A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia

BACKGROUND:Convalescent plasma is frequently administered to patients with Covid-19 and hasbeen reported, largely on the basis of observational data, to improve clinical outcomes.Minimal data are available from adequately powered randomized, controlled trials. METHODS:We randomly assigned hospitalized adult patients with severe Covid-19 pneumoniain a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome wasthe patient?s clinical status 30 days after the intervention, as measured on a six-pointordinal scale ranging from total recovery to death. RESULTS:A total of 228 patients were assigned to receive convalescent plasma and 105 toreceive placebo. The median time from the onset of symptoms to enrollment inthe trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the mostfrequent severity criterion for enrollment. The infused convalescent plasma had amedian titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to1:3200]. No patients were lost to follow-up. At day 30 day, no significant differencewas noted between the convalescent plasma group and the placebo group in thedistribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83(95% confidence interval [CI], 0.52 to 1.35; P=0.46). Overall mortality was 10.96%in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of −0.46 percentage points (95% CI, −7.8 to 6.8). Total SARS-CoV-2 antibodytiters tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS:no significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo.(PlasmAr ClinicalTrials.gov number, NCT04383535.)Fil: Simonovich, Ventura A.. Hospital Italiano. Departamento de Medicina. Servicio de Clinica Medica.; ArgentinaFil: Burgos Pratx, Leandro D.. Hospital Italiano. Departamento de Medicina. Servicio de Clinica Medica.; ArgentinaFil: Scibona, Paula. Hospital Italiano. Departamento de Medicina. Servicio de Clinica Medica.; ArgentinaFil: Beruto, Maria Valeria. No especifíca;Fil: Vallone, Miguel Gabriel. No especifíca;Fil: Vázquez, C.. No especifíca;Fil: Savoy, N.. No especifíca;Fil: Giunta, Diego Hernan. No especifíca;Fil: Pérez, L.G.. No especifíca;Fil: Sánchez, M.L.. No especifíca;Fil: Gamarnik, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ojeda, D.S.. No especifíca;Fil: Santoro, D.M.. No especifíca;Fil: Camino, P. J.. No especifíca;Fil: Antelo, S.. No especifíca;Fil: Rainero, K.. No especifíca;Fil: Vidiella, G. P.. No especifíca;Fil: Miyazaki, E. A.. No especifíca;Fil: Cornistein, W.. No especifíca;Fil: Trabadelo, O. A.. No especifíca;Fil: Ross, F. M.. No especifíca;Fil: Spotti, M.. No especifíca;Fil: Funtowicz, G.. No especifíca;Fil: Scordo, W. E.. No especifíca;Fil: Losso, M. H.. No especifíca;Fil: Ferniot, I.. No especifíca;Fil: Pardo, P. E.. No especifíca;Fil: Rodriguez, E.. No especifíca;Fil: Rucci, P.. No especifíca;Fil: Pasquali, J.. No especifíca;Fil: Fuentes, N. A.. No especifíca;Fil: Esperatti, M.. No especifíca;Fil: Speroni, G. A.. No especifíca;Fil: Nannini, Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Matteaccio, A.. No especifíca;Fil: Michelangelo, H.G.. No especifíca;Fil: Follmann, D.. No especifíca;Fil: Lane, H. Clifford. No especifíca;Fil: Belloso, Waldo Horacio. Hospital Italiano. Departamento de Medicina. Servicio de Clinica Medica.; Argentin

Repertoire of Intensive Care Unit Pneumonia Microbiota

Despite the considerable number of studies reported to date, the causative agents of pneumonia are not completely identified. We comprehensively applied modern and traditional laboratory diagnostic techniques to identify microbiota in patients who were admitted to or developed pneumonia in intensive care units (ICUs). During a three-year period, we tested the bronchoalveolar lavage (BAL) of patients with ventilator-associated pneumonia, community-acquired pneumonia, non-ventilator ICU pneumonia and aspiration pneumonia, and compared the results with those from patients without pneumonia (controls). Samples were tested by amplification of 16S rDNA, 18S rDNA genes followed by cloning and sequencing and by PCR to target specific pathogens. We also included culture, amoeba co-culture, detection of antibodies to selected agents and urinary antigen tests. Based on molecular testing, we identified a wide repertoire of 160 bacterial species of which 73 have not been previously reported in pneumonia. Moreover, we found 37 putative new bacterial phylotypes with a 16S rDNA gene divergence ≥98% from known phylotypes. We also identified 24 fungal species of which 6 have not been previously reported in pneumonia and 7 viruses. Patients can present up to 16 different microorganisms in a single BAL (mean ± SD; 3.77±2.93). Some pathogens considered to be typical for ICU pneumonia such as Pseudomonas aeruginosa and Streptococcus species can be detected as commonly in controls as in pneumonia patients which strikingly highlights the existence of a core pulmonary microbiota. Differences in the microbiota of different forms of pneumonia were documented

Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort

Objectives:We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies.Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries.Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT(> MIC) (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving beta-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P=0.012]. Additionally, in patients with a SOFA score of >= 9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P=0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P=0.025].Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections

Assessment of severity of intensive care unit-acquired pneumonia and association with etiology : a prospective study

Rationale: The current 2005 guidelines on hospital-acquired pneumonia do not take into account the severity of disease in the empiric antibiotic therapy algorithm, as it was in the former 1996 guidelines. Moreover, studies have shown that the 2005 guidelines predict potentially multi-drug resistant (MDR) microorganisms less accurately than the 1996 guidelines. We therefore evaluated the correlation between the severity of illness and the microbial etiology of Intensive care unit (ICU)-acquired pneumonia (ICUAP). Methods: Prospective, observational study in 6 medical and surgical ICUs with a total of 45 beds, from January-2007 to December-2011. We assessed the characteristics, microbiology, systemic inflammatory response and outcomes of 343 consecutive patients with ICUAP clustered according to the presence or not of MDR pathogens. Results: 208 patients had ventilator associated pneumonia (VAP) and 135 patients had non-ventilator ICUAP, of whom 90 needed subsequent intubation. 47% of the study population had septic shock at the onset of pneumonia and 38% developed it afterward. In 217 (63%) patients we determined etiology. The most frequently isolated pathogens were P. aeruginosa, Enterobacteriaceae, methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) S. aureus. 71 patients had early-onset pneumonia and no risk factor for MDR pathogens, while 272 had late-onset pneumonia and/or at least one risk factor. No differences were found in terms of severity scores (APACHE-II, SAPS-II, SOFA), clinical and inflammatory characteristics between these groups. 58 patients had a MDR causative agent. No differences were found in any clinical and inflammatory characteristic and severity criterion between patients with or without MDR, except for a trend to higher frequency of VAP (72% vs. 58%, p=0.063) in the MDR group. Patients with higher APACHE-II and SOFA scores and septic shock at the onset of pneumonia had a significantly lower survival rate both at 28 and 90-day, in presence of a high rate of initial adequate treatment. Conclusions: in patients affected by ICUAP severity of illness affects mortality but does not seem to affect etiology, particularly the presence of MDR pathogens

Impact of chronic liver disease in intensive care unit acquired pneumonia: a prospective study

PURPOSE: To assess the impact of chronic liver disease (CLD) on ICU-acquired pneumonia. METHODS: This was a prospective, observational study of the characteristics, microbiology, and outcomes of 343 consecutive patients with ICU-acquired pneumonia clustered according to the presence of CLD. RESULTS: Sixty-seven (20 %) patients had CLD (67 % had liver cirrhosis, LC), MELD score 26 \ub1 9, 20 % Child-Pugh class C). They presented higher severity scores than patients without CLD both on admission to the ICU (APACHE II, LC 19 \ub1 6 vs. other CLD 18 \ub1 6 vs. no CLD 16 \ub1 6; p < 0.001; SOFA, 10 \ub1 3 vs. 8 \ub1 4 vs. 7 \ub1 3; p < 0.001) and at onset of pneumonia (APACHE II, 19 \ub1 6 vs. 17 \ub1 6 vs. 16 \ub1 5; p = 0.001; SOFA, 11 \ub1 4 vs. 9 \ub1 4 vs. 7 \ub1 3; p < 0.001). Levels of CRP were lower in patients with LC than in the other two groups (day 1, 6.5 [2.5-11.5] vs. 13 [6-23] vs. 15.5 [8-24], p < 0.001, day 3, 6 [3-12] vs. 16 [9-21] vs. 11 [5-20], p = 0.001); all the other biomarkers were higher in LC and other CLD patients. LC patients had higher 28- and 90-day mortality (63 vs. 28 %, p < 0.001; 72 vs. 38 %, p < 0.001, respectively) than non-CLD patients. Presence of LC was independently associated with decreased 28- and 90-day survival (95 % confidence interval [CI], 1.982-17.250; p = 0.001; 95 % confidence interval [CI], 2.915-20.699, p = 0.001, respectively). CONCLUSIONS: In critically ill patients with ICU-acquired pneumonia, CLD is associated with a more severe clinical presentation and poor clinical outcomes. Moreover, LC is independently associated with 28- and 90-day mortality. The results of this study are important for future trials focused on mortality

Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS: a propensity score analysis

Background The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. Methods We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. Results Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0–25) and 25 (IQR 7–26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0–87) and 87 (IQR 0–88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177). Conclusions In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting

European Network for ICU-Related Respiratory Infections (ENIRRIs): a multinational, prospective, cohort study of nosocomial LRTI

PurposeLower respiratory tract infections (LRTI) are the most frequent infectious complication in patients admitted to the intensive care unit (ICU). We aim to report the clinical characteristics of ICU-admitted patients due to nosocomial LRTI and to describe their microbiology and clinical outcomes.MethodsA prospective observational study was conducted in 13 countries over two continents from 9th May 2016 until 16th August 2019. Characteristics and outcomes of ventilator-associated pneumonia (VAP), ventilator-associated tracheobronchitis (VAT), ICU hospital-acquired pneumonia (ICU-HAP), HAP that required invasive ventilation (VHAP), and HAP in patients transferred to the ICU without invasive mechanical ventilation were collected. The clinical diagnosis and treatments were per clinical practice and not per protocol. Descriptive statistics were used to compare the study groups.Results1060 patients with LRTI (72.5% male sex, median age 64 [50-74] years) were included in the study; 160 (15.1%) developed VAT, 556 (52.5%) VAP, 98 (9.2%) ICU-HAP, 152 (14.3%) HAP, and 94 (8.9%) VHAP. Patients with VHAP had higher serum procalcitonin (PCT) and Sequential Organ Failure Assessment (SOFA) scores. Patients with VAP or VHAP developed acute kidney injury, acute respiratory distress syndrome, multiple organ failure, or septic shock more often. One thousand eight patients had microbiological samples, and 711 (70.5%) had etiological microbiology identified. The most common microorganisms were Pseudomonas aeruginosa (18.4%) and Klebsiella spp (14.4%). In 382 patients (36%), the causative pathogen shows some antimicrobial resistance pattern. ICU, hospital and 28-day mortality were 30.8%, 37.5% and 27.5%, respectively. Patients with VHAP had the highest ICU, in-hospital and 28-day mortality rates.ConclusionVHAP patients presented the highest mortality among those admitted to the ICU. Multidrug-resistant pathogens frequently cause nosocomial LRTI in this multinational cohort study