CONTENTS

• Definition of a CF respiratory exacerbation
• Evaluation of respiratory deterioration in CF
• Management
  • CFTR-directed therapies
  • Antibiotic therapy
  • Airway clearance
  • Bronchodilator
  • Respiratory support (HFNC, NIV, intubation)
  • Nutritional support
  • Bowel regimen
  • Glycemic control
  • Physical therapy
  • (Steroid not indicated)
• Other topics related to CF
  • Diagnosis of CF ➡️
  • Hemoptysis in CF
  • Pneumothorax in CF
  • Cirrhosis in CF
  • Burkholderia cepacia complex
  • Nontuberculous mycobacteria in CF ➡️
  • Transplantation referral indications in CF ➡️
• Questions & discussion

abbreviations used in the pulmonary section: 4

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OHS: Obesity hypoventilation syndrome 📖
• OP: Organizing pneumonia 📖
• OSA: Obstructive sleep apnea 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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definition of a CF respiratory exacerbation

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• There is no universally accepted definition of exactly what qualifies as a CF pulmonary exacerbation. (30124523)
• Common symptoms include: (31659730) 
  • Worsening of cough, increased sputum volume and/or purulence.
  • Dyspnea, reduced exercise tolerance, worsening hypoxemia, impaired spirometry.
  • Impaired appetite, reduced weight.

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evaluation of respiratory deterioration in CF

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differential diagnosis

• Community-acquired pneumonia.
• Pneumothorax.
• Hemoptysis due to bronchial artery hemorrhage.
• Exacerbation of pulmonary hypertension.
• Allergic bronchopulmonary aspergillosis (ABPA).

data review:

• Baseline FEV1.
• Baseline blood gas values and/or bicarbonate level (? chronic hypercapnia).
• Microbiology history.
• Antibiotic history:
  • Prior clinical response to various antibiotics.
  • Any antibiotic allergies.
• Prior respiratory complications.

laboratory studies

• Routine laboratory studies (including CBC with differential).
• Viral PCR as appropriate (e.g., influenza, COVID)
• Sputum for culture and staining to identify bacterial, fungal, or mycobacterial pathogens:
  • These cultures often won't return rapidly enough to modify the patient's initial antimicrobial therapy, but this may be worthwhile to assist in longitudinal patient care over time.
  • Isolation of Aspergillus from the sputum may raise a concern for the possibility of ABPA (allergic bronchopulmonary aspergillosis), which affects ~7% of patients with cystic fibrosis. 📖
  • Nontuberculous mycobacteria may be clinically relevant pathogens in patients with cystic fibrosis (especially M. avium complex and M. abscessus). (Fishman 2023)

chest radiograph for all patients

• The main role for chest radiograph in CF exacerbation is to exclude alternative pathologies (especially pneumothorax).
• Most patients with CF pulmonary exacerbation will have a stable chest radiograph compared to prior radiographs (CF exacerbation generally does not produce a focal consolidation).
• New air-fluid levels may appear during a CF exacerbation, due to fluid partially filling pre-existing cystic airways. (Shepard 2019)

CT scan selectively

• Potential indications for CT scan may include investigation for:
  • Hemoptysis.
  • Possible pulmonary embolism.
  • Possible ABPA (allergic bronchopulmonary aspergillosis).
  • Possible NTM (nontuberculous mycobacteria).

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CFTR-directed therapies

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• Several therapies have recently become available that may correct or improve the CF-related transmembrane receptor (CFTR) function. These include:
  • Ivacaftor (CFTR potentiator, utilized in patients with gating mutations, such as G511D).
  • Lumacaftor or tezacaftor (corrector drugs that enhance intracellular processing of CFTR, utilized in patients with F508del mutation).
  • Combination therapy (e.g., elexacaftor/tezacaftor/ivacaftor, or Trikafta).
• The indications and selection of these therapies are beyond the scope of this chapter.
• CFTR-directed therapies should be continued during an exacerbation.
  • ⚠️ Abrupt withdrawal should be avoided, to prevent a withdrawal syndrome that may occur among patients with highly responsive mutations. (30077689)
• Numerous drug-drug interactions may occur with these therapies. When initiating a new medication, a drug interaction program may be useful to avoid drug-drug interactions (e.g., Medscape 🌊).

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antibiotic selection

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guidance to antibiotics based on sputum culture?

• Patients with CF are chronically colonized with an extremely complex microbiome of bacteria in their airways. Sputum cultures will reflect only a few of the bacteria residing in their lungs. This explains several phenomena:
  • Patients may improve despite being treated with antibiotics that don't cover bacteria isolated in their sputum.
  • Using specialized antimicrobial testing to guide therapy hasn't been shown to improve outcomes. (30124523)
  • Sputum culture and sensitivity are often not reproducible. (35236556)
• If possible, it makes some sense to cover organisms that have been isolated from sputum cultures. However, this available evidence indicates that this doesn't matter. (35236556)
• Pseudomonas aeruginosa is a very common pathogen among adults with cystic fibrosis. Adequate targeting of Pseudomonas is often a primary concern when designing antibiotic regimens. (Murray 2022) 
  • The new appearance of Pseudomonas is important if the patient isn't chronically colonized with Pseudomonas. Attempts should be made to eradicate Pseudomonas, even if the patient is otherwise stable clinically (e.g., 28 days of inhaled tobramycin 300 mg BID).

CF exacerbation: number and selection of systemic antibiotics

• There is little high-quality data regarding the number or type of antibiotics.
• If a patient previously responded well to one regimen of antibiotics, repeating that regimen may be reasonable. Alternatively, a different regimen might be rational if a prior regimen failed to work. (30124523)
• A longstanding debate has been whether two systemic anti-pseudomonal antibiotics are superior to a single agent. A retrospective study in pediatric cystic fibrosis found no difference between single or double-coverage of Pseudomonas. (34100912) Given the complexity and toxicity involved in double-coverage, a single systemic antibiotic against Pseudomonas seems optimal. (de Moraes 2024)
• Patients colonized with MRSA might benefit from the addition of an anti-MRSA agent. (Murray 2022)
• For patients with active influenza, antiviral therapy 📖 is frequently administered (although there is no substantive data to support this). (32890021)

CF exacerbation: role of nebulized antibiotics

• Nebulized antibiotics may achieve very high concentrations in sputum (considerably higher than systemic antibiotics). This makes nebulized antibiotic delivery a logical approach to airway-centered infection in bronchiectasis and CF. Although intravenous delivery of aminoglycosides is generally perceived as a more “aggressive” therapy, it's quite likely that in this situation, intravenous aminoglycosides are actually less effective and more toxic.
• The benefit of nebulized aminoglycosides is well-established for chronic outpatient therapy, but it has historically been unclear whether nebulized antibiotics are also helpful for patients during a CF exacerbation.
• One small crossover RCT found that nebulized tobramycin (300 mg BID) improved the time to next exacerbation as compared to intravenous tobramycin while causing less nephrotoxicity. (24219814) Likewise, a recent small RCT found benefit from nebulized aztreonam as compared to intravenous amikacin. (33358119)

CF exacerbation: the adequate dose of systemic antibiotic

• Patients with CF often have an elevated volume of distribution and ARC (augmented renal clearance).
• In the absence of renal dysfunction, antibiotics should often be dosed at the high end of accepted dosing ranges (table below). (30077689) 

CF exacerbation: duration of antibiotic therapy

• One retrospective study found that lung function plateaued after 8-10 days of therapy and that shorter courses did not increase the likelihood of relapse. (20581166) Another study found that treatment for <9 days correlated with an increased likelihood of relapse. (27139161)
• The best evidence is the prospective STOP2 RCT: (34469706)
  • After 7-10 days of therapy, 277 patients had improvement in symptoms and lung function. They were randomized to 10 days versus 14 days of therapy. No differences were observed.
  • After 7-10 days of therapy, 705 patients didn't have improvement in symptoms and lung function. They were randomized to 14 days of therapy versus 21 days of therapy. No differences were observed.
  • Based on this study, a 10-14 day duration of therapy is evidence-based (with length depending on whether patients display clinical improvement over the first 7-10 days).

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airway clearance therapy

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general

• There is little high-quality evidence regarding airway clearance. No single method of airway clearance has proven more effective than another. (Fishman 2023)
• If a patient has responded well to any specific therapies previously, these should be continued and intensified (e.g., percussion vests and handheld vibratory devices such as Acapella). Patients are usually familiar with which techniques are most effective for them.

inhaled dornase alpha (DNAse)

• The underlying pathophysiological problem in CF is inadequate chloride secretion into the airway, leading to thick inspissated secretions. DNase which makes secretions thinner by degrading long strands of DNA within them.
• DNAse has been shown to improve lung function and reduce pulmonary exacerbations, as maintenance therapy for CF.
• DNAse should generally be continued during a CF exacerbation, once or twice daily.

inhaled hypertonic saline

• Inhaled hypertonic saline may serve various purposes:
  • (1) Hydration of secretions.
  • (2) Bronchial irritant that promotes expectoration.
• RCTs have shown that among outpatients, inhaled hypertonic saline led to modest improvement in lung function and fewer pulmonary exacerbations. Hypertonic saline has also been demonstrated to hasten recovery during CF exacerbations. (32966813)
• Hypertonic saline should be utilized during pulmonary exacerbations if tolerated.
• Logistics:
  • Hypertonic saline may be utilized 2-4 times daily. Pretreatment with a bronchodilator may be useful to prevent bronchoconstriction if this is a problem.
  • 7% NaCl is generally utilized first (this is best studied).
  • 3-3.5% NaCl may be utilized if 7% NaCl isn't tolerated. (30077689)

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bronchodilator

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• Bronchodilator use should be individualized.
• Potential indications to use a bronchodilator may include:
  • Prior use and subjective benefit from a bronchodilator.
  • Pulmonary function tests show a positive bronchodilator response.
  • A combination of bronchodilators with hypertonic saline may prevent a bronchoconstrictive response from hypertonic saline (this combination was actually what was studied). (16421364)

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respiratory support

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selecting mode of respiratory support

• For patients with worsening hypercapnia or elevated work of breathing, treatment options include high-flow nasal cannula (HFNC), noninvasive ventilation (NIV), or intubation.
• There is no high-quality evidence regarding the use of these modes of ventilation in patients with CF. Consequently, the general principles regarding their use should be applied.
• High-flow nasal cannula (HFNC) is often an attractive support modality for patients with CF:
  • Allows for expectoration and airway clearance.
  • Allows for ongoing nutritional support.

invasive mechanical ventilation

• A favorable outcome from intubation is more likely if: (30077689)
  • There is an acute/treatable process.
  • Baseline FEV1 is higher (e.g., >25% predicted).
  • Lack of severely compromised nutritional status.
• For patients who are transplant candidates, intubation may serve as a bridge to transplantation. Transplantation centers should be involved in logistic planning as early as possible.
• Ventilation can be challenging in the context of severe airflow obstruction. The general principles utilized for these patients are largely similar to those utilized for patients with asthma, discussed further here: 📖
• Regarding sedation and analgesia, opioids should be minimized as able, to reduce the risk of DIOS (distal intestinal obstructive syndrome). (30077689)
• Intrapulmonary percussive ventilation (IPV) may allow for airway clearance to be performed while intubated, up to four times daily. (30077689)

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nutritional support

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exocrine pancreas dysfunction

• ~85% of patients with CF develop exocrine pancreatic dysfunction. (Murray 2022)
• Oral pancreatic enzymes should be continued (e.g., pancrelipase).
  • The dose may be titrated to reduce symptoms of malabsorption (e.g., cramping, flatulence, and fatty stools). However, guidelines recommend starting at 500 lipase units/kg/meal and increasing as necessary while limiting the dose to 2,500 lipase units/kg/meal and 10,000 lipase units/kg/day. (Murray 2022)

vitamin supplementation

• Patients may develop deficiencies of fat-soluble vitamins (due to pancreatic dysfunction).
• A daily multivitamin is a standard component of CF therapy. Specific vitamin supplements enriched in fat-soluble vitamins may be ideal (e.g., AquADEKs).

maintenance of adequate body mass index

• Weight loss is a major problem in advanced CF (e.g., it is a contraindication to lung transplantation). Goal BMI is >23 for men or >22 for women. (30077689, ERS handbook 3rd ed.)
• Adequate nutrition should be encouraged (e.g., supplementary calories, including protein shakes).
• Nutritional consultation should be considered.

nutritional support for intubated CF patient

• Caloric requirement:
  • Patients may require more calories than predicted based on standard weight-based formulas (e.g., 25 kCal/kg/day).
  • If available, indirect calorimetry may be used to determine the patient's actual energy needs. 📖
• Pancreatic enzyme replacement for patients with pancreatic dysfunction:
  • If an elemental tube feed formulation is available, this would be ideal. Pancreatic function isn't required to absorb elemental tube feeds (since they contain amino acids, short-chain triglycerides, and short-chain maltodextrins).
  • If an elemental tube formulation isn't available, some form of enteral pancreatic enzymes should be provided. Crushed tablets can clog feeding tubes. Some centers may have a system to infuse digestive enzymes in-line along with enteral nutrition. Consult with your nutritionist regarding which resources are available. (30077689)

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bowel regimen

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• Patients with CF may have reduced intestinal fluid secretion, causing a tendency to develop intestinal obstruction (distal intestinal obstruction syndrome, DIOS). If unattended to, this may become severe, leading to bowel obstruction and occasionally surgery.
• An aggressive bowel regimen is often appropriate, especially while hospitalized, e.g.:
  • Osmotic laxatives (e.g., polyethylene glycol).
  • Encourage adequate water intake.
• For patients with constipation or distension, there should be a low threshold for escalating therapy. Meglumine diatrizoate (Gastrografin) may be useful either orally and/or via enema.
• Ambulation and working with physical therapy will also improve bowel motility.

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glycemic control

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• CF-related diabetes increases with age, reaching a prevalence of ~50% among patients >40 years old. Patients also experience stress hyperglycemia and insulin resistance. (Shah 2019)
• Glucose levels should be followed and managed as necessary with insulin. Acute illness may cause insulin resistance, requiring dose escalation. (30077689)
• Given problems with malnutrition (as discussed above), hyperglycemia should not be managed with carbohydrate restriction.

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physical therapy

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• Aggressive physical therapy may be helpful, if tolerated.
  • Ambulation may promote secretion clearance and avoid atelectasis.
  • Ambulation may also promote gastrointestinal motility.
• The use of stationary bicycles and/or treadmills to promote exercise is ideal.

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steroid

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Corticosteroid is not generally indicated for the management of cystic fibrosis pulmonary exacerbations. Furthermore, steroid is often problematic in these patients:

• (1) Patients with cystic fibrosis often develop problems with osteoporosis.
• (2) Cystic fibrosis patients often have diabetes, which may be challenge to manage.

Potential indications for steroid:

• Patients with documented asthma (in which case a limited course and dose of steroid may be utilized, e.g., 50 mg/day for five days).
• Patients whose CF is complicated by ABPA (allergic bronchopulmonary aspergillosis). 📖

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hemoptysis in CF

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mild/scanty hemoptysis

• Small-volume hemoptysis is extremely common.
• Minor hemoptysis may occur as a component of a CF pulmonary exacerbation due to mucosal irritation.
• Treatment may involve:
  • Antibiotics and other treatments directed at a CF pulmonary exacerbation.
  • Airway clearance and inhaled therapies may generally be continued (low level of evidence, based on expert opinion). (de Moraes 2024)
  • Optimization of coagulation parameters (consider IV vitamin K since patients may have pancreatic dysfunction with fat-soluble vitamin malabsorption).

moderate/severe hemoptysis

• Expectoration of significant volumes of frank blood implies bleeding from a bronchial artery (similar to other forms of bronchiectasis).
• Epidemiology:
  • This is fairly common, with a lifetime incidence of ~5%. (Murray 2022)
  • Risk factors include older age and more advanced lung disease.
• Treatment:
  • Optimization of coagulation parameters (consider IV vitamin K since patients may have pancreatic dysfunction with fat-soluble vitamin malabsorption).
  • Airway clearance should be interrupted.
  • Short-term inhaled tranexamic acid should be considered. 📖
  • Treatment according to the algorithm for severe hemoptysis here: 📖. Pulmonary angiography and embolization may be helpful, even if the acute episode settles (since recurrence is common). Unfortunately, even if bronchial artery embolization is successful, recurrence often occurs – so severe hemoptysis is an indication to consider lung transplantation. 📖 (30077689)

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pneumothorax in CF

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epidemiology

• Up to 20% of patients will develop a pneumothorax. (Murray 2022)
• The risk of pneumothorax increases with advancing age and increasing disease severity.

management

• Chest tube drainage
  • Small and minimally symptomatic pneumothorax may be observed.
  • Larger or more symptomatic pneumothorax should be managed with chest tube drainage.
• Airway clearance and medications
  • Aerosolized medications should be continued.
  • More aggressive airway clearance therapies should be held (e.g., those involving positive pressure or percussive ventilation).
• Pleurodesis
  • Pleurodesis may prevent recurrence of pneumothorax. This may increase the complexity of subsequent lung transplant surgery, although recent studies have shown that pleurodesis doesn't substantially increase complications. (Murray 2022)
  • Pleurodesis is generally recommended after one recurrence of the pneumothorax. However, the recurrence rate is high, so many centers will consider pleurodesis following the first pneumothorax. (Fishman 2023)
  • The recommended method of pleurodesis is usually via thoracoscope or VATS (video assisted thoracoscopic surgery). VATS may be especially helpful for patients who have trapped lung, as it may be utilized to remove adhesions.
• More information: Guidelines on management 🌊

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cirrhosis in CF

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• Cystic fibrosis may lead to cirrhosis, due to desiccation of the biliary ducts with subsequent cholestasis.
• There should be a high index of suspicion for the possibility of liver disease and variceal bleeding in patients with cystic fibrosis (regardless of alcohol exposure).
• Management of cirrhosis and its complications is similar the management of cirrhosis among other patient populations.

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Burkholderia cepacia complex

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introduction

• B. cepacia complex is a group of gram-negative bacilli.
• If B. cepacia complex is isolated from a patient, this should suggest one of three possibilities: (26963355, 31259635)
  • Cystic fibrosis (the most common patient population affected).
  • Chronic granulomatous disease. 📖
  • Nosocomial outbreaks may rarely affect immunocompetent hosts.
• B. cepacia is a major problem for patients with cystic fibrosis. For example, it may be considered a contraindication to lung transplantation. The spectrum of disease manifestations is broad and unpredictable (ranging from indolent to acute infection).
• ⚠️ B. cepacia may be transmitted between patients who have cystic fibrosis, leading to nosocomial outbreaks. If you are caring for multiple patients with cystic fibrosis, all efforts must be made to avoid nosocomial transmission of B. cepacia between patients.

indolent infection with B. cepacia

• B. cepacia may cause chronic airway colonization.
• Similar to Pseudomonas, airway colonization may be associated with accelerated decline in lung function.

invasive infection (“cepacia syndrome”)

• Cepacia syndrome refers to a rapidly progressive systemic infection that may involve bacteremia, necrotizing pneumonia, and multiorgan failure.
• Cepacia syndrome is most often associated with genomovar II (Burkholderia multivorans) and genomovar III (Burkholderia cenocepacia). (Murray 2022)
• Mortality from cepacia syndrome is very high. Successful treatment has been reported in patients who received a combination of 3-5 antibiotics. (26963355)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

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