What laboratory tests are indicated for a patient with bilateral upper lung groundglass (ground glass) opacities?

Laboratory Workup for Bilateral Upper Lung Ground-Glass Opacities

For bilateral upper lung ground-glass opacities, immediately obtain serologic testing for connective tissue disease (ANA, RF, anti-CCP, myositis panel), infectious workup including HIV with CD4 count, respiratory pathogen testing for atypical organisms, and inflammatory markers (CRP, ESR), while prioritizing medication history for drug-induced pneumonitis. 1

Immediate Clinical Context Assessment

Before ordering labs, obtain critical historical information that directs the diagnostic workup:

• Medication exposure: Specifically ask about molecular targeting agents, immune checkpoint inhibitors, mycophenolate mofetil, and recent chemotherapy, as these commonly cause upper lobe drug-induced pneumonitis 1
• Immunosuppression status: Document HIV status, chronic hepatitis C, history of drug use, and organ transplantation history 1, 2
• Smoking history: Current or former smoking suggests respiratory bronchiolitis-ILD or desquamative interstitial pneumonia 1
• Autoimmune symptoms: Evaluate for joint pain, rash, muscle weakness, and Raynaud's phenomenon 1
• Recent radiation exposure: Consider radiation pneumonitis if exposure occurred within 3-12 weeks 1

Essential Laboratory Panel

Serologic Evaluation for Connective Tissue Disease

All patients with newly detected interstitial lung disease require serologic testing to exclude connective tissue disease, including: 1

• Antinuclear antibodies (ANA)
• Rheumatoid factor (RF)
• Anti-cyclic citrullinated peptide (anti-CCP)
• Myositis panel (anti-Jo-1, anti-synthetase antibodies)
• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)

Infectious Disease Workup

In immunocompromised patients or those with risk factors, obtain comprehensive infectious testing: 1, 2

• HIV testing with CD4 count if positive: PCP becomes most likely if CD4 <200, and upper lobe involvement, though atypical for PCP, can occur 2
• Respiratory nucleic acid detection: Test for atypical pathogens including Mycoplasma and Chlamydia 1, 2
• Sputum or bronchoscopy specimens: For Pneumocystis jirovecii, tuberculosis, and fungal organisms 1
• Fungal antigens: Particularly in immunocompromised patients 3

Inflammatory and Hematologic Markers

• Complete blood count with differential: Absolute lymphocyte count <0.8 × 10⁹/L warrants particular attention and repeat testing 3
• Procalcitonin: To assess for bacterial infection 3
• Soluble interleukin-2 receptor: Elevated levels may suggest lymphoproliferative disorders such as intravascular large B-cell lymphoma 4

Pattern-Specific Laboratory Considerations

For Suspected Hypersensitivity Pneumonitis

Upper lobe predominance with ground-glass opacities raises suspicion for hypersensitivity pneumonitis. Bronchoalveolar lavage (BAL) cellular analysis is critical, with lymphocyte predominance (typically >40%) indicating hypersensitivity pneumonitis or NSIP pattern. 5, 1

For Suspected Invasive Aspergillosis

In immunocompromised patients (HIV, solid organ transplant, ICU patients), obtain: 5

• Serum galactomannan (GM): Using cut-off of 0.5 ng/mL with sensitivity/specificity 60%/89% in non-haematological patients 5
• Serum beta-D-glucan (BDG): Using 140 pg/mL cut-off with sensitivity/specificity 100%/70% in ICU patients 5
• BAL galactomannan: Using cut-off ODI 1.0-1.5 with higher sensitivity/specificity than serum testing 5

For Suspected Drug-Induced Pneumonitis

No specific laboratory test confirms drug-induced pneumonitis; diagnosis relies on temporal correlation with medication use and exclusion of infection. However, obtain: 1

• BAL with neutrophil predominance suggesting drug-related pneumonitis 1
• Eosinophilia on BAL or peripheral blood suggesting drug reaction or eosinophilic pneumonia 1

When to Proceed to Invasive Diagnostics

Proceed to bronchoscopy with BAL when: 1, 3

• Ground-glass opacity persists beyond 4 weeks despite appropriate therapy
• Clinical deterioration occurs
• Initial non-invasive workup is non-diagnostic
• Differential diagnosis includes markedly different therapeutic strategies

BAL cellular analysis distinguishes between interstitial lung diseases: 1

• Neutrophil predominance: Idiopathic pulmonary fibrosis or drug-related pneumonitis
• Lymphocyte predominance: Hypersensitivity pneumonitis or NSIP
• Eosinophilia: Drug reaction or eosinophilic pneumonia

Critical Pitfalls to Avoid

• Do not delay bronchoscopy beyond 6-8 weeks in immunocompromised patients or those with progressive symptoms 3
• Do not overlook medication history, as drug-induced pneumonitis can occur with common antibiotics and requires drug discontinuation 3
• Do not assume upper lobe distribution excludes PCP in HIV-positive patients with CD4 <200, though peripheral sparing is more typical 2
• Do not forget to check for tuberculosis in patients with history of drug use and upper lobe predominance, even without cavitation early in disease 2