Cystic Fibrosis (CF): Brief Review

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Cystic fibrosis (CF) is an autosomal recessive disorder. CF is the most common lethal genetic disease in Caucasians with an estimated incidence of 1 in 2500. CF occurs in 1 in 17,000 African Americans.

Most cases are diagnosed in childhood. Median survival in the U.S. is 38 years.

C
CF
Caucasians
Children
CFTR gene mutation
Chronic lung infections
Cirrhosis
Chloride in sweat
Chest physiotherapy


Mind map of CF (click to enlarge the image).

Etiology

In CF, there is a mutation in the gene for a chloride conductance channel or regulator, the cystic fibrosis transmembrane conductance regulator (CFTR). There are 1,000 possible mutations but only one mutation (ΔF508) accounts for 70% of cases.


The location of the CFTR gene on chromosome 7. Image source: Wikipedia, public domain.

Clinical Features

CF affects:

- respiratory tract - obstruction of the airways and chronic infection occur
- GI tract - exocrine insufficiency leads to failure to thrive (FTT), maldigestion, diarrhea, and small-bowel obstruction; liver -- focal biliary cirrhosis
- GU tract - obstructive azoospermia in the vas deferens leads to sterility


Example of clubbing as seen with some CF patients. Image source: Wikipedia, public domain.

Nasal polyps occur in 6-48% of children with CF vs. 0.1% in healthy children. Always think of CF when you see a child with nasal polyps.

Diagnosis

Newborn screening for CF within 48 hours of birth is adopted by most states in the U.S. and the Western world.

The newborn screening for CF is not for CFTR mutations but for pancreatic trypsinogen (a blood test). The secondary screening for positive trypsinogen includes 36 mutations, if still negative, a further screening panel includes 1,500 mutations. A Cost Comparison of Newborn Screening for Cystic Fibrosis showed that immunoreactive trypsinogen (IRT)/DNA analysis worked better than IRT/repeat IRT (Pediatrics, 02/2012).

The genetic or clinical diagnosis is confirmed by elevated chloride or sodium in sweat. Concentrations between 30-60m Eq/L are borderline, values higher than 60 mEq/L are diagnostic in children. Normal adults have higher sweat chloride than children but only 4% of normal adults have sweat chloride higher than 60mEq/L and only 1% have levels over 80m Eq/L.

In babies aged 3 months or younger, results of 30-60 mEq/L are considered borderline and require retesting.

Sweat chloride test is both sensitive and specific. It is done only at centers accredited by the Cystic Fibrosis Foundation.

In history is suggestive of CF but the sweat chloride level is indeterminate, a mutational analysis of the CFTR gene can be done to confirm the diagnosis. The most common mutation in CF is a 3-base pair deletion which leads to absence of 1 amino acid (phenylalanine) fromCFTR. This genetic deletion (ΔF508) occurs in 70% of CFTR genes in CF patients in the U.S. Close to 1000 different mutations in the CFTR gene can produce the phenotype of CF.

Treatment

Nutritional therapy:

- pancreatic enzymes
- fat-soluble vitamins (ADEK)
- high-calorie diet

3-drug combinations of correctors and potentiators await approval but appear to be highly effective in patients with F508del mutation (90% of CF patients) https://buff.ly/2EqQHnR

Chest physiotherapy is widely used but there are no randomized controlled trials to confirm its benefits in CF. Most patients switch to vest for physical therapy later in childhood. Short acting beta agonist (SABA) via MDI should be used before CPT (percussion therapy).

Infection with Pseudomonas aeruginosa commonly occurs after 9 years of age. Treatment consists of IV β-lactam antibiotic and an aminoglycoside.

Recombinant human deoxyribonuclease (rDNase, dornase alfa) administered via a nebulizer reduces the viscosity of sputum and leads to improvement in pulmonary function. Nebulized hypertonic saline has a similar effect.

Most CF patients by age of 6 will be on SABA, Pulmozyme (rDNase), tobramycin. Hypertonic saline is also recommended but poorly tolerated.

Follow-up of patients with CF includes FEV1 and sputum culture every 3 months.

The only objective measure to define CF exacerbation is a fall in FEV1 of more than 10%.

Lung transplantation (either double-lung or heart-lung) prolongs life, the 2-year survival rate is 50-60%.

The Cystic Fibrosis Foundation has built a dynamic "pipeline" figure showing the new, established and possible future CF therapies - click here to see the figure.

The CFTR potentiator ivacaftor helps the 5% of patients with CF who have a missense mutation G551D. However, 90% of U.S. patients have a different mutation (NEJM, 2011). Kalydeco is an oral "CFTR potentiator" and is the first drug to target the CF cause.

Small but growing group of cystic fibrosis survivors over 40, or even 50, offers clues for care. Babies diagnosed with CF today are expected to live into their 50s (Chicago Tribune, 2010, http://goo.gl/Jtvv).

References

Allergy and Immunology MKSAP, 3rd edition.
Cystic Fibrosis. eMedicine.
Drug Development Pipeline. The Cystic Fibrosis Foundation.
Cystic fibrosis, Seminar. The Lancet, Volume 373, Issue 9678, Pages 1891 - 1904, 30 May 2009.

Audio and Video

Video: Boomer Esiason was a NFL quarterback in 1993 when he learned his young son, Gunnar, was afflicted with the deadly disease cystic fibrosis. YouTube. More: http://www.esiason.org.

Cystic Fibrosis. Case Notes. BBC 4, 02/2008.

Related reading

Cystic Fibrosis Foundation Lays Out New Treatment Guidelines. ScienceDaily, 2007.
CF Foundation Releases New Treatment Guidelines. Cystic Fibrosis Vancouver Chapter Website, 2007.
Blogging the end of a life: Death at 25 from CF. CNN. The blog's name 65_RedRoses, originated from her childhood inability to pronounce cystic fibrosis; she called it "65 roses."

VX-770, a CFTR potentiator, associated with within-subject improvements in CFTR and lung function - NEJM, 2010 http://goo.gl/a51zx
Fixing cystic fibrosis CFTR with correctors and potentiators. Off to a good start. Thorax, 2011.

Published: 02/08/2008
Updated: 01/17/2012