Lung Disease (Miscellaneous) Flashcards
Definition of pulmonary alveolar proteinosis (histopath)
Presence of finely granular, lipo-proteinaceous material filling pulmonary alveoli and terminal air spaces
- *syndrome not disease
- alveolar accumulation of surfactant
Most common cause of PAP
Autoimmune
= autoantibodies against GM-CSF which stimulates alveolar macrophages to clear surfactant
3 types of PAP
1) Congenital/Hereditary - disease of surfactant homeostasis, lysinuric protein intolerance
2) Secondary PAP
3) Autoimmune (GM-CSF Ab)
Causes of secondary PAP
- Hematologic (myelodysplasia, malignancies, aplastic anemia)
- Chronic infections (HIV)
- Toxic inhalation (silica metal fibres)
- Myelosuppression
Infections that can cause secondary PAP
- Nocardia
- Mycobacterium TB
- MAC
- Pneumocystis
- HIV
PAP finding on imaging, BAL and lung biopsy
CXR: diffuse granular alveolar and interstitial infiltrates
CT: crazy paving, ground glass, interlobular septal thickening
BAL: PAS + proteinaceous material
Histo: protein material and macrophages, type 2 cell hyperplasia
Micro: SP-B = abnormal disorganized lamellar bodies
ABCA3: fried egg appearance
Unique feature of PAP secondary to surfactant production disorder
If there is abnormal surfactant -> alveolar distortion and accumulation of abnormal surfactant
- *different clinical presentation than primary PAP
- doesn’t respond well to whole lung lavage
Causes of primary PAP
1) Hereditary: CSF2RA, CSF2RB - encodes GM-CSF receptor and alpha/beta chains (AR)
2) Autoimmune
What is the stain for surfactant?
Periodic acid-schiff reagent (PAS)
Treatment options for PAP
1) mild = watch
2) whole lung lavage
3) GM-CSF augmentation
4) Rituximab (anti-CD20 tx)
5) Bone marrow transplant
6) Lung transplant
6 pulmonary complications of inflammatory bowel disease
1) Bronchiectasis (most common)
2) Tracheal stenosis
3) Ileobronchial, colobronchial fistula
4) Cryptogenic organizing pneumonia
5) Granulomatous and necrobiotic nodules
6) ILD
Other: pulmonary vasculitis, drug induced disease, opportunistic infection, malignancy, pulmonary embolism
Slow vs forced vital capacity - which is better?
Forced: increased dynamic compression leading to airway collapse, decreased air mobilization and air trapping
Slow: unforced maneuver, less intrathoracic pressure, larger volume of air can be moved
higher in airway obstruction so use largest VC for FEV1/VC ratio
3 common CXR findings for Sarcoidosis
1) Normal
2) Bilateral hilar lymphadenopathy
3) Parenchymal infiltrates
(or combo of 3)
Imaging stages of Sarcoidosis
0 = normal 1 = bilateral hilar lymphadenopathy 2 = bilateral hilar lymphadenopathy + parenchymal infiltrates 3 = parenchymal infiltrates alone (4 = fibrosis)
Stage 1 = most common in children
Lab tests for Sarcodosis
- Increased ACE
- Hypercalciuria - urine Ca/Cr ratio
- Hypercalcemia
- Increased ESR
- Anemia
- Leukopenia
Hallmark histopath lesion of Sarcoidosis
Non-caseating granulomas (most located in perilymphatic areas)
Most common PFT abnormality in Sarcoidosis
Restrictive and reduction in DLCO
Criteria for consideration of steroids in Sarcodosis
1) Worsening symptoms
2) Decreased lung function
3) Progressive radiographic changes
1mg/kg/day x 4-6 weeks then taper, usually continue for 12-18 mos
relapse = increase steroid dose or alternate immunosuppression +/- cytotoxic treatment
Alternatives = methotrexate, hydroxychloroquine, infliximab
6 upper/lower airway manifestations of GPA
Upper: Sinusitis, nasal septal ulcers, subglottic stenosis
Lower: DAH, lung nodules, tracheobronchial stenosis, cavitary nodules
Specific blood test for GPA
PR3 ANCA
Histopathology of GPA
Necrotizing vasculitis of the small blood vessels without immune complex deposition
GPA triad
Upper airway
Lower airway
Renal disease
Usual presenting pulmonary symptoms of GPA
Dyspnea or chronic cough
Lung abnormalities found in Down Syndrome
Acinar hypoplasia
Subpleural cysts
Most common endoscopic finding in Down Syndrome
Tracheobronchomalacia
Factors predisposing to OSA in Down Syndrome
1) Midface hypoplasia
2) Relative macroglossia
3) Small upper airway with superficial tonsils
4) Increased secretions
5) Obesity
6) Hypotonia
Factors relating to increased rate of pulmonary infections in Down Syndrome
1) Decreased pulmonary reserve due to morphological differences
2) Poor immune function
3) GERD
4) Aspiration
5) CHD
6) Thoracic cage malformations
Approach to prevent and treat lower respiratory infections in Down Syndrome
1) Immunization
2) Immune: immunoglobulin levels, functional antibodies, lymphocyte subsets
3) Yearly flu shot
4) Pneumococcal vaccine after 2yrs
5) Consider prophylactic antibiotics with frequent infections
CV disease leading to pulmonary edema in Down Syndrome (3)
Pulmonary venous HTN
Decreased lymphatic flow
Left to Right shunts
5 causes of hypersensitivity pneumonitis
1) Birds (most common in children)
2) Farmer’s lung
3) Drugs
4) Bagassosis
5) Humidifiers
Pathologic findings on BAL and biopsy in hypersensitivity pneumonitis
BAL = lymphocytosis (increased CD8) and increased NK cells Bx = alveolitis, non-caseating granulomas, giant cells, foamy alveolar macrophages/fibrosis
Major criteria for hypersensitivity pneumonitis (need 4)
1) Symptoms compatible with hypersensitivity pneumonitis
2) Evidence of antigen exposure
3) Radiographic changes consistent with hypersensitivity pneumonitis
4) BAL lymphocytosis (CD8)
5) Lung biopsy with consistent histology
6) Positive natural challenge
CXR and HRCT findings of hypersensitivity pneumonitis
CXR: reticulonodular infiltrates, linear opacities
HRCT: Acute: GGO
Subacute: Micronodules, Air-trapping
Chronic: fibrosis +/- honeycombing, emphysema
Minor criteria for hypersensitivity pneumonitis (need 2)
1) Bibasilar rales
2) Decreased DLCO
3) Hypoxemia
4) Clinical presentation
Most common PFT abnormalities with hypersensitivity pneumonitis
Restriction with decreased volumes, low DLCO
Classic triad of subacute hypersensitivity pneumonitis
1) Interstitial lymphocytic-histiocytic cell infiltrate
2) Bronchiolitis obliterans
3) Non-necrotizing granulomas
Treatment for hypersensitivity pneumonitis
1) Stop antigen exposure
2) Steroids
3) Supportive
2 pulmonary and PFT findings of Scleroderma
- ILD
- Pulmonary HTN
- Aspiration
- Cardiomyopathy
- Bronchiectasis
- Hemorrhage
PFT = restriction and low DLCO
General pathology features of surfactant production disorders
- Alveolar epithelial cell type 2 hyperplasia
- Interstitial thickening with mesenchymal cells
- Fibrosis (later disease)
- Proteinaceous material and foamy macrophages
Histology findings specific for:
- NKX2-1
- SP-B
- ABCA3
NKX2-1: Alveolar simplification
SP-B: Poorly organized lamellar bodies
ABCA3: Absent or small, abnormally formed lamellar bodies with fried egg appearance
Components of Surfactant
80% phospholipids
8% protein
8% lipids (cholesterol)
Risk factors for Drug induced lung disease
1) Cumulative dose
2) Patient age
3) Prior/concurrent radiation
4) Oxygen therapy
5) Other toxic drugs
Criteria for drug-induced lung disease
1) History of ingestion of drug known to cause injury
2) Clinical manifestations caused by drug
3) Other causes ruled out
4) Improvement after drug discontinuation
5) Exacerbation with resuming drug
Usual BAL differential
Macrophages 80-90%
Lymphocytes 5-10%
Neutrophils 1-2%
Eosinophils 0-1%
Max Lidocaine dose for Bronch
4mg/kg
2% = 20mg/ml
1% = 10mg/ml
Pathology findings of constrictive and proliferative bronchiolitis obliterans
Constrictive: peribronchial fibrosis
Proliferative: airway obstruction by intraluminal polyps of inflammatory granulation tissue, masson bodies
Pathology lesions characteristic of cryptogenic organizing pneumonia
Excessive proliferation of granulation tissue -> consists of loose collagen-embedded fibroblasts and myofibroblasts involving alveolar ducts + alveoli +/- bronchiolar intraluminal polyps
Treatment of cryptogenic organizing pneumonia
Steroids (IV or PO)
Macrolides
BAL findings in:
1) Sarcoidosis
2) LCH
3) Hypersensitivity pneumonitis
4) Pulmonary hemorrhage
5) Aspiration
1) Lymphocytosis (increased CD4:CD8 ratio)
2) no eosinophils, stain S-100, CD1a, langerin
3) Acute = neutrophilia, >48hrs = lymphocytosis, increased CD8
4) Gross blood, increasing with each sample
5) Lipid laden macrophages
2 pathology features of desquamative interstitial pneumonitis
Foamy alveolar macrophages
Type 2 alveolar cell hyperplasia
Differences between acute and chronic eosinophilic pneumonia
Acute:
- children
- Smoking = risk
- Male predominance
- no underlying asthma risk
- presents as acute febrile illness
- BAL > 45% eos
- normal blood eosinophils
- some elevation in IgE
- responds to steroids
- No role for Xolair
What is crazy paving?
Ground glass opacity with superimposed interlobular and intralobular septal thickening
Causes of crazy paving
ARDS, bacterial pneumonia, PAP, DAH, sarcoidosis, vasculitis, pulmonary edema, chronic eosinophilic pneumonia, lipoid pneumonia, COP, PJP
Causes of a solitary pulmonary nodule
Mets
Infectious granuloma (TB, fungal, atypical mycobacteria), Infections (abscess, echinococcus, PJP, aspiration)
Benign (hamartoma, lipoma, fibroma)
Vascular (AVM, infarct)
Bronchogenic cyst
Inflammatory (GPA, rheumatoid inflammation, sarcoid)
Causes of diffuse pulmonary nodules
Inflammatory (GPA, Sarcoid)
Infection (TB, fungal, septic emboli)
Thrombotic
Mets/Malignancy
Consolidations without air bronchograms
Mass
Aspiration
Hemorrhage
Atelectasis
Primary “look” of PAP on imaging
Diffuse consolidative with interstitial pattern
What can fill alveoli?
Air Pus Blood FLuid Protein
Risk factors for Acute Chest Syndrome in Sickle Cell Anemia
Age (esp 2-4 yrs) Pulmonary infection (mycoplasma) Fat embolism Post-op atelectasis Low concentration of fetal hemoglobin Bronchospasm due to asthma Higher WBC count Genetics (HbSS)
What is the most important risk factor for CLD in Sickle Cell Anemia?
Recurrent ACS
Most common cause of death in Sickle Cell Anemia?
ACS (second most common cause of hospitalization)
Causes of chronic cough
Chronic = 4-8 weeks
Dry: Allergic rhinitis, asthma, GERD, TB malacia, habit cough, ILD, post infectious cough (pertussis, mycoplasma), drugs (ACEi)
Wet: CF, PCD, retained FB, Aspiration, immunodeficiency, chronic endobronchial suppurative disease (non CF bronchiectasis, PBB)
Other: chronic infection (TB, chlamydia, CMV), non-infective bronchitis, mediastinal mass
Causes of chronic pulmonary disease in HIV AIDS
1) Immune reconstitution inflammatory syndrome (develops in context of recovery of CD4 cells following initiation of ART)
2) ILD (lymphocytic infiltrate in the peribronchial and pervascular tissue and interlobular space)
3) Pulmonary HTN
4) Recurrent Infections
5) Bronchiectasis and BO
6) Malignancy
Risk factors for development of Immune Reconstitution Inflammatory Syndrome in HIV/AIDS
Low CD4 count prior to initiation of ART
Opportunistic infection treatment proximal in time to ART initiation
Path findings in Hypersensitivity Pneumonitis
Acute = Interstitial mononuclear cell infiltrates, Granulomas and foamy macrophages
Subacute = (classic triad) Interstitial lymphocytic-histolytic cell infiltrates, BO, scattered poorly formed non-necrotizing granulomas
Chronic = giant cells, granulomas, NSIP, UIP pattern
GPA 4 respiratory completions and two antibodies
Upper = chronic sinusitis , nasal septal perforation/ulcer, oral ulcers, subglottic stenosis Lower = tracheal or bronchial stenosis, diffuse alveolar hemorrhage , granulomas (nodules) Antibodies = PR3 and MPO ANCA, mostly PR3 which is more specific.
Bronchial cast, can be Cellular or acellular, mention what pathology finding in each and one example of each.
Type I – Inflammatory casts – contain fibrin and eosinophilic infiltrate , e.g.,CF, asthma
Type II – noninflammatory casts – acellular containing mucin and fibrin without inflammatory infiltrated e.g., plastic bronchitis in post-Fontan patient
BAL, proteinaceous secretions, PAS positive.
Diagnosis and 2 differentials
PAS stains for polysaccharide, glycoprotein, glycolipids), so this makes sense why PAS positive in fungal
Dx: Pulmonary Alveolar Proteinosis
Diff: Fungal infection (PAS positive)
ILD (Pulmonary fibrosis, sarcoidosis can be PAS positive)Surfactant protein deficiency (proteinaceous secretions)
Surfactant protein deficiency (proteinaceous secretions)
Periodic acid–Schiff (PAS) is a staining method used to detect polysaccharides such as glycogen, and mucosubstances such as glycoproteins, glycolipids and mucins in tissues.
NEHI, what is the staining, what do you see on pathology?
Microscopic findings:
- No specific diagnostic features of disease, with an absence of extensive inflammation, reactive injury, architectural distortion, and fibrosis seen on lung biopsy
- Minor and nonspecific changes involving the distal airways including:
- Mildly increased airway smooth muscle
- Mildly increased numbers of alveolar macrophages
- Increased number of ‘ clear cells’ within bronchioles
- Patchy mild peri airway lymphocytic inflammation and fibrosis commonly seen
Immunohistochemical Features:
- Consistent increase in Bombesin-immunoreactive cells within bronchioles
- > 75% of non cartilaginous airways contain immunopositive cells, present in small clusters (need 8-10 airways to evaluate)
- One or more bronchioles with > 10% of airway epithelial cells immunopositive
- Frequently increased size and number of neuroepithelial bodies around alveolar ducts.
PCD, Draw the ultrastructures What is the commonest defect. Name 2 diseases caused by sensory ciliopathy
Cilia Ultrastructure – Classic 9+2 Arrangement
Commonest defect = Outer dynein arm defect
Diseases due to sensory ciliopathy= PCKD, Bardet-Biedl Syndrome, Alstrom Syndrome, Joubert, Retinitis pigmentosa
CT with bronchiectasis: mention 3 finding that suggest it
Enlarged internal bronchial diameter
Signet ring sign (bronchi : vessel ratio >1.0)
Failure of airway to taper in lung periphery
Bronchial wall thickening ( Tram track)
Mucus plugging / impaction ( Tree in bud pattern)
Mosaic perfusion
Air trapping on expiration
Air-fluid levels in distended bronchi
Definition of Bronchiolitis Obliterans
Type of obstructive lung disease of the small airways.
It is a rare disease with characteristic features of fibrosis of terminal and distal bronchioles and spirometry showing airflow obstruction.
Pathogenesis of Bronchiolitis Obliterans
- Infection/other insult
- Injury/destruction of airway epithelium
- Acute and chronic inflammation leading to:
- Repair to healing OR repair by proliferation of granulation tissue - Fibrosis of airway wall and lumen
- Obliteration of airway lumen
**Subepithelial inflammation and fibrotic narrowing of bronchioles leading to in/complete obstruction
2 phases: inflammatory and fibrotic
Most common cause of paediatric bronchiolitis obliterans
Post Infectious
- Adenovirus (1,3,7,21)
- Measles, RSV, mycoplasma, influenza, parainfluenza
Etiologies for paediatric bronchiolitis obliterans apart from infection
Post-transplant (chronic rejection, GVHD)
Connective tissue disease (RA, Sjogrens, SLE)
Toxic fume inhalation (NO2, NH3)
Chronic hypersensitivity pneumonitis (avian, mold)
Aspiration (GERD, foreign body)
Drugs (Pencillamine, Cocaine)
SJS (idiopathic, drug-induced, infection related)
Presentation of paediatric bronchiolitis obliterans
most common = physiologic features of respiratory obstruction
- Progressive dyspnea, non-productive cough - weeks-months.
- O/E: Wheeze, crackle possible
- Children - “incomplete” recovery from respiratory illness, symptoms persist >60days.
PFT findings for paediatric bronchiolitis obliterans
Abnormality = Irreversible airway obstruction
- Spiro: N/↓ FVC, ↓FEV1, ↓V1/VC, ↓FEF25-75. No BD response.
- Pleth: Air-trapping, incr RV/TLC. Nrml TLC.
- Subset show restrictive or mixed disease.
- DLCO may be ↓ in severe or progressing dz.
CXR findings for paediatric bronchiolitis obliterans
Often normal.
Hyperinflation & incr linear/reticular/interstitial markings suggestive.
CT findings for paediatric bronchiolitis obliterans
High-Res CT - Inspiratory/Expiratory w/o contrast = definitive non-invasive test.
- Mosaic attenuation / perfusion = patchy areas of decreased lung density w/ reduced vascular caliber → due to bronchial air trapping
- Air-trapping - esp. on expiratory view
- Advanced disease: central bronchiectasis (large airways = dilated, thickened)
- Paucity of ground glass lesions.
BAL findings for paediatric bronchiolitis obliterans
Incr WBC - Incr. PMNs, Incr. Lymps acutely. Late: T-cell drive → Incr CD40
Gold standard test for diagnosing BO
Biopsy
- Complicated by patchy disease
- Often not done, at patient ill. Yield not ideal.
Clinically: Based on story, imaging - may be reasonable. HRCT important.
Outcome and prognosis of pediatric BO
- Natural history - highly variable
- Pediatric - Post-Infectious = Low mortality, high chronicity. Some improve gradually with time.
- Azithromycin - most effective - anti-inflammatory
- Difficult to Rx: little response to glucocorticoid, little consistent response to others
- Lung transplant for severe disease
Swyer-James develops in ⅓ = Unilateral hyperlucent lung, ↓ vascularity, air trapping = smaller, darker lung on chest radiograph
- CT shows actually bilateral disease: diffuse, asym, pathcy lobar air trapping
- Post-infectious, fibrotic healing of immature lung
Generally non-progressive if exposure ceases / cause resolved
Increased risk of mortality from respiratory disease
Transplant related BO generally progressive
Management of pediatric BO
- Supportive care: Oxygen, Nutrition, Antibiotics if infected, GERD management, flu vaccination
Acute Management:
- Pulse steroid: 30mg/kg max 1-gram, once daily x 3 days, then monthly 3-day treatments if initial is beneficial - no evidence of benefit
- IVIG, TNF-alpha has been used - little evidence
- Azithromycin chronic 3x/weekly - anti-inflammatory: decr PMNs, decr cytokines
- ICS, LTRAs have been trialed too
Risk Factors for Post-Infectious BO
- Hosp >30 days
- Multifocal pneumonia
- Hypoxia
- Hypercarbia
- Need for PICU
- Need for Mechanical Ventilation
- Corticosteroid or b2-agonist need during the acute illness
Characteristics of BO post transplant or HSCT
BO = primary non-infectious pulmonary complication of allogenic HSCT
- Typically w/n 2-years post-transplant, but may occur several years post
- Incidence ~5% post HSCT
- More common with acute GVHD - query form of chronic GVHD
- Assoc w/ Older age of donor/recipient, worse HLA match, GERD, aspiration, busulfan conditioning, low gamma-globulin levels, smokers.
- RSV, Paraflu w/n 100 days post transplant incr risk
- Solid lung transplant: 10-year risk of disease ~70%.
Tacrolimus = Less BO as compared to cyclosporine
Rx = Increase in immunosuppresive agents, adjuvant
Rx (macrolides, LTRA, ICS)
- The literature remains poor.
- Azithromycin response in ~50% (PFT improvement).
Characteristics of Cryptogenic Organizing Pneumonia
Formally known as BOOP (bronchiolitis obliterans with organizing pneumonia)
Histologically distinguished by patchy areas of consolidation with polypoid plugs of loose organizing connective tissue in the respiratory bronchioles and alveolar ducts
Proliferative bronchiolitis is manifest by patchy infiltrates on CXR and by restriction on PFT
Often improves with steroids (unlike other post HSCT complications) and macrocodes as adjunctive tx
Presentation of Cryptogenic Organizing Pneumonia
Subacute = < 3 mos
Non-specific symptoms - cough/dyspnea
Often mild hypoxemia
Requires exclusion of common causes of diffuse lung disease
Bronch findings in Cryptogenic Organizing Pneumonia
Bronch indicated in all suspected COP - rule out infections, consider malignancy
Mixed cell differential - lymphs 20-40%, CD4/CD8 ratio decreased, neuts 10%, Eos 5%
Most common cause of bronchiectasis in developed world
CF
Worldwide non-CF bronchiectasis more common
Characteristics of Bronchiectasis
Pathologic state of the conducting airways manifested by radiographic evidence of bronchial dilation and clinically by chronic productive or wet cough.
Characteristics of Chronic Supprative Lung Disease (CSLD)
Clinical syndrome where symptoms of chronic endobronchial suppuration exist with or without c-HRCT evidence of bronchiectasis.
Presentation: symptoms are identical to bronchiectasis, including a prolonged moist or productive cough responsive to antibiotics, hemoptysis, exertional dyspnea, increased airway reactivity, growth failure, and recurrent chest infections.
Best time to CT for bronchiectasis
Timing of scan is important - should be done during NON-ACUTE STATE
At least 2 CT scans required to meet definition of “irreversible bronchiectasis”
Causes of bronchiectasis
1) Impaired immune function
- SCID, CVID, AT, HIV etc
2) Ciliary dyskinesia (Primary, functional)
3) Abnormal mucus (CF)
4) Clinical syndromes
- Young’s syndrome, Yellow nail lymphedema syndrome, Marfan syndrome, Usher syndrome
5) Congenital tracheobronchomegtly
- Mounier-Kuhn syndrome, Williams-Campbell, Ehlers-Danlos
6) Aspiration syndromes
- Recurrent small volume, primary aspiration, TEF, GERD
7) Obstructive bronchiectasis (FB, tumour, LN)
8) Other pulmonary disease association
- ILD, BO, ABPA, BPD, Tracheobronchomalacia
9) Others
- Alpha-1 antitrypsin deficiency, post transplant, autoimmune, posttoxic fumes, eosinophilic lung disease
3 big etiologic risk factors for bronchiectasis
1) Structural airway abnormalities, such as bronchomalacia, endobronchial tuberculosis,
- central airway compression, or retained aspirated foreign bodies → impair mucous and
bacterial clearance.
2) Persistent airway injury and narrowing associated with bronchiolitis obliterans (due to viral injury or following lung transplantation)
3) Recurrent airway injury, such as aspiration syndromes
Additional factors: inhaled irritants/pollutants, impaired upper a/w defenses (sinus disease & eustachian tubes = sanctuary sites for bacteria, variations in host inflammatory response.
Other important etiologies
- Acute Lower Respiratory Infections (including pneumonia) - AKA Post-infectious
- Upper airway infection and aspiration
- Public Health Issues
- Genetics
Histopathology features of bronchiectasis
Neutrophilic inflammation (TNF-A, IL-8, IL-6)
Intraluminal secretion accumulation
Distal airway obliteration
Classification categories for bronchiectasis (Reid’s classifications)
Cylindrical
Varicose
Cystic (aka saccular)
Natural history with treatment for bronchiectasis
Rule of 3rds (w/ Rx): 1⁄3 improve, 1⁄3 stable but symptomatic, 1⁄3 worsen
Only significant predictor of FEV1 decline (1 study) for bronchiectasis
Only significant predictor of FEV1 decline (1 study) = freq of exacerbations requiring hosp
Characteristics of bronchiectasis disease progression
Local progression (ie 𝚫 to saccular) > extension to new areas, (both can occur)
Poor prognostic factors in bronchiectasis
+ve asthma
Bilateral involvement
Saccular bronchiectasis
Cardinal Sign of bronchiectasis
Chronic Wet Sounding Cough
Common symptoms of bronchiectasis
Persistent/recurrent wet or productive cough of purulent or mucopurulent sputum
Others:
○ Hyperinflation / chest wall deformity (5-60%)
○ Clubbing (5-60%) - may disappear post Rx.
○ Exertional dyspnea
○ Recurrent wheeze/chest infection
○ Hemoptysis - less common in children, may be presenting symptom (late)
○ Auscultation range from normal → coarse inspiratory crackles
○ Reduced oxygen saturations (late)
○ Pulmonary hypertension with associated cardiac findings (late)
Co-Morbid Conditions with bronchiectasis
Bronchiolitis obliterans Asthma GERD Hypertorphic osteoarthropathy Cardiac dysfxn +/-Pulmonary hypertension (late)
Goals of evaluation for bronchiectasis
- Confirm diagnosis
- Define distribution and severity of airway involvement
- Characterize extrapulmonary involvement (AKA cor-pulmonale)
- Identify treatable and familial causes of bronchiectasis
Features of bronchiectasis on chest HRCT scans (7)
- Signet ring sign
- Enlarged internal bronchial diameter
- Failure of airway to taper normally while progressing to lung periphery
- Presence of peripheral airways at CT periphery
- Presence of associated abnormalities
- bronchial wall thickening
- mucoid plugging or impaction - Mosaic perfusion
- Air trapping on expiration
Pitfalls in Diagnosis of Bronchiectasis on Chest HRCT scans
False Positives
- Physiologic constriction of pulmonary artery
- Artifacts from cardiac pulsation and respiratory motion
- Pseudobronchiectasis or transient bronchial atresia
- Increased bronchoarterial ratio in patients considered normal, asthmatics or high altitude
False Negatives
- Inappropriate HRCT protocol
- Poor image due to movement artifacts
- Nonuse of high resolution techniques
Components of the Bhalla scoring for bronchiectasis
1) Severity of bronchiectasis
2) Presence of peribronchial thickening
3) Extent of bronchiectasis (# BP segments)
Investigations as part of bronchiectasis workup for etiologies
Baseline immune function CBC HIV status Sweat test and genotype Radiology (CXR, HRCT) Aspergillosis serology Cilial biopsy Sputum
Additional: Bronchoscopy GERD investigations Barium swallow (TEF, esophageal abnormalities) Mantoux test Further immune tests Video fluoroscopy
Role of bronchoscopy in bronchiectasis workup
Indicated to identify obstructive bronchiectasis: Intraluminal (FB, tumor)
Mural (bronchomalacia)
Extramural
5 types of classification (5 = no abnormality, most common = type 1: mucosal abnormality/inflammation only)
Is spirometry sensitive for disease progression in bronchiectasis?
No - especially for localized disease (diffuse - FEV1 reflects disease severity not activity)
Other PFT abnormalities:
- high RV
- Lower aerobic capacity
- lower maximal ventilation at max exercise
Which diagnostic modality is most sensitive for disease progression in bronchiectasis
HRCT
Most common bugs for acute exacerbation of bronchiectasis
S. pneumo, non-typable H Flu, moraxella
Determinants of accelerated lung function decline in bronchiectasis
Frequency of hospital exacebation
Role for Antisecretagogues and mucoactive agents in non-CF bronchiectasis
Pulmozyme = contraindicated
Hypertonic saline = increases airway clearance, improves lung function and decreases exacerbation
Insufficient evidence to recommend macrolides routinely as anti-inflammatory
Chest physiology lacking in evidence
Indications for Lobectomy in bronchiectasis
Poor control of symptoms (purulent sputum, frequent exacerbations) despite optimal medical therapy
Poor growth in spite of optimal medical therapy
Severe and recurrent hemoptysis uncontrolled by bronchial artery embolization
(relative)
localized disease with moderate persistent symptoms
Contraindication for Lobectomy in bronchiectasis
Widespread bronchiectasis
Young child
Minimally symptomatic disease
Sputum characteristics in non-CF bronchiectasis
Neutrophilic
high IL-6, IL-8, TNF-alpha
Starling equation
Qf = Kf[(Pc − Pis) − σ(πpl − πis)]
Anatomic features to preserve gas exchange
1) Basement membranes of capillary endothelium and alveolar epithelium fused in some areas
2) Secreted matrix/structural proteins bw endothelial +epithelial basement membrane provides channel
for water and protein to travel to lymphatics for absorption
3) Pulmonary capillaries have a continuous endothelium w tight intercellular junctions
4) Alveolar epithelial membrane has tighter cellular junctions
5) Polyhedral shaped alveoli
2 main compartments in the lung in which edema fluid can move
- Interstitial spaces of alveolar capillary septae - accommodates few hundred mL (faster resolution)
- Alveolar space - accommodates 30mL/kg body weight
What do the juxtacapillary receptors do?
They are distributed throughout lung’s interstitium + are stimulated by the presence of edema (increased RR)
Different vascular forces that are present and determine net flow of fluid
1) Pulmonary capillary pressure = LA –PA pressure +40%
2) Interstitial Forces
3) Microvascular filtration coefficient and vascular permeability
4) Lymphatic clearance
What does Kf (filtration constant) mean?
A measure of a membrane’s permeability to water
Specifically, the volume of fluid filtered in unit time through a unit area of membrane per unit pressure difference
What does this coefficient σ mean in the Starling equation?
Vascular permeability/reflection coefficient .
Endothelial membrane has pores. Fluid filtering through a pore will drag some protein with it. The larger the protein relative to the size of the pore, the less protein will be dragged. When the protein is the same size or larger than the large, the relection coefficient is 1. As the size of the protein becomes smaller, σ approaches zero.
Mechanisms that cause pulmonary edema
- Increased capillary hydrostatic pressure (most common)
- Decreased capillary oncotic pressure
- Decreased interstitial hydrostatic pressure
- Increased pulmonary vascular surface area
- Increased vascular permeability in fluid-exchanging vessels
2 pathways for clearance of pulmonary fluid
1) Lymphatics (most important)
2) Venular end of the microvascular bed (where Pmv has decreased and the balance of Starling forces can favor reabsorption)
Alveolar edema fluid, after being actively transported across the epithelium, is returned to the circulation either by direct entry into the microvasculature across the thin side of alveolar capillary membrane or by the lymphatics after it has been translocated back to the interstitial space.
Steps of fluid accumulation in acute pulmonary edema
1) Normal alveolar walls and no excess fluid in perivascular connective tissue spaces.
2) Initial fluid leak. Fluid flows to the interstitial space (at subatmospheric pressure) around the conducting vessels and airways.
3) Tissue space fills, alveolar edema increases, and fluid begins to overflow into the alveoli, notably at the corners where curvature is pronounced.
4) Quantal filling. Individual alveoli reach a critical configuration at which existing inflation pressure can no longer maintain stability.
Distal lung units in different regions of the lung will be at different stages of fluid accumulation because of their regional differences in pressure, alveolar- capillary membrane integrity, and gravitationally dependent factors.
What effect does pulmonary edema have on airway resistance?
The presence of edema increases airway resistance.
As the airways narrow, closing volume increases and alveolar gas exchange is impaired because of the resultant low V/Q ratio. At this stage, hypocapnia results from the J receptor vagally mediated reflex hyperventilation independent of the presence of hypoxemia.
As edema worsens and alveolar flooding occurs, there is further hypoxemia as the blood shunts past nonventilating alveoli. Respiratory acidosis may supervene if the patient is depressed by sedation or if exhaustion develops.
Physical exam findings of pulmonary edema
- tachypnea (stimulation of J receptors)
- crackles (fluid in terminal airways)
- rhonchi + wheezes (when fluid moves up to larger airways)
- retractions (generate more negative pleural pressures to overcome decreased compliance)
- grunting (create PEEP to prevent collapse of distal lung units)
PFT findings in pulmonary edema
Initially, vascular engorgement can lead to increase in DLCO by increasing the amount of perfused vasculature — eventually reduced DLCO
With alveolar flooding, there is air trapping, increased vascular resistance, decreased lung volumes, decreased dynamic compliance, and progressive hypoxemia
Imaging findings with pulmonary edema
CXR
- Kerley (septal) lines: interlobular sheets of abnormally thickened or widened connective
tissue
- Peribronchial cuffing
- Alveolar filling defect with air bronchograms in severe forms
- Obstruction hyperinflation
CT
- Regional edema and microatelectasis = heterogenous and shift with the position of the patient (densities often appear in gravitationally dependent lung regions)
Clinical Disorders Causing Pulmonary Edema
1) High pressure pulmonary edema (L sided heart disease, obstructive lesions, heart failure, increased pulmonary blood flow etc)
2) Airway obstruction (diffuse small airway obstruction results in a lag in the expansion of the lung in spite of development of very negative intrathoracic pressure)
3) Re-expansion pulmonary edema
4) Neonatal RDS
5) Neurogenic pulmonary edema
6) Acute lung injury and ARDS
7) High Altitude pulmonary edema
8) Inhalation of toxic agents
Treatment for pulmonary edema
1) Reverse hypoxemia: O2, Positive pressure
2) Reduce the rate of fluid filtration (treat the disorder)
3) Minimize treatment related lung damage
4) Augment rate of clearance of airspace fluid
When can pulmonary edema be detected on CXR (how much fluid)
In adults: when extravascular lung water (EVLW) is increased by approximately 35%
High pressure vs low pressure pulmonary edema
high pressure (ie. CHF) vs high permeability pulmonary edema (ie. ARDS)
- most pts with pulmonary edema have both increased permeability and elevated pulmonary artery pressures
- no tests available to reliably distinguish bw 2 causes
Pathophysiology of ARDS
Consequence of inflammatory process at alveolar-capillary interface
Increased alveolar capillary permeability à flooding of alveoli with protein rich fluid, leading to:
- Impaired gas exchange
- Impaired surfactant function
Berlin Criteria for ARDS
Onset: Acute (within 7 days of an “event”)
CXR: Bilateral opacities
Not fully explained by cardiac failure or fluid overload Severity:
· Mild: PaO2:FiO2 = 200-300
· Moderate: PaO2:FiO2 = 100-200
· Severe: PaO2:FiO2 = < 100
4 stages of ARDS
- Triggered by direct or indirect injury
- Acute exudative phase with pulmonary edema, cytokine release, activated neutrophils
- Fibroproliferative phase (may lead to fibrosing alveolitis)
- Recovery Stage
Characteristics of acute exudative stage of ARDS
Pulmonary edema, cytokine release, activated neutrophils
Intrapulmonary shunting, reduced FRC, decreased compliance
CXR: diffuse bilateral homogenous parenchymal disease
CT: may see heterogeneity (severe damage to some lung, and less damage elsewhere)
3 functional lung regions described the acute exudative stage of ARDS
1) Fully aerated normal (typically non dependent) (AKA “Baby lung”)
2) Poorly aerated (injured by recruitable)
3) Non-aerated consolidated/atelectatic lung
Characteristics of fibroproliferative phase of ARDS
May lead to fibrosing alveolitis
Increased alveolar dead space, hypoxia, reduced lung
compliance
If patients progress to this stage, outcomes are worse
Characteristics of recovery stage of ARDS
Occurs within 10-14 days
Gradual improvement in lung compliance and oxygenation
Mechanism not well understood
Norm is for patients without underlying chronic lung disease to return to normal lung function
Most common cause of ARDS
Direct (pulmonary) causes
Major cause of Indirect (Extra-pulmonary) ARDS
Sepsis
Mechanism of injury for direct (pulmonary) causes of ARDS
Characterized by a primary injury to the alveolar epithelium
Results in intra-alveolar edema, reduced lung compliance, with preservation of chest wall compliance
Mechanism of injury for indirect (extra-pulmonary) causes of ARDS
Primary insult is systemic, with the major injury occurring to the capillary endothelium
Results in interstitial edema, with greater reduction of compliance in the chest wall
Pathology of direct (pulmonary) causes of ARDS
Predominantly consolidation
Differences in mechanism of injury and pathology may explain why pulmonary causes tend to have more refractory hypoxemia, with resistance to recruitment maneuvers and prone posturing, but respond better to surfactant
Pathology of indirect (extra-pulmonary) causes of ARDS
Predominantly atelectasis
Ways to measure severity in ARDS
Blood gas
Oxygenation Index (OI = (MAPxFiO2)/ PaO2)
Ventilation Index [VI = (PaCO2 x PIP x RR)/1000)]
Lung injury score: Incorporates CXR, PaO2/FiO2, PEEP and compliance - rarely used
Genes that have been linked to the susceptibility of ARDS or it’s clinical course
Surfactant Protein B, IL-6, Coagulation factor V (F5)
Differences Between Children and Adults in ARDS
1) Mechanical properties of lungs of children and infants differ from adults (Chest wall compliance is inversely related to age)
2) Infants have low inherent elastic recoil
3) Lung volume to body weight is greatest at 2 years
4) Mortality for children is less than adults
5) High FiO2 is associated with worse outcome in children, but not adults
Ways ventilation can worsen ARDS
Barotrauma : physical disruption of alveoli
Volutrauma: over-distention of alveoli
Atelectrauma: Recruitment and derecruitment of collapsed alveoli
Biotrauma: activation of inflammatory process
Oxygen toxicity
Ventilation strategies associated with lung injury in ARDS
High PIP, large Vt, Low PEEP, and +/- high FiO2 (High PEEP is protective)
Current ventilation recommendations for ARDS
Vt< 10ml/Kg
PIP < 30cmH20
Higher PEEP (5-20cmH2O)
Other modes of ventilation used in ARDS
Non-invasive
High Frequency Oscillatory Ventilation (HFO)
Airway Pressure Release Ventilation (APRV)
Neuronally Adjusted Ventilatory Assist (NAVA)
Adjuncts to mechanical ventilation in ARDS
Prone Posturing Inhaled Nitric Oxide (iNO) Surfactant Corticosteroids (controversial) Neuromuscular blocking agents (NMBA) Beta Adrenergics ECLS Tracheostomy
How may beta adrenergics help in ARDS?
Increased edema in ARDS is due to increased permeability and (to a lesser
extent) increased capillary hydrostatic pressure
B agonists may reduce edema by:
- Upregulation of Na transport
- Pulmonary vasodilation and reduction of pulmonary vascular pressure
(reduces capillary hydrostatic pressure)
- May independently decrease endothelial permeability
- In adults: lessened the lung water content and lessened the inspiratory airway pressures
- In children: may be associated with reduced mortality (no RTC)
Definition of Drowning
Process resulting in primary respiratory impairment from submersion/immersion in liquid’ – now encompasses fatal and non-fatal immersion
Causes of pulmonary injury from drowning
Aspiration
Infection
Lung injury
Theoretical difference between salt and fresh water (now proven to be the same)
Salt water: osmotic gradient – shift fluid into alveoli; does not result in significant hemodynamic compromise from fluid shifts in animals (more then freshwater)
Freshwater rapidly absorbed into systemic circulation and maybe edema secondary to neurogenic causes, forced inspiration against closed glottis and altered surfactant or pulmonary capillary permeability
chILD syndrome present if have 3 of these criteria
i. respiratory symptoms (coughing/rapid breathing/exercise intolerance)
ii. physical signs (crackles/adventitious breath sounds/clubbing/retractions etc)
iii. hypoxemia
iv. diffuse parenchymal abnormalities on imaging
AND must r/o more common causes of diffuse lung disease (CF, PCD, immunodeficiency, aspiration etc)
Children < 2 y.o.a with chILD tend to have diagnosis in category ‘more common in infancy’ and those > 2 y.o.a tend to have diagnosis in category ‘d/o related to systemic disease’ and ‘immunocompromised host’
chILD disorders more common in infancy
- Developmental D/O (ACD-MPV)
- Growth abnormality d/o (Pulmonary hypoplasia, CLD (neo or cardiac))
- Specific conditions of unknown etiology (NEHI, PIG)
- Surfactant dysfunction (Surfactant protein B or C def, ABCA def, NKX2.1 mutation)
chILD disorders related to systemic disease
Collagen vascular disease
Storage disease
Sarcoidosis
LCH
chILD disorders of the normal host/environmental exposure
Infection/post-infection
Hypersensitivity pneumonitis
Aspiration
Eosinophilic pneumonia
chILD disorders of immunocompromised host
Opportunistic infection
Transplantation and rejection
Therapeutic intervention (ie. chemotherapy)
Disorders masquerading as ILD
Pulm HTN
Cardiac dysfunction
VOD
Lymphatic d/o
General approach to the work-up of chILD
- Full Hx; O/E
- Specific investigations to r/o CF, PCD, aspiration, immunodeficiency, HP and autoimmune disease
- Imaging: CT better for NEHI, BO, HP, PAP
- Echo to assess for masqueraders
- Infant PFT’s if available (reliable in NEHI – a/w obstruction and gas trapping)
- Genetic testing
- Bronch/BAL: r/o anatomic abnormalities, PAS staining r/o infection
- Biopsy – if test results unclear; no other way to diagnose pulmonary hemorrhage with capillaritis,
PIG, alveolar simplification, ACD/MPV, NEHI, HP, follicular bronchiolitis etc
What is surfactant?
Mixture of lipid/proteins –> reduces ST at air-liquid interface and thus prevents alveolar collapse – critical function maintained by maintaining balance between production and clearance
complex mix of phospholipids/neutral lipids/specific proteins made by type II alveolar epithelial cell (AEC2)
stored in lamellar bodies and secreted by exocytosis into alveolar lumen
Most common d/o associated with disrupted surfactant homeostasis
RDS
RDS is due to surfactant deficiency from prematurity, however, number of d/o associated with single gene defects causing abnormal surfactant production or clearance (homeostasis)
