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Id Subject Object Predicate Lexical cue
T1 0-124 Sentence denotes Is the COVID-19 Pandemic a Good Time to Include Aspergillus Molecular Detection to Categorize Aspergillosis in ICU Patients?
T2 125-149 Sentence denotes A Monocentric Experience
T3 151-159 Sentence denotes Abstract
T4 160-175 Sentence denotes (1) Background:
T5 176-320 Sentence denotes The diagnosis of invasive aspergillosis (IA) in an intensive care unit (ICU) remains a challenge and the COVID-19 epidemic makes it even harder.
T6 321-430 Sentence denotes Here, we evaluated Aspergillus PCR input to help classifying IA in SARS-CoV-2-infected patients. (2) Methods:
T7 431-548 Sentence denotes 45 COVID-19 patients were prospectively monitored twice weekly for Aspergillus markers and anti-Aspergillus serology.
T8 549-685 Sentence denotes We evaluated the concordance between (I) Aspergillus PCR and culture in respiratory samples, and (II) blood PCR and serum galactomannan.
T9 686-798 Sentence denotes Patients were classified as putative/proven/colonized using AspICU algorithm and two other methods. (3) Results:
T10 799-963 Sentence denotes The concordance of techniques applied on respiratory and blood samples was moderate (kappa = 0.58 and kappa = 0.63, respectively), with a higher sensitivity of PCR.
T11 964-1030 Sentence denotes According to AspICU, 9/45 patients were classified as putative IA.
T12 1031-1177 Sentence denotes When incorporating PCR results, 15 were putative IA because they met all criteria, probably with a lack of specificity in the context of COVID-19.
T13 1178-1298 Sentence denotes Using a modified AspICU algorithm, eight patients were classified as colonized and seven as putative IA. (4) Conclusion:
T14 1299-1420 Sentence denotes An appreciation of the fungal burden using PCR and Aspergillus serology was added to propose a modified AspICU algorithm.
T15 1421-1556 Sentence denotes This proof of concept seemed relevant, as it was in agreement with the outcome of patients, but will need validation in larger cohorts.
T16 1558-1560 Sentence denotes 1.
T17 1561-1573 Sentence denotes Introduction
T18 1574-1756 Sentence denotes Molecular tools as diagnostic criteria for invasive fungal diseases (IFD) has long been questioned because of a lack of reproducibility and insufficient standardization of protocols.
T19 1757-1974 Sentence denotes Thanks to initiatives such as FPCRI (www.fpcri.eu [1]) and to the dramatic improvement of the quality assessment of molecular technics, Aspergillus PCR is now included in the new EORTC criteria for classification [2].
T20 1975-2147 Sentence denotes Regarding intensive care units (ICU) patients, the classification of IFD mainly refers on criteria adapted from neutropenic patients or relies on single center experiences.
T21 2148-2275 Sentence denotes One algorithm has emerged as a valuable tool to classify invasive aspergillosis (IA) in ICU patients: the AspICU algorithm [3].
T22 2276-2543 Sentence denotes This classification is considered as robust because it has been evaluated in patients for whom autopsy results were available, but it is quite awkward to use in routine practice, particularly in COVID-19 patients with clinical and CT-scan signs hard to interpret [4].
T23 2544-2625 Sentence denotes Besides, it does not include molecular markers, which are now used routinely [5].
T24 2626-2920 Sentence denotes During COVID-19, patients presenting an acute respiratory distress syndrome (ARDS) shared risk factors and underlying diseases classically reported for IA, such as intubation and mechanical ventilation, corticosteroid therapy, immunological storm with high production of inflammatory cytokines.
T25 2921-3110 Sentence denotes Warnings following preliminary cohort studies from various countries prompted the monitoring of fungal colonization and co-infections in SARS-CoV-2-infected patients hospitalized in an ICU.
T26 3111-3268 Sentence denotes However, the entry criterion for putative IA, according to Blot et al., is an Aspergillus-positive culture endotracheal aspirate, which may lack specificity.
T27 3269-3511 Sentence denotes In the recent review by Arastehfar et al. [6], many COVID-19-associated pulmonary aspergillosis (CAPA) benefited from galactomannan (GM) testing of bronchoalveolar fluid (BALF) or even of tracheal aspirates (not approved by the manufacturer).
T28 3512-3703 Sentence denotes However, some laboratories, such as ours, have stopped various manipulations of highly SARS-CoV-2-infected samples in order to limit the exposure of laboratory technicians to viral infection.
T29 3704-3880 Sentence denotes Then, direct examination of respiratory samples or galactomannan (GM) determination in broncho-alveolar lavage have thus been replaced by the systematic use of molecular tools.
T30 3881-4122 Sentence denotes While performances of blood biomarkers such as GM, (1-3)β-d-glucan (BDG) or Aspergillus DNA detection are well evaluated in neutropenic patients, their clinical value is far less known in other conditions and still need evaluation in an ICU.
T31 4123-4292 Sentence denotes Here, our objective was to evaluate the concordance between molecular detection of Aspergillus in respiratory and culture and concordance between blood PCR and serum GM.
T32 4293-4458 Sentence denotes We also aimed at assessing the ability of Aspergillus PCRs to help categorizing patients in the continuum of colonization to invasive infection in COVID-19 patients.
T33 4459-4513 Sentence denotes Arguments to complement AspICU criteria are suggested.
T34 4515-4517 Sentence denotes 2.
T35 4518-4539 Sentence denotes Materials and Methods
T36 4541-4545 Sentence denotes 2.1.
T37 4546-4568 Sentence denotes Population of Patients
T38 4569-4782 Sentence denotes Forty-five intubated and mechanically ventilated patients hospitalized in a “COVID-19 ICU” of Rennes teaching hospital were screened for this study and benefited from a systematic monitoring to detect Aspergillus.
T39 4783-4871 Sentence denotes The hospital’s ethics committee (N 20-56 obtained the 30 April 2020) approved the study.
T40 4872-5054 Sentence denotes The presence of SARS-CoV-2 in respiratory specimens (nasal and pharyngeal swabs or sputum) was detected by real time reverse transcription-polymerase chain reaction (RT-PCR) methods.
T41 5055-5395 Sentence denotes The following data were recorded: age, patient’s preexisting condition (current smoking, diabetes, hypertension, cardiovascular disease, pulmonary disease, and kidney disease), body mass index, ICU length of stay, duration of mechanical ventilation, ventilator-free days at day 28, need for prone position ventilation, and death in the ICU.
T42 5396-5491 Sentence denotes Initial clinical laboratory workup included a complete blood count and serum biochemical tests.
T43 5492-5553 Sentence denotes Chest CT scans were performed during the ICU hospitalization.
T44 5554-5756 Sentence denotes The Simplified Acute Physiology Score (SAPS II) and the Sepsis-Related Organ Failure Assessment (SOFA) score at admission in ICU, at day 7 and 14 days after admission were used to assess severity [7,8].
T45 5758-5762 Sentence denotes 2.2.
T46 5763-5784 Sentence denotes Aspergillus Detection
T47 5785-6056 Sentence denotes Respiratory samples, either bronchial or endotracheal aspirates or bronchoalveolar lavages, were systematic twice weekly and Aspergillus detection was performed using culture and real-time quantitative PCR, but GM was not performed to avoid any risk of lab contamination.
T48 6057-6161 Sentence denotes Briefly, respiratory samples were first digested using v/v digestEUR (Eurobio) for 30 min under shaking.
T49 6162-6374 Sentence denotes Mycological culture were performed after centrifugation of fluidified samples by inoculation of 100–200 µL of pellet on Sabouraud-Chloramphenicol dextrose Agar plates, and incubated for 7 days at 30 °C and 37 °C.
T50 6375-6620 Sentence denotes Mold identification at genus or species complex level was performed microscopically, and confirmed at species level using MALDI-ToF mass spectrometry (MALDI Biotyper, Bruker France, Marne-la-Vallée, France), after fungal material extraction [9].
T51 6621-6784 Sentence denotes Spectrum profiles were then submitted to the Mass Spectrometry Identification (MSI) online database for definitive identification (https://msi.happy-dev.fr/ [10]).
T52 6785-7089 Sentence denotes For molecular detection, 200 µL of plain fluidified respiratory sample underwent immediate SARS-CoV-2 inactivation by heating at 56 °C overnight in ATL Lysis buffer (Qiagen, Saint-Quentin Fallavier, France), before DNA extraction using the EZ1 DSP virus kit (Qiagen) on a EZ1 Advanced XL device (Qiagen).
T53 7090-7210 Sentence denotes Molecular detection of A. fumigatus was done using a 28S rDNA Aspergillus-targeted PCR, as previously published [11,12].
T54 7211-7560 Sentence denotes In case of Aspergillus positive culture and/or positive PCR in respiratory samples, additional tests were performed on serum, i.e., detection of GM (Platelia GM Aspergillus, Biorad, Marnes-la-Coquette, France), Aspergillus PCR and detection of anti-Aspergillus antibody by ELISA (Platelia IgG Aspergillus, Biorad) and in-house immunoelectrophoresis.
T55 7561-7795 Sentence denotes Briefly, Aspergillus PCR was performed on 1 mL of serum extracted using MagNA Pure 24 Total NA Isolation kit (Roche diagnostics, Meylan, France) on a MagNA Pure 24 device (Roche diagnostics), according to manufacturer recommendations.
T56 7796-7832 Sentence denotes DNA was eluted in a volume of 50 µL.
T57 7834-7838 Sentence denotes 2.3.
T58 7839-7859 Sentence denotes Statistical Analysis
T59 7860-8008 Sentence denotes Continuous variables were expressed as median (interquartile range, IQR) and compared using the nonparametric Mann–Whitney U or Kruskal–Wallis test.
T60 8009-8087 Sentence denotes Dunn’s correction tests were performed if multiple comparisons were requested.
T61 8088-8141 Sentence denotes Qualitative data were compared using Chi-square test.
T62 8142-8205 Sentence denotes Tests were two-sided with significance set at α less than 0.05.
T63 8206-8356 Sentence denotes Concordance between categorical results from diagnostic tests was performed using the percent agreement coefficient and Cohen’s kappa coefficient (κ).
T64 8357-8419 Sentence denotes When comparing quantitative data, an ANOVA test was performed.
T65 8420-8506 Sentence denotes All data were analyzed with GraphPad Prism 8.4 (GraphPad Software, La Jolla, CA, USA).
T66 8508-8510 Sentence denotes 3.
T67 8511-8518 Sentence denotes Results
T68 8520-8524 Sentence denotes 3.1.
T69 8525-8551 Sentence denotes Patient Aspergillus Status
T70 8552-8645 Sentence denotes A cohort of 45 COVID-19 intubated and mechanically ventilated patients for ARDS was followed.
T71 8646-8709 Sentence denotes Patients benefited from a systematic screening for Aspergillus.
T72 8710-8832 Sentence denotes Overall, 211 respiratory samples (culture and PCR) and 32 serum samples (GM detection and Aspergillus PCR) were collected.
T73 8833-8926 Sentence denotes The mean number of respiratory samples until patient discharge from ICU was 3.8 (median = 3).
T74 8927-9179 Sentence denotes We categorized these 45 patients according to the AspICU algorithm and propose two alternative classification methods presented in Table 1: the AspICU algorithm associated to PCR results in respiratory and serum samples, and a modified AspICU proposal.
T75 9180-9280 Sentence denotes Thirty patients did not present any biological criteria of aspergillosis with any of the algorithms.
T76 9281-9596 Sentence denotes According to the AspICU classification incorporating PCR detection, 15 were classified as having putative aspergillosis because they met all criteria reported by Blot et al., i.e., compatible clinical signs, abnormal thoracic medical imaging on CT scan and positive screening for Aspergillus on respiratory samples.
T77 9597-9966 Sentence denotes However, in this particular context of COVID-19 with all ARDS patients presenting compatible clinical signs and abnormal chest CT imaging in all likelihood lacking specificity, we decided to use a modified AspICU algorithm taking into account blood markers; we classified eight patients as colonized and seven patients with a putative/probable IA (Table 1 and Table 2).
T78 9968-9972 Sentence denotes 3.2.
T79 9973-10025 Sentence denotes Demographic, Clinical and Biological Characteristics
T80 10026-10138 Sentence denotes Demographic, clinical and biological baseline characteristics at admission are detailed in Table 3 and Table S1.
T81 10139-10307 Sentence denotes Basic demographic characteristics were well-balanced between the three groups of patients (no aspergillosis, Aspergillus colonization, putative/probable aspergillosis).
T82 10308-10396 Sentence denotes Of note, we observed a high proportion (71.1%) of male patients in the study population.
T83 10397-10549 Sentence denotes Clinical and biological baseline data did not differ among the three groups, except C-reactive protein which was higher in the “no aspergillosis” group.
T84 10550-10769 Sentence denotes Regarding the severity scores at admission, no differences were observed either, among the groups of patients, but SAPS II and SOFA scores at day one tended to be higher in patients with putative invasive aspergillosis.
T85 10771-10775 Sentence denotes 3.3.
T86 10776-10807 Sentence denotes Concordance of Diagnostic Tools
T87 10808-10885 Sentence denotes Table 4 gathers the results of the techniques used for Aspergillus detection.
T88 10886-11028 Sentence denotes DNA detection by PCR showed the highest sensitivity, with a number of positive respiratory samples near twice higher, compared to the culture.
T89 11029-11263 Sentence denotes Only one sample grew in culture, whereas PCR was negative, but the species obtained in culture was A. tubingensis (Nigri complex species), which is theoretically not amplified when using the 28S-targeted PCR specific for A. fumigatus.
T90 11264-11523 Sentence denotes Interestingly, the correlation between cultural and molecular quantification showed a significant difference between the two techniques, with a mean Cq threshold of 32.6 ± 0.7 when cultures were negative, highlighting the higher sensitivity of PCR (Figure 1).
T91 11524-11661 Sentence denotes Overall, the concordance coefficient between PCR and culture on respiratory samples was 90.52% with a Cohen’s Kappa coefficient of 0.588.
T92 11662-11751 Sentence denotes Regarding blood samples, three patients had a positive detection of a systemic biomarker:
T93 11752-11811 Sentence denotes 3/3 had a positive PCR and 2/3 had a positive GM (Table 5).
T94 11812-11936 Sentence denotes All three patients had a simultaneous detection of Aspergillus in respiratory samples by culture (n = 2) and/or PCR (n = 3).
T95 11937-12074 Sentence denotes Overall, the concordance coefficient between PCR and culture on respiratory samples was 93.75% with a Cohen’s Kappa coefficient of 0.632.
T96 12076-12080 Sentence denotes 3.4.
T97 12081-12150 Sentence denotes Relevance of Various Tests and Categorization of Patients and Outcome
T98 12151-12251 Sentence denotes Table 6 presents the classification of the 45 patients using original or modified AspICU algorithms.
T99 12252-12369 Sentence denotes It appears that using an AspICU algorithm, nine patients were considered as having a putative IA (22% of the cohort).
T100 12370-12603 Sentence denotes When including PCR, the number of patients with putative IA would increase from 9 to 15 (33%) patients, while most patients might be only colonized because all presented compatible clinical signs and abnormal chest CT scan (Table 5).
T101 12604-12770 Sentence denotes Regarding Aspergillus detection, eight patients had a single detection of fungi using culture and/or PCR in respiratory samples and thus were classified as colonized.
T102 12771-12933 Sentence denotes One of these patients had a concomitant GM detection in serum (index = 0.551), was not treated and is still alive, thus was considered as a false positive result.
T103 12934-13072 Sentence denotes Finally, seven (16%) patients presented a heavy burden of Aspergillus in the respiratory tract with repeated positive cultures and/or PCR.
T104 13073-13216 Sentence denotes In order to rule out a chronic colonization before the episode, an anti-Aspergillus antibody testing was performed and showed negative results.
T105 13217-13436 Sentence denotes These patients were classified as putative IA, and three of them could even be considered as probable IA because of a positive biomarker of angioinvasion (serum PCR and/or GM) in agreement with EORTC/MSG classification.
T106 13437-13561 Sentence denotes Interestingly, following these classification criteria, CT scan abnormalities showed a gradation according to patient group.
T107 13562-13827 Sentence denotes Diffuse reticular or alveolar opacities were observed in patients classified as probable IA (Figure 2), nodules in half of putative IA, and in colonized patients, only non-specific and hard to interpret signs in the context of COVID-19 infection could be described.
T108 13828-14095 Sentence denotes In addition, putative/probable aspergillosis patients appeared more severely ill than patients without aspergillosis, since SOFA score at day seven was significantly higher in this group (p = 0.01) with a continuum between no infection, colonization and IA (Table 5).
T109 14096-14307 Sentence denotes Similarly, the mean ICU length of stay increased significantly from 12 days in patients without aspergillosis to 23 days in colonized patients, and 27 days in putative/probable invasive aspergillosis (p = 0.02).
T110 14308-14404 Sentence denotes All patients with a putative/probable IA were treated either with voriconazole or isavuconazole.
T111 14405-14462 Sentence denotes Only one colonized patient was treated with voriconazole.
T112 14463-14677 Sentence denotes Six patients died; there was a trend towards higher mortality in the group of putative/probable IA compared to uninfected patients, although not significant (2/7; 28.6%) versus 4/30 (13.3%), respectively (Table 7).
T113 14679-14681 Sentence denotes 4.
T114 14682-14692 Sentence denotes Discussion
T115 14693-14916 Sentence denotes In France, the global burden of severe fungal infection is estimated at approximately 1,000,000 (1.47%) cases each year [13] and IFD account for a higher risk of mortality in patients with co-morbidities from 9 to 40% [14].
T116 14917-15090 Sentence denotes During the COVID-19 pandemic, warning messages considering similarities between Sars-CoV-2 and influenza infections stressed the importance of vigilance towards IFD [15,16].
T117 15091-15184 Sentence denotes Local experiences are now published and show high numbers of putative IA [17,18,19,20,21,22].
T118 15185-15350 Sentence denotes The diagnosis of IA still remains challenging because of a wide diversity of underlying conditions and growing number of criteria, particularly biological tools [6].
T119 15351-15644 Sentence denotes In deeply immunosuppressed patients, such as neutropenic patients, patients under antineoplastic and prolonged corticosteroid therapy or solid organ transplantation, criteria for classification of IFD and notably IA have recently been revised incorporating Aspergillus molecular detection [2].
T120 15645-15814 Sentence denotes In ICU, the AspICU algorithm published by Blot et al., [3] is a robust and helpful tool for aspergillosis classification but needs to be more evaluated and even updated.
T121 15815-16068 Sentence denotes In order to address limitations of the various classification definitions for ICU patients, the ongoing FUNgal infections Definitions in ICU patients (FUNDICU) project aims to develop a standard set of definitions for IFD in critically ill patients [5].
T122 16069-16189 Sentence denotes The breaking news of SARS-CoV-2 co-infection urges the need for a critical analysis of the criteria of AspICU algorithm.
T123 16190-16665 Sentence denotes Indeed, COVID-19 patients, particularly ARDS patients with mechanical ventilation, present with compatible clinical signs as depicted by the algorithm (refractory fever, pleuritic chest pain and rub, dyspnea, hemoptysis and worsening respiratory insufficiency, see [3] for full description) and CT-scan signs are hard to interpret because of COVID-19 CT-scan presentation, leading to absence or very poor discrimination between Aspergillus colonization and infection [19,23].
T124 16666-16874 Sentence denotes As a result, IA during COVID-19 has been reported with a possible overestimated high prevalence (until 30%), as favorable outcomes have been described in patients who did not receive any antifungal treatment.
T125 16875-17226 Sentence denotes In order to have a well-balanced patient management, limiting unnecessary and costly antifungal treatments while not neglecting the life-threatening feature of IA, we included A. fumigatus PCR as a monitoring tool for fungal detection in both respiratory and blood samples in addition to classical culture and GM approaches but with some restrictions.
T126 17227-17307 Sentence denotes As expected, PCR allowed detecting Aspergillus in much more respiratory samples.
T127 17308-17467 Sentence denotes We previously showed that PCR improved the detection of Aspergillus in BAL, with a particular added value in ICU patients compared to hematology patients [11].
T128 17468-17619 Sentence denotes Furthermore, PCR using in-house but also marketed kits is also capable of identifying specific gene mutations associated with azole resistance [11,24].
T129 17620-17749 Sentence denotes Besides, the sensitivity of GM detection in blood is less sensitive in ICU than for patients with hematological malignancies [5].
T130 17750-17890 Sentence denotes Here, the higher sensitivity of Aspergillus detection also incites us to adopt modified criteria for case definition to gain in specificity.
T131 17891-18352 Sentence denotes Two major changes were introduced to modify the granularity of the classification: (i) the first one is to combine Aspergillus detection in respiratory samples and anti-Aspergillus antibody testing, to distinguish chronic colonization (positive serology) from acute massive colonization (negative serology) and (ii) the second is to introduce of obvious biomarkers of angioinvasion (serum GM and blood PCR), similar to those of the EORTC/MSG classification [2].
T132 18353-18597 Sentence denotes Of note, the combination of positive culture, positive anti-Aspergillus antibody testing and positive GM in the context of chronic respiratory diseases characterized a transition step from chronic pulmonary aspergillosis to probable IA [25,26].
T133 18598-18919 Sentence denotes Using this refined classification, we were able to categorize our patients in five classes: no infection, colonization, putative IA, probable IA and proven IA (no case of proven IA in the cohort), with a better relevance than the initial AspICU classification, and better specificity than the AspICU + PCR classification.
T134 18920-19091 Sentence denotes The decision of antifungal treatment onset was taken according to this modified AspICU classification and the outcome observed gives confidence in this patient management.
T135 19092-19282 Sentence denotes Of course, the limitation of this work is the relatively small number of patients and should be evaluated on larger cohorts in order to correctly analyze the performance of this alternative.
T136 19283-19454 Sentence denotes A remaining question is also to determine the place of the serum biomarker (1,3)-β-d-glucan in ICU patients, a question that has recently been raised by Honoré et al. [27]
T137 19455-19651 Sentence denotes In conclusion, molecular techniques are now key tools for monitoring IFD, particularly IA as recently updated in the EORTC/MSG definitions, but also Pneumocystis jirovecii or mucorales infections.
T138 19652-19758 Sentence denotes Here, we suggest some adaptations of the AspICU clinical algorithm to gain in sensitivity and specificity.
T139 19759-19833 Sentence denotes Large multicentric data are needed to confirm this proof of concept study.
T140 19835-19858 Sentence denotes Supplementary Materials
T141 19859-19949 Sentence denotes The following are available online at https://www.mdpi.com/2309-608X/6/3/105/s1, Table S1:
T142 19950-20069 Sentence denotes Clinical and biological features of the 9 patients classified as putative aspergillosis according to Blot et al., 2012.
T143 20070-20106 Sentence denotes Click here for additional data file.
T144 20108-20128 Sentence denotes Author Contributions
T145 20129-20791 Sentence denotes Conceptualization, J.-P.G., F.R., H.G., J.-M.T. and F.R.-G.; Data curation, J.-P.G., H.G., R.P., M.L. and F.R.-G.; Formal analysis, J.-P.G., F.R., H.G., M.L., J.-M.T. and F.R.-G.; Investigation, J.-P.G., F.R., H.G., K.P., P.L.B., R.P., E.P., S.B., M.L.S., Y.L.T., P.S., M.L. and J.-M.T.; Methodology, J.-P.G., F.R., H.G.and F.R.-G.; Project administration, J.-P.G.; Resources, J.-P.G, F.R., H.G., K.P., P.L.B., R.P., E.P., S.B., M.L.S., Y.L.T., P.S., M.L., J.-M.T. and F.R.-G.; Software, F.R.; Supervision, J.-P.G. and F.R.-G.; Validation, J.-P.G., Y.L.T. and F.R.-G.; Writing—original draft, J.-P.G. and F.R.-G.; Writing—review & editing, F.R., H.G. and J.-M.T.
T146 20792-20868 Sentence denotes All authors have read and agreed to the published version of the manuscript.
T147 20870-20877 Sentence denotes Funding
T148 20878-20921 Sentence denotes This research received no external funding.
T149 20923-20944 Sentence denotes Conflicts of Interest
T150 20945-21034 Sentence denotes J.-P.G. received funds for communications and congress attendance from Pfizer and Gilead.
T151 21035-21095 Sentence denotes The other authors declare they have no conflict of interest.
T152 21097-21216 Sentence denotes Figure 1 Correlation between molecular and cultural quantification of Aspergillus burden in respiratory samples (rare:
T153 21217-21236 Sentence denotes 1–2 CFU/plate; few:
T154 21237-21339 Sentence denotes 2–5; numerous: >5). * significantly different with p < 0.05. ** significantly different with p < 0.01.
T155 21340-21447 Sentence denotes Figure 2 Computed tomography of the chest of patients with COVID-19 with secondary invasive aspergillosis.
T156 21448-21820 Sentence denotes Unenhanced chest CT in a 59-year-old man with COVID-19 and biological markers of invasive aspergillosis performed at baseline (A) and at 12-day follow-up (B) showing subpleural ground-glass and reticular opacities presumed to correspond to COVID-19 lesions (arrowheads) as well as a right apical consolidation area presumed to correspond to invasive aspergillosis (arrow).
T157 21821-22182 Sentence denotes Enhanced chest CT in a 69-year-old man with COVID-19 and biological markers of invasive aspergillosis showing at baseline (C) ground-glass opacities (arrowheads), and at 11-day follow-up (D) a left postero-basal consolidation presumed to correspond to invasive aspergillosis (arrow). (346-mm field of view, 512 × 512 image matrix, lung window (W1600/L-500 HU)).
T158 22183-22321 Sentence denotes Table 1 Diagnostic criteria of the AspICU clinical algorithm according to Blot et al., 2012, and proposal of a modified AspICU algorithm.
T159 22322-22499 Sentence denotes Classification AspICU According to Blot et al., 2012 [3] AspICU Algorithm Incorporating PCR Modified AspICU Algorithm Incorporating PCR, Serology and Angioinvasion Biomarkers
T160 22500-22775 Sentence denotes Definition of colonization Aspergillus-positive culture endotracheal aspirate alone Aspergillus-positive culture/PCR endotracheal aspirate alone Aspergillus-positive culture/PCR endotracheal aspirate in one sample, not confirmed on a second sample or using blood biomarker
T161 22776-22822 Sentence denotes Definition of putative IA >1 criterion among:
T162 22823-22825 Sentence denotes 1.
T163 22826-22879 Sentence denotes Aspergillus-positive culture endotracheal aspirate 2.
T164 22880-22908 Sentence denotes Compatible clinical signs 3.
T165 22909-22966 Sentence denotes Abnormal thoracic medical imaging on CT scan or X-ray 4a.
T166 22967-22991 Sentence denotes Host risk factors Or 4b.
T167 22992-23100 Sentence denotes Semiquantitative Aspergillus-positive culture of BAL fluid + positive direct microscopy >1 criterion among:
T168 23101-23103 Sentence denotes 1.
T169 23104-23161 Sentence denotes Aspergillus-positive culture/PCR endotracheal aspirate 2.
T170 23162-23190 Sentence denotes Compatible clinical signs 3.
T171 23191-23248 Sentence denotes Abnormal thoracic medical imaging on CT scan or X-ray 4a.
T172 23249-23273 Sentence denotes Host risk factors Or 4b.
T173 23274-23386 Sentence denotes Semiquantitative Aspergillus-positive culture/PCR of BAL fluid + positive direct microscopy >1 criterion among:
T174 23387-23389 Sentence denotes 1.
T175 23390-23515 Sentence denotes Aspergillus-positive culture/PCR endotracheal aspirate in repeated samples with negative anti-Aspergillus antibody testing 2.
T176 23516-23544 Sentence denotes Compatible clinical signs 3.
T177 23545-23602 Sentence denotes Abnormal thoracic medical imaging on CT scan or X-ray 4a.
T178 23603-23627 Sentence denotes Host risk factors Or 4b.
T179 23628-23719 Sentence denotes Semiquantitative Aspergillus-positive culture/PCR of BAL fluid + positive direct microscopy
T180 23720-23811 Sentence denotes Definition of probable IA - - Putative IA + one positive blood biomarker (GM and/or PCR)
T181 23812-23910 Sentence denotes Definition of proven IA Positive histopathology Positive histopathology Positive histopathology
T182 23911-23929 Sentence denotes GM: galactomannan.
T183 23930-24042 Sentence denotes Table 2 Classification of 45 COVID-19 patients with ARDS according to AspICU and to modified AspICU algorithms.
T184 24043-24220 Sentence denotes Classification AspICU According to Blot et al., 2012 [3] AspICU Algorithm Incorporating PCR Modified AspICU Algorithm Incorporating PCR, Serology and Angioinvasion Biomarkers
T185 24221-24245 Sentence denotes No infection 36 30 30
T186 24246-24267 Sentence denotes Colonization 0 0 8
T187 24268-24289 Sentence denotes Putative IA 9 15 4
T188 24290-24310 Sentence denotes Probable IA - - 3
T189 24311-24329 Sentence denotes Proven IA 0 0 0
T190 24330-24420 Sentence denotes Table 3 Demographic characteristics and clinical and biological baseline characteristics.
T191 24421-24591 Sentence denotes Demographic Characteristics All Patients (n = 45) No Aspergillosis (n = 30) Aspergillus Colonization (n = 8) Putative/Probable Invasive Aspergillosis (n = 7) p Value
T192 24592-24656 Sentence denotes Age, years 60 (53–71) 59 (54–68) 53 (51–71) 70 (63–75) 0.14
T193 24657-24746 Sentence denotes SexMen Women 32 (71.1)13 (28.9) 21 (70)9 (30) 7 (87.5)1 (12.5) 4 (57.1)3 (42.8) 0.42
T194 24747-24824 Sentence denotes BMI 27 (24.4–31.4) 27.5 (24.7–32.3) 27 (25.2–30.7) 25.2 (23.2–26.4) 0.99
T195 24825-24877 Sentence denotes Current smoking 3 (6.7) 2 (4.4) 0 1 (12.5) 0.54
T196 24878-24899 Sentence denotes Coexisting conditions
T197 24900-24947 Sentence denotes Any 31 (68.9) 19 (63) 6 (75) 6 (85.7) 0.47
T198 24948-25002 Sentence denotes Diabetes 17 (37.8) 12 (40) 3 (37.5) 2 (28.6) 0.74
T199 25003-25061 Sentence denotes Hypertension 15 (33.3) 7 (23.3) 5 (62.5) 3 (42.9) 0.1
T200 25062-25104 Sentence denotes Solid cancer 1 (2.2) 1 (3.3) 0 0 0.77
T201 25105-25151 Sentence denotes Hemopathy 2 (4.4) 1 (3.3) 0 1 (14.3) 0.54
T202 25152-25215 Sentence denotes Cardiovascular disease 3 (6.7) 3 (10) 2 (25) 2 (28.6) 0.34
T203 25216-25268 Sentence denotes Chronic obstructive pulmonary disease 0 0 0 0 -
T204 25269-25335 Sentence denotes Chronic kidney disease 4 (8.9) 2 (6.7) 1 (12.5) 1 (14.3) 0.83
T205 25336-25423 Sentence denotes Temperature (°C) 38 (37–38.9) 37.5 (337–38.4) 38.2 (37.9–39) 38.2 (37.7–38.8) 0.29
T206 25424-25503 Sentence denotes Heart rate (/min) 100 (80–110) 94 (80–110) 104 (100–110) 102 (85–119) 0.63
T207 25504-25581 Sentence denotes Systolic pressure 94 (87–107) 93 (85–105) 103 (100–109) 90 (82–102) 0.34
T208 25582-25678 Sentence denotes White blood cell count (109/L) 9.8 (6.8–12.9) 9.7 (6.9–13) 9.9 (7–10.7) 9.9 (6.7–12.9) 0.97
T209 25679-25769 Sentence denotes Neutrophil count (109/L) 7.9 (4.5–10.8) 7 (4.9–10.5) 8.5 (5.2–8.6) 5.6 (3.5–10.4) 0.8
T210 25770-25870 Sentence denotes Lymphocyte count (109/L) 0.81 (0.58–1.11) 0.83 (0.53–1.14) 0.7 (0.63–1.1) 0.72 (0.58–0.81) 0.87
T211 25871-25957 Sentence denotes Hemoglobin (g/L) 10.8 (9.5–12.5) 10 (9.4–12) 11.8 (10.6–13.6) 11 (10.5–13.6) 0.12
T212 25958-26046 Sentence denotes Platelet count (109/L) 264 (194–357) 282 (220–364) 244 (184–347) 162 (129–262) 0.12
T213 26047-26137 Sentence denotes Total bilirubin concentration (µmol/L) 8 (5.5–12) 8.5 (6–12) 11 (9–13) 7 (5.5–8) 0.72
T214 26138-26216 Sentence denotes Creatinine (µmol/L) 81 (53–162) 71 (51–109) 81 (73–173) 101 (82–184) 0.15
T215 26217-26314 Sentence denotes C-reactive protein (CRP) (mg/L) 157 (112–263) 155 (112–265) 112 (102–131) 112 (109–178) 0.03
T216 26315-26400 Sentence denotes Ratio of PaO2 to FiO2 152 (100–181) 164 (107–214) 120 (94–214) 136 (72–155) 0.25
T217 26401-26477 Sentence denotes SAPS II score on day 1 42 (31–57) 35 (30–58) 42 (21–55) 43 (35–82) 0.55
T218 26478-26543 Sentence denotes SOFA score on day 1 7 (2–11) 7 (4–10) 5 (2–10) 9 (2–12) 0.76
T219 26544-26602 Sentence denotes Data are presented as median (IQR: interquartiles), n (%).
T220 26603-26794 Sentence denotes P values comparing Aspergillus colonization, invasive aspergillosis and no aspergillosis groups are tested by Kruskal–Wallis (continuous variables) or Chi-square test (categorical variables).
T221 26795-26814 Sentence denotes Abbreviations: BMI:
T222 26815-26840 Sentence denotes Body mass index; SAPS II:
T223 26841-26884 Sentence denotes Simplified Acute Physiology Score II; SOFA:
T224 26885-26952 Sentence denotes Sequential Organ Failure Assessment, PaO2: arterial oxygen tension.
T225 26953-27065 Sentence denotes Table 4 Concordance of PCR and cultures on respiratory samples (n = 211) to detect the presence of Aspergillus.
T226 27066-27128 Sentence denotes Respiratory Samples Positive Culture Negative Culture Total
T227 27129-27153 Sentence denotes Positive PCR 15 19 34
T228 27154-27181 Sentence denotes Negative PCR 1 * 176 177
T229 27182-27201 Sentence denotes Total 16 191 211
T230 27202-27266 Sentence denotes * positive culture with Aspergillus tubingensis (Nigri section).
T231 27267-27348 Sentence denotes Table 5 Concordance of 28S PCR and galactomannan (GM) in serum samples (n = 32).
T232 27349-27395 Sentence denotes Serum Samples Positive GM Negative GM Total
T233 27396-27417 Sentence denotes Positive PCR 2 1 3
T234 27418-27441 Sentence denotes Negative PCR 1 28 29
T235 27442-27458 Sentence denotes Total 3 29 32
T236 27459-27541 Sentence denotes Table 6 Mycological results and classification of 45 COVID-19 patients with ARDS.
T237 27542-27617 Sentence denotes Patient Respiratory Samples Serum Samples IA Classification According to
T238 27618-27809 Sentence denotes Aspergillus Positive Culture (nb Samples) Positive 28S PCR (nb Samples) GM Index > 0.5 (nb Samples) Positive 28S PCR (nb Samples) AspICU (Blot et al., 2012) AspICU + PCR Modified AspICU
T239 27810-27853 Sentence denotes 1 5 5 2 2 putative putative probable
T240 27854-27897 Sentence denotes 2 2 2 1 1 putative putative probable
T241 27898-27945 Sentence denotes 3 0 3 0 1 no infection putative probable
T242 27946-27989 Sentence denotes 4 4 6 0 0 putative putative putative
T243 27990-28033 Sentence denotes 5 4 4 0 0 putative putative putative
T244 28034-28077 Sentence denotes 6 2 5 0 0 putative putative putative
T245 28078-28121 Sentence denotes 7 1 5 0 0 putative putative putative
T246 28122-28169 Sentence denotes 8 1 1 0 0 putative putative colonization
T247 28170-28217 Sentence denotes 9 1 0 1 0 putative putative colonization
T248 28218-28268 Sentence denotes 10 1 * 0 0 0 putative putative colonization
T249 28269-28321 Sentence denotes 11 0 1 0 0 no infection putative colonization
T250 28322-28374 Sentence denotes 12 0 1 0 0 no infection putative colonization
T251 28375-28427 Sentence denotes 13 0 1 0 0 no infection putative colonization
T252 28428-28480 Sentence denotes 14 0 1 0 0 no infection putative colonization
T253 28481-28533 Sentence denotes 15 0 1 0 0 no infection putative colonization
T254 28534-28593 Sentence denotes 16–45 0 0 0 0 no infection no infection no infection
T255 28594-28742 Sentence denotes Total 9 putative (22%) 36 no infection 15 putative (33%)30 no infection 3 probable (7%) 4 putative (9%) 8 colonizations (18%) 30 no infection
T256 28743-28746 Sentence denotes IA.
T257 28747-28815 Sentence denotes Invasive aspergillosis, 1 * Aspergillus tubingensis (Nigri section).
T258 28816-28908 Sentence denotes Table 7 Outcomes of patients with COVID-19-associated ARDS according to Aspergillus status.
T259 28909-29060 Sentence denotes Outcomes All Patients (n = 45) No Aspergillosis (n = 30) Aspergillus Colonization (n = 8) Putative/Probable Invasive Aspergillosis (n = 7) p Value
T260 29061-29147 Sentence denotes Duration of mechanical ventilation 17 (9–24) 17 (7–24) 18 (10–21) 18 (12–30) 0.66
T261 29148-29228 Sentence denotes Ventilator free days at day 28 11 (4–19) 11 (4–21) 10 (7–18) 10 (0–16) 0.64
T262 29229-29302 Sentence denotes Prone positioning ventilation 20 (44) 12 (46) 3 (37.5) 5 (71.4) 0.29
T263 29303-29370 Sentence denotes SOFA score on day 7 7 (5–11) 6 (5–10) 8 (7–10) 11 (10–12) 0.01
T264 29371-29434 Sentence denotes SOFA score on day 14 7 (2–10) 7 (2–9) 3 (1–7) 9 (2–12) 0.2
T265 29435-29507 Sentence denotes ICU length of stay 20 (12–27) 12 (11–23) 23 (16–51) 27 (20–36) 0.02
T266 29508-29561 Sentence denotes Death in ICU 6 (13.3) 4 (13.3) 0 2 * (28.6) 0.27
T267 29562-29620 Sentence denotes Data are presented as median (IQR: interquartiles), n (%).
T268 29621-29812 Sentence denotes P values comparing Aspergillus colonization, invasive aspergillosis and no aspergillosis groups are tested by Kruskal Wallis (continuous variables) or Chi-square test (categorical variables).
T269 29813-29832 Sentence denotes Abbreviations: ICU:
T270 29833-29859 Sentence denotes Intensive Care Unit, SOFA:
T271 29860-29925 Sentence denotes Sequential Organ Failure Assessment, * 1 putative and 1 probable.