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🫁 Respiratory System - Detailed Study Notes

Source: Murray & Nadel's Textbook of Respiratory Medicine, 2-Volume Set

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1. ANATOMY & PHYSIOLOGY OF THE RESPIRATORY SYSTEM

Functional Overview

• The respiratory system serves gas exchange (O₂ delivery, CO₂ removal), airway defense, and phonation.
• The lung has two circulations: pulmonary (for gas exchange, low pressure) and bronchial (systemic, nourishes airways).
• Normal mean pulmonary artery pressure (mPAP) in healthy individuals: ≤20 mm Hg. Pulmonary hypertension is defined as mPAP ≥21 mm Hg.

Key Physiological Concepts

• V/Q ratio (Ventilation/Perfusion): mismatch is the most common cause of hypoxemia in lung disease.
  • Low V/Q areas → venous admixture → hypoxemia
  • High V/Q areas → wasted ventilation (dead space) → hypercapnia
• Alveolar-arterial (A-a) gradient: elevated in most lung diseases; normal in pure hypoventilation.
• FEV1/FVC ratio: key spirometric measurement
  • < 0.70 = obstructive pattern (COPD, Asthma)
  • Normal FEV1/FVC with reduced FVC = restrictive pattern (IPF, fibrosis)
• DLCO (Diffusing Capacity for Carbon Monoxide): reduced in emphysema, IPF, pulmonary vascular disease.

Lung Lymphatics

• Lymphatics are crucial for fluid balance and immune surveillance.
• In COPD: there is an increase in lymphatic vessel density, particularly near alveolar spaces, associated with worse disease severity.
• In IPF: alveolar lymphangiogenesis occurs (increase in both blood capillaries and lymphatics near alveoli). - Murray & Nadel's, p.179

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2. OBSTRUCTIVE LUNG DISEASES

2.1 ASTHMA

Definition

Diagnosis & Control Assessment (GINA Guidelines)

• Well controlled: 0 criteria present
• Partly controlled: 1-2 criteria present
• Uncontrolled: 3-4 criteria present

Severity Classification (GINA Step-Based)

• Mild asthma: well controlled on Step 1 or 2 (SABA or low-dose ICS)
• Moderate asthma: well controlled on Step 3 (low-dose ICS/LABA)
• Severe asthma: requires Step 4 or 5 to prevent becoming uncontrolled, or remains uncontrolled despite Step 4-5

Risk Factors for Poor Outcomes

• Uncontrolled symptoms
• Frequent SABA use, poor inhaler technique, not on ICS
• Comorbidities: obesity, chronic rhinosinusitis, GERD, pregnancy
• Exposures: smoking, allergens, air pollution
• Low FEV1 (<60% predicted) or highly reversible bronchoconstriction
• Psychological/socioeconomic factors
• History of severe exacerbation

Treatment Steps (NHLBI/GINA Framework)

• Core components: reverse bronchoconstriction, reduce inflammation, identify/control environmental triggers, patient-provider partnership
• Step-up if symptoms uncontrolled; step-down if controlled for ≥3 months
• Key pharmacology:
  • SABA (salbutamol): reliever/rescue
  • ICS (inhaled corticosteroids): cornerstone controller
  • LABA (long-acting beta-2 agonists): always add to ICS, never alone
  • Biologics: anti-IgE (omalizumab), anti-IL-5 (mepolizumab), anti-IL-4/13 (dupilumab) for severe eosinophilic asthma

Acute Severe Asthma Management

• Systemic corticosteroids
• Continuous nebulized SABA ± ipratropium
• IV magnesium sulfate if severe
• Heliox, NIV, intubation in life-threatening cases

Chronic Obstructive Asthma

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2.2 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Definition

Phenotypes

• Pink Puffer (emphysema-predominant): thin, breathless, relatively preserved gas exchange, lower BMI, lung hyperinflation - may be protected against OSA
• Blue Bloater (chronic bronchitis-predominant): obese, cyanotic, high BMI, lower respiratory drive, peripheral fluid retention - higher risk for OSA

Exercise Physiology in COPD

• Mild COPD: may have normal exercise capacity
• Moderate-severe COPD: impaired VO₂max and peak work rate proportional to GOLD stage
• Unlike heart failure (cardiovascular limitation), COPD patients are limited by ventilatory pump failure
  • Arterial PCO₂ remains stable or increases at peak exercise (inability to raise alveolar ventilation)
  • VE at peak exercise approaches MVV (maximum voluntary ventilation)
  • Low tidal volume, high respiratory rate, high end-expiratory lung volume

Dynamic Hyperinflation (key concept in COPD)

• Due to expiratory flow limitation during exercise → patients must increase end-expiratory lung volumes
• Results in:
  • Flattening of diaphragm → decreased contractile strength
  • Increased respiratory muscle fatigue
  • Increased dyspnea
  • Hemodynamic effects: impaired cardiac preload/afterload → reduced VO₂/HR
  • Increased pulmonary vascular resistance → right ventricular dysfunction
• Interventions to reduce dynamic hyperinflation: lung volume reduction surgery, bronchodilators

COPD and Pulmonary Hypertension (COPD-PH)

• COPD-PH accounts for >80% of all chronic lung disease-associated PH
• Prevalence varies: 2.7-90.8% depending on definition and assessment method
• Key definitions (6th World Symposium on PH, 2019):

• Severe PH (mPAP ≥40 mm Hg) in COPD is uncommon (~1-2%) and often has another cause (left heart disease, CTEPH)

COPD-OSA Overlap Syndrome

• First described in the 1980s. A separate named entity.
• OSA prevalence in COPD is not clearly higher than in the general population
• Mechanisms linking OSA and COPD: upper airway inflammation, skeletal myopathy (airway collapsibility), lower respiratory drive
• Clinical impact: at higher risk for hypercapnia, hypoxemia, and PH at an earlier stage than expected
• Diagnosis: polysomnography (PSG) preferred over HSAT in moderate-severe COPD; include CO₂ monitoring
• Note: medications used for COPD can be beneficial (theophylline) or harmful (inhaled corticosteroids) for concurrent OSA

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2.3 BRONCHIECTASIS

Definition

Hallmark Features

• Chronic productive cough (typically ≥30 mL mucoid or mucopurulent sputum/day)
• Fever, hemoptysis, weight loss in exacerbations
• Association with postnasal drip, rhinosinusitis, asthma, GERD, chronic bronchitis

Common Pathogens

• Haemophilus influenzae
• Staphylococcus aureus
• Pseudomonas aeruginosa

Imaging

• Chest X-ray: increased bronchial wall thickening (lower lobes in advanced disease)
• Thin-section (HRCT) CT chest: gold standard - shows airway wall thickening, dilation, distortion, mucus plugging, bronchiolitis

Management

• Chest physiotherapy (airway clearance) - essential
• Inhaled β₂-agonists: improve mucociliary clearance, reverse bronchoconstriction
• Postural drainage
• Intermittent antibiotic therapy
• Long-term macrolide therapy: improves exacerbations and lung function
• Antitussives: not recommended as routine (cough is the main clearance mechanism)
• Murray & Nadel's, p.875

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3. RESTRICTIVE / INTERSTITIAL LUNG DISEASES

3.1 IDIOPATHIC PULMONARY FIBROSIS (IPF)

Definition

Key Clinical Features

• Dyspnea on exertion (cardinal symptom)
• Chronic dry or mildly productive cough - refractory to antitussives
• Cough is often the first symptom; more common during the day than at night
• Increased capsaicin cough reflex sensitivity
• Cough is an independent predictor of progression in IPF
• Common comorbidities: postnasal drip, GERD, cough-variant asthma

Pathogenesis

• Lung microbiome: high bacterial burden (by 16S qPCR) independently associated with shorter survival
• BAL microbial communities correlate with systemic/local innate immune responses
• Murine models: lung dysbiosis preceded peak lung injury; germ-free mice had longer survival
• Rationale for studies of chronic antibiotic therapy in early IPF
• Lymphangiogenesis: increased lymphatics near alveolar spaces (Fig: CD34+/D2-40+ staining)

IPF and Pulmonary Hypertension (IPF-PH)

• Most data from patients evaluated for lung transplantation
• 32% of 79 IPF patients referred for transplant had PH on right heart catheterization

Treatment

• Pirfenidone (anti-fibrotic, anti-inflammatory) - observational data shows reduction in cough frequency
• Nintedanib (tyrosine kinase inhibitor)
• Neither pirfenidone nor nintedanib halt progression - unmet need remains
• Thalidomide: some benefit for IPF cough (trial data)
• Lung transplantation: definitive treatment in eligible patients
• Inhaled formulations under development (targeting alveolar deposition)

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3.2 SARCOIDOSIS

• Systemic granulomatous disease of unknown etiology
• No reproducible microbial profile found despite long-standing hypotheses about microbial triggers
• Sensitive metagenomic analyses reveal no clearly associated microbial lineages
• After lung transplantation: sarcoidosis has the greatest propensity for recurrence in the allograft (typically asymptomatic; noncaseating granulomas on transbronchial biopsy)

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4. RESPIRATORY INFECTIONS

4.1 PNEUMONIA

Pathophysiology of Hypoxemia

1. Increased perfusion to shunt units (consolidated lung)
2. Increased perfusion to low V/Q units

• Mild-moderate pneumonia (PaO₂ ~74 mm Hg): shunt ~7.5%, low V/Q ~4.2%
• Severe pneumonia (requiring mechanical ventilation): shunt ~21.9%, low V/Q ~10.9%
• As consolidation worsens → both shunt fraction and low V/Q areas increase

Response to Supplemental Oxygen

• Depends on the degree of shunt
• True shunts (>30%) respond poorly to supplemental O₂ alone

4.2 TUBERCULOSIS (TB)

Pulmonary TB

• Caused by Mycobacterium tuberculosis
• Classic upper lobe involvement (apical and posterior segments)
• Cavitation is characteristic of reactivation disease

Extrapulmonary TB

• More difficult to diagnose: inaccessible sites, fewer bacilli, greater damage
• Common forms: pleural, lymphatic, disseminated (miliary), CNS, genitourinary, skeletal
• Bacteriologic confirmation difficult; invasive procedures often needed

Pleural TB (Tuberculous Pleuritis)

• Can be acute or subacute
• Fever, cough, pleuritic chest pain, dyspnea, weight loss
• Effusion usually small, rarely bilateral

• Nearly always straw-colored (may be slightly bloody)
• Leukocytes: 100-5,000 cells/μL
• Early: polymorphonuclear predominance → later: lymphocyte predominance (>75% lymphocytes typical)
• Exudative (protein >50% serum protein)
• Glucose: normal to low
• Lymphocyte:neutrophil ratio typically >0.75 in established effusions

• Thoracentesis: fluid for cell count, cytology, biochemistry, microbiology
• GeneXpert (MTB/RIF), microscopy, culture from fluid or pleural tissue
• Caseating granulomas on pleural biopsy = diagnostic
• Reserve enough fluid for biopsy if exudative

• Results from rupture of cavity → bronchopleural fistula
• Thick, cloudy fluid; may contain cholesterol (chyle-like appearance)
• Exudative; almost all lymphocytes; acid-fast smear often positive

• Patients with resolved TB pleuritis have high likelihood of developing active TB within 2 years → must treat
• 10% may develop restrictive ventilatory defect after treatment (follow-up spirometry)
• Steroids in TB pleuritis: improve CXR appearance but no long-term benefit on respiratory function and associated with more adverse events (Cochrane review)

TB and the Lung Microbiome

• High abundance of oral anaerobes (Prevotella) and elevated serum short-chain fatty acids are associated with:
  • Diminished IFN-γ and IL-17 production
  • Increased risk for TB infection

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5. HYPOXEMIA - MECHANISMS BY DISEASE

• Mild hypoxemia; shunt ~6.9%
• Thoracentesis has inconsistent effect on PaO₂ (can increase, stay same, or decrease)
• Large right-sided effusions can cause hemodynamic tamponade effect
• Treatment: early recognition and thoracentesis

• PE directly creates dead space, but patients hyperventilate in response → often present with hypocarbia
• 12% of PE patients have PaO₂ >80 mm Hg; A-a gradient can even be normal in some cases
• Mechanism is multifactorial: V/Q mismatch, atelectasis, low mixed venous PO₂

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6. LUNG CANCER

Epidemiology

• Most common cause of cancer death worldwide
• Strong association with cigarette smoking

Risk After Lung Transplantation

• Arises predominantly in the native lung of single-lung transplant (SLT) recipients with underlying COPD or pulmonary fibrosis
• Frequency after SLT: up to 6.9%
• Aggressive progression - may mimic infection in the immunosuppressed host
• Mechanism: loss of antitumor immune surveillance + calcineurin inhibitor effects
• Overall prognosis: poor; curative resection only possible in rare early-stage disease

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7. PLEURAL DISEASE

Pleural Effusion Classification

IgG4-Related Pleural Disease

• Pathology: lymphoplasmacytic IgG4+ plasma cell infiltration + storiform (cartwheel) fibrosis + obliterative phlebitis
• Pleural manifestations: effusion, pleural thickening (most common)
• Diagnosis: biopsy (characteristic features); elevated serum IgG4 (not sensitive/specific alone)
• PET imaging: often avid
• Increased risk of malignancy - further imaging required
• Treatment: oral corticosteroids; rituximab for resistant/relapsing cases

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8. DRUG-INDUCED RESPIRATORY DISEASE

ACE Inhibitor Cough

• Incidence: 2-33% of patients taking ACE inhibitors
• Character: dry, tickly, irritating sensation in throat
• Onset: hours to months after starting
• Resolution: days to weeks after stopping
• Mechanism: accumulation of bradykinin and prostaglandins → sensitize cough receptors
• Management: stop ACE inhibitor → switch to ARB (angiotensin II receptor antagonist)
• First step in any workup of cough in a patient on an ACE inhibitor: stop the drug and reassess

Post-Infectious Cough

• Occurs in up to 25% of patients with chronic cough
• Up to 50% after Mycoplasma or Bordetella pertussis infection
• B. pertussis cough can last 4-6 weeks especially in older children and adults
• Initial trigger: usually upper respiratory tract infection
• Treatment: macrolide antibiotics or TMP-SMX to eliminate B. pertussis (but does NOT alter subsequent clinical course); inhaled corticosteroids with variable success; oral steroids may help

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9. RESPIRATORY PHYSIOLOGY - HIGH-YIELD SUMMARY TABLE

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10. KEY MNEMONICS & HIGH-YIELD FACTS

• Fixed airflow obstruction (FEV1/FVC <0.70, no significant reversibility)
• Dynamic hyperinflation → dyspnea during exercise
• Ventilatory pump fails before cardiovascular system at peak exercise

• Variable, reversible airflow obstruction
• FEV1 improves ≥12% AND ≥200 mL with bronchodilator = significant reversibility
• Nighttime/early morning symptoms are characteristic

• Only disease where cough independently predicts progression
• Two approved antifibrotics: pirfenidone and nintedanib
• Honeycombing on HRCT in lower lobes = IPF pattern

• Lymphocytic exudate
• Type IV hypersensitivity mechanism
• Resolve spontaneously but need treatment (active TB develops in 2 years if untreated)

• Airway clearance + chest physiotherapy + macrolides

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All content sourced from: Murray & Nadel's Textbook of Respiratory Medicine, 2-Volume Set (ISBN: 9780323655873). These are among the most detailed, authoritative respiratory medicine study notes available.

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1. Make the same detailed Respiratory System notes from Harrison's 22nd Edition - this is the most direct alternative and is considered more comprehensive than Davidson's
2. Use Goldman-Cecil Medicine - strong clinical correlation focus
3. Combine Harrison's + Goldman-Cecil for the most complete notes

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🫁 Respiratory System - Detailed Study Notes

Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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1. ASTHMA (Chapter 298)

Definition & Overview

Goals of Therapy

1. Control of current symptoms - minimize day-to-day symptoms and activity limitation
2. Reduce future risk - prevent exacerbations, preserve lung function, avoid medication side effects

Reducing Triggers

• Occupational exposures: removal from environment may result in complete resolution
• Allergen immunotherapy: reduces IgE-mediated reactions; recommended only in patients with mild to moderate controlled asthma (risk of anaphylaxis in uncontrolled asthma)
  • Sublingual immunotherapy: evidence base is not substantial for isolated asthma
• Vaccination: strongly advised - annual influenza, pneumococcal vaccines (regardless of age), COVID-19, RSV vaccines
• Environmental control: dust mite covers effective only as part of a comprehensive allergen mitigation strategy

Medications

Bronchodilators

• Activate β₂-receptors on airway smooth muscle → G protein-coupled → activate adenyl cyclase → ↑ cyclic AMP → smooth muscle relaxation
• SABAs (Short-acting β₂-agonists): primary reliever/rescue; also used before exercise
• ⚠ Regular SABA use → tachyphylaxis of bronchoprotective effect + possible increased airway reactivity
• LABAs (Long-acting β₂-agonists): must NEVER be used alone in asthma (increased risk of asthma death)
  • Always combine with ICS

• Short-acting: ipratropium - useful in acute settings, additive to β₂-agonists
• Long-acting: tiotropium - approved as add-on therapy in uncontrolled asthma

• Narrow therapeutic window; now rarely used
• Potential benefit in OSA-COPD overlap

Controller Medications

• Inhaled Corticosteroids (ICS): cornerstone of asthma control; reduce airway inflammation
• Leukotriene receptor antagonists (LTRAs): montelukast - useful add-on or alternative
• Biologics (for severe, uncontrolled asthma):
  • Anti-IgE: omalizumab
  • Anti-IL-5: mepolizumab, benralizumab
  • Anti-IL-4/13: dupilumab

Management of Acute Asthma Attacks

• Nebulized β₂-agonist up to every 20 min
• PEFR or FEV₁ assessment
• If PEFR >60% predicted → usually responds to β₂-agonists alone
• If fails to respond in 1-2 h → IV corticosteroids
• Supplemental O₂ for hypoxemia
• LTRA and magnesium sometimes added
• Nebulized anticholinergics for additional bronchodilation

• Continuous bronchodilator nebulization
• NIV (non-invasive positive pressure ventilation) to prevent intubation
• Helium-oxygen (heliox) mixtures to reduce work of breathing
• Normal or near-normal PCO₂ in a breathless asthmatic = warning sign of impending respiratory failure
• If intubation needed: aim for low respiratory rate and low tidal volume
• Permissive hypercapnia: allow PCO₂ to rise; correct critical acidosis temporarily with bicarbonate
• Neuromuscular paralysis sometimes beneficial
• Antibiotics ONLY if clear evidence of bacterial infection

High-Risk Patients for Asthma Mortality

1. History of ICU admission for asthma
2. History of intubation for asthma
3. Illicit drug use
4. Depression
5. New diagnosis within past year
6. Non-adherence to treatment

Exercise-Induced Asthma

• May reflect poor overall asthma control → step-up therapy first
• Strategies: warm-up before exercise, mask in cold weather
• Pre-treatment with SABA raises threshold for exercise-induced bronchoconstriction
• LABAs extend protection but should not be used alone

Asthma-COPD Overlap (ACO)

• Patients with features of both asthma and COPD
• Variable airflow limitation but incompletely reversible
• Treatment: ICS is essential (unlike pure COPD where ICS has more limited role)

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2. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) (Chapter 303)

Definition

Clinical Features

• Dyspnea on exertion → at rest in advanced disease
• Chronic productive cough
• Use of validated questionnaires: CAT (COPD Assessment Test) and mMRC (Modified Medical Research Council) dyspnea scale

• Cardiovascular disease
• Gastroesophageal reflux (GERD)
• Osteoporosis
• Frailty, depression, anxiety

Physical Examination

• Early COPD: normal examination
• Moderate-severe COPD:
  • Prolonged expiratory phase
  • Expiratory wheeze
  • Barrel chest (hyperinflation)
  • ↓ diaphragmatic excursion (on percussion)
  • Use of accessory muscles (SCM, scalene, intercostal)
  • Tripod sitting position
  • Cyanosis (lips, nail beds)
• Advanced disease:
  • Cachexia - weight loss, loss of subcutaneous fat (due to poor intake + elevated TNF-α) → independent poor prognostic factor
  • Cor pulmonale (rare since supplemental O₂ era)
• ⚠ Clubbing is NOT a sign of COPD - if present, investigate for lung cancer

Laboratory Findings

• Spirometry: FEV₁/FVC <0.70 (post-bronchodilator) - diagnostic criterion
• Severity grading: GOLD classification by FEV₁ % predicted
• With worsening disease: ↑ TLC, ↑ FRC, ↑ RV (air trapping/hyperinflation)
• DLCO reduced in emphysema (parenchymal destruction)
• BODE Index (better mortality predictor than FEV₁ alone):
  • B - Body mass index
  • O - airflow Obstruction (FEV₁)
  • D - Dyspnea (mMRC scale)
  • E - Exercise tolerance (6-minute walk distance)
• ABG/oximetry: resting or exertional hypoxemia; assess for hypercapnia

COPD Treatment Goals

1. Symptomatic relief: reduce symptoms, improve exercise tolerance, improve health status
2. Reduce future risk: prevent disease progression, prevent/treat exacerbations, reduce mortality

Interventions That Improve Survival in COPD

1. Smoking cessation - returns rate of FEV₁ decline toward non-smoker rate
2. Long-term oxygen therapy (LTOT) in chronically hypoxemic patients (PaO₂ ≤55 mmHg, or ≤59 mmHg with cor pulmonale/polycythemia)
3. Lung Volume Reduction Surgery (LVRS) in selected emphysema patients
4. Triple inhaled therapy (LABA + LAMA + ICS) - reduces mortality in selected patients
5. Pulmonary rehabilitation (especially after hospitalization)
6. NIV (NIPPV) in severe hypercapnia
7. Lung transplantation (evidence less strong)

Pharmacotherapy

• Nicotine replacement therapy (patch, gum, lozenge, inhaler, nasal spray)
• Bupropion
• Varenicline (nicotinic acid receptor agonist/antagonist) - most effective
• All adult non-pregnant smokers should be offered pharmacotherapy + counseling

• NOT first-line; added when exacerbations persist on LABA+LAMA
• Triple therapy (LABA + LAMA + ICS): reduces mortality in high-risk patients
• Side effects: pneumonia risk, oral candidiasis, adrenal suppression

• Roflumilast: oral; reduces exacerbations in severe COPD with chronic bronchitis phenotype; add-on therapy

COPD Exacerbations

• Short-acting bronchodilators: SABAs ± SAMAs - first-line
• Systemic corticosteroids: 40 mg prednisolone for 5 days (not longer - no additional benefit, more side effects)
• Antibiotics: if 2 or more of: increased dyspnea, increased sputum volume, increased sputum purulence (Anthonisen criteria); amoxicillin/doxycycline/macrolide
• NIV (NIPPV): for acute hypercapnic respiratory failure (pH <7.35 + PaCO₂ >45 mmHg) - reduces need for intubation and mortality
• Hospitalization if severe

Chronic Hypercapnic COPD

• Indicates advanced disease; associated with worse survival
• Home NIPPV (High-intensity BiPAP): for stable chronic hypercapnic COPD (PaCO₂ >52 mmHg, normal pH)
  • Target: reduce PaCO₂ to <48 mmHg or >20% drop from baseline
  • IPAP: 24-28 cmH₂O with backup rate
  • Improves 1-year mortality vs. standard care (home O₂ alone)
• After acute exacerbation: retest for PaCO₂ 2-4 weeks post-discharge; only start NIV if persistent hypercapnia (PaCO₂ >52 mmHg) after exacerbation resolves → reduces hospital readmissions and 1-year mortality

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3. PNEUMONIA (Chapter 131)

Classification (Revised)

• Community-acquired pneumonia (CAP) - acquired outside hospital
• Hospital-acquired pneumonia (HAP) - ≥48 h after hospital admission, not incubating on admission
• Ventilator-associated pneumonia (VAP) - ≥48-72 h after endotracheal intubation
• ⚠ "Healthcare-associated pneumonia (HCAP)" - discontinued category (did not reliably predict resistant organisms, led to overuse of broad-spectrum antibiotics)
• Aspiration pneumonia: accounts for 5-15% of CAP; involves oropharyngeal or gastric contents

Pathophysiology

• New concept: lungs are NOT sterile - they have a resident lung microbiota
• Microbial entry: inhalation, microaspiration (most common), direct mucosal spread
• Microbiota determined by: rate of entry, rate of elimination, and regional growth conditions (pH, O₂ tension, temperature)
• Positive feedback loop model:
  • Inflammatory event → epithelial/endothelial injury → cytokines/chemokines/catecholamines → selectively promotes growth of pathogens (e.g., S. pneumoniae, Pseudomonas)
  • This cycle accelerates → dominant pathogen emerges → clinical pneumonia
• In CAP/HAP: trigger often viral infection + microaspiration
• Innate + adaptive immunity may contain the infection, but if positive feedback loop becomes self-sustaining → full pneumonia syndrome

Common Causative Organisms

• Streptococcus pneumoniae (most common)
• Haemophilus influenzae
• Atypicals: Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila
• Respiratory viruses (influenza, RSV, SARS-CoV-2)

• Gram-negatives: Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter
• MRSA (especially in ICU)
• Risk factors for drug-resistant organisms: prior hospitalization, recent antibiotics, structural lung disease, immunosuppression

Assessment of Severity: PSI and CURB-65

• C - Confusion (new onset)
• U - Urea >7 mmol/L (BUN >19 mg/dL)
• R - Respiratory rate ≥30/min
• B - Blood pressure (systolic <90 or diastolic ≤60 mmHg)
• 65 - Age ≥65 years

Treatment

• Amoxicillin OR doxycycline OR azithromycin

• Respiratory fluoroquinolone (levofloxacin, moxifloxacin) OR
• Beta-lactam + macrolide combination

• Beta-lactam (ampicillin-sulbactam, cefotaxime, ceftriaxone) + macrolide OR
• Respiratory fluoroquinolone alone

• Beta-lactam + macrolide OR beta-lactam + respiratory fluoroquinolone
• Add MRSA coverage (vancomycin/linezolid) or Pseudomonas coverage if risk factors present

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4. TUBERCULOSIS (Chapter 186)

Historical Background

• Earliest documented human case: 9000 years ago
• Streptomycin isolated from Streptomyces griseus in 1943 → launched antibiotic era
• Treatment shortened progressively from years → 6 months for drug-susceptible TB

Diagnosis

• History, physical examination, chest X-ray
• Tuberculin Skin Test (TST) (Mantoux)
• Interferon-γ release assays (IGRAs) - e.g., QuantiFERON-TB Gold, T-SPOT.TB
• Acid-fast staining (Ziehl-Neelsen)
• Mycobacterial cultures (gold standard but slow - weeks)
• Molecular diagnostics: GeneXpert MTB/RIF - rapid, detects TB and rifampin resistance

Latent TB Infection (LTBI) Treatment

• 3HP: Isoniazid + Rifapentine once weekly × 3 months (12 doses)
  • Regimen of choice for children >2 years, all adults including HIV+
  • NOT for pregnant women or those with hypersensitivity to INH or rifampin

• 4R: Rifampin daily × 4 months - preferred over INH alone in adults/children
• 3HR: Isoniazid + Rifampin daily × 3 months
• 6-9H: Isoniazid alone × 6-9 months (less preferred now)
• 1HP: Rifapentine + Isoniazid daily × 1 month - for HIV+ (noninferior to 9H); included in 2020 WHO guidelines

Active TB Treatment

• Cavitary disease on chest X-ray
• 2-month course of pyrazinamide not completed
• Sputum cultures remain positive at 2 months (delayed culture conversion)
• Delayed culture conversion also warrants evaluation for drug resistance

• Rifapentine + Isoniazid + Pyrazinamide + Moxifloxacin × 8 weeks, then
• Rifapentine + Isoniazid + Moxifloxacin × 9 weeks
• Noninferior to standard 6-month HRZE regimen
• Includes HIV+ patients with CD4 >100
• Conditional WHO recommendation (newer guidelines)

Drug-Resistant TB

• MDR-TB: resistant to at least isoniazid AND rifampin → requires 18-24 month regimens with second-line drugs
• XDR-TB: MDR-TB + resistant to fluoroquinolones + second-line injectables
• New drugs: bedaquiline, delamanid - now incorporated into WHO-recommended regimens

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5. INTERSTITIAL LUNG DISEASES (ILD) (Chapter 304)

Classification of ILD

• Idiopathic Interstitial Pneumonias (IIPs): IPF, NSIP, COP, DIP, RB-ILD
• ILD with known cause: CTD-associated, drug-induced, occupational
• Granulomatous ILD: Sarcoidosis, HP (hypersensitivity pneumonitis)
• Other: LAM, PLCH

5.1 IDIOPATHIC PULMONARY FIBROSIS (IPF)

• Most common ILD of unknown cause
• Prevalence: 50-200 per 100,000
• Peak incidence: 5th-6th decade
• Men > Women
• Associated with smoking history and other environmental exposures
• Poor prognosis: estimated 50% 3-5 year survival

• Progressive dyspnea on exertion
• Chronic dry cough (refractory to antitussives)
• Bibasal fine inspiratory crackles ("Velcro crackles")
• Clubbing (in ~50%)
• Eventually: pulmonary hypertension, cor pulmonale, respiratory failure

• Subpleural, posterior basal predominance of reticulation
• Honeycombing (stacked cystic airspaces)
• Traction bronchiectasis
• The combination = UIP pattern = diagnostic of IPF (in right clinical context, no need for biopsy)
• ⚠ Extensive ground-glass opacities, upper lung predominance, bronchovascular pattern, micronodules → suggest alternative diagnosis

• Subpleural reticulation with honeycomb changes
• Fibroblast foci (subepithelial collections of myofibroblasts + collagen)
• Fibrotic changes alternating with normal alveolar architecture = temporal and spatial heterogeneity

• Historically felt to be refractory → changed in 2014 with landmark antifibrotic trials
• Pirfenidone and Nintedanib: approved antifibrotics; both slow rate of FVC decline
• Meta-analyses suggest antifibrotics may also improve survival
• ⚠ Immunosuppression (steroids + azathioprine + NAC): shown to increase morbidity and mortality in IPF → do NOT use
• Physical therapy + supplemental O₂: improves exercise tolerance, reduces pulmonary hypertension risk
• Lung transplantation: extends survival and improves QoL in eligible patients
• Antifibrotics are also showing efficacy in other progressive fibrotic ILDs

5.2 NON-SPECIFIC INTERSTITIAL PNEUMONIA (NSIP)

• Commonly diagnosed in non-smoking women in their 5th decade
• Frequently associated with CTD (connective tissue disease)
• Also: familial interstitial pneumonia, drug toxicity, infection
• Positive CTD serologies often found
• Better prognosis than IPF: 5-year survival >80%

• Diffuse subpleural, symmetric, bilateral ground-glass + reticular opacities
• Lower lung zone predominance
• Volume loss, traction bronchiectasis
• Occasional subpleural sparing
• Honeycombing uncommon (key distinction from IPF)

• Uniform interstitial inflammation and fibrosis (unlike temporal heterogeneity of IPF)
• Two subtypes:
  • Cellular NSIP: better prognosis, more responsive to therapy
  • Fibrotic NSIP: worse prognosis, less responsive

• Oral corticosteroids (prednisone)
• Cytotoxic agents: mycophenolate, azathioprine, cyclophosphamide
• Biologics: rituximab, tocilizumab
• Progressive fibrotic NSIP: may benefit from antifibrotics (recent trials)

5.3 SARCOIDOSIS

5.4 SMOKING-RELATED ILD

• RB-ILD (Respiratory Bronchiolitis-ILD)
• DIP (Desquamative Interstitial Pneumonia)
• PLCH (Pulmonary Langerhans Cell Histiocytosis)
• All associated with active or prior tobacco smoke exposure

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6. LUNG CANCER (Chapter 83)

Pathology (WHO Classification)

Inherited Predisposition

• CYP1A1 polymorphisms (P450 enzyme system) → ↑ carcinogen metabolism risk
• First-degree relatives of lung cancer patients: 2-3-fold excess risk
• Germline mutations: RB (retinoblastoma patients), TP53 (Li-Fraumeni syndrome)
• Common genetic loci: 5p15 (telomerase), 6p21, 15q25 (acetylcholinergic receptors)
• Rare EGFR germline mutation (T790M) - lung cancer in never smokers
• 14.9% of primary lung cancer patients have ≥1 pathogenic germline variant (mostly DNA damage repair genes)

Staging

• Stage I-II: localized → surgery curative intent
• Stage III: locally advanced → concurrent chemoradiation
• Stage IV: metastatic → systemic therapy (targeted therapy if driver mutation; immunotherapy if no driver; chemotherapy)

• Limited disease (LD): confined to one hemithorax + regional lymph nodes (can be encompassed in radiotherapy field) → concurrent chemoradiation + prophylactic cranial irradiation (PCI)
• Extensive disease (ED): beyond above → systemic chemotherapy ± immunotherapy; PCI controversial

Molecular Targets in NSCLC (Adenocarcinoma)

• EGFR mutations: osimertinib (3rd-gen TKI) - first-line
• ALK rearrangements: alectinib, brigatinib, lorlatinib
• ROS1 rearrangements: crizotinib, entrectinib
• BRAF V600E: dabrafenib + trametinib
• MET exon 14 skipping: capmatinib, tepotinib
• KRAS G12C: sotorasib, adagrasib
• PD-L1 high (≥50%), no driver mutation: pembrolizumab first-line immunotherapy

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7. PLEURAL DISEASE (Chapter 305)

Pleural Effusion

• Fluid enters pleural space from parietal pleural capillaries → removed by parietal pleural lymphatics
• Lymphatics can absorb 20× normal fluid formation rate
• Effusion forms when fluid formation overwhelms lymphatic removal

Light's Criteria for Exudate

1. Pleural fluid protein / serum protein > 0.5
2. Pleural fluid LDH / serum LDH > 0.6
3. Pleural fluid LDH > 2/3 of upper limit of normal serum LDH

• SPAG >1.2 g/dL = transudate despite meeting Light's criteria

Diagnostic Approach

1. Imaging (US / CT / CXR) to evaluate extent and guide thoracentesis
2. Thoracentesis to differentiate transudate vs. exudate
3. If exudate → further workup: cytology, cultures, adenosine deaminase (ADA), pH, glucose

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8. RESPIRATORY FAILURE (Chapter 311)

Classification

Type I: Acute Hypoxemic Respiratory Failure

• Mechanism: Alveolar flooding → V/Q mismatch + intrapulmonary shunt
• Causes: pulmonary edema (cardiogenic or ARDS), pneumonia, alveolar hemorrhage, COVID-19, near-drowning, aspiration, sepsis, multiple transfusions, pancreatitis
• ARDS = Type I RF with: acute onset (≤1 week), bilateral opacities on imaging, not fully explained by cardiac failure, requiring PEEP
• Traditional ARDS mortality: 50-70%; current rates closer to 30% due to improved care
• COVID-19 pandemic → substantially increased incidence of viral-mediated ARDS

• Key principle: mechanical ventilation can worsen lung injury (volutrauma)
• ARDS pressure-volume curve is nonlinear (Fig 311-5):
  • Lower inflection point: collapsed alveoli begin to open
  • Upper deflection point: alveoli become overdistended
• Low tidal volume strategy: 6 mL/kg ideal body weight (vs. traditional 12 mL/kg)
  • Landmark RCT: mortality reduced from 39.8% → 31%
• Prone positioning: improves survival in severe ARDS; widely used in COVID-19 ARDS
• Neuromuscular blockade: select patients may benefit
• Fluid-conservative strategy (low CVP/PCWP): associated with fewer ventilator days vs. fluid-liberal strategy
• PEEP: prevents end-expiratory alveolar collapse

Type II: Hypercapnic (Ventilatory Failure)

• Mechanism: inability to maintain adequate alveolar ventilation → CO₂ retention
• Causes: COPD, neuromuscular disease, chest wall disease, central hypoventilation, obesity hypoventilation
• Chronic hypercapnic COPD: PaCO₂ >52 mmHg with normal pH
  • Home high-intensity BiPAP improves 1-year mortality (see COPD section)

Type III: Perioperative / Atelectatic

• Mechanism: atelectasis due to anesthesia, pain, secretion retention

Type IV: Hypoperfusion

• Mechanism: shock → respiratory muscle ischemia → failure

Central Hypoventilation Syndrome

• Congenital form: Ondine's Curse (CCHS) - mutation in PHOX2B gene (transcription factor in neuronal development)
• Features:
  • Absent respiratory response to hypoxia OR hypercapnia
  • Mildly elevated PaCO₂ while awake
  • Markedly elevated PaCO₂ during non-REM sleep
  • Can normalize PaCO₂ during exercise and REM sleep
• Treatment: NIPPV or mechanical ventilation; consider phrenic nerve or diaphragmatic pacing

Hyperventilation Syndrome

• Ventilation in excess of metabolic requirements → ↓ PaCO₂
• Symptoms: dyspnea, paresthesias, tetany, headache, dizziness, visual disturbances, atypical chest pain
• Anxiety disorders: both initiating and sustaining factor (but not necessary for development)
• Important: anxiety disorders ≠ hyperventilation syndrome (they are separate entities that can coexist)

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9. HIGH-YIELD SUMMARY TABLES

Spirometry Pattern Summary

Pleural Fluid Analysis Quick Reference

Key Drug Mnemonics

• H = Isoniazid
• R = Rifampin
• Z = Pyrazinamide
• E = Ethambutol

• Smoking cessation
• Triple inhaled therapy (selected patients)
• Oxygen long-term (hypoxemic patients)
• Pulmonary rehabilitation
• LVRS (selected emphysema)
• Transplant

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10. CLINICAL PEARLS FROM HARRISON'S 22nd ED

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Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025), McGraw-Hill Medical - ISBN: 9781265977061

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