Respiratory 3 - Hot topics in respiratory medicine (2) Flashcards
1
Q
What is the strongest risk factor for development of VTE?
A
Myocardial infarction in the last 3 months
2
Q
What are features of epidemiology of PE?
A
0.5-2/1000 per year
higher incidence in african americans, lower in Asians, Pacific Islanders
M:F 56 vs 48/100k
Females have lower recurrence rates
Increased risk with increasing age (risk doubles every decade after 40)
3
Q
What is the natural Hx of VTE?
A
30 day mortality for VTE 11%
90 day 9-17%
12 month 30%
Treatment reduces mortality to
4
Q
What are STRONG risk factors for VTE? (OR>10)
A
Fracture of LL Hospitalisation for CHF or AF/Flut Hip or knee replacement Major trauma Myocardial infarction within 3 months Previous VTE Spinal cord surgery
5
Q
What are moderate RFs for VTE? (OR 2-9)
A
Arthroscopic knee surgery AI diseases Blood transfusion CVLs Chemotherapy CHF/respiratory failure EPO HRT IVF Infection (esp pneumonia, UTI, HIV) IBD Cancer (higher if metastatic) OCP Paralytic stroke Post partum Superficial vein thrombosis Thrombophilia
6
Q
What are weak risk factors for VTE (OR
A
Bed rest >3 days DM HTN Immobility due to sitting Increasing age Laparoscopic surgery Obesity Pregnancy (up to 60x risk in T3, and 6 weeks post partum) Varicose veins
7
Q
What are expected VTE recurrence rates whilst on A/C?
A
2% at 2 weeks
6.4% at 3 months
8% at 6 months
Active cancer and failure to achieve therapeutic A/C increase the risk
8
Q
What are rates of late recurrence?
A
Generally >6 months, and off A/C
13% at 1 year
23% at 5 years
30% at 10 years
Recurrent risk higher in unprovoked VTE, multiple VTE, OCP, PE, proximal DVT and elevated d-dimer
9
Q
What clinical features are assigned the highest score in the Well’s rule?
A
Clinical signs of DVT = 3 Alternative diagnosis less likely than PE =3 Previous DVT/PE = 1.5 Heart rate >100 = 1.5 Surgery or immobilisation within 4 weeks = 1.5 Haemoptysis = 1 Active cancer = 1 >4 points = PE likely
10
Q
What clinical features are associated with the highest score on the geneva score?
A
HR >=95/min = 5 points Pain on lower limb venous palp/unilateral swelling = 4 Prev DVT/PE = 3 Unilateral lower limb pain = 3 HR 75-95 = 3 Surgery/# within 1/12 = 2 Haemoptysis = 2 Active cancer = 2 Age >65yo = 1
> 5 points = PE is likely
11
Q
What tests are best at diagnosis VTE?
A
CTPA - but good at overdiagnosis
VQ - high probability scan only
Compression USS
12
Q
What are tests for excluding VTE?
A
d-dimer - in low and intermediate risk groups
CTPA - if negative and high pre-test probability -requires further investigation
V/Q - low probability scan excludes VTE, but 50% are reported as non-diagnostic
13
Q
What is the most Specific d-dimer assay?
A
ELISA quantitative method has a negative LR of 0.01
Latex quant 0.2
Latex semiquant 0.20
Haemagllutination 0.31
14
Q
What is the role of CT venography in CTPA?
A
Addition of CTV to CTPA improves Sn but has no change in NPV or Sp - and results in higher radiation dosages
15
Q
What is the relationship between NPV, PPV and clinical probability in CTPA?
A
Has low PPV in low clinical probability groups, and a low NPV in high clinical probability groups.
When there is clinical discrepancy between clinical probability and CT results - should consider further testing
16
Q
What is the relationship between CTPA and overdiagnosis?
A
PE incidence increased following CTPA introduction, however there has been a progressive fall in PE mortality, with increasing rates of complications from anticoagulation.
CTPA will diagnose clinically unimportant emboli and lead to overtreatment.
17
Q
What is the significance of subsegmental PE?
A
Isolated subsegmental PE of questionable clinical significance.
9.4% of patients on MDCT
Inter-observer agreement low
? role of compression USS in this group
18
Q
What are features of VQ scanning?
A
3 outcomes - normal (excludes PE), High probability and non-Dx (50% of scans)
Lower radiation dose generally.
Usually for pts with contrast allergy, renal failure, myeloma.
Perfusion scan alone is adequate in patients with normal CXR
19
Q
What is the role of Comp USS in DVT/PE?
A
most PEs from DVT
70% pts with PE have DVT on venography
Comp USS - Sn >90%, Sp 95%, DVT ident in 30-50% of patients with PE
20
Q
What is the role of echo in PE?
A
only 30-40% of patients with PE have echo features consistent with PE.
NPV only 40-50%
Useful in stratification of patients who may be high risk
21
Q
What features make PE high risk?
A
Shock or hypotension
- SBP =40 for >15 minutes
not caused by arrhythmia, sepsis or hypovolaemia
22
Q
What are adverse prognostic factors in PE on imaging?
A
RV dysfunction 2ndary to PE = 2x mortality
Rv thrombus - 14 day mortality 21 vs 11%, 3 month 29 vs 16%
Co-existant DVT increases all cause mortality by 2 and increased specific PE mortality by 4.25
23
Q
What is the relationship between BNP and mortality in PE?
A
600 = increased risk of morbidity
24
Q
What are other prognostic serum factors in PE?
A
troponin elevation - OR5.24 for short term mortality and 9.44 PE-specific mortality
Hyponatraemia - mild 1.53 OR, 2 increases mortality from 1.6 to 17.3%
25
What is the role of PESI?
to identify low risk patients (low risk 1% mortality rate and 10% in high risk (at 30 days)
```
Simplified - >=1 point = high risk
Age >80 +1
Cancer +1
CHF +1
Chronic pulmonary disease +1
HR >110 +1
SBP
```
26
What patients are eligible for outpatient treatment of PE?
PESI I or II - no difference in VTE rates at 3 months and no significant difference in bleeding rates
Patients with BNP
27
What period of treatment is recommended with non-oral A/C in acute PE?
5-10 days, with overlap of warfarin with heparin
28
What are advantages of LMWH vs UFH?
lower mortality
lower recurrence rates
reduced thromboembolic events
less major bleeding
29
What is the role of testing for CYP2C9 and vit K epoxide reductase genes in warfarin?
genes account for >1/3 of variability of in warfarin dosing
| current evidence is equivocal as to clinical utility of testing
30
What is the duration of therapy for provoked DVT?
3 months
31
What is the duration of therapy in active cancer?
3-6 months, and consider indefinite treatment
LMWH is more effective than warfarin in these patients
20% risk of recurrence in 1st 12 months
32
What is the minimum treatment duration in patients with unprovoked DVT?
at least 3 months of treatment - if high risk of bleeding complications, limit to 3 months total duration.
If low or moderate risk - indefinite therapy
Reduce risk of recurrent VTE by 90% (warfarin), with 1% or higher annual risk of bleeding
33
What patients may benefit from indefinite treatment with vit K antag?
```
Recurrent VTE
Antiphospholipid syndrome
hereditary thrombophilia (homozygotes)
residual thrombus in prox veins
persistent RV dysfunction on echo
```
34
What is the role of aspirin post unprovoked DVT/PE
30-35% risk reduction in recurrence post std anticoag, but anticoag provides 50% reduction.
lower bleeding rates with aspirin
35
What is the role of NOACs in the long-term treatment of DVT/PE?
dabigatran non-inferior wrt efficacy and lower rates of major bleeding.
rivaroxaban - no difference in PE recurrence and minor decrease in major bleeding (t1/2 is short- risk of recurrence high w missed dose)
apixaban - non-inferior to warfarin, less major bleeding
edoxaban - less bleeding, non inferior
overall meta analysis, just reaches unity for bleeding risk favoured in noacs
36
What are absolute contraindications for thrombolysis in PE?
Haemorrhagic stroke or stroke of unknown origin at any time.
Ischaemic stroke in past 6 months.
CNS damage or neoplasms
Recent major trauma, surgery head injury in last 3/52
GI bleed in last month
Known bleeding risk
37
What are relative contraindications for thrombolysis in PE?
```
TIA in last 6 months
oral AC therapy
Pregnancy or one week post partum
Non-compressible puncture site
Traumatic resuscitation
Refractiory hypertension (>180)
Advanced liver disease
Infective endocarditis
Active peptic ulcer
```
38
In what patients is thrombolysis beneficial?
patients who are hypotensive/haemodynamically unstable have been shown to be afforded benefit in thrombolysis in PE
39
In submassive PE, what are the outcomes of thrombolysis?
Shown to reduce rates of therapy escalation but not mortality. Soft endpoint.
Intermediate risk PE - shown to increase bleeding, but not death.
Low dose thrombolysis has shown faster resolution of PE but similar rates of bleeding, recurrence and death.
40
What about low dose thrombolysis in massive PE?
Lower mortality and bleeding in low dose group, with no fatal recurrent VTE in either group (no comparison placebo arm)
41
What are features of IVC filters in PE?
reduced short term PE mortality
Increased risk of recurrent VTE ~20%
Post thrombotic syndrome in 40%
Occlusion of IVC - 22% at 5 years, 33% at 9 years regardless of A/C
42
What is the prognosis of untreated subsegmental PE?
no patients died of PE at 3 months if untreated, but 16% had bleeding complications if treated.
43
What is the definition of pulmonary hypertension?
PAPm >=25mmHg
Precapillary PH: PAPm >=25mmHg, PAWP =25mmHg, PAWP >15mmHg
44
What are classifications of pulmonary HTN?
1. Pulmonary arterial hypertension
2. PH due to LHD
3. PH due to lung Dz or hypoxia
4. Chronic thromboembolis PH
5. PH with unclear multifactorial mechanisms
45
What are causes of PAH?
Idiopathic PAH
Heritable PAH - BMPR 70%, ALK1, ENG, SMAD, CAV1, KCNK3
Drugs (cocaine, rapeseed, anorectic drugs)
Associated with:
CTD, HIV, portal HTN, Congenital heart disease, Schistosomiasis
46
What are clinical features of pAH
```
non specific:
dyspnoea
fatigue
syncope
peripheral oedema
angina
```
47
How is PAH diagnosed?
```
Requires clinical suspicion:
consider features of underlying disease
consider screening high risk groups:
- CTD
- HIV
- hereditary PAH
- ECG - Right axis deviation
- Spirometry and TCLO
- Anti-centromere Ab
- pro BNP
- Serum urate
- Echocardiogram (>=3.0 m/sec tricuspid regurgitation)
```
48
What is the relationship between screening and prognosis in SSc?
Improved survival when patients with SSc are screened for PAH
49
What is the best 1st screening test for PAH?
Echocardiogram - looking for tricuspid regurgitation, RVSP.
50
If a high or intermediate risk echo, what is the next step in PAH diagnosis?
Consider left heart disease and lung diseases - if confirmed, refer to PH centre for review if signs and Sx of severe PH/RV dysfunction.
If patient without symptoms, treat the underlying disease.
51
What is the next step if a patient lacks evidence of LHD or lung disease following positive screening echo in PAH?
Proceed to VQ scan - refer to PH centre
If CTEPH is possible - CTPA and RHC and pulmonary angio is indicated.
If no evidence of CTEPH - proceed to RHC - If negative, consider other causes, otherwise specifically look for causes of PAH
52
What are risk factors for group 1 PAH?
```
Connective tissue disease
HIV
portal hypertension
Congenital heart disease
schistosomiasis
```
53
What are definite drugs associated with PAH, group 1?
```
Aminorex
fenfluramine
dexfenfluramine
benfluorex
SSRIs
```
54
What are likely drugs associated with PAH, group 1?
Amphetamines
Dasatinib
L-tryptophan
Methamphetamines
55
What genetic mutations play a role in Group 1 PAH?
Bone morphogenetic protein (BMPR)
- inhibits smooth muscle and proliferation and induces apoptosis when normal
- vascular remodelling occurs in patients with mutations
- only 25% of patients with BMPR mut develop PAH, but 75% of familial PAH have BMPR mutations
- 40% of sporadic PAH have BMPR mutations
```
Others include
ALK1
5HTT
ENG
SMAD9
KCNK3
eukaryotic translation initiation factor 2 alpha kinase 4
```
56
What are poor prognostic factors in PAH?
```
Male
Age >51
CTD as etiology
Increasing NYHA functional class
Higher BNP/creat
Pericardial effusions
Lower DLCO
Higher mRAP
Lower CO/CI
Higher PVR or PVRI
```
57
What are the three primary factors driving PAH?
Vasoconstriction 2ndary to endothelial dysfunction
Remodelling
Thrombosis in situ
58
What are features of endothelial dysfunction in PAH?
Chronically reduced nitric oxide, and prostacyclin and increases in endothlin 1
Vascular remodelling results in plexiform lesions - vasoproliferation rather than vasoconstriction
Proliferation of endothelial and SM cells
Disordered angiogenesis
59
What is the role of Endothelin 1 in PAH?
potent vasoconstrictor - stimulates smooth muscle proliferation.
ET-A/ET-B receptor on smooth muscle - vasoconstriction
ET-B on endothelium - NO release and vasodilatation
Endothelin- 1 levels increased in plasma and lungs of PAH and correlate with disease activity and mortality
60
What are general therapies for all PH patients?
Treat the underlying disorder
Pulmonary rehab (improves QoL, WHO class and VO2 max, and 6MWT)
Exercise training (improved aerobic capacity and endurance)
Diuretics (no RCT evidence)
O2 if hypoxic
Anticoagulation - if IPAH, drug induced PAH, hereditary PAH, CTEPH
Infleunza and pneumococcal immunisation
61
What is the role of CCB in PAH?
Only to be used if evidence of vasoreactivity on testing.
only 10-25% have response
Large doses often needed (nifedipine used, not verapamil due to neg inotropic effect)
In those who respond, shown to improve 5 year survival.
No evidence in CTD-PAH as usually no reactivity
62
If first line therapy fails, what is indicated in class I PAH?
Sequential combo therapy - ERAs, prostanoids, PDE-5i or SGCS - if inadequate response on maximal therapy, consider BAS (balloon atrial septostomy) or referral to lung transplantation
63
What is the role of warfarin in PAH?
limited retrospective data showing improved survival.
recommended in IPAH, familial PAH, CTEPH
increased bleeding risk in SSc PAH
64
What is the MoA of prostaglandins in PAH?
Prostacyclin is potentiates cAMP in vascular smooth muscle and causes vavsodilation and antiproliferative effects.
Prostacyclin derivatives (prostacyclin, treprostini and iloprost) use this pathway.
65
What is the MoA of endothelin receptor antagonists in PAH?
prevent vasoconstriction by blocking endothelin A and B receptors on vascular smooth muscle cells - blocking vasoconstriction and proliferation
Bosentan, Macitentan (non-selective)
Ambrisentan (selective)
66
What is the MoA of pDE5 inhibitors in pulmonary hypertension?
NO produces vasodilation and inhibits proliferation.
Sildenafil and tadalafil both inbhit the breakdown of cGMP by phosphodiesterase 5, which is the target of nitric oxide in vascular smooth muscle
67
What are features of epoprostenol and prostacyclin in PAH?
Potent IV vasodilators
Increase IC cAMP
Inhibit plt aggregation
SEs - jaw pain, arthralgia, diarrhoea, CVC related complications.
Improves ETolerance, haemodynamics and survival at 1 and 5 years
68
What are features of treprostinil?
painful SC injection
| Improved 6MWT and survival, haemodynamics, ?survival
69
What are features of Illoprost?
Benefits: improved 6MWT, Functional class, QoL, dyspnoea
no change in haemodynamics, requires 6-12 inhalations a day due to short T1/2
70
What is selexipag?
prostacycline receptor agonist
limited data
addon therapy
improved haemodynamics, morbidity and mortality (combined endpoint)
71
What are examples of endothelin receptor antagonists?
Bosentan:
- A and B antagonist
- limited by hepatotoxicity
- improves 6MWT, functional class and symptoms
Ambrisentan
- selective endothelin A receptor antagonist
- less hepatotoxic
- ? worse ILD in IPF
- improved Sx, 6MWT, Functional class, PV haemodynamics, QoL
Macitentan
- endothelin receptor A+B antagonist
- nasopharyngitis and anaemia
- improves survival, WHO functional class and 6MWT
72
What are features of sildenafil?
increases intracellular concentration of cAMP and cGMP - pulmonary vasodilatation.
Improves haemodynamics, ET, WHO functional class, QoL
Mortality impact is unknown
73
What are features of Tadalafil?
Improves exercise capacity, and QoL
Delayed time to clinical worsening
Mortality impact unknown
74
What is the MoA and features of riociguat?
Vasodilator - stimulates soluble guanylate cyclase (sGC)
increased sensitivity of sGC to endogenous NO, and direct stimulator of NO receptor
Improves 6MWT, WHO functional class, symptoms and PVR
Similar benefits in CTEPH
Mortality impact unknown
75
What is the effect of combination therapy in PAH?
combination of epoprosteniol, bosentan and sildenafil leads to greater improvement on PVR vs epoprostenol or epoprostenol and bosentan alone
76
What is the role of lung transplantation in PAH?
indicated in pt with IPAH refractory to medical therapy
need preserved LV function
Severe RV dysfunction often improves
Higher rates of obliterative bronchiolitis in IPAH patients
3 year survival 50% in idioathic PAH
Atrial balloon septoplasty - balance between hypoxia and RHF, only in pts with severe RHF
77
What medications have been shown to improve survival in PAH?
Prostacyclin
Treprostinil
Bosentan (vs historical controls)
Macitentan (combined mortal/morbid)
78
What are the health effects of second hand smoke?
```
Increased heart disease
lung cancer
COPD
asthma exacerbations
SIDS
```
All cause mortality increased by 15% in non-smokers who live with smokers
79
What are predictors of dependence?
smoking within minutes of waking
| higher number of cigarettes smoked a day
80
What is the most powerful tool in reducing tobacco consumption?
price - 3-4% fall in consumption for every 10% increase in tobacco price
81
What is the most effective therapy for nicotine cessation?
varenicline - agonist antagonist to nicotine
23 vs 9% vs placebo
more effective than placebo, NRT and bupropion.
predominant Se is nausea 30% not dose dependent
Possible neuropsychiatric SEs including suicidal ideation
82
What are features of bupropion in smoking cessation?
Dopamine and norad reuptake inhibitor
at 12/12 significantly more patients ceased smoking vs placebo.
1/1000 risk of seizures
possible increase in suicidal ideation
83
What is the efficacy of counselling in smoking cessation?
increased length and number of sessions increases quit rates
| group = individual counselling
84
What are risk factors for primary pneumothorax?
```
Smoking #1 - RR from 7 - 102 depending on amount of smoking
FHx in 10%
Marfan's syndrome
Homocysteinuria
Throacic endometriosis
```
85
What are risk factors for secondary pneumothorax?
```
COPD responsible for 70%, increased risk with increasing obstruction
PJP - 30% will develop PTX
AIDS - 80% have had previous PJP infection
CF 6%
TB 6%
SSP more dangerous than PSP
Mortality 16%
>50% recurrence rate in COPD
```
86
What is the definition of a large PTX?
>2cm rim between lung margin at level of hilum.
| Size less important than Sx - CT more accurate than CXR
87
What is the relationship between spontaneous closure rates and primary and secondary pneumothorax?
Lower rates of primary closure in secondary spontaneous pneumothorax
88
What is the summary of BTS guidelines for PTX?
Small 2cm with dyspnoea.
small bore chest tube should be placed following any failed needle aspiration
89
What are risk factors for PTX recurrence?
```
Male sex
Tall
Low body weight
persistent smoking
emphysematous lung blebs
```
90
What are options for PTX?
Thoracotomy and pleurectomy - 1% recurrence
| VATS pleuradesis -
91
What are features of cylindrical bronchiectasis?
most common form
bronchi have uniform calibre
signet ring sign
tram track sign
92
What are features of varicose bronchiectasis?
relatively uncommon
| beaded appearance of bronchi
93
What are features of cystic bronchiectasis?
severe form
cyst like bronchi that can extend to the pleural surface
air fluid levels may be present
94
What is the cycle of bronchiectasis?
bacterial colonisation
inflammation
bronchial destruction
decreased airway clearance
95
What are causes of bronchiectasis?
```
post infectious
idiopathic
Primary ciliary dyskinesia
ABPA
immune defect
IBD
CTD (RA, Sjogren's)
Aspiration
Yellow nail syndrome
Obstruction/FB
Asthma
Congenital abn
Cystic fibrosis
A1AT deficiency
```
96
What are IX in bronchiectasis?
```
ABPA serology if asthma
Bacteria and myco culture sputum
Ig AEGM
Titres to pneumococcal vaccine
CF sweat test (2 x measurements)
CFTR mutation
ANA, RF, ACCP, SSA, SSB
A1AT level
consider bronchoscopy, GIT (IBD), nasal nitric oxide eval (1mary ciliary dyskinesia)
```
97
What are treatable causes of bronchiectasis?
```
CVID
ABPA
Infection (MAC)
Airway obstruction
IBD
RA
Aspiration
COPD (esp if FEV1
```
98
What are treatment strategies in bronchiectasis?
Airway clearance - neb agent, chest pthy, post drainage
Exercise program (improved 6MWT and exacerbations)
Sputum culture - treat non-pseudomonas, pseudomonas or NTM
Consider macrolide therapy if frequent exacerbations
99
What is the goal of antimicrobial therapy?
Treat patient, not sputum culture - unless 1st pseudomonas, in which case attempt eradication
Viral exacerbations common
Treat exacerbations - clinical Dx
100
What are proven therapies improving airway clerance?
PEP therapy - improved QoL, reduced cough/sputum, improved FEV1/FVC, reduced inflammatory markers
Nebulised hypertonic saline/mannitol
- improved bacteriology and QoL
DNAse potentially dangerous
No evidence for NAC
101
What is the rationale of macrolides in bronchiectasis?
Immunomodulatory and antibacterial effect (useful in >=2 exacerbations/year)
EMBRACE trial - found reduced exacerbation frequency in azithromycin three times/week.
No change in FEV1, no change in Sx based exacerbation, no change in colonisation, no change in QoL, temporary benefit
250mg dose showed reduced exacerbations, and increased AZI resistance and abdominal pain/diarrhoea
102
What must be performed before starting azithromycin therapy in bronchiectasis?
Sputum culture to exclude NTM colonisation
103
What are risk factors for QTc prolongation in azithromycin therapy?
```
existing QTc prolongation
Hx TDP
Hypo-K
Hypo-Mg
Significant bradycardia
Uncompensated HF
Treatment with quinidine, procainamide, amiodarone, sotalol
```
104
What is the outcome of erythromycin therapy in bronchiectasis?
reduced exacerbation frequency
reduced sputum volume
increased macrolide resistance
105
What are the most common pathogens in bronchiectasis?
1. H influenzae
2. moxarella catarrhallis
3. Pseudomonas aeruginosa (more rapid FEV1 decline)
4. S. aureus
5. Strep pneumonia
5. MAC
106
What is the method of pseudomonas eradication in bronchiectasis?
80% eradicated at 1st isolation
50% pseudomonas free at 14/12
Reduced exacerbation frequency
commence with cipro for 2 week, then if positive reculture - try IV Ab, further cipro and colisin inh, or colistin inh only
107
What is the role of steroids in bronchiectasis?
```
do not alter FEV1 rate of decline
ICD do not reduce exacerbation frequency
ICS may reduce sputum volume
? symbicort in reducing dyspnoea, cough and QoL
? atorvastatin in reducing cough and QoL
```
108
What are the three outcomes of Aspergillus infection of the lung?
Saprophytic - aspergilloma
Allergic - ABPA, HS pneumonitis
Invasive - invasive aspergillosis, chronic necrotising pulm aspergillosis, airway invasive aspergillosis
109
What proprotion of patients develop ABPA?
with asthma - 1-2%
2-15% of patients with CF (single CFTR mut increases risk)
Type 1 (immediate HS), type 3 (Ag-Ab complexes) and Type 4b (eosinophil rich inflammatory response)
Th2 predominant response
110
What are major and minor Dx criteria for ABPA?
```
Major (>=6 Dx)
asthma
fleeting pulmonary shadows
Positive skin prick test (type 1 HS)
Eosinophilia
Precipitating IgG Ab (aspergillus precipitans)
IgE >1000
Central bronchiectasis
RAST +Ve for aspergillus
```
Minor
Aspergillus in sputum
expectoration of brownish/black mucus plugs
delayed skin Rx to aspegillus (type III)
111
What is treatment of ABPA?
Oral steroids - induce remission during exacerbation
long term treatment does not prevent relapse.
slight increase in risk of invasive aspergillosis
Itraconazole - improves IGE but no impact on lung cuntion
limited evidence for Omalizumab
112
What are features of CF?
```
AR
1:20 heterozygote frequency
1:2000 homozygote frequency
CFTR gene >1300 mutations
deltaF 508 70% of cases
```
113
What is the diagnostic criteria for CF?
Require 2 Diagnostic criteria:
- Sx of CF in at least one organ system
- evidence of CFTR dysfunction - elevated sweat chrloride (60 raised)
- 2 disease causing CFTR mutations
- Abnomral nasal potentiate difference
98% are classic CF - organ plus sweat
2% non-classic
- normal or intermediate sweat choride
- single organ system involvement
- usually Dx in adulthood
- Lower incidence delta 508
- higher incidence of unusual mutations
114
What are classes of CFTR mutations?
Class I - absence of synthesis of CFTR
Class II -defective prot maturation - premature degradation, doesn't reach cell surface
Class III - disordered ion channel regulation - e.g. diminished ATP binding - non-functional protein
Class IV - defective chloride conduction - reduced ion channel function
Class V - reduced CFTR transcripts - reduced number of normal channels
Class VI - accelerated turnover from cell surface
Class I-III - more severe disease
115
What medical conditions are associated with CFTR mutation but do not meet CF criteria?
chronic rhinosinusitis
idiopathic bronchiectasis
Acute and chronic idiopathic pancreatitis
ABPA
congeintal bilateral absence of vas deferens
116
What are CF clinical syndromes?
Resp - S. aureus, haemophilus colonisation early, pseudomonal in 70%
Sinusitis in most - polyposis in 30%
Pancreatic disease - malnutrition, fat malabsorption - vit ADEK deficiency, pancreatic insufficiency in many
Distal ileal obstruction 15% (assoc with severe lung dz)
Biliary disease - mild hepatomegaly, rarely progressive fibrosis and portal HTN
Male infertility 95%
Female infertility 20% (2ndary amenorrhoea, malnutrition and thick cervical secretions)
CF arthropathy 2%
Osteoporosis
Recurrent venous thrombosis
Neprocalcinosis 90%
Nephrolithiasis 6%
117
What is the primary Ix for CF resp infections?
q3m sputum sampling and MCS
118
What are features of pseudomonas aeruginosa colonisation?
>70% of adults w CF are chronically infected with p. aeru
mucoid phenotype develops - biofilm formation, difficult to eradicate
uncommon in non-CF
non-mucoid type may be eradicated if treated early
mucoid associated with worse lung function
chronic azithromycin treatment may be beneficial
Ab susceptibility testing does not predict outcome in chronic infection
119
How is CF transmission reduced?
contact precautions for clinicians including mask
CF pts should wear masks in health care setting
should not congregate with other CF patients
>2m from other CF patients
single rooms for inpatient care
120
What are features of burkholderia cepacia complex in CF?
accellerated decline in lung function with chronic infection
usually MDR
worse outcomes with lung transplant
infection control measure important
121
What are features of NTM in CF patients?
MAC not associated with worse transplant outcomes
M abscessus associated with worse transplant outcomes
only treat NTM lf patients have clinical symptoms, worsening lung function or nodular infiltrates/cavitating disease
122
What is the rationale of Ab choice in CF?
base on previous sputum isolates
one antibiotic for each organism isolated
2 ab if possible for each gram negative isolated
Higher doses are required due to poor tissue penetration
no role for chronic/cyclical Ab
No role for routine tune up
123
What are the most common pathogens isolated in adults with CF?
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P. aeruginoa
S. aureus
MRSA
MDR-PA
S. maltophilia
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124
What is the role of ivacaftor in CF?
CFTR potentiator - only works in G551D mutation (defective channel opening)
4% of patients
increases chloride excretion and reduces excessive Na and fluid absorption
prevents airway dehydration and improves ciliary motility
Improved FEV1 in 7-10%
55% reduction in risk of exacerbation
Reduced hospitalisation
Weight gain
Not effective in delta f 508
125
What is the role of azithromycin in CF?
chronic azithromycin leads to improvements in FEV1
reduced exacerbations by 40%
decreased biofilm production
bacteriacidal on P aeruginosa
anti-inflammatory effect on cytokine production
