Cystic Fibrosis Flashcards
6 classes of CF mutations
1) protein synthesis defect
2) maturation defect (delF508)
3) gating defect (G551D)
4) conductance defect
5) reduced quantity
6) reduced stability
Component of Kalydeco and mutations covered
Ivacaftor -> gating potentiator
For class 3 mutations (ie. G551D) and 1 class 4 mutation (R117H)
>6 mos old
Components of Orkambi and mutations covered
Ivacaftor + Lumacaftor (corrector)
homozygous delF508
>2yrs old
Components of Symdeko and mutations covered
Tezacaftor + Ivacaftor
homozygous delF508 or 1 del F508 + 1 residual function mutation
>6yrs
Components of Trikafta and mutations covered
Tezacaftor + Ivacaftor + Elexacaftor
homozygous delF508 or 1 delF508 + another mutation
Side effects of Ivacaftor
serious = liver enzyme elevation, cataracts common = headache, abdo pain, diarrhea, dizziness
Side effects specific to Orkambi
chest tightness + hypertension
4 clinical presentations of invasive aspergillosis
1) Pulmonary
2) Tracheobronchitis
3) Rhinosinusitis
4) Disseminated disease
Common triad for pulmonary aspergillosis
Fever, pleuritic pain, hemoptysis
3 patterns of Tracheobronchitis due to Aspergillus
1) Obstruction
2) Ulcerative
3) Pseudomembranous
Imaging findings of pulmonary aspergillus
CXR = peripherally distributed lung nodules/masses CT = halo sign, air crescent sign
Testing for pulmonary aspergillus
fungal culture, histopath exam of tissue, galactomannan assay
sputum = need direct exam for hyphal elements + fungal culture
Why is Galactomannan useful for Aspergillus dx?
double sandwich enzyme -linked immunoassay
galactomannan = polysaccharide cell wall antigen of Aspergillus
Treatment for invasive pulmonary aspergillus
Voriconazole 6-12 weeks (alternatives = Isavuconazole, Ampho B)
Proven criteria for invasive pulmonary aspergillus
1) Histopath or cytopath exam of lung tissue = hyphae with evidence of associated tissue damage
OR
2) positive culture for Aspergillus from the lung
AND
3) clinically/radiologically abnormal site consistent with infection
Probable criteria for invasive pulmonary aspergillus
Host factor (neutropenia, transplant, steroids, chemo, cancer etc)
AND
mycological evidence
AND
clinical criteria consistent with infection
Most prominent cell type on BAL for Pseudomonas + cytokine associated with it
Neutrophils, IL-17
Basic regimen for eradication of 1st Pseudomonas
Inhaled Tobramycin 300mg BID x 28 days, repeat x 1 if regrowth
complete 1 course of IV abx if regrowth after that
Max dose of lipase in pancreatic enzymes and complication associated with this
10,000units/kg/day or 2500mg/kg/meal
Fibrosing colonopathy
Ranges for fecal elastase and pancreatic insufficiency
<100 = insufficient 100-200 = grey zone >200 = sufficient
Diagnostic criteria for CF
1+ phenotypic features of CF
OR hx CF sibling OR + NBS
AND
increase sweat chloride OR 2 CF mutations OR abnormal nasal epithelial ion transport
Definition of massive hemoptysis
≥ 240mls in 24 hours
Hemoptysis management in CF
H&P, ABCs CBC, cross match, coags, CXR Volume resus Admission Abx (treat like exacerbation) Stop NSAIDs, airway clearance, inhaled treatments CT chest + bronch D/C BiPAP as long as bleeding BAE if massive hemoptysis and unstable
Pneumothorax management in CF
vitals, probable admission, O2 tension = needle and chest tube unclear role for abx large pneumo = no airway clearance post resolution: no flying for 1-2 weeks, no weight lifting x 2 weeks, no spirometry, unclear re: exercise
Recurrent pneumothorax management in CF
Consider pleurodesis (preferred = surgical) *may make transplant harder later on
Mechanism of action of hypertonic saline in CF
osmotic agent and may increase airway surface liquid volume
increased coughing
possible outcomes: better lung function and decreased exacerbations
Mechanism of action of hemoptysis in CF
bronchial arteries or collateral vessels enlarge and may rupture into inflamed airway
also erosion into the vessels
worsened by: low vitamin K and underlying CFLD
3 effects of azithromycin in CF patients
1) Anti-inflammatory
2) Immunomodulatory
3) Antibiotic
Mechanism of action of azithromycin for decreasing bacterial virulence
1) inhibits pseudomonas growth, protein synthesis, and biofilm formation
2) decreases bacterial virulence factors for pseudomonas
3) most benefit in those + for Pseudomonas
Recommendations for Azithromycin in CF
1) Screen for non-TB mycobacteria prior to and periodic screening q6-12 mos
2) no azithro in patients with non-TB mycobacteria
3) recommended ≥ 6 yrs with pseudomonas to improve lung function and reduce exacerbations
4) can use it in those without pseudomonas but frequent exacerbation (recommends but not as strong as pseudomonas)
Most common cell type and cytokine in BAL of CF pt
Neutrophils
Cytokine: IL-8, IL-18, TNF alpha, IL-17
3 reasons for osteopenia in CF
FTT delayed pubertal development malabsorption of calcium, Mg, vit D, vit K Hepatobiliary dx reduced weight bearing activity chronic steroid use inadequate nutrient intake
Tests to prove smoking
Low DLCO (in absence of other causes) High carboxyhemoglobin (10-15%) Serum Cotinine (>3.1 ng/ml) Urine NNAL
Smoking cessation strategies
individual counselling
pharmacotherapy (nicotine replacement, bupropion, varenicline)
Ways that smoking hinders CF lungs
Decreases CFTR function
Increased cough and sputum production
increased frequency and severity of bacterial infection
Decreased appetite and lower nutritional status
Lung function decline
How does PEP help to clear secretions?
Resistance during exhalation = creation of back pressure
Results in build-up of gas pressure behind mucous through collateral ventilation
Move mucous from peripheral to central airways = coughing maneuvers
Suggested vaccines for CF
Influenza yearly ≥ 6 mos
RSV <2 yrs
Routine immunizations
Pneumovax (23-valent)
CF-related DM vs type 1 DM
CFRD:
- rarely associated with islet autoantibodies
- ketoacidosis rare
- screening = 2 hr OGTT
- also glucagon deficiency
Similar features = relative insulin deficiency related to islet cell destruction, polyuria, polydipsia, weight loss
Tx = insulin
Common hepatobiliary manifestations of CF
CFLD Portal HTN Cholestasis Gall bladder disease Hepato-pulmonary sx
Most common finding of CFLD on U/S
Hepatomegaly (looking for firm and nodular)
Gold standard to diagnose CFLD
Liver biopsy
looking for focal biliary cirrhosis
CFLD treatment
- Supportive
- Addressing complications of advance liver disease
- Hep A and B vaccination
- URSO = controversial
- 150% nutrition
- increase fat soluble vitamins
- screen for portal HTN
- screen for variceal bleed
- avoid ASA/NSAIDs
Diagnostic criteria for CFLD
Dx > 2 of: Hepatomegaly/Splenomegaly, persistent (>12mos) elevation in ALT or GGT (and get U/S + doppler, if still elevated in 6mos consult GI) and exclusion of other causes of liver disease, abnormal liver U/S findings
Tests to help determine pancreatic insufficiency
- Fecal elastase
- Stimulation of the pancreas and collect fluid
- Chymotrypsin
- U/S = look for atrophy/cystic changes
- Vitamin levels
- Fecal Fat collection
Meds to treat CF to stabilize FEV1
- Hypertonic Saline
- Dornase Alpha
- CFTR modulators
- Chronic pseudomonas treatment
- Chronic Azithromycin
When should CF be listed for transplant?
1) FEV1 <50% and rapidly declining
2) FEV1 <50% and co-morbidities
3) FEV1 <40%
Pseudomonas mechanisms of inhibition of lung defenses
- Induce damage in immune cells
- Virulence traits and secretion of virulence factors
- Epithelial injury -> loss of alveoli barrier -> biofilm
- Resistant to neutrophils
How is Pseudomonas biofilm produced?
1) Mucous provides anaerobic environment for bacterial growth
2) Decreased secretion of bactericidal compounds into CF airway
3) Increased DNA and actin
What is a biofilm?
bacterial community attached to a surface surrounded by extracellular matrix
Pseudomonas mechanisms of resistance
- Amp C beta-lactamase
- Extended spectrum beta-lactamase
- Downregulation of OprD
- Multidrug efflux pumps
- Biofilm formation
Possible reasons for CF deterioration
- Poor adherence to ACT and meds
- New bug/superimposed infection -> fungi, NTM, pseudomonas
- CFRD
- ABPA
- Smoking/vaping
- Pregnancy
- Weight loss/poor nutrition/enzyme compliance
- mental health
Minimum criteria for ABPA (6)
1) Asthma or CF
2) Worsening lung function without another etiology
3) + skin prick with Aspergillus
4) IgE ≥ 1000
5) Increased Aspergillus species specific IgE and IgG
6) New or recent abnormal CXR or CT findings not improved with abx or physio
Additional criteria for ABPA (4)
1) Increased blood eosinophilia ≥ 400 when not on steroids
2) Aspergillus species -specific precipitating antibodies
3) Central bronchiectasis (central varicose)
4) Aspergillus species-specific containing mucous plugs
Screening for ABPA in CF
1) high level of suspicion ≥ 6 yrs
2) total IgE annually
3) if >500, immediate cutaneous reactivity to aspergillus or IgE antibody
4) if positive, consider dx on basis of minimal criteria
ABPA treatment
1st = steroids -> Prednisone 0.5-2mg/kg.day 1-2 weeks then taper within 2-3 mos
2nd = antifungal: oral Itraconazole 5mg/kg/day x 3-6 mos (therapeutic drug monitoring and LFTs)
add -> BD, inhaled steroids etc only if indicated for asthma
Pertinent prednisone side effects in CF
Diabetes, cataracts, growth failure, osteopenia
Side effects of Itraconazole
Increased transaminases Liver failure (rare) Nausea/vomiting, abdo pain jaundice fatigue increased triglycerides headaches
Indications for antifungal treatment in ABPA (4)
Slow or poor response to steroids
Relapse
Steroid dependent
Steroid toxicity
Criteria for CF-related metabolic syndrome
- *Asymptomatic and positive NBS
1) Indeterminate sweat chloride (x2) and <2 CF-causing mutations
2) Normal sweat chloride + 2 CFTR mutations (only 1 known to cause CF)
Surveillance for CRMS/CF-SPID
1) Infants 30-59 - repeat sweat by 2 mos, if indeterminate - CFTR mutation analysis, 3rd sweat at 6 mos
2) CXR if symptomatic
3) If Pseudomonas - treat as per CF protocol
4) CF team q6mos x 1 yr then annually
5) OP swabs q visit
6) no routine airway clearance (unless dx)
7) recheck pancreatic status if FTT etc.
Characteristics of congenital bilateral absence of vas deferens (CFTR-RD)
1) Absence of palpable vas deferens
2) normal or increased FSH
3) Absence of intra-abdominal tract of VD and hypoplasia of seminal vesicles
4) pH <7.2, negative fructose + alpha 1-4 glucosidase
5) no developmental anomaly
Functional testing for CFTR (2)
1) Nasal potential difference
2) Intestinal current measurement
How does nasal potential difference work?
- based on difference of electric potential measured between a reference electrode and silver/silver chloride electrode
- inferior turbinate
- recordings during continuous flow of salt solutions
- measured in: saline, amiloride, chloride free amiloride, isoproteronol added to activate CFTR
- sum = index of CFTR function
- <40 = abnormal ( on 2 separate days)
How does intestinal current measurement work to assess CFTR function?
- record transepithelial short-circuit current or transepithelial voltage in rectal biopsies as measure of ion transport after stim with chloride secretagogues
- stimulates potassium channels - increasing driving force for luminal chloride
- in CF - activation fails to induce apical chloride secretion and results in inverse response
+ response = potassium secretion with no chloride
Bugs that are part of Mycobacterium Avium Complex (MAC)
M. Avium
M. Intracellulare
M. Chimaera
M. Kansasii
“slow growers”
Bugs that are part of M. Abscessus species complex (MABSC)
M. Abscessus (obviously…)
M. Massiliense
M. Balleti
“rapid growers”
**often younger with more severe disease, difficult treatment, worse response, more severe, may exclude from lung transplant
When to suspect NTM disease in CF
1) Constitutional or respiratory symptoms above baseline
2) Unexplained increased decline in lung function
3) Progressive radiographic diagnosis with no response to typical treatment
4) Treat typical CF pathogens first, max ACT, co-morbidities
Diagnostic criteria for NTM pulmonary disease
Clinical (need BOTH)
1) pulmonary symptoms, nodular opacities (or cavitary) on CXR or multifocal bronchectasis with multiple small nodules
2) exclusion of other diagnoses
Micro (need ONE)
1) positive culture from 2 expectorated sputum samples
2) positive culture from 1 bronchial wash or lavage
3) transbronchial or other lung biopsy with histopath features and positive NTM culture or 1 positive sputum or bronch washing positive for NTM
Histopathologic features of NTM
Granulomatous inflammation
Acid-fast bacilli
General treatment guidelines for NTM pulmonary disease
1) Treat 12 mos beyond culture conversion (after first negative culture, need 3 negative in total)
2) No macrolide monotherapy
3) Monthly AFB smears + cultures while on treatment
4) Should show clinical improvement in 3-6 mos
5) Treatment failure = no response after 6 mos of appropriate treatment or no conversion to AFB negative culture after 12 mos
Treatment of MAC pulmonary disease
1) No CF/cavitations: macrolide (zithromax), Rifampin, Ethambutol 3x/week PO
2) CF: daily of above
3) CF with resistance or unwell, cavitary lesion: 1-3 mos of IV amikacin with above
Risk factors for macrolide resistant MAC (2)
Macrolide monotherapy
Prior macrolide treatment with inadequate companion drugs
Treatment of M. Kansasii
**Think of TB treatment
Isoniazid, Rifampin, Ethambutol x 12 mos after 1st negative culture
Treatment of M. Abscessus species complex pulmonary disease
“For ABS you need CIT-ups”
Intensive + Continuation
I = 3-12 weeks of IV Amikacin + 1 of: Tigecycline, Imipenum, Cefoxitin
C = Inhaled Amikacin with 2-3 of: minocycline, moxifloxacin, linezolid, clofazimine
Monitoring for NTM treatment (side-effects)
- hearing loss
- vision changes
- renal impairment
- liver function
- bone marrow suppression
- *monitor vision closely for Ethambutol, Rifampin, Linezolid
Stages of ABPA
1 - Acute 2 - Remission 3 - Exacerbation 4 - Continuous Steroids 5 - Fibrotic
ABPA IgE level for CF vs Asthma
Asthma >1000
CF >500 (min), >1000 (classic)
Most common cause of ABPM (allergic bronchopulmonary mycosis)
Candida Albicans
In a CF patient with severe disease, how would you assess their safety to fly?
1) Hypoxic challenge testing
2) Spirometry (if <50% predicted, do HCT)
If SpO2 <90% - should have oxygen for flight
CFSPID criteria
1 - CFSPID if NBS shows high IRT and one mutation (inconclusive screen) with intermediate sweat x 2
2 - CFSPID if screen positive with two mutations (only one CF causing) and negative sweat
Follow in CF clinic with repeat CF testing at 2 months and 6 months , a small % may turn out to be CF (becomes sweat pos with symptoms of CF )
CF girl with osteopenia, 6 causes why might CF get that. (repeat)
Prolonged steroids Pancreatic insufficiency (both exocrine and endocrine) Low weight bearing exercises Delayed puberty Chronic pulmonary infections Malnutrition
What chromosome is the CFTR gene on?
7
Gold standard test for CF diagnosis
sweat chloride
Clinical features of CF at diagnosis in unscreened populations 0-2yrs
Failure to thrive
Steatorrhea
Recurrent chest infection including bronchiolitis/bronchitis
Meconium ileus
Rectal prolapse
Edema/hypoproteinemia/”kwashiorkor” skin changes
Severe pneumonia/empyema
Salt depletion syndrome
Prolonged neonatal jaundice
Vitamin K deficiency with bleeding diathesis
Clinical features of CF at diagnosis in unscreened populations 3-16yrs
Recurrent chest infections or "asthma" Clubbing and "idiopathic" bronchiectasis Steatorrhea Nasal polyps and sinusitis Chronic intestinal obstruction, intussusception Heat exhaustion with hyponatremia CF diagnosis in a relative
Clinical features of CF at diagnosis in unscreened populations in adulthood (often atypical CF)
Azoospermia/congenital absence of the vas deferent Bronchiectasis Chronic sinusitis Acute or chronic pancreatitis ABPA Focal biliary cirrhosis Abnormal glucose tolerance portal hypertension cholestasis/gall stones
Non-CF causes of a positive sweat test
Adrenal insufficiency or stress Anorexia Ectodermal dysplasia Eczema Fucosidosis G6PD deficiency Glycogen storage disease type 1 HIV infection Hypoparathyroidism Hypothyroidism Malnutrition Nephrogenic DI Pseudohypoaldosteronism
Most common disease-causing mutation in CF
Delta F508
Does failure to find 2 CF causing mutations mean no CF?
No
Some w/ CF (symptoms & +ve sweat) have no mutations in CFTR despite complete sequencing - suggests mutation may be in promoter, introns or distant controlling gene
Assessment of End Organ Involvement in CF
1) Pancreatic function testing: stool for fecal fat, fecal elastase 1 testing
2) Sputum/BAL/OP/Sinus aspirates: cultured for CF pathogens
3) CT chest: for subtle pulmonary changes not seen on CXR
4) CT sinus
5) U/S: for exam of vas deferens; post puberty can do semen analysis
6) Spirometry and multiple breath washout
What do you expect to seen on transepithelial potential difference measurements (nasal potential difference) in CF?
CF: more negative potential difference across respiratory epithelium
Nasal potential difference - measured at inferior turbinate
Results impacted by viral illness, rhinitis, polyps, genotype, catheter location
Fetal anomaly suspicious for CF
Fetal anomaly scans may detect meconium ileus via abn bowel echogenicity or perforation
Mutations w/ mild pancreatic phenotypes (R117H, R334W) may be associated with what?
borderline sweats; NPDs
Where in the body is the most demand for functional CFTR?
Male reproductive tract
Four major factors from genotype to phenotype in CF
- Severity of CFTR mutations
- Modifying genes
- Environmental factors
- Time
Characteristics of Atypical CF (with Symptoms)
- Various terms “equivocal cf”, “ctfr related d/o” & “variant CF” - Often sign organ involvement
- Sweat result may be neg, intermed or positive
- Genes may show 2, 1 or 0 mutations
- Diagnostic labeling / therapy should be tailored to phenotype
- Careful monitoring and timely mgmt reqd
Conditions that may be associated with an increase incidence of CFTR mutations but insufficient evidence to fulfill a CF diagnosis
- Pancreatitis: acute or recurrent
- Disseminated bronchiectasis
- Isolated obstructive azoospermia
- ABPA
- Diffuse panbronchiolitis
- Sclerosing cholangitis
- Neonatal hypertrypsinogenemia
- Rhinosinusitis
- Heat exhaustion
Characteristics of Atypical Cf (without Symptoms)
- Most common: NBS w/ ↑IRT AND
- 2-mutations, one not characterized as dz
causing OR - One-mutation and intermediate sweat
- NO clinical criteria for CF - no symptoms or end-organ manifest
- Term: “CFTR metabolic syndrome” proposed
- Possible that clinical feat may develop w/ time - but insufficient evidence to assign label of CF - Careful surveillance & repeat sweat testing at 6-months advised
- Therapy reserved for symptoms / end organ changes
Natural history of the CF lung
The CF lung is susceptible to infection - endobronchial infection induces an intense inflammatory response that leads to bronchiectasis and eventually respiratory failure.
Pathogenesis of CF lung disease
- caused by defects in (CFTR), a cyclic adenosine monophosphate (cAMP)-regulated chloride channel expressed on the surface of airway epithelial cells and the serous cells of the submucosal glands.
- CFTR is functionally linked to other apical channels, such as the calcium-dependent chloride channels and the epithelial sodium channel (ENaC), which reabsorbs Na in the airways.
- Aberrant expression or function of the CFTR in the airway leads not only to reduced chloride conductance but also to dysregulation of epithelial sodium channel activity.
- Failure of chloride secretion and massive sodium hyperabsorption result in dehydration of the airway surface.
- The desiccated secretions obstruct the airways and reduce mucociliary clearance, permitting bacterial infection to become established and allowing the inflammatory response to be amplified.
Micro evolution in CF lungs
Bacterial infection is highly localized to the endobronchial spaces.
Initially, S. aureus and H. influenzae.
-The prevalence of MRSA has greatly increased.
P. aeruginosa emerges as the predominant organism over time and most children with CF have had lung infection with P. aeruginosa by 3 years of age.
Acquisition of mucoid P. A from the lungs of a patient is associated with a poorer prognosis.
Burkholderia cepacia associated with rapidly progressive necrotizing pneumonia and mortality.
Respiratory viruses have the potential for injuring or altering the airway and can induce secretion of inflammatory mediators from respiratory epithelium.
Evolution of Pseudomonas in the CF lung
Early P. aeruginosa isolates have planktonic, motile, nonmucoid phenotypes.
Most patients eventually become chronically infected with mucoid P. aeruginosa that survives in the lung as biofilms, and these anaerobic, sessile communities of bacteria contribute to antibacterial resistance in the CF airway.
How often should CF patients be screened for mycobacterium?
Annually
Role of inflammation in CF
Although pulmonary infection contributes to the morbidity of patients with CF, the intense host inflammatory response hastens the progressive, suppurative pulmonary disease.
Inflammation in the CF lung is remarkably compartmentalized, with infection and inflammation primarily contained in the airway lumen, while the alveolar space is relatively spared.
(BAL) from CF patients has remarkably high concentrations of pro- inflammatory mediators, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and IL-8.
The inflammatory response in the CF airways is characterized by a massive influx of neutrophils
Role of the phagocytic system in CF
The phagocytic system affords protection against bacterial invasion, and neutrophil-derived proteases, such as neutrophil elastase, participate in the intralysosomal degradation of engulfed bacteria.
With disease progression, the protease burden in the CF airway overwhelms the existing antiprotease defense.
Neutrophil elastase. It digests diverse substrates, including structural proteins, which weakens the airway and results in bronchiectasis and bronchomalacia.
- Uninhibited neutrophil elastase can enhance the inflammatory response in the bronchi.
Prominent pathologic feature in CF
Bronchiectasis - More severe in upper lobes
Other:
Segmental hyperinflation or atelectasis results from airway obstruction. Lung overinflation, postinflammatory blebs, and bronchiectatic cystic lesions increase susceptibility to pneumothorax.
Over time, bronchial arteries become hypertrophied and can cause pulmonary hemorrhage. Chronic alveolar hypoxia and inflammatory changes contribute to P HTN and Cor pulmonale.
Pulmonary clinical manifestations of CF
- Mucociliary clearance is impaired throughout the conducting airways
- It is unusual for neonates to have respiratory symptoms
- Cough eventually becomes both the prominent symptom and increasingly productive. As the lung disease progresses, CF patients can experience exercise intolerance, dyspnea, and shortness of breath
- Persistent airway infection and inflammation cause bronchiectasis, begins in the upper lobes then progresses to involve the whole lung.
- Atelectasis often co-exists
- generates negative intrapleural pressure and dilates the associated bronchus, already weakened by the lytic enzymes released from the neutrophils in the purulent material in the airway
Pulmonary treatment of CF
- Airway clearance techniques
- Bronchodilators
- Inhaled recombinant DNAse or other mucolytic agents
- Antibiotics.
Characteristics of a CF pulmonary exacerbation
Increased respiratory symptoms such as cough, dyspnea, and sputum production, often accompanied by systemic symptoms such as fatigue, anorexia, and weight loss.
Pulmonary function values usually decrease during exacerbations, and a therapeutic goal is to restore the best baseline of pulmonary function.
Pulmonary exacerbations are treated with aggressive airway clearance techniques and antibiotic therapy based on bacterial isolates from sputum or oropharyngeal cultures.
Length of antibiotic therapy is determined by resolution of symptoms and return of lung function to its previous baseline or to a new plateau, usually 10-21 days.
Other pulmonary complications besides exacerbation in CF
- Chronic nasal congestion and rhinorrhea (Pansinusitis)
- Nasal polyposis
- Digital clubbing
- Hypertrophic pulmonary osteoarthropathy
- Hemoptysis
- Airway hyperactivity
- ABPA
- Cor pulmonale
- Pulmonary Hypertension
Fuchs criteria for CF pulmonary exacerbation
S/Sx:
- Change in sputum
- New/increased hemoptysis
- Increased cough
- Increased dyspnea
- Malaise
- Fatigue/lethargy
- Temperature > 38.8 C
Anorexia/weight loss
Sinus pain/tenderness
Change in sinus discharge
Change in exam of chest
Decrease >10% FEV1
Radiographic changes
Min number of criteria: 4
No min symptom duration
Abx: IV
Definition of ABPA
An inflammatory complication, clinically manifested by wheezing and cough refractory to standard therapies, is an intense immunologic response to surface colonization with the fungus Aspergillus fumigatus, characterized by:
1) clinical deterioration that is not explained by other etiologies
2) Elevated serum quantitative IgE (> 500)
3) Positive skin test to Aspergillus or elevated in vitro Aspergillus -specific IgE levels
4) Aspergillus-specific IgG levels or precipitins
Other features include pulmonary consolidations and central bronchiectasis.
Tx: Extended courses of high dose corticosteroids.
Factors that negatively affect CF prognosis
Malnutrition
Diabetes
Infection with P. aeruginosa and B. cepacia
Frequency of pulmonary exacerbations
Patients with atypical or pancreatic-sufficient forms of the disease have slower decline in pulmonary function
Weight loss, anorexia, exercise tolerance, and school attendance are important measures of pulmonary morbidity
CXR findings in CF
Lung hyperinflation
Peribronchial thickening
Mucous plugging
Atelectasis
Bronchiectasis is usually a later finding on plain chest films.
Index of disease severity in CF
The rate of FEV1 decline
Deteriorating FEV1 = key marker for disease progression.
Effective airway clearance is a critical to maintain lung health, physical removal of airway secretions is needed to do what?
1) Relieve airway obstruction.
2) Reduce infection and airway inflammation.
Active airway clearance therapies
Positive expiratory pressure
Active-cycle-of-breathing technique
Autogenic drainage
Passive airway clearance techniques
Percussion
Postural drainage
High-frequency chest wall oscillations
Agents aimed at rehydrating secretions in CF
Reduced mucous viscosity and associated increased mucociliary clearance is achieved by improved airway surface hydration
Ex: Mannitol and Hypertonic Saline
HS = acts directly as an osmotic agent and increases airway surface liquid volume and has been shown to reduce frequency of pulmonary exacerbation and enhance airway clearance
Role of inhaled mucoytics
The inspissated secretions are composed of pus with high concentrations of DNA from degraded neutrophils
Pulmozyme (Dornase Alfa): reduces sputum viscosity and increases mucous clearance
Another = N-acetyl-L-cysteine - classic mucolytic
Hydrolyzes disulphide bonds in mucin
Characteristics of P. Aeruginosa infection in CF
Chronic infection with P. aeruginosa portends a worse prognosis, and once established, is virtually impossible to eradicate.
Treated with two antibiotics of different classes in an attempt to prevent the emergence of resistance and also in the hopes of achieving synergy
The most common IV Abx: aminoglycoside with a β-lactam antibiotic.
Higher doses of systemic aminoglycosides are required because of increased clearance and altered pharmacokinetics, so drug concentrations must be monitored and maintained in the therapeutic window.
Suppressive therapy with inhaled antibiotics is appropriate for of patients who are chronically infected with P. aeruginosa.
With regards to macrolide treatment, what should you do with when nontuberculous mycobacteria are cultured from a patient with CF
It is recommended that routine macrolide therapy be discontinued to prevent the emergence of resistance.
Key points re: anti-inflammatory therapy in CF
The hypothesis that an overzealous immune response in patients with CF may be deleterious and provided rationale for early trials with anti-inflammatory therapy.
Options:
- Systemic steroids: lots of side effects
- ICS: no benefit
- High-dose ibuprofen: slows the annual rate of decline in lung function but side effects noted (GI)
- Azithromycin: anti-inflammatory effects
Azithromycin: better lung function, weight gain, and fewer pulmonary exacerbations
- N-acetylcysteine: EXAMa glutathione prodrug, depletion of antioxidants in the neutrophils and airway surface liquid in patients with CF given orally in high doses decreased sputum elastase activity in patients with CF.
Aspects of Preventative care in CF
1) Newborn screening: identify pre-symptomatic identification of nutritional and respiratory
complications.
2) Immunization: RSV prevention using palivizumab should be considered in all children younger than 2 years of age, and it is recommended in high-risk patients., Anti-pneumococcal vaccines recommended
3) Avoiding nutritional deficiencies.
4) Eradicating P. aeruginosa
Contraindications to lung transplant
- Malignancy in last 2 years
- Untreatable advanced dysfunction of another organ
- Non-curable extrapulmonary infection (not necessarily absolute)
- Documented non-adherence to therapy or inability to adhere to follow-up/therapy
- Untreated psychiatric conditions that interfere with adherence
- Absence of a consistent, reliable social support system
- Substance addition (EtOH, smoking, other)
Relative
- Age > 65
- Unstable/critical condition
- Severely limited functional status with poor rehab potential
- Colonization with highly resistant/virulent organisms
- Severe osteoporosis
- Other medical conditions that will get worse with lung transplant
Systemic manifestations of CF
FTT
Malnutrition/kwashiorkor
Micronutrient deficiencies
Esophageal manifestations of CF
GERD
Esophageal varices
Esophagitis/stricture
Pancreatic manifestations of CF
Pancreatic insufficiency
Pancreatitis
CF related diabetes
Intestinal manifestations of CF
Meconium ileus DIOS Constipation Rectal prolapse Fibrosing colonopathy
Hepatobiliary (extrahepatic) manifestations of CF
Microgallbladder Distended gallbladder Cholelithiasis Common bile duct stenosis Cholangiocarcinoma Sclerosing cholangitis
Hepatobiliary (intrahepatic) manifestations of CF
Neonatal cholestasis
Steatosis
Focal biliary cirrhosis
Multilobular cirrhosis
Reproductive manifestations of CF
Impaired fertility in women
Infertility due to obstructive azoospermia in men
Pathophysiology of pancreatic disease in CF
● abN ductal chloride + bicarb secretion
● for healthy pts, pancreas secretes 2.5L/day of bicarb rich fluid
o in pts w CF, impaired electrolyte transport leads to reduced fluid secretion protein hyper-concentration ductal obstruction + viscous secretions
● in the most severe form, pancreatic disease begins in utero
● rapid progression of acinar damage within the 1st yr of life in pts with pancreatic insufficiency replacement of pancreatic acini with fat + fibrous tissue
● to develop pancreatic insufficiency, >95% of pancreatic function must be lost
Pancreatic Phenotype in CF
~85% of CF pts are PI and require enzyme supps
- remaining 5% pts have adequate pancreatic reserve to allow for adequate nutrition and digestion (PS)
PI pts more likely to have meconium ileus, DIOS, + severe liver disease
PS patients as a group have lower mean sweat chloride concentrations, better PFTs, better survival
Newborn screening programs found ~60% pts are PI at diagnosis
Infants with PI have high IRT at diagnosis that decline to undetectable levels by age 7
Majority of PS infants progress to PI within the first 2-3 yrs of life
Genotype-Phenotype Correlation of pancreatic dysfunction in CF
PI and PS phenotypes associated with severe or mild mutations, respectively
Pts who are PI at diagnosis (or who progress to PI) carry severe mutations on both alleles
Pts who are PS carry at least one mild mutation
Mild allele confers dominant effect over the severe allele
Clinical presentation of pancreatic insufficiency
Sx: malnutrition/growth failure, meconium ileus, steatorrhea, rectal proplapse
Stool testing: undigested triglyceride, increased fecal fat losses following 72h study, low
fecal enzymes (fecal elastase)
Fat soluble vitamin deficiencies
Hypoalbumin, hypoproteinemia, edema, growth failure, ascites
Assessment of Pancreatic Function
Pancreatic fxn should be objective assessed at time of diagnosis
Pts who are PS should be monitored regularly for evidence of progression ot PI
Function can be assessed several ways:
- 72h fecal fat collection (+record fat intake)
- PI defined by fat loss >15% of intake in infants <6 mos; >7% of intake in older infants - serum trypsinogen
- at birth serum levels usually elevated, then decline to low-undetectable leves in PI pts by age 5-7
- PS pts show fluctuating levels w/I and above N range at all ages
- in pts who are PS at diagnosis and progress to PI, there’s a delayed decline in serum trypsinogen - fecal elastase -low in pts with PI
Management of Pancreatic Insufficiency
enteric-coated pH-resistance preparations mostly used
o developed to protect the enzymes from degradation by acid and pepsin in the
stomach
o allow for release of enzymes at pH 5.5-6 (enteric coating should dissolve in
proximal small intestine)
Dosing:
o infants 2000-4000 units lipase/120cc formula/breast milk o <4 y.o 1000-2500 units lipase/kg/meal
o >4 500-2500 units lipase/kg/meal
● max 10,000 units lipase/kg/day (risk of fibrosing colonopathy)
● pts should be on high-energy diet rich in fat
● enzymes should be stored in cool, dark place
Factors affecting response to enzymes
- Enzyme supplements (bad storage or expired)
- Poor compliance
- Dietary issues (excessive juice intake - carb malabsorption, inappropriate eating behavior - frequent small meals, high fat -fast foods)
- Low intestinal pH (inadequate breakdown of enteric coating -inability of CF pancreas to produce normal alkaline secretions that help neutralize acidic gastric contents entering the small bowel)
- Concurrent GI disorder (celiac disease, IBD, bacterial overgrowth)
Complications of Enzymes
Fibrosing colonopathy
Allergy
Characteristics of Fibrosing Colonopathy
Colonic narrowing with circular intramural fibrosis (limited to ascending colon or can extend to involve entire colon)
Barium enema: localized apple cord-like lesion in ascending colon, or entire colon can appear contracted and featureless
Increased bowel wall thickness
Histology: severe fibrosis lamina propria, superficial inflammation w eosinophils, cryptitis, apoptosis
Symptoms of Fibrosing Colonopathy
Obstructive symptoms Abdo pain Bloody diarrhea Poor weight gain Monitor closely for development of strictures
Risk factors for Fibrosing Colonopathy
Strong risk association with high dose pancreatic enzyme use
Other risk factors: history of DIOS, meconium ileus, intestinal surgery
Management of Fibrosing Colonopathy
Reduce dose of enzymes to within recommended range
Unclear long-term prognosis
Pathobiology of CFRD
Only pts with PI are at risk - Affects ~1/3 of CF pts
Incidence increases >age 10 (incidence 3-4%)
Family history of type 2 DM increases risk of CFRD 3x
Thought to result from accumulation of viscous secretions in pancreatic duct leading to
duct obstruction, progressive pancreatic fibrosis, fatty infiltration, amyloid deposition
Basal insulin secretion maintained in CFRD; reduction in insulin secretion in response to stimulation
Pts w CFRD have worse lung fxn and nutritional status + reduced survival…BUT treatment with insulin reverses the decline in pulmonary function and restores nutritional status
Microvascular complications (retinopathy, nephropathy) more common than macrovascular complications
Diagnosis of CFRD
Presenting sx usually: asymptomatic, present with subtle symptoms ie impaired growth/delayed puberty, unexplained decline in lung fxn
CFRD can be intermittent at first, occurring with stress ie. Infxn, steroid tx, nocturnal enteral feeds
Diagnostic tool: OGTT
HgbA1c not reliable; can be falsely low
Management of CFRD
Insulin therapy should be adjusted to allow appropriate energy intake for CF pts (35- 40% of calories from fat)
Initiation of insulin therapy results in stabilization of lung fxn and nutritional status
Insulin therapy should be tailored on an individual basis; no data on specific insulin regimens in pts with CFRD
o Most regimens combine basal bolus schedule with intermittent doses of short acting insulin at meal times
HbA1c measurements should be done to monitor long-term glycemic control
Pts should be screened annually for development of microvascular complications w eye exam + urinalysis for microalbuminuria
Pts with CFRD without fasting hyperglycemia are at risk of progression; monitored carefully; these pts may benefit from insulin therapy
Glucose value for CFRD + fasting hyperglycemia
≥ 7
Glucose value for CFRD without fasting hyperglycemia
<7 fasting
≥ 11.1 OGTT
Glucose value for Impaired glucose tolerance
< 7 fasting
7.8-11.1 OGTT
Normal glucose tolerance
< 7 fasting
< 7.8 OGTT
Pathophysiology of Intestinal disease in CF
CFTR localized to apical surface of intestinal crypt + villous cells
Mutations lead to impaired Cl and HCO3 secretion by epithelial cells reduced fluid content in intestinal lumen
Consequence of impaired fluid + lyte transport: meconium ileus in infants and DIOS in older children + adults
CF meconium has lower water content + high protein concentration – results in more viscous, adherent meconium on ileal surface, leading to luminal obstruction
Meconium ileus occurs in 15-20% of pts; usually in pts with 2 severe mutations (class I, II, III)
Characteristics of meconium ileus
Simple: bowel obstruction
Complicated: bowel obstruction + intrauterine complications
S/Sx of Meconium Ileus/DIOS
Abdo distention, bilious vomiting, no passage of stool
AXR: multiple dilated bowel loops with ground glass appearance +/- calcification in RLQ
Contrast enema: unused microcolon + ileal obstruction
Complications of Meconium Ileus/DIOS
50% of pts with MI develop complications: ileal atresia, necrosis, intestinal volvulus, meconium peritonitis secondary to bowel perf
Management of Meconium Ileus/DIOS
o Hypertonic contrast medium (Gastrogragin) will relieve obstruction via dissolution and passage of inspissated meconium
o Hypertonicity of these agents can lead to dehydration/fluid and lyte disturbances, IV fluid + lyte therapy recommended
o Failure of enema therapy indication for surgical intervention:
o Inspissated material can be manually disimpacted or irrigated and removed
o Ilestomy can be placed for instillation of N=acetylcysteine or gastrografin
o Surgical resection may be indicated in complicated cases
Survival of pts with MI >90% and long-term survival similar to CF pts without this complication
Characteristics of DIOS
Due to viscous intestinal contents, CF pts develop partial/complete bowel obstruction
Result of inspissated material in ileum/cecum/proximal colon
Occurs in 4-5% w CF (most of whom are PI); more common in pts w MI in infancy
Complete vs incomplete DIOS
Complete DIOS:
- Complete intestinal obstruction evidence by bilious vomiting or fluid levels in
small bowel on AXR
- Fecal mass in ileocecum o Abdo pain, distention
Incomplete DIOS:
o Short hx of abdo pain or distention
o Fecal mass in ileocecum but w/o signs of complete obstruction
DDx of DIOS
Appendicitis Appendiceal abscess Intussusception Crohn’s disease Fibrosing colonopathy
Management of DIOS
Mngmt: PEG3350, golytely, enema
CI to lavage: complete obstruction or signs of peritonitis
Characteristics of constipation in CF
Much more common than true DIOS
Differentiated from history: pts with DIOS have normal stool frequency ad consistency; pts w constipation have abdo cramping, altered frequency of BMS, difficulty passing stool
AXR shows diffuse distribution of fecal material throughout the colon
Tx: long term laxative use
Characteristics of rectal prolapse in CF
Mostly presents at young age (1mos-3 yrs)
More common in PI pts related to bulky stools
Rx: treat constipation + ensure appropriate dose enzymes
Characteristics of appendicitis in CF
Have high index of suspicion to avoid delay in diagnosis and increased risk of complications: abscess formation, perforation, portal vein thrombosis
Characteristics of intussusception in CF
Prevalence 1% in CF pts
Pts present w colicky abdo pain, vomiting, palpable mass w rectal bleeding
Mostly ileoileal or ileocolic
Lead point is mucoid fecal material adherent to intestinal mucosa
Diagnosis made be U/S, contrast enema, air enema
Surgical intervention for manual reduction/resection rarely required
Characteristics of Pseudomembranous Colitis in CF
50% of pts w CF colonized w C diff (may be related to chronic abx use)
Rare, but C Diff related colitis has been fatal in pts w CF
Sx: bloody diarrhea, toxic megacolon
Rx: metronidazole, oral vanco
Pts w toxic megacolon may need emerg subtotal colectomy
Is there an increased risk of GI malignancies in CF?
Yes
Reports of increased risk of GI malignancies in pts w CF
Ie. Cholangiocarcinoma, colon ca, pancreatic adenocarcinoma, intestinal adenocarcinoma
Increased risk in transplant pts due to immunosuppressants
Pathobiology of Hepatic disease in CF
Both intrahepatic and extrahepatic biliary tract abnormalities
CFTR is expressed at the apical surface of cholangiocytes and epithelium of gallbladder (not expressed in hepatocytes)
Plays role in ductal secretion and creates osmotic and electrogenic forces for passive movement of sodium and water
Apical chloride gradient may be involved in bicarbonate secretion
Most patients with CF have some minor focal hepatobiliary manifestations (only 5% develop severe liver disease with cirrhosis and portal HTN)
Median age = 10 yrs
No correlation between CFTR mutations and cirrhosis/portal HTN (but severe mutations are more likely to have liver disease)
Histology of Hepatic disease in CF
Structural changes of cholangiocytes
Abnormal CFTR with altered bile composition and increased mild acids with inspissation and obstruction of small bile ducts (may release pro inflammatory cytokines)
Clinical presentation of Hepatic disease in CF
CFLD is most important non-pulmonary cause of mortality
Hepatic biochemistry is a poor predictor of CFLD
There are genetic modifiers of CFLD in addition to CF causing mutation
Physical Exam
Hepatosplenomegaly suggests presence of significant liver disease · May shrink with disease progression
Biochemistry: ~ 40% of patients have abnormal values Fluctuate with time
§ If cirrhosis is present, important to assess coagulation and albumin to assess synthetic function
§ If liver enzymes are over 4 times the Upper limit of normal, consider biliary tract obstruction (stones, sludge)
Imaging and diagnostic tools for CF liver disease
U/S
§ Can show structure, size, texture etc of liver and spleen.
§ Doppler can demonstrate blood flow and occasionally varices
Hepatic elastography (Fibroscan) has been used to evaluate for CFLD § Uses U/S to asses the degree of liver stiffness, and can be used to identify fibrosis in other chronic liver diseases
Liver Biopsy is generally not recommended, unless considering a diagnosis other than CFLD
§ Disease is focal, so normal biopsy doesn’t exclude presence of disease
§ If performed, should use U/S guidance
§ Contraindications: uncorrectable coagulopathy, thrombocytopenia (< 80K, dilated intrahepatic ducts or veins, ascites, poor patient cooperation
Extrahepatic Complications of CFLD
- Microgallbladder
- Cholelithiasis
- Biliary tree abnormalities
- Cholangiocarcinoma
Intrahepatic Complications of CFLD
- Neonatal Cholestasis
- Hepatic Steatosis (abnormal retention of lipids within a cell)
- Focal Biliary Cirrhosis
- Multilobular Biliary Cirrhosis (most severe form)
Pathognomonic hepatic lesion of CF
Focal Biliary Cirrhosis
Management of CF liver disease
- Pharmacologic Interventions
- Nutrition
- Portal HTN and Hypersplenism
- Liver failure
Pharmacologic Interventions for CFLD
No specific therapy can alter course of Cirrhosis
Urso improves bile flow, may displace toxic bile acids, and improves bicarb secretion
o Improves biochemical tests but does not change long term outcome
o No beneficial effect on nutritional status
o Dose of 20mg/kg/day divided BID
Taurine has been recommended for CFLD due to taurine deficiency secondary to bile acid malabsorption
o RCT did not sow effect on liver function or fecal fat
Nutrition monitoring for CFLD
Those with CFLD are at higher risk for malnutrition
Higher energy requirements, due to increased fecal fat loss
- Do not restrict protein unless encephalopathy occurs
- Monitor fat soluble vitamin levels, with dose adjustment as necessary
Repeat level 1-2 months post dose change
Management of Portal HTN and Hypersplenism
- Counsel re: risk of variceal bleeding
- Also at risk of GI bleeding, and bleeding due to thrombocytopenia
- Avoid blunt abdo trauma (could lead to splenic rupture)
- Insufficient evidence for prophylactic treatment of portal hypertension before first variceal bleed
Beta blockade is useful in adults with known varices to prevent first hemorrhage
o No trials in children
o Risk of bronchospasm makes these agents less appealing
Treatment of variceal bleeding is the same as other causes of portal hypertension
o Packed red blood cells emergently
o Fresh frozen plasma for coagulopathy correction
o IV octreotide, PPI
o If not responsive to conservative measures, consider interventional endoscopy
Sclerotherapy, band ligation
o Some patients may need portosystemic shunt
Mean survival after first episode of variceal bleeding is 8.4 years
Treatment for CFLD liver failure
- May be stable for a number of years/decades
- Referral to transplant center before end stage liver disease is important given wait times
for cadaveric donors - Once hepatocellular dysfunction occurs:
o Symptomatic/supportive treatment
Treat coagulopathy, ascites, hypoglycemia, fluid and electrolytes, encephalopathy
Consider lactulose and protein restriction in encephalopathy
- 5 year survival post liver transplant is 90% - similar to liver transplant for other reasons
o No evidence that immune suppression affects pulmonary disease
- Can undergo lung transplant, then liver
Pathogenesis of malnutrition in CF
Increased energy losses in those with PI due to malabsorption/maldigestion o Increased energy losses with CFRD and CFLD
Reduced oral intake (anorexia due to resp illness, GER, DIOS, liver disease, sinus disease)
Increased resting energy expenditure (correlated with worsening pulmonary status, possibly due to inflammation and/or work of breathing)
Over time may see weight loss, and with that muscle loss, which affects respiratory status (vicious cycle)
Can be corrected with adequate caloric intake
Nutritional management in CF
- Need to have a multi-D approach
- Anthropometrics performed at each visit
- High energy diet with supplemental fat to optimize caloric intake
- If losing weight, assess energy in, energy out, and expenditure
- May need NG or G tubes
Signs of vitamin E deficiency
Hemolysis
Neuropathy
Signs of vitamin A deficiency
Night blindness
Keratomalacia
Pigmentary retinopathy
Signs of vitamin D deficiency
Poor bone mineralization - osteoporosis
Signs of vitamin K deficiency
Bleeding
Male infertility in CF
Majority of men with CF are infertile
- Due to obstructive azoospermia (Ie Congenital Bilateral Agenesis of Vas Deferens although other obstructions can happen too)
Of men who are infertile, > 2/3 carry at least one CFTR gene mutation
On extensive mutation analysis, 50% carry gene alterations on both alleles
All have at least one Class 4 or 5 mutation on one allele
Suggests male fertility tract is very sensitive to minor losses of CFTR function
