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)
Major components of surfactant
major lipid: phosphatidylcholine (PC), large fraction of which contains two palmitic acid side chains that are fully saturated (dipalmitoyl or disaturated phosphatidylcholine – DPPC or DSPC) and its presence is critical for surfactant function
Role of ABCA3
member of ATP-binding cassette family of membrane transporters
Located on limiting membrane of lamellar bodies and important for transport of phospholipids into lamellar bodies during surfactant synthesis
Role of SP-B and SP-C
Lowering surface tension- two extremely hydrophobic surfactant proteins which reduce ST in vitro and in-vivo surfactant deficiency in animals and both are present in the surfactant used for RDS
Role of SP-A and SP-D
important in local host defence because they can bind to variety of micro-organisms
Role of NKX2-1
(also called thyroid transcription factor)
A transcription factor that binds to promoter regions of DNA important for proper expression of the surfactant proteins
What happens after production/secretion of surfactant?
Surfactant is recycled into AEC2s and catabolized by alveolar macrophages
Catabolism dependent on macrophage maturation which depends on GM-CSF binding receptor at cell surface to initiate signaling events which regulates multiple alveolar macrophage functions including the ability to catabolize surfactant components
Clinical features/Pathophysiology of SP-B deficiency
- hydrophobic protein that reduces ST and plays role in regulation of other surf proteins
- encoded by single gene (SFTPB on Chrom 2) - produced by AEC2’s
- AR inheritance (loss of fxn mut – most often is frame-shift with Premature stop codon)
- increased in northern Europeans
- complete deficiency – results in lethal phenotype with clinical features similar to RDS that is only treatable with lung Tx
- partial SP-B deficiency – intermediate survival
- SPB has role in SPC processing, therefore SPB deficiency can cause increase in abnormal SPC and an SPC deficiency
Pathological findings of SP-B deficiency
i. interstitial fibrosis/AEC2 hyperplasia (seen in number of other d/o of surf production)
ii. alveolar proteinosis can be seen
iii. poorly organized lamellar bodies, with vacuolar inclusions
CXR would look like RDS - genetic testing and protein expression testing for SP deficiency
Tx for SP-B deficiency
Lung transplant
Clinical features/Pathophysiology of SP-C deficiency
- extremely hydrophobic peptide
- Single Gene, on Chrom 8
- SP-C, like SP-B, enhances ST lowering ppties of surfactant lipids and is present in mammalian derived surfactant preps used to treat RDS in neonates
- AD inheritance
- genetic modifiers seem to be important in the development of SP-C related lung disease
- de Novo mutations occur
- spectrum of disease – can be seen in the same family in an infant in one generation and in previous generations as adult ILD; also genes not on the SFTPC gene may also result in SP-C deficiency
- disease mechanisms:
i. may be from lack of functional SP-C
OR
ii. from toxic accumulation of abnormal proSP-C (may be directly toxic to AEC2’s) “Gain of toxic function”, ie the protein is misfolded and causes secondary damage
Clinical features in children/adults: chronic respiratory symptoms (dyspnea/cough) and signs (tachypnea, crackles), FTT, clubbing, hypoxemia and supplemental oxygen
Variable age of onset – some have distress after birth, others asymptomatic until adulthood - some children requiring mechanical vent may improve over time
Pathological findings of SP-C deficiency
- CXR/CT: ground glass opacities, peripheral cysts
- SP-C in BAL may be absent
- genetic testing and protein expression testing for SP deficiency
- Pathological findings:
i. can be non-specific – NSIP or chronic pneumonitis of infancy or DIP
Tx for SP-C deficiency
- no specific Tx exists - people have tried:
i. steroids
ii. hydroxychloroquine
iii. azithromycin - none of these have proven efficacy
Clinical features/Pathophysiology of ABCA3 deficiency
- member of ATP binding cassette family of transmembrane proteins
- hydrolyze ATP to transport substances across membranes – particularly important to transport DSPC/DPPC
- encoded by single gene (ABCA3 on Chrom 16) - expression – developmentally regulated with increased expression late in gestation and increased by glucocorticoids
- mostly expressed in AEC2’s – localize to limiting membrane of lamellar bodies
- Also expressed in kidney, gut, thyroid, brain - AR inheritance (loss of function mutation)
Present similar to SP-B deficiency – as patient with RDS and severe surfactant deficiency in term/near term infant; however, there is a milder form presenting later similar to children with SP- C deficiency, maybe due to some retained ABCA3 fuxn
- > 100 mutations described
- most frequent cause of surfactant deficiency
Pathologic findings for ABCA3 deficiency
- BAL
- markedly reduced DPPC content
- ultrastructural findings:
- absent/abnormal lamellar bodies
- small/dense inclusions eccentrically placed in abnormal lamellar bodies gives ‘fried egg’ appearance
- distinct from ultrastructural appearance in SP-B def where lamellar bodies are larger and loosely packed (these findings are in severe ABCA3 def)
Treatment for ABCA3 deficiency
no proven efficacious therapy
- steroids increase ABCA3 transcription in vitro, thus rationale for use of steroids to augment any remaining fuxn but not proven to help
- hydroxychloroquine and azithro have been used with little data to speak to efficacy
- lung Tx may be necessary with similar survival for age-matched controls
Clinical features/Pathophysiology of NKX2-1
- NKX2.1 – also called thyroid transcription factor (TTF1), is a TF important for development of thyroid gland, CNS (basal ganglia) and in lung - critical for expression of SPA, B, C & ABCA3
- On Chrom 14
- loss of one allele (haploinsufficiency) could result in lung disease
- mutation/deletion in NKX2.1 may result in neurologic symptoms (hypotonia/chorea), hypothyroidism and/or lung disease (not necessarily all three, but any combo)
- NKX2.1 important for expression of SP-A, B and C and ABCA3
- Unclear if it is the NXK2.1 or the resultant reduced expression of SPA,B,C or ABCA3 that causes lung disease
- mutations result in phenotype of RDS (surf def) and ILD (surf dysfunction)
- pulmonary infection because reduced SP-A
- variable spectrum of disease
Pathology of NKX2-1
Pathology
- Similar to those of other surfactant dysfunction - Alveolar simplification
What are disorders of Surfactant Clearance?
Referring to PAP
Heterogenous group of diseases defined histopathologically by finely granular, lipoproteinaceous material filling pulmonary alveoli and terminal airspaces
This material stains with eosin stain and periodic acid Schiff stain (PAS stain), has identical features to surfactant and frequently contains cholesterol needles
May also see alveolar distortion/fibrosis depending on underlying pathology variable histologic features result from variable diseases that can cause this picture
Pathogenesis of primary PAP
Autoimmune PAP – caused by autoantibodies to GM-CSF (granulocyte macrophage colony stimulating factor) which is very important in signaling for alveolar macrophages to catabolize surfactant – thus if have autoAb’s you hamper this signaling and get surfactant build-up PAP;
Hereditary forms of PAP – caused by abnormal GM-CSF receptor which are also referred to as primary PAP (CSF2RA, CSF2RB)
Pathogenesis of secondary PAP
Occurring in association with an underlying disease such as:
▪ Hematologic d/o (MDS, malignancy, aplastic anemia)
▪ Chronic infection (HIV)
▪ Toxic inhalation (silica, metal dust)
▪ Genetic disease (LPI)
▪ SCID
Clinical features/Pathophysiology of Autoimmune PAP
- 90% of all PAP
- caused by immune attack (autoAb) to GM-CSF that blocks signaling to alveolar macrophages neutralizing the ability to catabolize surfactant
- prevents terminal differentiation of alveolar macrophages
- impaired ability for defense and surf catabolism - also impairs Neutrophil host defenses
- thus patients not tolerate pulmonary infexn well
- surfactant accumulation w/in alveoli results in V/Q mismatch and hypoxemia
- can see lymphocytosis
- usually presents in 3rd – 4th decade of life - 2 x as common in men
Clinical features:
i. insidious onset
ii. diffuse bilateral lung infiltrates
iii. occasional hemoptysis/fever
iv. Clubbing is NOT a feature
- can be seen as early as 8 years of age
Treatment of Autoimmune PAP
i. Whole lung lavage – current standard; works well for most patients; improves survival/QOL; if late in course can become less effective
ii. Small series of GM-CSF augmentation being effective –not looked at prospectively evaluating indications/timing/route/duration etc and so more studies required
iii. Rituximab – small number of patients shown to be effective – requires more studies
Clinical features/Pathophysiology of PAP caused by autosomal recessive CSF2RA mutation
- results from deleterious variants of gene encoding the alpha-chain of GM-CSF receptor (CSF2RA)
Found on X and Y chromosomes - phenotypic variability demonstrated: age of presentation between 1 – 10 years, symptoms of dyspnea and fatigue of varying amounts, no auto-Ab’s, elevated serum GM-CSF
Investigations for PAP caused by autosomal recessive CSF2RA mutation
- CSF2RA genetic testing for mutation; also CSF2RA protein testing (absent in many)
- assess signaling induced by GM- CSF
- serum GM-CSF (would be elevated)
Treatment for PAP caused by autosomal recessive CSF2RA mutation
- symptomatic patients receive whole lung lavage with variable ranges of time between (months to more then 2 years)
- Likely no response to GM- CSF, as levels already high and receptor is abnormal
Clinical features/Pathophysiology of PAP caused by autosomal recessive CSF2RB mutation
Genetic defect in CSF2RB can cause phenotype of PAP - Due to abnormality in GM-CSF receptor abnormality
- have increased GM-CSF and no auto-Ab’s
- mechanism of PAP in lysinuric protein intolerance (LPI) not known; likely b/c abnormal alveolar macrophages as seen to recur in patient with PAP in LPI post heart-lung Tx suggesting it’s macrophage and not AEC2 and deficient surf
- of note, no genetic defects in GM-CSF production itself has been identified in causing PAP in humans
Treatment for PAP caused by autosomal recessive CSF2RB mutation
- Although thought no response to GM-CSF if the receptor is abn
- However if issue of binding affinity, more GM-CSF may help – trials w/inhaled GM- CSF underway
- Until then – whole lung lavage is mainstay
- Bone Marrow therapy may be curative (as macrophages are bone marrow derived)
Diagnostic approach to PAP
- Genetics
- Lung histopathology
- Lung/serum biomarkers
Risk factors for RDS in term infant
38 weeks, male, operative delivery and white race – absence of these or failure to improve w/in 7 – 10 days or FHx severe neonatal lung disease – think
surfactant d/o
For surfactant disorders with respiratory failure at birth - think of:
ABCA3, SP-B deficiency
If negative:
SP-C, NKX2-1
For respiratory distress + hypothyroidism, hypotonia and developmental delay
NKX2-1
If negative:
ABCA3, SP-C
For early onset chILD syndrome or surfactant dysfunction or unknown pathology
SP-C, ABCA3 (later = also SP-C)
if negative:
NKX2-1, SP-B (early onset)
PAP pathology, elevated GM-CSF
CSF2RA/B
if negative:
SP-C, SLC7A7
Presentation of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV)
FOXF1 - autosomal dominant
- Rare, generally lethal
- Early postnatal respiratory distress, PPHN (not responsive to typical treatment)
- Usually have other manifestations:
- Cardiac (HLH)
- GI (malrotation, atresia)
- Renal
- Usually term/near-term
- Presentation identical to PPHN
- Does not respond to therapy (Ie iNO, ECMO), or only responds transiently
Imaging findings of ACD/MPV
Normal, with subsequent development of hazy opacity
Histology features of ACD/MPV
- Pulmonary veins running along pulmonary arteries (essential to diagnosis)
- Reduction/absence of veins in intralobular septa
- Muscularization of pulmonary arteries/arterioles
- Reduced density of capillaries in alveolar walls
- +/- lobular architecture simplification with lymphangiectasia
Etiology/Pathogenesis of ACD/MPV
Thought to be caused by abnormalities in the FOXF1 gene (haploinsufficiency - loss of 1 gene, so loss of function)
- Associated cardiac and GI anomalies are due to haploinsufficiency of FOXC2 and FOXL1
- Unclear whether the arterial and lobular abnormalities are primary or secondary to vein misalignment.
- May have artery hypertrophy secondary to deficient lobular development and poor gas exchange with hypoxemia
Diagnosis of ACD/MPV
Clinical Hx:
- Severe hypoxemia and idiopathic pulmonary hypertension, with no anatomic cause
Biopsy:
- Hx is supportive, but diagnosis is established only with biopsy.
- Biopsy is limited by subtle findings, and if limited sample of lung obtained, or if disease is patchy
DDx of ACD/MPV
Surfactant metabolic abnormalities (SFTPB, ABCA3), PIG, Lymphangiectasia
Distinguish from disorders of lung development (Ie Congenital Alveolar dysplasia, pulmonary hypoplasia)
- These diseases may have lobular simplification and vascular changes, but will NOT have misalignment of pulmonary veins
Treatment of ACD/MPV
Supportive (ventilation, iNO, ECMO)
- Do not provide long term survival, longest is 101 days
- Lung transplant attempted
- Given grave prognosis, establishing diagnosis with lung biopsy or at autopsy is recommended
Clinical presentation of lung growth abnormalities
Occur in vast context: prematurity, prenatal pulmonary hypoplasia, Congenital heart disease, Chromosome abnormalities (T21), and normal children with early postnatal injury
In general, clinical severity out of proportion to known comorbidities/circumstances
Factors limiting Prenatal Lung Growth
- Oligohydramnios (PROM, renal obstruction)
- Restriction of thoracic volume (space occupying lesion/deformities)
- CNS and/or neuromuscular disorders → reduced fetal breathing
- Prem related BPD
- CHD
- Poor pulmonary blood flow (TET)
- Cyanotic disease with impaired alveolarization - Chromosomal Abnormalities
- T21 (impaired postnatal alveolarization)
- Other
Imaging findings of lung growth abnormalities
Variable, based on etiology, age, severity of abnormality.
- Subpleural cysts are often seen in pulmonary hypoplasia associated with T21
Histology relating to abnormalities of lung growth
Lung weight to body weight is most reliable parameter of lung growth (esp in prems)
Radial Alveolar count
- Number of transected alveoli with line drawn perpendicular from the center of a bronchiole
- Normal = 5 alveolar spaces
- Requires standard inflation (radial alveolar count is reduced in uninflated lungs)
- Reduced in pulmonary hypoplasia, often with prominent bronchovascular structures, widened interstitium
May see lobular simplification with alveolar enlargement with poor alveolarization of
postnatal onset (more common in sub-pleural space)
- PIG is a frequent finding in biopsies with impaired lung growth
Etiology/Pathophysiology of Lung growth disorders
Prenatal and postnatal insults can impact lung maturation/development
- Requires distention with liquid and fetal respiratory movements for growth
- Anything that impairs this can cause prenatal growth disorder
- Range of severity, depending on mechanism of hypoplasia, and timing of insult
- If early insult (< 16 wks GA), may affect branching and acinar development - Ie. renal, CDH
- If later (PROM), will affect acinar development only
- Postnatal abnormalities impact late alveolarization (typically subpleural)
- Multiple factors likely play a role (hypoxia, abnormal pulmonary blood flow)
DDx for lung growth abnormalities
Broad
- Other abnormalities of lung development (lymphangiectasia, ACD/MPV), PIG,
Surfactant production/metabolism
- Alveolar enlargement is often misinterpreted as emphysema or consequence of lung injury/remodeling
- No evidence of destructive process/fibrosis
Treatment/Prognosis of lung growth abnormalities
Supportive care
- Treatment of underlying conditions (this drives prognosis)
- Increased morbidity and mortality when compared to other causes of diffuse lung disease
- 34% mortality in the chILDRN study
- Prematurity and Pulm Hypertension were predictors of mortality
- Highest mortality with high degree of alveolar enlargement and simplification (severe lung growth abnormality) ~ 80% mortality
Clinical presentation of PIG
Only in neonates/young infants
- Typically become symptomatic in first few days to weeks of life, after initial “well period”
- PIG is often self limited, typically not diagnosed after 6 months of age
- Variable presentation
- From tachypnea/hypoxia to neonatal respiratory failure and pulmonary hypertension
- Term or preterm infants affected
- Often seen with other lung growth abnormalities (Ie chronic neonatal lung disease of prematurity, pulmonary hypoplasia, congenital heart disease, pulmonary hypertension, meconium aspiration etc)
Imaging findings of PIG
Diffuse infiltrates/hazy opacities on CXR
- No common CT changes
Histology of PIG
AKA cellular interstitial pneumonitis
- Increased glycogen laden mesenchymal cells in alveolar interstitium
- Biopsy: patchy or diffuse expansion of alveolar walls by “bland spindle shaped cells”
(pale/bubbly cytoplasm)
- There is no inflammation or fibrosis in interstitium
- Strong positive for Vimentin (mesenchimal marker)
- May be PAS stain positive (PAS = Periodic acid Schiff)
Fixatives will affect the preservation of glycogen, therefore PAS staining may be hard to demonstrate.
- EM is the best approach to reveal accumulation of glycogen in interstitial cells
Epidemiology of PIG
Most present within first 24 hours of birth, most with hypoxia at birth
- chILDRN study found that patchy PIG was found in ~ 40% of cases with lung growth abnormality (Ie. prematurity associated chronic lung disease, pulmonary hypoplasia, Trisomy 21, Congenital Heart Disease) and with vascular disorders mimicking ILD
- Rare to see in children > 6 months
Etiology of PIG
Accumulation of mesenchymal cells in interstitium may represent changes in the maturation of the pulmonary mesenchymal cells, versus proliferation of the mesenchymal cells for some reason
Diagnostic Approach for PIG
Only diagnosed with lung biopsy
- Diagnosis supported by neonate with respiratory compromise, especially when the severity of disease is disproportionate to degree of other conditions
DDx for PIG
Sepsis, CHD, Lung development disorder (ACD/MPV), Pulm hypoplasia, Pulmonary vascular disease, lymphangiectasia, surfactant production/metabolism
- PCD (frequently causes neonatal tachypnea/resp distress)
Treatment for PIG
Treatment is supportive (supplemental O2, occasionally mechanical ventilation, Pulmonary hypertension treatment)
- Mortality is rare (tends to be related to complications)
- Mortality is increased when pulmonary conditions occur with PIG
- Consider use of high dose pulse steroids (case report data)
- Consider the impact on postnatal alveolarization and neurodevelopment
Clinical Presentation of Neuroendocrine Cell Hyperplasia of Infancy (NEHI)
Rare disorder
- Otherwise healthy term/near-term infants
- Present with tachypnea and retractions (generally insidiously) within the first few months
to year of life
- Crackles are prominent, hypoxemia is common
- Rare to have wheeze
- May develop FTT
- Exacerbations with URTI
- Infant PFTs: profound air trapping, reduced FEV0.5 and FVC, elevated FRC, RV, and RV/TLC
Radiographic Findings of NEHI
May be normal, May show hyperinflation
CT is distinctive:
- Ground glass opacities centrally, and in RML and lingula
- Air trapping/mosaic appearance
Histology of NEHI
Lung biopsies often show minimal to no pathologic changes
- Pathologic diagnosis rests on finding increased proportion of neuroendocrine cells within airways
- Identified with bombesin and serotonin immunostaining
- 2 airways with more than 10% bombesin positive areas or cell numbers of the airway suggest diagnosis
- Need adequate sample (10-15 airways), often with multiple biopsy sites due to wide variability
Etiology of NEHI
Familial cases with affected siblings have been described (? genetic predisposition)
- Unknown whether the neuroendocrine cells are a marker of NEHI, or involved in pathogenesis
- Recent evidence looking at # of NE cells and severity suggests causal role
- Thought that NE cells play role in oxygen sensing and airway/arterial tone → ? NEHI leads to VQ mismatch
Diagnostic Approach for NEHI
Exclude more common causes - Infection, CF, CHD
- Lung biopsy is considered definitive diagnostic approach
- Pathologic interpretation should be interpreted by physician with experience in this field
- Given advances, many diagnoses are occurring without use of biopsy
- Important to know that NE cells are also seen with other conditions (BPD, SIDS, Pulmonary Hypertension, CF)
DDx:
Acute/chronic infection, asthma, airway injury, Bronchiolitis obliterans
Pulmonary hypoplasia, PIG, Surfactant production/metabolism disorders
Other lung conditions that can have neuroendocrine cells present
BPD
SIDS
Pulmonary Hypertension
CF
Treatment/prognosis of NEHI
Supportive Care
- Supplemental Oxygen, supplemental nutrition
- Corticosteroids are not helpful in most cases
- No deaths reported with this condition, no patients have required lung transplantation
- Most children show overall improvement
- Children may show symptoms with resp infections or exercise
Lung findings on Trisomy 21
Alveolar Simplification/impaired postnatal alveolarization
Subpleural cysts
Cystic Dilatation of alveoli, with hypertensive changes of pulmonary vasculature
Pulmonary features of JIA
- Pleuritis (especially with pericarditis). Consider SLE if isolated pleuritis and arthritis.
- Pneumonitis
- Interstitial reticular and nodular infiltrates
- Bronchiectasis
- Vasculitis/diffuse alveolar haemorrhage (DAH)
- PHT
- Lipoid pneumonia – from endogenous lipid
- BO
50% of asymptomatic pts have abnormal PFTs (usually restrictive) – muscle weakness evident by MIP & MEP
-50% of MAS have lung involvement (25% ventilated) = infiltrates, pneumonitis, edema, haemorrhage.
Pathology of Pulmonary features of JIA
- Pulmonary haemosiderosis
- Lymphoid follicular bronchiolitis
Treatment of Pulmonary features of JIA
- NSAIDs, MTX, TNF- a inhibitors (etanercept, adalimumab, infliximab), steroids, IL-1 antagonists (anakinra), IL-6 antagonist (toclizumab)
- Acute serositis = pulse steroids
- MAS = anakinra, cyclosporine
- MTX shown to not increase risk of pulmonary disease in children with arthritis.
Pulmonary features of SLE
- Pleuritis/pleural effusion exudate (9-32%)
- Acute pneumonitis is rare – fever, dry cough, dyspnea, pleuritic chest pain, tachypnea.
- CXR: infiltrates.
- Chronic ILD is extrememly rare – exertional dyspnea, cough, pleuritic chest pain, basal crackles. Usually with multisystem SLE.
- Pulmonary haemorrhage – usually w/lupus nephritis, concurrent infection.
- PHT (esp. if lupus anticoagulant or Raynaud’s)
- PE with antiphospholipid Ab
- Shrinking lung syndrome = dyspnea, pleuritic chest pain, tachypnea, CXR reduced volumes, raised diaphragms, basal atelectasis, PFTs restrictive. ?due to diaphragmatic dysfunction.
> 1/3 have abnormal PFTs, usually restrictive +/- diffusion.
Pleuritis was found to occur more frequently in patients
with a younger age at disease onset, and longer disease duration, who manifested more cumulative disease-related damage, and in those who had positive anti-Sm and anti-RNP antibodies
Pathology of Pulmonary features of SLE
Chronic ILD: alveolar wall thickening, interstitial fibrosis, interstitial lymphocytic infiltrates, granular deposits of Ig and Complement.
Treatment for Pulmonary features of SLE
-Corticosteroids for pleuritis.
-Pulsed steroids for pulmonary haemorrhage.
Long-term morbidity includes premature atherosclerosis and osteoporosis.
Pulmonary features of JDM
- ILD: irregular linear opacities with consolidation and ground- glass attenuation.
- Pneumomediastinum
- Aspiration pneumonia
- Hypoventilation
- Acute interstitial pneumonitis and BOOP
- Abnormal PFTs in 30-40%
- Muscle weakness
Pathology of Pulmonary features of JDM
Anti-Jo-1 Ab
Reduced MIP & MEP
Normal DLCO and increased RV without decreased FEV1/FVC - helps to distinguish respiratory muscle weakness from ILD
Treatment for Pulmonary features of JDM
High dose steroids
Cyclosporine
Cyclophosphamide
RItuximab
Pulmonary features of Scleroderma
- ILD (80%) – dyspnea, dry cough.
- CXR – ground-glass, reticular pattern, traction bronchiectasis.
- PAH (4-9%)
- Pleuritis and pleural effusions
- Bronchiectasis
- BOOP
- Alveolar hemorrhage
- Spontaneous pneumothorax with severe fibrosis
- Aspiration pneumonia with GERD
- Abnormal PFTs in 42-65% (restriction/diffusion)
ILD, PAH, and cardiomyopathy are dreaded organ manifestations associated with mortality in children
Pathology of Pulmonary features of Scleroderma
ILD - nonspecific interstitial pneumonitis.
Treatment of Pulmonary features of Scleroderma
Cyclophosphamide, other immunosuppressants
Pulmonary features of Mixed Connective Tissue Disorder
- Fibrosis*
- Pleural effusions*
- PAH*
- PE
- Pulmonary hemorrhage
- Diaphragmatic dysfunction
- Aspiration pneumonitis
It is characterized by the presence of high titer anti-U1 ribonucleoprotein (RNP) antibodies in combination with clinical features of SLE, SSc, or DM
Pulmonary features of Sarcoidosis
- Intrathoracic LN
- Parenchymal dz
- Dyspnea, wheeze, cough
- Parenchymal infiltrates may be nodular, fibrotic, or alveolar and tend to occur in the upper lobes.
- Pleural effusion, pneumothorax, pleural thickening, calcification, and atelectasis also have been reported.
Staging: 0 = nl (10% at presentation) I = bilateral hilar adenopathy II = BHL with parenchymal infiltrates (71%) III = parenchymal infiltrates without BHL (8.3%) IV = fibrosis -Pleural effusion -Pneumothorax -Pleural thickening -Calcification -Atelectasis
PFTs nil if stage 0/I – restrictive/diffusion, sometimes obstructed.
Pathology of Pulmonary features of Sarcoidosis
- Bronch = waxy yellow mucosal nodules, erythema, edema, granularity, cobblestoning of mucosa, bronchial stenosis.
- BAL lymphocytosis >85%; increased CD4:CD8 ratio (opposite in ILD with connective tissue disease).
- Diagnosis = typical clinical features + noncaseating granulomas on biopsy.
Treatment of Pulmonary features of Sarcoidosis
- Spontaneous remission in many
- Stage III likely to progress to fibrosis so most treated with steroids.
Pulmonary features of GPA
- Dyspnea, cough, hypoxia (19%)
- DAH
- Subglottic stenosis
- Upper airway: sinusitis, nasal septal ulceration/perforation, otitis media, mastoiditis, hearing loss, oral ulcers, nasal cartilage damage, saddle-nose deformity.
- CXR = nodules, fixed infiltrates, cavitations, mediastinal LN, effusion, pneumothorax.
Bloodwork for GPA
Anti-PR3
ANCA
Pathology of Pulmonary features of GPA
- Bronch: mucosal erythema, ulceration, hemorrhage, cobblestoning, nodules, polyps, submucosal tunneling, synechial bands, airway stenosis.
- Lung biopsy yield is low as disease is patchy.
Treatment of Pulmonary features of GPA
- Steroids and cyclophosphamide
- Obstructing airway lesions: intralesional steroids, surgical.
Pulmonary features of MPA
Pulmonary hemorrhage (30- 50%) – presents likely IPH
Bloodwork for MPA
- Anti-50%) – presents likely IPH myeloperoxidase (MPO)
- ANCA
- No granulomas
Pulmonary features of Churg-Strauss
- Migrating pulmonary infiltrates vs fixed infiltrates like Wegener’s
- Concomitant severe atopic asthma or allergic rhinitis (almost 100%)
Pathology of Pulmonary features of Churg-Strauss
Granulomatous
Pulmonary features of Sjogren’s syndrome
- Dry cough, obstruction, AHR
- ILD is rare
-ILD – LIP
Pulmonary features of IBD
- Abnormal PFTs (diffusion)
- Bronchiectasis
- reduced DLCO (most common)
- bronchial hyper-reactivity
- bronchiectasis (most common in adults)
-rare: tracheal stenosis, colobronchial/ileobronchial fistulaue, BO, granulomatous pulmonary nodues, pulmonary vasculitis, pleural effusions, BOOP
Pathognomonic lesions of Sarcoidosis
Noncaseating epithelioid cell granulomas
The granulomas consist of tightly organized collections of predominantly CD4+ T lymphocytes and mononuclear phagocytes (epithelioid cells, macrophages and multinucleated giant cells).
In the lung, most granulomas are located in the perilymphatic areas, including near bronchioles, in the subpleural space, and the perilobular spaces
The granulomatous lesions usually heal with preservation of lung parenchyma; however, in 20% to 25% of patients, fibroblasts proliferate at the periphery of the granuloma and produce fibrotic scar tissue.
What is Lofgren’s syndrome?
A triad of acute arthritis, bilateral hilar adenopathy (BHL), and erythema nodosum is a common presentation in 9% to 34% of adults but is less common in children.
DDx for non-caseating granulomas
1) Immunodeficiency syndromes (especially chronic granulomatous disease)
2) Fungal and mycobacterial infections, berylliosis,
3) Ulcerative colitis
4) Wegener’s granulomatosis
DDx for caseating granulomas
TB
When do you consider steroids in Sarcoidosis?
- Pulmonary sarcoidosis: Worsening pulmonary symptoms, deteriorating lung function, progressive radiographic changes (worsening of interstitial opacities, cavitation, progression of fibrosis with honeycombing, development of pulmonary hypertension).
- Cardiac, neurologic, ocular, renal involvement or hypercalcemia, even with mild symptoms, because
fatal arrhythmias, blindness, and renal failure may develop. - Severe debilitating symptoms from any organ involvement
Therapy is not indicated in asymptomatic children with stage I or II pulmonary disease with normal or mildly abnormal lung function.
Stage III disease needs to be followed closely because adult data suggest that the majority do not resolve, it may progress to pulmonary fibrosis, and most patients will require therapy in the future.
Steroid protocol for Sarcoidosis
Corticosteroid dosing typically is started at a relatively high dose (1 mg/kg/day depending on severity of disease) for 4 to 6 weeks and then is tapered.
- A response to therapy is usually seen within 6 to 12 weeks of initiation of therapy, with improvement in symptoms, pulmonary infiltrates, and lymphadenopathy on imaging and variable improvement in pulmonary function.
- Steroid needs to be continued for 12 to 18 months in order to prevent relapse of disease.
Steroid sparing agents:
- Methotrexate
- Hydroxychloroquine
- Infliximab
- Lung transplant for severe cases
Risk factors for worse prognosis in Sarcoidosis in chidlren
Erythema nodosum has been associated with a good prognosis while central nervous system involvement is associated with a poor prognosis.
DDx of acute respiratory deterioration in systemic inflammatory diseases
Infection Air leak Upper airway obstruction esp.GPA Acute pneumonitis or pleuritis DAH PE Progression of CLD Cardiac dysfunction
DDx of Respiratory symptoms in Systemic Inflammatory conditions
Generalized muscle weakness Deconditioning Cardiac Disease Thromboembolic disease Opportunistic infection Drug toxicity effects Inflammatory lung disease
Pattern of ventilatory impairment, DLCO and gas exchange characteristics with chest wall restriction/deformity
Restrictive defect with low MIPS/MEPS and low peak flow in more severe disease
DLCO preserved until severe loss of volume
With severe disease, hypoventilation results in hypercapnia and hypoxia with norma A-a gradient
Pattern of ventilatory impairment, DLCO and gas exchange characteristics with bronchiectasis
Obstructive defect
DLCO preserved until severe end stage disease
With end stage disease - hypoxia at rest
Pattern of ventilatory impairment, DLCO and gas exchange characteristics with DAH
Variable pattern but often restrictive
DLCO increase if hemorrhage is recent
During active bleeding, hypoxia often profound with a wide A-a gradient
Pattern of ventilatory impairment, DLCO and gas exchange characteristics with Pulmonary vascular disease
Normal PFTs
Reduced DLCO
Hypoxia at rest even with moderate pulmonary HTN
Pattern of ventilatory impairment, DLCO and gas exchange characteristics with Mixed disease: pulmonary fibrosis and muscle weakness
Restrictive defect, often severe
DLCO less reduced than expected for degree of restrictive defect
Hypoxia at rest or with exercise is frequent
Pulmonary manifestations of Macrophage Activating Syndrome
Lung infiltrates
Pneumonitis
Pulmonary hemorrhage
Pulmonary edema (which may result from myocardial dysfunction associated with the hypercytokinemia)
Leading pulmonary cause of death in SLE
Infection
SLE is associated with an increased risk of a wide range of infections, including bacterial, viral, mycobacterial, fungal, and parasitic infections, with the respiratory tract as one of the common sites
In addition immunosuppressive treatments to control the disease confer an increased risk of opportunistic infections such as pneumocystis, cytomegalovirus, and fungal infections.
Pulmonary histology of SLE
Alveolar wall thickening,
Interstitial fibrosis
Interstitial lymphocytic infiltrates
Granular deposits of immunoglobulin and complement.
Potential causes of pulmonary hypertension in SLE
Pulmonary vasculitis
Pulmonary thromboembolism
ILD
Valvular heart disease.
Most frequent pulmonary manifestation of the antiphospholipid antibody syndrome
Pulmonary embolism
What is shrinking lung syndrome?
Associated with SLE
Typically presents with progressive dyspnea, pleuritic chest pain, and tachypnea.
Chest radiographs may demonstrate reduced lung volumes, raised hemidiaphragms, and basal atelectasis
PFTs are usually restrictive.
Pulmonary complications of JDM
- ILD (may be Rapidly progressive)
a. BOOP
b. Pulmonary fibrosis
c. DAD - Pneumomediastinum
a. is a characteristic complication of adult DM with interstitial pneumonitis and has also been
reported in JDM - Aspiration pneumonia
- Hypoventilation
Major clinicopathologic variants of ANCA-associated small vessel vasculitis syndromes with frequent pulmonary involvement
GPA (formerly Wegener’s),
Microscopic polyangiitis (MPA),
Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss)
Isolated pulmonary capillaritis
ANCA-associated vasculitis (AAV) syndromes are characterized by necrotizing vasculitis of small vessels,
frequent pulmonary and renal involvement, and a paucity of immune deposits in the blood vessel wall.
DDx DAH & pulmonary-renal syndrome
ANCA-associated vasculitides
Goodpastures syndrome
SLE
Thromboembolic disese Infections
Imaging findings of GPA
*Nodules (90%) followed by fixed infiltrates (45%)
▪ Nodules tend to be multiple, greater than 5mm in diameter and cavitating in 17%
Airspace opacification usually correlated with clinical evidence of pulmonary hemorrhage
▪ Granulomatous lesions (necrotizing)
Ground glass opacification on CT (52%)
Pulmonary cavitations
Mediastinal lymphadenopathy
Pleural effusions
Pneumothoraces
Bronch findings with GPA
Mucosal erythema, edema, ulceration, hemorrhage, cobblestoning, nodules, polyps, submucosal tunneling, synechial bands, and airway stenosis
Endobronchial findings nonspecific, similar findings encountered with infections and sarcoidosis
Most common manifestation of tracheobroncial GPA
Subglottic stenosis
DDx of GPA
Infections (especially mycobacterial, fungal, or helminthic infections in addition to common viral and bacterial causes),
Other causes of pulmonary-renal syndrome (other ANCA-associated vasculitides, SLE, MCTD, Goodpasture syndrome)
Sarcoidosis,
UC with pulmonary involvement
Malignancy
Chronic granulomatous disease
What is Bronchiolitis Obliterans?
Small airway disease caused by injury leading to fibrosing and narrowing or complete obliteration
Causes of BO and clinical presentation
Causes: inhalation of toxins (hydrochloric acids); Inflammatory disease (SLE); post BMT or lung tx, infection
Focusing on post-infectious BO → leading cause is adenovirus (serotypes 3, 7, 21 have highest virulence); influenza, parainfluenza, measles, RSV, HMNV, varicella, mycoplasma
Initial presentation like bronchiolitis with fever, cough, wheeze, dyspnea and CXR showing peribronchial thickening and patchy bronchopneumonia with collapse/consolidation
Risk factors for BO
Hospitalization > 30 days, multifocal pneumonia, hypoxia, hypercapnea, PICU stay, need for mechanical ventilation
Clinical consequences of BO
Will have incomplete recovery of symptoms → may develop recurrent pneumonia, hyperinflation, bronchiectasis, Swyer-James syndrome
PFT findings in BO
Airflow obstruction with decreased FEV1, FEV1/FVC, mid-expiratory flow rates
lung volumes show increase RV and RV/TLC
BAL findings in BO
High WBC with increased neutrophils and lymphocytes with decreased CD4/CD8 ratio
Imaging findings in BO
HRCT shows mosaic perfusion, vascular attenuation, and expiratory air trapping (also can see bronchiectasis and atelectasis)
Components of a BO clinical score
Typical clinical hx 0-4
Documented adenoviral infection 0-3
HRCT showing mosaic perfusion 0-4
Score ≥ 7 predicted dx of BO with 100% specificity and 67% sensitivity but score < 7 did not accurately rule out dx
Gold standard for BO diagnosis
Lung bx is gold standard for dx but because heterogenous disease, sampling is a problem
Histopathology of BO
Inflammation of small airways → predom CD8 T lymphocytes filling the lumen of the small airways
Fibrous tissue creating varying degrees of luminal occlusion in the small airway (can have total
obliteration of the lumen by fibrotic tissue)
Note the proliferative type characterized by granulation tissue plugs (masson bodies) now is called BOOP = COP
Treatment of BO
Supportive care: O2, nutrition, avoid smoke/irritants, vaccinations, treat GER
▪ Small number improve with bronchodilators and ICS
▪ Systemic steroids- pulse dosing 30 mg/kg x 3 days, if deemed beneficial then repeat monthly x 3-6 mos
▪ Azithromycin
Structure of the Pulmonary Lymphatic System
Pulmonary lymphatic system composed of two interconnected pathways:
1) one drains the subpleural space and outer surface of the lung
2) the other follows bronchovascular bundles to drain the deeper portions of the lung
Hypothesized reasons for the development of respiratory disorders of the lymphatic system
1) Disordered Embryonic Development
- plays a role in pulmonary lymphangiectasia
- often presenting in the neonatal period
2) Disorders of Lymphatic Growth
- Presenting outside the neonatal period
- ie. lymphangiomatosis
Characteristics of Pulmonary Lymphangiectasia
Dilatation of pulmonary lymphatic vessels and disordered drainage = accumulation of lymph in lungs (spectrum of respiratory disease)
Most present neonatal period or infancy
Primary = abnormal lymphatic development (failure of regression of large lymphatic vessels)
Secondary = Obstructive process impeding lymph drainage
Chromosomal disorders associated: Noonan syndrome, Hennekam syndrome, Yellow Nail syndrome, Down syndrome
o More likely to have generalized disease
Clinical presentation of Pulmonary Lymphangiectasia
At birth develop respiratory distress → to respiratory failure. Can have chylous effusions but some do not have effusions.
Later in infancy or childhood present less severe: chronic tachypnea, recurrent cough, wheezing. PL has been associated w/ chylothorax, chylopericardium, and chylous ascites.
Diagnosis of Pulmonary Lymphangiectasia
CXR, high res. CT (thickening of peribronchovascular septa and septa surrounding lobules.)
Lung biopsy (gold standard - dilated lymphatic vessels in interlobular septa, near bronchovascular bundles, and/or within the pleura) Extrapulmonary disease manifestations: GI involvement, bony disease, or skin lesions from draining lymphatic glands.
Management of Pulmonary Lymphangiectasia
No cure, supportive tx
iNO, ECMO used with variable success
Natural course is variable; a high mortality rate if diagnosed in neonatal period.
Those who survive the neonatal period seem to eventually experience improvement of disease
What is Lymphangiomatosis?
Lymphangiomatosis = multiple lymphangiomas (less common)
o Affects multiple organs (liver, soft tissue, spleen, bones, mediastinum, lungs).
Characteristics of Gorham-Stout disease
Syndrome characterized by chylothorax, bone cysts, lymphangioma on biopsy
- Chylothorax = worse prognosis
- Proliferation of vascular structures in bone
- Symptoms of cough, dyspnea, pain
Gorham-Stout disease and lymphangiomatosis both occur sporadically without a known inheritance pattern
Clinical Presentation of Gorham-Stout disease
Disease of thorax can manifest in mediastinum, pleural space, chest wall, lungs or pericardium
May present with cough, chest pain, dyspnea, wheezing
Chylous effusion usually prominent
Diagnosis of Gorham-Stout disease
CXR - interstitial infiltrates, chest mass, effusions, or bony lesions.
HRCT - multiple lymphangiomas, smooth thickening of interlobular septa and bronchovascular bundles, ground-glass attenuation, or effusions
Biopsies of lesions - increased numbers of dilated lymphatic channels
Management of Gorham-Stout disease
Natural history = progressive growth of lymphangiomas that eventually compress vital structures.
Young age and respiratory involvement predict poor outcome
Therapy for severely symptomatic pleural effusions may include thoracentesis or pleurodesis.
When lymphangiomas are diffuse, complete surgical resection not possible.
Interferon-alpha 2b reported to halt lymphatic proliferation
o Consider this for Gorham stout disease as well
What is Lymphangiomyomatosis (LAM)?
Abnormal smooth muscle proliferation, cystic destruction in lung
● Typically childbearing years
○ recurrent pneumothoraces, dyspnea, lung cysts
● +/- chylous effusions
● Differentiated from lymphangiomatosis based on presence of lung cysts and immunohistochemistry
● May be associated with Tuberous Sclerosis (40% of women with TS)
What is Pulmonary Alveolar Microlithiasis?
Deposition of Ca phosphate calculi within alveoli
- related to disordered phosphate transfer
- Type II alveolar cells degrades surfactant. Phosphate is a waste product of this. May build up in cells unless properly removed.
Phosphate reuptake secondary to dysfunction of the SLC34A2 gene product causes formation of calcium phosphate microliths
Diff dx includes: sarcoidosis, TB, histoplasmosis, IPH
Autosomal Recessive
Clinical presentation of Pulmonary Alveolar Microlithiasis
Most asymptomatic, incidental finding or relative w/ finding.
Sx: dyspnea, cough, chest pain in only 1/2 of those affected.
At diagnosis, PFT usually normal; declining function occurs over decades
Diagnosis of Pulmonary Alveolar Microlithiasis
CXR –“Sandstorm” appearance; sandlike Ca-Phosphate micronodules - denser at lung bases
CT - micro nodules, ground-glass opacities, subpleural interstitial thickening, interlobular septal thickening
Management of Pulmonary Alveolar Microlithiasis
Lack of consensus regarding natural course
Reports describe development of pulmonary fibrosis followed by respiratory insufficiency, pulmonary HTN, death secondary to respiratory failure over decades after dx
No cure for PAM.
Lung tx successful in past
What is Gaucher disease?
Most common lysosomal storage disease
Mutation glucocerebrosidase gene = buildup of glucocerebroside
Glucocerebroside accumulates in macrophages = Gaucher or foam cells.
Infiltration of Gaucher cells may occur within alveoli, within interstitial spaces, around airways, or within pulmonary vasculature (infiltrative lung disease)
Autosomal Recessive
Clinical presentation of Gaucher disease
Clinical pulmonary disease uncommon but pts have abnormal PFT
Hepatopulmonary syndrome may also occur secondary to the liver disease
Imaging findings of pulmonary disease in Gaucher disease
CXR - reticulonodular changes
CT -ground-glass consolidation, interstitial involvement, alveolar opacities, bronchial wall thickening
Treatment of Gaucher disease
Enzyme replacement therapy decreases organomegaly, less successful in reversing existing pulmonary disease.
ERT may slow or prevent progressive decline in lung function.
Role of ERT in preventing lung disease not known.
Characteristics of Niemann Pick Type B
- Deficiency of acid sphingomyelinase = accumulation of sphingomyelin within cells/ tissues
- In lung, build-up of foam cells containing sphingomyelin in alveoli, alveolar walls, lymphatic spaces, pleural space -Rarely, severe form of ILD may present in infancy or early childhood
- In many cases, ILD more indolent, and survival into adulthood
AR
Clinical presentation of Niemann Pick Type B
- Presentation w/ hepatomegaly, splenomegaly, thrombocytopenia, dyslipidemia.
- Many also have ILD
- No neurologic involvement and often survive into adulthood
Imaging and PFT findings associated with Niemann Pick Type B
PFTs: decreased FVC, FEV1, and diffusing capacity
CT - ground-glass appearance, reticulonodular densities, thickening of interlobular septa, thickening of intralobular lines.
Treatment of pulmonary complications associated with Niemann Pick Type B
- No specific tx exists
- Whole lung lavage tried with varying results
- ?Future for enzyme replacement therapy
Pulmonary manifestations of NF-1
- Thoracic involvement: neurofibromas (often plexiform) can arise from the chest wall or posterior mediastinum
- Can surround vital structures -Malignant transformation can occur so consider bx
- Also associated with ILD
- Diffuse lung disease mainly in adult; not reported in children
AD
Imaging findings of NF-1 (pulmonary)
ILD appears as large, apical thin-walled bullae and basilar fibrosis
Pulmonary associations with Dyskeratosis Congenita
Pulmonary fibrosis
Characteristics of Alpha-1 Antitrypsin Deficiency
AAT inhibits enzymatic breakdown of lung tissue; dysfunction can lead to severe obstructive lung dz
One of most common inherited diseases worldwide but pulmonary manifestations of AAT deficiency is very rarely in children
Inherited in co-dominant manner >100 variants of the protein identified
Classification based on protease inhibitor (Pi) system
- F = Fast
- M = Medium
- S = Slow
- Z = Very Slow
- AAT inhibits proteolytic enzymes (trypsin, neutrophil elastase, collegenase, macrophage cathepsin)
- Co-dominant expression of both alleles determines serum level of AAT, level determines risk of disease
Not all at risk individuals develop disease, environmental factors influence: AAT deficiency and smoking = accelerated rate of disease development
Exposure to kerosene heaters, employment in agriculture, exposure to other pollutants from biomass fuel sources: all implicated in emphysema
Deficiency also causes liver disease (ranging from mild elevation of LFTs to cirrhosis & hepatic failure)
Pulmonary disease associated with Behcet’s disease
Pulmonary vasculitis can lead to hemorrhage, infarction, death -Lung disease in adults, reported in kids
Pulmonary artery aneurysms is most common resp presentation of dz (single or multifocal)
Present w/ hemoptysis
Pulmonary parenchymal dz also reported and associated w/ pleuritis, reticulondular or focal opacities, mass lesions, hilar enlargement; findings occur most likely secondary to hemorrhage, infarction related to pulmonary vasculitis
Pulmonary Complications of Radiation Tx
Whole lung irradiation for e.g. mets to the lung (Wilm’s tumor, sarcomas, hepatoblastoma)
Total body irradiation for e.g. preconditioning
- Acute pneumonitis – usually 30 to 90 days after tx with cough, dyspnea, hypoxemia and pleuritic pain
- Rx systemic steroids
- Imaging = Diffuse ground glass densities
Chronic fibrosis – appear 6 to 24 mos after tx, usually but not always proceeded by pneumonitis symptoms, most commonly presents with progressive dyspnea
- Imaging = Streaky densities, decreased lung volume or atelectasis, pleural thickening
Impair growth of bone, cartilage and muscle of thorax
Pulmonary Complications of Chemotherapy
Bleomycin, Dactinomycin have additive toxicity to radiation - can lead to pulmonary fibrosis
Actinomycin D, adriamycin cause radiation recall with delayed presentation of toxicity up to 6 weeks later
Busulfan, Cyclophosphamide, Methotrexate are other pulmonary toxins
Pulmonary Complications after Solid Organ Transplant
- Pulmonary edema, pleural effusions, ARDS
- Diaphragm dysfunction → resp distress, atelectasis, pneumonia
- Medication toxicity
- PTLD
Characteristics of PTLD
Immunosuppression → T lymphocyte depletion → uncontrolled EBV driven B cell proliferation → range from polyclonal B lymphocyte expansion to B cell lymphomas
Most common pulmonary PTLD sx: cough, dyspnea and upper airway obstruction
Imaging shows nodules but can also see LN, consolidations or effusion
Should biopsy and assess for EBV-early RNA (EBER) – staining cells
Median onset is within 24 mos of transplant
Spectrum from polymorphic – monomorphic (worst prognosis)
Risk Factors for PTLD
Seroconversion of EBV-naive recipient, high degree of immunosuppresion, Rh factor negativity, Rh mismatch, recipient CMV seronegativity
Treatment for PTLD
Tx is reduction of immunosuppresion (but may end up with graft rejection) +/- Rituximab, antivirals
Tx: reduce immunosuppresion, anti-CD20 agent (rituximab – if CD20 + histology), CHOP chemoTx (cyclophosphamide, prednisone)
Key points re: pulmonary complication of medication toxicity following solid organ transplant
mTOR drugs (sirolimus and everolimus) – can cause interstitial pneumonitis (but less nephrotoxic than calcineurin inhibitors)
Fever, dry cough, dyspnea with exertion, restrictive pattern on pfts
Imaging shows interstitial infiltrates, consolidation or ground glass opacities with lower lobe predominance
BAL/Bx show lymphocytic alveolitis, pulmonary hemorrhage and organizing pneumonia
Tx by stopping the med
Screening recommendations for pulmonary complications post HSCT
- Hx/PE
- CXR and HRCT
- PFTs: spirometry, lung volumes, DLCO, MIPs/MEPs
- 6 minute walk test
Early non-infectious pulmonary complications following HSCT (~ 30 days)
Oral mucositis Pulmonary edema PVOD Diffuse alveolar hemorrhage Idiopathic pneumonia syndrome Peri-engraftment RDS
At which point post HSCT could you see GVHD?
2 mos and beyond
Late non-infectious pulmonary complications following HSCT (> 90days)
ILD - COP
PTLD
BO
chronic GVHD
Diagnostic criteria of Idiopathic pneumonia syndrome post HSCT
Bimodal peak: 2 weeks and 6-7 weeks post
Clinical signs: dyspnea, non-productive cough, hypoxemia, crackles
PFT: restrictive pattern and CXR: diffuse infiltrates
BAL cultures neg (2nd BAL recommended 2-14 days after first)
Histology consistent with ILD-COP post HSCT
Patchy areas of consolidation with polypoid plugs of loose organizing connective tissue in the respiratory bronchioles and alveolar ducts
DDx of Airspace Consolidation
Hospital/Community acquired pneumonia Fungal pneumonia Aspiration pneumonitis/pneumonia Idiopathic Pneumonia syndrome TB/NTM DAH ARDS Pulmonary edema TRALI
DDx of Pulmonary Nodule
Discrete Fungal infection Nocardia infection Metastatic calcification PTLD Malignancy Septic emboli Tree-in-bud pattern Viral pneumonia Bacterial pneumonia BOS
DDx of Ground glass opacities
Pulmonary edema TRALI ARDS DAH CMV PJP Common viruses Drug toxicity
DDx of Mosaic Attenuation
Air trapping BOS Viral infection Vascular disease Pulmonary HTN/porto-pulmonary HTN Venous thromboembolism
Postulated reasons why lung transplant is less frequent than other organ transplants
Lower prevalence of end-stage pulmonary disease in children
Improved CF care
Lower procurement rate of donor lungs
Small number of pediatric lung Tx centers around world
Indications for Pediatric Lung Transplant
CF – end stage Pulmonary HTN (often times associated with CHD) Neonatal d/o – surfactant protein (B, C, ABCA3) deficiency, ACD ILD BO BPD Pulmonary hypoplasia Re-transplant
Absolute contraindications for lung transplant (Kendigs)
Active malignancy within 2 years Sepsis TB AIDS Severe neuromuscular disease Hepatitis C with histologic liver disease Extenuating social/compliance issues
Relative contraindications for lung transplant (Kendigs)
Pleurodesis Renal insufficiency Nutritional status (really low or high BMI) Mechanical ventilation Scoliosis Poorly controlled DM Osteoporsis B.cepacia
Assessment process of donor lungs
Donor lungs assessed with ABG’s, CXR, inspection, airway C/S, bronchoscopy
Donor hx reviewed for acute viral infection and serologies checked (hep A, B, C, HIV, VZV, CMV, EBV, HSV)
Post lung transplant management
Immunosuppression – triple immunosuppression (steroids/calcineurin inhibitor (tacro)/cell cycle inhibitor MMF/AZT)
Antimicrobials – IV Abx pre-peri-post transplant targeting recipient microbiology and donor micro (often known post-Tx); if no CF use Abx with good G+/G- coverage, ie. Tazo for 7 – 10 days
Septra for PCP proph (nebulized pantamidine is alternative)
Nystatin
CMV prophylaxis (variable from center to center – often involves some time of gancyclovir/valgancyclovir +/- CMVIg and serial monitoring of CMV PCR)
Re: monitoring – may need to use infant/toddler PFT’s; CXR; CT; bronchoscopy and TBBx
Immediate complications post lung transplant
Surgical complications:
- Bleed (pleural space, at anastomosis)
- Phrenic N injury
- Dehiscence of vascular/bronchial anastaomosis
- Require bronchoscopy surveillance 24-48hours post
- Primary graft dysfunction (PGD)
Infectious/Immunologic:
- Hyperacute rejection
- Acute rejection (as early as 1 week)
- Infection
Early (1-6 mos) complications post lung transplant
Infection (bacterial, viral – CMV, EBV, HSV, fungal)
Rejection (acute cellular, humoral (antibody) mediated
PTLD (as early as 1 month)
Medication side effects
Late (> 6 mos) complications post lung transplant
PTLD
Chronic allograft dysfunction - BO/BOS, RAS or simply CAD
Key points about primary graft dysfunction post lung transplant
Most common problem in first week post-transplant Related to re-implantation lung injury
Associated with procurement procedure, duration of ischemia, generation of hydroxyl radicals and pro-inflammatory cytokines during ischemia may be important
Characterized by ARDS type picture, DAD on path, marked hypoxemia and pulmonary infiltrates
Tx – supportive care
Timeline for hyper acute rejection post lung transplant
Within hours – rare; potentially catastrophic; associated with circulating recipient Ab’s that bind to donor HLA molecules on vascular endothelium
Causes profound graft ischemia – thus cross-match at time of transplant and if positive give plasmapharesis to prevent hyperacute rejection
Timeline for acute rejection post lung transplant
Acute rejection – can occur as early as 1 week post and as late as 2 – 3 years
Lymphocytic attack of graft
Symptoms – nonspecific – could be cough, fever, dyspnea, hypoxemia, radiographic change or no symptoms thus routine surveillance bronch with TBBx; Path = perivascular lymphocytic infiltrate
Tx = pulse steroids (10 mg/kg methylpred X 3 days)
Timeline for Ab mediated – humoral rejection post lung transplant
Can occur later (> 1 month post) from development of donor specific Ab’s (similar to hyperacute, but Ab’s not present at time of transplant, develop over time)
Dx criteria not exist; if sick/declining PFT’s/radiographic change and increase DSA (donor specific Ab) then Tx with PLEX +/- steroids +/- thymo +/- IVIG
Leading cause of mortality post lung transplant
BO/BOS: 60% at 6 years
Leading cause of mortality
One form of CAD
Dx – from PFT’s, worse function, TBBx showing: obliterated bronchioles with fibrous changes and collagen deposition in the lumen
RF’s – episode of acute rejection (particularly occurring > 3 months post-Tx), HLA Ab’s, GERD, respiratory viruses, non-compliance with immunosuppression
Tx – AZT 3X/week; thymo, re-transplant
Outcomes of lung transplant
Survival – 50% at 5 years (essentially)
Somatic growth is a problem for many patients post-Tx; likely because poor pre-Tx nutrition and use of steroids
There is some question regarding whether true lung growth occurs (IE: incr surface area for gas exchange) post transplant.
Causes of death: graft failure and infection are No. 1 in first year post; in first 30 days it’s surgical issues; BO is still the biggest obstacle long term
Management of Non-inflammatory Pleural Effusions and Transudates
Treatment is supportive and management of the specific underlying disorder.
Evacuation of a transudate after the initial diagnostic thoracentesis is indicated only for relief of dyspnea and other cardiorespiratory disturbances caused by mediastinal displacement.
Intercostal tube drainage may be provided in lieu of repeated thoracenteses, depending on the child’s tolerance of the procedures and the progression of the underlying disorder.
Diuretics administered to some patients may slow re-accumulation of the transudate and may decrease or eliminate the need for frequent thoracentesis.
Pleural transudates caused by fluid overload (e.g., from intravenous infusion) or overload of lymphatic drainage (e.g., ascites, peritoneal dialysis) may require only diuresis or may resolve spontaneously.
Characteristics of Hemothorax
Associated with trauma
Requires expansion of vascular volume and direct surgical repair sometimes
Thoracotomy indicated when
○ Need more than 20 mL/kg of blood
○ Ongoing blood loss > 3 mL/kg/hour
Chest tube always placed to avoid pleural adhesions
Principles of Chylothorax Management
- Drainage of effusion
2. Nutritional support (MCT to decrease flow of lymph, TPN, surveillance of nutritional status and immune competency)
Differential diagnosis of Chylous effusion
- Congenital
- Primary lymphagiectasia (syndromes = Noonan’s, Turners, Yellow Nail syndrome, Gotham, Milroy)
- Lymphangiomyomatosis
- Lymphagioleiomyomatosis
- Lymphangioma - Acquired
- Surgical trauma (post CHD surgery, post pacemaker placement, post lung resection, thoracic irradiation)
- Blunt thoracic trauma, seat belt injury
- Infiltration/mechanical obstruction (Lymphoma)
- Intraluminal lymphatic obstruction (Thoracic duct cyst, Thoracic duct thrombosis)
- Extraluminal lymphatic obstruction (TB, Sarcoid, Castleman’s disease, Extramedullary hematopoeisis)
- Increased venous pressure (CHF, Cardiomyopathy, Constrictive pericarditis, SVC/subclavian vein thrombosis)
- Transdiaphragmatic chyle movement (chylous ascites)
Chylous effusion - thoracentesis results
○ Appearance: milky, sanguinous, serosanguinous (Does not clear with centrifugation)
○ Exudative effusion by Light’s criteria
○ Lymphocyte predominant (usually > 80% - polyclonal populations of T cells)
○ Triglycerides > 1.24 mmol/L (110 mg/dL)
○ Cholesterol level < 5.18 mmol/L
○ If doubt - can look for chylomicrons on lipoprotein electrophoresis
Causes of inflammation of the pleural membrane (pleurisy, pleuritis)
Infection Neoplasm Trauma AI disease Systemic granulomatous disease
Most common pathogen causing empyema
S. Pneumo (and lesser extent S. Aureus)
Causes of non-tuberculous empyema
Aerobic
- S. pneumo
- S. aureus
- S. pyogenes
- H. influenzae type b
- E. coli
- Klebsiella
- Pseudomonas
Anaerobic
- Microaerophilic strep
- Fusobacterium
- Bacteroides melaninogenicus
- Peptococcus/Peptostreptococcus
- Catalase-negative, non-spore-forming, Gram-negative bacilli
Possible longterm sequelae of untreated empyema
Cavitary pneumonia
Bronchopleural fistula
Pneumothorax
Lung abscess (particularly with organisms such as S. aureus)
Empyema necessitans when purulent material perforates through the chest wall
Fibrothorax, trapped lung
■ Rare in children
■ Total duration on antibiotics: 3-4 weeks per CPS
Risk factors for spontaneous pneumothorax in older child
Male predominance
Tall, lean body habitus
Cigarette smoking
Air leak usually from rupture of apical blebs
Connective tissue disorders (Marfan, Birt-Hogg-Dube, follicular gene mutations)
Causes of secondary pneumothorax
Connective tissues disease Airway disease: CF, Bronchiectasis, Acute asthma ILD Post-infectious Malignancy Aspiration of FB Catamenial pneumothorax Congenital pulmonary malformations Neonatal pneumothorax
Mechanism of tension pneumothorax
Uncoupling of lung from chest wall
Continued airleak can elevate the intrapleural pressure to above atmospheric → tension pneumothorax
Leads to:
■ Collapse of ipsilateral lung
■ Contralateral overexpansion → increased retractive forces, pulls mediastinum towards it during expiration → compression of vascular structures → decreased venous return
■ Must generate high intrapleural pressures to ventilate normal lung → worsening ptx → hypoxemia/hypercapnea
■ Tachycardia worsens diastolic filling
History and Physical exam features of pneumothorax
Variable symptoms depending on severity of ptx
Decreased breath sounds on side of ptx, contralateral shift of heart sounds,
Sudden collapse on ventilator with reduced compliance, transillumination of chest in neonates
2 cm distance from lung to chest wall suggests a pneumothorax > 50%
Management options for pneumothorax
Gas absorption can be hastened by breathing 100% oxygen
■ Washout of nitrogen
■ Increase in venous pO2
■ pN2 goes to zero, and therefore venous gas pressure is about 617 mmHg less than atmospheric → gradient for reabsorption of gas
Large pneumothoraces require intervention
- Needle thoracentesis versus chest tube
- CT removed when no air leak for 24 hours and tube confirmed in place → can see oscillations of water meniscus with breathing motion (can be hard
to appreciate in young children)
- Clamp tube before removal
- If possible, chest tube removed during exp breath hold
Recurrent pneumothorax
- Consider pleurodesis
- VATS
Management of pneumothorax in CF
If persistent or recurrent, consider pleurodesis
Withhold PEP during treatment
Consider discussion with transplant team
Recurrent risk with spontaneous pneumothorax
Recurrence of spontaneous ptx common (40-87%)
Increase risk of recurrence if ptx slow to resolve, ongoing cigarette smoking
Risk factors for neonatal pneumothorax
Respiratory distress syndrome (RDS)
Meconium aspiration
Mechanical ventilation
Congenital renal malformations that result in oligohydramnios
What is pleural porosity?
Areas of disrupted mesothelial cells in the visceral pleura that may contribute to the risk of pneumothorax
Mechanism of spontaneous pneumothorax
Air accumulates under the parietal pleura external to the lung parenchyma - causes direct compression of the lung
Classically occurs at rest but may be precipitated by a maneuver that increases intra-thoracic pressure (Valsalva) or by lifting and straining.
What is the ball-valve effect with pneumothorax?
It occurs when air leaks into the pleural space and is unable to drain
Air will accumulate with each inspiratory effort and collect under “tension” = tension pneumo
Medical emergency - it may ultimately result in decreased cardiac output and arrest
Methods Used to Quantify Pneumothorax
Light method
Rhea method
Collins Method
Also:
Measuring the distance to the cupola or apical dome of the lung (considered large if greater than 3 cm to the apex), distance to the lateral edge (considered large if >2 cm) or complete dehiscence
Light method for quantifying pneumothorax
Volume (%) = 100 - [(average diameter lung)^3/(average diameter hemithorax)^3 x 100 ]
Rhea method for quantifying pneumothorax
Average of inter pleural distances (cm) at 3 points on erect CXR
- Apex
- Midpoint upper half of lung
- Midpoint lower half of lung
Use nomogram to convert into volume
Collins Method for quantifying pneumothorax
Size (%) = 4.2 + 4.7 [sum of inter pleural distances at apex, midpoint upper half of collapsed lung, and midpoint lower half of collapsed lung]
BTS recommendation for large pneumothorax measurement
The presence of a visible rim of >2 cm between the lung margin and chest wall at the level of the hilum
Can you scuba dive after a pneumothorax?
No
Adult pneumothorax guidelines recommend avoiding scuba diving unless a definitive surgical procedure, such as a bilateral pleurectomy, has been undertaken and normal lung function and chest CT have been confirmed postoperatively
What happens when you get a pneumo while diving?
There is a risk that if a pneumothorax occurs while the diver is under water, it will enlarge during the ascent in accordance with Boyle’s law, and the diver may develop a rapidly enlarg- ing pneumothorax—a potentially life-threatening situation.
Can you fly with a closed pneumothorax?
No
Patients with a closed pneumothorax should not fly owing to low cabin atmospheric pressure.
There should be no increased risk of developing a recurrent pneumothorax with flying after a PSP; however, the pneumothorax must be entirely resolved, with radiologic confirmation
The BTS air travel guidelines recommend that complete resolution of the pneumothorax be confirmed on CXR and that then a minimum 7 days should elapse prior to flying, with a longer delay if the pneumothorax was traumatic or if the patient has underlying lung disease
3 stages of pleural effusions
- Exudative stage—simple parapneumonic effusion with low leukocyte count.
- Fibrinopurulent stage—deposition of fibrin resulting in septations and loculations. An increase in leukocytes occurs and microorganisms invade the pleural space, resulting in purulent material filling the pleural cavity. A parapneumonic effusion that contains pus is defined as an empyema.
- Organizational stage—fibroblasts enter the pleural cavity, forming tight fibrous membranes.
Mechanism of pleural fluid accumulation with an infection
The process of pleural fluid accumulation is mediated by increased vascular permeability secondary to mesothelial cell cytokines including interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor (TNF)-α, and platelet activating factor.
Initially the fluid accumulating in the pleural space is an exudate resulting from the inflammatory process involving the pleura in response to an underlying pneumonia. The pleura leaks proteins and fluid and eventually leukocytes.
As the disease progresses, the number of leukocytes increases, and eventually the pleural cavity is infiltrated by organisms. When the fluid becomes purulent, it is called an empyema
How do loculations develop in pleural effusions?
As the disease progresses, there is increasing deposition of fibrinous material, which leads to septation and the formation of loculations.
This fibrinous material can obstruct the free flow of fluid and block the draining lymphatic stomata, thus preventing spontaneous resolution of normal lymphatic draining and often requiring an intervention to drain the fluid
How do the fibrous peels develop in the organizational stage of pleural effusions?
Fibroblasts penetrate the pleural cavity and can form a membrane called a peel. This peel is made of firm fibrous material that can impair lung function by “trapping” the lung and limiting recovery if not identified.
Although lung trapping is often seen in adult patients, it rarely occurs in children with empyema
When to consider empyema in a child with pneumonia?
Empyema should be considered in children who do not respond to appropriate antibiotics within 48 hours, as evident by ongoing fevers, toxicity, and respiratory distress. In this scenario a CXR should be undertaken to assess for progression of the pneumonia or pleural fluid collection.
Should children routinely undergo immunologic testing in the setting of a single empyema?
No
The BTS and Australian guidelines for pleural infection in children do not recommend that all otherwise healthy children routinely undergo immunologic testing in the setting of a single empyema.
However, the guidelines acknowledge that immune deficiency syndromes have been diagnosed in this way, and investigations should certainly be undertaken in the setting of a child with a history of repeated infections, unusual infections or a family history of immune deficiency.
Guidelines recommend that if S. aureus or P. aeruginosa is identified as the causative organism, a sweat test to exclude cystic fibrosis should be arranged.
Definition of PCD
Inherited disorder characterized by defects of motile cilia → impaired ciliary motion → ineffective mucociliary clearance → rhinitis, sinusitis, otitis media, and bronchitis → bronchiectasis
50% have situs inversus totalis or other laterality defects
(but 25% of patients with situs inversus have PCD)
Associated with male infertility due to defective sperm tail structure
Kartagener = clinical syndrome manifested by triad of situs inversus, chronic sinusitis and bronchiectasis
Location of Cilia
Large airways and contiguous structures (nares, sinuses, middle ear) are lined by ciliated, pseudostratified columnar epithelium
Other epithelia that contain motile cilia are the ependyma of the brain and fallopian tubes + flagella of sperm are similar in core structure
Mature resp ciliated cells have about 200 cilia with av. length of 6 um and diameter of 0.2 um
Composition of Cilia
Each cilium contains 9 doublets of microtubules arranged in an outer circle around 2
Microtubules are anchored by a basal body in the apical cytoplasm of the cell
● Tubulin – main protein of microtubules
● Nexin - links the outer microtubular doublets
● Radial spokes – connects outer microtubular doublets with central tubules
● Dynein – attached to microtubules as inner and outer arms (thought to participate in provision of energy for microtubule sliding through ATPase activity)
How do cilia move?
Ciliary motion = 2 phases
1) stroke phase: sweeps forward – tips of cilia contact the overlying mucous to propel it forward
2) recovery phase: cilia bend backward and extend in to the starting position for the stroke phase – lose contact with mucous
Beat frequency faster in the proximal airways than distal airways (12 beats/sec in the nose and trachea vs. 8 beats/sec in the bronchioles) and in kids than adults (13 beats/sec vs. 11.5 beats/sec)
Mucociliary transport rates can be as rapid as 20-30 mm/min
Main 2 dysfunction with cilia in PCD
- Ultrastructural (Dynein arms – 80% of PCD patients,
partial absence of inner dynein arms
can be seen in normal subjects) - Functional
Diagnostic tests for PCD
Nasal nitric oxide measurement Ciliary biopsy with electron microscopy PCD genetic testing panels Functional ciliary beat/waveform analysis with high speed videomicroscopy Immunofluorescence testing
Major clinical criteria for PCD diagnosis
1) Unexplained neonatal respiratory distress (at term birth) with lobar collapse and/or need for respiratory support with CPAP and/or oxygen for >24 hr
2) Any organ laterality defect - situs inversus totalis, situs ambiguous, or heterodoxy
3) Daily, year-round wet cough starting in first year of bronchiectasis on chest CT
4) Daily, year-round nasal congestion starting in first year of life or pan sinusitis on sinus CT
Clinical Features of PCD
Newborn: tachypnea, cough, hypoxemia
Children: chronic productive cough, recurrent/chronic resp infections, rhinitis/nasal congestion, sinusitis, chronic OM, bronchitis, pneumonia, clubbing
Adults: male infertility due to impaired sperm motility, questionable increased female infertility/ectopic pregnancies
Other potential issues: hydrocephalus (? defective ventricular ependymal cilia), defective leukocyte migration (? defective cytoplasmic microtubules)
Situs inversus totalis occurs in 50% of PCD patients → due to dysfunctional embryonic nodal cilia → random thoracoabdominal laterality
Heterotaxy (situs ambiguous) occurs in 6% → associated with CHD, abdominal situs inversus, polysplenia (left isomerism) and asplenia (right isomerism and Ivemark syndrome)
Imaging findings in PCD
Frequent (>60%)
- Hyperinflation
- Bronchial wall thickening
- Segmental or subsegmental atelectasis
- Mucosal thickening of the paranasal sinuses
Common (20-60%)
- Situs inversus
- Bronchiectasis
- Opacification of paranasal sinuses
100% adults have bronchiectasis – mostly in middle lobe, lingual and lower lobes
Important bugs in PCD
H flu, Staph, Strep pneumo or viridans
later Pseudomonas, mycobacterium avium and abscessus
Treatment of PCD
Enhance mucus clearance: chest physio +/- nebs
- NB: cough is an effective clearance mechanism in PCD patients
- Hypertonic saline NOT pulmozyme - pulmozyme assoc w/ worse outcomes (one study)
- Prevent resp infections: routine imm + pneumococcal and yearly flu, avoid smoke/pollutants
- Treat bacterial superinfections: antibiotics, tympanostomy, sinus drainage
- Lobectomy, Lung transplant
- Prognosis: Bronchiectasis + some degree of pulmonary disability. Many w/ normal/near-normal lifespan
Long term surveillance recommendations in PCD
CXR q2-4 years
CT consider at least once after 5-7 years
Airway microbiology cultures 2-4 times/year
Non-TB mycobacterial cultures q 2 years (and with unexplained decline)
PFT testing 2-4 times/yr
ABPA testing: IgE levels +/- evidence of aspergillum specificity at diagnosis, with new onset wheezing, unexplained clinical decline
Preventative therapies in PCD
Airway clearance: daily
Nasal sinus lavage: daily
Standard vaccinations: per local schedule
Influenza vaccine: Annually
Pathogenesis of Sickle Cell Anemia
Results from Hemoglobin-S (HbS) which polymerizes in the deoxygenated state
Polymerization -> Microvascular occlusion (any tissue) -> vaso-occlusion -> ischemia/infarction
Hemolysis results in release of intracellular RBC arginase (Arginine is the substrate for NO synthase, therefore Arginase depletes arginine levels) → depletion of NO
2. Free Hgb binds to NO, further reducing NO bioavailability
Decreased NO thought to lead to endothelial dysfxn → elevated TRJV (proxy for elevated pulmonary artery pressure)
Pulmonary manifestations of Sickle Cell Anemia
- Chronic Lung Disease -> PH
- Acute Chest Syndrome (ACS)
- Comorbid Asthma/SCD
- Sleep disordered Breathing
- Pulmonary Embolus - fat embolus, thromboembolic
- Plastic bronchitis (has been described)
Clinical manifestations of pulmonary disease in Sickle Cell Anemia
Most common:
- Infection with encapsulated bacteria (S. pneumo, H. flu)
- Pain crises
- Acute chest crisis (ACS)
- Cerebral infarcts - silent and overt
Characteristics of Acute Chest Syndrome in Sickle Cell Anemia
(Kendig)
- Fever +/- Respiratory Symptoms
- New radio-density on CXR
2nd most common reason for admission
- More common in SCD-SS, and SCD-𝛃0
- 50% with SCD-SS have at least one ACS
- Peak incidence 2-4 years
- One episode at 3 year or earlier = greatest RF for future ACS
Physical findings
- Inspiratory crackle (75%) > Wheeze (~33%)
- Leading cause of premature death in SCD
- Difficult to distinguish from viral illness / asthma
- Often no trigger found: ~50% of cases
- Causes: Infection 30% > Pulmonary Infarction 16% > Fat Embolus 8%
- Infection triggers: Viral, chlamydial, mycoplasma, bacteria, mixed.
Acute Chest Syndrome: Acute Treatment
Oxygen to maintain sats >92%
Monitoring
Antibiotics: typically cover S. pneumo (3rd gen ceph) & Atypicals (macrolide) as common in ACS
Salbutamol trial
May require blood transfusion, exchange transfusion
Intubation and ECMO have been required for some
NIV - acute improvement in RR, oxygen need, no difference in outcomes
Steroids NOT generally recommended: shorter stays, but increased rebound pain + rehosp.
Of note: Admission for VOC = RF for ACS
During VOC admission: incentive spirometry REDUCES rate of ACS
Prevention of Acute Chest Syndrome in Sickle Cell
- Treatment of underlying asthma
- Pre-operative blood transfusion
- Chronic transfusion for recurrent ACS (typically short-term <12mo)
- Maintenance of hydroxyurea
- Incentive spirometry during VOC - supposed to use q2h when awake
Pathogenesis of Chronic Lung Disease in Sickle Cell
Exact natural history remains unclear
- Speculation: Normal → Obstructive → Restrictive
- Typically Normal Early; Restrictive Late. But progression unclear.
- Both obstructive and restrictive disease more common in SCD than general population
- Chronic lung disease worst in SS-Disease
- CLD worse with age
- With age, restrictive disease > obstructive disease (mixed may also occur)
- Postulated that ACS contributes to restrictive disease
CT Findings in adulthood:
- Lobar volume loss = associated with ↓ FEV1, FVC, TLC
- Prominent central vessels
- Reticular pattern, and ground glass opacification
- Restrictive dz = 2° to fibrotic interstitial abnormalities
Reasons why patients have hypoxemia in SCD
Rightward shift on oxy-hgb desat curve: ↓ affinity of HbS, & Incr 2,3-DPG 2° to hemolysis
Dyshemoglobins incr: MthHb, COHgb2
Low PaO2 (IE due to V/Q mismatch, diffusion abnormality, etc.)
Low daytime awake SpO2 common in SCD
- Has been related to: ACS, older age, low HbF, OSA, asthma, Hgb-level
- Note: HbS is abnormal, oximeters not calibrated to HbS
- Also increased variability may occur, since SpO2 may be closer to steep part of curve
- Potential effects of low sats: pHTN/↑TRV, ACS, VOC, stroke / silent infarct, cognitive dysfunction
Why higher risk of sleep disordered breathing in sickle cell disease?
Theoretically higher risk: lymphoid hyperplasia, airway narrowing from bone marrow hyperplasia
Role of Atopy in Sickle cell disease
Positive methycholine found to be associated w/ IgE, high LDH (marker of hemolysis)
Airway hyper-responsiveness NOT assoc with increased ACS prevalence
Doctor diagnosed asthma in SCD associated with increased ACS, Pain crisis
DocDx asthma independent risk factor for death
Atopy (positive skin testing to an aeroallergen) occurs at a similar rate in SCD
-However positive skin testing assoc w/ recurrent ACS, & atopic asthma in SCD = ↑ACS
Chronic care recommendations for Sickle Cell Disease
Regular hematology follow-up
Involve pulmonologist if asthma suspected, or ANY ACS -Preventative strategies to prevent morbidity/mortality
Penicillin BID until 5 years
Conjugated vaccines (+extended vaccines) for S. pneumo, H. flu
Supplemental folic acid - maintain erythropoiesis
Hydroxyurea - to increase HbF - decreases ACS / pain crisis ~50%
Monitor adherence
PFT and lung volumes annually starting at age 6 (Spiro with every visit if they have asthma)
Lung volumes q5 years in children with no asthma or ACS episodes
Bronchodilator challenge should be done in those with obstruction on PFT
Give two respiratory manifestations (clinical or on testing) of chronic sickle cell disease
1) Restrictive or obstructive lung pattern on PFTs
2) Airway hyperresponsiveness
3) Low oxygen saturation
12 yo boy with SCD and history of multiple ACS. Diffusion capacity is 30%. Name 3 factors which may explain low diffusion capacity.
1) Pulmonary vascular disease (decreased perfusion secondary to sickled cells)
2) Anemia (should be adjusted based on HgB level)
3) Pulmonary hypertension
4) Fibrosis/ILD
Characteristics of Pulmonary Capillaritis
Also referred to as alveolar capillaritis, is characterized by neutrophilic infiltration of the alveolar septa (lung interstitium) -> necrosis of these structures, loss of capillary structural integrity and spilling of RBCs into the alveolar space and interstitium
Causes of Pulmonary Capillaritis
The systemic vasculitides Anti-glomerular basement membrane (anti-GBM, Goodpasture’s) disease Rheumatic diseases Certain drugs Idiopathic pulmonary hemosiderosis, Idiopathic pulmonary capillaritis
Idiopathic pulmonary capillaritis, also known as pauci-immune pulmonary capillaritis, is characterized by the histopathologic findings of pulmonary capillaritis, but without clinical or serologic evidence of an associated systemic illness
Characteristics of Isolated Pulmonary Capillaritis
Present with signs and symptoms of alveolar hemorrhage without renal or other systemic manifestation
Diffuse alveolar opacities on imaging
Low hemoglobin
Hemosiderin-laden macrophages on BAL
Normal kidney function
Associated with lower hemoglobin and higher ESR (compared to IPH)
Usually positive ANCA - if not, need biopsy
Characteristics of Pulmonary veno-occlusiove disease and pulmonary capillary hemangiomatosis (PVOD/PCH)
Subtype of group 1 (PAH)
PVOD may represent a common aberrant response to an inciting event of endothelial injury that leads to widespread fibrosis of pulmonary venules
Many patients with PVOD additionally have findings of capillary congestion and lymphadenopathy, but with a normal-sized left atrium and normal-sized major pulmonary veins
The presence of venous congestion and lymphadenopathy with a normal-sized left atrium and normal-sized major pulmonary veins are features that may help distinguish PH due to PVOD from other causes of post-capillary PH, namely that due to left-sided heart disease
These features are likely due to chronic pulmonary capillary hypertension, transudation of fluid into the interstitium, and enlargement of pulmonary lymphatic channels.
Biopsy findings of PVOD/PCH
PVOD is a fibroproliferative disease primarily affecting the small pulmonary veins with relative sparing of the larger veins.
The pathologic hallmark of PVOD is extensive and diffuse occlusion of the pulmonary veins due to smooth muscle hypertrophy and collagen matrix deposition (ie, fibrous tissue).
Characteristic triad of IPH
- Iron deficiency Anemia
- Hemoptysis
- Diffuse infiltrates on imaging
