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      Serial Detection of Circulating Mucorales DNA in Invasive Mucormycosis: A Retrospective Multicenter Evaluation

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          Abstract

          Invasive mucormycosis is a fungal infection with high mortality. Early diagnosis and initiation of appropriate treatment is essential to improve survival. However, current diagnostic tools suffer from low sensitivity, leading to delayed or missed diagnoses. Recently, several PCR assays for the detection of Mucorales DNA have been developed. We retrospectively assessed the diagnostic and kinetic properties of a commercial Mucorales PCR assay (MucorGenius ®, PathoNostics) on serial blood samples from patients with culture-positive invasive mucormycosis and found an overall sensitivity of 75%. Importantly, a positive test preceded a positive culture result by up to 81 days (median eight days, inter-quartile range 1.75–16.25). After initiation of appropriate therapy, the average levels of circulating DNA decreased after one week and stabilized after two weeks. In conclusion, detection of circulating Mucorales DNA appears to be a good, fast diagnostic test that often precedes the final diagnosis by several days to weeks. This test could be especially useful in cases in which sampling for culture or histopathology is not feasible.

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          Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis.

          Dimitrios Kontoyiannis, Edwin Lewis, Georgios Chamilos (2008)
          Zygomycosis is an emerging opportunistic mycosis among immunocompromised patients with a particularly poor prognosis. We analyzed the impact of delaying effective amphotericin B-based therapy on outcome among 70 consecutive patients with hematologic malignancy who had zygomycosis in our institution during the period 1989-2006. We used classification and regression tree analysis to identify the mortality breakpoint between early and delayed treatment. Delayed amphotericin B-based therapy (i.e., initiating treatment >/=6 days after diagnosis) resulted in a 2-fold increase in mortality rate at 12 weeks after diagnosis, compared with early treatment (82.9% vs. 48.6%); this remained constant across the years of the study and was an independent predictor of poor outcome (odds ratio, 8.1; 95% confidence interval, 1.7-38.2; P = .008) in multivariate analysis. Active malignancy (P = .003) and monocytopenia (P =.01) at the time of diagnosis of infection were also independently associated with a poor outcome, whereas salvage posaconazole-based therapy (P=.01) and neutrophil recovery (P = .009) were predictive of a favorable outcome. Because discriminating between zygomycosis and aspergillosis in a timely fashion is difficult, the pursuit of aggressive diagnostic strategies and prompt initiation of antifungal agents with activity against Zygomycetes should be considered for patients with hematological malignancy who are at an increased risk for zygomycosis.
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            Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF).

            L Millon, R Herbrecht, F Grenouillet … (2016)
            The main objective of this study was to assess the diagnostic performance of a set of three Mucorales quantitative PCR assays in a retrospective multicentre study. Mucormycosis cases were recorded thanks to the French prospective surveillance programme (RESSIF network). The day of sampling of the first histological or mycological positive specimen was defined as day 0 (D0). Detection of circulating DNA was performed on frozen serum samples collected from D-30 to D30, using quantitative PCR assays targeting Rhizomucor, Lichtheimia, Mucor/Rhizopus. Forty-four patients diagnosed with probable (n = 19) or proven (n = 25) mucormycosis were included. Thirty-six of the 44 patients (81%) had at least one PCR-positive serum. The first PCR-positive sample was observed 9 days (range 0-28 days) before diagnosis was made using mycological criteria and at least 2 days (range 0-24 days) before imaging. The identifications provided with the quantitative PCR assays were all concordant with culture and/or PCR-based identification of the causal species. Survival rate at D84 was significantly higher for patients with an initially positive PCR that became negative after treatment initiation than for patients whose PCR remained positive (48% and 4%, respectively; p <10(-6)). The median time for complete negativity of PCR was 7 days (range 3-19 days) after initiation of l-AmB treatment. Despite some limitations due to the retrospective design of the study, we showed that Mucorales quantitative PCR could not only confirm the mucormycosis diagnosis when other mycological arguments were present but could also anticipate this diagnosis. Quantification of DNA loads may also be a useful adjunct to treatment monitoring.
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              Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003).

              J Tarrand, Issam I Raad, Amar Safdar … (2006)
              We evaluated autopsy-proven invasive fungal infections (IFI) in patients with hematologic malignancies over three periods (1989-1993, 1994-1998, and 1999-2003). The autopsy rate declined significantly (67%-34%-26%, respectively p<0.0001). IFI were identified in 314 (31%) of 1017 autopsies. Most IFI (75%) were not diagnosed antemortem. The prevalence of invasive mold infections increased significantly (19%-24%-25% p=0.05) in parallel with the emergence of Zygomycetes (0.9%-4%-3%; p=0.03). The prevalence of all other IFI remained relatively constant. Among patients with invasive pulmonary aspergillosis, those with graft-versus-host disease had a histopathological pattern distinct from those with neutropenia. The complex and evolving epidemiology of IFI in severely immunocompromised patients is not well captured by current diagnostic methods.
              Article 0 comments Cited 80 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Fungi (Basel)
                Journal ID (iso-abbrev): J Fungi (Basel)
                Journal ID (publisher-id): jof
                Title: Journal of Fungi
                Publisher: MDPI
                ISSN (Electronic): 2309-608X
                Publication date (Electronic): 03 December 2019
                Publication date Collection: December 2019
                Volume: 5
                Issue: 4
                Electronic Location Identifier: 113
                Affiliations
                [1 ]Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
                [2 ]Department of Hematology, University Hospitals Leuven, 3000 Leuven, Belgium
                [3 ]Department of Laboratory Medicine, Medical Microbiology, AZ St Jan Bruges, 8000 Bruges, Belgium
                [4 ]Department of Laboratory Medicine and National Reference Centre for Mycosis, University Hospitals Leuven, 3000 Leuven, Belgium
                Author notes
                Author information
                https://orcid.org/0000-0002-1517-6426
                https://orcid.org/0000-0003-2079-1279
                Article
                Publisher ID: jof-05-00113
                DOI: 10.3390/jof5040113
                PMC ID: 6958450
                PubMed ID: 31816976
                SO-VID: 9d066f6b-bd4f-4435-a29d-d724014cc23a
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 October 2019
                Date accepted : 02 December 2019
                Categories
                Subject: Article

                Keywords: mucormycosis,mucorales,circulating dna,pcr,diagnosis
                Data availability:
                Keywords: mucormycosis, mucorales, circulating dna, pcr, diagnosis

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