Bronchiectasis, PCD & CF Flashcards
BRONCHIECTASIS
Define, outline the etiology, epidemiology & diagnostic criteria for bronchiectasis.
- *Bronchiectasis:** irreversible abnormal dilatation and anatomic distortion of the bronchial tree
- End stage of multiple disease processes
Females > Males
Incidence decreasing in industrialised countries, more common in crowded housing/low SES
- *Most common causes:**
- CF (Developed) → primary immunodeficiency
- Proximal airway narrowing (tumors, malacias, stenosis- ring/web, FB)
- Airway injury/infection (bronchiolitis obliterans, recurrent pneumonitis/pneumonia, ABPA)
- Altered host defences (CF, PCD, impaired cough)
- Altered immune states (PID, HIV/immunosupression)
Diagnostic criteria
1. Clinical: Chronic, recurrent cough (>3 episodes lasting >4weeks) +/- exertional dyspnoea, foul smelling breath, growth failure, clubbing, hyperinflation/chest wall abnormality
2. Radiological: XR/HRCT tram tracking, signet rings/dilated bronchi, gloved finger sign, PFTs- obstructive pattern
→ consider specialist referral if: abnormalities persisting CXR >6weeks, cough not responding to >4wks antibiotics, >3x episodes
→ absence of radiological findings = chronic suppurative lung disease
BRONCHIECTASIS
Outline the pathogenesis, clinical manifestations & classification of bronchiectasis
Pathogenesis
bronchi (lower airways) ectasis (inflammation)
Obstructive disease. Results from diseases that cause chronic nflammation in lower airways → leads to mucus plugs which obstruct airways. Immune cells (NF-Kb- releases IL1 & 8, TNF) → neutrophil activation damage epithelium & elastin (via elastase/MMP), deposition of collagen with wound healing (fibroblasts).
- Difficulty clearing secretions → worse infections → ongoing airway injury
- Hypoxia leads to vasoconstriction of pulmonary arterioles increasing vascular resistance (pulmonary hypertension → RVH → cor pulmonale)
- *Clinical manifestations**
- Productive cough ++ sputum, haemoptysus, fevers (when infective exacerbation), poor weight gain/anorexia
- Localised crackles, wheezing, digital clubbing, dyspnoea & hypoxemia when unwell
- History suggestive (CF- male, recurrent GI Sx, immune deficiency- recurrent ear/skin infections, severe eczema, recurrent aspiration/story of inhaled FB- choking/gasping)
- *Classification**
- Pre-bronchiectasis (reversible): recurrent/chronic infections- non-specific HRCT findings
- HRCT bronchiectasis (may persist, worsen or resolve): CT evidence
- Established (irreversible): >2 yrs
BRONCHIECTASIS
What are some investigations, management & complications, how can bronchiectasis be prevented?
Investigations
X-ray findings (non-specific)
- tram line (thickened bronchi), parallel lines (inflammation/ectasia), ring shadows (cross sectional thickening), toothpaste shadows (mucus impaction2nd-3rd order bronchioles), gloved finger (thickening + mucus)
- perihilar opacities
- increased bronchovascular markings
- crowding of bronchi
- decreased lung volume, increased air spaces, honeycombing (severe)
HRCT findings (gold standard for diagnosis)
- Increased bronchio-arterial ratio
1. Cylindrical: regular/thickened outline, tram-lines/signet rings, bronchial lumen ends abruptly
2. Varicose: beaded contour
3. Saccular: ballooning that ends in mucus plugs (most severe) - Lower lobes >upper lobes
- *Routine workup:** FBE, immunoglobulins, sweat test/CFTR, airway culture, PFT (obstructive, restrictive, mixed), aspergillus serology
- *Additional:** FeNO, nasal ciliary brushings (PCD), bronchoscopy, VFSS- aspiration, additional immune labs
Treatment:
Aim to decrease obstruction and treat infection
- Prevention: decrease smoke exposure, complete vaccines + pneumovax/flu, early diagnosis/treatment of infections/contributing diseases
- Antibiotics (based on previously cultured organisms), long term prophylaxis → pseudomonas
- Anti-inflammatory:- azithromycin, ibuprofen/steroids - not recommended
- Percussion/postural drainage
- Surgery: lobectomy, lung transplant
PRIMARY CILIARY DYSKINESIA (Kartagener Syndrome)
What is the structure/function of cilia
Outline epidemiology, pathogenesis & genetic determinants
PCD is an inherited disorder leading to impaired ciliary function (akinesia, dyskinesia, aplasia)
Epi/genetics:
1/12-20,000
5% of kids with recurrent respiratory conditions
Autosomal recessive, rarely AD/XLI
18 genes that encode cilia structure/function
Delayed diagnosis- often around 4yrs as difficult to diagnose
- *Key features:**
- *Chronic sinuopulmonary disease**
- *Persistent middle ear effusions**
- *Laterality defects**
- *Infertility**
Cilia structure:
9+2 microtubules- dyenins power beating
- Primary- sensory/signalling organelles, sense changes in environment (nephron, bile duct, brain)
- Motile- move debris/mucus, airways, sinuses, eustachian tube
- Nodal- embryonic- guide development of foetus
Pathophysiology:
Abnormality in cilia microtubules or dyenin arms → abnormal orientation on mucosal surfaces, prevents synchronised beating → impaired mucociliary escalator
- Most common = absence of dynein arms leads to poor movement (sperm & cilia)
PRIMARY CILIARY DYSKINESIA (Kartagener Syndrome)
What are the clinical features, investigations & treatment options. Outline prognosis
- *Clinical features:**
- Neonatal respiratory distress
- Persistent rhinosinusitis
- Chronic OM/CHL
- Chronic cough, recurrent pneumonia & bronchiectasis +/- clubbing
- L→R laterality defects - 25% have situs inversus, heterotaxy, congenital cardiac defects, asplenia/polysplenia
- Infertility (male - sperm dysfunction, female fallopian tubes)
- Case reports of hydrocephalus (ciliated ventricles) - if laterality defect/hydrocephalus antenatally =likely PCD
- X linked retinitis pigmentosa
Kartagener triad = 1) situs inversus totalis 2) chronic sinusitis 3) bronchiectasis
- *Common pathogens:**
- H. Influenze (non-typeable), S.Aureus, S. Pneumoniae, Pseudomonas*
- ENT bugs
DDx CF → would expect biliary/GI symptoms (absent in PCD)
Investigations:
Screening: nasal nitric oxide, mucociliary clearance test (inhalation of tracer)
Diagnostic: biopsy → transmission electron microscopy (Shortening or absence of dynein arms seen in 90% of cases with ultrastructural defects) ciliary beat frequency, high resolution/high speed digital imaging
- *Treatment:**
- No curative therapies
- Surveillance → PFT, imaging, cultures
- Enhance drainage (chest physio, percussion vests, PEEP devices)
- Treat infective exacerbations (inhled/systemic ABx)
- Grommets
- Sinus/nasal therapies
- *Prognosis**
- Many have normal lifespan
- Increasing LRTI burden with age → can progress to end stage lung disease
- Slower decline/better long term prognosis than CF
CYSTIC FIBROSIS
Outline the epidemiology and genetic factors contributing to CF
Cystic Fibrosis common life limiting genetic multi-system disease
- *Epidemiology**
- Caucasian populations (North Europe, America, Aus & NZ)
- Autosomal recessive
- 1 in 25 individuals are a carrier, 1 in 2500 liv births affected (in above population)
- Median survival late 30’s, 80% make it to 30’s
- *Genetics**
- *1. Genes:** on chromosome 7 → CFTR gene → encodes CFTR protein (1480 AA)
- 5 main classes of mutations 1→3 most severe, 4→5 more mild
- >1900 polymorphisms
- Most prevalent deletion of a single phenylalanine residue at amino acid 508 (ΔF508)
- 50% of CF patients (Northern European) homozygotes, 80% heterozygotes/ 90% heterozygotes in Aus
- W1282X 60% of Ashkenazi Jews with CF
- *2.** Structure: Chloride channel/other regulatory functions expressed on sweat glands & mucus producing cells (airways, GI/GU tract)
- ATP-binding cassette protein
- 2x 6 membrane spanning regions, 2x intracellular nucleotide binding folds, 1x R-domain with phosphorylation sites
- Channel usually activated by phosphorylation of R-domain, presence of ATP in binding folds
- Presentation: Complex relationship between genotype and phenotype
- More severe phenotype usually associated with pancreatic insufficiency, rapid progressive lung disease
- Class 1: Lack of protein production → NO CFTR
- Class 2: Defect in protein processing (CFTR trapped in R domain, does not migrate to surface) → substantially reduced protein (f508del)
- Class 3: Defect in regulation (CFTR not activated by ADP/phophorylation) → non functional channel present on membrane (G551D)
- Class 4: Reduced Cl- transport (CFTR present on membrane) - R117H
- Class 5: Reduced CFTR production (but present on membrane)
- Class 6: Accelerated turnover
CYSTIC FIBROSIS
What is the pathogenesis, natural history & prognosis
- *Key features**
- Decreased water in mucus (thicker secretions) → difficulty clearing → recurrent respiratory infections
- Increased chloride in sweat
- *Pathophysiology**
- Inability to secrete chloride leads to inability to secrete water (excessive reabsorption of sodium & water) → dried out, thick & proteinaceous secretions which are difficult to clear, affecting lungs, pancreas, hepatobiliary system, vas deferens.
- Elevated chloride levels in sweat (salts not reabsorbed from sweat)
Natural history
30% infants will have pseudomonas by age 3ys
90% infants will have bronchiectasis by 5yrs
Prognosis
Life limiting disorder
20% will die before 30yrs
Survival dramatically improved with new therapies
CYSTIC FIBROSIS
Outline history, exam & diagnostic criteria. Are there possible DDx? What is the nt
Clinical presentation/features
Most commonly diagnosed on newborn screening
20% Meconium ileus
45% Respiratory symptoms
28% Failure to thrive
- Chronic diarrhoea or rectal prolapse
- Steatorrhoea/fat globules in stool MCS
- *Examination**
- Chest: increased AP dimension, hyperresonance, scattered/localised crackles, expiratory wheeze
- Clubbing
- Cyanosis
- Abdomen: protuberant abdomen
- Decreased muscle mass, poor growth
- *DDx:**
- Primary immunodeficiency
- PCD
- Shwachman-Diamond syndrome- pancreatic insufficiency & recurrent haematological abnormalities
CYSTIC FIBROSIS
Outline screening tests and investigations, what is involved in diagnostic workup?
Testing
1. Newborn Screening (90% of cases)
- Guthrie card heel prick on D2-4 of life
- Measures serum trypsinogen via immunoreactive assay (IRT) → if over 99th centile likely to have one of 12 common gen mutations
- Then referred for sweat testing if +ve = refer to CF clinic (affected), if -ve = carrier
- If IRT raised but no gene on DNA testing then unlikely to have CF
- Early detection may lead to better prevention of complications/reduced morbidity- optimization of nutritional deficiencies
NOTE: Infants with positive newborn screen for CF, elevated immunoreactive trypsinogen and 1 or 2 copies of CFTR who have an initial negative sweat test and are asymptomatic – CFTR metabolic syndrome and should be followed clinically
- *2. Sweat testing**
- Gold standard for diagnosis
- Pilocarpine administered to skin via electric current → activates sweat glands
- Difficult to perform first 2weeks
- Diagnosis requires 2x positive results (must repeat if 1st pos)
- Lower readings = may retain pancreatic function
- False negatives related to many conditions
- >60 mEq/L of chloride diagnostic – lower in infants 30-40 mEq/L
- *3. DNA testing**
- Identifies >90% of cases containing 2x mutations
- Can sequence for entire library of known CFTR mutations if 12 most common not found & suspicious (+ve sweat test/screening)
- *4. Other**
- Nasal potential difference test (if diagnostic workup inconclusive)
- Electrolytes (Low Na, K)
- Blood gas (metabolic alkalosis)
- Exocrine pancreatic function → faecal elastase 1 activity (fresh stool), 72h stool total fat, stool gallery & diet history (quantify fat consumed, should absorb >93%)
- Endocrine pancreatic function → 2h OGTT yearly
- CXR (hyperinflation, bronchial thickening + plugging, patchy atelectasis, hilar opacities → bronchiectasis/cysts/ bowing of sternum/narrow cardiac shadow once advanced)
- Pulmonary function tests - obstructive with mod bronchodilator response, RV/FRC increased early, then restrictive changes later reduced TLV/VC (fibrosed lung with extensive injury)
- Sputum MCS/BAL: S. aureus, P. aeruginosa, B cepacia complex - strongly suggestive of diagnosis, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans, fungi, and NTM
- Sperm analysis - azoospermia
- Genetic counselling
CYSTIC FIBROSIS
Outline the respiratory clinical manifestations
Lungs
Mucociliary escalator impaired
- Leads to mucus plugging
- Inflammatory cascade involving proteases/immune signalling leading to airway inflammatory response → over time develop bronchiectasis
- Secretions also acidic- less antimicrobial function of mucus, impaired defenses against pathogens
- Recurrent infections & colonisation (MRSA/gram +ve in younger kids, gram -ves in older kids- pseudomonas)
Progression
- Key determinant of morbidity
- Genotype dependant
- Male + pancreatic sufficiency = slower progression
- Late stage = cor pulmonale → respiratory failure & death
- *Cough**- most constant symptom
- Initially dry/hacking → wet/productive ++ purulent mucus
- Most prominent in morning/after exercise
- *Sinus involvement**
- Opacified paranasal sinuses, frequent sinusitis
- Inflamed MM → obstruction, rhinorrhea +/- polyps
- Polyps usually in 15-20% of patients between 5-20yrs
- *Complications (later life)**
- ABPA: 15-30% patients, wheezizng/cough/dyspnoea
- Atelectsis
- Haemoptysus (airway erosion due to infection)
- Pneumothorax
- Bone and joint complications = CF associated arthropathy (elevation of periosteum in distal long bones- pain, erythema & effusions)
- *Infective exacerbations**
- Increased cough frequency/duration, increased sputum/change in appearence, SOB/reduced exercise tolerance, congestion, reduced appetite, fever, tachypnoea, increased WOB
- Change in CXR/PFT, leukocytosi, weight loss
- Hospitalisations for IVABx
- Preventative ‘tune up’
CYSTIC FIBROSIS
Outline gastrointestinal clinical manifestations
-
Meconium ileus (10-20%, neonate)
- 10-20% of newborns with CF (increased frequency if older sibling also had mec ileus)
- 80-90% w/ mec ileus have CF - highly predictive (other conditions associated incl. pancreatic stenosis)
- Abdominal distension, vomiting & failure to pass meconium 24-48h
- AXR dilated bowel with air fluid levels, ‘ground glass’ in lower abdomen, calcifications in peritoneum/scrotum if rupture
- Can lead to bowel rupture/peritonitis rarely
- Meconium plug - increased frequency in CF patients but less specific sign
- Rx NGT insertion/decompression, TPN for gut rest, gastrograffin enema can confirm diagnosis, surgical disempaction -
Distal intestinal obstruction syndrome (3-10%, older)
- Usually older >15yrs
- More severe mutations associated
- Accumulation of thick/tenacious muco-faeculent matter at terminal ileum/caecum → leads to partial/complete obstruction
- Can be caused/exacerbated by dehydration, illness w fever, reduced enzyme supps, liver disease, anticholinergic/opiates
- Cramping abdominal pain, distension, constipation, RIF mass
- AXR/USS to investigate
- Partial obstruction- continue enzymes, laxatives + hydration → bowel lavage via NGT
- May need to look at compliance/increase creon dose, address constipation factors
- Consider surgical consult if failing conservative management, -
Structural
- Rectal prolapse- Less common, more in older patients due to malnutrition/repetitive cough
- GERD- due to increased abdominal pressure, may exacerbate lung disease -
Malnutrition/nutrient deficiencies
- A- poor night vision
- D- poor bone density
- E- neurological dysfunction/haemolytic anemia
- K- low platelets→ bleeding diathesis -
Other
- Intussusception
- Subacute appendicitis/abscess
- Increased risk of colon/biliary tree cancers
- IBD Crohns 17x more likely
- C.Difficile infections
CYSTIC FIBROSIS
Outline pancreatic & hepatobiliary manifestations
Pancreatic system
Thick secretions plug pancreatic ducts
- Decreased exocrine & endocrine function
- Malabsorption (ADEK) & steatorrhoea?
- Failure to thrive
- Insulin dependant DM
Heptobiliary system
Secretion of thick, viscous bile & decreased alkalinity
- Damage/obstruction to small bile ducts
- Increased free radicals, decreased toxin management- damage to hepatocytes
- Activation of stellate cells → production of collagen → activation of cytokines → fibrosis/biliary cirrhosis
- *1. Exocrine pancreas insufficiency**
- >85% children show protein/fat malabsorption, ⅔rds present from birth then additional 20-25% within first years of life
- Most patients with f508 deletion, (R117H and 3849 = preserved pancreatic function)
- Failure to thrive & steatorrhoea
- Hypoglobulinaemia → oedema, deranged electrolyes/anemia
- *2. Endocrine pancreas insufficiency (CFRDM)**
- Impaired insulin secretion, insulin resistance
- Destruction of islet cells due to obstruction with thick mucus → exocrine damg → fibrosis
- Initially OGTT positive → fasting BGL/HbA1c positive
- Hyperglycemia, glucosuria/polyuria, polydipsia
- Contributes to reduced lifespan if poorly controlled (can exacerbate infections- pseudomonas/b.cepacia)
- Leads to growth delay, puberty delay
- Females, pancreatic insufficiency & f508deleion related
- Less microvascular complications
- *3. Pancreatitis**
- 10% of CF patients
- Recurrent acute in patients with residual function
- Biliary cirrhosis
* *Accounts for 5-8% of mortality – all have multilobular cirrhosis**
- Fatty liver/BC up to 70% patients, BC symptomatic in 5-7% , severe liver cirrhosis 10-15% (most w/ pancreatic insufficiency)
- Liver dysfunction in first 15yrs, up to 30% patients
- RFs: neonatal disease, pancreatic insufficiency, alpha-1-trypsin deficiency, meconium ileus
- Hepatomegaly, hypersplenism, varices, icterus, ascites, abdominal pin, deranged LFTs
- For workup: exclusion of other causes of liver disease – most important is celiac disease and partial alpha 1 deficiency
- Assess synthetic function of liver, Imaging – USS, Scintigraphic studies, MRCP and liver biopsy – may be required
- Can treat with ursodeoxycholic acid, fat soluble vitamins, H2 blockers
- If signs of end stage hepatic failure/impacting pulmonary function consider transplant
CYSTIC FIBROSIS
What are the treatment options, what are some complications and how are complications managed?
- *Key points**
- Decrease morbidity/mortality & maintain stable progress
- Early intervention
- 1-3mo appointments
CHEST
- *1. Chest physiotherapy**
- Manual techniques, postural drainage
- Active breathing cycle techniques
- Autogenic drainage
- PEEP/oscillatory PEP (i.e BiPAP)
- Exercise
- *2. Mucolytics**
- Hypertonic saline 6% → draws water into secretions to loosen mucus & improve clearence (needs bronchodilator premed)
- Human recombinant DNAse (pulmozyme/dornase alfa)- inhaled, breaks up exttracellular DNA to loosen mucus, improves pulmonary function/decreases exacerbations
- Mannitol (powder, inhaled) - osmotic agent
- *3. Antibiotics/monitor microbiology**
- Reduce intensity of infection to delay progressive damage
- Intermittent short course oral ABx to IV continuous ABx (single/multiple agent), aerosolised (tobramicin/colistin/gentamicin for pseudmonas, limited evidence)
- Prophylaxis first 2 yrs of life for staph
- Treat viral infections with ABx- 2/52 augmentin
- If pseudomonas - 2/52 ciprofloxacin → IV aminoglycoside/penicillin/3rd gen cefalosporin
- Azithromycin (250-500mg 3x weekly)- suppresses alginate production/increases PFTs in long term pseudomonas patients
- Successful eradication = 3x negative cultures 1mo apart, 1x negative BAL culture, 1x other negative culture 1mo apart
- *4. Bronchodilators**
- For patients with reversible obstruction/asthma
4. CFTR modulators
Ivacaftor (Class 3 gating mutations i.e G551D, S549N, V520F/Class 4 residual function mutations R117H, D115H, R347P)
- Small molecule potentiator
- Need 1 copy of each
- Children >2yrs
- Ineffective for class 1 or 2 mutation
Lumacaftor + ivacaftor / tezacaftor + ivacaftor
- Combined therapy my be effective in f508del
- >12yrs
GUT
- *1. Diet**
- High calorie diet - increased respiratory effort/metabolism
- Managing respiratory complications improves weight gain
- NG/PEG supplementation if not winning orally
- *2. Enzyme replacement**
- Creon - varying strengths/doses
- Avoid excessive doses as can lead to strictures
- Reduced DIOS rates
- *3. Vitamin/mineral supplements**
- ADEK supplementation +/- Zinc, iron
- CF specific brands available
- *4. CFRDM**
- Insulin, avoid steroids
- Long acting Nocte initially
- Give highest dose tolerated without hypoglycemia, if post prandial hyperglycemia can titrate up
CYSTIC FIBROSIS
Outline common chest infections in CF patients
Infections in CF patients
Common culprits
Staphylococcus Aureus
- Most common pathogen isolated in children
- <6mo age most prevalent, but remains significant throughout life
- 30-40% CF kids are colonised
- Increasing prevalence of MRSA infection, associated with worse survival
- Prophylaxis with augmentin duo <12mo
- IV flucloxacillin/cefalexin (clindamycin, vancomycin, teicoplanin if MRSA)
- Symptoms/damage significantly worsened if pseudomonas co-infection
- *Haemophillus Influenzae**
- Second most common pathogen <6mo
- Augmentin prophylaxis/treatment dosing for exacerbations
- *Pseudomonas Aeuriginosa**
- Around 1yrs, 30% by age 3 then increasing prevalence with age- 60% of adults colonised
- Progresses from intermittent colonisation to chronic infection
- Treat with inhaled tobramycin (2mo -> ongoing), oral ciprofloxacin (2/52)
- Risk factor for pulmonary decline/worsening survival
- *Burkholderia Cepacia**
- Chronic infection, ubiquitous bug with easy spread, difficult to treat
- Associated with rapid decline/shortened survival
- Subtypes genomovar 3 most severe
- Rx ciprofloxicin, co-trimoxazole, choloramphenicol
- Contraindication to transplant due to recurrent infection
- *Stenotrophamonas Maltophilia**
- Increasing prevalence
- Minimal impact on survival
- Safe to treat only if clinical symptoms (co-trimoxazole)
- *Mycoplasma (NTB)**
- Can form abscess complexe
- Prolonged treatment with multiple agents (4-6 weeks IV)
- Fevers, cystic lesions/multiple infiltrates
- Acid fast bacilli on micro
- *Allergic bronchopulmonary aspergillosis (ABPA)- fungal**
- Immunologic reaction to aspergillus species
- Most common aspergillus fumigatus
- 2-15% patients with CF, patients with pre-existing asthma
- Usually >6yrs
CYSTIC FIBROSIS
Outline pathphys, presentation, investigation & diagnosis of ABPA
Pathophysiology
- Aspergillus colonises bronchioles -> persistent inflammation -> IgE mediated response -> hypersensitivity & reactive airways disease (CD4+ Th2 cells) -> damage to bronchial wall (erosion of smooth muscle/cartillage) -> bronchiectasis/granlomatosis
Presentation
- Increasing cough/wheeze
- Orange/rust coloured sputum
- Reduced pulmonary function (PFTs)
Initial investigations/findings
- CXR findings- upper lobe & central infiltrates/ evidence of bronchiectasis:
- tram lines/ring shadows: thickened bronchial walls
- parallel lines: dilated/ectatic bronchi
- toothpaste shadows: impacted mucus in 2-4th segmental bronchi
- gloved finger shadows
- perihilar opacities
- IgE (elevated)
- Serum specific aspergillus IgE/ antibodies to A.Fumigatus
- Sputum culture +ve 60% cases
- SPT
Diagnosis
- Predisposing condition (asthma or CF)
- Positive SPT or specific IgE
- Elevated eosinophil count, radiographic findings, elevated total IgE, antibodies present
Treatment
- Prolonged/high dose steroids
- Antifungals- if unable to taper steroids
Anti-IgE- omalizumab (refrctory)
