Pulmonary exacerbations are a common event in the life of the patient with cystic fibrosis (CF). Although we do not have a specific definition of an exacerbation, in general we describe them as an acute worsening of respiratory signs and symptoms, such as cough and increased sputum, often accompanied by an acute decrease in lung function as measured by spirometry (ie, forced expiratory volume at 1 second [FEV₁])¹ Implicated causes of pulmonary exacerbations include viral infections, changes in the bacterial community, gastroesophageal reflux disease with aspiration, and exposure to environmental stimuli (eg, pollution, allergens).^2-9 However, some events may be due to poor adherence to therapies,¹⁰ so the pulmonary exacerbation may not be acute as much as the consequence of a growing process over time. In all, however, we believe various stimuli lead to worse respiratory symptoms because of the infection, inflammation, and airway obstruction. For these reasons, the standard treatment of a pulmonary exacerbation includes continuing chronic therapies, increasing airways-clearance therapies, and antibiotics.

Pulmonary exacerbations are associated with considerable morbidity and cost. They are generally resource intensive,^{11, 12} particularly if the patient is hospitalized and missing work or school; they have a negative effect on the patients' quality of life,^13-15; and they are associated with decreased survival.^16-19. Treatment goals are generally stated as returning the patient to baseline status. Typically, we do not objectively measure symptoms, so it is not easy to know whether the patient has fully recovered, but we do frequently measure lung function. We now have convincing evidence ²⁰ that many patients do not recover all of their lost lung function, and a fair percentage (15%) will lose a large amount of lung function (ie, >10%. This is a critical observation, as many clinicians use return to baseline lung function as their stated treatment goal, often leading to much longer courses of antibiotics.

There are a number of general hypotheses why patients may not fully recover their lung function. First could be the etiology of the exacerbation, ie, a viral infection that causes injury to the airways. The second hypothesis is that there are patient factors that contribute to the airways injury, such as the host inflammatory response, the underlying severity of their disease, or other comorbidities such as CF-related diabetes. Finally there may be treatment-related explanations why patients do not recover fully, which could include a delay in treatment or an inadequate treatment. For the first two hypotheses we would suggest that we need to implement prophylactic treatment to prevent exacerbations. Some examples might include greater adherence to the use of the chronic medications that have been shown to reduce the frequency of exacerbations, as well as proper immunization. Beyond that, we should look to develop novel treatments that might temporize the effect of an acute exacerbation (eg, antiinflammatory therapy). For the final hypothesis we must find methods to institute timely therapy as well as determine optimal therapeutic strategies.

A systematic review of important treatment factors found little published evidence to support much of what we do when we treat our patients. Simple questions remain unanswered, such as: How should we choose antibiotics? Should we treat with corticosteroids? How long should we continue antibiotics? The last question — determining the optimal duration of antibiotic therapy (as has already been evaluated in other types of lung infection, eg, hospital-acquired pneumonia) – is especially vital. Treating for too short a period risks treatment failure, but treating for too long not only adds to cost, but also increases the risk of toxicity from the medications. This is not trivial, as our patients are exposed to a large, cumulative dose of aminoglycosides over their lifetimes, potentially leading to an increased incidence of ototoxicity and nephrotoxicity.

In developing a solution, the first question to consider is whether we are likely to find that a fixed duration is optimal for most (if not all) patients or whether there is a clinical endpoint that could be reached. However, it has already been shown that exacerbation symptoms are not measured and that lung function does not return to baseline.²⁰ An ideal study that would compare two durations (longer vs shorter), and would be a placebo-controlled, blinded study in which the patients in the shorter-duration treatment arm would receive placebo for the final days to ensure that all patients would complete at the same time. However, this study design is impractical and costly, and enrollment would likely suffer. A pragmatic study would not be placebo-controlled or blinded but would present the challenge of when to measure the clinical endpoints. Do we measure at the completion of the antibiotics, which is not identical for the two groups, or at some later date that is common for all? What is the relevant clinical endpoint? Some examples could include an objective measure of symptoms (ie, a patient-reported outcome), pulmonary function, treatment failure (ie, treatment within a short period after completion of therapy), and time to next exacerbation.

Finally, we can look at the study design. Should this be a superiority study, where one treatment duration is hypothesized to result in better clinical outcomes than the other? Or should we design a noninferiority study, where the hypothesis is that patients would fare no worse with shorter treatment durations? Such trials may require a large number of patients so feasibility is a key issue when considering study design.

In conclusion, pulmonary exacerbations commonly occur in individuals with CF. We have existing therapies that can prevent some exacerbations and we need to find ways to encourage our patients to adhere to a regular treatment regimen. However, we still need novel therapies that may yet prove more effective in preventing exacerbations or ameliorating their consequences. Finally, while we lack evidence to define optimum treatment of pulmonary exacerbations, the CF community is poised to perform the research necessary to answer those key questions.

Commentary References
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