Cystic Fibrosis (Raf)

Question 1

CFSPID definition?

Answer 1

• CRMS and CFSPID are interchangeable terms for inconclusive diagnosis = Positive screen, but don’t have features of CF. These terms are specific for a newborn with an inconclusive diagnosis
• Ways to be in this category:
• Sweat chloride <30 and 2 CFTR mutations, 1 or which of uncertain significance
• Intermediate sweat chloride and 1 or 0 CF causing mutations

Question 2

reasons for osteopenia in CF?

Answer 2

• malnutrition
• fat malabsorption due to pancreatic insufficiency leading to vitamin D deficiency
• low weight bearing exercise
• delayed puberty
• hepatobiliary disease
• chronic corticosteroid use
• severity of lung disease

Question 3

How should patients with CF be screened for osteopenia?

Answer 3

DXA scan in ALL adults and children starting at 8 years of age or older if:

• Weight is <90% of ideal body weight
• FEV1<50%
• Glucocorticoids >=5 mg/kg/day for >=90 days/year
• Delayed puberty
• History of fracture
• (Practically, I think all kids >8 years of age get a DXA scan)
• If the above criteria isn’t met, then you would do DXA at 18 years of age

Question 4

CF patient with osteopenia. When should you consult endo?

Answer 4

When DXA is more than 1 standard deviation below the mean

Question 5

for CF, how often should DXA be completed if bone density is within 1 standard deviation of the mean?

Answer 5

Within 1 standard deviation is best case scenario–>CF guideline says every 5 years.
(If more than 1 standard deviation below the mean, then you repeat testing every 1-4 years)

Question 6

What is the incidence of CF?

Answer 6

1/3500 (Kendig’s)

Question 7

Describe pathogenesis of CF

Answer 7

• Main problem is in CFTR, which is cAMP regulated Cl AND HCO3 channel. This channel is on the apical surface.
• Normally, Cl is secreted through the channel and water follows chloride to increase airway surface liquid volume. CFTR downregulates ENAC channels to prevent Na reabsorption. HcO3 normally goes through the CFTR channel and is important for antimicrobial proteins in the airway.
• Problems in CF:
• impaired secretion of chloride
• upregulation of ENAC–>increased Na reabsorption
• The above cause decreased airway surface liquid volume, so the surface liquid will more difficult to clear via mucociliary clearance–>secondary infection
• Lack of HcO3 secretion will inactive antimicrobial proteins on the airway
• Other things that affect mucous texture:
• Since CFTR is expressed on the submucosal glands, there is abnormal production of mucous
• Inflammatory response out of proportion: Neutrophil products like DNA will also contribute to mucous thickness
• So combination of infection (due to changes in airway surface liquid) + overzealous immune response

Question 8

What are the benefits of hypertonic saline and it’s level of evidence recommendation?

Mechanism of hypertonic saline?

Answer 8

• Short term improvement in FEV1 of 3.44-5%, but one trial showed no difference in lung function at 48 weeks. That being said, some studies have shown improvement in FEV1 at 48 week by 68 mL or 3.2% (as per last year’s group answer)
• Reduce exacerbations in children >6 years of age
• Improves mucociliary clearance in children with mild lung disease
• Improvement in lung clearance index in preschool children (<6 years of age) (SHIP)
• Hypertonic saline is recommended for use in all stages of lung disease, but with a grade B recommendation, so lower than the grade A recommendation for use of pulmozyme in moderate to severe lung disease

Mechanism: osmotic agent, increases airway surface liquid, decreases mucous viscosity, improves mucociliary clearance

Outcomes at 1 year of use: improved FEV1, improved FVC, decreased pulmonary exacerbations by 66%–>so makes sense to consider hypertonic in patients with declining lung function, exacerbations

Question 9

What are adverse effects of hypertonic saline?

Answer 9

• Cough
• Bronchospasm
• G tube dislodgement or rupture

(No effect on pseudomonas colonization)

Question 10

What are the evidence based benefits of pulmozyme?

Answer 10

Mechanism: cleaves DNA (which is present in CF mucous due to neutrophils) and thereby decreases sputum viscosity

• 5.8% improvement in FEV1 over 6 months
• Decreased pulmonary exacerbations
• Not enough evidence to conclude if dornase alpha is better than other inhaled therapies

Question 11

Side effects of pulmozyme?

Answer 11

• Rash
• Voice alteration
• sore throat
• laryngitis
• chest pain

Question 12

For a newborn diagnosed with CF, how soon should they be seen at a CF centre?

Answer 12

Within 24-72 hours of diagnosis (1-3 days)

Question 13

Pancreatic enzyme replacement therapy dosing for infant? Can a generic pancreatic enzyme be used?

Answer 13

2000-5000 lipase units/feed to a maximum of 2500 U/kg/feed, maximum of 10,000 lipase units/kg/day

No, generic PERT cannot be used

Question 14

Which infants should be started on pancreatic enzyme replacement therapy?

Answer 14

• 2 CFTR mutations associated with pancreatic insufficiency
• Evidence of fat malabsorption: fecal elastase <200 (>300 is sufficient) microgram/gram or coefficient of fat absorption<85%
• Unequivocal signs of fat malabsorption, while awaiting confirmatory testing.

Of note, an infant with 1 pancreatic sufficient mutation does not need to be started on PERT upfront, unless criteria 2 or 3 above are met.

Question 15

For infants with CF, what type of feed is recommended?

Answer 15

• Preferred feed is human milk

- Next preferred: standard formula (no need for hydrolyzed formula upfront)

Question 16

For infants with CF, when is vitamin supplementation with A, D, E, K started?

Answer 16

• shortly after diagnosis

- vitamin levels should be checked 2 months after supplementation started and then annually

Question 17

What are the maintenance of health recommendations for infant newly diagnosed with CF?

Answer 17

Nutrition:

• Encourage breastfeeding
• Pancreatic enzyme replacement therapy, if indicated
• Vitamin A, D, E, K (shortly post diagnosis; newly diagnosed infants can actually have low levels of fat soluble vitamins and some of these, like vitamin E, are important for cognitive development)
• Salt supplementation 1/8 teaspoon daily, increased to 1/4 teaspoon daily at 6 months of age. Infants in hot climate, having vomiting or diarrhea will require more sodium supplementation. (If the serum sodium is actually low, then they have significant total body sodium depletion)

Respiratory:

• Important to be clear with families that even though there’s no obvious respiratory symptoms, there are changes in the lung early in life.
• Airway clearance should start in first few months of life. Ventolin b/f airway clearance with percussion and postural drainage, but the head down position should not be used.
• Smoke free environment
• Influenza vaccine patient and household contacts at >=6 months of age
• RSV vaccine: CF Foundation provides a “low quality” recommendation for consideration of RSV vaccine. But CPS RSV statement does not endorse the vaccine routinely for infants with CF
• Baseline CXR in first 3-6 months and again within first 2 years of life
• Oropharyngeal cultures: four times per year. First sample at first or second visit
• Frequency of follow up: every 1 month for first 6 months, every 1-2 months after 6 months of life
• Do initial baseline labs for everything, including vitamins within first 2-3 months of life

Use of step up pulmonary therapy:

• You can use pulmozyme and hypertonic saline in symptomatic infants, but insufficient evidence for routine use
• Insufficient evidence to recommend for or against chronic azithro in infants with chronic Pseudomonas (in contrast to older children)

Interesting:

• Insufficient evidence to recommend for or against eradication of MSSA or MRSA in asymptomatic infants
• Do not recommend prophylactic use of anti-staphylococcal antibiotics in asymptomatic infants

Question 18

In the care of infants with CF, why is there such a strong emphasis on growth?

Answer 18

• Not only do many infants have an obvious reason for poor growth (pancreatic insufficiency in 60% at birth and 90% by end of first year of life), but growth in infancy correlates with lung function in childhood
• The goal is “normal” growth
• Higher BMI at 2 years of age is associated with better lung function in childhood
• Ideal is 50th percentile weight for length status at 2 yars of age (that being said, there seems to be more focus on making sure the child is reaching their intrinsic growth potential)

Question 19

Infant with CF who is not growing well. Differential?

Answer 19

• Inadequate intake
• Undiagnosed pancreatic insufficiency–>repeat fecal elastase
• Inadequate PERT dose, expired enzyme, chewing enzyme, incorrect administration
• PPI (I think too much acidity will decrease efficacy of PERT)
• Could there be another diagnosis like celiac, C. diff
• Hyponatremia
• GERD, constipation, iron deficiency
• Consider zinc supplementation if adequate intake and PERT dose. With fat malabsorption, there can be fecal loss of zinc. Serum zinc level is not a good marker of zinc sufficiency
• infant with poor weight gain should be seen every 2-6 weeks

Question 20

What type of electrolyte abnormality are infants with CF prone to?

Answer 20

• Hypochloremic, hyponatremic, hypokalemic metabolic alkalosis
• dehydration

Occasionally, individuals with CF may develop subacute or chronic hypovolemia with hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis (sometimes known as pseudo-Bartter syndrome) [74]. In contrast with Bartter syndrome, urinary chloride excretion is low. (See “Bartter and Gitelman syndromes”.)

This condition is caused by excessive loss of sodium and chloride in sweat and may develop in CF patients with inadequate sodium intake. Infants are particularly at risk because the salt content of breast milk or infant formula may be insufficient, and sodium supplementation is required. Occasionally, this is a primary presenting feature of CF

Question 21

Health maintenance recommendations for preschooler with CF?

Answer 21

Vaccines:
* Pneumococcal polysaccharide (PPSV23, also known as pneumovax) at 8 weeks after pneumococcal conjugate (Prevnar = pneumococcal conjugate 13) vaccine –>practically, most preschoolers will have gotten their last dose of Prevnar at 12 months of age. The pneumococcal polysaccharide vaccine starts at age 2 years.

CXR every other year at minimum to monitor progression of lung disease

Hypertonic and saline pulmozyme are selectively, as opposed to routinely, offered

Growth target:

• BMI>=50%
• Weight for age>=10%
• Blood level fo fat soluble vitamins measured annually
• Addition of salt to meals/snacks, especially during summer months and in warm climates
• Annual evaluation for pancreatic insufficiency
• If terminal ileum bowel resection, then annual measurement of B12 (I imagine this would be in the case of meconium ileum

Question 22

Indications for lung transplant in a pediatric patient with CF?

Answer 22

Reasons to refer for lung transplant evaluation:
* Markers of shortened survival:
* 6 minute walk <400 metres
* Hypoxemia - at rest or exertion—>overnight oximetry
* Hypercarbia - PaCO2>50 on arterial blood gas
* Pulmonary hypertension
* FEV1<50% and rapidly declining (>20% decline within 12 months)
* FEV1<50% with markers of shortened survival stated above, as well as the markers of shortened survival in 12-16 below, which include:
* >2 exacerbations per year requiring IV antibiotics or 1 exacerbation requiring PPV, regardless of FEV1
* Massive hemoptysis (>240 mL) requiring ICU admission or bronchial artery embolization
* Pneumothorax
* Adults with BMI<18, <5% (I think you would consider this in kids as well)
* FEV1<40%
Although there are the above criteria, groups that could be referred even if the above criteria are not strictly met:
* young females
* individuals with short stature (height <162 cm)
* these guidelines are based on the idea that you want to refer early enough to avoid to avoid missing transplant window or such that you can refer to another centre if first centre declines

Question 23

When should you initiate a conversation about lung transplant with a CF patient? What should you try and optimize during that time?

Answer 23

FEV1<50% –>CF care team should initiate a discussion about lung transplant

Things to work on:

• Nutrition since BMI<5% is a modifiable contraindication to lung transplant
• CF related diabetes–>poor control results in weight loss, poor lung function, more exacerbations
• Psychosocial, mental health, substance use
• (Treatment for organisms like M. abscessus, which may affect candidacy for transplant - this was just me thinking)
• Physical conditioning
• Adherence
• At least annually, need to get 6 minute walk test, blood gas, echo, likely overnight oximetry (it’s only hypoxemia at rest or with exertion, which is considered a marker of shortened survival. I think this would be measured during 6 minute walk test)

Question 24

Median survival post lung transplant for CF?

Answer 24

9.5 years

Question 25

Which micro-oraganisms may impact the ability of a CF patient to receive lung transplant?

Answer 25

* Burkholderia cepacia complex: cenocepacia, gladioli, dolosa * nontuberculous mycobacteria: Mycobacterium abscesuss * molds like Scedopsorium prolificans

Question 26

What does the main CF guideline say about B2 agonist use?

Answer 26

They say insufficient evidence to recommend for or against use. (I presume this is in relation to their use with chest physio); this is consistent with the 2016 preschool statement. (The infant guideline is older and still recommends use of ventolin before chest physio). Practically, I wouldn't push this with patients.

Question 27

What are inhaled anti-pseudomonal antibiotics? Which ones are preferred?

Answer 27

- Tobramycin -->we generally start with torbamycin - Aztreonam (cayston) -->this is often the next antibiotic we go to if tobramycin is not tolerated or if want to add in another alternating monthly antibiotic. Of note, the only inhaled antipseudomonal antibiotics recommended by the CF foundation are tobramycin and aztreonam so it makes sense that these are the first 2 choices. - Colistin - Quinsar (levofloxacin)

Question 28

What is the CF foundation's recommendation re: pulmozyme? What is their recommendation for hypertonic saline? With respect to individuals >6 years of age How does the recommendation for these drugs change in infancy versus preschool versus school age above guidelines?

Answer 28

They have a strong recommendation for use of pulmozyme in moderate to severe lung disease. They have a moderate recommendation for it's use in mild lung disease. They provide a moderate recommendation for hypertonic saline use in all severity of lung disease. With respect to age related changes in this recommendation: Infancy (<2 years of age): pulmozyme and hypertonic in symptomatic infants Preschool (2-5 years): they don't recommend that everyone use pulmozyme and hypertonic, but they say it should be used based on individual circumstance >=6 years of age: they make a moderate recommendation for asymptomatic/mild lung disease to use hypertonic or pulmozyme. They make a strong recommendation for children with moderate to severe lung disease to use pulmozyme

Question 29

What are the CF Foundations recommendations for use of azithromycin?

Answer 29

- They make a moderate recommendation for it's use in patients with chronic pseudomonas (I would define chronic pseudomonas as 1 year of colonization, as based on the RCT) -->improves lung function and decreases exacerbations - they recommend it's use in patients without chronic pseudonomas, though less of a strong recommendation (grade C recommendation). In these patients, you are using azithromycin to decrease exacerbations. - Key point: sputum culture for NTM at baseline, 6 months and 12 months. If culture is positive for NTM, then stop azithro Leed's criteria for defining chronic pseudomonas: One of the most commonly used definitions in CF research are the Leeds criteria [7]. These criteria define “chronic P. aeruginosa infection” as > 50% of months with cough swabs/sputum cultures in the preceding 12 months that were positive for P. aeruginosa

Question 30

Indications for Ivacaftor? Outcomes for use of ivacaftor? Side effects of ivacaftor?

Answer 30

Need one copy of class 3 OR 1 of the class 4 mutations (R117H+5T) - G551D - non-G551D gating mutations (G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) R117H mutation (+5T since 5T is the one that is pathogenic) - Age of indication: 12 months and above (Canada). For U.S.: 6 months and older. Outcomes: - Improve FEV1 by about 10%. Start noticing this difference by 2 weeks - Decreased exacerbations - Improved sweat chloride - Decrease pseudomonas burden - Improved weight gain - Using LCI, they have been able to show benefits even for individuals with mild disease - In preschool children: improvements in sweat chloride, fecal elastase, but some increased transaminases Side effects: Side effects of ivacaftor: liver enzyme elevation and cataract are serious side effects-->eye exam before starting therapy and then periodically

Question 31

Is aerobic exercise a substitute for airway clearance?

Answer 31

No, it is adjunctive but not a substitute

Question 32

Which type of airway clearance is recommended?

Answer 32

- Recent Cochrane Review which compared different methods of airway clearance: neither was superior in terms of FEV1, but PEP was superior for decreased number of exacerbations. CF foundation guideline (which is old, from 2009) does not endorse a specific type of airway clearance. - Cochrane review in 2014: oscillatory PEP was equivalent to PEP - RCT in Canada in 2013 looking at PEP versus vest (HFCC = high frequency chest wall compression) -->no difference in lung function, but PEP was better in terms of number of exacerbations and time to first exacerbation

Question 33

How does PEP work?

Answer 33

With the PEP device, there is normal inhalation, but there is resistance during exhalation, which results in the creation of back pressure (positive expiratory pressure) - Create a PEP of 10-20 cm H20 for 12-15 breaths - This results in build up of gas pressure behind mucous through collateral ventilation (pores of Kohn, cannals of Lambert) - This positive pressure also stents the airway open, preventing premature closure, enabling movement of mucous - Through forced expiratory maneuvers (eg. huffing), the mucous can be moved from peripheral to central airways. Coughing maneuvers enables expectoration of mucous - Recent Cochrane Review which compared different methods of airway clearance: neither was superior in terms of FEV1, but PEP was superior for decreased number of exacerbations. CF foundation guideline (which is old, from 2009) does not endorse a specific type of airway clearance. Side effect: hemoptysis, nausea

Question 34

Diagnostic criteria for a classic case of ABPA in CF?

Answer 34

There are 5 criteria: - Acute or subacute clinical deterioration that is not attributable to another etiology - Total serum IgE > 1000, unless they are receiving systemic steroids. (Check IgE when patient is off steroids) - Positive IgE antibody to A. fumigatus or immediate cutaneous hypersensitivity to aspergillus - Precipitating antibody to A. fumigatus or serum IgG to A. fumigatus (this is practically difficult to accomplish) - New or recent infiltrate (or mucous plugging) on CXR or CT, which does NOT respond to antibiotics and standard physiotherapy - Need to meet all 5 criteria for classic ABPA (The ISHAM definition of ABPA is similar for asthma and CF, except for the lower IgE threshold for CF. The ISHAM criteria also includes eosinophilia (>500 cell/microL for CF)

Question 35

Minimal diagnostic criteria for ABPA?

Answer 35

- Acute of subacute clinical deterioration that is not attributable to another etiology - Total serum IgE > 500, unless they are receiving systemic steroids. (Check IgE when patient is off steroids) - Positive IgE antibody to A. fumigatus or immediate cutaneous hypersensitivity to aspergillus - One of: - Precipitating antibody to A. fumigatus or serum IgG to A. fumigatus (this is practically difficult to accomplish) - New or recent infiltrate (or mucous plugging) on CXR or CT, which does NOT respond to antibiotics and standard physiotherapy - So 4 criteria for minimal diagnostic criteria

Question 36

Difference between classic and minimal diagnostic criteria for ABPA in CF?

Answer 36

- Total IgE threshold of 1000 versus 500 - For the last 2 criteria (precipitating antibody/IgG A. fumigatus or imaging findings)-->need both for classic ABPA, but only 1 for minimal ABPA

Question 37

What are the imaging findings of ABPA?

Answer 37

- opacities, which can be fleeting - gloved finger shadow from mucous impaction - Tram line shadow - high attenuation mucous on CT --pathognomonic - central upper lobe saccular bronchiectasis - tree in bud, centrilobular nodules

Question 38

Pre-flight evaluation for patient with CF?

Answer 38

- spirometry - hypoxic challenge test if FEV1<50% - if saturation <90% on hypoxic challenge, then arrange for supplemental oxygen - if they had a pneumothorax, wait for 2 weeks post radiologic resolution, though they are increased risk for pneumo (if no definitive surgical management)

Question 39

Maximum dose of PERT?

Answer 39

10,000 U/kg/day or 2500 U/kg/meal

Question 40

Diarrhea in spite of adequate PERT?

Answer 40

- chewing enzymes - expired enzymes - enzymes at end of meal - hyperacidity (consider PPI) - small bowel bacterial overgrowth, C. dif - fibrosing colonopathy (CF related liver disease)

Question 41

Manifestations of CFRLD?

Answer 41

- Neonatal cholestasis - Cirrhosis - which could be focal biliary or multilobular. Interestingly focal biliary cirrhosis often starts in the pediatric years, can be asymptomatic without liver enzyme elevation or hepatomegaly. - Steatosis - Noncirrhotic portal hypertension

Question 42

How often are CF patients screened for NTM?

Answer 42

- Annually with a culture based method of sputum | - Oropharyngeal swab should not be sent (less reliable)

Question 43

If a CF patient on chronic azithro tests positive for NTM, what do you do?

Answer 43

- Stop azithro, while you are working them up for NTM disease (you may be partially treating with azithro monotherapy and causing resistance)

Question 44

How is M. abscessus treated?

Answer 44

Intensive phase: - Oral macrolide (ideally azithro) + 3-12 weeks of IV amikacin and one or more of: IV tigecycline, imipenem or cefoxitin (ABS needs CIT-ups) Continuation phase: - Oral macrolide (ideally azithro) - Inhaled amikacin - 2-3 of these oral antibiotics: minocycline, clofazamine, moxifloxacin, linezolid (guided, but not directed by susceptibility testing) - remember mmlc

Question 45

Can monotherapy for NTM?

Answer 45

No, similar to TB, it's pretty intensive to treat NTM

Question 46

How is M. avium complex pulmonary disease treated?

Answer 46

If clarithromycin sensitive, then treat with oral antibiotics: REA - rifampin, ethambutol, azithromycin ○ Treatment in CF patient with macrolide resistant MAC, systemically ill, AFB smear positive, or cavitary lesion on imaging: ○ 1-3 months of amikacin at the start of the treatment course, along with standard 3 oral antibiotics duration of treatment: 12 months beyond culture conversion. Culture conversion = negative culture x 3, first negative is time of culture conversion, as long as no positives (same treatment duration for M. abscessus) Practically, culture conversion itself would take a few months, so would probably end up treating NTM (abscessus or avium) for 15-18 months

Question 47

When should you consider IV amikacin for M. avium?

Answer 47

If one or more of the following signs of a more severe infection: - AFB smear positive respiratory tract samples - Radiological evidence of lung cavitation or severe infection - Systemic signs of illness - Macrolide resistance (mentioned in kendig's, but not CF guideline)

Question 48

How long is NTM treated for?

Answer 48

For 12 months after culture conversion (3 consecutive negative cultures, with date of conversion being the first culture), as long as there are no positive cultures

Question 49

How to monitor patients on NTM treatment?

Answer 49

- Expectorated or induced sputum samples every 4-8 weeks - Monitor for drug toxicity: hearing loss, vision loss, renal impairment, liver function abnormalities - HRCT scan before starting treatment and at end of treatment

Question 50

What sort of monitoring is required for IV amkacin or streptomycin?

Answer 50

These are both aminoglycoside antibiotics so need to monitor serum levels - risk of ototoxicity and nephrotoxicity

Question 51

Is persistent M. abscessus orM. avium in a patient with CF an absolute contraindication to transplant?

Answer 51

No, but ideally want to complete treatment successfully before listing for transplant

Question 52

Does finding NTM in CF patient's sputum mean they have NTM disease?

Answer 52

Probably not. The more pathogenic bacteria are Pseudomonas aeruginoa and Staph aureus. In most Cf patients with this finding, the positive culture could be transient or not associated with worsening dissease

Question 53

Which is worse for CF patient with NTM disease, abscessus or MAC?

Answer 53

Abscessus is worse since more intense clinical worse, intense therapy and hard to eradicate, may have implications for lung transplant

Question 54

Diagnostic criteria for NTM disease?

Answer 54

Need to have all of the following clinical criteria: - pulmonary symptoms - Radiology: CXR showing cavities or nodules OR CT showing multifocal bronchiectasis with multiple small nodules. Basically, at minimum, you need to have nodules. - Exclusion of other diagnoses Microbiologic criteria: need to have one of the following: - positive culture from 2 separate sputum samples (This really important to remember from CF patients, it has to be the same NTM species that is isolated) - positive culture from 1 BAL or wash (1 BAL as opposed to 2 sputum samples) - (last criteria is complicated and refers to biopsy related features along with culture)

Question 55

side effects of: - amikacin - tigecycline - cefoxitin - azithromycin - ethambutol - linezolid - rifampin

Answer 55

Amikacin: nephrotoxicity, ototoxicity Tigeclycine: nausea, vomiting, diarrhea, pancreatitis, hepatitis, hypoproteinemia Cefoxitin: fever, rash, eosinophilia, cytopenia Azithromycin: nausea, vomiting, diarrhea, prolonged QT, auditory/vestibular toxicity Ethambutol: optic neuritis, peripheral neuropathy - Linezolid: optic neuritis, cytopenia, peripheral neuropathy - rifampin: cytopenia, hepatitis, orange coloration of secretions, renal failure

Question 56

What is the most common co-morbidity in CF?

Answer 56

CF related diabetes

Question 57

Bad outcomes of CFRD?

Answer 57

Associated with lower survival, poor nutrition and faster lung function decline

Question 58

What is the gold standard screening test for CFRD?

Answer 58

2 hour (75 gram) Oral glucose tolerance test | This is contrast to type 1 diabetes, which is screened using fasting glucose or HbA1c

Question 59

At what age does screening for CFRD start?

Answer 59

>=10 years of age

Question 60

Is HbA1c recommended as a screening test for CFRD?

Answer 60

No

Question 61

When is self monitoring of blood glucose measurement recommended?

Answer 61

- During a pulmonary exacerbation where patients are either admitted for exacerbation, for IV antibiotics or systemic steroids-->for first 48 hours, pre and 2 hour post prandial BG measurement - For patients who are chronically on continuous enteral feeds, then do a mid and post glucose measurements. Measurements should be done when feeds are initiated and then monthly. (doesn't specify if it's overnight versus daytime, but it's probably usually overnight continuous feeds)

Question 62

Diagnostic criteria for CFRD?

Answer 62

- Same definitions as for diabetes in general. In a period of stable health: - Fasting glucose >= 7 - 2 hour oral glucose tolerance>=11.1 - HbA1C >=6.5 (but note HbA1c is often low in CF and can have normal HbA1c and still have CFRD) - All of the above need to confirmed on another day (total of 2 separate occasions) before you make a diagnosis in patient with acute illness: - persistence of fasting or post-prandial hyperglycemia (as defined above) after first 48 hours of illness-->so just finding abnormalities in the first 48 hours would not be enough to make a diagnosis. You would need to continue monitoring beyond first 48 hours.

Question 63

Patient with CF who has positive oral glucose tolerance test?

Answer 63

CF guideline advises repeating a positive test on a separate day to confirm the diagnosis, unless overt signs of hyperglycemia (polyuria, polydipsia) or random glucose >=11.1 (This would be the same for an elevated fasting glucose or elevated HbA1C) (I'm not sure if this happens in practice)

Question 64

What is preferred management agent for CFRD: insulin or oral hyperglycemic agents?

Answer 64

- Insulin is recommended | - Oral agents are not advised

Question 65

CF patient with diabetes on insulin. How often should they check BG?

Answer 65

checking at least 3 times daily

Question 66

In patient with CFRD, how often is HbA1c monitored and what is target?

Answer 66

monitored 4x per year, goal is <7%. (So HbA1c is not used for diagnosis since it's not sensitive enough, but it is used for follow up)

Question 67

How do you monitor for complications of CF related diabetes?

Answer 67

- BP measurement at every visit - start monitoring for microvascular complications annually (eg. retinopathy, nephropathy, neuropathy, diabetic foot) at 5 years post diagnosis

Question 68

What is an impaired glucose tolerance test?

Answer 68

Normal fasting glucose (<7), but 2 hour OGTT: 7.8 to <11.1

Question 69

Side effects of aminoglycosides? How to minimize side effects?

Answer 69

- Ototoxcicity - Nephrotoxicity - Extended interval dosing (once daily) as opposed to tid dosing-->lower basal level-->this is recommended by CF foundation and cochrane review (2016) showed no difference in FEV1, FVC with less nephrotoxicity in children

Question 70

CF and neutrophils. What are the key cytokines?

Answer 70

IL1, IL8, TNF alpha, LeukotrieneB4 IL6 IL8 - very important since it attracts neutrophils and activates them IL1B and TNF alpha also attract neutrophils and activate them (I think you could say either IL1 or IL1B for this answer) (I think I would pick IL8 as my preferred answer) Recall: Cytokine is a general term used for all signalling molecules while chemokines are specific cytokines that functions by attracting cells to sites of infection/inflammation - I would put the same cytokines whether this question is for CF or for asthma - IL17 and 22 are also important for neutrophil activity, I think I would go with IL17 if the question is about pseudomonas

Question 71

CF Foundation guideline recommendation re: use of beta agonist for maintenance of lung health?

Answer 71

Insufficient evidence to recommend for or against

Question 72

Causes of false positive sweat chloride?

Answer 72

Endocrine: hypothyroidism, hypoparathyroidism, adrenal insufficiency, pseudoaldosteronism, nephrogenic DI Malnutrition HIV Skin: eczema, ectodermal dysplasia Metabolic: G6PD, glycogen storage disease type 1

Question 73

Causes of false negative sweat chloride?

Answer 73

``` Edema Malnutrition Hyponatremia Insufficient sweat quantity Dilution ```

Question 74

Timing of sweat chloride in newborn?

Answer 74

>2 kg (Kendig's and CF guideline) >36 weeks (Cf guideline) >2 weeks (Kendig's, CF guidelines technically says >10 days) (do sweat chloride as soon as possible after these criteria are met since there's risk of hyponatremia dehydration so want to start therapy promptly; that being said can start therapy presumptively without confirmation of diagnosis)

Question 75

Treatment of ABPA in CF?

Answer 75

1st = steroids -> Prednisone 0.5-2mg/kg.day 1-2 weeks then taper within 2-3 mosthis is directly from CF guideline 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

Question 76

Describe the 6 classes of CF mutations

Answer 76

Class 1: no protein -->unable to translate protein because of premature stop codon or frameshift mutation Class 2: no traffic-->lack of proper protein folding results in endoplasmic reticulum degredation. Ex: F508del: loss of phenalaline at codon 508 causes misfolding of CFTR, since phenalaline was located at the first nucleotide binding fold. Misfolded proteins is noted by chaperones and get degradation of protein Class 3: no function -->protein trafficing and gets to cell surface, but defective channel gating b/c ATP isn't able to bind properly. For CFTR to be active, ATP has to bind to the ATP binding domains. In class 3 mutations, there is a problem with the ATP binding. Many of these mutations are “gating” variants, eg. G551D (glycine at codon 551is replaced with asparitic acid) Class 4: less function. chloride conduction properties of CFTR are altered, which affects the magnitude of effect of the channel and ion selectivity. So overall, the channel is less functional. This leads to a milder phenotype. Eg. R117H +5T Class 5: decreased number Class 6: less stable Class 4, 5 and 6 cause a milder phenotype Class 1, 2 and 3-->classic CF

Question 77

What is ivacaftor? What is lumacaftor? | Indications for orkambi? Outcomes of orkambi and side effects?

Answer 77

``` Ivacaftor = kalydeco = gating potentiator Lumacaftor = protein corrector -->using this by itself for patients with class 2 mutation doesn't provide much benefit. But when combined with ivacaftor, it's beneficial--->orokambi ``` Orokabmi: - must have 2 copies of delta F508 - age of indication: 2 years of age and older (both FDA and health canada) Outcomes: - 3-4% improvement in lung function - decreased exacerbations Side effects: bronchospasm, dyspnea, hypertension

Question 78

What does symdeko contain? Indication and age of approval? Side effects?

Answer 78

Symdeko = tezacaftor (corrector) + ivacaftor (potentiator) Indication: - 2 copies of DF508 or - 1 copy of a residual function mutation (that was tested)--these are generally class 4, 5 or 6 mutations - Age of approval: 6 years and up - Slightly more effective than orokambi (uptodate), less side effects (no chest tightness, bronchospasm, dyspnea or wheezing which has been reported with orkmabi) less drug interactions (since there is no lumacaftor, which is a CYP3A inducer, there isn't faster metabolism of CYP3A metabolized drugs) Benefit: - improvement in FEV1 by 4%, which is comparable to the benefit given by pulmozyme and hypertonic saline Side effects: - elevation of liver enzymes, so these should be periodically monitored

Question 79

What is triple therapy and indications?

Answer 79

Trikefta = tezacaftor + ivacaftor + elexacaftor (so 2 correctors and 1 potentiator) Indications: - must have 1 copy of DF508 and ages 12 and up

Question 80

For patients with a class 2 mutation, why does a corrector (eg. lumacaftor, tezacaftor) have to be used with a potentiator?

Answer 80

- when lumacaftor is used by itself on patients with DF508, only 1/3 of the structrurally normal protein reaches the cell surface -->no significant improvement in sweat chloride when lumacaftor is used by itself - there's probably both a gating problem and a traffiking problem for class 2 mutations - when lumacaftor and ivacaftor are used together: - 3-4% improvement in lung function - decreased exacerbations

Question 81

Which classes of medication interact with ivacaftor?

Answer 81

- Ivacaftor is broken down by CYP3A - Drugs that induce/increase activity of CYP3A will cause decreased ivacaftor levels: carbamazepine (tegretol), phenobarb, phenytoin, rifabutin, rifampin, st. john's wart -->no recommended to use these medications with ivacaftor. - Drugs that decrease/inhibitor activity of CYP3A will cause higher ivacaftor levels: azoles (eg. itraconazole, voriconazole), macrolides, clarithromycin, erythromycin, fluconazole -->need to dose adjust the ivacaftor - In general, if patients have liver impairment or on CYP3A inhibitor then you may dose adjustment

Question 82

What follow up monitoring is required for patients on ivacaftor?

Answer 82

- Liver enzymes before starting treatment, every 3 months for the first year, then annually. Interrupt a dose if liver enzymes are more than 5x upper limit of normal - Optho exam before starting therapy and follow up (they don't specify frequency of follow up exams)

Question 83

What are important drug interactions to note with orkabmi?

Answer 83

- Similar to ivacaftor, don't give it with a strong CYP3A inducer b/c then there will be decreased levels of ivacaftor - Drugs that are metabolized by CYP3A may need to be dose adjusted because lumacaftor lumacaftor is also a CYP3A inducer so there can faster clearance of these drugs: - Decreased effectiveness of hormonal contraception so need to use a back up form of contraception - Don't use orkambi in patients on immunosuppresive drugs like cyclosporine, sirolimus, tacrolimus - gastric acid blockers, anti-inflammatory, antidepressants may need to be dose adjusted - avoid in patients with advanced liver disease

Question 84

Which cytokine is associated with pseudomonas on BAL?

Answer 84

IL17 --->involved with proinflammatory gene expression and is more involved with established CF lung disease

Question 85

What is the recommendation for eradication of pseudomonas? Describe some of the trials that led to this recommendation.

Answer 85

CF Foundation guideline: - inhaled tobramycin 300 mg bid x 28 days (they don't specify if it's inhalation solution or what to do if patient is symptomatic) Elite trial: 28 days of tobramycin is as beneficial as 56 days for eradication of pseduomonas Epic trial: addition of cipro to inhaled tobra did not provide additional benefit Optimize trial: addition of azithro 3x/week to tobra decreased subsequent risk of pulmonary exacerbation Toronto protocol: - approach depends on if symptomatic or asymptomatic - symptomatic: IV antibiotics + 28 days of TIS. If still positive, then either TIS (tobramycin inhalation solution) or IV antibiotics + TIS. If still positive, then chronic maintenance therapy - Asymptomatic: TIS -->TIS again if still positive-->IV antibiotics + TIS if still positive - TIS was 300 mg/5 mL - IV antibiotics = ceftaz and tobra - Sputum cultures were repeated 1 week after cessation of therapy

Question 86

What is the typical maximum enzyme dose? | What enzyme dose is associated with fibrosing colonopathy?

Answer 86

10,000 U/kg/day or 2500 U/kg/meal or 4000 U/g of fat-->maximum daily dose (there's a huge window before you reach the dose for fibrosing colonopathy) Fibrosing colonpathy: >50000 U/kg/meal (typically enzymes are dosed as units of lipase per gram of fat, but can dose per kg if parents aren't able to judge fat content in food)

Question 87

Reasons for ongoing bulky stool in spite of taking pancreatic enzymes?

Answer 87

- expired - chewing the enzymes (this will deactivate the enzyme) - taken inappropriately such as at the end of meal - hyperacidity→giving a PPI will decreaes the pH in the intestine and help absorption. The enzymes are better absorbed in an alkaline environment. - Maybe a co-existing diagnosis like celiac, C. diff (especially if he has been on antibiotics), small bowel overgrowth (Kendig’s) Other: • Store at room temp. Extreme temps can destroy the enzymes (i.e. in a hot/frozen car, on window ledge, abrove stove, etc) • Effective for ~ 45 minutes after taking them • Some foods/drinks do not require enzymes (simple carb only → pop, juice, fruit, popsicles, hard candy, jello)

Question 88

How do we stratify fecal elastase levels?

Answer 88

>300: sufficient 100-300: intermediate <100: insufficient as per infant guideline, if fecal elastase <200, then enzyme supplementation

Question 89

Which organism are we worried about in the Burkholderia cepacia complex?

Answer 89

- We are somewhat concerned since 1/3 of patients with multivorans will have a decline in lung function, but multivorans is better than cenocepacia, which can cause cepacia syndrome - - Cenocepacia is bad for 2 reasons: rapid decline in lung function and cepacia syndrome (septicemia, pyrexia, necrotizing pneumonia with 20% mortality)

Question 90

What should you consider in CF patient who is having a pulmonary deterioration and requires intubation?

Answer 90

- Goals of care - Is there a reversible condition like pneumothorax or hemoptysis which may have better outcome - Candidate for transplant? Any micro-organisms which may affect consideration for transplant such as M. abscessus, Burkholderia cepacia complex, Scedosporium. - Panel reactive antibody status-->gives you a sense of HLA antigens that they react to and how hard to find a donor match - Candidate for ecmo ?

Question 91

Approach to hemoptysis in a patient with CF?

Answer 91

- Scant, mild-moderate versus massive hemoptysis - Scant: <5 mL --> no need for antibiotics, can continue airway clearance and biPAP. There's really nothing special for scant hemoptysis - Massive: >240 mL in 24 hours: antibiotics, stop airway clearance, stop biPAP, admission, if unstable then bronchial artery embolization. There is NO point in bronchoscopy b/c you will not be able to localize source of bleeding and it will waste time - Mild to moderate: 5-240 mL: need antibiotics, but no consensus about what to do for everything else (biPAP, airway clearance), probably ok to use aerosolized therapy General approach: - ABC - Type, screen, cross match - IV vasopressin - Vitamin K - may be low due to fat malabsorption or liver dysfunction - Bronchial artery embolization and likely CT prior - don't do bronchoscopy

Question 92

Causes of life-threatening hemoptysis?

Answer 92

- Infection: fungal, TB - Cancer - Bronchiectasis (Apart from CF, life-threatening hemoptysis is defined as >150 mL (1/2 cup) in 24 hours. I'm not sure why the CF guideline uses a more liberal definition)

Question 93

What are 3 mechanisms for the action of azithro in CF patients?

Answer 93

Evidence based: - in patients with chronic pseudomonas (defined as 1 year duration), treatment with azithro 3x per week-->improvement in lung function (6%), decreased exacerbations and improvement in weight - in patients without chronic pseudomonas colonization, no improvement in lung function, but 50% decrease in exacerbations and improvement in weight - Anti-inflammatory - decreases hosts inflammatory response against pseudomonas-->decreases neutrophil response, decreases IL8 - Decreases bacterial virulence: does NOT have a direct killing effect against pseudomonas, but it decreases virulence factors-->less protein production, less biofilm formation - Antibiotic: has a direct killing effect against other common CF bacteria like Staph aureus and H. influenza, but this isn't the main reason for use of azithro in CF (not sure if I would put this down as an answer)

Question 94

How do you prove that CF patient is smoking?

Answer 94

- Serum cotinine - Urine NNAL - The above are tobocco metabolites, which are not as good for differentiating active versus passive smoking - Other options which are less specific, but tell you more about active smoking: - Increased carboxyhemoglobin - Decreased DLCO - I think I would pick one from each category for the answer

Question 95

3 strategies to help a patient quit smoking?

Answer 95

- individual counselling/brief counselling - CBT - motivational enhacement - nicotine replacement product if regular smoking and age 12-18 years

Question 96

How does smoking hinder the CF lung?

Answer 96

- Increased frequency and severity of pulmonary exacerbations - Decreased appetite-->poor nutritional status - Faster decline in lung function

Question 97

What is the difference between Prevnar 13 (pneumococcal conjugate 13) and pneumovax 23 (pneumococcal polysaccharide 23 vaccine)?

Answer 97

Prevnar 13 - conjugate protein attached to the polysaccharide, given routinely as part of childhood immunization schedule, all doses are finished by about 12 months of age. Infants need the protein attached to the polysaccharide to mount an immune response. Pneumovax 23 - polysaccharide vaccine, given starting at age 2 years to patients with CF and other chronic lung disease. Provides additional protection against pneumococcal disease (prevnar 13 does provide a lot of protection - up to 97% - so it's good for general population use. (I believe that I got prevnar 13 and then 8 weeks later, will pneumovax 23, as part of starting biologic)

Question 98

Which vaccines are recommended for children with CF?

Answer 98

- routine vaccinations - RSV vaccine (soft recommendation) for children less than 2 years of age - influenza starting age >=6 months for children and family - pneumovax 23 (pneumococcal polysaccharide 23 vaccine) starting at age 2 years

Question 99

What is the pathophysiology of CFRD?

Answer 99

- Abnormal chloride function-->thick secretions-->obstruction of pancreatic ducts-->destruction of pancreas by it's intrinsic enzymes-->fibrosis,fatty infiltration - Main issue: lack of insulin production (which is similar to type 1 diabetes), though there is also increased glucagon production - As CFRD progresses and during pulmonary exacerbations, there is insulin resistance (so features of type 2 diabetes). -->this is why we check glucose during pulmonary exacerbations since it's a more sensitive time to pick up on insulin resistance. Infection, inflammation and use of steroids contributes to lack of sensitivity/resistance to insulin.

Question 100

What organs are involved in fat absorption and how is this relevant to CF?

Answer 100

- Pancreas makes digestive enzymes - Liver makes bile, which is stored and released by gallbladder - Bile is important to help breakdown fat so that it is more easily digest by enzymes, and also helps with fat absorption

Question 101

How is CFRD similar and different from type 1 diabetes?

Answer 101

- Key point: CFRD has features of both type 1 and type 2 diabetes - Similar to type 1: - presentation with polyuria, polydipsia, weight loss - main problem is decreased insulin production - treatment with insulin - both are prone to microvascular complications, though less common with CFRD Different than type 1: - not prone to ketosis - no auto-antibodies - in later stages and with exacerbations, there is increased insulin resistance - screen for CFRD with 2 hour OGTT, not with fasting glucose or HbA1c - rare to have macrovascular complications with CFRD - age of onset: type 1 starts in childhood. CFRD can start in childhood, but more so ages 18-24 years - CFRD starts insidiously, but type 1 starts acutely

Question 102

How is CFRD similar and different from type 2 diabetes?

Answer 102

Similar: - both can have insulin resistance, although decreased insulin production is main features of CFRD - both are not prone to ketosis - both have a more insidious presentation - both tend not to have autoantibodies - both are prone to microvascular complications, though this is less common for CFRD Different: - main issue in CFRD is decreased insulin production - CFRD is not prone to macrovascular complications - CFRD is treated with insulin - No use of oral antihyperglycemic agents with CFRD

Question 103

Which patients with CF can get pancreatitis? Why does pancreatitis happen?

Answer 103

- affects 20% patients with pancreatic sufficiency - 2 hit hypothesis: - Decreased CFTR function-->enough function to produce enzyme, but there is some obstruction of pancreatic ducts-->destruction of pancreas from enzyme (kind of life what would happen in utero in patients with pancreatic insufficiency) - Another hit: alcohol, drug, hypercalcemia

Question 104

What is CF related liver disease?

Answer 104

* CF related liver disease: broad umbrella term which includes: * Liver enzyme elevation: this is relatively common and affects about 50% of patients, but does NOT predict development of cirrhosis Cirrhosis: - Focal biliary - Multilobular cirrhosis – happens in 5-10% of patients with CF * Neonatal cholestasis: high conjugated bili, mimics biliary atresia, resolves by 3 months of age * Steathosis Gallbladder: - Cholelithiasis - Cholecystitis - microgallbladder

Question 105

Why does CF related liver disease?

Answer 105

* Not fully understood * Thick secretions cause obstruction of intra and extrahepatic bile ducts * Bile salt accumulate and these salts are toxicàhepatic stellate cells are activated and produce collagen * More common if two copies of class 1, 2 or 3 mutation

Question 106

What is the relationship between liver enzyme and elevation and development of cirrhosis in patients with CF?

Answer 106

- Relatively common to have liver enzyme elevation. This affects 50% of patients with CF. Liver enzymes can transiently elevate and then normalize - However, liver enzyme elevation >3x upper limit of normal is unusual and should work up further for liver disease

Question 107

Complications of cirrhosis in a patient with CF?

Answer 107

- portal hypertension-->splenomegaly, thormobocytopenia. Esophageal/gastric varices--> GI bleed (especially if there is also vitamin K deficiency). Avoid NSAIDs and ASA. - hepatopulmonary syndrome--this tends to happen in patients with portal hypertension. Liver either makes or fails to clear vasodilators-->dilatation of arteriovenous channels in lungs-->increased perfusion with same ventilation (V/Q mismatch)-->hypoxemia

Question 108

Management of CF related liver disease?

Answer 108

* NO good therapy to slow down fibrosis or reverse it * Ensure vaccination against Hep A and B are up to date Ursodiol is controversial * Nutrition: need to ensure appropriate doses of fat soluble vitamins and pancreatic enzymes - Steatohosis: optimize nutrition, look for essential fatty acid, carnitine, choline deficiency, assess for diabetes - Monitor fat soluble vitamin levels every 6-12 months. Patients may need higher doses of ADEK - If cholestasis, consider MCT formula, which will help with lipid absorption * Monitor for signs of portal hypertension: Esophageal and gastric varices: risk of acute bleeding. Avoid NSAIDs and salicyclic acid in children with varices * Splenomegaly, leucopenia, thrombocytopenia Hepatopulmonary syndrome Liver transplant

Question 109

Physical exam, labs and investigations for patient with CF related liver disease?

Answer 109

* Physical exam for stigmata: hepatosplenomegaly, clubbing, ascites, hemangioma, scleral icterus * Labs for transaminases, GGT, ALP, INR, PTT, albumin, ammonia, cholesterol, CBC (since there may be hypersplenism) * Screen for other causes of chronic liver disease: Wilson’s, autoimmune hepatitis, alpha 1 antitrypsin * Ultrasound + doppler to look for cirrhosis and signs of portal hypertension * Upper GI is only recommended for children with clinical evidence of varices (not routinely done for all patients with portal hypertension) Liver biopsy, but not routinely indicated

Question 110

How to screen for CF related liver disease?

Answer 110

- Annual transaminases - Physical exam looking for HSM Directly from CF guideline: Careful examination by palpation and percussion of liver and spleen size and texture at each visit. Consensus Conference Yearly panel of liver blood tests (AST, ALT, GGT) should be performed in all CF patients

Question 111

What are methods to assess pancreatic sufficiency/insufficiency?

Answer 111

- Fecal elastase - 72 hour fecal fat collection -->excretion of >15% of total fat intake. (coefficient of fat absorption<85%) - direct testing via collection of pancreatic fluid sample Less direct: - pancreatic ultrasound - vitamin levels

Question 112

What medications would stabilize FEV1 in a patient with CF?

Answer 112

- you could pretty such any of the medications that are typically used Hypertonic saline Dornase Alpha CFTR modulators Chronic Azithromycin for chronic pseudomonas (lung function improved by 6%) - apparently chronic inhaled therapy for pseudomonas also improves lung function

Question 113

Why is it important to screen for CFRLD via annual liver enzymes and a good physical for HSM?

Answer 113

CFRLD starts in childhood, median age of onset is age 10 years and it's the number 3 cause for liver transplant in late childhood

Question 114

CF patient with abdominal pain. DDX?

Answer 114

- DIOS - fat malabsorption due to new pancreatic insufficiency, inappropriate dosing/utilization of pancreatic enzymes, CF related liver disease - bacterial overgrowth - C. diff, especially if recent antibiotic use - pancreatitis, if they are pancreatic sufficient

Question 115

If you want to use chronic azithro in CF patient, what dose and frequency?

Answer 115

250 mg or 500 mg (depending on weight above or below 40 kg) 3x per week (optimize) but other studies have used different dosing Check for NTM before starting treatment and every 6-12 months

Question 116

For a patient with an intermediate sweat chloride, when should the sweat chloride be repeated?

Answer 116

- repeat within 1-2 months. (similar to the newborn screening algorithm, if it's still intermediate then send for genetics) - consider: genetics, fecal elastase

Question 117

When you are working up a patient for CF, what are the diagnostic labels you could apply?

Answer 117

- Cystic fibrosis - CFSPID -->this diagnosis specifically relates to the outcome of a newborn going through the screening algorithm - CFTR related disorder - monosymptomatic clinical entity, which has features of CFTR dysfunction, but doesn't meet criteria for CF. Eg. bronchiectasis, pancreatitis, congenital bilateral absence of vas deferans) - Not cystic fibrosis

Question 118

Do you need a sweat chloride to make a diagnosis of CF?

Answer 118

Technically, you don't need sweat chloride, but the sweat chloride is needed to confirm the diagnosis Can make a diagnosis with: - reason for clinical presentation (symptoms, family history, +newborn screen) - positive sweat chloride (>=60) or 2 CFTR causing mutations

Question 119

CF patient with pneumothorax. Do they need to be referred for lung transplant?

Answer 119

- Pneumothorax guideline couldn't come to consensus | - Recent transplant guideline suggests that if FEV1>50% + pneumothorax, then refer for transplant

Question 120

Management of pneumothorax in patient with CF?

Answer 120

Acute management: - use broader guidelines re: size of pneumothorax to decide if chest tube is indicated - NO consensus regarding use of antibiotics and if pneumothorax is symptom of exacerbation - Regardless of size: - No biPAP - No airway clearance - But can continue to use aerosolized therapies Post management: - No flying for 2 weeks (may be more restrictive than BTS which says 1 week post CXR resolution) - No weight lifting >5 pounds - No spirometry x 2 weeks

Question 121

CF patient with first episode of pneumothorax. Is pleurodesis recommended?

Answer 121

- No, it's not recommended after the first episode - Only recommended for recurrent, large pneumothorax - Surgical is preferred over chemical pleurodesis

Question 122

Mechanism for hemopytsis in patients with CF?

Answer 122

- Bronchial arteries become enlarged and tortuous and rupture into the airway - Associated: - infection can cause worsening airway inflammation - vitamin K deficiency

Question 123

Why is pseudomonas able to evade lung defences?

Answer 123

Early colonization: - Pilli and flagella enable it to attach to cells - Evades phagocytosis because it attaches to mucous and has an alginate coat - Alginate coat also promotes development of biofilm and tissue damag - Flagellin synthesis is down regulated, so evades detection by host - Biofilm formation enables pseudomonas to evade antibiotics - Exotoxins

Question 124

CF patient with declining lung function, despite therapy for chronic pseudomonas and admission for IV antibiotics. What organisms would you think about?

Answer 124

- NTM - Aspergillus-->ABPA, chronic bronchitis - Burkholderia cepacia complex

Question 125

Side effects of itraconazole?

Answer 125

- Hepatotoxicity - Nausea - Diarrhea - Headache - Rash - Itraconazole is a CYP3A4 inhibitor (decreases the activity of this enzyme, which metabolizes ivacaftor), so need to reduce the dose of ivacaftor (Voriconazole: photosensitivity, vision changes), liver injury

Question 126

Minimal function versus residual function CF mutation?

Answer 126

- Minimal function: class 1, 2 or 3 | - Residual function: class 4, 5 or 6

Question 127

QT prolonging agents in patient with CF?

Answer 127

* antimicrobials: * macrolide (azithromycin) * fluoroquinolone (ciprofloxacin) * anti-fungal (azoles)- eg. itraconazole * anti-depressant (ssri) * antiemetic (ondansetron) * GI motility agents (domperidone)

Question 128

Which drugs are made less effective by orokambi?

Answer 128

Lumacaftor is a cyp3A inducer and there are other liver enzymes that are affected. - hormonal contraceptive including OCP, IUD, various forms are not considered reliable - singulair - clarithomycin - itraconazole, voriconazole - not recommended to use - citalopram - omeprazole - ranitidine (the above is not the case for ivacaftor)

Question 129

If there is a probable newborn screen with 2 different CF mutations identified, is this definitely CF? What if there were 2 copies of DF508?

Answer 129

- The 2 different mutations could be either in cis or trans, we don't know. So this may not be CF and we need to get sweat chloride - If it's copies of DF508, they would need to be on different chromosomes. this is essentially CF, but we still need sweat chloride to confirm

Question 130

Newborn baby with positive newborn screen who has a positive sweat chloride. Do you need to repeat the sweat chloride?

Answer 130

Technically, you do not and this is a change from previous guidelines. (some people would say that practically, if the sweat chloride is very close to 60 and you don't already have 2 genes identified then makes to repeat it while waiting for full gene sequencing)

Question 131

Why can we not be reassured by an intermediate sweat chloride?

Answer 131

We can't be reassured because people can have CF with an intermediate sweat chloride. In an individual with 2 CF causing CFTR mutations, you only need a sweat chloride >30 to make a diagnosis of CF

Question 132

What is CFTR related disorder? How is this different than CFSPID?

Answer 132

CFTR related is the diagnosises that can be applied to a non-screened individual with inconclusive diagnosis: mono symptomatic clinical entity with symptoms such pancreatitis, bronchiectasis or congenital absence of vas defererans associated with CFTR dysfunction, but not meeting criteria for CF If a patient comes through the newborn screening algorithm with an inconclusive diagnosis-->CFSPID

Question 133

What are complications of bronchial artery embolization?

Answer 133

- chest pain - PE - hemoptysis (such as if the procedure is not effective) - transverse myelitis - esophageal a. atelectasis b. infection c. fluid overload/pulmonary edema d. haemorrhage e. Pulmonary embolism/migration of coil/glue f. Stroke (distal embolization) g. Air embolism h. Necrotic lung - Rare complications include transverse myelitis or bowel necrosis if spinal arteries or superior mesenteric artery are inadvertently embolized - also can get very rare cases of dysphagea due to effect on esophageal blood supply

Question 134

How often should liver enzymes be checked while on CFTR modulator?

Answer 134

- every 3 months for first year, then annually | - consider stopping if liver enzymes are >5x ULN

Question 135

side effects with triple therapy?

Answer 135

t). Adverse drug reactions that occurred more frequently in the triple combination therapy group compared with placebo included (reported here as percents) abdominal pain (14 versus 9), diarrhea (13 versus 7), rash (10 versus 5), increased blood alanine aminotransferase (ALT; 10 versus 5) or aspartate aminotransferase (AST; 9 versus 2), increased blood creatine phosphokinase (9 versus 4), rhinorrhea (8 versus 3), and "influenza" (7 versus 1). Liver function tests are recommended prior to elexacaftor-tezacaftor-ivacaftor treatment, every three months for the first year and then annually thereafter.

Question 136

Imaging findings for NTM?

Answer 136

- nodules - cavitation - tree in bud - bronchiectasis - consolidation

Question 137

CF patient who is systemically unwell. what would be pulmonary diagnoses?

Answer 137

- NTM can result in systemic symptoms | - cepacia complex (cause burkholderia cenocepacia)