Current SIDS research: time to resolve conflicting research hypotheses and collaborate.

From the earliest publications on cot death or sudden infant death syndrome (SIDS) through to this day, clinical pathology and epidemiology have strongly featured infection as a constant association. Despite mounting evidence of the role of viruses and common toxigenic bacteria in the pathogenesis of SIDS, a growing school of thought featuring a paradigm based on the triple risk hypothesis that encompasses vulnerability through deranged homoeostatic control of arousal and/or cardiorespiratory function has become the mainstream view and now dominates SIDS research. The mainstream hypothesis rarely acknowledges the role of infection despite its notional potential role as a cofactor in the triple hit idea. Decades of mainstream research that has focussed on central nervous system homoeostatic mechanisms of arousal, cardiorespiratory control and abnormal neurotransmission has not been able to provide consistent answers to the SIDS enigma. This paper examines the disparity between these two schools of thought and calls for a collaborative approach. IMPACT: The popular research hypothesis explaining sudden infant death syndrome features the triple risk hypothesis with central nervous system homoeostatic mechanisms controlling arousal and cardiorespiratory function. Intense investigation has not yielded convincing results. There is a necessity to consider other plausible hypotheses (e.g., common bacterial toxin hypothesis). The review scrutinises the triple risk hypothesis and CNS control of cardiorespiratory function and arousal and reveals its flaws. Infection-based hypotheses with their strong SIDS risk factor associations are reviewed in a new context.

The Science (or Nonscience) of Research Into Sudden Infant Death Syndrome (SIDS).

This Viewpoint paper presents a timely and constructive critique of mainstream SIDS research. It is concerning that twenty-first century medical science has not provided an answer to the tragic enigma of SIDS. The paper helps explain why this is so and illustrates possible shortcomings in the investigation of Sudden Infant Death Syndrome/Sudden Unexplained Infant Death (SIDS/SUID) by mainstream researchers. Mainstream findings are often based on questionable and dogmatic assumptions that return to founding notions such as the Triple Risk Hypothesis and the contention that the mechanisms underlying SIDS/SUID are heterogeneous in nature. The paper illustrates how the pathological findings in SIDS have been under-investigated (or ignored) and that key epidemiological risk factors have slipped from memory. This apparent amnesia has resulted in failure to use these established SIDS facts to substantiate the significance of various neuropathological, neurochemical, or other research findings. These unsupported findings and their derivative hypotheses are therefore ill-founded and lack scientific rigor. Conclusion: The deficits of SIDS "science" revealed in this paper explain why the SIDS enigma has not yet been solved. To make progress in understanding SIDS, it is important that researchers, as scientists, uphold standards of research. Encouragement for new directions of research is offered.

A mouse zoonotic virus (LCMV): A possible candidate in the causation of SIDS.

Lymphocytic choriomeningitis virus (LCMV) is a ubiquitous virus carried by rodents. It causes human disease through contact with infectious mouse faeces, urine or secretions. The virus initially infects the human respiratory tract and lungs and produces typical viral symptoms and signs. The infection is usually self-limiting and recovery is the norm. A small proportion of individuals may develop aseptic meningitis. It is hypothesised that in infancy the virus may cause respiratory tract infection through contact with mouse excreta. The infection could activate production of staphylococcal enterotoxin in babies who are colonised by Staphylococcus aureus. Indeed, a mouse animal model has shown that the combination of LCMV infection and introduction of enterotoxin B produces fatal haematogenous shock. Neither agent alone is lethal. Pathological (and physiological) evidence indicates shock could be the underlying terminal event in SIDS (the observed tissue damage seen in the heart and diaphragmatic muscles, and apoptosis observed in the brain and brainstem of SIDS cases). These features are consistent with a haematogenous shock event. The epidemiology of SIDS is entirely consistent with a mouse-related viral zoonosis. Moreover, rural cases of SIDS tend to feature more often than urban cases and their occurrence would be consistent with the dynamics of mouse populations. Low socioeconomic living conditions (a major risk factor for SIDS) is consistent with prevalence of mouse populations and poor hygienic conditions, with overcrowding. Prone sleeping would facilitate aspiration or ingestion of infectious material from contaminated surfaces. and poor hygienic conditions, with overcrowding, and prone sleeping would facilitate aspiration or ingestion of infectious material from contaminated surfaces. The epidemiology and pathology of SIDS and the dynamics and ubiquity of mouse populations together with human serological data would support the hypothesis that LCMV is a potential candidate as a key factor in the causation of SIDS.

Infection, Celestial Influences, and Sudden Infant Death Syndrome: A New Paradigm.

The etiology of sudden infant death syndrome (SIDS) still remains unclear. This situation would seem unprecedented for 21st-century medical science. This article explores scientific fields that have not been largely considered in investigating the etiology of SIDS so far. In this study, we examined previously ignored studies on heliobiology, celestial influences, and SIDS in the non-medical literature in an attempt to answer the following questions: is there a relationship between sunspot/solar activity and the occurrence of SIDS? Could there be alternative reasons for the decline in SIDS incidences in the 1990s that were originally attributed to the "Back-to-Sleep" campaign? We note that the decline coincided with the ~11-year cyclical diminution in sunspot numbers (SSNs). The SSN/SIDS relationship does not necessarily imply causality; however, it supports published data regarding sunspots, Schumann resonance, and geomagnetic effects. How solar energy could adversely influence a baby's existence remains conjectural. Observations in this respect suggest pathways involving melatonin and/or infection/inflammation.

Increased thymus weight in sudden infant death syndrome compared to controls: The role of sub-clinical infections.

OBJECTIVE: The goal of the present investigation is to analyze thymus, brain, heart, liver, and kidney weights in SIDS victims compared to controls. BACKGROUND: Epidemiologic risk factors for SIDS (eg, male gender, genetic, obstetric, environmental, smoke exposure, nonbreastfeeding, etc.) are consistent with an infectious process underlying many of these deaths. METHODS: Data from autopsy reports on 585 SIDS victims and comparison deaths (n = 294 control, n = 291 SIDS) were analyzed. Cases were obtained from Australia (n = 184 controls, n = 98 SIDS) and Russia (n = 122 controls, n = 181 SIDS). Log10 transform of thymus and other organ weights was computed because variables were skewed. Multivariate analysis of variance (MANOVA) of standardized log values were age-adjusted by multivariate analysis of covariance (MANCOVA). The standardized log10 thymus residual adjusted for age, brain and liver weights was computed for the final analysis. RESULTS: After controlling for age by MANCOVA, thymus, body, brain and liver weights were significantly higher among SIDS compared to non-SIDS victims. The largest difference as between covariate-adjusted log10 non-SIDS thymus weight differed (mean = 1.423, 95% CI: 1.393-1.452) and log10 non-SIDS thymus weight (mean = 1.269, 95% CI: 1.243-1.294) were significantly different (P < .0001). Heart weight was significantly lower in SIDS victims. DISCUSSION: When adjusted for confounders (age, body, and organ weights), SIDS victims have a significantly heavier thymus and brain compared to non-SIDS controls who died of trauma. This finding supports previously published studies that link infection to SIDS deaths.

SIDS, prone sleep position and infection: An overlooked epidemiological link in current SIDS research? Key evidence for the "Infection Hypothesis".

Mainstream researchers explain the etiology of SIDS with the cardiorespiratory paradigm. This has been the focus of intense study for many decades without providing consistent supporting data to link CNS findings to epidemiological risk factors or to the usual clinicopathological findings. Despite this, and the apparent oversight of the link between prone sleep position and respiratory infection, papers citing CNS, cardiac and sleep arousal findings continue to be published. Discovery of the prone sleep position risk factor provided tangential support for the cardiorespiratory control hypothesis which defines the mainstream approach. Despite many decades of research and huge expenditure, no aetiological answer has been forthcoming. In asking why?This paper exposes some of the shortcomings regarding this apparent oversight by mainstream SIDS researchers and examines the role of respiratory infection and puts the case for the "Infection Hypothesis." In addition, the paper provides encouragement to neuropathologists to examine the potential link between CNS findings and cardiac function (as opposed to respiratory function) in relation to infection and to examine possible correlates between CNS findings and established risk factors such as recent infection, contaminated sleeping surfaces, maternal/obstetric/higher birth, ethnicity, non-breast-feeding, male gender, etc. or with the usual gross pathological findings of SIDS (intrathoracic petechial hemorrhages, liquid blood, congested lungs). The shortcomings exposed through this review invite questions over current research directions and hopefully encourage research into other more plausible hypotheses, such as the infection paradigm.

Intestinal Microbiota Composition in Sudden Infant Death Syndrome and Age-Matched Controls.

OBJECTIVE: To assess whether features of the infant intestinal microbiome, including the carriage of toxigenic bacteria, are associated with sudden infant death syndrome (SIDS). STUDY DESIGN: We undertook a case-controlled analysis of fecal microbiology in SIDS. Fecal material was obtained from 44 cases and 44 aged-matched controls. Microbiota composition was determined by 16S ribosomal RNA gene amplicon sequencing and comparisons between cases and controls made based on both bacterial alpha diversity measures and unconstrained ordination. Specific quantitative polymerase chain reaction assays were used to determine intestinal carriage of Staphylococcus aureus, toxigenic Clostridium difficile, and pathogenic and nonpathogenic Escherichia coli. RESULTS: The microbial composition for the study population as a whole was consistent with previous studies of infants <12 months of age, with a correlation between alpha diversity and age (r2 = 0.08; P = .007). However, no difference was observed in alpha diversity between SIDS cases and controls (P > .4). Nonmetric multidimensional scaling also revealed no evidence of differences in microbiota dispersal between SIDS cases and controls (P = .4, permutational multivariate ANOVA test; Pseudo-F = 0.9), nor was a difference observed in microbiota dispersion (P = .19, PERMDISP test; F = 1.9). There were no significant intergroup differences in the carriage of S aureus, toxigenic C difficile, total E coli, or pathogenic E coli. CONCLUSIONS: We found no evidence of an association between altered intestinal microbiology and SIDS, or to support the development of strategies to reduce the incidence of SIDS that target intestinal microbiology.

Sudden Infant Death Syndrome, Infection, Prone Sleep Position, and Vagal Neuroimmunology.

Recent findings suggest that infection (and sepsis) stand alone as the only plausible mechanism of causation of sudden infant death syndrome (SIDS) and accordingly achieves congruence with all clinicopathological and epidemiological findings. This review examines the role of infection in the pathogenesis of SIDS in the context of the major risk factor of prone sleep position. The study explores how sleep position could interact with the immune system and inflammatory response via vagal neural connections, which could play key roles in gut and immune homeostasis. A plausible and congruent clinicopathological and epidemiological paradigm is suggested.

Infection: the neglected paradigm in SIDS research.

Despite decades of investigation and millions of dollars spent, the cause of sudden infant death syndrome (SIDS) eludes researchers. It is timely therefore to reconsider the reasons for this failure and to explore how research might go forward with better prospects. This review assesses SIDS research in the context of clinicopathological and epidemiological features and determines that only infection attains congruence.

Escherichia coli and Sudden Infant Death Syndrome.

This review examines the association of strains of Escherichia coli with sudden infant death syndrome (SIDS) and the possible role these bacteria play in this enigmatic condition. The review addresses evidence for E. coli in SIDS infants, potential sources of E. coli in the environment, colonization by commensal and pathogenic strains, the variety of currently accepted pathotypes, and how these pathotypes could compromise intestinal integrity and induce inflammation. Both intestinal and extraintestinal pathotypes are compared in relation to the apparent liability in which virulence traits can be gained or lost by strains of E. coli. The way in which E. coli infections fit with current views on infant sleeping position and other SIDS risk factors is highlighted.

Gut Microbiota and Immunity: Possible Role in Sudden Infant Death Syndrome.

The gut microbiome influences the development of the immune system of young mammals; the establishment of a normal gut microbiome is thought to be important for the health of the infant during its early development. As the role of bacteria in the causation of sudden infant death syndrome (SIDS) is backed by strong evidence, the balance between host immunity and potential bacterial pathogens is likely to be pivotal. Bacterial colonization of the infant colon is influenced by age, mode of delivery, diet, environment, and antibiotic exposure. The gut microbiome influences several systems including gut integrity and development of the immune system; therefore, gut microflora could be important in protection against bacteria and/or their toxins identified in SIDS infants. The aims of the review are to explore (1) the role of the gut microbiome in relation to the developmentally critical period in which most SIDS cases occur; (2) the mechanisms by which the gut microbiome might induce inflammation resulting in transit of bacteria from the lumen into the bloodstream; and (3) assessment of the clinical, physiological, pathological, and microbiological evidence for bacteremia leading to the final events in SIDS pathogenesis.

Gut microbiome in sudden infant death syndrome (SIDS) differs from that in healthy comparison babies and offers an explanation for the risk factor of prone position.

The role of bacteria in the causation of sudden infant death syndrome (SIDS) is gaining acceptance. Mainstream research favouring respiratory compromise has failed to provide a plausible pathogenetic mechanism despite many years of investigation and thousands of research papers. Bacterial colonisation of the colon of the human infant is influenced by many factors including age, mode of delivery, diet, environment, and antibiotic exposure. The gut microbiome influences development of the immune system. The gut microflora could be important in protection against the bacteria and/or their toxins purportedly involved in SIDS pathogenesis. The aim was to perform a preliminary investigation of the gut microflora in sudden infant death syndrome (SIDS) compared with live comparison babies. The intestinal contents from 52 SIDS, and 102 faecal samples from age-matched live comparison infants were screened by PCR to target 16s RNA genes of Clostridium innocuum, Cl. Perfringens, Cl. difficile, Bacteroides thetaiotaomicron and Staphylococcus aureus. Gut colonisation of the babies with these bacteria was analysed in relation to age, gender and type of feeding; and for SIDS babies sleeping position. Cl. difficile, Cl. innocuum and B. thetaiotaomicron were significantly associated with SIDS with 25%, 46% and 30% of cases PCR positive for these respective bacteria compared with only 6%, 23% and 8.8% respectively in the comparison group. SIDS babies had dual colonisation by both Cl. perfringens and Cl. difficile significantly more often than comparison babies and also with triple colonisation by Cl. perfringens, Cl. difficile and Cl. innocuum. SIDS babies were more often colonised by S. aureus than comparison babies. In addition, SIDS babies found prone were significantly more likely to be colonised by S. aureus than for other positions recorded (OR = ∞; CI = 2·04 - ∞). No significant differences between breast and bottle-fed SIDS babies was observed in regard to each clostridial bacterium, or S. aureus, however Cl. innocuum was found to be significantly associated with formula feeding in the comparison cohort. Comparison of breast and formula feeding of SIDS babies with live comparison babies revealed significant differences with regards to some of the clostridial bacteria. Age-specific differences in gut bacterial microbiome were observed in both SIDS and comparison healthy babies. This study gives an insight into differences in the gut bacterial microbiome of SIDS babies compared with healthy babies. These differences could be important in contributing to a baby's susceptibility to infection and therefore to SIDS. The association of S. aureus colonisation with prone sleep position supports the hypothesis that prone sleep position could increase the risk of ingestion/inhalation of bacteria contaminating the sleeping surface and could account for the increased risk of SIDS in babies who are put to sleep prone. The study provides impetus for broader studies into the gut microbiome of babies and could lead to effective approaches to SIDS prevention.

Iatrogenic blood-borne viral infections in refugee children from war and transition zones.

Pediatric infectious disease clinicians in industrialized countries may encounter iatrogenically transmitted HIV, hepatitis B virus, and hepatitis C virus infections in refugee children from Central Asia, Southeast Asia, and sub-Saharan Africa. The consequences of political collapse and/or civil war-work migration, prostitution, intravenous drug use, defective public health resources, and poor access to good medical care-all contribute to the spread of blood-borne viruses. Inadequate infection control practices by medical establishments can lead to iatrogenic infection of children. Summaries of 4 cases in refugee children in Australia are a salient reminder of this problem.

Genetic and clinical contributions to cerebral palsy: a multi-variable analysis.

AIM: This study aims to examine single nucleotide polymorphism (SNP) associations with cerebral palsy in a multi-variable analysis adjusting for potential clinical confounders and to assess SNP-SNP and SNP-maternal infection interactions as contributors to cerebral palsy. METHODS: A case control study including 587 children with cerebral palsy and 1154 control children without cerebral palsy. Thirty-nine candidate SNPs were genotyped in both mother and child. Data linkage to perinatal notes and cerebral palsy registers was performed with a supplementary maternal pregnancy questionnaire. History of known maternal infection during pregnancy was extracted from perinatal databases. RESULTS: Both maternal and fetal carriage of inducible nitric oxide synthase SNP rs1137933 were significantly negatively associated with cerebral palsy in infants born at less than 32 weeks gestation after adjustment for potential clinical confounders and correction for multiple testing (odds ratio 0.55, 95% confidence interval 0.38-0.79; odds ratio 0.57, 95% confidence interval 0.4-0.82, respectively). Analysis did not show any statistically significant SNP-SNP or SNP-maternal infection interactions after correction for multiple testing. CONCLUSIONS: Maternal and child inducible nitric oxide synthase SNPs are associated with reduced risk of cerebral palsy in infants born very preterm. There was no evidence for statistically significant SNP-SNP or SNP-maternal infection interactions as modulators of cerebral palsy risk.

Maternal and perinatal risk factors for SIDS: a novel analysis utilizing pregnancy outcome data.

UNLABELLED: A number of maternal and perinatal factors to increase an infant's risk of sudden infant death syndrome (SIDS) have been found in past investigations. We analysed data for potential SIDS risk factors including the presence of complications or conditions considered as detrimental to the infant's or mother's health. The data for 118 SIDS cases and 227 matched controls were obtained from a state pregnancy outcome unit. SIDS was found to be significantly more common in cases where the infant's mother was not in a relationship (i.e. divorced, separated or never married) (p = 0.005), if the infant was not the first born (p = 0.0001) and when the mother resided in a socioeconomically disadvantaged area (p = 0.03). CONCLUSION: Overall, this SIDS cohort appears to display classical SIDS associations, and our findings are consistent with those from other regions. This novel epidemiological tool opens the way for a national Australia-wide study using pregnancy outcome data collected by the individual states and could be helpful in assessing maternal and fetal risk factors for other paediatric medical conditions.

Cytomegalovirus and Epstein-Barr virus may be associated with some cases of cerebral palsy.

OBJECTIVE: Intrauterine infection is a risk factor for cerebral palsy. Previous work reported a high frequency of viral DNA in newborn screening cards from cerebral palsy cases and controls possibly due to contamination. METHODS: Retrospective case-control study using improved methodologies to minimize contamination during PCR-based detection of viral DNA sequences. Newborn screening cards of 339 Caucasian children with cerebral palsy and 594 controls were examined. Viruses tested were herpes simplex viruses 1 and 2 (HSV1 and 2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes viruses 6, 7 and 8 (HHV6, HHV7 and HHV8), and parvovirus B19. Genotyping was performed on DNA extracted from dried blood spots. RESULTS: CMV and EBV were detected in 5 (1.5%) and 3 (0.9%) of 339 cases, respectively, but not in controls (p = 0.047 and 0.006). Frequencies of detection of the other viruses examined were similar for cases and controls. DNA from at least one of the nine viruses tested was found in 4.4% of cases and 3.1% of controls [OR 1.4 95% CI (0.71-2.76)]. CONCLUSION: Evidence of congenital viral infection was uncommon in cases of cerebral palsy and controls. However, CMV and EBV were significantly associated with cerebral palsy.

Treatment of enterohemorrhagic Escherichia coli (EHEC) infection and hemolytic uremic syndrome (HUS).

Verotoxigenic Escherichia coli (VTEC) are a specialized group of E. coli that can cause severe colonic disease and renal failure. Their pathogenicity derives from virulence factors that enable the bacteria to colonize the colon and deliver extremely powerful toxins known as verotoxins (VT) or Shiga toxins (Stx) to the systemic circulation. The recent devastating E. coli O104:H4 epidemic in Europe has shown how helpless medical professionals are in terms of offering effective therapies. By examining the sources and distribution of these bacteria, and how they cause disease, we will be in a better position to prevent and treat the inevitable future cases of sporadic disease and victims of common source outbreaks. Due to the complexity of pathogenesis, it is likely a multitargeted approach is warranted. Developments in terms of these treatments are discussed.