Diffusing Capacity of the Lung for Carbon Monoxide (DLCO): A Practical Guide for the Internist

Dr Neeraj Manikath , claude.ai

Abstract

The diffusing capacity of the lung for carbon monoxide (DLCO) remains one of the most valuable yet underutilized pulmonary function tests in clinical practice. This comprehensive review provides internists with evidence-based guidance on when to order DLCO testing, how to interpret results in various clinical contexts, and practical pearls for integrating DLCO measurements into diagnostic algorithms. Understanding DLCO patterns can significantly enhance diagnostic accuracy in conditions ranging from interstitial lung disease to pulmonary vascular disorders, and can guide prognostic assessments and therapeutic decisions.

Introduction

The DLCO test measures the lung's ability to transfer gas from inhaled air to the pulmonary capillary blood. Since its introduction into clinical practice in the 1950s, DLCO has evolved from a research tool to an essential component of comprehensive pulmonary function assessment. Despite its clinical utility, many internists remain uncertain about appropriate ordering indications and result interpretation, particularly when faced with borderline values or unexpected findings.

The physiological basis of DLCO testing relies on carbon monoxide's high affinity for hemoglobin and its ability to cross the alveolar-capillary membrane. The measured DLCO represents a product of two components: the membrane diffusing capacity (DM) and the pulmonary capillary blood volume (VC). This dual nature explains why DLCO abnormalities can reflect diverse pathophysiological processes affecting either the alveolar-capillary membrane or the pulmonary vasculature.

Physiological Principles and Measurement Technique

The Single-Breath Technique

The standard single-breath DLCO test involves several precisely timed steps. The patient exhales to residual volume, then rapidly inhales a test gas mixture containing 0.3% carbon monoxide, 0.3% tracer gas (typically helium or methane), 21% oxygen, and balance nitrogen to total lung capacity. After a 10-second breath-hold, the patient exhales rapidly, and an alveolar gas sample is analyzed after discarding the first 750-1000 mL (anatomic dead space plus mixing volume).

Pearl #1: The breath-hold time significantly affects DLCO values. Each additional second of breath-holding increases measured DLCO by approximately 3%. This explains why patients who struggle to hold their breath for the full 10 seconds may have falsely low results.

Factors Affecting DLCO Measurement

Multiple physiological and technical factors influence DLCO measurements:

Lung Volume: DLCO correlates directly with lung volume. Conditions reducing lung volume (restrictive lung disease, thoracic cage abnormalities) lower absolute DLCO values even when gas exchange per unit lung volume remains normal. This has led to the calculation of DLCO/VA (KCO), where VA represents alveolar volume.

Hemoglobin Concentration: DLCO varies linearly with hemoglobin concentration. Anemia reduces DLCO by decreasing the amount of hemoglobin available for CO binding in pulmonary capillaries. Conversely, polycythemia increases DLCO. Standard correction formulas exist, but their accuracy remains debated. For males: corrected DLCO = measured DLCO × (1.7 × Hb)/(10.22 + Hb). For females: corrected DLCO = measured DLCO × (1.7 × Hb)/(9.38 + Hb).

Carboxyhemoglobin: Cigarette smoking within 24 hours can significantly reduce DLCO by occupying hemoglobin-binding sites. Patients should abstain from smoking for at least 24 hours before testing.

Alveolar Oxygen Tension: High altitude or supplemental oxygen administration affects DLCO through changes in alveolar oxygen tension and its competition with carbon monoxide for hemoglobin binding.

Pearl #2: Always obtain a complete blood count before or concurrent with DLCO testing. A hemoglobin of 10 g/dL can reduce measured DLCO by approximately 20% below actual values.

Clinical Indications for DLCO Testing

Evaluation of Dyspnea

DLCO testing proves invaluable when spirometry and lung volumes fail to explain dyspnea. In patients with unexplained breathlessness and normal spirometry, an isolated reduction in DLCO should prompt investigation for:

Early interstitial lung disease
Pulmonary vascular disease
Occult emphysema (particularly in younger patients with alpha-1 antitrypsin deficiency)
Heart failure with preserved ejection fraction

Hack #1: In a patient with unexplained dyspnea, normal spirometry, and reduced DLCO, order high-resolution CT chest imaging before proceeding with right heart catheterization. Many cases of early interstitial lung disease present with isolated DLCO reduction months before radiographic changes become apparent.

Interstitial Lung Disease

DLCO represents one of the most sensitive markers of interstitial lung disease (ILD) and often decreases before spirometric abnormalities emerge. In idiopathic pulmonary fibrosis (IPF), baseline DLCO predicts mortality, with values below 40% predicted associated with significantly worse outcomes. Serial DLCO measurements help track disease progression and treatment response.

The pattern of pulmonary function abnormalities can provide diagnostic clues. IPF typically shows reduced DLCO disproportionate to lung volume reduction (restrictive pattern), while hypersensitivity pneumonitis may show a similar pattern. Sarcoidosis more commonly shows proportionate reductions in both DLCO and lung volumes early in disease.

Pearl #3: In patients with ILD, a decline in DLCO of ≥15% over 6-12 months indicates significant disease progression and should prompt reassessment of therapeutic strategies, even if radiographic changes appear minimal.

Chronic Obstructive Pulmonary Disease and Emphysema

In COPD, DLCO helps differentiate emphysema-predominant disease from chronic bronchitis-predominant disease. Emphysema destroys alveolar-capillary units, reducing DLCO, while chronic bronchitis primarily affects airways with relative preservation of gas exchange. This distinction has prognostic implications, as emphysema-predominant COPD carries worse outcomes.

Oyster #1: A patient with significant airflow obstruction (FEV1/FVC <0.70) but preserved or elevated DLCO should raise suspicion for asthma rather than COPD, even in older patients with smoking history. This finding can fundamentally alter management.

DLCO also helps identify candidates for lung volume reduction surgery or bronchoscopic interventions. Patients with heterogeneous emphysema and DLCO >20% predicted tend to respond better to these procedures.

Pulmonary Vascular Disease

Isolated DLCO reduction represents an early and sensitive marker of pulmonary vascular disease. In pulmonary arterial hypertension (PAH), DLCO typically decreases before radiographic changes or symptoms become prominent. A DLCO <60% predicted in a patient with systemic sclerosis warrants echocardiographic screening for PAH.

In chronic thromboembolic pulmonary hypertension (CTEPH), DLCO reduction correlates with the extent of vascular obstruction. Following treatment (surgical or medical), improvement in DLCO reflects successful restoration of pulmonary blood flow.

Hack #2: In systemic sclerosis patients, measure DLCO annually as part of routine surveillance. A decline of ≥10% should trigger comprehensive evaluation for pulmonary hypertension or ILD progression, including right heart catheterization and high-resolution CT imaging.

Heart Failure

DLCO patterns in heart failure depend on chronicity and severity. Acute cardiogenic pulmonary edema may paradoxically increase DLCO due to increased pulmonary capillary blood volume. However, chronic heart failure typically reduces DLCO through multiple mechanisms: alveolar-capillary membrane thickening from chronic interstitial edema, reduced cardiac output limiting pulmonary capillary perfusion, and pulmonary vascular remodeling.

Pearl #4: DLCO improves following successful treatment of heart failure. Lack of improvement despite clinical and radiographic resolution of congestion suggests concomitant parenchymal lung disease requiring further investigation.

Preoperative Risk Assessment

DLCO provides valuable prognostic information for patients undergoing thoracic surgery or major non-cardiothoracic surgery. For lung resection candidates, DLCO <40% predicted significantly increases perioperative risk. Predicted postoperative DLCO, calculated based on the amount of functional lung tissue to be removed, helps guide surgical decision-making.

In non-thoracic surgery, reduced DLCO independently predicts postoperative pulmonary complications, particularly in patients undergoing upper abdominal or cardiac procedures.

Drug Toxicity Monitoring

Several medications cause dose-dependent or idiosyncratic pulmonary toxicity detectable through DLCO monitoring:

Bleomycin: DLCO decline often precedes radiographic changes. Many centers obtain baseline DLCO before initiating therapy and monitor serially, particularly when cumulative doses exceed 200 units.
Amiodarone: Annual DLCO monitoring helps detect early pulmonary toxicity, which may present insidiously.
Methotrexate: DLCO monitoring assists in detecting pneumonitis, though clinical symptoms and imaging remain primary diagnostic tools.
Immune checkpoint inhibitors: Baseline and serial DLCO measurements can help identify pneumonitis before extensive parenchymal damage occurs.

Interpretation Framework

Normal Values and Thresholds

DLCO results are expressed as a percentage of predicted values derived from reference equations accounting for age, sex, height, and ethnicity. The lower limit of normal (LLN), defined as the fifth percentile of the reference population, provides a more accurate threshold than the traditional 80% of predicted.

Generally accepted interpretation:

≥80% predicted (or above LLN): Normal
60-80% predicted: Mild reduction
40-60% predicted: Moderate reduction
<40% predicted: Severe reduction

Pearl #5: Always interpret DLCO in conjunction with spirometry, lung volumes, and the DLCO/VA ratio. The pattern of abnormalities provides far more diagnostic information than isolated values.

Understanding DLCO/VA (KCO)

DLCO/VA, also called KCO (transfer coefficient), represents DLCO corrected for alveolar volume. Interpretation requires understanding that DLCO/VA can be elevated, normal, or reduced even when absolute DLCO is low.

Elevated DLCO/VA with reduced DLCO suggests:

Restrictive chest wall disease (obesity, kyphoscoliosis)
Reduced lung volumes from extrapulmonary restriction
Incomplete alveolar expansion during testing
Early interstitial lung disease affecting only portions of the lung
Pneumonectomy or lobectomy

Reduced DLCO/VA with reduced DLCO suggests:

Emphysema
ILD affecting the alveolar-capillary membrane
Pulmonary vascular disease
Anemia (both parameters correct toward normal with hemoglobin adjustment)

Normal or elevated DLCO/VA with normal DLCO: Normal finding

Oyster #2: An obese patient with reduced absolute DLCO but elevated DLCO/VA likely has normal gas exchange, with reduced DLCO reflecting decreased lung volumes from chest wall restriction. This distinction prevents unnecessary evaluation for parenchymal lung disease.

Pattern Recognition Approach

Combined Patterns with Spirometry

Obstructive pattern (reduced FEV1/FVC) with reduced DLCO:

Emphysema (DLCO typically <60% predicted)
Combined pulmonary fibrosis and emphysema (CPFE)
Lymphangioleiomyomatosis

Obstructive pattern with normal or elevated DLCO:

Asthma
Chronic bronchitis without emphysema
Upper airway obstruction

Restrictive pattern (reduced TLC) with reduced DLCO:

ILD (most common)
Pulmonary vascular disease with secondary fibrotic changes
Combined heart and lung disease

Restrictive pattern with normal DLCO:

Chest wall restriction (obesity, kyphoscoliosis, neuromuscular disease)
Pleural disease
Early sarcoidosis (granulomas reduce volumes before significantly affecting gas exchange)

Normal spirometry with isolated DLCO reduction:

Early ILD (most sensitive finding)
Pulmonary vascular disease
Early emphysema
Anemia
Heart failure with preserved ejection fraction

Hack #3: When encountering isolated DLCO reduction with normal spirometry in a young patient, always consider pulmonary vascular disease, particularly if the patient has risk factors such as connective tissue disease, congenital heart disease, or unexplained exertional dyspnea. This pattern in a young female should raise suspicion for PAH.

Special Populations and Clinical Scenarios

Athletes and Elevated DLCO

Endurance athletes often demonstrate DLCO values 120-140% of predicted due to increased pulmonary capillary blood volume and optimized ventilation-perfusion matching. This finding represents a physiological adaptation rather than pathology.

Pregnancy

Pregnancy increases plasma volume and cardiac output, typically increasing DLCO by 5-10% during the second trimester. DLCO decreases slightly in the third trimester due to mechanical limitations on lung expansion.

Acute Hemorrhage

Alveolar hemorrhage, whether from Goodpasture syndrome, granulomatosis with polyangiitis, or other causes, can transiently increase DLCO due to hemoglobin in alveolar spaces binding carbon monoxide. This counterintuitive finding resolves as hemorrhage clears.

Pearl #6: In a patient with suspected ILD who demonstrates surprisingly normal or elevated DLCO despite extensive ground-glass opacities on imaging, consider acute alveolar hemorrhage. Bronchoscopy with bronchoalveolar lavage can confirm the diagnosis.

Smokers

Active smokers demonstrate reduced DLCO for multiple reasons: emphysematous changes, increased carboxyhemoglobin levels, and early ILD changes. Even asymptomatic young smokers may show DLCO reductions of 10-20% compared to never-smokers.

Prognostic Value

Beyond diagnosis, DLCO provides powerful prognostic information across multiple conditions:

Idiopathic Pulmonary Fibrosis: DLCO <40% predicted at diagnosis predicts median survival of approximately 2-3 years without transplantation. Composite scores incorporating DLCO (GAP index: Gender, Age, Physiology) provide validated prognostic estimates.

COPD: In patients with severe COPD, DLCO adds prognostic information beyond FEV1 alone. DLCO <40% predicted identifies patients at highest risk for mortality and may influence candidacy for lung transplantation evaluation.

Systemic Sclerosis: DLCO decline predicts mortality independently of ILD extent on imaging. Patients with baseline DLCO <70% predicted have significantly reduced survival.

Pulmonary Hypertension: DLCO <40% predicted at diagnosis predicts worse outcomes. Improvement in DLCO following treatment correlates with hemodynamic improvement and survival benefit.

Limitations and Pitfalls

Technical Issues

Test quality depends on patient cooperation and proper technique. Common technical errors include:

Inadequate breath-hold time (falsely reduces DLCO)
Air leak during breath-hold (falsely reduces DLCO)
Inadequate inspiratory effort (reduces VA, may affect DLCO/VA interpretation)
Recent smoking or supplemental oxygen use

Hack #4: If DLCO results seem inconsistent with clinical presentation, review the actual test tracing and VA measurement. A VA substantially lower than TLC measured by body plethysmography suggests poor inspiratory effort or test technique, rather than true pathology.

Interpretive Challenges

Combined Pathologies: Patients with both emphysema and pulmonary fibrosis (CPFE syndrome) may demonstrate preserved lung volumes and spirometry despite significant parenchymal disease. DLCO reduction may be the primary objective evidence of impairment.

Discordance Between Imaging and Physiology: Some patients demonstrate extensive radiographic abnormalities with relatively preserved DLCO, while others show significant DLCO reduction with minimal imaging findings. Clinical correlation and consideration of disease-specific patterns guide interpretation.

Pearl #7: In CPFE, spirometry may appear relatively normal due to opposing effects of emphysema (reduced elastic recoil) and fibrosis (increased elastic recoil). However, DLCO is markedly reduced, and these patients often demonstrate severe exercise-induced desaturation disproportionate to resting pulmonary function.

Practical Clinical Algorithms

Unexplained Dyspnea

Obtain complete PFTs including DLCO, spirometry, and lung volumes
If DLCO reduced with normal spirometry → high-resolution CT chest
If CT shows ILD → refer to pulmonary subspecialist for further evaluation
If CT normal → consider echocardiography, consider pulmonary vascular disease evaluation
Correct for anemia if hemoglobin <12 g/dL in females or <13 g/dL in males

Systemic Sclerosis Screening

Baseline DLCO at diagnosis
Annual DLCO monitoring
Decline ≥10% → high-resolution CT and echocardiography
DLCO <70% predicted → consider right heart catheterization to exclude PAH

Monitoring ILD Treatment

Baseline PFTs including DLCO before treatment initiation
Repeat at 3-6 months, then every 6-12 months
Decline in FVC ≥10% or DLCO ≥15% indicates significant progression
Consider both absolute and relative changes from baseline

Emerging Concepts and Future Directions

DLCO in COVID-19

Post-COVID-19 patients frequently demonstrate persistent DLCO reduction months after acute illness, even when chest imaging normalizes. This finding correlates with persistent dyspnea and exercise limitation. The mechanism likely involves microvascular injury and endothelial dysfunction. Serial DLCO monitoring helps track recovery and identifies patients requiring prolonged follow-up.

DLCO Variability and Precision

Recent studies emphasize the importance of understanding DLCO variability. Within-individual coefficient of variation ranges from 5-10%, meaning changes <10-15% may reflect measurement variability rather than true physiological change. This has implications for longitudinal monitoring and clinical trial design.

Novel Applications

Research continues to explore DLCO's role in conditions beyond traditional indications, including:

Identifying subclinical lung disease in rheumatologic conditions
Predicting outcomes in obesity hypoventilation syndrome
Assessing lung involvement in long COVID syndrome
Risk stratification for venous thromboembolism

Conclusion

DLCO testing provides internists with a powerful, non-invasive tool for evaluating a wide range of pulmonary and systemic conditions. Proper test selection, careful attention to technical factors affecting measurement, and systematic interpretation in conjunction with other pulmonary function parameters maximize diagnostic yield. Understanding DLCO patterns enhances diagnostic accuracy, guides prognostic assessments, and informs therapeutic decisions across multiple disease states.

The key to effective DLCO utilization lies in recognizing that isolated values provide limited information. Instead, DLCO should be interpreted within the broader clinical context, incorporating patient symptoms, physical examination findings, imaging studies, and other pulmonary function parameters. Pattern recognition—identifying characteristic combinations of spirometric, volume, and DLCO abnormalities—enables internists to narrow differential diagnoses and direct subsequent evaluation efficiently.

As medicine advances toward precision diagnostics and personalized treatment approaches, DLCO monitoring will likely play an expanding role in disease phenotyping, treatment response assessment, and risk stratification. Internists who master DLCO interpretation position themselves to provide superior diagnostic and prognostic insights for their patients with respiratory complaints.

Key Takeaway Pearls

Always correct DLCO for hemoglobin concentration
Interpret DLCO with spirometry and lung volumes, not in isolation
Isolated DLCO reduction warrants high-resolution CT imaging
In systemic sclerosis, annual DLCO screening detects pulmonary complications early
DLCO <40% predicted carries significant prognostic implications across multiple diseases
Elevated DLCO/VA with reduced absolute DLCO suggests extrapulmonary restriction
Technical quality affects results—review actual test data when findings seem discordant with clinical presentation

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Note: This review provides practical, evidence-based guidance for internists. Local protocols and subspecialty consultation should guide management decisions in complex cases.