Prophylaxis in hereditary angioedema: a United Kingdom Delphi consensus.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

Differential Diagnosis: Hepatic Complications in Inborn Errors of Immunity.

Inborn errors of immunity (IEIs) are a heterogeneous group of diverse clinical and genetic phenotypes that have an estimated combined prevalence as high as 1/1000. Increased risk of frequent, severe, or opportunistic infections is a common feature of IEIs, but there are also diverse immune-mediated, non-infective complications that are associated with significant morbidity and mortality. As patient survival increases, these are becoming more apparent within the liver. Hepatic involvement of IEIs may not only manifest as infections, but also nodular regenerative hyperplasia, granulomatous disease, autoimmune hepatitis and malignancy. As therapeutic options for patients are expanding, with both pharmaceutical treatments as well as haematopoietic stem cell transplant (HSCT), iatrogenic liver injury is increasingly common and important to identify. This review article summarises the spectrum of hepatic complications seen in IEIs, and highlights the challenges of management within this patient cohort, where immunosuppression is poorly tolerated. Early recognition and prompt diagnosis of potential hepatic complications is therefore crucial in ensuring potentially reversible causes are treated, but significant uncertainty remains regarding best practice for many features of immune dysregulation with limited high-quality evidence.

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.

Recurrent Campylobacter jejuni Infection in an Immunodeficient Patient Treated with Repeated Faecal Microbiota Transplant (FMT)-A Case Report.

There is limited evidence to guide successful treatment of recurrent Campylobacter infection in patients with common variable immunodeficiency (CVID) already managed on regular immunoglobulin therapy. The role of faecal microbiota transplant (FMT) is uncertain. We report a case of recurrent Campylobacter jejuni infection in a patient with CVID treated with repeated FMT with 18 months of symptom resolution prior to relapse.

Illustrative Case Series and Narrative Review of Therapeutic Failure of Immunotherapy for Allergic Rhinitis.

This is a series of 4 cases (3 therapeutic failure and 1 early relapse) in adult patients treated with allergen immunotherapy (AIT) for allergic rhinitis (AR) in our immunotherapy clinic, which treats 110 new patients per year. AIT includes both subcutaneous and sublingual routes. The current national/international AIT recommendations and the literature have been searched to identify guidance for the optimal management of therapeutic failure of AIT in AR. There is scant information available to support clinicians when treatment failure and/or intolerable side effects occur. The importance is highlighted for developing the guidance and evidence base for the benefit of this patient subgroup. The potential strategies that clinicians have proposed are discussed in this article, though it is acknowledged that these are mostly not evidence-based.

A Multicenter Evaluation of Diagnosis and Management of Omega-5 Gliadin Allergy (Also Known as Wheat-Dependent Exercise-Induced Anaphylaxis) in 132 Adults.

BACKGROUND: Omega-5 gliadin allergy (also known as wheat-dependent exercise-induced anaphylaxis) is a rare allergy to wheat that often presents with intermittent severe anaphylaxis in the context of a cofactor, such as exercise. OBJECTIVE: To undertake a detailed clinical characterization of the largest cohort of patients with omega-5 gliadin allergy to date. METHODS: We retrospectively analyzed the demographic characteristics, presentation, investigation, and management of 132 patients presenting with omega-5 gliadin allergy in 4 UK centers. RESULTS: There were significant delays in diagnosis of 1 to 5 years (40% of patients) and more than 5 years (29% of patients). The commonest cofactors were exercise (80%), alcohol (25%), and nonsteroidal anti-inflammatory drugs (9%). A minority of patients (11%) had no identifiable cofactor. The level of specific IgE to omega-5 gliadin does not predict the severity of allergic reactions. Patients who adhered to a gluten-free diet and those who avoided wheat in combination with exercise achieved the largest reductions in subsequent allergic reactions of 67% and 69%, respectively. CONCLUSION: Omega-5 gliadin allergy is a rare wheat allergy that presents with severe anaphylaxis. The diagnosis is frequently delayed, and therefore we recommend that all adult patients presenting with anaphylaxis of unclear cause should have omega-5 gliadin specific IgE tested. A gluten-free diet or avoidance of wheat-based meals in combination with exercise (if the cofactor is exercise) helps to significantly decrease the risk of future allergic reactions. However, antihistamines and an epinephrine autoinjector must always be prescribed because one-third of patients continue to have allergic reactions despite dietary advice.

The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects.

Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent 2 sides of the same coin. Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency. On the other hand, more common autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a polygenic inheritance pattern. Not surprisingly, the genes implicated in single-gene disorders have also been shown to be linked to polygenic disorders. In this review article, we discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiologic pathways and clinical features of monogenic defects that result in autoimmune disease. We also explore the hypotheses underlying the development of autoimmune disease and the overlap between immunodeficiency and autoimmunity.

An update on the hyper-IgE syndromes.

The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used.

"A rose is a rose is a rose," but CVID is Not CVID common variable immune deficiency (CVID), what do we know in 2011?

Common variable immune deficiency (CVID) is the commonest symptomatic primary immunodeficiency and represents a heterogenous collection of disorders resulting mostly in antibody deficiency and recurrent infections. However, autoimmunity, granulomatous inflammation and malignancy frequently occur as part of the syndrome. The etiology of the condition has been poorly understood although in recent years, significant progress has been made in elucidating genetic mechanisms that can result in a CVID phenotype. In parallel to this, advances in treatment of the condition have also resulted in improved survival and quality of life for patients. There still remains significant work to be done in improving our understanding of the disease. In addition, recognition of the condition remains poor with significant diagnostic delays and avoidable morbidity. In this article, we review CVID with a particular focus on the areas of improving diagnosis and classification, recent developments in understanding the underlying etiology and genetics; and current treatment and monitoring recommendations for patients.

Successful desensitization to immunoglobulin A in a case of transfusion-related anaphylaxis.

BACKGROUND: A history of anaphylaxis after transfusion of immunoglobulin A (IgA)-containing blood products in selective IgA-deficient (sIgAD) patients can be a major problem, particularly in emergencies, when large quantities of blood products are required. CASE REPORT: A 19-year-old woman with end-stage Type 2 autoimmune hepatitis required liver transplantation as her only remaining treatment option. However, she also had sIgAD, anti-IgA antibodies, and episodes of anaphylaxis after receiving IgA-containing blood products. Liver transplantation would have been extremely challenging due to the difficulty of obtaining sufficient blood products from suitable IgA-deficient donors. Hence, it became imperative to devise a protocol to desensitize her to IgA-containing blood products. RESULTS: Using a continuous infusion of an IgA-enriched (6 mg/mL IgA) immunoglobulin preparation with gradual increases in concentration, she was successfully desensitized to IgA. Consequently, she was able to receive standard platelets, fresh-frozen plasma, and red blood cells with no complications. CONCLUSION: This approach could prove very useful in similar cases that may require administration of large quantities of blood products particularly in emergency lifesaving circumstances.

The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency.

SUMMARY: The identification of mutations in the inducible costimulator (ICOS) gene in nine patients with common variable immunodeficiency (CVID) was a major breakthrough. CVID is a complex, highly heterogeneous primary immunodeficiency disease, and the discovery of these mutations revealed a molecular basis. ICOS belongs to the CD28 family of costimulatory molecules and is expressed exclusively on activated T cells. It has at least three critical functions: germinal center formation, isotype class switching, and the development of memory B cells. The discovery of human ICOS deficiency showed that a monogenic disorder could account for the full spectrum of manifestations seen in childhood and adulthood-onset CVID, including autoimmune, inflammatory, and malignant disease complications, as well as recurrent infections. Moreover, this discovery showed that a disorder which had previously been perceived as a B-cell disease might in fact have its genetic origin in human T cells. In this article, we review the role of ICOS in the mammalian immune system and human disease, as well as the discovery and characteristics of patients with ICOS deficiency. Finally, we also discuss how these 'human knockouts' have contributed to our understanding of ICOS functions and have suggested potential avenues for using therapeutic ICOS manipulation to treat other diseases.

Hypogammaglobulinaemia.

This article reviews the primary immunodeficiencies that result in hypogammaglobulinemia or predominantly antibody deficiency disorders. This group makes up the largest proportion of patients with primary immunodeficiency. Significant advances have been made in understanding the molecular basis and clinical characteristics of patients with the more severe forms of antibody deficiency in the last 6 years. Recognition of these disorders remains poor with significant diagnostic delay. The milder forms of antibody deficiency disorders, especially those with normal total serum immunoglobulin G levels, remain poorly characterized and understood. Further work remains to be done in understanding and recognizing these syndromes to benefit patient care and foster further knowledge of the immune system.

Common variable immunodeficiency: an update on etiology and management.

Common variable immunodeficiency (CVID) represents a heterogeneous group of primary antibody deficiency disorders characterized by recurrent infection and by inflammatory, granulomatous, and autoimmune complications. Recently, there have been significant advances in understanding the pathogenesis of the disease, with five genetic mutations identified in patients who have a CVID phenotype. Clinical care also has progressed with refinements in treatment and the development of classification schemes for prognostic and research purposes. Significant delays in diagnosis remain, however. It is likely that more genetic defects will be identified in the future, further shrinking the pool of patients who have CVID of unknown cause.