Infections In Early Infancy Research Articles

Neurodevelopmental outcomes following possible serious bacterial infection in early infancy in Karachi, Pakistan: a prospective cohort study

BackgroundPakistan reports a significant burden of neonatal mortality, with infections as one of the major causes. We aim to assess the long-term impact of early infancy infections on neurodevelopmental outcomes during later childhood.MethodsWe conducted a prospective follow-up study of the cohort enrolled at the Karachi site of the Aetiology of Neonatal Infection in South Asia (ANISA) during 2019–2020. Children with a possible serious bacterial infection (based on the WHO IMCI algorithm) at early infancy were assessed for neurodevelopment at 6–9 years of age and compared with healthy controls. The Ten Questions (TQS) questionnaire, Strengths and Difficulties Questionnaire (SDQ), and Parent’s Evaluation of Developmental Stage Assessment Level (PEDS: DM-AL) neurodevelopmental assessment tools, were administered and scored by the research staff who were blinded to the child’s exposure status. Generalized Structural Equation Modelling (GSEM) was employed to verify relationships and associations among developmental milestones, anthropometry, and sociodemographic variables.ResultsA total of 398 children (241 cases and 157 controls) completed neurodevelopmental and growth assessments. Cases had a significantly higher rate of abnormal TQS scores (54.5% vs. 35.0%, p-value 0.001), greater delays in motor milestones (21.2% vs. 12.1%, p-value 0.02), lower fine motor skills (78.4 ± 1.4 vs. 83.2 ± 1.5, p-value 0.02). The receptive language skills were well-developed in both groups. According to the logistic regression model, exposure to infection during the first 59 days of life was associated with delayed TQS milestones (β = -0.6, 95% CI -1.2,-0.04), TQS hearing domain (β = -0.3, 95% CI: -1.2 to 0.7), PEDS: DM-AL fine motor domain (β = -1.3, 95% CI: -4.4 to 1.7), PEDS: DM-AL receptive language development (β = -1.1, 95% CI: -3.7 to 1.4) and child anthropometric measurements such as weight and height (β = -0.2, 95% CI: -0.4 to 0.01 and β = -0.2, 95% CI: -0.4 to -0.01, respectively). Early pSBI exposure was positively associated with PEDS: DM-AL self-help domain (β = 0.6, 95% CI: -1.2 to 2.4) and SDQ-P overall score (β = 0.02, 95% CI: -0.3 to 0.3).ConclusionChildren exposed to PSBI during early infancy have higher rates of abnormal development, motor delays, and lower fine motor skills during later childhood in Pakistan. Socioeconomic challenges and limited healthcare access contribute to these challenges, highlighting the need for long-term follow-ups with integrated neurodevelopment assessments.

Effects of COVID-19 pandemic–associated reduction in respiratory infections on infantile asthma development

BackgroundIt is speculated that the COVID-19 pandemic associated reduction in the prevalence of respiratory tract infections has influenced on the incidence of asthma in infants. ObjectivesWe investigated an association between the reduction in viral infections and the reduction in asthma in infants. MethodsThe subjects were infants born in the early stages of the COVID-19 pandemic in Japan, which began in February 2020. A questionnaire survey related to asthma and allergy was conducted at 18 months and 3 years old. These results were compared to those of age-matched infants during the non-pandemic period. ResultsThere were no epidemics of viral infectious diseases until the target child was 18 months old. At 18 months, the incidence of asthma/asthmatic bronchitis diagnosed by physicians in pandemic infants was significantly lower than that in non-pandemic infants. In 3-year-old infants, no marked difference was observed between non-pandemic infants and pandemic infants, except for an increase in RSV infection in pandemic infants. In a comparative study of the same infants at 18 months and 3 years old, an increased prevalence of asthma/asthmatic bronchitis was observed in pandemic infants. Furthermore, the incidence of asthma after RSV infection in pandemic infants was significantly lower than that in non-pandemic infants. ConclusionThe COVID-19 pandemic-associated reduction in respiratory tract infections may have reduced the incidence of asthma in infancy, and RSV infection after 18 months old had little effect on the onset of asthma. These results indicate the importance of preventing respiratory tract infections in early infancy.

A Case Report on Unusual Manifestations of Acquired Cytomegalovirus Infection in Preterm Baby

Cytomegalovirus (CMV) infection in early infancy arises more commonly as congenital infection or less commonly is acquired postnatally, although exact differentiation between both categories could be difficult. We hereby describe the case of severe CMV infection in a 2-month-old infant who was born prematurely of a twin pregnancy at 29.4 weeks. The baby presented with an array of skin manifestations comprising target lesions, papulovesicles, ulcers, and crusting along with systemic involvement (bronchopneumonia). We report this case to highlight the various unusual cutaneous manifestations of CMV infection in infancy and to raise the awareness among clinicians for the early diagnosis and prompt treatment.

High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity.

Thymic stromal lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1-24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as 'high TSLP' or 'low TSLP' for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflammatory chemokines. These findings present a new paradigm underlying the production of TSLP in the human infant airway epithelium following early life viral exposure and shed light on the long-term impact of viral respiratory illnesses during early infancy and beyond childhood.

Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK

Mutations affecting T-cell receptor (TCR) signaling typically cause combined immunodeficiency (CID) due to varying degrees of disturbed T-cell homeostasis and differentiation. Here, we describe two cousins with CID due to a novel nonsense mutation in LCK and investigate the effect of this novel nonsense mutation on TCR signaling, T-cell function, and differentiation.Patients underwent clinical, genetic, and immunological investigations. The effect was addressed in primary cells and LCK-deficient T-cell lines after expression of mutated LCK.ResultsBoth patients primarily presented with infections in early infancy. The LCK mutation led to reduced expression of a truncated LCK protein lacking a substantial part of the kinase domain and two critical regulatory tyrosine residues. T cells were oligoclonal, and especially naïve CD4 and CD8 T-cell counts were reduced, but regulatory and memory including circulating follicular helper T cells were less severely affected. A diagnostic hallmark of this immunodeficiency is the reduced surface expression of CD4. Despite severely impaired TCR signaling mTOR activation was partially preserved in patients’ T cells. LCK-deficient T-cell lines reconstituted with mutant LCK corroborated partially preserved signaling. Despite detectable differentiation of memory and effector T cells, their function was severely disturbed. NK cell cytotoxicity was unaffected.Residual TCR signaling in LCK deficiency allows for reduced, but detectable T-cell differentiation, while T-cell function is severely disturbed. Our findings expand the previous report on one single patient on the central role of LCK in human T-cell development and function.Graphical

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India.

BackgroundSevere Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce.ObjectiveTo describe clinical and laboratory features of SCID diagnosed at immunology centers across India.MethodsA detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID.ResultsWe obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9), PNP (3), RFXAP (3), CIITA (2), RFXANK (2), NHEJ1 (2), CD3E (2), CD3D (2), RFX5 (2), ZAP70 (2), STK4 (1), CORO1A (1), STIM1 (1), PRKDC (1), AK2 (1), DOCK2 (1), and SP100 (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%).ConclusionWe document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.

First-in-human administration of a live-attenuated RSV vaccine lacking the G-protein assessing safety, tolerability, shedding and immunogenicity: a randomized controlled trial

BackgroundHuman respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent morbidity and mortality amongst infants and young children but could also reduce transmission to elderly. The RSVΔG vaccine consists of a live-attenuated RSV that lacks the G attachment protein. RSVΔG is severely impaired in binding to host cells and exhibits reduced infectivity in preclinical studies. Intranasal immunization of cotton rats with RSVΔG vaccine protected against replication of wildtype RSV, without inducing enhanced disease. MethodsWe performed a first-in-human trial with primary objective to evaluate safety and shedding of RSVΔG (6.5 log10 CCID50) after intranasal administration. Healthy adults aged between 18 and 50, with RSV neutralizing serum titers below 9.6 log2, received a single dose of either vaccine or placebo (n = 48, ratio 3:1). In addition to safety and tolerability, nasal viral load, and systemic and humoral immune responses were assessed at selected time points until 4 weeks after immunization. ResultsIntranasal administration of RSVΔG was well tolerated with no findings of clinical concern. No infectious virus was detected in nasal wash samples. Similar to other live-attenuated RSV vaccines, neutralizing antibody response following inoculation was limited in seropositive adults. ConclusionsA single dose of 6.5 log10 CCID50 of RSVΔG was safe and well-tolerated in seropositive healthy adults. RSVΔG was sufficiently attenuated but there were no signs of induction of antibodies. Safety and immunogenicity can now be explored in children and eventually in seronegative infants.Clinical trial register: NTR7173/EudraCT number 2016‐002437‐30.

Nucleic Acid Testing for Diagnosis of Perinatally Acquired Hepatitis C Virus Infection in Early Infancy.

Most US children with perinatal hepatitis C virus (HCV) exposure fail to receive the recommended anti-HCV antibody test at age ≥18 months. Earlier testing for viral RNA might facilitate increased screening, but sensitivity of this approach has not been established. We hypothesized that modern HCV-RNA RT-PCR platforms would adequately detect infected infants. Nationwide Children's Hospital electronic health records from 1/1/2008 to 30/6/2018 were reviewed to identify perinatally exposed infants tested by HCV-RNA RT-PCR at age 2-6 months. Diagnostic performance was determined using a composite case definition: (1) infected children had positive repeat HCV-RNA testing or positive anti-HCV at age ≥24 months; (2) uninfected children lacked these criteria and had negative anti-HCV at age ≥18 months. 770 perinatally exposed infants underwent HCV-RNA testing at age 2-6 months. Of these, 28 (3.6%) tested positive; viremia was confirmed in all who underwent repeat testing (n = 27). Among 742 infants with negative HCV-RNA results, 226 received follow-up anti-HCV testing at age ≥18 months, of whom 223 tested negative. Three children had low-positive anti-HCV results at age 18-24 months that were negative upon retesting after age 24 months, possibly indicating waning maternal antibodies. Using the composite case definitions, early HCV-RNA screening demonstrated sensitivity of 100% (87.5-100%, Wilson-Brown 95% CI) and specificity of 100% (98.3-100%). Modern HCV-RNA RT-PCR assays have excellent sensitivity for early diagnosis of perinatally acquired infection and could aid HCV surveillance given the substantial loss to follow-up at ≥18 months of age.

An Investigation of Japanese Neonatal and Maternal Antibody Status against Pertussis.

To clarify the pertussis immune status of the Japanese population, we investigated levels of serum pertussis toxin (PT)-specific immunoglobulin G (IgG) antibody in infants and mothers between April 2016 and March 2018. A total of 206 infants (n = 22, < 32 weeks of gestational age [wGA]; n = 70, 32-36 wGA; n = 114, ≥ 37 wGA) and 170 mothers were enrolled. The maternal seroprevalence and antibody geometric mean titer (GMT) were 52.4% and 10.7 EU/mL, respectively. The antibody GMT, seroprevalence, and mean ratio of infant to maternal antibody titers of infants at < 32 wGA were 3.2 EU/mL, 13.6%, and 42.5%, respectively, and were significantly lower than those of infants at 32-36 wGA (9.7 EU/mL, 54.3%, and 110.2%) and infants at ≥ 37 wGA (12.1 EU/mL, 57.9%, and 112.6%). Of the 21 infants who underwent a second examination, five were positive in the first examination. Of those five, the GMT for PT had decreased by an average of 52.6% at 4.3- week intervals. In the second examination, two infants were seropositive. Approximately half of the mothers and infants were negative for anti-PT antibody. Thus, new vaccination strategies, such as the vaccination of pregnant women, are needed to prevent pertussis infection in early infancy.

The prevalence of vesicoureteral reflux in infants with first urinary tract infection following circumcision is similar to infants with UTI not following circumcision.

Urinary tract infections (UTIs) are common serious bacterial infections in early infancy. Ritual circumcision in neonates may increase the risk of UTI within 2weeks of the procedure. The aims of this study were to assess the prevalence and risk factors for vesicoureteral reflux (VUR) among young infants with first UTI following circumcision, and compare it with the prevalence of VUR among young infants with first UTI not related to circumcision. In this retrospective cohort study, the medical records of all children aged 0-100days who were diagnosed with UTI at Shaare Zedek Medical Center between 2005 and 2012 were reviewed for demographic, clinical and laboratory data and for the presence of VUR in voiding cystourethrography (VCUG). Four hundred and sixty eight cases of UTI were included. Infants with post-circumcision UTI in our study were more likely to have associated bacteremia and abnormal renal function tests. VCUG was done for 166 infants (35%). There was no statistically significant difference in the prevalence of abnormal VCUG between infants with UTI following circumcision, in comparison to infants with UTI not following circumcision (30% vs. 36%, p = NS). The decision regarding the need for radiographic evaluation and prophylactic antibiotic treatment following UTI should be made regardless if infection was related to circumcision.

Jaundice as sign of Urinary Tract Infection in Early Infancy: A hospital based Observational study

Jaundice as sign of Urinary Tract Infection in Early Infancy: A hospital based Observational study

Effects of Respiratory Syncytial Virus Infection in Infancy on Asthma and Respiratory Allergy in 6-Year-Old Children.

The purpose of this study was to examine the association between respiratory syncytial virus (RSV) infection in early infancy and health conditions such as asthma and respiratory allergies at 6 years of age in a cohort of US children born at term with no medical issues at birth. Data (1542 records) from the Infant Feeding Practices Study II and the Year Six Follow-Up study were used in the analysis. Descriptive statistics and logistic regression were conducted to estimate the magnitude and direction of potential associations between children's health conditions such as asthma, hay fever, or respiratory allergy, and RSV infection during infancy. A substantial proportion of children with RSV infection in infancy were reported to have developed asthma (10.3%) and hay fever or respiratory allergy (9.4%) by 6 years of age. Analyses revealed that children with RSV infection in infancy were more likely to develop asthma (odds ratio 1.99, 95% confidence interval 1.06-3.74), and hay fever or respiratory allergy (odds ratio 2.13, 95% confidence interval 1.28-3.57) by 6 years of age. In addition, the risk of developing asthma and hay fever or respiratory allergy by 6 years of age increased considerably with a family history of these conditions. Our findings support the need for understanding and monitoring the long-term health outcomes of RSV infection in infancy. Appropriate prevention and treatment measures for RSV infection during infancy may reduce the incidence of associated long-term adverse health outcomes. Knowledge of the long-term complications of RSV infection in infancy, such as asthma, hay fever, or respiratory allergy, can aid in the prevention and better management of these health conditions.

Uncomplicated Late-Onset Group B Streptococcal Bacteremia: Can We Do Less Than 10 Days IV?

* Abbreviations: GBS — : group B streptococcal IV — : intravenous LO-GBS — : late-onset group B streptococcal Late-onset group B streptococcal (LO-GBS) bacteremia remains a common serious infection in early infancy. It can be associated with meningitis, osteomyelitis, or other focal sites of infection but often occurs as uncomplicated bloodstream infection. Current authoritative sources recommend 10 days of intravenous (IV) antimicrobial therapy for uncomplicated LO-GBS bacteremia.1,2 In this issue of Pediatrics , Coon et al3 report an observational, comparative effectiveness study that revealed no difference in group B streptococcus (GBS) recurrence risk in young infants treated with shortened IV courses (≤8 days of IV therapy) versus prolonged courses (>8 days) for uncomplicated bacteremia. We know that 10 days IV works well for this infection and is effective and safe, right? So, why wrestle with questions about duration of therapy? With a growing literature on potential impacts of antimicrobial therapy on the infant microbiome that may matter later in life, risks of antimicrobial resistance, risks associated with hospitalization in general, financial and social burdens of hospitalizations on families, and well-described IV catheter-associated risks during home IV therapy, addressing this question is reasonable. A place to start is, “How did we come to recommendations of 10 days of IV therapy for this entity?” In his 1990 review of recommended durations of antimicrobial therapy for bacterial meningitis in children, Radetsky4 stated, “…the standards for … Address correspondence to Charles R. Woods, MD, MS, Department of Pediatrics, University of Tennessee College of Medicine–Chattanooga, Children's Hospital at Erlanger, 910 Blackford St, Chattanooga, TN 37403. E-mail: charles.woods{at}erlanger.org

Chronic Granulomatous Disease: A Study of Two Cases with Fungal Infection in Early Infancy

Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder, characterized by nicotinamide adenine dinucleotide phosphate oxidase system dysfunction. This will result in p...

Enteroaggregative Escherichia coli Subclinical Infection and Coinfections and Impaired Child Growth in the MAL-ED Cohort Study.

We evaluated the impact of subclinical enteroaggregative Escherichia coli (EAEC) infection alone and in combination with other pathogens in the first 6 months of life on child growth. Nondiarrheal samples from 1684 children across 8 Multisite Birth Cohort Study, Malnutrition and Enteric Diseases (MAL-ED) sites in Asia, Africa, and Latin America were tested monthly; more than 90% of children were followed-up twice weekly for the first 6 months of life. Children with subclinical EAEC infection did not show altered growth between enrollment and 6 months. Conversely, EAEC coinfection with any other pathogen was negatively associated with delta weight-for-length (P < 0.05) and weight-for-age (P > 0.05) z scores between 0 and 6 months. The presence of 2 or more pathogens without EAEC was not significantly associated with delta weight-for-length and weight-for-age. The most frequent EAEC coinfections included Campylobacter spp, heat-labile toxin-producing enterotoxigenic E coli, Cryptosporidium spp, and atypical enteropathogenic E coli. Myeloperoxidase levels were increased with EAEC coinfection (P < 0.05). EAEC pathogen codetection was associated with lower neopterin levels compared to those of no-pathogen control children (P < 0.05). Mothers of children with EAEC coinfections had lower levels of education, poorer hygiene and sanitation, lower socioeconomic status, and lower breast-feeding rates compared to mothers of children in whom no pathogen was detected (P < 0.05). These data emphasize the public health importance of subclinical EAEC infection in early infancy in association with other pathogens and the need for improved maternal and child care, hygiene, sanitation, and socioeconomic factors.

Progression of Type 2 Helper T Cell–Type Inflammation and Airway Remodeling in a Rodent Model of Naturally Acquired Subclinical Primary Pneumocystis Infection

Subclinical primary Pneumocystis infection is the most common pulmonary infection in early infancy, making it important to determine whether it damages the lung. Pneumocystis peaks at 2 to 5 months of age, when respiratory morbidity coincidently increases. We have documented that Pneumocystis increases mucus production in infant lungs, and animal models reveal lung lesions that warrant characterization. Herein, immunocompetent rats infected at birth with Pneumocystis by cohabitation, to resemble community-acquired infection, underwent lung assessments at 45, 60, and 75 days of age. Lungs fixed by vascular perfusion to prevent collapse during necropsy were used for morphometry evaluations of mucus production, airway epithelial thickening, perivascular and peribronchiolar inflammation, and structural airway remodeling. Changes in these histologic features indicate lung disease. Selected immune markers were assessed in parallel using fresh-frozen lung tissue from sibling rats of the same cages. Sequential activation of NF-κB and an increased Gata3/T-bet mRNA level ratio, consistent with a type 2 helper T-cell-type inflammatory response, and subacute fibrosis were recognized. Therefore, documenting subclinical Pneumocystis infection induces lung disease in the immunocompetent host. Taken together with the peak age of primary Pneumocystis infection, results warrant investigating the clinical impact of this often subclinical infection on the severity of respiratory diseases in early infancy. This model can also be used to assess the effects of airway insults, including coinfections by recognized respiratory pathogens.

Human Parechovirus Infection in Neonates and Children: An Overview

Pediatricians are becoming increasingly aware of the emergence of human parechovirus (HPeV) following several reports of potentially life-threatening infection in early infancy across the globe from Europe to Australia with episodic seasonal outbreaks. The severity of the HPeV infection varies widely from sporadic mild respiratory or gastrointestinal tract infection in older children to epidemic severe sepsis, myocarditis, and meningoencephalitis in young infants up to 3 months of age. Early complete recovery may sometimes be falsely reassuring, which later can lead to poor neurodevelopmental outcomes. The underlying causative viral agent of meningoencephalitis may remain elusive if a specific laboratory test for HPeV is not requested. Unlike Enterovirus (EV), cerebrospinal fluid (CSF) analysis in HPeV infection may remain misleadingly normal without pleocytosis or abnormal glucose and protein values even in PCR-positive cases. In this review article we attempt to summarize the important clinical information relevant to the practicing pediatricians about HPeV, particularly about its most pathogenic type, HPeV genotype 3 (HPeV3) along with its complications, possible treatment options, and future research direction.

Development and maturation of norovirus antibodies in childhood

The burden of norovirus (NoV) gastroenteritis is substantial in young children. Maternal antibodies are thought to protect a child from NoV infection in early infancy but subsequent development of NoV-specific protective immunity in children is still largely unexplored.We have determined NoV-specific antibody seroconversion to GII.4 virus-like particles as an indicator of NoV infection in two children prospectively followed from birth to eight years of age. Blocking activity and affinity maturation of maternal and serum IgG antibodies were evaluated.Our results show that multiple infections occur in children up to eight years of age. The titer, blocking activity and avidity of maternal antibodies determined susceptibility of an infant to NoV infection. NoV GII.4-specific antibodies with high blocking potential and avidity were developed at two to three years of age and were retained throughout the follow-up. Subsequent NoV infections may have contributed to the duration of protective NoV-specific immune responses that lasted for several years.This study adds to current understanding of the duration of passive protection by maternal antibodies and the duration and quality of acquired immunity following primary and subsequent NoV infections in infants and young children, who are the main target group for NoV vaccine development.

Airway Mucosal Immune-suppression in Neonates of Mothers Receiving A(H1N1)pnd09 Vaccination During Pregnancy

It is recommended to vaccinate pregnant women against influenza. A possible impact on the immune expression of the fetus has never been studied. We aim to study the immune signature in the upper airways and the incidence of infections in neonates born to mothers receiving Influenza A(H1N1)pnd09 vaccination during pregnancy. One hundred and fifty-six women from the unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC2010) received Influenza A(H1N1)pnd09-vaccination during the 2009 pandemic. Fifty-one mothers received the vaccine during pregnancy and 105 after pregnancy; 332 neonates of nonvaccinated mothers were included as secondary controls. Nasal mucosal lining fluid was sampled in 488 neonates and assessed for interleukin (IL)-12p70, IP-10, interferon-gamma (IFN)-γ, tumor necrosis factor-alpha (TNF)-α, MIP-1β, MCP-1, MCP-4, IL-4, IL-5, IL-13, eotaxin-1, eotaxin-3, TARC, MDC, IL-17, IL-1β, IL-8, transforming growth factor beta (TGF)-β1, IL-10 and IL-2. Infections were monitored the first year of life by daily diary cards and clinical controls. Neonates of mothers vaccinated during pregnancy had significant up-regulation of TGF-β1 [ratio = 1.52 (1.22-1.90), P = 0.0002], and corresponding down-regulation (P < 0.05) of IL-12p70, IFN-γ, IL-5, eotaxin-1, TARC, MDC, IL-8 in comparison to those vaccinated after pregnancy. The lag-time from vaccination during pregnancy to assessment of the immune signature showed significant and positive association to up-regulation of TGF-β1 levels (P = 0.0003) and significant negative association to other mediators. The study was not powered to study differences in the incidence of infections in early infancy which did not differ between the study groups. Influenza A(H1N1)pnd09 vaccination during pregnancy up-regulates TGF-β1 and down-regulates key mediators of the protective immunity.

G.P.155: A first Asian MEGF10 myopathy due to novel homozygous mutation

Recessive mutations in Multiple epidermal growth factor-like domains 10 (MEGF10) are known to cause the syndrome of early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). We found a novel <i>MEGF10</i> mutation by whole exome sequencing (WES) in a Japanese patient with EMRDD. The patient is a 9-year-old boy from a non-consanguineous family. There is no family history of neuromuscular disease. He was born at 39 weeks of gestational age. Although peri- and neonatal periods were uneventful, he had frequent respiratory infections in early infancy. At age 1 year and 6 months he developed respiratory failure for which mechanical ventilation was necessary, in addition to facial and limbs muscle weakness, finger joint contracture, and areflexia. Muscle biopsy at age 1 year and 9 months showed unspecific changes with moderate fiber size variation and type 2 fiber atrophy. At age 2 years NIPPV was started. He could stand alone at 2 years and 5 months, walk alone at 2 years and 9 months old. At age 9 years he was found to have proximal muscle weakness with Gowers' sign, although he was still ambulant. Scoliosis was also developed. Serum CK levels were normal. Second muscle biopsy at age 9 years revealed marked fiber size variation, moth-eaten appearance in some fibers, adipose tissue infiltration, and endomysial fibrosis, reflecting chronic progressive course of myopathic disease. WES identified a homozygous frameshift mutation (c.129_130delTG p.Thr43 fsX9). On western blotting MEGF10 was absent in the patient's muscle, whereas it was increased in DMD muscle. Together with clinical and pathological manifestations compatible with EMARDD, we concluded that the disease is caused by <i>MEGF10</i> mutation in the patient. This is the first report of Asian EMARDD.