Immunogenicity and protective capacity of a CpG ODN adjuvanted alum adsorbed bivalent meningococcal outer membrane vesicle vaccine.

Invasive meningococcal disease (IMD) is caused by Neisseria meningitidis, with the main serogroups responsible for the disease being A, B, C, W, X, and Y. To date, several vaccines targeting N. meningitidis have been developed albeit with a short-lived protection. Given that MenW and MenB are the most common causes of IMD in Europe, Turkey, and the Middle East, we aimed to develop an outer membrane vesicle (OMV) based bivalent vaccine as the heterologous antigen source. Herein, we compared the immunogenicity, and breadth of serum bactericidal activity (SBA) assay-based protective coverage of OMV vaccine to the X serotype with existing commercial meningococcal conjugate and polysaccharide (PS) vaccines in a murine model. BALB/c mice were immunized with preclinical batches of the W + B OMV vaccine, either adjuvanted with Alum, CpG ODN, or their combinations, and compared with a MenACYW conjugate vaccine (NimenrixTM, Pfizer), and a MenB OMV-based vaccine (Bexsero®, GSK), The immune responses were assessed through enzyme-linked immunosorbent assay (ELISA) and SBA assay. Antibody responses and SBA titers were significantly higher in the W + B OMV vaccine when adjuvanted with Alum or CpG ODN, as compared to the control groups. Moreover, the SBA titers were not only significantly higher than those achieved with available conjugated ACYW vaccines but also on par with the 4CMenB vaccines. In conclusion, the W + B OMV vaccine demonstrated the capacity to elicit robust antibody responses, surpassing or matching the levels induced by licensed meningococcal vaccines. Consequently, the W + B OMV vaccine could potentially serve as a viable alternative or supplement to existing meningococcal vaccines.

Plasma Extracellular Vesicles Derived from Pediatric COVID-19 Patients Modulate Monocyte and T Cell Immune Responses Based on Disease Severity.

BACKGROUND: The COVID-19 pandemic has caused significant morbidity and mortality globally. The role of plasma-derived extracellular vesicles (EVs) in pediatric COVID-19 patients remains unclear. METHODS: We isolated EVs from healthy controls (n = 13) and pediatric COVID-19 patients (n = 104) with varying severity during acute and convalescent phases using serial ultracentrifugation. EV effects on healthy PBMCs, naïve CD4+ T cells, and monocytes were assessed through in vitro assays, flow cytometry, and ELISA. RESULTS: Our findings indicate that COVID-19 severity correlates with diverse immune responses. Severe acute cases exhibited increased cytokine levels, decreased IFNγ levels, and lower CD4+ T cell and monocyte counts, suggesting immunosuppression. EVs from severe acute patients stimulated healthy cells to express higher PDL1, increased Th2 and Treg cells, reduced IFNγ secretion, and altered Th1/Th17 ratios. Patient-derived EVs significantly reduced proinflammatory cytokine production by monocytes (p < .001 for mild, p = .0025 for severe cases) and decreased CD4+ T cell (p = .043) and monocyte (p = .033) populations in stimulated healthy PBMCs. CONCLUSION: This study reveals the complex relationship between immunological responses and EV-mediated effects, emphasizing the impact of COVID-19 severity. We highlight the potential role of plasma-derived EVs in early-stage immunosuppression in severe COVID-19 patients.

Acute kidney injury in children with moderate-severe COVID-19 and multisystem inflammatory syndrome in children: a referral center experience.

BACKGROUND: Data on the characteristics of acute kidney injury (AKI) in pediatric COVID-19 and MIS-C are limited. We aimed to define the frequency, associated factors and early outcome of AKI in moderate, severe or critical COVID-19 and MIS-C; and to present a tertiary referral center experience from Türkiye. METHODS: Hospitalized patients ≤ 18 years of age with confirmed COVID-19 or MIS-C at Ihsan Dogramaci Children's Hospital, Hacettepe University, between March 2020-December 2021 were enrolled. The characteristics of AKI in the COVID-19 group were investigated in moderate, severe and critically ill patients; patients with mild COVID-19 were excluded. RESULTS: The median (Q1-Q3) age in the COVID-19 (n = 66) and MIS-C (n = 111) groups was 10.7 years (3.9-15.2) and 8.7 years (4.5-12.7), respectively. The frequency of AKI was 22.7% (15/66) in COVID-19 and 15.3% (17/111) in MIS-C; all MIS-C patients with AKI and 73.3% (11/15) of COVID-19 patients with AKI had AKI at the time of admission. Multivariate analyses revealed need for vasoactive/inotropic agents [Odds ratio (OR) 19.233, p = 0.002] and presence of vomiting and/or diarrhea (OR 4.465, p = 0.036) as independent risk factors of AKI in COVID-19 patients; and need for vasoactive/inotropic agents (OR 22.542, p = 0.020), procalcitonin and ferritin levels as independent risk factors of AKI in the MIS-C group. Age was correlated with lymphocyte count (r = -0.513, p < 0.001) and troponin level (r = 0.518, p < 0.001) in MIS-C patients. Length of hospital stay was significantly longer in both groups with AKI, compared to those without AKI. Mortality was 9.1% in the COVID-19 group; and was associated with AKI (p = 0.021). There was no mortality in MIS-C patients. AKI recovery at discharge was 63.6% in COVID-19 survivors and 100% in MIS-C patients. CONCLUSIONS: Independent risk factors for AKI were need for vasoactive/inotropic agents and vomiting/diarrhea in moderate, severe or critical COVID-19 patients; and need for vasoactive/inotropic agents and severe inflammation in MIS-C patients. Our findings suggest that inflammation and cardiac dysfunction are associated with AKI in MIS-C patients; and the association with age in this group merits further studies in larger groups. Early outcome is favorable; long-term follow-up for kidney functions is needed.

Is the high dose extended infusion of meropenem useful in the treatment of highly resistant gram-negative bacteria in children?

OBJECTIVES: Multidrug resistant infections present a treatment challenge for clinicians. These infections have been associated with increased morbidity and mortality. Recently, there has been increasing discussion in the literature that high dose extended infusion of meropenem may be helpful. We aimed to evaluate the clinical efficacy of high dose extended infusion of meropenem in the treatment of highly resistant Gram-negative infections. METHODS: This retrospective observational study was conducted between December 2014 and December 2020 at Hacettepe University Ihsan Dogramaci Children's Hospital. Clinical and microbiological data of children diagnosed with invasive multidrug and extremely drug resistant Gram-negative infections were studied. The findings of patients given high dose extended infusion of meropenem were compared with patients who received colistin or tigecycline. RESULTS: Overall, 158 pediatric patients infected with multidrug and extremely drug resistant gram-negatives were enrolled; 76 treated with high-dose prolonged infusion of meropenem; 60 treated with colistin and 22 with tigecycline. The overall clinical response at the end of the treatment was 81.6 % in meropenem group, 83.3 % in colistin group and 77.3 % in tigecycline group (P = 0.821). Microbiological response at the end of the treatment was 81.1 % in meropenem group, 76.4 % in colistin group and 72.2 % in tigecycline group (P = 0.694). CONCLUSION: Meropenem, with an adjusted dose (high-dose and extended), seems a crucial and robust fighting agent in the treatment of pediatric patients infected with highly-resistant Gram-negative bacteria. It may also be useful in preventing the use of the latest fighting tools such as colistin and tigecycline during the antibacterial stewardship process.

Changing Disease Course of Crimean-Congo Hemorrhagic Fever in Children, Turkey.

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.

Methylprednisolone use in children with severe pneumonia caused by severe acute respiratory syndrome coronavirus 2.

BACKGROUND: This study aimed to evaluate the effectiveness and optimal use of corticosteroids in children with severe coronavirus disease 2019 (COVID-19) pneumonia, for which effective treatment is still lacking with respect to this population. METHODS: We conducted a retrospective study and included patients (aged < 18 years) with severe COVID-19 pneumonia and/or acute respiratory distress syndrome (ARDS) who received standard doses (2-4 mg/kg/day) and high doses (>250 mg/day) of methylprednisolone (MPZ). We adjusted for patients on steroid treatments with a propensity score and compared the side effects of different MPZ doses and patient survival. RESULTS: Fifty-nine patients were included: 61% were male, the median age was 8, interquartile range (IQR) 2-15) years. The overall survival was 84.4% in patients treated with standard-dose MPZ (n = 45, 76.3%) and 92.2% in patients treated with high-dose MPZ (n = 14, 23.7%; p = 0.67). The demographic, clinical, and laboratory data did not differ significantly after propensity score matching, apart from bradycardia, which was a prominent feature of the high-dose group. The clinical and radiological response rates on day 7 were higher and the need for invasive mechanical ventilation (IMV) was lower in the high-dose group. CONCLUSION: The patients with high-dose MPZ had better clinical and radiological responses than those with standard-dose MPZ, although the mortality rate did not differ between standard and high-dose regimens of MPZ.

The comparison of COVID-19 vs seasonal influenza in children.

BACKGROUND: Influenza in children has been well described, whereas there has been a paucity of pediatric data regarding COVID-19. It is crucial for clinicians to differentiate cases of COVID-19 from cases of influenza because of the upcoming influenza season in the new pandemic era. METHODS: This retrospective study included pediatric patients who were diagnosed with laboratory-confirmed COVID-19 between March and September 2020, or seasonal influenza between October 2019 and March 2020. RESULTS: A total of 315 children were included in this study; 151 were diagnosed with influenza and 164 had confirmed COVID-19. The median age of patients with COVID-19 was 10 years (interquartile range [IQR]: 3-15 years), whereas the median age of patients with influenza was 4 years (IQR: 1-6 years) (p = 0.001). In the COVID-19 group, 6.3% of patients had underlying diseases, the most frequent being neurological conditions (3%). In the influenza group, 20.9% of patients had an underlying disease, the most frequent being asthma (14.5%). Fever (odds ratio [OR]: 20.476; 95% confidence interval [CI]: 2.438-171.995; p = 0.005), dyspnea/tachypnea (OR 13.950; 95% CI: 2.607-74.634; p = 0.002), and increased C-reactive protein (CRP) (OR: 7.650; 95% CI: 2.094-27.955; p = 0.002) were main predictors of influenza diagnosis in comparison to COVID-19. Lymphopenia was detected in 43.2% of patients with influenza and 19.9% of patients with COVID-19 (p = 0.001). CONCLUSIONS: The accurate differentiation between "influenza or COVID-19" seems possible by evaluating a combination of factors including cough, fever, vomiting, leucopenia, lymphopenia, pneumonia, in pediatric patients with high CRP as well as age.

New-Onset Ocular Myasthenia after Multisystem Inflammatory Syndrome in Children.

Neurologic complications have been associated with multisystem inflammatory syndrome in children, possibly involving autoimmune mechanisms. Here, we report a 6-year-old girl who developed myasthenia 11 weeks after severe acute respiratory syndrome coronavirus 2 infection and 8 weeks after the onset of severe multisystem inflammatory syndrome in children.

The difference of the inflammatory milieu in MIS-C and severe COVID-19.

BACKGROUND: Coronavirus disease 19 (COVID-19) may have a severe course in children. Multisystem inflammatory syndrome in children (MIS-C) is the post-COVID complication characterized by an exaggerated inflammation, observed in children. However, data on the underlying pathophysiology are sparse. We therefore aimed to assess the cytokine and chemokine profiles of children with MIS-C and compare these to life-threatening severe SARS-CoV-2 and healthy controls (HCs) to shed light on disease pathophysiology. METHODS: Samples of 31 children with MIS-C, 10 with severe/critical COVID-19 and 11 HCs were included. Cytokine and chemokine profiles were studied and compared in between groups. RESULTS: Most cytokines and chemokines related to IL-1 family and IFN-γ pathway (including IL-18 and MIG/CXCL9) and IL-17A were significantly higher in the MIS-C group when compared to the severe/critical COVID-19 group and HCs. IP-10/CXCL10 and IL-10 were higher in both MIS-C patients and severe/critical COVID-19 compared to HCs. CONCLUSION: Our results suggest that IL-1 and IFN-γ pathways play an important role in the pathophysiology of MIS-C. IMPACT: This study defines a pattern of distinctive immune responses in children with MIS-C and in patients with severe/critical COVID-19. As the COVID-19 pandemic continues, biomarkers to identify MIS-C risk are needed to guide our management that study results may shed light on it.

Age and C-reactive protein as modifiers of Kocher criteria in pediatric septic knee monoarthritis.

INTRODUCTION: Although Kocher criteria can distinguish a septic hip from an aseptic cause, they may not apply to a septic knee. We aimed to identify predictors to discriminate septic and aseptic causes of acute knee monoarthritis in children who underwent arthrocentesis. METHODS: We conducted a retrospective cohort study among children who underwent arthrocentesis for suspected septic arthritis of the knee. Collected data included demographic, clinical and laboratory characteristics. We performed univariate and multivariable analyses to identify predictors of the septic knee. We further investigated accuracy of different predictive models. RESULTS: A total of 60 patients who underwent arthrocentesis for suspected knee septic arthritis were included in this study. Septic arthritis of the knee was confirmed in 32 (53%) patients. Age ≤ 5 years (OR 4.237, [95% CI 1.270-14.127], p = 0.019), WBC > 12,000 cells/mm3 (OR 5.059, [95% CI 1.424-17.970], p = 0.012), and CRP > 2 mg/dL (OR 3.180, [0.895-11.298], p = 0.074) were the most important predictors of a septic knee. Three-tier model comprising these three factors (AUC 0.766) and 4-tier model with addition of fever >38.5°C (AUC 0.776) performed better than Kocher criteria (AUC 0.677), modified Kocher criteria (AUC 0.699) and Full Model (adding age ≤ 5 years and CRP >2 mg/dL to Kocher criteria) (AUC 0.746). Full Model successfully ruled out septic arthritis if all 6 criteria were negative. CONCLUSION: Based on these findings, we propose an algorithm to identify low, intermediate and high-risk patients for knee septic arthritis. Our proposed two-step algorithm incorporating major (age, WBC, CRP) and minor (fever, ESR, non-weight bearing) criteria can serve as a simple decision-support tool to justify arthrocentesis in children with suspected knee septic arthritis.