CYSTIC FIBROSIS(CF)

TICHA BRANDON TITA TEMBI

MS5/FHS/UBa
 PLAN
• Introduction
– Definition
– Epidemiology
– Mutations
• Pathogenesis
• Clinical manifestations
– Pulmonary
– Gastrointestinal
• Diagnosis and assessment
• Treatment
• Complications
• Questions
• References
 INTRODUCTION
DEFINITION:
• It is an inherited(autosomal recessive trait)
multisystem disorder of children and adults with the
primary defect being dysfunction of the cystic fibrosis
transmembrane conductance regulator(CFTR).
• CFTR protein is expressed largely in epithelial cells of
airways, gastrointestinal tract(including the pancreas
and biliary system), the sweat glands, the
genitourinary system.
• CFTR functions primarily as a chloride channel
INTRODUCTION II
EPIDEMIOLOGY
INTRODUCTION III
CFTR Mutations
INTRODUCTION IV
CFTR Mutations
 INTRODUCTION V
• Individuals with classes I, II, and III genotypes, on
average have shorter survival than those with
“milder” genotypes( IV or V).
• Long standing observations of cystic fibrosis of
fundermental pathologic importance:
– Failure to clear mucus secretions
– A paucity(few) of water in in mucus secretions
– An elevated salt content of sweat and other secretions
– Chronic infection limited to the respiratory tract.
PATHOGENESIS
 PATHOGENESIS II
• In addition it has been suggested that CFTR
dysfunction results in an altered microenvironment
with:
– low HCO3 and
– a more acidic pH,
thus altering mucus rheology and aggravating poor
mucociliary clearance.
• Airflow obstruction at the level of small airways is
the earliest observable physiologic abnormaly of
therespiratory system
 PATHOGENESIS III
• Because the function of sweat gland duct cells is to absorb
rather than secrete chloride, salt is not retrieved from the
isotonic primary sweat as it is transported to the skin surface;
chloride and sodium levels are consequently elevated.
• Chronic bronchiolitis and bronchitis are the initial lung
manifestations but after months to years, structural changes in
airway walls produce bronchiolectasis and bronchiectasis.
• There is a high prevalence in patients with CF of airway
colonization with:
– Staphylococcus aureus
– Pseudomonas aeruginosa
– and Burkholderia cepacia complex
 CLINICAL MANIFESTATIONS
• Pulmonary and gastrointestinal presentations predorminate
RESPIRATORY TRACT
• SYMPTOMS
 Cough(most constant)
 Initially dry and hacking→loose and productive
 Mostly upon rising in the morning/after activity
 Purulent expectoration
 Intermintent prolonged acute respiratory tract infection (eg pneumonia)

 Wheezing( post extensive bronchiolitis especially in first year of life)

 Progressive exercise intolerance
 Shortness of breath
 Poor weight gain and growth
 CLINICAL MANIFESTATIONS II
RESPIRATORY TRACT
PHYSICAL EXAM
EARLY
– ↑ anterior posterior diameter
– Generalized hyperresonance
– Cattered/localized coarse crackles
– Digital clubbing
– Expiratory wheeze (especially in young children)
LATE
– Cyanosis
– Hemoptysis
– Look for physical signs of late complications as atelectasis,
pneumothorax
 CLINICAL MANIFESTATIONS III
RESPIRATORY TRACT
• Nasal obstruction
• Rhinorrhea
NB: Even though the paranasal sinuses are
virtually always opacified radiographically, acute
sinusitis is infrequent. Nasal polypes are
troublesome between the 5 and 20yrs of age
and present with nasal obstruction and
rhinorrhea.
 CLINICAL MANIFESTATIONS IV
GASTROINTESTINAL TRACT.
• In 10-15% of newborns with CF, the ilium is
completely obstructed with
meconium(meconium ileus).
– Abdominal distension
– Vomitting
– Failure to pass meconium in the first 24-48H.
PLAIN ABDOMINAL X-RAY SHOW:
– Dilated loops of bowel with air-fluid level and
– Infrequently collection of groung gla material in the
lower central abdomen.
MECONIUM ILEUS
 CLINICAL MANIFESTATIONS VI
GASTROINTESTINAL TRACT
• Meconium peritonitis:
– Rare
– Occurs from intrauterine rupture of the bowel and
– Detected radiographically as presence of peritoneal/scrotal calcification .
• Exocrine pancreatic insufficiency(85% of children):
– SYMPTOMS
• Frequent, bulky and greasy stool
• Failure to gain weight even with adequate food intake

– SIGNS
• Protuberant abdomen
• Decreased muscle mass
• Poor growth/delayed maturation
 CLINICAL MANIFESTATIONS VII
GASTROINTESTINAL TRACT
• Less common GI manifestatons
– Intussusception
–F ecal impaction of the cecum with
aymptomatic RLQ mass
– Epigastric pain(duodenal inflammation)
– Esophagitis(GER)(common in older
children/adults)
– Deficiency of fat soluble vitamins(A,D,E,K) and
consequences
 CLINICAL MANIFESTATIONS VIII
GASTROINTESTINAL TRACT
• Focal biliary cirrhosis:
– secondary to blockage of intrahepatic bile ducts
– It is uncommon in early life
– This process can proceed to symptomatic
multilobular biliary cirrhosis
• MANIFESTATIONS: Icterus, Ascitis,
Hematemesis(ruptured esophageal varices), evidence of
hyperplenism
• Cholelithiasis: biliary colic especially in second
decade of life
 CLINICAL MANIFESTATIONS IX
CF-Related Diabetes and Pancreatitis
• Occurs especially in 2 decade
• Polyuria, weight loss, hyperglycemia and
glucosuria present
• Ketoacidosis usually not present
• Reccurrent acute pancreatitis especially in
those with residual exocrine pancreatic
function
 CLINICAL MANIFESTATIONS X
GENITOURINARY
• Delayed sexual development( average of 2years)
• >95% of males are azoospermic(obliterated or
atretic vas deference, epidydymis and seminal
vesicles)
• Females:
– Secondary amenorrhea
– Decreased fertility
– Urinary incontinence associated with cough(18-47%)
 CLINICAL MANIFESTATIONS XI
SWEAT GLANDS
• Excessive loss of salt in the sweat predisposes
young children to salt depletion episodes,
especially during episodes of gastroenteritis
and during warm weather.
• Frequently, parents notice:
– salt “frosting” of the skin or
– a salty taste when they kiss the child.
NB: A few genotypes are associated with
normal sweat chloride values.
 DIAGNOSIS AND ASSESTMENT
• The diagnosis of CF has been based on a
positive quantitative test sweat test (Cl- ≥ 60
mEq/l) in conjunction with one or more of the
following:
a) Typical COPD
b) Documented excocrine pancreatic insufficiency
c) Positive family history
DIAGNOSIS AND ASSESTMENT II
 DIAGNOSIS AND ASSESTMENT III
A. SWEAT CHLORIDE TEST
B. DNA TESTING
i. Several commercial labs test for 30-96 of the most of common
mutations. It identifies ≥ 90% of individuals who carry 2CF mutations.
ii. It is possible to test for all the > 1900 mutations
C. PANCREATIC FUNCTION
i. Quantification of elastase-1 activity by ELISA
ii. Check for fat malabsorbtion( 72H collection sample)(Normally > 93% of
ingested fat is absorbed)
iii. For encocrine pancreatic function, do modified yearly monitoring with a
2H OGTT after 10 years of age.
 DIAGNOSIS AND ASSESTMENT IV
CHEST X-RAY
D. Suggestive but not specific
– Hyperinflation of lung fields ± infiltrates
– Bronchial thickening and plugging (bronchiectasis) usually
appears first in the upper lobes
– Nodular densities, patchy atelectasis and confluent
infiltrates
– Hilar lymph nodes may be prominent
– In advanced disease: cyst formation, extensive
bronchiectasis, dilated pulmonary artery segment,
segmental/lobar atelectasis, marked
hyperinflation(depressed diaphragms, ant bowing of
sternum, narrow cardiac hadow)
 DIAGNOSIS AND ASSESTMENT V

E. CT OF THE THORAX
• Best morphologic test
• Can detect localized thickenning of airway walls,
mucus plugging, focal hyperinflation and early
bronchiectasis.
F. RADIOGRAPH OF PARANASAL SINUSES
• Panopacification and often failure of frontal sinus
development
G. 2 TRIMESTER ULTRALSOUND
• May Meconium obstruction
 DIAGNOSIS AND ASSESTMENT VI
H. PULMONARY FUNCTION TEST( between 4-6 yrs)
– Obstructive pulmonary involvement(↓ FEV1,
↓ FEV1/FVC)
– ↓ in mid maximal flow rate ia an early functional
change and reflects small airway obstruction)
– Restrictive changes(↓ TLC, ↓ VC) correlate with
extensive lung injury and fibrosis
– NB: the finding of obstructive airwaydisease and
modest response to bronchiodilator are consistent
with CF of all ages.
 DIAGNOSIS AND ASSESTMENT VII
I. MICROBIOLOGICAL STUDIES:
• Sputum culture for the 3 organism earlier
mentioned. Rarely other atypical organisms are
gotten( mycoplasma, fungi, viruses,…)
• Fiberoptic bronchoscopy to gather lower
respiratory tract secretions in infants and
children who do not expectorate.
J. Prenatal diagosis and newborn screening is
also done.
 TREATMENT
GENERAL APPROACH TO CARE
• Initial efforts after diagnosis should be intensive and
should include:
– baseline assessment,
– initiation of treatment,
– clearing of pulmonary involvement
– education of the patient and parents(adequate hydration
(oral) especially in hot weather or acute gastroenteritis)
– Follow up every 1-3 months depending on the age at
diagnosis( Emphasis on pulmonary history)
 TREATMENT II
• Major component of treatment are pulmonary and nutritional
treatment.
PULMONARY TREATMENT
AIMS: clear secretions, control infection.
1. Inhalation Therapy
• Aerosol therapy is used to deliver medications and hydrate the
lower respiratory tract.
• Human recombinant DNase (2.5 mg), given as a single daily
aerosol dose, improves pulmonary function, decreases the
number of pulmonary exacerbations, and promotes a sense of
well-being in patients who have moderate disease and purulent
secretions.
 PULMONARY TREATMENT
Inhalation Therapy

• Another mucolytic agent, N-acetylcysteine, nebulized

as a 5-10% solution following β2-agonist nebulization,
is useful for airway clearance and may potentially
augment airway levels of the antioxidant, glutathione.
• Nebulized hypertonic saline, acting as a hyperosmolar
agent, is believed to draw water into the airway and
rehydrate mucus and enhance mucocilliary clearance.
• Aerosolized antibiotics are often used when the
airways are colonized with Pseudomonas as part of
daily therapy.
 PULMONARY TREATMENT
2. Airway Clearance Therapy
• Airway clearance treatment usually consists of
chest percussion combined with postural
drainage and derives its rationale from the
idea that cough clears mucus from large
airways but chest vibrations are required to
move secretions from small airways, where
expiratory flow rates are low.
 ANTIBIOTIC THERAPY
• The goal is to reduce the intensity of endobronchial
infection and to delay progressive lung damage.
• Dosages for some antibiotics are often 2-3 times the
amount recommended for minor infections because
patients with CF have:
– proportionately more lean body mass and higher
clearance rates for many antibiotics than other individuals.
– In addition, it is difficult to achieve effective drug levels of
many antimicrobials in respiratory tract secretions.
• Can be oral, aerosol or intravenous(based on severity)
ANTIBIOTHERAPY
 ANTIBIOTHERAPY
• The usual course of therapy is ≥2 weeks
• Another indication for aerosolized antibiotic
therapy is to eradicate P. aeruginosa in the airways
after initial colonization.
• Early infection may be cleared for months to
several years by several protocols,
– including oral ciprofloxacin and/or aerosolized colistin or
tobramycin.
• However, once chronically established, P.
aeruginosa infection is rarely eradicated.
FOLLOW UP
 PULMONARY TREATMENT
Bronchodilator Therapy

• Reversible airway obstruction occurs in many children with CF,

sometimes in conjunction with frank asthma or acute
bronchopulmonary aspergillosis.
• Reversible obstruction is defined as improvement of ≥12% in
flow rates after inhalation of a bronchodilator.
Antiinflammatory Agents
• Ibuprofen, given long term (dose adjusted to achieve a peak
serum concentration of 50-100 μg/mL) for 4 yr, is associated
with a slowing of disease progression, particularly in younger
patients with mild lung disease.
• This is the only antiinflammatory agent with documented
efficacy in the patient population
 GASTROINTESTINAL TREATMENT
PANCREATIC ENZYME REPLACEMENT:
• Pancreatic exocrine replacement therapy given with
ingested food reduces but does not fully correct
stool fat and nitrogen losses.
• Administration of excessive doses has been linked to
colonic strictures requiring surgery. Consequently,
enzyme replacement should not exceed 2,500 lipase
units/kg/meal in most circumstances.
VITAMIN AND MINERAL SUPPLEMENTS
– A, D, E, K and check iron status.
COMPLICATIONS
MANAGE
THEM
ACCORDINGLY
 Q1
• The inpatient pediatric team is discussing the causes of
failure to thrive (FTT) as they evaluate a 9-month-old
infant with weight and length below the 5th percentile.
Which of the following should be included in the
differential diagnosis of infant who is not thriving?
(A) Small atrial septal defect
(B) Acute bacterial meningitis
(C) Cystic fibrosis
(D) Recurrent otitis media
(E) Mild intermittent asthma
 Q2
A2-year-old Caucasian male presents with failure to thrive,
chronic diarrhea, and recurrent pneumonia. Though his family
history is negative for cystic fibrosis, a sweat test reveals a
sodium concentration of 120 mg/dL. Which of the following is
the appropriate next step in
caring for this infant?
(A) iron
(B) vitamin B12 and folic acid
(C) pancreatic enzyme supplementation
(D) copper and magnesium
(E) parenteral diuretics
 REFERENCES
• Nelson’s textbook of pediatrics 20th edition
• Lange Q&A pediatrics
THANK YOU