Samantha Strickler, DO
Assistant Professor of Emergency Medicine and Critical Care Medicine, Emory University
“It had been three weeks since I had last seen E-. He looked up at me from behind his glasses as he sat in his ICU bed. ‘How are you doing?’ He shrugged his shoulders and gave me a tired grin. He did not remember me. When I last saw him, he had just been intubated for an acute pulmonary exacerbation of his cystic fibrosis. He had since developed septic shock and underwent a tracheostomy. Now he was wearing a trach collar. He looked thinner than I had remembered. I couldn’t help but think, he’s only four years younger than me.”
As a result of a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR), people with cystic fibrosis (CF) are afflicted with a systemic disease that thickens and increases the viscosity of the most seemingly insignificant secretions.2 Due to this underlying pathology, people with CF develop chronic pulmonary inflammation and consequent infections. They will often develop diabetes mellitus and issues with the biliary system and bowel. Men specifically can also have issues with infertility. According to the most recent data from the Cystic Fibrosis Foundation (CFF) Patient Registry, more than 30,000 people in the United States are affected by CF.3 Sadly, pulmonary issues account for 66.8% of the mortality associated with CF.1 In 2017, 43% of adults and 24% of children with CF experienced one or more acute pulmonary exacerbations (APEs).4 Considering the significant burden of APEs, early aggressive treatment needs to be implemented in the emergency department (ED) and continued after admission, especially when it is to the intensive care unit.
Although CF has been recognized as a systemic disease since 1938, a precise definition of an APE has yet to be established.5-7 Generally speaking, an APE in CF is described as an acute worsening of pulmonary function. Patients with CF may report an increase in cough and/or sputum production, dyspnea, chest pain, loss of appetite, weight loss, and/or hemoptysis. Quantitatively, this may be characterized by a decrease in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). After each exacerbation, pulmonary function often fails to return to baseline.
Historically, APEs in CF patients have been attributed to several infectious pathogens. Among them, Pseudomonas aeruginosa has been and continues to be the most prevalent bacteria, occurring in 90% of people by adulthood.8 Due to the underlying issues of inflammation and difficulty with secretion clearance, people with CF become chronically infected with P. aeruginosa. Current research suggests that the growth and virulence of this bacterium changes during APEs.9
Several other bacteria have also been identified in sputum from people with CF during APEs. Included among them are Staphylococcus aureus (methicillin sensitive and resistant), Burkholderia cepacia, nontuberculous mycobacteria (Mycobacterium abscessus complex, Mycobacterium avium complex), Stenotrophomonas maltophilia, and Achromobacter species.3,10 Viruses have also been identified in cultures during APEs, including rhinovirus, coronavirus, and parainfluenza.10 Recently, there has been an increased interest in examining the microbiome and mycobiome in the lungs of people with CF to better understand the virulence patterns of pathogens and their contribution to APEs.
The management of APEs is complex, requiring a multidisciplinary team including physicians (emergency medicine, intensivists, infectious disease, psychiatrists, pulmonologists), respiratory therapists, nurses, and nutritionists. This has consequently resulted in the establishment of 282 CF care programs throughout the United States.3 Patients who present to the emergency department and require admission are often transferred to one of these centers for continuation of coordinated care.
According to the most recent guidelines published by the Cystic Fibrosis Foundation (https://www.cff.org), treatment of APEs includes IV antibiotics, increased airway clearance therapy (ACT), and continuation of chronic medications.5,6,11,12 Current guidelines recommend dual therapy for the treatment of P. aeruginosa. A review of practice at CF centers revealed that the most common combination of anti-pseudomonal antibiotics administered is an IV aminoglycoside (most commonly tobramycin) and an IV beta-lactam (most commonly piperacillin-tazobactam).8,13 Antibiotic selection is also influenced by previous culture data and associated resistance.
Dosing of antibiotics for anti-pseudomonal coverage in people with CF is quite different compared to people who do not have CF. Specifically, once daily dosing for tobramycin, rather than multiple daily doses, has been found to be an effective treatment strategy in this patient population. This regimen has been found to be efficacious while reducing the risk of nephrotoxicity, ototoxicity, and vestibulotoxicity.8 Tobramycin is dosed at 10 mg/kg, with peak concentration goal of 20-40 mg/L and trough concentration goal of less than 1 mg/kg. For anti-pseudomonal beta-lactams, there are several dosing strategies seen in clinical practice including intermittent, extended, and continuous dosing.8 In a review of clinical practice of CF centers, it was found that these institutions predominantly utilized intermittent (52%) and continuous dosing (41%) in adults.13 To date, the CFF has been unable make a recommendation on duration of antibiotic treatment for an APE due to a paucity of data. There is, however, a general consensus among practitioners to treat for 10-14 days and extend antibiotic course if clinically warranted.8
Historically, airway clearance therapy (ACT) has been a mainstay in the chronic management of CF. It is also considered to be an essential component in the treatment of APEs. There are numerous types of ACT, including postural and percussive drainage (P&PD), positive expiratory pressure (PEP), active-cycle-of-breathing technique (ACBT), autogenic drainage (AD), oscillatory PEP (OPEP), and high-frequency chest compression (HFCC). A review of the literature comparing these various types of ACT showed a lack of data to support the use of one type of ACT over another. Consequently, choice of ACT is dictated by patient’s preference, ability to coordinate, and/or underlying pathology (ie, pneumothorax). According to the most recent guidelines, the CFF recommends an increase in duration and frequency of ACT during an APE.11 However, no quantitative recommendations have been made.5
During an APE, treatment also includes continuation of chronic medications used for the ongoing management of CF. Bronchodilators, specifically beta agonists, should be continued and utilized in conjunction with nebulized hypertonic saline, dornase alfa, and ACT. Currently, it is recommended that caution be exercised when continuing inhaled tobramycin and initiating IV tobramycin in people with chronic P aeroginosa infections. Concomitant use of IV and inhaled tobramycin makes it difficult to interpret serum peak/trough concentration levels and increases risk of drug toxicity.8 If inhaled tobramycin is continued, the CFF recommends the following order of administration of therapies: bronchodilator, hypertonic saline, dornase alfa, ACT, followed by tobramycin.5 At this time, current guidelines do not support the use of inhaled or oral steroids, inhaled ipratropium, inhaled N-acetylcysteine, or leukotriene inhibitors in the management of APEs.
During an APE, patients may develop hemoptysis, which requires urgent or emergent treatment. Hemoptysis can also arise independently of other APE symptoms, prompting a patient with CF to seek treatment in the ED. Consensus guidelines on management of hemoptysis were most recently published by the CFF in 2010.14 For massive hemoptysis (> 240 mL), bronchial arterial embolization (BAE) was recommended for unstable patients. Bronchoscopy was considered to be an impractical treatment strategy and not recommended. For patients with massive hemoptysis, the committee further recommended stopping ACT and hypertonic saline, due to concern for disruption of clot formation. For patients with mild to moderate hemoptysis (>5 mL but < 240 mL), a general consensus could not be reached. In patients with scant hemoptysis (< 5 mL), ACT and hypertonic saline were felt to be beneficial and should be continued. Lastly, the committee recommended initiation of antibiotics for possible APE when hemoptysis occurred by itself.
Cystic fibrosis is an incredibly complex genetic disease, which requires an equally dynamic and multifaceted approach when acute pulmonary exacerbations occur. Emergency medicine physicians play a unique role in this approach, often initiating the first doses of antibiotics, breathing treatments, and airway clearance therapies. Furthermore, emergency medicine physicians serve as ambassadors for patients with CF, helping to coordinate care between the admitting team, the infectious disease team, and the patient’s pulmonologist during acute pulmonary exacerbations. Early aggressive management in an organized approach is imperative for the effective delivery of treatment in this terrifyingly young patient population.
1. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2016 Annual Data Report. https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2016-Patient-Registry-Annual-Data-Report.pdf. Published 2017.
2. Spoonhower KA, Davis PB. Epidemiology of cystic fibrosis. Clin Chest Med. 2016 Mar;37(1):1-8.
3. Cystic Fibrosis Foundation. About Cystic Fibrosis. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Published 2018. Accessed August 17, 2018.
4. Cystic Fibrosis Foundation. 2017 Cystic Fibrosis Foundation Patient Registry Highlights. https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2017-Cystic-Fibrosis-Foundation-Patient-Registry-Highlights.pdf. Published 2017.
5. Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009 Nov 1;180(9):802-8.
6. Stenbit AE, Flume PA. Pulmonary exacerbations in cystic fibrosis. Curr Opin Pulm Med. 2011 Nov;17(6):422-7.
7. Andersen D. Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathologic study. Am J Dis Child. 1938 Aug;56(2):344-99.
8. Talwalkar JS, Murray TS. The approach to pseudomonas aeruginosa in cystic fibrosis. Clin Chest Med. 2016 Mar;37(1):69-81.
9. Vasil ML, Darwin AJ. Regulation of Bacterial Virulence. Washington, DC: ASM Press, American Society of Microbiology; 2013.
10. Huang YJ, Lipuma J. The microbiome in cystic fibrosis. Clin Chest Med. 2016 Mar;37(1):59-67.
11. Flume PA, Robinson KA, O’Sullivan BP, et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care. 2009 April;54(4):522-37.
12. Mogayzel PJ, Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013 Apr 1;187(7):680-9.
13. Zobell JT, Epps K, Kittell F, et al. Tobramycin and beta-lactam antibiotic use in cystic fibrosis exacerbations: a pharmacist approach. J Pediatr Phramacol Ther. 2016 May-Jun;21(3):239-46.
14. Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med. 2010 Aug 1;182(3):298-306.