Recommendation: Every patient with HAE should be considered for home therapy and self-administration training, once the diagnosis of C1INH deficiency (hereditary or acquired angioedema) is confirmed.
Prophylaxis should be optimised, but home therapy need not be delayed since training can take place alongside other treatments. Attacks occur despite prophylaxis in most patients. Requirement to attend a medical facility inevitably results in delayed treatment, and many attacks are not treated at all. This contributes to the social and economic disadvantage associated with HAE. For this reason, eligibility for home therapy should be inclusive. It is strongly recommended that patients train with an 'home therapy partner' (a family member or friend who can provide support, advice and may additionally be trained to perform the therapy administration).
(i) Extremes of age;
1. Children: C1INH home therapy is recommended for children with frequent or disruptive attacks, where a responsible adult is available and willing to undertake training. Experience with haemophilia suggests that it is beneficial for children to be encouraged to take an active part in their treatment with a view to independent administration in their early teens .
Comment: Prepubertal children typically experience fewer attacks than adolescents and adults. However, some have frequent attacks which disrupt education and family life[36, 37]. Prophylaxis with attenuated androgens is not recommended, and tranexamic acid may be of limited benefit. pdC1INH is effective for treatment of children and home therapy has been used successfully in this age group (W Kreutz; personal communication). Icatibant has not been tested in children under 18 years and is not yet recommended for this age group.
2. Elderly: Advanced age is not a contraindication to home therapy, providing patient and home therapy partner can function safely and effectively.
(ii) Pregnancy and breastfeeding: pdC1INH home therapy appears safe and effective and is recommended for pregnant and lactating women[28, 32, 38].
Comment: Attack frequency increases in the first trimester of pregnancy for approximately 38%  of women. Prophylaxis with attenuated androgens or tranexamic acid is not recommended in pregnancy. Home or self-administration should be considered for control of symptoms for pregnant and lactating women. Women with HAE contemplating pregnancy should consider home self-administration training.
(iii) Lack of home therapy partner: While presence of a trained 'home therapy partner' is highly desirable, lack of a partner does not exclude the possibility of self-administration, if a risk-benefit assessment is favourable
Comment: Those without an infusion partner may include students and patients undertaking travel for work purposes. Patients living alone may experience particular difficulty in travelling to hospital, and therefore may be more likely to present late or to leave severe attacks untreated if unable to self-administer. These groups are likely to gain the greatest benefit from the ability to prevent and control attacks. We recommend that extra care is taken with arrangements for access to medical back-up where an infusion partner is not available. Subcutaneous agents such as icatibant could be considered as an alternatives to pdC1INH for therapy because of ease of administration. However, more experience is needed (see below). Ecallantide is not currently recommended for selfadministration because of the risk of anaphylactoid reactions.
2. Attack Treatment; infusion timing and regimen
Treatment is recommended as soon as the patient identifies symptoms, which, if untreated, are likely to develop into a moderate or severe attack.
Attack treatment with pdC1INH, rhC1INH, icatibant, or ecallantide is likely to be most effective when given early in the course of the attack . Individualised 'on demand treatment' during the initial or prodromal stages of an attack enables patients to achieve almost complete freedom from symptoms . The dose of pdC1INH treatment may be individually adjusted depending on response. For airway events, the dose should be 20 units/kg rounded up to the next highest vial. For treatment of other attacks, the best dosage and timing of administration may differ from that reported in randomised controlled studies which necessarily evaluates fixed regimens in established attacks. Individual requirements may be evaluated by the patient, with guidance from the physician. Many patients have found doses lower than the licensed dose of 20 units/kg pdC1INH effective, with doses of 500-1000 units sufficing for many attacks[22, 37, 39, 40]. A dose-finding trial for home therapy with pdC1INH is needed.
Short term prophylaxis with pdC1INH is recommended for high risk events. In patients with frequent attacks this may include emotionally stressful events such as exams, interviews, busy work periods and major family events, as well as cover for medical and dental procedures.
Long-term pdC1INH prophylaxis may be required, in some cases, to control very frequent attacks.
Comment: pdC1INH is effective in short and long-term prophylaxis. Controversy exists as to the relative advantages of long-term prophylaxis compared with treatment of early symptoms. PdC1INH (Cinryze™) is licensed in the USA for long-term prophylaxis (1000 units twice weekly). Long-term prophylaxis reduces attack frequency and severity, and improves quality of life . However, breakthrough attacks are frequent and the total usage of pdC1INH is often increased[14, 26]. Although control may be improved by adjustment of dose and frequency of treatments, many, but not all, experts prefer early symptomatic treatment.
Icatibant, ecallantide and rhC1INH have short half-lives and are therefore not recommended for prophylaxis at this time[20, 21, 41].
4. Route of administration
Recommendation: Most experts recommend venepuncture with a small (e.g. 28G) butterfly needle infusion set on each occasion that treatment with C1INH is required.
Comment: Self-administration is associated with a low incidence of cannulation failure and may preserve veins more effectively than hospital-based care. Indwelling central line devices may be considered in exceptional cases where venous access in a timely manner would otherwise not be possible. However, the requirement for treatment is lifelong and indwelling devices have a finite life. Complications associated with indwelling venous ports, particularly infection and occlusion, may be serious and are also likely to increase the frequency of attacks. For these reasons, venous ports should be avoided where possible. Icatibant given subcutaneously may be considered where venous access is difficult.
5. Site of attack
Recommendation: Patients should be encouraged to treat any attack at any site interfering with activities of daily living or which is likely to be associated with further disabling attacks.
(i) Laryngeal/upper airway attacks: Attacks affecting head and neck should always be treated even if symptoms are mild because of the potential for rapid progression to laryngeal obstruction. Patients are strongly advised to seek emergency medical assistance for all intraoral attacks and should home-administer treatment while awaiting transfer to hospital.
(ii) Cutaneous attacks: Treatment with pdC1INH, rhC1INH, icatibant or ecallantide is effective. Mild attacks may not require treatment or may respond to oral tranexamic acid. Definitive treatment is recommended for attacks that have potential to interfere with daily activities.
(iii) Abdominal attacks: Treatment is likely to reduce HAE-related disability and socioeconomic disadvantage.
Comment: With the exception of attacks affecting the head and neck, which may progress to laryngeal obstruction symptoms are self limiting after 1-5 days and patients may choose to leave these untreated or to use symptomatic treatment.
Responsibilities of the doctor: We recommend that:
The physician is responsible for carrying out an assessment of the risks and benefits of home-administration. They should ensure that the patient and treatment partner are able to provide fully informed consent, in particular with respect to:
Blood product origin of pdC1INH
Appropriate treatment of attacks
Management of HAE-related emergencies
Management of treatment-associated side effects
The physician should ensure that a treatment plan for 24 hour local emergency assistance and specialist advice are available and that the patient and local hospital have written information.
The patient should be issued with appropriate emergency treatment (at least one treatment dose pdC1INH), as this is unlikely to be immediately available in every medical facility.
The physician is responsible for ensuring that the patient and partner are competent with the medical and technical aspects of home administration. On-line resources provide helpful support [for example: http://www.haecanada.com]. These should not be a substitute for direct access to advice from the specialist centre.
In practice, training may be delegated to a trained specialist nurse.
Responsibilities of the patient/treatment partner: We recommend that:
The patient, with the support of the administration partner, should be prepared to take responsibility for the decision to treat, the technical aspects of safe use of pdC1INH or other acute treatment and the safe disposal of used equipment. Patients should keep an accurate note of treatments and dates, including the lot numbers of products used.
Patients should undertake to attend regular follow up and refresher training, and to seek prompt assistance from their emergency medical facility or from their physician or specialist nurse in the event of any query or difficulty.
Patients should be aware of, and should accept, the partial transfer from the physician of responsibility for their medical care, and the wider responsibility to the HAE community of ensuring that home administration is practised safely and effectively.
The patient should retain the option of returning to hospital/clinic-based acute care at any time, or of leaving the home-administration programme.
Written consent is advised.
7. Training programme
Recommendation: The training programme, which may be led by an appropriately trained and experienced specialist nurse or physician, should be conducted over several sessions to ensure that patient and treatment partner have had sufficient practice to be familiar and confident with technical and medical aspects of self-administration.
The patient should have received the proposed home treatment for an attack on at least one occasion prior to home therapy. Ideally, the patient/partner should treat an attack under medical supervision, prior to home therapy. However, in practice this may not always be possible.
When training is complete, there should be an assessment to ensure that the patient and partner's knowledge and technical ability are sufficient.
Refresher training should be planned at regular intervals, usually at least every 12 months.
Training should include:
Appropriate use of treatment product(s) (pdC1INH, rhC1INH, icatibant)Management of emergencies, including when to seek professional help.
Supply & storage of treatment products Handwashing and aseptic technique Preparation of equipment Product checking (dose/expiry date) Reconstitution of products if needed Intravenous access Administration of medication, including infusion rate Disposal of equipment Record keeping (batch number, attack record)
8. Other HAE-like syndromes
(i) Acquired C1 inhibitor deficiency
Patients with acquired C1INH deficiency may also benefit from home therapy. In some, but not all cases, higher doses of C1INH may be required[26, 42]. Icatibant is likely to be an attractive option in this case .
(ii) HAE type 3
HAE type 3, although similar to other hereditary angioedemas, is not associated with C1INH deficiency [44–46]. This document does not consider HAE3, although if effective acute treatments are identified, the same principles will apply.
9. Emerging therapies
PdC1INH has the widest availability and licensure. Icatibant and ecallantide have variable licensure and rhC1INH is applying for licensure. Availability of products will vary by jurisdiction.
Recommendation: Icatibant, where available, may be considered as an alternative to C1INH for home therapy.
Comment: Icatibant has the advantage of subcutaneous administration and, unlike C1INH, is supplied in a prefilled syringe. Approximately 10% will need a second dose of icatibant, and patients should hold a backup dose.
By reducing the need for technical expertise, icatibant has the potential to revolutionise the management of HAE. However, it is not yet licensed for self-administration and experience is very limited. There is no experience of icatibant in children nor pregnant or lactating women and for this reason, icatibant cannot currently be recommended for these groups. Further information from currently ongoing self-administration trial and registry data will be vital in strengthening this recommendation.
Ecallantide: As with icatibant, ecallantide is administered by the subcutaneous route. Anaphylactic reactions have been reported and for this reason, the FDA has mandated a registration program that requires an informed consent that treatment with ecallantide only be performed in the office of a physician experienced and equipped to treat anaphylaxis. In light of this self-treatment at home is not yet possible for ecallantide. At the present time, due to lack of data, ecallantide is not recommended in pregnant, nor lactating women, or children under the age of 16 years.
Recombinant C1 inhibitor: Rhucin, a recombinant C1INH, is currently in development. It is likely to be an alternative to pdC1INH for the treatment of acute attacks. It has a shorter half-life than pdC1INH, therefore its role in prophylaxis is uncertain.