25. Cystic fibrosis. Flashcards
what is the etiology of cystic fibrosis ?
autosomal recessive disorder caused by mutation in the CFTR gene
The most common mutation is Delta F508 on chromosome 7
2nd most common hereditary metabolic disorder among white populations
what is the pathophysiology of cystic fibrosis ?
Mutated CFTR gene → misfolded protein → retained protein in rough endoplasmic reticulum (RER)
that is unable to reach the cell membrane → defective chloride channel → inability to transport intracellular chloride ions across the membrane →decreased secretion of chloride by exocrine glands →increased resorption of sodium into the cellular space → increased sodium reabsorption leads to increased water resorption
→ produce hyperviscous secretions from exocrine glands and thicker mucus secretions on epithelial linings → accumulation of secretions and blockage of exocrine glands / mucous pluggin → chronic infl. → organ damag
most commonly affected organs → sinuses, lungs, pancreas, biliary and hepatic systems, intestines, and sweat glands
reduce the function of airway defness and promote bacterial adhesion to the airway epithelium → this leads to chronic airway infections and eventually to → bronchial damage (bronchiectasis)
what are the clinical manifestation of cystic fibrosis?
gastro
1) meconium ileus at birth and intestinal obstruction later in life
2) failure to thrive
3) pancreatitis - obstruction of the pancreatic ductules by thickened secretion
= autodigestion of the pancreas = type-1 diabetes mellitus ( > 30 years old.)
foul smelling steatorrhea,
colicky abdominal pain,
and malabsorption of nutrients from foods. Specifically, fat-soluble vitamins A, D, E, and K are notably deficient
biliary ductules may be plugged with secretions leading to :
Obstructive cirrhosis and post-hepatic hyperbilirubinemia
focal biliary cirrhosis, cholelithiasis,
periportal fibrosis,
liver cirrhosis,
portal hypertension
secondary to this : esophageal varices, splenomegaly
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respiratory
1) Mucus plugging in the bronchioles results in an obstructive lung disease
optimal for bacterial growth is created within the airways
chronic inflammation leading to further thick purulent sputum production
and bronchiectasis
2) secretion viscosity increases which obstruct the sinus ostia.
ciliary dysfunction, increased inflammatory mediators, and increased bacterial colonization with pathogens such as Pseudomonas aeruginosa = chronic sinusitis
and nasal polps may develop
recurrent chronic productive cough
pseudomonas aureignosa
expiratory wheeze (obstruction)
barrel chest
moist rales
hyperessonace on percussion
chronic bronchitis
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sweat glands
salty skin
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Frequent fractures due to osteopenia
Kyphoscoliosis
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Nephrolithiasis, nephrocalcinosis
Frequent urinary tract infections
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Men: usually infertile Obstructive azoospermia is common, spermatogenesis may be intact The vas deferens may be absent. Undescended testicle
Women: reduced fertility
Viscous cervical mucus can
Menstrual abnormalities (e.g., amenorrhea)
Delayed development of secondary sexual characteristics
most common cause of recurrent pulmonary infection in infancy?
S. aureus , H influenza
P. aeruginosa is the most common cause of recurrent pulmonary infections in adulthood. followed by aspergillus
Infections with Pseudomonas aeruginosa → rapid decline in pulmonary function (patients with CF go through multiple antibiotic courses in their lifetime → increasing resistance of Pseudomonas aeruginosa to commonly used antibiotics)
what is the diagnosis of cystic fibrosis?
median age of diagnosis is 6 to 8 months
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The criteria for diagnosing CF
Positivenewborn screening (NBS), a positive family history, or presence of typical features (e.g., chronic sinopulmonary disease, gastrointestinal and nutritional irregularities, syndromes of salt loss, obstructive azoospermia) PLUS one of the following
1) Elevated sweat chloride 2 than 60 mEq/L on two occasions
30–59 mmol/L are considered intermediate range and require genetic analysis
A chloride concentration < 30 mmol/L implies that CF is unlikely
should be conducted in patients > 2 weeks of age and > 2 kg in weight
2) DNA testing Two disease-causing CFTR mutations and a sweat chloride test result ≥ 30 mmol/L
3) Abnormal nasal potential difference
indication : unclear findings in sweat and DNA tests despite the presence of typical clinical features of CF
Voltage measurements before and after the nose is perfused with different solutions show abnormal epithelial secretion of chloride
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neonatal screening
ositive NBS test result alone does not confirm CF
immunoreactive trypsinogen (IRT), a pancreatic enzyme
Through
heel-prick
High levels
DNA assay
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Bronchoalveolar lavage
sputum culture - ommonly positive for Haemophilus influenza, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, Escherichia coli, or Klebsiella pneumoniae.
====== Supportive tests Stool: ↓ chymotrypsin and pancreatic elastase Imaging X-ray/CT chest shows: Hyperinflation Reticulonodular pattern
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Pulmonary function - Spirometry - major tool for evaluating and monitoring disease state and progression in CF
Pulmonary function tests:
↓ FEV1:FVC ratio and ↑ residual volume (RV) and total lung capacity (TLC) ratio
how do you treat cystic fibrosis ?
pulmonary disease is the most common cause of mortality in cystic fibrosis
Pulmonary illness should be managed with two primary goals: prevent/ treat the infection and improve oxygenation.
In Infants : All children should be started on a narrow spectrum prophylactic antibiotic (flucloxacillin) against SA at diagnosis, and should remain on it until at least 5 years of age
Oral cephalosporins should be avoided, because of concerns about increased PA isolation
mucociliary clearance
bronchodilators
mucolytics
Long-term oxygen inhalation therapy
(Lung transplantation is a treatment option for patients with end-stage lung disease who are physically fit for surgery)
diet
CFTR modulators
children chronically
infected with HI (≥ 2 isolates of HI in one year) will require what ?
Haemophilus influenzae (HI): appropriate prophylaxis (co-amoxiclav)
should be treated regardless of symptoms
Stop flucloxacillin.
co-amoxiclav for 2 weeks which can be combined with clarithromycin if necessary
fail to respond to a 4 week course of oral antibiotics should receive a 2 week course of intravenous antibiotic therapy
Pseudomonas aeruginosa (PA) Patients chronically infected with PA (≥ 2 isolates of PA in one year) should receive what ?
twice daily nebulised colistin for the foreseeable future. This may be alternated with nebulised tobramycin on an alternate month basis. Additionally, consideration should be given to using long term azithromycin in patients chronically infected with PA. It has been shown to have anti-inflammatory effects and to interfere with biofilm formation in such CF patients
when SA is found how do we treat it ?
Increasing the Flucloxacillin to 25mg/kg four times daily
Adding another oral anti-staphylococcal antibiotic for 2 weeks e.g. Clarithromycin/Azithromycin/ Fusidic acid/ Rifampicin
If SA persists then consider:
Extending the course of oral antibiotics to 6 weeks in total
or
Commencing intravenous therapy with two agents for two weeks
It is reasonable to attempt to eradicate SA from respiratory cultures even if the child appears well with what ?
combination oral therapy with rifampicin and fusidic acid
still persists
twice daily nebulised vancomycin
teicoplanin or oral linezolid
can be repeated if the MRSA fails to respond, before intravenous
therapy is considered
The treatment regime for first isolation of PA
3 weeks oral ciprofloxacin
PLUS
3 months twice daily of nebulised Colistin
Repeat cultures x 3
(at least 1 month apart)
patient fails to eradicate the PA with oral therapy, remains WELL and is > 6years, then consider treatment with 1 month of twice daily inhaled tobramycin.
if they remain symptomatic, have deteriorated or are < 6years and failure to eradicate the PA should result in a 2 week course of dual therapy IV antibiotics.
(two IV agents to reduce the risk of resistance)
in fully sensitive organism, intravenous ceftazidime and tobramycin would be the usual first choice
PLUS
Nebulised Colistin x 3/12
Similarly, failure to eradicate with inhaled tobramycin should result in IV antibiotics for 2 weeks
PLUS
Nebulised Colistin x 3/12
ALL PATIENTS WILL HAVE MONTHLY SPUTUM/COUGH SWAB/NPA TAKEN FOLLOWING 1ST ISOLATION OF PA FOR THE FIRST 3 MONTHS
2nd isolation
as above on 1st isolation PLUS lifelong twice daily nebulised antibiotics (1ST choice, colistin)
Long term oral azithromycin should be considered in all patients chronically infected with PA.
Patients chronically infected with PA who are unstable may benefit from
alternate month colistin and tobramycin nebulisers
treatment for URTI (such as mainly viral)
Double prophylaxis x 48hours.If no response, change to co-amoxiclav x 48 hours
increase mucociliary clearance and to reduce the viscosity of mucus in the airways.
Aerosolized dornase alpha
Hypertonic saline nebulization
what is given as bronchodilators ?
albuterol
