c1 esterase inhibitor deficiency ( c1 inhibitor deficiency ) is a rare disorder that may be genetic ( hereditary angioedema , hae ) 1 or less commonly acquired ( acquired angioedema , aae ) 2 . the disease has an estimated prevalence of 1 : 50  000 ; any ethnic group may be affected , and many cases are undiagnosed 35 . c1 inhibitor deficiency manifests with episodic attacks of bradykinin - mediated localized subcutaneous and/or submucosal swellings , with a predilection for the face , extremities , gut , genitals , oropharynx and upper respiratory tract 6 . abdominal attacks are extremely painful and disruptive , while laryngeal swelling is life - threatening and accounts for the very significant lifetime mortality reported from historical data 68 . the evidence base for disease management has expanded significantly since the first uk consensus document was published in 2005 9 . for acute therapy , extensive data are now available for two new drugs that target the bradykinin pathway 1017 , for two established plasma - derived c1 inhibitor replacement products 1820 and for a novel recombinant c1 inhibitor concentrate product 2123 . further evidence supports the use of home therapy for acute attacks , an approach with clear benefits for patients and the wider health economy 2428 . the effectiveness of regular c1 inhibitor concentrate injections for long - term prophylaxis is now established more firmly , presenting an alternative to attenuated androgens for selected patients 19,29 . in parallel with these advances in medical management , focused research efforts have revolutionized our understanding of the impact of c1 inhibitor deficiency on the physical , emotional and economic health of patients and their families 5,3034 , thus informing the application of this improved evidence base . a number of documents have translated these data into evidence - based guidelines 24,3541 , but none fully reflect the priorities and organization of services for c1 inhibitor - deficient patients in the united kingdom . with these considerations in mind , the united kingdom primary immunodeficiency network ( uk pin  a cross - disciplinary professional association ) and the patient group hereditary angioedema uk ( hae uk ) jointly commissioned this project to update the 2005 uk consensus document . the uk national health service ( nhs ) is dealing with unprecedented financial pressure , and while successive governments have continued to pledge commitment to a health - care system that is free at the point of demand , traditional hospital - based models of health care are unlikely to be affordable for the united kingdom in the long term . recent government initiatives have focused on community and patient - centred  integrated ' care , both as a means to ensure long - term affordability and to improve social and medical outcomes 42 . there has also been increased awareness of more rare diseases , with the needs of affected patients recognized in uk initiatives 43 . finally , there is a perception that the provision of specialist services for c1 inhibitor - deficient patients varies geographically 44 , with possible underlying factors including the availability of funding for high - cost drugs and the location of major centres of expertise . in england , these considerations have contributed to radical reform of specialist services for patients with c1 inhibitor deficiency and other rare diseases : centralized funding has been devolved to nhs england , with the commissioning specification encouraging expert patient - centred care , coordinated by specialist centres that fulfil predefined standards 45 . the organization of services in other uk nations differs : in wales , all patients access services at the immunodeficiency centre in cardiff , with centrally commissioned resources transferred from health boards ; in scotland , patients access local services or travel across unitary health board areas where this is not possible , with high - cost medicines accessed through a pharmacy board structure overseen by the scottish medicines committee ; in northern ireland , services are centralized to the regional immunology service in belfast , with a local process for the approval of high - cost drugs . it was not felt appropriate to replicate the excellent work that has produced a plethora of recent evidence - based guidelines in the field of c1 inhibitor deficiency 24,3541 . instead , we sought to produce a uk - specific document that is complementary to existing guidelines . to achieve this aim , the guidelines have been produced using the delphi method , a structured process that aims to produce consensus among a group of experts . this document , together with standards for specialist services issued by uk pin 46 , provides a framework for the management of c1 inhibitor - deficient patients in the united kingdom . the research design for the consensus was based on the delphi method : respondents are presented with a series of statements , each of which is scored for agreement using a four - point likert scale , as follows : strongly agree , tend to agree , tend to disagree , strongly disagree . following the first round of responses , any statements considered contentious ( typically less than 66% of respondents agree ) may be reviewed , with the final list of statements representing the consensus . the questionnaire was developed by the hae consensus steering group , which included a patient representative , eight physicians with a specialist interest in the disease and three specialist nurses . throughout a day of discussion on 26 september 2012 , the steering group agreed a total of 48 consensus statements across 11 themes . when developing these statements , the steering group considered developments in the evidence base , published guidelines for specialist services 45,46 and personal experiences . the statements were incorporated into a consensus questionnaire , with a slightly modified plain - language version generated for patient use . questionnaires were sent to all uk - based physicians and specialist nurses known to be involved in the management of c1 inhibitor - deficient patients , and additionally to the membership of key professional organizations ( table1 ) . patients were invited to express their opinion by hae uk . two subsequent opportunities to complete the questionnaire were provided by electronic mail , and additional paper copies were distributed at professional and academic meetings . the process was facilitated by triducive ltd , who collated the anonymized data for consideration by the panel . a second meeting was held on 18 november 2013 to discuss the findings and approve the consensus statements . ninety - one health - care workers ( 51 consultant immunologists and/or allergists , 10 specialist registrars training in clinical immunology or allergy , 14 immunology specialist nurses , 16 other or unknown designations ) responded , representing the majority of health - care professionals who care actively for this patient group . a high degree of consensus was obtained during the first round , with more than 90% of respondents indicating  strongly agree ' or  tend to agree ' to all the statements and few abstentions ( supporting information , table s1 ) . as all statements achieved consensus in excess of 90% , no iterative amendment was required . consensus was highest among patient respondents , with more than 97% agreement to all statements . among health - care workers , agreement of > 90% was achieved in response to 47 of 48 questions ; statement 20  concerning use of anti - fibrinolytics in prophylaxis  achieved 88.8% agreement . in general , most statements elicited  strong agreement ' , with  tend to disagree ' and  strongly disagree ' rarely observed . consensus remained extremely high when analysed by occupation or speciality , although small numbers limit the interpretation of subgroup analysis . alignment of these statements to accreditation standards for specialist centres published by uk pin is described in supporting information , table s2 . hae  =  hereditary angioedema ; qol  =  quality of life a facility for freetext comments was utilized by a minority of respondents to comment on the statements and study process : one respondent criticized the document for being too  centralist ' and another suggested that the definition of  specialist centre ' should be kept flexible enough to allow for different models of care . some questions ( for example , concerning children or new medications ) were indicated as inappropriate for those without specific expertise . we note that some respondents did not comment on all statements , presumably denoting lack of expertise or opinion with regard to a particular statement ( see supporting information , table s1 ) . we present here an updated uk consensus for the management of patients with c1 inhibitor deficiency . the consensus was developed using the delphi method , an established process for the collation of opinion from a group of experts . according to this process , respondents indicate agreement with statements in rounds ; after each round , facilitators collate and anonymize the responses to guide amendment of the statements for future rounds . the process is completed when predefined levels of consensus are reached . this method was pursued in order to produce guidelines that are complementary to recent publications 24,3541 and with an emphasis on uk services . a particularly important development is an improved evidence base to guide the management of acute attacks . the dosing of c1 inhibitor concentrate ( statement 17 ) was particularly emphasized , given the availability of guidance from robust trial data 1821 . however , clinical experience suggests that individualized dosing is appropriate , including higher doses where treatment is delayed and lower doses when treatment is immediately available ( statement 18 ) . in keeping with other recent guidelines 24,3541 , the document supports the wider use of acute treatment for disabling attacks ( statement 3 ) rather than limiting treatment to severe episodes . statement 2 ( treatment of hae should follow international guidance and standards , while considering the resources available in the united kingdom ) and statement 12 ( patients should take medication according to clinical need rather than financial considerations ) could perhaps be considered to conflict . we would emphasize , however , that as currently worded , the consensus for statements 2 and 3 does not mandate treatment for all attacks  rather , less serious attacks are considered to be potentially treatable . consideration of treatment costs will form part of the decision process when weighing up whether or not symptoms are sufficiently disabling to warrant therapy within the parameters of statement 12 . regarding long - term prophylaxis , the value of closely monitored androgens with appropriate monitoring is endorsed ( statements 2125 ) . a greater emphasis is placed on long - term prophylaxis with c1 inhibitor concentrate ( statement 27 ) , reflecting an improved evidence base 19,29 and increased experience among clinicians and patients . long - term prophylaxis with tranexamic acid continues to be supported in the paediatric setting where options are limited ( statement 46 ) . a more guarded statement was supported ( with 88.9% consensus among health - care workers ) for the general use of this agent for long - term prophylaxis ( statement 20 ) ; this was the only statement to achieve consensus below 90% , reflecting a weak evidence base and mixed practice . saule and colleagues published an observational series including 16 women with hereditary angioedema , describing modest benefit from progestagens in long - term prophylaxis 47 . the authors recommended either desogestrel 75 mg daily ( cerazette ) , medroxyprogesterone acetate ( depo - provera ) or norethisterone 10 mg daily . a statement about the role of progestagens as long - term prophylaxis was not included in this document because the relevant paper was not published at the time of the steering group meeting . the results also indicate strong consensus on aspects of service organization and delivery , showing overwhelming support for specialist services ( statements 59 ) , and patient self - management and home therapy ( statement 4 ) . we welcome the principle of patient - centred , community - based care , supported by easily accessible specialist expertise and , where appropriate , local centres . the haemophilia model of self - administration of intravenous medications by patients and their families demonstrates that this model is feasible and cost - effective . the net financial effects of such an approach as applied to c1 inhibitor deficiency in the united kingdom have not been defined , but data from denmark demonstrate the benefits of the approach in reducing hospital attendance and the burden of disease 48 . the results of the consensus indicate clearly that both patients and health - care workers endorse this model for c1 inhibitor deficiency , in order to ensure that patients can achieve their full potential by early education and training in the prevention and management of acute attacks the consensus involves scientific evidence , but does not involve rigorous review of scientific evidence in order to produce guidance . it does not seek to replicate or replace their work , but rather adds another form of expert opinion evidence to the literature . compared to the generation of evidence - based guidelines by small panels of experts , the delphi method is more inclusive and gathers opinion from a larger number of professionals . the anonymity of respondents may temper domination of the process by opinion leaders and encourages free expression . however , the issue is not completely resolved , as the question set is determined by a steering group . another key difficulty is selection of the panel members : a very inclusive process may produce an invalid consensus by including responses from respondents who lack expertise in the field , whereas an overly exclusive process may not reflect a true consensus . we attempted to engage with a wide variety of stakeholders outside the clinical immunology and allergy community by collaborating with relevant professional bodies , distributing paper copies at professional meetings and permitting peer - to - peer distribution of questionnaires . a significant number of responses was obtained from outside the immunology and allergy community which , in addition to 51 responses from clinical immunologists and/or allergists , is felt to capture the large majority of health - care workers involved directly in the management of this disease . as these respondents work independently in specialist centres throughout the united kingdom , we can be confident that the remarkably high consensus does not reflect training or service led by small number of opinion leaders . however , it must be acknowledged that the uk allergy and immunology community constitutes a small group with a long - standing tradition of cooperation through organizations such as uk pin . in addition , the methodology does not permit the calculation of a defined response rate . compared to the health - care worker data set , results from patient respondents are less robust due to relatively small numbers ( n  =  36 ) and the risk of ascertainment bias . the assumption that all participants are equal in terms of knowledge and experience represents another weakness of the methodology . this probably accounts for a relatively high number of abstentions among respondents for several more technical statements , notably 24 , 25 , 45 and 46 . finally , where successive rounds are utilized , the risk is that the process may mould , rather than simply collate , opinion ; this was not a concern in this project , as consensus was reached within a single round . despite the shortcomings , the very high level of consensus among health - care workers and a small sample of patients indicate strong alignment of opinion . this project has not addressed explicitly hereditary bradykinin - mediated angioedema that is not related to c1 inhibitor deficiency 49 , but many of the statements would be applicable to this group , whose specific needs are also addressed in a separate consensus document 50 . although the document is uk - centric , the themes of quality improvement , patient - centred care and increasing health - care costs are a focus and challenge for most higher - income nations at the current time . while responses are confidential and not individually available to the steering committee , those responding have been invited to support this paper publically . sixty - four of 91 health - care professionals indicated their publicly declared support and are listed ( table3 ) as the uk 2014 c1 inhibitor deficiency consensus group . the manuscript was written by h. j. l. and m. d. t. and critiqued by all authors . she has received funding to attend conferences and other educational events , acted as medical adviser or speaker , has received donations to her departmental funds and has received financial and other assistance with patient care projects from the following companies : biocryst , csl behring , sobi biovitrum , shire , dyax and viropharma . m. d. t. has received travel grants from shire and viropharma , has provided remunerated in - house training to staff at csl - behring and has attended advisory boards hosted by shire , viropharma and swedish orphan biovitrum . he has provided remunerated in - house training to staff at csl - behring and has attended advisory boards hosted by shire , viropharma and csl - behring . f. a. has received travel grants from shire and attended advisory panels hosted by shire and csl - behring . c. b. has received travel grants to attend scientific meetings and attended advisory boards hosted by shire , viropharma and csl - behring . c. s. has received travel grants from shire , csl behring , and viropharma . she has attended advisory boards for shire and viropharma and contributed to the construction of csl - behring hae website . david edgar has received travel grants from shire and csl behring and attended an advisory board for csl - behring . m. g. has been a member of advisory panels for shire , csl - behring and viropharma . s. s. has received travel grants to attend scientific meetings and attended advisory boards hosted by shire , sobi biovitrum and viropharma . s. j. reports consulting , speaker , travel , advisory board and research support from csl behring , baxter , bpl , biotest , sobi , shire , viropharma and octapharma . additional supporting information may be found in the online version of this article at the publisher 's web - site : table s1 . alignment of uk c1 inhibitor consensus statements with uk primary immunodeficiency network ( ukpin ) accreditation standards .
c1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life - threatening angioedema . here 
 we present an updated 2014 united kingdom consensus document for the management of c1 inhibitor - deficient patients , representing a joint venture between the united kingdom primary immunodeficiency network and hereditary angioedema uk . to develop the consensus 
 , we assembled a multi - disciplinary steering group of clinicians , nurses and a patient representative . 
 this steering group first met in 2012 , developing a total of 48 recommendations across 11 themes . 
 the statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a likert scale . 
 all 48 statements achieved a high degree of consensus , indicating strong alignment of opinion . 
 the recommendations have evolved significantly since the 2005 document , with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment , greater emphasis on home therapy for acute attacks and a strong focus on service organization .