What is the utility of donor-specific cell-free DNA (DS cfDNA) in monitoring rejection in lung transplant patients?

Utility of Donor-Specific Cell-Free DNA in Lung Transplant Rejection Monitoring

Donor-specific cell-free DNA (DS cfDNA) shows promise as a non-invasive biomarker for detecting acute rejection and chronic lung allograft dysfunction (CLAD) in lung transplant recipients, with high negative predictive value that could potentially reduce the need for invasive bronchoscopies. 1, 2

Current Evidence for DS cfDNA in Lung Transplant Monitoring

Diagnostic Performance

• DS cfDNA levels are significantly elevated in patients with acute rejection (median 2.17%) compared to stable patients (median 0.71%) and those with chronic lung allograft dysfunction (median 1.07%) 1
• Using a threshold of 1.17%, DS cfDNA demonstrates sensitivity of 89.19% and specificity of 86.47% for detecting acute rejection in lung transplant recipients 1
• For CLAD detection, an optimal threshold of 0.89% provides sensitivity of 95.00% and specificity of 76.99% 1

Clinical Implementation

• DS cfDNA has demonstrated particular value as a surveillance tool with high negative predictive value (96.5%) when using a threshold of <1.0%, potentially allowing clinicians to rule out rejection without invasive procedures 2
• The test shows acceptable performance characteristics but has limited specificity for distinguishing between different causes of allograft injury (rejection vs. infection) 3

Relationship to Other Biomarkers and Clinical Parameters

• DS cfDNA levels show an inverse relationship with tacrolimus trough concentrations (P=.027) and anellovirus abundance (P<.001), suggesting it correlates with the degree of immunosuppression 4
• Elevated levels of donor-derived cell-free DNA have been observed before clinical diagnosis of antibody-mediated rejection (ABMR) and are associated with concurrent rises in donor-specific antibody (DSA) levels 5
• During acute rejection episodes, DS cfDNA levels are significantly higher (1.49% vs 0.26%) compared to stable control time points 4

Technical Considerations

• Droplet digital PCR (ddPCR) methods targeting mismatched HLA loci between donor and recipient can accurately detect donor-derived DNA fractions as low as 0.2% of total cfDNA 6
• The average false positive rate is approximately 1 per 800,000 molecules, indicating high analytical specificity 6

Limitations and Knowledge Gaps

• There is insufficient evidence regarding the optimal frequency of DS cfDNA testing for longitudinal monitoring 5
• More studies are needed to demonstrate the clinical utility of DS cfDNA compared to other immune biomarkers for improving risk stratification 5
• There remains an unmet need for studies integrating DS cfDNA results with allograft function, histologic data, and clinical assessment in lung transplantation 5

Practical Implementation

• DS cfDNA may be most valuable as part of a home-based surveillance program, potentially reducing the need for surveillance bronchoscopies 2
• A threshold of <1.0% DS cfDNA appears useful for ruling out acute rejection and infection, supporting its use as a non-invasive surveillance tool 2
• For patients with elevated DS cfDNA (≥1.0%), further evaluation with bronchoscopy and biopsy may still be warranted to determine the specific cause of allograft injury 3, 2

Potential Pitfalls

• DS cfDNA alone cannot distinguish between different causes of allograft injury (rejection, infection, or other forms of injury) 3
• The test has lower specificity (87.7%) than sensitivity (73.9%) for detecting acute lung allograft dysfunction during surveillance, resulting in potential false positives 2
• Interpretation should consider the patient's clinical status, as DS cfDNA levels may be affected by the degree of immunosuppression 4