US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema

Scientific and clinical progress together with the development of effective novel therapeutic options has engendered multiple important changes in the diagnosis and management of hereditary angioedema (HAE). We now update and extend the 2013 United States Hereditary Angioedema Association Medical Advisory Board guidelines for the treatment and management of HAE. The guidelines are based on a comprehensive literature review with recommendations indicating both the strength of our recommendation and the quality of the underlying evidence. Guidelines are provided regarding the classification, diagnosis, on-demand treatment, prophylactic treatment, special considerations for women and children, development of a comprehensive management and monitoring plan, and assessment of burden of illness for both HAE due to C1 inhibitor deficiency and HAE with normal C1 inhibitor. Advances in HAE treatment now allow the development of management plans that can help many patients with HAE lead a normal life. Achieving this goal requires that physicians be familiar with the diagnostic and therapeutic transformations that have occurred in recent years. Scientific and clinical progress together with the development of effective novel therapeutic options has engendered multiple important changes in the diagnosis and management of hereditary angioedema (HAE). We now update and extend the 2013 United States Hereditary Angioedema Association Medical Advisory Board guidelines for the treatment and management of HAE. The guidelines are based on a comprehensive literature review with recommendations indicating both the strength of our recommendation and the quality of the underlying evidence. Guidelines are provided regarding the classification, diagnosis, on-demand treatment, prophylactic treatment, special considerations for women and children, development of a comprehensive management and monitoring plan, and assessment of burden of illness for both HAE due to C1 inhibitor deficiency and HAE with normal C1 inhibitor. Advances in HAE treatment now allow the development of management plans that can help many patients with HAE lead a normal life. Achieving this goal requires that physicians be familiar with the diagnostic and therapeutic transformations that have occurred in recent years. Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by episodic unpredictable swelling. The United States Hereditary Angioedema Association Medical Advisory Board (US HAEA MAB) published guidelines for HAE management in 2013.1Zuraw B.L. Banerji A. Bernstein J.A. Busse P.J. Christiansen S.C. Davis-Lorton M. et al.US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency.J Allergy Clin Immunol Pract. 2013; 1: 458-467Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar In the 6 years since that publication, considerable progress has been made in our classification and understanding of HAE as well as major changes in the therapeutic armamentarium. This document reflects our current understanding of HAE and serves as a foundation for clinicians to optimize its diagnosis and management. Resources available for the diagnosis and treatment of HAE vary widely between different countries. International differences also exist in the regulatory approvals of medicines to treat HAE. This paper focuses on the current situation in the United States, reflecting the consensus of a broad panel of expert US HAE physicians. The US HAEA MAB consists of 11 clinicians, each of whom treats large numbers of patients with HAE. In 2013, the US HAEA MAB published recommendations for the management of HAE due to C1 inhibitor (C1INH) deficiency (HAE-C1INH). This document builds upon the 2013 paper, updating and expanding those recommendations to reflect the rapid progress during the intervening years and incorporating recommendations for HAE with normal C1INH (HAE-nl-C1INH). This report has been divided into 7 sections: (1) classification and pathophysiology; (2) diagnosis; (3) treatment; (4) specific issues for children; (5) specific issues for women; (6) management plans; and (7) disease burden and impact on quality of life (QoL). Each recommendation reflects both the strength of the authors' recommendation (strong or weak) and the quality of the underlying evidence (high, moderate, or low).2Andrews J.C. Schunemann H.J. Oxman A.D. Pottie K. Meerpohl J.J. Coello P.A. et al.GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction and strength.J Clin Epidemiol. 2013; 66: 726-735Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar The methodology used to develop the recommendations is available in this article's Online Repository at www.jaci-inpractice.org. All recommendations were approved by a unanimous vote. The recommendations are presented in Table I.Table ISummary of recommendationsSectionRecommendationStrength of recommendationQuality of evidence1. Classification and pathophysiology of HAEHAE should be broadly divided into HAE due to C1INH deficiency (HAE-C1INH) and HAE-nl-C1INH. HAE-C1INH is further subdivided into type I and type II, which appear to be clinically similar. HAE-nl-C1INH is further subdivided based on the underlying mutation or unknown in cases where the mutation has not been found.StrongHigh2. Diagnosis of HAERecognition of clinical symptoms associated with HAE is a critical step in guiding appropriate diagnostic tests. Common HAE symptoms include recurrent cutaneous angioedema (in the absence of urticaria), abdominal symptoms from gastrointestinal angioedema, and airway symptoms due oropharyngeal/laryngeal swelling.StrongHighWhen HAE is suspected based on the clinical presentation, appropriate testing includes measurement of the serum C4 level, C1INH antigenic level, and C1INH functional level. Low C4 plus low C1INH antigenic or functional levels are consistent with a diagnosis of HAE-C1INH.StrongHighBecause of the autosomal dominant inheritance pattern and significant clinical risk associated with HAE, screening should be performed in all first-degree relatives of an affected individual.StrongHighWhen a diagnosis of HAE-nl-C1INH is suspected based on symptoms and normal C1INH tests, additional genetic tests for factor XII, plasminogen, angiopoetin-1, and kininogen mutations should be performed when available. Diagnosis of HAE-U should involve the input of an HAE specialist.StrongLow3A. On-demand treatment of HAE attacksPatients must have ready access to effective on-demand medication to administer at the onset of an HAE attack. An FDA-approved on-demand HAE medication (ecallantide, icatibant, pdC1INH, or rhC1INH) should be used as first-line treatment for attacks whenever possible.StrongHigh for HAE C1INH; low for HAE-nl-C1INHOn-demand treatment of HAE attacks should be self-administered (or administered by a caregiver) whenever feasible except when treating with ecallantide that needs to be administered by a health care provider.StrongHigh for HAE C1INH; low for HAE-nl-C1INHAll HAE attacks are eligible for treatment irrespective of the location of the swelling or the severity of the attack.StrongHigh for HAE C1INH; low for HAE-nl-C1INH3B. Prophylactic treatmentShort-term prophylaxis is indicated when patients are at increased risk of having an attack associated with known triggers such as invasive dental or medical procedures or stressful life events.Strong for HAE-C1INH; weak for HAE-nl-C1INHModerate for HAE C1INH; low for HAE-nl-C1INHThe decision on when to use long-term prophylactic treatment cannot be made on rigid criteria but should reflect the needs of the individual patient.StrongHigh for HAE C1INH; low for HAE-nl-C1INHLong-term prophylactic treatment of HAE-C1INH should include first-line medications (IV C1INH, SC C1INH, or lanadelumab).StrongHighProgestin-only medication or an antifibrinolytic drug should be considered for initial long-term prophylactic treatment of HAE-nl-C1INH.WeakLow4. Additional considerations for childrenHAE-C1INH often presents in childhood and an early diagnosis is essential for minimizing the risks of morbidity and mortality.StrongHighIndications for the use of first-line HAE medications are the same in children as in adults, although regulatory differences affect the use of some medications depending on the child's age.StrongModerate5. Specific issues in the management of HAE in womenExogenous estrogens such as birth control pills or hormonal replacement therapy can precipitate HAE attacks and should therefore be used only with caution in individuals with HAE.StrongModerateDuring pregnancy and breast-feeding, C1INH is the recommended HAE medication for use as either on-demand or prophylactic therapy.StrongModerate6. Management plansHAE management plans must be individualized to each patient's needs due to wide variability in HAE symptoms, response to and tolerance of various HAE medications, and numerous factors impacting clinical course and quality of life. Treatment plans should be monitored regularly and adjusted based on the needs of the patient.StrongModerateHAE management plans should include: (A) effective on-demand medication for every patient, (B) consideration of long-term prophylactic medications to prevent HAE attacks, and (C) use of short-term prophylactic medications before medical procedures or other events known to trigger HAE symptoms.StrongModerateConsultation with an HAE expert physician is recommended to optimize individualized treatment plans, assist with coordination of care, and provide important patient and family education.StrongLowPatients should maintain a symptom/treatment diary to monitor angioedema symptoms, medication requirements, and any adverse effects of treatment. These data should be reviewed regularly at follow-up visits.WeakLow7. Burden of illnessClinicians should explicitly consider the impact of HAE on their patients' lives.StrongLowManagement plans should be individualized to lessen the burden of illness and provide patients with HAE with a normal quality of life.StrongLowEconomic considerations should not be the determining factor in deciding the physician's recommendations for optimal management of HAE.StrongLowC1INH, C1 inhibitor; FDA, Food and Drug Administration; HAE, hereditary angioedema; HAE-nl-C1INH, HAE with normal C1INH; IV, intravenous; pdC1INH, plasma-derived C1INH; rhC1INH, recombinant human; SC, subcutaneous. Open table in a new tab C1INH, C1 inhibitor; FDA, Food and Drug Administration; HAE, hereditary angioedema; HAE-nl-C1INH, HAE with normal C1INH; IV, intravenous; pdC1INH, plasma-derived C1INH; rhC1INH, recombinant human; SC, subcutaneous. This section will very briefly summarize the current classification of HAE and its pathophysiology. The clinical presentation of HAE is also reviewed, focusing on characteristics that help distinguish HAE from other forms of angioedema. HAE can be broadly divided into 2 fundamental types: HAE-C1INH or HAE-nl-C1INH (Figure 1). HAE-C1INH is further divided into 2 subtypes: type I HAE, characterized by deficient levels of C1INH protein and function; and type II HAE, characterized by the normal level of C1INH protein that is dysfunctional, resulting in diminished C1INH functional activity.3Donaldson V.H. Evans R.R. A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C'1-esterase.Am J Med. 1963; 35: 37-44Abstract Full Text PDF PubMed Google Scholar,4Rosen F.S. Pensky J. Donaldson V. Charache P. Hereditary angioneurotic edema: two genetic variants.Science. 1965; 148: 957-958Crossref PubMed Google Scholar Both type I and type II HAE are caused by mutations in the gene that encodes C1INH (SERPING1).5Zuraw B.L. Clinical practice. Hereditary angioedema.N Engl J Med. 2008; 359: 1027-1036Crossref PubMed Scopus (525) Google Scholar The estimated prevalence of type I and type II HAE is 1 per 50,000, suggesting that there are approximately 6000 affected individuals in the United States. HAE-nl-C1INH was first described in 20006Binkley K.E. Davis III, A. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema.J Allergy Clin Immunol. 2000; 106: 546-550Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar,7Bork K. Barnstedt S.E. Koch P. Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women.Lancet. 2000; 356: 213-217Abstract Full Text Full Text PDF PubMed Google Scholar and is not as well understood as HAE-C1INH. At the current time, there are 5 subtypes of HAE-nl-C1INH based on the underlying mutation8Zuraw B.L. Hereditary angioedema with normal C1 inhibitor: four types and counting.J Allergy Clin Immunol. 2018; 141: 884-885Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar: HAE-FXII is due to mutations in F12, the gene encoding coagulation FXII9Cichon S. Martin L. Hennies H.C. Muller F. Van Driessche K. Karpushova A. et al.Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.Am J Hum Genet. 2006; 79: 1098-1104Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar; HAE-PLG is due to mutations in PLG, the gene encoding plasminogen10Bork K. Wulff K. Steinmuller-Magin L. Braenne I. Staubach-Renz P. Witzke G. et al.Hereditary angioedema with a mutation in the plasminogen gene.Allergy. 2018; 73: 442-445Crossref PubMed Scopus (111) Google Scholar; HAE-ANGPT1 is due to mutations in ANGPT1, the gene encoding angiopoietin-111Bafunno V. Firinu D. D'Apolito M. Cordisco G. Loffredo S. Leccese A. et al.Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema.J Allergy Clin Immunol. 2017; 141: 1009-1017Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar; HAE-KNG1 is due to a mutation in the kininogen 1 gene12Bork K. Wulff K. Rossmann H. Steinmuller-Magin L. Braenne I. Witzke G. et al.Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin.Allergy. 2019; 74: 2479-2481Crossref PubMed Scopus (41) Google Scholar; and HAE-unknown (HAE-U) represents patients with HAE-nl-C1INH for whom the responsible mutation has not yet been defined. The overall prevalence of HAE-nl-C1INH is not known. HAE-XII comprises approximately 20% of HAE-nl-C1INH cases in Europe but for reasons that are not clear is exceedingly rare in the United States.13Cicardi M. Zuraw B.L. Angioedema due to bradykinin dysregulation.J Allergy Clin Immunol Pract. 2018; 6: 1132-1141Abstract Full Text Full Text PDF PubMed Google Scholar HAE-nl-C1INH was previously referred to as type III HAE, but this term is obsolete and should not be used. There is strong evidence that the mediator of swelling in HAE-C1INH is bradykinin (reviewed in the paper by Zuraw and Christiansen14Zuraw B.L. Christiansen S.C. HAE pathophysiology and underlying mechanisms.Clin Rev Allergy Immunol. 2016; 51: 216-229Crossref PubMed Scopus (49) Google Scholar). Cleavage of high-molecular-weight kininogen by plasma kallikrein results in generation of bradykinin. This occurs with activation of contact system proteases (factor XIIa and plasma kallikrein), which are normally regulated by C1INH. Bradykinin leads to angioedema by binding to the bradykinin B2 receptor resulting in vascular permeability. A role for the bradykinin B1 receptor in HAE attacks has been postulated but not proven.15Hofman Z.L.M. Relan A. Zeerleeder S. Drouet C. Zuraw B.L. Hack E. Angioedema attacks of hereditary angioedema: local manifestations of a systemic activation process.J Allergy Clin Immunol. 2016; 138: 359-366Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Several features suggest that HAE-nl-C1INH, like HAE-C1INH, may be bradykinin mediated, including the lack of response to antihistamines, corticosteroids, and epinephrine; and the favorable response to bradykinin pathway–targeted medications to a similar degree as seen in HAE-C1INH.13Cicardi M. Zuraw B.L. Angioedema due to bradykinin dysregulation.J Allergy Clin Immunol Pract. 2018; 6: 1132-1141Abstract Full Text Full Text PDF PubMed Google Scholar The best evidence for a key role of bradykinin in HAE-nl-C1INH comes from studies of HAE-FXII. The most common form of HAE-FXII, p.Thr309Lys, was recently shown to enhance susceptibility of contact system activation (presumably leading to generation of bradykinin) ex vivo and in vivo.16Bjorkqvist J. de Maat S. Lewandrowski U. Di Gennaro A. Oschatz C. Schonig K. et al.Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III.J Clin Invest. 2015; 125: 3132-3146Crossref PubMed Scopus (99) Google Scholar F12 mutations associated with HAE-FXII were also shown to enhance susceptibility of FXII to activation by plasmin.17de Maat S. Bjorkqvist J. Suffritti C. Wiesenekker C.P. Nagtegaal W. Koekman A. et al.Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations.J Allergy Clin Immunol. 2016; 138: 1414-1423Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar In contrast, HAE-ANGPT1 appears to involve a loss of an endothelial cell brake on vascular permeability,11Bafunno V. Firinu D. D'Apolito M. Cordisco G. Loffredo S. Leccese A. et al.Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema.J Allergy Clin Immunol. 2017; 141: 1009-1017Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar suggesting that these patients may be susceptible to multiple mediators of increased vascular permeability. The timely diagnosis of HAE is dependent on recognition of suggestive clinical symptoms. HAE has a highly variable clinical course with numerous presentations and symptoms, but the hallmarks of all forms of HAE are recurrent angioedema causing cutaneous swelling, abdominal symptoms from gastrointestinal angioedema, and respiratory symptoms due to airway involvement. HAE is not associated with urticaria or pruritus, but can have prodromal symptoms of erythema marginatum, an evanescent, nonpruritic macular rash that may mimic urticaria.18Rasmussen E.R. de Freitas P.V. Bygum A. Urticaria and prodromal symptoms including erythema marginatum in Danish patients with hereditary angioedema.Acta Derm Venereol. 2016; 96: 373-376Crossref PubMed Scopus (24) Google Scholar,19Kemp J.G. Craig T.J. Variability of prodromal signs and symptoms associated with hereditary angioedema attacks: a literature review.Allergy Asthma Proc. 2009; 30: 493-499Crossref PubMed Scopus (23) Google Scholar Exogenous estrogens or angiotensin-converting enzyme inhibitors often make symptoms worse. HAE symptoms often progress to maximal severity over several hours. HAE swelling is protracted, compared with histamine-induced angioedema; untreated HAE angioedema symptoms commonly last 3 to 5 days from start to resolution with considerable morbidity and mortality if not treated with effective medication.20Bork K. Meng G. Staubach P. Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course.Am J Med. 2006; 119: 267-274Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar Importantly, HAE symptoms do not respond to antihistamines, corticosteroids, or epinephrine; this lack of clinical response to common mast cell–targeted treatments is an important clue in the history of patients affected by HAE. Persistent swelling for weeks or longer is not consistent with HAE. HAE is an autosomal dominant disorder, signifying that each child of a patient with HAE has a 50% potential for inheritance. HAE-C1INH typically becomes symptomatic during childhood or young adulthood, sometimes as early as 2 years of age. Approximately 50% of HAE-C1INH manifest symptoms of swelling by the age of 10,21Christiansen S.C. Davis D.K. Castaldo A.J. Zuraw B.L. Pediatric hereditary angioedema: onset, diagnostic delay, and disease severity.Clin Pediatr (Phila). 2016; 55: 935-942Crossref PubMed Scopus (26) Google Scholar with the frequency and severity of attacks often increasing after puberty. Almost all patients with HAE-C1INH manifest symptoms by the age of 20, although rare patients never experience symptoms. The severity and frequency of swelling in HAE is highly variable, even between different affected members of the same family. The clinical presentation of HAE-nl-C1INH is similar to HAE-C1INH though some differences may exist. Angioedema symptoms may affect the face and tongue more frequently in HAE-nl-C1INH with fewer abdominal symptoms compared with HAE-C1INH. HAE-nl-C1INH is also autosomal dominant, although the penetrance is variable and often lower than for HAE-C1INH. Females with HAE-nl-C1INH are more likely to be symptomatic than males, and the swelling is often estrogen-sensitive such that exposure to endogenous or exogenous estrogens is a strong exacerbating factor, especially in HAE-FXII.22Bork K. Wulff K. Witzke G. Hardt J. Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations.Allergy. 2015; 70: 1004-1012Crossref PubMed Scopus (64) Google Scholar Rare cases of HAE-nl-C1INH in males have been described. HAE-nl-C1INH symptoms typically begin in late teenage or early adult years.22Bork K. Wulff K. Witzke G. Hardt J. Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations.Allergy. 2015; 70: 1004-1012Crossref PubMed Scopus (64) Google Scholar Given the clinical variability associated with bradykinin-mediated angioedema, laboratory testing is indicated in any patient with suggestive clinical symptoms. Laboratory testing is necessary to identify or exclude HAE-C1INH. A serum C4 level is a useful screening test for HAE-C1INH. Sensitivity varies from 81% to 96% on screening of C1INH-deficient patients between angioedema episodes23Tarzi M.D. Hickey A. Forster T. Mohammadi M. Longhurst H.J. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema.Clin Exp Immunol. 2007; 149: 513-516Crossref PubMed Scopus (71) Google Scholar,24Zanichelli A. Arcoleo F. Barca M.P. Borrelli P. Bova M. Cancian M. et al.A nationwide survey of hereditary angioedema due to C1 inhibitor deficiency in Italy.Orphanet J Rare Dis. 2015; 10: 11Crossref PubMed Scopus (67) Google Scholar; however, a normal C4 during an angioedema episode excludes the diagnosis of HAE-C1NH. Measurement of C1INH protein antigenic and functional levels is necessary to definitively confirm or exclude HAE-C1INH and should be ordered when the clinical suspicion for HAE is high. C1INH quantitative and functional levels are low (<50% of normal) in type I HAE, whereas only the functional level is low (<50% of normal) in type II HAE.5Zuraw B.L. Clinical practice. Hereditary angioedema.N Engl J Med. 2008; 359: 1027-1036Crossref PubMed Scopus (525) Google Scholar Once C1INH deficiency has been established by laboratory testing, further repeated testing is neither necessary nor useful; however, repeat testing should be done if the diagnosis is unclear. In patients with onset of isolated angioedema symptoms after the age of 40 or with concomitant lymphoproliferative or autoimmune conditions, a C1q level is useful to help distinguish between HAE-C1INH and acquired C1INH deficiency. C1q levels are decreased in 80% of acquired C1INH deficiency and rarely low in HAE-C1INH.25Zanichelli A. Azin G.M. Wu M.A. Suffritti C. Maggioni L. Caccia S. et al.Diagnosis, course, and management of angioedema in patients with acquired C1-inhibitor deficiency.J Allergy Clin Immunol Pract. 2017; 5: 1307-1313Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Lab results must always be interpreted in conjunction with clinical history. The 2 commercially available functional C1INH assays (ELISA and chromogenic) demonstrate differences in sensitivity and specificity. The chromogenic assay is the more sensitive test for C1INH deficiency.26Wagenaar-Bos I.G. Drouet C. Aygoren-Pursun E. Bork K. Bucher C. Bygum A. et al.Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations.J Immunol Methods. 2008; 338: 14-20Crossref PubMed Scopus (58) Google Scholar,27Li H.H. Busse P. Lumry W.R. Frazer-Abel A. Levy H. Steele T. et al.Comparison of chromogenic and ELISA functional C1 inhibitor tests in diagnosing hereditary angioedema.J Allergy Clin Immunol Pract. 2015; 3: 200-205Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Chromogenic functional testing should be considered, therefore, in any patient when the diagnosis of HAE-C1INH is uncertain. Proper handling and prompt processing of blood samples is important for accurate C1INH functional testing.26Wagenaar-Bos I.G. Drouet C. Aygoren-Pursun E. Bork K. Bucher C. Bygum A. et al.Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations.J Immunol Methods. 2008; 338: 14-20Crossref PubMed Scopus (58) Google Scholar C1INH concentrates and anabolic androgen treatment may affect complement test results; therefore, these medications could be discontinued for at least 2 weeks (with ready access to on-demand medications) if diagnostic testing is necessary.28Sheffer A.L. Fearon D.T. Austen K.F. Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angioedema.J Allergy Clin Immunol. 1979; 64: 275-280Abstract Full Text PDF PubMed Scopus (26) Google Scholar The biochemical tests for HAE-C1INH are sufficiently sensitive and specific such that genetic sequencing for SERPING1 mutations is usually unnecessary for establishing the diagnosis.13Cicardi M. Zuraw B.L. Angioedema due to bradykinin dysregulation.J Allergy Clin Immunol Pract. 2018; 6: 1132-1141Abstract Full Text Full Text PDF PubMed Google Scholar Specific clinical scenarios where genetic testing may be necessary include differentiating HAE-C1INH from acquired C1INH deficiency in patients without a clear family history, prenatal testing due to family request, or situations where biochemical C1INH test results are repeatedly equivocal. Once a diagnosis of HAE has been confirmed by laboratory testing, testing of parents, siblings, and children should be strongly encouraged. The testing of infants within the first year of life is an area of some uncertainty. Previously, C1INH testing was not recommended before 12 months of age due to highly variable C4 and C1INH antigenic levels in the first year of life.29Farkas H. Martinez-Saguer I. Bork K. Bowen T. Craig T. Frank M. et al.International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency.Allergy. 2017; 72: 300-313Crossref PubMed Scopus (76) Google Scholar More recent data suggest that C1INH functional assays are sensitive and specific in diagnosing C1INH deficiency in young infants such that functional testing could be considered earlier than 1 year of age if necessary.30Pedrosa M. Phillips-Angles E. Lopez-Lera A. Lopez-Trascasa M. Caballero T. Complement study versus CINH gene testing for the diagnosis of type I hereditary angioedema in children.J Clin Immunol. 2016; 36: 16-18Crossref PubMed Scopus (18) Google Scholar If the underlying mutation is known, screening can be done at any age. HAE-nl-C1INH presents a diagnostic challenge given the current lack of a validated biochemical test to confirm the diagnosis.31Lara-Marquez M.L. Christiansen S.C. Riedl M.A. Herschbach J. Zuraw B.L. Threshold-stimulated kallikrein activity distinguishes bradykinin- from histamine-mediated angioedema.Clin Exp Allergy. 2018; 48: 1429-1438Crossref PubMed Scopus (15) Google Scholar Genetic testing may be helpful in confirming HAE-nl-C1INH. The most common mutations linked to HAE-nl-C1INH involving the F12 gene can be detected by a commercially available PCR assay, whereas a comprehensive assessment of all of the genes implicated in HAE-nl-C1INH is commercially available through licensed laboratories using custom-targeted whole-exome sequencing approaches. It is anticipated that next-generation sequencing panels including the genes linked to HAE-nl-C1INH will become available as this technology is adopted by more clinical laboratories. In addition, the identified mutations only account for a subset of HAE-nl-C1INH, such that individuals affected by HAE of unknown etiology (HAE-U) remain, without an available confirmatory biomarker or diagnostic test. The diagnosis of HAE-nl-C1INH frequently must be made based on clinical criteria as previously published and refined31Lara-Marquez M.L. Christiansen S.C. Riedl M.A. Herschbach J. Zuraw B.L. Threshold-stimulated kallikrein activity distinguishes bradykinin- from histamine-mediated angioedema.Clin Exp Allergy. 2018; 48: 1429-1438Crossref PubMed Scopus (15) Google Scholar,32Zuraw B.L. Bork K. Binkley K.E. Banerji A. Christiansen S.C. Castaldo A. et al.Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel.Allergy Asthma Proc. 2012; 33: S145-S156Crossref PubMed Google Scholar (Table II).Table IICriteria for the diagnosis of HAEWeightCriteriaHAE-C1INH RequiredA history of recurrent angioedema in the absence of concomitant urticaria and no concomitant use of medication known to cause angioedema RequiredLow (<50% of normal) C1INH antigenic or functional level RequiredLow C4 level (either at baseline or during an attack) SupportiveDemonstration of a pathologic SERPING1 mutation (not required for diagnosis)Family history of recurrent angioedemaAge of symptom onset <40HAE-nl-C1INH RequiredA history of recurrent angioedema in the absence of concomitant urticaria and no concomitant use of