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Published on: March 22, 2012
Plasma Cell-free DNA Associated With Risk of Mortality and Chronic Lung Allograft Dysfunction Among Lung Transplant
Yasir Hamad1, Joby Mathew2, Temesgen Andargie3,4
1Pulmonary, Critical Care, and Sleep Division, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN.
Background:
Aspergillus species is a common pathogen in lung transplant patients. However, existing clinical standards rely on a complex constellation of clinical, radiological, and microbiologic criteria with limited sensitivity to differentiate between invasive Aspergillus infection and colonization. We therefore tested whether a molecular measure of allograft injury-donor-derived cell-free DNA (dd-cfDNA)-better identifies invasive aspergillosis compared with current guidelines-based classification.
Methods:
This multicenter prospective cohort study included lung transplant patients. Microbiological isolates of Aspergillus were matched with temporally available dd-cfDNA data. Invasive aspergillosis was defined either by clinical criteria using published guidelines or by molecular criteria (dd-cfDNA >1%).
Results:
Among 177 lung transplant recipients, 33 patients had 34 positive Aspergillus results. Of those, 16 met clinical criteria and 19 met molecular criteria of invasive aspergillosis. Eighteen met clinical criteria and 15 met molecular criteria for colonization. Patients who met molecular criteria for invasive disease had significantly reduced chronic lung allograft dysfunction-free survival (hazard ratio, 10.5; 95% confidence interval, 1.34-82.1; P = 0.03) compared with the patients with colonization. In contrast, classification based on clinical criteria was not associated with worse outcomes (hazard ratio, 2.3; 95% confidence interval, 0.7-7.8; P = 0.19).
Conclusions:
Invasive aspergillosis, as defined by molecular criteria (dd-cfDNA >1%), was associated with reduced chronic lung allograft dysfunction-free survival in lung transplant recipients.
Insights
Donor-derived cell-free DNA (dd-cfDNA) molecular criteria better identified invasive aspergillosis in lung transplant patients. This molecular measure predicted reduced allograft survival, unlike current clinical guidelines.
Area of Science:
- Transplant immunology
- Infectious diseases
- Molecular diagnostics
Background:
- Aspergillus species are common lung transplant pathogens.
- Current diagnostic criteria for invasive aspergillosis lack sensitivity.
- Distinguishing infection from colonization is challenging.
Purpose of the Study:
- To evaluate donor-derived cell-free DNA (dd-cfDNA) as a molecular marker for invasive aspergillosis.
- To compare the diagnostic performance of dd-cfDNA with existing clinical guidelines.
- To assess the association of molecularly defined invasive aspergillosis with transplant outcomes.
Main Methods:
- Multicenter prospective cohort study of lung transplant recipients.
- Matched Aspergillus isolates with dd-cfDNA data.
- Defined invasive aspergillosis using clinical guidelines or molecular criteria (dd-cfDNA >1%).
Main Results:
- 19 of 33 patients with Aspergillus met molecular criteria for invasive disease, versus 16 for clinical criteria.
- Molecular criteria for invasive aspergillosis significantly predicted reduced chronic lung allograft dysfunction-free survival (HR, 10.5; P=0.03).
- Clinical criteria classification did not significantly associate with worse outcomes (HR, 2.3; P=0.19).
Conclusions:
- Molecularly defined invasive aspergillosis using dd-cfDNA >1% is associated with poorer outcomes in lung transplant recipients.
- dd-cfDNA offers a sensitive molecular measure for identifying invasive aspergillosis.
- This molecular approach may improve patient management and prognostication.
