1. Introduction

Drug-induced pulmonary diseases (DIPDs) encompass a diverse group of lung injuries directly attributable to medications. These conditions can mimic common pulmonary afflictions such as infection and inflammatory lung injury, often leading to delayed recognition, particularly in critically ill patients where polypharmacy is common.

Definition and Clinical Significance

• Definition: DIPDs are characterized by various lung injury patterns caused by drugs, including interstitial pneumonia, organizing pneumonia, Acute Respiratory Distress Syndrome (ARDS), eosinophilic pneumonia, and pulmonary hemorrhage.
• Clinical significance: DIPDs account for approximately 3–5% of all interstitial lung disease cases. They are frequently under-recognized in Intensive Care Unit (ICU) settings due to their nonspecific clinical features and the complexity introduced by multiple concurrent medications.

2. Epidemiology

DIPDs are often underdiagnosed in critically ill patient cohorts. Current incidence estimates primarily rely on retrospective series and expert consensus rather than prospective data specifically from ICU populations.

• Incidence: Estimated to comprise about 3–5% of all interstitial lung disease (ILD) cases. Over 400 drugs have been implicated as potential causes of pulmonary toxicity.
• ICU Risk Factors: The risk of developing DIPDs is amplified in the ICU due to factors such as advanced age, multiple comorbidities, pre-existing organ dysfunction, and polypharmacy.
• Outcomes: Early recognition of DIPD and prompt withdrawal of the offending agent are critical for improving survival and limiting the development of irreversible pulmonary fibrosis. Conversely, delayed diagnosis can lead to increased ventilator days, prolonged ICU length of stay, and higher mortality rates.

3. Risk Factors

The risk of developing DIPD is a complex interplay between host susceptibility and the characteristics of drug exposure.

A. Patient-Related Risk Factors

• Age ≥60 years
• Pre-existing lung disease (e.g., interstitial lung disease, COPD)
• Renal or hepatic impairment (leading to impaired drug clearance)
• Comorbidities such as diabetes mellitus
• Genetic predisposition (e.g., certain HLA alleles associated with increased risk for specific drugs)

B. Drug-Related Risk Factors

• High cumulative dose (e.g., amiodarone >400 mg/day; bleomycin >400–500 units total cumulative dose)
• Prolonged duration of therapy
• Polypharmacy, especially with other known pneumotoxic agents or cytochrome P450 (CYP) inhibitors
• Combination immunotherapies (e.g., anti-PD1/PDL1 agents combined with anti-CTLA4 agents)
• Impaired drug excretion (e.g., nitrofurantoin in patients with creatinine clearance < 30 mL/min)

4. Common Causative Agents

While many drugs can cause pulmonary toxicity, a core group of agents accounts for the majority of DIPD cases. Each drug often has characteristic latency periods, radiographic patterns, and specific monitoring requirements.

5. Clinical Presentations

The clinical presentation of DIPDs can range from acute, fulminant respiratory failure to chronic, insidious onset of symptoms. Presentations are often nonspecific, further complicating diagnosis.

Common Symptoms and Signs

• Symptoms: Progressive dyspnea (most common), dry or nonproductive cough, chest discomfort or pain, fever (particularly in acute forms).
• Signs: Hypoxemia, bilateral inspiratory crackles on auscultation, tachypnea, signs of respiratory distress (e.g., use of accessory muscles).

Time Course of Onset

• Acute (hours to days):
  • Nitrofurantoin (acute hypersensitivity reaction)
  • Acute amiodarone toxicity (less common than chronic)
  • Some presentations of ICI pneumonitis
• Subacute (days to weeks):
  • Methotrexate-induced hypersensitivity pneumonitis
  • Organizing pneumonia pattern from various drugs
• Chronic (months to years):
  • Bleomycin-induced pulmonary fibrosis
  • Chronic nitrofurantoin-induced lung disease
  • Chronic amiodarone pulmonary toxicity

6. Diagnostic Approach

The diagnosis of DIPD primarily relies on establishing a temporal association between drug exposure and symptom onset, meticulous exclusion of other potential etiologies, characteristic imaging patterns, and often, multidisciplinary input.

A. Temporal Relationship

Carefully correlate the onset of pulmonary symptoms with the known latency periods of any suspected drugs. A detailed medication history, including start dates, dosage, and duration of therapy, is essential.

B. Exclusion of Infection

Infection is a common mimic of DIPD. Investigations should include:

• Sputum cultures (if productive cough) and blood cultures.
• Bronchoalveolar lavage (BAL) if indicated, for cell count with differential, cultures (bacterial, fungal, viral, mycobacterial), and cytology.
  • BAL findings suggestive of certain DIPD patterns: lymphocytosis (hypersensitivity pneumonitis), eosinophilia (acute eosinophilic pneumonia), neutrophilia (diffuse alveolar damage – DAD).

C. Radiographic Evaluation

• Chest X-ray (CXR): Often shows bilateral infiltrates, reticular patterns, or consolidations, but may be normal in early stages or mild cases.
• High-Resolution Computed Tomography (HRCT): The imaging modality of choice. Common patterns include ground-glass opacities, organizing pneumonia (OP), nonspecific interstitial pneumonia (NSIP), diffuse alveolar damage (DAD), and centrilobular nodules.

D. Differential Diagnoses

A broad range of conditions must be considered and excluded:

• Infectious pneumonia (bacterial, viral, fungal, atypical)
• Acute Respiratory Distress Syndrome (ARDS) from other causes
• Cardiogenic pulmonary edema
• Pulmonary hemorrhage from other causes (e.g., vasculitis)
• Malignancy (e.g., lymphangitic carcinomatosis, primary lung cancer)
• Exacerbation of underlying interstitial lung disease

E. Diagnostic Algorithm

7. Clinical Pearls and Pitfalls

• Thorough Medication Review: Always conduct a meticulous medication-timeline review, including over-the-counter drugs and supplements. DIPDs are often missed due to an incomplete medication history.
• Multidisciplinary Collaboration: Engage early with a multidisciplinary team, including pulmonology, infectious diseases, rheumatology/oncology (as appropriate), and clinical pharmacy. This collaborative approach enhances diagnostic accuracy and management.
• Nonspecific Imaging: Recognize that radiographic patterns in DIPD often lack specificity. Integrate imaging findings with clinical presentation, laboratory data, and the temporal relationship to drug exposure.
• Rechallenge Contraindication: Rechallenge with the suspected offending agent is generally contraindicated, especially for severe (Grade 3–4) pulmonary reactions, due to the risk of recurrent and potentially life-threatening toxicity.
• Diagnosis of Exclusion: There is no single gold standard diagnostic test for DIPD. The diagnosis remains largely clinical and is often one of exclusion after ruling out other more common causes.
• Stay Updated: Regularly cross-check suspected agents against an up-to-date, reliable database (e.g., www.pneumotox.com) as new information on drug-induced lung injuries continually emerges.