14 lung Flashcards
1
Q
How do you differentiate bronchi from bronchioles?
A
Bronchi have cartilage and submucosal glands within the walls
2
Q
What is the acinus (lung anatomy)?
A
The part of the lung distal to the terminal bronchiole - composed of respiratory bronchioles that proceed into alveolar ducts and alveolar sacs
3
Q
Describe the microscopic composition of the alveolar walls.
A
Capillary endothelium
Basement membrane and surrounding interstitial tissue
Alveolar epithelium
Alveolar macrophages
4
Q
What cells compose the pulmonary interstitium?
A
Fine elastic fibers, small bundles of collagen, a few fibroblast-like cells, smooth muscle cells, mast cells, rare mononuclear cells
5
Q
What are alveolar macrophages?
A
Mononuclear cells of phagocytic lineage, usually lying free within the alveolar space. Often contain phagocytosed carbon particles.
6
Q
What cell types are found in alveolar epithelium?
A
Two principal cell types - type I pneumocytes, type II pneumocytes
7
Q
What is the difference between Type I pneumocytes and Type II pneumocytes?
A
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.
8
Q
What are pores of Kohn?
A
Pores between the alveolar walls which permit passage of bacteria and exudates between adjacent alveoli
9
Q
What are the three divisions into which lung diseases are organized?
A
Lung diseases that affect…
The airways
The interstitium
The pulmonary vascular system
10
Q
What is atelectasis?
A
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%
11
Q
What processes occur following atelectasis?
A
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.
12
Q
What are the three forms of atelectasis?
A
Resorption atelectasis
Compression atelectasis
Contraction atelectasis
13
Q
What is resorption atelectasis?
A
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
14
Q
What is the most common cause of resorption atelectasis?
A
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.
15
Q
What is compression atelectasis?
A
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
16
Q
What may cause compression atelectasis?
A
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
17
Q
What is contraction atelectasis?
A
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.
18
Q
Which forms of atelectasis are reversible? Irreversible?
A
Contraction atelectasis - irreversible
Compression atelectasis - reversible
Resorption atelectasis - reversible
19
Q
How does acute lung injury manifest clinically?
A
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
20
Q
What is ARDS?
A
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
21
Q
What are the basic causes of ARDS?
A
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.
22
Q
Describe the onset of ARDS
A
Rapid onset of life threatening respiratory insufficiency
Cyanosis
Severe arterial hypoxemia that is refractory to oxygen therapy
Progression to multisystem organ failure
23
Q
What is the histological manifestation of ARDS?
A
Diffuse alveolar damage - DAD
24
Q
What are the two barriers forming the alveolar capillary membrane?
A
Microvascular endothelium
Alveolar epithelium
25
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
26
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)
27
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
28
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
29
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
30
In acute phase of ARDS, what is the gross appearance of the lungs?
Dark red, firm, airless, heavy
Diffuse bilateral infiltrates on xray
31
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
32
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
33
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
34
What is the current prognosis for ARDS?
About 60% mortality rate
35
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)
36
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.
37
If a patient survives ARDS without any chronic sequela, how long does it take to regain normal respiratory function?
6-12 months
38
What are the two categories of diffuse pulmonary diseases?
Obstructive disease (airway disease)
Restrictive disease
39
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
40
What characterizes restrictive disease?
Characterized by reduced expansion of lung parenchyma accompanied by decreased total lung capacity.
41
What are the major diffuse obstructive disorders of the lungs?
Emphysema
Chronic bronchitis
Bronchiectasis
Asthma
42
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
43
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)
44
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
45
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)
46
What are some chronic restrictive lung diseases?
Pneumoconioses
Interstitial fibrosis of unknown etiology
Infiltrative conditions (sarcoidosis)
47
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
48
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
49
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.
50
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
```
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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
51
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
52
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.
53
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
54
What are the main pathological changes in small-airway disease, bronchiolitis?
Inflammatory scarring
| Obliteration of bronchioles
55
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.
56
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)
57
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
58
Is COPD reversible or irreversible?
Irreversible
59
What characterizes Emphysema?
Abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.
60
What are the four types of emphysema?
Centriacinar
Panacinar
Distal acinar
Irregular
61
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.
62
Which type of emphysema is most commonly seen as a consequence of smoking cigarettes (without congenital deficiency of alpha-1 antitrypsin)?
Centracinar (centrilobular) Emphysema
63
Which type of emphysema is most common in those with congenital deficiency of alpha-1 antitrypsin?
Panacinar (Panlobular) Emphysema
64
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.
65
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.
66
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.
67
In which individuals is distal acinar (paraseptal) emphysema more common?
This type probably underlies many of the cases of spontaneous pneumothorax in young adults.
68
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.
69
What is the most common form of emphysema, though usually it is asymptomatic?
Irregular emphysema
70
What critical imbalances favor the development of emphysema?
The protease-antiprotease imbalance
| Oxidant-antioxidant imbalance
71
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.
72
What percentage of individuals homozygous for Z allele (and thus deficiency of alpha-1 antitrypsin) develop sympatomatic emphysema?
More than 80%
73
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
74
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"
75
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
76
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
77
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
78
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
79
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
80
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.
81
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.
82
How may a patient present with mediastinal (interstitial) emphysema?
Marked swelling of the head and neck and crackling crepitation all over the chest.
83
How is chronic bronchitis defined?
A persistent productive cough for at least 3 consecutive months in at least 2 consecutive years.
84
What are the three general forms of bronchitis?
Simple chronic bronchitis
Chronic asthmatic bronchitis
Chronic obstructive bronchitis
85
What is simple chronic bronchitis?
The productive cough raises mucoid sputum but airflow is not obstructed
86
What is chronic asthmatic bronchitis?
Hyper-responsive airways with intermittent bronchospasm and wheezing
87
What is chronic obstructive bronchitis?
A subpopulation who develops chronic outflow obstruction, usually with evidence of associated emphysema
88
What is the distinctive characteristic of chronic bronchitis?
Hypersecretion of mucus
89
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
90
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.
91
What triad is associated with asthma?
1. Intermittent and reversible airway obstruction
2. Chronic bronchial inflammation with eosinophils
3. Bronchial smooth muscle cell hypertrophy and hyperreactivity
92
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.
93
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
94
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
95
What kind of airway remodeling changes occur in asthma?
Hypertrophy of bronchial smooth muscle
| Deposition of subepithelial collagen
96
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
97
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
98
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.
99
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.
100
What is occupational asthma?
This form is stimulated by fumes, organic and chemical dusts, gases, and other chemicals in a person's work environment.
101
What are Curschmann spirals?
Whorls of shed epithelium found within mucus plugs
102
What are Charcot-Leyden crystals?
Collections of crystalloids made up of eosinophil proteins
103
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.
104
Is bronchiectasis a primary or secondary disease?
Secondary to persisting infection or obstruction caused by a variety of conditions
105
What are the characteristic symptoms of bronchiectasis?
Cough and expectoration of copious amounts of purulent sputum
106
What conditions most commonly predispose a person to bronchiectasis?
Bronchial obstruction
Congenital or hereditary conditions (cystic fibrosis, immunodeficiency, Kartagener syndrome)
Necrotizing/suppurative pneumonia
107
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
108
What may develop in chronic cases of bronchiectasis?
Peribronchiolar fibrosis
| Lung abscess from necrosis of the bronchial or bronchiolar walls
109
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
110
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.
111
What is the hallmark of diffuse interstitial (restrictive, infiltrative) lung diseases?
Reduced compliance
112
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
113
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.
114
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.
115
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
116
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
117
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
118
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
119
What is the gold standard for diagnosing IPF?
Surgical lung biopsy - used to diagnose IPF and exclude other causes of pulmonary fibrosis
120
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
121
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.
122
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
123
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.
124
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.
125
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
126
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.
127
What are the three most common mineral dust pneumoconioses?
Simple and complicated coal workers' pneumoconiosis - Coal dust
Silicosis - silica
Asbestosis - asbestos
128
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
129
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
130
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
131
What is complicated coal workers' pneumoconiosis?
Also known as progressive massive fibrosis
Fibrosis is extensive and lung function is compromised
132
What is the clinical course of CWP?
Usually a benign disease that produces little decrement in lung function
133
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
134
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.
135
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.
136
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
137
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
138
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.
139
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.
140
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
141
What cancers are far more common in asbestosis than the general population?
Bronchogenic carcinoma 5-fold increase
| Mesothelioma 1000-fold increase
142
What is sarcoidosis?
A multisystem disease of unknown etiology characterized by noncaseating granulomas in many tissues and organs.
143
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.
144
What is a major presenting characteristic in addition to multisystemic granulomas?
Bilateral hilar lymphadenopathy or lung involvement (or both) - visible on CXR
145
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
146
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
147
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
148
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
149
What is hypersensitivity pneumonitis?
An immunologically mediated inflammatory lung disease that primarily affects the alveoli and is therefore often called allergic alveolitis
150
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
151
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
152
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
153
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.
154
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
155
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
156
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
157
What is secondary eosinophilia?
A pulmonary eosinophilia
Seen in association with asthma, drug allergies, certain forms of vasculitis, etc.
158
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.
159
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.
160
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.
161
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
162
What are the odds a patient with one pulmonary embolism will develop a second one?
30% chance
1% incidence
10% of hospital deaths
163
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
164
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
165
What is the proportional strength of pulmonary blood pressure to systemic blood pressure?
Pulmonary blood pressure is 1/8 that of systemic blood pressure
166
What is the technical definition of pulmonary hypertension?
When pulmonary pressures reach 1/4 or more of systemic pressure levels.
167
What are some causes for pulmonary hypertension?
Chronic obstructive or interstitial lung disease
Recurrent pulmonary emboli
Antecedent heart disease (mitral stenosis, congenital left-to-right shunts)
168
How does chronic obstructive or interstitial lung disease cause pulmonary hypertension?
There is destruction of lung parenchyma and consequent reduction in alveolar capillaries - causing increased pulmonary arterial resistance and secondarily, elevated arterial pressure.
169
How do recurrent pulmonary emboli lead to pulmonary hypertension?
Reduction in the functional cross-sectional area of the pulmonary vascular bed, in turn, leads to increased vascular resistance
170
How does antecedent heart disease like mitral stenosis and congenital left-to-right shunting lead to increased pulmonary hypertension?
These increase left atrial pressure, leading to higher pulmonary venous pressures and ultimately pulmonary arterial hypertension.
171
What is primary, or idiopathic, pulmonary hypertension?
Pulmonary hypertension that occurs even without any known causes of increased pulmonary pressure are excluded. Most are sporadic and only 6% have the familial form with an autosomal dominant form of inheritance.
172
What is the probable underlying basis for most forms of pulmonary hypertension?
Pulmonary endothelial cell and/or vascular smooth muscle dysfunction
173
Describe the pathogenesis of secondary pulmonary hypertension.
An underlying disorder results in endothelial cell dysfunction, which reduces production of vasodilatory agents like NO and prostacyclin, while increasing synthesis of vasoconstrictive mediators like endothelin. Also production of growth factors and cytokines that induce the migration and replication of vascular smooth muscle and elaboration of the ECM.
174
Describe the pathogenesis of primary pulmonary hypertension
Particularly in the familial form, TGF-b signaling pathway has emerged as a key mediator of endothelial and smooth muscle dysfunction. Specifically bone morphogenetic protein receptor type 2 (BMPR2) - which binds to TGF-b pathway ligands.
Mutations of BMPR2 have been found in 50% of familial cases
Loss of function of BMPR2 leads to abnormal vascular endothelial and pulmonary smooth muscle proliferation.
175
What is the BMPR2 gene and how does it relate to pulmonary hypertension?
Mutations that cause loss of function of bone morphogenetic protein receptor type 2 are found in 50% of familial cases of primary pulmonary hypertension
Results in abnormal (usually monoclonal) vascular endothelial and smooth muscle proliferation.
The gene may have limited penetrance, as not all people with the defect develop pulmonary hypertension.
176
What vascular alterations are seen in pulmonary hypertension?
Atheromas in main elastic arteries
Proliferation of myointimal cells and SM cells causing thickening of the intima and media with narrowing of the lumen in medium-sized muscular arteries
Thickening, medial hypertrophy, and reduplication of the internal and external elastic membranes of smaller arteries and arterioles.
177
Describe the clinical course of secondary pulmonary hypertension.
Develops at any age, usually reflects the underlying disease (pulmonary or cardiac) with accentuation of respiratory insufficiency and right-sided heart strain.
178
Describe the clinical course of primary pulmonary hypertension.
Almost always encountered in young persons, more often women, and marked by fatigue, syncope (particularly with exercise), dyspnea on exertion, and sometimes chest pain.
They eventually develop severe respiratory insufficiency and cyanosis, and death from right-sided heart failure (decompensated cor pulmonale) within 2-5 years of diagnosis.
179
What treatment is available for primary pulmonary hypertension?
Respiratory distress can be eased by vasodilators and antithrombotic agents
Lung transplant the only hope for a better prognosis
180
What is the triad associated with diffuse alveolar hemorrhage syndromes?
Hemoptysis
Anemia
Diffuse pulmonary infiltrates
181
What is Goodpasture syndrome?
Prototype disorder of diffuse alveolar hemorrhage syndromes. Uncommon.
Characterized by proliferative, usually rapidly progressing glomerulonephritis and hemorrhagic interstitial pneumonitis.
The lesions are caused by antibodies targeting non-collagenous domain of the alpha-3 chain of collagen IV. Detected in more than 90% of patients with Goodpasture syndrome.
182
Describe the morphology of a classic case of diffuse alveolar hemorrhage.
Lungs are heavy, with areas of red-brown consolidation.
Microscopic - focal necrosis of alveolar walls associated with intra-alveolar hemorrhages, fibrous thickening of the septa, and hypertrophy of septal lining cells.
Hemosiderin is seen a few days after an acute presentation.
Linear pattern of immunoglobulin deposition is the sine qua non of diagnosis in renal biopsy specimens - also seen along the alveolar septa.
183
What are some treatments for Goodpasture syndrome?
Plasmapheresis and immunosuppressive therapy have improved the prognosis
Plasma exchange removes offending antibodies, while immunosuppression inhibits antibody production.
With severe renal disease, renal transplantation is eventually required.
184
What is Pulmonary Angiitis and Granulomatosis also known as Wegener Granulomatosis?
Wegener granulomatosis is the prototype of the group of vasculitidis known as pulmonary angiitis and granulomatosis
80% develop upper respiratory or pulmonary manifestations - lesions are characterized by a combination of necrotizing vasculitis (angiitis) and parenchymal necrotizing granulomatous inflammation.
Pulmonary vessels show necrotizing granulomas, often acute and chronic inflammation are intermingled with fibrinoid necrosis.
185
How does Wegener Granulomatosis manifest?
Upper respiratory symptoms (chronic sinusitis, epistaxis, nasal perforation), pulmonary symptoms (cough, hemoptysis, chest pain).
186
What are some radiological characteristics of Wegeners Granulomatosis?
Multiple nodular densities - represent confluence of the necrotizing granulomas, some undergo cavitation
187
Why are pulmonary infections so prevalent?
1. Epithelial surfaces of the lung are constantly exposed to liters of variously contaminated air
2. Nasopharyngeal flora re regularly aspirated during sleep, even by healthy persons
3. Other common lung diseases render the lung parenchyma vulnerable to virulent organisms
188
What is pneumonia?
Can be broadly defined as any infection in the lung
May present as acute, fulminant clinical disease or as chronic disease with a more protracted course.
189
What is bronchopneumonia vs lobar pneumonia?
Bronchopneumonia implies a patchy distribution of inflammation that generally involves more than one lobe.
Lobar pneumonia - the contiguous airspaces of part or all of a lobe are homogenously filled with an exudate that can be visualized on radiographs as a lobar or segmental consolidation.
190
What organism is responsible for 90% of lobar pneumonias?
Streptococcus pneumoniae.
191
What is the best way to classify pneumonias?
Classify by their specific etiological agent or, if no pathogen can be isolated, by the clinical setting in which infection occurs.
192
Describe the onset of community acquired acute pneumonias and their causative organisms.
The most common cause of community-acquired acute pneumonia is bacterial, typically following a viral URTI
Onset: abrupt, high fever, shaking chills, pleuritic chest pain, productive mucopurulent cough - occasional hemoptysis.
Streptococcus pneumoniae is the most common causative organism.
193
Which groups of individuals are most often infected with Streptococcus pneumoniae?
Those with underlying chronic diseases like CHF, COPD, diabetes
Those with congenital or acquired immunoglobulin defects
Those with decreased or absent splenic function
194
What is the morphology of a Streptococcal pneumoniae infection causing pneumonia?
MOst often the lower lobes or the right middle lobe are involved
Without antibiotics, it would progress from congestion, to red hepatization, then gray hepatization, then resolution.
195
Describe each of the four stages of Streptococcus pneumoniae infection.
Congestion - affected lobe(s) are heavy, red, boggy - histology reveals vascular congestion, proteinaceous fluid, scattered neutrophils, bacteria in the alveoli.
Red heparinization - the lobe has a liver-like consistency, alveolar spaces are packed with neutrophils, red cells, and fibrin
Gray hepatization - llung is dry, gray, and firm because the red cells are lysed, while the fibrinosuppurative exudate persists within the alveoli
Resolution - in uncomplicated cases, exudates within the alveoli are enzymatically digested to produce granular, semilfluid debris that is resorbed, ingested by macrophages, coughed up, or organized by fibroblasts growing into it.
196
Describe the bronchopneumatic pattern of pneumonia (streptococcus)
There are foci of inflammatory consolidation in patches throughout one or several lobes, most often bilateral and basal.
Well-developed lesions up to 3-4 cm in diameter are slightly elevated and are gray-red to yellow. Confluence may occur and produce the appearance of a lobar consolidation.
Surrounding tissue usually hyperemic and edematous.
197
What are some complications of Streptococcus pneumoniae pneumona?
Tissue destruction and necrosis = abscess formation
Suppurative material may accumulate in the pleural cavity, producing an empyema
Organization of the intra-alveolar exudate may convert areas of the lung into solid fibrous tissue
Bacterial dissemination - meningitis, arthritis, infective endocarditis - more likely with serotype 3 pneumococci
198
What are six pathogens implicated in community acquired acute pneumonias besides Streptococcus pneumoniae?
```
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
Klebsiella pneumoniae
Pseudomonas aeruginosa
Legionella pneumophila
```
199
Describe Haemophilus influenzae and its role in community acquired acute pnuemonia.
Encapsulated and unencapsulated cause CAAP - encapsulated is dangerous in children.
Adults at risk include those with chronic pulmonary diseases. H. influenzae is the most common bacterial cause of acute exacerbation of COPD.
Encapsulated H. influenzae type b was formerly an important cause of epiglottitis and suppurative meningitis in children but vaccination reduces the risk.
One of the three organisms that causes most cases of otitis media.
200
What is the most common bacterial cause of acute exacerbation of COPD? Second most common?
Haemophilus influenzae
Second: Moraxella catarrhalis
201
Describe Moraxella catarrhalis and its role in community acquired acute pneumonia.
M. catarrhalis is an increasing cause of bacterial pneumonia especially in elderly
Second most common bacterial cause of acute exacerbation of COPD
Constitutes one of the three most common causes of otitis media.
202
Describe Staphylococcus aureus and its role in community acquired acute pneumonia.
An important cause of secondary bacterial pneumonia in children and healthy adults after viral respiratory illnesses
Staphylococcus pnuemonia is associated with high incidence of complications - including lung abscesses and empyema
Staphyloccal pneumonia occuring in association with right-sided staphylococcal endocarditis is a serious complication of IV drug abuse
Also an important cause of nosocomial pneumonia
203
Describe Klebsiella pneumonia and its role in community acquired acute pneumonia.
K. pneumoniae is the most frequent cause of gram negative bacterial pneumonia.
Frequently afflicts debilitated and malnourished persons, like alcoholics
Thick and gelatinous sputum is characteristic because the organism produces an abundant viscid capsular polysaccharide, which the individual may have difficulty coughing up
204
What is the most common gram negative organism that causes bacterial pneumonia?
Klebsiella pneumoniae
205
Describe Pseudomonas aeruginosa and its role in community acquired acute pneumonia.
Most commonly seen in nosocomial infections
Common in patients who are neutropenic, usually secondary to chemotherapy, extensive burns, those requiring mechanical ventilation
Propensity to invade blood vessels at the site of infection with consequent extra-pulmonary spread; Fulminant disease, death often occurs within a matter of days.
Histologically - coagulation necrosis of the pulmonary parenchyma with organisms invading the walls of necrotic blood vessels (Pseudomonas vasculitis)
206
Describe Legionella pneumophila and its role in community acquired acute pneumonia.
The agent of legionnaire disease - Pontaic fever is related, and self-limited.
Flourishes in artificial aquatic environments - transmission via aerosolized organisms or aspiration of contaminated water
Common in those with cardiac, renal, immunologic, or hematologic disease. Organ transplant recipients are particularly susceptible.
May be quite severe, frequently requiring hospitalization, and immunosuppressed individuals may have fatality of 30-50%
Rapid diagnosis via Legionella antigens in urine or by positive fluorescent antibody test on sputum samples - culture is gold standard for Dx.
207
What is community acquired atypical pneumonia?
Pneumonia, but atypical because of the moderate amounts of sputum, absence of physical findings of consolidation, moderate elevation of white cell count, lack of alveolar exudates.
208
What organisms often cause community acquired atypical pneumonia?
Mycoplasma pneumoniae is the most common
Mostly among children and young adults
Sporadic or local epidemics in closed communities
Also caused by viruses: infuenza type A, B; RSV; adenovirus; rhinovirus; rubeola; varicella;
Chalmydia pneumoniae
Coxiella burnetti
209
Describe the morphology of community acquired atypical pneumonia.
Patchy or whole lobes bilaterally or unilaterally
Macroscopically - affected areas are red-blue, congested, subcrepitant
Inflammatory region is largely confined within the walls of the alveoli
Septa widened and edematous, contain mononuclear infiltrates of lymphocytes, histiocytes, and occasionally plasma cells.
Remarkably free of cellular exudate, but hyaline membranes may develop in full-blown diffuse alveolar damage.
210
Which has a good amount of cellular exudate - bacterial pneumonia or atypical pneumonia
Bacterial pneumonia has cellular exudate
211
Describe the clinical course of community acquired atypical pneumonias.
Extremely varied
May go undiagnosed and appear like a severe URTI or "chest cold"
May present as fulminant life-threatening infection in imunocompromised patients
Onset usually acute, nonspecific febrile ilness - headache, malaise, cough, minimal sputum.
Edema, exudation, may be respiratory distress seemingly out of proportion to the physical and radiographic findings.
212
How do you diagnose community acquired atypical pneumonia? Treat?
Test for Mycoplasma antigens and PCR testing for Mycoplasma DNA
Often treated with Macrolides since they are effective against Mycoplasma and Chlamydia pneumoniae
213
How is SARS distinct clinically from the other coronaviruses, which cause 1/3 of URTIs?
SARS-CoV differs in that it is more able to infect the lower respiratory tract and induce viremia.
214
What are the symptoms of SARS?
Patient becomes ill 2-10 days after exposure
Symptoms: fever, myalgia, headache, chills, diarrhea;
Respiratory symptoms include dry cough, dyspnea
215
What are some of the histological/morphological characteristics of lungs of SARS patients?
Lungs demonstrate DAD and multinucleated giant cells
216
What are nosocomial pneumonias?
Hospital-acquired pneumonias
More often caused by organisms in the group "Ventilator-associated pneumonia"
Gram-negative rods (Enterobacteriaceae and Pseudomonas spp) and Staphylococcus aureus are the most common isolates.
Streptococcus pneumoniae is NOT a major pathogen in nosocomial infections.
217
What is aspiration pneumonia?
Occurs in markedly debilitated patients or those who aspirate gastric contents either while unconscious or during repeated vomiting
Resulting pneumonia is partly chemical from gastric acid, and partly bacterial - aerobes are more common than anaerobes, but often is necrotizing and pursues a fulminant clinical course.
Those who survive often suffer abscesses
218
What is a lung abscess?
A localized area of suppurative necrosis within the pulmonary parenchyma, resulting in the formation of one or more large cavities.
219
How are the organisms that cause lung abscesses introduced?
Aspiration of infective material
Aspiration of gastric contents
Complication of necrotizing bacterial pneumonias, especially Staphylococcus aureus, Streptococcus pyogenes, Klebsiella pneumoniae, Pseudomonas spp. Rarely type 3 pneumonocci. Mycotic infections and bronchiectasis also.
Bronchial obstruction
Septic embolism
Hematogenous spread of bacteria in disseminated pyogenic infection
Anaerobic bacteria are present in almost all lung abscesses, sometimes in vast numbers. Exclusive isolates in 1/3-2/3 of cases.
220
What are the most frequent anaerobic bacteria encountered in lung absesses?
```
Prevotella
Fusobacterium
Bacteroides
Peptostreptococcus
Microaerophilic streptococci
```
221
Where do pulmonary abscesses most often occur?
Most often occur on the right side since the airway is more vertical. Most are single.
Tend to occur in the posterior segment of the upper lobe and in the apical segments of the lower lobe.
222
What is the clinical course of a lung abscess?
Prominent cough that yields copious amounts of foul-smelling, purulent, sanguineous sputum - occasional hemoptysis.
Fever, malaise, finger clubbing, weight loss, anemia
Infective abscesses in 10-15% of persons with bronchogenic carcinoma - so if lung abscess is in an older person must consider carcinoma.
Secondary amyloidosis may develop in chronic cases.
223
How are lung abscesses treated?
Treatment includes antibiotic therapy and surgical drainage.
Mortality rate ~10%
224
What are the two broad groups of lung cancers?
Small-cell lung cancer (SCLC)
Non-small-cell lung cancer (NSCLC)
225
What is the difference between the SCLC and NSCLC clinically and treatment-wise?
SCLC = metastasized by the time of Dx and are not curable by surgery - MUST be treated with chemotherapy w/ or w/o radiation
NSCLC = usually respond poorly to chemotherapy, better to do surgery
226
What are some genetic differences between SCLC and NSCLC?
SCLC - characterized by a high frequency of RB gene mutations
NSCLC - p16/CDKN2A gene is commonly inactivated. ALso there are activating KRAS and EGFR oncogene mutations.
227
What is the sequence of genetic molecular events leading to a pulmonary carcinoma?
Inactivation of tumor suppressor genes on chromosome 3p is an early event
p53 mutations and KRAS oncogene activation occur later
A subset of adenocarcinomas have mutations in epidermal growth factor receptor
228
Statistically how many cases of lung cancer occur in smokers or those who stopped recently?
90%
229
In which are neuroendocrine markers (dense core granules, expression of chromogranin, neuron-specific enolase and synaptophysin) present - SCLC or NSCLC?
Present in SCLC
Absent in NSCLC
230
In which type, NSCLC or SCLC, is mucin present?
Present in adenocarcinomas (NSCLC)
Absent in SCLC
231
What peptide hormones are produced in SCLC?
Adrenocorticotropic hormone, antidiuretic hormone, gastrin-releasing peptide, calcitonin
232
What peptide hormones are produced in NSCLC?
Parathyroid hormone-related peptide (PTH-rp) in squamous cell carcinoma
233
How do carcinomas in the lungs begin and develop?
Start as small mucosal lesions that are firm and gray-white
May form intraluminal masses, invade the bronchial mucosa, form large bulky masses pushing into adjacent lung parenchyma
Some masses undergo cavitation caused by central necrosis or develop focal areas of hemorrhage
May extend to the pleura, invade the pleural cavity and chest wall, and spread to adjacent intrathoracic structures.
Distant spread via the lymphatics or hematogenous route
234
In what gender are squamous cell carcinomas more common?
Men > Women
235
How do squamous cell carcinomas develop?
CLosely correlated with smoking
Tend to arise centrally in major bronchi
Spread to local hilar nodes
Disseminate outside the thorax later than other types
Large lesions may undergo central necrosis, with resulting cavitation
Often preceded by years of squamous metaplasia or dysplasia in the bronchial epithelium
236
What is carcinoma in situ?
A phase during which atypical cells may be identified in cytological smears of sputum or in bronchial lavage fluids or brushings, although the lesion is asymptomatic and undetectable on radiographs.
237
Are squamous cell carcinomas well differentiated or not?
They can range from being well differentiated with keratin pearls and intercellular bridges, to poorly differentiated neoplasms having only minimal residual squamous features
238
What is an adenocarcinoma and how does it start?
They occur as central lesions but are usually more peripheral - in relation to peripheral lung scars (not caused by the scars though)
Grow slowly in general, form smaller masses, but metastasize early.
239
What is the most common type of lung cancer in women and nonsmokers?
Adenocarcinoma
240
Describe the histological features of an adenocarcinoma.
Various types:
They are acinar - gland forming
Papillary
Solid
Solid variants require demonstration of intracellular mucin production by special stains to establish that it is an adenocarcinoma
241
What is an atypical adenomatous hyperplasia?
The putative precursor of peripheral adenocarcinomas - well-demarcated focus of epithelial proliferation composed of cuboidal to low-columnar cells resembling Clara cells or type 2 pneumocytes. Various cytologic atypia (nuclear hyperchromasia, pleomorphism, prominent nucleoli
242
What are bronchioloalveolar carcinomas? (BAC)
A subtype of adenocarcinomas - involve peripheral parts of the lung either as a single nodule ore as multiple diffuse nodules. May produce pneumonia-like consolidation.
KEY FEATURE: Growth along preexisting structures and preservation of alveolar architecture.
243
What is a key feature of bronchioloalveolar carcinoma?
They grow along preexisting structures and preserve the alveolar architecture.
244
What are BASCs?
Bronchioalveolar stem cells
245
What is the role of BASCs in neoplasm?
Bronchioalveolar stem cells, following lung ingjury, undergo expansion, replenishing the normal cell types (Clara cells, alveolar cells) - facilitating epithelial regeneration - it is thought they incur the initiating oncogenic event so the cells escape normal check point mechanisms and result in pulmonary adenocarcinomas.
246
What are large-cell carcinomas?
Undifferentiated malignant epithelial tumors that lack the features of small-cell lung cancer and glandular or squamous differentiation
247
How do small-cell lung carcinomas typically appear?
Pale gray, centrally located masses with extension into the lung parenchyma and early involvement of the hilar and mediastinal nodes.
Composed of tumor cells with a round to fusiform shape, scant cytoplasm, and finely granular chromatin.
248
Which cancer, NSCLC or SCLC, most often causes paraneoplastic syndrome?
Small cell lung carcinoma SCLC
249
Which tumor cells originate from pulmonary neuroendocrine cells?
SCLC Small cell lung carcinoma
250
From what cell line do carcinoid (SCLC) tumors originate?
Pulmonary neuroendocrine cells.
251
What is a Pancoast tumor?
A tumor that is destroying the first and second ribs, sometimes thoracic vertebrae
They are apical tumors that invade the brachial or cervical sympathetic plexusand cause severe pain in the distribution of the ulnar nerve or to produce Horner syndrome.
252
What are the symptoms of Horner syndrome?
Ipsilateral enophthalmos, ptosis, miosis, and anhidrosis
253
What is chronic pneumonia?
A localized lesion in an immunocompetent person, with or without regional lymph node involvement. Typically granulomatous inflammation - due to bacteria or fungi.
254
What is the most common cause of death resulting from a single infectious agent?
Tuberculosis
Mycobacterium tuberculosis
255
What are some disease states that increase the risk of Tuberculosis?
```
Diabetes mellitus
Hodgkin disease
Chronic lung disease (silicosis)
Chronic renal failure
Malnutrition
Alcoholism
Immunosuppression
```
256
What factor is the single most important risk to developing tuberculosis?
Decrease in the capacity to maintain T cell-mediated immunity against the infectious agent.
257
What diseases or infections can produce false-negatives for PPDs?
```
Certain viral infections
Sarcoidosis
Malnutrition
Hodgkin's Lymphoma
Immunosuppression
Overwhelming active Tuberculosis
```
258
How does the tuberculosis bacillus behave once it enters a macrophage?
It inhibits normal microbicidal responses by manipulation of endosomal pH and arrest of endosomal maturation
Impaired phagolysosome formation, unhindered mycobacterial proliferation
Bacillary proliferation within the pulmonary alveolar macrophages and air spaces, with resulting bacteremia and seeding of multiple sites.
259
What is the role of IFN-gamma in the response to Tuberculosis?
IFN-gamma is released by the CD4+ T cells of the TH1 subset, and activate macrophages. The macrophages release...
TNF - recruits monocytes and activates them into epithelioid histiocytes, forming granulomatous response
Expression of the iNOS (inducible NO-synthasse) gene which elevates nitric oxide levels and helps oxidize things, and generate reactive nitrogen intermediates.
ROS generation, antibacterial activity
260
What is primary tuberculosis?
Tuberculosis that develops in a previously unexposed, unsensitized individual
261
What is a Ghon focus? Ghon complex?
A 1 to 1.5cm area of gray-white inflammatory consolidation - usually undergoes caseous necrosis.
Tends to occur in the upper part of the lower lobe, or the lower part of the upper lobe.
Combination of parenchymal lesion and nodal involvement - Ghon complex.
262
What is a Ranke complex?
After the Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification, it is called a Ranke complex.
263
Describe the morphological spectrum of tuberculosis granulomas/tubercles.
Central granular caseation, surrounded by epithelioid and multinucleated giant cells
Foamy histiocytes are packed with mycobacteria
Fibroblastic rim punctuated by lymphocytes
264
What are the chief implications of primary tuberculosis?
Induces hypersensitivity and increased resistance
The foci of scarring may harbor viable bacilli for years
Disease may develop without interruption into so-called progressive primary tuberculosis
265
What are some characteristics of progressive primary tuberculosis?
Acute bacterial pneumonia
Lower, middle lobe consolidation
Hilar adenopathy, pleural effusion
Cavitation is rare
Complication - lymphohematogenous dissemination - tuberculous meningitis and miliary tuberculosis
266
What is secondary tuberculosis?
Also known as reactivation or postprimary tuberculosis
A pattern of disease that arises in a previously TB-sensitized host
Only develops in about 5% of those who have primary TB
267
Where does secondary tuberculosis tend to occur?
Classically located in the apex of one or both upper lobes
Possibly from high oxygen tension?
268
What are some characteristics of secondary tuberculosis?
Cavitation occurs readily
Less involvement of regional lymph nodes
Localized in apex of one or both upper lobes
Very prevalent in HIV-positive patients
269
Why would an immunocompetent individual have a positive sputum-smear for AFB compared to an immunocompromised individual with a higher bacterial load?
Immunocompetent individuals with secondary TB have more tissue damage, resulting in more exposure of the bacteria to the sputum
In immunocompromised individuals, the bacteria are concealed within the cells, so fewer bacteria are in the sputum.
270
Describe an initial lesion in tuberculosis.
Usually less than 2 cm in diameter, small focus of consolidation, firm, sharply circumscribed, gray-white to yellow areas that have a variable amount of central caseation and peripheral fibrosis.
May go through progressive fibrous encapsulation, leaving only fibrocalcific scars.
Active lesions show characteristic coalescent tubercles with central caseation.
271
How do the lesions appear in progressive pulmonary tuberculosis?
Apical lesion enlarges with expansion of the area of caseation
Erosion into a bronchus evacuates the caseous center, creating a ragged, irregular cavity lined by caseous material - poorly walled off by fibrous tissue
Hemoptysis occurs from erosion of blood vessels
272
What is miliary pulmonary disease, and what are some characteristics?
Organisms drain through lymphatics into the lymphatic ducts and empty into the right side of the heart, entering pulmonary arteries.
Individual lesions are either microscopic or small, visible foci of yellow-white consolidation scattered through the lung parenchyma (miliary = millet).
May coalesce with total consolidation of large regions, entire lobes
273
What are some developments associated with progressive pulmonary tuberculosis?
Pleural effusions
Tuberculosis empyema
Obliterative fibrous pleuritis
274
What is systemic miliary tuberculosis?
When infective foci in the lungs seed the pulmonary venous return to the heart, the organisms subsequently disseminate through the systemic arterial system.
Most prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis
275
What is isolated-organ tuberculosis?
May appear in any one of the organs or tissues seeded hematogenously and may be the presenting manifestation of tuberculosis.
```
Organs involved:
Meninges - tuberculous meningitis
Kidneys - renal tuberculosis
Adrenals - formerly part of Addison disease
Bones - osteomyelitis
Fallopian tubes - salpingitis
Pott disease - vertebrae involvement
```
276
What is the most common form of extrapulmonary tuberculosis?
Lymphadenitis - usually in the cervical region - "scrofula"
Unifocal in HIV-negative people, otherwise multifocal with systemic symptoms and pulmonary or other organ involvement by active tuberculosis.
277
What is intestinal tuberculosis?
A form of tuberculosis contracted by ingesting contaminated milk - used to be more common,but now is a complication of protracted advanced secondary tuberculosis, secondary to the swallowing of coughed-up infective material.
Tends to cause mucosal lymphoid aggregates of the small and large bowel which undergo inflammatory enlargement with ulceration of the overlying mucosa
278
How are tuberculosis bacilli identified?
Conventional cultures may take up to 10 weeks
Some liquid media-based radiometric assays can give an answer within 2 weeks
PCR amplification is even mroe rapid
Sputum acid-fast stains, or use of fluorescent auramine rhodamine; Two sputum exams are required before conferring sputum negativity
279
What is the gold standard for identifying M. tuberculosis in a patient?
Cultures - because it also allows for testing of drug susceptibility
280
What are some nontuberculous mycobacterial diseases/pathogens?
M. avium-intracellulare
M. kansasii
M. abscessus
May present as upper lobe cavitary disease, mimicking TB, especially in individuals with long-standing history of smoking or alcoholism.
Presents as a chronic but clinically localized pulmonary disease.
281
What is the effect of M. avium in HIV-positive patients?
Presents as disseminated disease, associated with systemic symptoms (fever, night sweats, weight loss)
Hepatosplenomegaly
Lymphadenopathy
GI symptoms: diarrhea, malabsorption
Foamy histiocytes "plugged" with atypical mycobacteria
282
Describe H. capsulatum. What does it cause?
Histoplasmosis
Endemic in Ohio, central Mississippi River valley, along the Appalachians.
Warm moist soil, enriched by bat and bird droppings provides the ideal medium for growth of the mycelial form, which produces infectious spores.
283
Describe the morphology of H. capsulatum.
Round to oval, small yeast forms measuring 2-5 micrometers in diameter.
284
Describe C. immitis. What does it cause?
Coccidioidomycosis
Endemic in the Southwest and Far West of US, especially in the San Joaquin Valley, where it is known as "valley fever"
285
Describe the morphology of C. immitis.
Thick-walled, nonbudding spherules, 20-60 micrometers in diameter, often filled with small endospores.
286
Describe B. dermatitidis. What does it cause?
Blastomycosis
Endemic area is confined in the US to areas overlapping with those where histoplasmosis is found.
287
Describe the morphology of B. dermatitidis.
Round to oval, larger than Histoplasma (5-25 micrometers in diameter). Reproduce by characteristic "broad based" budding
288
What are the three main clinical manifestation categories for Histoplasmosis, Coccidioidomycosis, or Blastomycosis?
Acute (primary) Pulmonary Infection
Chronic (cavitary) Pulmonary Disease
Disseminated Miliary Disease
289
How does Histoplasmosis, Coccidoidomycosis, or Blastomycosis start, with primary pulmonary infection?
There are nodules, composed of aggregates of macrophages stuffed with organisms, and associated with similar lesions in the regional lymph nodes
Develop into small granulomas with giant cells, may develop central necrosis and later fibrosis and calcification. Similarity to primary TB is striking
290
How is Acute (primary) Pulmonary Infection by a dimorphic fungus differentiated from TB?
Must identify the yeast forms - with a periodic acid-Schiff or silver stain.
291
Describe the clinical presentation of Acute (primary) Pulmonary infection with a dimorphic fungus?
Clinically resembles a "flulike" syndrome, often self limited. In a vulnerable host, chronic cavitary pulmonary disease develops, with predilection for the upper lobe.
292
Describe the clinical presentation of Chronic (cavitary) Pulmonary Disease from a dimorphic fungus.
Tends to affect the upper lobe and resembles the secondary form of TB
There may be perihilar mass lesions that resemble bronchogenic carcinoma radiologically
Cough, hemoptysis, and some dyspnea/chest pain may appear
293
Describe disseminated disease caused by a dimorphic fungus.
There are no well-formed granulomas
Focal collections of phagocytes stuffed with yeast forms are seen within cells of the mononuclear phagocyte system, including in the liver, spleen, lymph nodes, lymphoid tissue of GI tract, and bone marrow.
Adrenals and meninges may be involved, and in a minority of cases, ulcers form in the nose and mouth, on the tongue, or in the larynx.
294
Describe the clinical presentation of disseminated disease caused by a dimorphic fungus.
A hectic, febrile illness with hepatosplenomegaly, anemia, leukoplakia, and thrombocytopenia. Cutaneous infections with disseminated Blastomyces frequently induce striking epithelial hyperplasia, which may be mistaken for SCC
295
What are some pulmonary opportunistic pathogens (bacteria, viruses, fungi)? Yes there are a gajillion, but what has Robbins mentioned?
Bacteria: Pseudomonas aeruginosa, Mycobacterium species, Legionella pneumophila, Listeria monocytogenes
Viruses - Cytomegalovirus, Herpesvirus
Fungi - Pneumocystis jiroveci, Candida species, Aspergillus species, Cryptococcus neoformans
296
What are some signs of CMV at the cellular level?
Cytomegalovirus is a member of the herpesvirus family, may produce a variety of disease manifestations
Infected cells exhibit gigantism of entire cell and the nucleus. Enlarged inclusion with a clear halo - giving an "owl's eye" cell appearance.
297
What are the different modes of transmission of CMV?
Transplacentally --> Fetus, Congenital CMV
Cervical or vaginal secretions at birth, or later through breast milk - Perinatal CMV
Venereal transmission in those over 15 years old - also spreads via respiratory secretions and fecal-oral
Iatrogenic transmission at any age
298
What is CMV mononucleosis?
In healthy young children and adults, disease is almost always asymptomatic
50-100% of adults demonstrate anti-CMV antibodies
Most common manifestation in immunocompetent hosts is an infectious mono-like illness with fevver, atypical lymphocytosis, lymphadenopathy, and hepatomegaly accompanied by abnormal LFTs, suggesting mild hepatitis. Most recover without sequelae but excretion of virus may occur for months to years afterwards.
Remains latent in leukocytes
299
What are the common immunosuppressed groups that get clinical CMV?
Recipients of organ transplants - heart, liver, kidney - CMV usually from the donor but reactivation may occur.
Recipients of allogeneic BMTs - usually reactivation of latent CMV in the recipient
Persons with AIDS - reactivation of latent infection and are also infected by their sexual partners. CMV is the most common opportunistic viral pathogen in AIDS.
300
What is the most common opportunistic viral pathogen in patients with AIDS?
CMV - Cytomegalovirus
301
What organ systems are most often affected by CMV in immunosuppressed patients?
Lungs - Pneumonitis
GI tract - Colitis
Retina - Retinitis
302
Describe the behavior of P. jiroveci in immunocompetent and immunocompromised patients.
An opportunistic infectious agent - nearly everyone is exposed by age 5 - remains latent
Reactivation and clinical disease almost exclusively in immunocompromised patients. Mostly in AIDS patients and malnourished infants.
Largely confined to the lungs.
303
Describe the microscopic morphology of the lungs with Pneumocystis pneumonia.
Involved areas demonstrate intra-alveolar foamy, pink-staining exudate with H&E stains ("cotton candy" exudate), and septa are thickened by edema and a minimal mononuclear infiltrate.
Organism can be revealed in trophozoite or encysted form.
Silver stains reveal cup-shaped cyst walls (5-8 micrometers in diameter) in the alveolar exudates.
Trophozoites can be revealed with methylene blue or Giemsa stains in sputum samples of about 50% of patients.
304
What is the most common clinical presentation of Pneumocystis pneumonia?
Fever, dry cough, dyspnea (and immunocompromised state) with bilateral perihilar and basal infiltrates
Hypoxia, often there is a restrictive lung defect, BAL is best way to identify the organism.
305
What is the most frequent disease-causing fungus?
Candida albicans
306
Describe the morphology of C. albicans.
Yeastlike forms - blastoconidia. Pseudohyphae, and true hyphae. Pseudohyphae are an important diagnostic clue and represent budding yeast cells joined end-to-end at constrictions, simulating true fungal hyphae. Organisms may be visible with routine hematoxylin and eosin stains, but a variety of "fungal" stains (Gomori methenamine-silver, periodic acid-Schiff) are used to highlight the pathogens.
307
Describe the oral pattern of infection of C. albicans.
Most common pattern: superficial infection on mucosal surfaces of oral cavity - "thrush". Florid proliferation creates gray-white, dirty-looking pseudomembranes composed of matted organisms and inflammatory debris.
Deeper there is mucosal hyperemia and inflammation.
308
What groups are most at risk for oral candidiasis (thrush)?
Newborns
Debilitated Patients
Children receiving oral corticosteroids for asthma
After a course of broad-spectrum antibiotics that destroy competing flora
HIV-positive patients
309
Describe Candida vaginitis.
Extremely common vaginal infection in women, especially hose who are diabetic, pregnant, or on oral contraceptive pills.
Usually associated with intense itching and a thick, curdlike discharge.
310
Describe Candida esophagitis.
Common in AIDS patients and those with hematolymphoid malignancies
Present with dysphagia, retrosternal pain. Endoscopy reveals white plaques and pseudomembranes resembling oral thrush on the esophageal mucosa.
311
What is cutaneous candidiasis?
Presents in many forms, including infection of the nail proper (onychomycosis), nail folds (paronychia), hair follicles (folliculitis), moist, intertriginous skin such as armpits or webs of the fingers and toes (intertrigo), and penile skin (balanitis). "Diaper rash" is often a cutaneous candidal infection.
312
What is chronic mucocutaneous candidiasis?
A chronic refractory disease afflicting the mucous membranes, skin, hair, and nails - it is associated with underlying T-cell defects.
Associated conditions include endocrinopathies (most often hypoparathyroidism and Addison disease) and the presence of autoantibodies. Disseminated candidiasis is rare.
313
What are some common patterns associated with invasive candidiasis?
Bloodborne dissemination of organisms to various tissues or organs may occur via...
Renal abscesses
Myocardial abscesses and endocarditis
Brain involvement (meningitis, parenchymal microabscesses)
Endophthalmitis (any eye structure)
Hepatic abscesses
Candida pneumonia, usually with bilateral nodular infiltrates, resembling Pneumocystis pneumonia.
Patients with acute leukemias who are profoundly neutropenic post-chemo are very prone to systemic disease.
314
Describe Cryptococcosis and its pathogenicity.
Caused by C. neoformans, rarely in healthy people. Almost only in immunocompromised hosts, particularly those with AIDS or hematolymphoid malignancies.
Manifests as pulmonary, CNS, or disseminated disease. Most likely acquired by inhalating soil or bird droppings - localizes in the lungs and disseminates - favorite site is the meninges.
315
What disease is associated with soap bubble lesions in the perivascular Virchow-Robin spaces?
Cryptococcosis of the meninges
316
What are some opportunistic molds?
Mucormycosis and invasive aspergillosis.
Always limited to immunocompromised hosts, with hematolymphoid malignancies, profound neutropenia, corticosteroid therapy, or post-allogeneic BMT
317
Describe the morphology of Mucormycosis and Aspergillus species.
Mucormycosis, caused by Zygomycetes - nonseptate hyphae that branch at right angles
Rhizopus/Mucor are the two fungi that are important within the Zygomycetes class.
Aspergillus - septate hyphae, branch at acute angles
318
Describe the morphology of Cryptococcus.
5-10 micrometer yeast, thick gelatinous capsule, reproduces by budding.
Unlike Candida, pseudohyphal or true hyphal forms are not seen. Capsule is invaluable to diagnosis - in routine H&E stains it is not easily seen but a clear "halo" can be seen around the individual fungi representing the capsule.
The capsular polysaccharide antigen is the substrate for the cryptococcal latex agglutination assay, which is positive for more than 95% of patients with the organism.
319
What kind of local reaction is more characteristic of Zygomycetes and Aspergillus?
A nondistinctive, suppurative, sometimes granulomatous reaction with a predilection for invading blood vessel walls, causing vascular necrosis and infarction
320
Describe rhinocerebral and pulmonary mucormycosis.
Zygomycetes tend to colonize the nasal cavity, sinuses, and then spread to the brain, orbit, and other structures there.
Diabetics are more likely to develop rhinocerebral mucormycosis. Pulmonary disease can be localized or present radiologically with diffuse "miliary" involvement.
321
Describe invasive aspergillosis.
Almost exclusively in immunosuppressed patients. Fungus preferentially localizes to the lungs, presents as a necrotizing pneumonia.
Tend to invade blood vessels, so systemic dissemination (to brain) may be a fatal complication.
322
What is allergic bronchopulmonary aspergillosis?
It occurs in patients with asthma who develop an exacerbation of symptoms caused by a type I hypersensitivity against the fungus growing in the bronchi.
These patients tend to have circulating IgE antibodies against Aspergillus and peripheral eosinophilia.
323
What is an Aspergilloma?
A "fungus ball" which occurs by colonization of preexisting pulmonary cavities by the fungus May act as ball valves, occluding the cavity and thus predisposing to infection and hemoptysis
324
What are some of the most commonly implicated organisms in HIV-related pulmonary infections?
S. pneumoniae
S. aureus
H. influenzae
Gram-negative rods
325
What are some common noninfectious diseases that may cause pulmonary infiltrates in HIV-infected individuals?
Kaposi's sarcoma
Pulmonary non-Hodgkin lymphoma
Primary lung cancer
326
How can CD4+ T cell count be used to narrow down a DDx for HIV-infected patients with a pulmonary infection?
Bacterial and Tubercular infections are more likely at higher CD4 counts > 200 cells/mm3
Pneumocystis pneumonia strikes below < 200 cell/mm3
CMV and M. avium complex infections are uncommon until CD4 counts are < 50 cells/mm3
327
What is the most common cell of origin of primary lung cancers?
Bronchial epithelial cells - site of origin of 95% of primary lung tumors (carcinomas)
5% are a miscellaneous group that includes bronchial carcinoids, mesenchymal malignancies, lymphomas, a few benign lesions.
328
What is the most common benign lesion in the lungs?
A hamartoma - discrete, small (3-4 cm), spherical, appear as "coin" or "button" lesions on chest radiographs. Consist mainly of mature cartilage but may be mixed with fat, fibrous tissue, blood vessels in varying proportions.
329
What are the four major histological types of carcinomas of the lung?
Squamous cell carcinoma
Adenocarcinoma
Small-cell carcinoma
Large-cell carcinoma
330
What is the most common primary tumor arising in women, lifetime nonsmokers, and persons younger than 45 years?
Adenocarcinomas
331
What are the two broad groups into which lung cancers are classified?
Small-cell lung cancer
Non-small-cell lung cancer
332
What types of cancers are included in NSCLC?
Adenocarcinomas
Large Cell Carcinomas
Squamous Cell Carcinomas
333
Why have carcinomas been divided into the large categories of Non-small cell and small cell?
SCLCs have metastasized by the time of diagnosis and hence are not curable by surgery. Best treated by chemotherapy, with or without radiation.
NSCLCs respond poorly to chemotherapy, and are better treated with surgery
334
What are the genetic differences between SCLCs and NSCLCs?
SCLC - high frequency of RB gene mutations.
NSCLC - p16/CDKN2A are inactivated in NSCLC. KRAS and EGFR oncogene mutations are found in adenocarcinomas.
335
What is EGFR and how does it relate to lung cancer?
EGFR is epidermal growth factor receptor, and mutations in these receptors result in a subset of adenocarcinomas common in non-smoking women of the Far East.
Luckily, there is a class of drugs that inhibits EGFR signaling, and is effective against this type of cancer.
336
Which types of cancers have the strongest association with tobacco exposure?
Squamous Cell Carcinoma
| Small-Cell Carcinoma
337
Describe how exposure to tobacco smoke leads to morphological changes progressing to cancer.
Particularly in squamous cell carcinoma...
```
Innocuous basal cell hyperplasia
Squamous cell metaplasia
Squamous dysplasia
Carcinoma in situ
Invasive cancer
```
338
Describe SCLCs histologically.
Scant cytoplasm
Small hyperchromatic nuclei with fine chromatin pattern
Nucleoli indistinct
Diffuse sheets of cells
339
Describe NSCLC histologically.
Abundant cytoplasm
Pleomorphic nuclei with coarse chromatin pattern
Nucleoli often prominent
Glandular or squamous architecture
340
In which, SCLC or NSCLC, is it more common to find neuroendocrine markers, such as dense core granules, expression of chromogranin, neuron-specific enolase and synaptophysin?
SCLC
341
In which type of lung cancer is mucin present?
NSCLC - adenocarcinomas
342
What kinds of peptide hormones are produced in SCLCs?
Adrenocorticotropic hormone
ADH
Gastrin-releasing peptide
Calcitonin
343
What kinds of peptide hormones are produced in NSCLCs?
PTH-related peptide in SCC
344
Describe the distribution and etiology of SCCs
More common in men than women
Closely correlated with smoking
Tend to arise centrally in major bronchi
Spread to local hilar nodes
345
What causes cavitation in lung cancers?
The lesions may undergo central necrosis, causing them to fall in on themselves
346
What are some morphologies that precede SCC?
Squamous metaplasia or dysplasia
| Carcinoma in situ
347
Describe the morphology of SCCs
A well defined tumor mass, may obstruct lumen of a major bronchus and cause distal atelectasis and infection
Range from well-differentiated squamous cell neoplasms with keratin pearls and intercellular bridges, to poorly differentiated neoplasms having only residual squamous cell features.
348
What is an adenocarcinoma (in the lung)?
A NSCLC
May occur as a central lesion but usually are more peripheral. Many arise in relation to peripheral lung scars (causal or secondary?)
Adenocarcinomas are most common in women and nonsmokers - grow slowly, form smaller masses than others, metastasize widely at an early stage, and assume a variety of forms.
349
What are the three general forms of adenocarcinoma?
Acinar (gland forming)
Papillary
Solid types
350
Describe the putative precursor of peripheral adenocarcinomas.
Atypical adenomatous hyperplasia - recognized as a well-demarcated focus of epithelial proliferation composed of cuboidal to low-columnar cells resembling Clara cells or type 2 alveolar pneumocytes which demonstrate various degrees of cytologic atypia.
Lesions are monoclonal, share many molecular aberrations associated with adenocarcinomas like KRAS mutations.
351
What is a bronchioloalveolar carcinoma?
A subtype of adenocarcinoma - they involve peripheral parts of the lung, either as a single nodule or as multiple diffuse nodules that may coalesce to produce pneumonia-like consolidation.
352
What is the key feature of a BAC?
A BAC, or bronchioloalveolar carcinoma, is most noted for growth along preexisting structures and preservation of alveolar architecture.
They grow in a monolayer along the alevolar septa, which serves as a scaffold for their lepidic growth pattern (like butterflies on a fence).
353
What are the two subtypes of BACs?
Mucinous and Nonmucinous
Mucinous - comprising tall, columnar cells with prominent cytoplasmic and intra-alveolar mucin
354
What is a proposed mechanism through which some invasive adenocarcinomas of the lung arise?
Atypical adenomatous hyperplasia-bronchioloalveolar carcinoma-invasive adenocarcinoma sequence
355
What are bronchoalveolar stem cells?
A population of multipotent cells at the bronchoalveolar duct junction - they undergo expansion after peripheral lung injury and replenish the normal cell types found there - like bronchiolar Clara cells and alveolar cells.
It is possible that BASCs incur the initiating oncogenic event and these cells escape normal 'checkpoint' mechanisms, resulting in pulmonary adenocarcinomas.
356
What are large-cell carcinomas?
Undifferentiated malignant epithelial tumors that lack the cytologic features of SCCs and glandular or squamous differentiation. They typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm.
Possibly represent SCCs or adenocarcinomas that are so poorly differentiated that they can no longer be recognized by microscopy.
357
What are small-cell lung carcinomas?
SCLCs generally appear as pale gray centrally located masses without extension into the lung parenchyma and early involvement of the hilar and mediastinal nodes.
358
Describe the tumor cells found in SCLCs.
SCLCs are composed of tumor cells with a round to fusiform shape, scant cytoplasm, and finely granular chromatin.
Mitotic figures are frequently seen, and despite the appellation of "small" the neoplastic cells are usually twice the size of resting lymphocytes.
There is necrosis, and the cells are markedly fragile, often showing fragmentation and "crush artifact" in small biopsy specimens.
359
From what type of cell is an SCLC derived, and what are some special characteristics?
They are derived from neuroendocrine cells, and express a variety of neuroendocrine markers, in addition to a host of polypeptide hormones.
There is nuclear molding from close apposition of tumor cells that have scant cytoplasm.
360
What is a Pancoast tumor?
An apical neoplasm, which may cause symptoms by pressing on important structures.
There are a variety of clinical symptoms - some includes destruction of the 1st and 2nd ribs, sometimes thoracic vertebrae, etc.
361
Describe the clinical course of a carcinoma of the lung.
They tend to be silent, insidious lesions that more often than not have spread so as to be unresectable before they produce symptoms
Chronic expectoration and cough may be the sole symptoms. Other problems may include hoarseness, chest pain, superior vena caval syndrome, pericardial or pleural effusion, or persistent segmental atelectasis or pneumonitis.
By then, usually the prognosis sucks. Tumor presents with symptoms emanating from metastatic spread to the brain, liver, or bones - although the adrenals may be nearly obliterated, adrenal insufficiency (Addison disease) is uncommon because islands of cortical cells sufficient to maintain adrenal function usually persist.
362
Which as a better prognosis, NSCLC or SCLC?
NSCLC
363
Why are NSCLCs more treatable than SCLCs?
NSCLCs may be detected before metastasis or local spread, cure is possible by lobectomy or pneumonectomy
SCLCs tend to have metastasized, and surgical resection is not an option. They are sensitive to chemotherapy, but inevitably recur. Median survival is 1 year.
364
What are some paraneoplastic syndromes associated with lung cancer?
3-10% of lung cancer patients will get...
Hypercalcemia (oversecretion of PTH-related peptide)
Cushing syndrome (increased adrenocorticotropic hormone)
SIADH
Neuromuscular syndromes like myasthenic syndrome, peripheral neuropathy, polymyositis
Clubbing of fingers, hypertrophic pulmonary osteoarthropathy
Hematologic manifestations, including migratory thrombophlebitis, nonbacterial endocarditis, and DIC
365
What paraneoplastic syndrome is most commonly associated with SCC? Adenocarcinomas?
SCC - hypercalcemia
Adenocarcinoma - hematologic syndromes
366
From what cells do bronchial carcinoids originate?
Thought to arise from Kulchitsky cells (neuroendocrine cells) that line the bronchial mucosa and resemble intestinal carcinoids.
These cancer cells contain dense-core neurosecretory granules in their cytoplasm and rarely may secrete hormonally active polypeptides. May occur as part of the multiple endocrine neoplasia syndrome.
367
Describe the prognosis for bronchial carcinoids.
Appear at an early age (around 40 years) and represent about 5% of all pulmonary neoplasms
They are often resectable and curable.
368
Describe the morphology of bronchial carcinoids.
Originate in main-stem bronchi and grow in one of two patterns - obstructing polypoid, spherical, intraluminal mass; or a mucosal plaque penetrating the bronchial wall to fan out in the peribronchial tissue (callar-button llesion)
369
Describe the histology of bronchial carcinoids.
Composed of nests of uniform cells that have regular round nuclei with "salt and pepper" chromatin, absent or rare mitoses, and little pleomorphism.
370
Describe the histology/morphology of an atypical bronchial carcinoid.
A carcinoid that displays a higher mitotic rate, increased cytologic variability, and focal necrosis
Higher incidence of lymph node and distant metastasis than "typical" carcinoids and fare worse.
20-40% have p53 mutations.
371
What are some typical clinical presentation symptoms specific to bronchial carcinoids?
They present with finding related to their growth, so hemoptysis, cough, recurrent bronchial and pulmonary infections.
Some are asymptomatic, and discovered by chance on CXR
Carcinoid syndrome - intermittent attacks of diarrhea, flushing, and cyanosis.
372
What are two important primary disorders of the lung?
Primary intrapleural bacterial infections
Primary neoplasm of the pleura known as a malignant mesothelioma
373
What is the most common cause of fluid in the pleural cavity?
Hydrothorax from CHF
374
What kind of fluid in the pleural cavity suggests pleuritis?
An exudate characterized by protein content > 2.9 gm/dL and inflammatory cells
375
What are the four principal causes of a pleural exudate?
Microbial invasion through either direct extension of a pulmonary infection or blood borne seeding (suppurative pleuritis or empyema)
Cancer (bronchogenic carcinoma, metastatic neoplasms to the lung or pleural surface, mesothelioma)
Pulmonary infarction
Viral pleuritis
Less commonly: SLE, rheumatoid arthritis, uremia, previous thoracic surgery.
376
What is a common underlying cause of hemorrhagic pleuritis in patients older than 40, who are afebrile, in no pain, and have a negative PPD?
Cancer
377
What is pneumothorax, and how does it occur?
Pneumothorax refers to air or other gas in the pleural sac.
May occur in young, healthy individuals without any known pulmonary disease (simple or spontaneous pneumothorax) or as the result of some thoracic or lung disorder (secondary pneumothorax) like emphysema or a fractured rib.
378
What are some pulmonary lesions close to the pleural surface which may cause secondary pneumothorax?
Emphysema
Lung abscess
Tuberculosis
Carcinoma
Mechanical ventilatory support with high pressure may also trigger secondary pneumothorax
379
Describe a ball-valve leak and the complication it produces with pneumothorax.
It may create a tension pneumothorax that shifts the mediastinum. Compromise of pulmonary circulation may follow and even be fatal - if the leak seals and the lung is not re-expanded within a few weeks, so much scarring may occur that it can never b e fully re-expanded. Serous fluid collects and creates hydropneumothorax, and the lung becomes vulnerable to infection.
380
What is Hemothorax?
A collection of whole blood in the pleural cavity - a complication of a ruptured intrathoracic aortic aneurysm that is almost always fatal. The blood will clot within the pleural cavity, making it more complicated.
381
What is Chylothorax?
A pleural collection of a milky lymphatic fluid containing microglobules of lipid - the total volume of fluid may not be large, but chylothorax is always significant because it implies obstruction of the major lymph ducts, usually by an intrathoracic cancer.
382
What is a malignant mesothelioma?
Rare cancer of mesothelial cells - usually arising in the parietal or visceral pleura (also in peritoneum, pericardium).
Mostly from asbestos exposure.
383
Describe the morphology of a malignant mesothelioma.
Starts with extensive pleural fibrosis and plaque formation
These tumors begin in a localized area and then spread widely, and lung tends to become ensheathed in a yellow-white firm sometimes gelatinous layer of tumor that obliterates the pleural space.
384
What are the three morphological patterns of malignant mesotheliomas?
Epithelial - in which cuboidal cells line tubular and microcystic spaces, into which small papillary buds project. Most common pattern.
Sarcomatoid - spindled and sometimes fibroblastic-appearing cells grow in nondistinctive sheets
Biphasic - both sarcomatoid and epithelioid areas
385
What somatic mutations have been observed in malignant mesotheliomas?
p16/CDKN2A on chromosome 9p21 and NF2 on chromosome 22q12
386
With what virus are nasopharyngeal carcinomas strongly associated?
EBV - it is found in nearly all nasopharyngeal carcinomas.
387
What are the three histological variants of nasopharyngeal carcinomas?
Keratinizing squamous cell carcinoma
Nonkeratinizing squamous cell carcinoma
Undifferentiated carcinoma
*Undifferentiated carcinoma is the most common and most closely linked with EBV
388
What are some characteristics of an undifferentiated nasopharyngeal carcinoma
Large epithelial cells with indistinct cell borders (syncytial growth) and prominent eosinophilic nucleoli
Also there is a strong influx of mature lymphocytes, giving these neoplasms the other name lymphoepitheliomas - despite the fact the lymphocytes are not part of the neoplastic process, nor are the tumors benign.
389
What is the nature of a nasopharyngeal carcinoma?
It invades locally, spreads to cervical lymph nodes, and then metastasizes to distant sites. Tend to be raadiosensitive, and the 5 year survival rates are 50% even for advanced cancers.
390
What are some common tumors of the larynx? Most common presentation?
Vocal cord nodules
Papillomas
Squamous cell carcinomas
Presentation: Hoarseness
391
What is a vocal cord nodule (polyp)?
Smooth, hemispherical protrusions - usually less than 0.5cm in diameter, located on the true vocal cords.
Composed of fibrous tissue, covered by stratified squamous mucosa, usually intact but can be ulcerated by contact trauma with the other vocal cord. Lesions occur in heavy smokers or singers, suggesting they are the result of chronic irritation or abuse.
392
What is a laryngeal papilloma or squamous papilloma of the larynx?
A benign neoplasm, usually on the true vocal cords, that forms a soft, raspberry-like excrescence rarely more than 1cm in diameter.
393
Describe the histology of a laryngeal papilloma or squamous papilloma of the larynx.
These small benign neoplasms tend to consist of multiple slender finger-like projections supported by central fibrovascular cores and covered by an orderly, typical, stratified squamous epithelium.
Trauma may lead to ulceration, hemoptysis
394
What is recurrent respiratory papillomatosis?
RRP - recurring, multiple papillomas in children - they are caused by HPV types 6 and 11, and do not become malignant. Often they spontaneously regress at puberty. Cancerous transformation is rare.
Infection probably occurs via vertical transmission.
395
Describe the etiology of carcinoma of the larynx.
Usually in those 40+ years old, males (7:1 ratio). Environmental influences are important - almost all cases occur in smokers; Alcohol and asbestos may play a role.
Most are squamous cell lesions, rarely adenocarcinomas. The tumor develops on the vocal cords (glottic tumors) or below the cords.
396
Describe the histology of carcinoma of the larynx.
Usually follows the typical progression of squamous cell carcinoma. They begin as in situ lesions that later appear as pearly gray, wrinkled plaques on the mucosal surface, ultimately ulcerating and fungating.
Glottic tumors are usually keratinizing, well-to-moderately differentiated squamous cell carcinomas. Nonkeratinizing, poorly differentiated carcinomas may be seen as well.
397
How does carcinoma of the larynx present clinically? What is the prognosis?
Typically manifests with persistent hoarseness. The location of the tumor has a significant effect on prognosis - about 90% are confined to the larynx at diagnosis. There is sparse lymphatic supply as well. Therefore these types aren't so difficult to treat.
The subglottic tumors may be clinically quiet and present later.
1/3 mortality - usually from infection of the distal respiratory passages or widespread metastases and cachexia.
398
Mechanism of occupational asthma?
Underlying mechanisms vary according to stimulus and may involve type 1 hypersensitivity and hypersensitivity of unknown origin.
399
Mechanism of intrinsic asthma?
Virus induced inflammation of the respiratory tract lowers the threshold of the subepithelial vagal receptors to irritants.
Aspirin inhibits the cyclooxygenase pathway of arachidonic metabolism without affecting the lipoxygenase route and therefore tips the balance towards the formation of leukotrienes that have bronchoconstrictor actions.
400
What is the late phase of an asthma attack? When does it start and how long does it persist?
leucocyte infiltration of tissues with eosinophils, neutrophils, basophils, monocytes and helper T cells causing tissue destruction
Recruited cells (especially eosinophils) amplify and sustain the inflammatory response without additional exposure to antigen. Eosinophils may cause epithelial damage by producing major basic protein and eosinophil cationic protein. Major basic protein also causes bronchoconstriction.
Late phase starts at 4-8 hours and persists for 12-24 hours.
401
What is the pathology of the initial phase of asthma?
vascular leakage (causing oedema), smooth muscle spasm (causing bronchoconstriction), and mucous secretion. Evident within 5-10minutes, resolving at 60 minutes
Mediated by histamine, leukotrienes
402
What are the most important mediators in asthma?
```
Leukotrienes C4, D4, E4
Acetylcholine
Histamine
Prostaglandin D2
PAF
IL1, IL6, TNF
```
In addition there is direct stimulation of subepithelial parasympathetic receptors that provoke bronchoconstriction via central and local reflexes.
403
What is the macroscopic appearance of lungs with asthma?
Lungs are overinflated and there may be small areas of atelectasis.
Occlusion of bronchi and bronchiloes by mucous plugs.
404
What is the microscopic appearance of lungs with asthma? 6 features
1. Mucus plugs contain whorls of shed epithelium (curschmann spirals) in addition to numerous eosinophils.
2. Thickening of basement membrane of bronchial epithelium.
3. Oedema and inflammatory infiltrate of the bronchial walls.
4. Prominent eosinophils.
5. Increase in size of submucosal glands.
6. Hypertrophy of bronchial wall muscle due to prolonged bronchoconstriction.
405
What is the pathogenesis of atopic asthma?
Triggering antigens include dusts, pollens, animal dander, foods
Pathogenesis is analogous to type 1 hypersensitivity.
1. Antigen is presented to T helper cells by APCs.
2. Helper T cells then produce various cytokines including IL3, 4, 5. IL4 essential for turning on IgE producing B cells.
3. IgE binds to Fc portion of mast cell receptors.
4. Exposure of antigen to pre-sensitised IgE coated mast cells on the mucosal surface leads to release of chemical mediators. Degranulation and release of primary mediators:
Primary mediators (granule contents): Histamine, adenosine. Chemotactic mediators. Heparin.
Enzymes (proteases, acid
hydrolases).
De novo synthesis of secondary mediators. Secondary mediators
Leukotrienes B4, C4, D4. Prostaglandins D2. PAF. Cytokines TNF, IL1, IL2, IL4, IL5, IL6, GM-CSF.
Initial mediator release from mast cells causes opening of the mucosal intercellular tight junctions and enhances penetration of antigen to more numerous submucosal mast cells.
Mediators can also be produced by inflammatory cells already present in asthmatics suffering a recurrent attack.
Epithelial cells may also produce a large number of mediators in response to infection, drugs, gases and other mediators. Eotaxin is produced and this attacts eosinophils
406
What are the 3 types of emphysema and which is most common?
Incidence related to smoking and environmental pollutants.
Centriacinar:
95% of cases. Mostly related to smoking (and coal dust)
Often in combination with chronic bronchitis.
Panacinar
Suggestive of alpha 1 antitrypsin deficiency
Paraseptal
Associated with development of spontaneous pneumothorax.
Irregular
Associated with scarring due to other cause (infection). Very common and often subclinical.
407
What is the preotease-antiprotease theory of emphysema?
Protease-antiprotease theory:
Alveolar wall destruction results from an imbalance between proteases (elastases) and antiproteases in the lung (alpha 1 antitrypsin, secretory leukoprotease inhibitor, alpha 1 macroglobulin)
Elastases originate from neutrophils, macrophages, mast cells, pancreas and bacteria.
High protease activity and antiprotease activity results in emphysema.
Cigarette smoke causes:
1. Increased neutrophil and macrophage recruitment
2. Increased release of elastase from neutrophils.
3. Increased elastase activity in macrophages
4. Formation of oxygen free radicals that inhibit antiproteases.
408
What are the clinical features of emphysema?
Typically asymptomatic until one third of lung incapacitated.
Insidious clinical onset in 5th-8th decades
Characterised by dyspnoea, cough, wheeze.
Airflow obstruction
Lungs are hyperexpanded
409
What is the lung morphology in the 3 types of emphysema?
Do each of these affect the upper or lower lobe?
Defined in terms of its anatomical distribution
Centriacinar
Involves central or proximal acinus (respiratory bronchioles)
Distal alveoli are spared.
Upper zones mostly affected.
Panacinar
Acini are uniformly enlarged from respiratory bronchiole to alveolus.
More common in
lower zones
Paraseptal
Proximal acinus is normal but distal acinus is involved. Upper zones mostly affected particularly at lobule margins. Occurs adjacent to areas of fibrosis, scarring or atelectasis.
Irregular
Irregular areas of emphysema associated with areas of scarring
410
What is the microscopic lung appearance in emphysema?
Abnormal fenestrations, destruction of septal walls, fusion of alveoli, blebs, bullae
