Liquid Biopsy for Invasive Mold Infections in Hematopoietic Cell Transplant Recipients With Pneumonia Through Next-Generation Sequencing of Microbial Cell-Free DNA in Plasma

被引:77
作者
Hill, Joshua A. [1 ,2 ]
Dalai, Sudeb C. [3 ,4 ]
Hong, David K. [3 ]
Ahmed, Asim A. [3 ]
Ho, Carine [3 ]
Hollemon, Desiree [3 ]
Blair, Lily [3 ]
Maalouf, Joyce [1 ]
Keane-Candib, Jacob [1 ]
Stevens-Ayers, Terry [1 ]
Boeckh, Michael [1 ,2 ]
Blauwkamp, Timothy A. [3 ]
Fisher, Cynthia E. [1 ,2 ]
机构
[1] Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,MS E-400, Seattle, WA 98109 USA
[2] Univ Washington, Seattle, WA 98195 USA
[3] Karius Inc, Redwood City, CA USA
[4] Stanford Univ, Sch Med, Stanford, CA 94305 USA
基金
美国国家卫生研究院;
关键词
pneumonia; mold; Aspergillus; transplant; HCT; next-generation sequencing; cell-free DNA; FUNGAL-INFECTIONS; DISEASES SOCIETY; DIAGNOSIS; ASPERGILLOSIS; PCR; RECOMMENDATIONS; GALACTOMANNAN; EPIDEMIOLOGY; DEFINITIONS; PULMONARY;
D O I
10.1093/cid/ciaa1639
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Noninvasive diagnostic options are limited for invasive mold infections (IMIs). We evaluated the performance of a plasma microbial cell-free DNA sequencing (mcfDNA-Seq) test for diagnosing pulmonary IMI after hematopoietic cell transplant (HCT). Methods. We retrospectively assessed the diagnostic performance of plasma mcfDNA-Seq next-generation sequencing in 114 HCT recipients with pneumonia after HCT who had stored plasma obtained within 14 days of diagnosis of proven/probable Aspergillus IMI (n = 51), proven/probable non-Aspergillus IMI (n = 24), possible IMI (n = 20), and non-IMI controls (n = 19). Sequences were aligned to a database including >400 fungi. Organisms above a fixed significance threshold were reported. Results. Among 75 patients with proven/probable pulmonary IMI, mcfDNA-Seq detected >= 1 pathogenic mold in 38 patients (sensitivity, 51% [95% confidence interval {CI}, 39%-62%]). When restricted to samples obtained within 3 days of diagnosis, sensitivity increased to 61%. McfDNA-Seq had higher sensitivity for proven/probable non-Aspergillus IMI (sensitivity, 79% [95% CI, 56%-93%]) compared with Aspergillus IMI (sensitivity, 31% [95% CI, 19%-46%]). McfDNA-Seq also identified non-Aspergillus molds in an additional 7 patients in the Aspergillus subgroup and Aspergillus in 1 patient with possible IMI. Among 19 non-IMI pneumonia controls, mcfDNA-Seq was negative in all samples, suggesting a high specificity (95% CI, 82%-100%) and up to 100% positive predictive value (PPV) with estimated negative predictive values (NPVs) of 81%-99%. The mcfDNA-Seq assay was complementary to serum galactomannan index testing; in combination, they were positive in 84% of individuals with proven/probable pulmonary IMI. Conclusions. Noninvasive mcfDNA-Seq had moderate sensitivity and high specificity, NPV, and PPV for pulmonary IMI after HCT, particularly for non-Aspergillus species.
引用
收藏
页码:E3876 / E3883
页数:8
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