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Virus Infections and Sudden Death in Infancy: The Role of Interferon-?.

ABSTRACT: Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-? (IFN-?) is a major response to virus infection, we examined (1) the frequency of single nucleotide polymorphism (SNP), IFNG T?+?874A, in SIDS infants, their parents, and ethnic groups with different incidences of SIDS; (2) model systems with a monocytic cell line (THP-1) and human peripheral blood monocytes (PBMC) for effects of levels of IFN-? on inflammatory responses to bacterial antigens identified in SIDS; (3) interactions between genetic and environmental factors on IFN-? responses. IFNG T?+?874A genotypes were determined for SIDS infants from three countries; families who had a SIDS death; populations with high (Indigenous Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. The effect of IFN-? on cytokine responses to endotoxin was examined in model systems with THP-1 cells and human PBMC. The IFN-? responses to endotoxin and toxic shock syndrome toxin (TSST-1) were assessed in relation to genotype, gender, and reported smoking. There was a marginal association with IFNG T?+?874A genotype and SIDS (p?=?0.06). Indigenous Australians had significantly higher proportions of the IFNG T?+?874A SNP (TT) associated with high responses of IFN-?. THP-1 cells showed a dose dependent effect of IFN-? on cytokine responses to endotoxin. For PBMC, IFN-? enhanced interleukin (IL)-1?, IL-6, and tumor necrosis factor-? responses but reduced IL-8 and IL-10 responses. Active smoking had a suppressive effect on baseline levels of IFN-?. There was no effect of gender or genotype on IFN-? responses to bacterial antigens tested; however, significant differences were observed between genotypes in relation to smoking. The results indicate virus infections contribute to dysregulation of cytokine responses to bacterial antigens and studies on physiological effects of genetic factors must include controls for recent or concurrent infection and exposure to cigarette smoke.

SUBMITTER: Moscovis SM

PROVIDER: S-EPMC4356164 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Virus Infections and Sudden Death in Infancy: The Role of Interferon-γ.

Moscovis Sophia M SM Gordon Ann E AE Al Madani Osama M OM Gleeson Maree M Scott Rodney J RJ Hall Sharron T ST Burns Christine C Blackwell Caroline C

Frontiers in immunology 20150311

Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-γ (IFN-γ) is a major response to virus infection, we examined (1) the frequency of single nucleotide polymorphism (SNP), IFNG T + 874A, in SIDS infants, their parents, and ethnic groups with different incidences of SIDS; (2) model systems with a monocytic cell line (THP-1) and human peripheral blood monocytes (PBMC) for effects of levels of IFN-γ on inflammatory responses to bacterial antigens ident ...[more]

PMID: 25814991

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Project description:ObjectiveOgival palate (i.e., a narrow and high-arched palate) is usually described in obstructive breath disorder but has been found in infants unexpectedly deceased. We studied the association between ogival palate and sudden unexpected death in infancy (SUDI) on the basis of a computed tomography (CT) evaluation.MethodsWe conducted a monocentric case-control study of children under 2 years of age who died of SUDI, for which a head CT scan and an autopsy were performed between 2011 and 2018. Each case was matched by sex and age (± 30 days) to two controls selected among living children in the same center who benefited from a cranio-encephalic CT scan. Four parameters of the hard palate were measured by CT: height, width, length, and sagittal angle; the height/width ratio was calculated. The presence of an ogival palate was also subjectively evaluated by the radiologists, independently from the measurements. Standardized odds ratios (OR) were calculated using conditional logistic regression models, all expressed for +1 standard deviation (SD).ResultsThirty-two deceased children were matched to 64 living control children. Mean ages were 5.0 and 5.3 months, respectively. Twenty-eight cases were considered to have died as a result of SIDS. The mean heights of the hard palate were significantly higher in the deceased children [4.1 (± 0.7) millimeters (mm)] than in the living children [3.2 (± 0.6) mm], with OR (+1SD) = 4.30 (95% confidence interval [CI], 2.04-9.06, P = 0.0001). The mean widths of the hard palate were 21.0 (± 1.9) mm and 23.2 (± 2.1) mm, respectively, with OR = 0.15 (95% CI, 0.06-0.40, P = 0.0001). The mean sagittal angles were significantly more acute in deceased children [134.5° (± 9.3)] than in living children [142.9° (± 8.1)], with OR = 0.28 (95% CI, 0.14-0.56, P = 0.0003). The mean height/width ratios were 19.8 (± 3.7) and 14.1 (± 3.3), respectively, with OR = 6.10 (95% CI, 2.50-14.9, P = 0.0001). The hard palate was subjectively considered as ogival in 59.4% (19/32) of the cases versus 12.5% (8/64) of the controls.ConclusionRadiological features of the ogival palate were strongly associated with SUDI. This observation still needs to be confirmed and the corresponding clinical features must be identified.

Project description:Background: The incidence of sudden unexpected death in infancy (SUDI), which includes sudden infant death syndrome (SIDS), has declined in developed countries since the 1980s, including the Netherlands. To identify improvement opportunities in SUDI prevention, we monitored the adherence of parents to the prevention advice on infant care habits over the past 20 years, especially in relation to the SUDI incidence over time. Potential changes in parental adherence between the latest surveys are of specific interest, as these indicate where current focus is needed. Methods: Description of the prevalence of infant care factors related to the risk of SUDI, assessed from five Dutch national surveys from 1999 to 2017 among parents of infants under 12 months, and analysis of the potential differences in these prevalences between the two latest surveys in 2010/11 and 2017 with a z-test. Results: Supine sleeping position decreased from the highest prevalence of 92% in 2010/11, to 83% in 2017. Sleep sack use has increased to 55%, the highest prevalence up to now. Avoiding a duvet has remained reasonably stable since 2002/03 and now 95% of parents do not use a duvet. The prevalence of room-sharing, without sharing the bed, increased from 14% in 1999 to the highest prevalence in 2017 (31%). However, also bed-sharing almost doubled from 5.6% in 2010/11 to 10% in 2017. Breastfeeding decreased between 1999 and 2010/11, but increased from 34% in 2010/11 to 42% in 2017. An increased prevalence of mothers who abstained from smoking during pregnancy, as well as both parents not smoking, was observed, although mostly higher educated parents showed this beneficial behavior. Discussion and Conclusion: Much has already been achieved first by decreasing prone sleeping since the 80's, and subsequently promoting supine as the safest sleep position. The decrease in duvet use and smoking, and an increase in breastfeeding have also had impact. Indications of a recent decreased prevalence of the supine sleeping position and higher prevalence of bed-sharing might relate to the slightly increasing SUDI incidence in the Netherlands. Renewed attention for prevention of SUDI and specific advice targeting high-risk groups is needed. Modern, picture driven information via internet is recommended.

Project description:BACKGROUND:Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes. METHODS:To address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS:In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data. CONCLUSION:We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.

Dataset Information

Virus Infections and Sudden Death in Infancy: The Role of Interferon-?.

Publications

Virus Infections and Sudden Death in Infancy: The Role of Interferon-γ.

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