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1.
Clin Imaging ; 90: 11-18, 2022 Jul 23.
Article in English | MEDLINE | ID: covidwho-1956102

ABSTRACT

PURPOSE: Common CT abnormalities of pulmonary aspergillosis represent a cavity with air-meniscus sign, nodule, mass, and consolidation having an angio-invasive pattern. This study aims to conduct a systematic review and an individual patient-level image analysis of CT findings of COVID-19-associated pulmonary aspergillosis (CAPA). METHODS: A systematic literature search was conducted to identify studies reporting CT findings of CAPA as of January 7, 2021. We summarized study-level clinical and CT findings of CAPA and collected individual patient CT images by inviting corresponding authors. The CT findings were categorized into four groups: group 1, typical appearance of COVID-19; group 2, indeterminate appearance of COVID-19; group 3, atypical for COVID-19 without cavities; and group 4, atypical for COVID-19 with cavities. In group 2, cases had only minor discrepant findings including solid nodules, isolated airspace consolidation with negligible ground-glass opacities, centrilobular micronodules, bronchial abnormalities, and cavities. RESULTS: The literature search identified 89 patients from 25 studies, and we collected CT images from 35 CAPA patients (mean age 62.4 ± 14.6 years; 21 men): group 1, thirteen patients (37.1%); group 2, eight patients (22.9%); group 3, six patients (17.1%); and group 4, eight patients (22.9%). Eight of the 14 patients (57.1%) with an atypical appearance had bronchial abnormalities, whereas only one (7.1%) had an angio-invasive fungal pattern. In the study-level analysis, cavities were reported in 12 of 54 patients (22.2%). CONCLUSION: CAPA can frequently manifest as COVID-19 pneumonia without common CT abnormalities of pulmonary aspergillosis. If abnormalities exist on CT images, CAPA may frequently accompany bronchial abnormalities.

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-320305

ABSTRACT

Acute respiratory distress syndrome (ARDS) is the main complication of COVID-19, requiring admission to Intensive Care Unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS specifically differs from other causes of ARDS remains unknown. To address this crucial question, we built 3 cohorts of patients categorized in COVID-19neg ARDSpos, COVID-19pos ARDSpos, and COVID-19pos ARDSneg, and compared their immune landscape analyzed by high-dimensional mass cytometry on peripheral blood followed by artificial intelligence analysis. A cell signature associating S100A9/calprotectin-producing CD169pos monocytes, plasmablasts, and Th1 cells was specifically found in COVID-19pos ARDSpos, unlike COVID-19neg ARDSpos patients. Moreover, this signature was essentially shared with COVID-19pos ARDSneg patients, suggesting that severe COVID-19 patients, whatever they experienced or not ARDS, display similar immune profiles. We also showed an increase in CD14pos HLA-DRlow and CD14low CD16pos monocytes correlated to the occurrence of adverse events during ICU stay. Our study demonstrates that COVID-19-associated ARDS display a specific immune profile, and might benefit from personalized therapy in addition to standard ARDS management.Funding: This work was supported by the University hospital of Rennes, CFTR² (COVID-19 Fast Track Recherche Rennes) grant (to F.R.)and by the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche (ANR), Flash Covid-19 joint grant (HARMONICOV to M.Cog.)Conflict of Interest: J.Fer., F.R., S.L.G., J.D., M.Le., M.G., N.B., C.V., M.La., I.B., M.Cor., S.L., J.Feu., M. Cog. declare no competing interest. M.R., S.C., V.K.T., J.M.T., and K.T. are the inventors of a patent EP 20305642.9 “A method for early detection of propensity to severe clinical manifestations Methods” submitted June 11th 2020 under University hospital of Rennes and Scailyte AG names.Ethical Approval: The study design was approved by our ethic committee (CHU Rennes, n°35RC20_9795_HARMONICOV, ClinicalTrials.gov Identifier: NCT04373200) and informed consent was obtained from patients in accordance with the Declaration of Helsinki.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-319960

ABSTRACT

Background: Invasive pulmonary aspergillosis (IPA) in intensive care unit patients is a major concern, in particular for those with acute respiratory distress syndrome (ARDS). As observed previously for influenza-associated ARDS, the SARS-CoV-2 pandemic has shown a high proportion of COVID-19 patients with ARDS to be at risk of developing invasive fungal diseases.MethodsWe used the new international definitions of influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) to compare the demographic, clinical, biological and radiological aspects of IAPA and CAPA in a monocentric retrospective study.ResultsAmong the 120 ARDS patients included, we observed equivalent prevalence of IPA in Influenza and COVID-19 populations: 17 IAPA (23.9%) and 10 CAPA (20.4%). There were no significant differences in demographic or admission characteristics between patients with and without IPA. Kaplan-Meier curves showed significantly higher 90-day mortality for IPA patients overall (p = 0.032), whereas mortality did not differ between CAPA and IAPA. The duration of mechanical ventilation was higher for IPA patients (23 days [IQR 17–40] than those without (17 days [IQR 9–25], p  = 0.038). Patients with COVID-19 and influenza associated ARDS treated with corticosteroids were more likely to develop IPA. Radiological findings of IPA in both populations using the new criteria increased sensitivity but with still poor specificity. Nonetheless, they also showed interesting differences between IAPA and CAPA with a higher proportion of features suggestive of IPA in IAPA patients. Lastly, therapeutic drug monitoring also appeared challenging since a wide proportion of IPA patients had low plasma voriconazole concentrations, with a significant higher delay to reach voriconazole concentrations > 2mg/L in CAPA versus IAPA patients ( p  = 0.045).ConclusionsICU patients presenting with ARDS during COVID-19 are very similar to those with severe influenza pneumonia in terms of prevalence of IPA and outcome, while CAPA is mainly favored by advanced age irrespective of the background. The dramatic consequences on the patients' prognosis emphasize the need for a better awareness in these particular populations. Larger prospective studies may help in designing the most well-adapted personalized management to prevent IPA, which represents a high burden of death in severe COVID-19 and Influenza pneumonia.

4.
Virol J ; 18(1): 211, 2021 10 29.
Article in English | MEDLINE | ID: covidwho-1622247

ABSTRACT

BACKGROUND: The SARS-CoV-2 virus is the causing agent of the Coronavirus disease 2019 (COVID-19) characterized by a huge pro-inflammatory response and coagulation disorders that may lead to for its severe forms, in organ failure or even death. As major players of thrombo-inflammation, platelets release large amounts of immunomodulatory molecules and regulate leukocyte and endothelial activity, which are both altered in COVID-19. Altogether, this makes platelets a very likely actor of the thrombo-inflammatory complications of COVID-19. Thus, we propose to identify a platelet inflammatory signature of severe COVID-19 specifically modulated throughout the course of the disease. METHODS: Luminex technology and enzyme-linked immunosorbent assay were used to assess plasma levels of platelet inflammatory markers in patients with severe acute respiratory syndrome coronavirus 2 infection on admission and for 14 days afterwards. RESULTS: In accordance with the observations of other teams, we evidence that the plasma levels of the platelet soluble (s)CD40L is significantly elevated in the early stages of the disease. Interestingly we observe that the plasma level of sCD40L decreases overtime while that of sCD62P increases significantly. CONCLUSIONS: Our data suggest that there is a platelet signature of inflammatory response to SARS-COv-2 infection which varies overtime and could serve as monitoring biomarkers of patient inflammatory state. CLINICAL TRIAL REGISTRATION NUMBER: 2020-A01100-39; title: Human Ab Response & immunoMONItoring of COVID-19 Patients, registration date: 05/25/2020; URL of the registry: https://clinicaltrials.gov/ct2/history/NCT04373200?V_5=View .


Subject(s)
Biomarkers/blood , Blood Platelets/immunology , COVID-19 , Inflammation , Adult , Aged , COVID-19/blood , COVID-19/immunology , Female , Humans , Inflammation/blood , Inflammation/immunology , Male , Middle Aged , Young Adult
5.
Int J Mol Sci ; 23(1)2021 Dec 22.
Article in English | MEDLINE | ID: covidwho-1580701

ABSTRACT

Using drugs to treat COVID-19 symptoms may induce adverse effects and modify patient outcomes. These adverse events may be further aggravated in obese patients, who often present different illnesses such as metabolic-associated fatty liver disease. In Rennes University Hospital, several drug such as hydroxychloroquine (HCQ) have been used in the clinical trial HARMONICOV to treat COVID-19 patients, including obese patients. The aim of this study is to determine whether HCQ metabolism and hepatotoxicity are worsened in obese patients using an in vivo/in vitro approach. Liquid chromatography high resolution mass spectrometry in combination with untargeted screening and molecular networking were employed to study drug metabolism in vivo (patient's plasma) and in vitro (HepaRG cells and RPTEC cells). In addition, HepaRG cells model were used to reproduce pathophysiological features of obese patient metabolism, i.e., in the condition of hepatic steatosis. The metabolic signature of HCQ was modified in HepaRG cells cultured under a steatosis condition and a new metabolite was detected (carboxychloroquine). The RPTEC model was found to produce only one metabolite. A higher cytotoxicity of HCQ was observed in HepaRG cells exposed to exogenous fatty acids, while neutral lipid accumulation (steatosis) was further enhanced in these cells. These in vitro data were compared with the biological parameters of 17 COVID-19 patients treated with HCQ included in the HARMONICOV cohort. Overall, our data suggest that steatosis may be a risk factor for altered drug metabolism and possibly toxicity of HCQ.


Subject(s)
Antiviral Agents/adverse effects , Antiviral Agents/metabolism , COVID-19/drug therapy , Hydroxychloroquine/adverse effects , Hydroxychloroquine/metabolism , Aged , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/metabolism , Cell Line , Cell Survival/drug effects , Chemical and Drug Induced Liver Injury/metabolism , Correlation of Data , Drug-Related Side Effects and Adverse Reactions , Fatty Acids/pharmacology , Fatty Liver/complications , Fatty Liver/metabolism , Female , Humans , Hydroxychloroquine/therapeutic use , Linear Models , Male , Metabolic Networks and Pathways , Middle Aged , Obesity/complications , Obesity/metabolism , Risk Factors
6.
Lancet Respir Med ; 10(2): 180-190, 2022 02.
Article in English | MEDLINE | ID: covidwho-1537209

ABSTRACT

BACKGROUND: Patients with severe COVID-19 have emerged as a population at high risk of invasive fungal infections (IFIs). However, to our knowledge, the prevalence of IFIs has not yet been assessed in large populations of mechanically ventilated patients. We aimed to identify the prevalence, risk factors, and mortality associated with IFIs in mechanically ventilated patients with COVID-19 under intensive care. METHODS: We performed a national, multicentre, observational cohort study in 18 French intensive care units (ICUs). We retrospectively and prospectively enrolled adult patients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and requiring mechanical ventilation for acute respiratory distress syndrome, with all demographic and clinical and biological follow-up data anonymised and collected from electronic case report forms. Patients were systematically screened for respiratory fungal microorganisms once or twice a week during the period of mechanical ventilation up to ICU discharge. The primary outcome was the prevalence of IFIs in all eligible participants with a minimum of three microbiological samples screened during ICU admission, with proven or probable (pr/pb) COVID-19-associated pulmonary aspergillosis (CAPA) classified according to the recent ECMM/ISHAM definitions. Secondary outcomes were risk factors of pr/pb CAPA, ICU mortality between the pr/pb CAPA and non-pr/pb CAPA groups, and associations of pr/pb CAPA and related variables with ICU mortality, identified by regression models. The MYCOVID study is registered with ClinicalTrials.gov, NCT04368221. FINDINGS: Between Feb 29 and July 9, 2020, we enrolled 565 mechanically ventilated patients with COVID-19. 509 patients with at least three screening samples were analysed (mean age 59·4 years [SD 12·5], 400 [79%] men). 128 (25%) patients had 138 episodes of pr/pb or possible IFIs. 76 (15%) patients fulfilled the criteria for pr/pb CAPA. According to multivariate analysis, age older than 62 years (odds ratio [OR] 2·34 [95% CI 1·39-3·92], p=0·0013), treatment with dexamethasone and anti-IL-6 (OR 2·71 [1·12-6·56], p=0·027), and long duration of mechanical ventilation (>14 days; OR 2·16 [1·14-4·09], p=0·019) were independently associated with pr/pb CAPA. 38 (7%) patients had one or more other pr/pb IFIs: 32 (6%) had candidaemia, six (1%) had invasive mucormycosis, and one (<1%) had invasive fusariosis. Multivariate analysis of associations with death, adjusted for candidaemia, for the 509 patients identified three significant factors: age older than 62 years (hazard ratio [HR] 1·71 [95% CI 1·26-2·32], p=0·0005), solid organ transplantation (HR 2·46 [1·53-3·95], p=0·0002), and pr/pb CAPA (HR 1·45 [95% CI 1·03-2·03], p=0·033). At time of ICU discharge, survival curves showed that overall ICU mortality was significantly higher in patients with pr/pb CAPA than in those without, at 61·8% (95% CI 50·0-72·8) versus 32·1% (27·7-36·7; p<0·0001). INTERPRETATION: This study shows the high prevalence of invasive pulmonary aspergillosis and candidaemia and high mortality associated with pr/pb CAPA in mechanically ventilated patients with COVID-19. These findings highlight the need for active surveillance of fungal pathogens in patients with severe COVID-19. FUNDING: Pfizer.


Subject(s)
COVID-19 , Pulmonary Aspergillosis , Adolescent , Adult , Child, Preschool , Humans , Intensive Care Units , Male , Middle Aged , Respiration, Artificial , Retrospective Studies , SARS-CoV-2
8.
Cell Rep Med ; 2(6): 100291, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1307253

ABSTRACT

Acute respiratory distress syndrome (ARDS) is the main complication of coronavirus disease 2019 (COVID-19), requiring admission to the intensive care unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS differs from other causes of ARDS remains unknown. To address this question, here, we build 3 cohorts of patients categorized in COVID-19-ARDS+, COVID-19+ARDS+, and COVID-19+ARDS-, and compare, by high-dimensional mass cytometry, their immune landscape. A cell signature associating S100A9/calprotectin-producing CD169+ monocytes, plasmablasts, and Th1 cells is found in COVID-19+ARDS+, unlike COVID-19-ARDS+ patients. Moreover, this signature is essentially shared with COVID-19+ARDS- patients, suggesting that severe COVID-19 patients, whether or not they experience ARDS, display similar immune profiles. We show an increase in CD14+HLA-DRlow and CD14lowCD16+ monocytes correlating to the occurrence of adverse events during the ICU stay. We demonstrate that COVID-19-associated ARDS displays a specific immune profile and may benefit from personalized therapy in addition to standard ARDS management.


Subject(s)
COVID-19/pathology , Leukocytes, Mononuclear/metabolism , Respiratory Distress Syndrome/immunology , Aged , COVID-19/complications , COVID-19/virology , Cohort Studies , Evolution, Molecular , Female , HLA-DR Antigens/metabolism , Humans , Intensive Care Units , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Lipopolysaccharide Receptors/metabolism , Machine Learning , Male , Middle Aged , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/pathology , SARS-CoV-2/isolation & purification , Sialic Acid Binding Ig-like Lectin 1/metabolism , Th1 Cells/cytology , Th1 Cells/immunology , Th1 Cells/metabolism
9.
J Fungi (Basel) ; 7(5)2021 May 15.
Article in English | MEDLINE | ID: covidwho-1234760

ABSTRACT

Invasive pulmonary aspergillosis (IPA) in intensive care unit patients is a major concern. Influenza-associated acute respiratory distress syndrome (ARDS) and severe COVID-19 patients are both at risk of developing invasive fungal diseases. We used the new international definitions of influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) to compare the demographic, clinical, biological, and radiological aspects of IAPA and CAPA in a monocentric retrospective study. A total of 120 patients were included, 71 with influenza and 49 with COVID-19-associated ARDS. Among them, 27 fulfilled the newly published criteria of IPA: 17/71 IAPA (23.9%) and 10/49 CAPA (20.4%). Kaplan-Meier curves showed significantly higher 90-day mortality for IPA patients overall (p = 0.032), whereas mortality did not differ between CAPA and IAPA patients. Radiological findings showed differences between IAPA and CAPA, with a higher proportion of features suggestive of IPA during IAPA. Lastly, a wide proportion of IPA patients had low plasma voriconazole concentrations with a higher delay to reach concentrations > 2 mg/L in CAPA vs. IAPA patients (p = 0.045). Severe COVID-19 and influenza patients appeared very similar in terms of prevalence of IPA and outcome. The dramatic consequences on the patients' prognosis emphasize the need for a better awareness in these particular populations.

11.
Chest ; 159(6): 2417-2427, 2021 06.
Article in English | MEDLINE | ID: covidwho-1131172

ABSTRACT

BACKGROUND: Because of the high risk of thrombotic complications (TCs) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent. RESEARCH QUESTION: What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC? STUDY DESIGN AND METHODS: All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight. RESULTS: Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75). INTERPRETATION: High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill patients with COVID-19 without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04405869; URL: www.clinicaltrials.gov.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/complications , COVID-19/therapy , Critical Care , Thrombosis/epidemiology , Thrombosis/prevention & control , Aged , Female , France , Humans , Incidence , Male , Middle Aged , Pulmonary Embolism/epidemiology , Retrospective Studies , Venous Thromboembolism/epidemiology
12.
J Clin Immunol ; 41(3): 515-525, 2021 04.
Article in English | MEDLINE | ID: covidwho-1002122

ABSTRACT

PURPOSE: The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients. METHODS: A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission. RESULTS: We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation. CONCLUSIONS: The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality.


Subject(s)
Arginine/metabolism , COVID-19/complications , Lymphopenia/etiology , Myeloid-Derived Suppressor Cells/physiology , Respiratory Distress Syndrome/immunology , SARS-CoV-2 , Aged , Cross Infection/etiology , Female , Humans , Male , Middle Aged , Prospective Studies , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Severity of Illness Index
14.
J Fungi (Basel) ; 6(3)2020 Jul 10.
Article in English | MEDLINE | ID: covidwho-646390

ABSTRACT

(1) Background: The diagnosis of invasive aspergillosis (IA) in an intensive care unit (ICU)remains a challenge and the COVID-19 epidemic makes it even harder. Here, we evaluatedAspergillus PCR input to help classifying IA in SARS-CoV-2-infected patients. (2) Methods: 45COVID-19 patients were prospectively monitored twice weekly for Aspergillus markers and anti-Aspergillus serology. We evaluated the concordance between (Ι) Aspergillus PCR and culture inrespiratory samples, and (ΙΙ) blood PCR and serum galactomannan. Patients were classified asputative/proven/colonized using AspICU algorithm and two other methods. (3) Results: Theconcordance of techniques applied on respiratory and blood samples was moderate (kappa = 0.58and kappa = 0.63, respectively), with a higher sensitivity of PCR. According to AspICU, 9/45 patientswere classified as putative IA. When incorporating PCR results, 15 were putative IA because theymet all criteria, probably with a lack of specificity in the context of COVID-19. Using a modifiedAspICU algorithm, eight patients were classified as colonized and seven as putative IA. (4)Conclusion: An appreciation of the fungal burden using PCR and Aspergillus serology was addedto propose a modified AspICU algorithm. This proof of concept seemed relevant, as it was inagreement with the outcome of patients, but will need validation in larger cohorts.

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