Nova proposta para diagnóstico do angioedema hereditário com papel filtro
New diagnostic approach to hereditary angioedema using filter paper
Maine Luellah Demaret Bardou; Rosemeire Navickas Constantino-Silva; Maria Luiza Oliva-Alonso; Ana Júlia Ribeiro Teixeira; Pedro Giavina-Bianchi; Eli Mansour; Solange Oliveira Rodrigues Valle; Anete Sevciovic Grumach
Resumo
Introdução: O angioedema hereditário (AEH) é raro, caracterizado por edema em subcutâneo, trato gastrointestinal e vias aéreas superiores. A deficiência do inibidor de C1 decorre da mutação em SERPING1 (AEH-C1-INH) que resulta em acúmulo de bradicinina e maior permeabilidade endotelial. O AEH também pode apresentar-se com C1-INH normal. A avaliação funcional do C1- INH permite detectar as duas formas de AEH-C1-INH. O objetivo do estudo foi avaliar a triagem de pacientes usando amostras de gota de sangue seca (DBS - Dried blood spot) em papel filtro comparada à técnica atual por ensaio cromogênico. Métodos: Estudo multicêntrico, prospectivo, em pacientes com AEH subdivididos em: G1 - AEH-C1-INH (n = 53; tipos 1 = 48 e 2 = 5); G2-AEH com mutação de FXII (AEH-FXII) (n = 30) e G3–AEH sem mutação conhecida (AEH-UNK) (n = 10) e G4 - Controle (n = 10). Realizadas dosagens de C4 e C1-INH (imunodifusão radial); C1-INH funcional (ensaio cromogênico e DBS). A avaliação estatística utilizou o programa GraphPad Prism. O protocolo foi aprovado pelo Comitê de Ética (CAAE:41812720010010082). Resultados: Valores de C4 e C1-INHq resultaram em mediana de 9,14 e 8,9 mg/dL para G1; G2 de 33,2 e 34,2 mg/dL; G3 de 35,3 e 29,4 mg/dL e G4 32,2 mg/dL e 35,3 mg/dL respectivamente. Valores de fC1-INH pelo ensaio cromogênico e por DBS resultaram em mediana de 35% e 0% em G1; G2 de 120% e 81%; G3 de 120% e 91%; e em G4 de 32,2% e 35,3%, respectivamente. G1 com 42/53 amostras (79,2%) e 53/53 (100%) com fC1-INH reduzida respectivamente. Em G2 30/30 (100%) e 28/30 (93,7%) com fC1-INH acima de 50% respectivamente. Para G3 e para G4 a fC1-INH estava normal em ambas as técnicas. Conclusão: O fC1-INH pela técnica em DBS permite identificar os pacientes com AEH-C1-INH com maior precisão que o ensaio cromogênico. Trata-se de coleta simples, de fácil transporte, facilitando o diagnóstico de AEH-C1-INH.
Palavras-chave
Abstract
Introduction: Hereditary angioedema (HAE) is a rare disease characterized by edema in the subcutaneous tissue, gastrointestinal tract, and upper airways. C1 inhibitor deficiency is caused by a SERPING1 mutation (HAE-C1-INH) that results in bradykinin accumulation and increased endothelial permeability. HAE may also present with normal C1-INH. Functional assessment of C1-INH allows the detection of both forms of HAE-C1-INH. This study aimed to evaluate patient screening using dried blood spots (DBS) on filter paper compared with the current technique using chromogenic assays. Methods: A multicenter prospective study of patients with HAE divided into: G1 – HAE-C1-INH (n=53; types 1=48 and 2=5); G2 – HAE with FXII mutation (HAE-FXII) (n=30); G3 – HAE with unknown mutation (HAE-UNK) (n=10); and G4 – Control (n=10). C4 and C1-INH levels were measured (radial immunodiffusion); functional C1-INH levels were assessed using chromogenic assay and DBS. Statistical analysis used GraphPad Prism. The protocol was approved by the Ethics Committee (CAAE:41812720010010082). Results: The median C4 and C1- INHq levels were, respectively, 9.14 and 8.9 mg/dL for G1; 33.2 and 34.2 mg/dL for G2; 35.3 and 29.4 mg/dL for G3; and 32.2 and 35.3 mg/dL for G4. The median fC1-INH levels obtained by chromogenic assay and by DBS were, respectively, 35% and 0% for G1; 120% and 81% for G2; 120% and 91% for G3; and 32.2% and 35.3% for G4. G1 had 42/53 samples (79.2%) and 53/53 (100%) with reduced fC1-INH, respectively. In G2, 30/30 (100%) and 28/30 (93.7%) had fC1-INH above 50%, respectively. In G3 and G4, fC1- INH was normal with both techniques. Conclusion: The fC1-INH measured in DBS samples allows a more precise identification of patients with HAE-C1-INH than using the chromogenic assay. DBS samples are simple to collect and easy to transport, facilitating the diagnosis of HAE-C1-INH.
Keywords
References
1. Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014;69(5):602-16.
2. Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. 2020;382(12):1136-48.
3. Maurer M, Magerl M, Betschel S, Aberer W, Ansotegui IJ, Aygören-Pürsün E, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022 Jul;77(7):1961-90.
4. Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med (Lond). 2019;80(7):391-8.
5. Wagenaar-Bos IG, Drouet C, Aygören-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(1-2):14-20.
6. López Lera A. Pathophysiology and underlying mechanisms in hereditary angioedema. Balkan Med J. 2021;38(2):82-8.
7. Sainz IM, Pixley RA, Colman RW. Fifty years of research on the plasma kallikrein-kinin system: from protein structure and function to cell biology and in-vivo pathophysiology. Thromb Haemost. 2007;98(1):77-83.
8. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2006;343(4):1286-9.
9. Bork K, Wulff K, Steinmüller-Magin L, Braenne I, Staubach-Renz P, Witzke G, et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2018;73(2):442-50.
10. Bafunno 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. 2018;141(3):1009-17.
11. Bork K, Wulff K, Rossmann H, Steinmüller-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(12):2479-81.
12. Ariano A, D'Apolito M, Bova M, Bellanti F, Loffredo S, D'Andrea G, et al. A myoferlin gain-of-function variant associates with a new type of hereditary angioedema. Allergy. 2020;75(11):2989-92.
13. Bork K, Wulff K, Möhl BS, Steinmüller-Magin L, Witzke G, Hardt J, et al. Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation. J Allergy Clin Immunol. 2021;148(4):1041-8.
14. Vincent D, Parsopoulou F, Martin L, Gaboriaud C, Demongeot J, Loules G, et al. Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency. J Allergy Clin Immunol Glob. 2024;3(2):100223.
15. D'Apolito M, Santacroce R, Vazquez DO, Cordisco G, Fantini CA, D'Andrea G, et al. DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology. J Allergy Clin Immunol. 2024 Sep;154(3):698-706.
16. Germenis AE, Rijavec M, Veronez CL. Leveraging Genetics for Hereditary Angioedema: A Road Map to Precision Medicine. Clin Rev Allergy Immunol. 2021;60(3):416-28.
17. Germenis AE, Cicardi M. Driving towards Precision Medicine for angioedema without wheals. J Autoimmun. 2019;104:102312.
18. Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61(2):110-7.
19. Veronez CL, Mendes AR, Leite CS, Gomes CP, Grumach AS, Pesquero JB, et al. The Panorama of Primary Angioedema in the Brazilian Population. J Allergy Clin Immunol Pract. 2021;9(6):2293-304.e5.
20. Serpa FS, Cruz AAS, Condino Neto A, Silva ECF, Franco JM, Mello JML, et al. O atendimento médico de pacientes com doenças imunoalérgicas no Brasil: reflexões e propostas para a melhoria - Carta de Belo Horizonte. Arq Asma Alerg Imunol. 2017;1(4):327-34.
21. Lai Y, Zhang G, Zhou Z, Inhaber N, Bernstein JA, Chockalingam PS, et al. A novel functional C1 inhibitor activity assay in dried blood spot for diagnosis of Hereditary angioedema. Clin Chim Acta. 2020;504:155-62.
22. Betschel S, Badiou J, Binkley K, Borici-Mazi R, Hébert J, Kanani A, et al. The International/Canadian Hereditary Angioedema Guideline. Allergy Asthma Clin Immunol. 2019;15:72.
23. Bork K, Siedlecki K, Bosch S, Schopf RE, Kreuz W. Asphyxiation by laryngeal edema in patients with hereditary angioedema. Mayo Clin Proc. 2000;75(4):349-54.
24. Giavina-Bianchi P, Arruda LK, Aun MV, Campos RA, Chong-Neto HJ, Constantino-Silva RN, et al. Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis. Clinics (Sao Paulo). 2018;73:e310.
25. Minafra FG, Gonçalves TR, Alves TM, Pinto JA. The Mortality from Hereditary Angioedema Worldwide: a Review of the Real-World Data Literature. Clin Rev Allergy Immunol. 2022;62(1):232-9.
26. Serpa FS, Urrutia-Pereira M, Costa E, DiGesu RW, Guidacci MFRC, Cruz AS, et al. A especialidade de Alergia e Imunologia Clínica nos diferentes níveis de atenção à saúde no Brasil. Arq Asma Alerg Imunol. 2018;2(3):335-43.
27. Grupo de Estudos Brasileiro em Angioedema Hereditário, GEBRAH [Internet]. Available from: https://gebraeh.com.br/diagnostico-laboratorial/. Accessed may/2024.
28. Tarzi MD, Hickey A, Förster T, Mohammadi M, Longhurst HJ. 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(3):513-6.
29. Charest-Morin X, Betschel S, Borici-Mazi R, Kanani A, Lacuesta G, Rivard G-É, et al. The diagnosis of hereditary angioedema with C1 inhibitor deficiency: a survey of Canadian physicians and laboratories. Allergy, Asthma & Clinical Immunology. 2018;14(1):83.
Submitted date:
05/30/2024
Accepted date:
08/04/2024
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email