Hospital Medicine

Cystic fibrosis

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Cystic Fibrosis Pulmonary Exacerbation Management

I. What every physician needs to know.

Cystic fibrosis (CF) is an autosomal recessive multi-system genetic disease characterized by abnormal transport of chloride and sodium across epithelium, leading to thick, viscous secretions in the sinuses, lungs, pancreas, liver, and intestine (See Figure 1). This comes in the form of:

Figure 1.

Manifestations of Cystic Fibrosis.

  • Bronchiectasis with life-threatening recurrent lung infections

  • Obstruction of the pancreas that results in pancreatic exocrine impairment resulting in nutritional deficiencies, malnutrition, and in some individuals, diabetes mellitus

II. Diagnostic Confirmation: Are you sure your patient has cystic fibrosis?

Suspect cystic fibrosis based on the presence of BOTH following criteria:

  1. Typical clinical presentation of cystic fibrosis such as:

    • Chronic sinopulmonary disease with typical CF pathogens Staphylococcus aureus, Pseudomonas, Haemophilus

    • Characteristic gastrointestinal and nutritional abnormalities (pancreatic insufficiency, recurrent pancreatitis, etc.)

    • Salt loss syndromes

    • Obstructive azoospermia

AND

  1. Laboratory evidence of cystic fibrosis transmembranous regulator (CFTR) malfunction.

    • An elevated sweat chloride concentration (greater than 60 millimoles/L [mmol/L]) on two or more occasions

    • Identification of mutations in each cystic fibrosis transmembrane conductance regulator (CFTR) protein gene known to cause CF

    • Abnormal nasal potential difference

A. History Part I: Pattern Recognition:

A typical adult patients has:

  • Recurrent sinus infections and polyps

  • Bronchiectasis with upper lobe predominance initially that ultimately involves all lobes

  • Recurrent pulmonary infections with Pseudomonas species, Staph Aureus, Burkholderia cepacia

  • Pancreatic insufficiency

  • Malabsorption with nutritional deficiencies resulting in failure to thrive

  • Diabetes mellitus

B. History Part 2: Prevalence:

  • Cystic fibrosis affects about 30,000 children and adults in the United States; 100,000 patients worldwide

  • About 1,000 new cases are diagnosed each year

  • Most patients are diagnosed by age 2 years (70%); 5% of patients are diagnosed after age 16 years

  • Autosomal recessive inheritance

  • Most commonly seen in Caucasians (about 4% of all whites carry a single cystic fibrosis mutation)

C. History Part 3: Competing diagnoses that can mimic cystic fibrosis.

Before the diagnosis is made in children, physicians must differentiate CF from the following other diseases:

  • Primary ciliary dyskinesia

  • Asthma

  • Celiac disease

  • Gastroesophageal reflux disease (GERD)

  • Primary immunodeficiency

  • Bronchiectasis

  • Sinusitis

  • Failure to thrive

  • Protein losing enteropathy

In the adult CF patients, those who present with worsening pulmonary symptoms, the differential diagnosis besides exacerbation of underlying disease includes:

  • Pneumonia

  • Pneumothorax

  • Asthma exacerbation (if patient has a concomitant diagnosis of asthma)

  • Allergic bronchopulmonary aspergillosis (ABPA)

  • Aspergillus causing mycetoma

  • Influenza

  • Atypical mycobacterial infection

In adult CF patients who present with worsening abdominal pain, the differential diagnosis includes:

  • Distal intestinal obstruction syndrome

  • Intestinal perforation

  • Biliary tract infection

  • Cholelithiasis or choleducolithiasis

  • Pancreatitis

  • GERD

  • Diabetic ketoacidosis (DKA)

  • Ileus (especially is on opioids)

  • Musculoskeletal pain due to severe coughing

D. Physical Examination Findings.

  • Wheezing

  • Prolonged expiratory phase

  • Rhonchi or rales

  • Tachypnea

  • Tachycardia

  • Nasal polyps

  • Cachexia with muscle wasting

  • Clubbing of fingers

  • Typical exacerbations lack fever (unlike pneumonia)

E. What diagnostic tests should be performed?

  • Complete blood count (CBC) with differential

  • Basic Metabolic Profile (BMP)

  • Lipase (if abdominal pain)

  • Hepatic function panel (if abdominal pain)

  • Urinalysis and culture, if indicated

  • Arterial blood gas (ABG) if evidence of hypoxemia (room air sat <88%) or serum bicarbonate is elevated

  • Bedside spirometry (serve as baseline to assess response to therapy)

  • Sputum culture and sensitivities (request lab to culture for Staphylococcus aureus and Burkholderia cepacia)

  • Immunoglobulin E (IgE)

  • Acid fast bacilli (AFB) sputum stain and culture (consider once a year or in patients with poor response to antibiotic therapy)

  • Blood cultures only if patient has high fever with infiltrates or indwelling venous catheter

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Most adult patients have already been diagnosed as children with CF. If not, both a cystic fibrosis gene mutation panel can be ordered as well as a sweat chloride test. The diagnosis is established based on both the clinical presentation (phenotype) and positive tests on sweat chloride, as well as gene treating demonstrating presence of two known CF gene mutations.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • Posteroanterior and lateral chest X-ray - typical cystic fibrosis exacerbations lack dramatic infiltrates unlike pneumonia

  • Abdominal ultrasound (if abdominal pain - evaluate for gallstones)

  • Three-way abdominal series (if presenting with abdominal complaints) - evaluating for distal ileal obstruction whose appearance on X-ray is similar to small bowel obstruction

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Sweat chloride testing is one routine test to help establish the diagnosis of CF, along with genetic mutation testing. However, this test needs to be interpreted in the context of the clinical picture. Based on consensus expert panels, the sweat chloride is divided into three groups based on its measured value:

  • <39 mmol/L - CF is unlikely

  • 40-59 mmol/L - intermediate result

  • Above 60 mmol/L - indicative of CF

Individuals with intermediate results should undergo repeat sweat chloride testing and further evaluation, including detailed clinical assessment and more extensive CFTR gene mutation analysis.

III. Default Management.

The basic principles for management of acute exacerbations are focused on mucus clearing strategies and treating underlying bacterial pathogens.

1. Antibiotics are directed at typical bacterial pathogens:

  • Pseudomonas aeruginosa is the most common pathogen. In an acute setting patients must be treated with 2 anti-pseudomonal antibiotics. There is no role for inhaled antibiotics in the setting of acute exacerbation. Choice of antibiotics is based on either current or most recent antibiotic sensitivity patterns

  • Staphylococcus aureus is second most common pathogen

2. Bronchodilators - airflow obstruction is central feature of CF:

  • Albuterol/ipratropium in nebulized form (DUONEB®) is scheduled every 4 hours around the clock

  • Nebulized albuterol is scheduled every 2 hours if there is shortness of breath

3. Airway clearance strategies:

  • Inhaled deoxyribonucleas (DNase) is used to decrease the viscosity of sputum. Dose is 2.5 milligrams (mg) nebulized twice a day

  • Inhaled hypertonic saline 4ml of 7% solution nebulized four times a day

These therapies should be used in combination in most patients unless the patient is intolerant of either one.

4. Chest physiotherapy - most patients are familiar with the varying modalities and have their preferences.

  • Classic physiotherapy done by percussion with postural drainage

  • TheraVest® - high frequency chest wall oscillation vest

  • Flutter or acapella valve

  • Positive expiratory pressure device

5. Anti-inflammatory therapy:

  • Macrolide antibiotics

    • Azithromycin 500 mg oral (po) daily. While the anti-inflammatory properties are a class effect, azithromycin has the most evidence for its use as well as the least drug-drug interactions when compared to other drugs in this class.

  • Corticosteroids

    • Have a very limited role in CF exacerbations unless the patient has concomitant asthma. For those patients, if their asthma is contributing to their pulmonary symptoms, a trial of systemic steroids for a short duration can be prescribed. There currently exists no standard dosing schedule.

6. Supplemental oxygen as clinically indicated.

A. Immediate management.

Same as above.

B. Physical Examination Tips to Guide Management.

  • Monitoring improvement in both tachycardia and tachypnea

  • Monitoring lung sounds

  • Monitoring bowel movements and abdominal exam

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

  • Patient with pulmonary exacerbation do not usually require daily labs

  • Monitor creatinine every 2-3 days while on antibiotics, especially aminoglycosides

  • Antibiotic trough levels. Frequency of testing will vary on the specific antibiotics used as well as any changes in dosing that occurs

D. Long-term management.

Complete pulmonary function tests need to be done annually at the least.

E. Common Pitfalls and Side-Effects of Management

The patient needs to be monitored for potential side effects of antibiotic therapy. Beta-lactamase and aminoglycoside antibiotics are the most frequently prescribed classes of drugs in CF patients. Interesting pharmacokinetics have been observed in CF patients when compared to non-cystic fibrosis patients with these two classes of antibiotics. CF patients exhibit an increase in the volume of distribution of the drugs (due to their lean body mass) as well as an increased body clearance of both classes of antibiotics. This leads to the need for high dosing of both classes of drugs in CF patients.

  • Beta lactamase antibiotic monitoring includes at least weekly:

    • CBC to monitor for leukopenia, anemia

    • serum creatinine to monitor renal function

  • Aminoglycoside antibiotics monitoring includes:

    • serum creatinine to monitor renal function weekly

    • monitor daily while inpatient for ototoxicity and vestibular toxicity

    • trough levels to prevent dosing on a high trough level that can lead to organ toxicity

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Renally adjust dosing for all antibiotics.

B. Liver Insufficiency.

No change to standard therapy.

C. Systolic and Diastolic Heart Failure

  • Rare for CF patient to develop systolic or diastolic heart failure

  • No change in standard management

D. Coronary Artery Disease or Peripheral Vascular Disease

  • Rare for CF patient to develop coronary artery disease (CAD) and peripheral vascular disease (PVD)

  • No change in standard management

E. Diabetes or other Endocrine issues

  • Many CF patients have concomitant diabetes due to destruction of the pancreas that accompanies the disease. The balance is the increased caloric intake that these patients require to maintain adequate nutritional status while trying to control hyperglycemia. Thus diet restriction is often not used for these patients (usually have a high caloric, high fat diet ordered). Goals for hyperglycemia are no different than that for any other diabetics.

  • Insulin therapy is generally the only therapy used for diabetes.

F. Malignancy

  • Rare for CF patient to develop malignancy

  • No change in standard management

G. Immunosuppression (HIV, chronic steroids, etc).

No change to standard therapy

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard therapy

I. Gastrointestinal or Nutrition Issues

1. Constipation - frequent problem due to dehydration of bowel mucus resulting in distal intestinal obstruction syndrome.

  • treatment usually includes Miralax®, Fleet® enemas, magnesium citrate, or Go-lytely®

2. Pancreatic insufficiency - most patients take replacement enzymes.

  • usual dose is 1000-2000 units lipase/kilogram/meal and snacks

  • continuing outpatient dose is usually all that is required

3. Vitamin supplementation- patients are at risk for fat soluble vitamin deficiency.

  • all patients should receive vitamin ADEK twice a day

J. Hematologic or Coagulation Issues

Patients can have elevated international normalized ratio (INR) due to vitamin K deficiency. Patients require vitamin K 5 mg subcutaneous daily until INR normalizes.

K. Dementia or Psychiatric Illness/Treatment

No change to standard therapy.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

  • If acute worsening of dyspnea or pleuritic chest pain develops - consider spontaneous pneumothorax-stat chest X-ray

  • Minor hemoptysis is not uncommon in CF patients. If develops, discontinue chest physiotherapy until resolves.

  • Major hemoptysis (>240 milliliter [ml\L] in 24 hours or more >100 ml for several days) is less common and unusually responds to antibiotics and avoidance of chest physiotherapy. If becomes life-threatening consider elective intubation and referral for pulmonary embolization of affected lung.

B. Anticipated Length of Stay.

Most patients are in the hospital for 3-7 days.

C. When is the Patient Ready for Discharge?

  • Most cystic fibrosis patients are well versed in their illness. Therefore most patients will tell you when they are ready to go home.

  • Other signs, resting heart rate <100 beats per minute

  • Resolution of fever and leukocytosis

  • Improvement in sputum consistency

  • If not chronically on oxygen therapy as outpatient, resolution of hypoxemia

D. Arranging for Clinic Follow-up

Most patients are followed very closely in either a CF multi-disciplinary clinic or by a pulmonary specialist. They often have excellent access to outpatient follow-up given the uniqueness of their illness.

1. When should clinic follow up be arranged and with whom.

Initial follow-up should be within 2 weeks of discharge from hospital with either CF clinic or primary pulmonologist.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

  • Weekly CBC and BMP while on antibiotics

  • Trough levels of certain antibiotics (i.e.. vancomycin, aminoglycosides) - this frequency of tests is dictated by previous levels and any change in dosing

E. Placement Considerations.

  • Home infusion company is required. Patient’s pulmonary exacerbations are treated with intravenous (IV) antibiotics for 14-21 days

  • Home health often required for labs, central venous catheter care

  • Patients often require frequent treatments with IV antibiotic therapy, thus consider ordering a port-a-cath if patient does not already have. If patient does not desire a more permanent central catheter, then peripherally inserted central catheter (PICC) will be required. Place early in the hospital stay.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

  • Pneumovax®

  • Influenza vaccination

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

  • Pneumovax®

  • Yearly influenza vaccination

  • DVT prophylaxis only indicated if patient severely limited in physical mobility

VII. What’s the Evidence?

Ivacaftor was approved by FDA to treat CF patients older than 2 years with certain mutations. This medication works by potentiating the activity of CFTR. A combination of Ivacaftor and Lumcaftor was then introduced to treat patient with 2 other mutations (including the most common one) that are older than 12 years of age.

**The original source for this chapter was Dr. John MacMillan Jr. The chapter was revised for this program by Dr. George Mansour.

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