Cystic Fibrosis Flashcards
What is Cystic Fibrosis?
Chronic, multisystem disease
Primary morbidity and mortality: Respiratory complications
Additional manifestations: Digestive, reproductive, and integumental system
Autosomal Recessive
What is the CFTR protein?
CF gene encodes for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein
- Ion channel that controls movement of Na and H2O into and out of cells
–> mutations alter this function
What are the types of CFTR mutations?
Class I: lack of protein production
Class II: Protein trafficking defect - early degeneration
Class III: Defective regulation
Class IV: Reduced chloride transport through CFTR
Class V: reduced production
Class VI: decreased stability of CFTR
How is a diagnosis of CF made?
If the patient has One of these:
>=1 typical phenotypic features of CF
- Sibling with CF
- Positive newborn screening test
- *PLUS** one of these:
- Elevated sweat chloride on 2 occasions
- 2 known disease-causing CFTR mutations
- Abnormal nasal potential difference
What are the two primary systems involved in CF?
Respiratory system
Digestive system
What is the characteristic presentation of respiratory disease in CF?
Lung infection and inflammation can occur shortly after birth
- Cycles of infection and inflammation damage the lungs and decrease lung function (FEV1)
Incidence of pulmonary exacerbations increases with age
Progressive lung diseasse is the leading cause of death in CF
What are the pulmonary manifestations of CF?
- Chronic cough
- Sputum production
- recurrent infection
- bronchiectasis
- hemoptysis
- Pneumothorax
- Allergic bronchopulmonary aspergillosis
- Pulmonary arterial HTN
- Respiratory insufficiency/failure
What is the pathogenesis of Lung disease in CF?
Abnormal CFTR gene –> abnormal CFTR protein –> Abnormal Salt transport –> abnormal mucus –> impaired clearance –> infection –> inflammatory response –> bronchiectasis
How does CF affect lung clearance?
Normally, mucociliary transport in the lungs is dependent on movement of mucus by ciliated airway epithelial cells
–> cilia beat freely within an airway surface fluid layer which is maintained through a balance of chloride secretion and Na absorption
In CF, too little chloride is pumped out of the epithelial cells and too much Na is reabsorbed; H2O follows Na and the mucus becomes depleted
–> cilia are compressed and can no longer beat freely, and mucostasis occurs
What happens to mucus producing goblet cells in CF?
They undergo both hyperplasia and metaplasia, with extension into bronchioles where they are not usually seen
Submucosal glands are also hypertophied, leading to increased mucus production
How does infection affect mucus in CF patients?
Chronic inflammation, with neutrophilic invasion and lyses within CF mucus, as well as chronic infection, result in highly thickened secretions
–> adding to the already thickened mucus
–> this thickened secretions and mucus lead to increased susceptibility to bacterial infection, further affecting the lungs of a CF patient
When do structural changes in CF lung disease begin to occur?
Early!
In mild forms of CF, changes are seen as early as 6yrs old
How can airway clearance be improved with CF?
High frequency chest wall oscillation
–> literally shake mucus loose, then “huff cough” to remove mucus
What are the common phenotypic features of CF?
CF PANCREAS
- *C**hronic respiratory disease
- *F**ailure to thrive
- *P**olyps (nasal)
- *A**lkalosis, metabolic
- *N**eonatal intestinal obstruction
- *C**lubbing of fingers
- *R**ectal prolapse
- *E**lectrolytes increased in sweat
- *A**spermia/absent Vas Deferens
- *S**putum - S.aureas/P.aeruginosa
What is the sweat test used for diagnosis of CF?
Mild electrical current pushes medicine into skin to cause sweating
–> sweat is collected and salt content is measured
Results:
> 60mmol/L = CF
40-60mmol/L = borderline-further investigation needed
>29 mmol/L in infants is borderline
What is the nasal potential difference used to diagnose CF?
Measures Cl ion secretion of CFTR protein after isoproterenol challenge
–> absent in CF nasal epithelium
- Technically challenging; lab must do regularly to be good at it
What is the newborn screening used to screen for CF?
Immunoreactive trypsinogen (IRT)
–> cutoff varies by state
IRT (pancreatic enzyme precursor, elevated in CF) –> if elevated, get Mutation analysis –> if positive get Sweat test because there are many normal mutations of CFTR
How are CF patients’ respiratory disease monitored?
Isolation of organisms from sputum cultures is completed on a regular basis
- -> Must tell the lab it is a CF patient
- Specimen will be handled differently
- All Gram(-) isolates will be identified
- Mucoid samples will be processed by hand
How do you get a sputum sample from a patient too young to cough up something?
Throat culture can be performed
Mucociliary tree will bring sputum and pathogens to the back of the throat, where it can be swabbed
What are the common pathogens isolated from CF patient respiratory tracts?
S. aureas
Burkholderia cepacia
Pseudomonas aeruginosa
What are the characteristics of S. aureus?
Gram + cocci
Has role in inflammation damage of CF
Common in CF isolates
Have to be concerned about MRSA
Usually first pathogen isolated in CF patients
What is the treatment for S. aureus?
MSSA:
Naficillin
Cefazolin
Oxacillin
etc.
MRSA:
Vancomycin
Septra
Clindamycin
Linezolid
MRSA is assoc. w/decreased CF survival
What are the characteristics of Burkholderia cepacia complex?
Used to be considered a pseudomonas, but now understood as a complex of different genomovars
- only certain genomovars are assoc. with poor prognosis
Usually far in progression of CF
May be colonization or active infection
Usually highly resistant to many antibiotics
Due to extremely poor outcomes of lung transplants with BCC, most transplant teams won’t even accept lungs colonized with it
What is Cepacia Syndrome?
End stage lung function with:
Fevers
Weight loss
“feeling bad”
What are characteristics of P. aeruginosa?
Gram (-) rod
Catalase +
Oxidase +
Aerobic
Flagella provide motility
Antibiotic resistance ranges from exquisitely sensitive to pan-resistant
Smells like grapes or blue tortilla chips when grown in lab
P. aeruginosa converts to a mucoid phenotype by the production of alginate - seen infrequently in populations w/o CF, but is manifested by over 66% of CF patients
What is the treatment of Pseudomonas?
Due to Pseudomonas’ ability to develop resistance while actually receiving appropriate doses of an Abx, generally CF patients are “double covered”
- One Abx from two different classes
Typically use an anti-pseudomonal penicillin or cephalosporin + aminoglycoside or fluoroquinoline (cipro)
- Penicillins:
Piperacillin-tazobactam, Ticarcillin-Sulbactam
- Cephalosporins:
Ceftazadime, Cefepime
- Aminoglycosides:
Amikacin, Tobramycin, Gentamycin
What are the anti-pseudomonal drugs used?
Antispeudomonal penicillins (ticarcillin, piperacillin)
3rd Gen cephalosporins (ceftazadime)
4th Gen Cephalosporins (Cefepime)
Monobactam (Aztreonam)
Carbapenems (imipenem, meropenem)
Fluoroquinolones (Ciprofloxacin and levofloxacin)
Colistin (for MDR P. aeruginosa)
(These are in the order used as the patient becomes resistant)
How are CF exacerbations treated?
With antibiotics to cover the infection they are experiencing
Duration of therapy depends on response
- at least tow weeks, average is 1 month
- All anti-pseudomonal drugs are IV except fluoroquinolones, so patients must either be able to give their own treatment or stay in the hospital for the duration of treatment
What is the daily treatment for CF?
Daily Ibuprofen to decrease inflammation and
Macrolides as they also have an anti-inflammatory property and reduce exacerbations
- *Inhaled Tobramycin** often used to decrease colonization, improve lung function, weight gain, and decrease respiratory symptoms
- 28 days on, 28 days off to reduce resistance
- Inhaled Aztreonam may also be used for similar results
What are the benefits of daily macrolide use for CF patients?
Macrolides have inherent anti-inflammatory propertie
- May reduce
sputum viscoelasticity
Airway adhesion of P. aeruginosa
disrupt the integrity of biofilm
and
impair the transformation of non-mucoid pseudomonos to more virulent mucoid phenotypes
What vaccinations are absolutely required of CF patients?
Influenza vaccine
Pneumococcal vaccine
Palivizamab (mAb against RSV)
What are the negative impacts on CF patients of taking life-long drug treatments?
- Long-term antibiotic side effects:
Diarrhea
Yeast infections
Allergies
C. diff infections
Selecting out resistant bugs
- Often need central venous access
Blood clots
Complications of surgery
line infections
- Drug side effects can wear down body
Hepatitis
Pancreatitis
Renal failure or nephritis
Bone marrow suppression and anemia
What are common GI symptoms of CF?
Pancreatic Insufficiency
Pancreatitis
Meconium ileus
Distal Intestinal obstruction syndrome (DIOS)
Intussusception
Rectal prolapse
Gastroesophageal reflux (GERD)
Small intestinal bacterial overgrowth (SIBO)
Hepatobiliary disease
What are symptoms of the pancreatic insufficiency seen in CF?
Obstruction of pancreatic ducts (releasing bicarb) and consequent destruction of acinar tissue (releasing pancreatic enzymes) leads to PI
symptoms:
Steatorrhea: Oily, bulky, foul-smelling stools
“floaters”
Failure to thrive
Abdominal distention
Fat soluble vitamin deficiency
How is pancreatic insufficiency diagnosed?
Fecal elastase levels
- *72hr stool sample w/dietary inventory**
- fat excretion >7% is abnormal
Secretin stimulation test
What is the pancreatic enzyme replacement therapy used for CF patients?
varying amount of lipase, protease, amylase
Granules/microspheres coated with pH-sensitive material
Improves fecal fat absorption in pts with PI
Acid suppression increases efficacy of enzymes
How does meconium ileus develop? (with respect to CF)
Earliest manifestation of CF
CF meconium = Increased albumin and decreased H2O, minerals –> “gelatinous meconium” –> Increased mucus production from goblet cells –> thicker, viscous texture –> inspissation of meconium –> partial or total obstruction at level of T1
What are symptoms of Meconium ileus?
Usually present during first 3 days of life
Abdominal distention
Bilious vomiting
Failure to pass meconium
Uncomplicated type: no other GI pathology, only obstruction
Complicated type: Associated with perforation, peritoniti, volvulus
*usually requires surgery*
What is Distal intestinal obstruction syndrome? How is the diagnosis made?
Acute complete, or partial, obstruction of ileocecum
Due to poorly controlled fat malabosrption, dehydration
Diagnosis is made clinically:
Acute abdominal pain
palpable RLQ mass
KUB shows stool in ileum/cecum with “bubbly” granular opacity
May have history of constipation, but can have normal stool patterns
What are the treatments for DIOS?
GI lavage with PEG (i.e. miralax, Go-lyltely) is usually preferred method for treatment
- Enemas containing N-acetylcysteine or gastrogafrin have been used
- Proper hydration, dose optimization of PERT needed
What are the symptoms of intussusception?
Similar risk factors to DIOS with inspissated bowel serving as lead point:
Presents with:
colicky abdominal pain
Bilious vomiting
Rectal bleeding
–> water soluble contrast enema may be more effective than air
What about CF contributes to rectal prolapse?
Constipation
malnutrition
chronic cough
pelvic muscle weakness
What is Small Intestinal Bacterial Overgrowth (SIBO)?
Characterized by abnormally increased # of bacteria in upper GI
- Transforms nutrients into non-absorbable and toxic substances
Contributes to:
Fat malabsorption
malnutrition by deconjugating bile salts
intereres with ability to emulsify fats
What are symptoms of SIBO? How is it diagnosed? Treatment?
Bloating
Gassiness
Flatulence
Abdominal pain
Diarrhea
–> diagnosed with H2 breath test
–> empiric Tx is often appropriate
How does CF cause hepatobiliary disease?
Defective CFTR in biliary epithelial cells –> Impaired secretory function of bile flow –> Cholestasis, bile plugging, damage to biliary tree –> Periportal fibrosis –> bridging fibrosis –> cirrhosis
What is the treatment for CF related hepatobiliary disease?
Optimize nutrition
Correct fat soluble vit. deficiency
Increase essential FAs
Ursodiol
Debate regarding long-term effectiveness, but generally indicated for:
Cholestasis, fibrosis, cirrhosis
liver transplant
