The #neonatal Fc #receptor is a pan- #echovirus receptor (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

The neonatal Fc receptor is a pan-echovirus receptor

Stefanie Morosky, Alexandra I. Wells, Kathryn Lemon, Azia S. Evans, Sandra Schamus, Christopher J. Bakkenist, and Carolyn B. Coyne

PNAS published ahead of print February 11, 2019 / DOI: https://doi.org/10.1073/pnas.1817341116

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved January 9, 2019 (received for review October 8, 2018)

 

Significance

Echoviruses are associated with aseptic meningitis and induce severe and sometimes fatal disease in neonates and young infants. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. FcRn is expressed on the surface of the human placenta, and throughout life on intestinal enterocytes, liver hepatocytes, and in the microvascular endothelial cells that line the blood–brain barrier. This pattern of expression is consistent with the organ sites targeted by echoviruses in humans, as the primary entry site of infection is the intestinal and secondary sites of infection include the liver and brain. These findings provide important insights into echovirus pathogenesis and may explain the enhanced susceptibility of neonates to echovirus-induced disease.

 

Abstract

Echoviruses are amongst the most common causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease, including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglobulin (β2M) renders cells resistant to infection by a panel of echoviruses at the stage of virus attachment, and that a blocking antibody to β2M inhibits echovirus infection in cell lines and in primary human intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders nonpermissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echovirus particles and neutralizes infection. Lastly, we show that neonatal mice expressing human FcRn are more susceptible to echovirus infection by the enteral route. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.

echovirus – neonatal Fc receptor – enterovirus – virus receptor – FcRn

 

Footnotes

1 S.M. and A.I.W. contributed equally to this work.

2 To whom correspondence should be addressed. Email: coynec2@pitt.edu.

Author contributions: A.I.W., K.L., C.J.B., and C.B.C. designed research; S.M., A.I.W., K.L., A.S.E., S.S., C.J.B., and C.B.C. performed research; S.M., A.I.W., K.L., A.S.E., S.S., C.J.B., and C.B.C. analyzed data; and S.M., A.I.W., A.S.E., C.J.B., and C.B.C. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1817341116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Enterovirus; Echovirus; Pediatrics.

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#Neurological #Complications of #Congenital #Zika Virus #Infection (Pediatr Neurol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Pediatr Neurol. 2018 Nov 22. pii: S0887-8994(18)30685-4. doi: 10.1016/j.pediatrneurol.2018.11.003. [Epub ahead of print]

Neurological Complications of Congenital Zika Virus Infection.

Marques VM1, Santos CS2, Santiago IG3, Marques SM1, Nunes Brasil MDG3, Lima TT4, Costa PS5.

Author information: 1 Department of Pediatrics, School of Medicine, Universidade Federal de Goiás – UFG, Goiânia, GO, Brazil. 2 Department of Pediatric Neurology, Universidade Federal de São Paulo – UNIFESP, São Paulo, SP, Brazil. 3 Department of Pediatric Neurology, Hospital das Clínicas, Universidade Federal de Goiás – UFG, Goiânia, GO, Brazil. 4 Department of Ophtalmology, Hospital das Clínicas, Universidade Federal de Goiás – UFG, Goiânia, GO, Brazil. 5 Department of Pediatrics, School of Medicine, Universidade Federal de Goiás – UFG, Goiânia, GO, Brazil. Electronic address: paulosucasas@ufg.br.

 

Abstract

BACKGROUND:

In utero Zika virus infection resulted in many newborns with congenital defects; this public health issue was followed by unprecedented scientific productivity in this field. Many questions remain about congenital Zika virus infection and its maternal transmission, pathogenesis, clinical events, and the resulting neurological damage. There are few review articles that synthesize the current knowledge of congenital neurological complications as well as the gaps in the pediatric literature.

OBJECTIVE:

We review the full range of data on neurological complications in the newborns and infants born to Zika virus-infected women.

METHODS:

A research question (PCC: Population, newborns and infants of infected mothers; Concept, neurological outcomes at birth; Context, congenital Zika virus infection) was created to guide our review in searching several databases: PubMed, Lilacs, CINAHL, Cochrane Library, and OpenGrey literature. A total of 34 articles were included in the final review.

RESULTS:

Central nervous system calcifications, mainly at the cortical-subcortical junction, were the most prevalent neurological birth defects related to Zika infection (104/112, 92.9% from seven studies). Also, microcephaly occurred in 39.7% of all infected infants (1561/3931 patients in all the studies) and ventriculomegaly and/or hydrocephalus occurred in 63.1% (157/249 patients analyzed in 12 studies). A total of 10 articles detailed ocular findings, including macular lesions, focal pigment mottling of the retina, chorioretinal atrophy, optic nerve abnormalities, cataract, microphthalmia, and strabismus, among others.

CONCLUSIONS:

Neurological and related malformations are common lesions in individuals with congenital Zika syndrome. Long-term follow-up studies in this field are lacking.

Copyright © 2018 Elsevier Inc. All rights reserved.

KEYWORDS: Zika virus infection; congenital; infant; microcephaly; newborn

PMID: 30591235 DOI: 10.1016/j.pediatrneurol.2018.11.003

Keywords: Zika Virus; Zika Congenital Infection; Neurology; Pediatrics.

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#Surveillance of #enteroviruses from #paediatric patients attended at a tertiary #hospital in #Catalonia from 2014 to 2017 (J Clin Virol., abstract)

[Source: Science Direct, full page: (LINK). Abstract, edited.]

Journal of Clinical Virology / Available online 30 November 2018 / In Press, Accepted Manuscript

Surveillance of enteroviruses from paediatric patients attended at a tertiary hospital in Catalonia from 2014 to 2017

Cristina Andrés a, Jorgina Vila b, Laura Gimferrer a , Maria Piñana a, Juliana Esperalba a, Maria Gema Codina a, Meritxell Barnés b, Mariadel Carmen Martín a, Francisco Fuentes a, Susana Rubio a, Pilar Alcubilla a, Carlos Rodrigo b, Tomàs Pumarola a, Andrés Antón a

{a} Respiratory Viruses Unit, Virology Section, Microbiology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; {b} Paediatric Hospitalisation Unit, Department of Paediatrics, Hospital Universitari Maternoinfantil Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Received 4 September 2018, Revised 26 October 2018, Accepted 16 November 2018, Available online 30 November 2018.

DOI: https://doi.org/10.1016/j.jcv.2018.11.004

 

Highlights

  • The study reports virological and clinical enterovirus surveillance in Catalonia.
  • The four enterovirus species cocirculated, distinguishing up to 27 different types.
  • Most of neurological studied cases were from the 2016 spring outbreak.
  • EV-A71 was one of the most detected EV, mostly during the outbreak.
  • Rhombencephalitis cases were related to EV-A71 infection.
  • EV-D68 was associated with lower respiratory tract infections.
  • Necessity to perform EV surveillance in primary care settings.

 

Abstract

Background

Enterovirus (EV) infections are usually asymptomatic or mild, but symptomatic infections can evolve to severe complications. Outbreaks of EV-A71 and EV-D68 have been recently reported worldwide, sometimes related to severe clinical outcomes.

Objective

To describe EV genetic diversity and the clinical outcomes from paediatric patients attended at a tertiary university hospital in Barcelona (Catalonia, Spain) from 2014 to 2017.

Study design

Specimens were collected from paediatric (<17 years old) cases with suspicion of respiratory tract infection or EV infection. EV laboratory-confirmation was performed by specific real-time multiplex RT-PCR assay. Partial viral VP1 protein was sequenced for genetic characterisation by phylogenetic analyses.

Results

A total of 376 (7%) from 5,703 cases were EV laboratory-confirmed. Phylogenetic analyses of VP1 (210; 81%) sequences distinguished up to 27 different EV types distributed within EV-A (82; 40%), EV-B (90; 42%), EV-C (5; 2%), and EV-D (33; 15%), in addition to 50 (19%) rhinoviruses. The most predominant were EV-A71 (37; 45%) and EV-D68 (32; 99%). EV-A71 was highly related to neurological complications (25/39, 63%), of which 20/39 were rhombencephalitis, and most EV-D68 (28/32, 88%) were associated with lower respiratory tract infections (LRTI), and exceptionally one (3%) with flaccid paralysis.

Conclusions

EV-A71 and EV-D68 were the most detected EV in respiratory specimens. EV-A71 was highly related to neurological disease and EV-D68 was often associated with LRTI. However, both potential relatedness to neurological diseases makes the monitoring of EV circulation obligatory.

Keywords: enteroviruses – respiratory infections – surveillance – genetic diversity – molecular epidemiology – paediatric population

© 2018 Elsevier B.V. All rights reserved.

Keywords: Enterovirus; EV-A71; EV-D68; Rhomboencephalitis; AFP; Spain.

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#Effectiveness of #influenza #vaccination on influenza-associated #hospitalisations over time among #children in #HK: a test-negative case-control study (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Effectiveness of influenza vaccination on influenza-associated hospitalisations over time among children in Hong Kong: a test-negative case-control study

Shuo Feng, PhD *, Susan S Chiu, MD *, Eunice L Y Chan, BA, Mike Y W Kwan, MBBS, Joshua S C Wong, MBBS, Chi-Wai Leung, MBBS, Yiu Chung Lau, BSc, Sheena G Sullivan, PhD, Prof J S Malik Peiris, PhD, Prof Benjamin J Cowling, PhD

Published: November 12, 2018 / DOIhttps://doi.org/10.1016/S2213-2600(18)30419-3

 

Summary

Background

The protection conferred by influenza vaccination is generally thought to last less than a year, necessitating annual revaccination. However, the speed with which influenza vaccine effectiveness might decline during a year is unknown, which is of particular importance for locations with year-round influenza activity. We aimed to assess how influenza vaccine effectiveness changes by time intervals between vaccination and admission to hospital, taking advantage of almost year-round circulation of influenza in Hong Kong.

Methods

In this test-negative case-control study, we analysed vaccine effectiveness in children (aged 6 months to 17 years) who were admitted to hospital in Hong Kong over 5 consecutive years (2012–17). We included those who were admitted to general wards in four public hospitals in Hong Kong with a fever (≥38°C) and any respiratory symptom, such as runny nose, cough, or sore throat. We used direct immunofluorescence assay and reverse transcription PCR to detect influenza virus infection, and recorded children’s influenza immunisation history. We compared characteristics of positive cases and negative controls and examined how vaccine effectiveness changed by time between vaccination and admission to hospital with regression analyses.

Findings

Between Sept 1, 2012, and Aug 31, 2017, we enrolled 15 695 children hospitalised for respiratory infections, including 2500 (15·9%) who tested positive for influenza A or B and 13 195 (84·1%) who tested negative. 159 (6·4%) influenza-positive cases and 1445 (11·0%) influenza-negative cases had been vaccinated. Most vaccinations were done by December of each influenza vaccination season. Influenza-related admissions to hospital occurred year-round, with peaks in January through March in most years and a large summer peak in 2016; pooled vaccine effectiveness for children of all ages was 79% (95% CI 42–92) for September to December, 67% (57–74) for January to April, and 43% (25–57) for May to August. Vaccine effectiveness against influenza A or B was estimated as 79% (95% CI 64–88) within 0·5–2 months of vaccination, 60% (46–71) within >2–4 months, 57% (39–70) within >4–6 months, and 45% (22–61) within >6–9 months. In separate analyses by type and subtype, we estimated that vaccine effectiveness declined by 2–5 percentage points per month.

Interpretation

Influenza vaccine effectiveness decreased during the 9 months after vaccination in children in Hong Kong. Our findings confirm the importance of annual vaccination in children. Influenza vaccines that provide broader and longer-lasting protection are needed to provide year-round protection in regions with irregular influenza seasonality or lengthy periods of influenza activity.

Funding

Health and Medical Research Fund, Hong Kong and the Research Grants Council, Hong Kong.

Keywords: Seasonal Influenza; Vaccines; HK.

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#Paediatric #ARDS #incidence and #epidemiology (PARDIE): an international, observational study (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): an international, observational study

Robinder G Khemani, MD, Lincoln Smith, MD, Yolanda M Lopez-Fernandez, MD, Jeni Kwok, JD, Rica Morzov, RN, Margaret J Klein, MS, Nadir Yehya, MD, Prof Douglas Willson, MD, Martin C J Kneyber, MD, Jon Lillie, MBBS, Analia Fernandez, MD, Prof Christopher J L Newth, MD, Prof Philippe Jouvet, MD, Prof Neal J Thomas, MD, on behalf of thePediatric Acute Respiratory Distress syndrome Incidence and Epidemiology (PARDIE) Investigators† and thePediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network

Published: October 22, 2018 / DOI: https://doi.org/10.1016/S2213-2600(18)30344-8

 

Summary

Background

Paediatric acute respiratory distress syndrome (PARDS) is associated with high mortality in children, but until recently no paediatric-specific diagnostic criteria existed. The Pediatric Acute Lung Injury Consensus Conference (PALICC) definition was developed to overcome limitations of the Berlin definition, which was designed and validated for adults. We aimed to determine the incidence and outcomes of children who meet the PALICC definition of PARDS.

Methods

In this international, prospective, cross-sectional, observational study, 145 paediatric intensive care units (PICUs) from 27 countries were recruited, and over a continuous 5 day period across 10 weeks all patients were screened for enrolment. Patients were included if they had a new diagnosis of PARDS that met PALICC criteria during the study week. Exclusion criteria included meeting PARDS criteria more than 24 h before screening, cyanotic heart disease, active perinatal lung disease, and preparation or recovery from a cardiac intervention. Data were collected on the PICU characteristics, patient demographics, and elements of PARDS (ie, PARDS risk factors, hypoxaemia severity metrics, type of ventilation), comorbidities, chest imaging, arterial blood gas measurements, and pulse oximetry. The primary outcome was PICU mortality. Secondary outcomes included 90 day mortality, duration of invasive mechanical and non-invasive ventilation, and cause of death.

Findings

Between May 9, 2016, and June 16, 2017, during the 10 study weeks, 23 280 patients were admitted to participating PICUs, of whom 744 (3·2%) were identified as having PARDS. 95% (708 of 744) of patients had complete data for analysis, with 17% (121 of 708; 95% CI 14–20) mortality, whereas only 32% (230 of 708) of patients met Berlin criteria with 27% (61 of 230) mortality. Based on hypoxaemia severity at PARDS diagnosis, mortality was similar among those who were non-invasively ventilated and with mild or moderate PARDS (10–15%), but higher for those with severe PARDS (33% [54 of 165; 95% CI 26–41]). 50% (80 of 160) of non-invasively ventilated patients with PARDS were subsequently intubated, with 25% (20 of 80; 95% CI 16–36) mortality. By use of PALICC PARDS definition, severity of PARDS at 6 h after initial diagnosis (area under the curve [AUC] 0·69, 95% CI 0·62–0·76) discriminates PICU mortality better than severity at PARDS diagnosis (AUC 0·64, 0·58–0·71), and outperforms Berlin severity groups at 6 h (0·64, 0·58–0·70; p=0·01).

Interpretation

The PALICC definition identified more children as having PARDS than the Berlin definition, and PALICC PARDS severity groupings improved the stratification of mortality risk, particularly when applied 6 h after PARDS diagnosis. The PALICC PARDS framework should be considered for use in future epidemiological and therapeutic research among children with PARDS.

Funding

University of Southern California Clinical Translational Science Institute, Sainte Justine Children’s Hospital, University of Montreal, Canada, Réseau en Santé Respiratoire du Fonds de Recherche Quebec-Santé, and Children’s Hospital Los Angeles, Department of Anesthesiology and Critical Care Medicine.

Keywords: ARDS; Pediatrics.

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#Risk of #Infection and #Sepsis in #Pediatric Patients with Traumatic #Brain #Injury Admitted to Hospital Following Major Trauma (Sci Rep., abstract)

[Source: Scientific Reports, fu ll page: (LINK). Abstract, edited.]

Risk of Infection and Sepsis in Pediatric Patients with Traumatic Brain Injury Admitted to Hospital Following Major Trauma

Anjli Pandya, Kathleen Helen Chaput, Andrea Schertzer, Diane Moser, Jonathan Guilfoyle, Sherry MacGillivray, Jaime Blackwood, Ari R. Joffe & Graham C. Thompson

Scientific Reports, volume 8, Article number: 9798 (2018)

 

Abstract

Head injury accounts for 29% of all traumatic deaths in children. Sepsis is significantly associated with an increased risk of mortality in adult traumatic brain injury patients. In the pediatric population, this relationship is not well understood. The objective of this study was to compare the proportion of pediatric traumatic brain injury (TBI) patients and trauma patients without brain injury (NTBI) who developed sepsis or any infection during their index hospital admission. We performed a retrospective study of all trauma patients <18 years of age, admitted to trauma centres in Alberta, Canada from January 1, 2003 to December 31, 2012. Patients who died within 24 hrs of trauma (n = 147) and those with burns as the primary mechanism of injury (n = 53) were excluded. Hospital admission data for the remaining 2556 patients was analyzed. 1727 TBI patients and 829 NTBI patients were included. TBI was associated with lower odds of developing sepsis (OR 0.32 95% CI 0.14–0.77 p = 0.011). TBI was not found to be independently associated with developing any infectious complication after adjusting for confounding by Injury Severity Score (OR 1.25 95% CI 0.90–1.74 p = 0.180). These relationships warrant further study.

Keywords: Sepsis; Neurology.

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Postnatal #Zika virus #infection is associated with persistent abnormalities in #brain #structure, function, and behavior in #infant #macaques (Sci Transl Med., abstract)

[Source: Science Translational Medicine, full page: (LINK). Abstract, edited.]

Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques

Maud Mavigner1,  Jessica Raper2,  Zsofia Kovacs-Balint2, Sanjeev Gumber2, Justin T. O’Neal3, Siddhartha K. Bhaumik1, Xiaodong Zhang2, Jakob Habib1, Cameron Mattingly1, Circe E. McDonald3, Victoria Avanzato1, Mark W. Burke4, Diogo M. Magnani5, Varian K. Bailey5, David I. Watkins5, Thomas H. Vanderford2, Damien Fair6, Eric Earl6, Eric Feczko6, Martin Styner7, Sherrie M. Jean2, Joyce K. Cohen2, Guido Silvestri2,8, R. Paul Johnson2, David H. O’Connor9, Jens Wrammert1, Mehul S. Suthar1,3, Mar M. Sanchez2,10, Maria C. Alvarado2,10 and Ann Chahroudi1,2,11,*

1 Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA. 2 Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA. 3 Emory Vaccine Center, Atlanta, GA 30329, USA. 4 Department of Physiology and Biophysics, Howard University, Washington, DC 20060, USA. 5 Department of Pathology, University of Miami, Miami, FL 33146, USA. 6 Oregon Health and Science University, Portland, OR 97239, USA. 7 Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA. 8 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. 9 Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA. 10 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA. 11 Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA.

*Corresponding author. Email: achahro@emory.edu

Science Translational Medicine  04 Apr 2018: Vol. 10, Issue 435, eaao6975 / DOI: 10.1126/scitranslmed.aao6975

 

Postnatal perturbation by Zika virus

Much of the concern surrounding Zika virus infections focuses on fetuses infected in utero. Mavigner et al. reasoned that this neurotropic virus may have deleterious effects even after birth, so they set up a postnatal infection model to investigate. They found that infant rhesus macaques infected with Zika virus also had peripheral and central nervous system pathology. Longitudinal magnetic resonance imaging studies revealed that macaques that had been infected with Zika virus had structural and functional abnormalities and also altered emotional responses. These differences persisted months after the virus had been cleared. Although the work involved a small number of animals, their results suggest that infants and young children exposed to Zika virus should undergo more than just routine monitoring.

 

Abstract

The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid tropism and neurotropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain areas involved in emotional behavior and arousal functions, including weakened amygdala-hippocampal connectivity in two of two ZIKV-infected infant RMs several months after clearance of ZIKV RNA from peripheral blood. ZIKV infection also results in distinct alterations in the species-typical emotional reactivity to acute stress, which were predicted by the weak amygdala-hippocampal FC. We demonstrate that postnatal ZIKV infection of infants in this model affects neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted.

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
http://www.sciencemag.org/about/science-licenses-journal-article-reuse

This is an article distributed under the terms of the Science Journals Default License.

Keywords: Zika Virus; Pediatrics; Neuroinvasion.

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