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C1-inhibitor concentrate home therapy for hereditary angioedema:
a viable, effective treatment option
H. J. Longhurst,* S. Carr† and K. Khair‡ *Barts and The London NHS Trust, Department Economic and political factors have led to the increased use of home therapy
of Immunopathology, London, UK, †Barts and The London NHS Trust, Department of programmes for patients who have traditionally been treated in hospital.
Paediatric Respiratory Medicine, London, UK, Many patients with hereditary angioedema (HAE) experience intermittent
and ‡Great Ormond Street Hospital, London, UK 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
Correspondence: Dr Hilary Longhurst, Barts are currently being established. This paper reviews the extent of use of these
programmes and summarizes the advantages and potential disadvantages of
Immunopathology, 51–53 Bartholomew Close, the concept so far.
Keywords:
angioedema, home therapy, quality of life Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution OnlineOpen:
Economic and political factors have contributed to the Introduction
increased use of home therapy programmes for patients who Hereditary angioedema (HAE) is an autosomal dominant would have been treated previously in hospital. One group of condition resulting from partial deficiency of C1 inhibitor patients who may benefit from home therapy is those with (C1-INH) [1]. It is a rare disease, thought to affect between HAE. This paper uses published data (Medline) to assess the one in 10 000 and one in 50 000 people worldwide [2].
use of C1-INH concentrate home therapy in patients with Acquired angioedema (AAE), which is also due to C1-INH HAE, and includes evaluations of both the recommenda- deficiency, is phenotypically similar to HAE, although it is tions for patient selection for home therapy and the associated typically with lymphoproliferative disease, or with documented benefits of self-administration of C1-INH Patients with C1-INH deficiency have reduced amounts of functional C1-INH, which at times of physiological or psy- chological stress is insufficient to control local inflammatorypathways. The complement and contact systems are acti- Data have been collected from a Medline search of the vated, and excess bradykinin is generated [4]. It is this English language literature to identify papers that included increased bradykinin production that is believed to be the information on the use of C1-INH concentrate as home main factor in the development of local oedema [4]. Oedema therapy in patients with HAE. The search included the years may occur at any site, but most commonly affects the sub- from 1985, the year that pasteurized C1-INH concentrate cutaneous tissue, causing swelling of the limbs, face, trunk or replacement therapy was introduced, to August 2006. The genitalia [1]. Oedema can also affect the mucous membranes keywords used for the search were ‘C1-inhibitor’, ‘C1- of the gastrointestinal (GI) tract, causing abdominal pain, inhibitor concentrate’, ‘C1-esterase inhibitor’, ‘C1-esterase often with diarrhoea and/or vomiting, and the mucous inhibitor concentrate’, ‘C1-INH’, ‘C1-INH concentrate’, membranes of the larynx, causing laryngeal oedema, which ‘C1EI’ and ‘C1EI concentrate’, combined with ‘C1-inhibitor may lead to death by asphyxiation [5–7].
Journal compilation 2006 British Society for Immunology, Clinical and Experimental Immunology Table 1. Papers detailing the use of C1 inhibitor (C1-INH) concentrate home therapy in patients with hereditary angioedema (HAE)*.
treatment time associated withless severe and shorter durationof attacks Reduced frequency of attacksReduced frequency of life-threatening attacksNo adverse events Limited duration of benefit inpatient with AAE *Patients suffered from HAE unless otherwise stated. †Reporting on the same cohort.
deficiency’, ‘hereditary angio(o)edema’, ‘HAE’, ‘hereditary frequency of attacks. In addition, C1-INH had an excellent angioneurotic (o)edema’ and ‘HANE’. These groups of key- words were then put together, alone and in combination,with the search terms ‘home’, ‘self-administration’, ‘self-administered’, ‘outpatient’ and ‘home-based’. The articles Discussion
were retrieved and analysed. Pertinent articles known to theauthors but not appearing in the Medline search results were Treatment of hereditary angioedema
Frequent or severe HAE attacks are disabling for the patient.
Consequently, such attacks are an indication for regular pro-phylaxis, usually with attenuated androgens such as danazol that increase hepatic production of C1-INH [14,15].
We found six relevant papers: two case series [8,9] with two However, attenuated androgens may cause unacceptable side and 43 patients, respectively; two further papers [10,11] effects such as virilization [16] or hepatic abnormalities [17], which included information describing patients on home or may be contraindicated otherwise, for example in women therapy (although this was not the main focus of the papers); who wish to become pregnant [18]. Fibrinolytic agents such and two further case series, which were available in abstract as tranexamic acid or epsilon aminocaproic acid are alterna- form only [12,13]. The papers are detailed in Table 1.
tive prophylactic agents, although the evidence base for their Patients were treated with C1-INH, given either on use is less certain [19,20]. Despite prophylaxis, many patients demand at the onset of an attack or as regular prophylaxis.
continue to experience intermittent severe attacks that C1-INH was self-administered or infused by a family interrupt their activities of daily living and may be member at home. The results showed that where prophylac- life-threatening. These attacks are treated with C1-INH con- tic C1-INH was given, patients experienced improved centrate, which in most cases brings about a response within quality of life (QoL) and reduced severity, duration and 30–90 min [21]. Licensed C1-INH products are available in Journal compilation 2006 British Society for Immunology, Clinical and Experimental Immunology Germany, Austria, Switzerland, France, Hungary, Argentina, attack per month, repeated hospital admissions result in Japan (Berinert P®, ZLB Behring, Marburg, Germany) and severe disruption to everyday life, affecting the ability to work and carry out domestic duties, impairing patients’ con- Netherlands). In other European countries, including the fidence to travel too far from the local hospital and creating United Kingdom, and in the United States, C1-INH is used anxiety. For these patients, or for patients living in remote on a named-patient basis, or is completely unavailable.
areas where access to a hospital may be difficult, home C1-INH infusion is administered traditionally in hospital, therapy (self-infusion or infusion by a family member) is usually in the emergency department. However, this usually the best option and is likely to result in greatly approach can lead to delays in administering treatment.
Emergency department staff may be unfamiliar with HAEand patients may not be triaged as urgent. Delays may occur Patient selection for home therapy in hereditary
in locating C1-INH, which is not a routine stock item for angioedema
most hospitals. Such delays necessitate higher C1-INH dosesto control the attack, unnecessary hospital admissions and, The available data suggest that patients included on C1-INH occasionally, severe adverse incidents, including death home infusion programmes must fulfil certain criteria [5,8,22]. Death rates from HAE-related laryngeal oedema of [8–13]: patients must have proven C1-INH deficiency as 30–40% have been reported. Although the majority of determined by typical symptoms, low C1-INH protein or deaths occur in undiagnosed patients, there remains an function and low C4 complement. Genetic diagnosis is not avoidable mortality in those who are diagnosed [1,5].
widely available, but may be useful where diagnosis is Children with C1-INH deficiency are not usually consid- unclear. Oral prophylaxis must be optimized. Patients must ered for home therapy in the United Kingdom, as there are have sufficiently frequent attacks; the recommended fre- no paediatric home therapy programmes. Fortunately, HAE quency varies between centres, but is usually a minimum of is usually mild in preadolescence. However, prophylactic one attack every 3 months [18]. However, patients with less options are limited: long-term attenuated androgens present frequent attacks may also benefit from home therapy and significant risks, including growth retardation, and are not should be considered on an individual basis. Patients should recommended [23,24]. Our literature search revealed that be motivated to comply with the home therapy programme one German centre does provide home therapy for children and be fully informed as to the risks and benefits. C1-INH severely affected with HAE, suggesting that this option is should be stored at 2–8°C, although limited data suggest that feasible for selected cases. Rusicke et al. describe how lyophilized C1-INH concentrate may be stable at room tem- on-demand C1-INH therapy is their first-line therapy for perature (25°C) for up to 6 months [26]. Twenty-four-hour children, with regular prophylaxis for those who experience access to help and advice should be available, including the very frequent attacks [13]. More than 50% of their cohort of option of emergency hospital treatment [18].
325 patients infuse at home, although the proportion of Training programmes in the United Kingdom and the these who are children is not stated. The authors claim that Netherlands include practical aspects of C1-INH administra- severe attacks are prevented, and hospital time and absence tion: hygiene and cannulation techniques, as well as from school is reduced (although detailed figures are not indications for C1-INH infusion and management of emergencies [9,18]. Attacks should be severe enough to Recently, consensus documents providing recommenda- warrant C1-INH treatment – usually severe abdominal pain tions on the management of HAE have been published by or orofacial oedema – but not so severe as to require expert panels in Canada and the United Kingdom [18,25].
hospitalization; for example, attacks causing symptoms of Both the Canadian and UK documents recommend offering laryngeal obstruction. However, if airway obstruction is patients the option of home therapy. In spite of a recent imminent, treatment may be expedited by home administra- increase in interest in home therapy in those countries where tion of C1-INH concentrate while awaiting the arrival of C1-INH is available [9], there is little published literature on ambulance transport to hospital. Patients should be advised this topic and a relative lack of information available for to consult a physician if the symptoms of an attack are atypi- cal, as the onset of an appendicitis or GI infection maypresent with symptoms similar to abdominal attacks of HAE.
The need for home therapy in hereditary angioedema
Government directives supporting home therapy
As C1-INH can be difficult to obtain at short notice, practi-tioners are strongly recommended to ensure that patients In many countries, the relationship between patient and have a supply of C1-INH to keep in the refrigerator at home medical professionals is changing. Nurses and paramedics [5,18,25,26]. For the majority of patients, who have infre- are taking on tasks that were previously the responsibility of quent attacks, C1-INH is taken to the local hospital for doctors, and many patients expect to take an active role in infusion. For those patients experiencing more than one their own management. Facilitated by the internet, the Journal compilation 2006 British Society for Immunology, Clinical and Experimental Immunology growth of self-help groups such as the UK Primary Immu- a significant reduction in time to start of symptomatic relief, nodeficiency Association (PiA) and HAE International and in time to complete resolution of the attack, compared (HAEI) has enabled patients to ‘network’ on a far wider scale with the five ‘historical control’ attacks immediately prior to than previously. Patients are increasingly aware of initiatives entry into the self-administration programme. Historical that can improve their QoL and, as a result, many patients control attacks did not respond significantly differently to are requesting the option of home therapy. Initiatives such as C1-INH concentrate compared with attacks in control the UK NHS Plan and ‘Expert Patient’ programmes seek to patients who did not self-administer. The authors attributed give patients the knowledge and confidence to take a more the reduction in time to onset of relief and attack duration to active role in their own management [27,28].
the reduced attack-to-treatment time associated with self-administration. These observations are in accordance withBork’s observational study, which reported that abdominal Established home therapy programmes
attacks treated with C1-INH concentrate within 2 h of onset Intravenous home therapy programmes exist for a variety of showed significant reduction in time to onset of relief com- conditions, including intravenous immunoglobulins for pared with attacks where treatment was delayed [11]. This antibody deficiency [29,30] and intravenous antibiotics for study did not report separate outcomes on the subgroup of patients with a variety of underlying conditions [31–36].
25 patients who self-infused. However, Rusicke et al. [13] These programmes have helped establish the feasibility and commented on the reduced attack-to-treatment time asso- cost-effectiveness of home therapy. However, perhaps the ciated with home therapy. Reduced attack frequency was also closest parallel with C1-INH home therapy programmes is reported by Bork et al. [11], Kreuz et al. [12] and Rusicke haemophilia home therapy. Like C1-INH, clotting factors for et al. [13] in patients who infused prophylactically.
haemophilia can be used prophylactically or as an emergency Reports from other home therapy programmes also indicate major benefits. Immunoglobulin home therapy is Home therapy has been available in haemophilia since the associated with greater patient independence, convenience, 1980s and is now considered ‘routine’. Most paediatric comfort and economic benefit [39,40]. A recent study patients are receiving home therapy by 18 months of age, as showed that home therapy significantly improved health, it is impractical for them to attend hospital several times a school/social functioning (in children) and significantly week for treatment or preventative therapy [37]. For children reduced emotional distress and limitations on personal time at high risk of bleeding, regular prophylaxis with clotting [40]. In a similar study, home therapy with immunoglobulin factors can be given; for others, prompt treatment of any significantly improved QoL [41]. Patients in both surveys bleeds or prophylaxis of high-risk events is preferable.
preferred home- to hospital-based therapy [40,41]. For Current UK guidelines [38] suggest regular prophylaxis for patients with haemophilia, home therapy is associated with those who have declared themselves phenotypically severe reduced pain and disability, improved QoL and reduced hos- (by virtue of two of more haemarthroses) and, for the others, pitalization and time off work or school [38]. The availability access to coagulation factors for administration at home, a of home therapy has also been associated with improved life local hospital or a haemophilia centre.
expectancy [42]. Two of the case series in our analysis men-tioned improved QoL for HAE patients with access to hometherapy, although formal studies are lacking [12,13].
Benefits of home therapy
A major issue for patients with HAE is the delay and The results of our Medline search included a recent paper by difficulty in accessing emergency care. Better awareness of Levi et al., who reported the experiences of 31 patients with HAE among medical staff and better liaison with emergency C1-INH deficiency who were trained to self-administer departments is important, but can be difficult when medical C1-INH [9]. Patients, who all suffered from frequent, severe staff change frequently, as is the case in most emergency angioedema attacks, self-administered 1000 units of C1-INH departments. Patient education is important to ensure concentrate shortly after the onset of severe abdominal, oro- prompt attendance at hospital at an early stage of the attack.
facial or laryngeal attacks. Twelve patients, who had very However, travelling time is likely to be a limiting factor. For frequent attacks (> 1 every 10 days) were treated additionally those patients with rapid-onset attacks, or who live far from with prophylactic C1-INH concentrate every 5–7 days. Mean the hospital, the resulting delay may pose a significant risk.
follow-up was 3·5 years (range 0·9–5·1). All patients were Access to emergency treatment can often be expedited only trained successfully, and reported very low levels of technical failure with venepuncture (< 2%). There were no adverseevents of sufficient severity to require medical assistance.
Home therapy for acquired angioedema
Self-administration of regular prophylactic C1-INH concentrate resulted in a significant reduction in attack Interestingly, the Levi study group included three patients frequency, with seven of 12 patients reporting complete with AAE, whose benefit did not differ significantly from freedom from attacks. Patients self-treating attacks reported those with HAE. C1-INH concentrate appears effective in Journal compilation 2006 British Society for Immunology, Clinical and Experimental Immunology the management of acute attacks of AAE, even when reactions. C1-INH is extremely well tolerated [1,50,51], and C1-INH antibodies are present, although some patients may our analysis did not reveal any treatment-related adverse require higher doses or become resistant to treatment [1,3].
events [8–13]. However, because it is a plasma product, Bork and Witzke reported a patient with frequent AAE C1-INH raises particular concerns for patients and physi- attacks who was treated with C1-INH 1000 units every cians regarding virus transmission, particularly viral hepati- 5 days [8]. Treatment was initially successful, but after tis and HIV [52]. It is a regulatory requirement in Europe 10 months the patient became progressively resistant [53] for plasma donors to undergo a comprehensive health (Table 1). Despite reservations about its durability, C1-INH screen. Each donation is then screened using serological home therapy remains an option for patients with AAE.
methods for the presence of HIV, hepatitis B (HBV) andhepatitis C (HCV). All plasma-derived medicinal products Funding and resources
such as C1-INH concentrate are also recommended toundergo additional testing for HCV using the polymerase C1-INH is currently considered an expensive treatment option (approximately £290/€425 for 500 units). Home The most widely available C1-INH concentrates undergo therapy has the potential to increase overall use of C1-INH several additional voluntary safety checks, including the by treating attacks that would previously have gone testing of individual pools via PCR for HIV-1, hepatitis A, untreated, although published data do not suggest that this is HBV and parvovirus B19 [54,55], in addition to HCV.
the case when compared with optimum hospital-based The plasma then enters the manufacturing process, where it undergoes further virus inactivation and removal steps.
However, untreated attacks are costly in social, pharmaco- economic and QoL terms. HAE is a lifelong condition, which chromatography, in accordance with the Committee for usually becomes symptomatic in adolescence. Attacks may Proprietary Medicinal Products’ guidelines. Since its intro- be precipitated by emotional stress, minor infections or duction in 1985, approximately 200 000 standard 500 unit oestrogens [18,43]. Consequently, young adults are particu- doses of the most widely available pasteurized C1-INH larly at risk of frequent attacks and the lifetime economic concentrate have been sold globally, and no apparent cases cost of disrupted education and employment is likely to be considerable. Additionally, under-treated attacks – where the patient presents late – have major direct costs, as higherdoses of C1-INH are required and hospital admission ismore probable [11]. Studies in antibody therapy and hae- Conclusion
mophilia show that home therapy is the most cost-effective Recent UK and Canadian consensus documents providing option for delivering this type of care [44–46]. Cost–benefit recommendations on the management of HAE have studies in HAE are required urgently.
endorsed the option of home therapy for HAE patients. This Funding of treatments is coming under increased scrutiny choice should potentially be made available to all HAE in both insurance-based and taxation-based health-care patients, including those who suffer only infrequent attacks, systems. C1-INH is unlicensed in several countries. In the and children. The opportunity for patients to manage their United States it is not Food and Drug Administration (FDA) health enriches QoL, as the now-routine home administra- approved, but can be administered for compassionate use.
tion of home haemophilia and immunoglobulin replace- Without FDA approval, HAE sufferers must pay the entire ment therapies have shown. However, C1-INH is still an cost of the therapy themselves. Licensing studies are under expensive treatment option. Therefore, prophylaxis should way for both plasma-derived and recombinant C1-INH and be optimized in HAE patients, especially those who have for other therapies for acute attacks of HAE. Access to frequent, severe or rapid onset of attacks. If prophylaxis is C1-INH, whether hospital- or home-based, is likely to ineffective, such patients should be prioritized for C1-INH remain suboptimal until licensed products are available.
Even if licensed, the manufacturing costs of plasma-derived Many patients are now requesting home therapy, as aware- C1-INH are likely to be out of reach for many middle- and ness of its advantages increases through self-help network- low-income countries. In the long term, recombinant ing, and this should be encouraged. C1-INH is currently not C1-INH or inhibitors of the bradykinin–kallikrein pathway licensed in many European countries, including the United may provide a solution [47–49]. In theory, kallikrein- or Kingdom or the United States, and many physicians and bradykinin-pathway inhibitors also provide an option for funding authorities are reluctant to endorse new initiatives patients with AAE who are resistant to C1-INH.
for rare diseases. However, given the proven efficacy andsafety of C1-INH, licensing concerns can be overcome by Safety of C1-inhibitor concentrate
referring patients to specialist HAE centres, who retain Products used for home infusion need to demonstrate a high overall responsibility for clinical management and who have standard of safety with respect to immunological or allergic Journal compilation 2006 British Society for Immunology, Clinical and Experimental Immunology A review of the current situation in HAE management 15 Agostoni A, Cicardi M, Martignoni GC, Bergamaschini L, Marasini suggests that home therapy is indeed a viable and effective B. Danazol and stanozolol in long-term prophylactic treatment of option that should be considered highly beneficial for hereditary angioedema. J Allergy Clin Immunol 1980; 65:75–9.
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Journal compilation 2006 British Society for Immunology, Clinical and Experimental Immunology

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