Drug-Induced Lung Diseases

(Fishman's Pulmonary Diseases and Disorders, 5th Ed. - Chapters 64 & 65)

I. INTRODUCTION AND EPIDEMIOLOGY

II. GENERAL PRINCIPLES (TABLE 65-1, Fishman's)

III. MECHANISMS OF PULMONARY INJURY

1. Oxidant injury - Well-established for nitrofurantoin, mitomycin C, and bleomycin. Biotransformation generates reactive oxygen species (H₂O₂, •HO, O₂⁻•), promoting lipid peroxidation, glutathione depletion, and cell death.
2. Immunologic/inflammatory cell-mediated injury - Lymphocytic or neutrophilic alveolitis; drug metabolite-protein adducts can act as immunogens. Complement-mediated injury is implicated for drugs causing ARDS (opiates, β-agonists).
3. Interference with matrix formation/alveolar repair
4. Abnormal protease/antiprotease balance
5. Interference with lipid/phospholipid metabolism - Well-established for amiodarone (cellular sequestration of phospholipids).

IV. DIAGNOSTIC APPROACH

1. History of drug exposure
2. Clinical signs, radiologic findings, and histopathology consistent with previously reported toxicity
3. Alternate diagnoses excluded (infection, systemic disease, malignancy)
4. Findings regress with drug discontinuation and/or treatment

V. CLINICAL SYNDROMES AND PATTERNS

A. Interstitial Pneumonitis / Pulmonary Fibrosis (Chronic Pneumonitis)

• NSIP (Non-Specific Interstitial Pneumonia) - most common
• UIP (Usual Interstitial Pneumonia)
• Organizing Pneumonia (OP)
• DIP (Desquamative Interstitial Pneumonia)

B. Eosinophilic Pneumonia (PIE)

• Systemic symptoms (rash, fever) accompany respiratory symptoms
• Marked peripheral blood eosinophilia (>1000 cells/mL) suggests drug-induced (vs. idiopathic, where count is more modest)
• Resolves on drug discontinuation, often without corticosteroids; relapse as steroids are tapered is rare (unlike idiopathic CEP)

C. Hypersensitivity Pneumonitis

• Acute onset dyspnea, cough, and fever
• Radiograph: diffuse reticular or peripheral alveolar infiltrates, sometimes with pleural effusion
• Histopathology: necrotizing granulomas, chronic bronchiolitis, chronic interstitial inflammation with or without fibrosis
• Most cases resolve with drug discontinuation; a minority (10%) require corticosteroids

D. Pulmonary Edema / ARDS (Noncardiogenic)

• Drugs causing ARDS: opiates, β-agonists, hydrochlorothiazide (HCTZ), aspirin (salicylate toxicity)
• HCTZ: acute dyspnea, hypoxemia, fever, tachycardia, hypotension, shock - immunologically mediated capillary leak (IgG deposition on alveolar membrane, elevated IgM)
• Rechallenge causes recrudescent pulmonary edema - not recommended

E. Bronchospasm and Anaphylaxis

• NSAIDs/Aspirin: account for up to 24% of bronchoconstrictive reactions
• Beta-blockers: particularly nonselective agents (propranolol); β1-selective agents better tolerated but still require caution in asthmatics
• Mechanisms: IgE-mediated, non-IgE-mediated (anaphylactoid), alteration in COX/lipoxygenase pathways, mast cell activation
• Penicillin: most important cause of anaphylaxis, accounting for up to 75% of cases annually in the USA

F. Constrictive Bronchiolitis

• Agents: D-penicillamine, gold salts (used in RA treatment)
• Symptoms: dyspnea with or without wheeze, cough
• HRCT: centrilobular nodules, tree-in-bud opacities, mosaic attenuation (air trapping)
• Spirometry may not detect small airway disease until obstruction is severe

G. Pulmonary Hypertension

• Drugs implicated: dasatinib, amphetamines, methamphetamines, cocaine
• Onset is subtle; often presents late with significant vascular compromise
• Potential for vascular collapse and death - requires early recognition

H. Diffuse Alveolar Hemorrhage (DAH)

• Associated with: hydralazine, propylthiouracil (PTU) - can cause ANCA-positive vasculitis
• Also seen with anticoagulants, penicillamine, sirolimus

I. ACE Inhibitor-Induced Cough and Angioedema

• Dry cough occurs in 5-20% of patients on ACEi; mechanism: bradykinin accumulation (ACE normally degrades bradykinin)
• Angioedema: life-threatening; higher incidence in African Americans (also higher risk of intubation)
• Mechanism: elevated circulating bradykinin → vasodilatation and capillary leak
• Treatment: corticosteroids, H1/H2-blockers, epinephrine; switch to ARB

J. Drug-Induced SLE with Pleuropulmonary Involvement

• Hydralazine: 50% of patients on >200 mg/day develop positive ANA; 10% develop clinical symptoms; drug-induced SLE more frequent if cumulative dose exceeds 100 g
• Pleuropulmonary manifestations occur in 30% of affected subjects: subacute ILD/NSIP, OP, DAH
• Also: acebutolol, propranolol, labetalol, pindolol

VI. SPECIFIC DRUGS IN DETAIL

A. BLEOMYCIN (Cytotoxic Antibiotic)

• Used for: lymphomas, germ cell tumors, squamous cell cancers of H&N
• Lung susceptibility: relative lack of inactivating enzyme bleomycin hydrolase
• Mechanism: endothelial injury via oxidative stress → inflammatory cell influx (macrophages, neutrophils, lymphocytes) → perivascular edema → cytokine elaboration (TNF-α, TGF-β, IL-6, IL-1) → fibroblast activation → fibrosis
• Clinical syndromes: chronic pneumonitis → pulmonary fibrosis; rare fulminant variant with acute respiratory failure; hypersensitivity pneumonitis; chest pain syndrome
• Risk factors: cumulative dose >400 units; supplemental oxygen; therapeutic radiation; renal insufficiency; age >70 years; additional cytotoxic drugs
• Treatment: discontinue drug + corticosteroids

B. MITOMYCIN-C

• Syndromes: chronic pneumonitis/fibrosis; rare fulminant ARDS after single dose; acute dyspnea/bronchospasm
• Hemolytic Uremic Syndrome (HUS): microangiopathic hemolytic anemia + thrombocytopenia + renal insufficiency + noncardiogenic pulmonary edema ± alveolar hemorrhage
• Risk factors: oxygen therapy, radiation, additional cytotoxic drugs
• Bronchospasm risk is heightened with concurrent vinca alkaloid use (can recur with vinca rechallenge alone)
• Poor response to plasmapheresis or corticosteroids for HUS

C. METHOTREXATE (Low-dose, non-chemotherapy use)

• Used in RA, psoriasis; low-dose MTX pneumonitis is a well-recognized complication
• Histopathology: BAL shows lymphocytic alveolitis (immune mechanism supported by lymphocytic BAL profile - CD4+ T cells)
• Risk factors (ANCA-based multicenter study): diabetes, rheumatoid lung involvement, hypoalbuminemia, prior DMARD use, older age
• Radiograph: bilateral interstitial/alveolar infiltrates; may show pleural effusion
• Treatment: discontinue drug + corticosteroids; typically responds well
• Rechallenge is not recommended

D. AMIODARONE

• Most commonly studied of all non-chemotherapy agents
• Mechanism: disruption of phospholipid metabolism (phospholipidosis) - amiodarone and its metabolite desethylamiodarone accumulate in lysosomes, preventing phospholipid degradation → "foamy" lamellar body-laden macrophages (hallmark on BAL and biopsy)
• Clinical: insidious dyspnea, cough, low-grade fever; bilateral infiltrates on CXR
• HRCT: high-density (hyperattenuating) consolidation/ground-glass due to iodine content
• PFTs: reduced DLCO (most sensitive), restrictive pattern
• Histopathology: foamy alveolar macrophages, NSIP or OP pattern
• Risk: cumulative dose, dose >400 mg/day, duration >2 months; prior lung disease
• Treatment: reduce/stop drug; corticosteroids; long half-life means months for resolution

E. NITROFURANTOIN

• Two distinct forms:
  • Acute (within days to weeks): fever, chills, cough, dyspnea, peripheral blood eosinophilia - hypersensitivity mechanism; rapid resolution on stopping drug
  • Chronic (months to years): insidious onset, progressive ILD/fibrosis, less eosinophilia
• Mechanism: oxidant injury (reactive oxygen species generation)
• One of the most frequent causes of drug-induced eosinophilic pneumonia

F. BEVACIZUMAB (Anti-VEGF monoclonal antibody)

• Complications: pulmonary hemorrhage (risk factors: cavitary tumor, squamous cell histology); tracheoesophageal fistula (with concurrent mediastinal radiation)
• Excluded from trials if cavitary lung disease or squamous cell histology present

G. CHECKPOINT INHIBITORS (Immune Checkpoint Inhibitors - ICIs)

• Anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab), anti-CTLA-4 (ipilimumab)
• Immune-related pneumonitis (irAP) is the most clinically significant pulmonary toxicity
• Incidence: 2-5% for anti-PD-1 monotherapy; higher with combination ICI therapy
• Presentation: dyspnea, cough, chest pain; can be life-threatening
• Grading (Grades 1-4): Grade 1 = asymptomatic radiographic changes; Grade 4 = life-threatening respiratory failure
• Treatment: Grade 1 - hold ICI, monitoring; Grade 2 - hold + prednisolone 1 mg/kg; Grades 3-4 - permanently discontinue + high-dose corticosteroids (methylprednisolone 2 mg/kg)

H. TNF-α INHIBITORS (Biologics)

• Etanercept, infliximab, adalimumab: used in RA, ankylosing spondylitis, psoriasis
• Pulmonary complications:
  • Sarcoid-like granulomatous disease (paradoxical - these agents also used to treat refractory sarcoidosis; ~50% compatible with stage 2 sarcoidosis; two-thirds resolve with drug discontinuation)
  • ILD/interstitial pneumonitis (OP pattern most common)
  • Lupus-like syndrome with serositis/pleuropulmonary involvement (positive ANA, anti-dsDNA); risk = 10/10,000 patient-years

VII. PATTERN RECOGNITION: KEY DRUGS BY SYNDROME

VIII. MANAGEMENT PRINCIPLES

1. Identify and discontinue the culprit drug (most important step)
2. Corticosteroids are the mainstay for moderate-to-severe cases (prednisolone 0.5-1 mg/kg/day, tapered over weeks to months)
3. Exclude infection before starting corticosteroids (especially opportunistic infections in immunocompromised patients)
4. Supportive care (oxygen, mechanical ventilation for ARDS if required)
5. Rechallenge is not recommended - recrudescence confirms diagnosis but carries risk
6. Monitor for relapse during steroid taper (rare in drug-induced disease; frequent relapse suggests alternate diagnosis)
7. Use Pneumotox.com database for updated drug-toxicity profiles

IX. IMPACT OF CONCURRENT EXPOSURES

• Oxygen + bleomycin: well-established potentiation of lung injury (additive oxidant mechanism) - avoid high FiO₂ in patients with bleomycin history
• Cigarette smoke: may influence lung injury through induction of cytochrome P450 enzymes
• Radiation therapy concurrent with cytotoxic drugs: increased risk; also "radiation recall" phenomenon (actinomycin-D, doxorubicin)