Cystic Fibrosis (Raf) Flashcards
CFSPID definition?
- 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
reasons for osteopenia in CF?
- 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
How should patients with CF be screened for osteopenia?
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
CF patient with osteopenia. When should you consult endo?
When DXA is more than 1 standard deviation below the mean
for CF, how often should DXA be completed if bone density is within 1 standard deviation of the mean?
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)
What is the incidence of CF?
1/3500 (Kendig’s)
Describe pathogenesis of CF
- 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
What are the benefits of hypertonic saline and it’s level of evidence recommendation?
Mechanism of hypertonic saline?
- 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
What are adverse effects of hypertonic saline?
- Cough
- Bronchospasm
- G tube dislodgement or rupture
(No effect on pseudomonas colonization)
What are the evidence based benefits of pulmozyme?
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
Side effects of pulmozyme?
- Rash
- Voice alteration
- sore throat
- laryngitis
- chest pain
For a newborn diagnosed with CF, how soon should they be seen at a CF centre?
Within 24-72 hours of diagnosis (1-3 days)
Pancreatic enzyme replacement therapy dosing for infant? Can a generic pancreatic enzyme be used?
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
Which infants should be started on pancreatic enzyme replacement therapy?
- 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.
For infants with CF, what type of feed is recommended?
- Preferred feed is human milk
- Next preferred: standard formula (no need for hydrolyzed formula upfront)
For infants with CF, when is vitamin supplementation with A, D, E, K started?
- shortly after diagnosis
- vitamin levels should be checked 2 months after supplementation started and then annually
What are the maintenance of health recommendations for infant newly diagnosed with CF?
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
In the care of infants with CF, why is there such a strong emphasis on growth?
- 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)
Infant with CF who is not growing well. Differential?
- 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
What type of electrolyte abnormality are infants with CF prone to?
- 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
Health maintenance recommendations for preschooler with CF?
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
Indications for lung transplant in a pediatric patient with CF?
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
When should you initiate a conversation about lung transplant with a CF patient? What should you try and optimize during that time?
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)
Median survival post lung transplant for CF?
9.5 years
Which micro-oraganisms may impact the ability of a CF patient to receive lung transplant?
- Burkholderia cepacia complex: cenocepacia, gladioli, dolosa
- nontuberculous mycobacteria: Mycobacterium abscesuss
- molds like Scedopsorium prolificans
What does the main CF guideline say about B2 agonist use?
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.
What are inhaled anti-pseudomonal antibiotics? Which ones are preferred?
- 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)
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?
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
What are the CF Foundations recommendations for use of azithromycin?
- 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
Indications for Ivacaftor? Outcomes for use of ivacaftor? Side effects of ivacaftor?
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
Is aerobic exercise a substitute for airway clearance?
No, it is adjunctive but not a substitute
Which type of airway clearance is recommended?
- 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
How does PEP work?
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
Diagnostic criteria for a classic case of ABPA in CF?
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)
Minimal diagnostic criteria for ABPA?
- 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
Difference between classic and minimal diagnostic criteria for ABPA in CF?
- 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
What are the imaging findings of ABPA?
- 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
Pre-flight evaluation for patient with CF?
- 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)
Maximum dose of PERT?
10,000 U/kg/day or 2500 U/kg/meal
Diarrhea in spite of adequate PERT?
- chewing enzymes
- expired enzymes
- enzymes at end of meal
- hyperacidity (consider PPI)
- small bowel bacterial overgrowth, C. dif
- fibrosing colonopathy
(CF related liver disease)
Manifestations of CFRLD?
- 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
How often are CF patients screened for NTM?
- Annually with a culture based method of sputum
- Oropharyngeal swab should not be sent (less reliable)
If a CF patient on chronic azithro tests positive for NTM, what do you do?
- Stop azithro, while you are working them up for NTM disease
(you may be partially treating with azithro monotherapy and causing resistance)
How is M. abscessus treated?
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
Can monotherapy for NTM?
No, similar to TB, it’s pretty intensive to treat NTM
How is M. avium complex pulmonary disease treated?
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
When should you consider IV amikacin for M. avium?
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)
How long is NTM treated for?
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
How to monitor patients on NTM treatment?
- 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
What sort of monitoring is required for IV amkacin or streptomycin?
These are both aminoglycoside antibiotics so need to monitor serum levels
- risk of ototoxicity and nephrotoxicity
Is persistent M. abscessus orM. avium in a patient with CF an absolute contraindication to transplant?
No, but ideally want to complete treatment successfully before listing for transplant
Does finding NTM in CF patient’s sputum mean they have NTM disease?
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
Which is worse for CF patient with NTM disease, abscessus or MAC?
Abscessus is worse since more intense clinical worse, intense therapy and hard to eradicate, may have implications for lung transplant
Diagnostic criteria for NTM disease?
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)
