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Diretrizes brasileiras para o tratamento farmacológico pulmonar na fibrose cística. Documento oficial da Sociedade Brasileira de Pneumologia e Tisiologia

RESUMO

A fibrose cística (FC) é uma doença genética que resulta em disfunção da proteína reguladora de condutância transmembrana da FC (CFTR), que é um canal de cloro e bicarbonato expresso na porção apical de células epiteliais de diversos órgãos. A disfunção dessa proteína resulta em manifestações clínicas diversas, envolvendo primariamente os sistemas respiratório e gastrointestinal com redução da qualidade e expectativa de vida. A FC ainda é uma patologia incurável, porém o horizonte terapêutico e prognóstico é hoje totalmente distinto e muito mais favorável. O objetivo destas diretrizes foi definir recomendações brasileiras baseadas em evidências em relação ao emprego de agentes farmacológicos no tratamento pulmonar da FC. As perguntas PICO (acrônimo baseado em perguntas referentes aos Pacientes de interesse, Intervenção a ser estudada, Comparação da intervenção e Outcome [desfecho] de interesse) abordaram aspectos relativos ao uso de moduladores de CFTR (ivacaftor, lumacaftor + ivacaftor e tezacaftor + ivacaftor), uso de dornase alfa, terapia de erradicação e supressão crônica de Pseudomonas aeruginosa, e erradicação de Staphylococcus aureus resistente a meticilina e do complexo Burkholderia cepacia. Para a formulação das perguntas, um grupo de especialistas brasileiros foi reunido e realizou-se uma revisão sistemática sobre os temas, com meta-análise quando aplicável. Os resultados encontrados foram analisados quanto à força das evidências compiladas, sendo concebidas recomendações seguindo a metodologia GRADE. Os autores acreditam que o presente documento represente um importante avanço a ser incorporado na abordagem de pacientes com FC, objetivando principalmente favorecer seu manejo, podendo se tornar uma ferramenta auxiliar na definição de políticas públicas relacionadas à FC.

Descritores:
Fibrose cística; Abordagem GRADE; Fibrose cística/tratamento farmacológico; Guia de prática clínica

ABSTRACT

Cystic fibrosis (CF) is a genetic disease that results in dysfunction of the CF transmembrane conductance regulator (CFTR) protein, which is a chloride and bicarbonate channel expressed in the apical portion of epithelial cells of various organs. Dysfunction of that protein results in diverse clinical manifestations, primarily involving the respiratory and gastrointestinal systems, impairing quality of life and reducing life expectancy. Although CF is still an incurable pathology, the therapeutic and prognostic perspectives are now totally different and much more favorable. The purpose of these guidelines is to define evidence-based recommendations regarding the use of pharmacological agents in the treatment of the pulmonary symptoms of CF in Brazil. Questions in the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) format were employed to address aspects related to the use of modulators of this protein (ivacaftor, lumacaftor+ivacaftor, and tezacaftor+ivacaftor), use of dornase alfa, eradication therapy and chronic suppression of Pseudomonas aeruginosa, and eradication of methicillin-resistant Staphylococcus aureus and Burkholderia cepacia complex. To formulate the PICO questions, a group of Brazilian specialists was assembled and a systematic review was carried out on the themes, with meta-analysis when applicable. The results obtained were analyzed in terms of the strength of the evidence compiled, the recommendations being devised by employing the GRADE approach. We believe that these guidelines represent a major advance to be incorporated into the approach to patients with CF, mainly aiming to favor the management of the disease, and could become an auxiliary tool in the definition of public policies related to CF.

Keywords:
Cystic fibrosis; GRADE approach; Cystic fibrosis/drug treatment; Clinical practice guide

INTRODUÇÃO

A fibrose cística (FC) é uma doença genética que resulta em disfunção da proteína cystic fibrosis transmembrane conductance regulator (CFTR, reguladora de condutância transmembrana da FC), que é um canal de cloro e bicarbonato expresso na porção apical de células epiteliais em diversos órgãos do corpo humano.11 Ratjen F, Bell SC, Rowe SM, Goss CH, Quittner AL, Bush A. Cystic fibrosis. Nat Rev Dis Primers. 2015;1:15010. https://doi.org/10.1038/nrdp.2015.10
https://doi.org/10.1038/nrdp.2015.10...
A disfunção da proteína CFTR resulta em manifestações multissistêmicas com redução da qualidade e expectativa de vida.22 Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, et al. The future of cystic fibrosis care: a global perspective [published correction appears in Lancet Respir Med. 2019 Dec;7(12):e40]. Lancet Respir Med. 2020;8(1):65-124. https://doi.org/10.1016/S2213-2600(19)30337-6
https://doi.org/10.1016/S2213-2600(19)30...

A FC ainda é uma patologia incurável, mas o horizonte terapêutico é atualmente mais favorável por conta da descoberta de moduladores da proteína CFTR.33 Elborn JS. CFTR Modulators: Deciding What Is Best for Individuals in an Era of Precision Medicine. Ann Am Thorac Soc. 2018;15(3):298-300. https://doi.org/10.1513/AnnalsATS.201712-951ED
https://doi.org/10.1513/AnnalsATS.201712...
,44 Habib AR, Kajbafzadeh M, Desai S, Yang CL, Skolnik K, Quon BS. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis. Sci Rep. 2019;9(1):7234. https://doi.org/10.1038/s41598-019-43652-2
https://doi.org/10.1038/s41598-019-43652...
Historicamente, o tratamento dos indivíduos com FC foi desenvolvido para suprir deficiências ou modificar aspectos básicos da fisiopatologia da doença.55 Flume PA, Robinson KA, O'Sullivan BP, Finder JD, Vender RL, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care. 2009;54(4):522-537.

6 Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680-689. https://doi.org/10.1164/rccm.201207-1160OE
https://doi.org/10.1164/rccm.201207-1160...

7 Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43(3):219-245. https://doi.org/10.1590/s1806-37562017000000065
https://doi.org/10.1590/s1806-3756201700...
-88 Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018;17(2):153-178. https://doi.org/10.1016/j.jcf.2018.02.006
https://doi.org/10.1016/j.jcf.2018.02.00...

Com o surgimento dos moduladores da proteína CFTR, revisões sistemáticas sobre as evidências de seus benefícios em desfechos de saúde para pessoas com FC foram publicadas.33 Elborn JS. CFTR Modulators: Deciding What Is Best for Individuals in an Era of Precision Medicine. Ann Am Thorac Soc. 2018;15(3):298-300. https://doi.org/10.1513/AnnalsATS.201712-951ED
https://doi.org/10.1513/AnnalsATS.201712...
,44 Habib AR, Kajbafzadeh M, Desai S, Yang CL, Skolnik K, Quon BS. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis. Sci Rep. 2019;9(1):7234. https://doi.org/10.1038/s41598-019-43652-2
https://doi.org/10.1038/s41598-019-43652...
,99 Guimbellot J, Sharma J, Rowe SM. Toward inclusive therapy with CFTR modulators: Progress and challenges. Pediatr Pulmonol. 2017;52(S48):S4-S14. https://doi.org/10.1002/ppul.23773
https://doi.org/10.1002/ppul.23773...
,1010 Chaudary N. Triplet CFTR modulators: future prospects for treatment of cystic fibrosis. Ther Clin Risk Manag. 2018;14:2375-2383. https://doi.org/10.2147/TCRM.S147164
https://doi.org/10.2147/TCRM.S147164...
No início da elaboração das presentes diretrizes, os moduladores da proteína CFTR com aprovação da Agência Nacional de Vigilância Sanitária (ANVISA) eram os medicamentos ivacaftor1111 Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. https://doi.org/10.1056/NEJMoa1105185
https://doi.org/10.1056/NEJMoa1105185...
e as associações lumacaftor + ivacaftor1212 Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231. https://doi.org/10.1056/NEJMoa1409547
https://doi.org/10.1056/NEJMoa1409547...
e tezacaftor + ivacaftor.1313 Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. https://doi.org/10.1056/NEJMoa1709846
https://doi.org/10.1056/NEJMoa1709846...
,1414 Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017;377(21):2024-2035. https://doi.org/10.1056/NEJMoa1709847
https://doi.org/10.1056/NEJMoa1709847...
No final de 2020, o ivacaftor foi incorporado ao Sistema Único de Saúde para uso em indivíduos com FC com idade igual ou superior a 6 anos e com variantes genéticas de regulação (gating). Em 2022, a Agência Nacional de Vigilância Sanitária aprovou a terapia tripla (elexacaftor + tezacaftor + ivacaftor), que se mostrou altamente efetiva para indivíduos com FC portadores da variante genética F508del, mesmo que em heterozigose.1515 Heijerman HGM, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2020 May 30;395(10238):1694]. Lancet. 2019;394(10212):1940-1948. https://doi.org/10.1016/S0140-6736(19)32597-8
https://doi.org/10.1016/S0140-6736(19)32...
,1616 Middleton PG, Mall MA, Drevínek P, Lands LC, McKone EF, Polineni D, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381(19):1809-1819. https://doi.org/10.1056/NEJMoa1908639
https://doi.org/10.1056/NEJMoa1908639...
Devido à aprovação recente dessa associação, sua avaliação não foi incorporada no escopo destas diretrizes.

Quanto aos tratamentos clássicos, a dornase alfa1717 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-642. https://doi.org/10.1056/NEJM199409083311003
https://doi.org/10.1056/NEJM199409083311...
é um dos tratamentos incorporados ao Sistema Único de Saúde há mais tempo e que ainda suscita dúvidas quanto ao seu real impacto em desfechos relevantes, como mortalidade e frequência de exacerbações pulmonares.1818 Goss CH, MacNeill SJ, Quinton HB, Marshall BC, Elbert A, Knapp EA, et al. Children and young adults with CF in the USA have better lung function compared with the UK. Thorax. 2015;70(3):229-236. https://doi.org/10.1136/thoraxjnl-2014-205718
https://doi.org/10.1136/thoraxjnl-2014-2...

19 Yang C, Montgomery M. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2021;3(3):CD001127. https://doi.org/10.1002/14651858.CD001127.pub5
https://doi.org/10.1002/14651858.CD00112...
-2020 Grupo Brasileiro de Estudos de Fibrose Cística (GBEFC) [homepage on the Internet]. Curitiba: GBEFC; c2023 [cited 2023 Feb 4]. Registro Brasileiro de Fibrose Cística 2019. [Adobe Acrobat document, 61p.]. Available from: http://portalgbefc.org.br/ckfinder/userfiles/files/REBRAFC_2019.pdf
http://portalgbefc.org.br/ckfinder/userf...

Estratégias de manejo das infecções respiratórias na FC são bastante heterogêneas. Uma avaliação das evidências que suportam os esquemas de erradicação de patógenos como Pseudomonas aeruginosa,2121 Mogayzel PJ Jr, Naureckas ET, Robinson KA, Brady C, Guill M, Lahiri T, et al. Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc. 2014;11(10):1640-1650. https://doi.org/10.1513/AnnalsATS.201404-166OC
https://doi.org/10.1513/AnnalsATS.201404...
methicillin-resistant Staphylococcus aureus (MRSA, Staphylococcus aureus resistente à meticilina)2222 Lo DK, Muhlebach MS, Smyth AR. Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis. Cochrane Database Syst Rev. 2018;7(7):CD009650. https://doi.org/10.1002/14651858.CD009650.pub4
https://doi.org/10.1002/14651858.CD00965...
e cepas do complexo Burkholderia cepacia2323 Garcia BA, Carden JL, Goodwin DL, Smith TA, Gaggar A, Leon K, et al. Implementation of a successful eradication protocol for Burkholderia Cepacia complex in cystic fibrosis patients. BMC Pulm Med. 2018;18(1):35. https://doi.org/10.1186/s12890-018-0594-8
https://doi.org/10.1186/s12890-018-0594-...
poderia trazer um posicionamento mais claro sobre os riscos e benefícios desses tratamentos. Por fim, outra prática comum no tratamento de pessoas com FC é a terapia de supressão da infecção crônica por P. aeruginosa com antibioticoterapia inalatória. Diante do impacto desse tratamento, que impõe longos períodos de nebulização na rotina dos indivíduos,2424 Sawicki GS, Tiddens H. Managing treatment complexity in cystic fibrosis: challenges and opportunities. Pediatr Pulmonol. 2012;47(6):523-533. https://doi.org/10.1002/ppul.22546
https://doi.org/10.1002/ppul.22546...
o tema foi também incluído no presente trabalho.

Desse modo, este artigo especial teve o objetivo de realizar uma revisão sistemática e meta-análise de dados da literatura envolvendo aspectos do tratamento de indivíduos com FC no que concerne ao uso de moduladores da proteína CFTR, dornase alfa e estratégias de erradicação e supressão de patógenos comumente associados a infecções respiratórias nesses indivíduos.

MÉTODOS

As etapas do desenvolvimento das diretrizes seguiram o modelo aprovado e proposto pela Sociedade Brasileira de Pneumologia e Tisiologia, utilizando-se a metodologia Grading of Recommendations Assessment, Development, and Evaluation (GRADE)2525 Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-926. https://doi.org/10.1136/bmj.39489.470347.AD
https://doi.org/10.1136/bmj.39489.470347...
e perguntas no formato designado PICO (Pacientes de interesse, Intervenção a ser estudada, Comparação da intervenção e Outcome [desfecho] de interesse).2626 Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ; et al. What is "quality of evidence" and why is it important to clinicians?. BMJ. 2008;336(7651):995-998. https://doi.org/10.1136/bmj.39490.551019.BE
https://doi.org/10.1136/bmj.39490.551019...
Realizou-se uma reunião virtual em 14/05/2019 para a aprovação da metodologia empregada entre os coordenadores (dois especialistas em FC e dois metodologistas), um paciente e um comitê de experts. Os especialistas formularam perguntas sobre o tratamento farmacológico de pacientes portadores de FC no formato PICO. Em seguida, realizou-se uma votação para a seleção das oito perguntas mais relevantes. Os desfechos de interesse para cada pergunta foram definidos a priori e classificados como críticos ou importantes (Quadro 1).

Quadro 1
Perguntas e respectivos desfechos selecionados para a confecção das diretrizes.

A busca de artigos e a realização da meta-análise foram realizadas por uma equipe de metodologistas experientes, contratados para a realização destas diretrizes. O projeto foi registrado na plataforma International Prospective Register of Systematic Reviews (PROSPERO; Protocolo CRD42020173901). Os bancos de dados MEDLINE e EMBASE foram utilizados para a realização da busca. Foram incluídos na pesquisa ensaios clínicos, estudos de caso-controle e estudos de coorte, com a utilização de palavras-chave pré-estabelecidas pelos coordenadores especialistas, sem restrição de data ou idioma (Quadro S1).

Subsequentemente realizou-se uma avaliação independente dos artigos através dos títulos e resumos. A etapa seguinte avaliou a inclusão dos artigos pela análise qualitativa dos mesmos em sua íntegra por duas metodologistas separadamente; essa seleção foi posteriormente validada pelos coordenadores especialistas. Os motivos de inclusão ou exclusão foram registrados e estão apresentados no material suplementar (Figuras S1 a S8).

Quando apropriado, dados sobre as intervenções farmacológicas foram agrupados, e meta-análises foram realizadas, de maneira independente, pela equipe de metodologia contratada. Para cada uma das oito perguntas PICO, a qualidade das evidências dos estudos incluídos nas meta-análises foi avaliada conforme a metodologia GRADE, através de tabelas de evidência, empregando-se o programa GRADEpro Guideline Development Tool (McMaster University, Hamilton, ON, Canadá).

A qualidade da evidência depende do delineamento, da implementação dos estudos e dos riscos de viés e pode ser classificada em alta, moderada, baixa ou muito baixa (Quadros 2 e 3).2525 Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-926. https://doi.org/10.1136/bmj.39489.470347.AD
https://doi.org/10.1136/bmj.39489.470347...

Quadro 2
Interpretação da qualidade de evidência segundo o sistema Grading of Recommendations Assessment, Development and Evaluation (GRADE).
Quadro 3
Fatores que podem afetar a qualidade da evidência.a

Em dezembro de 2021, o grupo de trabalho reuniu-se para a revisão das evidências e realização de recomendações para cada pergunta conforme a metodologia GRADE. As recomendações foram classificadas em fortes ou condicionais, conforme a certeza sobre a força e qualidade de evidência. Usamos o termo “recomendamos” para recomendações fortes e “sugerimos” para recomendações condicionais. O Quadro 4 mostra interpretações sugeridas dessas recomendações (Tabelas S1 a S8).2626 Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ; et al. What is "quality of evidence" and why is it important to clinicians?. BMJ. 2008;336(7651):995-998. https://doi.org/10.1136/bmj.39490.551019.BE
https://doi.org/10.1136/bmj.39490.551019...
,2727 Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations [published correction appears in BMJ. 2008 Jun 21;336(7658): doi:10.1136/bmj.a402]. BMJ. 2008;336(7652):1049-1051. https://doi.org/10.1136/bmj.a402

Quadro 4
Implicações das recomendações do sistema Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Pergunta 1. Devemos recomendar tratamento com ivacaftor em pacientes com FC portadores de mutações no gene CFTR de regulação (classe 3) ou condutividade (classe 4)?

O ivacaftor é um modulador da proteína CFTR. Esse fármaco atua como potencializador da CFTR, objetivando tratar a disfunção subjacente a esta alteração genética. Sua ação regula a abertura do canal de cloro presente na membrana celular, restaurando a reologia do muco nas vias aéreas.

Em 2012, a agência americana Food and Drug Administration aprovou o uso de ivacaftor para pacientes com FC acima de 12 anos de idade.1111 Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. https://doi.org/10.1056/NEJMoa1105185
https://doi.org/10.1056/NEJMoa1105185...
Trata-se do primeiro fármaco aprovado para FC cuja ação terapêutica é o problema básico da doença, caracterizada pela disfunção da proteína CFTR. Em seguida, diversos ensaios clínicos foram realizados, possibilitando a expansão do uso do medicamento para pacientes a partir de 6 anos de idade.

Evidências

Os estudos analisados sobre o uso de ivacaftor para diferentes desfechos totalizaram 28 publicações (Figura S1 e Quadro S2).1111 Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. https://doi.org/10.1056/NEJMoa1105185
https://doi.org/10.1056/NEJMoa1105185...
,2828 Abou Alaiwa MH, Launspach JL, Grogan B, Carter S, Zabner J, Stoltz DA, et al. Ivacaftor-induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis. JCI Insight. 2018;3(15):e121468. https://doi.org/10.1172/jci.insight.121468
https://doi.org/10.1172/jci.insight.1214...

29 Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363(21):1991-2003. https://doi.org/10.1056/NEJMoa0909825
https://doi.org/10.1056/NEJMoa0909825...

30 Barry PJ, Plant BJ, Nair A, Bicknell S, Simmonds NJ, Bell NJ, et al. Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease. Chest. 2014;146(1):152-158. https://doi.org/10.1378/chest.13-2397
https://doi.org/10.1378/chest.13-2397...

31 Bessonova L, Volkova N, Higgins M, Bengtsson L, Tian S, Simard C, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. 2018;73(8):731-740. https://doi.org/10.1136/thoraxjnl-2017-210394
https://doi.org/10.1136/thoraxjnl-2017-2...

32 Borowitz D, Lubarsky B, Wilschanski M, Munck A, Gelfond D, Bodewes F, et al. Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor. Dig Dis Sci. 2016;61(1):198-207. https://doi.org/10.1007/s10620-015-3834-2
https://doi.org/10.1007/s10620-015-3834-...

33 Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219-1225. https://doi.org/10.1164/rccm.201301-0153OC
https://doi.org/10.1164/rccm.201301-0153...

34 De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014;13(6):674-680. https://doi.org/10.1016/j.jcf.2014.09.005
https://doi.org/10.1016/j.jcf.2014.09.00...

35 Donaldson SH, Laube BL, Corcoran TE, Bhambhvani P, Zeman K, Ceppe A, et al. Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR. JCI Insight. 2018;3(24):e122695. https://doi.org/10.1172/jci.insight.122695
https://doi.org/10.1172/jci.insight.1226...

36 Edgeworth D, Keating D, Ellis M, Button B, Williams E, Clark D, et al. Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients: a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment. Clin Sci (Lond). 2017;131(15):2037-2045. https://doi.org/10.1042/CS20170995
https://doi.org/10.1042/CS20170995...

37 Gomez-Pastrana D, Nwokoro C, McLean M, Brown S, Christiansen N, Pao CS. Real-world effectiveness of ivacaftor in children with cystic fibrosis and the G551D mutation [Article in Spanish]. An Pediatr (Engl Ed). 2019;90(3):148-156. https://doi.org/10.1016/j.anpedi.2018.05.022
https://doi.org/10.1016/j.anpedi.2018.05...

38 Guerra L, D'Oria S, Favia M, Castellani S, Santostasi T, Polizzi AM, et al. CFTR-dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy. Pediatr Pulmonol. 2017;52(7):900-908. https://doi.org/10.1002/ppul.23712
https://doi.org/10.1002/ppul.23712...

39 Guimbellot J, Solomon GM, Baines A, Heltshe SL, VanDalfsen J, Joseloff E, et al. Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations. J Cyst Fibros. 2019;18(1):102-109. https://doi.org/10.1016/j.jcf.2018.04.004
https://doi.org/10.1016/j.jcf.2018.04.00...

40 Harris JK, Wagner BD, Zemanick ET, Robertson CE, Stevens MJ, Heltshe SL, et al. Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation. Ann Am Thorac Soc. 2020;17(2):212-220. https://doi.org/10.1513/AnnalsATS.201907-493OC
https://doi.org/10.1513/AnnalsATS.201907...

41 Hebestreit H, Sauer-Heilborn A, Fischer R, Käding M, Mainz JG. Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. J Cyst Fibros. 2013;12(6):599-603. https://doi.org/10.1016/j.jcf.2013.05.006
https://doi.org/10.1016/j.jcf.2013.05.00...

42 Hubert D, Dehillotte C, Munck A, David V, Baek J, Mely L, et al. Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2years of treatment with ivacaftor in a real-world setting. J Cyst Fibros. 2018;17(1):89-95. https://doi.org/10.1016/j.jcf.2017.07.001
https://doi.org/10.1016/j.jcf.2017.07.00...

43 McKone EF, Borowitz D, Drevinek P, Griese M, Konstan MW, Wainwright C, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med. 2014;2(11):902-910. https://doi.org/10.1016/S2213-2600(14)70218-8
https://doi.org/10.1016/S2213-2600(14)70...

44 Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015;3(7):524-533. https://doi.org/10.1016/S2213-2600(15)00201-5
https://doi.org/10.1016/S2213-2600(15)00...

45 Quittner A, Suthoff E, Rendas-Baum R, Bayliss MS, Sermet-Gaudelus I, Castiglione B, et al. Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation: patient-reported outcomes in the STRIVE randomized, controlled trial. Health Qual Life Outcomes. 2015;13:93. https://doi.org/10.1186/s12955-015-0293-6
https://doi.org/10.1186/s12955-015-0293-...

46 Ronan NJ, Einarsson GG, Twomey M, Mooney D, Mullane D, NiChroinin M, et al. CORK Study in Cystic Fibrosis: Sustained Improvements in Ultra-Low-Dose Chest CT Scores After CFTR Modulation With Ivacaftor. Chest. 2018;153(2):395-403. https://doi.org/10.1016/j.chest.2017.10.005
https://doi.org/10.1016/j.chest.2017.10....

47 Rosenfeld M, Wainwright CE, Higgins M, Wang LT, McKee C, Campbell D, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study [published correction appears in Lancet Respir Med. 2018 Jul;6(7):e35] [published correction appears in Lancet Respir Med. 2019 Apr;7(4):e15]. Lancet Respir Med. 2018;6(7):545-553. https://doi.org/10.1016/S2213-2600(18)30202-9
https://doi.org/10.1016/S2213-2600(18)30...

48 Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014;190(2):175-184. https://doi.org/10.1164/rccm.201404-0703OC
https://doi.org/10.1164/rccm.201404-0703...

49 Salvatore D, Carnovale V, Iacotucci P, Braggion C, Castellani C, Cimino G, et al. Effectivenesss of ivacaftor in severe cystic fibrosis patients and non-G551D gating mutations. Pediatr Pulmonol. 2019;54(9):1398-1403. https://doi.org/10.1002/ppul.24424
https://doi.org/10.1002/ppul.24424...

50 Sheikh SI, Long FR, McCoy KS, Johnson T, Ryan-Wenger NA, Hayes D Jr. Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation. J Cyst Fibros. 2015;14(1):84-89. https://doi.org/10.1016/j.jcf.2014.06.011
https://doi.org/10.1016/j.jcf.2014.06.01...

51 Sheikh SI, Long FR, McCoy KS, Johnson T, Ryan-Wenger NA, Hayes D Jr. Ivacaftor improves appearance of sinus disease on computerised tomography in cystic fibrosis patients with G551D mutation. Clin Otolaryngol. 2015;40(1):16-21. https://doi.org/10.1111/coa.12310
https://doi.org/10.1111/coa.12310...

52 Stallings VA, Sainath N, Oberle M, Bertolaso C, Schall JI. Energy Balance and Mechanisms of Weight Gain with Ivacaftor Treatment of Cystic Fibrosis Gating Mutations. J Pediatr. 2018;201:229-237.e4. https://doi.org/10.1016/j.jpeds.2018.05.018
https://doi.org/10.1016/j.jpeds.2018.05....

53 Taylor-Cousar J, Niknian M, Gilmartin G, Pilewski JM; VX11-770-901 investigators. Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States. J Cyst Fibros. 2016;15(1):116-122. https://doi.org/10.1016/j.jcf.2015.01.008
https://doi.org/10.1016/j.jcf.2015.01.00...
-5454 van de Peppel IP, Doktorova M, Berkers G, de Jonge HR, Houwen RHJ, Verkade HJ, et al. IVACAFTOR restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation. J Cyst Fibros. 2019;18(2):286-293. https://doi.org/10.1016/j.jcf.2018.09.001
https://doi.org/10.1016/j.jcf.2018.09.00...
Dos 28 estudos incluídos na revisão, 8 foram ensaios clínicos randomizados (ECR).1111 Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. https://doi.org/10.1056/NEJMoa1105185
https://doi.org/10.1056/NEJMoa1105185...
,2929 Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363(21):1991-2003. https://doi.org/10.1056/NEJMoa0909825
https://doi.org/10.1056/NEJMoa0909825...
,3232 Borowitz D, Lubarsky B, Wilschanski M, Munck A, Gelfond D, Bodewes F, et al. Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor. Dig Dis Sci. 2016;61(1):198-207. https://doi.org/10.1007/s10620-015-3834-2
https://doi.org/10.1007/s10620-015-3834-...

33 Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219-1225. https://doi.org/10.1164/rccm.201301-0153OC
https://doi.org/10.1164/rccm.201301-0153...
-3434 De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014;13(6):674-680. https://doi.org/10.1016/j.jcf.2014.09.005
https://doi.org/10.1016/j.jcf.2014.09.00...
,3636 Edgeworth D, Keating D, Ellis M, Button B, Williams E, Clark D, et al. Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients: a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment. Clin Sci (Lond). 2017;131(15):2037-2045. https://doi.org/10.1042/CS20170995
https://doi.org/10.1042/CS20170995...
,4444 Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015;3(7):524-533. https://doi.org/10.1016/S2213-2600(15)00201-5
https://doi.org/10.1016/S2213-2600(15)00...
,4545 Quittner A, Suthoff E, Rendas-Baum R, Bayliss MS, Sermet-Gaudelus I, Castiglione B, et al. Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation: patient-reported outcomes in the STRIVE randomized, controlled trial. Health Qual Life Outcomes. 2015;13:93. https://doi.org/10.1186/s12955-015-0293-6
https://doi.org/10.1186/s12955-015-0293-...
Embora nem todos tenham investigado os mesmos conjuntos de desfechos, na sua abrangência, os artigos demonstraram efeito terapêutico benéfico do ivacaftor nos pacientes portadores de mutações de regulação (classe 3) ou condutividade (classe 4).

Uma descrição detalhada dos achados pode ser encontrada no material suplementar (Pergunta S1). O resumo da qualidade das evidências dos artigos selecionados para esta questão 1 está listado nas Tabelas S1A e S1B.

Em 2020, Volkova et al.5555 Volkova N, Moy K, Evans J, Campbell D, Tian S, Simard C, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. J Cyst Fibros. 2020;19(1):68-79. https://doi.org/10.1016/j.jcf.2019.05.015
https://doi.org/10.1016/j.jcf.2019.05.01...
avaliaram a progressão da doença (estudo de vida real) em pacientes tratados com ivacaftor por 5 anos. Foram avaliados pacientes incluídos em registros de FC nos EUA e no Reino Unido, os quais mantêm alto grau de integridade de dados. Foram analisados 635 casos vs. 1.875 controles no registro americano e 247 casos vs. 1.230 controles no registro britânico. Os autores observaram que o grupo ivacaftor apresentou melhor função pulmonar, melhor estado nutricional e menor frequência de exacerbações e de hospitalizações ao final de 5 anos de seguimento quando comparados a seus valores basais ou ao grupo controle (terapia padrão sem ivacaftor).5555 Volkova N, Moy K, Evans J, Campbell D, Tian S, Simard C, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. J Cyst Fibros. 2020;19(1):68-79. https://doi.org/10.1016/j.jcf.2019.05.015
https://doi.org/10.1016/j.jcf.2019.05.01...

Recomendação

Para pacientes com FC e ao menos uma mutação de regulação (classe 3) ou condutividade (classe 4), nós sugerimos o uso de ivacaftor (recomendação condicional, muito baixa qualidade de evidência).

Comentários

Os resultados nos estudos de vida real do uso de ivacaftor são semelhantes aos observados nos estudos clínicos, favorecendo seu efeito positivo como droga modificadora da progressão natural da doença. A muito baixa qualidade da evidência encontrada decorre da alta heterogeneidade dos estudos avaliados, uma vez que o presente método de revisão sistemática incluiu a análise tanto de ensaios clínicos como de estudos observacionais. Os estudos avaliados incluíram somente pacientes com idade ≥ 6 anos, não sendo possível extrapolar a recomendação para a faixa etária mais precoce.

Pergunta 2. Devemos recomendar o tratamento com a associação lumacaftor + ivacaftor em pacientes com FC homozigotos F508del?

O lumacaftor e o ivacaftor são moduladores da proteína CFTR. O lumacaftor é um corretor da CFTR, que atua no processamento da proteína, corrigindo seu formato, com consequente aumento da sua quantidade na superfície da membrana celular.44 Habib AR, Kajbafzadeh M, Desai S, Yang CL, Skolnik K, Quon BS. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis. Sci Rep. 2019;9(1):7234. https://doi.org/10.1038/s41598-019-43652-2
https://doi.org/10.1038/s41598-019-43652...

A terapia combinada foi avaliada em pacientes fibrocísticos com 6 anos ou mais, homozigotos para a mutação de classe II F508del. Os resultados indicaram uma redução no número de exacerbações pulmonares, aumento discreto do VEF1, melhora no estado nutricional e na qualidade de vida e redução dos níveis de cloreto no suor.1212 Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231. https://doi.org/10.1056/NEJMoa1409547
https://doi.org/10.1056/NEJMoa1409547...
,5656 Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2):107-118. https://doi.org/10.1016/S2213-2600(16)30427-1
https://doi.org/10.1016/S2213-2600(16)30...

57 Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial [published correction appears in Lancet Respir Med. 2017 Aug;5(8):e28]. Lancet Respir Med. 2017;5(7):557-567. https://doi.org/10.1016/S2213-2600(17)30215-1
https://doi.org/10.1016/S2213-2600(17)30...

58 Burgel PR, Munck A, Durieu I, Chiron R, Mely L, Prevotat A, et al. Real-Life Safety and Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2020;201(2):188-197. https://doi.org/10.1164/rccm.201906-1227OC
https://doi.org/10.1164/rccm.201906-1227...

59 Diab-Cáceres L, Girón-Moreno RM, Pastor-Sanz MT, Quintana-Gallego E, Delgado-Pecellín I, Blanco-Aparicio M, et al. Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish Experience. Arch Bronconeumol (Engl Ed). 2018;54(12):614-618. https://doi.org/10.1016/j.arbr.2018.05.020
https://doi.org/10.1016/j.arbr.2018.05.0...
-6060 Graeber SY, Dopfer C, Naehrlich L, Gyulumyan L, Scheuermann H, Hirtz S, et al. Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2018;197(11):1433-1442. https://doi.org/10.1164/rccm.201710-1983OC
https://doi.org/10.1164/rccm.201710-1983...

A associação de lumacaftor + ivacaftor foi aprovada por diversas agências internacionais, incluindo a ANVISA, frente aos benefícios apresentados. Além disso, a associação demonstrou um perfil aceitável de segurança, com a maioria dos pacientes completando o regime terapêutico prescrito e tendo baixa incidência de eventos adversos relevantes.1212 Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231. https://doi.org/10.1056/NEJMoa1409547
https://doi.org/10.1056/NEJMoa1409547...
,5656 Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2):107-118. https://doi.org/10.1016/S2213-2600(16)30427-1
https://doi.org/10.1016/S2213-2600(16)30...
,5757 Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial [published correction appears in Lancet Respir Med. 2017 Aug;5(8):e28]. Lancet Respir Med. 2017;5(7):557-567. https://doi.org/10.1016/S2213-2600(17)30215-1
https://doi.org/10.1016/S2213-2600(17)30...

Evidências

Utilizando-se da metodologia descrita, foram selecionados 15 estudos, que foram posteriormente incluídos para leitura, revisão e síntese das evidências (Figura S2 e Quadro S3).1212 Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231. https://doi.org/10.1056/NEJMoa1409547
https://doi.org/10.1056/NEJMoa1409547...
,5656 Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2):107-118. https://doi.org/10.1016/S2213-2600(16)30427-1
https://doi.org/10.1016/S2213-2600(16)30...

57 Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial [published correction appears in Lancet Respir Med. 2017 Aug;5(8):e28]. Lancet Respir Med. 2017;5(7):557-567. https://doi.org/10.1016/S2213-2600(17)30215-1
https://doi.org/10.1016/S2213-2600(17)30...

58 Burgel PR, Munck A, Durieu I, Chiron R, Mely L, Prevotat A, et al. Real-Life Safety and Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2020;201(2):188-197. https://doi.org/10.1164/rccm.201906-1227OC
https://doi.org/10.1164/rccm.201906-1227...

59 Diab-Cáceres L, Girón-Moreno RM, Pastor-Sanz MT, Quintana-Gallego E, Delgado-Pecellín I, Blanco-Aparicio M, et al. Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish Experience. Arch Bronconeumol (Engl Ed). 2018;54(12):614-618. https://doi.org/10.1016/j.arbr.2018.05.020
https://doi.org/10.1016/j.arbr.2018.05.0...

60 Graeber SY, Dopfer C, Naehrlich L, Gyulumyan L, Scheuermann H, Hirtz S, et al. Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2018;197(11):1433-1442. https://doi.org/10.1164/rccm.201710-1983OC
https://doi.org/10.1164/rccm.201710-1983...

61 Hubert D, Chiron R, Camara B, Grenet D, Prévotat A, Bassinet L, et al. Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease. J Cyst Fibros. 2017;16(3):388-391. https://doi.org/10.1016/j.jcf.2017.03.003
https://doi.org/10.1016/j.jcf.2017.03.00...

62 Jennings MT, Dezube R, Paranjape S, West NE, Hong G, Braun A, et al. An Observational Study of Outcomes and Tolerances in Patients with Cystic Fibrosis Initiated on Lumacaftor/Ivacaftor. Ann Am Thorac Soc. 2017;14(11):1662-1666. https://doi.org/10.1513/AnnalsATS.201701-058OC
https://doi.org/10.1513/AnnalsATS.201701...

63 Masson A, Schneider-Futschik EK, Baatallah N, Nguyen-Khoa T, Girodon E, Hatton A, et al. Predictive factors for lumacaftor/ivacaftor clinical response. J Cyst Fibros. 2019;18(3):368-374. https://doi.org/10.1016/j.jcf.2018.12.011
https://doi.org/10.1016/j.jcf.2018.12.01...

64 McNamara JJ, McColley SA, Marigowda G, Liu F, Tian S, Owen CA, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019;7(4):325-335. https://doi.org/10.1016/S2213-2600(18)30460-0
https://doi.org/10.1016/S2213-2600(18)30...

65 Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M; et al. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912-920. https://doi.org/10.1164/rccm.201608-1754OC
https://doi.org/10.1164/rccm.201608-1754...

66 Murer C, Huber LC, Kurowski T, Hirt A, Robinson CA, Bürgi U, et al. First experience in Switzerland in Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease enrolled in a lumacaftor-ivacaftor therapy trial - preliminary results. Swiss Med Wkly. 2018;148:w14593. https://doi.org/10.4414/smw.2018.14593
https://doi.org/10.4414/smw.2018.14593...

67 Taylor-Cousar JL, Jain M, Barto TL, Haddad T, Atkinson J, Tian S, et al. Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR. J Cyst Fibros. 2018;17(2):228-235. https://doi.org/10.1016/j.jcf.2017.09.012
https://doi.org/10.1016/j.jcf.2017.09.01...

68 Tesell MA, Alper CJ, Bacon R, Greenwood BC, Lenz K, Jeffrey PL, et al. Effect of Lumacaftor/Ivacaftor on Pulmonary Exacerbation Rates in Members with Cystic Fibrosis in a Medicaid Population. J Manag Care Spec Pharm. 2019;25(9):1021-1025. https://doi.org/10.18553/jmcp.2019.25.9.1021
https://doi.org/10.18553/jmcp.2019.25.9....
-6969 Wark PAB, Cookson K, Thiruchelvam T, Brannan J, Dorahy DJ. Lumacaftor/ Ivacaftor improves exercise tolerance in patients with Cystic Fibrosis and severe airflow obstruction. BMC Pulm Med. 2019;19(1):106. https://doi.org/10.1186/s12890-019-0866-y
https://doi.org/10.1186/s12890-019-0866-...

Dos 15 estudos selecionados, apenas 2 foram ECR.1212 Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231. https://doi.org/10.1056/NEJMoa1409547
https://doi.org/10.1056/NEJMoa1409547...
,5757 Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial [published correction appears in Lancet Respir Med. 2017 Aug;5(8):e28]. Lancet Respir Med. 2017;5(7):557-567. https://doi.org/10.1016/S2213-2600(17)30215-1
https://doi.org/10.1016/S2213-2600(17)30...
Embora nem todos tenham investigado os mesmos conjuntos de desfechos, na sua abrangência, os artigos demonstraram efeito terapêutico benéfico da combinação lumacaftor + ivacaftor nos pacientes homozigotos para F508del.

Uma descrição detalhada dos achados pode ser encontrada no material suplementar (Pergunta S2). O resumo da qualidade das evidências dos artigos selecionados para esta questão 2 está listado nas Tabelas S2A e S2B.

Recomendação

Para pacientes com FC e mutação F508del em homozigose nós não sugerimos o uso de lumacaftor + ivacaftor (recomendação condicional, muito baixa qualidade de evidência).

Comentários

A combinação de um fármaco corretor com outro potencializador da CFTR pode beneficiar pacientes homozigotos para F508del, representando um diferencial no tratamento de aproximadamente 45% dos indivíduos portadores de FC e dessa mutação. Entretanto, a presente revisão sistemática não foi capaz de encontrar resultados significativos em relação aos desfechos clínicos considerados críticos. Os achados positivos encontrados nos desfechos considerados importantes foram apenas marginais. Devido à qualidade de evidência muito baixa para a maior parte dos desfechos avaliados, alguns pacientes podem se beneficiar do tratamento; porém, não sugerimos o uso da associação de lumacaftor + ivacaftor para o tratamento de pacientes com FC e presença de mutação F508del em homozigose. É importante ressaltar que novas classes de moduladores como tezacaftor + ivacaftor1313 Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. https://doi.org/10.1056/NEJMoa1709846
https://doi.org/10.1056/NEJMoa1709846...
e, mais recentemente, a associação tripla (elexacaftor + tezacaftor + ivacaftor)1515 Heijerman HGM, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2020 May 30;395(10238):1694]. Lancet. 2019;394(10212):1940-1948. https://doi.org/10.1016/S0140-6736(19)32597-8
https://doi.org/10.1016/S0140-6736(19)32...
foram aprovados e apresentaram um perfil melhor de eficácia e segurança para essa população.

Pergunta 3. Devemos recomendar o tratamento com a associação tezacaftor + ivacaftor em pacientes com FC homozigotos para F508del ou heterozigotos para F508del e com mutações de função residual?

O tezacaftor é uma molécula corretora da proteína CFTR que se liga a essa proteína melhorando seu processamento e trânsito através da célula até a membrana celular.99 Guimbellot J, Sharma J, Rowe SM. Toward inclusive therapy with CFTR modulators: Progress and challenges. Pediatr Pulmonol. 2017;52(S48):S4-S14. https://doi.org/10.1002/ppul.23773
https://doi.org/10.1002/ppul.23773...

A associação tezacaftor + ivacaftor foi avaliada em estudos de fase 3 envolvendo pacientes com FC acima de 12 anos homozigotos para a mutação F508del1313 Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. https://doi.org/10.1056/NEJMoa1709846
https://doi.org/10.1056/NEJMoa1709846...
bem como para pacientes heterozigotos F508del mais mutação de função residual.1414 Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017;377(21):2024-2035. https://doi.org/10.1056/NEJMoa1709847
https://doi.org/10.1056/NEJMoa1709847...
Naqueles estudos, a associação tezacaftor + ivacaftor demonstrou melhora significativa na função pulmonar, redução no número de exacerbações e ganho nutricional com adequado perfil de segurança. Resultados semelhantes foram verificados em pacientes entre 6 e 11 anos.7070 Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32(4):277-287. https://doi.org/10.1002/ppul.2009.abs
https://doi.org/10.1002/ppul.2009.abs...

71 Blanchard AC, Horton E, Stanojevic S, Taylor L, Waters V, Ratjen F. Effectiveness of a stepwise Pseudomonas aeruginosa eradication protocol in children with cystic fibrosis. J Cyst Fibros. 2017;16(3):395-400. https://doi.org/10.1016/j.jcf.2017.01.007
https://doi.org/10.1016/j.jcf.2017.01.00...
-7272 Claude F, Rochat I, Hafen GM. No benefit of longer eradication therapy of Pseudomonas aeruginosa primoinfections in pediatric cystic fibrosis. BMC Res Notes. 2019;12(1):115. https://doi.org/10.1186/s13104-019-4157-8
https://doi.org/10.1186/s13104-019-4157-...
Dessa forma, a associação tezacaftor + ivacaftor foi aprovada para uso em pacientes em diversos países, incluindo no Brasil.

Evidências

Foram selecionados 5 artigos1313 Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. https://doi.org/10.1056/NEJMoa1709846
https://doi.org/10.1056/NEJMoa1709846...
,1414 Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017;377(21):2024-2035. https://doi.org/10.1056/NEJMoa1709847
https://doi.org/10.1056/NEJMoa1709847...
,7070 Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32(4):277-287. https://doi.org/10.1002/ppul.2009.abs
https://doi.org/10.1002/ppul.2009.abs...

71 Blanchard AC, Horton E, Stanojevic S, Taylor L, Waters V, Ratjen F. Effectiveness of a stepwise Pseudomonas aeruginosa eradication protocol in children with cystic fibrosis. J Cyst Fibros. 2017;16(3):395-400. https://doi.org/10.1016/j.jcf.2017.01.007
https://doi.org/10.1016/j.jcf.2017.01.00...
-7272 Claude F, Rochat I, Hafen GM. No benefit of longer eradication therapy of Pseudomonas aeruginosa primoinfections in pediatric cystic fibrosis. BMC Res Notes. 2019;12(1):115. https://doi.org/10.1186/s13104-019-4157-8
https://doi.org/10.1186/s13104-019-4157-...
a partir da metodologia descrita (Figura S3 e Quadro S4), sendo 4 ECR e 1 estudo observacional. Todos avaliaram mais de um desfecho, entre eles IMC, qualidade de vida, eventos adversos, ocorrência de exacerbações, função pulmonar e mortalidade.1313 Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. https://doi.org/10.1056/NEJMoa1709846
https://doi.org/10.1056/NEJMoa1709846...
,1414 Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017;377(21):2024-2035. https://doi.org/10.1056/NEJMoa1709847
https://doi.org/10.1056/NEJMoa1709847...
,7070 Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32(4):277-287. https://doi.org/10.1002/ppul.2009.abs
https://doi.org/10.1002/ppul.2009.abs...

71 Blanchard AC, Horton E, Stanojevic S, Taylor L, Waters V, Ratjen F. Effectiveness of a stepwise Pseudomonas aeruginosa eradication protocol in children with cystic fibrosis. J Cyst Fibros. 2017;16(3):395-400. https://doi.org/10.1016/j.jcf.2017.01.007
https://doi.org/10.1016/j.jcf.2017.01.00...
-7272 Claude F, Rochat I, Hafen GM. No benefit of longer eradication therapy of Pseudomonas aeruginosa primoinfections in pediatric cystic fibrosis. BMC Res Notes. 2019;12(1):115. https://doi.org/10.1186/s13104-019-4157-8
https://doi.org/10.1186/s13104-019-4157-...

O resumo da qualidade das evidências dos artigos selecionados para esta questão 3 está listado na Tabela S3. Uma descrição detalhada dos achados pode ser encontrada no material suplementar (Pergunta S3).

Recomendação

Para pacientes com FC e mutação F508del em homozigose ou F508del em heterozigose mais mutação de função residual, nós sugerimos o uso de tezacaftor + ivacaftor (recomendação condicional, muito baixa qualidade de evidência).

Comentários

O uso da associação tezacaftor +ivacaftor foi avaliado em pacientes portadores de mutações F508del em homozigose e em portadores heterozigotos para F508del mais mutação de função residual em indivíduos a partir de 6 anos. O principal efeito do fármaco foi encontrado na função pulmonar. O ganho de VEF1, apesar de modesto, quando considerado em contexto de doença que cursa com queda progressiva da função pulmonar, parece significativo. É importante ressaltar que os benefícios clínicos obtidos em pacientes portadores de função residual parecem superiores aos encontrados em pacientes homozigotos F508del. Não houve diferença na ocorrência de eventos adversos entre os grupos controle e tezacaftor + ivacaftor em todos os estudos avaliados. A maioria dos eventos adversos verificados foi leve e não levou a descontinuação da associação. Além disso, muitos dos eventos encontrados podem estar relacionados à própria doença (tais como aumento da secreção pulmonar e aumento da tosse), evidenciando o perfil adequado de segurança do medicamento.1313 Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. https://doi.org/10.1056/NEJMoa1709846
https://doi.org/10.1056/NEJMoa1709846...
,1414 Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017;377(21):2024-2035. https://doi.org/10.1056/NEJMoa1709847
https://doi.org/10.1056/NEJMoa1709847...
,7070 Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32(4):277-287. https://doi.org/10.1002/ppul.2009.abs
https://doi.org/10.1002/ppul.2009.abs...

71 Blanchard AC, Horton E, Stanojevic S, Taylor L, Waters V, Ratjen F. Effectiveness of a stepwise Pseudomonas aeruginosa eradication protocol in children with cystic fibrosis. J Cyst Fibros. 2017;16(3):395-400. https://doi.org/10.1016/j.jcf.2017.01.007
https://doi.org/10.1016/j.jcf.2017.01.00...
-7272 Claude F, Rochat I, Hafen GM. No benefit of longer eradication therapy of Pseudomonas aeruginosa primoinfections in pediatric cystic fibrosis. BMC Res Notes. 2019;12(1):115. https://doi.org/10.1186/s13104-019-4157-8
https://doi.org/10.1186/s13104-019-4157-...

Pergunta 4. Em indivíduos com FC, devemos recomendar a erradicação da infecção por P. aeruginosa?

As infecções do trato respiratório são frequentes nos indivíduos com FC, havendo maior susceptibilidade para a infecção por alguns micro-organismos, dentre os quais P. aeruginosa. A infecção por esse patógeno é considerada um grande preditor de morbidade e mortalidade da doença7373 Davies JC, Sermet-Gaudelus I, Naehrlich L, Harris RS, Campbell D, Ahluwalia N, et al. A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation. J Cyst Fibros. 2021;20(1):68-77. https://doi.org/10.1016/j.jcf.2020.07.023
https://doi.org/10.1016/j.jcf.2020.07.02...
e de perda da função pulmonar acentuada.7474 Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, et al. Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med. 2018;197(2):214-224. https://doi.org/10.1164/rccm.201704-0717OC
https://doi.org/10.1164/rccm.201704-0717...
Desde a década de 1990, os centros de referência de FC têm utilizado esquemas de erradicação precoce desse micro-organismo, objetivando retardar a progressão para a infecção crônica e seus desfechos desfavoráveis.

Evidências

Empregando-se a metodologia descrita, foram selecionados 17 artigos,7575 Walker S, Flume P, McNamara J, Solomon M, Chilvers M, Chmiel J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis. J Cyst Fibros. 2019;18(5):708-713. https://doi.org/10.1016/j.jcf.2019.06.009
https://doi.org/10.1016/j.jcf.2019.06.00...

76 Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34(2):91-100. https://doi.org/10.1002/ppul.10127
https://doi.org/10.1002/ppul.10127...

77 Cohen-Cymberknoh M, Gilead N, Gartner S, Rovira S, Blau H, Mussaffi H, et al. Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis. J Cyst Fibros. 2016;15(6):776-782. https://doi.org/10.1016/j.jcf.2016.04.006
https://doi.org/10.1016/j.jcf.2016.04.00...

78 Emiralioglu N, Yalcin E, Meral A, Sener B, Dogru D, Ozcelik U, et al. The success of the different eradication therapy regimens for Pseudomonas aeruginosa in cystic fibrosis. J Clin Pharm Ther. 2016;41(4):419-423. https://doi.org/10.1111/jcpt.12407
https://doi.org/10.1111/jcpt.12407...

79 Frederiksen B, Koch C, Høiby N. Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol. 1997;23(5):330-335. https://doi.org/10.1002/(SICI)1099-0496(199705)23:5<330::AID-PPUL4>3.0.CO;2-O
https://doi.org/10.1002/(SICI)1099-0496(...

80 Giugno H, Castaños C, Lubatti A, Pinheiro JL, Hernández C, González Pena H. Early antibiotic treatment for eradication of initial infection by Pseudomonas aeruginosa in patients with cystic fibrosis. Arch Argent Pediatr. 2010;108(2):141-147. https://doi.org/10.1590/S0325-00752010000200009
https://doi.org/10.1590/S0325-0075201000...

81 Hewer SCL, Smyth AR, Brown M, Jones AP, Hickey H, Kenna D, et al. Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial. Lancet Respir Med. 2020;8(10):975-986. https://doi.org/10.1016/S2213-2600(20)30331-3
https://doi.org/10.1016/S2213-2600(20)30...

82 Kenny SL, Shaw TD, Downey DG, Moore JE, Rendall JC, Elborn JS. Eradication of Pseudomonas aeruginosa in adults with cystic fibrosis. BMJ Open Respir Res. 2014;1(1):e000021. https://doi.org/10.1136/bmjresp-2014-000021
https://doi.org/10.1136/bmjresp-2014-000...

83 Mayer-Hamblett N, Kloster M, Rosenfeld M, Gibson RL, Retsch-Bogart GZ, Emerson J, et al. Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis. Clin Infect Dis. 2015;61(5):707-715. https://doi.org/10.1093/cid/civ377
https://doi.org/10.1093/cid/civ377...

84 Proesmans M, Vermeulen F, Boulanger L, Verhaegen J, De Boeck K. Comparison of two treatment regimens for eradication of Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros. 2013;12(1):29-34. https://doi.org/10.1016/j.jcf.2012.06.001
https://doi.org/10.1016/j.jcf.2012.06.00...

85 Ratjen F, Munck A, Kho P, Angyalosi G; ELITE Study Group. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax. 2010;65(4):286-291. https://doi.org/10.1136/thx.2009.121657
https://doi.org/10.1136/thx.2009.121657...

86 Ratjen F, Moeller A, McKinney ML, Asherova I, Alon N, Maykut R, et al. Eradication of early P. aeruginosa infection in children <7 years of age with cystic fibrosis: The early study. J Cyst Fibros. 2019;18(1):78-85. https://doi.org/10.1016/j.jcf.2018.04.002
https://doi.org/10.1016/j.jcf.2018.04.00...

87 Taccetti G, Campana S, Festini F, Mascherini M, Döring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J. 2005;26(3):458-461. https://doi.org/10.1183/09031936.05.00009605
https://doi.org/10.1183/09031936.05.0000...

88 Taccetti G, Bianchini E, Cariani L, Buzzetti R, Costantini D, Trevisan F, et al. Early antibiotic treatment for Pseudomonas aeruginosa eradication in patients with cystic fibrosis: a randomised multicentre study comparing two different protocols. Thorax. 2012;67(10):853-859. https://doi.org/10.1136/thoraxjnl-2011-200832
https://doi.org/10.1136/thoraxjnl-2011-2...

89 Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011;165(9):847-856. https://doi.org/10.1001/archpediatrics.2011.136
https://doi.org/10.1001/archpediatrics.2...

90 Valerius NH, Koch C, Høiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. Lancet. 1991;338(8769):725-726. https://doi.org/10.1016/0140-6736(91)91446-2
https://doi.org/10.1016/0140-6736(91)914...
-9191 Wiesemann HG, Steinkamp G, Ratjen F, Bauernfeind A, Przyklenk B, Döring G, et al. Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis. Pediatr Pulmonol. 1998;25(2):88-92. https://doi.org/10.1002/(SICI)1099-0496(199802)25:2<88::AID-PPUL3>3.0.CO;2-J
https://doi.org/10.1002/(SICI)...
dos quais 10 eram estudos observacionais7575 Walker S, Flume P, McNamara J, Solomon M, Chilvers M, Chmiel J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis. J Cyst Fibros. 2019;18(5):708-713. https://doi.org/10.1016/j.jcf.2019.06.009
https://doi.org/10.1016/j.jcf.2019.06.00...

76 Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34(2):91-100. https://doi.org/10.1002/ppul.10127
https://doi.org/10.1002/ppul.10127...

77 Cohen-Cymberknoh M, Gilead N, Gartner S, Rovira S, Blau H, Mussaffi H, et al. Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis. J Cyst Fibros. 2016;15(6):776-782. https://doi.org/10.1016/j.jcf.2016.04.006
https://doi.org/10.1016/j.jcf.2016.04.00...

78 Emiralioglu N, Yalcin E, Meral A, Sener B, Dogru D, Ozcelik U, et al. The success of the different eradication therapy regimens for Pseudomonas aeruginosa in cystic fibrosis. J Clin Pharm Ther. 2016;41(4):419-423. https://doi.org/10.1111/jcpt.12407
https://doi.org/10.1111/jcpt.12407...

79 Frederiksen B, Koch C, Høiby N. Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol. 1997;23(5):330-335. https://doi.org/10.1002/(SICI)1099-0496(199705)23:5<330::AID-PPUL4>3.0.CO;2-O
https://doi.org/10.1002/(SICI)1099-0496(...
-8080 Giugno H, Castaños C, Lubatti A, Pinheiro JL, Hernández C, González Pena H. Early antibiotic treatment for eradication of initial infection by Pseudomonas aeruginosa in patients with cystic fibrosis. Arch Argent Pediatr. 2010;108(2):141-147. https://doi.org/10.1590/S0325-00752010000200009
https://doi.org/10.1590/S0325-0075201000...
,8282 Kenny SL, Shaw TD, Downey DG, Moore JE, Rendall JC, Elborn JS. Eradication of Pseudomonas aeruginosa in adults with cystic fibrosis. BMJ Open Respir Res. 2014;1(1):e000021. https://doi.org/10.1136/bmjresp-2014-000021
https://doi.org/10.1136/bmjresp-2014-000...
,8383 Mayer-Hamblett N, Kloster M, Rosenfeld M, Gibson RL, Retsch-Bogart GZ, Emerson J, et al. Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis. Clin Infect Dis. 2015;61(5):707-715. https://doi.org/10.1093/cid/civ377
https://doi.org/10.1093/cid/civ377...
,8686 Ratjen F, Moeller A, McKinney ML, Asherova I, Alon N, Maykut R, et al. Eradication of early P. aeruginosa infection in children <7 years of age with cystic fibrosis: The early study. J Cyst Fibros. 2019;18(1):78-85. https://doi.org/10.1016/j.jcf.2018.04.002
https://doi.org/10.1016/j.jcf.2018.04.00...
,8787 Taccetti G, Campana S, Festini F, Mascherini M, Döring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J. 2005;26(3):458-461. https://doi.org/10.1183/09031936.05.00009605
https://doi.org/10.1183/09031936.05.0000...
e 7 ECR,8181 Hewer SCL, Smyth AR, Brown M, Jones AP, Hickey H, Kenna D, et al. Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial. Lancet Respir Med. 2020;8(10):975-986. https://doi.org/10.1016/S2213-2600(20)30331-3
https://doi.org/10.1016/S2213-2600(20)30...
,8484 Proesmans M, Vermeulen F, Boulanger L, Verhaegen J, De Boeck K. Comparison of two treatment regimens for eradication of Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros. 2013;12(1):29-34. https://doi.org/10.1016/j.jcf.2012.06.001
https://doi.org/10.1016/j.jcf.2012.06.00...
,8585 Ratjen F, Munck A, Kho P, Angyalosi G; ELITE Study Group. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax. 2010;65(4):286-291. https://doi.org/10.1136/thx.2009.121657
https://doi.org/10.1136/thx.2009.121657...
,8888 Taccetti G, Bianchini E, Cariani L, Buzzetti R, Costantini D, Trevisan F, et al. Early antibiotic treatment for Pseudomonas aeruginosa eradication in patients with cystic fibrosis: a randomised multicentre study comparing two different protocols. Thorax. 2012;67(10):853-859. https://doi.org/10.1136/thoraxjnl-2011-200832
https://doi.org/10.1136/thoraxjnl-2011-2...

89 Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011;165(9):847-856. https://doi.org/10.1001/archpediatrics.2011.136
https://doi.org/10.1001/archpediatrics.2...

90 Valerius NH, Koch C, Høiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. Lancet. 1991;338(8769):725-726. https://doi.org/10.1016/0140-6736(91)91446-2
https://doi.org/10.1016/0140-6736(91)914...
-9191 Wiesemann HG, Steinkamp G, Ratjen F, Bauernfeind A, Przyklenk B, Döring G, et al. Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis. Pediatr Pulmonol. 1998;25(2):88-92. https://doi.org/10.1002/(SICI)1099-0496(199802)25:2<88::AID-PPUL3>3.0.CO;2-J
https://doi.org/10.1002/(SICI)...
realizados em 1980-2019 e publicados em 1991-2020. O número de indivíduos incluídos nos estudos variou de 11 a 304, sendo que 12 estudos tiveram um número amostral inferior a 200 (Figura S4 e Quadro S5).

O resumo da qualidade das evidências dos artigos selecionados para esta questão 4 está listado na Tabela S4. Uma descrição detalhada dos achados pode ser encontrada no material suplementar (Pergunta S4)

Recomendação

Para indivíduos com FC, nós não temos evidências suficientes para recomendar ou não recomendar o uso da terapia de erradicação para P. aeruginosa.

Comentários

É bem estabelecida a associação entre a infecção por P. aeruginosa e desfechos desfavoráveis na FC. Além disso, a terapia de erradicação já se tornou uma prática incorporada à rotina dos centros de referência, dificultando a realização de novos estudos no assunto. A revisão da literatura possibilitou incluir um número limitado de estudos, sendo a maioria de caráter observacional e, no geral, com pequeno número de indivíduos incluídos. Tais características podem induzir ao achado de resultados inconsistentes, impossibilitando a criação de uma recomendação apropriada sobre o tema. Apesar de ser uma prática recomendada por diversas diretrizes internacionais e nacionais, novos estudos sobre o tema são necessários para a comprovação de eficácia e segurança da terapia de erradicação desse patógeno, sobretudo na era de uso dos moduladores da CFTR.

Pergunta 5. Devemos recomendar tratamento supressivo com antimicrobianos inalatórios em pacientes com FC e infecção crônica por P. aeruginosa?

Por mecanismos complexos, P. aeruginosa adapta-se e pode permanecer nas vias aéreas dos pacientes com FC por longos períodos. A cronicidade da infecção na FC é definida como a detecção do patógeno em mais de 50% das amostras de secreção respiratória em um período de 12 meses.9292 Lee TW, Brownlee KG, Conway SP, Denton M, Littlewood JM. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cyst Fibros. 2003;2(1):29-34. https://doi.org/10.1016/S1569-1993(02)00141-8
https://doi.org/10.1016/S1569-1993(02)00...
A infecção crônica por P. aeruginosa pode atingir até 60% dos pacientes na vida adulta e está associada a progressão da doença pulmonar e maior mortalidade.2121 Mogayzel PJ Jr, Naureckas ET, Robinson KA, Brady C, Guill M, Lahiri T, et al. Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc. 2014;11(10):1640-1650. https://doi.org/10.1513/AnnalsATS.201404-166OC
https://doi.org/10.1513/AnnalsATS.201404...
,9393 Lund-Palau H, Turnbull AR, Bush A, Bardin E, Cameron L, Soren O, et al. Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches. Expert Rev Respir Med. 2016;10(6):685-697. https://doi.org/10.1080/17476348.2016.1177460
https://doi.org/10.1080/17476348.2016.11...
,9494 Flume PA, VanDevanter DR, Morgan EE, Dudley MN, Loutit JS, Bell SC, et al. A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. J Cyst Fibros. 2016;15(4):495-502. https://doi.org/10.1016/j.jcf.2015.12.004
https://doi.org/10.1016/j.jcf.2015.12.00...
Os antimicrobianos inalatórios são amplamente utilizados para o tratamento supressivo de P. aeruginosa nos pacientes com infecção crônica e visam reduzir as consequências da presença do patógeno nas vias aéreas. As opções de medicamentos inalatórios para o tratamento supressivo incluem, classicamente, colistimetato, tobramicina e, mais recentemente, aztreonam.9393 Lund-Palau H, Turnbull AR, Bush A, Bardin E, Cameron L, Soren O, et al. Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches. Expert Rev Respir Med. 2016;10(6):685-697. https://doi.org/10.1080/17476348.2016.1177460
https://doi.org/10.1080/17476348.2016.11...

Evidências

Em função da metodologia utilizada, 25 estudos foram selecionados.9494 Flume PA, VanDevanter DR, Morgan EE, Dudley MN, Loutit JS, Bell SC, et al. A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. J Cyst Fibros. 2016;15(4):495-502. https://doi.org/10.1016/j.jcf.2015.12.004
https://doi.org/10.1016/j.jcf.2015.12.00...

95 Assael BM, Pressler T, Bilton D, Fayon M, Fischer R, Chiron R, et al. Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial. J Cyst Fibros. 2013;12(2):130-140. https://doi.org/10.1016/j.jcf.2012.07.006
https://doi.org/10.1016/j.jcf.2012.07.00...

96 Chuchalin A, Csiszér E, Gyurkovics K, Bartnicka MT, Sands D, Kapranov N, et al. A formulation of aerosolized tobramycin (Bramitob) in the treatment of patients with cystic fibrosis and Pseudomonas aeruginosa infection: a double-blind, placebo-controlled, multicenter study. Paediatr Drugs. 2007;9 Suppl 1:21-31. https://doi.org/10.2165/00148581-200709001-00004
https://doi.org/10.2165/00148581-2007090...

97 Geller DE, Flume PA, Staab D, Fischer R, Loutit JS, Conrad DJ; et al. Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011;183(11):1510-1516. https://doi.org/10.1164/rccm.201008-1293OC
https://doi.org/10.1164/rccm.201008-1293...

98 Hodson ME, Penketh AR, Batten JC. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet. 1981;2(8256):1137-1139. https://doi.org/10.1016/S0140-6736(81)90588-2
https://doi.org/10.1016/S0140-6736(81)90...

99 Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002;20(3):658-664. https://doi.org/10.1183/09031936.02.00248102
https://doi.org/10.1183/09031936.02.0024...

100 Jensen T, Pedersen SS, Garne S, Heilmann C, Høiby N, Koch C. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J Antimicrob Chemother. 1987;19(6):831-838. https://doi.org/10.1093/jac/19.6.831
https://doi.org/10.1093/jac/19.6.831...

101 Konstan MW, Geller DE, Minic P, Brockhaus F, Zhang J, Angyalosi G. Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol. 2011;46(3):230-238. https://doi.org/10.1002/ppul.21356
https://doi.org/10.1002/ppul.21356...

102 Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros. 2011;10(1):54-61. https://doi.org/10.1016/j.jcf.2010.10.003
https://doi.org/10.1016/j.jcf.2010.10.00...

103 Kun P, Landau LI, Phelan PD. Nebulized gentamicin in children and adolescents with cystic fibrosis. Aust Paediatr J. 1984;20(1):43-45. https://doi.org/10.1111/j.1440-1754.1984.tb00035.x
https://doi.org/10.1111/j.1440-1754.1984...

104 Lenoir G, Antypkin YG, Miano A, Moretti P, Zanda M, Varoli G, et al. Efficacy, safety, and local pharmacokinetics of highly concentrated nebulized tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Paediatr Drugs. 2007;9 Suppl 1:11-20. https://doi.org/10.2165/00148581-200709001-00003
https://doi.org/10.2165/00148581-2007090...

105 MacLusky IB, Gold R, Corey M, Levison H. Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Pediatr Pulmonol. 1989;7(1):42-48. https://doi.org/10.1002/ppul.1950070110
https://doi.org/10.1002/ppul.1950070110...

106 McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178(9):921-928. https://doi.org/10.1164/rccm.200712-1804OC
https://doi.org/10.1164/rccm.200712-1804...

107 Moss RB. Administration of aerosolized antibiotics in cystic fibrosis patients. Chest. 2001;120(3 Suppl):107S-113S. https://doi.org/10.1378/chest.120.3_suppl.107S
https://doi.org/10.1378/chest.120.3_supp...

108 Murphy TD, Anbar RD, Lester LA, Nasr SZ, Nickerson B, VanDevanter DR, et al. Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease. Pediatr Pulmonol. 2004;38(4):314-320. https://doi.org/10.1002/ppul.20097
https://doi.org/10.1002/ppul.20097...

109 Nasr SZ, Sakmar E, Christodoulou E, Eckhardt BP, Streetman DS, Strouse PJ. The use of high resolution computerized tomography (HRCT) of the chest in evaluating the effect of tobramycin solution for inhalation in cystic fibrosis lung disease. Pediatr Pulmonol. 2010;45(5):440-449. https://doi.org/10.1002/ppul.21188
https://doi.org/10.1002/ppul.21188...

110 Nikolaizik WH, Vietzke D, Ratjen F. A pilot study to compare tobramycin 80 mg injectable preparation with 300 mg solution for inhalation in cystic fibrosis patients. Can Respir J. 2008;15(5):259-262. https://doi.org/10.1155/2008/202464
https://doi.org/10.1155/2008/202464...

111 Quintana-Gallego E, Lopez-Campos JL, Calero C, Dapena FJ. Nebulized colistin versus tobramycin in the treatment of chronic Pseudomonas colonization in cystic fibrosis patients [Article in Spanish]. Med Clin (Barc). 2014;142(2):59-63. https://doi.org/10.1016/j.medcli.2012.11.026
https://doi.org/10.1016/j.medcli.2012.11...

112 Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340(1):23-30. https://doi.org/10.1056/NEJM199901073400104
https://doi.org/10.1056/NEJM199901073400...

113 Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM, McCoy KS, Montgomery AB, et al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest. 2009;135(5):1223-1232. https://doi.org/10.1378/chest.08-1421
https://doi.org/10.1378/chest.08-1421...

114 Schuster A, Haliburn C, Döring G, Goldman MH; Freedom Study Group. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax. 2013;68(4):344-350. https://doi.org/10.1136/thoraxjnl-2012-202059
https://doi.org/10.1136/thoraxjnl-2012-2...

115 Stead RJ, Hodson ME, Batten JC. Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa. Br J Dis Chest. 1987;81(3):272-279. https://doi.org/10.1016/0007-0971(87)90161-6
https://doi.org/10.1016/0007-0971(87)901...

116 Stuart Elborn J, Geller DE, Conrad D, Aaron SD, Smyth AR, Fischer R, et al. A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients. J Cyst Fibros. 2015;14(4):507-514. https://doi.org/10.1016/j.jcf.2014.12.013
https://doi.org/10.1016/j.jcf.2014.12.01...

117 Toukan Y, Gur M, Hakim FH, Geffen Y, Bar-Yoseph R, Nir V, et al. Intermittent inhaled tobramycin and systemic cytokines response in CF patients with Pseudomonas aeruginosa. Clin Invest Med. 2018;41(3):E136-E143. https://doi.org/10.25011/cim.v41i3.30792
https://doi.org/10.25011/cim.v41i3.30792...
-118118 Westerman EM, Le Brun PP, Touw DJ, Frijlink HW, Heijerman HG. Effect of nebulized colistin sulphate and colistin sulphomethate on lung function in patients with cystic fibrosis: a pilot study. J Cyst Fibros. 2004;3(1):23-28. https://doi.org/10.1016/j.jcf.2003.12.005
https://doi.org/10.1016/j.jcf.2003.12.00...
Cinco foram estudos observacionais101101 Konstan MW, Geller DE, Minic P, Brockhaus F, Zhang J, Angyalosi G. Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol. 2011;46(3):230-238. https://doi.org/10.1002/ppul.21356
https://doi.org/10.1002/ppul.21356...

102 Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros. 2011;10(1):54-61. https://doi.org/10.1016/j.jcf.2010.10.003
https://doi.org/10.1016/j.jcf.2010.10.00...
-103103 Kun P, Landau LI, Phelan PD. Nebulized gentamicin in children and adolescents with cystic fibrosis. Aust Paediatr J. 1984;20(1):43-45. https://doi.org/10.1111/j.1440-1754.1984.tb00035.x
https://doi.org/10.1111/j.1440-1754.1984...
,109109 Nasr SZ, Sakmar E, Christodoulou E, Eckhardt BP, Streetman DS, Strouse PJ. The use of high resolution computerized tomography (HRCT) of the chest in evaluating the effect of tobramycin solution for inhalation in cystic fibrosis lung disease. Pediatr Pulmonol. 2010;45(5):440-449. https://doi.org/10.1002/ppul.21188
https://doi.org/10.1002/ppul.21188...
,117117 Toukan Y, Gur M, Hakim FH, Geffen Y, Bar-Yoseph R, Nir V, et al. Intermittent inhaled tobramycin and systemic cytokines response in CF patients with Pseudomonas aeruginosa. Clin Invest Med. 2018;41(3):E136-E143. https://doi.org/10.25011/cim.v41i3.30792
https://doi.org/10.25011/cim.v41i3.30792...
e os demais classificados como ECR, realizados entre 1995 e 2008. Nove estudos apresentaram amostras superiores a 200, dos quais 2 deles incluíram mais de 500 indivíduos (Figura S5 e Quadro S6).

O resumo da qualidade das evidências dos artigos selecionados para esta questão 5 está listado na Tabela S5. Uma descrição detalhada dos achados pode ser encontrada no material suplementar (Pergunta S5).

Recomendação

Para pacientes com FC e colonização crônica por P. aeruginosa, nós sugerimos terapia de supressão crônica com antibióticos inalatórios (recomendação condicional, muito baixa qualidade de evidência).

Comentários

Ainda que nem todos os estudos tenham analisado exatamente os mesmos conjuntos de desfechos, na sua totalidade, eles apontam a favor do tratamento inalatório de pacientes com colonização crônica por P. aeruginosa em relação a melhora funcional, melhora da qualidade de vida e menor mortalidade. Vale ressaltar que, apesar de possíveis benefícios, há heterogeneidade nos estudos, o que resulta numa baixa qualidade de evidência.

Pergunta 6. Devemos recomendar tratamento antimicrobiano de erradicação em pacientes com FC e colonização das vias aéreas por MRSA?

A infecção crônica por MRSA está associada a piores desfechos clínicos em pacientes com FC.119119 Dasenbrook EC, Checkley W, Merlo CA, Konstan MW, Lechtzin N, Boyle MP. Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA. 2010;303(23):2386-2392. https://doi.org/10.1001/jama.2010.791
https://doi.org/10.1001/jama.2010.791...
Existem diferentes esquemas antimicrobianos para erradicação desse patógeno, incluindo combinações de medicamentos orais, tópicos e inalatórios. Existe também grande variabilidade quanto ao tempo de tratamento, e alguns advogam que o tratamento combinado seria mais efetivo que a monoterapia.120120 Hall H, Gadhok R, Alshafi K, Bilton D, Simmonds NJ. Eradication of respiratory tract MRSA at a large adult cystic fibrosis centre. Respir Med. 2015;109(3):357-363. https://doi.org/10.1016/j.rmed.2015.01.013
https://doi.org/10.1016/j.rmed.2015.01.0...
,121121 Vallières E, Rendall JC, Moore JE, McCaughan J, Hoeritzauer AI, Tunney MM, et al. MRSA eradication of newly acquired lower respiratory tract infection in cystic fibrosis. ERJ Open Res. 2016;2(1):00064-2015. https://doi.org/10.1183/23120541.00064-2015
https://doi.org/10.1183/23120541.00064-2...
Entretanto, ainda não existe consenso na literatura e se questiona se existem evidências científicas robustas de que a erradicação de MRSA seja benéfica aos pacientes com FC.122122 Vanderhelst E, De Wachter E, Willekens J, Schuermans D, Vincken W, Malfroot A, et al. Increase in ventilated air spaces after eradication of chronic methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients. Acta Clin Belg. 2015;70(1):30-33. https://doi.org/10.1179/2295333714Y.0000000079
https://doi.org/10.1179/2295333714Y.0000...
,123123 Dolce D, Neri S, Grisotto L, Campana S, Ravenni N, Miselli F, et al. Methicillin-resistant Staphylococcus aureus eradication in cystic fibrosis patients: A randomized multicenter study. PLoS One. 2019;14(3):e0213497. https://doi.org/10.1371/journal.pone.0213497
https://doi.org/10.1371/journal.pone.021...

Evidências

De acordo com a metodologia empregada (Figura S6 e Quadro S7), foram selecionados 8 estudos.120120 Hall H, Gadhok R, Alshafi K, Bilton D, Simmonds NJ. Eradication of respiratory tract MRSA at a large adult cystic fibrosis centre. Respir Med. 2015;109(3):357-363. https://doi.org/10.1016/j.rmed.2015.01.013
https://doi.org/10.1016/j.rmed.2015.01.0...

121 Vallières E, Rendall JC, Moore JE, McCaughan J, Hoeritzauer AI, Tunney MM, et al. MRSA eradication of newly acquired lower respiratory tract infection in cystic fibrosis. ERJ Open Res. 2016;2(1):00064-2015. https://doi.org/10.1183/23120541.00064-2015
https://doi.org/10.1183/23120541.00064-2...

122 Vanderhelst E, De Wachter E, Willekens J, Schuermans D, Vincken W, Malfroot A, et al. Increase in ventilated air spaces after eradication of chronic methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients. Acta Clin Belg. 2015;70(1):30-33. https://doi.org/10.1179/2295333714Y.0000000079
https://doi.org/10.1179/2295333714Y.0000...

123 Dolce D, Neri S, Grisotto L, Campana S, Ravenni N, Miselli F, et al. Methicillin-resistant Staphylococcus aureus eradication in cystic fibrosis patients: A randomized multicenter study. PLoS One. 2019;14(3):e0213497. https://doi.org/10.1371/journal.pone.0213497
https://doi.org/10.1371/journal.pone.021...

124 Garske LA, Kidd TJ, Gan R, Bunting JP, Franks CA, Coulter C, et al. Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection. J Hosp Infect. 2004;56(3):208-214. https://doi.org/10.1016/j.jhin.2003.12.003
https://doi.org/10.1016/j.jhin.2003.12.0...

125 Kappler M, Nagel F, Feilcke M, Kröner C, Pawlita I, Naehrig S, et al. Eradication of methicillin resistant Staphylococcus aureus detected for the first time in cystic fibrosis: A single center observational study. Pediatr Pulmonol. 2016;51(10):1010-1019. https://doi.org/10.1002/ppul.23519
https://doi.org/10.1002/ppul.23519...

126 Muhlebach MS, Beckett V, Popowitch E, Miller MB, Baines A, Mayer-Hamblett N, et al. Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax. 2017;72(4):318-326. https://doi.org/10.1136/thoraxjnl-2016-208949
https://doi.org/10.1136/thoraxjnl-2016-2...
-127127 Solís A, Brown D, Hughes J, Van Saene HK, Heaf DP. Methicillin-resistant Staphylococcus aureus in children with cystic fibrosis: An eradication protocol. Pediatr Pulmonol. 2003;36(3):189-195. https://doi.org/10.1002/ppul.10231
https://doi.org/10.1002/ppul.10231...
Desses, apenas 2 são ECR123123 Dolce D, Neri S, Grisotto L, Campana S, Ravenni N, Miselli F, et al. Methicillin-resistant Staphylococcus aureus eradication in cystic fibrosis patients: A randomized multicenter study. PLoS One. 2019;14(3):e0213497. https://doi.org/10.1371/journal.pone.0213497
https://doi.org/10.1371/journal.pone.021...
,126126 Muhlebach MS, Beckett V, Popowitch E, Miller MB, Baines A, Mayer-Hamblett N, et al. Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax. 2017;72(4):318-326. https://doi.org/10.1136/thoraxjnl-2016-208949
https://doi.org/10.1136/thoraxjnl-2016-2...
e os outros 6 são estudos observacionais.120120 Hall H, Gadhok R, Alshafi K, Bilton D, Simmonds NJ. Eradication of respiratory tract MRSA at a large adult cystic fibrosis centre. Respir Med. 2015;109(3):357-363. https://doi.org/10.1016/j.rmed.2015.01.013
https://doi.org/10.1016/j.rmed.2015.01.0...

121 Vallières E, Rendall JC, Moore JE, McCaughan J, Hoeritzauer AI, Tunney MM, et al. MRSA eradication of newly acquired lower respiratory tract infection in cystic fibrosis. ERJ Open Res. 2016;2(1):00064-2015. https://doi.org/10.1183/23120541.00064-2015
https://doi.org/10.1183/23120541.00064-2...
-122122 Vanderhelst E, De Wachter E, Willekens J, Schuermans D, Vincken W, Malfroot A, et al. Increase in ventilated air spaces after eradication of chronic methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients. Acta Clin Belg. 2015;70(1):30-33. https://doi.org/10.1179/2295333714Y.0000000079
https://doi.org/10.1179/2295333714Y.0000...
,124124 Garske LA, Kidd TJ, Gan R, Bunting JP, Franks CA, Coulter C, et al. Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection. J Hosp Infect. 2004;56(3):208-214. https://doi.org/10.1016/j.jhin.2003.12.003
https://doi.org/10.1016/j.jhin.2003.12.0...
,125125 Kappler M, Nagel F, Feilcke M, Kröner C, Pawlita I, Naehrig S, et al. Eradication of methicillin resistant Staphylococcus aureus detected for the first time in cystic fibrosis: A single center observational study. Pediatr Pulmonol. 2016;51(10):1010-1019. https://doi.org/10.1002/ppul.23519
https://doi.org/10.1002/ppul.23519...
,127127 Solís A, Brown D, Hughes J, Van Saene HK, Heaf DP. Methicillin-resistant Staphylococcus aureus in children with cystic fibrosis: An eradication protocol. Pediatr Pulmonol. 2003;36(3):189-195. https://doi.org/10.1002/ppul.10231
https://doi.org/10.1002/ppul.10231...

O resumo da qualidade das evidências dos artigos selecionados para esta questão 6 está listado nas Tabelas S6A e S6B. Uma descrição detalhada dos achados pode ser encontrada no material suplementar (Pergunta S6).

Recomendação

Para pacientes com FC, nós não temos evidências suficientes para recomendar ou não recomendar o uso da terapia de erradicação para MRSA.

Comentários

Todos os estudos avaliaram a taxa de erradicação, mas usando protocolos de tratamento diferentes, assim como distintas formas de avaliar a erradicação em cada estudo (curto vs. longo prazo). Todos os estudos avaliados incluíram amostras com menos de 70 indivíduos. Existe uma chance de que, com novos estudos e principalmente com o aumento do número de sujeitos investigados, ocorra uma mudança no grau de confiança dessa recomendação.

Pergunta 7. Devemos recomendar dornase alfa nebulizada para pacientes com FC com idade ≥ 6 anos?

Nos pacientes com FC, DNA extracelular proveniente de leucócitos é constantemente liberado nas vias aéreas que se acumulam nas secreções pulmonares em decorrência da inflamação e infecção crônicas.1818 Goss CH, MacNeill SJ, Quinton HB, Marshall BC, Elbert A, Knapp EA, et al. Children and young adults with CF in the USA have better lung function compared with the UK. Thorax. 2015;70(3):229-236. https://doi.org/10.1136/thoraxjnl-2014-205718
https://doi.org/10.1136/thoraxjnl-2014-2...
Consequentemente, observa-se aumento da viscosidade e tenacidade do muco. A dornase alfa é uma enzima capaz de clivar o DNA extracelular contido no muco, reduzir sua viscosidade e promover o aumento do clareamento de secreções.128128 Yang C, Montgomery M. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2021;3(3):CD001127. https://doi.org/10.1002/14651858.CD001127.pub5
https://doi.org/10.1002/14651858.CD00112...

A dornase alfa é administrada de forma inalatória, na dose habitual de 2,5 mg uma vez ao dia, devendo ser utilizada conjuntamente com outras técnicas de clareamento das vias aéreas.1717 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-642. https://doi.org/10.1056/NEJM199409083311003
https://doi.org/10.1056/NEJM199409083311...
,128128 Yang C, Montgomery M. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2021;3(3):CD001127. https://doi.org/10.1002/14651858.CD001127.pub5
https://doi.org/10.1002/14651858.CD00112...

Nos estudos de fase I e II, o uso da dornase alfa nebulizada em pacientes com FC mostrou ser seguro e levou ao aumento do VEF1 no curto prazo, associado à melhora de sintomas e de qualidade de vida.129129 Aitken ML, Burke W, McDonald G, Shak S, Montgomery AB, Smith A. Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. A phase 1 study. JAMA. 1992;267(14):1947-1951. https://doi.org/10.1001/jama.1992.03480140073036
https://doi.org/10.1001/jama.1992.034801...
,130130 Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson WW, Jolley C, et al. A preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of cystic fibrosis. N Engl J Med. 1992;326(12):812-815. https://doi.org/10.1056/NEJM199203193261207
https://doi.org/10.1056/NEJM199203193261...
Posteriormente, foi demonstrada manutenção dos benefícios no longo prazo com melhora sustentada do VEF1, redução do risco de exacerbações e bom perfil de segurança.128128 Yang C, Montgomery M. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2021;3(3):CD001127. https://doi.org/10.1002/14651858.CD001127.pub5
https://doi.org/10.1002/14651858.CD00112...

Evidências

Foram 32 estudos selecionados1717 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-642. https://doi.org/10.1056/NEJM199409083311003
https://doi.org/10.1056/NEJM199409083311...
,131131 Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R, et al. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J. 2011;37(4):806-812. https://doi.org/10.1183/09031936.00072510
https://doi.org/10.1183/09031936.0007251...

132 Bakker EM, Volpi S, Salonini E, van der Wiel-Kooij EC, Sintnicolaas CJ, Hop WC, et al. Improved treatment response to dornase alfa in cystic fibrosis patients using controlled inhalation. Eur Respir J. 2011;38(6):1328-1335. https://doi.org/10.1183/09031936.00006211
https://doi.org/10.1183/09031936.0000621...

133 Barker M, Franke E, Böhle M, Pfannenstiel C, Heimann G. Effect of DNase on exercise capacity in cystic fibrosis. Pediatr Pulmonol. 2004;38(1):70-74. https://doi.org/10.1002/ppul.20048
https://doi.org/10.1002/ppul.20048...

134 Bakker EM, Volpi S, Salonini E, van der Wiel-Kooij EC, Sintnicolaas CJ, Hop WC, Assael BM, Merkus PJ, Tiddens HA. Improved treatment response to dornase alfa in cystic fibrosis patients using controlled inhalation. Eur Respir J. 2011 Dec;38(6):1328-35. https://doi.org/10.1183/09031936.00006211
https://doi.org/10.1183/09031936.0000621...

135 Böllert FG, Paton JY, Marshall TG, Calvert J, Greening AP, Innes JA. Recombinant DNase in cystic fibrosis: a protocol for targeted introduction through n-of-1 trials. Scottish Cystic Fibrosis Group. Eur Respir J. 1999;13(1):107-113. https://doi.org/10.1183/09031936.99.13105399
https://doi.org/10.1183/09031936.99.1310...

136 Fiel SB, Fuchs HJ, Johnson C, Gonda I, Clark AR. Comparison of three jet nebulizer aerosol delivery systems used to administer recombinant human DNase I to patients with cystic fibrosis. The Pulmozyme rhDNase Study Group. Chest. 1995;108(1):153-156. https://doi.org/10.1378/chest.108.1.153
https://doi.org/10.1378/chest.108.1.153...

137 Frederiksen B, Pressler T, Hansen A, Koch C, Høiby N. Effect of aerosolized rhDNase (Pulmozyme) on pulmonary colonization in patients with cystic fibrosis. Acta Paediatr. 2006;95(9):1070-1074. https://doi.org/10.1080/08035250600752466
https://doi.org/10.1080/0803525060075246...

138 Furuya ME, Lezana-Fernández JL, Vargas MH, Hernández-Sierra JF, Ramírez-Figueroa JL. Efficacy of human recombinant DNase in pediatric patients with cystic fibrosis. Arch Med Res. 2001;32(1):30-34. https://doi.org/10.1016/S0188-4409(00)00258-7
https://doi.org/10.1016/S0188-4409(00)00...

139 Heijerman HG, van Rossem RN, Bakker W. Effect of rhDNase on lung function and quality of life in adult cystic fibrosis patients. Neth J Med. 1995;46(6):293-297. https://doi.org/10.1016/0300-2977(95)00022-F
https://doi.org/10.1016/0300-2977(95)000...

140 Hodson M. Multicenter study of rhDNase in cystic fibrosis with severe pulmonary involvement [Article in French]. Arch Pediatr. 1995;2(7):679-681. https://doi.org/10.1016/0929-693X(96)81226-7
https://doi.org/10.1016/0929-693X(96)812...

141 McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group. Chest. 1996;110(4):889-895. https://doi.org/10.1378/chest.110.4.889
https://doi.org/10.1378/chest.110.4.889...

142 Minasian C, Wallis C, Metcalfe C, Bush A. Comparison of inhaled mannitol, daily rhDNase and a combination of both in children with cystic fibrosis: a randomised trial. Thorax. 2010;65(1):51-56. https://doi.org/10.1136/thx.2009.116970
https://doi.org/10.1136/thx.2009.116970...

143 Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ, et al. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr. 2001;139(6):813-820. https://doi.org/10.1067/mpd.2001.118570
https://doi.org/10.1067/mpd.2001.118570...

144 Robinson TE, Goris ML, Zhu HJ, Chen X, Bhise P, Sheikh F, et al. Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. Chest. 2005;128(4):2327-2335. https://doi.org/10.1378/chest.128.4.2327
https://doi.org/10.1378/chest.128.4.2327...

145 Robinson M, Hemming AL, Moriarty C, Eberl S, Bye PT. Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis. Pediatr Pulmonol. 2000;30(1):16-24. https://doi.org/10.1002/1099-0496(200007)30:1<16::AID-PPUL4>3.0.CO;2-H
https://doi.org/10.1002/1099-0496(200007...

146 Shah PL, Scott SF, Knight RA, Marriott C, Ranasinha C, Hodson ME. In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis. Thorax. 1996;51(2):119-125. https://doi.org/10.1136/thx.51.2.119
https://doi.org/10.1136/thx.51.2.119...

147 Suri R, Metcalfe C, Lees B, Grieve R, Flather M, Normand C, et al. Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Lancet. 2001;358(9290):1316-1321. https://doi.org/10.1016/S0140-6736(01)06412-1
https://doi.org/10.1016/S0140-6736(01)06...

148 Bonestroo HJ, Slieker MG, Arets HG. No positive effect of rhdnase on the pulmonary colonization in children with cystic fibrosis. Monaldi Arch Chest Dis. 2010;73(1):12-17. https://doi.org/10.4081/monaldi.2010.308
https://doi.org/10.4081/monaldi.2010.308...

149 Cobos N, Danés I, Gartner S, González M, Liñán S, Arnau JM. DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres. DNase National Study Group. Eur J Pediatr. 2000;159(3):176-181. https://doi.org/10.1007/s004310050046
https://doi.org/10.1007/s004310050046...

150 Davies J, Trindade MT, Wallis C, Rosenthal M, Crawford O, Bush A. Retrospective review of the effects of rhDNase in children with cystic fibrosis. Pediatr Pulmonol. 1997;23(4):243-248. https://doi.org/10.1002/(SICI)1099-0496(199704)23:4<243::AID-PPUL1>3.0.CO;2-N
https://doi.org/10.1002/(SICI)1099-0496(...

151 Derelle J, Bertolo-Houriez E, Marchal F, Weber M, Virion JM, Vidailhet M. Respiratory evolution of patient with mucoviscidosis treated with mucolytic agents plus dornase alfa [Article in French]. Arch Pediatr. 1998;5(4):371-377. https://doi.org/10.1016/S0929-693X(98)80022-5
https://doi.org/10.1016/S0929-693X(98)80...

152 Harms HK, Matouk E, Tournier G, von der Hardt H, Weller PH, Romano L, et al. Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group. Pediatr Pulmonol. 1998;26(3):155-161. https://doi.org/10.1002/(SICI)1099-0496(199809)26:3<155::AID-PPUL1>3.0.CO;2-K
https://doi.org/10.1002/(SICI)1099-0496(...

153 Hodson ME, McKenzie S, Harms HK, Koch C, Mastella G, Navarro J, et al. Dornase alfa in the treatment of cystic fibrosis in Europe: a report from the Epidemiologic Registry of Cystic Fibrosis. Pediatr Pulmonol. 2003;36(5):427-432. https://doi.org/10.1002/ppul.10348
https://doi.org/10.1002/ppul.10348...

154 Johnson CA, Butler SM, Konstan MW, Breen TJ, Morgan WJ. Estimating effectiveness in an observational study: a case study of dornase alfa in cystic fibrosis. The Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. J Pediatr. 1999;134(6):734-739. https://doi.org/10.1016/S0022-3476(99)70290-8
https://doi.org/10.1016/S0022-3476(99)70...

155 Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A, et al. Clinical use of dornase alpha is associated with a slower rate of FEV1 decline in cystic fibrosis. Pediatr Pulmonol. 2011;46(6):545-553. https://doi.org/10.1002/ppul.21388
https://doi.org/10.1002/ppul.21388...

156 Milla CE. Long-term effects of aerosolised rhDNase on pulmonary disease progression in patients with cystic fibrosis. Thorax. 1998;53(12):1014-1017. https://doi.org/10.1136/thx.53.12.1014
https://doi.org/10.1136/thx.53.12.1014...

157 Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA, et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis--a one-year prospective study. Pediatr Pulmonol. 2010;45(9):874-882. https://doi.org/10.1002/ppul.21267
https://doi.org/10.1002/ppul.21267...

158 Rozov T, Silva FA, Santana MA, Adde FV, Mendes RH; Brazilian Cystic Fibrosis Multicenter Study Group. A first-year dornase alfa treatment impact on clinical parameters of patients with cystic fibrosis: the Brazilian cystic fibrosis multicenter study. Rev Paul Pediatr. 2013;31(4):420-430. https://doi.org/10.1590/S0103-05822013000400002
https://doi.org/10.1590/S0103-0582201300...

159 Shah PL, Conway S, Scott SF, Rainisio M, Wildman M, Stableforth D, et al. A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period. Respiration. 2001;68(2):160-164. https://doi.org/10.1159/000050486
https://doi.org/10.1159/000050486...

160 Shah PL, Scott SF, Geddes DM, Hodson ME. Two years experience with recombinant human DNase I in the treatment of pulmonary disease in cystic fibrosis. Respir Med. 1995;89(7):499-502. https://doi.org/10.1016/0954-6111(95)90126-4
https://doi.org/10.1016/0954-6111(95)901...
-161161 Wizla-Derambure N, Michaud L, Sardet A, Deschildre A, Loeuille GA, Tassin E, et al. Effect of rhDNase on the respiratory function and nutritional status of children and adolescents with mucoviscidosis [Article in French]. Arch Pediatr. 1998;5(4):378-383. https://doi.org/10.1016/S0929-693X(98)80023-7
https://doi.org/10.1016/S0929-693X(98)80...
, sendo 18 ECR1717 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-642. https://doi.org/10.1056/NEJM199409083311003
https://doi.org/10.1056/NEJM199409083311...
,131131 Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R, et al. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J. 2011;37(4):806-812. https://doi.org/10.1183/09031936.00072510
https://doi.org/10.1183/09031936.0007251...

132 Bakker EM, Volpi S, Salonini E, van der Wiel-Kooij EC, Sintnicolaas CJ, Hop WC, et al. Improved treatment response to dornase alfa in cystic fibrosis patients using controlled inhalation. Eur Respir J. 2011;38(6):1328-1335. https://doi.org/10.1183/09031936.00006211
https://doi.org/10.1183/09031936.0000621...

133 Barker M, Franke E, Böhle M, Pfannenstiel C, Heimann G. Effect of DNase on exercise capacity in cystic fibrosis. Pediatr Pulmonol. 2004;38(1):70-74. https://doi.org/10.1002/ppul.20048
https://doi.org/10.1002/ppul.20048...

134 Bakker EM, Volpi S, Salonini E, van der Wiel-Kooij EC, Sintnicolaas CJ, Hop WC, Assael BM, Merkus PJ, Tiddens HA. Improved treatment response to dornase alfa in cystic fibrosis patients using controlled inhalation. Eur Respir J. 2011 Dec;38(6):1328-35. https://doi.org/10.1183/09031936.00006211
https://doi.org/10.1183/09031936.0000621...
-135135 Böllert FG, Paton JY, Marshall TG, Calvert J, Greening AP, Innes JA. Recombinant DNase in cystic fibrosis: a protocol for targeted introduction through n-of-1 trials. Scottish Cystic Fibrosis Group. Eur Respir J. 1999;13(1):107-113. https://doi.org/10.1183/09031936.99.13105399
https://doi.org/10.1183/09031936.99.1310...
,140140 Hodson M. Multicenter study of rhDNase in cystic fibrosis with severe pulmonary involvement [Article in French]. Arch Pediatr. 1995;2(7):679-681. https://doi.org/10.1016/0929-693X(96)81226-7
https://doi.org/10.1016/0929-693X(96)812...

141 McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group. Chest. 1996;110(4):889-895. https://doi.org/10.1378/chest.110.4.889
https://doi.org/10.1378/chest.110.4.889...
-142142 Minasian C, Wallis C, Metcalfe C, Bush A. Comparison of inhaled mannitol, daily rhDNase and a combination of both in children with cystic fibrosis: a randomised trial. Thorax. 2010;65(1):51-56. https://doi.org/10.1136/thx.2009.116970
https://doi.org/10.1136/thx.2009.116970...
,144144 Robinson TE, Goris ML, Zhu HJ, Chen X, Bhise P, Sheikh F, et al. Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. Chest. 2005;128(4):2327-2335. https://doi.org/10.1378/chest.128.4.2327
https://doi.org/10.1378/chest.128.4.2327...
,145145 Robinson M, Hemming AL, Moriarty C, Eberl S, Bye PT. Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis. Pediatr Pulmonol. 2000;30(1):16-24. https://doi.org/10.1002/1099-0496(200007)30:1<16::AID-PPUL4>3.0.CO;2-H
https://doi.org/10.1002/1099-0496(200007...
,149149 Cobos N, Danés I, Gartner S, González M, Liñán S, Arnau JM. DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres. DNase National Study Group. Eur J Pediatr. 2000;159(3):176-181. https://doi.org/10.1007/s004310050046
https://doi.org/10.1007/s004310050046...
,151151 Derelle J, Bertolo-Houriez E, Marchal F, Weber M, Virion JM, Vidailhet M. Respiratory evolution of patient with mucoviscidosis treated with mucolytic agents plus dornase alfa [Article in French]. Arch Pediatr. 1998;5(4):371-377. https://doi.org/10.1016/S0929-693X(98)80022-5
https://doi.org/10.1016/S0929-693X(98)80...

152 Harms HK, Matouk E, Tournier G, von der Hardt H, Weller PH, Romano L, et al. Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group. Pediatr Pulmonol. 1998;26(3):155-161. https://doi.org/10.1002/(SICI)1099-0496(199809)26:3<155::AID-PPUL1>3.0.CO;2-K
https://doi.org/10.1002/(SICI)1099-0496(...

153 Hodson ME, McKenzie S, Harms HK, Koch C, Mastella G, Navarro J, et al. Dornase alfa in the treatment of cystic fibrosis in Europe: a report from the Epidemiologic Registry of Cystic Fibrosis. Pediatr Pulmonol. 2003;36(5):427-432. https://doi.org/10.1002/ppul.10348
https://doi.org/10.1002/ppul.10348...
-154154 Johnson CA, Butler SM, Konstan MW, Breen TJ, Morgan WJ. Estimating effectiveness in an observational study: a case study of dornase alfa in cystic fibrosis. The Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. J Pediatr. 1999;134(6):734-739. https://doi.org/10.1016/S0022-3476(99)70290-8
https://doi.org/10.1016/S0022-3476(99)70...
,159159 Shah PL, Conway S, Scott SF, Rainisio M, Wildman M, Stableforth D, et al. A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period. Respiration. 2001;68(2):160-164. https://doi.org/10.1159/000050486
https://doi.org/10.1159/000050486...
,160160 Shah PL, Scott SF, Geddes DM, Hodson ME. Two years experience with recombinant human DNase I in the treatment of pulmonary disease in cystic fibrosis. Respir Med. 1995;89(7):499-502. https://doi.org/10.1016/0954-6111(95)90126-4
https://doi.org/10.1016/0954-6111(95)901...
que compararam o uso da dornase alfa a placebo e 14 estudos observacionais.136136 Fiel SB, Fuchs HJ, Johnson C, Gonda I, Clark AR. Comparison of three jet nebulizer aerosol delivery systems used to administer recombinant human DNase I to patients with cystic fibrosis. The Pulmozyme rhDNase Study Group. Chest. 1995;108(1):153-156. https://doi.org/10.1378/chest.108.1.153
https://doi.org/10.1378/chest.108.1.153...

137 Frederiksen B, Pressler T, Hansen A, Koch C, Høiby N. Effect of aerosolized rhDNase (Pulmozyme) on pulmonary colonization in patients with cystic fibrosis. Acta Paediatr. 2006;95(9):1070-1074. https://doi.org/10.1080/08035250600752466
https://doi.org/10.1080/0803525060075246...

138 Furuya ME, Lezana-Fernández JL, Vargas MH, Hernández-Sierra JF, Ramírez-Figueroa JL. Efficacy of human recombinant DNase in pediatric patients with cystic fibrosis. Arch Med Res. 2001;32(1):30-34. https://doi.org/10.1016/S0188-4409(00)00258-7
https://doi.org/10.1016/S0188-4409(00)00...
-139139 Heijerman HG, van Rossem RN, Bakker W. Effect of rhDNase on lung function and quality of life in adult cystic fibrosis patients. Neth J Med. 1995;46(6):293-297. https://doi.org/10.1016/0300-2977(95)00022-F
https://doi.org/10.1016/0300-2977(95)000...
,143143 Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ, et al. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr. 2001;139(6):813-820. https://doi.org/10.1067/mpd.2001.118570
https://doi.org/10.1067/mpd.2001.118570...
,146146 Shah PL, Scott SF, Knight RA, Marriott C, Ranasinha C, Hodson ME. In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis. Thorax. 1996;51(2):119-125. https://doi.org/10.1136/thx.51.2.119
https://doi.org/10.1136/thx.51.2.119...

147 Suri R, Metcalfe C, Lees B, Grieve R, Flather M, Normand C, et al. Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Lancet. 2001;358(9290):1316-1321. https://doi.org/10.1016/S0140-6736(01)06412-1
https://doi.org/10.1016/S0140-6736(01)06...
-148148 Bonestroo HJ, Slieker MG, Arets HG. No positive effect of rhdnase on the pulmonary colonization in children with cystic fibrosis. Monaldi Arch Chest Dis. 2010;73(1):12-17. https://doi.org/10.4081/monaldi.2010.308
https://doi.org/10.4081/monaldi.2010.308...
,150150 Davies J, Trindade MT, Wallis C, Rosenthal M, Crawford O, Bush A. Retrospective review of the effects of rhDNase in children with cystic fibrosis. Pediatr Pulmonol. 1997;23(4):243-248. https://doi.org/10.1002/(SICI)1099-0496(199704)23:4<243::AID-PPUL1>3.0.CO;2-N
https://doi.org/10.1002/(SICI)1099-0496(...
,155155 Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A, et al. Clinical use of dornase alpha is associated with a slower rate of FEV1 decline in cystic fibrosis. Pediatr Pulmonol. 2011;46(6):545-553. https://doi.org/10.1002/ppul.21388
https://doi.org/10.1002/ppul.21388...

156 Milla CE. Long-term effects of aerosolised rhDNase on pulmonary disease progression in patients with cystic fibrosis. Thorax. 1998;53(12):1014-1017. https://doi.org/10.1136/thx.53.12.1014
https://doi.org/10.1136/thx.53.12.1014...

157 Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA, et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis--a one-year prospective study. Pediatr Pulmonol. 2010;45(9):874-882. https://doi.org/10.1002/ppul.21267
https://doi.org/10.1002/ppul.21267...
-158158 Rozov T, Silva FA, Santana MA, Adde FV, Mendes RH; Brazilian Cystic Fibrosis Multicenter Study Group. A first-year dornase alfa treatment impact on clinical parameters of patients with cystic fibrosis: the Brazilian cystic fibrosis multicenter study. Rev Paul Pediatr. 2013;31(4):420-430. https://doi.org/10.1590/S0103-05822013000400002
https://doi.org/10.1590/S0103-0582201300...
,161161 Wizla-Derambure N, Michaud L, Sardet A, Deschildre A, Loeuille GA, Tassin E, et al. Effect of rhDNase on the respiratory function and nutritional status of children and adolescents with mucoviscidosis [Article in French]. Arch Pediatr. 1998;5(4):378-383. https://doi.org/10.1016/S0929-693X(98)80023-7
https://doi.org/10.1016/S0929-693X(98)80...
(Ver Figura S7 e Quadro S8)

O resumo da qualidade das evidências dos artigos selecionados para esta questão 7 está listado nas Tabelas S7A e S7B. Uma descrição detalhada dos achados pode ser encontrada no material suplementar (Pergunta S7).

Recomendação

Para pacientes com FC, nós sugerimos o uso de dornase alfa inalatória (recomendação condicional, muito baixa qualidade de evidência).

Comentários

A diferença nas taxas de mortalidade não pôde ser comprovada, pois poucos pacientes morreram nos grupos intervenção e placebo, e as diferenças não foram, portanto, significativas. Dois ECR avaliaram efeitos adversos,1717 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-642. https://doi.org/10.1056/NEJM199409083311003
https://doi.org/10.1056/NEJM199409083311...
,149149 Cobos N, Danés I, Gartner S, González M, Liñán S, Arnau JM. DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres. DNase National Study Group. Eur J Pediatr. 2000;159(3):176-181. https://doi.org/10.1007/s004310050046
https://doi.org/10.1007/s004310050046...
não havendo diferença significativa na frequência de eventos entre os dois grupos. Um ECR e 2 estudos observacionais,131131 Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R, et al. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J. 2011;37(4):806-812. https://doi.org/10.1183/09031936.00072510
https://doi.org/10.1183/09031936.0007251...
,155155 Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A, et al. Clinical use of dornase alpha is associated with a slower rate of FEV1 decline in cystic fibrosis. Pediatr Pulmonol. 2011;46(6):545-553. https://doi.org/10.1002/ppul.21388
https://doi.org/10.1002/ppul.21388...
,156156 Milla CE. Long-term effects of aerosolised rhDNase on pulmonary disease progression in patients with cystic fibrosis. Thorax. 1998;53(12):1014-1017. https://doi.org/10.1136/thx.53.12.1014
https://doi.org/10.1136/thx.53.12.1014...
que avaliaram qualidade de vida, demonstraram melhora no grupo de tratamento.

Nove ECR1717 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-642. https://doi.org/10.1056/NEJM199409083311003
https://doi.org/10.1056/NEJM199409083311...
,131131 Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R, et al. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J. 2011;37(4):806-812. https://doi.org/10.1183/09031936.00072510
https://doi.org/10.1183/09031936.0007251...
,141141 McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group. Chest. 1996;110(4):889-895. https://doi.org/10.1378/chest.110.4.889
https://doi.org/10.1378/chest.110.4.889...
,142142 Minasian C, Wallis C, Metcalfe C, Bush A. Comparison of inhaled mannitol, daily rhDNase and a combination of both in children with cystic fibrosis: a randomised trial. Thorax. 2010;65(1):51-56. https://doi.org/10.1136/thx.2009.116970
https://doi.org/10.1136/thx.2009.116970...
,144144 Robinson TE, Goris ML, Zhu HJ, Chen X, Bhise P, Sheikh F, et al. Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. Chest. 2005;128(4):2327-2335. https://doi.org/10.1378/chest.128.4.2327
https://doi.org/10.1378/chest.128.4.2327...
,149149 Cobos N, Danés I, Gartner S, González M, Liñán S, Arnau JM. DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres. DNase National Study Group. Eur J Pediatr. 2000;159(3):176-181. https://doi.org/10.1007/s004310050046
https://doi.org/10.1007/s004310050046...
,152152 Harms HK, Matouk E, Tournier G, von der Hardt H, Weller PH, Romano L, et al. Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group. Pediatr Pulmonol. 1998;26(3):155-161. https://doi.org/10.1002/(SICI)1099-0496(199809)26:3<155::AID-PPUL1>3.0.CO;2-K
https://doi.org/10.1002/(SICI)1099-0496(...
,154154 Johnson CA, Butler SM, Konstan MW, Breen TJ, Morgan WJ. Estimating effectiveness in an observational study: a case study of dornase alfa in cystic fibrosis. The Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. J Pediatr. 1999;134(6):734-739. https://doi.org/10.1016/S0022-3476(99)70290-8
https://doi.org/10.1016/S0022-3476(99)70...
,160160 Shah PL, Scott SF, Geddes DM, Hodson ME. Two years experience with recombinant human DNase I in the treatment of pulmonary disease in cystic fibrosis. Respir Med. 1995;89(7):499-502. https://doi.org/10.1016/0954-6111(95)90126-4
https://doi.org/10.1016/0954-6111(95)901...
avaliados conjuntamente demonstraram um valor de VEF1 5% mais elevado nos pacientes que receberam alfa dornase do que no grupo placebo. Embora seja uma melhora modesta, o VEF1 é um proxy de mortalidade em estudos populacionais. Ainda, 2 ECR1717 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-642. https://doi.org/10.1056/NEJM199409083311003
https://doi.org/10.1056/NEJM199409083311...
,152152 Harms HK, Matouk E, Tournier G, von der Hardt H, Weller PH, Romano L, et al. Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group. Pediatr Pulmonol. 1998;26(3):155-161. https://doi.org/10.1002/(SICI)1099-0496(199809)26:3<155::AID-PPUL1>3.0.CO;2-K
https://doi.org/10.1002/(SICI)1099-0496(...
demonstraram redução de 7% nas exacerbações no grupo intervenção em relação ao grupo placebo. Esse desfecho é importante, pois a redução das exacerbações se relaciona com desfechos favoráveis de função pulmonar e, de forma indireta, de mortalidade.

A pesquisa de referências para essas diretrizes não incluiu estudos com crianças menores de 6 anos de idade, não sendo possível extrapolar a recomendação para a faixa etária mais precoce.

Pergunta 8. Devemos recomendar tratamento antimicrobiano de erradicação em pacientes com FC e colonização das vias aéreas por cepas do complexo B. cepacia?

O complexo B. cepacia agrupa 22 espécies,162162 LiPuma JJ, Spilker T, Gill LH, Campbell PW 3rd, Liu L, Mahenthiralingam E. Disproportionate distribution of Burkholderia cepacia complex species and transmissibility markers in cystic fibrosis. Am J Respir Crit Care Med. 2001;164(1):92-96. https://doi.org/10.1164/ajrccm.164.1.2011153
https://doi.org/10.1164/ajrccm.164.1.201...
sendo B. multivorans e B. cenocepacia as mais comuns em FC. O quadro clínico é muito variável, caracterizado desde infecção crônica oligossintomática até quadros graves cursando com pneumonia necrosante, insuficiência respiratória e sepse (síndrome cepacia).163163 Zlosnik JE, Zhou G, Brant R, Henry DA, Hird TJ, Mahenthiralingam E, et al. Burkholderia species infections in patients with cystic fibrosis in British Columbia, Canada. 30 years' experience. Ann Am Thorac Soc. 2015;12(1):70-78. https://doi.org/10.1513/AnnalsATS.201408-395OC
https://doi.org/10.1513/AnnalsATS.201408...
O complexo B. cepacia tem um perfil de resistência bacteriana peculiar, o que torna difícil a escolha de tratamento antibiótico, sendo comumente sugerida a associação de drogas antimicrobianas, preferencialmente guiada por antibiograma.164164 Horsley A, Webb K, Bright-Thomas R, Govan J, Jones A. Can early Burkholderia cepacia complex infection in cystic fibrosis be eradicated with antibiotic therapy?. Front Cell Infect Microbiol. 2011;1:18. https://doi.org/10.3389/fcimb.2011.00018
https://doi.org/10.3389/fcimb.2011.00018...

Evidências

De acordo com a metodologia empregada (Figura S8 e Quadro S9), 3 estudos foram incluídos ao final do processo de revisão.2323 Garcia BA, Carden JL, Goodwin DL, Smith TA, Gaggar A, Leon K, et al. Implementation of a successful eradication protocol for Burkholderia Cepacia complex in cystic fibrosis patients. BMC Pulm Med. 2018;18(1):35. https://doi.org/10.1186/s12890-018-0594-8
https://doi.org/10.1186/s12890-018-0594-...
,165165 Tullis DE, Burns JL, Retsch-Bogart GZ, Bresnik M, Henig NR, Lewis SA, et al. Inhaled aztreonam for chronic Burkholderia infection in cystic fibrosis: a placebo-controlled trial. J Cyst Fibros. 2014;13(3):296-305. https://doi.org/10.1016/j.jcf.2013.08.011
https://doi.org/10.1016/j.jcf.2013.08.01...
,166166 Uluer AZ, Waltz DA, Kalish LA, Adams S, Gerard C, Ericson DA. Inhaled amiloride and tobramycin solutions fail to eradicate Burkholderia dolosa in patients with cystic fibrosis. J Cyst Fibros. 2013;12(1):54-59. https://doi.org/10.1016/j.jcf.2012.06.006
https://doi.org/10.1016/j.jcf.2012.06.00...
Apenas 1 estudo foi caracterizado como ECR.165165 Tullis DE, Burns JL, Retsch-Bogart GZ, Bresnik M, Henig NR, Lewis SA, et al. Inhaled aztreonam for chronic Burkholderia infection in cystic fibrosis: a placebo-controlled trial. J Cyst Fibros. 2014;13(3):296-305. https://doi.org/10.1016/j.jcf.2013.08.011
https://doi.org/10.1016/j.jcf.2013.08.01...

O resumo da qualidade das evidências dos artigos selecionados para esta questão 8 está listado nas Tabelas S8A e S8B. Uma descrição detalhada dos achados pode ser encontrada no material suplementar (Pergunta S8).

Recomendação

Para pacientes com FC, nós não temos evidências suficientes para recomendar ou não recomendar o uso da terapia de erradicação para o complexo B. cepacia.

Comentários

Nenhum dos estudos selecionados mostrou benefícios do tratamento quando avaliados tantos os desfechos críticos considerados importantes na metodologia destas diretrizes. Foram encontrados poucos estudos na literatura sobre o tema, sendo a maioria de baixa qualidade metodológica e grande heterogeneidade entre si. Os regimes de erradicação descritos não eram padronizados. O aumento de eventos adversos encontrados com o uso de aztreonam inalatório não pode ser extrapolado para outros regimes terapêuticos, ainda mais por esse não ser um antibiótico comumente recomendado para esse tipo de infecção. Diante disso, o comitê destas diretrizes julga não ser possível realizar uma recomendação nem a favor nem contra essa terapia devido à escassez de informações publicadas. Novos estudos são necessários para melhor avaliação dessa questão.

CONSIDERAÇÕES FINAIS

Um resumo com as recomendações para o tratamento farmacológico da doença respiratória na FC está apresentado no Quadro 5.

Quadro 5
Resumo das recomendações para tratamento farmacológico pulmonar na fibrose cística.

Cabe ao prescritor identificar e reconhecer que diferentes tratamentos podem ser adequados para um mesmo paciente ou para grupos diferentes, e que a ele compete ajudá-los e aos seus familiares a tomar decisões consistentes e bem fundamentadas, coerentes com a força das recomendações e a qualidade das evidências existentes. Não foram consideradas a análise de custos e os aspectos de farmacoeconomia nestas recomendações.

Embora ainda não haja um fármaco com capacidade curativa na FC, as presentes diretrizes sugerem diversas intervenções com potencial benéfico para o tratamento da doença. Algumas drogas como dornase alfa e estratégias de controle da infecção crônica por P. aeruginosa já estão aprovadas há mais de uma década e são consideradas como terapia padrão no manejo desses indivíduos. Entretanto, essas terapias atuam no controle das consequências da doença como muco espesso e exacerbações infecciosas de repetição. Mais recentemente, uma nova classe de medicamentos, os moduladores da CFTR, inicia uma nova fase no tratamento da FC por agir na causa base da doença.99 Guimbellot J, Sharma J, Rowe SM. Toward inclusive therapy with CFTR modulators: Progress and challenges. Pediatr Pulmonol. 2017;52(S48):S4-S14. https://doi.org/10.1002/ppul.23773
https://doi.org/10.1002/ppul.23773...
Ganhos substanciais de função pulmonar e redução nas taxas de exacerbação foram encontrados em pacientes sob uso de ivacaftor com mutações classe 31111 Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. https://doi.org/10.1056/NEJMoa1105185
https://doi.org/10.1056/NEJMoa1105185...
e de tezacaftor + ivacaftor naqueles com função residual.1414 Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017;377(21):2024-2035. https://doi.org/10.1056/NEJMoa1709847
https://doi.org/10.1056/NEJMoa1709847...
Entretanto, apesar de benefícios estatisticamente significantes, esses resultados não foram igualmente encontrados em portadores de FC com mutação F508del em homozigose sob uso de lumacaftor + ivacaftor1212 Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231. https://doi.org/10.1056/NEJMoa1409547
https://doi.org/10.1056/NEJMoa1409547...
ou tezacaftor + ivacaftor.1313 Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. https://doi.org/10.1056/NEJMoa1709846
https://doi.org/10.1056/NEJMoa1709846...
Esses dados apontam a necessidade da adequada avaliação dos benefícios de cada tratamento de acordo com a população avaliada. A terapia com moduladores da CFTR pode ser considerada como uma terapia alvo e escolhida conforme a ação dos diferentes fármacos para grupos específicos de mutações do CFTR. Mais recentemente, uma nova combinação tripla de moduladores da CFTR (elexacaftor + tezacaftor + ivacaftor) parece ser uma opção eficaz e segura para pacientes com a presença de pelo menos um alelo F508del.1515 Heijerman HGM, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2020 May 30;395(10238):1694]. Lancet. 2019;394(10212):1940-1948. https://doi.org/10.1016/S0140-6736(19)32597-8
https://doi.org/10.1016/S0140-6736(19)32...
,1616 Middleton PG, Mall MA, Drevínek P, Lands LC, McKone EF, Polineni D, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381(19):1809-1819. https://doi.org/10.1056/NEJMoa1908639
https://doi.org/10.1056/NEJMoa1908639...

Frente aos diversos avanços encontrados no manejo da FC nos últimos anos, recomenda-se que mesmo tratamentos comprovadamente eficazes, como dornase alfa e terapia de supressão crônica de P. aeruginosa, sejam reavaliados futuramente conforme maior acesso ao uso dos moduladores da CFTR em pacientes elegíveis.

Sobre as outras intervenções avaliadas, o painel de especialistas não foi capaz de emitir uma recomendação baseada em evidências pela baixa qualidade das informações obtidas para a erradicação de P. aeruginosa, MRSA e complexo B. cepacia. Mais estudos sobre o tema são necessários para uma recomendação formal. Entretanto, o médico clínico deve avaliar as particularidades de cada paciente e reconhecer possíveis benefícios dessas terapias em casos selecionados.

Deve ser enfatizado que estas diretrizes buscaram responder oito das principais intervenções farmacológicas relacionadas ao tratamento respiratório da FC. Outras terapias, como nebulização com salina hipertônica e uso crônico de macrolídeos, não foram avaliadas neste documento, o que não significa que não apresentem benefício clínico ou que não possam ser usadas conforme critérios de elegibilidade próprios. Cuidados não farmacológicos também são essenciais no manejo da FC, incluindo vacinação, atividade física, fisioterapia respiratória e reabilitação pulmonar. Por fim, por se tratar de uma doença multissistêmica, o paciente deve ser cuidado de forma multidisciplinar, envolvendo aspectos gastrointestinais, endocrinológicos e otorrinolaringológicos não contemplados no escopo destas diretrizes.77 Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43(3):219-245. https://doi.org/10.1590/s1806-37562017000000065
https://doi.org/10.1590/s1806-3756201700...

É relevante esclarecer que a qualidade muito baixa de evidência de algumas recomendações não significa que elas não devam ser consideradas ou implementadas. Nestas diretrizes, optou-se pela inclusão tanto de ECR como de estudos observacionais com o intuito de mais bem avaliar o efeito de algumas terapias aprovadas há muitos anos para FC. Por um lado, essa estratégia permite a avaliação de uma ampla amostra de pacientes com grande validade externa. Por outro lado, aumenta a incerteza dos resultados por vieses inerentes aos diversos tipos de estudos. É importante ressaltar que o achado consistente de resultados tanto em ECR como em estudos observacionais favorece a aplicabilidade clínica dessas intervenções para uma maior proporção de pacientes com FC. Além disso, as presentes recomendações estão em concordância com outras diretrizes internacionais.88 Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018;17(2):153-178. https://doi.org/10.1016/j.jcf.2018.02.006
https://doi.org/10.1016/j.jcf.2018.02.00...

Acreditamos que o documento em questão represente uma importante ferramenta a ser incorporada na abordagem de pacientes com FC, objetivando principalmente favorecer o seu manejo, bem como auxiliando a definição de políticas públicas relacionadas à doença.

AGRADECIMENTOS

Agradecemos o apoio metodológico e estatístico da Dra. Ana Menezes e Dr. Fernando Wehrmeister durante o desenvolvimento deste trabalho.

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  • Apoio financeiro:

    Este projeto recebeu apoio financeiro parcial através de um apoio educacional irrestrito do laboratório Vertex Farmacêutica do Brasil Ltda, São Paulo (SP) Brasil.

Datas de Publicação

  • Publicação nesta coleção
    15 Maio 2023
  • Data do Fascículo
    2023

Histórico

  • Recebido
    19 Mar 2023
  • Aceito
    31 Mar 2023
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E-mail: jbp@sbpt.org.br