In this study evaluating BNT162b2, vaccine effectiveness against hospitalization for Covid-19 in the delta-predominant period among adolescents 12 to 18 years of age was more than 90%; during the ...omicron period, vaccine effectiveness was 40% against hospitalization and 79% against critical illness. Vaccine effectiveness against hospitalization was 68% among children 5 to 11 years of age.
There are many people living in a permanent vegetative state in the United States. We report the first case of a patient in permanent vegetative state (PVS) who developed paroxysmal sympathetic ...hyperactivity (sympathetic storm) 8 months after the hypoxic brain injury that lead to PVS.
Paroxysmal sympathetic hyperactivity is a relatively common complication early in the course of traumatic brain injury. Recognition of the clinical presentation of this syndrome is important to palliative and hospice care providers who may be caring for patients with PVS. The treatment of sympathic hyperactivity to reduce potential physical suffering includes medications targeted to the sympathetic nervous system.
Investigators used a case–control, test-negative design to assess the effectiveness of the BNT162b2 vaccine in adolescents for the prevention of Covid-19–related hospitalization, ICU admission, or ...receipt of life support. Among 445 case patients and 777 controls, of the 180 patients admitted to an ICU, only 2 had been fully vaccinated; all 7 deaths occurred in unvaccinated patients.
IMPORTANCE: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. OBJECTIVE: To understand ...the range and severity of neurologic involvement among children and adolescents associated with COVID-19. SETTING, DESIGN, AND PARTICIPANTS: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features. EXPOSURES: Severe acute respiratory syndrome coronavirus 2. MAIN OUTCOMES AND MEASURES: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. RESULTS: Of 1695 patients (909 54% male; median interquartile range age, 9.1 2.4-15.3 years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 22%) compared with those without (113 of 1330 8%), but a similar number were previously healthy (195 53% vs 723 54%) and met criteria for multisystem inflammatory syndrome in children (126 35% vs 490 37%). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 49% vs 72 22%). Of 43 patients who developed COVID-19–related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. CONCLUSIONS AND RELEVANCE: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.
In this study, maternal vaccination with an mRNA vaccine during pregnancy was less common among infants hospitalized for Covid-19 than among controls. The effectiveness of maternal vaccination ...against Covid-19 hospitalization of infants was 52% overall and was greater when delta, rather than omicron, was predominant.
Thymopoiesis is a complex process dependent on precise signals from the supporting thymic stromal microenvironment that orchestrates the progression of precursor T cells through well-defined ...maturation stages. It is well documented that the decline in thymic size and function with age is in part correlated with an increase in sex steroids. This age-related decline in function can be detrimental to the recovery of the thymus in patients receiving radio or chemo-therapy with hematopoietic stem cell transplantation (HSCT). Delayed immune reconstitution, especially in the T cell lineage, is associated with an increased risk of opportunistic infections and malignant relapses. Therefore strategies to enhance thymic reconstitution has the potential to decrease the period of T cell lymphopenia and increase overall clinical outcome.
In the process of evaluating the effects of sex steroids in the decline of the thymic function, we found a decrease in the expression of the key thymopoietic factors IL-7, CCL25 and Delta-like 4 (DLL4) by thymic stromal cells after testosterone treatment (Figure 1A). We then addressed if these transcriptional changes were the result of a direct regulation by the androgen receptor (AR). Using a computational approach, and subsequently confirmed by ChIP studies, we found that AR directly bound and negatively regulated the promoter of DLL4, a critical gene involved in T cell commitment and differentiation. We and others have previously shown that sex steroid ablation (SSA) can regenerate young and aged immune system by promoting bone marrow and thymic lymphopoiesis and promoting recovery from autologous and allogeneic HSCT. However the mechanisms underlying the sex steroid-mediate thymic involution and its regeneration after SSA are poorly understood. Moreover, one of the main drawbacks to standard clinical methods of sex steroid ablation using luteinizing hormone releasing hormone (LHRH) agonists (LHRH-Ag) is the initial surge in sex steroids they cause. To address this, we employed a novel class of LHRH-antagonists (LHRH-Ant) that rapidly block the secretion of sex steroids without causing their initial surge that can be even more detrimental to thymopoiesis. Mice treated with LHRH-Ant showed a significantly faster increase in thymic cellularity compared with LHRH-Ag treated mice (Figure 1B). Given the negative regulation of DLL4 by the AR, we hypothesized that DLL4 expression would conversely increase after SSA in vivo. Indeed, we found a significant increase in DLL4 expression after SSA and also an increase in genes downstream of DLL4, such as Ptcra, Hes1 and Cd25 (Figure 1C). We next evaluated if treatment with the LHRH-Ant would provide a faster immune recovery after injury to the immune system. We found that mice treated with LHRH-Ant showed a faster thymic regeneration after total body irradiation (TBI) compared to the control irradiated mice (Figure 1D) and enhanced viral clearance (Figure 1E). Finally, we also found that LHRH-Ant enhanced thymic and peripheral reconstitution up to 3 months after allo-HSCT (Figure 1F).
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In conclusion, we found that down-regulation of DLL4 may represent one of the mechanisms underlying the effects of sex steroids on thymic function. We demonstrate that SSA with a novel LHRH-Ant increases DLL4 expression and enhances thymic and peripheral T cell recovery and function after immune injury. These findings suggest that the employment of a LHRH-Ant, which is already in clinical use for prostate cancer patients, represents a novel therapeutic strategy to enhance immune recovery and function in immunocompromised patients.
No relevant conflicts of interest to declare.
Allogeneic and autologous natural killer (NK) cell-based therapies have proven to be safe in patients with hematological malignancies across multiple clinical trials. However, at present, only a ...small percentage of patients who have received NK cell based therapy have achieved complete remissions. NK cells must first traffic into the tumor microenvironment in order to effectively lyse tumor targets in vivo. Many hematological malignancies reside in or metastasize through bone marrow (BM) compartments. Recent studies in both murine and macaque models evaluating NK cell distribution following intravenous (i.v.) infusion unexpectedly revealed preferential trafficking into liver tissue over BM niches, which for hematological malignancies is undesirable. Therefore, we evaluated surface expression and mRNA transcript abundance of critical chemotactic receptors and adhesion molecules in primary fresh and ex vivo expanded NK cells.
NK cells from six healthy donor PBMC samples were expanded for 14 days ex vivo, using two different irradiated feeder cell lines (either EBV-infected LCL or K562 cells with membrane-bound IL-21 and 41BBL). mRNA from fresh and expanded NK cells was sequenced and analyzed for differential gene expression. We observed the transcriptome of NK cells expanded with the two different feeder cell lines were similar, with only 13 differentially expressed genes. However, we observed the transcriptional landscape between fresh and expanded NK cells to be vastly different (Figure 1A). As expected, amongst the thousands of differentially expressed genes, mitotic phase transitions and DNA replication were pathways that were strongly enriched in expanded compared to fresh NK cells. Further, expanded NK cells had a robust amplification in mRNA transcription of known surface cytotoxicity and activation receptors, as well as enhanced mRNA transcription of chemotactic ligands that are implicated in bridging the innate and adaptive immune responsesincluding XCL1, XCL2, CCL5, CXCL16, and CXCL8. Remarkably, we found expanded NK cells had upregulated mRNA transcription and surface expression of CCR1, CCR5, CXCR3, and CXCR6, coupled with a substantial decrease in mRNA transcription and surface expression of CXCR4 (Figure 1B). We postulate that this particular shift in molecular expression may have the net effect of routing adoptively transferred NK cells out of the circulation into liver and other inflammatory environments, ultimately impeding cellular trafficking into the bone marrow (BM). To test this hypothesis, we used CRISPR/Cas9 to disrupt the CCR5 gene which has upregulated expression in expanded NK cells. Five days following ex-vivo expansion, NK cells were electroporated with a mix of 3 sgRNAs targeting CCR5, complexed with Cas9. Electroporated cultures harvested on day 14 maintained their proliferative capacity and had a substantial reduction in CCR5 expression (22%) compared to non-electroporated control NK cells (88%; Figure 1C). Both expanded NK cell populations were then injected i.v. into NSG mice, with blood, BM, lungs, and livers being harvested 24 hours following infusion. Disrupting CCR5 in NK cells significantly reduced cellular trafficking into the liver compared to control NK cells (p<.01). Moreover, the percentage of infused CCR5 CRISPR/Cas9 disrupted NK cells in the circulation was increased compared to control NK cells (Figure 1D).
In conclusion, these collective data reveal NK cells undergo profound transcriptional changes when cultivated ex vivo. Many chemotactic receptors that were previously unknown to be impacted by ex vivo expansion were discovered to have a shift in transcriptional regulation which would be predicted to compromise NK cell homing to the bone-marrow. Importantly, we show for the first time that CRISPR gene-editing of chemokine receptors can be used as a novel strategy to redirect NK cell trafficking in vivo, which could bolster the effectiveness of adoptive NK cell immunotherapy for hematological malignancies and other cancers.
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No relevant conflicts of interest to declare.
Abstract
Pediatric hematopoietic stem cell transplant recipients are at risk for acquiring a variety of lower respiratory tract infections (LRTI), which result in frequent pediatric intensive care ...unit admission with high mortality. Recent advances in conditioning regimens, opportunistic infection prophylaxis, diagnostic tools, and treatment modalities have broadly impacted our understanding of LRTI among these vulnerable patients. In this review, the most common bacteria, viruses, and fungi causing LRTI in pediatric hematopoietic stem cell transplant patients are discussed.
Multisystem inflammatory syndrome in children (MIS-C), linked to antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with considerable morbidity. ...Prevention of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) by vaccination might also decrease MIS-C likelihood.
In a multicenter, case-control, public health investigation of children ages 5-18 years hospitalized from 1 July 2021 to 7 April 2022, we compared the odds of being fully vaccinated (2 doses of BNT162b2 vaccine ≥28 days before hospital admission) between MIS-C case-patients and hospital-based controls who tested negative for SARS-CoV-2. These associations were examined by age group, timing of vaccination, and periods of Delta and Omicron variant predominance using multivariable logistic regression.
We compared 304 MIS-C case-patients (280 92% unvaccinated) with 502 controls (346 69% unvaccinated). MIS-C was associated with decreased likelihood of vaccination (adjusted OR aOR: .16; 95% CI: .10-.26), including among children ages 5-11 years (aOR: .22; 95% CI: .10-.52), ages 12-18 years (aOR: .10; 95% CI: .05-.19), and during the Delta (aOR: .06; 95% CI: .02-.15) and Omicron (aOR: .22; 95% CI: .11-.42) variant-predominant periods. This association persisted beyond 120 days after the second dose (aOR: .08; 95% CI: .03-.22) in 12-18-year-olds. Among all MIS-C case-patients, 187 (62%) required intensive care unit admission and 280 (92%) vaccine-eligible case-patients were unvaccinated.
Vaccination with 2 doses of BNT162b2 is associated with reduced likelihood of MIS-C in children ages 5-18 years. Most vaccine-eligible hospitalized patients with MIS-C were unvaccinated.
Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients.
We compared demographics, ...clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity.
Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 years vs 13.8 years), less likely to be non-Hispanic Black (14.5% vs 27.6%) or Hispanic (24.0% vs 36.2%), and less likely to have ≥1 underlying condition (66.4% vs 78.5%) or be obese (21.4% vs 42.2%), and a shorter hospital stay (median, 5 days vs 7 days). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life support in children with influenza vs COVID-19 were similar (adjusted odds ratio, 1.30; 95% confidence interval, .78-2.15; P = .32).
Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.
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