14 lung Flashcards
How do you differentiate bronchi from bronchioles?
Bronchi have cartilage and submucosal glands within the walls
What is the acinus (lung anatomy)?
The part of the lung distal to the terminal bronchiole - composed of respiratory bronchioles that proceed into alveolar ducts and alveolar sacs
Describe the microscopic composition of the alveolar walls.
Capillary endothelium
Basement membrane and surrounding interstitial tissue
Alveolar epithelium
Alveolar macrophages
What cells compose the pulmonary interstitium?
Fine elastic fibers, small bundles of collagen, a few fibroblast-like cells, smooth muscle cells, mast cells, rare mononuclear cells
What are alveolar macrophages?
Mononuclear cells of phagocytic lineage, usually lying free within the alveolar space. Often contain phagocytosed carbon particles.
What cell types are found in alveolar epithelium?
Two principal cell types - type I pneumocytes, type II pneumocytes
What is the difference between Type I pneumocytes and Type II pneumocytes?
Type I pneumocytes are flattened, platelike cells covering 95% of the alveolar surface
Type II pneumocytes are rounded, and are the source of pulmonary surfactant. They are the main cell type involved in repair of alveolar epithelium when type I cells are damaged.
What are pores of Kohn?
Pores between the alveolar walls which permit passage of bacteria and exudates between adjacent alveoli
What are the three divisions into which lung diseases are organized?
Lung diseases that affect…
The airways
The interstitium
The pulmonary vascular system
What is atelectasis?
Also known as collapse - loss of lung volume caused by inadequate expansion of airspaces.
Either incomplete expansion or collapse of previously inflated lung producing areas of airless parenchyma
If complete collapse of one lung occurs, five sixths of blood is routed to the normal lung resulting in only mild desaturation to 90%
What processes occur following atelectasis?
Inadequate expansion of airspaces results in shunting of inadequately oxygenated blood from pulmonary arteries into veins - giving rise to a ventilation-perfusion imbalance and hypoxia.
What are the three forms of atelectasis?
Resorption atelectasis
Compression atelectasis
Contraction atelectasis
What is resorption atelectasis?
Occurs when an obstruction prevents air from reaching distal airways. The air already present becomes absorbed and alveolar collapse follows.
Asthma, chronic bronchitis, bronchiectasis, aspiration of FB
What is the most common cause of resorption atelectasis?
Obstruction of a bronchus by a mucous or mucopurulent plug - frequently occurs postoperatively but may also complicate bronchial asthma, bronchiectasis, chronic bronchitis, or aspiration of foreign bodies.
What is compression atelectasis?
Sometimes called passive or relaxation atelectasis - usually associated with accumulations of fluid, blood, or air within the pleural cavity - mechanically collapses the adjacent lung.
Cardiac failure, lung Ca, peritonitis, subdiaphragmatic abscesses
What may cause compression atelectasis?
Pleural effusions (CHF) Pneumothorax - air leaks into the pleural cavity Basal atelectasis from elevated position of the diaphragm in bedridden patients, patients with ascites, and pre/post-op
What is contraction atelectasis?
Also known as cicratization - occurs when either local or generalized fibrotic changes in the lung or pleura hamper expansion and increase elastic recoil during expiration.
Which forms of atelectasis are reversible? Irreversible?
Contraction atelectasis - irreversible
Compression atelectasis - reversible
Resorption atelectasis - reversible
How does acute lung injury manifest clinically?
Acute onset of dyspnea
Decreased arterial oxygen pressure (hypoxemia)
Development of bilateral pulmonary infiltrates on radiographs
Absence of clinical evidence of primary left-sided heart failure
What is ARDS?
Acute Respiratory Distress Syndrome
Acute capillary endothelial injury or alveolar epithelium.
Damage results in Increased capillary permeability Interstitial then intra-alveolar oedema
Fibrin exudation
Formation of hyaline membranes
Capillary injury is probably due to release of mediators. Mediators either originate from macrophages or neutrophils.
Damage mediated by: Cytokines Oxygen free radicals Complement Enzymes Eicosanoids.
Endotoxins are particularly important in initiating these cellular events. Endotoxins cause:
Release of cytokines from macrophages Leucocyte and endothelial activation Amplifies complement-mediated response of neutrophils
Exudate and diffuse tissue destruction result in scarring
What are the basic causes of ARDS?
Diffuse alveolar capillary and epithelial damage, resulting from an imbalance of pro-inflammatory and anti-inflammatory mediators.
Associated with either direct injury to the lung or indirect injury in the setting of a systemic process.
Describe the onset of ARDS
Rapid onset of life threatening respiratory insufficiency
Cyanosis
Severe arterial hypoxemia that is refractory to oxygen therapy
Progression to multisystem organ failure
What is the histological manifestation of ARDS?
Diffuse alveolar damage - DAD
What are the two barriers forming the alveolar capillary membrane?
Microvascular endothelium
Alveolar epithelium
What are the acute consequences of damage to the alveolar capillary membrane?
Increased vascular permeability
Alveolar flooding
Loss of diffusion capacity
Widespread surfactant abnormalities from type II pneumocyte damage
What transcriptional factor may play a large role in shifting the pro/anti-inflammatory balance in favor of a pro-inflammatory state?
Nuclear factor kB (NF-kB)
What are some indirect causes of lung injury which may result in ARDS?
Commonly - Sepsis, severe trauma with shock
Uncommonly - Cardiopulmonary bypass, acute pancreatitis, drug overdose, transfusion of blood products, uremia
What are some direct causes of lung injury which may result in ARDS?
Commonly - Pneumonia, Aspiration of gastric contents
Uncommonly - Pulmonary contusion, fat embolism, near-drowning, inhalation injury, reperfusion injury after lung transplantation
How do pulmonary macrophages react in ARDS?
Pulmonary macrophages - increased synthesis of IL-8 (neutrophil chemotaxis, activator)
IL-1 and TNF are also released, which lead to endothelial activation
In acute phase of ARDS, what is the gross appearance of the lungs?
Dark red, firm, airless, heavy
Diffuse bilateral infiltrates on xray
What are the microscopic findings in the lungs in acute ARDS?
Capillary congestion
Necrosis of alveolar epithelial cells
Interstitial and intra-alveolar edema and hemorrhage
Collections of neutrophils in capillaries
Hyaline membranes, especially lining the alveolar ducts
What is seen microscopically in the organizing stage of ARDS?
Marked proliferation of type II pneumocytes in an attempt to regenerate the alveolar lining
Organization of fibrin exudates with intra-alveolar fibrosis
Thickening of alveolar septa, and proliferation of interstitial cells with deposition of collagen
How soon after the original lung event does the clinical syndrome of ARDS present?
85% of patients present with ARDS within 72 hours of precipitating event
What is the current prognosis for ARDS?
About 60% mortality rate
What are some factors which predict a poor outcome with ARDS?
Advanced age
Underlying bacteremia (sepsis)
Development of multisystem failure (especially cardiac, renal, or hepatic)
If a patient survives the acute stage of ARDS, what sequela may be present?
There may be diffuse interstitial fibrosis, which may continue to compromise respiratory function.
If a patient survives ARDS without any chronic sequela, how long does it take to regain normal respiratory function?
6-12 months
What are the two categories of diffuse pulmonary diseases?
Obstructive disease (airway disease)
Restrictive disease
What characterizes obstructive disease (airway disease)?
Characterized by limitation of airflow, usually resulting from an increase in resistance caused by partial or complete obstruction at any level
What characterizes restrictive disease?
Characterized by reduced expansion of lung parenchyma accompanied by decreased total lung capacity.
What are the major diffuse obstructive disorders of the lungs?
Emphysema
Chronic bronchitis
Bronchiectasis
Asthma
What changes are seen in TLC and FVC in diffuse obstructive disorders? WHat is the hallmark?
TLC and FVC are either normal are increased
Hallmark - decreased expiratory flow rate, measured by forced expiratory volume at 1 second (FEV1)
The ratio of FEV1 to FVC is characteristically decreased
What are the physiological causes of expiratory obstruction in diffuse obstructive disorders?
May be from anatomic airway narrowing, classically observed in asthma, or loss of elastic recoil (emphysema)
What is the FVC and FVC/FEV1 ratio in diffuse restrictive lung diseases?
FVC is reduced and expiratory flow rate is normal or reduced proportionally
As ar esult, the ratio of FEV1/FVC is near normal
What kinds of conditions may cause diffuse restrictive lung diseases?
Chest wall disorders in the presence of normal lungs - severe obesity, diseases of the pleura, neuromuscular disorders (Guillan-Barre)
Acute or chronic interstitial lung diseases (ARDS)
What are some chronic restrictive lung diseases?
Pneumoconioses
Interstitial fibrosis of unknown etiology
Infiltrative conditions (sarcoidosis)
What are the main pathological changes in chronic bronchitis?
Define chronic bronchitis?
Chronic irritation by inhaled substances leads to: Bronchiolitis occurs early in the disease and causes early, mild airway obstruction
Hypersecretion of mucus in large airways due to hypertrophy of submucosal glands in the trachea and bronchi is the dominant lesion
Hypersecretion of mucus in small airways
occurs later due to increase in goblet cell number and size.
In addition to chronic irritation, inhaled substances (including cigarette smoke) results in:
Poor function of the ciliary escalator
Direct damage to the airway epithelium
Inhibition of bronchial and alveolar leucocytes.
Infection plays a secondary role.
Persistent cough with sputum production for at least 3 months in any 2 consecutive years
What causes chronic bronchitis and what are the major S/S?
What is the macroscopic and microscopic pathology in chronic bronchitis?
What is the reid index?
Caused by tobacco smoke, air pollutants
4-10 times more common in smokers independent of other factors.
Most frequent in middle aged men.
Macroscopic
Hyperaemia and swelling of the mucous membranes with excessive secretions layering the epithelial surfaces. Secretions may fill the airway lumen.
In small airways, bronchiolitis obliterans may result.
Microscopic
Minor increaser in goblet cell number, moderate increase in size.
Goblet cell metaplasia.
Clustering of alveolar macrophages
Inflammatory infiltrate (bronchiolitis)
Fibrosis of bronchiolar walls.
Bronchial epithelium may exhibit squamous metaplasia and dysplasia.
Reid index measures thickness of mucous gland layer compared with thickness of wall between epithelium and cartilage.
Simple chronic bronchitis Productive cough with no evidence of airflow obstruction.
Chronic asthmatic bronchitis Productive cough plus hyperreactive airways with intermittent bronchospasm and wheezing due to reversible obstruction of small airways.
Chronic bronchitis forms part of a spectrum of disease included under the umbrella term COPD.
Complications
Infection Congestive cardiac failure Cor pulmonale Dysplasia of respiratory epithelium
What are the main pathological changes in Bronchiectasis?
Chronic necrotising infection of the bronchi and bronchiloes leading to or associated with abnormal irreversible dilatation of these airways
Airway dilation
Scarring
Macroscopic
Most commonly affects lower lobes, particularly vertically orientated airways and distal bronchi and bronchiloes.
Airways are dilated to 4 times normal in either a cylindroid or saccular pattern.
Microscopic
Intense acute and chronic inflammatory exudate within the walls of the bronchi and bronchioles associated with desquamation of the epithelium and areas of necrotising ulceration. There may also be abscess formation and scarring.
What causes Bronchiectasis? What are the major S/S?
Chronic necrotising infection of the bronchi and bronchiloes leading to or associated with abnormal irreversible dilatation of these airways
Caused by persistent or severe infections: Bronchial obstruction Tumour Foreign body Mucous impaction
Congenital or hereditary conditions: Congenital bronchiectasis Cystic fibrosis Immunodeficiency diseases Kartageners syndrome (bronchiectasis, sinusitis, situs inversus due to ciliary defect)
Infection
Necrotising pneumonia most commonly due to TB or staphyloccal pneumonia.
Bronchial obstruction results in resorption of air distal to the blockage and subsequent atelectasis. This is accompanied by acute inflammation on the bronchial wall and presence of intraluminal secretions. These initial changes are reversible.
Irreversible change occurs if the obstruction persists or if there is added infection.
Infection results in further bronchial wall inflammation, weakening and dilatation.
S/S: Cough, purulent sputum, fever
What are the main pathological changes in Asthma?
Chronic relapsing and remitting inflammatory disorder characterised by hyper-reactive airways leading to episodic reversible broncho- constriction owing to increased responsiveness of the tracheo- bronchial tree to various stimuli.
Smooth muscle hyperplasia
Excessive mucus
Inflammation
What are the main causes of Asthma? S/S?
Chronic relapsing and remitting inflammatory disorder characterised by hyper-reactive airways leading to episodic reversible broncho- constriction owing to increased responsiveness of the tracheo- bronchial tree to various stimuli.
Common disorder increasing in frequency in western world.
Traditionally grouped into extrinsic and intrinsic. Extrinsic asthma: Mediated by type 1 hypersensitivity.
Atopic (most common form)
Occupational
Allergic broncho- pulmonary aspergillosis
Intrinsic asthma
Induced by diverse non- immune mechanisms including aspirin infection, irritants, stress, cold air, exercise.
Atopic asthma
Genetic predisposition - possibly due to defects in antigen presentation, T cell activation, or regulation of cytokine production.
What are the major pathological changes in emphysema?
Abnormal permanent enlargement of the airspaces distal to the terminal bronchiole accompanied by destruction of their walls and without fibrosis
Airspace enlargement
Wall destruction
What are the main pathological changes in small-airway disease, bronchiolitis?
Inflammatory scarring
Obliteration of bronchioles
How does one differently define emphysema and chronic bronchitis?
Emphysema is defined by its specific morphology
Chronic bronchitis is defined on the basis of clinical features such as the presence of chronic and recurring cough with excessive mucus secretion.
Where is emphysema localized anatomically compared to chronic bronchitis?
Chronic bronchitis affects both the large and small airways (if small then bronchiolitis)
Emphysema is restricted to the acinus (respiratory bronchiole, alveolar ducts and alveoli)
How many individuals in the US have COPD? How significant is it as a cause of death?
10% of people in the US have COPD
It is the 4th leading cause of death in the US
Is COPD reversible or irreversible?
Irreversible
What characterizes Emphysema?
Abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.
What are the four types of emphysema?
Centriacinar
Panacinar
Distal acinar
Irregular
What is centracinar (centrilobular) emphysema?
This pattern involves the lobules - the central or proximal parts of the acini, formed by respiratory broncioles, are affected, while distal alveoli are spared.
As a result, emphyesmatous and normal airspaces exist within the same acinus and lobule. More common and severe in the upper lobes, particularly the apices.
Which type of emphysema is most commonly seen as a consequence of smoking cigarettes (without congenital deficiency of alpha-1 antitrypsin)?
Centracinar (centrilobular) Emphysema
Which type of emphysema is most common in those with congenital deficiency of alpha-1 antitrypsin?
Panacinar (Panlobular) Emphysema
What is panacinar (panlobular) emphysema?
The acini are uniformly enlarged from the level of the respiratory bronciole to the terminal blind alveoli - tends to occur more commonly in the lower lung lobes and in individuals with alpha-1 antitrypsin congenital deficiency.
What is distal acinar (paraseptal) emphysema?
The proximal portion of the acinus is normal but the distal part is primarily involved. The emphysema is more striking adjacent to the pleura, along the lobular connective tissue septa, and at the margins of the lobules.
It tends to occur adjacent to areas of fibrosis, scarring, or atelectasis and is usually more severe in the upper half of the lungs.
What are some characteristic findings in distal acinar (paraseptal) emphysema?
Multiple, contiguous enlarged airspaces that range in diameter from 0.5 to more than 2.0 cm, sometimes forming cyst-like structures with progressive enlargement - bullae.
In which individuals is distal acinar (paraseptal) emphysema more common?
This type probably underlies many of the cases of spontaneous pneumothorax in young adults.
What is irregular emphysema?
It is “irregular” because the acinus is irregularly involved - almost always associated with scarring - resulting from healed inflammatory diseases.
Though clinically asymptomatic, may be the most common form of emphysema.
What is the most common form of emphysema, though usually it is asymptomatic?
Irregular emphysema
What critical imbalances favor the development of emphysema?
The protease-antiprotease imbalance
Oxidant-antioxidant imbalance
Describe the protease-antiprotease imbalance hypothesis with regards to emphysema.
Patients with genetic deficiency of antiprotease alpha-1 antitrypsin, a major inhibitor of proteases secreted by neutrophils, have a greater chance of developing pulmonary emphysema.
What percentage of individuals homozygous for Z allele (and thus deficiency of alpha-1 antitrypsin) develop sympatomatic emphysema?
More than 80%
Describe the pathogenesis of emphysema.
Neutrophils and macrophages accumulate in alveoli, in smokers or from other stimuli.
NF-kB is activated, resulting in production of TNF and chemokines like IL-8, which attract and activate more neutrophils.
Neutrophils release their granules which include proteases, resulting in tissue damage
Elastase activity in macrophages is enhanced by smoking as well
How does emphysema progress clinically?
Dyspnea is the first symptom - also cough and wheezing of patients also have chronic bronchitis or asthmatic bronchitis
Weight loss is common and may be severe
PFTs reveal reduced FEV1 and normal or near FVC - hence the ratio of FEV1 to FVC is reduced.
Barrel chest (increased AP diameter)
“Pink puffers”
Describe an emphysema presentation described as “blue bloaters”.
Patients have emphysema and pronounced chronic bronchitis - history of recurrent infections with purulent sputum
Less prominent dyspnea and respiratory drive, so hypoxic, cyanotic
Tend to be obese and first medical visit associated with CHF (cor pulmonale) and edema
How does secondary pulmonary hypertension develop in patients with emphysema?
It is a gradual onset
It arises from both hypoxia-induced pulmonary vascular spasm and loss of pulmonary capillary surface area from alveolar destruction
When emphysema results in death, what specific sequelae of emphysema may be primarily responsible?
Right-sided heart failure (cor pulmonale)
Pulmonary failure with Respiratory acidosis, Hypoxia, Coma
What is compensatory emphysema?
A term used to designate the compensatory dilation of alveoli in response to loss of lung substance elsewhere - occurs in residual lung parenchyma after surgical removal of a diseased lung or lobe
What is obstructive overinflation?
Results when the lung expands because air is trapped within it - a common cause is subtotal obstruction by a tumor or foreign object. May be a life-threatening emergency
What is bullous emphysema?
Any form of emphysema that produces large subpleural blebs or bullae.
Bullae are localized accentuations of one of the four forms of emphysema, are often subpleural, and may rupture leading to pneumothorax.
What is mediastinal (interstitial) emphysema?
Designates the entrance of air into the connective tissue stroma of the lung, mediastinum, and subcutaneous tissue. May occur spontaneously with sudden increase in intra-alveolar pressure (as with vomiting or violent coughing) that causes a tear with dissection of air into the interstitium.
How may a patient present with mediastinal (interstitial) emphysema?
Marked swelling of the head and neck and crackling crepitation all over the chest.
How is chronic bronchitis defined?
A persistent productive cough for at least 3 consecutive months in at least 2 consecutive years.
What are the three general forms of bronchitis?
Simple chronic bronchitis
Chronic asthmatic bronchitis
Chronic obstructive bronchitis
What is simple chronic bronchitis?
The productive cough raises mucoid sputum but airflow is not obstructed
What is chronic asthmatic bronchitis?
Hyper-responsive airways with intermittent bronchospasm and wheezing
What is chronic obstructive bronchitis?
A subpopulation who develops chronic outflow obstruction, usually with evidence of associated emphysema
What is the distinctive characteristic of chronic bronchitis?
Hypersecretion of mucus
What is the clinical course of chronic bronchitis?
A prominent cough with indefinite production of sputum
COPD with outflow obstruction
Hypercapnia, hypoxia, cyanosis
Eventually may be complicated by pulmonary hypertension and cardiac failure, along with recurrent infections and respiratory failure
What is Asthma?
A chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and/or early in the morning.
What triad is associated with asthma?
- Intermittent and reversible airway obstruction
- Chronic bronchial inflammation with eosinophils
- Bronchial smooth muscle cell hypertrophy and hyperreactivity
What is the difference between extrinsic/atopic asthma and instrinsic/non-atopic asthma?
Extrinsic/atopic asthma - 70% of cases - due to IgE and TH2 mediated immune responses to environmental antigens
Intrinsic/non-atopic asthma - 30% of patients - triggered by non-immune stimuli such as aspirin; pulmonary infections, especially those caused by viruses; cold; psychological stress; exercise; and inhaled irritants.
What are the major etiological factors for asthma?
Genetic predisposition to type I hypersensitivity
Acute and chronic airway inflammation
Bronchial hyper-responsiveness to a variety of stimuli
Which interleukein released by TH2 is responsible for stimulating IgE production? For activating eosinophils? For stimulating mucus production?
IL-4 - stimulates IgE production
IL-5 - activates eosinophils
IL-13 - stimulates mucus production
What kind of airway remodeling changes occur in asthma?
Hypertrophy of bronchial smooth muscle
Deposition of subepithelial collagen
What inflammatory mediators have been implicated in the acute-phase response in asthma?
Leukotrienes C4, D4, E - cause prolonged bronchoconstriction, increase vascular permeability, increase mucin secretion
Acetylcholine - released from intrapulmonary motor nerves, causing airway smooth muscle constriction by direct stimulation of muscarinic receptors
Histamine - bronchospasm, increased vascular permeability
Prostaglandin D2 - bronchoconstriction and dilatation
Platelet-activating factor - aggregation of platelets and release of histamine from their granules
What is the late-phase reaction in asthma?
It may start 4-8 hours after the initial reaction and persist for 12-24 hours or more.
Eosinophils are key in the late phase
How do eosinophils play a role in asthma?
They contain major basic protein and eosinophil cationic protein, which is directly toxic to airway epithelial cells.
Eosinophil peroxidase causes tissue damage through oxidative stress
Overall - they amplify and sustain the inflammatory response without additional exposure to the triggering antigen.
What is drug-induced asthma?
Some pharmacological agents induce asthma - aspirin is the most common.
They present with recurrent rhinitis and nasal polyps, urticaria, and bronchospasm.
What is occupational asthma?
This form is stimulated by fumes, organic and chemical dusts, gases, and other chemicals in a person’s work environment.
What are Curschmann spirals?
Whorls of shed epithelium found within mucus plugs
What are Charcot-Leyden crystals?
Collections of crystalloids made up of eosinophil proteins
What is bronchiectasis?
Permanent dilation of bronchi and bronchioles caused by destruction of the muscle and elastic supporting tissue, resulting from or associated with chronic necrotizing infections.
Is bronchiectasis a primary or secondary disease?
Secondary to persisting infection or obstruction caused by a variety of conditions
What are the characteristic symptoms of bronchiectasis?
Cough and expectoration of copious amounts of purulent sputum
What conditions most commonly predispose a person to bronchiectasis?
Bronchial obstruction
Congenital or hereditary conditions (cystic fibrosis, immunodeficiency, Kartagener syndrome)
Necrotizing/suppurative pneumonia
Describe the morphology of bronchiectasis?
Airways are dilated, maybe 4x their normal diameter
Inflammatory exudate within the walls of the bronchi and bronchioles
Desquamation of lining epithelium causes areas of ulceration
Mixed flora may be cultured
May be fibrosis due to extent of damage
What may develop in chronic cases of bronchiectasis?
Peribronchiolar fibrosis
Lung abscess from necrosis of the bronchial or bronchiolar walls
What is the clinical course of bronchiectasis?
Severe, persistent cough with expectoration of mucopurulent, sometimes fetid, sputum
Flecks of blood or frank hemoptysis may occur
Symptoms are episodic, precipitated by URTIs or new pathogens
Clubbing of the fingers may develop
Significant obstructive ventilatory defects develop - hypoxemia, hypercapnia, pulmonary HTN, rarely cor pulmonale
Metastatic brain abscesses and reactive amyloidosis are uncommon complications
What characterizes diffuse interstitial (restrictive, infiltrative) lung diseases?
Characterized by diffuse and usually chronic involvement of the pulmonary connective tissue, principally the most peripheral and delicate interstitium in the alveolar walls.
What is the hallmark of diffuse interstitial (restrictive, infiltrative) lung diseases?
Reduced compliance
Describe the pathogenesis of restrictive, infiltrative lung diseases?
Earliest manifestation is alveolitis - accumulation of inflammatory and immune effector cells within the alveolar walls and spaces
Persistence results in cellular interactions involving lymphocytes, macrophages, and neutrophils which lead to parenchymal injury, proliferation of fibroblasts, and progressive interstitial fibrosis.
Activation of pulmonary macrophages is a key event in the pathogenesis of interstitial fibrosis
What factors are secreted by alveolar macrophages in interstitial lung disease that contribute to pathogenesis?
They secrete a host of “fibrogenic” factors - including fibroblast growth factor, transforming growth factor beta, and platelet-derived growth factor, which can attract fibroblasts as well as stimulate their proliferation.
Type I pneumocytes are destroyed and type II pneumocytes proliferate.
Describe idiopathic pulmonary fibrosis (IPF)
Also known as cryptogenic fibrosing alveolitis - refers to a pulmonary disorder of unknown etiology characterized by diffuse interstitial fibrosis - most severe cases result in severe hypoxemia and cyanosis.
What patient demographic is most often affected by idiopathic pulmonary fibrosis?
Males more often than females
2/3 are over 60 years old at presentation
What is the histological pattern for IPF?
UIP - usual interstitial pneumonia
This is required for diagnosis of IPF
Hallmark - patchy, interstitial fibrosis which varies in intensity
Earliest lesions contain exuberant fibroblastic proliferation, and appear as fibroblastic foci.
Temporal heterogeneity - early and late lesions
Honeycomb fibrosis - alveolar collapse and formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epithelium
Patchy interstitial inflammation - mostly alveolar septal infiltrate and lymphocytes with occasional plasma cells, mast cells, eosinophils
Some secondary pulmonary hypertensive changes
What are gross features of lungs with IPF?
Cobblestone appearance of the pleural surfaces, because of retraction of scars along the interlobular septa
Cut surface - shows fibrosis (firm, rubbery white areas) with lower lobe predominance and a distinctive distribution in the subpleural regions along the interlobular septa.
Honeycomb fibrosis - alveolar collapse and formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epithelium
How does IPF progress clinically?
Presents insidiously
Gradual onset of a nonproductive cough and progressive dyspnea
“dry” or “Velcro”-like crackles during inspiration
Cyanosis, cor pulmonale, peripheral edema may develop in the later stages
Mean survival is 3 years or less after diagnosis
What is the gold standard for diagnosing IPF?
Surgical lung biopsy - used to diagnose IPF and exclude other causes of pulmonary fibrosis
What is nonspecific interstitial pneumonia?
A diffuse interstitial lung disease of unknown etiology - biopsies fail to show diagnostic features of other well-characterized interstitial diseases
“Wastebasket” type of diagnosis - must differentiate between this and UIP
What are the histological signs of non-specific interstitial pneumonia?
Two patterns - cellular and fibrosing
Cellular pattern - composed of mild-moderate chronic interstitial inflammation (lymphocytes, few plasma cells) in a uniform or patchy distribution
Fibrosing pattern - diffuse or patchy interstitial fibrosis, without the temporal heterogeneity of UIP. Fibroblastic foci are absent.
How does a patient present with non-specific interstitial pneumonia?
Patient presents with dyspnea and cough of several months’ duration
Patients with the cellular pattern have a better outcome than those with fibrosing pattern or UIP
What is cryptogenic organizing pneumonia?
Synonymous with “bronchiolitis obliterans organizing pneumonia”
Patient presents with cough and dyspnea, radiographs show subpleural or peribronchial patchy areas of airspace consolidation.
What are the histological signs of cryptogenic organizing pneumonia?
Characterized by the presence of polypoid plugs of loose organizing connective tissue within alveolar ducts, alveoli and often bronchioles. Connective tissue is all the same age and the underlying lung architecture is normal.
What is the clinical course of cryptogenic organizing pneumonia? Treatments?
Some individuals recover spontaneously but most require treatment with oral steroids for 6 months or longer
What is pneumoconiosis?
A term originally coined to describe the non-neoplastic lung reaction to inhalation of mineral dusts - broadened now to include diseases induced by organic as well as inorganic particulates and some also regard chemical fume and vapor-induced non-neoplastic lung diseases as pneumoconioses.
What are the three most common mineral dust pneumoconioses?
Simple and complicated coal workers’ pneumoconiosis - Coal dust
Silicosis - silica
Asbestosis - asbestos
What is more dangerous in a mineral dust pneumoconiosis - large particles or small particles?
Particles between 1 and 5 micrometers are most dangerous because they get lodged at the bifurcation of the distal airways
Any larger and they can be dislodged or removed
Any smaller and they pass in and out of the alveoli, often without substantial deposition and injury
How do inhaled particles produce pneumoconioses?
The pulmonary alveolar macrophage is a key cellular element in the initiation and perpetuation of lung injury and fibrosis - the more reactive particles trigger the macrophages to release a number of products that mediate an inflammatory response and initiate fibroblast proliferation and collagen deposition.
Some particles may reach lymphatics by drainage or marcophages, and initiate immune response leading to amplification and extension of local reaction
Tobacco makes it all worse
What is simple coal workers’ pneumoconiosis?
Accumulations of macrophages in reaction to coal dust in the lungs occur with little to no pulmonary dysfunction
< 10% of cases may progress to PMF/complicated CWP
What is complicated coal workers’ pneumoconiosis?
Also known as progressive massive fibrosis
Fibrosis is extensive and lung function is compromised
What is the clinical course of CWP?
Usually a benign disease that produces little decrement in lung function
What is the clinical course of CWP progressed to PMF?
Increasing pulmonary dysfunction
Pulmonary hypertension
Cor pulmonale
Tendency to progress even in the absence of further exposure
Describe silicosis.
Currently the most prevalent chronic occupational disease in the world - caused by inhalation of crystalline silica - mostly in occupational settings.
After inhalation, the particles are ingested by macrophages, and cause activation and release of mediators by pulmonary macrophages, including IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals, and fibrogenic cytokines.
What is the morphology of silicosis?
There are silicotic nodules - characterized grossly in their early stages by tiny, barely palpable, discrete, pale-to-blackened (if there’s coal) nodules in the upper zones of the lungs.
Microscopically - nodules demonstrate concentrically arranged hyalinized collagen fibers surrounding an amorphous center.
Distinctive “whorled” appearance of the collagen fibers
Polarized microscopy reveals weakly birefringent silica particles, mostly at the center of the nodules.
What is the clinical course of silicosis?
Usually detected in the routine CXRs of asymptomatic workers
CXR: show fine nodularity in the upper zones of the lung but PFTs normal or moderately affected
May progress to PMF if not detected early enough
What upper respiratory problems are linked to asbestos exposure?
Parenchymal interstitial fibrosis (asbestosis)
Localized fibrous plaques or, rarely, diffuse fibrosis in the pleura
Pleural effusions
Bronchogenic carcinoma
Malignant pleural and peritoneal mesotheliomas
Laryngeal carcinoma
Describe the different forms of asbestos and which is more hazardous.
Two distinct forms of asbestos - serpentine (curly flexible fiber) and amphibole (straight, stiff, brittle fiber)
Amphiboles are more pathogenic than the serpentine chrysotile. The serpentine ones are more likely to become impacted in the upper respiratory passages and removed by the mucociliary elevator, or if they get stuck they are leached from tissues because they are more soluble than amphiboles.
Amphiboles align themselves in the airstream and are delivered deeper into the lungs, where they may penetrate epithelial cells and reach the interstitium.
Describe the morphology seen in asbestosis.
Diffuse pulmonary interstitial fibrosis
Asbestos bodies - golden brown, fusiform or beaded rods with a translucent center - consist of asbestos fibers coated with an iron-containing proteinaceous material - arise when macrophages attempt to phagocytose asbestos fibers. Iron derived from phagocyte ferritin.
Starts in the lower lobes and subpleurally but middle an upper lobes become affected later
Enlarged airspaces from fibrous tissue contracting, forming honeycombed lungs
Pleural plaques - most common manifestation of asbestos exposure and are well-circumscribed plaques of dense collagen, often containing calcium. Most often on the anterior and posterolateral aspects of the parietal pleura and over the domes of the diaphragm.
What is the clinical course of asbestosis?
Clinically indistinguishable from other diffuse interstitial lung diseases.
Progressively worsening dyspnea 10-20 years after exposure. Accompanied with productive cough
Disease may remain static or progress to CHF, cor pulmonale, death
Pleural plaques usually asymptomatic and are detected on radiographs as circumscribed densities
Bronchogenic carcinomas and malignant mesotheliomas develop in workers exposed to asbestos
What cancers are far more common in asbestosis than the general population?
Bronchogenic carcinoma 5-fold increase
Mesothelioma 1000-fold increase
What is sarcoidosis?
A multisystem disease of unknown etiology characterized by noncaseating granulomas in many tissues and organs.
How is sarcoidosis diagnosed?
It is a diagnosis of exclusion, so other diseases including mycobacterial or fungal infections and berylliosis must be ruled out first.
What is a major presenting characteristic in addition to multisystemic granulomas?
Bilateral hilar lymphadenopathy or lung involvement (or both) - visible on CXR
What demographic tends to get sarcoidosis?
Adults younger than 40 years old
High incidence in Danish and Swedish populations and US African Americans (10x greater than US Caucasians)
Supposedly more common in nonsmokers than smokers
What may be encountered in a patient with sarcoidosis?
Hilar and paratracheal lymph nodes enlarged
Skin lesions - erythema nodosum
Lupus pernio
Involvement of the eye and lacrimal glands
Noncaseating epithelioid granulomas - diffuse over the body - discrete, compact collection of epithelioid cells rimmed by an outer zone of largely CD4+ T cells, with macrophages and eosinophilic cytoplasm and vesicular nuclei, may see multinucleated giant cells
Lung involvement
Bone marrow involvement
Spleen and liver may contain granulomas
What is the clinical course for sarcoidosis?
Usually asymptomatic and discovered as bilateral hilar adenopathy or an accidental finding at autopsy.
Some symptoms: peripheral lymphadenopathy, cutaneous lesions, eye involvement, splenomegaly, hepatomegaly
Gradual appearance of respiratory symptoms, constitutional S/S
Presence of noncaseating granulomas in a lung or lymph node biopsy suggests sarcoidosis - other identifiable causes must be excluded first
What percentage of people with sarcoidosis go into remission with minimal or no residual manifestations?
How many develop permanent lung or visual problems?
Other problems?
65-70% recover with minimal or no residual manifestations
20% develop permanent lung dysfunction or visual impairment
10-15% succumb to progressive pulmonary fibrosis and cor pulmonale
What is hypersensitivity pneumonitis?
An immunologically mediated inflammatory lung disease that primarily affects the alveoli and is therefore often called allergic alveolitis
How does hypersensitivity pneumonitis present?
Predominantly restrictive lung disease
Decreased diffusion capacity, lung compliance, total lung volume
Occupational exposures are diverse, syndromes share common clinical pathologic findings and probably have very similar pathophysiology
What is the morphology of hypersensitivity pneumonitis?
Patchy mononuclear cell infiltrates in the pulmonary interstitium
Peribronchiolar accentuation
Lymphocytes, some plasma cells and epithelioid cells are present
Variable numbers of neutrophils
Interstitial noncaseating granulomas are present in 2/3+ of cases - usually in peribronchiolar location
In advanced cases, diffuse interstitial fibrosis occurs
What is the clinical course of hypersensitivity pneumonitis?
It may present as an acute reaction with fever, cough, dyspnea, constitutional complaints 4-8 hours after exposure
Chronic disease - insidious onset of cough, dyspnea, malaise, weight loss - diagnosis of acute form usually obvious from temporal relationship of symptoms to exposure to the incriminating antigen
If antigenic exposure is terminated after acute attacks there is complete resolution within days
Failure to remove eventually results in a chronic interstitial pulmonary disease without the acute exacerbations seen on antigen re-exposure
What is pulmonary eosinophilia?
A group of clinical and pathologic pulmonary entities characterized by an infiltration and activation of eosinophils, the latter by elevated levels of alveolar IL-5.
What are the categories of pulmonary eosinophilia?
Acute eosinophilic pneumonia with respiratory failure
Simple pulmonary eosinophilia (Loffler syndrome)
Tropical eosinophilia
Secondary eosinophilia
Idiopathic chronic eosinophilia
What is acute eosinophilic pneumonia with respiratory failure?
It is a pulmonary eosinophilia
Characterized by rapid onset of fever, dyspnea, hypoxia, diffuse pulmonary infiltrates on CXR
Bronchioalveolar lavage fluid typically contains 25%+ eosinophils - prompt response to corticosteroids
What is simple pulmonary eosinophilia (Loffler syndrome)?
It is a pulmonary eosinophilia
Characterized by transient pulmonary lesions, eosinophilia in the blood, and a benign clinical course.
The alveolar septa are thickened by an infiltrate containing eosinophils and occasional giant cells
What is secondary eosinophilia?
A pulmonary eosinophilia
Seen in association with asthma, drug allergies, certain forms of vasculitis, etc.
What is idiopathic chronic eosinophilic pneumonia?
A pulmonary eosinophilia
Characterized by aggregates of lymphocytes and eosinophils within the septal walls and the alveolar spaces - typically in the periphery of the lung fields, and accompanied by high fever, night sweats and dyspnea
This is a disease of exclusion, once other causes of pulmonary eosinophilia are ruled out.
What are some smoking-related interstitial diseases?
Desquamative interstitial pneumonia (DIP)
Emphysema
Respiratory bronchiolitis
Chronic bronchitis
Accumulation of large numbers of macrophages with abundant cytoplasm containing dusty brown pigment - smoker’s macrophages - in the airspace.
Describe the general morphology of pulmonary infarcts.
Wedge shaped, with base at the pleural surface and apex pointing toward the hilus of the lung
Raised, red-blue areas in the early stages.
Adjacent surface usually covered by a fibrinous exudate.
Occluded vessel usually near the apex of the infarcted areas - red cells lyse within 48 hours and infarct pales, eventually becoming red-brown as hemosiderin is produced.
Fibrous replacement begins at the margins as a gray-white peripheral zone and eventually converts the infarct into a scar that is contracted below the level of the lung substance.
What is the hallmark of a fresh pulmonary infarct?
Coagulative necrosis of the lung parenchyma in the area of hemorrhage
In young healthy populations, small infarcts result in haemorrhages as the lung parenchyma is sustained by the bronchial vessels.
In older populations or those with inadequate circulation, infarct may result.
3/4 of infarcts affect the lower lobes and vary in size from barely visible to lobar
What are the odds a patient with one pulmonary embolism will develop a second one?
30% chance
1% incidence
10% of hospital deaths
What are some prophylactic therapies for patients with risk of pulmonary embolism?
Early ambulation for postoperative and postpartum patients
Elastic stockings
Intermittent pneumatic compression and isometric leg exercises for bedridden patients
Anti-coagulation
What are some nonthrombotic forms of pulmonary embolism?
Foreign body embolism - associated with IV drug abuse (talc causing granulomatous response, etc.)
Bone marrow embolism - presence of hematopoietic and fat elements within pulmonary circulation - after massive trauma and in patients with bone infarction secondary to sickle cell anemia
Amniotic fluid embolism
Air embolism
