups and emesis resolved after of 2 days of intravenous acyclovir. 21 days of treatment were completed with oral valacyclovir. He remained free of hiccups during the remaining hospital stay and follow up. This case illustrates an exceptionally rare presentation of herpetic esophagitis in an immunocompromised host. As novel immunotherapeutic/suppressive agents continue to emerge, the evolving role of herpes virus prophylaxis and diagnosis of atypical presentations in new host populations is a topic of growing importance.

Effect of menses on clearance of Y-chromosome in vaginal fluid: implications for a biomarker of recent sexual activity.

Self-reported sexual behaviors are subject to bias. We previously developed a polymerase chain reaction for the detection of Y-chromosome sequences in vaginal fluid as a potential biomarker of recent sexual activity. In this study, we found menses results in lower Y-chromosome concentrations but with similar decay patterns as non-menstrual samples.

Condom use and vaginal Y-chromosome detection: the specificity of a potential biomarker.

OBJECTIVE: Detection of vaginal Y-chromosome sequences (YCS) may be a useful biomarker to validate sexual behavior reporting in women. We describe the effects of condom use on the detection of vaginal YCS. METHODS: Fifty-six women were asked to abstain from sexual intercourse for 14 days. On day 15, participants were asked to engage in sexual intercourse with their male partners using condoms. Self-collected vaginal swabs were obtained on days 14, 16, and 17. YCS were detected using the Roche LightCycler with the use of positive controls. RESULTS: Fourty-four of 56 women completed the study. Five women (11.4%) had detectable YCS. The overall specificity of the YCS assay with condom use was 92% (95% CI: 80%-98%). Although women who reported receptive oral sex and digital penetration within 48 hours of swab collection had a higher detection rate of YCS [RR 2.3 (95% CI: 1.1-4.6) and 3.6 (95%CI: 1.6-8.5), respectively], the mean concentration of YCS was much less than that associated with unprotected vaginal intercourse (P <0.001) CONCLUSIONS: Condom use during intercourse appears to prevent vaginal YCS detection; this may be a useful biomarker to validate self-reported condom use.