Lecture 11: Cystic Fibrosis and Bronchiectasis Flashcards
what is the cystic fibrosis?
An autosomal recessive disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which leads to defective chloride channels and hyperviscosity of exocrine gland secretions. Can result in meconium ileus, chronic respiratory infections leading to bronchiectasis, pancreatic insufficiency, and obstructive azoospermia in males. Associated with congenital bilateral absence of the vas deferens.
what is the most common life-shortening autosomal recessive disorder in Western Caucasian populations
CF
what are the features of CF?
- -Abnormal apical membrane chloride channel defect resulting in reduced volume and increased hyper-viscosity of mucosal secretions leading to end-organ damage.
- -It is a multisystem disorder but most commonly affects the respiratory and gastrointestinal tracts.
- -The majority of deaths are due to respiratory disease and failure.
- -In the past, the majority of deaths occurred in childhood. Now, most of the deaths occur in the adult patient population.
what is the most common cause of death in CF?
The majority of deaths are due to respiratory disease and failure.
what is used for sweat testing?
A laboratory test commonly used to diagnose cystic fibrosis. It involves measuring the amount of chloride in the patient’s sweat following chemical stimulation of the sweat glands with pilocarpine; chloride levels > 60 mmol/L on two or more occasions are consistent with cystic fibrosis.
immunoreactive trypsinogen is used to…
diagnose CF
A proenzyme of trypsin that accumulates in the blood of newborns with cystic fibrosis. Serum concentrations can be assessed as part of newborn screening for this condition.
what is the epidemiology of CF?
1) Second most common hereditary metabolic disorder in white populations
- -Most common lethal genetic disorder in white populations
2) Incidence
- -Non-Hispanic whites: ∼1/3300
- -1:2500 (U.S. & Continental Europe)
- -1:1700 (IRL) ~ 35-40 new PWCF/ annum
3) Heterozygote frequency among non-Hispanic whites: 1/25
4) CF gene mutation frequency
- -1:35 Continental Europe
- -1:25 U.K. Anglo Saxon descent
- -1:17 Irish Celtic descent
what is the most common mutation in CF?
- -The most common mutation is delta F508 on chromosome 7.
- -Delta F508 (ΔF508 mutation) denotes the absence of the amino acid phenylalanine (F) in position 508 of the protein (present in 70% of non-Hispanic white patients with CF).
what are the other most common mutations in CF?
G551D (11.3%), R117H (4.2%)
Delta F508 mutation results in…
absence of the amino acid phenylalanine (F) in position 508 of the protein
which amino acid is absent in mutated CFTR protein?
phenylalanine
what are the classes of mutations responsible for CF?
- -Class I: Defective synthesis
e. g.G542X, 621+1 G→T - -Class II: Defective processing
e. g. delF508 - -Class III :Defective regulation
e. g. G551D, Y569D - -Class IV :Defective conductance
e. g. R117H - -Class V :Reduced quantity
e. g. 3849+10kb→T - -Class VI: Increased turnover
what is the pathophysiology of CF?
Mutated CFTR gene (ΔF508 mutation) → misfolded protein → defective protein is retained in the rough endoplasmic reticulum (rER) for degradation → ATP-gated chloride channel is absent on the cell surface of epithelial cells throughout the body (e.g., intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs)
what is the role of CFTR in sweat glans?
- -In sweat glands: The chloride channel is responsible for transporting Cl- from the lumen into the cell (reabsorption).
- -Defective ATP-gated chloride channel → inability to reabsorb Cl- from the lumen of the sweat glands → reduced reabsorption of Na+ and H2O → excessive loss of salt and elevated levels of NaCl in sweat
what is the role of CFTR in other exocrine glands?
- -In all other exocrine glands: The chloride channel is responsible for transporting Cl- from the cell into the lumen (secretion).
1) Defective ATP-gated chloride channel → inability to transport intracellular Cl- across the cell membrane → reduced secretion of Cl- → accumulation of intracellular Cl- → ↑ Na+ reabsorption (via ENaC) → ↑ H2O reabsorption → formation of hyperviscous mucus → accumulation of secretions and blockage of small passages of affected organs → chronic inflammation and remodeling → organ damage - -↑ Na+ reabsorption → transepithelial potential difference between interstitial fluid and the epithelial surface increases (i.e., becomes more negative: e.g., from normal -13 mv to abnormal -25 mv)
why in CF there is transepithelial potential difference?
Increased reabsorption of positive sodium ions into the epithelial cells results in a more negative charge on the epithelial surface, increasing the transepithelial potential difference. In patients with intact CFTR channels, positive sodium ions stay on the epithelial surface, increasing the positive epithelial charge, which decreases the potential difference.
what is the molecular biology of CF?
- -CFTR Gene mutation (Chromosome 7)
- -Cl- Channel defect
- -Defective epithelial ion transport
- -Airway surface liquid dehydration
- -Defective mucociliary clearance
- -Bacterial colonization
- -Neutrophilic inflammation
- -Panbronchiectasis
how CF is diagnosed?
1) Clinical + Hx in sibling +newborn screening
2) sweat test + positive nasal potential difference + 2 mutations
what is the clinical presentation if CF in infancy?
- -Failure to thrive
- -Meconium ileus/ intestinal obstruction
- -Testing – sibling with CF
what is the clinical presentation if CF in childhood
- -Failure to reach growth milestones
- -Recurrent chest infections
- -Abdominal cramps/diarrhea
what is the meconium ileus?
An intestinal obstruction caused by failure to pass meconium. Typically manifests in the first three days of life with abdominal distension. Can have associated vomiting. Associated with cystic fibrosis in ~ 90% of cases.
what are the features of pancreatic disease in CF?
1) Pancreatitis
2) )Exocrine pancreatic insufficiency
- -Foul-smelling steatorrhea (fatty stools) may occur.
- -Malabsorption
- -Abdominal distention
- -Diarrhea
- -Deficiency of fat-soluble vitamins (e.g., night blindness due to vitamin A deficiency, rickets due to vitamin D deficiency)
3) CF-related diabetes mellitus (CFRD)
what are the liver and bile duct abnormalities of CF?
- -Cholecystolithiasis, cholestasis
- -Fatty metamorphosis of the liver, eventually progressing to liver cirrhosis
- -Biliary cirrhosis with portal hypertension
what are the clinical manifestations of CF?
- -Pan-Bronchiectasis
- -Pancreatic insufficiency
- -Nasal Polyps/Sinusitis
- -CF related Diabetes
- -CF Renal disease
- -Liver disease
- -Intestinal obstruction/ DIOS
- -CBAVD
- -Osteoporosis
what are the respiratory disease manifestations in CF?
1) Respiratory symptoms are common in adulthood.
2) Obstructive lung disease with bronchiectasis
3) Chronic sinusitis; nasal polyps may eventually develop
4) Recurrent or chronic productive cough and pulmonary infections with characteristic microorganisms
- -S. aureus is the most common cause of recurrent pulmonary infection in infancy and childhood.
- -P. aeruginosa is the most common cause of recurrent pulmonary infections in adulthood.
- -Dangerous bacteria (especially Pseudomonas aeruginosa) are easily transmitted to patients with CF → rapid decline in pulmonary function and increased risk of death (multiple antibiotic courses in their lifetime → high resistance to commonly used antibiotics!)
- -Expiratory wheezing (obstruction), barrel chest , moist rales (indicate pneumonia), hyperresonance to percussion
- -Signs of chronic respiratory insufficiency: digital clubbing associated with chronic hypoxia
5) Airway hyperreactivity (e.g., wheezing)
what bacteria most commonly cause respiratory tract diseases in childhood vs adulthood?
- -S. aureus is the most common cause of recurrent pulmonary infection in infancy and childhood.
- -P. aeruginosa is the most common cause of recurrent pulmonary infections in adulthood.
exacerbation of respiratory diseases manifests as…
- -increased productive cough
- -sputum - increased volume, purulence, and viscidity
- -SOB
- -Wheeze
- -Haemoptysis
- -nasal/ sinus symptoms
- -the duration of onset – a few days- a couple of weeks
respiratory microbiology in CF?
- -Pseudomonas Aeruginosa!
- -Staph Aureus!
- -Stenotrophomonas Maltophilia
- -Burkholderia Cepacia Complex!!
- -Atypical Mycobacteria
- -Aspergillus!
- -Candida!
what are the causes of infertility with CF in males?
- -Obstructive azoospermia is common.
- -The vas deferens may also be absent (Viscous mucus obstructs the formation of the vas deferens during the development of the genital tract.)
- -Undescended testicle
what are the causes of infertility with CF in females?
- -viscous cervical mucus can obstruct fertilization.
- -Menstrual abnormalities (e.g., amenorrhea) : hese menstrual abnormalities are related to viscous cervical mucus and poor growth and development from chronic pulmonary conditions and malnutrition. They may also impact fertility.
what are the non-specific respiratory complications of CF?
- -Haemoptysis – can be intermittent, mild/moderate/severe
- -Pneumothorax (pleuradiesis contraindicated)
- -Allergic bronchopulmonary aspergillosis – wheeze, unresponsive to antibiotics, thick mucus plugs, raised IgE
- -Atelectasis – due to mucus plugging. Can cause acute SOB and hypoxaemia (desaturation)
- -Advanced disease – Type II Respiratory failure, Pulmonary hypertension with Cor Pulmonale
what is the reason for rectal prolapse in CF?
Excessive straining because of chronic constipation and diarrhea lead to weakening of the pelvic structures fixating the rectum; possibly related to a late diagnosis and inadequate treatment of CF
what are the gastrointestinal manifestations in CF?
1) Large bowel
- -Constipation
- -Colonic carcinoma (in older patients 30 years)
2) Small bowel
- -Distal intestinal obstruction syndrome (DIOS) – –recurrent abdo pain, no definitive clinical findings, abdominal CT diagnosis
3) Upper GI
- -Vomiting, GORD – common with coughing
- -Advanced disease – delayed gastric emptying – early satiety and vomiting
what are the gastrointestinal manifestations in CF?
1) Large bowel
- -Constipation
- -Colonic carcinoma (in older patients 30 years)
2) Small bowel
- -Distal intestinal obstruction syndrome (DIOS) – –recurrent abdominal pain, no definitive clinical findings, abdominal CT diagnosis
3) Upper GI
- -Vomiting, GERD – common with coughing
- -Advanced disease – delayed gastric emptying – early satiety and vomiting
what is the DIOS?
Distal intestinal obstruction syndrome (DIOS) involves obstruction of the distal part of the small intestines by thickened intestinal content and occurs in about 20% of mainly adult individuals with cystic fibrosis.
DIOS tends to occur in older individuals with pancreatic insufficiency. Individuals with DIOS may be predisposed to bowel obstruction, though it is a separate entity than true constipation.
what are the other diseases associated with CF?
–Liver disease – focal biliary cirrhosis, fatty infiltration, can lead to cirrhosis with splenomegaly, varices
CF related diabetes
–Nasal polyps/ pansinusitis – recurrent frontal headaches, nasal congestion
–Low bone mineral density/ osteoporosis – assymptomatic, significance unknown, no increase in incidence of fractures
–Growth retardation/ Delayed puberty
–Obstructive azospermia – functional sterility in males (due to CBAVD)
–CF Renal disease – distinct entity, compounded by aminoglycoside usage, and diabetes
what are the general inspection findings in CF?
- decreased BMI, Delayed puberty
- -Clubbed, Cyanosis
what are the chest P/E findings in CF?
- -Hyperinflation, Portacath
- -Crepitations, Wheeze
what are the abdominal P/E findings in CF?
- -Hepatosplenomegaly
- -PEG tube
what are the diagnostic criteria of CF?
1) Typical clinical manifestations of CF: chronic sinopulmonary disease, gastrointestinal and nutritional irregularities, syndromes of salt loss, obstructive azoospermia
2) AND evidence of CFTR dysfunction
- -Sweat chloride ≥ 60 mmol/L on two occasions
- -OR CFTR gene mutation
- -OR abnormal nasal potential difference test
how neonates are screened for CF?
1) ↑ Immunoreactive trypsinogen (IRT)
- -Usually the first screening assay performed on neonates
- -Detects elevated levels of IRT in heel-prick blood
2) DNA assay
- -Either primary screening test or confirmation of CF after abnormal IRT result
- -Identification of common CFTR mutations
what is the maintenance treatment of CF?
1) Nebulized/Inhaled therapies
- -Nebulized anti-pseudomonal antibiotics – Tobramycin, Colistin, Aztreonam
- -Nebulized DNAase – Dornase Alpha (‘Pulmozyme’)
- -Nebulized 7% Hypertonic Saline
- -Inhaled/ Nebulized bronchodilators – Salbutamol, Ipratropium
- -Concurrent asthma – ‘Seretide’ (Salmeterol/Fluticasone) or ‘Symbicort’ (Formoterol/Budesonide)
2) Anti-inflammatories
- -Azithromycin (orally, alternate days)
how ABPA is treated?
Daily oral prednisolone or Monthly iv Methylprednisolone ± Oral Itraconozole (12-18 months)
what is the treatment of malabsorption in CF?
Pancreatic enzyme tablets – ‘Creon’ Vitamin ADEK – ‘Aquadek’ Proton pump inhibitors Oral nutritional supplements PEG feeds – ‘Perative’, ‘Nutrison
how respiratory exacerbation of CF is treated?
- -i.v. antibiotics – 2 weeks/ 2 agents
- -Intensive airway clearance/chest physio
what antibiotics are used to CF respiratory exacerbations?
- -Anti-pseudomonals – Piptazobactam, colomycin, tobramycin, meropenem
- -Staph Aureus – Flucloxacillin
- -MRSA – Vancomycin
- -Stenotrophomonas – Cotrimoxazole (‘Septrin’)
- -Aspergillus colonization – Itraconozole (oral) x 6 weeks
what are the measures of respiratory physiotherapy?
PEP mask
Flutter valve
Acapella
BiPAP
what parameters are monitored in CF outpatient?
FEV1
BMI
Sputum CF culture
what parameters are monitored annually in CF?
- -OGTT (or Hb A1C)
- -Liver U/S
- -Vitamin Levels
- -Bone Densitometry
- -CXR (Review date of last HRCT)
- -IgE, RAST Aspergillus
- -FBC, U&E, LFT’s, Ca/Phos, Protein, Albumin
what are indications and contraindications of lung transplantation in CF patients?
1) Referral when baseline FEV1 < 30% predicted
2) Contraindications
- -Colonization with Burkholderia Cepacia Complex
- -BMI < 17
what is the average life expectancy in CF?
39 years
what is the future of the CF treatment?
- -Gene therapy
- -Newer forms of existing classes of medications – anti-inflammatories, new nebulized antibiotics, airway clearance medications,
- -Potentiators & correctors (small molecules)
what is the ivacaftor?
A CFTR modulator used to treat patients who are homozygous for the F508del mutation in the CFTR gene. Improves chloride transport by increasing the likelihood that the chloride channel of CFTR protein is open. Used in combination with lumacaftor.
- -Normalization of sweat Chloride test
- -FEV1 & BMI normalization
- -Ivacaftor is the only drug that can be used as a monotherapy in patients with a rare G551D mutation in the CFTR gene.
what is the lumacaftor?
A CFTR modulator used to treat patients who are homozygous for the F508del mutation in the CFTR gene. Improves the conformational stability of the defective protein, which leads to increased intracellular processing and trafficking of functional protein to the cell surface. Used in combination with ivacaftor.
what is the role of hypertonic saline and dornase alfa?
Both hypertonic saline and dornase alpha decrease the viscosity of thick secretions in the airways and increase mucociliary clearance, preventing bacterial infection and allowing air to flow better.
what NSAID slows disease progression?
High-dose ibuprofen has been shown to reduce respiratory disease progression
what is the recommended diet in CF?
- -Additional sodium chloride intake
- -High-energy diet to compensate for increased demand
- -Pancreatic enzyme supplements
- -Oral supplementation of lipophilic vitamins A, D, K, and E
what are the CFTR modulators used in CF?
1) Ivacaftor: improves Cl- transport by increasing the likelihood that the Cl- channel is open at the cell surface.
- -Combination therapy with either tezacaftor or lumacaftor
2) Lumacaftor: improves the conformational stability of the defective CFTR protein, which leads to increased intracellular processing and trafficking of functional CFTR protein to the cell surface
2) Tezacaftor: increases the amount of mature CFTR protein on the cell surface by improving intracellular processing and trafficking of the CFTR protein
what is the bronchiectasis?
disease state defined by localized, irreversible dilation of part of the bronchial tree caused by destruction of the muscle and elastic tissue. It is classified as an obstructive lung disease, along with emphysema, bronchitis, asthma, and cystic fibrosis. Involved bronchi are dilated, inflamed, and easily collapsible, resulting in airflow obstruction and impaired clearance of secretions. Bronchiectasis is associated with a wide range of disorders .
what are the causes of bronchiectasis?
1) Previous infections
- -Tuberculosis
- -Measles
- -Pertusis (Whooping cough)
2) Cystic Fibrosis
3) Primary cilliary dyskinesia , Young’s syndrome (Kartagener’s syndrome – triad)
4) Immunoglobulin deficiency syndromes
5) Allergic Bronchopulmonary Aspergillosis
6) alfa-1 antitrypsin def
7) Recurrent aspiration
8) Idiopathic
what are the signs and symptoms of bronchiectasis?
- -Productive cough
- -Recurrent lower respiratory tract infections
- -Intermittent Haemoptysis
* *Symptoms x years
what are the complications of bronchiectasis?
- -Complications
1) Respiratory failure
2) Massive haemoptysis
3) Amyloidosis
what are the clinical signs of bronchiectasis?
± Clubbing
Coarse crepitations
± Wheeze
what investigations should be performed in bronchiectasis?
- -HRCT Thorax
- -Serum immunoglobulins – IgG subclasses, IgA
- -IgE & RAST testing
- -Mannan binding lectin
- -alfa-1 antitrypsin levels
- -Sputum C&S; AFB cultures, ± Bronchoscopy
- -Sweat testing, CF genotyping
what is the treatment of acute exacerbation of bronchiectasis?
Antibiotics x 10-14 days
Cover gram-negative organisms
what is the maintenance treatment of bronchiectasis?
- -Chest physiotherapy
- -Nebulized DNAase?, Nebulized antibiotics?
- -Azithromycin alternate days?
what are the characteristics findings of bronchiectasis during imaging?
1) Chest x-ray (best initial test)
- -Inflammation and fibrosis of bronchial walls lead to the appearance of parallel “tram track” lines
- -Thin-walled cysts (i.e., dilated bronchi forming sacs), possibly with air-fluid levels
- -Late-stage bronchiectasis: honeycombing
2) High-resolution computer tomography (HRCT): confirmatory test
- -Dilated bronchi with thickened walls; possible signet-ring appearance and tram track lines
- -Cysts, especially at bronchial ends in lower lobes, and honeycombing
