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.

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.

Palavras-chave: Fibrose cística; Abordagem GRADE; Fibrose cística/tratamento farmacológico; Guia de prática clínica.

 
INTRODUCTION
 
Cystic fibrosis (CF) is a genetic disease that results in dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is a chloride and bicarbonate channel expressed in the apical membrane of epithelial cells in various organs of the human body.(1) Dysfunction of the CFTR protein results in multisystemic manifestations, impairing quality of life and reducing life expectancy.(2)
 
Although CF is still an incurable pathology, the therapeutic perspective is currently more favorable due to the discovery of CFTR modulators.(3,4) Historically, treatments for individuals with CF were developed to overcome deficiencies or to modify basic aspects of the pathophysiology of the disease.(5-8)
 
The emergence of CFTR modulators has prompted systematic reviews on the evidence for their beneficial effects on health outcomes for individuals with CF.(3,4,9,10) When these guidelines were first being devised, the CFTR modulators approved by the Brazilian Agência Nacional de Vigilância Sanitária (ANVISA, National Health Regulatory Agency) were ivacaftor(11) and two drug combinations: lumacaftor+ivacaftor(12); and tezacaftor+ivacaftor.(13,14) At the end of 2020, ivacaftor was incorporated into the Brazilian Unified Health Care System for use in individuals with CF ≥ 6 years of age and with genetic regulation (gating) mutations. In 2022, the Brazilian National Health Regulatory Agency approved triple therapy (elexacaftor+tezacaftor+ivacaftor), which proved to be highly effective for individuals with CF carrying the F508del genetic mutation, even for those who are heterozygous for that mutation.(15,16) Because that drug combination was approved so recently, it was not evaluated in these guidelines.
 
One of classical treatments for CF, dornase alfa,(17) has long been incorporated into the Brazilian Unified Health Care System. However, questions persist regarding its true impact on relevant outcomes, such as mortality and the frequency of pulmonary exacerbations.(18-20)
 
Management strategies for respiratory infections in CF are quite heterogeneous. An evaluation of the evidence supporting eradication regimens for pathogens such as Pseudomonas aeruginosa,(21) methicillin-resistant Staphylococcus aureus (MRSA),(22) and strains of the Burkholderia cepacia complex(23) could help clarify positions on the risks and benefits of such regimens. Another common practice in the treatment of individuals with CF is suppression therapy for chronic P. aeruginosa infection with inhaled antibiotic therapy. Given the impact of this treatment, which imposes long periods of nebulization,(24) the topic was also addressed in the guidelines presented here.
 
The aim of this special article is to carry out a systematic review and meta-analysis of data from the literature involving aspects of the treatment of individuals with CF regarding the use of CFTR modulators and dornase alfa, as well as strategies for the eradication and suppression of pathogens commonly associated with respiratory infections in such individuals.
 
METHODS
 
The steps for developing the guidelines followed the model proposed and approved by the Brazilian Thoracic Association, which employs the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach,(25) together with questions in the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) format.(26) On May 15, 2019, a virtual meeting, involving four coordinators (two CF specialists and two methodologists), one patient, and a committee of experts, was held for the approval of the methodology used. The experts formulated PICO questions about the pharmacological treatment of patients with CF. A vote was then taken to select the eight most relevant questions. The outcomes of interest for each question were defined a priori and classified as critical or important (Chart 1).
 

 
The search for articles and the meta-analysis were carried out by a team of experienced methodologists, hired for the purpose of devising these guidelines. The project was registered on the International Prospective Register of Systematic Reviews (PROSPERO) platform (Protocol no. CRD42020173901). The searches were carried out in the MEDLINE and EMBASE databases. Clinical trials, case-control studies and cohort studies were included, with keywords pre-established by the specialist coordinators, with no date or language restrictions (Chart S1).
 
We first evaluated the articles on the basis of their titles and abstracts. Two methodologists, working independently, then performed a qualitative analysis of the full texts and selected articles to be included. Their selections were subsequently validated by the specialist coordinators. The reasons for inclusion or exclusion are presented in the supplementary material (Figures S1 to S8).
 
When appropriate, data on pharmacological interventions were pooled and meta-analyses were performed independently by the team of methodologists. For each of the eight PICO questions, the quality of evidence of each of the studies included in the meta-analyses was assessed by employing the GRADE approach, through the use of evidence tables, with the GRADEpro Guideline Development Tool (McMaster University, Hamilton, ON, Canada).
 
For any given study, the quality of evidence depends on the design, the implementation, and the risks of bias. As detailed in Charts 2 and 3, the quality of evidence can be classified as high, moderate, low, or very low.(25)
 

 
In December of 2021, a working group met to review the evidence and make recommendations for each question according to the GRADE approach. The recommendations were classified as strong or conditional, according to degree of certainty regarding the strength and quality of the evidence. We use the term “recommend” for strong recommendations and “suggest” for conditional recommendations. Chart 4 shows the proposed interpretations of those recommendations,(26,27) which are detailed in Tables S1 to S8.
 

 
Question 1. Should we recommend treatment with ivacaftor in CF patients with class III (gating) or class IV (conduction) mutations in the CFTR gene?
 
Ivacaftor is a CFTR modulator. It acts as a CFTR potentiator, aimed at treating the dysfunction underlying this genetic alteration. It regulates the opening of the chlorine channel present in the cell membrane, restoring healthy mucus rheology in the airways.
 
In 2012, the US Food and Drug Administration approved the use of ivacaftor for CF patients ≥ 12 years of age.(11) It is the first drug approved for CF whose therapeutic action targets the basic problem of the disease, characterized by CFTR protein dysfunction. Various clinical trials were subsequently carried out, the results of which allowed the use of the drug to be extended to patients ≥ 6 years of age.
 
Evidence
 
Among the studies analyzed, there were 28 on the use of ivacaftor, for a variety of outcomes,(12,28-54) as shown in Figure S1 and Chart S2. Of those 28 studies, 8 were randomized controlled trials (RCTs). (11,29,32 34,36,44,45) Although not all investigated the same sets of outcomes, the articles collectively demonstrated a beneficial therapeutic effect of ivacaftor in patients with class III (gating) or class IV (conduction) mutations.
 
A detailed description of the findings can be found in the Supplementary Material (Question S1). The quality of evidence of the selected articles for this question is summarized in Tables S1A and S1B.
 
In 2020, Volkova et al.(55) evaluated disease progression (real-life study) in CF patients treated with ivacaftor for 5 years. Patients enrolled in US and UK CF registries, which maintain a high degree of data integrity, were evaluated. The authors analyzed 635 cases versus 1,875 controls in the US registry and 247 cases versus 1,230 controls in the UK registry. They observed that, at the end of the 5-year follow-up period, the ivacaftor group patients had better lung function and better nutritional status, as well as a lower frequency of exacerbations and hospitalizations, when compared with their baseline values and with the values obtained for the standard therapy without ivacaftor (control) group.(55)
 
Recommendation

 
 
Comments
 
The results obtained in real-life studies of the use of ivacaftor are similar to those obtained in clinical studies, indicating that it has a positive effect as a modifying drug in the natural progression of CF. The very low quality of the evidence found is due to the high heterogeneity of the studies evaluated, given that our systematic review included clinical trials and observational studies. The studies evaluated included only patients ≥ 6 years of age, and it is not possible to extrapolate the recommendation to any younger age group.
 
Question 2. Should we recommend treatment with lumacaftor+ivacaftor in CF patients homozygous for the F508del mutation?
 
Lumacaftor and ivacaftor are both CFTR modulators. Lumacaftor is a CFTR corrector, which acts in the processing of the protein, correcting its format and consequently increasing in its quantity on the cell membrane.(4)
 
Combination therapy was evaluated in CF patients aged 6 years or older who were homozygous for the F508del class II  mutation. The results indicated a reduction in the number of pulmonary exacerbations, a slight increase in FEV1, improved nutritional status, better quality of life, and a reduction in sweat chloride levels.(12,56-60)
 
In view of the benefits it presents, the use of lumacaftor+ivacaftor has been approved by various international agencies, including the Brazilian ANVISA. In addition, that combination has been shown to have an acceptable safety profile, satisfactory patient adherence (the majority of patients completing the prescribed therapeutic regimen), and a low incidence of relevant adverse events.(13,58-60)
 
Evidence
 
Using the methodology described, we selected 16 articles.(12,56-69) All of those articles were later included for reading, review, and synthesis of evidence (Figure S2 and Chart S3).
 
Of the 15 studies selected, only 2 were RCTs. (12,57) Although not all investigated the same sets of outcomes, they collectively demonstrated that lumacaftor+ivacaftor has a beneficial therapeutic effect in patients homozygous for the F508del mutation.
 
A detailed description of the findings can be found in the Supplementary Material (Question S2). For each of the articles, the quality of evidence for this question is summarized in Tables S2A and S2B.
 
Recommendation

 
 
Comments
 
The combination of a CFTR corrector and a CFTR potentiator can benefit patients homozygous for F508del, representing a differential in the treatment of approximately 45% of individuals with CF and that mutation. However, in the present systematic review, we identified no significant results regarding clinical outcomes that were considered critical. The positive findings obtained for the outcomes that were considered important were only marginal. Some patients may benefit from treatment. However, given the very low quality of evidence for most of the outcomes assessed, we do not suggest the use of lumacaftor+ivacaftor for the treatment of CF patients homozygous for the F508del mutation. It is important to emphasize that new classes/combinations of modulators, such as tezacaftor+ivacaftor(13) and, more recently, the triple combination (elexacaftor+tezacaftor+ivacaftor),(15) have been approved and have been shown to have better efficacy and safety profiles in this population.
 
Question 3. Should we recommend treatment with tezacaftor+ivacaftor in CF patients homozygous for F508del or heterozygous for F508del and with residual function mutations?
 
Tezacaftor is a CFTR corrector that binds to the protein, improving its processing and trafficking through the cell to the cell membrane.(9)
 
The use of tezacaftor+ivacaftor was evaluated in phase III studies involving CF patients ≥ 12 years of age who were homozygous for the F508del mutation,(13) as well as for patients who were heterozygous for the F508del mutation and had a residual function mutation. (14) In those studies, the use of tezacaftor+ivacaftor was found to provide a significant improvement in lung function, a reduction in the number of exacerbations, and nutritional gain, with an adequate safety profile. Similar results were obtained in patients between 6 and 11 years of age. (70 72) Therefore, tezacaftor+ivacaftor was approved for use in patients in several countries, including Brazil.
 
Evidence
 
As shown in Figure S3 and Chart S4, 5 articles were selected by using the methodology described: 4 RCTs and 1 observational study.(13,14,70-72) All of the studies assessed more than one outcome, including BMI, quality of life, adverse events, occurrence of exacerbations, lung function, and mortality.(13,14,70-72)
 
For each of the articles, the quality of evidence for this question is summarized in Table S3. A detailed description of the findings can be found in the Supplementary Material (Question S3).
 
Recommendation

 
 
Comments
 
The use of tezacaftor+ivacaftor was evaluated in CF patients ≥ 6 years of age who were homozygous for F508del or heterozygous for F508del and with a residual function mutation. The main effect of the drug was on lung function. The gain in FEV1, albeit modest, seems significant when considered in the context of a disease that leads to a progressive decline in lung function. It is important to point out that the clinical benefits obtained in patients with a residual function mutation seem to be greater than those found in patients homozygous for F508del. In all of the studies evaluated, there was no difference between the control and tezacaftor+ivacaftor groups in terms of the occurrence of adverse events. Most of the adverse events observed were mild and did not lead to discontinuation of the treatment. In addition, many of the events reported (such as increased pulmonary secretion and increased coughing) can be attributed to the disease itself, which attests to the adequate safety profile of the drug.(13,14,70-72)
 
Question 4. Should we recommend eradicating P. aeruginosa infection in individuals with CF?
 
Respiratory tract infections are common in individuals with CF, who are more susceptible to infection with certain microorganisms, including P. aeruginosa. Infection with this pathogen is considered a major predictor of morbidity and mortality from CF,(73) as well as of a severe loss of lung function.(74) Since the 1990s, CF referral centers have used regimens for early eradication of P. aeruginosa, aiming to delay the progression to chronic infection and its unfavorable outcomes.
 
Evidence
 
Using the methodology described, we selected 17 articles, conducted between 1980 and 2019 and published between 1991 and 2020,(75-91) of which 10 were observational studies(75-80,82,83,86,87) and 7 were RCTs.(81,84,85,88-91) The number of individuals included in the studies ranged from 11 to 304, and 12 of the studies had a sample size of less than 200 (Figure S4 and Chart S5).
 
For each of the articles, the quality of evidence for this question is summarized in Table S4. A detailed description of the findings can be found in the Supplementary Material (Question S4).
 
Recommendation

 
 
Comments
 
The association between P. aeruginosa infection and poor CF outcomes is well established. In addition, eradication therapy has already been incorporated into the routine of referral centers, making it difficult to carry out new studies on the subject. The literature review made it possible to include a limited number of studies, most of which were observational in nature and, in general, had small sample sizes. Such characteristics can lead to inconsistent results, making it impossible to make an appropriate recommendation on the subject. Despite being a practice recommended in several national and international guidelines, further studies are needed to determine the efficacy and safety of P. aeruginosa eradication therapy, especially in the era of CFTR modulator use.
 
Question 5. Should we recommend treatment with inhaled antimicrobials in patients with CF and chronic P. aeruginosa infection?
 
Through complex mechanisms, P. aeruginosa adapts to and can remain in the airways of CF patients for long periods. Chronic infection in CF is defined as detection of the pathogen in more than 50% of respiratory secretion samples over a 12-month period. (92) Chronic infection with P. aeruginosa can affect up to 60% of patients in adult life and is associated with progression of lung disease and higher mortality.(21,93,94) Inhaled antimicrobials are widely used for the suppression of P. aeruginosa in patients with chronic infection, and their use is aimed at reducing the consequences of the presence of the pathogen in the airways. Inhaled drug options for such treatment classically include colistimethate, tobramycin, and, more recently, aztreonam.(93)
 
Evidence
 
Using the methodology described, we selected 25 studies carried out between 1995 and 2008.(94-118) Five were observational studies(101-103,109,117) and the others were classified as RCTs. Samples sizes were over 200 in 9 of the studies, of which 2 included more than 500 individuals (Figure S5 and Chart S6).
 
For each of the articles, the quality of evidence for this question is summarized in Table S5. A detailed description of the findings can be found in the Supplementary Material (Question S5).
 
Recommendation

 
 
Comments
 
Although not all of the studies analyzed exactly the same sets of outcomes, as a whole, they point in favor of the use of inhalation treatment of patients with chronic P. aeruginosa colonization, because such treatment can result in functional improvement, better quality of life, and lower mortality in those patients. It should be borne in mind that, despite the potential benefits, there is heterogeneity among the studies evaluated, resulting in a low quality of evidence.
 
Question 6. Should we recommend antimicrobial eradication treatment in CF patients with MRSA colonization of the airways?
 
Chronic MRSA infection is associated with worse clinical outcomes in CF patients.(119) There are various antimicrobial regimens for eradicating this pathogen, including combinations of oral, topical, and inhaled drugs. There is also great variability regarding treatment time, and some authors argue that combined treatment is more effective than is monotherapy.(120,121) However, there is still no consensus in the literature and it is questionable whether there is robust scientific evidence that MRSA eradication is beneficial for CF patients.(122,123)
 
Evidence
 
Using the methodology described, we selected 8 studies (Figure S6 and Chart S7).(120-127) Of those, only 2 are RCTs(123,126) and the other 6 are observational studies.(120-122,124,125,127)
 
For each of the articles, the quality of evidence for this question is summarized in Tables S6A and S6B. A detailed description of the findings can be found in the Supplementary Material (Question S6).
 
Recommendation

 
 
Comments
 
Although all of the studies assessed the eradication rate, they employed different treatment protocols, as well as different means of assessing eradication (short- vs. long-term follow-up). All of the studies evaluated had sample sizes of less than 70 individuals. It is possible that further studies, especially studies with larger patient samples, will result in a change in the confidence level of this recommendation.
 
Question 7. Should we recommend nebulized dornase alfa for CF patients ≥ 6 years of age?
 
In CF patients, chronic inflammation and infection results in extracellular DNA from leukocytes being constantly released into the airways and accumulating in lung secretions.(18) Consequently, there is an increase in the viscosity and adhesion of mucus. Dornase alfa is an enzyme capable of cleaving the extracellular DNA contained in mucus, reducing its viscosity and promoting greater clearance of secretions.(128)
 
Dornase alfa is administered by inhalation, at the usual dose of 2.5 mg once a day, and should be used in conjunction with other airway clearance techniques.(17,128)
 
In phase I and II studies, the use of nebulized dornase alfa in CF patients proved to be safe and led to an increase in FEV1 in the short term, together with improvements in symptoms and quality of life.(129,130) Subsequent studies demonstrated the maintenance of benefits in the long term, with sustained improvement in FEV1, a reduced risk of exacerbations, and a good safety profile.(128)
 
Evidence
 
We selected 32 studies,(17,131-161) 18 of which were RCTs that compared the use of dornase alfa with placebo,(17,131-135,140-142,144,145,149,151-154,159,160) and 14 were observational studies,(136-139,143,146-148,150,155-158,161) as illustrated in Figure S7 and Chart S8.
 
For each of the articles, the quality of evidence for this question is summarized in Tables S7A and S7B. A detailed description of the findings can be found in the Supplementary Material (Question S7).
 
Recommendation

 
 
Comments
 
The differences in mortality rates between the intervention and placebo groups were not significant, because few patients died. Two RCTs evaluated adverse effects(17,149) and found no significant differences in terms of the frequency of adverse events. One RCT and two observational studies(131,155,156) assessing quality of life demonstrated improvements in the intervention groups.
 
Nine RCTs,(17,131,141,142,144,149,152,154,160) evaluated collectively, showed that FEV1 values were 5% higher among patients receiving dornase alfa than among those receiving a placebo. Although that is a modest improvement, FEV1 is a proxy for mortality in population studies. In addition, 2 RCTs(17,152) demonstrated that the rate of exacerbations was 7% lower in the intervention groups than in the placebo groups. This outcome is important, because a reduction in exacerbations is associated with favorable lung function outcomes and, indirectly, with lower mortality.
 
The search of the literature for these guidelines did not include studies involving children under 6 years of age. Therefore, it is not possible to extrapolate this recommendation to any younger age group.
 
Question 8. Should we recommend antimicrobial eradication treatment in CF patients with airway colonization by B. cepacia complex strains?
 
The B. cepacia complex comprises 22 species,(162) the most common of which in CF are B. multivorans and B. cenocepacia. The clinical picture is quite variable, ranging from chronic, oligosymptomatic infection to severe cases, with necrotizing pneumonia, respiratory failure, and sepsis (cepacia syndrome). (163) The B. cepacia complex has a peculiar bacterial resistance profile, which makes the choice of antibiotic treatment difficult, and a combination of antimicrobial drugs is commonly suggested, preferably guided by antimicrobial susceptibility testing.(164)
 
Evidence
 
Using the methodology described, we selected 3 studies,(23,165,166) as illustrated in Figure S8 and Chart S9. Only 1 study was characterized as an RCT.(165)
 
For each of the articles, the quality of evidence for this question is summarized in Tables S8A and S8B. A detailed description of the findings can be found in the Supplementary Material (Question S8).
 
Recommendation

 
 
Comments
 
None of the selected studies showed any benefits of eradication therapy for B. cepacia complex when evaluating the many critical outcomes considered important in the methodology of these guidelines. Only a few studies on the subject were found in the literature. Most of those studies had low methodological quality, and there was considerable heterogeneity among them. The eradication regimens described were not standardized. The higher rates of adverse events found with the use of inhaled aztreonam cannot be extrapolated to other therapeutic regimens, especially because that antibiotic is not commonly recommended for this type of infection. Therefore, our guideline committee decided that it is not possible to make a recommendation either for or against this therapy, given the scarcity of published information. Further studies are needed in order to evaluate this issue in greater detail.
 
FINAL CONSIDERATIONS
 
A summary of the recommendations for the pharmacological treatment of respiratory disease in CF is presented in Chart 5.
 

 
It is up to the prescribers to determine which treatments are appropriate for a given patient or group of patients, and that it is up to them to help patients and their families make consistent and well-founded decisions, consistent with the strength of the recommendations and the quality of existing evidence. Cost analyses and pharmacoeconomic aspects were not considered in these recommendations.
 
Although there is still no drug with curative capacity in CF, the present guidelines suggest several interventions with potential benefits for the treatment of the disease. Some drugs, such as dornase alfa, and strategies to control chronic infection by P. aeruginosa have been approved for more than a decade and are considered standard therapy in the management of CF. However, those interventions work to control the consequences of the disease, such as increased mucus viscosity and recurrent infectious exacerbations. More recently, a new class of drugs, CFTR modulators, has initiated a new phase in the treatment of CF by acting on the underlying cause of the disease.(9) Substantial gains in lung function and reduction in exacerbation rates were found when ivacaftor was used in patients with class III mutations(11) and when tezacaftor+ivacaftor was used in patients with residual function mutations.(14) However, despite the statistically significant benefits, such results were not achieved in CF patients homozygous for the F508del mutation who were treated with lumacaftor+ivacaftor(12) or tezacaftor+ivacaftor.(13) These data indicate the need for an adequate assessment of the benefits of each treatment according to the population evaluated. Treatment with CFTR modulators can be considered a targeted therapy, and CFTR modulators are chosen according to the action of different drugs on specific groups of CFTR mutations. A new triple combination of CFTR modulators (elexacaftor+tezacaftor+ivacaftor) appears to be an effective and safe option for patients with at least one F508del allele.(15,16)
 
In view of the many advances in the management of CF in recent years, it is recommended that even proven effective treatments, such as dornase alfa and chronic P. aeruginosa suppression therapy, be reassessed in the future, given the greater access to CFTR modulators in eligible patients.
 
Regarding the other interventions evaluated, the expert panel was not able to issue an evidence-based recommendation because of the low quality of the evidence obtained for the eradication of P. aeruginosa, MRSA, and B. cepacia complex. More studies on the topic are needed in order to make a formal recommendation. However, clinical physicians must evaluate the particularities of each patient and recognize the possible benefits of these therapies in selected cases.
 
It should be borne in mind that these guidelines sought to answer questions regarding only eight of the main pharmacological interventions for the treatment of the respiratory consequences of CF. Other therapies, such as nebulization with hypertonic saline and long-term use of macrolides, were not evaluated in these guidelines. That does not mean that such therapies do not present clinical benefits or that they cannot be used according to their own eligibility criteria. Nonpharmacological care, including vaccination, physical activity, respiratory physiotherapy, and pulmonary rehabilitation, is also essential in the management of CF. Finally, because CF is a multisystemic disease, the patient must be cared for in a multidisciplinary way, involving gastrointestinal, endocrinological, and otolaryngological aspects that were not within the scope of these guidelines.(7)
 
It is important to clarify that the very low quality of evidence for some recommendations does not mean that they should not be considered or implemented. In these guidelines, it was decided that RCT and observational studies should be included, with the aim of better evaluating the effect of some therapies approved many years ago for CF. This strategy allows the evaluation of a large sample of patients with high external validity. However, it increases the uncertainty of the results because of the biases inherent to the different study designs. It is important to emphasize that the consistent finding of results in RCT and observational studies favors the clinical applicability of these interventions for a greater proportion of patients with CF. In addition, our recommendations are in line with those of other international guidelines.(8)
 
We believe that these guidelines constitute an important tool to be incorporated into the approach to patients with CF, mainly aiming to favor its management, as well as helping define public policies related to the disease.
 
ACKNOWLEDGMENTS
 
We would like to thank Dr. Anna Menezes and Dr. Fernando Wehrmeister for the methodological and statistical support during the development of this project.
 
AUTHOR CONTRIBUTIONS
 
All of the authors actively participated in the process of devising these guidelines and were involved in the formulation of the questions, the choice of outcomes to be evaluated, and the reviewing of the obtained results. All of the authors approved the final version of the manuscript.
 
CONFLICTS OF INTEREST
 
None declared.
 
REFERENCES
 
1.            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
2.            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
3.            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
4.            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
5.            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
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
8.            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
9.            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
10.          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
11.          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
12.          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
13.          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
14.          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
15.          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
16.          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
17.          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
18.          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
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
20.          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
21.          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
22.          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
23.          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
24.          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
25.          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
26.          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
27.          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
28.          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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
54.          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
55.          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
56.          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
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
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
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
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
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
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
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
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
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
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
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
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
69.          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
70.          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
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
72.          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
73.          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
74.          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
75.          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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
91.          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
92.          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
93.          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
94.          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
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
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
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
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
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
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
101.        Konstan MW, Geller DE, Minić 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
118.        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
119.        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
120.        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
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
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
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
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
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
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
127.        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
128.        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
129.        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
130.        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
131.        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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
161.        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
162.        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
163.        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
164.        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
165.        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
166.        Uluer AZ, Waltz DA, Kalish LA, Adams S, Gerard C, Ericson DA. Inhaled amilori-de and tobramycin solutions fail to eradicate Burkholderia dolosa in patients with cys-tic fibrosis. J Cyst Fibros. 2013;12(1):54-59. https://doi.org/10.1016/j.jcf.2012.06.006