Bronchiectasis & Cystic Fibrosis

Question 1

bronchiectasis - overview & clinical definition

Answer 1

*IRREVERSIBLE DILATION OF THE AIRWAY
*commonly associated with the medium-large airways
*mucous commonly present
*can be focal or diffuse disease
*most easily diagnosed on CT of the chest, but can be seen on CXR

Question 2

non-CF bronchiectasis - clinical manifestations

Answer 2

*anatomic distortion of airways results in recurrent infections that manifest as:
-CHRONIC COUGH (productive or non-productive)
-dyspnea
-wheezing
-HEMOPTYSIS
-nonspecific symptoms (fatigue or weight loss)
-found in all ages, women > men

Question 3

etiologies of bronchiectasis

Answer 3

1. post-infectious: TUBERCULOSIS (most common cause), other infections
2. anatomic disease
3. immune-related diseases
4. immune deficiencies
5. GENETIC (CYSTIC FIBROSIS, primary ciliary dyskinesia, alpha-1 antitrypsin deficiency)
6. idiopathic

Question 4

most common causes of bronchiectasis

Answer 4

*TUBERCULOSIS is the #1 cause
*genetic abnormalities are another important cause:
1. cystic fibrosis
2. primary ciliary dyskinesia
3. alpha1 antitrypsin deficiency

Question 5

primary ciliary dyskinesia (PCD) - inheritance pattern & genes involved

Answer 5

*AUTOSOMAL RECESSIVE disorder
*most common genes involved: DNAI1 and DNAH5
*50% have situs inversus totalis [all of the organs are inverted]- due to role of cilia in fetal development

Question 6

genes involves in primary ciliary dyskinesia

Answer 6

*DNAI1 and DNAH5

Question 7

non-CF bronchiectasis - diagnosis

Answer 7

*symptoms are non-specific
*diagnosis relies on radiographic images
*CXR: “tram tracks” and peribronchial cuffing (bronchial wall thickening)
*CT SCAN: defined by either…
1. lack of bronchial tapering (visibility of peripheral airways)
2. bronchial dilation to a diameter greater than that of the accompanying artery = “SIGNET RING”

Question 8

Signet Ring on CT of chest is indicative of…

Answer 8

bronchiectasis

note - signet ring means bronchial dilation to a diameter greater than that of the accompanying artery

Question 9

bronchiectasis - genetic workup

Answer 9

*CF testing
*A1AT level and genotype
*PCD genetic testing

Question 10

bronchiectasis treatment

Answer 10

1. airway clearance (clearing airways of mucous plugs = AUGMNETED AIRWAY CLEARANCE TECHNIQUES):
   -flutter valves, high-frequency chest oscillation, etc
   -bronchodilators
2. prevention (vaccines)
3. antibiotics for exacerbations (acute infections)

Question 11

bronchiectasis - complications

Answer 11

*HEMOPTYSIS (coughing up blood) - can be life threatening
*empyema
*lung abscess
*Cor pulmonale

Question 12

cystic fibrosis - inheritance pattern & genes involved

Answer 12

*AUTOSOMAL RECESSIVE
*results from a dysfunction CF Transmembrane Conductance Regulator (CFTR)
*encoded by CFTR gene on Chromosome 7

Question 13

cystic fibrosis pedigree: if both parents are carriers…

Answer 13

*25% chance of normal genetics
*50% chance of carrier status
*25% chance of disease

Question 14

cystic fibrosis pedigree: if 1 normal parent and 1 carrier parent

Answer 14

*50% chance of normal genetics
*50% chance of carrier status

Question 15

cystic fibrosis pedigree: carrier parent with a CF parent

Answer 15

*50% chance of carrier
*50% chance of disease

Question 16

function of CF transmembrane conductance regulator (CFTR) - general

Answer 16

*CFTR functions as a CHLORIDE CHANNEL
*inhibits sodium transport through the epithelial sodium channels in airways
*expressed in various tissues, including:
-LUNGS
-SWEAT GLANDS
-pancreas
-liver

Question 17

normal function of CFTR in SWEAT GLANDS

Answer 17

*CFTR present on the membrane of the sweat duct, facing the lumen
*when we sweat, CFTR is REABSORBING CHLORIDE into the cell; sodium follows; results in hypotonic sweat

Question 18

normal function of CFTR in LUNGS

Answer 18

*CFTR moves chloride (Cl-) from the cells INTO THE AIRWAYS; sodium follows, as does water
*this is good, because fluid helps keep the secretions loose

Question 19

function of CFTR in the SWEAT GLANDS in CF patients

Answer 19

*CFTR is not present, so we cannot reabsorb the Cl- from sweat
*therefore, sodium also stays in the sweat
*results in hypertonic sweat (excess chloride and sodium in the sweat because we are not reabsorbing it)

Question 20

function of CFTR in the LUNGS in CF patients

Answer 20

*CFTR is NOT moving chloride INTO the airway, so sodium and water remain in the cells, rather than the airway
*results in dry, dehydrated mucous, which is difficult to clear and plugs the airways

Question 21

cystic fibrosis: diagnostic testing

Answer 21

*newborn screening: immunoreactive Trypsinogen
*sweat chloride testing:
-induce sweating and measure amount of chloride
-elevated sweat chloride is considered diagnostic
*GENETIC TESTING:
1. genotyping
2. full sequencing to look for genetic variants

Question 22

homozygous deltaF508 (class II) cystic fibrosis

Answer 22

*most common mutation found in cystic fibrosis
*deltaF508: missing phenylalanine (F) at position 508
*misfolded CFTR protein → retained in rough ER and doesn’t reach the cell membrane (trafficked to proteasome) → inhibits chloride transport
*causes hyperviscous secretions, blocks ducts and airways leading to damage of organs

Question 23

cystic fibrosis - clinical presentation

Answer 23

*CF is a systemic disease and affects multiple organ systems:
-respiratory symptoms (bronchiectasis, recurrent infections, respiratory failure)
-GI symptoms (meconium ileus)
-pancreatic issues
-failure to thrive/malnutrition
-infertility (esp. in men)

Question 24

cystic fibrosis - treatments

Answer 24

*airway clearing techniques
*CFTR modulators
*thinning secretions (mucolytics, hypertonic saline)
*bronchodilators
*anti-inflammatories (azithromycin)

Question 25

cystic fibrosis: antimicrobial therapy

Answer 25

*CF-related bronchiectasis is a cycle of INFECTION, inflammation, and impaired mucociliary clearance
*most common pathogens:
-peds = S. aureus
-adults = PSEUDOMONAS
*PSEUDOMONAS contributes greatly to morbidity/mortality

Question 26

cystic fibrosis - signs and symptoms of an exacerbation of pulmonary infection

Answer 26

*increased frequency and duration of cough
*increase in sputum volume
*HEMOPTYSIS
*fever or leukocytosis
*weight loss
*increased respiratory rate
*CHANGE IN SPIROMETRY (decrease in FEV1 from baseline)

Question 27

CFTR modulators

Answer 27

1. protein potentiation - improve chloride transport efficiency (ex. Ivacaftor)
2. protein stabilization - improve protein delivery to cell surface (ex. lumacaftor, tezacaftor, etc)

Question 28

cystic fibrosis - complications

Answer 28

*hemoptysis (can be life-threatening)
*allergic bronchopulmonary aspergillosis (ABPA)
*pneumothorax
*Cor pulmonale