Cystic Fibrosis

Definitions
Cystic fibrosis (CF) is an autosomal-recessive genetic condition that most prominently affects the lungs and pancreas.The intestinal tract, liver, endocrine system, reproductive organs, and skin can all be involved.

Epidemiology
the most common lethal inherited disease in the Caucasian population
Number of infants born with CF in relation to the total number of live births in the US:

• 1 in 2,270 Ashkenazi Jewish Caucasian
• 1 in 3,000 Caucasians
• 1 in 10,000 Hispanics
• 1 in 15,000 African Americans
• 1 in 35,100 Asian Americans (reported frequency in Japan of 1 in 350,00)

Ireland has an incidence of 1 in 3000, and the world’s highest carrier rate= 1 in 19

Aetiology
CFTR gene (cystic fibrosis transmembrane conductance regulator) on chromose 7 which encodes for a protein that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). More than 1,500 mutations exist that can cause phenotypic CF, all of which are recessively inherited. Most common is loss of the phenylalanine residue at 508th position (deltaF508),

Pathophysiology
Abnormal CFTR function leads to abnormally viscous secretions that alter organ function.
The lungs:Obstruction, infection, and inflammation negatively affect lung growth, structure, and function:

• Decreased mucociliary clearance
• Infection is accompanied by an intense neutrophilic response.
• Degradation of supporting tissues causes bronchiectasis and eventual failure.

Risk Factors
Phenotypical severity depends on

• CFTR mutation
• other modifier genes (CFTM1 for meconium ileus)
• environmental factors- tobacco smoke, gastroesophageal reflux, respiratory virus infection

Presentation
Physical findings
Rhonchi and/or crackles:

• Hyper-resonance on percussion
• Nasal polyps, facial pain

Hepatosplenomegaly when cirrhosis present

Digital clubbing

Ddx

Pulmonary	difficult athma, chronic bronchitis, Recurrent pneumonia, Chronic/recurrent sinusitis, severe allergic rhinitis.
GI	Celiac disease; Protein-losing enteropathy; Pancreatitis of unknown etiology; Shwachman-Diamond syndrome

Investigation

Prenatal testing	Chorionic villous testing for CF can be performed at 10-12 weeks' gestation. The only benefit to CF diagnosis at this stage is to offer termination of pregnancy. Prenatal testing is currently being offered less and less frequently because of the ever-increasing predicted lifespan of these patients
Newborn screening	by measuring immunoreactive trypsin in the blood spot for the Guthrie test. 30.7% of new cases by newborn screen a positive effect on growth when infants were diagnosed early by screening.
Sweat chloride test	application of a medication that stimulates sweating (pilocarpine). To deliver the medication through the skin, iontophoresis is used to, whereby one electrode is placed onto the applied medication and an electric current is passed to a separate electrode on the skin. The resultant sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium and chloride [Cl] >60 mmol/L is diagnostic. [Cl] between 30-60 mmol/L = within the reference range or may represent heterozygous carriers. These carriers, thus, cannot be accurately identified with a sweat chloride test. This test can be inaccurate in very young infants or if an inadequate volume is collected. Repeat testing after equivocal results.
Genetic testing	Genetic testing via blood tests can detect carrier status with up to 95% sensitivity. Sensitivity depends on the population and the mutations for which they are screened. Testing is recommended for individuals with a positive family history and for couples planning a pregnancy, but it is not necessarily indicated for the general population
CXR	Hyperinflation early in disease Bronchial thickening and plugging Nodular densities, patchy atelectasis, and confluent infiltrates Bronchiectasis Chest radiograph of a patient with advanced cystic fibrosis. Note marked hyperinflation, peribronchial thickening, and bilateral infiltrates with evidence of bronchiectasis especially of the upper lobes.
Follow up	Sputum culture (common CF organisms) Pulmonary function tests (PFTs) 72-hour fecal fat Stool elastase Oral glucose tolerance test (OGTT) Head CT: abnormal sinus CT findings are nearly universal in CF and may include mucosal thickening, intralumenal sinus polyps, and sinus effusions. Many children with CF never develop aerated frontal sinuses. Chest CT (not routine): Useful when unusual findings noted on CXR Dual energy x-ray absorptiometry

Management
While infants born with cystic fibrosis 70 years ago would have been unlikely to live beyond their first year, infants today are likely to live well into adulthood.

Permanent IV access	Like peripherally inserted central catheter (PICC line) or Port-a-Cath.
Education	importance of nasal toilet
Antibiotics, IV	S. aureus: Zosyn or nafcillin MRSA: Vancomycin or linezolid P. aeruginosa: Zosyn or ceftazidime plus aminoglycoside (tobramycin) B. cepacia: ≥3 drugs based on synergy studies
Antibiotics, oral	S. aureus: Bactrim or cephalexin P. aeruginosa: Fluoroquinolones ciprofloxacin orazithromycin
Antibiotics, inhaled	TOBI (tobramycin 300 mg/dose via nebulizer) Colistin (more commonly used in Europe) Cayston
Inhalation therapy	β-agonist in conjunction with chest physiotherapy Recombinant human DNAse Hypertonic saline
Anti-inflammatory agents	Oral steroids (useful in setting of ABPA) Ibuprofen (high dose)
GI	Pancreatic enzymes:Use in pancreatic-insufficient patients Vitamin supplementation:Fat-soluble vitamins (A, D, E, and K) Liver disease (cholestasis): Ursodeoxycholic acid
Endocrine	CF-related diabetes:Dietary restrictions should be avoided CF-related bone disease:Consider bisphosphonate therapy if history of pathologic fracture or transplant Hypogonadism:Consider replacement of testosterone or estrogen Male infertility caused by absence of the vas deferens may be overcome with testicular sperm extraction(TEST),
Admission criteria	Pulmonary exacerbation (most common reason for admission): Increased cough, sputum production, and decreased pulmonary function Bowel obstruction or Pancreatitis
Phisiotherapy	Chest physiotherapy with postural drainage: Percussive therapy to loosen up secretions VEST (airway clearance system) Flutter valve or acapella intrapulmonary percussive ventilator(IPV). Biphasic Cuirass Ventilation
IV Fluids	Increased salt loss increases risk of hyponatremic hypochloremic dehydration.
Feeding/Diet	poor growth- feeding tube
Vitamin	A,D,E,K
Diabetes	It mixes features of type 1 & type 2 : cystic fibrosis-related diabetes (CFRD) insulin injections or an insulin pump unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.
Osteoporosis	Vit D, calcium, bipohosponates
Follow-up	All patients should be followed in a CF center (accredited sites are listed at www.cff.org). Upon discharge for a pulmonary exacerbation, follow-up with their CF provider within 2–4 weeks. Routine clinic visits every 3 months, with airway cultures and pulmonary function testing Annual comprehensive nutritional evaluation with morphometric analysis Yearly OGTT after 14 years of age Screening for osteoporosis every 1–4 years after the age of 18 years
Surgery	Lung transplantation reserved for patients with limited life expectancy (FEV1 <30% predicted) Liver transplantation Reserved for progressive liver failure and/or portal hypertension with GI bleeding endoscopic procedures Wide middle meatal antrostomies Anterior and posterior ethmoidectomies Removal of polypoid disease in the frontal recess Others Sphenoid sinusotomy Septoplasty Resection of the anterior edge of the middle turbinate to allow ease of postoperative inspection and irrigation Postoperative details include the following: Keep patients hospitalized until pulmonary function is clearly adequate for discharge (generally at least 1 night). Aggressively administer irrigations using normal saline or hypertonic sodium chloride solution. Postoperative cleaning seems to help prevent synechia formation. Young patients who cannot tolerate this procedure can briefly return to the operating room 2-3 weeks later for this purpose.

Prognosis

• Most recent median survival is 37.4 years, as of 2007 CF Foundation Patient Registry
• Progression of lung disease usually determines length of survival.

• Sinusitis is not a curable aspect of CF."Studies show that polypectomy alone in these patients leads to a recurrence rate of 89%, but when polypectomy is combined with another sinus procedure (Caldwell-Luc or ethmoidectomy), this rate drops to 35%
• Many patients need a subsequent procedure for polyp regrowth after polypectomy and FESS; therefore, these procedures should be viewed as treatments and not necessarily cures