• Autosomal Recessive  -- must have two copies of faulty alleles
• Defect on chromosome 7 that codes for Cystic Fibrosis Transmembrane Conductance Regulator
• Base pair deletion -- ΔF508

• Mediated by cAMP in epithelial cells, CFTR normally regulates Na+, Cl-, and secondarily H2O across cell membranes
• In patients with Cystic Fibrosis, the transporter is defected or is not at the apical membrane at all
• Na+ and Cl- is not transported into the lumen and hence H2O is reabsorbed
• Dehydrated and viscous secretions are ineffectively cleared and cause luminal obstruction, scarring, and dysfunction
• This defect occurs in the cells of the respiratory, hepatobiliary, gastrointestinal, and reproductive tracts, along with the pancreas and sweat glands

• Chronic cough
• Failure to thrive
• Pancreatic insufficiency
• Alkalosis
• Neonatal intestinal obstruction/Nasal polyps
• Clubbing/CXR findings
• Rectal Prolapse
• Electrolyte abnormalities
• Absence of vas deferens/pulmonary cilia
• Sputum

Neonatal Screening

Increased immunoreactive trypsinogen (IRT)

Clinical Features of CF plus:

• Sweat chloride test -- positive > 60 mEq/L, need two positive tests to confirm CF

OR

• Genotyping -- need two known CFTR mutations to confirm CF

• Obstruction of airway with thick mucus results in air trapping, bronchiectasis, atelactasis
• Increased infection risk due ot thick mucus acting as an excellent growth medium for microorganisms
• Bacterial progression leads to elevated levels of inflammatory mediators such as TNFα, IL-1 and IL-2, and Neutrophil elastase

• Cough/sputum production
• Wheeze/air trapping
• Radiographic abnormalities
• Evidence of obstruction on pulmonary function tests
• Digital clubbing
• Nasal polyps

Mild

FEV1 > 70-89% predicted

Moderate

FEV1 40-69% predicted

Severe

FEV1 < 40% predicted

Initial

• Staphylococcus aureus
• Haemophilus influenzae
• Streptococcus pneumoniae

Colonization

• Pseudomonas aeruginosa
• Burkholderia cepacia
• Stenotrophomonas maltophilia
  

Symptoms

• Increased frequency and duration of cough
• Increased sputum production
• Change in appearance of sputum
• Shortness of breath
• Decreased exercise
• Decreased appetite
• Increased congestion in chest

Signs

• Increased respiratory rate
• Intercostal retractions
• Decrease in pulmonary function consistent with obstructive airway
• Fever and leukocytosis
• Weight loss
• New infiltrate

• Exercise
• Hydration
• Breathing techniques
• Conventional Chest Physiotherapy (percussion with cupped hand/vibrator, postural drainage)
• Oscillating positive expiratory pressure devices
• High-frequency chest wall oscillation

• Oral penicillins, cephalosporins
• Ex: dicloxacillin, cephalexin

• Combo therapy
• Duration: 14-21 days
• For synergistic activity and to prevent resistance
• Ex: ceftazidime + Aminoglycoside, Piperacillin + Aminoglycoside

• Aztreonam
• Ceftazidime
• Ciprofloxacin
• Meropenem
• Pipercillin
• Ticarcillin/Clavulanate
• Tobramycin

Limit use of fluoroquinolones to prevent resistance

Tobramycin can be used with:

• Ticarcillin+clavulanate
• Pipercillin+tazobactam
• Ceftazadime
• Cefepime
• Meropenem
• Imipenem/cilastatin
• Aztreonam

• Vancomycin
• Linezolid
• Bactrim

• Role -- adjunct to antibiotics for treatment, home maintenance therapy
• Improved drug delivery to site of infection
• Reduced systemic exposure
• However, concern of emerging resistance

• Bronchospasm -- some require SABA prior
• Increased cough
• Hoarseness

• > 6 yr
• + P. aeruginosa

TOBI (Tobramycin)

• BID, alternating months
• Increases FEV1 ~10%, decreases hospital days and use of IV antibiotics

Cayston (Aztreonam)

• TID, alternating months, takes less than 5 min to use
• Increases FEV1 ~ 10%, decreases symptoms
• Only available at CF specialty pharmacies

• Pulmozyme (Dornase Alfa)
• Mucomyst (N-acetylcysteine)
• Recombinant Human Deoxyribonuclease I (rhDNAse)
• Inhaled Mannitol

Role

Mucolytic therapy, reduces sputum viscosity

Criteria

> 6 yrs

Benefits

Decreased pulmonary exacerbations, decreased need for IV antibiotics, increases FEV1 by 5%

Role

Mucolytic therapy, thins sputum, induces expectoration

Routine use not recommended

MOA

• Cleaves the DNA in sputum
• Reduces sputum viscosity and/or its adherence to epithelial airways
• Improves mucociliary sputum clearance and lung function

AE

• Hoarseness
• Pharyngitis

Disadvantages

• COSTLY

MOA

• Mucolytic therapy
• An osmotic agent that increases the water content of the airway surface liquid
• Improves clearance of mucus

Benefits

• FEV1 increased from baseline by 7%

Short Acting Beta2 Agonists

• Role: mobilize sputum
• Scheduled albuterol vs levalbulerol
• Controversial benefits
• Adjunctive therapy to CPT

Theophylline

• Role: reactive airway disease
• Concern for toxicity
• Reserved ONLY for patients with documented improvements

Glucocorticoids

• Little role in long term therapy
• Limited documented benefits for pulse and inhaled therapy
• Concern for AE

High Dose Ibuprofen

• Plasma concentration 50-100 mcg/ml
• AE: GI, nephrotoxicity
• Concern for intermittent low dose

Macrolides

• Azithromycin
• Criteria: > 6 yr, + P. aeruginosa
• Benefits: increases FEV1 by ~6%, decreases hospital stays and IV antibiotics, weight gain

Role

Increases mucociliary clearance

Criteria

> 6 yr with mild-mod disease

AE

Coughing, sore throat, chest tightness

Benefits

Increased sputum clearance, increased lung function, decreased exacerbations, decreased need for IV antibiotics

• Inhaled Tobramycin (mod-severe disease)
• Dornase alfa (mod-severe disease)

• Inhaled Tobramycin (Asx - mild disease)
• Dornase alfa (Asx - mild disease)
• Hypertonic saline
• Ibuprofen
• Macrolides
• Inhaled Beta-agonists

• Oral Corticosteroids (age 6-18)
• Inhaled corticosteroids
• Anti-staph antibiotics

Causes

P. aeruginosa, H. influenzae, Streptococcus, and/or Anaerobes

Treatment of Nasal Polyps

Topical steroids/antihistamines for allergic symptoms

Some patients require surgical removal

• Exocrine pancreatic insufficiency
• Fat-soluble vitamin deficiencies
• Meconium ileus
• Distal Intestinal Obstruction Syndrome
• Rectal prolapse
• Gastroesophageal reflux
• Recurrent pancreatitis
• Hepatobiliary disease
• Failure to thrive
• Hypoproteinemia-edema

• Increased caloric requirements
• Oral supplements (ensure, scandishakes)
• Enteral feeding (nocturnal feeding)
• Pharmacological agents -- Anabolic agents, cyproheptadine -- not recommended for routine use

Role

Achieve adequate nutrition, abolish GI symptoms, achieve normal bowel function

• Agents vary in amylase:lipase:protease ratios
• Generic enzymes are NOT bioequivalent/interchangeable

• Based on lipase activity
• Individualize dosing, titrate to response
• initiate 500-1000 lipase units/kg/meal
• Normal requirements 1500-2000 lipase units/kg/meal
• Avoid > 2500 lipase units/kg/meal due to increased risk of fibrosing colonopathy
• Take before each meal/snack

Fat Soluble Vitamin Replacement

• Vit A 5000-10000 IU daily
• Vit D 400-800 IU daily
• Vit E 100-400 IU daily
• Vit K 0.3-0.5 mg daily
• > 8 yrs: ADEK 1 vitamin BID
• Monitor Vit A,D,E levels yearly

Beta-Carotene

Calcium

Iron

Zinc

Sodium

Antacids, H2 Receptor Antagonists, and PPI

Decreases HCO3- secretion, gastric acid causes decreased absorption of pancreatic enyzmes

Metoclopramide + the agents above for gastroesophageal reflux

Improves bile flow, displaces toxic bile acids that accumulates in liver disease

• Treatment of Portal Hypertension
• Prophylaxis for variceal bleeding

Causes

Insulin deficiency

Age of Onset

18-21 yrs

Individualized Insulin Regimen

• Split dose NPH/regular insulin
• Lispro before meals/Lantus HS
• Insulin pump therapy

Monitoring

• > 10 yr should be tested every year for CFRD
• Diagnosing and treating CFRD earlier results in better outcomes

Non-Pharmacological Treatment

• Weight bearing exercise
• Avoid tobacco, alcohol, caffeinated/carbonated beverages

Calcium

9 yrs: 1300-1500 mg daily

Vitamin D

• 0-1 yr: 400 IU daily
• > 1 yr: 800 IU daily
• Monitor 25(OH)D levels yearly (nl 30-60 ng/ml)

Vitamin K

Magnesium

Zinc

Copper

Regular visits usually quarterly

Annual Visits

• Multidisciplinary approach
• History and physical
• Lab measurements
• Sputum/throat swab culture
• Spirometry
• Oral glucose tolerance test (> 10 yrs)
• DEXA (> 18 yrs or > 8 yrs with RF)
• Education

• Increased pulmonary vascular resistance
• Fixed pulmonary vascular obstruction
• Cor pulmonale and CHF
• Patients with FEV1 < 30%, PaO2 < 50 mmHg, or PCO2 > 50 mmHg have about a 50% chance of surviving 2 yrs
• Lung transplant is very risky and the supply of good lungs for transplant is limited