Cystic fibrosis

DR ZAHRA ROSHANZAMIR
PEDIATRIC PULMONOLOGY
In The Name of GOD
 EPIDEMIOLOGY
• Cystic fibrosis (CF) is a life-shortening autosomal recessive
disorder that affects over 70,000 individuals worldwide. Although
found predominantly in people of European descent, CF is
reported among all races and ethnicities.
 EPIDEMIOLOGY
• The gene for CF, located on the long arm of chromosome 7, encodes for the cystic fibrosis
transmembrane conductance regulator (CFTR), a chloride channel located on the apical surface
of epithelial cells.
• CFTR is important for the proper movement of salt and water across cell membranes and
maintaining the appropriate composition of various secretions, especially in the airways, liver, and
pancreas.
• The most common mutation is a deletion of three base pairs resulting in the absence of
phenylalanine at the 508 position (Phe508del, F508del).
• Nearly 2,000 mutations of the CFTR gene have been identified to date
 Epidemiology
• The secretory and absorptive characteristics of epithelial cells are affected by
abnormal CFTR, resulting in the clinical manifestations of CF.
• The altered chloride ion conductance in the sweat gland results in
excessively high sweat sodium and chloride levels. This is the basis for the
sweat chloride test, which is still the standard diagnostic test for this
disorder.
It is positive (elevated sweat chloride ≥60 mEq/L) in 99% of patients with
CF.
 Clinical manifestation
• The respiratory epithelium of patients with CF exhibits marked impermeability to chloride and
an excessive reabsorption of sodium. This leads to thicker airway secretions, resulting in
airway obstruction and impaired mucociliary transport.
• This, in turn, leads to endobronchial colonization with bacteria,especially Staphylococcus
aureus and Pseudomonas aeruginosa.

• Chronic bronchial infection results in persistent or recurrent cough that is often productive of
sputum, especially in older children. Chronic airway infection leads to airway obstruction
and bronchiectasis and, eventually, to pulmonary insufficiency and premature death..
 Clinical manifestation
• The median age of survival is currently>40 years.
• Digital clubbing is common in patients with CF,even in those without
significant lung disease.
• Chronic sinusitis and nasal polyposis are common
 Clinical manifestation
• Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity
reaction toAspergillus in the CF airways. It causes airway inflammation/
obstruction and aggravates CF lung disease.
• The treatment for ABPA is systemic corticosteroids (prednisone) and
antifungal agents (itraconazole)
 Clinical manifestation
• Ninety percent of patients with CF are born with exocrine
pancreatic insufficiency. The inspissation of mucus and
subsequent destruction of the pancreatic ducts result in the
inability to excrete pancreatic enzymes into the intestine. This
leads to malabsorption of proteins, sugars (to a lesser extent),
and especially fat.
 Clinical manifestation
• Fat malabsorption manifests clinically as steatorrhea (large, foul-smelling stools),
deficiencies of fat soluble vitamins (A, D, E, and K), and failure to thrive.
• Protein malabsorption can present early in infancy as hypoproteinemia and peripheral
edema.
• Approximately 10% of patients with CF are born with intestinal obstruction caused by
inspissated meconium (meconium ileus). In older patients, intestinal
obstruction may result from thick inspissated mucus in theintestinal lumen (distal
intestinal obstruction syndrome[DIOS]
 Clinical manifestation
• The failure of the sweat ducts to conserve sodium and chloride may lead
to hyponatremia and hypochloremic metabolic alkalosis, especially in
infants.
 Clinical manifestation
• The diagnosis of CF should be seriously considered in any infant presenting with
failure to thrive, cholestatic jaundice, chronic respiratory symptoms, or electrolyte
abnormalities (hyponatremia,hypochloremia, metabolic alkalosis)

Any child with nasal polyps, especially those younger than 12 years, should be
evaluated for CF. All siblings of patients with CF should also be evaluated.
• All U.S. states have newborn screening for CF, based either on elevated
immunoreactive trypsinogen (IRT) levels or DNA tests, identifying the
majority of infants with CF, but there are both false-positive and
falsenegative results. Therefore the diagnostic test of choice is still
the sweat test.
 DIAGNOSIS
• The presence of one or more typical clinical features of CF
(chronic pulmonary disease, characteristic gastrointestinal
and nutritional abnormalities, salt loss syndromes, or
obstructive azoospermia) AND
• Two elevated sweat chloride tests performed at an accredited
CF Foundation certified laboratory (positive if the value is
≥60 mEq/L, borderline if 30-59 mEq/L, and negative if
<30 mEq/L, with adequate sweat collection) OR
• Two mutationsknown to cause Cfidentified by DNAanalysis
OR
• A characteristic abnormality in ion transport across nasal
epithelium demonstrated in vivo (nasal potential difference
testing)
• For those identified by positive newborn screening or
because a sibling has CF, positive sweat chloride testing or
the presence of known disease-causing DNA mutations are
the only criteria required for diagnosis, as clinical symptoms
may not be manifested early in life.
 TREATMENT
• The treatment of CF is multifactorial. Most maintenance therapies are directed toward the
gastrointestinal and pulmonary complications. Presently, there is no effective single cure for CF
• Precision therapies, known as CFTR modulators, target genotype-specific functional defects of the
CFTR protein. Ivacaftor, the first CFTR modulator approved by FDA is a small molecule potentiator
that improves CFTR function in a small group of CF individuals who have an abnormal gating
mechanism of their CFTR protein,

• The second FDA-approved medication is a combination of ivacaftor and lumacaftor, approved for
individuals with two copies F508del. It has been associated with a modest but significant improvement
in lung function, improved body mass index
 Treatment
• Management of pulmonary exacerbations is directed toward facilitating
clearance of secretions from the airways and minimizing the
effects of chronic bronchial infection. Airway secretion clearance
techniques (chest physiotherapy) help remove mucus from the airways,
and aerosolized DNAse and 7% hypertonic saline, both delivered by
nebulizer, decrease the viscosity of mucus
 Treatment
• Antibiotic therapy is important in controlling chronic infection. Monitoring pulmonary
bacterial flora via airway cultures and providing aggressive therapy with appropriate
antibiotics (oral, aerosolized, and intravenous [IV]) help to slow the progression of lung
disease. Patients often require2-3–week courses of high-dose IV antibiotics and aggressive
chest physiotherapy to treat pulmonary exacerbations.

• Antibiotics are selected based on organisms identified by sputum culture. If patients are
unable to provide sputum, then a throat culture for CF pathogens can be used to direct therapy
 Treatment

Exocrine pancreatic insufficiency is treated with entericcoated pancreatic enzyme

capsules, which contain lipase and proteases. Patients with CF are encouraged to
follow high-calorie diets, often with the addition of nutritional supplements. Even
with optimal pancreatic enzyme replacement, stool losses of fat and protein may be
high. Fat should not be withheld from the diet, even when significant steatorrhea
exists
Primary Ciliary Dyskinesia
 Etiology
• Primary ciliary dyskinesia (PCD, immotile cilia syndrome) is
an inherited disorder in which there is absent or disordered
movement of the cilia leading to a spectrum of clinical manifestations.
This disorder affects approximately 1 in 15,000-20,000 live births,
although the actual incidence may be higher because of a limited ability to
definitively diagnose affected patients.
 Clinical manifestation
• Clinical manifestations include neonatal respiratory distress,
chronic cough, chronic nasal congestion, middle ear effusions,
chronic pansinusitis, laterality defects (e.g., situs inversus),
infertility, and bronchiectasis.
• Kartagener syndrome, the triadof situs inversus, pansinusitis, and bronchiectasis, accounts
or approximately 50% of cases. Males are infertile as a result
of immotile sperm. Because the cilia fail to beat normally,secretions accumulate in the
airways, and endobronchial infection results. Chronic infection, if untreated, leads to
bronchiectasis by early adulthood.
 Diagnostic Studies

• PCD diagnosis has historically relied on a combination of clinical

features and ultrastructural analysis of respiratory cilia by
electron microscopy, obtained from scrapings/biopsy of nasal
or airway epithelium.
• Results may be difficult to interpret as chronic infection and inflammation
may also lead to ultrastructural abnormalities in nasal cilia
 Diagnostic Studies

• The measurement of nasal nitric oxide has been used as a screening

tool for PCD. Low nasal nitric oxide values (<77 nL/min) are
consistent with PCD
 TREATMENT
• Treatment is geared toward treating infections and improving
clearance of respiratory secretions.. Surveillance cultures help identify organisms involved
and guide antibiotic therapy.
• Most children require placement of pressure equalization (PE) tubes for management of
recurrent otitis media. Chest physiotherapy and prompt treatment of bacterial infections are
helpful, but the course of the disease tends to be slowly progressive. Inhaled hypertonic saline
may improve cough clearance and has been shown in the short term to improve lung function.
Antiinflammatory antibiotics, such as low-dose macrolides, may reduce the number of
exacerbations per year.