Cystic Fibrosis Flashcards
6 classes of CF mutations
1) protein synthesis defect
2) maturation defect (delF508)
3) gating defect (G551D)
4) conductance defect
5) reduced quantity
6) reduced stability
Component of Kalydeco and mutations covered
Ivacaftor -> gating potentiator
For class 3 mutations (ie. G551D) and 1 class 4 mutation (R117H)
>6 mos old
Components of Orkambi and mutations covered
Ivacaftor + Lumacaftor (corrector)
homozygous delF508
>2yrs old
Components of Symdeko and mutations covered
Tezacaftor + Ivacaftor
homozygous delF508 or 1 del F508 + 1 residual function mutation
>6yrs
Components of Trikafta and mutations covered
Tezacaftor + Ivacaftor + Elexacaftor
homozygous delF508 or 1 delF508 + another mutation
Side effects of Ivacaftor
serious = liver enzyme elevation, cataracts common = headache, abdo pain, diarrhea, dizziness
Side effects specific to Orkambi
chest tightness + hypertension
4 clinical presentations of invasive aspergillosis
1) Pulmonary
2) Tracheobronchitis
3) Rhinosinusitis
4) Disseminated disease
Common triad for pulmonary aspergillosis
Fever, pleuritic pain, hemoptysis
3 patterns of Tracheobronchitis due to Aspergillus
1) Obstruction
2) Ulcerative
3) Pseudomembranous
Imaging findings of pulmonary aspergillus
CXR = peripherally distributed lung nodules/masses CT = halo sign, air crescent sign
Testing for pulmonary aspergillus
fungal culture, histopath exam of tissue, galactomannan assay
sputum = need direct exam for hyphal elements + fungal culture
Why is Galactomannan useful for Aspergillus dx?
double sandwich enzyme -linked immunoassay
galactomannan = polysaccharide cell wall antigen of Aspergillus
Treatment for invasive pulmonary aspergillus
Voriconazole 6-12 weeks (alternatives = Isavuconazole, Ampho B)
Proven criteria for invasive pulmonary aspergillus
1) Histopath or cytopath exam of lung tissue = hyphae with evidence of associated tissue damage
OR
2) positive culture for Aspergillus from the lung
AND
3) clinically/radiologically abnormal site consistent with infection
Probable criteria for invasive pulmonary aspergillus
Host factor (neutropenia, transplant, steroids, chemo, cancer etc)
AND
mycological evidence
AND
clinical criteria consistent with infection
Most prominent cell type on BAL for Pseudomonas + cytokine associated with it
Neutrophils, IL-17
Basic regimen for eradication of 1st Pseudomonas
Inhaled Tobramycin 300mg BID x 28 days, repeat x 1 if regrowth
complete 1 course of IV abx if regrowth after that
Max dose of lipase in pancreatic enzymes and complication associated with this
10,000units/kg/day or 2500mg/kg/meal
Fibrosing colonopathy
Ranges for fecal elastase and pancreatic insufficiency
<100 = insufficient 100-200 = grey zone >200 = sufficient
Diagnostic criteria for CF
1+ phenotypic features of CF
OR hx CF sibling OR + NBS
AND
increase sweat chloride OR 2 CF mutations OR abnormal nasal epithelial ion transport
Definition of massive hemoptysis
≥ 240mls in 24 hours
Hemoptysis management in CF
H&P, ABCs CBC, cross match, coags, CXR Volume resus Admission Abx (treat like exacerbation) Stop NSAIDs, airway clearance, inhaled treatments CT chest + bronch D/C BiPAP as long as bleeding BAE if massive hemoptysis and unstable
Pneumothorax management in CF
vitals, probable admission, O2 tension = needle and chest tube unclear role for abx large pneumo = no airway clearance post resolution: no flying for 1-2 weeks, no weight lifting x 2 weeks, no spirometry, unclear re: exercise
Recurrent pneumothorax management in CF
Consider pleurodesis (preferred = surgical) *may make transplant harder later on
Mechanism of action of hypertonic saline in CF
osmotic agent and may increase airway surface liquid volume
increased coughing
possible outcomes: better lung function and decreased exacerbations
Mechanism of action of hemoptysis in CF
bronchial arteries or collateral vessels enlarge and may rupture into inflamed airway
also erosion into the vessels
worsened by: low vitamin K and underlying CFLD
3 effects of azithromycin in CF patients
1) Anti-inflammatory
2) Immunomodulatory
3) Antibiotic
Mechanism of action of azithromycin for decreasing bacterial virulence
1) inhibits pseudomonas growth, protein synthesis, and biofilm formation
2) decreases bacterial virulence factors for pseudomonas
3) most benefit in those + for Pseudomonas
Recommendations for Azithromycin in CF
1) Screen for non-TB mycobacteria prior to and periodic screening q6-12 mos
2) no azithro in patients with non-TB mycobacteria
3) recommended ≥ 6 yrs with pseudomonas to improve lung function and reduce exacerbations
4) can use it in those without pseudomonas but frequent exacerbation (recommends but not as strong as pseudomonas)
Most common cell type and cytokine in BAL of CF pt
Neutrophils
Cytokine: IL-8, IL-18, TNF alpha, IL-17
3 reasons for osteopenia in CF
FTT delayed pubertal development malabsorption of calcium, Mg, vit D, vit K Hepatobiliary dx reduced weight bearing activity chronic steroid use inadequate nutrient intake
Tests to prove smoking
Low DLCO (in absence of other causes) High carboxyhemoglobin (10-15%) Serum Cotinine (>3.1 ng/ml) Urine NNAL
Smoking cessation strategies
individual counselling
pharmacotherapy (nicotine replacement, bupropion, varenicline)
Ways that smoking hinders CF lungs
Decreases CFTR function
Increased cough and sputum production
increased frequency and severity of bacterial infection
Decreased appetite and lower nutritional status
Lung function decline
How does PEP help to clear secretions?
Resistance during exhalation = creation of back pressure
Results in build-up of gas pressure behind mucous through collateral ventilation
Move mucous from peripheral to central airways = coughing maneuvers
Suggested vaccines for CF
Influenza yearly ≥ 6 mos
RSV <2 yrs
Routine immunizations
Pneumovax (23-valent)
CF-related DM vs type 1 DM
CFRD:
- rarely associated with islet autoantibodies
- ketoacidosis rare
- screening = 2 hr OGTT
- also glucagon deficiency
Similar features = relative insulin deficiency related to islet cell destruction, polyuria, polydipsia, weight loss
Tx = insulin
Common hepatobiliary manifestations of CF
CFLD Portal HTN Cholestasis Gall bladder disease Hepato-pulmonary sx
Most common finding of CFLD on U/S
Hepatomegaly (looking for firm and nodular)
Gold standard to diagnose CFLD
Liver biopsy
looking for focal biliary cirrhosis
CFLD treatment
- Supportive
- Addressing complications of advance liver disease
- Hep A and B vaccination
- URSO = controversial
- 150% nutrition
- increase fat soluble vitamins
- screen for portal HTN
- screen for variceal bleed
- avoid ASA/NSAIDs
Diagnostic criteria for CFLD
Dx > 2 of: Hepatomegaly/Splenomegaly, persistent (>12mos) elevation in ALT or GGT (and get U/S + doppler, if still elevated in 6mos consult GI) and exclusion of other causes of liver disease, abnormal liver U/S findings
Tests to help determine pancreatic insufficiency
- Fecal elastase
- Stimulation of the pancreas and collect fluid
- Chymotrypsin
- U/S = look for atrophy/cystic changes
- Vitamin levels
- Fecal Fat collection
Meds to treat CF to stabilize FEV1
- Hypertonic Saline
- Dornase Alpha
- CFTR modulators
- Chronic pseudomonas treatment
- Chronic Azithromycin
When should CF be listed for transplant?
1) FEV1 <50% and rapidly declining
2) FEV1 <50% and co-morbidities
3) FEV1 <40%
Pseudomonas mechanisms of inhibition of lung defenses
- Induce damage in immune cells
- Virulence traits and secretion of virulence factors
- Epithelial injury -> loss of alveoli barrier -> biofilm
- Resistant to neutrophils
How is Pseudomonas biofilm produced?
1) Mucous provides anaerobic environment for bacterial growth
2) Decreased secretion of bactericidal compounds into CF airway
3) Increased DNA and actin
What is a biofilm?
bacterial community attached to a surface surrounded by extracellular matrix
Pseudomonas mechanisms of resistance
- Amp C beta-lactamase
- Extended spectrum beta-lactamase
- Downregulation of OprD
- Multidrug efflux pumps
- Biofilm formation
Possible reasons for CF deterioration
- Poor adherence to ACT and meds
- New bug/superimposed infection -> fungi, NTM, pseudomonas
- CFRD
- ABPA
- Smoking/vaping
- Pregnancy
- Weight loss/poor nutrition/enzyme compliance
- mental health
Minimum criteria for ABPA (6)
1) Asthma or CF
2) Worsening lung function without another etiology
3) + skin prick with Aspergillus
4) IgE ≥ 1000
5) Increased Aspergillus species specific IgE and IgG
6) New or recent abnormal CXR or CT findings not improved with abx or physio
Additional criteria for ABPA (4)
1) Increased blood eosinophilia ≥ 400 when not on steroids
2) Aspergillus species -specific precipitating antibodies
3) Central bronchiectasis (central varicose)
4) Aspergillus species-specific containing mucous plugs
Screening for ABPA in CF
1) high level of suspicion ≥ 6 yrs
2) total IgE annually
3) if >500, immediate cutaneous reactivity to aspergillus or IgE antibody
4) if positive, consider dx on basis of minimal criteria
ABPA treatment
1st = steroids -> Prednisone 0.5-2mg/kg.day 1-2 weeks then taper within 2-3 mos
2nd = antifungal: oral Itraconazole 5mg/kg/day x 3-6 mos (therapeutic drug monitoring and LFTs)
add -> BD, inhaled steroids etc only if indicated for asthma
Pertinent prednisone side effects in CF
Diabetes, cataracts, growth failure, osteopenia
Side effects of Itraconazole
Increased transaminases Liver failure (rare) Nausea/vomiting, abdo pain jaundice fatigue increased triglycerides headaches
Indications for antifungal treatment in ABPA (4)
Slow or poor response to steroids
Relapse
Steroid dependent
Steroid toxicity
Criteria for CF-related metabolic syndrome
- *Asymptomatic and positive NBS
1) Indeterminate sweat chloride (x2) and <2 CF-causing mutations
2) Normal sweat chloride + 2 CFTR mutations (only 1 known to cause CF)
Surveillance for CRMS/CF-SPID
1) Infants 30-59 - repeat sweat by 2 mos, if indeterminate - CFTR mutation analysis, 3rd sweat at 6 mos
2) CXR if symptomatic
3) If Pseudomonas - treat as per CF protocol
4) CF team q6mos x 1 yr then annually
5) OP swabs q visit
6) no routine airway clearance (unless dx)
7) recheck pancreatic status if FTT etc.
Characteristics of congenital bilateral absence of vas deferens (CFTR-RD)
1) Absence of palpable vas deferens
2) normal or increased FSH
3) Absence of intra-abdominal tract of VD and hypoplasia of seminal vesicles
4) pH <7.2, negative fructose + alpha 1-4 glucosidase
5) no developmental anomaly
Functional testing for CFTR (2)
1) Nasal potential difference
2) Intestinal current measurement
How does nasal potential difference work?
- based on difference of electric potential measured between a reference electrode and silver/silver chloride electrode
- inferior turbinate
- recordings during continuous flow of salt solutions
- measured in: saline, amiloride, chloride free amiloride, isoproteronol added to activate CFTR
- sum = index of CFTR function
- <40 = abnormal ( on 2 separate days)
How does intestinal current measurement work to assess CFTR function?
- record transepithelial short-circuit current or transepithelial voltage in rectal biopsies as measure of ion transport after stim with chloride secretagogues
- stimulates potassium channels - increasing driving force for luminal chloride
- in CF - activation fails to induce apical chloride secretion and results in inverse response
+ response = potassium secretion with no chloride
Bugs that are part of Mycobacterium Avium Complex (MAC)
M. Avium
M. Intracellulare
M. Chimaera
M. Kansasii
“slow growers”
Bugs that are part of M. Abscessus species complex (MABSC)
M. Abscessus (obviously…)
M. Massiliense
M. Balleti
“rapid growers”
**often younger with more severe disease, difficult treatment, worse response, more severe, may exclude from lung transplant
When to suspect NTM disease in CF
1) Constitutional or respiratory symptoms above baseline
2) Unexplained increased decline in lung function
3) Progressive radiographic diagnosis with no response to typical treatment
4) Treat typical CF pathogens first, max ACT, co-morbidities
Diagnostic criteria for NTM pulmonary disease
Clinical (need BOTH)
1) pulmonary symptoms, nodular opacities (or cavitary) on CXR or multifocal bronchectasis with multiple small nodules
2) exclusion of other diagnoses
Micro (need ONE)
1) positive culture from 2 expectorated sputum samples
2) positive culture from 1 bronchial wash or lavage
3) transbronchial or other lung biopsy with histopath features and positive NTM culture or 1 positive sputum or bronch washing positive for NTM
Histopathologic features of NTM
Granulomatous inflammation
Acid-fast bacilli
General treatment guidelines for NTM pulmonary disease
1) Treat 12 mos beyond culture conversion (after first negative culture, need 3 negative in total)
2) No macrolide monotherapy
3) Monthly AFB smears + cultures while on treatment
4) Should show clinical improvement in 3-6 mos
5) Treatment failure = no response after 6 mos of appropriate treatment or no conversion to AFB negative culture after 12 mos
Treatment of MAC pulmonary disease
1) No CF/cavitations: macrolide (zithromax), Rifampin, Ethambutol 3x/week PO
2) CF: daily of above
3) CF with resistance or unwell, cavitary lesion: 1-3 mos of IV amikacin with above
Risk factors for macrolide resistant MAC (2)
Macrolide monotherapy
Prior macrolide treatment with inadequate companion drugs
Treatment of M. Kansasii
**Think of TB treatment
Isoniazid, Rifampin, Ethambutol x 12 mos after 1st negative culture