Brazilian guidelines for the pharmacological treatment of the pulmonary symptoms of cystic fibrosis. Official document of the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association)

Athanazio, Rodrigo Abensur; Tanni, Suzana Erico; Ferreira, Juliana; Dalcin, Paulo de Tarso Roth; Fuccio, Marcelo B de; Esposito, Concetta; Canan, Mariane Gonçalves Martynychen; Coelho, Liana Sousa; Firmida, Mônica de Cássia; Almeida, Marina Buarque de; Marostica, Paulo José Cauduro; Monte, Luciana de Freitas Velloso; Souza, Edna Lúcia; Pinto, Leonardo Araujo; Rached, Samia Zahi; Oliveira, Verônica Stasiak Bednarczuk de; Riedi, Carlos Antonio; Silva Filho, Luiz Vicente Ribeiro Ferreira da

doi:10.36416/1806-3756/e20230040

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SPECIAL ARTICLE • J. bras. pneumol. 49 (2) • 2023 • https://doi.org/10.36416/1806-3756/e20230040 copy

Brazilian guidelines for the pharmacological treatment of the pulmonary symptoms of cystic fibrosis. Official document of the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association)

Authorship SCIMAGO INSTITUTIONS RANKINGS

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

Question	Critical outcomes	Important outcomes
1. Should we recommend treatment with ivacaftor in patients with CF who carry class III (gating) or class IV (conduction) mutations in the CFTR gene?	Mortality Quality of life Adverse events	Lung function Exacerbations BMI variation
2. Should we recommend treatment with lumacaftor+ivacaftor in CF patients homozygous for the F508del mutation?	Mortality Quality of life Adverse events	Lung function Exacerbations BMI variation
3. Should we recommend treatment with tezacaftor+ivacaftor in CF patients homozygous for F508del or heterozygous for F508del and with residual function mutations?	Mortality Quality of life Adverse events	Lung function Exacerbations BMI variation
4. Should we recommend treatment with inhaled antimicrobials in patients with CF and chronic P. aeruginosa infection?	Mortality Adverse events Time free from P. aeruginosa infection	Eradication of P. aeruginosa Lung function Exacerbations BMI variation
5. Should we recommend treatment with inhaled antimicrobials in patients with CF and chronic P. aeruginosa infection	Mortality Quality of life Adverse events	Lung function Exacerbations BMI variation
6. Should we recommend antimicrobial eradication treatment in CF patients with MRSA colonization of the airways?	Mortality Eradication of MRSA Adverse events Quality of life	Lung function Exacerbations
7. Should we recommend nebulized dornase alfa for CF patients ≥ 6 years of age?	Mortality Quality of life Adverse events	Lung function Exacerbations BMI variation
8. Should we recommend antimicrobial eradication treatment in CF patients with airway colonization by Burkholderia cepacia complex strains?	Mortality Eradication of B. cepacia Quality of life Adverse events	Lung function Exacerbations BMI variation

GRADE quality of evidence	Implications	Examples
High (⊕⊕⊕⊕)	Future research is unlikely to change the level of confidence in the estimated effect; we are confident that we can expect a very similar effect in the population for which the recommendation is intended.	Randomized trials without serious limitations Well-executed observational studies with very large effect sizes
Moderate (⊕⊕⊕○)	Future research is likely to have a major impact on the level of confidence in the estimated effect and could change this estimate.	Randomized trials with serious limitations Well-executed observational studies with large effect sizes
Low (⊕⊕○○)	Future research is likely to have a major impact on the level of confidence in the estimated effect and is likely to change that estimate.	Randomized trials with very serious limitations Observational studies without special strengths or serious limitations
Very low (⊕○○○)	Any estimate of an effect is very uncertain.	Randomized trials with very serious limitations and inconsistent results Observational studies with serious limitations Nonsystematic clinical observational studies (e.g., case series or case reports)

Quality of evidence	Situations that can lower the grade	Situations that can raise the grade
• High • Moderate • Low • Very low	• Risk of bias • Indirect evidence • Inconsistency • Imprecision • Publication bias	• Strong association, no plausible confounding factors • Evidence of a dose-response relationship • Known plausible confounding factors that reduce the effects

Target audience	Strong GRADE recommendation		Conditional GRADE recommendation
Target audience	We recommend	We do not recommend	We suggest	We do not suggest
Patients	Most individuals would want the intervention to be indicated, and only a small number would not accept this recommendation.	Most individuals would not want the intervention to be indicated, and only a small number would accept this recommendation.	Most individuals would like the intervention to be indicated, although a considerable number would not accept this recommendation.	Most individuals would not want the intervention to be indicated, although a considerable number would accept this recommendation.
Health professionals	Most patients should receive the recommended intervention.		The professional must recognize that different choices can be appropriate for each patient and should help patients make a decision consistent with their values and preferences.
Policy makers	The recommendation can be adopted as health policy in most situations.		Substantial debate and stakeholder involvement is required.

Question	Recommendation	Grade of recommendation	Quality of evidence
1. Should we recommend treatment with ivacaftor in patients with CF who carry class III (gating) or class IV (conduction) mutations in the CFTR gene?	We suggest the use	Conditional	Very low
2. Should we recommend treatment with lumacaftor+ivacaftor in CF patients homozygous for the F508del mutation?	We do not suggest the use	Conditional	Very low
3. Should we recommend treatment with tezacaftor+ivacaftor in CF patients homozygous for F508del or heterozygous for F508del and with residual function mutations?	We suggest the use	Conditional	Very low
4. Should we recommend treatment with inhaled antimicrobials in patients with CF and chronic P. aeruginosa infection?	No recommendation
5. Should we recommend treatment with inhaled antimicrobials in patients with CF and chronic P. aeruginosa infection	We suggest the use	Conditional	Very low
6. Should we recommend antimicrobial eradication treatment in CF patients with MRSA colonization of the airways?	No recommendation
7. Should we recommend nebulized dornase alfa for CF patients ≥ 6 years of age?	We suggest the use	Conditional	Very low
8. Should we recommend antimicrobial eradication treatment in CF patients with airway colonization by Burkholderia cepacia complex strains?	No recommendation

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E-mail: jbp@sbpt.org.br

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[1] Correspondence to: Rodrigo A Athanazio. Avenida Dr. Enéas de Carvalho Aguiar, 44, CEP 05403-000, São Paulo, SP, Brasil. Tel.: 55 11 2661-5695. E-mail: rathanazio@yahoo.com.br