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The Pediatric Infectious Disease Journal Apr 2024Multiplex polymerase chain reaction assays have the potential to reduce antibiotic use and shorten length of inpatient stay in children with suspected central nervous... (Observational Study)
Observational Study
BACKGROUND
Multiplex polymerase chain reaction assays have the potential to reduce antibiotic use and shorten length of inpatient stay in children with suspected central nervous system infection by obtaining an early microbiological diagnosis. The clinical impact of the implementation of the BioFire FilmArray Meningitis/Encephalitis Panel on the management of childhood meningitis was evaluated at the John Radcliffe Hospital in Oxford and Children's Health Ireland at Temple Street in Dublin.
METHODS
Children who had lumbar punctures performed as part of a septic screen were identified retrospectively through clinical discharge coding and microbiology databases from April 2017 to December 2018. Anonymized clinical and laboratory data were collected. Comparison of antibiotic use, length of stay and outcome at discharge was made with a historical cohort in Oxford (2012-2016), presenting before implementation of the FilmArray.
RESULTS
The study included 460 children who had a lumbar puncture as part of an evaluation for suspected central nervous system infection. Twelve bacterial cases were identified on the FilmArray that were not detected by conventional bacterial culture. Bacterial culture identified one additional case of bacterial meningitis, caused by Escherichia coli , which had not been identified on the FilmArray. Duration of antibiotics was shorter in children when FilmArray was used than before its implementation; enterovirus meningitis (median: 4 vs. 5 days), human parechovirus meningitis (median: 4 vs. 4.5 days) and culture/FilmArray-negative cerebrospinal fluid (median: 4 vs. 6 days).
CONCLUSIONS
The use of a FilmArray can identify additional bacterial cases of meningitis in children that had been negative by traditional culture methods. Children with viral meningitis and culture-negative meningitis received shorter courses of antibiotics and had shorter hospital stays when FilmArray was used. Large studies to evaluate the clinical impact and cost effectiveness of incorporating the FilmArray into routine testing are warranted.
Topics: Child; Humans; Encephalitis; Retrospective Studies; Meningitis; Cohort Studies; Meningitis, Bacterial; Bacteria; Multiplex Polymerase Chain Reaction; Central Nervous System Infections; Anti-Bacterial Agents; Meningitis, Viral
PubMed: 38190645
DOI: 10.1097/INF.0000000000004236 -
Emerging Microbes & Infections Dec 2024Enterovirus A71 (EV-A71) is the main pathogen causing hand, foot and mouth disease (HFMD) in children and occasionally associated with neurological diseases such as...
Enterovirus A71 (EV-A71) is the main pathogen causing hand, foot and mouth disease (HFMD) in children and occasionally associated with neurological diseases such as aseptic meningitis, brainstem encephalitis (BE) and acute flaccid paralysis. We report here that cellular pseudokinase tribbles 3 (TRIB3) facilitates the infection of EV-A71 via dual mechanisms. In one hand, TRIB3 maintains the metabolic stability of scavenger receptor class B member 2 (SCARB2), the receptor of EV-A71, to enhance the infectious entry and spreading of the virus. On the other hand, TRIB3 facilitates the replication of EV-A71 RNA in a SCARB2-independent manner. The critical role of TRIB3 in EV-A71 infection and pathogenesis was further demonstrated in mice. In comparison to wild-type C57BL/6 mice, EV-A71 infection in TRIB3 knockdown mice () resulted in significantly lower viral loads in muscular tissues and reduced lethality and severity of clinical scores and tissue pathology. In addition, TRIB3 also promoted the replication of coxsackievirus B3 (CVB3) and coxsackievirus A16 (CVA16) . In conclusion, our results suggest that TRIB3 is one of key host cellular proteins required for the infection and pathogenesis of EV-A71 and some other human enteroviruses and may thus be a potential therapeutic target for combating the infection of those viruses.
Topics: Animals; Child; Humans; Mice; Enterovirus; Enterovirus A, Human; Enterovirus Infections; Hand, Foot and Mouth Disease; Mice, Inbred C57BL
PubMed: 38240287
DOI: 10.1080/22221751.2024.2307514 -
Neurological Research Feb 2024Infections of the central nervous system (CNS) are potentially life-threatening and can cause serious morbidity. We evaluated the clinical value of metagenomic...
BACKGROUND
Infections of the central nervous system (CNS) are potentially life-threatening and can cause serious morbidity. We evaluated the clinical value of metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious encephalitis and meningitis and explored the factors affecting the results of mNGS.
METHODS
Patients with suspected cases of encephalitis or meningitis who presented in Northern Jiangsu People's Hospital from 1 March 2018 to 30 September 2022 were collected. Demographic, historical, and clinical information were obtained, and cerebrospinal fluid (CSF) samples were treated with mNGS. The pathogen was identified using National Center for Biotechnology Information (NCBI) GenBank sequence data.
RESULTS
Ninety-six patients were screened and finally 90 subjects enrolled. Of the 90 enrolled cases, 67 (74.4%) were diagnosed with central nervous system infections, which included 48 cases (71.6%) of viral infection, 11 (12.2%) of bacterial infection, 5 (7.5%) of mycobacterium tuberculosis, 2 (3.0%) of fungal infection, and 1 (1.5%) of rickettsia infection. From these cases, mNGS identified 40 (44.4%) true-positive cases, 3 (3.3%) false-positive case, 22 (24.4%) true-negative cases, and 25 (27.8%) false-negative cases. The sensitivity and specificity of mNGS were 61.5% and 88%, respectively. mNGS of CSF could show a higher positive rate in patients with marked CSF abnormalities, including elevated protein concentrations and monocyte counts.
CONCLUSION
mNGS of CSF is an effective method for detecting infectious encephalitis and meningitis, and the results should be analyzed combined with conventional microbiological testing results.
Topics: Humans; Retrospective Studies; Meningitis; Infectious Encephalitis; Encephalitis; Sensitivity and Specificity; High-Throughput Nucleotide Sequencing
PubMed: 37931016
DOI: 10.1080/01616412.2023.2265243 -
World Journal of Clinical Cases Oct 2023Varicella-zoster virus (VZV) is a common viral infection, but meningitis is a rare complication of VZV infection. The cerebrospinal fluid glucose of viral meningitis is...
BACKGROUND
Varicella-zoster virus (VZV) is a common viral infection, but meningitis is a rare complication of VZV infection. The cerebrospinal fluid glucose of viral meningitis is usually within the normal range, which is different from bacteria, fungi, and cancerous meningitis. This paper reports a case of VZV meningitis with hypoglycorrhachia and the relevant literature was reviewed.
CASE SUMMARY
We report a case of an immunocompetent 39-year-old male, presenting with severe headache and fevers, without meningeal signs or exanthem, found to have VZV meningitis by the metagenomic next-generation sequencing of cerebrospinal fluid. The cerebrospinal fluid analysis revealed hypoglycorrhachia (cerebrospinal fluid glucose of 2.16) and he was treated successfully with intravenous acyclovir. Our literature review identified only ten cases diagnosed with VZV meningitis with hypoglycorrhachia previously reported to date in the English literature whose cerebrospinal fluid glucose was from 1.6 to 2.7mmol/L, with a ratio of cerebrospinal fluid to serum glucose from 0.30 to 0.49.
CONCLUSION
Although rare, the cerebrospinal fluid of patients with VZV meningitis may have hypoglycorrhachia, which broadens the understanding of the disease.
PubMed: 37946771
DOI: 10.12998/wjcc.v11.i29.7101 -
Clinical and Experimental Medicine Oct 2023We sought to explore the relationship between body mass index (BMI) and neurologic outcomes following acute COVID-19 infection. We conducted a retrospective electronic...
We sought to explore the relationship between body mass index (BMI) and neurologic outcomes following acute COVID-19 infection. We conducted a retrospective electronic medical record-based cohort study enrolling adults with laboratory-confirmed acute COVID-19 infection who presented to 1 of 12 academic and community hospitals in Southwestern Ontario, Canada between April 1, 2020 and July 31, 2021. Primary subjective (anosmia, dysgeusia, and/or headache) and objective (aseptic meningitis, ataxia, delirium, encephalopathy, encephalitis, intracranial hemorrhage, ischemic stroke, and/or seizure) composite neurologic outcomes were assessed, comparing obese and overweight individuals to those with underweight/normal BMI indices, adjusting for baseline characteristics. Secondary outcomes (severity of illness, length of hospital stay, SARS-CoV-2 viral load, mortality) were similarly analyzed. A total of 1437 enrolled individuals, of whom 307 (21%), 456 (32%), and 674 (47%) were underweight/normal, overweight, and obese, respectively. On multivariable analysis, there was no association between BMI category and the composite outcome for subjective (odds ratio [OR] 1.17, 95% CI 0.84-1.64, Bonferroni p = 1.00 for obese; OR 1.02, 95% CI 0.70-1.48; Bonferroni p = 1.00 for overweight) and objective (OR 0.74, 95% CI 0.42-1.30, p = 0.29 for obese; OR = 0.80, 95% CI 0.45-1.43, p = 0.45 for overweight) neurologic manifestations. There was no association between BMI category and any secondary outcome measure and no evidence of effect modification by age or sex. This study demonstrates the absence of an association between BMI and neurologic manifestations following acute COVID-19 illness. Prospective studies using standardized data collection tools and direct measures of body fat are warranted to obtain more valid effect estimates.
Topics: Adult; Humans; Body Mass Index; Overweight; COVID-19; Retrospective Studies; Thinness; Prospective Studies; Cohort Studies; SARS-CoV-2; Obesity
PubMed: 36525126
DOI: 10.1007/s10238-022-00965-3 -
Clinical Cancer Research : An Official... May 2024Combination of chemotherapy with programmed cell death 1 (PD-1) blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how...
PURPOSE
Combination of chemotherapy with programmed cell death 1 (PD-1) blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how chemotherapy affects the response of exhausted CD8 T cells to PD-1 blockade.
EXPERIMENTAL DESIGN
We used the well-established mouse model of T-cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of chemotherapy (cisplatin+pemetrexed) on T-cell response to PD-1 blockade, in the absence of the impact of chemotherapy on antigen release and presentation observed in tumor models.
RESULTS
When concomitantly administered with PD-1 blockade, chemotherapy affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of IFNγ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared with PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed chemotherapy, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by chemotherapy partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant chemotherapy, ultimately resulting in impaired overall CD8 T-cell effector functions.
CONCLUSIONS
In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T-cell functions. See related commentary by Vignali and Luke, p. 1705.
Topics: Animals; CD8-Positive T-Lymphocytes; Mice; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Lymphocytic choriomeningitis virus; Disease Models, Animal; Cisplatin; Lymphocytic Choriomeningitis; Humans; Antineoplastic Combined Chemotherapy Protocols; Mice, Inbred C57BL; Lung Neoplasms
PubMed: 37992307
DOI: 10.1158/1078-0432.CCR-23-1316 -
PLoS Pathogens Nov 2023Neuropilin-1 (Nrp-1) expression on CD8+ T cells has been identified in tumor-infiltrating lymphocytes and in persistent murine gamma-herpes virus infections, where it...
Neuropilin-1 (Nrp-1) expression on CD8+ T cells has been identified in tumor-infiltrating lymphocytes and in persistent murine gamma-herpes virus infections, where it interferes with the development of long-lived memory T cell responses. In parasitic and acute viral infections, the role of Nrp-1 expression on CD8+ T cells remains unclear. Here, we demonstrate a strong induction of Nrp-1 expression on CD8+ T cells in Plasmodium berghei ANKA (PbA)-infected mice that correlated with neurological deficits of experimental cerebral malaria (ECM). Likewise, the frequency of Nrp-1+CD8+ T cells was significantly elevated and correlated with liver damage in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. Transcriptomic and flow cytometric analyses revealed a highly activated phenotype of Nrp-1+CD8+ T cells from infected mice. Correspondingly, in vitro experiments showed rapid induction of Nrp-1 expression on CD8+ T cells after stimulation in conjunction with increased expression of activation-associated molecules. Strikingly, T cell-specific Nrp-1 ablation resulted in reduced numbers of activated T cells in the brain of PbA-infected mice as well as in spleen and liver of LCMV-infected mice and alleviated the severity of ECM and LCMV-induced liver pathology. Mechanistically, we identified reduced blood-brain barrier leakage associated with reduced parasite sequestration in the brain of PbA-infected mice with T cell-specific Nrp-1 deficiency. In conclusion, Nrp-1 expression on CD8+ T cells represents a very early activation marker that exacerbates deleterious CD8+ T cell responses during both, parasitic PbA and acute LCMV infections.
Topics: Mice; Animals; Neuropilin-1; Parasites; Malaria, Cerebral; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; CD8-Positive T-Lymphocytes; Mice, Inbred C57BL
PubMed: 38019895
DOI: 10.1371/journal.ppat.1011837 -
Cell Death & Disease Dec 2023Acute infection and chronic infection are the two most common fates of pathogenic virus infections. While several factors that contribute to these fates are described,...
Acute infection and chronic infection are the two most common fates of pathogenic virus infections. While several factors that contribute to these fates are described, the critical control points and the mechanisms that underlie infection fate regulation are incompletely understood. Using the acute and chronic lymphocytic choriomeningitis virus (LCMV) infection model of mice, we find that the early dynamic pattern of the IFN-I response is a differentiating trait between both infection fates. Acute-infected mice generate a 2-wave IFN-I response while chronic-infected mice generate only a 1-wave response. The underlying cause is a temporal difference in CD8 T cell-mediated killing of splenic marginal zone CD169+ macrophages. It occurs later in acute infection and thus enables CD169+ marginal zone macrophages to produce the 2nd IFN-I wave. This is required for subsequent immune events including induction of inflammatory macrophages, generation of effector CD8+ T cells and virus clearance. Importantly, these benefits come at a cost for the host in the form of spleen fibrosis. Due to an earlier marginal zone destruction, these ordered immune events are deregulated in chronic infection. Our findings demonstrate the critical importance of kinetically well-coordinated sequential immune events for acute infection control and highlights that it may come at a cost for the host organism.
Topics: Mice; Animals; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Persistent Infection; Mice, Inbred C57BL; CD8-Positive T-Lymphocytes; Macrophages
PubMed: 38110339
DOI: 10.1038/s41419-023-06374-y -
Fluids and Barriers of the CNS Feb 2024Interpretation of cerebrospinal fluid (CSF) studies can be challenging in preterm infants. We hypothesized that intraventricular hemorrhage (IVH), post-hemorrhagic...
BACKGROUND
Interpretation of cerebrospinal fluid (CSF) studies can be challenging in preterm infants. We hypothesized that intraventricular hemorrhage (IVH), post-hemorrhagic hydrocephalus (PHH), and infection (meningitis) promote pro-inflammatory CSF conditions reflected in CSF parameters.
METHODS
Biochemical and cytological profiles of lumbar CSF and peripheral blood samples were analyzed for 81 control, 29 IVH grade 1/2 (IVH), 13 IVH grade 3/4 (IVH), 15 PHH, 20 culture-confirmed bacterial meningitis (BM), and 27 viral meningitis (VM) infants at 36.5 ± 4 weeks estimated gestational age.
RESULTS
PHH infants had higher (p < 0.02) CSF total cell and red blood cell (RBC) counts compared to control, IVH, BM, and VM infants. No differences in white blood cell (WBC) count were found between IVH, PHH, BM, and VM infants. CSF neutrophil counts increased (p ≤ 0.03) for all groups compared to controls except IVH. CSF protein levels were higher (p ≤ 0.02) and CSF glucose levels were lower (p ≤ 0.003) for PHH infants compared to all other groups. In peripheral blood, PHH infants had higher (p ≤ 0.001) WBC counts and lower (p ≤ 0.03) hemoglobin and hematocrit than all groups except for IVH.
CONCLUSIONS
Similarities in CSF parameters may reflect common pathological processes in the inflammatory response and show the complexity associated with interpreting CSF profiles, especially in PHH and meningitis/ventriculitis.
Topics: Infant; Infant, Newborn; Humans; Infant, Premature; Clinical Relevance; Cerebral Hemorrhage; Hydrocephalus; Central Nervous System Infections; Meningitis; Cerebrospinal Fluid
PubMed: 38383424
DOI: 10.1186/s12987-024-00512-0 -
Journal of the International AIDS... Oct 2023With the scaling up of vertical HIV transmission prevention programmes, the HIV-related population profile of children in South Africa has shifted. We described temporal...
INTRODUCTION
With the scaling up of vertical HIV transmission prevention programmes, the HIV-related population profile of children in South Africa has shifted. We described temporal changes in HIV-related characteristics of children, aged ≤3 years (up to the third birthday), with infectious disease hospitalisations across the Western Cape province.
METHODS
We used routinely collected electronic data to identify children born in the Western Cape with infectious disease hospital records for lower respiratory tract infections, diarrhoea, meningitis and tuberculous meningitis, from 2008 to 2021. Linked maternal and child unique identifiers were used to extract pregnancy, HIV-related, laboratory, pharmacy and hospitalisation data. We described temporal changes in child HIV exposure and acquisition status, timing of maternal HIV diagnosis and antiretroviral therapy (ART) start, infant exposure to maternal ART and timing thereof, and maternal CD4 and HIV viral load closest to delivery. We used logistic and multinomial regression to assess changes in characteristics between the Pre-Option B+ (2008-2013), Option B+ (2013-2016) and Universal ART periods (2016-2021).
RESULTS
Among 52,811 children aged ≤3 years with hospitalisations, the proportion living with HIV dreased from 7.0% (2008) to 1.1% (2021), while those exposed to HIV and uninfected increased from 14.0% (2008) to 16.1% (2021) with a peak of 18.3% in 2017. Among mothers with HIV (n = 9873), the proportion diagnosed with HIV and starting ART before pregnancy increased from 20.2% to 69.2% and 5.8% to 59.0%, respectively, between 2008 and 2021. Children hospitalised during the Universal ART period had eight times higher odds (Odds Ratio: 8.41; 95% CI: 7.36-9.61) of exposure to maternal ART versus children admitted Pre-Option B+. Among mothers of children exposed to HIV and uninfected with CD4 records (n = 7523), the proportion with CD4 <350 cells/μl decreased from 90.6% (2008) to 27.8% (2021).
CONCLUSIONS
In recent years, among children hospitalised with infectious diseases, there were fewer children with perinatally acquired HIV, while an increased proportion of those without HIV acquisition are exposed to maternal HIV and ART. There is a need to look beyond paediatric HIV prevalence and consider child exposure to HIV and ART among children without HIV, when assessing the HIV epidemic's impact on child health services.
Topics: Infant; Pregnancy; Female; Child; Humans; HIV Infections; Pregnancy Complications, Infectious; South Africa; Acquired Immunodeficiency Syndrome; Mothers; Infectious Disease Transmission, Vertical
PubMed: 37909168
DOI: 10.1002/jia2.26151