Moderate-to-severe ARDS: COVID-19 patients compared to influenza patients for ventilator parameters and mortality.

Background: This study aimed to compare ventilatory parameters recorded in the first days of acute respiratory distress syndrome (ARDS) and mortality at day 60 between coronavirus disease 2019 (COVID-19) and influenza ARDS patients with arterial oxygen tension (P aO2 )/inspiratory oxygen fraction (F IO2 ) ≤150 mmHg. Methods: We compared 244 COVID-19 ARDS patients with 106 influenza ARDS patients. Driving pressure, respiratory system compliance (C rs), ventilator ratio, corrected minute ventilation (V'Ecorr) and surrogate of mechanical power (index=(4×driving pressure)+respiratory rate) were calculated from day 1 to day 5 of ARDS. A propensity score analysis and a principal component analysis (PCA) were performed. Results: On day 1 of ARDS, COVID-19 patients had significantly higher P aO2 /F IO2 (median (interquartile range) 97 (79-129.2) versus 83 (62.2-114) mmHg; p=0.001), and lower driving pressure (13.0 (11.0-16.0) versus 14.0 (12.0-16.7) cmH2O; p=0.01), ventilatory ratio (2.08 (1.73-2.49 versus 2.52 (1.97-3.03); p<0.001), V'Ecorr (12.7 (10.2-14.9) versus 14.9 (11.6-18.6) L·min-1; p<0.001) and index (80 (70-89) versus 84 (75-94); p=0.004). PCA demonstrated an important overlap of ventilatory parameters recorded on day 1 between the two groups. From day 1 to day 5, repeated values of P aO2 /F IO2 , arterial carbon dioxide tension, ventilatory ratio and V'Ecorr differed significantly between influenza and COVID-19 patients in the unmatched and matched populations. Mortality at day 60 did not differ significantly after matching (29% versus 21.7%; p=0.43). Conclusions: Ventilation was more impaired in influenza than in COVID-19 ARDS patients on the first day of ARDS with an important overlap of values. However, mortality at day 60 did not differ significantly in the matched population.

Demultiplexing Ig repertoires by parallel mRNA/DNA sequencing shows major differential alterations in severe COVID-19.

To understand the fine differential elements that can lead to or prevent acute respiratory distress syndrome (ARDS) in COVID-19 patients, it is crucial to investigate the immune response architecture. We herein dissected the multiple layers of B cell responses by flow cytometry and Ig repertoire analysis from acute phase to recovery. Flow cytometry with FlowSOM analysis showed major changes associated with COVID-19 inflammation such as an increase of double-negative B-cells and ongoing plasma cell differentiation. This paralleled COVID-19-driven expansion of two disconnected B-cell repertoires. Demultiplexing successive DNA and RNA Ig repertoire patterns characterized an early expansion of IgG1 clonotypes with atypically long and uncharged CDR3, the abundance of this inflammatory repertoire being correlated with ARDS and likely pejorative. A superimposed convergent response included convergent anti-SARS-CoV-2 clonotypes. It featured progressively increasing somatic hypermutation together with normal-length or short CDR3 and it persisted until a quiescent memory B-cell stage after recovery.

Moderate to severe ARDS: COVID-19 patients compared to influenza patients for ventilator parameters and mortality

Background This study aimed to compare ventilatory parameters recorded the first days of ARDS, and mortality at day 60 between COVID-19 and influenza ARDS patients with PaO2/FiO2≤150 mmHg. Methods We compared 244 COVID-19 ARDS patients with 106 influenza ARDS patients. Driving pressure (DP), respiratory system compliance (CRs), ventilator ratio (VR), corrected minute ventilation (VEcorr), and surrogate of mechanical power [index=(4×DP)+respiratory rate] were calculated from day1 to day 5 of ARDS. A propensity score analysis and a principal component analysis (PCA) were performed. Results On day 1 of ARDS, COVID-19 patients had significantly higher PaO2/FiO2 ratio (median [IQR], 97 mmHg [79–129] versus 83 [62.2–114]), p=0.001), and lower DP (13 cmH20 [11–16.0] versus 14 [12.0–16.7], p=0.01), VR (2.08 [1.73–2.49 versus 2.52 [1.97–3.03], p<0.001), VEcorr (12.7 L·mn−1 [10.2–14.9] versus 14.9 [11.6–18.6], p<0.001), index (80 [70–89] versus 84 [75–94], p=0.004). PCA demonstrated an important overlap of ventilatory parameters recorded on day 1 between the two groups. From day 1 to day 5 repeated values of PaO2/FiO2 ratio, PaCO2, VR and VEcorr differed significantly between influenza and COVID-19 patients in the unmatched and matched populations. Mortality at day 60 did not differ significantly after matching (29% versus 21.7%, p=0.43). Conclusions Ventilation was more impaired in influenza than in COVID-19 ARDS patients the first day of ARDS with important overlap of values. However, mortality at day 60 did not differ significantly in the matched population. In COVID-19 and influenza patients with mild to moderate ARDS managed similarly for mechanical ventilation, dead space estimates were higher in COVID-19 patients than in influenza patients the first days of ARDS and short-term mortality similar.

Acquired agitation in acute respiratory distress syndrome with COVID-19 compared to influenza patients: a propensity score matching observational study.

BACKGROUND: A growing body of evidence reports that agitation and encephalopathy are frequent in critically ill Covid-19 patients. We aimed to assess agitation's incidence and risk factors in critically ill ARDS patients with Covid-19. For that purpose, we compared SARS-CoV-2 acute respiratory distress syndrome (ARDS) patients with a population of influenza ARDS patients, given that the influenza virus is also known for its neurotropism and ability to induce encephalopathy. METHODS: We included all the patients with laboratory-confirmed Covid-19 infection and ARDS admitted to our medical intensive care unit (ICU) between March 10th, 2020 and April 16th, 2021, and all the patients with laboratory-confirmed influenza infection and ARDS admitted to our ICU between April 10th, 2006 and February 8th, 2020. Clinical and biological data were prospectively collected and retrospectively analyzed. We also recorded previously known factors associated with agitation (ICU length of stay, length of invasive ventilation, SOFA score and SAPS II at admission, sedative and opioids consumption, time to defecation). Agitation was defined as a day with Richmond Agitation Sedation Scale greater than 0 after exclusion of other causes of delirium and pain. We compared the prevalence of agitation among Covid-19 patients during their ICU stay and in those with influenza patients. RESULTS: We included 241 patients (median age 62 years [53-70], 158 males (65.5%)), including 146 patients with Covid-19 and 95 patients with Influenza. One hundred eleven (46.1%) patients had agitation during their ICU stay. Patients with Covid-19 had significantly more agitation than patients with influenza (respectively 80 patients (54.8%) and 31 patients (32.6%), p < 0.01). After matching with a propensity score, Covid-19 patients remained more agitated than influenza patients (49 (51.6% vs 32 (33.7%), p = 0.006). Agitation remained independently associated with mortality after adjustment for other factors (HR = 1.85, 95% CI 1.37-2.49, p < 0.001). CONCLUSION: Agitation in ARDS Covid-19 patients was more frequent than in ARDS influenza patients and was not associated with common risk factors, such as severity of illness or sedation. Systemic hyperinflammation might be responsible for these neurological manifestations, but there is no specific management to our knowledge.

Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study.

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.

Comparative immune profiling of acute respiratory distress syndrome patients with or without SARS-CoV-2 infection.

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.

Influenza- and COVID-19-Associated Pulmonary Aspergillosis: Are the Pictures Different?

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.

Successful heart transplantation for COVID-19-associated post-infectious fulminant myocarditis.

Various clinical presentations of the 2019 coronavirus disease (COVID-19) have been described, including post-infectious acute and fulminant myocarditis. Here, we describe the case of a young patient admitted for COVID-19-associated post-infectious fulminant myocarditis. Despite optimal pharmacologic management, haemodynamic status worsened requiring support by veno-arterial extracorporeal membrane oxygenation. Emergent heart transplantation was required at Day 11 given the absence of cardiac function improvement. The diagnosis of post-infectious COVID-19-associated myocarditis was made from both pathologic examination of the explanted heart and positive SARS-CoV-2 serology.

Inter-hospital transport of critically ill patients to manage the intensive care unit surge during the COVID-19 pandemic in France.

BACKGROUND: The COVID-19 pandemic led authorities to evacuate via various travel modalities critically ill ventilated patients into less crowded units. However, it is not known if interhospital transport impacts COVID-19 patient's mortality in intensive care units (ICUs). A cohort from three French University Hospitals was analysed in ICUs between 15th of March and the 15th of April 2020. Patients admitted to ICU with positive COVID-19 test and mechanically ventilated were recruited. RESULTS: Among the 133 patients included in the study, 95 (71%) were male patients and median age was 63 years old (interquartile range: 54-71). Overall ICU mortality was 11%. Mode of transport included train (48 patients), ambulance (6 patients), and plane plus helicopter (14 patients). During their ICU stay, 7 (10%) transferred patients and 8 (12%) non-transferred patients died (p = 0.71). Median SAPS II score at admission was 33 (interquartile range: 25-46) for the transferred group and 35 (27-42) for non-transferred patients (p = 0.53). SOFA score at admission was 4 (3-6) for the transferred group versus 3 (2-5) for the non-transferred group (p = 0.25). In the transferred group, median PaO2/FiO2 ratio (P/F) value in the 24 h before departure was 197 mmHg (160-250) and remained 166 mmHg (125-222) in the first 24 h post arrival (p = 0.13). During the evacuation 46 (68%) and 21 (31%) of the patients, respectively, benefited from neuromuscular blocking agents and from vasopressors. Transferred and non-transferred patients had similar rate of nosocomial infections, 37/68 (54%) versus 34/65 (52%), respectively (p = 0.80). Median length of mechanical ventilation was significantly increased in the transferred group compared to the non-transferred group, 18 days (11-24) and 14 days (8-20), respectively (p = 0.007). Finally, ICU and hospital length of stay did not differ between groups. CONCLUSIONS: In France, inter-hospital evacuation of COVID-19 ventilated ICU patients did not appear to increase mortality and therefore could be proposed to manage ICU surges in the future.

SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage.

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.

Is the COVID-19 Pandemic a Good Time to Include Aspergillus Molecular Detection to Categorize Aspergillosis in ICU Patients? A Monocentric Experience.

(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.