Pulmonary Exacerbations Clinical Care Guidelines

Pulmonary exacerbations are common among people with cystic fibrosis, yet little is known about best treatment practices. These guidelines were developed by consensus based on expert opinion and a review of the medical literature.

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Pulmonary Exacerbations Clinical Care Guidelines: Executive Summary

Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC, Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009 Nov 1;180(9):802-8. doi: 10.1164/rccm.200812-1845PP. Epub 2009 Sep 3.

Cystic fibrosis is characterized by chronic respiratory infections resulting in progressive loss of lung function and decreased survival, and is marked by acute worsening of symptoms, called pulmonary exacerbations (PEx). Although there is no widely accepted definition of PEx, they generally entail an increase in respiratory symptoms (e.g., increased cough, sputum production, shortness of breath) accompanied by an acute decrease in lung function.

PEx occur commonly in the life of an individual with CF, with more than 17,000 events treated with intravenous (IV) antibiotics recorded in the Cystic Fibrosis Foundation Patient Registry in 2015. There are currently no guidelines about best practices for duration of antibiotics, route and dosing of antibiotics, location of treatment (i.e., home or hospital), and other possible therapies, such as steroids. The CF Pulmonary Guidelines: Treatment of Pulmonary Exacerbations was published in 2009. To create those guidelines, a systematic review was performed to establish best treatment practices.

However, the committee found that there was a lack of evidence to support specific treatment recommendations for most questions. Where appropriate, a consensus-based recommendation was made linking to other chronic therapy guidelines. Additionally, the need for dedicated research was recognized to establish specific treatment guidelines. The establishment of evidence-based guidelines is a priority to the CF Foundation, and the first interventional study evaluating pulmonary exacerbations is currently underway.

Methodology

A multidisciplinary committee of experts developed specific questions related to the treatment of pulmonary exacerbations. A systematic literature review was conducted and reviewed by the committee. The committee then drafted and voted on recommendations. The final recommendations were graded using the U.S. Preventative Task Force (USPSTF) Scheme. Find additional information about the USPSTF grading definitions.

Recommendations

Recommendations Evaluation of the Evidence
1. Site of treatment:

The CF Foundation recommends against the delivery of IV antibiotics in a nonhospital setting, unless resources and support equivalent to the hospital setting can be assured for the treatment of an acute exacerbation of pulmonary disease.
Recommendation: I
2. Continuing chronic medications for maintenance of lung health:

The CF Foundation recommends continuing chronic therapies for maintenance of lung health during treatment of an acute exacerbation of pulmonary disease.
Recommendation: B
3. Continuing inhaled antibiotics used as a chronic therapy:

The CF Foundation concludes that there is insufficient evidence to recommend for or against continued use of inhaled antibiotics in patients treated with the same antibiotics intravenously for the treatment of an acute exacerbation of pulmonary disease.
Recommendation: I
4. Continuing airway clearance therapies for maintenance of lung health:

The CF Foundation recommends that airway clearance therapy be increased as part of the treatment of an acute exacerbation of pulmonary disease.
Recommendation: B
5. Number of antibiotics to treat Pseudomonas aeruginosa:

The CF Foundation concludes that there is insufficient evidence to recommend the use of a single antibiotic as being equivalent to the use of more than one antibiotic class for treatment of a Pseudomonas infection during an acute exacerbation of pulmonary disease.
Recommendation: I
6. Dosing of antibiotics:

Aminoglycoside dosing: The CF Foundation recommends that once-daily dosing of aminoglycosides is preferable to three-times daily dosing for treatment of an acute exacerbation of pulmonary disease.
Recommendation: C
7. Dosing of antibiotics:

Beta-lactam (b-lactam) dosing: The CF Foundation concludes that there is insufficient evidence to recommend the continuous infusion of b-lactam antibiotics for treatment of an acute exacerbation of pulmonary disease.
Recommendation: I
8. Duration of antibiotic treatment:

The CF Foundation concludes that there is insufficient evidence to recommend an optimal duration of antibiotic treatment of an acute exacerbation of pulmonary disease.
Recommendation: I
9. Synergy testing:

The CF Foundation recommends against the use of synergy testing as part of the routine evaluation of the patient with an acute exacerbation of pulmonary disease and multidrug-resistant bacteria.
Recommendation: D
10. Corticosteroids:

The CF Foundation concludes that there is insufficient evidence to recommend the routine use of corticosteroids in the treatment of an acute exacerbation of pulmonary disease.
Recommendation: I

Unanswered Questions

The committee identified important questions relevant to pulmonary exacerbation treatment decisions. The systematic review found a lack of high-quality data to address most of these questions, for which additional studies are needed.

Since the publication of the 2009 guidelines, there has been some progress in addressing these questions. However, they still do not provide sufficient guidance upon which to suggest a change in the recommendations. For example:

  • A study of inhaled tobramycin given in conjunction with IV tobramycin found that the timing of the inhaled dose may influence the assessment of pharmacokinetic parameters, but it did not determine if there was any difference in efficacy or safety.
  • An analysis of the CF Foundation Patient Registry revealed that receiving IV antibiotic treatments for less than nine days and receiving IV antibiotics without hospitalization were significant risk factors for IV retreatment within 30 days of completion of an exacerbation treatment. Although this does not answer the question of optimal duration nor best site for treatment, it does suggest that treatment decisions can impact outcomes for pulmonary exacerbations.
  • An analysis of IV antibiotics administered in the hospital versus at home was found to be equivalent in terms of long-term lung function decline and time between PEx. The question of best site of treatment has yet to be answered.

Future Directions

The CF Foundation has determined that identifying best practices for the treatment of pulmonary exacerbations is a high priority. They have already supported an observational study, the Standardized Treatment of Pulmonary Exacerbations (STOP) study (clinicaltrials.gov NCT02109822), with the aims of establishing key information needed for the design of interventional trials and clinical equipoise among treating clinicians. The manuscripts reporting the results of this observational study are noted below.

  • The first manuscript (Sanders et al. 2017) describes PEx and how patients present (duration of symptoms and mean lung function drop), physician goals for treatment of PEx, and clinical equipoise for future interventional studies of PEx.
  • The second manuscript (West et al. 2017) describes the end of treatment for a PEx, evaluates physician treatment practices, and describes patient outcomes after treatment for the PEx.
  • The third manuscript (VanDevanter et al. 2017) describes the rationalization of clinical endpoints for interventional trials in PEx in CF.

These findings helped design the first interventional study, Standardized Treatment of Pulmonary Exacerbations II (STOP 2) study (clinicaltrials.gov NCT02781610), looking at durations of intravenous antibiotic therapy, which is currently underway. There are additional questions that could be addressed once this study is completed. Examples include: timing of initiation of antibiotics, antibiotic selection and dosing to maximize efficacy and reduce toxicity, and the site of antibiotic delivery (home versus hospital).

  1. How should we choose initial antibiotic regimens (e.g., selection of antibiotics, doses, delivery method, and duration of infusion)?
  2. What is the best method of delivering antibiotics (e.g., topical, systemic, or both)?
  3. Is there a benefit to the use of corticosteroids?
  4. Are hospital and home treatment truly equivalent, or does one site result in better outcomes?
  5. Are there biomarkers that offer prognostic value that would impact treatment decisions?

Further Reading

Relevant manuscripts published after the original guidelines are listed below. These manuscripts have not been reviewed or endorsed by the guidelines committee.

  • Stenbit AE, Bullington WM, Heh JL, Flume PA. Timing of inhaled tobramycin affects assessment of intravenous tobramycin pharmacokinetic monitoring. J Cyst Fibros. 2013 Jul;12(4):403-6. doi: 10.1016/j.jcf.2012.11.007. Epub 2012 Dec 20.
  • VanDevanter DR, Flume PA, Morris N, Konstan MW. Probability of IV antibiotic retreatment within thirty days is associated with duration and location of IV antibiotic treatment for pulmonary exacerbation in cystic fibrosis. J Cyst Fibros. 2016 Nov;15(6):783-790. doi: 10/1016/j.jcf.2016.04.005. Epub 2016 Apr 29.
  • Collaco JM, Green DM, Cutting GR, Naughton KM, Mogayzel PJ Jr. Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1137-43. doi: 10.1164/rccm.201001-0057OC. Epub 2010 Jun 25.
  • Sanders DB, Solomon GM, Beckett VV, West NE, Daines CL, Heltshe SL, VanDevanter DR, et al. Standardized Treatment of Pulmonary Exacerbations (STOP) study: Observations at the initiation of intravenous antibiotics for cystic fibrosis pulmonary exacerbations. J Cyst Fibros. 2017 Sep; 16(5):592-599. doi: 0.1016/j.jcf.2017.04.005. Epub 2017 Apr 29.
  • West NE, Beckett VV, Jain R, Sanders DB, Nick JA, Heltshe SL, et al. Standardized Treatment of Pulmonary exacerbations (STOP) Study: Physician treatment practices and outcomes for individuals with cystic fibrosis with pulmonary exacerbations. J Cyst Fibros. 2017 Sep; 16(5):600-606. doi: 10.1016/j.jcf.2017.04.003. Epub 2017 Apr 29.
  • VanDevanter DR, Heltshe SL, Spahr J, Beckett VV, Daines CL, Dasenbrook EC, et al. Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis. J Cyst Fibros. 2017 Sep; 16(5):607-615. doi: 10.1016/j.jcf.2017.04.004. Epub 2017 Apr 21.
  • Stanojevic S, McDonald A, Waters V, MacDonald S, Horton E, Tullis E, Ratjen F. Effect of pulmonary exacerbations treated with oral antibiotics on clinical outcomes in cystic fibrosis. Thorax. 2017 Apr;72(4):327-332. doi: 10.1136/ thoraxjnl-2016-208450. Epub 2016 Aug 18.
  • Sanders DB, Bittner RC, Rosenfeld M, Redding GJ, Goss CH. Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonol. 2011 Apr;46(4):393-400. doi: 10.1002/ppul.21374. Epub 2010 Oct 21.
  • Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med. 2010 Sep 1;182(5):627-32. doi: 10.1164/rccm.200909-1421OC. Epub 2010 May 12.
  • Heltshe SL, Goss CH, Thompson V, Sagel SD, Sanders DB, Marshall BC, Flume PA. Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis. Thorax. 2016 Mar;71(3):223-9. doi: 10.1136/thoraxjnl-2014-206750. Epub 2015 Apr 24.

This executive summary was prepared by:

Natalie E. West, MHS, MD, (John Hopkins University, Baltimore) and Patrick A. Flume, MD, (Medical University of South Carolina, Charleston, S.C.)

The guidelines were published in November 2008, they were reviewed in April 2019 and it was determined that no update is needed at this time.

 

 

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