Respiratory Pathophysiology
Key Concepts
AIRWAYS DISEASES
Asthma (Chapter 5, Weiberger)
Asthma is a respiratory condition characterized by reversible airway narrowing (hyperreactivity) and
intermittent episodes of bronchoconstriction.
I. Etiology – Not very well known
a. Genetic Predisposition – people with asthma often have underlying allergies as
defined by allergic conditions (rhinitis, eczema) and skin tests. Asthma frequently
exacerbated by the substances they are allergic to (dust, pollen, etc)
b. Environmental Factors – exposure to specific allergens during childhood. Maternal
smoking also implicated due to increased immune responsiveness of the child
II. Pathogenesis – all asthmatics, whether allergy (“extrinsic”) or non-allergy (“intrinsic”) mediated
have a common feature of airway inflammation, which is usually caused by eosinophils and
neutrophils, leading ultimately to epithelial damage. A number of mediators released from
inflammatory cells alter the extracellular environment of bronchial smooth muscle, causing
increased responsiveness to bronchoconstrictive stimuli (PG’s, leukotrienes, IL-5, IL-4).
a. Common Provocative Stimuli
i. Allergen Exposure – dust mites, domestic animals, etc. Once Ag binds
circulating IgE, mast cell Fc receptors cause degranulation (Histamine,
leukotrienes and many others)
1. Histamine – contracts bronchial SM, increase vascular
permeability, stimulation of irritant pathway. Note: asthma does
not respond to anti-histamines
2. Leukotrienes – synthesized by mast cells following Ag exposure.
Effects similar to histamine
ii. Inhaled Irritants – cigarette, inorganic dust. Stimulate irritant receptors
located on walls of larynx, trachea, large bronchi
iii. RTI’s – mechanism not clear
iv. Exercise – cold, dry air causes bronchoconstriction due to changes in ionic
environment, mediator release
III. Pathology
a. Epithelial damage with “fragile” epithelium and detachment of surface
b. Hypertrophy and hyperplasia of SM
c. Thickening of basement membrane
d. Enlargement of mucous secreting apparatus
e. Edema and cellular infiltrates w/in bronchial wall
IV. Pathophysiology – ultimately, contraction of smooth muscle in bronchial walls, mucosal edema,
and luminal secretions cause an increase in airway resistance and thus obstructive lung disease
a. Difficulty on both insp and exp, however exp is harder because of positive pleural
pressure causing collapse of airways – best seen on FEV (high Ppl)
b. PFT’s – decreased FEV1, FVC and a low FEV1/FVC ratio. Also evidence of air
trapping, increase in FRC, RV (most impressive change) and sometimes TLC.
Between attacks normal.
i. FRC increased because 1) more time is required for expiration, so you can’t
get rid of previous breath before next one, and 2) persistent activity of
inspiratory muscles
ii. TLC – perhaps elastic recoil decreased, inspiratory muscles stronger?
c. Gas Exchange –
i. ABG’s show low PO2 and low PCO2
ii. V/Q mismatch due to low V and relatively maintained Q. Despite low O 2,
patients are usually able to hyperventilate and blow off CO2.
Clinical Features – wheezing is most common on expiration. Severe asthma attacks
are called status asthmaticus
V. Diagnosis – clinical history of reversible bronchoconstriction, sputum with eos, provocation
tests (cold air, cholinergics, histamine), PFT’s
VI. Treatment – mostly geared towards stopping the bronchoconstriction associated with asthma.
Essentially two types, SM relaxers, and Anti-inflammatories
a. B2 agonists – increase levels of cAMP in the SM and mast cells reduce contraction
b. Methylxanthines (theophylline) – phosphodiesterates inhibitors which increase
cAMP levels
c. Anticholinergics – also block ACh constriction
d. Corticosteroids (prednisone) – reduce transcription of certain cytokines (IL’s, TNFalpha, etc). Work both acutely and chronically.
d.
Emphysema
Emphysema is a diagnosis characterized by pathology: dilation and destruction of air spaces distal to the
terminal bronchioles. Most often caused by smoking. Frequently co-exists with CB
I.
Etiology and Pathogenesis
a. Smoking – Loss of mucociliary transport in larger airways; Mucus gland hypertrophy,
airway wall hyperplasia; Induces bronchiolar narrowing, inflammation and fibrosis;
i. Protease-antiprotease hypothesis: PMNs in the alveoli have elastase in them
which degrades the elastin in the alveoli BUT alpha1-antitrypsin present in the
lung usually inhibits this elastase. Disturbing this balance either by smoking
(thought to create antitrypsin deficiency) or frank antitrypsin deficiency results
in increased proteolytic activity and emphysema.
b. Air pollution, Infection and Genetic deficiencies of Antitrypsin cause
emphysema…PiMZ intermediate antitrypsin levels, PiZZ very low this is the most
important form.
II.
Pathology
a. Destruction of alveolar walls and enlargement of terminal air spaces
i. Panacinar emphysema = entire acinus beyond terminal bronchiole (resp.
bronchiole, alv duct and alveolus) is enlarged, diffuse destruction
macroscopically. Associated with ANTITRYPSIN deficiency
ii. Centrilobular emphysema = respiratory bronchiole is predominantly involved
with alveolar sparing. Looks more patchy macroscopically with the infarct
around the bronchioles. Associated with SMOKING
III.
Pathophysiology
a. Expiration is prolonged so FEV & FEV/FVC are decreased
b. Air trapping occurs due to lower elastic recoil which leads to lower overall Palv or lower
driving pressure for expiratory airflow. EPP is reached too soon and air trapping results
in increased RV with TLC staying roughly the same or increasing slightly due to loss of
Pel to balance out the chest wall’s desire to expand.
c. Since elastic recoil has gone down in emphysema, there is also a simultaneous loss of
radial traction holding airways open which promotes airways collapse during maximal
expirationIncreased RV.
d. FRC is the balance between Pel and P chest wall…since Pel has decreased, the Pcw is
unopposed and FRC goes up slightly.
e. Not as much hypoxemia due to shunt as there is in CB; Hypercapnia due to
hypoventilation of alveoli
f. Cor pulmonale secondary to hypoxic vasoconstriction…polycythemia is chronic
hypoxemia. Destruction of alveoli also comes with loss of pulmonary capillaries leading
to high resistance to blood flow in remaining pulm vascular bed.
IV.
Clinical Features
a. “Type A” – pink puffer. Not terribly hypoxemic, PaO2 is relatively normal because not
that much V/Q mismatch since alveoli and capillaries are destroyed simulataneously.
b. Moderately elevated CO2 due to loss of surface area for CO2 blowoff. Dyspnea and
elevated minute ventilation result to blow off excess CO2 increased work of breathing
c. Exacerbating factor usually infection of viral origin. Air pollutants and bronchospasm
d. Cachetic, using accessory muscles to help breathe, not cyanotic, no peripheral edema
Dx & Tx
a. CXR hyperinflation, increased markings in emphysema, flat diaphragm
b. Decreased FEV, FEV/FVC; Increased RV, FRC and moderately the TLC
c. DLCO decreased in emphysema due to loss of surface area, nl in CB.
d. Not that hypoxic or hypercapnic
e. Tx limited: basically stop smoking, brochodilators (if hyperreactive component
suspected), antibiotics (prevent superinfection) and supplemental O2 to improve
hypoxemia if needed, antitrypsin if that’s the problem. Lung resection and/or transplant
V.
An Aside
I.
Work of breathing
i. work required to move chest and lung
ii. W = P x V
iii. Can be illustrated on P-V curve
iv. Work of I
1. the higher the airway R or air flow, the greater work involved
v. work of E
1. normally, work of E can be accomplished by PE stored in stretched elastic
structures and released during passive E
b. Higher the breathing rate, the faster the flow rates and the larger non-elastic work has to be
done
c. Greater the volume of air moved with each breath, the larger part of the work done by elastic
forces
d. Patients with obstructive and restrictive lung diseases employ breathing patterns that
minimize work of breathing
i. restrictive—minimize elastic work by shallow breaths and rapid breathing
ii. obstructive—minimize airway R by breathing slow and deep
Chronic Bronchitis (Chapter 6, w/ COPD)
Chronic Bronchitis is a clinical diagnosis for patients with productive sputum and chronic cough present on
most days for 3 consecutive months for not less than 2 years. Tied to emphysema by catchall of COPD
I.
Etiology and Pathogenesis
a. Smoking – affects the bronchi, the bronchioles and pulmonary parenchyma
i. Bronchi – increase in mucus secretion, thickening of airway wall due to
hypertrophy and hyperplasia of mucus glands.
ii. Mucociliary clearance is reduced
iii. Bronchioles – causes bronchiolar narrowing, inflammation and fibrosis with
airflow obstruction
iv. Parenchyma – destruction of interstitium due to increases in elastase as
elaborated by PMN’s and alveolar MO’s, which are increased in response to
smoking
b. Air Pollution
c. Infection – usually don’t initiate disease, but can exacerbate
d. Genetic predisposition – most classically studied is alpha1 antitrypsin deficiency. A1T
usually inhibits the activity of elastase. In it’s absence, the destructive activities of
elastase are high and alveolar destruction takes place
II.
Pathology –
a. Mucus secretion – hypertrophy and hyperplasia of the mucus glands. High ratio of
glands to total wall thickness (Reid Index)
b. Bronchial walls show evidence of inflammatory reactions
c. Decreased luminal diameter in small airways
III.
Pathophysiology – increases in amount of mucus production not necessarily related to the
functional impairment of the patient
a.
IV.
V.
Overall change in the cross-sectional area of the bronchi, causing increased airway
resistance
b. PFT’s – Decreased FEV1, FVC, and FEV1/FVC ratio. Bronchodilators do not always
improve situation (as opposed to asthma)
c. FRC, RV increased due to air trapping. Usually DLCO is normal in pure chronic
bronchitis.
d. Gas exchange – V/Q mismatch because ventilation is poor and perfusion is relatively
constant (some movement of perfusion away from poorly ventilated alveolar units is
attempted, but not complete)
e. Alveolar hypoventilation causes hypercapnia – 1) increased work of breathing, 2)
changes in ventilatory drive, 3) V/Q mismatch
f. Possible pulmonary hypertension – pulmonary vasoconstriction in the face of low PO2
causes increased Rpulm and right-sided heart failure (cor pulmonale)
g. These patients are referred to as “blue bloaters” due to hypoxemia and hypercapnia – 1)
cyanosis and 2) peripheral edema due to right sided heart failure
Diagnosis – made clinically using above criteria. Increased interstitial markings can be seen
on the CXR. Of course, PFT’s. Blood gases show increased PCO2 and decreased PO2.
Treatment
a. Bronchodilators – even though not as important a factor as in asthma, these drugs are still
used for minor benefit
b. Treat all RTI’s and prophylax for infections
c. Administer supplemental O2 to resolve hypoxia
d. Lung volume reduction surgery – 1) improves function of the diaphragm, 2) improves
elastic recoil of the lung
e. Lung transplant
Bronchiectasis
Bronchiectasis is irreversible dilation of the airways caused by inflammatory destruction of the walls
I.
Etiology and Pathogenesis
a. Infection – viral and bacterial infections (TB, fungi, aspergillus)
b. Obstruction – dilation behind the obstruction (tumors, mucus, Kartagener’s syndrome,
which is an immune problem)
II.
Pathology – evident on gross inspection; extreme dilation of the airways filled with purulent
secretion. Increased arterial supply to these vessels may cause bleeding and hemoptysis
III.
Pathophysiology – similar to other obstructive diseases, although PFT’s may be perfectly
normal
IV.
Clinical features – cough, copious sputum production, possible hemoptysis. Blood gases are
normal unless there is underlying CB.
V.
Diagnosis – clinical diagnosis based on sputum production, hemoptysis or both. CXR may
show increased marking, crowded vessels, or “ring” shadows corresponding to dilated
airways. CT is the gold standard for diagnosis (lung windows)
VI.
Treatment – Antibiotics, bronchopulmonary drainage, and bronchodilators. Make best
attempts to keep infection under control
Cystic Fibrosis
I.
Etiology and Pathogenesis
a. Autosomal recessive, most commonly F508 deletion (70% of cases) in chromosome 7
which codes for an ATP binding region on the CFTR gene that is responsible for
Chloride transport.
II.
III.
IV.
b. How this affects solute transport
Pathology & Pathophysiology
a. Salty sweat (above 60mg is considered diagnostic in infants)
b. Thick mucus plugs in brochi and bronchioles  superimposed pneumonitis
brochiectasis
c. Loss of mucociliary transport due to mucus plugging facilitates infection with S. aureus
or Pseudomonas.
d. Type “B” COPDer – Blue bloater or bronchitis type with hypoxemia due to significant
V/Q component due to massive shunt. Hypercapnic as well so increase in work of
breathing.
e. Hypoxic vasoconstriction  Cor pulmonale which can cause RVH.
f. Decreased pancreatic secretions  Fat malabsorption  Meconium in neonate,
stearrhea.
g. Male infertility
h. Homozygotes have CF, Heterozygotes carriers but may express some characterisitcs
Clinical Features
a. Obstructive sx – wheezes, rales, rhonchi, clubbing…
b. Complications: Pneumothorax, Hemoptysis, Cor pulm
Diagnosis & Treatment
a. Decreased FEV1, FVC, FEV/FVC; Increased RV, No emphysematous changes
b. CXR full of mucus bilaterally…
c. Rx: Antibiotics to prophylax and treat against infections, Drainage using chest PT
postural drainage, and brochodilators
Pneumoconiosis, Hypersensitivity Pneumonitis, etc (Chapter 10)
Pneumoconiosis is defined as interstitial lung disease caused by inhalation of inorganic dusts including
silica, asbestos, coal, talc, mica, aluminum, beryllium.
I.
Silicosis
a. Silica most often a component of rock or sand
b. Silica is toxic to MO’s. MO’s ingest the particulates, which proceed to activate and
ultimately destroy the MO. This sets off a cascade of inflammatory mediators that
initiate and perpetuate an alveolitis
c. Pathologically, silicosis is marked by silicotic nodules which are composed of connective
tissue and fibrotic debris
d. On CXR, you can appreciate rounded opacities and nodules (simple pneumoconiosis).
When these nodules start to expand and coalesce, the disease is termed complicated
e. Silicosis is a predisposing factor for mycobacteria (impaired MO’s)
II.
Coal Worker’s Pneumoconiosis
a.
b.
III.
IV.
V.
VI.
VII.
Exposure to coal dust, which is less toxic than silica
Pathologically, see coal macule, which is a focal collection of coal surrounded by
relatively little tissue
c. Complicated disease also known as progressive massive fibrosis, a condition that can
result in PFT changes
Asbestosis
a. Characterized by diffuse interstitial fibrosis and a propensity for developing neoplasm,
esp. bronchogenic CA and mesothelioma
b. High risk professions include shipyard, construction, and auto workers
c. Pathogenesis – asbestos activates MO’s, which then attract other inflammatory cells
including PMN’s and lymphocytes. Unlike silica, asbestos is not toxic to MO’s,
however, it causes MO’s to release a lot of toxic mediators (fibronectin, IGF-1, PDGF),
which cause fibroblast recruitment and ultimately interstitial fibrosis
d. Pathology – characteristic finding is the ferruginous body, a dumbbell-shaped, rustcolored body found in MO’s. Not pathomnemonic, though
e. CXR shows pleural thickening, linear streaking, and possible effusion
f. Physical finding may include clubbing
Berylliosis
a. Due to metal dust of Be
b. Type IV (delayed type, T cell mediated) hypersensitivity reaction. Lymphocytes show
increased proliferation when exposed to Be. This is how the disease is diagnosed
c. Mechanism of disease not fully elucidated. Does the Be react with the T-cell directly, or
does Be cause something else to become antigenic. Either way T H1 cells are the active
ones
Hypersensitivity Pneumonitis
a. Immune mediated interstitial lung disease (extrinsic allergic alveolitis)
b. Antigens are usually inhaled organic dusts, microorgs, plant proteins, etc
c. Pathogenesis – currently believed that these diseases are Type IV or III mediated immune
responses. T-cells recruit MO’s which then form granulomas and possibly activate
complement
d. Pathology – Lymphocytes, MO’s. Granulomas, which are poorly formed (as opposed to
Sarcoid)
e. Diagnosis – HP’s generally present very differently. Either acute or chronic – having a
clear antigen exposure aids in the diagnosis of HP
f. CXR – acute shows diffuse and patchy infiltrates. Chronic shows more nodular
characteristics
Drug-Induced Interstitial Lung Disease
a. Chemotherapeutics cause interstitial disease (bleomycin, mitomycin, etc)
b. Caused by direct toxicity to the alveolar cells, as well as by generation of toxic oxygen
radicals
c. Pathology – Atypical type II alveolar epithelial cells with large nuclei
Radiation induced lung disease
a. Divided into early and late phase fibrosis. Acute radiation pneumonitis develops 1 to 3
months following radiation course, late phase occurs 6-12 months following therapy
b. Toxicity to capillary endothelial cells and type I alveolar cells are thought to be the
mechanism of disease
c. Treated with corticosteroids
IPF
I.
Etiology & Pathogenesis
a. Unknown antigen stimulates a neutrophilic alveolitis that is the prominent feature of IPF
b. Two main components as with all interstitial diseases are inflammation and fibrosis.
c. Two subtypes: Usual Interstitial Pneumonitis (UIP) and Desquamative Intersititial
Pneumonitis (DIP).
i. UIP has more prominent fibrosis and is associated with poorer outcome
II.
III.
IV.
ii. DIP has alveolar macrophages found in the alveolar spaces that have surfact in
their lamellar bodies…this is associated with a better outcome and is more
responsive to steroid tx.
Path & Pathophys
a. Lots of fibrosis and many different kinds of inflammatory cells (IPF tends to have more
PMNs than lymphocytes but they may be present as well)
b. No granulomas (indicates Sarcoid or Hypersensitivity Pneumo)
c. Later stages you might see cystic developments and progression to a honey-comb lung
with dense scarring indicative of severe fibrosis
d. Overall: like other Restrictive diseases you have an Increase in elastic recoil which has
many effects:
i. Increases work of breathing because you need to generate more positive
inspiratory pressure to oppose the Pel of lung on inspiration: so you take smaller
tidal breaths to decrease work of breathing and maintain alveolar ventilation
ii. lowers TLC (balance btw Pel inwards and max force of inspiratory muscles
outwards, Pel wins) and a lower FRC (balance btw Pel inwards and Pcw
outwards, Pel wins)…RV lowered as well but not as much
iii. Decrease DLCO due to fibrosis and progressive loss of gas exchange surface
area
iv. V/Q mismatch hypoxemia, w/ PCO2 relatively normal or low due to increased
minute ventilation
Clinical Features
a. Dyspnea, crackles or rales @ lung bases, clubbing
Dx & Tx
a. CXR reticulonodular or cystic spaces CT better
b. Antinuclear antibodies are + (indicating DNA breakdown products/inflammatory
process)
c. Steroids or other immunosuppressants – work better in the DIP form of disease
Sarcoidosis
Sarcoidosis is defined as a disorder in which multiple organ systems may have non-caseating granulomas,
with the lung being the most commonly affected organ.
I.
Etiology and Pathogenesis
a. Sarcoid is a disease that particularly affects young black women, although other ethnic
groups and males are also affected
b. Most prevalent disease of unknown cause affecting the alveolar wall
c. People with sarcoid have been shown to have hyperactive humoral immunity and
depressed cellular immunity
d. Although not fully elucidated, presumably an Ag recognized by MO’s and T cells
activate a number of cytokines recruiting MO’s and stimulating B cells to produce Ab’s
(high T cell activity in lung lowers peripheral T cell activity)
e. Activated MO’s secrete factors (TGF-B, fibrinectin, IGF, etc) that recruit fibroblasts and
ultimately cause fibrosis
f. The exact Ag and the immunologic/genetic mechanism by which sarcoid develops is as
yet undetermined
II.
Pathology – non-caseating granulomas with multinucleated giant cells and without necrosis;
may also see an alveolitis composed of MO’s and lymphocytes
III.
Pathophysiology – typical for that of interstitial lung diseases
a. Decreased compliance due to interstitial fibrosis
b. Small volumes – RV, TLC, FRC, VC are reduced. FEV1/FVC ratio may be normal or
high
c. Impaired diffusion, which is not primarily caused by interstitial thickening, but rather by
decreased gas exchange area
d. Impaired small airway function – large airways spared
Gas exchange problems – V/Q mismatch in the primary cause of hypoxemia and relative
hypocapnia. Exercise induced hypoxemia thought to be caused by diffusion
abnormalities, not necessarily V/Q matching. PCO2 usually normal
f. Pulmonary Hypertension – 1) chronic hypoxemia causes vasoconstriction in the
pulmonary vasculature to improve V/Q matching. 2) alveolar capillary destruction and
fibrosis causes impedance to flow
Diagnosis
a. usually present with non-productive cough and dyspnea, although other granulomas may
also present (eye, skin, lots of others)
b. Show anergy on delayed type hypersensitivity reactions
c. CXR shows enlarged hilar lymph nodes, diffuse interstitial lung disease, or both
d. Biopsy confirms non-caseating granulomas
Treatment – corticosteroids, although titration is difficult and symptoms often alleviate
without treatment
e.
IV.
V.
ARDS
ARDS is any one of a number of acute interstitial disease processes that involve a disturbance in the normal
epithelial/endothelial border between alveoli and capillaries in the pulm parenchyma. Pulm capillary
permeability is messed up which yields a proteinaceous exudates in the interstititium.
I.
Etiology & Pathogenesis
a. Multiple causes some inhaled (gastric aspiration, chemicals, fresh water, chronic
oxygenation, NO2, Pneumocystis and viral pneumonia), some enter via pulm circulation
(sepsis, DIC, fat emboli etc.)
b. Somehow Injury to Type 1 epitelial cells of alveoli happens. Neutrophil theory involves
activation of complement C5aaggregation of neutrophilsrelease toxic free
radicals…endotoxins and/or macrophages might play a role as well.
II.
Path & Pathophys
a. Damage: destruction of type I alveolar cells,
b. Exudative Phase: interstitial and alveolar fluid, alveolar collapse, inflammatory cell
infiltrates, HYALINE membranes – fibrin, cellular debris, plasma protein on alv surface
c. Proliferative Phase: hyperplasia of type II alv cells
d. Shunt obviously…so hypoxemia. Also V/Q mismatching from irregular destruction of
parenchyma. O2 improves only the V/Q issue.
e. Fluid in alveoli inactivates surfactant making the alveoli collapse more easily
f. Pulm HTN due to hypoxic vasoconstrict + obliteration of vessels (microthrombi and
edema)
g. Restrictive disease pattern: decreased lung volumes, decreased FRC, decreased lung
compliance
III.
Clinical Features
a. Dyspnea, tachypnea
b. Rales & Rhonchi
c. Hypoxemia, nl PCO2 or hypocapnic (depends on vent. rate), AaDO2 wide (V/Q)
IV.
Dx & Tx
a. R/o cardiogenic cause of edema (check pcw & LA pressure)
b. CXR: Intersitital edema
c. Treat underlying cause, steroids, oxygen supplementation, NO vasodilator in regions that
are well ventilated to improve V/Q
Pulmonary Embolus
I.
II.
Etiology and Pathogenesis
a. Mostly due to DVTs which are due to Virchow’s Triad: Injury, Stasis, Hypercoag (ISH)
b. Take note of: Prolonged sitting, Airplane travel, Bedrest, surgery (particularly knee/hip
replacement), OCPs, post-partum state, genetic deficiency of Antithrombin, protein C &
S or Factor V Leidin (genetic lack of susceptibility to Protein C)
Pathology
a.
III.
IV.
V.
Rare necrosis of lung tissue because of double circulation (pulm artery and bronchial
artery)…usually presents as congestive atelectasis (parenchymal hemorrhage + edema)
b. Often recanalizes
Pathophys
a. V/Q to infinity (increase V, 0 Q)  increased physiologic dead space  hypoxemia
b. Hypocapnia because you increase minute ventilation to blow off excess CO2 (resp.
alkalosis)
c. Increased pulm vasc resistance, possible RVF and JVD
d. Chemical mediators released from thrombus  vasoconstriction
Clinical Features
a. Dyspnea, Pleuritic chest pain, hemoptysis, syncope
b. Possible pleural friction rub if pulm infarct extends all the way to the pleura.
Dx & Tx:
a. V/Q scan abnormalities, CXR shows enlargement of pulm artery near hilum
(Westermark’s sign) hard to read. Pulm angio also diagnostic
b. Anticoag with LMWH and maintenance warfarin (can be done prophylactically)
c. Thrombolysis (tpa, streptokinase)
Pulmonary Hypertension (Chapter 14)
Pulmonary Hypertension is defined as frank increases in intravascular pressure within the pulmonary
circulation. The consequence of PHtn is right ventricular hypertrophy, regardless of the primary cause of
the increased pressures
I.
Pathogenesis – a number of etiologic causes
a. Occlusion of a sufficient cross-sectional area (e.g. PE), which may cause dilation in the
acute setting (not enough time to develop hypertrophy), or in a chronic condition –
straight RV hypertrophy
b. Decreased cross-sectional area due to arterial or arteriolar wall thickening (scleroderma,
primary PHtn)
c. Cross-sectional area compromised by primary parenchymal disease with loss of arterioles
due to destruction of alveolar walls (interstitial disease, emphysema)
d. Vasoconstriction in the face of hypoxia or acidosis, which is reversible if gases are
restored (Chronic Bronchitis)
e. Left-to-Right shunt causes eventual thickening of arterial walls and increased resistance.
PHtn can become so severe, that a right-to-left (Eisenmenger’s) shunt can occur
f. Left-sided back-up (increased LA pressure)
II.
Symptoms
a. Dyspnea
b. Substernal chest pain exacerbated on exertion, due perhaps to the increased workload of
the RV and subsequent RV ischemia
c. Exertional fatigue and syncope because of an inability to adequately compensate during
times of exertion
III.
Physical Signs
a. Accentuation of P2 sound
b. RVH causes RV heave which can be felt
c. S4 or S3 sound heard on right side
d. Possible increased JVP or peripheral edema
IV.
Diagnosis
a. If primary injury at the level of artery or arteriole, CXR shows increased size of
pulmonary arteries in response to distal disease (periphery shows tapered vasculature).
Seen as an enlargement of cardiac silhouette
b. If primary injury b/c of increased flow or shunt, CXR shows increased pulmonary blood
flow or redistributed blood flow (from base to apex)
c. Perfusion scanning can show if the primary cause is PE
d. PFT’s are useful for determining if airflow obstruction or restricted lung volumes are
responsible
e. ABG’s can be used to determine if hypoxia or pH have to do with etiology
V.
VI.
VII.
f. Echo, ECG and cath can diagnose RVH and increased PA pressures
Primary Pulmonary Hypertension
a. Disease of unknown cause affecting women between 20 and 40
b. Associated with certain drugs and Raynaud’s syndrome (excessive vasoconstriction of
peripheral vasculature in the cold) indicate that excessive constriction may be involved
c. Treated with PGI2 or inhaled NO
Pulmonary Htn 20 to Airway or Parenchymal Lung disease
a. The most common causes of cor pulmonale are obstructive and interstitial lung disease
b. “Blue Bloaters” are the most susceptible to disease due to XS hypoxia, respiratory
acidosis, polycythemia (increased viscosity), and possible co-existent emphysema
c. Treatment is O2
Pulmonary arterial Htn due to Pulmonary Venous Htn
a. Increased venous pressures due to high LA pressure
b. Chronic high P causes venous and capillary dilation as well as extravasation of RBC’s in
the lung parenchyma
c. Pathologically, alveolar MO’s phagocytose RBC’s and show increased hemosiderin,
which can be detected with iron stains of the sputum
d. CXR shows blood redistributed to the apices, interstitial and alveolar edema, and
Kerley’s B lines (small lines extending to the pleura at the lung bases)
Pleural Effusion
I.
II.
III.
IV.
General info on pleura
a. Visceral pleura have two blood supplies: systemic arteries (bronchial arteries) bring
oxygenated blood to pleura and pulmonary veins (which have oxygenated blood in them)
drain this deoxygenated blood away (shunt). Parietal pleura has systemic vasculature and
stomas to drain the pleural space into the lymphatics
b. Pleural fluid is filtered mainly from parietal pleura into the pleural space and then
resorbed through stomas into the lymphatics
Two types of Pleural effusion
a. Transudate – Low protein content, due to elevation of hydrostatic pressure (forces watery
component into pleural space)
i. CHF, Left-sided heart failure, buildup of fluid in lung parenchyma which spills
over into the pleural space
ii. Decrease in plasma oncotic pressure (hypoproteinemia secondary to
glomerulonephrotis (holes in the glomerulus which cause proteinuria)) so no
driving force on water back into the capillaries
iii. Ascitic fluid travels through holes in the diaphragm into the pleural space.
b. Exudate – Fluid with protein in it. Two causes (Infection and Malignancy)
i. Infection
1. Parenchyma out to pleura: Bacterial pneumonia (parapneumonic
effusion) or TB. If it has organisms + PMNs/MOs in the fluid call it an
empyema
2. Pleura infections: SLE and Rheumatoid Arthritis
ii. Malignancy
1. Intrapulonary or hematogneous
2. Lymphatic stomas blocked by tumor foci
Clinical Features
a. Pleuritic chest pain, dyspnea, fever, friction rub, egophony, dullness to percussion
Dx & Tx
a. CXR: blunted costophrenic angle
b. Thoracocentesis: exudative if:
i. If pleural fluid/serum ratio > .5
ii. If pleural fluid/serum LDH ratio > .6
iii. If pleural fluid LDH > .66*upper limit of normal serum LDH
c. Possible restrictive pattern of lung disease if effusion is large enough
d.
Drain the fucker or just treat with antibiotics and wait. Sometimes with recurrent
effusions, they’ll weld the parietal to the visceral pleura by injecting an irritant
Pneumothorax
I.
Etio & pathogenesis:
a. Trauma, needle or catheter or some kind of bleb or air pocket in lung that busted out
allowing communication btw alveoli and pleural space (see pneumocystis, necrotizing
pneumonia, cysts etc.).
b. Primary spontaneous pneumothorax probably has to do with one of these blebbing things
that ruptures into the pleural space.
c. Mechanical ventilators can cause spontaneous pneumothroax
d. Tension pneumothorax: add air to pneumothorax on inspiration, flap closes on expiration
doesn’t allow air to escape…gradual buildup of air
Pathophys
a. Lung collapse
b. Mediastinal/tracheal shift away from pneumothorax
c. CV collapse if decrease in IVC or SVC venous return due to increase in intrathoracic
pressure
Clincal Features
a. Chest pain, dyspnea, hyperresonance, tracheal deviation, decreased breath sounds/tactile
fremitus
Dx & Tx
a. CXR: line of lung usually at apex in smaller pneumothorax
b. Resolves spontaneously when hole is closed because blood gases are at lower pressure
than gas in the pleural space so it will be spontaneously resorbed. Administer O2 at
100% to hasten recovery…this works because increasing %O2 replaces blood nitrogen
completely which is then unloaded in tissues and causes a huge gradient for nitrogen and
oxygen in pneumothorax.
c. Tap the pneumothorax if hemodynamic collapse is suspected (you can hear the air come
out).
II.
III.
IV.
Ventilatory Response
I.
To Hypoxia:
a. Ventilation increases only after PO2 falls below 60 torr
b. However, ventilation increases linearly with respect to O2 saturation (with every drop in
%sat, there is a direct increase in ventilation)
To Hypercapnia
a. Ventilatory response increases linearly with respect to PCO2 (with every increase in
PCO2, there is a direct increase in ventilation)
b. In chronic hypercapnia, this direct ventilatory response is blunted because kidneys retain
bicarb which adequately buffers the excess H+ ions and the central chemoreceptors don’t
see the decrease in pH
II.
Cheyne-Stokes breathing
I.
Etiology & pathogenesis
a. CHF and CNS disease
b. Problem with the feedback system to ventilatory control.
c. Basically you have this cycling effect where the central chemoreceptors detect
lowered pH and increase vent rate but overshoot and then lower vent rate to apnea
and then increase it again…delay due to slowed circulation in CHF or instability of
resp. control in CNS disease
Sleep Apnea
I.
Types
Obstructive – drive to breathe still present but obstruction of airway prevents inspiratory
airflow (excess soft tissue in upper airway, REM sleep inhbits upper airway muscles etc).
Airflow resumes due to microarousals (gets out of REM sleep), then inspiratory muscle
control lost again and cycle continues.
b. Central – no drive to breathe, no resp. muscle activity
c. Mixed – features of both
Clinical Features
a. Disordered resp. during sleep
b. Daytime hypersomnolence
c. CV complication – prolonged hypoxemia, pulm HTN  cor pulmonale RVH.
Tx:
a. Obstructive: Nasasl CPAP – maintain positive pressure on the airway during sleep…also
there’s a surgery to remove redundant soft tissue
b. Central: Resp. stimulants including a phrenic nerve pacemaker to stimulate
diaphragm…weight loss helps also
a.
II.
III.
Lung Cancer (Chapter 20)
I.
II.
III.
Etiology
d. Smoking –
i. single most important risk factor for developing Lung CA
ii. Exact factor responsible has yet to be determined
iii. Risk for lung CA decreases after smoking cessation
iv. Initial cellular changes (epithelial dysplasia, ciliary dysfunction, nuclear
changes) happen long before carcinoma develops
e. Occupational Factors
i. Classically asbestos, which most often causes carcinoma of the lung, but
may also produce a very rare mesothelioma
ii. Arsenic, ionizing radiation, haloethers, aromatic hydrocarbons, etc are all
implicated
f. Genetic Factors
i. Lung CA develops in some heavy smokers and not others making a genetic
factor likely
ii. Increased risk due to family members who have lung CA
iii. Candidate genes include cyt P-450, which should clear carcinogens
g. Parenchymal Scarring
i. Scar tissue can be a locus for cancer formation, called scar carcinoma
ii. Usually a result of old injury like TB, pulmonary fibrosis
Pathogenesis
a. Because of cellular heterogeneity within the tumor, transformed cell is likely to be of
stem cell origin
b. A number of proteins controlling cell growth have been implicated in the progression
of lung cancer, both proto-oncogenes and tumor suppressor genes
c. These include ras, myc, retinoblastoma and p53 (most common and found to be
associated with benzopyrene in cigarette smoke)
Pathology – often called bronchogenic carcinoma, meaning that many lung cancers arise
from bronchi or bronchial structures, but this is not always the case
a. Squamous Cell Carcinoma – non small cell carcinoma strongly related to smoking
i. Originate from the bronchial wall
ii. Progress from metaplasia of columnar epithelium to squamous 
carcinoma in situ  invades bronchial mucosa  clinical findings 
metastasis
iii. Tumors show keratin, “squamous pearls” and intercellular bridges
iv. Located at large airways, which causes obstruction and distal atelectasis
v. Best prognosis of all lung cancers
b. Small Cell Carcinoma
IV.
V.
VI.
i. 20% of all – oat cell is the most common of these, which arise from
proximal airways
ii. Oat cells appear as small darkly stained cells with sparse cytoplasm
iii. Local growth follows submucosa, but rapidly invades local lymph and
blood. Hilar and mediastinal nodes are most frequently involved
iv. Metastases are very common affecting the brain, liver, bone, adrenal
c. Adenocarcinoma
i. Most frequent type of lung cancer (~1/3), arising from the bronchiole or
alveolar walls, often appearing at the site of scarring
ii. Tendency to poorly form mucus-secreting glands, which present as solitary
peripheral nodules
iii. Spread to hilar and mediastinal lymph nodes, metastasizes to distant sites,
but not as malignant as small cell
d. Large Cell Carcinoma
i. Most difficult carcinoma to define given that it is the miscellaneous
category for lung CA’s
ii. Behave very similar to adenocarcinoma
Symptoms (certain symptoms indicate types of carcinoma)
a. Usually cough and hemoptysis
b. Bronchial obstruction shows postobstructive pneumonia, dyspnea
c. Pleural involvement
d. Adjacent structures – heart, esophagus
e. Complications of mediastinal involvement – SVC obstruct, phrenic/laryngeal n.
f. Metastases to brain, bone, liver, adrenal
g. XS hormone production: ACTH, ADH, PTH
h. Non-specific CA – weight loss, fatigue, nausea
Diagnostic Approach
a. CXR/CT most important tools for diagnosis
b. Location of the lesion is also important for confirming histologic finding
c. Biopsy can determine whether nodes are reactive or tumor involved
d. Staging done by TNM system (tumor, nodes, metastases)
e. Microscopic evaluation based on the Pathology above is important to determine the
exact type of cancer (important for treatment)
f. Functional assessment is important to determine if a surgical approach is viable. I.e.
if function is poor in non-involved lung areas, resection may not be an option
Therapy – despite advances, 5 year survival is only 13 percent
a. Surgical intervention may be indicated for non-small cell CA
b. Radiation and Chemotherapy are done on a case-by-case method
Pneumonia
Sixth most common cause of death. Community-acquired and hospital-acquired.
I.
Etiology and Pathogenesis
a. Two routes to lower respiratory tract: inhalation and aspiration, can also get there through
bacteremia and seeding of alveoli (Staph A. due to IDU)
b. BACTERIA:
i. Pneumococcus = S. Pneumonia. Gram+ diplococci. Most common cause of
community-acquired pneumonia. Frequently follows viral prodrome. Many
antigenic types of polysaccharide capsule
ii. S. Aureus – Gram+ clusters. Often secondary to influenza, hospitalization, IDU
bacteremia
iii. H. flu = Gram– coccobacillus
iv. Klebsiella = Gram– rod. Alcoholics. GI tract
v. Pseudomonas = Gram– bacteria in hospitalized patients
vi. Legionella = Gram- bacillus outbreak and in common water sources
vii. Chlamydia pneumonia = Obligate intracellular parasite. Gram- bacteria
c. VIRUSES:
II.
III.
IV.
V.
i. Influenza
ii. RSV
d. Mycoplasma
i. Young adults mostly. Community-acquired (walking pneumonia). Insidious
onset, usually self-limited
Pathology
a. Lobar pneumonia = usually due to pneumococcus. Entire lobe of lung affected. Bacteria
move from acinus to acinus via the pores of Kohn. Alveolar disease
b. Bronchopneumonia = Patchy diffuse infiltrate. Distal airways inflammation. Staph and
Gram– bacilli.
c. Interstitial pneumonia = Within interstitial walls. Viral pneumonias and mycoplasma.
Pathophys
a. V/Q mismatch…shunt and subsequent hypoxemia.
b. CO2 retention blown off hyperventilating so hypocapnic
Clinical Fever
a. Fever w/ chills, cough w/ sputum, dyspnea, pleuritic chest pain, crackles
b. Pneumococcal pneumonia: yellow, green or rust-colored sputum…onset abrupt w/ fever
& chills.
c. Mycoplasma: insidious onset
d. Staph and Gram negs: very ill…hospitalized etc.
Dx & Tx
a. CXR: lobar (pneumococcus, kleb), patchy (staph and gram negs) or interstitial
(mycoplasma) edema distribution pattern
b. Sputum will have PMNs and bacteria
c. Treatments
i. Pneumococcus – penicillin + erythromycin
ii. Staph (penicillinase) so give penicillins that resist the penicillinase
iii. H Flu – cephalosporins
iv. Gram negs – aminoglycosides
v. Mycoplasma & Legionella – erythromycin
vi. C. pneumonia – Tetracycline + erythromycin
d. Comm. Acquired
i. Outpatient <60yo no complications: Pneumococcus, mycoplasma, RSV
ii. Outpatient >60yo + complications: Pneumococcus, H. flu, RSV, Gram negs, S.
aureus
iii. Need to be Hospitalized: Pneumococcus, H. Flu, Gram neg enteric bacilli, S.
aureus
iv. Hospitalized in ICU: Pneumococcus, Legionella, Enterics
e. Hosp. acquired
i. Enteric gram negs, S. aureus, pseudomonas, legionella
f. Abscesses formed by anerobic bacteria…but s. aureus and gram neg enterics also cause
lung abscesses
g. Empyema – parapneumonic effusion, anerobes, s. aureus cause empyema…drainage
necessary
TB and non-TB mycobacterial infection
Infectious agent is small, aerobic, rod-shaped bacterium that retain special stains after exposure to acid
(acid fast bacilli) – Spread is through small aerosol droplets usually from 1um to 5um allowing for
exposure to the distal parenchyma
I.
Etiology and Pathogenesis
a. Primary infection – usually goes unnoticed by the host, however cell-mediated (Type
IV) immnity develops within a few weeks. In 10% of cases, bodies defenses are
unable to cope leading to primary progressive TB
b. Reactivation TB – following this initial exposure, many TB bacilli are able to lie
dormant, neither proliferating nor causing clinically active disease. In situations of
II.
III.
IV.
V.
VI.
VII.
immunocompromised or excessive physiological stress, the balance can be tipped
and clinical disease may become apparent
c. Miliary TB – hematogenous spread causing disseminated findings
Pathology – depends varying on the stage of the infection
a. Delayed Hypersensitivity – usually occur at lung apices
i. Granulomas – collections of phagocytic cells called epithelioid histiocytes
ii. Caseous necrosis –foci of necrosis and softening at center of Ghon Complex
iii. Fibrosis and scarring due to healing mechanisms
b. Spread to peripheral organs – evidence of disease may become apparent at kidney,
liver, adrenals, bones, or CNS via hematogenous spread
Pathophysiology –
a. Chronic infection – TB is a wasting disease presenting with weight loss, wasting and
loss of appetite (Consumption)
b. Chronic destructive process in lung – because the scarring and fibrosis tends to affect
posterior and apical portions of the lung, function (O2, PFT’s, V/Q) tends to be
relatively preserved
Clinical Manifestations
a. Systemic symptoms – weight loss, fever, night sweats
b. Pulmonary symptoms – hemoptysis, cough, sputum
c. Abnormal CXR finding with or without other symptoms
Diagnosis –
a. PPD test – used to measure primary exposure. False negatives can occur due to nonTB mycobacteria, or previous vaccination
b. CXR
i. Primary - non-specific infiltrate, hilar lymph nodes, calcifications in the
parenchyma and granulomas
ii. Reactivation – apical and posterior segments of upper lobes and superior
segment of lower lobes. Infiltrates, cavities, nodules, scarring, and
contraction can been seen
c. Staining of sputum with acid-fast stain – difficult to detect latent disease
d. Culture – definitive diagnosis, however, takes quite a while to culture
Therapy
a. Standard of care is PIRE – pyrazinamide, isoniazid, rifampin, ethambutol
b. May also be isolated if adherence to strict regimen is suspect
Non-TB mycobacteria – found in soil, water and dust
a. Most common is Mycobacterium avium-intracellulare (MAI)
b. Found in two settings 1) underlying lung disease, 2) immunocompromised