What are the causes of abnormal Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) results in patients, particularly those with a history of smoking or exposure to lung irritants?

Causes of Abnormal DLCO

Abnormal DLCO results from either decreased values (indicating impaired gas exchange from parenchymal lung disease, pulmonary vascular disorders, or anemia) or increased values (seen in asthma, obesity, and intrapulmonary hemorrhage), with the clinical interpretation requiring integration with spirometry and lung volumes to identify the underlying pathophysiology. 1

Decreased DLCO: Primary Causes

Parenchymal Lung Diseases

• Interstitial lung diseases (ILD), sarcoidosis, and pulmonary fibrosis characteristically demonstrate low DLCO, particularly when accompanied by restrictive lung volumes 1, 2
• Emphysema is the primary consideration when low DLCO accompanies airflow obstruction on spirometry 1, 3
• In ex-smokers with normal spirometry, abnormal DLCO may indicate early or mild emphysema not yet detectable on standard CT imaging, associated with worse symptoms, reduced exercise capacity, and impaired quality of life 4
• Combined emphysema and pulmonary fibrosis almost always shows reduced DLCO even when spirometry appears pseudonormalized, emphasizing the need to interpret pulmonary function alongside lung imaging 3, 5, 3

Pulmonary Vascular Disorders

• Pulmonary arterial hypertension (PAH) typically shows decreased DLCO, with values <45% predicted associated with poor outcomes and increased mortality 5, 3, 5, 3
• The differential diagnosis of low DLCO in PAH specifically includes pulmonary veno-occlusive disease (PVOD) and PAH associated with scleroderma 5, 3, 5, 3
• Chronic pulmonary embolism and primary pulmonary hypertension demonstrate low DLCO, with or without restriction of lung volumes 1, 2

Obstructive Lung Disease Patterns

• COPD with reduced DLCO indicates emphysematous destruction rather than pure airway disease, diagnosed by irreversible airflow obstruction, increased residual volumes, and reduced DLCO 3, 5, 3
• In GOLD stage I COPD patients with normal spirometry, DLCO <60% predicted identifies a subgroup with increased mortality risk, more dyspnea, lower exercise capacity, and worse clinical presentation 6
• Lymphangioleiomyomatosis presents with airway obstruction and low DLCO 1

Hematologic Causes

• Anemia reduces hemoglobin available for CO binding, causing falsely low DLCO values that do not reflect true gas exchange abnormalities 1, 2, 7
• Always adjust DLCO for hemoglobin levels before interpreting results, especially when monitoring for drug toxicity or in patients receiving chemotherapy 1, 2, 7

Increased DLCO: Causes

Conditions Associated with Elevated Values

• Asthma characteristically shows high DLCO 1, 2
• Obesity is associated with elevated DLCO values 1, 2
• Intrapulmonary hemorrhage produces high DLCO due to increased hemoglobin in alveolar spaces available for CO binding 1, 2

Diagnostic Algorithm Based on Spirometry Pattern

Normal Spirometry with Abnormal DLCO

• When spirometry and lung volumes are normal but DLCO is reduced, consider early parenchymal disease, pulmonary vascular disorders, early ILD, or early emphysema 1, 2
• More than 40% of patients with normal FEV₁ (>80% predicted) may have reduced DLCO (<80% predicted), making this test critical when spirometry appears reassuring but symptoms persist 2

Restrictive Pattern with Abnormal DLCO

• Normal DLCO with restriction suggests chest wall or neuromuscular disorders rather than parenchymal disease 1, 2, 7
• Decreased DLCO with restriction indicates interstitial lung diseases, with the magnitude of DLCO reduction often exceeding the volume loss in parenchymal abnormalities 1, 2, 7

Obstructive Pattern with Abnormal DLCO

• Decreased DLCO with airflow obstruction strongly suggests emphysema rather than pure airway disease 1, 3, 7
• The combination helps differentiate emphysematous COPD from asthmatic airway obstruction, which typically shows normal or elevated DLCO 1

Critical Interpretation Caveats

Adjustment Requirements

• Always correct for hemoglobin first before attributing low DLCO to lung pathology, as anemia falsely lowers DLCO without reflecting true gas exchange abnormalities 1, 2, 7
• Adjust for carboxyhaemoglobin levels, particularly important in active smokers and when monitoring for drug toxicity 1

DLCO/VA Ratio Limitations

• The relationship between DLCO and lung volume is not linear, making DLCO/VA an imperfect normalization method 1, 7
• When DLCO loss exceeds volume loss (low DLCO and low DLCO/VA), this pattern strongly suggests parenchymal abnormalities rather than extraparenchymal restriction 1, 7
• Examine DLCO/VA and VA separately rather than relying solely on their ratio, as this provides information on disease pathophysiology not obtainable from their product alone 1

Prognostic Significance

• Reduced DLCO predicts cardiopulmonary complications and mortality even in patients with otherwise normal FEV₁, emphasizing its importance beyond diagnosis for risk stratification 2, 7
• In patients with severe and critical COVID-19, DLCO impairment occurs in up to 80% at ICU discharge and 50-70% at 3-month follow-up, warranting routine testing at 3 months regardless of symptoms 2