Early Aggressive Intervention in Cystic Fibrosis: Is It Time To Redefine Our “Best Practice” Strategies?

Abstract

Among many unresolved issues in the treatment of cystic fibrosis (CF), certainly two of the most important decisions that clinicians and patients with CF must face are when and how to aggressively combat this multifaceted disorder to achieve the best outcome. In their article (see page 20), Johnson et al provide compelling data in support of aggressive intervention to improve long-term outcomes in patients with CF. This observational study, which utilizes data collected in the Epidemiologic Study of Cystic Fibrosis database, reviews the management of > 18,000 patients with CF, aged 6 to > 18 years, collected over a 2-year period (1995 to 1996). Based on standard CF interventions prescribed at the physicians' discretion, they found that in CF centers where patients were monitored and treated more frequently, there were “significant and clinically relevant differences across sites in lung health as measured by FEV1.” The thesis that increased patient surveillance leads to increased intervention and yields improved outcomes is reasonable, and it has important ramifications for patient management, despite the potential confounders associated with the use of observational study data to infer best practice habits. That said, these findings leave the issues of exactly when and how frequently (as well as with which agents) to intervene unresolved.When to initiate treatment in a patient with CF remains somewhat of a quandary. Certainly, intervention in the presence of an exacerbation is necessary. However, is it appropriate to treat inflammation in the absence of infection, and, if so, when and in which patients? Taking this issue up a notch, we also need to determine the most clinically meaningful goals for treating Pseudomonas aeruginosa, a major contributor to loss of lung function. Several researchers believe that the goal of therapy should be an approach that concurrently provides prophylaxis (through cohort isolation), eradication, and chronic suppression of Pseudomonas as the best approach to delay loss of lung function; however, the threat of increased bacterial resistance concerns many clinicians due to the potential risk for future IV antibiotic treatment failure.Speaking to the issue of timing, the extent to which regional pediatric and adolescent care practices may dictate or carry over into the practice of adult CF care remains unclear, and elucidating the nuances of care variances is critical if we are to fully appreciate the impact of timing. This report by Johnson et al, which does not separate findings by type of CF care center (ie, pediatric, pediatric/adult, or adult), falls short of advancing our understanding of this issue. Since practice habits differ throughout the country, perhaps assessing the impact of aggressive intervention in adolescent or adult (only) centers would provide additional insight into this matter. Alternatively, if adolescent and adult care differs substantially from that given to young patients with CF, what clinical impact on CF morbidity and mortality might be achieved by uniformly modifying the care of our pediatric patients?Next, if aggressive intervention does meaningfully delay decline of FEV1, as this report suggests, we must determine which interventions are most effective in which type of patients with CF. There are significant data in the current literature, based on our understanding of the pathogenesis of CF lung disease, to support that inflammation and infection progress in the absence of an acute exacerbation or significant clinical deterioration,1Konstan MW Berger M Current understanding of the inflammatory process in cystic fibrosis: onset and etiology.Pediatr Pulmonol. 1997; 24: 137-142Crossref PubMed Scopus (2) Google Scholar2Konstan MW Hilliard KA Norvell TM et al.Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation.Am J Respir Crit Care Med. 1994; 150: 448-454Crossref PubMed Scopus (473) Google Scholar even in clinically stable infants.3Khan TZ Wagener JS Bost T et al.Early pulmonary inflammation in infants with cystic fibrosis.Am J Respir Crit Care Med. 1995; 151: 1075-1082PubMed Google Scholar4Dakin CJ Numa AH Wang HE et al.Inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis.Am J Respir Crit Care Med. 2002; 165: 904-910Crossref PubMed Scopus (208) Google Scholar5Ranganathan SC Dezateux C Bush A et al.Airway function in infants newly diagnosed with cystic fibrosis.Lancet. 2001; 358: 1964-1965Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar The pathophysiologic premise is borne out in a few clinical studies of early or aggressive therapy, including the tobramycin solution for inhalation (TOBI; Chiron Biopharmaceuticals; Emeryville, CA) trial,6Ramsey BW Pepe MS Quan JM et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1134) Google Scholar the dornase alfa early intervention trial,7Quan JM Tiddens HAWM Sy JP 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: 813-820Abstract Full Text PDF PubMed Scopus (260) Google Scholar the antibiotic prophylaxis in cystic fibrosis study,8Stutman HR Lieberman JM Nussbaum E et al.Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial.J Pediatr. 2002; 140: 299-305Abstract Full Text PDF PubMed Scopus (136) Google Scholar and the ibuprofen trial.9Konstan MW Byard PH Hoppel CL et al.Effect of high-dose ibuprofen in patients with cystic fibrosis.N Engl J Med. 1995; 332: 848-854Crossref PubMed Scopus (647) Google Scholar Further, a growing body of clinical data suggest that early anti-inflammatory therapy9Konstan MW Byard PH Hoppel CL et al.Effect of high-dose ibuprofen in patients with cystic fibrosis.N Engl J Med. 1995; 332: 848-854Crossref PubMed Scopus (647) Google Scholar10Eigen H Rosenstein BJ A multicenter study of alternate-day prednisone in patients with cystic fibrosis.J Pediatr. 1995; 126: 515-523Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar and early antimicrobial therapy11Frederiksen B Lanng S Koch C et al.Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment.Pediatr Pulmonol. 1996; 21: 153-158Crossref PubMed Scopus (238) Google Scholar reduce the frequency and duration of chronic infection with possible delays in the progression of CF lung disease. Yet, according to recently published data by Oermann and colleagues,12Oermann CM Sockrider MM Konstan MW The use of anti-inflammatory medications in cystic fibrosis: trends and physician attitudes.Chest. 1999; 115: 1053-1058Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar “despite a compelling rationale and considerable interest in the use of anti-inflammatory drugs to slow pulmonary deterioration in CF patients, little is known regarding the prevalence of their use and nothing is known regarding the prescribing patterns of these drugs among CF care providers.” This statement also may be applicable to antibiotic therapies as well. Study data support the use of aggressive antibiotic intervention to prevent13Heinzl B Eber E Oberwaldner B et al.Effects of inhaled gentamicin prophylaxis on acquisition of Pseudomonas aeruginosa in children with cystic fibrosis: a pilot study.Pediatr Pulmonol. 2002; 33: 32-37Crossref PubMed Scopus (51) Google Scholar or delay14Wiesemann HG Steinkamp G Ratjen F 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: 88-92Crossref PubMed Scopus (180) Google Scholar15Ratjen F Döring G Nikolaizik WH Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis.Lancet. 2001; 358: 983-984Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar the acquisition of P aeruginosa in patients with CF to preserve lung function. Long-term intermittent inhaled antibiotic prophylaxis16Moss RB Long-term benefits of inhaled tobramycin in adolescent patient with cystic fibrosis.Chest. 2001; 121: 55-63Abstract Full Text Full Text PDF Scopus (143) Google Scholar has been shown to improve and modify the rate of lung function decline observed in patients with CF (when compared to patients with CF not receiving ongoing prophylaxis). However, it remains unclear which single approach—or combination of strategies—yield the best outcome.Trends in antibiotic therapy have evolved since the 2-year period of data collection reported in this study. In particular, our use of oral and inhaled antibiotics in patients with CF has greatly increased, and these changes in treatment modalities have given rise to new management strategies and concerns—specifically, the looming specter of increasing bacterial resistance. Traditional logic held that increasing numbers in resistant isolates represented an important risk factor for antibiotic treatment failure. In their report, Burns et al17Burns JL Van Dalfsen JM Shawar RM et al.Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis.J Infect Dis. 1991; 179: 1190-1196Crossref Scopus (256) Google Scholar suggest that withholding treatment (in an effort to avoid increased minimum inhibitory concentrations) probably represented a greater risk to patients than the presence of resistant isolates (alone). In a later study, Smith et al18Smith AL Fiel SB Mayer-Hamblett N et al.Lack of association between in vitro antibiotic susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration in cystic fibrosis.Chest. 2003; (in press)Google Scholar showed that there was no correlation between the effectiveness of IV antibiotic treatment for acute exacerbations and in vitro antibiotic susceptibility tests of isolates from patients with CF, calling traditional microbiologic principles into question—at least for patients with CF colonized/infected with P aeruginosa. The data by Johnson and colleagues provides a longitudinal analysis of rate of intervention as a function of pulmonary status. More recently, some clinicians are thinking outside the traditional model of stepped interventions in response to a pulmonary exacerbation, and planning for long-term, outcome-oriented interventions. Examining outcome as a function of intervention may represent a next step toward enhancing our capacity for CF disease management.Not withstanding some of the limitations of the study by Johnson et al to assist us in understanding the risks and benefits of early intervention, this report offers additional support to existing CF care guidelines and practice habits. It also punctuates the potential timeliness for a well-designed, multicenter, placebo-controlled, randomized trial designed to measure outcome as a function of intervention. If an ethical and practically feasible randomized trial (RCT) can be designed, it is decidedly preferable to an observational study. RCTs yield effect estimates and SE values to assess both measured and unmeasured confounding variables. In CF research, however, we are often faced with the task of deciding whether existing observational data can be carefully employed as an effective substitute for RCTs in the development of treatment recommendations—given the caveat that interpretations of observational data are especially vulnerable to unmeasured confounders.Currently, in place of the time and expense that a RCT trial will surely entail, we possess data that clearly map the indolent progression and inflammation in the asymptomatic patient with CF. We have tomes of mortality data that elucidate the rapidity of disease progression following acquisition of P aeruginosa in patients with CF, despite our inability to fully describe the mechanisms of disease. We may never achieve an understanding of all of the issues that impact CF care and outcomes. In the interim, however, we have a wealth of experience-based medicine for guidance. Quan and colleagues7Quan JM Tiddens HAWM Sy JP 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: 813-820Abstract Full Text PDF PubMed Scopus (260) Google Scholar showed that young patients with CF treated with dornase alfa had improvements in lung function and a reduction in the risk of exacerbations requiring IV antibiotics over a 96-week period. Ramsey and colleagues6Ramsey BW Pepe MS Quan JM et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1134) Google Scholar found that aggressive intermittent treatment of P aeruginosa-infected patients with inhaled tobramycin improved pulmonary function, decreased the density of P aeruginosa in sputum, and decreased risk of hospitalization. Utilizing an early anti-Pseudomonas aeruginosa treatment regimen that included elective IV antibiotics for 14 days every third month, Frederiksen et al11Frederiksen B Lanng S Koch C et al.Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment.Pediatr Pulmonol. 1996; 21: 153-158Crossref PubMed Scopus (238) Google Scholar demonstrated improved survival in a Danish study population with an increased probability of survival to 40 years in > 80% of their cohort, and this list continues. While these and other studies have greatly increased our strategic capabilities to manage CF outcomes more effectively, the perfect approach to CF management may elude us because of the array of care variables. Among many unresolved issues in the treatment of cystic fibrosis (CF), certainly two of the most important decisions that clinicians and patients with CF must face are when and how to aggressively combat this multifaceted disorder to achieve the best outcome. In their article (see page 20), Johnson et al provide compelling data in support of aggressive intervention to improve long-term outcomes in patients with CF. This observational study, which utilizes data collected in the Epidemiologic Study of Cystic Fibrosis database, reviews the management of > 18,000 patients with CF, aged 6 to > 18 years, collected over a 2-year period (1995 to 1996). Based on standard CF interventions prescribed at the physicians' discretion, they found that in CF centers where patients were monitored and treated more frequently, there were “significant and clinically relevant differences across sites in lung health as measured by FEV1.” The thesis that increased patient surveillance leads to increased intervention and yields improved outcomes is reasonable, and it has important ramifications for patient management, despite the potential confounders associated with the use of observational study data to infer best practice habits. That said, these findings leave the issues of exactly when and how frequently (as well as with which agents) to intervene unresolved. When to initiate treatment in a patient with CF remains somewhat of a quandary. Certainly, intervention in the presence of an exacerbation is necessary. However, is it appropriate to treat inflammation in the absence of infection, and, if so, when and in which patients? Taking this issue up a notch, we also need to determine the most clinically meaningful goals for treating Pseudomonas aeruginosa, a major contributor to loss of lung function. Several researchers believe that the goal of therapy should be an approach that concurrently provides prophylaxis (through cohort isolation), eradication, and chronic suppression of Pseudomonas as the best approach to delay loss of lung function; however, the threat of increased bacterial resistance concerns many clinicians due to the potential risk for future IV antibiotic treatment failure. Speaking to the issue of timing, the extent to which regional pediatric and adolescent care practices may dictate or carry over into the practice of adult CF care remains unclear, and elucidating the nuances of care variances is critical if we are to fully appreciate the impact of timing. This report by Johnson et al, which does not separate findings by type of CF care center (ie, pediatric, pediatric/adult, or adult), falls short of advancing our understanding of this issue. Since practice habits differ throughout the country, perhaps assessing the impact of aggressive intervention in adolescent or adult (only) centers would provide additional insight into this matter. Alternatively, if adolescent and adult care differs substantially from that given to young patients with CF, what clinical impact on CF morbidity and mortality might be achieved by uniformly modifying the care of our pediatric patients? Next, if aggressive intervention does meaningfully delay decline of FEV1, as this report suggests, we must determine which interventions are most effective in which type of patients with CF. There are significant data in the current literature, based on our understanding of the pathogenesis of CF lung disease, to support that inflammation and infection progress in the absence of an acute exacerbation or significant clinical deterioration,1Konstan MW Berger M Current understanding of the inflammatory process in cystic fibrosis: onset and etiology.Pediatr Pulmonol. 1997; 24: 137-142Crossref PubMed Scopus (2) Google Scholar2Konstan MW Hilliard KA Norvell TM et al.Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation.Am J Respir Crit Care Med. 1994; 150: 448-454Crossref PubMed Scopus (473) Google Scholar even in clinically stable infants.3Khan TZ Wagener JS Bost T et al.Early pulmonary inflammation in infants with cystic fibrosis.Am J Respir Crit Care Med. 1995; 151: 1075-1082PubMed Google Scholar4Dakin CJ Numa AH Wang HE et al.Inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis.Am J Respir Crit Care Med. 2002; 165: 904-910Crossref PubMed Scopus (208) Google Scholar5Ranganathan SC Dezateux C Bush A et al.Airway function in infants newly diagnosed with cystic fibrosis.Lancet. 2001; 358: 1964-1965Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar The pathophysiologic premise is borne out in a few clinical studies of early or aggressive therapy, including the tobramycin solution for inhalation (TOBI; Chiron Biopharmaceuticals; Emeryville, CA) trial,6Ramsey BW Pepe MS Quan JM et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1134) Google Scholar the dornase alfa early intervention trial,7Quan JM Tiddens HAWM Sy JP 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: 813-820Abstract Full Text PDF PubMed Scopus (260) Google Scholar the antibiotic prophylaxis in cystic fibrosis study,8Stutman HR Lieberman JM Nussbaum E et al.Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial.J Pediatr. 2002; 140: 299-305Abstract Full Text PDF PubMed Scopus (136) Google Scholar and the ibuprofen trial.9Konstan MW Byard PH Hoppel CL et al.Effect of high-dose ibuprofen in patients with cystic fibrosis.N Engl J Med. 1995; 332: 848-854Crossref PubMed Scopus (647) Google Scholar Further, a growing body of clinical data suggest that early anti-inflammatory therapy9Konstan MW Byard PH Hoppel CL et al.Effect of high-dose ibuprofen in patients with cystic fibrosis.N Engl J Med. 1995; 332: 848-854Crossref PubMed Scopus (647) Google Scholar10Eigen H Rosenstein BJ A multicenter study of alternate-day prednisone in patients with cystic fibrosis.J Pediatr. 1995; 126: 515-523Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar and early antimicrobial therapy11Frederiksen B Lanng S Koch C et al.Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment.Pediatr Pulmonol. 1996; 21: 153-158Crossref PubMed Scopus (238) Google Scholar reduce the frequency and duration of chronic infection with possible delays in the progression of CF lung disease. Yet, according to recently published data by Oermann and colleagues,12Oermann CM Sockrider MM Konstan MW The use of anti-inflammatory medications in cystic fibrosis: trends and physician attitudes.Chest. 1999; 115: 1053-1058Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar “despite a compelling rationale and considerable interest in the use of anti-inflammatory drugs to slow pulmonary deterioration in CF patients, little is known regarding the prevalence of their use and nothing is known regarding the prescribing patterns of these drugs among CF care providers.” This statement also may be applicable to antibiotic therapies as well. Study data support the use of aggressive antibiotic intervention to prevent13Heinzl B Eber E Oberwaldner B et al.Effects of inhaled gentamicin prophylaxis on acquisition of Pseudomonas aeruginosa in children with cystic fibrosis: a pilot study.Pediatr Pulmonol. 2002; 33: 32-37Crossref PubMed Scopus (51) Google Scholar or delay14Wiesemann HG Steinkamp G Ratjen F 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: 88-92Crossref PubMed Scopus (180) Google Scholar15Ratjen F Döring G Nikolaizik WH Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis.Lancet. 2001; 358: 983-984Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar the acquisition of P aeruginosa in patients with CF to preserve lung function. Long-term intermittent inhaled antibiotic prophylaxis16Moss RB Long-term benefits of inhaled tobramycin in adolescent patient with cystic fibrosis.Chest. 2001; 121: 55-63Abstract Full Text Full Text PDF Scopus (143) Google Scholar has been shown to improve and modify the rate of lung function decline observed in patients with CF (when compared to patients with CF not receiving ongoing prophylaxis). However, it remains unclear which single approach—or combination of strategies—yield the best outcome. Trends in antibiotic therapy have evolved since the 2-year period of data collection reported in this study. In particular, our use of oral and inhaled antibiotics in patients with CF has greatly increased, and these changes in treatment modalities have given rise to new management strategies and concerns—specifically, the looming specter of increasing bacterial resistance. Traditional logic held that increasing numbers in resistant isolates represented an important risk factor for antibiotic treatment failure. In their report, Burns et al17Burns JL Van Dalfsen JM Shawar RM et al.Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis.J Infect Dis. 1991; 179: 1190-1196Crossref Scopus (256) Google Scholar suggest that withholding treatment (in an effort to avoid increased minimum inhibitory concentrations) probably represented a greater risk to patients than the presence of resistant isolates (alone). In a later study, Smith et al18Smith AL Fiel SB Mayer-Hamblett N et al.Lack of association between in vitro antibiotic susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration in cystic fibrosis.Chest. 2003; (in press)Google Scholar showed that there was no correlation between the effectiveness of IV antibiotic treatment for acute exacerbations and in vitro antibiotic susceptibility tests of isolates from patients with CF, calling traditional microbiologic principles into question—at least for patients with CF colonized/infected with P aeruginosa. The data by Johnson and colleagues provides a longitudinal analysis of rate of intervention as a function of pulmonary status. More recently, some clinicians are thinking outside the traditional model of stepped interventions in response to a pulmonary exacerbation, and planning for long-term, outcome-oriented interventions. Examining outcome as a function of intervention may represent a next step toward enhancing our capacity for CF disease management. Not withstanding some of the limitations of the study by Johnson et al to assist us in understanding the risks and benefits of early intervention, this report offers additional support to existing CF care guidelines and practice habits. It also punctuates the potential timeliness for a well-designed, multicenter, placebo-controlled, randomized trial designed to measure outcome as a function of intervention. If an ethical and practically feasible randomized trial (RCT) can be designed, it is decidedly preferable to an observational study. RCTs yield effect estimates and SE values to assess both measured and unmeasured confounding variables. In CF research, however, we are often faced with the task of deciding whether existing observational data can be carefully employed as an effective substitute for RCTs in the development of treatment recommendations—given the caveat that interpretations of observational data are especially vulnerable to unmeasured confounders. Currently, in place of the time and expense that a RCT trial will surely entail, we possess data that clearly map the indolent progression and inflammation in the asymptomatic patient with CF. We have tomes of mortality data that elucidate the rapidity of disease progression following acquisition of P aeruginosa in patients with CF, despite our inability to fully describe the mechanisms of disease. We may never achieve an understanding of all of the issues that impact CF care and outcomes. In the interim, however, we have a wealth of experience-based medicine for guidance. Quan and colleagues7Quan JM Tiddens HAWM Sy JP 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: 813-820Abstract Full Text PDF PubMed Scopus (260) Google Scholar showed that young patients with CF treated with dornase alfa had improvements in lung function and a reduction in the risk of exacerbations requiring IV antibiotics over a 96-week period. Ramsey and colleagues6Ramsey BW Pepe MS Quan JM et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1134) Google Scholar found that aggressive intermittent treatment of P aeruginosa-infected patients with inhaled tobramycin improved pulmonary function, decreased the density of P aeruginosa in sputum, and decreased risk of hospitalization. Utilizing an early anti-Pseudomonas aeruginosa treatment regimen that included elective IV antibiotics for 14 days every third month, Frederiksen et al11Frederiksen B Lanng S Koch C et al.Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment.Pediatr Pulmonol. 1996; 21: 153-158Crossref PubMed Scopus (238) Google Scholar demonstrated improved survival in a Danish study population with an increased probability of survival to 40 years in > 80% of their cohort, and this list continues. While these and other studies have greatly increased our strategic capabilities to manage CF outcomes more effectively, the perfect approach to CF management may elude us because of the array of care variables.