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Dr. Fiel is Professor and Chief, Division of Pulmonary and Critical Care Medicine, Drexel University College of Medicine, MCP and Hahnemann Hospitals.
Correspondence to: Stanley B. Fiel, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Drexel University College of Medicine, MCP Hospital, 3300 Henry Ave, Philadelphia, PA 19129
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,1 2 even in clinically stable infants.3 4 5 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,6 the dornase alfa early intervention trial,7 the antibiotic prophylaxis in cystic fibrosis study,8 and the ibuprofen trial.9 Further, a growing body of clinical data suggest that early anti-inflammatory therapy9 10 and early antimicrobial therapy11 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,12 "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 prevent13 or delay14 15 the acquisition of P aeruginosa in patients with CF to preserve lung function. Long-term intermittent inhaled antibiotic prophylaxis16 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 al17 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 al18 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 colleagues7 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 colleagues6 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 al11 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.
References
This article has been cited by other articles:
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  M. H. Baumann and D. D. Gutterman American College of Chest Physicians Evidence-Based Guidelines-the Next Generation: Considering Resource Use and Evolution to a Single Grading System Chest, January 1, 2006; 129(1): 10 - 12. [Full Text] [PDF]
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