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Journal of Neuroinflammation Jun 2024Pediatric acute transverse myelitis (ATM) accounts for 20-30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical...
BACKGROUND
Pediatric acute transverse myelitis (ATM) accounts for 20-30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease.
METHODS
We compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response.
RESULTS
We found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis.
CONCLUSIONS
Discordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC.
Topics: Humans; Myelitis, Transverse; Animals; Female; Astrocytes; Child; Mice; Male; Adolescent; Plasma Cells; Autoantibodies; Mice, Inbred C57BL; Cells, Cultured; Child, Preschool; Immunoglobulin G; Spinal Cord
PubMed: 38915059
DOI: 10.1186/s12974-024-03127-2 -
Cureus May 2024Dengue, commonly referred to as 'breakbone fever,' is a mosquito-borne arboviral infection transmitted by , featuring an average incubation period of approximately seven... (Review)
Review
Dengue, commonly referred to as 'breakbone fever,' is a mosquito-borne arboviral infection transmitted by , featuring an average incubation period of approximately seven days. Key cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor (TNF)-α, and interleukin (IL)-10 are pivotal in the pathogenesis of dengue. Travelers are particularly susceptible to contracting dengue fever, with disease severity often associated with CD8+ T cell response. Without proper hospitalization during severe cases like dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS), mortality rates can escalate to 50%. Dengue fever can lead to various complications, including neurological manifestations such as encephalopathy, encephalitis, cerebral venous thrombosis, myelitis, posterior reversible encephalopathy syndrome, strokes (both ischemic and hemorrhagic), immune-mediated neurological syndromes (such as mononeuropathy, acute transverse myelitis, Guillain-Barre syndrome, and acute disseminated encephalomyelitis), and neuromuscular complications. Treatment protocols typically involve assessing disease activity using composite indices, pursuing treatment objectives, and administering intravenous fluids according to symptomatology. Given the absence of specific antiviral treatment for dengue, supportive care, particularly hydration, remains paramount during the early stages. It is crucial to recognize that dengue viruses may contribute to the development of neurological disorders, particularly in regions where dengue is endemic. Furthermore, there is a necessity for well-defined criteria for specific neurological complications. Primary prevention strategies primarily revolve around vector control measures, which play a critical role in curtailing the spread of dengue.
PubMed: 38910682
DOI: 10.7759/cureus.60961 -
Vaccine Jun 2024Standardizing case definitions for priority vaccine safety conditions facilitates uniform evaluation and consolidation of data obtained from different settings. The...
INTRODUCTION
Standardizing case definitions for priority vaccine safety conditions facilitates uniform evaluation and consolidation of data obtained from different settings. The Brighton Collaboration case definitions (BCCD) were created to support this harmonization and enable classification from level 1 (most certain) to level 5 (not a case) of certainty. Assessing the performance of BCCD in practice is critical, particularly in resource-limited settings, where many new vaccines may be introduced without prior monitoring in high-income countries. We assessed the performance of BCCD in Addis Ababa, Ethiopia, as applicable to COVID-19 and other vaccines.
METHODS
Active surveillance was conducted at Tikur Anbessa Specialized Hospital, the largest referral hospital in Ethiopia. During June 1, 2022-May 31, 2023, three trained physicians prospectively identified patients eligible for COVID-19 vaccination (regardless of vaccine receipt) who presented with one or more of eleven pre-specified adverse events of special interest (AESI) from the emergency department and inpatient wards. Standardized data collection forms were used to capture patient information and assign level of certainty (LOC), regardless of vaccination status for COVID-19. We conducted descriptive analysis to characterize cases and the LOCs reached for each AESI.
RESULTS
We detected 203 AESI cases. The most detected conditions were thrombosis and thromboembolism (n = 100, 49 %) and generalized convulsions (n = 38, 19 %). Ninety-six percent of the cases were confirmed at levels 1-3 (n = 187) or level 5 (n = 9) LOC. Non-classifiable (level 4) cases were observed for pericarditis (n = 2), encephalitis (n = 2), myelitis (n = 2), and generalized convulsion (n = 1).
CONCLUSION
The BCCD were successfully applied in > 95 % of cases in a large referral hospital in Ethiopia, with generalized convulsion, pericarditis, and encephalomyelitis as the exceptions. We recommend further evaluation in other low-resource settings, particularly in rural or non-referral hospitals, to gain additional insights into performance of these definitions for revision or adaptation, as needed.
PubMed: 38909000
DOI: 10.1016/j.vaccine.2024.06.046 -
JMIR Public Health and Surveillance Jun 2024Geospatial data reporting from surveillance and immunization efforts is a key aspect of the World Health Organization (WHO) Global Polio Eradication Initiative in...
Geospatial data reporting from surveillance and immunization efforts is a key aspect of the World Health Organization (WHO) Global Polio Eradication Initiative in Africa. These activities are coordinated through the WHO Regional Office for Africa Geographic Information Systems Centre. To ensure the accuracy of field-collected data, the WHO Regional Office for Africa Geographic Information Systems Centre has developed mobile phone apps such as electronic surveillance (eSURV) and integrated supportive supervision (ISS) geospatial data collection programs. While eSURV and ISS have played a vital role in efforts to eradicate polio and control other communicable diseases in Africa, disease surveillance efforts have been hampered by incomplete and inaccurate listings of health care sites throughout the continent. To address this shortcoming, data compiled from eSURV and ISS are being used to develop, update, and validate a Health Facility master list for the WHO African region that contains comprehensive listings of the names, locations, and types of health facilities in each member state. The WHO and Ministry of Health field officers are responsible for documenting and transmitting the relevant geospatial location information regarding health facilities and traditional medicine sites using the eSURV and ISS form; this information is then used to update the Health Facility master list and is also made available to national ministries of health to update their respective health facility lists. This consolidation of health facility information into a single registry is expected to improve disease surveillance and facilitate epidemiologic research for the Global Polio Eradication Initiative, as well as aid public health efforts directed at other diseases across the African continent. This review examines active surveillance using eSURV at the district, country, and regional levels, highlighting its role in supporting polio surveillance and immunization efforts, as well as its potential to serve as a fundamental basis for broader public health initiatives and research throughout Africa.
Topics: World Health Organization; Humans; Poliomyelitis; Africa; Health Facilities; Population Surveillance; Geographic Information Systems; Disease Eradication
PubMed: 38904997
DOI: 10.2196/54250 -
Journal of Central Nervous System... 2024Appropriate treatment reduces the severity and duration of relapses in demyelinating diseases of Central Nervous System (CNS). If high-dose corticosteroids treatment...
BACKGROUND
Appropriate treatment reduces the severity and duration of relapses in demyelinating diseases of Central Nervous System (CNS). If high-dose corticosteroids treatment fails, therapeutic plasma exchange (TPE) is considered as a rescue treatment.
OBJECTIVES
This study aimed to investigate early clinical response and complications of TPE and prognostic factors in CNS demyelinating relapses.
DESIGN
This prospective observational study was designed in a tertiary center during one year.
METHODS
All adult patients diagnosed corticosteroid-resistant Multiple Sclerosis (MS), NeuroMyelitis Optica Spectrum Disorder (NMOSD), idiotypic Transverse Myelitis or Clinical Isolated Syndrome relapses, were eligible. Clinical response is defined based on Expanded Disability Status Scale (EDSS) at discharge. Clinical and laboratory complications recorded.
RESULTS
Seventy-two patients were analyzed which 58.3% patients were female. MS was diagnosed for 61.1% of cases. Thirty-five patients (48.6%) responded and the mean differences of EDSS significantly decreased 0.60 score (CI95%:0.44-.77). Electrolyte imbalances and thrombocytopenia occurred in 80.6% and 55.6% of cases respectively and 40.3% of patients had systemic reactions. However, 26.4% patients experienced moderate to severe complications. In patients with moderate to severe disability, responders were younger (MD: 8.42 years, CI95%: 1.67-15.17) and had lower EDSS score at admission (median:6, IQR: 5.5-6 against 7.5 IQR: 6.5-8). The risk of failure was higher in active progressive MS patients compared with RRMS patients (OR: 6.06, CI 95%:1.37-26.76). Patients with thrombocytopenia were hospitalized more than others (MD: 1.5 days, CI 95%: 0-3). Females were more prone to hypokalemia and systemic reactions (OR: 3.11, CI 95%:1.17-8.24 and OR: 6.67, CI 95%:2.14-20.81 respectively).
CONCLUSION
The most common indication of TPE was corticosteroid-resistant severe MS relapses. About half of the patients presented an early clinical response. Lower disability, younger age and RRMS diagnosis are prognostic factors of better response. One out of four patients experienced moderate to severe complications, mainly electrolyte imbalances and systemic reactions. Appropriate interventions against these complications should be considered during TPE, especially in females.
PubMed: 38903856
DOI: 10.1177/11795735241262738 -
Enfermedades Infecciosas Y... Jun 2024
PubMed: 38902158
DOI: 10.1016/j.eimce.2024.04.008 -
Science (New York, N.Y.) Jun 20242024 target of ending all transmission will likely be missed.
2024 target of ending all transmission will likely be missed.
Topics: Humans; Afghanistan; Disease Eradication; Pakistan; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Vaccination
PubMed: 38900881
DOI: 10.1126/science.adr1507 -
Cancer Medicine Jun 2024Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective...
INTRODUCTION
Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center.
METHODS
All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan-Meier method.
RESULTS
Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti-PD-1 plus anti-CTLA-4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes-related ketoacidosis (n = 8), immune-related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2-6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0-NA).
CONCLUSION
The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long-term survival.
Topics: Humans; Immune Checkpoint Inhibitors; Male; Female; Intensive Care Units; Retrospective Studies; Middle Aged; Aged; Neoplasms; Adult; Incidence; Drug-Related Side Effects and Adverse Reactions; Aged, 80 and over; CTLA-4 Antigen
PubMed: 38899457
DOI: 10.1002/cam4.7302 -
The Neurohospitalist Jul 2024Elsberg Syndrome is a presumed infectious lumbosacral radiculitis, with or without accompanying lumbar myelitis, that is often attributed to herpes simplex virus type 2...
INTRODUCTION
Elsberg Syndrome is a presumed infectious lumbosacral radiculitis, with or without accompanying lumbar myelitis, that is often attributed to herpes simplex virus type 2 (HSV-2).
CASE
A 58-year-old man presented with lower extremity anesthesia, ataxic gait, radiological evidence of radiculitis, and CSF albuminocytologic dissociation. Polymerase chain reaction testing of CSF confirmed HSV-2 infection.
CONCLUSION
A variety of presentations are reported within the scope of Elsberg Syndrome, potentially with distinct disease mechanisms. Delayed onset of neurological symptoms after resolution of rash and absence of pleocytosis raises the possibility that some patients meeting criteria for Elsberg Syndrome have a post-infectious immune-mediated neuropathy. We advise a lower threshold for PCR testing of herpes viruses in patients with acute neuropathy and albuminocytologic dissociation, particularly in cases with early sacral involvement.
PubMed: 38895011
DOI: 10.1177/19418744241233621 -
Journal of Virology Jun 2024Enterovirus D68 (EV-D68) is a picornavirus associated with severe respiratory illness and a paralytic disease called acute flaccid myelitis in infants. Currently, no...
UNLABELLED
Enterovirus D68 (EV-D68) is a picornavirus associated with severe respiratory illness and a paralytic disease called acute flaccid myelitis in infants. Currently, no protective vaccines or antivirals are available to combat this virus. Like other enteroviruses, EV-D68 uses components of the cellular autophagy pathway to rewire membranes for its replication. Here, we show that transcription factor EB (TFEB), the master transcriptional regulator of autophagy and lysosomal biogenesis, is crucial for EV-D68 infection. Knockdown of TFEB attenuated EV-D68 genomic RNA replication but did not impact viral binding or entry into host cells. The 3C protease of EV-D68 cleaves TFEB at the N-terminus at glutamine 60 (Q60) immediately post-peak viral RNA replication, disrupting TFEB-RagC interaction and restricting TFEB transport to the surface of the lysosome. Despite this, TFEB remained mostly cytosolic during EV-D68 infection. Overexpression of a TFEB mutant construct lacking the RagC-binding domain, but not the wild-type construct, blocks autophagy and increases EV-D68 nonlytic release in H1HeLa cells but not in autophagy-defective ATG7 KO H1HeLa cells. Our results identify TFEB as a vital host factor regulating multiple stages of the EV-D68 lifecycle and suggest that TFEB could be a promising target for antiviral development against EV-D68.
IMPORTANCE
Enteroviruses are among the most significant causes of human disease. Some enteroviruses are responsible for severe paralytic diseases such as poliomyelitis or acute flaccid myelitis. The latter disease is associated with multiple non-polio enterovirus species, including enterovirus D68 (EV-D68), enterovirus 71, and coxsackievirus B3 (CVB3). Here, we demonstrate that EV-D68 interacts with a host transcription factor, transcription factor EB (TFEB), to promote viral RNA(vRNA) replication and regulate the egress of virions from cells. TFEB was previously implicated in the viral egress of CVB3, and the viral protease 3C cleaves TFEB during infection. Here, we show that EV-D68 3C protease also cleaves TFEB after the peak of vRNA replication. This cleavage disrupts TFEB interaction with the host protein RagC, which changes the localization and regulation of TFEB. TFEB lacking a RagC-binding domain inhibits autophagic flux and promotes virus egress. These mechanistic insights highlight how common host factors affect closely related, medically important viruses differently.
PubMed: 38888347
DOI: 10.1128/jvi.00556-24