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

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

ICU-Acquired Pneumonia With or Without Etiologic Diagnosis: A Comparison of Outcomes

OBJECTIVES: The impact of ICU-acquired pneumonia without etiologic diagnosis on patients' outcomes is largely unknown. We compared the clinical characteristics, inflammatory response, and outcomes between patients with and without microbiologically confirmed ICU-acquired pneumonia. DESIGN: Prospective observational study. SETTING: ICUs of a university teaching hospital. PATIENTS: We prospectively collected 270 consecutive patients with ICU-acquired pneumonia. Patients were clustered according to positive or negative microbiologic results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the characteristics and outcomes between both groups. Negative microbiology was found in 82 patients (30%). Both groups had similar baseline severity scores. Patients with negative microbiology presented more frequently chronic renal failure (15 [18%] vs 11 [6%]; p = 0.003), chronic heart disorders (35 [43%] vs 55 [29%]; p = 0.044), less frequently previous intubation (44 [54%] vs 135 [72%]; p = 0.006), more severe hypoxemia (PaO2/FIO2: 165\u2009\ub1\u200973 mm\u2009Hg vs 199\u2009\ub1\u200979 mm\u2009Hg; p = 0.001), and shorter ICU stay before the onset of pneumonia (5\u2009\ub1\u20095 days vs 7\u2009\ub1\u20099 days; p = 0.001) compared with patients with positive microbiology. The systemic inflammatory response was similar between both groups. Negative microbiology resulted in less changes of empiric treatment (33 [40%] vs 112 [60%]; p = 0.005) and shorter total duration of antimicrobials (13\u2009\ub1\u20096 days vs 17\u2009\ub1\u200912 days; p = 0.006) than positive microbiology. Following adjustment for potential confounders, patients with positive microbiology had higher hospital mortality (adjusted odds ratio 2.96, 95% confidence interval 1.24-7.04, p = 0.014) and lower 90-day survival (adjusted hazard ratio 0.50, 95% confidence interval 0.27-0.94, p = 0.031), with a nonsignificant lower 28-day survival. CONCLUSIONS: Although the possible influence of previous intubation in mortality of both groups is not completely discarded, negative microbiologic findings in clinically suspected ICU-acquired pneumonia are associated with less frequent previous intubation, shorter duration of antimicrobial treatment, and better survival. Future studies should corroborate the presence of pneumonia in patients with suspected ICU-acquired pneumonia and negative microbiology

Real-time images of tidal recruitment using lung ultrasound

Background: Ventilator-induced lung injury is a form of mechanical damage leading to a pulmonary inflammatory response related to the use of mechanical ventilation enhanced by the presence of atelectasis. One proposed mechanism of this injury is the repetitive opening and closing of collapsed alveoli and small airways within these atelectatic areas-a phenomenon called tidal recruitment. The presence of tidal recruitment is difficult to detect, even with high-resolution images of the lungs like CT scan. The purpose of this article is to give evidence of tidal recruitment by lung ultrasound. Findings: A standard lung ultrasound inspection detected lung zones of atelectasis in mechanically ventilated patients. With a linear probe placed in the intercostal oblique position. We observed tidal recruitment within atelectasis as an improvement in aeration at the end of inspiration followed by the re-collapse at the end of expiration. This mechanism disappeared after the performance of a lung recruitment maneuver. Conclusions: Lung ultrasound was helpful in detecting the presence of atelectasis and tidal recruitment and in confirming their resolution after a lung recruitment maneuver

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

Intensive care unit-acquired pneumonia due to Pseudomonas aeruginosa with and without multidrug resistance

Objective: . Pseudomonas aeruginosa often presents multi-drug resistance (MDR) in intensive care unit (ICU)-acquired pneumonia (ICUAP), possibly resulting in inappropriate empiric treatment and worse outcomes. We aimed to identify patients with ICUAP at risk for these pathogens in order to improve treatment selection and outcomes. Methods: We prospectively assessed 222 consecutive immunocompetent ICUAP patients confirmed microbiologically. We determined the characteristics, risk factors, systemic inflammatory response and outcomes of . P. aeruginosa pneumonia (Pa-ICUAP), compared to other aetiologies. We also compared patients with MDR . vs. non-MDR Pa-ICUAP. Results: . Pseudomonas aeruginosa was the most frequent aetiology (64, 29%); 22 (34%) cases had MDR. Independent predictors for Pa-ICUAP were prior airway colonization by . P. aeruginosa, previous antibiotic treatment, solid cancer and shock; alcohol abuse and pleural effusion were independently associated to lower risk for Pa-ICUAP. Chronic liver disease independently predicted MDR among Pa-ICUAP. The inflammatory biomarkers were similar between all groups. Patients with Pa-ICUAP had lower unadjusted 90-day survival (p = 0.049). However, the 90-day survival adjusted for confounding factors using a propensity score did not differ between all groups. Conclusion: . Pseudomonas aeruginosa remains the most frequent aetiology of ICUAP, with high prevalence of MDR. These risk factors should be taken into account to avoid inappropriate empiric antibiotics for Pa-ICUAP. . Pseudomonas aeruginosa, regardless multidrug resistance, was not associated with different propensity-adjusted survival

Impact of Candida spp. isolation in the respiratory tract in patients with intensive care unit-acquired pneumonia

In immunocompetent patients with nosocomial pneumonia, the relationship between Candida spp. isolation in respiratory samples and outcomes or association with other pathogens is controversial. We therefore compared the characteristics and outcomes of patients with intensive care unit-acquired pneumonia (ICUAP), with or without Candida spp. isolation in the respiratory tract. In this prospective non-interventional study, we assessed 385 consecutive immunocompetent patients with ICUAP, according to the presence or absence of Candida spp. in lower respiratory tract samples. Candida spp. was isolated in at least one sample in 82 (21%) patients. Patients with Candida spp. had higher severity scores and organ dysfunction at admission and at onset of pneumonia. In multivariate analysis, previous surgery, diabetes mellitus and higher Simplified Acute Physiology Score II at ICU admission independently predicted isolation of Candida spp. There were no significant differences in the rate of specific aetiological pathogens, the systemic inflammatory response, and length of stay between patients with and without Candida spp. Mortality was also similar, even adjusted for potential confounders in propensity-adjusted multivariate analyses (adjusted hazard ratio 1.08, 95% CI 0.57-2.05, p 0.80 for 28-day mortality and adjusted hazard ratio 1.38, 95% CI 0.81-2.35, p 0.24 for 90-day mortality). Antifungal therapy was more frequently prescribed in patients with Candida spp. in respiratory samples but did not influence outcomes. Candida spp. airway isolation in patients with ICUAP is associated with more initial disease severity but does not influence outcomes in these patients, regardless of the use or not of antifungal therapy