What is the differential diagnosis for a patient with dyspnea and new centrilobular nodularity, more pronounced on the right side than the left, on chest radiograph?

Differential Diagnosis for Centrilobular Nodularity with Dyspnea

The differential diagnosis for new centrilobular nodularity (right greater than left) with dyspnea includes infectious bronchiolitis (particularly atypical infections or tuberculosis), hypersensitivity pneumonitis, small airways disease (including diffuse panbronchiolitis and eosinophilic bronchiolitis), aspiration, and pulmonary vascular disease including pulmonary hypertension. 1, 2, 3

Primary Diagnostic Considerations

Infectious and Inflammatory Small Airways Disease

Centrilobular nodules represent disease centered on the terminal and respiratory bronchioles, appearing as nodules located a few millimeters from the pleural surface and interlobular septa. 4 The right-sided predominance suggests:

• Aspiration bronchiolitis should be considered first given the asymmetric distribution, as the right mainstem bronchus is more vertical and prone to aspiration 4
• Infectious bronchiolitis from atypical organisms, tuberculosis, or fungal infections can present with centrilobular nodules and dyspnea 1, 4
• Tree-in-bud pattern (centrilobular nodules connected to branching linear structures) strongly suggests active endobronchial infection or inflammation 1

Hypersensitivity Pneumonitis

Occupational or environmental exposure history is critical, as hypersensitivity pneumonitis characteristically presents with centrilobular nodules, dyspnea, and cough. 2 Key features include:

• Symptoms that improve away from exposure and recur upon re-exposure 2
• Diffuse centrilobular nodules with ground-glass attenuation on CT 2
• Lymphocytic alveolitis on bronchoalveolar lavage 2

Diffuse Panbronchiolitis

This distinct small airways disease presents with centrilobular nodules, dyspnea, chronic cough with purulent sputum, and obstructive physiology. 1 Diagnostic features include:

• Bilateral basal-predominant centrilobular nodules (<5 mm) with tree-in-bud pattern 1
• Bronchiolectasis and mosaic air-trapping on expiratory CT 1
• Most common in patients of Japanese, Korean, or Chinese descent 1
• Untreated disease carries 50% mortality at 5 years, but low-dose macrolide therapy (erythromycin 200-600 mg/day) significantly improves survival and symptoms 1

Eosinophilic Bronchiolitis

Consider this diagnosis when centrilobular nodules are accompanied by peripheral eosinophilia and asthma-like symptoms that fail to respond to bronchodilators. 3 Features include:

• Marked blood eosinophilia with BAL eosinophilia 3
• Centrilobular nodules with bronchial/bronchiolar wall thickening 3
• Obstructive and restrictive ventilatory impairment 3
• Responsive to oral corticosteroids (prednisolone 30 mg daily) 3

Pulmonary Vascular Disease

Pulmonary hypertension can manifest with centrilobular ground-glass nodules representing dilated centrilobular arterioles. 1 Look for:

• Main pulmonary artery diameter >29 mm or MPA:ascending aorta ratio >1 1
• Right ventricular enlargement and septal flattening 1
• Centrilobular ground-glass nodules associated with enlarged tortuous centrilobular arterioles in idiopathic pulmonary arterial hypertension 1

Algorithmic Diagnostic Approach

Step 1: Initial Imaging Evaluation

Obtain chest CT without IV contrast as the primary imaging modality, as it is superior to chest radiograph for characterizing centrilobular nodules and identifying secondary findings. 1 Specific CT features to assess:

• Presence of tree-in-bud pattern (suggests active infection/inflammation) 1, 4
• Mosaic attenuation on inspiratory images with air-trapping on expiratory images (suggests small airways disease) 1
• Ground-glass versus solid nodules 4
• Associated findings: bronchial wall thickening, bronchiolectasis, lymphadenopathy 1, 3

Step 2: Clinical Context Integration

Obtain targeted history focusing on:

• Occupational/environmental exposures (birds, mold, mushroom spores, organic dusts) 2
• Temporal relationship of symptoms to exposures (improvement away from work/home) 2
• Aspiration risk factors (dysphagia, neurologic disease, GERD) 4
• Geographic origin or ethnicity (Asian descent increases DPB likelihood) 1
• Medication history (drug-induced bronchiolitis) 1
• Smoking history (relevant for Langerhans cell histiocytosis, respiratory bronchiolitis) 5

Step 3: Laboratory and Functional Assessment

Order the following based on CT pattern:

• Complete blood count with differential to identify eosinophilia 3
• Pulmonary function tests showing obstruction suggest small airways disease; restriction with obstruction suggests eosinophilic bronchiolitis 1, 3
• Sputum culture and AFB smear if tree-in-bud pattern present 1

Step 4: Advanced Diagnostic Procedures

When diagnosis remains uncertain after initial workup:

• Bronchoscopy with BAL to assess for lymphocytosis (hypersensitivity pneumonitis), eosinophilia (eosinophilic bronchiolitis), or infection 1, 2, 3
• Surgical lung biopsy may be necessary for definitive diagnosis of diffuse panbronchiolitis or organizing pneumonia when clinical and radiographic features are atypical 1, 6

Critical Pitfalls to Avoid

Do not mistake centrilobular nodules for random or perilymphatic nodules, as this fundamentally changes the differential diagnosis. 4 Centrilobular nodules spare the pleural surfaces and fissures, unlike random nodules (hematogenous spread) or perilymphatic nodules (sarcoidosis, lymphangitic carcinomatosis) 4

Do not delay treatment of diffuse panbronchiolitis once suspected, as early macrolide therapy dramatically improves the otherwise poor prognosis. 1 A trial of low-dose erythromycin is reasonable when characteristic CT findings are present in the appropriate clinical setting, even before biopsy confirmation 1

Asymmetric distribution (right > left) should prompt specific consideration of aspiration, as this is uncommon in most diffuse small airways diseases. 4 Evaluate for aspiration risk factors and consider modified barium swallow if clinical suspicion is high 4

In patients with occupational exposures, failure to remove the patient from the exposure will result in progressive disease despite treatment. 2 Symptom recurrence upon return to work is pathognomonic for hypersensitivity pneumonitis 2