Performance of Repeated Measures of (1–3)-β-D-Glucan, Mannan Antigen, and Antimannan Antibodies for the Diagnosis of Invasive Candidiasis in ICU Patients: A Preplanned Ancillary Analysis of the EMPIRICUS Randomized Clinical Trial
Authors: Dupuis Claire , Le bihan Clément , Maubon Daniele , Calvet Laure , Ruckly Stéphane , Schwebel Carole , Bouadma Lila , Azoulay Elie , Cornet Muriel , Timsit Jean-Francois ,   Empiricus Study Group, Hamidfar-Roy Rebecca , Ciroldi Magalie , Paugam-Burtz Clichy Catherine , Foucrier Arnaud , Navellou Jean Christophe , Wolff Michel , Timsit Jean-Francois , Bouadma Lila , Mourvillier Bruno , Sonneville Romain , Chemam Sarah , Gruson Didier , Souweine Bertrand , Lautrette Alexandre , Charles Pierre Emmanuel , Bruyere Rémi , Hamet Maël , Allaouchiche Bernard , Guillaume Christian , Ber Charles-Eric , Prothet Johanne , Rimmele Thomas , Argaud Laurent , Simon Marie , Cour Martin , Hernu Romain , Jaber Samir , Jung Boris , Conseil Mathieu , Coisel Yannael , Belafia Fouad , Klouche Kada , Amigues Laurent , Machado Sonia , Serveaux Marianne , Chastre Jean , Trouillet Jean-Louis , Cousson Joël , Raclot Pascal , Floch Thierry , Zeni Fabrice , Darmon Michael , Pichon Matthias , Coudrot Maud , Ninet Sebastien , Diconne Eric , Schlemmer Benoit , Azoulay Elie , Lemiale Virginie , Maziers Nicolas , Meziani Ferhat , Schnell David , Boisrame-Helms Julie , Neagu-Anca Raluca , Delabranche Xavier , Martinet Olivier , Garrouste-Orgeas Maité , Misset Benoit , Brunee Fabrice , Laurent Virginie , Lacave Guillaume , Bedos Jean-Pierre , Hammi Khadija , Styfalova Lenka , Fritzsch Joelle , Letrou Sophie , Estevez Lucie , Devaux Therese , Dubien Celine , Bayarassou Soumia , Faure Catherine Jouvene , de La Salle Sylvie , Prades Albert , Rodriguez Annie , Meur Pierre , Warchol Magda , El Haouari Hanane , Theodose Igor , Fournier Julien , Cavelot Sebastien , Kodja Lilia Bakir , Faure Marie Joyeux , Tacco Frédéric , Roos Sonia , Dupre Karima , Abazid Malek , Essert Michele , Arnaud Philippe , Papy Emmanuelle , Ghezzoul Bellabes , Gerbouin Olivier , Peccoux Sandrine Corny , Fagnoni Philippe , Millaret Anne , Pivot Christine , Gerard Cecile , Breuker Cyril , Castet Audrey , Charbonnier Fanny , Legrand Maryline , Mordini Julia , Chambrin Isabelle Madeleine , Clauss Anne Hutt , Cherifi Mohamed , Pattyn Anne , Cornet Murielle , Maubon Danièle , Benveniste Eliane , Grenouillet Fréderic , Chochillon Christian , Accoberry Isabelle , Pons Denis , Mrozek Natacha , Dalle Frédéric , Picot Stephane , Beyerle Francoise , Bienvenu Anne-Lise , Bourgeois Nathalie , Fekkar Arnaud , Toubas Dominique , Raberin Hélène , Candolfi Ermanno , Bru Valérie , Kitzis Marie Dominique , Senghor Yaye , Palette Catherine , Ruckly Stéphane , Vesin Aurélien , Mira Jean-Paul , Zahar Jean-Ralph , Larrey Dominique , Zarski Jean-Pierre , Zahar Jean-Ralph , Mira Jean-Paul , Larrey Dominique , Zarski Jean-Pierre , Schir Edith 
Published: March 2021

Abstract

Background
We aimed to assess the prognostic value of repeated measurements of serum (1–3)-β-D-glucan (BDG), mannan-antigen (mannan-Ag), and antimannan antibodies (antimannan-Ab) for the occurrence of invasive candidiasis (IC) in a high-risk nonimmunocompromised population.

Methods
This was a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial, including nonimmunocompromised critically ill patients with intensive care unit–acquired sepsis, multiple Candida colonization, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. BDG (&gt;80 and &gt;250 pg/mL), mannan-Ag (&gt;125 pg/mL), and antimannan-Ab (&gt;10 AU) were collected repeatedly. We used cause-specific hazard models. Biomarkers were assessed at baseline in the whole cohort (cohort 1). Baseline covariates and/or repeated measurements and/or increased biomarkers were then studied in the subgroup of patients who were still alive at day 3 and free of IC (cohort 2).

Results
Two hundred thirty-four patients were included, and 215 were still alive and free of IC at day 3. IC developed in 27 patients (11.5%), and day 28 mortality was 29.1%. Finally, BDG &gt;80 pg/mL at inclusion was associated with an increased risk of IC (CSHR[IC], 4.67; 95% CI, 1.61–13.5) but not death (CSHR[death], 1.20; 95% CI, 0.71–2.02).

Conclusions
Among high-risk patients, a first measurement of BDG &gt;80 pg/mL was strongly associated with the occurrence of IC. Neither a cutoff of 250 pg/mL nor repeated measurements of fungal biomarkers seemed to be useful to predict the occurrence of IC. The cumulative risk of IC in the placebo group if BDG &gt;80 pg/mL was 25.39%, which calls into question the efficacy of empirical therapy in this subgroup.