JOURNAL ARTICLE<\/p>\n\n\n\n
Background<\/p>\n\n\n\n
New and minimally invasive tools to aid the diagnosis of invasive fungal diseases (IFD) are urgently needed as the immunocompromised population at highest risk increases. Advancements in molecular technology have rendered new diagnostics more readily available for clinical use.<\/p>\n\n\n\n
Methods<\/p>\n\n\n\n
This case-control study used prospectively collected archived plasma specimens and data from the Aspergillus Technology Consortium Repository to investigate the diagnostic performance of microbial cell-free DNA (mcfDNA) sequencing as a minimally invasive diagnostic for IFDs in a population of high-risk immunocompromised hosts including hematologic malignancy, stem cell, and solid organ transplants patients. The 2008 Mycoses Study Group\/European Organization for the Research and Treatment of Cancer diagnostic criteria served as the gold standard for test performance.<\/p>\n\n\n\n
Results<\/p>\n\n\n\n
Sixty-five adult subjects with proven or probable IFD and 65 controls without IFD were included. Among IFD episodes\u00a0Aspergillus<\/em>\u00a0was the most common pathogen (70.8%, 46\/65), followed by Mucorales (10.8%, 7\/65). Overall, sensitivity was 47.7% and specificity was 100%. Sensitivity varied based on disease certainty and pathogen; sensitivity was higher in proven versus probable IFD (60.0% vs 37.1%, respectively) and higher for subjects with invasive mucormycosis (100%) compared with aspergillosis (45.7%).<\/p>\n\n\n\n Table 1.<\/strong> Demographic and Clinical Characteristics<\/p>\n\n\n\n Table 2.<\/strong> Invasive Fungal Diseases (N = 65)<\/p>\n\n\n\n Table 3.<\/strong> Performance of Plasma mcfDNA Sequencing for Diagnosis of IFD Based on Specimen Collection Time Relative to MSG\/EORTC Diagnosis Date<\/p>\n\n\n\n Conclusions<\/p>\n\n\n\n A positive result by mcfDNA sequencing may reduce the need for invasive sampling in patients with suspected IFD. In this exploratory analysis, its high sensitivity and specificity for invasive mucormycosis suggests it could be useful for early treatment and intervention of this IFD. Future studies should focus on understanding how specific factors impact the sensitivity of mcfDNA sequencing for invasive aspergillosis.<\/p>\n","protected":false},"excerpt":{"rendered":" JOURNAL ARTICLE Plasma Microbial Cell-free DNA Metageno […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[32,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/29985"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=29985"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/29985\/revisions"}],"predecessor-version":[{"id":29986,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/29985\/revisions\/29986"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=29985"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=29985"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=29985"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Characteristic<\/th> IFDsa<\/a><\/sup> (N = 65)<\/th> Controls (N = 65)<\/th><\/tr><\/thead> Age in years, median (IQR)<\/td> 63 (18)<\/td> 60.0 (15.5)<\/td><\/tr> Female<\/td> 24.6% (16)<\/td> 36.9% (24)<\/td><\/tr> Race, White<\/td> 84.6% (55)<\/td> 92.3 (60)<\/td><\/tr> Underlying condition<\/td> <\/td> <\/td><\/tr> \u2003Solid organ transplant<\/td> 47.7% (31)<\/td> 52.3% (34)<\/td><\/tr> \u2003\u2003Lung<\/td> 35.4% (23)<\/td> 52.3% (34)<\/td><\/tr> \u2003\u2003Heart<\/td> 10.8% (7)<\/td> 0.0% (0)<\/td><\/tr> \u2003\u2003Kidney<\/td> 1.5% (1)<\/td> 0.0% (0)<\/td><\/tr> \u2003Hematopoietic stem cell transplant<\/td> 20.0% (13)<\/td> 24.6% (16)<\/td><\/tr> \u2003\u2003Allogeneic<\/td> 13.8% (9)<\/td> 23.1% (15)<\/td><\/tr> \u2003\u2003Autologous<\/td> 6.2% (4)<\/td> 0.0% (0)<\/td><\/tr> \u2003\u2003Syngeneic<\/td> 0.0% (0)<\/td> 1.5% (1)<\/td><\/tr> \u2003HIV\/AIDS<\/td> 1.5% (1)<\/td> 0.0%<\/td><\/tr> \u2003Hematologic malignancy<\/td> 24.6% (16)<\/td> 23.1% (15)<\/td><\/tr> \u2003Pulmonary disease<\/td> 6.2% (4)<\/td> 0.0% (0)<\/td><\/tr> Neutropenic at the time of specimen collectionb<\/a><\/sup><\/td> 15.4% (10)<\/td> 21.9% (14)<\/td><\/tr> Prior IFDc<\/a><\/sup><\/td> 16.9% (11)<\/td> 4.6% (3)<\/td><\/tr> On systemic antifungal therapy at time of specimen collection<\/td> 89.2%% (58)<\/td> 49.2%% (32)<\/td><\/tr> On active antifungal therapy at time of specimen collection<\/td> 76.9% (50)<\/td> NA<\/td><\/tr> Specimen collected inpatient<\/td> 81.5% (53)<\/td> 64.6% (42)<\/td><\/tr><\/tbody><\/table>
a<\/sup>Defined per 2008 MSG\/EORTC definitions.
b<\/sup>Neutropenia defined as absolute neutrophil count <500 per microliter.
c<\/sup>Prior IFD was defined as an IFD that occurred \u22658 weeks before the index IFD or <8 weeks before the index IFD and with appropriate treatment and resolution of symptoms and documented mycologic clearance before index IFD diagnosis.<\/figcaption><\/figure>\n\n\n\n<\/td> MSG\/EORTC Disease Category<\/th><\/tr> Proven (n = 30)<\/th> Probable (n = 35)<\/th><\/tr><\/thead> Causative pathogen by usual care diagnostics<\/td><\/tr> \u2003Mold<\/td><\/tr> \u2003\u2003Aspergillus<\/em>a<\/a>,b<\/a><\/sup><\/td> 36.7% (11)<\/td> 77.1% (27)<\/td><\/tr> \u2003\u2003Fusarium<\/em><\/td> 0.0% (0)<\/td> 2.9% (1)<\/td><\/tr> \u2003\u2003Scedosporium<\/em><\/td> 3.3% (1)<\/td> 0.0% (0)<\/td><\/tr> \u2003\u2003Mucoralesc<\/a><\/sup><\/td> 16.7% (5)<\/td> 2.9% (1)<\/td><\/tr> \u2003\u2003Otherd<\/a><\/sup><\/td> 13.3% (4)<\/td> 2.9% (1)<\/td><\/tr> \u2003\u2003Multiple fungal pathogense<\/a><\/sup><\/td> 16.7% (5)<\/td> 14.3% (5)<\/td><\/tr> \u2003Yeast<\/td><\/tr> \u2003\u2003Candida<\/em><\/td> 6.7% (2)<\/td> 0.0% (0)<\/td><\/tr> \u2003\u2003Cryptococcus<\/em><\/td> 3.3% (1)<\/td> 0.0% (0)<\/td><\/tr> \u2003\u2003Trichosporon<\/em><\/td> 3.3% (1)<\/td> 0.0% (0)<\/td><\/tr> Infection site<\/td><\/tr> \u2003Lung<\/td> 83.3% (25)<\/td> 97.1% (34)<\/td><\/tr> \u2003Sinus<\/td> 3.3% (1)<\/td> 2.9% (1)<\/td><\/tr> \u2003Blood<\/td> 0.0% (0)<\/td> 0.0% (0)<\/td><\/tr> \u2003Disseminatedf<\/a><\/sup><\/td> 13.3% (4)<\/td> 0.0% (0)<\/td><\/tr> Response to therapy 8 wk after MSG\/EORTC diagnosis date<\/td> <\/td> <\/td><\/tr> \u2003Complete\/partial<\/td> 60.0% (18)<\/td> 60.0% (21)<\/td><\/tr> \u2003Stable<\/td> 10.0% (3)<\/td> 11.4% (4)<\/td><\/tr> \u2003Progression\/death<\/td> 30.0% (9)<\/td> 28.6% (10)<\/td><\/tr> Overall mortalityg<\/a><\/sup><\/td> 20.0% (6)<\/td> 28.6% (8)<\/td><\/tr><\/tbody><\/table>
a<\/sup>Aspergillus species included:\u00a0A. fumigatus<\/em>,\u00a0A. terreus<\/em>,\u00a0A. flavus<\/em>,\u00a0A. niger<\/em>,\u00a0A. ustus<\/em>.
b<\/sup>Three invasive Aspergillosis episodes included 2 or more\u00a0Aspergillus<\/em>\u00a0species (A. fumigatus<\/em>\u00a0+\u00a0A. terreus<\/em>;\u00a0A. fumigatus<\/em>\u00a0+\u00a0A. flavus<\/em>\u00a0+\u00a0A. niger<\/em>;\u00a0A. fumigatus<\/em>\u00a0+\u00a0A. terreus<\/em>).
c<\/sup>Mucorales included: Rhizopus species, Mucor species, Rhizomucor species.
d<\/sup>Other included: Mold, not otherwise specified; hyaline hyphomycete mold.
e<\/sup>Multiple fungal pathogens was defined as pathogens recovered from same specimen or on separate specimens collected for the same or worsening clinical syndrome within 8 weeks of index IFD MSG diagnosis date and included:\u00a0Aspergillus niger<\/em>\u00a0+ yeast (probable\u00a0Candida<\/em>);\u00a0Aspergillus fumigatus<\/em>\u00a0+\u00a0Aspergillus terreus<\/em>\u00a0+\u00a0Scopulariopsis<\/em>\u00a0species;\u00a0Aspergillus terreus<\/em>\u00a0+\u00a0Penicillium<\/em>\u00a0NOS; NOS\u00a0Aspergillus flavus<\/em>\u00a0+\u00a0Aspergillus terreus<\/em>\u00a0+\u00a0Aspergillus niger<\/em>\u00a0+\u00a0Aspergillus ochraceous<\/em>\u00a0group +\u00a0Curvularia<\/em>\u00a0NOS +\u00a0Penicillium<\/em>\u00a0NOS;\u00a0Aspergillus niger<\/em>\u00a0+\u00a0Penicillium<\/em>\u00a0NOS +\u00a0Chrysosporium<\/em>\u00a0NOS;\u00a0Aspergillus flavus<\/em>\u00a0+\u00a0Cryptococcus neoformans<\/em>;\u00a0Aspergillus flavus<\/em>\u00a0+\u00a0Geotrichum<\/em>\u00a0species;\u00a0Aspergillus fumigatus<\/em>\u00a0+\u00a0Paecilomyces lilacinus<\/em>;\u00a0Penicillium citrinum<\/em>\u00a0+\u00a0Paecilomyces variotti<\/em>;\u00a0Cunninghamella<\/em>\u00a0+ hyaline hyphomycete mold NOS.
f<\/sup>Two or more sites of infection: sites of dissemination included lungs, skin, peritoneum, sinus, brain, mediastinum, kidney.
g<\/sup>At 8 weeks after MSG\/EORTC diagnosis date; discharge to hospice contributed to overall mortality.<\/figcaption><\/figure>\n\n\n\n<\/td> N<\/th> Sensitivity<\/th> Specificity<\/th><\/tr><\/thead> Timing of specimen collection (median [IQR] days)<\/td><\/tr> \u2003All specimens (median 6 [9] days)<\/td> 65<\/td> 47.7%<\/td> 100%<\/td><\/tr> \u2003Within 14 (median 5 [5]) days of MSG\/EORTC diagnosis<\/td> 56<\/td> 51.8%<\/td> 100%<\/td><\/tr> \u2003Within 7 (median 3 [3]) days of MSG\/EORTC diagnosis<\/td> 40<\/td> 52.5%<\/td> 100%<\/td><\/tr> Proven versus probable infection (all specimens, n = 65)<\/td><\/tr> \u2003Proven IFD<\/td> 30<\/td> 60.0%<\/td> 100%<\/td><\/tr> \u2003Probable IFD<\/td> 35<\/td> 37.1%<\/td> 100%<\/td><\/tr> Causative pathogen (all specimens, n = 65)<\/td><\/tr> \u2003Aspergillus<\/em> speciesa<\/a><\/sup><\/td> 46<\/td> 45.7%<\/td> 100%<\/td><\/tr> \u2003Mucoralesa<\/a><\/sup><\/td> 7<\/td> 100%<\/td> 100%<\/td><\/tr><\/tbody><\/table>
a<\/sup>Included samples with multiple fungal pathogens.<\/figcaption><\/figure>\n\n\n\n