Cystic Fibrosis

Question 1

Pattern of inheritance of Cystic Fibrosis

Answer 1

Autosomal recessive

Question 2

Major morbidity & Mortality associated with Cystic Fibrosis

Answer 2

Pulmonary Compromise characterized by copious hyperviscous and adherent secretions that obstructs the small and medium sized airways

Question 3

Bacterial flora routinely cultured from CF sputum

Answer 3

PSH
Pseudomonas aeruginosa
Staphylococcus aureus
Haemophilus influenza

Question 4

Manifestation of >30% of adults with disease

Answer 4

CF-related diabetes mellitus

Question 5

Most common genetic abnormality in Cystic Fibrosis

Answer 5

Class II defects: CFTR mutation that disrupt protein maturation

Question 6

~90% of individuals with CF carry atleast one _____ mutation

Answer 6

F508del mutation

Question 7

Cardinal Test for Cystic Fibrosis

Answer 7

Sweat Electrolyte Measurements

Question 8

Mainstay of Diagnosis in patients with CF

Answer 8

Sweat test electrolytes following PILOCARPINE IONTOPHORESIS

Question 9

First approved compound of CFTR modulator that potentiates mutant CFTR gating and stimulates ion transport

Answer 9

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.

Question 10

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

Answer 10

TRIPLE COMBINATION THERAPY
-Elexacaftor
-Tezacaftor
-Ivacaftor

Question 11

Drugs administered routinely for Cystic Fibrosis patients

Answer 11

1. Recombinant DNAse aerosols (degrade DNA strands that contribute to mucus viscosity)
2. Nebulized Hypertonic Saline (serves to augment periciliary fluid layer, activate mucociliary clearance & mobilize inspissated airway secretions

Question 12

Standard means to promote clearance of airway mucus

Answer 12

Chest physiotherapy several times a day

Question 13

Poor prognostic indicators of Cystic Fibrosis

Answer 13

Sputum culture containing:
-Burkholderia cepacia complex
-Pseudomonas aeruginosa
-Atypical mycobacteria
-Staphylococcus aureus (may be associated)

Question 14

Typical inpatient antibiotic coverage for Cystic Fibrosis

Answer 14

Combination drug therapy with an Aminoglycoside + Beta-lactam for at least 14 days

Question 15

Maximal improvement in lung function after antibiotic therapy

Answer 15

Achieved by 8-10 days

Question 16

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?

Answer 16

Hypersensitivity to Aspergillus
(allergic bronchopulmonary aspergillosis)

Question 17

Serves as an anion channel in the apical plasma membranes of the epithelial cells and regulates the volume and composition of exocrine secretion

Answer 17

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Question 18

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.

Answer 18

Pseudomonas aeruginosa

Question 19

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.

Answer 19

Cystic Fibrosis of the Pancreas

Question 20

Tenacious exocrine secretions

Answer 20

Concretions

Question 21

Sequelae of exocrine pancreatic insufficiency

Answer 21

1. Chronic Malabsorption
2. Poor growth
3. Fat-soluble vitamin deficiency (ADEK)
4. High levels of blood immunoreactive trypsinogen
5. Loss of pancreatic islet cell mass

Question 22

Multilobar cirrhosis is seen in ____% of patients

Answer 22

4-15% of patients with CF

Question 23

Presentation of CF in 10-20% of newborns with CF

Answer 23

Meconium Ileus

Question 24

___% of Men with CF are infertile due to _____

Answer 24

-99%
-complete involution of vas deferens and infertility (despite functioning spermatogenesis)

Question 25

TRUE OR FALSE
Males with CF can conceive children through in vitro fertilization

Answer 25

TRUE

Question 26

CFTR-deficient airway cells exhibit depleted periciliary fluid layer, causing ___ (2)

Answer 26

1. Ciliary Collapse
2. Failure to clear overlying mucus

Question 27

The CF airway is characterized by an aggressive, unrelenting, neutrophilic inflammatory response with release of proteases and oxidants leading to ______ (2)

Answer 27

1. Airway remodelling
2. Bronchiectasis

Question 28

CFTR mutations that disrupts protein maturation

Answer 28

Class II defects

Question 29

Prior to advent of newborn screening, CF classically presented in childhood as

Answer 29

1. Chronic productive cough
2. Malabsorption
3. Steatorrhea
4. Failure to thrive

Question 30

The harbinger of a new era for CF therapeutics directed at treating the most fundamental causes of this disease

Answer 30

Ivacaftor

Question 31

Examples of FDA approved corrector molecules that repair CFTR misfolding, partially overcoming defective F508delCFTR biogenesis

Answer 31

Lumacaftor
Tezacaftor

Question 32

Standard of care for patients with CF

Answer 32

1. Exogenous pancreatic enzymes taken with meals
2. Nutritional supplementation
3. Anti-inflammatory medications
4. Bronchodilators
5. Chronic or periodic administration of oral or aerosolized antibioitics

Question 33

Among patients with CF, malabsorption, chronic inflammation, and endocrine abnormalities can lead to _______

Answer 33

Poor bone mineralization

Management:
1. Vitamin D
2. Calcium

Question 34

Other respiratory sequelae of CF that may require hospitalization

Answer 34

1. Pneumothorax
2. Hemoptysis

Question 35

For end-stage CF pulmonary failure, trasplantation is a viable therapeutic option with median survival of ______

Answer 35

>9 years among adults with disease

Question 36

Threshold for Lung Transplant referral in Cystic Fibrosis patients

Answer 36

FEV1 <30% predicted
Higher if with significant pulmonary hypertension

Question 37

CFTR proteins contains how many amino acids?

Answer 37

1480 amino acids

Question 38

Fully processed from of CFTR is found in?

Answer 38

Plasma membrane in normal epithelia

Question 39

CFTR gene is located in

Answer 39

Chromosome 7

Question 40

Absence of CFTR synthesis is labeled as which class ?

Answer 40

Class I defect

G542X
R553X
W1282X

Premature termination codon replaces glycine, arginine, tryptophan at positions 542, 553 1282

Question 41

Disordered gating/Regulation is labeled as which class?

Answer 41

Class III defect

G551D (glycine to aspartic acid replacement at CFTR postion 551)

Inability to transport Cl and HCO3 in the presence of ATP

Question 42

Defective conductance through the ion channel pore is labeled as which class?

Answer 42

Class IV defect

Question 43

A reduced number of CFTR transcripts due to a promoter or splicing abnormality is labeled as which class?

Answer 43

Class V defect

Question 44

Accelerated turnover from the cell surface is labeled as which class?

Answer 44

Class VI defect

Question 45

This can serve as specific test for CF if both CFTR genotypes and Sweat electrolytes are inconclusive

Answer 45

In vivo measurement of ion transport across the nasal airways

Question 46

Represents biooelectric findings specific for Cystic Fibrosis

Answer 46

Elevated (Na-dependent) transepithelial charge separation across airway epithelial tissue and persistent failure of isoprotenol-dependent Cl secretion

Question 47

“Severe” defects that impair CFTR activity predictive of pancreatic insufficiency

Answer 47

F508del
G551D
Truncation alleles

Question 48

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.

Answer 48

Mucoid phenotype
Alginate exoproduct