This case series examines whether interleukin 7 (IL-7) is associated with restored host protective immunity in patients with severe coronavirus disease 2019 (COVID-19) and immunosuppression.
Agitation of platelet units stored at room temperature is performed routinely to maintain platelet function, and leukoreduction of blood products is the standard of care in many countries to reduce ...immune consequences of transfusion. The effect of agitation and leukoreduction on whole blood stored at 4°C requires investigation, as reductions in hemostatic capacity of whole blood may reduce its efficacy in treating trauma-induced coagulopathy and platelet dysfunction. We hypothesize that agitation of whole blood will not affect hemostatic function and that leukoreduction will reduce hemostatic function of whole blood.
In this in vitro randomized controlled study, 21 units of leukoreduced and 20 nonleukoreduced whole blood units were each randomly assigned into four agitation groups. Hemostatic parameters were measured using viscoelastic assays (rotational thromboelastometry-Extrinsic Screening Test (ROTEM-EXTEM) and thromboelastography (TEG) platelet mapping), impedance aggregometry (agonists-adenosine phosphate, arachidonic acid, thrombin receptor activating peptide, and collagen), and a thrombin generation assay from these whole blood units before and after filtration and on 0, 5, 10, and 15 days of storage at 4°C.
Leukoreduction compared to nonleukoreduction reduced platelet concentration on Day 0. Viscoelastic measures and thrombin generation parameters revealed significant reduction in hemostatic function between the leukoreduced units and the nonleukoreduced units at a few time points. Leukoreduced units consistently demonstrated reduced platelet aggregation compared to the nonleukoreduced units. Agitation methods did not significantly affect any of the hemostatic parameters examined.
Leukoreduction of whole blood with a platelet-sparing filter caused a moderate but significant reduction in some measures of whole blood hemostatic function most evident early in storage. The benefits of leukoreduction should be weighed against the potential reduced hemostatic function of leukoreduced units. Agitation of whole blood is not required to maintain hemostatic function.
In vitro randomized controlled trial, level 1.
BACKGROUND
Invasive Fusarium infection is relatively refractory to available antifungal agents. Invasive fusariosis (IF) occurs almost exclusively in the setting of profound neutropenia and/or ...systemic corticosteroid use. Treatment guidelines for IF are not well established, including the role of granulocyte transfusions (GTs) to counter neutropenia.
STUDY DESIGN AND METHODS
We conducted a systematic review, identifying IF cases where GTs were used as adjunctive therapy to antifungal agents and also report a single‐center case series detailing our experience (1996‐2012) of all IF cases treated with antifungal agents and GTs. In the systematic review cases, GTs were predominantly collected from nonstimulated donors whereas, in the case series, they were universally derived from dexamethasone‐ and granulocyte–colony‐stimulating factor–stimulated donors.
RESULTS
Twenty‐three patients met inclusion criteria for the systematic review and 11 for the case series. Response rates after GTs were 30 and 91% in the review and case series, respectively. Survival to hospital discharge remained low at 30 and 45%, respectively. Ten patients in the systematic review and three in the case series failed to achieve hematopoietic recovery and none of these survived. In the case series, donor‐stimulated GTs generated mean “same‐day” neutrophil increments of 3.35 × 109 ± 1.24 × 109/L and mean overall posttransfusion neutrophil increments of 2.46 × 109 ± 0.85 × 109/L. Progressive decrements in neutrophil response to GTs in two cases were attributed to GT‐related HLA alloimmunization.
CONCLUSION
In patients with IF, donor‐stimulated GTs may contribute to high response rates by effectively bridging periods of neutropenia or marrow suppression. However, their utility in the absence of neutrophil recovery remains questionable.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Describe the frequency with which transfusion and medications that modulate lung injury are administered to children meeting at-risk for pediatric acute respiratory distress syndrome (ARF-PARDS) ...criteria and evaluate for associations of transfusion, fluid balance, nutrition, and medications with unfavorable clinical outcomes.
Secondary analysis of the Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study, a prospective point prevalence study. All enrolled ARF-PARDS patients were included unless they developed subsequent pediatric acute respiratory distress syndrome (PARDS) within 24 hours of PICU admission or PICU length of stay was less than 24 hours. Univariate and multivariable analyses were used to identify associations between therapies given during the first 2 calendar days after ARF-PARDS diagnosis and subsequent PARDS diagnosis (primary outcome), 28-day PICU-free days (PFDs), and 28-day ventilator-free days (VFDs).
Thirty-seven international PICUs.
Two hundred sixty-seven children meeting Pediatric Acute Lung Injury Consensus Conference ARF-PARDS criteria.
None.
During the first 2 days after meeting ARF-PARDS criteria, 55% of subjects received beta-agonists, 42% received corticosteroids, 28% received diuretics, and 9% were transfused. Subsequent PARDS (15%) was associated with platelet transfusion (n = 11; adjusted odds ratio: 4.75 95% CI 1.03-21.92) and diuretics (n = 74; 2.55 1.19-5.46) in multivariable analyses that adjusted for comorbidities, PARDS risk factor, initial oxygen saturation by pulse oximetry:Fio2 ratio, and initial type of ventilation. Beta-agonists were associated with lower adjusted odds of subsequent PARDS (0.43 0.19-0.98). Platelets and diuretics were also associated with fewer PFDs and fewer VFDs in the multivariable models, and TPN was associated with fewer PFDs. Corticosteroids, net fluid balance, and volume of enteral feeding were not associated with the primary or secondary outcomes.
There is an independent association between platelet transfusion, diuretic administration, and unfavorable outcomes in children at risk for PARDS, although this may be related to treatment bias and unmeasured confounders. Nevertheless, prospective evaluation of the role of these management strategies on outcomes in children with ARF-PARDS is needed.
We pursued a study of immune responses in coronavirus disease 2019 (COVID-19) and influenza patients. Compared to patients with influenza, patients with COVID-19 exhibited largely equivalent ...lymphocyte counts, fewer monocytes, and lower surface human leukocyte antigen (HLA)-class II expression on selected monocyte populations. Furthermore, decreased HLA-DR on intermediate monocytes predicted severe COVID-19 disease. In contrast to prevailing assumptions, very few (7 of 168) patients with COVID-19 exhibited cytokine profiles indicative of cytokine storm syndrome. After controlling for multiple factors including age and sample time point, patients with COVID-19 exhibited lower cytokine levels than patients with influenza. Up-regulation of IL-6, G-CSF, IL-1RA, and MCP1 predicted death in patients with COVID-19 but were not statistically higher than patients with influenza. Single-cell transcriptional profiling revealed profound suppression of interferon signaling among patients with COVID-19. When considered across the spectrum of peripheral immune profiles, patients with COVID-19 are less inflamed than patients with influenza.
To date, there are no published guidelines to direct RBC transfusion decision-making specifically for critically ill children. We present the recommendations from the Pediatric Critical Care ...Transfusion and Anemia Expertise Initiative.
Consensus conference series of multidisciplinary, international experts in RBC transfusion management of critically ill children.
Not applicable.
None.
Children with, or children at risk for, critical illness who receive or are at risk for receiving a RBC transfusion.
A panel of 38 content and four methodology experts met over the course of 2 years to develop evidence-based, and when evidence lacking, expert consensus-based recommendations regarding decision-making for RBC transfusion management and research priorities for transfusion in critically ill children. The experts focused on nine specific populations of critically ill children: general, respiratory failure, nonhemorrhagic shock, nonlife-threatening bleeding or hemorrhagic shock, acute brain injury, acquired/congenital heart disease, sickle cell/oncology/transplant, extracorporeal membrane oxygenation/ventricular assist/ renal replacement support, and alternative processing. Data to formulate evidence-based and expert consensus recommendations were selected based on searches of PubMed, EMBASE, and Cochrane Library from 1980 to May 2017. Agreement was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method.
The Transfusion and Anemia Expertise Initiative consensus conference developed and reached consensus on a total of 102 recommendations (57 clinical 20 evidence based, 37 expert consensus, 45 research recommendations). All final recommendations met agreement, defined a priori as greater than 80%. A decision tree to aid clinicians was created based on the clinical recommendations.
The Transfusion and Anemia Expertise Initiative recommendations provide important clinical guidance and applicable tools to avoid unnecessary RBC transfusions. Research recommendations identify areas of focus for future investigation to improve outcomes and safety for RBC transfusion.
(
) affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally,
poses clinical challenges due to its resistance to multiple antibiotics. ...Herein, we investigated the synergistic effect of dual β-lactams sulopenem and cefuroxime (CXM) or the combination of sulopenem and CXM with β-lactamase inhibitors BLIs-avibactam (AVI) or durlobactam (DUR). The sulopenem-CXM combination yielded low minimum inhibitory concentration (MIC) values for 54 clinical
isolates and ATCC19977 (MIC
and MIC
≤0.25 µg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ~1.5 Log
CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in an additional reduction of CFUs (~3 Log
for sulopenem-CXM and AVI and ~4 Log
for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (Ldts; Ldt
-Ldt
), penicillin-binding-protein B (PBP B), and D,D-carboxypeptidase (DDC). Acyl complexes, identified via mass spectrometry analysis, demonstrated the binding of sulopenem with Ldt
-Ldt
, DDC, and PBP B and CXM with Ldt
and PBP B. Molecular docking and mass spectrometry data suggest the formation of a covalent adduct between sulopenem and Ldt
after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring and the establishment of a thioester bond linking the Ldt
with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLIs. These findings potentially broaden the selection of oral therapeutic agents to combat
.
Treating infections from
(Mab), particularly those resistant to common antibiotics like macrolides, is notoriously difficult, akin to a never-ending struggle for healthcare providers. The rate of treatment failure is even higher than that seen with multidrug-resistant tuberculosis. The role of combination β-lactams in inhibiting L,D-transpeptidation, the major peptidoglycan crosslink reaction in Mab, is an area of intense investigation, and clinicians have utilized this approach in the treatment of macrolide-resistant Mab, with reports showing clinical success. In our study, we found that cefuroxime and sulopenem, when used together, display a significant synergistic effect. If this promising result seen in lab settings, translates well into real-world clinical effectiveness, it could revolutionize current treatment methods. This combination could either replace the need for more complex intravenous medications or serve as a "step down" to an oral medication regimen. Such a shift would be much easier for patients to manage, enhancing their comfort and likelihood of sticking to the treatment plan, which could lead to better outcomes in tackling these tough infections. Our research delved into how these drugs inhibit cell wall synthesis, examined time-kill data and binding studies, and provided a scientific basis for the observed synergy in cell-based assays.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with excessive coagulation, thrombosis, and mortality.
To provide insight into mechanisms that contribute to ...excessive coagulation in coronavirus 2019 (COVID-19) disease.
Blood from COVID-19 patients was investigated for coagulation–related gene expression and functional activities.
Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from severe COVID-19 patients revealed a 5.2-fold increase in tissue factor (TF F3 gene) transcript expression levels (P < .05), the trigger of extrinsic coagulation; a 7.7-fold increase in C1-inhibitor (SERPING1 gene; P < .01) transcript expression levels, an inhibitor of intrinsic coagulation; and a 4.4-fold increase in anticoagulant thrombomodulin (TM THBD gene) transcript expression levels (P < .001). Bulk RNA-seq analysis of sorted CD14+ monocytes on an independent cohort of COVID-19 patients confirmed these findings (P < .05). Indicative of excessive coagulation, 41% of COVID-19 patients’ plasma samples contained high D-dimer levels (P < .0001); of these, 19% demonstrated extracellular vesicle TF activity (P = .109). COVID-19 patients’ ex vivo plasma–based thrombin generation correlated positively with D-dimer levels (P < .01). Plasma procoagulant extracellular vesicles were elevated ∼9-fold in COVID-19 patients (P < .01). Public scRNA-seq data sets from bronchoalveolar lung fluid and our peripheral blood mononuclear cell scRNA-seq data show CD14+ monocytes/macrophages TF transcript expression levels are elevated in severe but not mild or moderate COVID-19 patients.
Beyond local lung injury, SARS-CoV-2 infection increases systemic TF (F3) transcript levels and elevates circulating extracellular vesicles that likely contribute to disease-associated coagulation, thrombosis, and related mortality.
•Severe coronavirus 2019 (COVID-19) disease is associated with thrombosis.•Circulating monocytes from patients with severe COVID-19 show elevated tissue factor transcripts.•Circulating procoagulant extracellular vesicles are also elevated.•Elevated monocyte tissue factor expression likely contributes to thrombosis in severe COVID-19 disease.
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GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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