Longhurst et al. Allergy, Asthma & Clinical Immunology 2010, 6:22
`http://wwaacijournal.com/content/G/I /22
`
`ALLERGY, ASTHMA & CLINICAL
`IMMUNOLOGY
`
`AACI
`
`REVIEW
`
`Open Access
`
`HAE international home therapy consensus
`document
`
`Hilary J Longhurst", Henriette Farkasz, Timothy Craig3, Emel Aygoren PUrsiin‘, Claire Bethune5, Janne Bjorkanderé,
`Konrad Bork7, Laurence Bouillets, Henrik Boyseng, Anette Bygumw, Teresa Caballero“, Marco Cicardi‘z,
`John Dempster'3, Mark Gompels”, Jimmy Gooi‘s, Sofia Grigoriadouw, Ursula Huffer”, Wolfhart Kreuz‘s,
`Marcel M Levi‘9, Janet Long”, Inmaculada Martinez Saguerz‘, Michel Raguetzz, Avner Reshef23, Tom Bowen”,
`Bruce Zuraw”
`
`Abstract
`
`inhibitor deficiency, HAE) is associated with intermittent swellings which are disabling
`Hereditary angioedema (Cl
`and may be fatal. Efi‘ective treatments are available and these are most useful when given early in the course of
`the swelling. The requirement to attend a medical facility for parenteral treatment results in delays. Home therapy
`ofl‘ers the possibility of earlier treatment and better symptom control, enabling patients to live more healthy, pro
`ductive lives. This paper examines the evidence for patient controlled home treatment of acute attacks ('self or
`assisted administration') and suggests a framework for patients and physicians interested in participating in home
`or self administration programmes. It represents the opinion of the authors who have a wide range of expert
`experience in the management of HAE.
`
`reproduction in any merflum. provided the original work is properly cited
`
`vomiting or diarrhoea[3,6]. Patients are typically unable
`to undertake their daily activities of living for one or
`more days, and may be less productive for a few days
`subsequent to attack because of residual angioedema
`and fatigue. Peripheral swellings may prevent wearing of
`shoes, operation of machinery or may cause disfigure—
`ment, thus interfering with work or other activities [7].
`Laryngeal swellings comprise a small minority (around
`2%) of attacks but may cause death from airway
`obstruction[2]. Although for most patients laryngeal
`attacks are infrequent and the case fatality of each attack
`is low, there is a significant lifetime mortality[3,8]. Fear
`of laryngeal attacks and the need for access to lifesaving,
`specialist emergency treatment confers considerable
`restrictions on patients and their families. In particular,
`travel for work or pleasure is often curtailed. Attacks
`are more likely to occur at times of emotional stress,
`and therefore are more likely to occur during examina-
`tions or busy periods at work. Thus, those affected by
`HAE and their families are subject to employment and
`educational disadvantage [9- 1 1] .
`
`Introduction
`
`Hereditary angioedema (HAE) is an autosomal domi-
`nant condition caused by a partial deficiency of C1 inhi—
`bitor (CIINH). CIINH controls a variety of local
`inflammatory pathways. Insufficient regulation of the
`classical complement pathway causes consumption of
`the complement component C4, resulting in typical
`diagnostic abnormalities. Insufficient inhibition of kallik—
`rein results in overproduction of bradykinin, and episo-
`dic swelling from excess local bradykinin[1]. Swellings
`are typically of slow onset over several hours and last
`1—5 days, although some patients may also experience
`rapid onset swellings[2]. Almost any part of the body
`may be affected, although the subcutaneous and submu-
`cosal structures of limbs, genitals, face, mouth and
`bowel are the usual sites of swelling. Swellings are
`referred to as acute attacks and are interspersed by
`asymptomatic periods of days, weeks or months[3-5].
`Attacks are associated with reversible disability.
`Abdominal attacks are associated with the extreme pain
`of bowel obstruction or visceral swelling, and with
`
`" Correspondence hIlaryJonghurst@bartsandthelondon.nhs.uk
`'Department of Immunology, Barts and the London NHS Trust. London, UK
`Full list of author lnfonnatlon ls available at the end of the artlde
`
`C Biollllecl Central
`
`O 2010 Longhurst et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
`Commons Attribution License (http://creativecommomorgfllcemes/by/ZO), which permits unrestricted use. distribution and
`
`CSL EXHIBIT 1046
`CSL v. Shire
`
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`Treatment options
`The frequency and severity of attacks is reduced by oral
`prophylaxis with attenuated androgens or tranexamic
`acid, or by regular intravenous infusion of C1INH con-
`centrate[12-14]. However, prophylaxis does not comple-
`tely abolish attacks[14]. Moreover, many patients cannot
`benefit from oral prophylaxis because of contraindica-
`tions, side effects, or lack of efficacy[13,15,16]. Immedi-
`ate access to effective acute treatment is therefore
`required for all patients.
`Replacement therapy with plasma-derived C1INH
`(pdC1INH) is effective and has been used successfully
`for over 25 years to attenuate or prevent attacks at all
`sites [17-19]. More recently, icatibant, a bradykinin
`receptor inhibitor, and ecallantide, a kallikrein inhibitor,
`have been shown to be effective at treating attacks
`[20,21]. Icatibant was licensed for acute angioedema
`attacks in patients with C1-inhibitor deficiency in the
`European Union and several other countries in 2008.
`Ecallantide was licensed for acute attacks in the USA in
`2009. After treatment with either icatibant, ecallantide
`or C1INH, onset of relief can be expected within 30 to
`60 minutes, with full resolution taking a few hours to
`longer than 24 hours in established attacks[14,17,20-23].
`Observational studies demonstrate faster relief and
`reduced attack severity when C1INH is given early
`[6,24]. Similarly, icatibant or ecallantide may be more
`effective when given early, although this is yet to be
`demonstrated in clinical studies.
`The requirement to travel to a medical facility for
`acute treatment implies at least half a day away from
`home, school, or work. In the emergency room setting,
`patients with HAE attacks may not be prioritised over
`competing emergencies such as patients with heart
`attacks, stroke or severe injury. This leads to further
`delay, with increased risk of treatment failure and longer
`recovery times. Health care staff, unfamiliar with HAE,
`are reluctant to treat early, when signs are mild or
`absent, contributing further to the delay and disability.
`Owing to the reversibility of most attacks, patients
`themselves may choose to stay at home with sympto-
`matic treatment rather than struggle with access to ther-
`apy in the emergency room. This increases absenteeism
`from work, school, or home responsibilities. For laryn-
`geal attacks, such delay may be fatal. Even where acute
`treatment is available, it is estimated that only 5-25% of
`attacks receive definitive treatment (Cicardi, personal
`communication). Home infusion programmes have been
`established in centres with an interest in HAE, and have
`the potential to overcome many of the difficulties asso-
`ciated with health care facility-based treatment[25-28].
`Experience shows that access to self or assisted infu-
`sion with C1INH reduces severity and duration of
`
`attacks, improves HAE-related quality of life, reduces
`time off work, education or domestic duties, is safe, and
`is very popular with participants[23-30]. Self infusion is
`endorsed by the UK, Danish and Canadian-Hungarian
`consensuses[25,31-34]. Neither UK nor the Canadian
`Consensus documents place restrictions on entry to the
`programme, other than to note that the diagnosis of
`HAE should be proven, prophylactic therapy optimised
`(UK document) and that an ‘infusion partner’ (UK) or
`‘instruction and support’ (Canadian- Hungarian) should
`be available[27,31-34]. The Danish home therapy pro-
`gramme considers patients who have more than one
`moderate or severe attack every 4 weeks, although in
`practice, these restrictions are relaxed where necessary
`[25,27].
`The C1 inhibitor deficiency workshop was first held in
`1999 in Vizegrád, Hungary and has been a biennial
`Hungarian event since then. It brings together patients,
`physicians, nurses, basic and clinical scientists, blood
`product suppliers and representatives of the pharmaceu-
`tical industry with a common interest in HAE and its
`management. Similarly,
`the Canadian Hereditary
`Angioedema Network (CHAEN)/Réseau d’angioedème
`héréditaire du Canada (RAHC) has organised confer-
`ences in 2003, 2006 and 2010, with the aim of develop-
`ing and updating consensus recommendations for HAE
`management http://www.haecanada.com. These work-
`shops are attended by experts from all over the world
`and represent an unprecedented opportunity to pool
`experience and to share information, with the aim of
`improving the physical, psychological and economic
`wellbeing of those affected by HAE. This article sum-
`marises consensus opinion, resulting from debates at the
`Hungarian C1 Inhibitor 2009 Workshop and the Cana-
`dian Hereditary Angioedema Network (CHAEN)/Réseau
`d’angioedème héréditaire du Canada (RAHC) consensus
`meeting held in Toronto in May 2010 (Appendix 1).
`Home therapy/self-administration in this article,
`refers to treatment given in a non-health care set-
`ting; given by the patient, a trained relative or friend,
`outside of a healthcare facility.
`
`Methods
`Participants at the 6th C1 Inhibitor Deficiency Work-
`shop, held in Budapest in May 2009, were invited to a
`moderated discussion with the aim of forming a consen-
`sus approach to home therapy for patients with HAE.
`Published literature was found using a PubMed search,
`with the terms “C1 inhibitor” or “hereditary angioe-
`dema” and “home therapy” or “self-infusion”. Additional
`data were found from references in the papers found in
`the search and from abstracts known to the authors, not
`listed in PubMed. These data were summarised by HL
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`and presented as a basis for further discussion. The dis-
`cussion was chaired by a physician/immunologist (HL)
`and moderated by a representative of the US patients’
`association (JL), adult and paediatric physicians, and
`physician scientists (TC, WK, BZ). The consensus docu-
`ment summarising discussions was drafted by HL and
`the facilitators (TC, WK, BZ). This draft was used as a
`basis for debate and modification at the Canadian
`Toronto May 2010 Consensus Meeting. To date, most
`self-administration treatment has been limited to
`plasma-derived C1INH (pdC1INH) replacement but is
`expected to involve other agents as they become avail-
`able (icatibant, recombinant C1INH, other therapies as
`they become licensed and available).
`
`Recommendations
`1. Inclusions/exclusions
`Recommendation: Every patient with HAE should be
`considered for home therapy and self-administration
`training, once the diagnosis of C1INH deficiency (her-
`editary 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 pro-
`phylaxis in most patients. Requirement to attend a
`medical facility inevitably results in delayed treatment,
`and many attacks are not treated at all. This contri-
`butes to the social and economic disadvantage asso-
`ciated with HAE. For this reason, eligibility for home
`therapy should be inclusive. It is strongly recom-
`mended that patients train with an ‘home therapy part-
`ner’ (a family member or friend who can provide
`support, advice and may additionally be trained to per-
`form the therapy administration).
`Special situations
`(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 indepen-
`dent administration in their early teens [35].
`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[13]. 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 part-
`ner 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 tri-
`mester of pregnancy for approximately 38% [36] of
`women. Prophylaxis with attenuated androgens or tra-
`nexamic 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 there-
`fore 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 recom-
`mend 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 iden-
`tifies symptoms, which,
`if untreated, are likely to
`develop into a moderate or severe attack.
`Comment:
`Attack treatment with pdC1INH, rhC1INH, icatibant,
`or ecallantide is likely to be most effective when given
`early in the course of the attack [22]. Individualised ‘on
`demand treatment’ during the initial or prodromal
`stages of an attack enables patients to achieve almost
`complete freedom from symptoms [24]. 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[18]. For treatment of other attacks, the best dosage
`and timing of administration may differ from that
`reported in randomised controlled studies which neces-
`sarily evaluates fixed regimens in established attacks[18].
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`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 suffi-
`cing for many attacks[22,37,39,40]. A dose-finding trial
`for home therapy with pdC1INH is needed.
`
`3. Prophylaxis
`Short term prophylaxis with pdC1INH is recom-
`mended 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 [14]. However, breakthrough attacks are frequent
`and the total usage of pdC1INH is often increased
`[14,26]. Although control may be improved by adjust-
`ment 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 prophy-
`laxis at this time[20,21,41].
`
`4. Route of administration
`Recommendation: Most experts recommend venepunc-
`ture 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[26]. 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 ser-
`ious 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 symp-
`toms are mild because of the potential for rapid pro-
`gression to laryngeal obstruction[2]. 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[13]. Definitive treatment is recom-
`mended 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[2] symptoms are self limiting after 1-5 days
`and patients may choose to leave these untreated or to
`use symptomatic treatment.
`
`6. Counselling/consent
`Responsibilities of the doctor: We recommend that:
`(i) The physician is responsible for carrying out an
`assessment of the risks and benefits of home-administra-
`tion. They should ensure that the patient and treatment
`partner are able to provide fully informed consent, in
`particular with respect to:
`
`1. Blood product origin of pdC1INH
`2. Appropriate treatment of attacks
`3. Management of HAE-related emergencies
`4. Management of treatment-associated side effects
`
`(ii) 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 hospi-
`tal have written information.
`(iii) 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.
`(iv) 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 spe-
`cialist nurse.
`Responsibilities of the patient/treatment partner:
`We recommend that:
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`(i) 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.
`(ii) Patients should undertake to attend regular follow
`up and refresher training, and to seek prompt assistance
`from their emergency medical facility or from their phy-
`sician or specialist nurse in the event of any query or
`difficulty.
`(iii) 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 administra-
`tion is practised safely and effectively.
`The patient should retain the option of returning to
`hospital/clinic-based acute care at any time, or of leav-
`ing 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 spe-
`cialist nurse or physician, should be conducted over sev-
`eral 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 assess-
`ment to ensure that the patient and partner’s knowledge
`and technical ability are sufficient.
`Refresher training should be planned at regular inter-
`vals, usually at least every 12 months.
`Training should include:
`Appropriate use of treatment product(s) (pdC1INH,
`rhC1INH, icatibant)Management of emergencies, includ-
`ing when to seek professional help.
`Supply & storage of treatment productsHandwashing
`and aseptic techniquePreparation of equipmentProduct
`checking (dose/expiry date)Reconstitution of products if
`neededIntravenous accessAdministration of medication,
`including infusion rateDisposal of equipmentRecord
`keeping (batch number, attack record)
`
`doses of C1INH may be required[26,42]. Icatibant is
`likely to be an attractive option in this case [43].
`(ii) HAE type 3
`HAE type 3, although similar to other hereditary angioe-
`demas, is not associated with C1INH deficiency [44-46].
`This document does not consider HAE3, although if
`effective acute treatments are identified, the same prin-
`ciples will apply.
`
`9. Emerging therapies
`PdC1INH has the widest availability and licensure. Icati-
`bant and ecallantide have variable licensure and
`rhC1INH is applying for licensure. Availability of pro-
`ducts will vary by jurisdiction.
`Icatibant
`Recommendation: Icatibant, where available, may be
`considered as an alternative to C1INH for home
`therapy.
`Comment: Icatibant has the advantage of subcuta-
`neous administration and, unlike C1INH, is supplied in
`a prefilled syringe. Approximately 10% will need a sec-
`ond dose of icatibant[20], 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-administra-
`tion and experience is very limited. There is no experi-
`ence 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 adminis-
`tered by the subcutaneous route. Anaphylactic reactions
`have been reported[47] 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, there-
`fore its role in prophylaxis is uncertain[41].
`
`8. Other HAE-like syndromes
`(i) Acquired C1 inhibitor deficiency
`Patients with acquired C1INH deficiency may also bene-
`fit from home therapy. In some, but not all cases, higher
`
`Conclusion
`Every patient with HAE should have the immediate
`means to control an acute attack quickly and effectively,
`in order to minimise impact on physical, social and
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`
`economic wellbeing to themselves and their family.
`Similar to the haemophilia home care model that has
`worked so well for many years[35], the option of home
`and self-administration offers the prospect of achieving
`the aim of ‘each C1 inhibitor deficient (HAE) patient to
`be able to manage his/her symptoms proactively in such
`a way that they maintain personal safety and minimal
`disruption in living a healthy and productive life’[32].
`
`Appendix 1. Recommendations: summary
`Inclusions
`Home therapy training should be inclusive.
`Extremes of age or lack of infusion partner are not
`necessarily contraindications. Patients with HAE, with
`acquired angioedema (acquired C1 inhibitor deficiency),
`and, where treatment is available, HAE3, should be
`included.
`Prophylaxis, if required, should be optimised while
`home therapy training is ongoing.
`
`Attack Treatment
`Attacks should be treated as early as possible.
`Dose of C1 inhibitor should be individualised.
`Prophylactic pdC1 inhibitor regimens may occasion-
`ally be necessary.
`
`Site of attack
`Attacks at all sites may be self-treated at home. In the
`case of laryngeal oedema, urgent transfer to hospital is
`recommended after treatment.
`
`Counselling/consent
`Physician and patient should take joint and individual
`responsibility for the safe and appropriate use of home
`therapy.
`
`Training programme
`Should take part in a centre experienced in HAE
`management.
`Should offer ongoing support and refresher training.
`
`Emerging therapies
`pd C1 inhibitor home therapy programmes are well
`established.
`rC1 inhibitor is likely to offer an alternative for acute
`treatment when licensed.
`Icatibant offers great potential for expanding access to
`treatment because of its ease of administration.
`Ecallantide is not recommended for home therapy
`
`Author details
`1Department of Immunology, Barts and the London NHS Trust, London, UK.
`23rd Department of Internal Medicine, Faculty of Medicine, Semmelweis
`University, Budapest, Hungary. 3Departments of Medicine and Pediatrics,
`
`Penn State University, Hershey, Pennsylvania, USA. 4Johann Wolfgang
`Goethe University, Frankfurt/Main, Germany. 5Department of Immunology,
`Plymouth Hospitals NHS Trust, UK. 6Dept of Internal Medicin, Ryhov County
`Hospital, SE 55185 Jönköping, Sweden. 7Department of Dermatology,
`University Hospital of the Johannes Gutenberg University of Mainz, Mainz,
`Germany. 8Department of Medicine, CHU de Grenoble, Grenoble, France.
`9Executive Director, HAE International, Denmark. 10Department of
`Dermatology and Allergy Centre, Odense University Hospital, Denmark.
`11Hospital La Paz Health Research Institute, Madrid, Spain. 12Department of
`Internal Medicine, Universita degli Studi di Milano, Ospedale L. Sacco, Milan,
`Italy. 13Department of Immunology, Barts and the London NHS Trust,
`London, UK. 14Department of Immunology, Southmead Hospital, Bristol, UK.
`15Department of Immunology, St James’ Hospital, Leeds, UK. 16Department
`of Immunology, Barts and the London NHS Trust, London, UK. 17HAE
`association, Germany. 18Johann Wolfgang Goethe University, Frankfurt/Main,
`Germany. 19Academic Medical Center, University of Amsterdam, Amsterdam,
`Netherlands. 20US HAEA Executive Vice President; US HAEA Patient Registry,
`USA. 21Johann Wolfgang Goethe University, Frankfurt/Main, Germany. 22HAE
`Association, France. 23Tel Hashomer, and Sackler Faculty of Medicine, Tel
`Aviv University, Ramat Aviv, Israel. 24Departments of Medicine and
`Paediatrics, University of Calgary, Calgary, Alberta, Canada. 25University of
`California, San Diego, San Diego, California, USA.
`
`Authors’ contributions
`HL chaired home therapy debates and facilitated consensus at the Budapest
`workshop and Toronto CHAEN meetings. TC, JL, WK, BZ acted as faciliators/
`expert panel at the debate at the Budapest workshop. HL prepared the
`manuscript. All authors have read, revised and approved the manuscript and
`have participated in one or more of the debates, or in the subsequent
`discussions.
`
`Competing interests
`Many of the authors have either entered consultancy with or have been
`involved in educational programs and their organization, had direct funding
`from, have been speakers for, or have had consultation agreements with
`CSL Behring, Dyax, Jerini, Pharming, ViroPharma, Shire. The HAE International
`Home Therapy Consensus Document was arrived at following debate during
`the Hungarian C1 Inhibitor 2009 Workshop, held in Budapest May 22/24,
`2009 and the Canadian Hereditary Angioedema Network (CHAEN)/Réseau
`Canadien d’angioédème héréditaire (RCAH) second meeting held May 15th/
`16th, 2010, Toronto, Canada. CHAEN was cosponsored by CHAEN/RCAH, the
`Canadian Society of Allergy and Clinical Immunology, and the University of
`Calgary and was funded through an unrestricted educational grant from CSL
`Behring. Publication of this manuscript is sponsored by University of Calgary.
`
`Received: 29 May 2010 Accepted: 28 July 2010 Published: 28 July 2010
`
`2.
`
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