Pulmonary Function Tests (PFTs)

• PFTs have three components:
  • Spirometry - Measures air flow (volume over time). Key for obstructive lung disease. Provides values like FEV₁ (Forced Expiratory Volume in 1 second) and FVC (Forced Vital Capacity). The ratio FEV₁/FVC is critical for diagnosing obstruction.
  • Lung Volumes - Measures static volumes (e.g. Total Lung Capacity (TLC), Residual Volume (RV)). Important for identifying restrictive lung disease (TLC is low in restriction).
  • Diffusing Capacity (DLCO) - Assesses gas exchange across alveolar-capillary membrane using carbon monoxide. Helps localize impairment to alveoli, interstitium, or capillaries.
• Indication: Ordered for unexplained dyspnea after ruling out cardiac causes and anemia. It helps distinguish if the cause is pulmonary and what type of dysfunction (obstructive vs restrictive vs others).
• Full PFTs are done in lab (patient performs forced exhalations, breath-holding, etc.). They can also assess bronchodilator response (spirometry before and after inhaled bronchodilator to check reversibility) and perform bronchoprovocation (e.g. methacholine challenge for asthma) if needed.
• During spirometry, patient takes a maximal breath to TLC and then blasts air out forcefully. Values measured:
  • FEV₁: Volume exhaled in first second - ↓ disproportionately in obstruction.
  • FVC: Total volume exhaled - can be ↓ in both obstruction and restriction (for different reasons).
  • FEV₁/FVC ratio: Key index - low ratio (<70% predicted) defines obstruction. Normal or high ratio in pure restriction (FEV₁ and FVC reduced proportionally or FVC more reduced).
• Always interpret PFTs in context: Check the FEV₁/FVC ratio first (obstructive if low). If ratio normal or high but volumes low, think restrictive (confirm with TLC). Incorporate DLCO to further characterize (see DLCO section).

 

Obstructive Lung Disease

• FEV₁/FVC ratio <70% (of predicted) defines an obstructive pattern In obstruction, FEV₁ is much more reduced than FVC, so the ratio drops.
• Diseases: Chronic obstructive pulmonary diseases (COPD = emphysema + chronic bronchitis), Asthma, Bronchiectasis, etc (Asthma is now considered part of chronic obstructive airway diseases family.)
• Lung volumes: Obstructive lungs tend to have elevated TLC and RV due to air trapping/hyperinflation This leads to flattened diaphragms on CXR and “barrel chest.” Patients often adapt by pursed-lip breathing to slowly release trapped air
• FEV₁ ↓, FVC ↓, ratio ↓. Vital capacity may be somewhat reduced (air gets trapped and cannot be exhaled), but FEV₁ drops more.
• DLCO in obstruction: Depends on the pathology:
  • Emphysema: Low DLCO (destruction of alveoli/capillaries)
  • Chronic Bronchitis: Normal DLCO (airway disease, alveoli intact)
  • Asthma: Normal or high DLCO (↑ pulmonary capillary blood volume in well-ventilated alveoli; asthma often has preserved membrane)
• Key point: The FEV₁/FVC ratio is always low in obstructive lung diseases (and remains <70% in mild, moderate, severe, very severe stages of COPD)

 

Restrictive Lung Disease

• Total Lung Capacity (TLC) <80% predicted is the hallmark of a restrictive pattern A low TLC confirms restriction (spirometry alone is not enough - FEV₁ and FVC are low in both obstructive and restrictive, so measure TLC).
• FEV₁/FVC ratio in restriction is often normal or high This is because FVC is reduced (small lung volumes) as much or more than FEV₁. In intrinsic (intra-pulmonary) restriction, FVC drops disproportionately (raising ratio >0.7); in extrinsic restriction, both decline proportionally (ratio ~normal).
• Types of restriction:
  • Intrinsic (inside lung parenchyma): e.g. pulmonary fibrosis, interstitial lung diseases. Small stiff lungs → ↓TLC. DLCO is typically low (thickened/damaged alveolar membrane)
  • Extrinsic (external to lung): e.g. obesity, pleural effusion, neuromuscular weakness (myasthenia, ALS), chest wall deformity (kyphoscoliosis). Lungs are mechanically restricted but parenchyma normal → DLCO is normal (gas exchange surface intact)
• Both intrinsic & extrinsic restriction show low TLC. Check DLCO to differentiate:
  • Intrinsic: DLCO low (interstitial damage).
  • Extrinsic: DLCO preserved (normal alveoli/capillaries)
• FEV₁ and FVC are both reduced roughly in tandem (or FVC more so). Patients have small lung volumes but flow is not obstructed. Flow-volume loop looks like a “scaled-down” normal loop (proportional reduction in all volumes)
• Common causes of a restrictive PFT pattern include:
  • Parenchymal lung disease (e.g. Idiopathic Pulmonary Fibrosis, pneumoconioses, granulomatous diseases).
  • Chest wall disorders (e.g. kyphosis, obesity).
  • Neuromuscular conditions (e.g. ALS, muscular dystrophy) affecting respiratory muscles.

 

Diffusing Capacity (DLCO)

• DLCO (Diffusion capacity for CO): Measures gas transfer from alveoli to capillary blood. CO uptake reflects the integrity of alveolar-capillary surface area and membrane.
• DLCO is low in conditions that impair gas exchange:
  • Emphysema: destruction of alveoli → ↓surface area
  • Interstitial lung disease (fibrosis): thickened/scarred interstitium → ↓diffusion
  • Pulmonary vascular disease: e.g. pulmonary emboli or primary pulmonary hypertension (less blood flow in capillaries) - can cause isolated low DLCO.
  • Anemia: less hemoglobin to bind CO (so always correct DLCO for hemoglobin)
• DLCO is normal in:
  • Chronic bronchitis: airway disease with intact alveoli (normal membrane and blood flow)
  • Extrinsic restriction: e.g. obesity or muscle weakness - lungs are small but alveolar units are healthy, so diffusion is preserved
• DLCO can be higher than normal in:
  • Asthma: possibly elevated due to increased pulmonary capillary blood volume when airways are open (or normal DLCO despite obstruction)
  • Polycythemia: more RBCs to take up CO.
  • Pulmonary hemorrhage (e.g. Goodpasture’s): CO avidly binds to intra-alveolar hemoglobin.
• Use of DLCO in PFT interpretation:
  • In Obstructive disease: Low DLCO suggests emphysema; Normal DLCO suggests chronic bronchitis; High/normal DLCO can be seen in asthma
  • In Restrictive disease: Low DLCO suggests intrinsic lung disease (fibrosis); Normal DLCO with low volumes suggests extrinsic cause (e.g. obesity)
  • Isolated low DLCO (normal spirometry & volumes) suggests pulmonary vascular disease (e.g. isolated pulmonary hypertension) - for example, in scleroderma patient with normal lung volumes but low DLCO, think pulmonary arterial hypertension
• Technical note: Always correct DLCO for the patient’s hemoglobin (Anemia can falsely lower DLCO; polycythemia can raise it.)

 

Flow Volume Loops

• The flow-volume loop plots airflow (Y-axis) against lung volume (X-axis) during a forced expiration and inspiration. Shape matters - characteristic patterns can identify types of obstruction
• Normal loop: Rapid peak expiratory flow then a smooth decline; symmetric inspiratory curve below the X-axis
• Obstructive loop: Low peak flow and a scooped-out (concave) expiratory limb Lung volumes are increased (loop shifted left on X-axis indicating ↑TLC). Example: COPD or asthma - slow prolonged exhalation.
• Restrictive loop: Diminished volumes (narrow loop shifted to the right - low TLC) but near-normal shape Flows may be high relative to volume. The curve is basically a scaled-down normal loop (because lungs are smaller). Both FEV₁ and FVC reduced, ratio normal or high.
• Fixed Upper Airway Obstruction: Flattening of both inspiratory and expiratory curves (volume-independent flow limitation) Causes: e.g. tracheal stenosis (post-intubation stricture) - patient can’t fully breathe in or out through a narrowed segment.
• Variable Extrathoracic Obstruction: Flattening of the inspiratory portion (bottom of loop) with normal expiratory curve Example: Vocal cord dysfunction - on inspiration, negative pressure collapses a floppy extrathoracic airway; expiration (positive pressure) is fine. Often seen in young anxious patients misdiagnosed as asthma (wheezing absent; managed with speech therapy)
• Variable Intrathoracic Obstruction: Flattening of expiratory portion (top of loop) with relatively normal inspiration Example: Tracheomalacia (within thorax) - during forced expiration, intrathoracic pressure collapses the airway, limiting flow out; inspiration is relatively unimpaired.

 

Asthma

• Definition: Chronic inflammatory airway disease characterized by reversible airflow obstruction and bronchial hyperresponsiveness. Asthma causes episodic wheezing, cough, dyspnea, often worse at night or early morning.
• Types of Asthma:
  • Allergic (Atopic, Extrinsic): Most common form (>90%). Triggered by inhaled allergens (dust mites, pollen, pet dander, mold, etc). Linked with personal or family history of atopy (eczema, allergic rhinitis). Classic IgE-mediated immune activation.
  • Non-Allergic (Intrinsic): Triggers include exercise, cold air, viral infections, air pollutants, stress, or medications (e.g. aspirin-exacerbated respiratory disease). Not IgE-mediated.
• Immunology (allergic asthma focus): Inhaled antigen is processed by airway dendritic cells (antigen-presenting cells) and presented to Th2 CD4⁺ T-cells Th2 cells release cytokines:
  • IL-4 and IL-13: stimulate B-cells to produce IgE.
  • IL-5: recruits and activates eosinophils (the major inflammatory cell in asthma)
  Mast cells armed with IgE degranulate on re-exposure, releasing mediators that cause bronchoconstriction, mucus production, and edema. Key inflammatory cells: dendritic cells, CD4 Th2 cells, eosinophils , mast cells. (Neutrophils may dominate in severe or neutrophilic asthma phenotypes.)
• Clinical Features: Recurrent episodes of wheezing, dyspnea, chest tightness, and cough (often nocturnal or early morning). Symptoms are variable and may be exercise-induced or triggered by allergens/irritants. Between attacks, exam can be normal if asthma is well-controlled.
• Diagnosis:
  • Spirometry: shows obstruction (low FEV₁/FVC) that is largely or fully reversible with bronchodilator (FEV₁ increases by ≥12% and ≥200 mL after albuterol). If baseline spirometry is normal but suspicion high, perform a bronchoprovocation test (e.g. methacholine challenge) - a significant drop in FEV₁ with methacholine indicates hyperreactive airways
  • Peak flow monitoring: can be used in outpatient or ER settings to quantify obstruction and response to treatment during acute exacerbations.
• Management: Stepwise therapy:
  • Inhaled short-acting β₂-agonist (SABA) (e.g. albuterol) as needed for quick relief of symptoms.
  • Inhaled corticosteroids (ICS) - cornerstone for persistent asthma (controls airway inflammation). Start low-dose ICS for mild persistent symptoms (e.g. more than 2 episodes per week).
  • LABAs (long-acting β-agonists) or LTRAs (leukotriene receptor antagonists like montelukast) - add-on for moderate asthma not controlled on ICS alone. (LABA is always combined with ICS, never monotherapy in asthma.)
  • Additional controllers: tiotropium (LAMA) can be added in certain patients; oral theophylline is third-line (due to side effects).
  • Biologic therapies: for severe refractory asthma phenotypes:
    • Anti-IgE (omalizumab): for moderate-to-severe allergic asthma with high IgE levels not controlled by standard therapy Given subcutaneously; risk of anaphylaxis (patients carry epinephrine) (Do not follow IgE levels after starting omalizumab - drug elevates total IgE by preventing its clearance )
    • Anti-IL-5 therapies (mepolizumab, reslizumab, benralizumab): for eosinophilic asthma - reduce eosinophil activation Use in patients with high eosinophil counts and frequent exacerbations despite ICS/LABA
    • Anti-IL-4/13 (dupilumab): for severe type 2 inflammation asthma
  • Acute exacerbation management: Short-course systemic corticosteroids (e.g. prednisone) for moderate or severe flare-ups , along with frequent SABA (nebulized albuterol) and ipratropium (SAMA) bronchodilators Oxygen if needed. Assess for impending respiratory failure (fatigue, rising CO₂) - may need ventilatory support.
• Prognosis & special notes: Asthma is typically reversible, especially early in disease. Long-standing poorly-controlled asthma can lead to airway remodeling and a component of fixed obstruction. Always address triggers and co-morbidities (allergic rhinitis, GERD). Patient education on inhaler technique and avoidance of triggers is crucial.

 

COPD (Chronic Obstructive Pulmonary Disease)

• Definition: Chronic, progressive obstruction of airflow that is not fully reversible. Encompasses Emphysema (destruction of alveoli) and Chronic Bronchitis (cough productive of sputum for ≥3 months in 2 consecutive years). Often co-exist to varying degrees. *Asthma-COPD overlap (ACO)* is recognized (some COPD patients have reversible/asthmatic features)
• Etiology: Smoking is the leading cause (preventable!) Others: biomass fuel exposure, occupational dusts/chemicals. Alpha-1 antitrypsin deficiency causes early panacinar emphysema (especially if young and non-smoker). Smoking causes chronic inflammation and protease release that destroy alveolar walls (emphysema) and stimulate mucus hypersecretion and airway plugging (bronchitis)
• Diagnosis: Spirometry with FEV₁/FVC <70% post-bronchodilator confirms persistent obstruction. COPD is not fully reversible (post-bronchodilator FEV₁ improvement is small). Severity grading uses FEV₁% predicted:
  • Mild: FEV₁ ≥80% pred
  • Moderate: 50-79%
  • Severe: 30-49%
  • Very severe: <30%
  (All have FEV₁/FVC <0.7)
• Symptoms: Typically in middle-aged or older patients with smoking history. Chronic productive cough (especially in morning), dyspnea on exertion, wheezing. In advanced disease, weight loss and muscle wasting. Chronic bronchitis (“blue bloater” stereotype): overweight, cyanotic, chronic cough. Emphysema (“pink puffer” stereotype): thin, pursed-lip breathing, barrel chest due to hyperinflation, distant breath sounds.
• Management (Chronic COPD):
  • Smoking cessation - most important intervention! Improves survival and slows decline Offer counseling and pharmacotherapy (nicotine replacement, bupropion, varenicline)
  • Vaccinations: Annual influenza and periodic pneumococcal vaccines to reduce respiratory infection risk
  • Bronchodilators: Mainstay for symptom control.
    • Short-acting (SABA like albuterol, and/or short-acting anticholinergic like ipratropium) for quick relief or mild intermittent symptoms.
    • Long-acting bronchodilators for persistent symptoms: LAMA (tiotropium) and/or LABA (salmeterol, formoterol). Often a LAMA/LABA combo is used in moderate disease *Pulmonary rehabilitation* is introduced for moderate COPD to improve exercise tolerance
  • Inhaled Corticosteroids (ICS): Added in severe COPD with frequent exacerbations. ICS can reduce exacerbation frequency (especially if asthmatic features), but carry risk of pneumonia and thrush Use ICS/LABA in patients with repeated flare-ups. *Note:* ICS are not as universally indicated in COPD as in asthma - use depends on exacerbation history.
  • Oxygen therapy: The only therapy proven to prolong life in advanced COPD. Indicated if chronic hypoxemia (SaO₂ ≤88% or PaO₂ ≤55 mmHg at rest, or ≤59 mmHg with signs of cor pulmonale/polycythemia). Aim for ≥15 hours/day of supplemental O₂. Improves survival and quality of life.
  • Other measures: Lung volume reduction surgery (for selected emphysema patients with predominant upper-lobe disease and low exercise capacity), or lung transplant in very severe cases. Treat comorbidities (nutrition, muscle wasting, depression).
• Management of Acute COPD Exacerbation: (Triggered by infections, air pollution, etc.) Give supplemental oxygen (target 88-92% O₂ sat), short-acting bronchodilators (neb SABA ± ipratropium), systemic corticosteroids (e.g. prednisone ~5 days), and antibiotics if evidence of infection (e.g. increased sputum purulence). Consider noninvasive positive-pressure ventilation (BiPAP) for hypercapnic respiratory failure. Intubation and mechanical ventilation if needed for severe respiratory failure.
• Follow-up & Monitoring: Regular assessments of symptoms (mMRC dyspnea scale, CAT score) and exacerbation history. These, along with FEV₁, guide “ABCD” group classification for COPD severity and help tailor therapy For example, frequent exacerbators (Groups C and D) benefit from more aggressive therapy (LAMA or LAMA/LABA, add ICS if eosinophils high, etc).
• Exacerbation prevention: besides smoking cessation and vaccines, some patients benefit from roflumilast (PDE-4 inhibitor) if chronic bronchitis with frequent exacerbations, or long-term macrolide therapy in select cases. Pulmonary rehab is extremely beneficial for exercise tolerance and symptom control

 

Interstitial Lung Disease (ILD)

• Overview: ILDs (aka Diffuse Parenchymal Lung Diseases, DPLD) are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lung interstitium (and often alveoli). Causes include idiopathic (e.g. IPF), connective tissue diseases, environmental/occupational exposures, granulomatous diseases, etc. Despite different etiologies, ILDs share many clinical and physiologic similarities
• Common Features of ILDs:
  • Symptoms: Progressive exertional dyspnea and dry cough. (Patients usually have insidious onset of breathlessness over months to years.) Fatigue and weight loss can occur in advanced disease.
  • PFTs: Restrictive pattern - low TLC, low FVC, low FEV₁, with normal or elevated FEV₁/FVC ratio. **DLCO is reduced** (impaired gas exchange) This intrinsic restrictive pattern is seen in essentially all ILDs.
  • Imaging: Bilateral reticular or nodular opacities on chest X-ray (often in lung bases). High-resolution CT (HRCT) is the diagnostic imaging of choice - can show patterns like honeycombing, reticulation, ground-glass opacities, nodules, etc **HRCT is indicated in ILD workup** (especially for idiopathic pulmonary fibrosis, where a classic UIP pattern on HRCT can obviate the need for biopsy)
  • Impaired oxygenation: Elevated A-a gradient and often resting or exertional hypoxemia Desaturation with exercise is common due to diffusion limitation.
  • Physical exam: Fine “Velcro” inspiratory crackles at lung bases (especially in IPF) Digital clubbing is frequent in idiopathic pulmonary fibrosis (up to 50%) and some other fibrotic ILDs Signs of pulmonary hypertension or cor pulmonale can appear late (loud P2, edema).
• Diagnosis:
  • Detailed history is critical - ask about occupational exposures (silica, asbestos, coal dust), environmental exposures (mold, birds for hypersensitivity pneumonitis), drug history (amiodarone, bleomycin, methotrexate, nitrofurantoin, etc can cause ILD) , and systemic disease symptoms (rash, joint pain, dry eyes/mouth, etc. suggesting connective tissue disease).
  • Labs: Check autoimmune serologies if CTD (connective tissue disease) is suspected (e.g. ANA, RF, anti-CCP, anti-Scl-70, etc.), although ILD can precede overt CTD.
  • Imaging: HRCT chest is invaluable - specific ILDs have characteristic patterns. UIP pattern (usual interstitial pneumonia) on HRCT - basal subpleural reticular fibrosis with honeycombing - strongly suggests Idiopathic Pulmonary Fibrosis (IPF) in the right context Ground-glass opacities suggest inflammation (e.g. NSIP, COP or HP). Nodules might suggest sarcoid or silicosis. Pleural plaques suggest asbestosis, etc.
  • Biopsy: Often required for definitive diagnosis, especially if imaging is not classic. The gold standard is lung biopsy with histopathology Options: bronchoscopic transbronchial biopsy (less invasive, small samples), or surgical (VATS) lung biopsy (larger sample). A bronchoalveolar lavage (BAL) can aid in some cases (e.g. lymphocytic BAL in hypersensitivity pneumonitis, or rule out infection) Multidisciplinary discussion (pulmonologist, radiologist, pathologist) is used to integrate data for diagnosis
• Idiopathic Pulmonary Fibrosis (IPF): The prototypical ILD (idiopathic fibrosing interstitial pneumonia).
  • Usually age >50, often male, with gradual dyspnea and dry cough over months. Examination shows Velcro crackles and clubbing
  • HRCT: UIP pattern - honeycombing (clustered cystic airspaces) in subpleural/basal areas, reticular septal thickening, and traction bronchiectasis Minimal ground-glass. If classic, diagnosis can be made clinically
  • Biopsy (if done): UIP histology with patchy interstitial fibrosis and fibroblast foci
  • No known cause (diagnosis of exclusion): must rule out connective tissue disease, chronic HP, drugs, etc. before labeling “idiopathic”
  • Prognosis is poor - progressive fibrosis with median survival ~3-5 years. No cure aside from lung transplant. Management: antifibrotic agents (pirfenidone, nintedanib) can slow progression; oxygen for hypoxia; pulmonary rehab; early referral for transplant. Supportive care and palliative care are important (IPF has high mortality, ~50% at 5 years)
• Other ILDs (brief):
  • Connective Tissue Disease ILD: Rheumatoid arthritis, scleroderma (systemic sclerosis), Sjögren’s, polymyositis/dermatomyositis, and others can all cause ILD Often a NSIP pattern. Treat the underlying CTD; immunosuppressants like mycophenolate (CellCept) are used for scleroderma ILD
  • Pneumoconioses: Occupational dust exposures - e.g. Silicosis (upper lobe nodules, eggshell node calcifications), Coal worker’s pneumoconiosis, Asbestosis (lower lobe fibrosis + pleural plaques, risk of mesothelioma). No specific treatments (avoid exposure, supportive care).
  • Hypersensitivity Pneumonitis (extrinsic allergic alveolitis): Immune-mediated ILD due to inhaled organic antigens (moldy hay, bird droppings, etc.). Causes recurrent fevers, cough, dyspnea hours after exposure. Chronic exposure leads to fibrosis. Avoidance is key; steroids can help acute episodes.
  • Organizing Pneumonia (COP/BOOP): Post-infectious or idiopathic (cryptogenic organizing pneumonia) - subacute flu-like illness with patchy lung opacities, responds to corticosteroids.
• Treatment (general ILD): Varies by cause. Many ILDs are managed with immunosuppressive therapy (e.g. corticosteroids, azathioprine, mycophenolate, or cyclophosphamide for inflammatory types like NSIP or CTD-ILD). Idiopathic Pulmonary Fibrosis does not respond to immunosuppression - use antifibrotics. Remove offending exposures (drugs, antigens). For advanced fibrosis, consider lung transplantation. Supportive care: oxygen, pulmonary rehabilitation.

 

Sarcoidosis

• Definition: A systemic granulomatous disease of unknown cause, characterized by non-caseating granulomas in involved organs Lungs are affected in ~90% of cases, but any organ can be involved (skin, eyes, lymph nodes, liver, heart, etc.)
• Typical Patient: Young to middle-aged adult (20-40s), more common in African-Americans (in US). Often detected incidentally on chest X-ray (asymptomatic hilar adenopathy) or presents with cough, dyspnea, or systemic symptoms (fever, weight loss, fatigue).
• Imaging Stages (pulmonary):
  • Stage I: Bilateral hilar lymphadenopathy (BHL) ± right paratracheal node enlargement, with normal lung parenchyma. Often asymptomatic - discovered on routine CXR.
  • Stage II: BHL + diffuse parenchymal infiltrates (usually reticular or ground-glass opacities).
  • Stage III: Parenchymal infiltrates with shrinking/absent hilar nodes.
  • Stage IV: Pulmonary fibrosis (volume loss, scarring, advanced fibrotic changes).
  (Stages don’t necessarily reflect disease chronicity but are used descriptively.) Many Stage I cases resolve spontaneously.
• Signs and Symptoms:
  • Lungs: Dry cough, dyspnea, chest discomfort. Crackles are not always present (sarcoid can have normal breath sounds). Hilar adenopathy may cause no symptoms.
  • Skin: Various lesions. Classic is Lupus pernio - chronic violaceous raised discoloration on nose/cheeks/ears (pathognomonic of sarcoid) Also Erythema nodosum - tender red nodules on shins (often part of acute presentation, Löfgren’s syndrome)
  • Eyes: Uveitis (anterior or posterior) can cause blurred vision, photophobia - requires prompt treatment to prevent vision loss
  • Reticuloendothelial: Lymphadenopathy (hilar, mediastinal, peripheral nodes), hepatosplenomegaly can occur.
  • Heart: Cardiac sarcoid (granulomas in myocardium) - can cause arrhythmias, heart block, heart failure. Consider in sarcoid patients with syncope or conduction abnormalities
  • Neurosarcoidosis: Can involve facial nerve (Bell’s palsy), meninges, hypothalamus/pituitary (diabetes insipidus), etc., though these are less common.
  • General: Fever, fatigue, weight loss can occur. Hypercalcemia is a notorious lab finding (macrophages in granulomas produce excess 1α-hydroxylase → ↑activated vitamin D) - leads to high calcium and high calcitriol levels
• Löfgren’s Syndrome: An acute form of sarcoidosis with triad of erythema nodosum, bilateral hilar adenopathy, and arthritis (often ankles) , often with fever. This presentation has a good prognosis and often self-resolves.
• Heerfordt’s Syndrome (uveoparotid fever): A rare sarcoid presentation of parotid gland enlargement, uveitis, fever, and sometimes facial nerve palsy Can be confused with Sjögren’s (due to parotid swelling)
• Diagnosis:
  • Biopsy of affected organ showing non-caseating granulomas is diagnostic (after excluding other causes of granulomas like TB, fungi, berylliosis). Easy biopsy targets: palpable lymph nodes, skin lesions, or transbronchial lung biopsy via bronchoscopy (yield ~50-90% if lung/nodes involved). Endobronchial ultrasound-guided needle aspiration (EBUS) of mediastinal lymph nodes is a high-yield, minimally invasive approach
  • Laboratory: Elevated serum ACE level in ~60% of patients (not very specific, but classic teaching). Hypercalcemia and high calcitriol levels (1,25-OH vitamin D) due to granuloma activity Elevated alkaline phosphatase if liver involved.
  • Imaging: Chest X-ray and CT show hilar adenopathy ± infiltrates. Scans may show the 1-2-3 sign (right paratracheal and bilateral hilar nodes). Cardiac MRI or PET can help assess cardiac sarcoid if suspected.
• Management:
  • No treatment needed for asymptomatic Stage I disease (isolated hilar adenopathy) - many cases resolve spontaneously Also, acute Löfgren’s syndrome often resolves on its own; NSAIDs can help arthritis symptoms.
  • Corticosteroids are first-line for active disease - indicated if patient has significant symptoms or organ involvement that is moderate or severe (especially eye, heart, CNS, lung function impairment, hypercalcemia) Example: Prednisone daily, then taper over months. Most patients respond, but long-term therapy (12+ months) is often needed to prevent relapse.
  • Steroid-sparing agents for chronic sarcoid or intolerance to steroids:
    • Methotrexate - commonly used as a second-line agent (non-biologic DMARD) to help wean steroids
    • Azathioprine or leflunomide - other immunosuppressants used in refractory cases
    • Hydroxychloroquine - an antimalarial, not very potent for inflammation but useful for certain manifestations: good for treating chronic skin lesions and can help with sarcoid-associated hypercalcemia (Requires regular eye exams due to retinal toxicity risk.)
    • TNF-α inhibitors (infliximab, adalimumab) - effective in some refractory cases (especially neurosarcoid or advanced pulmonary sarcoid) Must screen for Hep B/C and latent TB before starting
    • Acthar gel (repository corticotropin) - an ACTH analog injection that has anti-inflammatory effects via melanocortin receptors, approved for pulmonary sarcoidosis. Consider in refractory disease or if intolerant to steroids
  • Monitor patients for disease activity - periodic pulmonary function tests, imaging, and lab markers (ACE level can follow trend but is not always reliable). Many require long-term low-dose therapy to maintain remission.

 

Nodules

• Pulmonary nodule: a rounded opacity ≤3 cm in diameter, surrounded by lung parenchyma (larger >3 cm is considered a mass). Increasing use of CT scans has led to more incidental solitary pulmonary nodules (SPN) being discovered
• Benign vs Malignant: The vast majority of small nodules are benign Only a small fraction represent early lung cancer or metastatic disease Common benign nodules include healed granulomas (from prior TB or histo) and hamartomas (benign tumor of disorganized lung tissue)
• Some lesions mimic nodules on imaging but aren’t true nodules:
  • Pulmonary arteriovenous malformation (AVM): vascular tangle that appears as a nodule - suspect if patient has hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)
  • Rounded atelectasis: scarred, folded lung from prior pleural disease (TB, asbestos) that looks like a mass
  • Pulmonary sequestration: an accessory lung segment with its own blood supply - can appear mass-like
  • Old TB tuberculoma: calcified granuloma from prior TB - benign but often heavily calcified
• Imaging characteristics suggesting benignity:
  • Calcification: certain patterns of calcification (central, concentric, or “popcorn” calcifications) are reassuring for benign etiologies (granuloma or hamartoma) e.g. Popcorn calcification is classic for hamartoma
  • Size: very small nodules (<6 mm) in low-risk patients are unlikely malignant.
  • Growth rate: malignant nodules tend to double in size over months (between ~1-2 years). Benign nodules (like granulomas) may remain stable for years or grow very slowly or not at all. A nodule unchanged for >2 years is likely benign.
  • Borders: Spiculated or irregular edges raise concern for malignancy, whereas smooth, well-defined edges are more often benign (though not definitive).
• Initial approach to an incidentally found nodule:
  • First, review old imaging Comparing to prior chest X-rays or CTs can show if the nodule is new or has been stable. A stable size for 2+ years = likely benign
  • Assess patient risk factors: older age, significant smoking history, or history of prior malignancy increase probability of cancer
  • Obtain a high-quality CT chest (if nodule was seen on plain film) to characterize size, shape, density (solid vs subsolid ground-glass), and calcifications
• Risk stratification & guidelines:
  • Use criteria (like Fleischner Society guidelines) to determine follow-up:
    • <6 mm: If low-risk patient, no routine follow-up needed (If high-risk, may do a short-interval CT, but generally tiny nodules are observed.)
    • 6-8 mm: Typically recommend follow-up CT at interval (e.g. 6-12 months) depending on risk factors.
    • >8 mm: Consider further evaluation - PET/CT scan to assess metabolic activity, and/or tissue sampling (biopsy) or excision, given higher malignancy risk.
  • Ground-glass nodules: tend to represent indolent adenocarcinoma in situ or atypical hyperplasia if persistent. Guidelines suggest longer follow up (up to 5 years) for ground-glass lesions ≥6 mm
• High-risk features that warrant aggressive evaluation: nodule >8-10 mm, spiculation, upper lobe location, FDG-PET positive uptake, patient >60, smoker or previous cancer. These will often go to biopsy or surgical resection. PET scan: useful for nodules >~8 mm - high uptake (hypermetabolic) suggests malignancy. Note: some infections/inflammation can be PET-positive, and PET can miss indolent cancers.
• Management summary: Small nodules in low-risk individuals - observe with periodic CTs. Larger or suspicious nodules - get a PET scan and/or biopsy (transthoracic needle biopsy or bronchoscopic biopsy depending on location). If high suspicion, go straight to surgical resection (which provides diagnosis and treatment in one). Always weigh the patient’s surgical risk in decision-making.

 

Pleural Effusion

• Presentation: Pleuritic chest pain, dyspnea, or cough if effusion is moderate-to-large. On exam: decreased breath sounds, dullness to percussion, decreased tactile fremitus over fluid, and sometimes egophony at upper fluid level. Large effusions can cause tracheal deviation away from the effusion.
• Diagnosis:
  • Chest X-ray: Blunting of costophrenic angle on upright PA film; lateral decubitus X-ray can confirm fluid layering and estimate volume (≥1 cm layering = enough fluid to tap) An effusion can masquerade as a lower lobe opacity on supine film (fluid layers posteriorly).
  • Lung ultrasound: the best bedside test - shows an anechoic or hypoechoic fluid collection, can distinguish free vs loculated fluid, and guides thoracentesis
  • CT chest: very sensitive for small effusions and can identify underlying lung pathology, but usually done after thoracentesis (fluid can obscure masses; post-drainage CT helps see underlying lung)
• Thoracentesis: indicated for new unexplained effusions >~1 cm. Analyze the fluid to determine etiology. Obtain:
  • Chemistries: protein, LDH (for Light’s criteria), glucose, pH.
  • Cell count with differential: very important Neutrophil-predominant indicates acute process (parapneumonic effusion/empyema). Lymphocyte-predominant suggests TB or malignancy
  • Microbiology: Gram stain and culture (for empyema), AFB stain/culture (if TB effusion suspected).
  • Cytology: for malignant effusion. (One thoracentesis has ~60% yield for cancer cells; repeating increases yield to ~80% with second, ~90% with third tap)
• Light’s Criteria - Transudate vs Exudate: Fluid is exudative if ≥1 of 3 criteria met :
  • Fluid protein / Serum protein > 0.5
  • Fluid LDH / Serum LDH > 0.6
  • Fluid LDH > 2/3 the upper normal limit of serum LDH
  Transudate if all 3 criteria are negative (Only 1 needs positive for exudate.) Light’s is very sensitive for exudates (to not miss cancer or infection) , and highly specific for transudates when all criteria are negative.
• Common Transudates: caused by systemic factors altering hydrostatic or oncotic pressure.
  • CHF (most common overall), especially left ventricular failure - high pulmonary venous pressure causes bilateral (or right-sided) effusions.
  • Cirrhosis (hepatic hydrothorax): ascites fluid moves into pleural space (usually right side) - low protein, low LDH transudate.
  • Nephrotic syndrome: low plasma protein → low oncotic pressure.
  • Others: Hypoalbuminemia of any cause, peritoneal dialysis, and in some cases, acute atelectasis or central venous catheter occlusion can cause small transudates. *Pulmonary embolism* can occasionally cause a transudative effusion, but more often PE effusions are exudative.
• Common Exudates: caused by local factors increasing pleural permeability or lymphatic blockage.
  • Pneumonia (Parapneumonic effusion): very common exudate. Uncomplicated parapneumonic effusions are sterile and resolve with antibiotics; complicated ones have bacterial invasion (but not gross pus) - typically low pH <7.2, low glucose <60 mg/dL, high LDH, needing chest tube drainage; **Empyema** is frank pus in pleural space or positive pleural fluid culture - requires prompt chest tube drainage
  • Malignancy: lung cancer, breast cancer, lymphoma frequently cause exudative effusions (often hemorrhagic). Malignant effusions often recur; options include indwelling pleural catheter (e.g. PleurX) or pleurodesis (talc) for palliation
  • TB pleurisy: Tuberculous effusion is typically lymphocyte-rich, exudative, and can have very high protein. ADA (adenosine deaminase) level is often elevated. Biopsy of pleura may be needed for diagnosis (reveals caseating granulomas).
  • Pulmonary Embolism: causes exudative effusion ~80% of the time (often small and bloody). Mechanism: ischemic inflammation of pleura. Always consider PE in unexplained effusions, especially if patient has risk factors.
  • Other causes: Rheumatologic (e.g. rheumatoid pleurisy - very low glucose, low pH; lupus pleuritis), pancreatitis (left-side effusion with high amylase), esophageal rupture (high amylase too, food particles, very low pH), post-CABG, chylothorax (milky fluid from thoracic duct injury, high triglycerides >110 mg/dL).
• Fluid analysis pearls:
  • Glucose & pH: Very low pleural glucose or pH indicates **complicated** effusion (likely empyema or rheumatoid effusion, or advanced malignancy). Normal pleural fluid pH ≈7.60; if pH <7.2, likely need chest tube drainage (empyema)
  • Cell count: Neutrophils dominate in acute empyema/parapneumonic effusion. Lymphocytes dominate in TB or cancer Eosinophils >10% often from air or blood in pleural space (e.g. prior thoracentesis, pneumothorax, not usually diagnostic of a specific disease).
  • Clotting of fluid: suggests high fibrinogen - often empyema (fibrin deposition causing loculations).
• Treatment: Address underlying cause plus drain fluid when necessary.
  • For transudates - treat the cause (diuresis for CHF, etc.). Large symptomatic transudates can be tapped for relief, but they often reaccumulate if underlying issue persists.
  • For parapneumonic effusions - if uncomplicated (clear fluid, pH >7.3, glucose >60, not loculated), treat pneumonia with antibiotics and observe effusion. If complicated or empyema (pH <7.2, glucose <60, positive culture, or frank pus), **chest tube drainage** is indicated Intrapleural tPA/DNase can help drain loculations. Surgical decortication if unable to clear loculated thick pus.
  • Malignant effusions - if recurrent and symptomatic, options include repeated thoracenteses, indwelling pleural catheter (allows home drainage) , or chemical pleurodesis (instill talc or doxycycline to scar pleura together) Goal is palliation of dyspnea.
  • Hemothorax (blood in pleural space, fluid hematocrit >50% of blood) - require chest tube drainage to avoid fibrothorax, and management of the bleeding source (trauma vs vessel rupture).
  • Chylothorax - treat underlying cause (e.g. lymphoma, surgical thoracic duct injury). Often requires chest tube and dietary modification (medium-chain triglyceride diet or TPN) and sometimes surgical thoracic duct ligation or pleurodesis.

Pleural Fluid Analysis	Transudative Effusion	Exudative Effusion
Mechanism	Systemic factors  ↑hydrostatic or ↓oncotic pressure	Local factors  inflammation, ↑capillary permeability, lymph blockage
Light’s Criteria	All three criteria negative	Fluid Prot / Serum Prot > 0.5 Fluid LDH / Serum LDH > 0.6 Fluid LDH > two-thirds upper-limit normal serum LDH
Appearance	Clear, straw (CHF may appear serosanguineous)	Cloudy or turbid → empyema Bloody → malignancy or PE Milky → chylous
Glucose	≈ serum glucose	Often < serum glucose (very low in empyema or rheumatoid effusion)
pH	About 7.4 to 7.5 (normal pleural pH ≈ 7.60)	Below 7.30 (below 7.20 in complicated parapneumonic / empyema)
Examples	CHF, cirrhosis (hepatic hydrothorax), nephrotic syndrome, myxedema	Pneumonia (parapneumonic), cancer, TB, PE, pancreatitis, rheumatoid / lupus

 

Latent and Active Tuberculosis (TB)

• Pathogen: Mycobacterium tuberculosis (acid-fast bacillus) spread via airborne droplets (coughing, etc.) Primarily affects lungs (pulmonary TB) but can involve almost any organ (extrapulmonary TB: lymph nodes, pleura, bone (Pott’s disease), CNS, etc.).
• Outcomes of infection: After inhalation, TB can result in:
  • Latent TB Infection (LTBI): Immune system contains the infection. Bacteria remain dormant (primarily in healed granulomas), and the patient has no symptoms and is not contagious ~90% of infected individuals enter latent phase.
  • Active TB Disease: Either primary active TB soon after infection, or reactivation TB years later. The bacteria multiply and cause clinical illness. Symptomatic and contagious. Classic symptoms: fevers, night sweats, weight loss, fatigue, and chronic cough (initially dry, progressing to productive, with hemoptysis in some) TB can also present with extrapulmonary signs depending on organ (e.g. scrofula - TB lymphadenitis in the neck, Pott’s spine pain, meningitis, etc.).
• Latent TB Testing: Indicated for asymptomatic individuals at risk (close contacts of TB cases, immigrants from high-prevalence regions, healthcare workers, immunosuppressed patients, etc.) Do not use latent TB tests on someone with active TB signs - if TB is suspected clinically, proceed to diagnostic tests (sputum AFB, CXR)
  • Tuberculin Skin Test (TST, PPD): Intradermal injection of tuberculin; read 48-72h later. Measure induration (not redness) A positive threshold depends on risk factors:
    • ≥5 mm: positive for highest-risk - HIV-infected, immunosuppressed (e.g. organ transplant, TNF-α blockers), recent TB contacts, or CXR with old TB changes
    • ≥10 mm: positive for moderate risk - e.g. recent immigrants from endemic areas, IV drug users, residents/employees of prisons, shelters, healthcare workers, patients with silicosis, diabetes, CKD, etc., children <4, etc. (includes most “healthy” healthcare workers)
    • ≥15 mm: positive for persons with no known risk factors (this group shouldn’t normally be tested)
    Two-step testing: done for initial testing in adults who will be periodically screened (healthcare, etc.) to catch remote infections. If first PPD is negative, a second is placed ~1-3 weeks later to “boost” immune memory - if the second is positive, it’s a booster effect (latent TB from long ago, not a new conversion) This prevents confusing a boosted reaction later for a new infection
  • Interferon-Gamma Release Assays (IGRA): Blood tests (e.g. QuantiFERON-TB Gold, T-SPOT.TB) that measure T-cell release of interferon-γ in response to TB-specific antigens Not affected by BCG vaccine (preferred for BCG-vaccinated individuals) Only require one visit. An “indeterminate” result can occur (repeat test or use alternative method) IGRAs are increasingly the test of choice for latent TB due to convenience and specificity
• Management of Latent TB: Not an emergency - treat latent TB after ruling out active disease (never treat “latent” TB with one drug if patient actually has active TB - that monotherapy could breed resistance!) Ensure CXR is clear and patient has no symptoms before treating latent TB.
  • Treatment greatly reduces risk of future reactivation (which is ~10% lifetime for immunocompetent, but ~10% per year if HIV+) It’s most beneficial in young or higher-risk patients - in an elderly low-risk person, weigh risk/benefit of drug toxicity
  • Preferred regimen: Isoniazid (INH) for 9 months (with vitamin B₆ supplementation) - historically the gold standard Efficacy ~90% if taken properly.
  • Alternative regimens:
    • INH for 6 months (not quite as effective as 9, but an option if 9 mo can’t be completed).
    • INH + Rifapentine once weekly for 3 months (12 doses DOT) - convenient and increasingly used (high completion rates).
    • Rifampin daily for 4 months - used if INH resistance or intolerance.
  • Monitor for hepatotoxicity during therapy - check baseline liver enzymes, and periodically if risk factors. INH can cause hepatitis (risk increases with age & alcohol use). Rifampin also hepatotoxic and causes orange body fluids. Educate patient about symptoms of hepatitis (stop drug if anorexia, nausea, jaundice).
  • Follow-up: Ensure adherence (especially with longer regimens). If using INH, give pyridoxine (B₆) to prevent peripheral neuropathy
• Active TB Disease - Diagnosis:
  • Clinical suspicion: Chronic cough & constitutional signs, risk factors (e.g. homelessness, known exposure, immunosuppression). Classic exam: apical rales in lungs; but can be variable. Extrapulmonary TB presents with organ-specific findings (e.g. lymph node TB - chronic lymphadenopathy; skeletal TB - back pain, etc.).
  • Isolation: Anyone suspected of pulmonary TB should be placed in airborne isolation (negative-pressure room) and staff should wear fit-tested N95 masks
  • CXR: Reactivation TB classically shows fibrocavitary lesions in upper lobes or superior segments of lower lobes. Primary TB might show middle/lower lobe consolidation with hilar adenopathy, or even a normal CXR. Miliary TB shows diffuse millet-seed nodules. However, imaging is not definitive - need microbiologic confirmation.
  • Sputum testing: Obtain at least 3 sputum specimens (expectorated or induced) for:
    • AFB smear (Ziehl-Neelsen stain): Quick result. AFB smear-positive indicates a high mycobacterial burden and infectiousness However, smear can be negative in ~50% of active TB cases (especially HIV+ or extrapulmonary) - cannot rule out TB
    • Mycobacterial culture: Gold standard for diagnosis and drug susceptibility testing Culture can take 1-8 weeks (average ~3-4 weeks) since TB is slow-growing. Keep cultures up to 8 weeks before calling negative.
    • NAAT/PCR (e.g. Xpert MTB/RIF): Rapid molecular test that detects TB DNA and common rifampin-resistance mutations Can confirm TB within 1-2 days and guide therapy (rifampin resistance as proxy for MDR-TB). A positive AFB smear + positive PCR is diagnostic If PCR is available, it’s usually done on at least the first sputum sample.
    If sputum can’t be obtained, consider bronchoscopy with bronchoalveolar lavage to collect samples For extrapulmonary TB, obtain biopsy or aspirate of affected site (e.g. lymph node, bone marrow) for AFB stain, culture, histology.
• Active TB - Treatment: Requires multiple drugs for an adequate duration to eradicate the infection and prevent resistance.
  • Initial phase: **4-drug therapy for 2 months** - Isoniazid + Rifampin + Pyrazinamide + Ethambutol (often abbreviated “RIPE”). This kills most of the bacteria quickly Ethambutol can be stopped if isolate is confirmed sensitive to INH & Rif (EM added initially as insurance against resistance).
  • Continuation phase: After 2 months, if isolate is pansensitive and patient responding, drop PZA and EMB. Continue INH + Rifampin for 4 more months (to complete a total of 6 months therapy) This longer phase kills persistent organisms. Total = 6 months for drug-sensitive TB (extended to 9 months or more in some cases - e.g. CNS TB, bone TB, or if culture still positive at 2 months).
  • Directly Observed Therapy (DOT): recommended for all TB treatment to ensure adherence, especially in intermittent dosing regimens.
  • Monitoring: Baseline tests: liver enzymes, bilirubin (INH, RIF, PZA are hepatotoxic); uric acid (PZA causes hyperuricemia); vision testing (EMB can cause optic neuritis - test visual acuity and color perception periodically). Monthly clinical review for adherence and side effects.
  • Side effects mnemonic “RIPE”:
    • Isoniazid (INH): Hepatitis (monitor LFTs), peripheral neuropathy (prevent with pyridoxine/B₆) , rare sideroblastic anemia or seizures (B₆ deficiency). Also a cause of drug-induced lupus.
    • Rifampin (RIF): Hepatotoxicity, orange-red discoloration of urine, tears, sweat (harmless but patients should be warned - can stain contact lenses) Many drug interactions (strong inducer of CYP450 - watch out with HIV drugs, warfarin, OCPs).
    • Pyrazinamide (PZA): Hepatotoxic, can cause severe hyperuricemia (almost always raises uric acid; can precipitate gout flares), and GI upset. Also contraindicated in pregnancy (in some guidelines)
    • Ethambutol (EMB): Dose-related optic neuritis (decreased visual acuity, red-green color blindness - “E for Eyes”) Requires baseline and periodic eye exams. Otherwise, fairly safe; reduce dose in renal failure.
  • If patient is still culture-positive after 2 months of therapy, it suggests possible inadequate adherence or resistant organisms - extend total therapy to 9 months and ensure susceptibilities are checked.
  • Resistance considerations:
    • Multi-drug resistant TB (MDR-TB): TB resistant to at least INH and Rifampin Requires use of second-line drugs and longer treatment (18-24+ months) - e.g. fluoroquinolones, injectables (amikacin, etc.), bedaquiline, linezolid, etc. Treat in specialized centers.
    • Extensively drug-resistant TB (XDR-TB): MDR plus resistance to a fluoroquinolone and an injectable agent - very difficult to treat Emerging threat globally.
• Follow-up and Infection Control: A patient on TB treatment is typically considered non-infectious after **2 weeks** of appropriate therapy if responding (and with AFB smears converting to negative), but this must be confirmed by public health guidance. For household contacts, evaluate and treat latent TB. Report all TB cases to public health for contact tracing and DOT arrangement.

 

Pulmonary Embolism (PE) and Deep Venous Thrombosis (DVT)

• Pathophysiology: DVT (usually in deep veins of legs, e.g. iliac, femoral, popliteal) can dislodge and travel to pulmonary arteries → Pulmonary Embolism. PE causes ventilation-perfusion mismatch (areas ventilated but not perfused), leading to hypoxemia, and can cause pulmonary hypertension and right heart strain acutely.
• Risk factors (Virchow’s triad):
  • Venous stasis: immobility (bed rest, long plane/car rides), hospitalization, paralysis, prolonged sitting.
  • Endothelial injury: surgery (especially orthopedic), trauma, central venous catheters (PICC lines predispose to upper extremity DVTs)
  • Hypercoagulability: cancer (especially adenocarcinomas can cause migratory thrombophlebitis), estrogen (OCPs, HRT), pregnancy/postpartum , antiphospholipid syndrome, inherited thrombophilias (Factor V Leiden, prothrombin gene mutation, protein C/S or ATIII deficiency), inflammatory diseases (IBD, lupus), nephrotic syndrome, obesity, smoking, and age >50 all contribute
  Many hospitalized patients have multiple risk factors (e.g. cancer + immobility + recent surgery).
• Clinical Presentation of PE:
  • Classic triad: sudden onset dyspnea, pleuritic chest pain, and hemoptysis - but this triad is infrequent. More common: acute dyspnea unexplained by auscultation, tachypnea, tachycardia, and pleuritic pain. Cough or mild hemoptysis in some.
  • Signs: Tachycardia is the most common sign. Tachypnea also common. Low-grade fever may occur. Hypoxemia (low O₂ sat). If large PE: hypotension, signs of shock, or syncope. Signs of DVT may be present (unilateral leg swelling, calf pain).
  • Exam: Often normal chest exam or maybe subtle pleural rub. Loud P2 or JVD if massive PE straining the right heart. If infarction, patient may have pleural friction rub and hemoptysis (pulmonary infarct).
• Clinical Presentation of DVT: Unilateral leg swelling, pain, redness, warmth. Calf or thigh tenderness (Homan’s sign - pain on foot dorsiflexion - is neither sensitive nor specific, but boards might mention it). DVTs most commonly affect left leg (left iliac vein compressed - May-Thurner syndrome) However, any deep vein (including upper extremity with central lines, or pelvic veins) can thrombose and cause PE
• Diagnosis - Pretest Probability: Use Wells criteria for DVT and for PE to stratify patients (based on symptoms, risk factors, exam findings).
  • If suspicion is low (Wells low) - get a high-sensitivity D-Dimer blood test. A normal D-dimer (<500 ng/mL) effectively rules out DVT/PE in low-risk patients
  • If moderate or high suspicion - skip D-dimer and go straight to imaging, because a negative D-dimer won’t sway you if pretest is high
• DVT Imaging:
  • Doppler ultrasound of the leg - test of choice for DVT Duplex US showing non-compressible vein with clot confirms DVT. It’s noninvasive and sensitive for proximal DVT. If US is negative but suspicion remains (e.g. high D-dimer, persistent symptoms), can repeat US in a week or consider venography.
  • Venography is the historical gold standard but invasive (IV contrast in foot) and rarely done now
  • MRI venography can detect pelvic DVTs but is not first-line due to cost and limited availability.
• PE Imaging:
  • CT Pulmonary Angiography (CTPA): the diagnostic test of choice for PE (non-invasive gold standard) Spiral CT with IV contrast visualizes emboli in pulmonary arteries. High sensitivity and specificity in central vessels (less for tiny subsegmental clots). Requires patient to tolerate IV contrast and lie flat holding breath - careful in those with renal failure or pregnancy.
  • Ventilation/Perfusion (V/Q) scan: nuclear medicine scan - inhale radiotracer for ventilation, inject for perfusion, look for mismatched perfusion defects. Used when CT is contraindicated (contrast allergy, renal failure, pregnancy) Results can be “high probability” (multiple segmental perfusion defects with normal ventilation - treat as PE) , “normal” (rules out PE), or “indeterminate”. Indeterminate V/Q requires further workup (like leg Doppler, or proceed to CTA if possible) **Note:** V/Q most useful if baseline CXR is normal - otherwise more likely to be nondiagnostic
  • Other tests (not diagnostic alone):
    • CXR - often normal. May show subtle signs: Westermark’s sign (region of oligaemia distal to clot) , Hampton’s hump (peripheral wedge of opacity due to infarct) , small pleural effusion, or atelectasis These findings are rare and not sensitive.
    • EKG - sinus tachycardia most common finding Classic S1Q3T3 pattern (S wave in lead I, Q wave in III, inverted T in III) indicates acute right heart strain, but is infrequent May see RBBB or T wave inversions V1-4. EKG is not diagnostic.
    • ABG - often shows acute respiratory alkalosis (low CO₂ from hyperventilation) and widened A-a gradient with hypoxemia Not specific, but hypoxemia in a patient with clear lungs should raise suspicion.
  • If a DVT is found in a symptomatic patient with chest pain/breathing issues, one can essentially diagnose a PE (since the treatment is the same) For example, in a pregnant patient with leg DVT and chest symptoms, may avoid radiation by treating presumptive PE. In an ICU patient who can’t be moved for CT, finding a DVT on ultrasound often suffices to start anticoagulation
• Initial Management of DVT/PE:
  • Anticoagulation - mainstay therapy. Start as soon as PE/DVT is diagnosed (or strongly suspected with high pretest probability, even before imaging, unless contraindicated). Options:
    • Low Molecular Weight Heparin (LMWH): e.g. enoxaparin. SC injection, weight-based, reliable dose effect. Preferred in many cases (e.g. cancer-associated thrombosis, pregnancy) because of ease and no need for lab monitoring Avoid if severe renal failure (use IV heparin then).
    • Unfractionated IV Heparin: Useful if high bleeding risk (short half-life, reversible) or if expecting to perform thrombolysis (UFH can be briefly stopped). Titrate to aPTT. Often chosen for massive PE or if hypotensive (in case urgent thrombectomy needed)
    • Fondaparinux: SC factor Xa inhibitor, given daily. Often used if history of HIT. Similar to LMWH in ease
    • DOACs (Direct Oral Anticoagulants): Now first-line for many DVT/PE: e.g. rivaroxaban, apixaban (factor Xa inhibitors), or dabigatran (direct thrombin inhibitor). Rivaroxaban and apixaban can be started immediately (oral monotherapy). Dabigatran and edoxaban are started after initial heparin lead-in. DOACs do not require lab INR monitoring. Apixaban and rivaroxaban are commonly used due to convenience and efficacy.
    • Warfarin (Vitamin K antagonist): Was traditional therapy. If used, must overlap (“bridge”) with heparin for at least 5 days and until INR is 2-3 for ≥24h Always start heparin first before warfarin to avoid transient hypercoagulability (warfarin initially drops protein C/S levels) - prevent skin necrosis Warfarin requires INR monitoring and has dietary and drug interactions.
  • Thrombolysis: (tPA) indicated for massive PE causing hemodynamic instability (shock) or if evidence of right ventricular failure with hemodynamic compromise. It’s considered in submassive PE (RV strain) if the patient is deteriorating. Contraindications: major bleeding risk, recent surgery, hemorrhagic stroke history, etc.
  • Inferior Vena Cava (IVC) filter: indicated if anticoagulation is contraindicated (e.g. active bleeding, hemorrhagic stroke) or if recurrent PE despite anticoagulation. A filter in the IVC catches clots from legs. Filters can be temporary or permanent. Downside: long-term filter can thrombose or cause leg swelling.
  • Supportive: Oxygen for hypoxemia; IV fluids and vasopressors if hypotensive. Intubation for severe hypoxemia or respiratory failure. In massive PE with cardiac arrest, consider thrombolysis during CPR if no contraindications.
• Chronic Management and Secondary Prevention:
  • Duration of anticoagulation:
    • Provoked DVT/PE (with transient risk factor like surgery, immobilization): anticoagulate for ~3 months is typically sufficient
    • Unprovoked (idiopathic) first DVT/PE: At least 3 months, then reassess risk/benefit. Many patients will benefit from extended therapy (6-12 months or indefinitely) if bleed risk is low, because recurrence risk is significant when unprovoked.
    • Recurrent VTE or ongoing risk factors (e.g. active cancer, antiphospholipid syndrome): consider indefinite anticoagulation (lifelong)
    • Cancer-associated thrombosis: Treat until cancer is in remission (at least 3-6 months, often longer as cancer is an ongoing risk). LMWH or DOACs are preferred over warfarin in malignancy.
  • Risk factor evaluation: For unprovoked VTE, perform age-appropriate cancer screening (don’t go chasing every tumor with extensive blind testing) Also consider testing for inherited thrombophilia if appropriate (especially if young patient, family history, unusual clot site) - but remember, do not test during acute thrombosis or while on warfarin/heparin as results can be skewed If needed, hold warfarin for ~2 weeks then test Protein C/S, AT III levels Genetic tests (Factor V Leiden, prothrombin gene) and antiphospholipid antibody tests can be done anytime (not affected by AC)
  • Special “hypercoagulable” tests:
    • Arterial clot or recurrent miscarriages - check antiphospholipid syndrome (Lupus anticoagulant, anticardiolipin, β2-glycoprotein). Arterial clot can also be seen in heparin-induced HIT (check platelet counts in heparin exposure)
    • Warfarin skin necrosis - suspect Protein C deficiency
    • Young patient with unexplained hepatic vein (Budd-Chiari) or portal vein thrombosis - think myeloproliferative disorders (e.g. Polycythemia Vera with JAK2 mutation)
    • Unusual site like hepatic or cerebral vein - work up thoroughly for APS, myeloproliferative disease, etc.
    *Remember:* A positive thrombophilia test doesn’t always mandate anticoagulation if the patient never had a clot; and a negative workup doesn’t change the need to treat an actual clot. The presence of an inherited thrombophilia mainly might influence decisions on duration of therapy (e.g. homozygous Factor V Leiden or ATIII deficiency lean toward indefinite treatment).
  • Prevention: In hospitalized patients (especially post-op orthopedic or immobile patients), use DVT prophylaxis - low-dose heparin or LMWH, pneumatic compression devices, and early ambulation. Identify and mitigate reversible risk factors (e.g. minimize indwelling central lines if possible, encourage mobility on long flights, etc.).