Hilary Longhurst

Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: Consensus report of an International Working Group

To cite this article: Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, Reshef A, Zuraw B on behalf of HAWK (Hereditary Angioedema International Working Group). Evidence‐based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012; 67: 147–157.

Hereditary angio-oedema

Hereditary angio-oedema is caused by a heterozygous deficiency of C1 inhibitor. This inhibitor regulates several inflammatory pathways, and patients with hereditary angio-oedema have intermittent cutaneous or mucosal swellings because of a failure to control local production of bradykinin. Swellings typically evolve in several hours and persist for a few days. In addition to orofacial angio-oedema, painless swellings affect peripheries, which causes disfigurement or interference with work and other activities of daily living. Angio-oedema affecting the gastrointestinal tract or abdominal viscera causes severe pain often with vomiting due to oedematous bowel obstruction. About 2% of swellings involve the larynx and can be fatal if untreated. About 50% of patients have laryngeal swellings that are potentially fatal despite prophylaxis. In this Seminar we review the clinical features, diagnosis, and management of hereditary angio-oedema, with specific emphasis on the new treatments available for acute swellings.

Disease expression in women with hereditary angioedema

OBJECTIVE Fluctuations in sex hormones can trigger angioedema attacks in women with hereditary angioedema. Combined oral contraceptive therapies, as well as pregnancy, can induce severe attacks. The course of angioedema may be very variable in different women. STUDY DESIGN Within the PREHAEAT project launched by the European Union, data on 150 postpubertal women with hereditary angioedema were collected in 8 countries, using a patient-based questionnaire. RESULTS Puberty worsened the disease for 62%. Combined oral contraceptives worsened the disease for 79%, whereas progestogen-only pills improved it for 64%. During pregnancies, 38% of women had more attacks, but 30% had fewer attacks. Vaginal delivery was usually uncomplicated. Attacks occurred within 48 hours in only 6% of cases. Those more severely affected during menses had more symptoms during pregnancies, suggesting a hormone-sensitive phenotype for some patients. CONCLUSION The course of angioedema in women with C1 inhibitor deficiency is affected by physiologic hormonal changes; consequently, physicians should take these into account when advising on management.

C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option.

Economic and political factors have led to the increased use of home therapy programmes for patients who have traditionally been treated in hospital. Many patients with hereditary angioedema (HAE) experience intermittent severe attacks that affect their quality of life and may be life‐threatening. These attacks are treated with C1‐inhibitor concentrate which, for most patients, is infused at the local hospital. Home therapy programmes for HAE are currently being established. This paper reviews the extent of use of these programmes and summarizes the advantages and potential disadvantages of the concept so far.

Hereditary Angioedema Attacks Resolve Faster and Are Shorter after Early Icatibant Treatment

Background Attacks of hereditary angioedema (HAE) are unpredictable and, if affecting the upper airway, can be lethal. Icatibant is used for physician- or patient self-administered symptomatic treatment of HAE attacks in adults. Its mode of action includes disruption of the bradykinin pathway via blockade of the bradykinin B2 receptor. Early treatment is believed to shorten attack duration and prevent severe outcomes; however, evidence to support these benefits is lacking. Objective To examine the impact of timing of icatibant administration on the duration and resolution of HAE type I and II attacks. Methods The Icatibant Outcome Survey is an international, prospective, observational study for patients treated with icatibant. Data on timings and outcomes of icatibant treatment for HAE attacks were collected between July 2009–February 2012. A mixed-model of repeated measures was performed for 426 attacks in 136 HAE type I and II patients. Results Attack duration was significantly shorter in patients treated <1 hour of attack onset compared with those treated ≥1 hour (6.1 hours versus 16.8 hours [p<0.001]). Similar significant effects were observed for <2 hours versus ≥2 hours (7.2 hours versus 20.2 hours [p<0.001]) and <5 hours versus ≥5 hours (8.0 hours versus 23.5 hours [p<0.001]). Treatment within 1 hour of attack onset also significantly reduced time to attack resolution (5.8 hours versus 8.8 hours [p<0.05]). Self-administrators were more likely to treat early and experience shorter attacks than those treated by a healthcare professional. Conclusion Early blockade of the bradykinin B2 receptor with icatibant, particularly within the first hour of attack onset, significantly reduced attack duration and time to attack resolution.

An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema

Reduced levels of serum C4 have been considered a ubiquitous finding in hereditary angio‐oedema (HAE), and consequently low C4 is often used to ‘request manage’ access to C1 inhibitor assays in the United Kingdom. However, in our experience normal C4 may occasionally be compatible with HAE. We audited the results of serum C4, C1 inhibitor antigen (C1inhA) and C1 inhibitor function (C1inhF) in 49 HAE patients, compared to a control group of 58 unaffected subjects. The sensitivity of low serum C4 for HAE among untreated patients was 81%; levels of complement C4 were within the normal range on nine separate occasions in five untreated HAE patients. Molecular genetic analysis of these individuals demonstrated novel mutations in the C1 inhibitor gene. The supplied reference ranges for the Quidel C1inhF enzyme‐linked immunosorbent assay (ELISA) system appear to be too low, with a sensitivity of just 57% for HAE. Following optimization of the reference ranges using receiver operating characteristic analysis, low C1inhF was found to be 78% sensitive and 100% specific for HAE. The diagnosis of HAE is not excluded by normal levels of complement C4. We conclude that C1 inhibitor studies should be performed regardless of serum C4 where a high index of clinical suspicion exists.

Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations.

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of potentially life-threatening angioedema. The most widespread underlying genetic deficiency is a heterozygous deficiency of the serine protease inhibitor C1 esterase inhibitor (C1-Inh). In addition to low C4 levels, the most important laboratory parameter for correct diagnosis of HAE or angioedema due to acquired C1-Inh deficiency is reduced C1-Inh function (fC1-Inh). No direct recommendations about the assays for fC1-Inh or sample handling conditions are available, although this would prove especially useful when a laboratory first starts to offer assays on fC1-Inh for HAE diagnosis. In the present study we evaluated the performance of fC1-Inh assays in the 15 different laboratories that are specialised in HAE diagnostics and assessed inter-laboratory variation with each laboratory using their own assays and standards. A double-blind survey was conducted using plasma/serum samples from healthy donors and HAE patients and the uniformity of HAE diagnosis was evaluated. It can be concluded that the diagnosis of fC1-Inh deficiency was made correctly in most cases in this survey. We can recommend the chromogenic assay for the determination of fC1-Inh, while the complex ELISA needs further investigation.

Canadian hereditary angioedema guideline

Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe

BackgroundHereditary angioedema (HAE) is a rare, debilitating, and potentially life-threatening disease characterized by recurrent edema attacks. Important advances in HAE treatment have been made, including the development of new therapies for treating or preventing attacks. Nevertheless, the disease is still frequently misdiagnosed and inappropriately treated, potentially exposing patients with laryngeal attacks to the risk of asphyxiation.MethodsThe Icatibant Outcome Survey (IOS) is an international, observational study that documents the clinical outcome of HAE patients eligible for treatment with icatibant. Patient ages at first symptoms and at diagnosis were recorded at enrolment, and the delay between first symptoms and diagnosis was calculated.ResultsThe median [range] diagnostic delay in HAE type I and II patients across eight countries was 8.5 years [0–62.0]. The median delay in diagnosis was longer for HAE type II versus type I (21 versus 8 years, respectively), although this did not quite reach statistical significance.ConclusionsAlthough it can be difficult to differentiate HAE symptoms from those of more common angioedema sub-types (e.g. idiopathic or acquired angioedema), our results show that HAE type I and II patients have an unacceptable delay in diagnosis, even those with a family history of the disease. Raising physician awareness of this disabling and potentially fatal disease may lead to a more accurate diagnosis and timely treatment.

Helicobacter pylori infection as a triggering factor of attacks in patients with hereditary angioedema.

Background:  Helicobacter pylori infection is considered among the causative factors of urticaria and angioedema. Having conducted a study on 65 patients, Hungarian authors reported in 2001 that successful eradication of H. pylori is followed by a significant reduction in the number of attacks in patients with hereditary angioedema (HAE). The present study aimed to reinvestigate the relationship between H. pylori infection and the attack rate in the framework of an international collaborative study.