What non‑infectious causes could explain shortness of breath in a patient with a leukocyte count of 25 × 10⁹/L and a completely negative infectious workup?

Non-Infectious Causes of Shortness of Breath with Leukocytosis

Your patient with SOB and a WBC of 25,000 with negative infectious workup most likely has a non-infectious pulmonary process, cardiac dysfunction, or a primary hematologic disorder—start with chest radiography immediately, followed by transthoracic echocardiography and chest CT without contrast if initial imaging is unrevealing. 1, 2

Diagnostic Approach

First-Line Imaging

• Chest radiography is the appropriate first-line modality for evaluating dyspnea of non-cardiovascular origin 1
• Transthoracic echocardiography is essential to evaluate for cardiac causes including cardiomyopathy, valvular disease, pericardial effusion, and diastolic dysfunction 2

Second-Line Imaging Based on Initial Findings

• Chest CT without contrast is appropriate when etiology remains unclear after chest X-ray, particularly for evaluating COPD, small airways disease, interstitial lung disease, or post-COVID complications 1
• Inspiratory/expiratory CT should be considered to detect air trapping in small airways disease 1
• Chest CT with contrast may be indicated if pleural disease, chest wall pathology, or pulmonary vascular disease is suspected 1

Key Non-Infectious Etiologies to Consider

Pulmonary Causes

• Chronic obstructive pulmonary disease and small airways disease can present with leukocytosis due to systemic inflammation 1
• Interstitial lung disease and pulmonary fibrosis may cause both dyspnea and elevated white cell counts through inflammatory mechanisms 3
• Pulmonary hypertension should be evaluated with echocardiography initially 2
• Diffuse alveolar hemorrhage can occur in immunosuppressed states and present with dyspnea and leukocytosis 3

Cardiac Causes

• Congestive heart failure accounts for a significant proportion of chronic dyspnea cases 1, 2
• Myocardial ischemia or cardiomyopathy (both ischemic and non-ischemic) 2
• Valvular heart disease including aortic stenosis/insufficiency and mitral valve disease 2
• Pericardial disease including effusion, tamponade, or constrictive pericarditis 2

Hematologic/Oncologic Causes

• Primary bone marrow disorders including chronic leukemias and myeloproliferative disorders should be strongly suspected with WBC of 25,000 4
• Leukemoid reaction can occur with extreme neutrophilia and mimic leukemia—check leukocyte alkaline phosphatase (LAP) to distinguish from chronic myeloid leukemia 5
• Brain gliomas have been associated with elevated neutrophil-to-lymphocyte ratios, though this is less likely to present primarily with SOB 6

Systemic/Inflammatory Causes

• Medication-induced leukocytosis from corticosteroids, lithium, or beta-agonists can occur alongside respiratory symptoms 4
• Physical or emotional stress can elevate WBC counts and may coexist with other causes of dyspnea 4
• Chronic kidney disease can cause dyspnea through multiple mechanisms including fluid overload, pulmonary hypertension, and systemic inflammation 7

Critical Red Flags

Immediate Concerns

• WBC >100,000/mm³ represents a medical emergency due to risk of brain infarction and hemorrhage from hyperviscosity 4
• Concurrent abnormalities in red blood cells or platelets strongly suggest primary bone marrow disorder 4
• Weight loss, hepatosplenomegaly, or lymphadenopathy increase suspicion for hematologic malignancy 4

Laboratory Workup Beyond Infectious Studies

• Complete blood count with differential to characterize the leukocytosis (neutrophilic vs. lymphocytic vs. eosinophilic) 4
• Leukocyte alkaline phosphatase (LAP) if leukemoid reaction vs. chronic myeloid leukemia is being considered 5
• BNP or NT-proBNP to evaluate for heart failure 2
• Peripheral blood smear to look for immature cells, blasts, or dysplastic features suggesting primary marrow disorder 4

Common Pitfalls to Avoid

• Do not assume all leukocytosis is infectious—physical stress, medications, and primary bone marrow disorders are important alternative explanations 4
• Do not overlook cardiac causes—approximately 85% of chronic dyspnea cases are cardiac or pulmonary in origin, with heart failure being a leading cause 1
• Do not delay hematology consultation if WBC remains elevated without clear explanation, especially with counts >25,000 or concurrent cytopenias 4
• Remember that >30% of chronic dyspnea cases are multifactorial—one diagnosis does not exclude others 1