A 58-year-old man with hypertension has been on enalapril 10 mg daily for 3 years with good blood pressure control. He now presents with a 2-week history of persistent dry cough, dyspnea on exertion, and wheezing. Chest X-ray shows bilateral interstitial infiltrates. Pulmonary function tests reveal a restrictive pattern. His serum creatinine has risen from 0.9 mg/dL (baseline) to 1.8 mg/dL. Echocardiography shows normal ejection fraction and no signs of pulmonary edema. Bronchoscopy with bronchoalveolar lavage (BAL) shows lymphocytic infiltration. After discontinuing enalapril, symptoms gradually resolve over 4 weeks. Which classification of adverse drug reaction best describes this presentation?
A. Type A reaction (augmented dose-dependent effect)
B. Type D reaction (delayed teratogenic or carcinogenic effect)
C. Type C reaction (chronic cumulative toxicity)
D. Type B reaction (bizarre idiosyncratic immune-mediated effect)
Explanation
Classification of ACE Inhibitor–Induced Pulmonary Toxicity
Clinical Presentation Analysis
The patient develops insidious pulmonary infiltration (interstitial pneumonitis with restrictive physiology), elevated creatinine, and lymphocytic inflammation after 3 years of enalapril therapy. Symptoms resolve after drug discontinuation.
Type B (Idiosyncratic) Reaction Characteristics
Key Point
Type B reactions are bizarre, non-dose-dependent, unpredictable adverse effects that occur in genetically susceptible individuals and are NOT related to the drug's known pharmacological properties.
Why This Is Type B, Not Type A or C
Distinguishing Type B from Type A
Table
Criterion
Type A
Type B
Dose-dependent
Yes
No
Frequency
Common (10–20%)
Rare (0.1–1%)
Mechanism
Exaggerated pharmacology
Genetic/immunological hypersensitivity
Predictability
Predictable in all users
Unpredictable; only in susceptible individuals
Onset
Immediate to early
Variable; can be delayed
Why Not Type A?
ACE inhibitors' pharmacological action is vasodilation and angiotensin II suppression → hypotension, hyperkalemia, cough (from bradykinin accumulation).
Interstitial pneumonitis with lymphocytic infiltration is NOT an exaggeration of these effects.
Not all patients on enalapril develop pulmonary toxicity—it occurs only in susceptible individuals (Type B hallmark).
The dose (10 mg) is standard; no dose escalation preceded the reaction.
Why Not Type C (Chronic Toxicity)?
Type C reactions:
Develop insidiously over months to years of cumulative exposure.
Result from direct tissue damage or metabolite accumulation.
The lymphocytic BAL infiltrate is the smoking gun for immune-mediated (Type B) pathology, not dose-dependent toxicity.
Type B Reactions: Classic Drugs and Manifestations
Table
Drug
Type B Reaction
ACE inhibitors
Pulmonary infiltrates, drug-induced lupus
Sulfasalazine
Hemolytic anemia, agranulocytosis, colitis
Allopurinol
Stevens-Johnson syndrome, DRESS syndrome
Phenytoin
Phenytoin hypersensitivity syndrome
NSAIDs
Asthma exacerbation (in aspirin-sensitive patients)
Why Reversibility Matters
Key Point
Type B reactions are often reversible upon drug discontinuation because they are not due to cumulative tissue damage but rather to an acute immune response. This patient's symptom resolution over 4 weeks after stopping enalapril is typical of Type B reactions.
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