Cystic Fibrosis Flashcards
Pattern of inheritance of Cystic Fibrosis
Autosomal recessive
Major morbidity & Mortality associated with Cystic Fibrosis
Pulmonary Compromise characterized by copious hyperviscous and adherent secretions that obstructs the small and medium sized airways
Bacterial flora routinely cultured from CF sputum
PSH
Pseudomonas aeruginosa
Staphylococcus aureus
Haemophilus influenza
Manifestation of >30% of adults with disease
CF-related diabetes mellitus
Most common genetic abnormality in Cystic Fibrosis
Class II defects: CFTR mutation that disrupt protein maturation
~90% of individuals with CF carry atleast one _____ mutation
F508del mutation
Cardinal Test for Cystic Fibrosis
Sweat Electrolyte Measurements
Mainstay of Diagnosis in patients with CF
Sweat test electrolytes following PILOCARPINE IONTOPHORESIS
First approved compound of CFTR modulator that potentiates mutant CFTR gating and stimulates ion transport
Ivacaftor
MOA: overcomes G551D CFTR gating defect, and individuals carrying this mutation exhibit pronounced improvement of lung function, weight gain. Sweat chloride values are significantly reduced by the drug.
Highly effective Modulator Treatment (HEMTs) for Cystic Fibrosis, which benefits >90% of individuals with the disease. Causes marked enhancement of the FEV1, fewer respiratory exacerbations, improved quality of life and diminished sweat chloride
TRIPLE COMBINATION THERAPY
-Elexacaftor
-Tezacaftor
-Ivacaftor
Drugs administered routinely for Cystic Fibrosis patients
- Recombinant DNAse aerosols (degrade DNA strands that contribute to mucus viscosity)
- Nebulized Hypertonic Saline (serves to augment periciliary fluid layer, activate mucociliary clearance & mobilize inspissated airway secretions
Standard means to promote clearance of airway mucus
Chest physiotherapy several times a day
Poor prognostic indicators of Cystic Fibrosis
Sputum culture containing:
-Burkholderia cepacia complex
-Pseudomonas aeruginosa
-Atypical mycobacteria
-Staphylococcus aureus (may be associated)
Typical inpatient antibiotic coverage for Cystic Fibrosis
Combination drug therapy with an Aminoglycoside + Beta-lactam for at least 14 days
Maximal improvement in lung function after antibiotic therapy
Achieved by 8-10 days
What should be considered in individuals who have absence of favorable response to aggressive inpatient treatment, usually seen in ~5% of individuals with Cystic Fibrosis?
Hypersensitivity to Aspergillus
(allergic bronchopulmonary aspergillosis)
Serves as an anion channel in the apical plasma membranes of the epithelial cells and regulates the volume and composition of exocrine secretion
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
This organism further aggravates respiratory decline. It exhibit a stereotypic mode of pathogenesis
A sentinel and early colonization event often engenders lifelong pulmonary infection by the same genetic strain.
Pseudomonas aeruginosa
Refers to profound tissue destruction of the exocrine pancreas, with fibrotic scarring and/or fatty replacement, cyst formation, loss of acinar tissue, and ablation of normal pancreatic architecture.
Cystic Fibrosis of the Pancreas
Tenacious exocrine secretions
Concretions
Sequelae of exocrine pancreatic insufficiency
- Chronic Malabsorption
- Poor growth
- Fat-soluble vitamin deficiency (ADEK)
- High levels of blood immunoreactive trypsinogen
- Loss of pancreatic islet cell mass
Multilobar cirrhosis is seen in ____% of patients
4-15% of patients with CF
Presentation of CF in 10-20% of newborns with CF
Meconium Ileus
___% of Men with CF are infertile due to _____
-99%
-complete involution of vas deferens and infertility (despite functioning spermatogenesis)
TRUE OR FALSE
Males with CF can conceive children through in vitro fertilization
TRUE
CFTR-deficient airway cells exhibit depleted periciliary fluid layer, causing ___ (2)
- Ciliary Collapse
- Failure to clear overlying mucus
The CF airway is characterized by an aggressive, unrelenting, neutrophilic inflammatory response with release of proteases and oxidants leading to ______ (2)
- Airway remodelling
- Bronchiectasis
CFTR mutations that disrupts protein maturation
Class II defects
Prior to advent of newborn screening, CF classically presented in childhood as
- Chronic productive cough
- Malabsorption
- Steatorrhea
- Failure to thrive
The harbinger of a new era for CF therapeutics directed at treating the most fundamental causes of this disease
Ivacaftor
Examples of FDA approved corrector molecules that repair CFTR misfolding, partially overcoming defective F508delCFTR biogenesis
Lumacaftor
Tezacaftor
Standard of care for patients with CF
- Exogenous pancreatic enzymes taken with meals
- Nutritional supplementation
- Anti-inflammatory medications
- Bronchodilators
- Chronic or periodic administration of oral or aerosolized antibioitics
Among patients with CF, malabsorption, chronic inflammation, and endocrine abnormalities can lead to _______
Poor bone mineralization
Management:
1. Vitamin D
2. Calcium
Other respiratory sequelae of CF that may require hospitalization
- Pneumothorax
- Hemoptysis
For end-stage CF pulmonary failure, trasplantation is a viable therapeutic option with median survival of ______
>9 years among adults with disease
Threshold for Lung Transplant referral in Cystic Fibrosis patients
FEV1 <30% predicted
Higher if with significant pulmonary hypertension
CFTR proteins contains how many amino acids?
1480 amino acids
Fully processed from of CFTR is found in?
Plasma membrane in normal epithelia
CFTR gene is located in
Chromosome 7
Absence of CFTR synthesis is labeled as which class ?
Class I defect
G542X
R553X
W1282X
Premature termination codon replaces glycine, arginine, tryptophan at positions 542, 553 1282
Disordered gating/Regulation is labeled as which class?
Class III defect
G551D (glycine to aspartic acid replacement at CFTR postion 551)
Inability to transport Cl and HCO3 in the presence of ATP
Defective conductance through the ion channel pore is labeled as which class?
Class IV defect
A reduced number of CFTR transcripts due to a promoter or splicing abnormality is labeled as which class?
Class V defect
Accelerated turnover from the cell surface is labeled as which class?
Class VI defect
This can serve as specific test for CF if both CFTR genotypes and Sweat electrolytes are inconclusive
In vivo measurement of ion transport across the nasal airways
Represents biooelectric findings specific for Cystic Fibrosis
Elevated (Na-dependent) transepithelial charge separation across airway epithelial tissue and persistent failure of isoprotenol-dependent Cl secretion
“Severe” defects that impair CFTR activity predictive of pancreatic insufficiency
F508del
G551D
Truncation alleles
Over a period of many years, P. aeruginosa evolves in CF lungs to adopt a ______ phenotype. Attributable to release of _______ that confers selective advantage for the pathogen and poor prognosis for the host.
Mucoid phenotype
Alginate exoproduct
