The Lung Flashcards
respiratory system embryology
Outgrowth from the ventral wall of the foregut
Lobar bronchi lined with what and do what
Columnar calibrated epithelium with abundant subepithelial glands that produce mucus, which impedes the entry of microbes
Tell my about the lungs double arterial supply
Pulmonary arteries from the heart carry de oxygenated blood to the alveoli
Bronchial arteries from the aorta carry oxygenated blood to the parenchyma
Lining of the respiratory tract
Pseudostratified ciliated columnar epithelium with goblet cells
Neuroendocrine cells are present that release several factors
-serotonin 5HT, calcitonin, gastrin releasing peptide (bombesin)
Mucus secreting goblet cells and submucosal glands are dispersed through the walls of the trachea and bronchi, but not the bronchioles and distal
Exception: what are the vocal cords lined by
Stratified squamous epithelium
Alveolar epithelium
Continuous layer of two cell types
Alveolar epithelium type I
95%
Flattened and plate like
Rounded type II pneumocytes alveolar epithelium
Synthesize surfactant
Repair alveolar epithelium by giving rise to type I—stem cel like
Pulmonary hypoplasia
Defective lung development due to abnormalities that compress the lung or impede normal expansion in utero (diaphragmatic hernia or oligohydramnios)
Diminished weight, volume, and acinar number for body weight and gestational age
If severe, can be fatal in the early neonatal period
Foregut cysts
Due to abnormal detachment of primitive foregut
Most often in hilum or middle mediastinum
Bronchogenic (most common), esophageal, or enteric—depending ont he wall structure
Bronchogenic cysts
Most commmon and is rarely connected to the tracheobronchial tree
Lined with ciliated pseudostratified columnar epithelium with glands, cartilage and smooth muscle in the wall
Usually found incidentally of there is compression of nearby structures
Pulmonary sequesteration lung tissue
Lacks any connection to the airway system
Has abnormal vascular supply arising from the aorta or its branches
Extra lobar sequesteration
Lack connection to the airway system and are external to the lung
Has own pleura
Generally come to attention as mass lesions in infants
Often associated with other congenital anomalies
Intra lobar sequesteration
Occur within the lung parenchyma
Does not have its own pleura
Lack connection to the airway system
Occur in older children due to recurrent localized infection or bronchiectasis
Neonatal RDS
Most common where a layer of hyaline proteinaceous material int he peripheral airspace’s of infants who have the condition
Other causes of neonatal respiratory distress syndrome
Excessive sedation of mom, fetal head delivery during birth, aspiration of blood or amniotic fluid, or intrauterine hypoxia fromthe umbilical cord around the neck
How does neonatal respiratory distress present
Preterm with appropriate weight, may need assistance breathing during the first few minutes, then normal, then problems in 30 min, cyanosis in a few hours
Lungs RSD
Fine rales in lung fields
CXR RSD
Uniform minute reticulogranular densities that look like ground glass
Prognosis neonatal RSD
Infant will typically be able to survive if the therapy is able to keep them alive for the first few days
Who gets neonatal RSD
Males, maternal diabetes, delivery by C section
Pathogensisof RDS
Immaturity of th lungs is the most important thing for RDS to develop
Happens to 60% of infants bone less than 28 weeks
Fundamental problem is a lack of surfactant and thus too much surface tension int he alveoli
Surfactant composition
Defense proteins: SP-A and SP-D
Surfactant proteins : SP-B, SP-C and surfactant lipids
-can measure these in an amniocentesis
Surfactant genes
SFTPB, SFTBC
Surfactant defiency issue
Infants need the surfactant to properly inhale with less effort, but if they don’t have any then each progressive breath the lungs collapse a little more
This problem of stiff atelectatic lungs is compounded by a soft thoracic wallet hat is pulled in as the diaphragm descends
Progressive atelectasis and reduced lung compliance->
Protein rich, fibrin rich exudation into the alveolar spaces with the formation of hyaline membranes
- fibrin hyaline membranes are barriers to gas exchange->CO2 retention and hypoxemia
- hypoxemia impairs further surfactant synthesis
Hypoventilation !!!
What does hypoventilation from RSD lead to
Acidosis and pulmonary vasoconstriction (from the relative hypoxia) leading to pulmonary hypoperfusion causing tissue damage and plasma leak into the alveoli
Ultimately there are necrotic cells and fibrin deposition with a hyaline membrane being laid down and exacerbating the problem in a viscous cycle
Surfactant synthesis
Produced by type II pneumocytes
Modulated by cortisol (glucocorticoids most important*), prolactin, thyroxine, and TGFB
Conditions associated with what increase ___ release and lower the risk of developing RDS
Intrauterine stress and FGR
Corticosteroid
Diabetic mom
Increased glucose in mother leads to increased insulin in fetuses. Increased insulin in fetus inhibits synthesis of surfactant by way of inhibiting the steroids leading to a greater risk of RDS
- infants of diabetic mom have higher risk of developing RDS
- treat with corticosteroid therapy
How treat infant of diabetic mother
Corticosteroid therapy
Labor and surfactant
Labor increases surfactant synthesis
C section before onset of labor
Increases risk of RDS
C section is less stressful for baby and labor increases surfactant
Morphology RDS
Lungs are normal size, solid airless, and reddish purple in color
Alveoli are poorly developed and collapsed—atelectasis
Necrotic cells (including type II pneumocytes) can be seen early and later they are incorporated within eosinophilic hyaline membranes that are also composed of fibrin
NEVER seen in stillborn
Infants that survive more than 48 hours will have reparative changes int he lungs where the alveolar epithelium proliferated under the surface of the membrane and detach into the airspace where is digested by macrophages
Clinical features of RDS
Clinical course and prognosis depends on the maturity and birth weight of the infant and the promptness of institution of therapy (administration of surfactant: poractant Alfa, bear tang, calfactant)
Best thing to do is delay labor long enough to reach maturity or induce maturation of the lungs
Best way to check on lung maturity
Sample the phospholipids in the amniotic fluid
- phosphatidylcholine is important for surfactant
- measure a lecithin: phosphatidylcholine ratio; want it to be greater than 2:1?
In uncomplicated cases of RDS when get recovery
3-4 days
Complications from high concentration of ventilator administered oxygen for prolonged periods for infants with RDS
Retrolental fibroplasia
Bronchopulmonary dysplasia
Retrolental fibrosis(retinopathy of prematurity)
Phase I: hyperoxaluria; expression of VEGF is decreased and causing endothelial cell apoptosis
Phase II:VEGF levels rebound after return to relatively hypoxic room air
-induced retinal vessel proliferation (neovascularization) that is characteristic of the retina lesions
Bronchopulmonary dysplasia
Major abnormality: striking decrease in alveolar septation (manifested as large, simplified alveolar structures) and a dysmorphic capillary configuration
caused by a potentially reversible impairment in the development of alveolar septation at the “saccular stage”
Multiple factors: hyperoxemia, hyperventilation, prematurity, inflammatory cytokines (TNF, IL-1, IL-6, and IL-8), and vascular maldevelopment
Infants who recover from RDS are at an increased risk of
PDA, intraventricular hemorrhage, necrotizing enterocolitis
Atelectasis (collapse)
Incomplete expansion of the lungs (neonatal atelectasis) or collapse of previously inflated lung producing areas of relatively airless pulmonary parenchyma
Can reduce oxygenation and predispose to infection
Reversible (except in contraction)
Resorption atelectasis=obstruction
Complete airway obstruction
air is resorbed from the dependent alveoli which then collapse
Mediastinum shifts towards the affected lung because lung volume is diminished
most often caused by excessive secretions (mucus plug) or exudates within smaller bronchi as may occur in bronchial asthma, chronic bronchitis, bronchiectasis, or post-operative setting
Can also be due to aspiration or tumor fragments
Compressive atelectasis=pleural effusion
occur whenever significant volumes of fluid accumulate within the pleural cavity
Transudate (hydrothorax), exudate (pleural effusion), blood (hemothorax), air (pneumothorax), tumor
Effusion from cardiac failure/neoplasm
Blood from aneurysm rupture
Mediastinum shifts away from the affected lung
Contraction atelectasis =fibrosis
focal or generalized pulmonary or pleural fibrosis prevent full expansion
Mediastinum can shift toward the affected lung if it is ipsilateral, no change if it is bilateral
Irreversible
Pulmonary edema
leakage of excessive interstitial fluid in alveolar spaces due to:
Increased hydrostatic pressure
Increased capillary permeability
Leads to heavy, wet lungs regardless of etiology
Decreased oxygenation – diffusion barrier is increased –> cyanosis, dyspnea, low O2 sat
Predisposes patient to infection
Therapy and outcome depend on the etiology
Hemodynamic pulmonary edema
Engorged alveolar capillaries
due to increased hydrostatic pressure, often a result of left-sided heart failure
Fluid accumulation occurs in basal regions of lower lungs first (dependent edema)
Granular, pink precipitates in the alveolar spaces
Chronically leads to brown, firm lungs (brown induration) due to interstitial fibrosis and hemosiderin laden macrophages (pathognomonic “heart failure cells”)
Edema caused by microvascular (alveolar injury
due to injury of the alveolar septa
inflammatory exudate that leaks into the interstitial space and, in more severe cases, the alveoli
in most forms of pneumonia, the edema remains localized and is overshadowed by the manifestations of infection
If diffuse/severe can lead to Acute Respiratory Distress Syndrome (ARDS)
Acute lung injury and acute respiratory distress syndrome (diffuse alveolar damage)
Ok
Noncardiogenic pulmonary edema (acute lung injury ALI)
Abrupt onset of hypoxemia and bilateral pulmonary infiltrates in the absence of heart failure
Increased pulmonary vascular permeability due to epithelial cell death
ARDS is a manifestation of severe ALI/DAD
ARDS and ALI are associated with inflammation-associated increases in pulmonary vascular permeability, edema, and epithelial cell death
histologically, this is recognized as diffuse alveolar damage (DAD)
due to localized or systemic insult
Sepsis, diffuse pulmonary edema, gastric aspiration, and trauma account for more than 50% of the cases
Worse prognosis in smokers and alcoholics
pathogenesis is a “viscous cycle of increasing inflammation and pulmonary damage
ARDS is a manifestation of
Severe ALI/DAD
ALI/ARDS: endothelial activation
There is injury to pneumocyte injury that is recognized by resident macrophages (“dust cells”)
Can also be activated by systemic factors in times of sepsis
Then there is increased endothelial permeability and adhesion molecules
There are also increased production and secretion of procoagulant proteins and chemokines
ALI/ARDS: adhesion and extravasion of neutrophils
neutrophils come in and degranulate –> release inflammatory mediators including proteases, reactive oxygen species, and cytokines
macrophage inhibitory factor (MIF) helps to sustain the pro-inflammatory response
result: increased recruitment and adhesion of leukocytes –> more endothelial injury –> local thrombosis
this cycle of inflammation and endothelial damage lies at the heart of ALI/ARDS
ALI/ARDS: accumulation if intraalveolar fluid and formation of hyaline membranes
The alveolar caps become leaky and allow the edema to come in
Type II pneumocytes are damaged which results in surfactant-related issues (i.e. gas exchange becomes worse –> shortness of breath)
The protein-rich fluid and dead epithelial cells then forms in hyaline membranes (characteristic of ALI/ARDS
ALI?ARDS: resolution of injury
Impeded due to epithelial necrosis and inflammatory damage that impairs edema resorption
Eventually, if the inflammation lessens then the macrophages can clean everything up and heal the damaged areas with fibrogenic factors (i.e. TGF-β and PDGF)
There is then fibrosis of the alveolar walls and bronchiolar stem cell replacement of pneumocytes
Type II Pneumocytes replace the pneumocytes, act as stem cells
ALI?ARDS: acute morphology
Lungs are diffusely firm, red, boggy and heavy (hyperemic and congested?)
Congestion with interstitial and intraalveolar edema, inflammation, fibrin deposition, and diffuse alveolar damage
Lined with hyaline membranes (composed of necrotic epithelial debris and exuded proteins)
morphologically similar to those seen in hyaline membrane diseases of neonates
alveolar hyaline membranes consist of fibrin-rich edema fluid mixed with the cytoplasmic and lipid remnants of necrotic epithelial cells (protein-rich exudate)
Characteristic histologic picture of ARDS is that of hyaline membranes lining alveolar walls. Edema, scattered neutrophils and macrophages, and epithelial necrosis are also present
ALI/ARDS: organizing stage morphology
Type II pneumocyte proliferation
Granulation tissue forms in the alveolar walls as a response to the hyaline membranes
most cases: granulation tissue resolves and leaves only minimal functional impairment
can progress to interstitial fibrosis with severe scarring
Superimposed bronchopneumonia can be fatal
ALI/ARDS: clinical
LI/ARDS: Clinical
ALI or ARDS patients are usually already admitted for one of the predisposing conditions (e.g. sepsis, severe head trauma)
Dyspnea and tachypnea are characteristic –> cyanosis, hypoxemia, respiratory failure, and the appearance of diffuse bilateral infiltrates follow
hypoxemia may be refractory to oxygen therapy due to ventilation/perfusion mismatching
Respiratory acidosis can develop (can’t blow off CO2 as effectively –> buildup of CO2 –> acidosis)
Stiff lungs from the lack of surfactant can develop early in the course
Functional abnormalities are not evenly distributed
Poorly aerated regions are still perfused = V/Q mismatch & hypoxemia
Ventilation is occurring, but there in not as much perfusion as expected
Mortality ALI/ARDS
40% secondary to sepsis of multi organ failrue
ALI/ARDS:treatment
Mechanical ventilation while treating the underlying cause
no proven specific treatments – treatment of the underlying cause has improved
Most patients will recover, but many of them can still have physical and cognitive impairment
most deaths are attributable to sepsis or multiorgan failure and, in some cases, direct lung injury
In minority of cases, exudate and diffuse tissue destruction –> scarring, interstitial fibrosis, and chronic pulmonary disease
Acute interstitial pneumonia (idiopathic (ALI/DAD)
Widespread ALI of unknown etiology with a rapidly progressive clinical course
Present with acute respiratory failure within 3 weeks of URI
Imaging/pathology identical to organizing ALI
Average age: 59; No gender preference
33-74% mortality, typically in first 12 months
Morphology is the same as the organizing stage of ALI
Progresses rapidly with most deaths occurring in 1-2 months
Survivors are prone to recurrence and chronic interstitial disease
Obstructive and restrictivelung diseases
Increased resistance to airflow due to partial or complete obstruction at any level
Decreased maximal flow rates during forced expiration
FEV1 / FVC < 0.8
Restrictive lung disease
Decreased expansion of the lung parenchyma and decreased total lung capacity
Chest wall disorders (e.g. severe obesity, pleural diseases, kyphoscoliosis, and poliomyelitis)
Chronic interstitial and infiltrative disease (e.g. pneumoconioses and interstitial fibrosis)
Proportionate Decreased in lung capacity and FEV1 –> FEV1 / FVC is normal
Chest wall disorders
Severe obesity, pleural diseases, kyphoscoliosis, and poliomyelitis
Chronic interstitial and infiltrating disease
Pneumoconiosis and infiltrative disease
Obstructive lung disease FEV1/FVC
Restrictive lung disease FEV1/FVC
Normal
Obstructive lung disease examples
COPD(emphysema, chronic bronchitis)
Asthma
Bronchiectasis
Chronic bronchitis
Anatomical site-bronchus
Major pathological changes-mucous gland hyperplasia, hypersecretion
Etiology:tobacco smoke, air pollutants
Signs and symptoms :fought sputum production
Bronchiectasis
An atomic site: bronchi
Major pathology changes: airway dilation and scarring
Etiology: persistent or severe necrotizing infections
Signs and symptoms: cough, pursuant sputum, fever
Asthma
Anatomic site: bronchus
Major pathological changes: smooth msucle hyperplasia, excess mucus, inflammation
Etiology: immunologic or unknown; drug induced
Signs and symptoms: episodic wheezing, cough, dyspnea
Emphysema
Anatomic site: acinus
Major pathological changes: airspace enlargement, wall destruction->blebs
Etiology: tobacco smoke: highly
Signs and symptoms: dyspnea
Small airway disease(variant of chronic bronchiolitis)
Can be seen with any form of obstructive disease or as an isolated finding: contributes to obstruction both in emphysema and chronic bronchitis
Reversible bronchitis
Asthma == reversible bronchospasm
chronic bronchitis and emphysema == irreversible bronchospasm
*Generally
COPD
C ommonly includes emphysema and chronic bronchitis
Increased risk: Cigarette smoking, female, African American, environmental/occupational pollutants, airway hyperresponsiveness, genetic polymorphisms
Emphysema
I rreversible enlargement of airspaces distal to the terminal bronchioles
Alveolar wall destruction without obvious fibrosis, except in the small airways
Classified by anatomic distribution within the lobule – centriacinar, panacinar, paraseptal, and irregular
lobule == cluster of acini (terminal respiratory units)
*only the first two cause clinically significant airflow obstruction
Centriacinar (centrilobular emphysema)
Destruction and enlargement of the central or proximal parts of the acini, formed by respiratory bronchioles, sparing distal alveoli
Emphysematous and normal airspaces exist within the same acinus and lobule
Predominantly upper lobes and apices
When severe, the distal acini may be involved (difficult to distinguish against panacinar emphysema)
Heavy smokers and often associated with chronic bronchitis (COPD)
Most common form of emphysema 95% of cases
Where is centriacinar emphysema, who gets it
Upper lobes and spices
Smokers
Most common form of emphysema
Centriacinar emphysema
Panacinar (panlobular) emphysema
Uniform destruction and enlargement of the entire acini from the level of the respiratory bronchiole to the terminal blind alveoli
Common in the lower zones and anterior margins of the lung
Most severe at the lung bases
Associated with α1-antitrypsin deficiency
Distal acinar emphysema
Proximal acinus is normal; distal acinus is predominantly affected
Prominent near the pleura, along septa and lobules and occurs adjacent to fibrosis/scarring/atelectasis
More severe in the upper half of the lungs
Multiple, continuous, enlarged airspaces that may sometimes form cyst-like structures – “blebs”
Commonly the underlying lesion in spontaneous pneumothorax in the young
Airspace enlargement with fibrosis (irregular emphysema)
Acinus is irregularly involved
Invariable associated with scaring
Clinically insignificant
Pathogenesis of emphysema
parenchymal destruction == emphysema
airway disease == bronchiolitis and chronic bronchitis
Emphysema pathogenesis L inflammatory mediators
Increased levels in the affected areas – leukotriene B4, IL-8, TBF, and others
Released by resident epithelial cells and macrophages
Attract inflammatory cells from circulation (chemotaxis)
Amplify inflammation (cytokines)
Induce structural changes (GFs)
Emphysema pathogenesis : protease antiprotease balance
connective tissue is broken down by enzymes released from the inflammatory and epithelial cells
Loss of elastic tissue = respiratory bronchiole collapse during expiration causing functional obstruction
Deficiency of antiproteases (may be genetic) is common in patients with emphysema
α1-antitrypsin == anti-protease; deficiency upsets the balance –> panlobular emphysema
trypsin is a protease; anti-trypsin is an anti-protease – don’t get fucked up on words
Emphysema pathogenesis: oxidative stress
Oxidants are produced by tobacco smoke, from alveolar damage, and from inflammatory cells
NFR2 inactivation: significantly increased sensitivity to tobacco smoke
NFR2 is a sensor for oxidants in alveolar epithelial cells
Activated by intracellular oxidants to upregulate genes that protect from oxidant damage
NFR2 == transcription factor that upregulates expression of multiple genes that protect cells from oxidant damage
Emphysema pathogenesis : infection
Thought to exacerbate the associated inflammation and chronic bronchitis
A1 antitrypsin (anti-protease) and emphysema
Found in 1% of all patients
anti-protease: protects against proteases, especially elastase (released by neutrophils)
Much more likely to cause emphysema, especially if the patient smokes
Encoded on the Pi locus of chromosome 14
patients with the Z allele have decreased serum levels and 80% of homozygotes (piZZ) will develop symptomatic panacinar emphysema which is even more accelerated and severe if the patient smokes
Nicotinic acetylcholine receptor and emphysema
Some genetic variants of the receptor can lead to an increased risk for the disease
Makes smoking more addictive and thus increases the risk of the disease
smoke more and smoking is even worse for you
Physiology emphysema
small airways are normally held open by the elastic recoil of the lung parenchyma
loss of elastic tissue in the walls of alveoli that surround respiratory bronchioles reduces radial traction and thus causes the respiratory bronchioles to collapse during expiration –> functional airflow obstruction
Smoking and airway changes, found even in young smokers
goblet cell hyperplasia and mucus plugging of the lumen
inflammatory infiltrates in bronchial walls – neutrophils, macrophages, B-cells, and T-cells
bronchiolar wall thickening due to fibrosis and smooth muscle hypertrophy –> increased airway obstruction
Emphysema morphology
Diffuse disease: voluminous lungs that overlap the heart
Alveolar wall rupture can produce huge airspaces (blebs and bullae) that are more commonly found in the upper 2/3 of the lungs that compresses the bronchioles and vasculature
Alveolar spaces are enlarged and separated by thin septa with only focal centriacinar fibrosis
The Pores of Kohn are large and look to be clubbed shape and protrude blindly into the alveolar spaces
Septal capillaries are compressed and bloodless
CLINCIALLY emphysema
Dyspnea, wheezing, cough begin to occur when 1/3 of pulmonary parenchyma is lost
Cough and expectorant are very variable and depend on the level of the associated bronchitis
Severe weight loss (confused with occult cancer)
Barrel chested, dyspneic, hunched over, breathes through pursed lips
impaired expiratory airflow (best measured through spirometry) is the key to diagnosis
‘Pink puffers’ well oxygenated at rest due to overventilation
chronic bronchitis == blue bloaters
emphysema == pink puffers
Prognosis emphysema
Development of cor pulmonale is a poor prognostic factor
Death due to:
Coronary Artery Disease
Respiratory Failure
Right Heart Failure
Massive collapse of lungs 2° to pneumothorax
Treat emphysema
Smoking cessation
O2 therapy
Long acting bronchodilators (tiotropiums and ipratropium) with inhaled corticosteroids
physical therapy
Bullectomy
Lung volume reduction surgery (select patients)
Lung transplant (select patients)
α1-antitrypsin replacement therapy is currently being evaluated
Other forms of emphysema
Associated with lung overinflation or focal emphysematous change
Compensatory hyperinflation emphysema
Dilation of alveoli in response to loss of lung parenchyma elsewhere
hyper-expansion of residual lung parenchyma following surgical removal of diseased lung or lobe
Obstructive overinflation emphysema
Foreign body (tumor, foreign object) creates a subtotal obstruction – the lung expands because air is trapped
Congenital Lobar Overinflation in infants due to hypoplasia of bronchial cartilage
sometimes associated with other congenital cardiac and lung abnormalities
Overinflation in Obstructive Lesions
Ball-valve phenomenon which admits air on inspiration but traps it on expiration
Collaterals introduce air behind the obstruction
pores of Kohn
canals of Lambert (bronchioalveolar connections)
Can be life-threatening as the affected lung can compress the remaining lung
Bulbous emphysema
Large sub-pleural bullae or blebs that can occur with any type of emphysema
Bullae: spaces of air that are greater than 1cm
Occurs near the apex
Often near old tuberculous scarring
Rupture can cause pneumothorax
Interstitial emphysema
Entry of air into connective tissue of the lung, mediastinum, or subcutaneous tissue
In most cases is due to alveolar tears in pulmonary emphysema allowing air to enter the stroma of the lungs, but can also be due to chest wound or fractured rib
rapid increases in pressure within the alveolar sacs (e.g. coughing with bronchiolar obstruction)
premature infants on positive pressure ventilation are most at risk
Artificially ventilated adults
Chronic bronchitis
Persistent cough with sputum production for at least three months in at least two consecutive years in the absence of other identifiable causes
Can accelerate decline in lung function, cause cor pulmonale and HF or atypical metaplasia of respiratory epithelium (fertile grounds for cancerous transformation)
Common in smokers and smog-laden cities
COPD spectrum == emphysema to chronic bronchitis
most patients have features of both
associate Reid Index with Chronic Bronchitis
Pathogenesis chronic bronchitis
Predominantly due to chronic irritation from inhaled substances/irritants such as tobacco smoke (90% of patients also smoke) and also dust from grain, silica, or cotton
earliest feature == hypersecretion of mucus in the large airways
associated with hypertrophy of the submucosal glands in the trachea and bronchi
With time there is increased numbers of goblet cells in the smaller airways too
Chronic inflammation leads to fibrosis and obstruction of the small airways
Exacerbated by 2° infections
Smoking inhibits cilia to prevent the clearing of mucous and thus increased risk of infection
Morphology chronic bronchitis
Hyperemia (excessive blood vessels)
Edema of lung mucous membranes
mild chronic inflammation of the airways (predominantly lymphocytes) and enlargement of the mucus-secreting glands of the trachea and bronchi – characteristic features of chronic bronchitis
Mucinous secretions filling airways
Mucous gland hyperplasia
hyperplasia == increase in size
Reid Index == ratio of the thickness of the mucous gland layer to the thickness of the wall between the epithelium and the cartilage
Normally is .4 or 40%; increased in chronic bronchitis in proportion to the severity and duration
associate Reid Index with chronic bronchitis – just the glandular component
don’t use the Reid Index for asthma
Bronchiolar inflammation, fibrosis, and gland hyperplasia leads to airway obstruction
Bronchial epithelium may exhibit squamous metaplasia + dysplasia
There is marked narrowing of bronchioles caused by mucus plugging, inflammation, and fibrosis
Severe: bronchiolitis obliterans (fibrosis causes obliteration of the lumen in severe cases
Clinical chronic bronchitis
y
Persistent cough productive of sparse sputum for at least three consecutive months in at least two consecutive years
eventually, dyspnea on exertion develops
hypercapnia (retain CO2), hypoxemia and mild cyanosis over time – “blue bloaters”
chronic bronchitis == blue bloaters
emphysema == pink puffers
Can lead to cor pulmonale and heart failure
Death is possible from further impairment of respiratory function due to superimposed acute infections
Asthma
disorder of the conducting airways
episodic reversible bronchospasm due to smooth muscle hyperreactivity, inflammation of the bronchial walls, and increased mucus production
Leads to cough, wheeze, chest tightness, and breathlessness, especially at night and in the morning
Classes of asthma
Atopic (most common0
Nonatopic
Atopic asthma
Classic IgE-mediated (Type I) hypersensitivity reaction triggered by environmental allergens (e.g. pollen, food) that is synergistically triggered by other proinflammatory things in the environment and viral infections
Early onset allergic asthma
Associated with TH2 helper T cell mediated inflammation and responds well to treatment with corticosteroids
Genetic atopic asthma
Family history common
Skin test atopic asthma
Immediate wheal and far reaction to the antigen they are sensitized to
Serum test atopic asthma
Levels of allergen sensitization shown by RAST which can detect the presence of IgE antibodies that are specific for individual allergens
Nonatopic asthma
No evidence of allergen sensitization
Negative skin test
Genetic involvement less common
viral respiratory infections are common triggers, as well as inhaled air pollutants (smoking, sulfur dioxide, ozone, and nitrogen dioxide == smog) that can cause chronic airway inflammation and hyperreactivity
ozone has no pathologic effects; it is only an irritant
Can even be caused by cold or exercise
Drug induced asthma (triad asthma)
Aspirin sensitive asthma == uncommon; occurs in individuals with recurrent rhinitis and nasal polyps
exquisitely sensitive to small doses of aspirin and other NSAIDs
asthmatic attacks + urticaria (hives)
Inhibition of COX pathway –> decreased PGE2 –> increase in pro-inflammatory leukotrienes
NSAIDs
More likely to occur in individuals with recurrent rhinitis and nasal polyps
Occupational asthma
Minute quantities of chemicals induces signs and symptoms after repeated exposure
Varying underlying mechanisms
Asthmatic bronchitis
Seen in smokers
Early phase atopic asthma
TH2 hyperreactivity leads to:
IL-4: production of IgE – “5Always and 4Ever”
IL-5: activates eosinophils
IL-13: stimulates bronchial submucosal glands to secrete mucous and B-cells to make more IgE
Antigen binding to IgE coated mast cells causes primary and secondary mediator release that cause:
T-lymphocytes and epithelial cells secrete chemokines that recruit more T-lymphocytes and eosinophils and exacerbate the problem
Early phase atopic asthma
Bronchoconstriction triggered by direct stimulation of subepithelial vagal (parasympathetic) receptors through both central and local reflexes
increased mucus production
variable degrees of vasodilation
increased vascular permeability
Late phase atopic asthma (hours
dominated by the recruitment of leukocytes, notably eosinophils, neutrophils, and more T-cells
Persistent bronchospasm and edema
Leukocytic infiltration
Epithelial damage and loss
Repeated bouts lead to airway remodeling – asthma == airway remodeling
Hypertrophy and hyperplasia of bronchial smooth muscle and mucus glands
Increased vascularity
Increased deposition of subepithelial collagen
TH2 is the dominant cell type
TH17 T-cells are also present and they are the ones that recruit neutrophils
down regulation of IL-17 == cold abscesses
Mediators whose role in asthmatic bronchospasm is clearly supported by. Pharmacological intervention
Leukotrienes C4, D4, E4
Acetylcholine
Leukotrients C4, D4, E4
Prolonged bronchoconstriction, vascular permeability, and mucus secretion
Acetylcholine
Stimulation of muscarinic receptors causing airway smooth muscle constriction
Mediators found in asthmatic bronchospasm, but not significant targets of pharmaceutical intervention
Histamine PGD2 PAF Cytokines and chemokines ^might prove important in certain types of chronic or non allergic asthma
Histamine:
Bronchoconstrictor
PGD2
Bronchoconstriction and vasodilation
Asthma genetics
Patients with atopic asthma are more likely to have other allergic disorders like allergic rhinitis and eczema
Implicated genes can affect 1° or 2° immune responses, tissue remodeling or the patients response to therapy
Gene cluster involving IL3, IL4 IL5 IL9 IL13 and IL4R, on chromosome 5q
Polymorphism in the IL13 gene have the strongest and most consistent association with asthma
Genetics asthma
IL4R HLA class II
ADAM33 leads to bronchial smooth muscle and fibroblast proliferation
B2-adrenergic receptor (airway reactivity)
YKL-40: increased levels of the China tase-like glycoproteins is directly correlated with disease severity , airway remodeling, and decreased pulmonary function
Environmental factors
City Living – there are many airborne pollutants that may initiate the TH2 response; city life limits the exposure of very young children to certain antigens
infections themselves are not a cause of asthma
young children with aeroallergen sensitization who develop lower respiratory tract viral infections (rhinovirus type C, respiratory syncytial virus) have 10-30x increased risk of developing persistent and/or severe asthma
viral and bacterial infections are associated with acute exacerbations of the disease
airway remodeling = structural changes in the bronchial wall brought on as a result of repeated bouts of allergen exposure and immune reactions; irreversible component
hypertrophy and hyperplasia of bronchial smooth muscle
epithelial injury
increased airway vascularity
increased subepithelial mucus gland hypertrophy
deposition of subepithelial collagen
Asthma morphology
The following is especially found in patients with status asthmaticus
Overinflated lungs with patchy atelectasis
Mucus plugging of airways that also contains shed epithelium
Whorled mucus plugs (Curschmann spirals)
Microscopic lung edema, with eosinophils and Charcot-Leyden crystals (eosinophilic protein galectin-10)
Airway remodeling == irreversible component; this is seen in asthma
Thickening of airway wall
Subbasement membrane fibrosis (deposited I and III collagen)
Increased vascularity
Bronchial wall smooth muscle and mucosal gland hypertrophy
Clinical course asthma
Attacks can be hours long Chest tightness Prolonged expiration Peripheral blood eosinophilia Wheezing Dyspnea Cough **atopic dermatitis**: rash on flexural surfaces asthma == eosinophils, IL-5, Curschmann spirals, Charcot-Leyden crystals
Status asthmaticus
Severe form of asthma where the paroxysm persists for days and weeks
Airflow obstruction may be so severe it causes cyanosis or death
Asthma and puberty
About half of the cases will remit, but lots of cases will return in adulthood
Bronchiectasis
Destruction of smooth muscle and elastic tissue by chronic necrotizing infections that leads to permanent dilation of bronchi and bronchioles
becoming less common due to infection control
Etiology bronchiectasis
Congenital or hereditary conditions like cystic fibrosis and primary ciliary dyskinesia
Infection(s), including *necrotizing pneumonia caused by bacteria, viruses, and fungi
Bronchial obstruction, due to tumor, foreign body, or mucus impaction
bronchiectasis is localized to the obstructed lung segment
Chronic inflammatory states: RA, lupus, IBD, COPD, post-lung/bone marrow transplant
25-50% of cases are idiopathic
Pathogenesis bronchiectasis
Obstruction and infection are both necessary but can occur in either order
Bronchial obstruction impairs normal clearing mechanisms
secretions pool distal to the obstruction and can lead to secondary infection and inflammation
Severe infections can lead to inflammation accompanied by necrosis, fibrosis, and eventually airway dilation
The smaller airways can become obliterated: bronchiolitis obliterans
Cystic fibrosis
Abnormal function or loss of an epithelial chloride channel (CFTR) on chromosome 7
CFTR transports Cl
Sweat glands: from the surface into the cell
Other epithelia: from the cell to the lumen
CFTR ENaC
CFTR inhibits ENaC which is found on epithelial cell apical surfaces (except on sweat glands) and thus in CF it is overactive taking up water and Na+ ions from the mucus in the lungs
What does dehydration of the airway mucus lead to in CF
T he dehydration of the airway mucus leads to decreased ciliary activity and an inability for the body to clear mucous and microbes –> airway obstruction, predispose to (necrotizing) infection –> bronchiectasis
primary defect in ion transport –> defective mucociliary action and airway obstruction by thick secretions
chronic bacterial infections are common –> widespread damage to airway walls
Bacterial pathogenesis CF
Staphylococcus aureus, haemophilus influenzae, and burkholderia capacia
Pseudomonas aeruginosa CF
Can produce a mucosa capsule (alginate)->protective biofilm
Primary ciliary dyskinesia
Autosomal recessive
Defect in ciliary motor proteins (dynein) –> retention of secretions –> recurrent infection –> bronchiectasis
Half of patients also have Kartagener Syndrome: situs inversus or partial lateralizing abnormality, bronchiectasis, and sinusitis
Males usually infertile due to sperm dysmotility
Allergic bronchopulmonary asperigillosis
Occurs in patients with asthma and cystic fibrosis who develop periods of exacerbation and remission which can lead to proximal bronchiectasis and fibrotic lung disease
Hypersensitivity to the fungus aspergillus fumigatus
Activation of TH2 helper T cells that recruit eosinophils and other leukocytes
Elevated IgE serum antibodies to the fungus
Characterized by formation of mucous plugs and intense airway inflammation with eosinophils
Bronchiectasis morphology
Most severe changes in the peripheral lower lobes
Affects the more distal bronchi and bronchioles, especially the vertical ones
Can affect just a single lung segment if caused by tumors or aspiration of a foreign body
Airways may be dilated up to 4x the normal size
Appear cystic and filled with mucopurulent secretions
In severe cases there can be inflammatory exudation within the walls of the airways that is associated with desquamation of the lining epithelium and lots of ulceration
For the rest of the tissue there may be pseudo stratification of the columnar cells or squamous metaplasia
Sometimes the necrosis can lead to abscesses
If chronic, there can be severe fibrosis and obliteration of the lumens
Bronchiectasis common pathogens
Staphylococcus (clusters), streptococcus (chains), enterics (gram negatives), anaerobic and microaerophilic pathogens (especially in pediatric populations), Haemophilus influenzae (vaccine), and pseudomonas aeruginosa
Bronchiectasis clincial course
signs and symptoms are often episodic and precipitated by URI
Persistent, severe cough
May be associated with morning or positional changes draining collected pus/secretions into the bronchi
Fever, orthopnea, dyspnea, and cyanosis
Abundant purulent sputum that is foul smelling and sometimes bloody
Complications bronchiectasis
Cor pulmonale
Brain abscess
Amyloidosis
Restrictive lung disorders
Chronic interstitial and infiltrative diseases
- pneumoconiosis
- interstitial fibrosis of unknown etiology
Chest wall disorders
-neuromuscular diseases (poliomyelitis, severe obesity, pleural diseases, kyphoscoliosis
Chronic interstitial pulmonary disease
signs and symptoms are often episodic and precipitated by URI
Persistent, severe cough
May be associated with morning or positional changes draining collected pus/secretions into the bronchi
Fever, orthopnea, dyspnea, and cyanosis
Abundant purulent sputum that is foul smelling and sometimes bloody
What happens in chronic interstitial pulmonary disease
L ong term development of cor pulmonale and 2° pulmonary HTN
May be difficult to distinguish in late stages because all result in scarring and gross destruction of the lung
End-Stage, or Honeycomb Lung
CXR: bilateral lesions that take the form of small nodules, irregular lines, or ground glass shadows that all indicate interstitial fibrosis
Fibrosing diseases
Ok
Idiopathic pulmonary fibrosis -MUC5B
Clinicopathologic syndrome of unknown cause with progressive interstitial pulmonary fibrosis and respiratory failure
Appears to occur in patients who are genetically susceptible to aberrant repair of recurrent alveolar epithelial cell injuries due to environmental exposures
Profibrotic response
Histologically, usual interstitial pneumonia (UIP) must be distinguished from other causes
UIP == nonspecific pattern of fibrosis shared with connective tissue diseases, chronic hypersensitivity pneumonia, and asbestosis
prototypic of restrictive lung disease
Risk factors for IPF
Environmental factors: Cigarette smoking, viruses, persistent GERD, metal fumes, wood dust, farming, hairdressers, and stone-polishing
Genetic factors:
MUC5B: Increased mucin secretion that increases susceptibility to downstream fibrosis
this accounts for 1/3 of cases
problems in creating surfactant –> unfolded protein response –> harms type II pneumocytes
Telomerase: loss-of-function (i.e. autosomal recessive) mutations in TERT and TERC
Age > 50 (this is an older person disease
Morphology IPF
histological pattern of fibrosis is referred to as usual interstitial pneumonia (UIP)
this can usually be found on its characteristic appearance in CT scans
Lower lobe predominance
Patchy interstitial fibrosis (frim rubbery white areas) in sub-pleural and interlobular septal distribution
Heterogenous lesions of different ages
Earliest lesions contain lots of fibroblastic proliferation (fibroblastic foci)
With time areas become more collagenous and less cellular
Dense fibrosis and cystic spaces lined with hyperplastic type II pneumocytes or bronchiolar epithelium (end-stage lung, or honeycomb lung)
May see signs of pulmonary artery hypertensive changes and diffuse alveolar damage (DAD == ARDS
Clinical IPF
55-75 years old at presentation with variable deterioration
Gradually progressive DOE and dry cough
Late: hypoxemia, cyanosis and clubbing despite anti-inflammatories and anti-proliferatives
Median survival: 3 years after diagnosis
Lung transplant is only definitive therapy
Only definitive treatment IPF
Lung transplant
Non specific interstitial pneumonia
Diffusely fibrosing disease of unknown etiology
lung biopsies lack the diagnostic features of any of the other well-characterized interstitial diseases
Morphology nonspecific interstitial pneumonia
Cellular pattern
Mild/moderate chronic interstitial inflammation with lymphocytes and a few plasma cells
Uniform or patchy distribution
Fibrosing pattern
Diffuse or patchy interstitial fibrotic lesions of the same stage (vs other UIP)
fibroblastic foci, honeycombing, hyaline membranes and granulomas are absent
Clinical nonspecific interstitial pneumonia
patients have chronic dyspnea and cough for several months
patients have a much better prognosis vs other interstitial pneumonias
Nonsmoking females in 6th decade
CT: bilateral, symmetric, predominantly lower lobe reticular opacities
Cellular pattern patients tend to be younger than those with fibrosing and have a better prognosis
Crypto genie organizing pneumonia
formerly known as: (bronchiolitis obliterans organizing pneumonia (BOOP)
Unknown etiology
Cough, dyspnea
Patchy subpleural or peribronchial consolidation on CXR
*Masson Bodies: polypoid plugs of loose organizing connective tissue within alveolar ducts, alveoli, and often bronchioles
Lesions are all of the same age
No interstitial fibrosis or honeycombing, the lung architecture is normal
patients may recover spontaneously, but most require six months of steroids
Identical morphologic changes with infections/inflammatory lung injury
organizing pneumonia with intra-alveolar fibrosis is most often seen as a response to infections or inflammatory injury of the lungs
Rheumatoid arthritis on the lung (caplan syndrome=RA and pneumonicosis)
30-40% of patients have pulmonary involvement in one of five ways
Chronic pleuritis (+/- effusion)
Diffuse interstitial pneumonitis and fibrosis
Intrapulmonary rheumatoid nodules
Follicular bronchiolitis
Pulmonary HTN
Systemic sclerosis (scleroderma) on the lung
Diffuse interstitial fibrosis (nonspecific interstitial pattern more common than usual interstitial pattern) and pleural involvement occurs in this systemic autoimmune disease
anti-DNA topoisomerase antibodies
Systemic lupus erythematous
Patchy, transient parenchymal infiltrates or occasionally severe lupus pneumonitis, as well as pleurisy and pleural effusions may occur
anti-dsDNA, anti-Smith antibodies
Chronic interstitial lung disease
diffuse interstitial fibrosis of the lung –> restrictive lung diseases
decreased lung compliance and decreased forced vital capacity, proportionally –> Normal FEV:FVC ratio
Pneumoconiosis=fibrosing patterna
Definition
Non-neoplastic lung reaction to inhalation of mineral dusts, organic and inorganic particulates, and chemical fumes/vapors encountered in the workplace
result from well-defined occupational exposure to specific airborne agents as well as ambient air pollution, especially in urban environments (carbon dust from internal combustion engines)
Genetic predisposition is likely because only a small percentage of exposed people develop occupational respiratory disease
Pathogenesis pneumoconiosis
depends on:
amount of dust retained in the airway and lung (concentration, exposure)
cigarette smoking impairs mucociliary clearance and significantly increases the accumulation of dust in the lungs + adds more shit
tobacco smoke worsens the effects of all inhaled mineral dusts, especially asbestos
Size, shape, particle buoyancy
1-5μm reach terminal alveoli and settle in lining (small particles are worse than large particles)
Physiochemical reactivity (toxicity) and particle solubility
small and highly soluble: rapid onset lung damage and acute lung injury
large and less soluble: more likely to resist dissolution, persist for years, and evoke fibrosing collagenous pneumoconioses (e.g. silicosis)
possible additional effects of other irritants (e.g. concomitant tobacco smoking)
The particles may also be taken up by the epithelial cells or cross through and interact directly with macrophages and fibroblasts
Particles may enter the lymphatics to initiate immune response or cause auto-immune
Coal workers pneumoconiosis
Spectrum of disease due to inhalation of coal particles and other forms of carbon dust
Asymptomatic anthracosis
simple coal workers pneumoconiosis: little to no pulmonary dysfunction
complicated coal workers’ pneumoconiosis aka progressive massive fibrosis (PMF)
lung function is compromised
Can develop emphysema and chronic bronchitis independent of smoking
Presence of silica in the coal dust leads to worse and progressive disease
favors progressive disease
Morphology coal workers pneumoconiosis
Anthracosis
macrophage take up inhaled carbon dust and accumulate in interstitial tissue
Black pigmented lesions formed by coal laden macrophages accumulate in the connective tissue along the pleural lymphatics or in organized lymphoid tissue along the bronchi or in the lung hilum
Simple Coal Workers Pneumoconiosis
1-2mm coal macules with carbon-laden macrophages or slightly larger coal nodules that also contain a delineated network of collagen fibers
concentrated in the upper lobes and upper zones of the lower lobes
primarily adjacent to respiratory bronchioles (site of initial dust accumulation)
With time there can be dilation of adjacent alveoli that gives rise to centrilobular emphysema
Complicated Coal Workers Pneumoconiosis (CCWP)
also known as Progressive Massive Fibrosis
occurs on a background of simple disease; requires years to develop
multiple, intensely blackened scars 1 cm or larger consisting of dense collagen and pigment
center of the lesion is often necrotic, most likely due to local ischemia
Clinical coal workers pneumoconiosis
Generally benign, as mild forms have little effect on lung function
CCWP may develop causing increased pulmonary dysfunction
Pulmonary HTN
Cor pulmonale
CCWP can continue to worsen, even if exposure is eliminated
Does not raise susceptibility of tuberculosis or cancer (in the absence of smoking)
domestic indoor use of “smoky coal” (bituminous) for cooking and heating is associated with an increased risk of lung cancer death for both women and men
Silicosis
Definition
Common lung disease due to inhalation of pro-inflammatory crystalline silicone dioxide
slowly progressing, nodular, fibrosing pneumoconiosis that takes decades
Increased risk in African Americans
acute silicosis: characterized by the accumulation of abundant lipoproteinaceous material within alveoli
etiology == heavy exposure over months to a few years
Most prevalent chronic occupational disease in the world
Silicosis pathogenesis
crystalline forms of silica (quartz, cristobalite, and tridymite) are much more fibrogenic than amorphous
phagocytosed silica crystals activate the inflammasome –> oxidants, cytokines (IL-1 and IL-18), and GFs –> fibroblast proliferation and collagen deposition
Slowly growing collagenous scars – takes decades to develop
Coalesce: progressive massive fibrosis
Morphology silicosis
Nodules are pale or black from coal dust in the beginning
Become larger, more diffuse with progression forming large areas of massive fibrosis (scars) that contains a central area of whorled collagen surrounded by dust laden macrophages
histologic hallmark lesion characterized by a central area of whorled collagen fibers with a more peripheral zone of dust-laden macrophages
Some may have central softening and cavitation from superimposed tuberculosis or ischemia
Initial collagenous nodules in upper lung or hilar lymph nodes
Thin sheets of calcification can happen around the lymph nodes (called egg shell calcification on CXR)
calcium surrounding a zone lacking calcification
silicosis == egg shell calcifications
Polarized light: (weakly) birefringent silica particles
Silicosis clinical
CXR with fine nodularity in upper lungs
pulmonary function tests are either normal or moderately affected early in the course
SOB develops later in course with progressive massive fibrosis (most patients do not develop SOB)
Continues to worsen even if exposure is eliminated
Increased susceptibility to tuberculosis
Onset is variable but usually slow and insidious (10-30 years after exposure), but can rarely be rapid with intense exposure
2x increased risk for lung cancer
Asbestos
Family of proinflammatory crystalline hydrated silicates associated with pulmonary fibrosis, carcinoma, mesothelioma and other cancers
Think of shipyard workers, construction, demolition (ceiling insulation
Asbestos related illness
Localized fibrous plaques or diffuse pleural fibrosis
Pleural effusions (recurrent)
Parenchymal interstitial fibrosis (asbestosis)
Lung carcinoma
Mesothelioma: malignant tumor derived from the lining cells of pleural surfaces
Laryngeal, ovarian, extrapulmonary neoplasms
Increased risk of autoimmune or cardiovascular disease
Forms of asbestos
Amphiboles
Serpentine
Amphiboles asbestos
More pathogenic form due to their aerodynamic properties and solubility
Once trapped, gradually leach due to solubility
Serpentine asbestos
Less pathogenic form due to flexible curled shape
More likely to become impacted in the upper respiratory passages and subsequently removed by mucocillary elevator
Less pathogenic serpentine(chrysotile) accounts for what percent of asbestos used in injury
90%
Pathogenesis asbestos
both amphiboles and serpentines are fibrogenic, and increasing doses are associated with a higher incidence of asbestos-related disease (follows a dose-response curve)
asbestos can also act as a tumor initiator and promoter – unlike other inorganic dusts
asbestos fibers activate the inflammasome and stimulate the release of proinflammatory factors and fibrogenic mediators
Alveolar macrophages ingest the inhaled fibers and produce mediators when activated
Fibers act as tumor initiators and promoters
Oncogenic effects may be due to free-radical generation
Tumorgenicity due to adsorption of potentially toxic substances on the fibers
Initial injury occurs at the branch points of small airways and ducts
Morphology asbestos
Morphology
Asbestosis: indistinguishable from diffuse interstitial fibrosis (honeycomb pattern) except for the presence of asbestos bodies
In contrast to coal workers’ and silicosis, asbestosis begins in the lower lungs and works its way up. The scarring can cause pulmonary HTN and cor pulmonale
Asbestos Bodies: pathognomonic, golden brown, fusiform or beaded rods ‘dumbbell shaped’ with translucent center and consist of asbestos fibers coated with iron-containing proteinaceous material
Prussian Blue stain stains iron (saw this in GI with Wilson’s disease)
Arise via ingestion of asbestos fibers by macrophages
Rarely single bodies can be found in healthy people
aka Ferruginous Bodies
Pleural plaques: well circumscribed plaques of dense collagen, no asbestos bodies, occur with exposure
Most common manifestation of asbestos exposure
Found on the anterior and posterolateral aspects of the parietal pleura and over the domes of the diaphragm
Number and size of the plaques does not correlate with the level or time since exposure
Rarely pleural effusions or visceral pleural fibrosis may occur and bind the lung to the thoracic wall
localized pleural plaques are asymptomatic
Clincial asbestos
Clinically
Dyspnea may occur as the first signs and symptoms 20-30 years after exposure
cough associated with production of sputum is likely due to smoking rather than asbestosis
CXR: irregular linear densities seen bilaterally in lower lobes (plaques)
disease can be static or progress
Honeycomb pattern with advanced pneumoconiosis
Increased risk of lung cancer if also smoke cigarettes
Grim prognosis with concurrent pulmonary/pleural malignancy
Drug induced lung disease
Drug Induced Lung Disease
Cytotoxic drugs used in cancer therapy (e.g. bleomycin): pulmonary damage and fibrosis as a result of direct toxicity and by stimulating the influx of inflammatory cells into the alveoli
Amiodarone: preferentially concentrated in the lung –> pneumonitis
ACEI: cough (“very common”)
IV drug use → pulmonary infection
particulate matter in IV drugs –> wedge in the pulmonary microvasculature –> granulomas and fibrosis
Radiation pneumonitis
well-known complication of therapeutic radiation of thoracic tumors (lung, esophageal, breast, mediastinal)
Acute: Occurs 1-6 months post exposure
lymphocytic alveolitis, hypersensitivity pneumonitis
Fever, Dyspnea not proportional to area radiated
Pleural effusion
Infiltrates in an area of previous irradiation
treatment: steroids
Chronic radiation pneumonitis
c: occurs if treatment does not take care of the acute
pulmonary fibrosis
Sequelae of the repair process of the damaged cells
Diffuse alveolar damage (DAD) –> ARDS
Severe atypia of hyperplastic type II cells and fibroblasts
Epithelial cell atypia and foam cells in vessel walls
Sarcoidosis
efinition
multi-system granulomatous disease of unknown etiology that can involve several organs and tissues
Lung involvement or bilateral hilar lymphadenopathy in 90% of cases
Diagnosis of exclusion
non-caseating granulomas in various tissues from no identifiable cause
only TB leads to caseating granulomas
Who gets sarcoidosis
Most common in patients < 40
US: common in the south
10x more likely in African Americans, rare in Chinese and Southeast Asians
More common in females
Pathogenesis sarcoidosis
Accumulation of oligoclonal activated CD4+ T cells (5-15:1 CD4 to CD8)
Increased TH1 cytokine production (IL2, IFN-γ) causing T cell expansion and macrophage activation
Increased TNF, IL-8, and macrophage inflammatory protein 1α –> granuloma formation
Bronchoalveolar TNF level is a marker for disease activity
Cutaneous anergy to common skin test antigens (tuberculin, candida)
Polyclonal hypergammaglobulinemia
Genetic factors sarcoidosis
HLA-A1, HLA-BB (class I)
Morphology sarcoidosis
well-formed, non-necrotizing granulomas with tightly clustered epithelioid macrophages and giant cells
Granulomas may become enclosed within fibrous rims or may eventually be replaced by hyaline fibrous scars
Can coalesce and make small, non-cavitated, noncaseating nodules, located mostly along the lymphatics around bronchi and blood vessels
high frequency of granulomas in the bronchial submucosa accounts for the high diagnostic yield of bronchoscopic biopsies
Schaumann bodies: Laminated, calcified proteinaceous concretions
characteristic of granulomatous disease, not pathognomonic
Asteroid bodies: Stellate inclusions within giant cells
characteristic of granulomatous disease, not pathognomonic
The lesions are likely to heal in the lungs and there are often various stages of fibrosis or hyalinization present
Lymph nodes sarcoidosis
I nvolved in almost all cases, especially the hilar and mediastinal nodes
Enlarged, discrete, and sometimes calcified
Tonsils can be affected too
Spleen and liver sarcoidosis
S cattered granulomas, especially around the portal triads
Bone marrow sarcoidosis
Lesions with phalangeal predilection
Small circumscribed areas of bone resorption within the marrow creating a diffuse reticulated pattern with widening of the shafts or new bone on the outer surfaces
Skin sarcoidosis
Discrete subcutaneous nodules or erythematous scaling plaques
URI sarcoidosis
Mucus membrane lesions
Eye sarcoidosis
Iridocyclitis: may lead to corneal opacities, glaucoma, and total loss of vision
Decreased lacrimation from inflammation
Mikulicz syndrome
Bilateral sarcoidosis of the major salivary glands (parotid, submaxilllary, sublingual)
Sounds like mucus? So therefore saliva
Muscle sarcoidosis
May be asymptomatic
Myopathy: weakness, aches, tenderness, fatigue
Other locations for granulomas in bod (sarcoidosis0
Heart, kidney, CNS, endocrine glands (espicially pituitary)
Clincial sarcoidosis
linically
May be collateral finding, or patient may present with respiratory abnormalities or constitutional signs and symptoms (i.e. fever, fatigue, weight loss, anorexia, night sweats)
Diagnosed via biopsy: non-caseating granulomas
rule out other diagnosis based on cultures and stains – sarcoidosis == diagnosis of exclusion
Unpredictable course
65-70% recover with minimal or no residual manifestations
20% have permanent loss of some lung function or some permanent visual impairment
10-15% some die of cardiac or central nervous system damage; most succumb to progressive pulmonary fibrosis and cor pulmonale
Hypersensitivity pneumonitis
Spectrum of immunologically-mediated interstitial disorders due to inhaled organic antigens
Primarily affect the alveoli – extrinsic alveolar alveolitis
Types of hypersensitivity pneumonitis
F armers lung: actinomycetes spores in hay (thermophilic bacteria)
Pigeon breeders lung: proteins from bird feathers or excreta
Humidifier/AC lung: bacteria in heated H2O reservoir
Immune reaction hypersensitivity pneumonitis
Acute phase: proinflammatory chemokines (macrophage nflammatory protein 1a, IL-8)
Increased CD4+ and CD8+ T lymphocytes
Antibodies to causative agent in serum
Complement and immunoglobulins in vessel walls
Morphology hypersensitivity pneumonitis
Interstitial pneumonitis and interstitial fibrosis of the bronchioles
Noncaseating granulomas in 2/3 of patients == T-cell mediated (Type IV) hypersensitivity reactions
Early cessation of exposure can prevent progression to serious chronic fibrosis and honeycomb lung
Intra-alveolar infiltrate
Clinical hypersensitive pneumonitis
Variable clinical presentation
Acutely: recurring fever, dyspnea, cough, leukocytosis 4-6 hours after exposure that may last for days
CXR: micronodular interstitial infiltrates
Pulmonary Function Tests indicate restrictive lung disease (FEV1:FVC ratio is normal)
Progressive exposure: respiratory failure, dyspnea, cyanosis and decrease in total lung capacity and compliance
Pulmonary eosinophilia
Increased IL-5 levels attract eosinophils
“5Always and 4Ever” except 5 also attracts eosinophils…
Relatively rare
Acute eosinophilic pneumonia with respiratory failure
Unknown etiology
Rapid onset fever, dyspnea and hypoxemic respiratory failure
CXR: diffuse infiltrates
Broncheolar lavage > 25% eosinophils
Diffuse alveolar damage (DAD) == histologic feature of ARDS
Prompt response to corticosteroids
Secondary eosinophilia
Induced by Infection (parasitic, fungal, bacterial) Hypersensitivity pneumonitis Drug allergies Association with asthma, allergic bronchopulmonary aspergillosis or Churg-Strauss Syndrome (vasculitis, asthma, MPO-ANCA/p-ANCA
Idiopathic chronic eosinophilic pneumonia
Unknown etiology
diagnosis of exclusion
Focal lung consolidation with extensive lymphocyte and eosinophil infiltration into the walls and the alveolar spaces
Cough, fever, night sweats, dyspnea, weight loss
Steroid responsive
Smoking related interstitial disease
Ok
Desquamative interstitial pneumonia ==DIP (past or present smoker disease)
Large, patchy collections of “Smoker’s Macrophages” in alveoli of a current or former smoker
DIP morphology
Smoker’s Macrophage: lots of cytoplasm with dusty brown pigment and granular iron; lamellar bodies composed of surfactant inside phagocytic vacuoles
Alveolar septa are thickened by a sparse inflammatory infiltrate of lymphocytes, plasma cells, and a few eosinophils
Alveolar septa are lined by plump, cuboidal pneumocytes
If there is any interstitial fibrosis, it is mild
Emphysema is typically present
Clincial DIP
4-5th decade, no gender preference
Insidious onset of dyspnea + dry cough over weeks to months
Digit clubbing
Pulmonary Function Tests: mild restrictive disease with moderate reduction in diffusing capacity
Excellent response to steroids and smoking cessation
Respiratory bronchiolitis associated interstitial lung disease
Gradual dyspnea and cough of current smokers in their 4th - 5th decade
Peribronchiolar inflammation and fibrosis
Morphology respiratory bronchiolitis associated interstitial lung disease
Patchy bronchiolar accumulations of “Smoker’s Macrophages” in 1st and 2nd order respiratory bronchioles
Can also be found in the alveolar ducts
Mild peribronchiolar fibrosis is seen that expands the contiguous alveolar septa
Centrilobular emphysema is common, but not severe
Desquamative interstitial pneumonia is often found in different parts of the same lung
Clinical respiratory bronchiolitis associated interstitial UAG disease
Insidious onset of dyspnea + dry cough over weeks to months
Smoking cessation = improvement
Pulmonary langerhans cell histiocytosis
R are disease of young adult smokers
Most cases resolve with smoking cessation – suggests that the lesions are a reactive inflammatory process
Focal collections of Langerhans cells (and eosinophils)
Langerhans Cells – immature resident dendritic cells
Airway destruction and alveolar damage leads to irregular cystic spaces
CXR: cystic and nodular abnormalities
Positive for S100, CD1a, CD207 (langerin), and are negative for CD68
Langerhans cells may acquire a BRAF mutation that can lead to a neoplastic process that requires lung transplant
Pulmonary alveolar proteinis (PAP)
Rare entity characterized by surfactant accumulation in alveoli and bronchioles
Defects related to GM-CSF or pulmonary macrophage dysfunction
Accumulation of surfactant in intraalveolar and bronchiolar spaces
CXR: bilateral patchy, asymmetric pulmonary o
Types of pulmonary alveolar proteinosis
Autoimmune
Secondary
Hereditary
Autoimmune pulmonary alveolar proteinosis
Autoantibodies against GMCSF cause a functional deficiency, impairing surfactant clearance by macrophages
Primarily occurs in adults
90% of all PAP cases
No familial predisposition
Secondary pulmonary alveolar proteinosis
Uncommon
Associated with many diseases that may impair macrophage maturation or function causing inadequate clearance of surfactant from alveolar spaces
May follow exposure to irritating dusts/chemicals or in immunocompromised patients
Hereditary pulmonary alveolar proteinosis
Occurs in neonates and is rapidly fatal
Mutations of GMCSF production or signaling
Extremely rare
Morphology pulmonary alveolar proteinosis
Morphologically
Alveoli are filled with granular pink precipitate composed of surfactant proteins
Also contain cholesterol clefts
Periodic Acid-Schiff (PAS) positive – PAP is PAS positive
Consolidation of large areas of the lungs with minimal inflammation
Marked Increased in size and weight of the lungs
Surfactant lamellae in type II pneumocytes are
Clincial Pap
Cough with abundant sputum containing chunks of gelatinous material – pathognomonic
Signs and symptoms may last years with febrile illness
High risk for development of 2° infection
Progressive dyspnea, cyanosis, and respiratory insufficiency may occur
May also be benign with resolution of lesions
Treatment: whole lung lavage regardless of underlying defect and GMCSF therapy
Surfactant dysfunction disorders
Ok
Surfactant dysfunction disorder mutation
Collection of mutations that leads to problems with surfactant
ATP binding cassette protein member 3 (ABCA3)
Autosomal recessive, presents in 1st months with rapidly progressive respiratory failure leading to death
Sometimes found in older kids and adults that have chronic interstitial lung disease
Small lamellar bodies with electron dense cores are diagnostic
Most commonly mutated surfactant gene
Surfactant protein B
Autosomal recessive, infant is full term but rapidly develops progressive respiratory distress shortly following birth; death at 3-6 months
Lack of surfactant protein B
Surfactant protein c
Autosomal dominant with variable penetrance and clinical course
Second most common mutation
Lack of surfactant protein C
Morphology surfactant dysfunction disorder mutations
Variable amount of intra-alveolar granular material, type II pneumocyte hyperplasia, interstitial fibrosis, and alveolar simplification
Abnormalities in lamellar bodies in type II pneumocytes
Diseases of vascular origin
Ok
Large vessel pulmonary thrombosis
Rare
Develop in presence of pulmonary HTN, pulmonary atherosclerosis, and heart failure
Pulmonary embolism : who and what
Common in bedridden patients or those with predisposing hypercoagulability
occur in 30% of severe burns, trauma, or fracture patients
occur in 10% of patient who die acutely in hospitals
DVT responsible for 95% of cases
Pulmonary embolism:pathogenesis
Occur in patient predisposed to clotting
Cardiac disease, cancer, prolonged immobilization, hip fracture, hypercoagulability (factor V Leiden), oral contraceptives/pregnancy, obesity, IV lines
Response depends on extent of obstruction, size of occluded vessel, number of emboli, CV status and release of vasoactive factors from platelets at thrombosis site
Leads to respiratory compromise and/or hemodynamic compromise
Morphology pulmonary embolism
Morphology
If the emboli are small enough to travel to the peripheral vessels, then it can cause hemorrhage if there is still adequate blood flow to the area or infarct if the patient has compromised cardiovascular function
Most of the time the infarcts occur to the lower lobes and there are multiple lesions
The infarcts take on a wedge with the apex pointing towards the hilum where the embolus is lodged
Look for lines of Zahn on autopsy to know if it post-mortem vs. ante-mortem
lines of Zahn present == ante-mortem
Septic infarcts: if there are pathogens in the embolus then it will cause there to be neutrophils present
Pulmonary embolism: appearance of the infarct over time
pulmonary infarct is classically hemorrhagic and appears red-blue in early stages with the apposed pleural surface covered by a fibrinous exudate – overlying fibrinous pleuritis –> pleural friction rub
The RBCs begin to lyse within 48 hours and leads to infarct to become paler and red-brown as hemosiderin is produced
Eventually there is fibrous replacement that begins at the margins as a gray-white peripheral zone and is eventually converted into a contracted scar
Clincial pulmonary embolism : large
Large Pulmonary Embolus
Instantaneous death due to electromechanical dissociation: EKG has rhythm but no blood is entering pulmonary circulation so there is no pulse
If the patient lives, then they may appear as though they are having an MI with severe chest pain, dyspnea, and shock
Clincial pulmonary embolism: Small
S mall-medium Pulmonary Emboli
Can have similar effects as large emboli but are more likely to be clinically silent
Clincial pulmonary embolism
Present as transient chest pain, hemoptysis, cough, fever
May eventually have fibrinous pleuritis that can produce a friction rub
CXR: there may be a wedge shaped infiltrate 12-36h after the infarct
DVTs are diagnosed by duplex ultrasound
If enough occur and heal to cause contraction, there can be pulmonary HTN and cor pulmonale
Prophylactic treatment pulmonary embolism
Important prophylactic therapy in patients who have had PE to prevent recurrence
anti-coagulation therapy to prevent future clots; fibrinolytic therapy to break apart current clots
If not possible patient should receive an IVC filter to prevent clots from reaching the lungs
Pulmonary HTN
Mean pulmonary artery pressure>25mmHg at rest
Five WHO classifications pulmonary HTN
Five WHO Classifications
pulmonary arterial hypertension – diverse collection of disorders that all primarily impact small pulmonary muscular arteries
pulmonary hypertension secondary to left-heart failure
pulmonary hypertension stemming from lung parenchymal disease or hypoxemia
chronic thromboembolic pulmonary hypertension
pulmonary hypertension of multifactorial basis
Cause of pulmonary HTN
e due to:
Chronic obstructive or interstitial disease (group 3)
Antecedent congenital or acquired heart disease (group 2)
e.g. mitral stenosis
Recurrent thromboemboli (group 4)
Autoimmune disease (group 1)
e.g. systemic sclerosis (scleroderma)
Obstructive sleep apnea (group 3) –> pulmonary hypertension and cor pulmonale
associated with obesity and hypoxemia
Idiopathic or familial
up to 80% of idiopathic pulmonary HTN has a genetic basis (autosomal dominant
Familial pulmonary HTN
Bone Morphogenetic Protein Receptor Type 2 (BMPR2): inhibits proliferation, favoring apoptosis
first mutation to be discovered in familial pulmonary HTN
inactivating mutations are found in 75% of familial cases and 25% of sporadic cases
other mutations that converge on the BMPR2 pathway have also been found
Mutations lead to vascular smooth muscle hyperplasia and increased vascular resistance
Environmental influence or maybe 2-hit is needed to cause diseas
Secondary pulmonary HTN
Endothelial dysfunction leads to
Increased vascular tone
Promotes thrombosis
Increased production of cytokines that promote smooth muscle cell proliferation and/or matrix synthesis
Morphology pulmonary HTN
Pul monary HTN: Morphology
pulmonary artery atherosclerosis
Medial hypertrophy of pulmonary muscular and elastic arteries, especially the arterioles and small arteries
Right Ventricular Hypertrophy
Plexiform lesions: Tufts within capillary channels produce a vascular plexus that spans the lumens of dilated, thin-walled, small arteries that may go outside the vessel
Found with 1° pulmonary HTN, HIV (both group 1) and congenital CV anomalies (L2R shunts) (group 2)
Numerous organized thrombi (indicate PE
Clinical pulmonary HTN
Idiopathic is most common in women 20-40 years old
Evident only with advanced disease
Progresses to severe respiratory insufficiency and decompensated cor pulmonale (+/- superimposed thromboembolism, pneumonia)
Death from decompensated cor pulmonale, often with superimposed thromboembolism and pneumonia, usually ensues within 2-5 years in 80% of patients
Treatment: vasodilation and lung transplantation
Diffuse pulmonary hemorrhage syndromes
use Pulmonary Hemorrhage Syndromes
Goodpasture syndrome: lung and kidney disease, anti-BM antibodies
Wegener’s polyangiitis with granulomatosis == lung and kidney disease, but with PR3-ANCA/c-ANCA
Idiopathic pulmonary hemosiderosis
Vasculitis-associated hemorrhage
found in conditions such as hypersensitivity angiitis, Wegener granulomatosis (polyangiitis with granulomatosis), and systemic lupus erythematosus
Goodpasture syndrome
Autoantibodies against the non-collagenous domain of collagen IV α3 chain (anti-Basement Membrane)
Basement membrane destruction in renal glomeruli and pulmonary alveoli
Rapidly progressive glomerulonephritis + necrotizing hemorrhagic interstitial pneumonitis
Teens to late 20s, especially males
Common in active smokers
Good pasture risk factors
Smoking, dry cleaning, viral infection
HLA-DRB1*1501 and *1502
Morphology good pasture
Heavy lungs with areas of red-brown consolidation
Lungs with focal alveolar wall necrosis
Intraalveolar hemorrhage + hemosiderin laden macrophages
Later: fibrous thickening of the septae, hypertrophy of type II pneumocytes, and organization of blood in the alveolar spaces
Immunofluorescence shows linear Ig depositions along septal basement membranes – renal throwback
Clincial good pasture
Hemoptysis with focal pulmonary consolidations on CXR (necrotizing interstitial pneumonitis)
also hematuria from the rapidly progressive glomerulonephritis (RPGN)
Most common cause of death: uremia
Treatment: plasmapheresis + immunosuppression therapy should ameliorate lung hemorrhage and glomerulonephritis
will emergently perform plasmapheresis in the middle of the night
Idiopathic pulmonary hemosiderosis
Etiology unknown disease of children Intermittent diffuse alveolar hemorrhage Present with cough + hemoptysis similar to Goodpasture syndrome but there are no anti-basement membrane antibodies detected in serum Treatment: long-term immunosuppression Favorable response Long term patients may develop other immune disorders
Polyangitis with granulomatosis (Wagner’s)
PR3-ANCA/ c-ANCA (pr-thrEE cEE; C is the 3rd letter of the alphabet)
Autoimmune disease
Present with hemoptysis
most often involves the upper respiratory tract and/or lungs
transbronchial lung biopsy might provide the only tissue available for diagnosis
Capillaritis – this is a vasculitis, after all
Scattered, poorly formed granulomas (sarcoidosis has well defined granulomas)
granulomas with variable necrosis
Pulmonary infections: local defense compromise
Loss or suppression of the cough reflex Injury to the mucociliary apparatus Accumulation of secretions Interference with phagocytosis or bactericidal actions of alveolar macrophages Pulmonary congestion and edema
Pyogenic bacterial infections
Incidence increases when defects in innate or humoral immunity are present
May also be due to MyD88 germline mutation
MyD88 == adaptor for several TLRs that are important for activation of NFκB
Intracellular microbe infection
Defects in cell mediated immunity can lead to this type of infection
Includes mycobacteria, herpes, and pneumocystis jiroveci
pneumocystis jiroveci == low virulence
Most common cause of death with pulmonary infections
Most common cause of deaths in influenza epidemics == superimposed bacterial pneumonia
Community acquired pneumonia
Co mmunity Acquired Acute Pneumonia
Lung infection in otherwise healthy individuals acquired from the normal environment
Bacterial or viral
Bacterial Infection
Increased CRP and procalcitonin levels – these are acute phase reactants (IL-6)
Often follows a viral URI
Causes alveoli to be filled with inflammatory exudate causing consolidation of pulmonary tissue
Predisposition: age extremes, chronic disease (CHF, COPD, DM), congenital or acquired immunodeficiency, compromised splenic function (Sickle Cell Anemia or Trait)
Strep pneumonia
Most common cause of community acquired pneumonia; distribution of inflammation is lobar
Diagnosis: examine gram stained sputum
Gram +ve, lancet-shaped diplococci; encapsulated
Endogenous flora in 20% of adults, beware of false-positives
isolation of pneumococci from blood cultures is more specific but less sensitive (on 20-30% of patients have positive blood cultures in the early phase of illness)
Vaccines for those at high risk contain capsular polysaccharides from common serotypes
Haemophilus influenzae
Most common bacterial cause of acute exacerbation of COPD
Pleomorphic, gram -ve
Encapsulated or unencapsulated
six serotypes of encapsulated: A through F (Type B is the most virulent)
capsular polysaccharide b is incorporated in the widely used vaccine
Haemophilus influenza can lead to what
Pink eye
Lower respiratory infection and suppurative meningitis in children (vaccine)
Older patients: septicemia, endocarditis, pyelonephritis, cholecystitis, and suppurative arthritis
Unencapsulated haemophilus influenza (non typeable)
Unencapsulated Haemophilus influenzae (aka non-typeable)
Less virulent
Spread along the surface of the upper respiratory tract
Can lead to:
Otitis media
Sinusitis
Bronchopneumonia
Kids are at more risk if they are premature or have cancer
HEMOPHIIUS INFLUENZA PNEUMONIA
Can follow a viral URI
Pediatric emergency
High mortality rate
Descending laryngotracheobronchitis can lead to airway obstruction
Small bronchi are plugged with dense, fibrin rich exudates with neutrophils
Lobular, patchy consolidation (may become confluent and involve the entire lung lobe
Moraxella catarrhalis pneumonia
Bacterial pneumonia commonly in the elderly
second most common bacterial cause of COPD exacerbation
Otitis media in children
associate with COPD and upper respiratory infection
Three most common causes of otitis medi
Streptococcus Pneumoniae: gram +ve, lancet shaped diplococci
Haemophilus Influenzae: gram -ve, pleomorphic
grown on chocolate agar (along with Legionella)
Moraxella Catarrhalis:
Staphylococcus aureus pneumonia
2° bacterial pneumonia in children and healthy adults post-viral respiratory illness
children: following measles
children and adults: following influenza
Several complications: Lung abscess, empyema
IV drug users are at increased risk in association with endocarditis
Often hospital acquired pneumonia (nosocomial)
usually secondary to viral respiratory infections
Klebsiella pneumonia
Most frequent cause of gram (-) bacterial pneumonia
Affects debilitated patients, chronic alcoholics, and malnourished individuals – especially chronic alcoholics
Three A’s: Alcoholics, Aspiration, Abscesses
*thick, mucoid (blood tinged) sputum – “Currant jelly sputum” – Buzzwords for Boards
Organism produces viscid capsular polysaccharide, difficult to expectorate
Pseudomonas aeruginosa pneumonia
Pseudomonas aeruginosa pneumonia
Common cause of nosocomial infection
Invades blood vessels to spread systemically
Common in cystic fibrosis, burn patients, and patients with neutropenia
Legionella pneumonia pneumonia
egionella pneumophila pneumonia
Causative agent of Legionnaire’s disease and Pontiac fever
Flourishes in artificial aquatic environments (e.g. HVAC systems)
Spreads through aerosolization or aspiration of contaminated water
Severe pneumonia in immunocompromised patients, especially patients who have had organ transplant (50% fatal) – “seen particularly in organ transplant recipients”
Diagnose: culture (gold standard), antigens in urine, or antibodies in sputum
lobar pattern on CXR, pulse-temperature dissociation
lives in amoebas
“like mycobacterium tuberculosis, this is a facultative intracellular parasite (lives in macrophages and free living amoebas)”
grown on chocolate agar; use a silver stain to detect; urine antigens
urine antigens == legionella, streptococcus pneumoniae
can enter a low-metabolic state and survive in a biofilm
Mycoplasma pneumonia ==walking pneumonia
Sporadic infection or as local epidemics in closed communities such as schools, military camps, or prisons
Common in children and young adults
“walking pneumonia”
“cold agglutinants”
“bullous myringitis” – Bullous myringitisis an infection of the tympanic membrane (the eardrum). Small fluid-filled blisters form on the eardrum and cause severe pain.
Morphology lobular bronchopneumonia
Patchy exudative consolidation of the lung parenchyma
Focal areas of palpable consolidation that are typically bilateral and basal
Well-developed lesions are slightly elevated, dry, granular, grey-red to yellow, and poorly demarcated at the margins
Acute neutrophilic suppurative exudation filling bronchi, bronchioles and alveoli that eventually resolves
CXR: focal opacities
Morphology lobar pneumonia
Consolidation of a large portion of a lobe or an entire lobe
CXR: whole lobe is radiopaque
streptococcus pneumoniae == most common cause of community-acquired acute pneumonia and the pattern of inflammation is lobar
Four Stages of Inflammation
Congestion: heavy, boggy, red lung; vascular engorgement, alveolar fluid with few neutrophils and lots of bacteria
Red hepatization: massive neutrophilic exudation with RBCs and fibrin that fill the alveolar spaces
red, firm, and airless with a liver like consistency
Grey hepatization: progressive disintegration of red cells and persistence of fibrinosuppurative exudate that leads to a grey-brown color
sequelae of red hepatization
Resolution: progressive enzymatic digestion of exudates –> granular, semifluid debris that is resorbed, ingested by macrophages, expectorated, or organized by fibroblast growing into it. May even extend to the surface as pleuritic
Pneumonia complciations
Abscess formation (especially from Type 3 pneumococci or klebsiella) due to tissue destruction and necrosis Empyema: intrapleural fibrosuppurative reaction infection spreads into pleural cavity causing fibrinosuppurative reaction Bacteremic dissemination to heart valves, pericardium, brain, kidneys, spleen, etc. --> endocarditis, meningitis, suppurative arthritis, etc
Community acquired bacterial pneumonia clincial
Abrupt onset of high fever, shaking chills (rigors), productive cough, and occasional hemoptysis
Pleural involvement: pleuritic chest pain + friction rub
treatment: antibiotics change course of disease within 48-72 hours
Community acquired viral pneumonia
Alveoli fluid transudation
Upper airways loss of normal mucociliary clearance can predispose to 2° infection
interstitial infiltrates
Morphology community acquired viral pneumonia
Patchy or lobar areas of congestion without consolidation (atypical)
Interstitial pneumonitis occurs with widened, edematous alveolar walls and mononuclear inflammation
Hyaline membranes = diffuse alveolar damage
Cytopathic changes may occur, including cell death and secondary inflammation
Influenza virus
Single stranded RNA virus with 8 strands bound by a nucleoprotein that determines the virus type (A, B or C)
Hemagglutinin (H1-3) attach virus to target cells via sialic acid residues on surface polysaccharides
antibodies against hemagglutinin prevent infection
“glue attaches things”
Neuraminidase (N1-2) facilitate release of newly formed virions that are budding from infected cells by cleaving sialic acid residues
antibodies against neuraminidase ameliorate infection (Tamiflu)
“is the other one”
Type A infects humans, pigs, horses, and birds and are the major cause of pandemics and epidemics
Type B and C do not mutate, so childhood infection conveys life-long antibody protection
Influenza epidemic
due to mutation in hemagluttinin and neuraminidase proteins (antigenic drift constant because viral RNA polymerase lacks proofreading capability) that create new viral strains which elude antibodies produced to prior exposure to other strains
New strains bear some resemblance to prior strains and there is often some resistance to infection in some patients
Influenza pandemic
Hemagluttinin and neuraminidase genes are replaced due to recombination of influenza virus with animal influenza viruses (antigenic shift)
All individuals are susceptible to the new virus as it is a completely new viral strain
Pathogenesis influenza virus
Hemagluttinin and neuraminidase genes are replaced due to recombination of influenza virus with animal influenza viruses (antigenic shift)
All individuals are susceptible to the new virus as it is a completely new viral strain
Pathogenesis
Enters pneumocytes, inhibits Na+ channels which leads to electrolyte and water in the alveolar lumen
Death of infected cells via mRNA translation + apoptosis which exacerbates fluid accumulation
Releases “danger signals” activating resident macrophage
Induces release of inflammatory mediators
Nearby pulmonary endothelium is activated allowing neutrophil extravasation into the interstitium
May cause ARDS or lead to 2° bacterial pneumonia
Staphylococcus aureus superimposed on top of influenza infection can cause life-threatening 2° pneumonias
H5N1
high mortality rate – the virus is deadly
transmission is inefficient – fear is that it will recombine with a highly virulent strain (H1N1, swine flu)
Spread through wild and domestic birds – Avian Flu
Is spread throughout the body, not confined to the lung – systemic
Tropism of the hemagluttinin protein is due to ability to be cleaved by diverse proteases, where most are only cleaved in the lung
Human metapneumovirus
Paramyxovirus
Associated with upper and lower respiratory infections
Causes bronchiolitis and pneumonia in the young, old, and immunocompromised
clinically indistinguishable from those caused by human respiratory syncytial virus
RSV == #1, MPV == #2 – clinically, they look exactly the same
occurs in early childhood and reinfection is common throughout life
treatment for immunocompromised patients with ribavirin (anti-viral agent)
no current vaccine
Severe acute respiratory syndrome
Coronavirus that infects the lower respiratory tree and spreads systemically
Appeared suddenly in 2002 in China and has not been seen since 2004
Transmitted through respiratory secretions
Dry cough, malaise, myalgia, and fever
1/3 recover, remainder progress to severe respiratory disease, 10% die
Fatal cases have diffuse alveolar damage + multinucleated giant cells
Viral infection: morphology
URI with mucosal hyperemia, swelling, lymphomonocytic and plasmacytic infiltration of submucosa, mucus overproduction which may plug sinuses or Eustachian tubes leading to suppurative 2° bacterial infection
Viral tonsillitis is common in kids resulting in hyperplasia within the Waldeyer ring
Lung involvement: red-blue areas with congestion
Interstitial inflammatory reaction involving walls of the alveoli causing wide alveolar septa
If complicated by ARDS, pink hyaline membranes line alveolar walls
Viral laryngotracheobronchitis and bronchiolitis
Vocal cord swelling and abundant mucus production
Bronchocilliary impairment invites 2° infection
Focal lung atelectasis due to plugging of small airways (obstruction –> resorption atelectasis)
Fibrosis may result if presence of exudates in terminal airways is prolonged and can lead to obliterative bronchiolitis and permanent lung damage
superimposed bacterial infection may cause ulcerative bronchitis and bacterial pneumonia
Clincial influenza infection
Lung infection can be patchy or extensive
involved areas are red-blue and congested
interstitial inflammatory reaction involving the alveolar wall tissue with edema + lymphocytes and macrophage
Disease extent depends on host immune status, virulence of infecting strain and presence/absence of other complicating factors
Variable progression with headache, fever, muscle aches/pains in legs
Few localizing signs and symptoms, and may masquerade as URI or chest colds
Edema and exudation cause V/Q mismatch causing signs and symptoms out of proportion to scant physical findings
Usually mild and resolve spontaneously
Heath care associated pneumonia risk factors
Recent hospitalization of 2+ days
Presentation from a nursing home/long term facility
Attending hospital/hemodialysis clinic
Recent IV antibiotic therapy, chemotherapy or wound care
More commonly infected with methicillin resistant Staphylococcus Aureus (MRSA) and Pseudomonas Aeruginosa
Increased mortality vs. community acquired pneumonia
Hospital acquired pneumonia
Pulmonary infection acquired in the course of a hospital stay
Increased risk with underlying disease, immunosuppression, prolonged antibiotic therapy, invasive access devices
Very increased risk if patient is on mechanical ventilation (Gram -ve bacilli)
Most commonly caused by:
Gram +ve cocci: Staphylococcus Aureus and Streptococcus Pneumonia
Gram -ve rods: Enterobacteriaceae and Pseudomonas
Gram -ve bacilli: ventilator associated pneumonia
Aspiration pneumonia
Occurs in markedly debilitated patients with abnormal gag and swallowing reflexes Pneumonia is chemical + bacterial Aerobes > anaerobes Fulminant necrotizing pneumonia Frequent cause of death Complication in survivors: lung abscess Klebsiella
Micro aspiration
Occurs in almost all people, especially in patients with GERD
Results in inconsequential poorly formed non-necrotizing granulomas
Multinucleated foreign body cell reaction
May exacerbate preexisting lung diseases like asthma, interstitial fibrosis, and lung rejection
Lung (pulmonary) abscess
Local suppurative necrosis of lung tissue
Air fluid levels are very characteristic
Lung abscess common pathogens
Streptococci, Staphylococcus Aureus, many gram -ve organisms
Commonly mixed infection due to aspiration which means many anaerobic oral cavity organisms (Bacteroides, Fusobacterium, Peptococcus *60%)
Other causes lung abscess
Antecedent primary lung infection from things like Staphylococcus aureus, Klebsiella pneumoniae, and type 3 pneumococcus
Septic embolism
Neoplasia obstructing the bronchopulmonary segment
Bacteria spreading from somewhere else in the bod
Location of abscess based on cause
Aspiration based ones are more common on the right and single
Pneumonia based abscesses are typically located basally and are found in multiple diffusely scattered
Septic based abscesses are multiple and can involve any region of the lung
Morphology lung abscess
Single or multiple
Microscopic to large cavities
Histology: suppurative destruction of the lung parenchyma within the central area of cavitation
Pus or air depending on available drainage
Chronically may be surrounded by a reactive fibrous wall surrounding large, poorly demarcated, fetid, green-black gangrene
Superimposed saprophytic infections are prone to develop within the necrotic debris
Ok
Clinical pulmonary abscess
Presents as cough, fever, chest pain, weight loss, and copious amounts of foul smelling purulent or sanguineous sputum
bronchiectasis and lung abscess == foul smelling sputum
Clubbing of the fingers can develop in a few weeks
Can be complicated by extension into pleural cavity, hemorrhage, septic embolization, 2° amyloidosis
Confirm with CXR
treatment: antimicrobials resolve most cases with a scar
Primary cryptogenic lung abscess
When there is no discernible basis for the abscess formation
Chronic pneumonia
Localized inflammation in immunocompetent patients without regional lymph node involvement
Asymptomatic
Limited granulomatous disease
In immunocompromised patients the infection can become disseminated
Fulminant, widespread disease
Histoplasmosis capsulatum
Intracellular pathogen of phagocytes, endemic to Ohio and Mississippi river valleys (midwest)
Acquired via inhalation of dust with bird/bat excreta (caves)
bird can also –> hypersensitive pneumonitis
Mainly only infects immunocompromised patients
macrophages are the major target of infection
Types of infection progression (similar to Tb) in histoplasmosis capsulatum
Self-limited, latent, 1° pulmonary involvement which may result in coin lesions on CXR
Chronic, progressive, 2° lung disease localized to the lung apices causing cough, fever, and night sweats
Spread to extrapulmonary sites (e.g. mediastinum, adrenals, liver, meninges)
widely disseminated disease in immunocompromised patients
Morphology histoplasma capsulatum
Produces granulomas with caseating, coagulative necrosis which undergo fibrosis and concentric calcification (tree-bark appearance) – can eventually lead to bronchiectasis?
Silver stain identifies 3-5 micron cysts of the fungus that can persist for years (and differentiates this fungus from tuberculosis)
Fulminant disseminated histoplasmosis: Immunocompromised patients. Focal accumulations of mononuclear phagocytes filled with fungal yeasts throughout the body, NO granulomas
for fungal infections, stain with silver or PAS
3-5 micrometer pear shaped intracellular yeast
Clinical histoplasma capsulatum
Look for the antigens in the tissues in the beginning and then antibodies after 2-6 weeks
coin lesion differential: histoplasma, hamartoma, adenocarcinoma
Blastomyces dermatiditis
Soil dwelling, dimorphic fungus that occurs in central and southeast USA (Florida)
also Canada, Mexico, Middle East, Africa, and India
Different forms of blastomyces dermatiditis
Pulmonary, disseminated or primary cutaneous (rare)
Clincial presentation of pulmonary blastomycosis
Usually upper lobe involvement with abrupt productive cough, head ache, chest pain, weight loss, fever, abdominal pain, night sweats, chills, and anorexia
CXR: lobar consolidation, multi-lobar infiltrates, perihilar infiltrates, multiple nodules, miliary infiltrates
Upper lobes are most commonly involved
Typically resolves spontaneously
Morphology blastomyces dermatiditis
(BBBB) Blastomycosis: broad based budding
Immunocompetent host: suppurative granulomas with persistence of yeast cells due to limited macrophage capabilities to kill this fungus
5- 15 micron yeast cells that divide by broad based budding
Thick double-contoured cell wall with visible nuclei
Involvement of the skin and larynx is associated with marked epithelial hyperplasia, can be mistaken for squamous cell carcinoma
5-15 micrometers yeast with broad based budding
Coccidioidomycosis
outhwest USA, Mexico deserts (Arizona) everyone who inhales the spores of Coccidioides immitis becomes infected and develops a delayed-type hypersensitivity reaction to the fungus Inhaled spores (arthroconidia) block fusion of the phagosome and lysosome in the macrophage and resist intracellular killing
Inhaled spores (arthroconidia) block fusion of the phagosome and lysosome in the macrophage and resist intracellular killing
Clincal coccidiodomycosis
Most cases are asymptomatic
San Joaquin Valley Fever complex: 10% of infected people develop lung lesions, fever, cough, pleuritic pains, erythema nodosum, and erythema multiforme
less than 1% of people develop disseminated Coccidioides immitis infection which involves the skin and meninges (Filipinos and African-Americans are at increased risk of disseminated disease
Morphology coccidioidomycosis
Within macrophages, the fungus is seen as thick-walled, nonbudding spherules 20-60 microns and filled with endospores
Spherule rupture, releasing endospores causes a superimposed pyogenic reaction and may recruit neutrophils
Lesions can be granulomatous or pyogenic or mixed, with the disseminated type favoring more of the pyogenic type
20-60 micrometer nonbudding spherules
Pneumonia int he immunocompromised host
Opportunistic infections rarely affect normal hosts, but in this setting can cause life-threatening pneumonia
appearance of a pulmonary infiltrate, with or without signs of infection (e.g. fever), is serious in patients whose immune system is suppressed by disease, immunosuppressive therapy for transplant, chemotherapy, or irradiation
Often multiple organisms are involved
Bacteria: Pseudomonas, Legionella, Listeria, mycobacteria
Viruses: CMV, herpes
Fungi: Pneumocystis jiroveci (AIDS defining), Candida, Aspergillus, phycomycetes, Cryptococcus neoformans
Pulmonary disease in HIV
Serious issues can be caused by the “normal” lower respiratory infection pathogens (Streptococcus pneumonia, Staphylococcus aureus, Haemophilus influenza, gram -ve rods)
the usual pathogens are among the more serious
bacterial pneumonias in HIV patients are more common, more severe, and more often associated with bacteremia than in those without HIV infection
Pulmonary disease may be due to multiple causes and signs and symptoms can be atypical
Base on the Stage of Disease (HIV/AIDS)
CD4+ > 200 = bacterial and tubercular infection
CD4+ 50-200 = Pneumocystis – AIDS defining illness
CD4+ < 50 = CMV, fungal and Mycobacterium avium
Indications for lung transplant
Emphysema (pink puffer)
[chronic bronchitis == blue bloater] – not candidate for lung transplant
Idiopathic pulmonary fibrosis == end stage lung, honeycomb lung
Cystic Fibrosis
1° pulmonary HTN
Single or double lung transplant
Usually single
Infections lung transplant
Early are bacterial
ganciclovir prophylaxis and matching of donor-recipient CMV status == reduced frequency and severity of CMV pneumonia (because everyone has CMV but nobody is sick with CMV)
Most common 3-12 months post-operative
Acute rejection: all patients to varying degrees despite immunosuppression
If fungal: due to aspergillus and candida
Lung transplant rejection: acute
inflammatory infiltrates around small vessels or in the submucosa of airways
Several weeks to months after surgery, but may also present years later
Fever, dyspnea, cough, radiologic infiltrates
Looks like infection, so need biopsy to rule out pathogens
Inflammatory infiltrates
Lung transplant chronic rejection
Happens to at least 50% of patients after 3-5 years
Cough, dyspnea, and irreversible decrease in lung function due to pulmonary fibrosis
Bronchiolitis obliterans partial or complete occlusion of small airways by fibrosis +/- inflammation; patchy; difficult to treat
Tumors of th lung
90-95% carcinoma
5% bronchial carcinoid
2-5% mesenchymal and other miscellaneous
Lung cancer facts
Most frequently diagnosed major cancer in the world
Most common cause of cancer mortality worldwide
Mostly due to tobacco smoke
Commonly occurs between 40-70 years old
Types of lung cancer
Small cell – TB, TP53, and MYC
Non-small cell
Squamous cell – RB, TP53, p40, hypercalcemia, keratin pearls and intercellular bridges
Adenocarcinomas – EGFR, ALK, ROS, MET, RET, KRAS
Tobacco and lung cancer
Females have Increased susceptibility to the associated carcinogens
Risk of lung cancer is proportional to the amount and duration of smoking
Cessation decreases risk after 10 years, but not to baseline
Individuals with P450 polymorphisms have a greater risk of lung cancer due to activation of pro-carcinogens
Increased chromosome breakage sensitivity in peripheral blood lymphocytes = 10x risk
Industrial hazard lung cancer
Asbestos (10-30 year latency, 5x risk, if smoker 55x)
Arsenic
Chromium
Uranium (exposed miners 4x risk, if smoker then 10x risk)
Nickel
Vinyl chloride – hepatic adenocarcinoma
Mustard gas
Ionizing radiation (Hiroshima, Nagasaki, Chernobyl
Air pollution lung cancer
Add to risk of lung cancer in those who smoke via inflammation and repair
Squamous cell carcinoma
Loss of tumor suppressor genes due to tobacco smoke exposure
Loss of CDKN2A (3p, 9p) = loss of p16 (RB)
Loss of TP53 (17p) *highest frequency of TP53 mutations of all histologic types of lung carcinoma
highly associated with exposure to tobacco smoke and harbors diverse genetic aberrations, many of which are chromosomal deletions involving tumor suppressor loci (two hits needed)
Loss of RB
Amplification of FGFR1
More common in the central/hilar region of the lung
squamous cell carcinoma is more common (20%) than small cell carcinoma (14%)
keratin pearls and intercellular bridges
Small cell carcinoma
Strongest association with smoking TP53 loss of function (75-90%) RB mutations are most likely (~100%) in small cell carcinomas Chromosome 3p deletion MYC amplification Aggressive, high mortality
Adenocarcinoma
Gain-of-function of GF receptor signaling pathways
Tyrosine kinases: EGFR, ALK, ROS, MET, RET, KRAS
KRAS mutations are the worst
More common in the peripheral lung
Precursor lesions
Atypical adenomatous hyperplasia (≤ 5mm)
Adenocarcinoma in situ < 3 cm; mucinous, atypical cells
Lung cancer in never smokers
More common in women
Most are adenocarcinomas
More likely to have EGFR mutation, and almost never have KRAS mutations
TP53 is less common than in those who smoke
Precursor lesion lung cancer
Squamous dysplasia and CIS
Atypical adenomatous hyperplasia
Adenocarcinoma in situ
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Tumor classification
Via the predominant histologic appearance, though multiple histologies can be present in one tumor
clinical significance is still undetermined
four major histologic subtypes
Adenocarcinoma (38%)
Squamous cell carcinoma (20%)
Small cell carcinoma (14%)
treat with chemotherapy because almost all are metastatic at presentation
Large cell carcinoma (3%)
Other (25%)
Atypical adenomatous hyperplasia
Single or multiple, small lesion characterized by dysplastic pneumocytes lining alveolar walls that are mildly fibrotic
In the lung adjacent to invasive tissue or away from it
Adenocarcinoma in situ
Single (favorable) or multiple in the terminal bronchioloalveolar regions
Composed entirely of dysplastic cells growing along preexisting alveolar septae
lepidic?
Excessive dysplasia (more than atypical adenomatous hyperplasia)
Tall, columnar
+/- intracellular mucin (mucinous vs. nonmucinous)
No gender specificity, no association with smoking
Dismal prognosis if diffuse
tumors 3 cm or less in diameter characterized by pure growth along pre-existing structures (lepidic pattern) without stromal invasion
lepidic == rind, skin, or membrane
epithelium are normal, lining cells are abnormal
Adenocarcinoma
Most common lung cancer in the absence of smoking
Common in the peripheral lung
Malignant epithelial tumor with glandular differentiation or mucin production
Grow in various patterns
majority express thyroid transcription factor 1 (TTF-1)
Lepidic pattern of spread as tumor cells crawl along pre-existing alveolar septa without stromal invasion
Associated with TTF1 and napsin A
Grow more slowly, but metastasize earlier vs. squamous cell carcinoma
Micro-invasive adenocarcinoma
Tumors ≤ 3cm with a small invasive component (≤ 5mm)
Associated with scarring and peripheral lepidic growth pattern
Better outcome vs. invasive carcinoma of comparable size
Mucinous adenocarcinoma
S olitary or multiple nodules
Potentially consolidate an entire lobe with tumor cells resembling lobar pneumonia
less likely to be cured with surgery
Spread aerogenously forming satellite tumors
Squamous cell carcinoma
Commonly in men, strongly associated with smoking
most common lung cancer associated with smoking
because this is more likely than squamous cell cancer (20% vs 14%… not how stats work but OK)
Antedated squamous metaplasia/dysplasia in the bronchial epithelium that transforms to CIS
CIS is cytologically identifiable by sputum or lavage, but undetected on CXR and is asymptomatic
Can grow to obstruct the bronchus causing distal atelectasis and infection
May penetrate the wall of the bronchus and infiltrate peribronchial tissue
Histology squamous cell carcinoma
‘Cauliflower’ mass
Grey/white, firm neoplastic tissue
If there is hemorrhage or necrosis, they appear as red-yellow mottling and can cavitate
Keratinization (squamous pearls) or intercellular bridges
There is more that is seen in well differentiated tumors and is only focally present in undifferentiated tumors
Increased mitotic activity in poorly differentiated tumors
Closest correlation with smoking
Commonly in the central/hilar region
Associated with p53 and p40 markers
Late metastases
Surrounding tissue is typically dysplastic
Paraneoplastic Syndromes == hypercalcemia
Paraneoplastic syndrome squamous cell carcinoma
Hypercalcemia
Small cell carcinoma
Highly malignant, metastasizing widely (high grade), almost always fatal
Strongest lung cancer association with smoking
Arises in the major bronchi or in the periphery of the lung – central
There is no known pre-invasive phase
Small cells with scant cytoplasm, ill-defined borders, finely granular nuclear chromatin (salt & pepper) + lack of nucleoli
Nuclear molding is prominent
High mitotic count
Don’t show glandular or squamous organization
Necrosis is common and often extensive
Azzopardi effect: Basophilic staining of vascular walls due to encrustation by DNA from necrotic tumor cells
Cells may originate from neuroendocrine progenitor cells with dense-core neurosecretory granules
Expression of chromogranin, synaptophysin, CD57, hormonal secretion (paraneoplastic)
Lung cancer most commonly associated with ectopic hormone production
BLC2 found on immunohistochemistry
Paraneoplastic Syndromes == SIADH and Cushing (ectopic cortisol)
Combined small cell carcinoma
Small cell carcinoma is mixed with non small cell histologies
May resemble sarcoma
Large cell carcinoma
Undifferentiated malignant epithelial tumor lacking cytologic features of other lung cancers
Diagnosis of exclusion
Variant may express neuroendocrine components, but tumor cell size is much larger than small cell carcinoma
Prominent nucleoli
Carcinoma spread
May extend onto the pleural surface, spread within the pleural cavity or into the pericardium
Most cases (> 50%) metastasize to the bronchial, tracheal and mediastinal lymph nodes
Lymphatic and hematogenous spread occurs
Metastasize early except squamous cell carcinoma
Metastasis may be the first manifestation
50% of metastatic cases involve the adrenals
Other common sites include liver, brain and bone
Combined carcinoma
Combined carcinoma
Where there are more than 1 type of tumor cell present in the mass
happens in approximately 10% of all lung carcinomas
Complications of carcinoma
partial obstruction –> focal emphysema
total obstruction –> Atelectasis (resorption kind)
impaired drainage –> Suppurative or ulcerative bronchitis or bronchiectasis
Pulmonary abscesses
Superior vena cava syndrome
Pericarditis
Pleuritis
Invasion of neural structures near trachea → Horner syndrome *Pancoast tumors
Partial Ptosis
Anhidrosis
Miosis (increase in sympathetics, constricted pupil
Lung cancer clinical course
Cough, weight loss, chest pain, dyspnea
Poor prognosis, especially with metastasis (common to adrenals, brain, liver and bone)
adenocarcinoma and squamous cell carcinoma tend to remain localized longer and have a slightly better prognosis than do the undifferentiated cancers, which are usually advanced by the time they are discovered
small cell cancer (oat cell cancer) is virtually always fatal
5 year survival
52% if disease is localized at presentation
22% with regional metastases
4% with distant metastases
Survival is prolonged if targeting adenocarcinoma that have the EGFR mutation – just like breast cancer
Survival is reduced if there is a KRAS mutation (worse prognosis)
Small cell carcinoma: sensitive to radiation and chemotherapy if localized, but most patients present with metastases
Pathoma: “so small the surgeon can’t see it”
Lung cancer and paraneoplastic syndromes : small cell carcinoma
Small Cell Carcinoma
SIADH: hyponatremia due to inappropriate/excess ADH secretion
Cushing Syndrome: ACTH
Paraneoplastic syndromes with squamous cell arcinoma
Hypercalcemia: parathormone, parathyroid hormone-related peptide, PGE2, cytokines
Hypocalcemia: calcitonin
Gynecomastia: gonadotropins
Carcinoid syndrome: 5HT, bradykinin, MEN1
Lambert Eaton myasthenic syndrome
Muscle weakness due to auto-antibodies directed against the neuronal Ca++ channel
better with activity
myasthenia gravis == fatigable ptosis (better with rest)
Hypertrophic pulmonary osteoarthropathy (associated with clubbing of the fingers)
Acanthosis nigricans
Peripheral neuropathy (sensory)
Leukemoid reaction
Hypercoagulable states (Trousseau
Pancoast tumors
Apical Lung Cancer arising from the superior pulmonary sulcus tend to invade neural structures near trachea (cervical sympathetic plexus)
Horner Syndrome: ptosis, miosis, anhidrosis – “PAM is horny”
Ipsilateral severe pain in ulnar nerve distribution
Neuroendocrine proliferation’s and tumors
Ok
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Precursor to the development of tumorlets and typical or atypical carcinoids
tumorlet == small, inconsequential (benign), hyperplastic nest of neuroendocrine cells seen in areas of scarring or chronic inflammation
carcinoids may occur in patients with multiple endocrine neoplasia (MEN) type 1
Rare disorder
Carcinoid tumors
Typical or atypical, low-grade malignant epithelial neoplasms
Epidemiology
< 40 years, no gender specificity
20-40% are nonsmokers
Morphology carcinoid tumors
May arise centrally or peripherally
Central may protrude into bronchial lumen and are covered by an intact mucosa
Peripheral are solid and nodular
Organoid, trabecular, palisading, ribbon, or rosette-like arrangements of cells separated by a delicate fibrovascular stroma
Cells are regular and have a uniform round nuclei and a moderate amount of eosinophilic cytoplasm
Most are confined to mainstem bronchi
May penetrate bronchial wall, fanning out ‘collar button lesion’
Clincial carcinoid tumros
Coughing, hemoptysis, impaired drainage, bronchiectasis, emphysema, and atelectasis can all happen secondarily to the growing lesion
Carcinoid syndrome: intermittent attacks of diarrhea, flushing, and cyanosis occurring in 10% of patients
due to tumor secretion of vasoactive amines (5HT)
5 year, 95% survival for typical
5 year, 70% survival for atypical
Typica carcinoid tumor
Fewer than 2 mitosis/10 high powered fields
Atypical carcinoid tumor
Increased pleomorphism Prominent nuclei Increased mitotic activity Increased risk of lymphatic invasion 2-10 mitoses/10 high-powered fields and/or foci of necrosis
Lung hamartoma
Radio-opacity ‘coin lesion’ on routine CXR
coin lesions on CXR == histoplasma, lung hamartoma, adenocarcinoma
Well circumscribed, solitary – low-grade, benign?
Nodules of connective tissue (cartilage, fibrous, fat) intersected by epithelial clefts
Can be cancerous if associated with chromosome problems with 6 or 12
Lymphangioleiomyomatosis
Young women of childbearing age present with dyspnea or spontaneous pneumothorax
Proliferation of perivascular epithelioid cells with markers of melanocytes and smooth muscle cells
Cystic, emphysema like expansion of terminal airspaces, thickening interstitium and obstruction of lymphatic vessels
lesional epithelioid cells appear to frequently harbor loss of function mutations in the tumor suppressor TSC2, one of the loci linked to tuberous sclerosis
tuberin == negative regulator of mTOR (mutation leads to increased mTOR activity)
mTOR plays a function in regulating metabolism
Slow progression over several decades
Definitive treatment: lung transplantation
Inflammatory myofibroblasts tumor
Children, no gender preference
Fever, cough, chest pain, hemoptysis
Grey/white, round, well defined single peripheral mass, with calcium deposits
Proliferation of fibroblasts, myofibroblasts, lymphocytes, plasma cells
Peripheral fibrosis
Some have ALK mutation
Treatment with ALK inhibitors have produced response
Most common site of metastatic neoplas: lung
multiple discrete nodules (cannonball lesions) are scattered throughout all lobes, more being at the periphery
Pleura
Ok
Pleural effusion
Normally 15 ml of serous, acellular, clear fluid lubricates the pleural surface
May occur due to
Increased hydrostatic pressure (CHF)
Increased vascular permeability (pneumonia)
Increased negative intrapleural pressure (atelectasis)
Decreased oncotic pressure (nephrotic syndrome)
Decreased lymphatic drainage (carcinomatosis
Inflammatory pleural effusion
Associated with underlying pulmonary inflammation
tuberculosis, pneumonia, infarct, abscess, systemic disease
Fluid exudate is resorbed with resolution or organization of fibrinous components
Respiratory distress may occur due to fluid accumulation compressing the lung
Suppurative pleuritis (empyema)
Reflects pleural space infection causing accumulation of pus (yellow, creamy
Cause of suppurative pleuritis (empyema)
Likely due to bacterial or mycotic seeding via spread from intrapulmonary infection
Less frequently due to lymphatic or hematogenous spread from a distant source
Rarely due to infection below the diaphragm (liver abscess), more common on the right side
Morphology suppurative pleuritis
Loculated, yellow-green, creamy pus with neutrophils and other leukocytes
chylothorax == milky white
Small, localized volume
Commonly, organizes into dense, tough fibrous adhesions that obliterate the pleural space or envelop the lungs, significantly restricting pulmonary expansion
Hemorrhagic pleuritis
Sanguineous inflammatory exudates due to bleeding disorders, neoplasm, or rickettsial disease
Look for exfoliated tumor cells
Must differentiate from hemothorax
Hydrothorax
Noninflammatory pleural effusion within the pleural cavity
Clear, straw-colored fluid
unilateral or bilateral
most common cause is cardiac failure, and thus it is often accompanied by pulmonary congestion and edema
Usually due to heart failure, but also in renal failure and liver cirrhosis
Hemothorax
Noninflammatory pleural effusion
Blood in the pleural cavity
Fatal complication of ruptured aortic aneurysm or vascular trauma
May occur post-operatively
Chylothorax
Noninflammatory pleural effusion
Accumulation of milky fluid (often of lymphatic origin)
pus is creamy and yellow
Milky white due to emulsified fats
due to thoracic duct trauma or obstruction causing secondary rupture of major lymphatic ducts, usually malignancies
Spontaneous idiopathic pneumothorax
Young patients
Rupture of small, peripheral, usually apical sub-pleural blebs
Subsides as air is resorbed
Recurrent attacks may occur and are disabling
Tension pneumothorax
Defect between airways and pleura act as a one way valve
Air enters during inspiration but is not released during expiration
Progressively increasing pleural pressure compresses the contralateral lung and mediastinal structures (possibly fatal)
trachea deviates away from the side of the tension pneumothorax
Pleural tumors
Usually metastatic tumors from the lung and breast
Leads to serous or serous-sanguineous effusion that contains neoplastic cells
careful cytologic examination of the sediment is of considerable diagnostic value
Solitary fibrous tumor
Noninvasive, solitary fibrous tumor
Attached to pleural surface via a pedicle – pedunculated?
Small or large
Morphology solitary fibrous tumours
Solitary fibrous tumor with dense fibrous tissue with occasional cysts filled with viscous fluid
Whorls of reticulin and collagen fibers with interspersed spindle cells resembling fibroblasts
CD34 +ve and Keratin -ve
malignant mesotheliomas show the opposite phenotype
Inversion of chromosome 12 (NAB2 -STAT6 rearrangement)
NAB2-STAT6 –> fusion gene virtually unique to solitary fibrous tumor
hypothesized to be a key driver of tumor development
No relation to asbestos exposure
Resection is curative
Malignant mesothelioma ==cytokeratin +ve
Uncommon tumor of mesothelioma cells int he visceral or parietal pleura
Epidemiology malignant mesothelioma
90% of cases are related to asbestos exposure
25-45 year latency
Smoking has no impact (< risk than lung carcinoma)
Asbestos bodies and plaques may be seen
Mutations malignant mesothelioma
Chromosome 9: CDKN2A/INK4A deletion (tumor suppressor)
Chromosome p16 deletion
Morphology malignant mesothelioma
Tumor is spread diffusely over the lung surface and fissures to form an encasing soft, gelatinous, gray-pink tumor sheathe Three Patterns Epithelioid (60%) Sarcomatoid (20%) Biphasic/mixed (20%)
Epithelial malignant mesothelioma
Epithelium like cells form tubules and papillary projections resembling adenocarcinomas with cuboidal, columnar, or flattened cells
+ve for cytokeratin proteins, calretinin, WT1 (Wilms Tumor), cytokeratin 5/6 and D2-40
opposite of a solitary fibrous mass
Sarcomatoid pattern malignant mesothelioma
Sarcomatoid Pattern
Malignant, spindle-shaped cells resembling a fibrosarcoma
Lower expression of markers seen in other morphologic patterns
Usually cytokeratin +ve
Biphasic/mixed pattern malignant mesothelioma
Contains both epitheliooid and sarcomatoid patterns
Clinic malignant mesothelioma
Chest pain, dyspnea, recurrent pleural effusions
20% with pulmonary asbestosis (fibrosis)
Metastasize to the hilar lymph nodes, lung, liver and other organs
50% 1 year mortality, few survive > 2 years
Can arise in other areas (peritoneum, pericardium, etc.) And if affects the GI tract, can lead to death due to intestinal obstruction or inanition
