Cystic Fibrosis + Bronchiectasis + ABPA Flashcards
Mutation in CF and pathophysiology
Autosomal recessive
Mutation in CFTR gene located on chromosome 7
Leads to DEFECTIVE CHLORIDE CHANNELS
The disorder affects particularly the:
- Respiratory system (85% of mortality causes)
- Pancreas
- Sweat glands
- Male reproductive system
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
In all other Exocrine Glands (e.g., in the GI tract or lungs)
-The chloride channel is responsible for transporting Cl- from the cell into the lumen (secretion).
-Defective ATP-gated chloride channel → inability to transport intracellular Cl- across the cell membrane → reduced secretion of Cl- and H2O → accumulation of intracellular Cl- → ↑ Na+ reabsorption (via ENaC - epithelial Na channel) → ↑ 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., negative charge increases; e.g., from normal -13 mv to abnormal -25 mv
Most common mutation in CF
Most common mutation is delta F508. Others include G551D
Delta F508 mutation interferes with protein folding and channel gating activity.
Diagnosis of CF
At least one of the following:
- Positive newborn screening test
- History of CF in a sibling
- One of more typical phenotypic features of CF:
- Chronic pulmonary disease
- Chronic sinusitis
- Gastrointestinal and nutritional abnormalities
- Salt loss syndromes
- Obstructive azoospermia
PLUS one of the following:
1. Sweat chloride testing with a chloride value ≥ 60 mmol/L
2. Two CFTR gene variants known to cause CF on separate alleles (and a sweat chloride test result ≥ 30 mmol/L)
3. Abnormal nasal potential difference test or intestinal current measurement
Nasal Potential Difference Test: Voltage measurements before and after the nose is perfused with different solutions show abnormal epithelial secretion of chloride (e.g., more negative baseline potential difference and no difference in nasal potential difference after administration of a chloride-free solution).
Types of CF
- Classic CF 98% of cases
- Elevated sweat chloride and multisystem disease - Non Classic CF 2% of cases
- Normal or intermediate sweat chloride
- Single organ system involvement
- Usually present with GI symptoms, diabetes or infertility
- usually dx in adulthood
- Lower incidence of Delta F508 mutations
- Higher incidence of unusual CFTR mutations
Different classes/phenotypes of CFTR
Class 1: nil synthesis of CFTR
Class 2: reduced trafficking, delta F508 mutation (folding defect/processing) - CFTR protein is created, but misfolded keeping it from reaching the cell surface.
Class 3: reduced gating, G551D mutation (channel opening/gating defect) - CFTR protein is created and reaches cell surface but does not function properly.
Class 4: reduced conductance (ion transport defect/channel conductance defect) - the opening in the CFTR protein ion channel is faulty
Class 5: reduced synthesis - CFTR is created in sufficient quantities
Class 6: instability of GFTR
What infection is pathognomonic for CF?
Infection with Burkholderia
cepacia is pathognomonic for CF.
Gram negative
Antimicrobial agents that are effective against B. cepacia complex in vitro include trimethoprim-sulfamethoxazole, ceftazidime, carbapenems, ureidopenicillins, fluoroquinolones, minocyline, and chloramphenicol.
Tobramycin
Ciprofloxacin + inhaled colistin, ceftazidime, meropenem
What are some CF clinical syndromes and co-morbidities?
Associated comorbidities in adults with CF include diabetes mellitus (present in up to 30% of patients), infertility due to azoospermia (present in 95% of men), osteoporosis (present in 23% of patients), and liver
disease. Liver disease occurs in 10% of patients with CF. The most common abnormality is fatty infiltration and intrahepatic cholestasis, with up to 5% to 15% of patients developing multilobular cirrhosis and portal hypertension.
- Respiratory
- Staph aureus, Haemophilus influenza colonisation early in life
- Pseudomonal colonisation ~70% - Sinusitis in most 90-100%
- Pancreatic Disease - DIABETES
- Malnutrition/Fat malabsorption
- Vit A/D/E/K deficiency
- Pancreatic insufficiency - Anaemia
- Aquagenic wrinkling
- C diff
- Increased risk of malignancies
- Infertility due to azoospermia
- Osteoporosis
10 Liver disease occurs in 10% of patients with CF. The most common abnormality is fatty infiltration and intrahepatic cholestasis, with up to 5% to 15% of patients developing multilobular cirrhosis and portal hypertension,
Treatment in CF
- Antimicrobials
- Airway Clearance
- Anti-Inflammatory
- CFTR Modulators
- Antimicrobials
- Acute exacerbations
- Chronic infection
- Require routine sputum MCS every 3 months to guide therapy.
- Pseudomonas >70% are chronically infected = chronic treatment with azithromycin 500mg TDS - improvements in FEV1, reduced exacerbations, anti-inflammatory effect on cytokine production.
- Exacerbations: 50% are viral, increased air pollution also increase exacerbation frequency
- Airway Clearance
- Chest physiotherapy
- Mucoactive therapy:
o Inhaled dornase alpha (DNase) - improved FEV1 by 6%, reduced exacerbation
o Inhaled hypertonic saline - reduced exacerbation frequency, no impact on FEV1
o Positive expiratory pressure (PEP) therapy - reduced exacerbation frequency
- Physical activity
- Anti-inflammatory
- Macrolides
- New drugs - CFTR Modulators
CF Respiratory Infections
Burkholderia cepacia complex
- Chronic infection results in accelerated decline in lung function
- Usually multidrug resistant
- Worse outcomes with lung transplantation
Non-tuberculosis myocbateria in 10-20%
- MAC not associated with worse transplant outcomes
- M abscessus associated with worse lung function and transplant complications.
- Only treat NTM infections if evidence of clinical symptoms, worsening lung function or nodular infiltrates or cavitating disease.
CFTR Modulators
Ivacaftor (Kalydeco):
- CFTR potentiator, useful in G551D mutation (type III), opens the channel of the protein.
- Improved FEV1 ~7-10%
- 55% exacerbation risk reduction
- Reduced hospitalisation
- Weight gain
- Not effective in delta 508 mutation
- Texacaftor: CFTR corrector, moves the protein onto the cell surface
- Elexacaftor: CFTR corrector, moves the protein onto the cell surface
- Ivacaftor + Texacaftor (SYMDECO) OR Ivacaftor + Lumacaftor for homozygous DF508 mutations
- Lumacaftor partially corrects misfolding
- Ivacaftor improves channel gating activity
Elexacaftor/Ivacaftor/Texacftor (TRIKAFTA) for heterozygous DF508 mutation and homozygous.
individual patients
When is pretransplant warranted for CF and what are the contraindications
Pretransplant assessment is warranted if:
- FEV1 < 30% predicted
- Rapid decline in FEV1 despite optimal treatment
- Malnutrition and diabetes
- Frequent exacerbations
- Recurrent massive haemoptysis which cannot be controlled by bronchial artery embolisation
- Relapsing/complicated pneumthorax
Contraindications
- Age >65yo
- Critical/unstable clinical situation
- Limited functional status
- Colonisation with Burkholderia cenocepacia (GN), Burkholderia galdoli, Mycobacteria abscessus
Features of bronchiectasis
A chronic respiratory disease characterised by a clinical syndrome of:
- cough
- sputum production
- bronchial infection
- abnormal and permanent dilatation of the bronchi
CT features of bronchiectasis
Bronchiectasis is defined by bronchial dilatation as suggested by one or more of the following
- Bronchoarterial ratio > 1 (internal airway lumen vs adjacent pulmonary artery)
Signet ring sign is seen in bronchiectasis when the dilated bronchus and accompanying pulmonary artery branch are seen in cross-section. The bronchus and artery should be the same size, whereas in bronchiectasis, the bronchus is markedly dilated.
- Lack of airway tapering
- Airway visible within 1 cm of costal pleural space or
- Touching mediastinal pleura
The following indirect signs are commonly associated with bronchiectasis
- Bronchial wall thickening
- Mucus impacting
- Mosaic perfusion/air trapping on expiratory CT
What is the classification of bronchiectasis?
FOCAL VS DIFFUSE
FOCAL
Focal bronchiectasis may occur due to either:
- Extrinsic Changes: airway tumor, aspirated foreign body, scarred or stenotic airway, enlarged LN
- Intrinsic Changes: bronchial atresia
- Twisting or displacement of airways after a lobar resection
Recurrent or persistent lobar pneumonia is a key feature
DIFFUSE Diffuse bronchiectasis is more commonly associated with underlying systemic or infectious disease (bacterial infection, nontuberculous mycobacterial [NTM] infection, reactivated tuberculosis, cystic fibrosis [CF]). - Infections - Congenital conditions, eg: CF - Immunodeficiency conditions, eg; CVID, eg: chlorine inhalation - Rheumatological conditions.eg: RA - Toxin or drug exposure
What are the causes of focal bronchiectasis?
- Infections Post viral: adenovirus, measles, influenza, pertussis, varicella, HIV Mycobacterium Aspergillus (ABPA) Severe bacterial infections
- Congenital conditions Primary ciliary dyskinesia CF Alpha- 1 antitrypsin deficiency Marfans Syndrome Pulmonary sequestration
- Immunodeficiency conditions
Primary hypogammaglobulinaemia
Secondary - cancer (CLL), myeloma, chemotherapy or immune modulation - Rheumatological conditions
RA, SLE, Sjogren’s Syndrome - Toxin or drug exposure
What is primary ciliary dyskinesia?
- Immotile cilia syndrome
- Autosomal recessive with variable penetrance with incidence of 1:15000
- Absence or shortening of dynein arms in cilia
- Diagnosis: ciliary motility study
- Primary ciliary dyskinesia can be either central or
diffuse lung involvement. - Ciliary dysfunction prevents the clearance of mucous from the lungs, paranasal sinuses and middle ears.
Clinical Features
- Bronchiectasis
- Chronic sinusitis
- Agenesis of frontal sinuses
- RECURRENT OTITIS MEDIA*
- Some will have Kartagener’s syndrome: bronchiectasis, sinusitis, situs inversus
Kartagener’s syndrome is a rare, autosomal recessive genetic ciliary disorder comprising the triad of situs inversus, chronic sinusitis, and bronchiectasis. The basic problem lies in the defective movement of cilia, leading to recurrent chest infections, ear/nose/throat symptoms, and infertility.
