RESPIRATORY ` RESPIRATORY—PATHOLOGY SEC TION III 699

Acute respiratory distress syndrome

PATHOPHYSIOLOGY Alveolar insult Ž release of pro-inflammatory cytokines Ž neutrophil recruitment, activation,
and release of toxic mediators (eg, reactive oxygen species, proteases, etc) Ž capillary endothelial
damage and  vessel permeability Ž leakage of protein-rich fluid into alveoli Ž formation of
intra-alveolar hyaline membranes (arrows in A ) and noncardiogenic pulmonary edema (normal
PCWP) Ž  compliance and mismatch Ž hypoxic vasoconstriction Ž  pulmonary
vascular resistance.
Loss of surfactant also contributes to alveolar collapse (eg, preterm infants, drowning).
CAUSES Sepsis (most common), aspiration pneumonia, burns, trauma, pancreatitis, drowning injuries.
DIAGNOSIS Diagnosis of exclusion with the following criteria (ARDS):
ƒ Abnormal chest X-ray (bilateral lung opacities) B
ƒ Respiratory failure within 1 week of alveolar insult
ƒ Decreased PaO2/FIO2 (ratio < 300, hypoxemia due to  intrapulmonary shunting and diffusion
abnormalities)
ƒ Symptoms of respiratory failure are not due to HF/fluid overload
CONSEQUENCES Impaired gas exchange,  lung compliance; pulmonary hypertension.
MANAGEMENT Treat the underlying cause.
Mechanical ventilation:  tidal volume,  PEEP (keeps alveoli open during expiration).
A B
Endotracheal tube

Right internal jugular line

Diffuse opacities Diffuse opacities

Sleep apnea Repeated cessation of breathing > 10 seconds during sleep Ž disrupted sleep Ž daytime
somnolence. Diagnosis confirmed by sleep study.
Nocturnal hypoxia Ž systemic and pulmonary hypertension, arrhythmias (atrial fibrillation/flutter),
sudden death.
Hypoxia Ž  EPO release Ž  erythropoiesis.
Obstructive sleep Respiratory effort against airway obstruction. Pao2 is usually normal during the day. Associated with
apnea obesity, loud snoring, daytime sleepiness. Usually caused by excess parapharyngeal/oropharyngeal
tissue in adults, adenotonsillar hypertrophy in children. Treatment: weight loss, CPAP, dental
devices, hypoglossal nerve stimulation, upper airway surgery.
Central sleep apnea Impaired respiratory effort due to CNS injury/toxicity, Congestive HF, opioids. May be associated
with Cheyne-Stokes respirations (oscillations between apnea and hyperpnea). Treatment: positive
airway pressure.

Obesity Also called Pickwickian syndrome. Obesity (BMI ≥ 30 kg/m2) Ž hypoventilation Ž  Paco2 during
hypoventilation waking hours (retention);  Pao2 and  Paco2 during sleep. Treatment: weight loss, positive airway
syndrome pressure.

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Pulmonary Elevated mean pulmonary artery pressure (> 20 mm Hg) at rest. Results in arteriosclerosis, medial
hypertension hypertrophy, intimal fibrosis of pulmonary arteries, plexiform lesions.  pulmonary vascular
resistance Ž  RV pressure Ž RVH (parasternal heave on examination), RV failure.
ETIOLOGIES
Pulmonary arterial Often idiopathic. Females > males. Heritable PAH can be due to an inactivating mutation
hypertension in BMPR2 gene (normally inhibits vascular smooth muscle proliferation); poor prognosis.
(group 1) Pulmonary vasculature endothelial dysfunction results in  vasoconstrictors (eg, endothelin) and
 vasodilators (eg, NO and prostacyclins).
Other causes include drugs (eg, amphetamines, cocaine), connective tissue disease, HIV infection,
portal hypertension, congenital heart disease, schistosomiasis.
Left heart disease Causes include systolic/diastolic dysfunction and valvular disease.
(group 2)
Lung diseases or Destruction of lung parenchyma (eg, COPD), lung inflammation/fibrosis (eg, interstitial lung
hypoxia (group 3) diseases), hypoxemic vasoconstriction (eg, obstructive sleep apnea, living in high altitude).
Chronic Recurrent microthrombi Ž  cross-sectional area of pulmonary vascular bed.
thromboembolic
(group 4)
Multifactorial Causes include hematologic, systemic, and metabolic disorders, along with compression of the
(group 5) pulmonary vasculature by a tumor.

Physical findings in select lung diseases

ABNORMALITY BREATH SOUNDS PERCUSSION FREMITUS TRACHEAL DEVIATION
Pleural effusion  Dull  None if small
Away from side of lesion
if large
Atelectasis  Dull  Toward side of lesion
Simple pneumothorax  Hyperresonant  None
Tension  Hyperresonant  Away from side of lesion
pneumothorax
Consolidation Bronchial breath sounds; Dull  None
(lobar pneumonia, late inspiratory crackles,
pulmonary edema) egophony, whispered
pectoriloquy

Digital clubbing Increased angle between nail bed and nail plate (> 180°) A . Pathophysiology not well understood;
A in patients with intrapulmonary shunt, platelets and megakaryocytes become lodged in digital
vasculature Ž local release of PDGF and VEGF. Can be hereditary or acquired. Causes include
respiratory diseases (eg, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis, lung cancer),
cardiovascular diseases (eg, cyanotic congenital heart disease), infections (eg, lung abscess, TB),
and others (eg, IBD). Not typically associated with COPD or asthma.

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Atelectasis Alveolar collapse (right upper lobe collapse against mediastinum in A ). Multiple causes:
A ƒ Obstructive—airway obstruction prevents new air from reaching distal airways, old air is
resorbed (eg, foreign body, mucous plug, tumor)
ƒ Compressive—external compression on lung decreases lung volumes (eg, space-occupying
lesion, pleural effusion)
ƒ Contraction (cicatrization)—scarring of lung parenchyma that distorts alveoli (eg, sarcoidosis)
ƒ Adhesive—due to lack of surfactant (eg, NRDS in premature infants)
Decreased via incentive spirometry or  PEEP during mechanical ventilation.

Obstruction

Pleura

Lung
parenchyma

Pleural effusion, Scarring

air, tumor
Obstructive Compressive Contraction Adhesive

Pleural effusions Excess accumulation of fluid A between pleural layers Ž restricted lung expansion during
inspiration. Can be treated with thoracentesis to remove/reduce fluid B . Based on the Light’s
criteria, fluid is consistent with an exudate if pleural fluid protein/serum protein > 0.5, pleural
fluid LDH/serum LDH > 0.6, or pleural fluid LDH > 2/3 upper limit of normal serum LDH.
Exudate Cloudy fluid (cellular). Due to infection (eg, pneumonia, tuberculosis), malignancy, connective
tissue disease, lymphatic (chylothorax), trauma. Often requires drainage due to  risk of infection.
Transudate Clear fluid (hypocellular). Due to  hydrostatic pressure (eg, HF, Na+ retention) and/or  oncotic
pressure (eg, nephrotic syndrome, cirrhosis).
Normal Exudate Transudate

Increased
hydrostatic
pressure

Plasma Fluid, inflammatory cells, Vascular Fluid leakage Decreased colloid

proteins and protein leakage permeability oncotic pressure

A B

Pretreatment Pretreatment Post-treatment Post-treatment

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Pneumothorax Accumulation of air in pleural space A . Dyspnea, uneven chest expansion. Chest pain,  tactile
fremitus, hyperresonance, and diminished breath sounds, all on the affected side.
Primary spontaneous Due to rupture of apical subpleural bleb or cysts. Occurs most frequently in tall, thin, young males.
pneumothorax Associated with tobacco smoking.
Secondary Due to diseased lung (eg, bullae in emphysema, Marfan syndrome, infections), mechanical
spontaneous ventilation with use of high pressures Ž barotrauma.
pneumothorax
Traumatic Caused by blunt (eg, rib fracture), penetrating (eg, gunshot), or iatrogenic (eg, central line
pneumothorax placement, lung biopsy, barotrauma due to mechanical ventilation) trauma.
Tension Can be from any of the above. Air enters pleural space but cannot exit. Increasing trapped air
pneumothorax Ž tension pneumothorax. Trachea deviates away from affected lung B . May lead to increased
intrathoracic pressure Ž mediastinal displacement Ž kinking of IVC Ž  venous return
Ž  cardiac output, obstructive shock (hypotension, tachycardia), jugular venous distention.
Needs immediate needle decompression and chest tube placement.
A B

Air in pleural
space
Tracheal
deviation

Partially Collapsed
collapsed lung lung

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 RESPIRATORY ` RESPIRATORY—PATHOLOGY SEC TION III 703

Pneumonia
TYPE TYPICAL ORGANISMS CHARACTERISTICS
Lobar pneumonia S pneumoniae (most common), Legionella, Intra-alveolar exudate Ž consolidation A ; may
A Klebsiella involve entire lobe or the whole lung.

Bronchopneumonia S pneumoniae, S aureus, H influenzae, Acute inflammatory infiltrates from bronchioles

Klebsiella into adjacent alveoli; patchy distribution
involving ≥ 1 lobe.
Interstitial (atypical) Mycoplasma, Chlamydophila pneumoniae, Diffuse patchy inflammation localized to
pneumonia Chlamydophila psittaci, Legionella, Coxiella interstitial areas at alveolar walls; CXR shows
B
burnetii, viruses (RSV, CMV, influenza, bilateral multifocal opacities B . Generally
adenovirus) follows a more indolent course (“walking”
pneumonia).

Cryptogenic Etiology unknown. ⊝ sputum and blood Formerly called bronchiolitis obliterans
organizing cultures, often responds to glucocorticoids but organizing pneumonia (BOOP). Noninfectious
pneumonia not to antibiotics. pneumonia characterized by inflammation of
bronchioles and surrounding structure.
Aspiration pneumonia Aspiration of oropharyngeal or gastric contents Presents days after aspiration event in dependent
Ž pulmonary infection. lung segment. More common in RLL if sitting
Risk factors: altered mental status ( cough up and RUL if lying down due to bronchial
reflex or glottic closure), dysphagia, neurologic anatomy. Can progress to abscess.
disorders (eg, stroke), invasive tubes (eg,
Aspiration (chemical) pneumonitis—presents
nasogastric tube).
hours after aspiration event. Due to gastric acid–
mediated inflammation. Presents with infiltrates
in lower lobe(s) and resolves with supportive
treatment.

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Natural history of lobar pneumonia

Congestion Red hepatization Gray hepatization Resolution
DAYS 1–2 3–4 5–7 8+
FINDINGS Red-purple, partial Red-brown consolidation Uniformly gray Enzymatic digestion
consolidation of Exudate with fibrin, Exudate full of WBCs, of exudate by
parenchyma bacteria, RBCs, WBCs lysed RBCs, and macrophages
Exudate with mostly Reversible fibrin
bacteria

Healthy Healthy Healthy Healthy Healthy

alveolus alveolus alveolus alveolus alveolus

Macrophage
Macrophage
MacrophageMacrophage Macrophage
Capillary Capillary Capillary Capillary
Bacteria BacteriaCapillary
Bacteria Bacteria Bacteria
Lysed Lysed Lysed Lysed Lysed
Exudate WBC
Exudate WBCExudateRBC Exudate
FibrinExudate RBC Exudate
FibrinExudate
FibrinExudate
WBC WBC WBC RBC Fibrin
RBC Fibrin
RBC RBC
RBC RBC RBC Exudate
RBC Exudate
Normal Congestion Red hepatization Gray hepatization Resolution

Lung abscess Localized collection of pus within parenchyma. Lung abscess 2° to aspiration is most often found
A
Caused by aspiration of oropharyngeal contents in right lung. Location depends on patient’s
(especially in patients predisposed to loss of position during aspiration: RLL if upright,
consciousness [eg, alcohol overuse, epilepsy]) RUL or RML if recumbent.
or bronchial obstruction (eg, cancer).
Air-fluid levels A often seen on CXR;
presence suggests cavitation. Due to
anaerobes (eg, Bacteroides, Fusobacterium,
Peptostreptococcus) or S aureus.
Treatment: antibiotics, drainage, or surgery.

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Lung cancer Leading cause of cancer death. SPHERE of complications: Superior vena cava/
Presentation: cough, hemoptysis, bronchial thoracic outlet syndromes, Pancoast tumor, Horner
obstruction, wheezing, pneumonic “coin” syndrome, Endocrine (paraneoplastic), Recurrent
lesion on CXR or noncalcified nodule on CT. laryngeal nerve compression (hoarseness),
Sites of metastases from lung cancer: liver Effusions (pleural or pericardial).
(jaundice, hepatomegaly), adrenals, bone Risk factors include tobacco smoking, secondhand
(pathologic fracture), brain; “Lung ‘mets’ smoke, radiation, environmental exposures (eg,
Love affective boneheads and brainiacs.” radon, asbestos), pulmonary fibrosis, family history.
In the lung, metastases (usually multiple Squamous and small cell carcinomas are sentral
lesions) are more common than 1° (central) and often caused by tobacco smoking.
neoplasms. Most often from breast, colon, Hamartomas are found incidentally on imaging,
prostate, and bladder cancer. appearing as well-circumscribed mass.
TYPE LOCATION CHARACTERISTICS HISTOLOGY
Small cell
Small cell (oat cell) Central Undifferentiated Ž very aggressive. Neoplasm of
carcinoma May cause neurologic paraneoplastic syndromes (eg, neuroendocrine
Lambert-Eaton myasthenic syndrome, paraneoplastic Kulchitsky cells Ž small
myelitis, encephalitis, subacute cerebellar degeneration) dark blue cells A .
and endocrine paraneoplastic syndromes (Cushing Chromogranin A ⊕,
syndrome, SIADH). Amplification of myc oncogenes neuron-specific
common. Managed with chemotherapy +/– radiation. enolase ⊕,
synaptophysin ⊕.
Non–small cell
Adenocarcinoma Peripheral Most common 1° lung cancer. Most common subtype Glandular pattern, often
in people who do not smoke. More common in females stains mucin ⊕ B .
than males. Activating mutations include KRAS, EGFR, Bronchioloalveolar subtype:
and ALK. Associated with hypertrophic osteoarthropathy grows along alveolar septa
(clubbing). Ž apparent “thickening”
Bronchioloalveolar subtype (adenocarcinoma in situ): of alveolar walls. Tall,
CXR often shows hazy infiltrates similar to pneumonia; columnar cells containing
better prognosis. mucus.
Squamous cell Central Hilar mass C arising from bronchus; cavitation; cigarettes; Keratin pearls D and
carcinoma hypercalcemia (produces PTHrP). intercellular bridges
(desmosomes).
Large cell Peripheral Highly anaplastic undifferentiated tumor. Strong Pleomorphic giant
carcinoma association with tobacco smoking. May produce hCG cells E .
Ž gynecomastia (enlarged breasts). Less responsive to
chemotherapy; removed surgically. Poor prognosis.
Bronchial carcinoid Central or Excellent prognosis; metastasis rare. Symptoms due to mass Nests of neuroendocrine
tumor peripheral effect (wheezing) or carcinoid syndrome (flushing, diarrhea). cells; chromogranin A ⊕.
A B C D E

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Pancoast tumor Also called superior sulcus tumor. Carcinoma that occurs in the apex of lung A may cause
A
Pancoast syndrome by invading/compressing local structures.
Compression of locoregional structures may cause array of findings:
ƒ Recurrent laryngeal nerve Ž hoarseness
ƒ Stellate ganglion Ž Horner syndrome (ipsilateral ptosis, miosis, anhidrosis)
1st rib
ƒ Superior vena cava Ž SVC syndrome
Mass ƒ Brachiocephalic vein Ž brachiocephalic syndrome (unilateral symptoms)
ƒ Brachial plexus Ž shoulder pain, sensorimotor deficits (eg, atrophy of intrinsic muscles of the
hand)
ƒ Phrenic nerve Ž hemidiaphragm paralysis (hemidiaphragm elevation on CXR)

Superior vena cava Obstruction of the SVC (eg, thrombus,

syndrome tumor) impairs blood drainage from the
A
head (“facial plethora”; note blanching after Jugular venous
fingertip pressure in A ), neck (jugular venous distention
Upper extremity
distension, laryngeal/pharyngeal edema), and venous distention
Thrombus/
obstruction
upper extremities (edema). Commonly caused
by malignancy (eg, mediastinal mass, Pancoast
tumor) and thrombosis from indwelling
catheters. Medical emergency. Can raise
intracranial pressure (if obstruction is severe)
Ž headaches, dizziness,  risk of aneurysm/
rupture of intracranial arteries.

` RESPIRATORY—PHARMACOLOGY

H1-blockers
First generation
CLINICAL USE
ADVERSE EFFECTS
Second generation
CLINICAL USE
ADVERSE EFFECTS
Also called antihistamines. Reversible inhibitors of H1 histamine receptors. May function as neutral
antagonists or inverse agonists.
Diphenhydramine, dimenhydrinate, Names usually contain “-en/-ine” or “-en/-ate.”
chlorpheniramine, doxylamine.
Allergy, motion sickness, vomiting in pregnancy,
sleep aid.
Sedation, antimuscarinic, anti-α-adrenergic.
Loratadine, fexofenadine, desloratadine, Names usually end in “-adine.” Setirizine
cetirizine. (cetirizine) is second-generation agent.
Allergy.
Far less sedating than 1st generation because of
 entry into CNS.

Dextromethorphan Antitussive (antagonizes NMDA glutamate receptors). Synthetic codeine analog. Has mild opioid
effect when used in excess. Naloxone can be given for overdose. Mild abuse potential. May cause
serotonin syndrome if combined with other serotonergic agents.

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Pseudoephedrine, phenylephrine
MECHANISM Activation of α-adrenergic receptors in nasal mucosa Ž local vasoconstriction.
CLINICAL USE Reduce hyperemia, edema (used as nasal decongestants); open obstructed eustachian tubes.
ADVERSE EFFECTS Hypertension. Rebound congestion (rhinitis medicamentosa) if used more than 4–6 days.
Associated with tachyphylaxis. Can also cause CNS stimulation/anxiety (pseudoephedrine).

Pulmonary hypertension drugs

DRUG MECHANISM CLINICAL NOTES
Endothelin receptor Competitively antagonizes endothelin-1 Hepatotoxic (monitor LFTs).
antagonists receptors Ž  pulmonary vascular resistance. Example: bosentan.
PDE-5 inhibitors Inhibits PDE-5 Ž  cGMP Ž prolonged Also used to treat erectile dysfunction.
vasodilatory effect of NO. Contraindicated when taking nitroglycerin
or other nitrates (due to risk of severe
hypotension).
Example: sildenafil.
Prostacyclin analogs PGI2 (prostacyclin) with direct vasodilatory Adverse effects: flushing, jaw pain.
effects on pulmonary and systemic arterial Examples: epoprostenol, iloprost.
vascular beds. Inhibits platelet aggregation.

Endothelin pathway Nitric oxide pathway Prostacyclin pathway

L-arginine
Endothelium Proendothelin Arachadonic acid
L-citrulline

Endothelin-1 Nitric oxide Prostacyclin

Basement Endothelin
membrane receptor Prostacyclin
antagonist Nitrates PDE-5 inhibitors analogs
Endothelin
receptor

cGMP GTP
PIP₂ IP₃
Smooth muscle cAMP
 Ca2+

Vasoconstriction and Vasodilation and

 proliferation  proliferation

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Asthma drugs Bronchoconstriction is mediated by (1) inflammatory processes and (2) parasympathetic tone;
therapy is directed at these 2 pathways.
Inhaled β2-agonists Albuterol, salmeterol, formoterol—relax bronchial smooth muscle. Can cause tremor,
arrhythmia. Albuterol is short-acting, used for acute symptoms. Salmeterol and formoterol are
long-acting.
Inhaled Fluticasone, budesonide—inhibit the synthesis of virtually all cytokines. Inactivate NF-κB, the
glucocorticoids transcription factor that induces production of TNF-α and other inflammatory agents. 1st-line
therapy for chronic asthma. Use a spacer or rinse mouth after use to prevent oral thrush.
Muscarinic Tiotropium, ipratropium—competitively block muscarinic receptors, preventing
antagonists bronchoconstriction. Also used for COPD. Tiotropium is long acting.
Antileukotrienes Montelukast, zafirlukast—block leukotriene receptors (CysLT1). Especially good for aspirin-
induced and exercise-induced asthma.
Zileuton—5-lipoxygenase inhibitor.  conversion of arachidonic acid to leukotrienes. Hepatotoxic.
Anti-IgE monoclonal Omalizumab—binds mostly unbound serum IgE and blocks binding to FcεRI. Used in allergic
therapy asthma with  IgE levels resistant to inhaled glucocorticoids and long-acting β2-agonists.
Methylxanthines Theophylline—likely causes bronchodilation by inhibiting phosphodiesterase Ž  cAMP
levels due to  cAMP hydrolysis. Limited use due to narrow therapeutic index (cardiotoxicity,
neurotoxicity); metabolized by cytochrome P-450. Blocks actions of adenosine.
PDE-4 Inhibitors Roflumilast—inhibits phosphodiesterase Ž  cAMP Ž bronchodilation,  airway inflammation.
Used in COPD to reduce exacerbations.
Chromones Cromolyn—prevents mast cell degranulation. Prevents acute asthma symptoms. Rarely used.
Anti-IL-5 monoclonal Prevents eosinophil differentiation, maturation, activation, and survival mediated by IL-5
therapy stimulation. For maintenance therapy in severe eosinophilic asthma.
Mepolizumab, reslizumab—against IL-5. Benralizumab—against IL-5 receptor α.
Avoidance Exposure to allergen
(eg, dust, pollen) Allergen-
specific IgE
Th2 cell Fc receptor for IgE

Glucocorticoids Anti-IgE monoclonal therapy

Fluticasone Omalizumab
Budesonide
Mepolizumab
IL-5 Reslizumab
Chromones
Mast cell Cromolyn
Benralizumab degranulation
IL-5Rα
Proinflammatory mediators
(eg, leukotrienes, histamine, interleukins)
Eosinophil

ACUTE RESPONSE (bronchoconstriction) CHRONIC RESPONSE (inflammation)

β₂-agonists AMP Muscarinic antagonists

ATP Proinflammatory cytokines
Tiotropium
Methylxanthines Ipratropium
AC PDE Theophylline Adenosine
cAMP ACh
PDE-4 inhibitors
Roflumilast (COPD only)

Bronchodilation Bronchial tone Bronchoconstriction

Mucous secretion Phospholipase A₂

Plasma exudation
Eosinophil recruitment CysLT1 Antileukotrienes Glucocorticoids
receptor Montelukast Arachidonic acid Fluticasone
Zafirlukast Budesonide

Antileukotrienes
5-Lipoxygenase COX1/COX2
Zileuton Prostaglandins
Prostacyclin
Leukotrienes
Thromboxane

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