Alteration in regulation of inflammatory response to influenza a virus and endotoxin in suckling rat pups: a potential relationship to sudden infant death syndrome

Data increasingly implicate a possible role of immune and inflammatory responses to infection in sudden infant death syndrome (SIDS). We have previously described a dual challenge model that results in pathology, organ damage, vascular collapse and unexplained death similar to that seen in SIDS. In this study, we examined changes in inflammatory cytokine mRNA in the lung and liver and regulation of pathways associated with nitric oxide production. Our data suggest that priming of the immune system by mild viral infection disturbs normal inflammatory response to endotoxin. This results in an increased nitric oxide synthase production, most likely the cause of liver pathology and clotting abnormalities.     

Sudden infant death syndrome, virus infections and cytokines

Many epidemiological risk factors identified for sudden infant death syndrome (SIDS) suggest a viral aetiology, e.g. exposure to cigarette smoke and winter peak, mild respiratory symptoms. Virus infections and bacterial toxins induce cytokine activity and it has been suggested that uncontrolled inflammatory mediators could be involved in some cases of SIDS. The aim of this review was to assess the evidence for virus infection in SIDS and to examine those findings in relation to individual variations in cytokine responses and various pathophysiological mechanisms proposed for SIDS such as sleep derangement, hypoxia, cardiac arrhythmia, vascular hypotonicity and hypoglycaemia.     

Sudden infant death syndrome, infection and inflammatory responses

Sudden infant death syndrome (SIDS) is sudden unexpected death in infancy for which there is no explanation after review of the history, a death scene investigation and a thorough autopsy. The use of common diagnostic criteria is a prerequisite for discussing the importance of infection, inflammatory responses and trigger mechanism in SIDS. Several observations of immune stimulation in the periphery and of interleukin-6 elevation in the cerebrospinal fluid of SIDS victims explain how infections can play a role in precipitating these deaths. Finally, these findings and important risk factors for SIDS are integrated in the concept of a vicious circle for understanding the death mechanism. The vicious circle is a concept to elucidate the interactions between unfavourable factors, including deficient auto-resuscitation, and how this could result in death.     

An infectious aetiology of sudden infant death syndrome

Due attention has been given to infectious agents and immune responses to infection in sudden infant death syndrome (SIDS). It has been acknowledged that the pathological, epidemiological and genotypic findings in SIDS infants suggest an infectious aetiology possibly being potentiated by immunoregulatory polymorphisms, however, the cause of SIDS is a mystery and remains open to debate. Consistent pathological findings are seen which display similarities to the pathogenesis of toxaemic shock and/or sepsis. The major risk factors for SIDS parallel those for increased colonization and serious bacterial infections and the natural variation in the incidence of SIDS cases is typical of an infectious disease. The roles played by viral infection, immunoregulatory genes and suspected bacterial species are discussed herein.     

IL-10 gene polymorphisms in infectious disease and SIDS

Interleukin-10 (IL-10) is a regulatory cytokine, and its principal role in vivo is to limit inflammatory response. IL-10 has been shown to influence both the susceptibility and course of various diseases, and the different polymorphisms in the IL-10 gene promoter have been associated with disease prevalence and severity. The genes involved in the immune system are also assumed to be of importance with regard to sudden infant death syndrome (SIDS), and specific haplotypes in the IL-10 gene promoter have been reported associated both with SIDS and sudden unexpected death due to infection.     

The role of infection in sudden infant death syndrome

Studies on the potential role of infectious agents in sudden infant death syndrome (SIDS) have been published over the years in a variety of journals. The aim of this special issue of FEMS Immunology and Medical Microbiology is to bring together a group of the most recent studies from Europe, Australia and Canada which cover epidemiology and laboratory studies examining hypotheses relating to infection and inflammation in SIDS. The articles in this issue examine evidence for the involvement of specific micro-organisms in SIDS and the problems relating to experimental studies on infection in relation to the underlying pathology of these deaths. There is an update on the evidence for the common bacterial hypothesis proposed in 1987 examining risk factors identified in epidemiological studies, particularly how the prone sleeping position could affect bacterial colonisation or induction of toxins. Evidence for induction of inflammatory responses in SIDS infants is reviewed and the relation of these responses to mechanisms proposed as causes of death assessed. Factors found to be associated with reduction of the risk of SIDS (breast feeding and immunisation) are examined in relation to some of the toxigenic bacteria implicated in these deaths. Finally, the high incidence of SIDS in some ethnic groups is examined as a potential model to investigate the contributions of genetic, environmental and cultural differences to susceptibility of infants not only to SIDS but to serious respiratory tract infections.     

Development of mucosal immunity in the first year of life and relationship to sudden infant death syndrome

The common mucosal immune system (CMIS) is an interconnecting network of immune structures that provides effective immunity to mucosal surfaces. The structures of the mucosal immune system are fully developed in utero by 28 weeks gestation, but in the absence of intrauterine infection, activation does not occur until after birth. Mucosal immune responses occur rapidly in the first weeks of life in response to extensive antigenic exposure. Maturation of the mucosal immune system and establishment of protective immunity varies between individuals but is usually fully developed in the first year of life, irrespective of gestational age at birth. In addition to exposure to pathogenic and commensal bacteria, the major modifier of the developmental patterns in the neonatal period is infant feeding practices. A period of heightened immune responses occurs during the maturation process, particularly between 1 and 6 months, which coincides with the age range during which most cases of sudden infant death syndrome (SIDS) occur. A hyper-immune mucosal response has been a common finding in infants whose death is classified as SIDS, particularly if in association with a prior upper respiratory infection. Inappropriate mucosal immune responses to an otherwise innocuous common antigen and the resulting inflammatory processes have been proposed as factors contributing to SIDS.     

Sudden infant death syndrome and Canadian Aboriginals: bacteria and infections

Aboriginal populations in Canada, America and Australia have higher incidences of sudden infant death syndrome (SIDS) than non-Aboriginal groups. Canadian Aboriginal populations (known also as first nation, native or Indian) experience infant morbidity/mortality rates 3-7 times that of non-Aboriginals, with upper track respiratory infection and SIDS recorded as the leading causes. The aim of this investigation was to examine the home environment of Aboriginal infants, particularly during winter months when respiratory tract infections and SIDS are more common. Environmental bacteria, fungi and air particulates were examined in the residences of Aboriginal infants during visits to individual homes on an Aboriginal reserve. The physical histories of SIDS victims were gathered from medical files. Air and surfaces were sampled by agar strips which were processed by a commercial laboratory. The levels of fungi, bacteria and air particulate rates recorded in the reserve homes of Aboriginal infants registered levels considered to be detrimental to the health of the inhabitants. Such extreme levels could contribute to the high incidence of respiratory disease and SIDS experienced by Canadian Aboriginal infants.     

Animal models of sudden unexplained death

The etiology of sudden infant death syndrome (SIDS) is unknown but thought to be multifactorial. Several animal models have been developed that induce death without pre-existing symptoms and with pathology similar to that seen in SIDS infants; however, the relevance of these animal models to the events leading to SIDS remains elusive, in part because animal models are as varied as the potential causes of SIDS. In addition, it is difficult to find an animal model that can accurately reflect the genetic, developmental and environmental risk factors for SIDS. Comparisons between species can prove difficult but animal models provide a useful tool for evaluating potential mechanisms related to sudden unexplained death. This review focuses on models developed to examine the association of infection and inflammation with mechanisms proposed to explain sudden unexplained death.     

Toxigenic bacteria and sudden infant death syndrome (SIDS): nasopharyngeal flora during the first year of life

Many developmental and environmental risk factors for sudden infant death syndrome (SIDS) are similar to those for susceptibility to respiratory tract infection, and toxigenic bacteria have been implicated in some SIDS cases. We assessed nasopharyngeal flora of healthy infants in relation to risk factors to determine which species best lit the mathematical model proposed for the common bacterial toxin hypothesis and if these findings complemented results obtained from SIDS cases which occurred during the period of the survey. Longitudinal studies were carried out between April 1993 and March 1996 on 253 healthy infants and their mothers. 150 from a multiply deprived area, 103 from an affluent area. Concurrent SIDS infants (37) were screened for nasopharyngeal flora. Among healthy infants < or = 3 months of age, the predominant isolate was Staphylococcus aureus 57% compared with 86% for SIDS infants in that age range (P< 0.02). There were significant associations between isolation of different species from both mother and baby but no association between isolation of any species with: area of residence: parental smoking habits; breast or bottle feeding; symptoms of viral infection: seasonality. We conclude that S. aureus fits the mathematical model for SIDS. Both staphylococci and/or their toxins were identified in a significant proportion of SIDS cases. Isolation of staphylococci from healthy infants was associated with the 2-4-month age range, a risk factor consistently found in all epidemiological studies of SIDS. This might reflect the developmental stage in which 80-90% of infants express the Lewis(a) antigen which we have shown to be one of the receptors for S. aureus.     

Is Sudden Infant Death Syndrome Associated with Helicobacter pylori Infection in Children?

Helicobacter pylori infection has recently been implicated in the pathogenesis of sudden infant death syndrome (SIDS). We investigated this association. Twenty-five pairs of gastric and tracheal tissue specimens obtained from autopsies of 25 children with previous diagnoses of SIDS were available for this study. The presence of H. pylori organisms was evaluated by three different methods: histology (hematoxylin-eosin or Giemsa staining), immunohistochemistry, and nested polymerase chain reaction technique. We were unable to confirm the presence of H. pylori organisms by the first two methods. H. pylori DNA was identified by nested polymerase chain reaction in six different tissue specimens (stomach, 4; trachea, 2). In no case was H. pylori DNA detected in both tissues. We concluded that H. pylori infection is most likely not associated with SIDS.     

SIDS pathogenesis: pathological findings indicate infection and inflammatory responses are involved

This article explores the pathological evidence that supports the hypothesis that infection and inflammation are underlying mechanisms in SIDS. It reviews the pathological findings in relation to the risk factors reported for SIDS and compares these findings with other hypotheses suggested as causes of these unexplained deaths in infants. The roles of environmental factors and bacterial products such as soluble curlin detectable in SIDS sera in triggering cytokine cascades and aberrant inflammatory responses resulting in a toxic shock-like event are also explored. Areas for future research are outlined.     

Ethnicity, infection and sudden infant death syndrome

Epidemiological studies found the incidence of SIDS among Indigenous groups such as Aboriginal Australians, New Zealand Maoris and Native Americans were significantly higher than those for non-Indigenous groups within the same countries. Among other groups such as Asian families in Britain, the incidence of SIDS has been lower than among groups of European origin. Cultural and childrearing practices as well as socio-economic factors have been proposed to explain the greater risk of SIDS among Indigenous peoples; however, there are no definitive data to account for the differences observed. We addressed the differences among ethnic groups in relation to susceptibility to infection because there is evidence from studies of populations of European origin that infectious agents, particularly toxigenic bacteria might trigger the events leading to SIDS. The risk factors for SIDS parallel those for susceptibility to infections in infants, particularly respiratory tract infections which are also major health problems among Indigenous groups. Many of the risk factors identified in epidemiological studies of SIDS could affect three stages in the infectious process: (1) frequency or density of colonisation by the toxigenic species implicated in SIDS; (2) induction of temperature-sensitive toxins; (3) modulation of the inflammatory responses to infection or toxins. In this review we compare genetic, developmental and environmental risk factors for SIDS in ethnic groups with different incidences of SIDS: low (Asians in Britain); moderate (European/Caucasian); high (Aboriginal Australian). Our findings indicate: (1) the major difference was high levels of exposure to cigarette smoke among infants in the high risk groups; (2) cigarette smoke significantly reduced the anti-inflammatory cytokine interleukin-10 responses which control pro-inflammatory responses implicated in SIDS; (3) the most significant effect of cigarette smoke on reduction of IL-10 responses was observed for donors with a single nucleotide polymorphism for the IL-10 gene that is predominant among both Asian and Aboriginal populations. If genetic makeup were a major factor for susceptibility to SIDS, the incidence of these deaths should be similar for both populations. They are, however, significantly different and most likely reflect differences in maternal smoking which could affect frequency and density of colonisation of infants by potentially pathogenic bacteria and induction and control of inflammatory responses.     

Change in immunisation schedule and sudden infant death syndrome in Hungary

Infant mortality in Hungary was higher than in other European countries; however, the reported incidence of sudden infant death syndrome (SIDS) has been lower than those for Western Europe and the United States. Childhood immunisation has been reported to be a protective factor for SIDS. In Britain, the change to an earlier immunisation schedule for diphtheria, pertussis, and tetanus appeared to be associated with a shift in the age distribution of SIDS. In 1999, immunisation for Haemophilus influenzae type b (Hib) was introduced for Hungarian infants at the age of 2 months. Data for total infant mortality and SIDS in Hungary were analysed between 1990 and 2002. Infection was the major cause of death among Hungarian infants followed by SIDS. Following introduction of Hib immunisation, there was a decrease in deaths due to meningitis from an average of 3.5% of all infant deaths between 1990 and 1998 to an average of 1% of all infant deaths between 1999 and 2002 (p=0.00). There was also a significant decrease in the proportion of SIDS in the age range > or =2 months from 48% in the earlier period to 39% after introduction of the vaccine (p=0.03). The decrease in SIDS might be due in part to decrease in unrecognised Hib infections or to induction of antibodies by the tetanus toxoid to which the Hib polysaccharide is conjugated that are cross reactive with bacterial toxins implicated in SIDS.     

Cortisol levels and control of inflammatory responses to toxic shock syndrome toxin-1 (TSST-1): the prevalence of night-time deaths in sudden infant death syndrome (SIDS)

There is evidence that inflammatory responses have been induced in the tissues and body fluids of many SIDS infants. We suggested that some of these deaths are due to uncontrolled inflammatory responses to infectious agents and possibly cigarette smoke. The majority of SIDS deaths occur during the 2-4 month age range when infants have decreasing levels of maternal antibodies to infectious agents. Most deaths occur during the early hours of the morning. Adults are more susceptible to inflammatory responses at night due to lower levels of cortisol associated with circadian rhythm patterns. Infants develop these patterns between the ages of 7 weeks and 4 months, at which time their night-time cortisol levels drop dramatically. The objective of this study was to use an in vitro model system to assess the effects of different cortisol levels on proinflammatory cytokine production in response to the staphylococcal toxic shock syndrome toxin-1 (TSST-1) which has been identified in a significant number of SIDS infants. Levels of cortisol present in infants at night and during the day before and after the development of the circadian rhythm pattern were examined. Human buffy coats (n = 9) were stimulated with TSST-1 and responses assessed over 72 hours by a bioassay for tumour necrosis factor-alpha (TNF-alpha) and an enzyme linked immunosorbent assay (ELISA) for interleukin-6 (IL-6). Cortisol levels present in an infant at night after development of circadian rhythm (< or = 5 microg dl(-1)), did not significantly increase or decrease production of either TNF-alpha or IL-6. Concentrations of cortisol greater than 5 microg dl(-1) usually found in infants during the day or at night prior to the physiological change significantly decreased production of TNF-alpha at 12 hours and of IL-6 at 12 and 16 hours. Only cortisol levels greater than 5 microg dl(-1) significantly decreased production of the pro-inflammatory cytokines by human buffy coats stimulated with TSST-1. If the switch to the circadian rhythm pattern occurs in an infant when maternal antibodies are still present or after they have developed their own active immunity, the infant could neutralise common viruses, toxins or bacteria: however, if this switch occurs in an infant when antibody levels are low, this could be a window of vulnerability during which infants are at an increased risk of death if uncontrolled inflammatory responses are induced by infectious agents or their products.     

Infectious agents, the inflammatory responses of infants and sudden infant death syndrome (SIDS)

There is no convincing epidemiological or pathological evidence that particular infectious agents cause sudden infant death syndrome (SIDS); therefore, we have explored the concept that synergy between bacterial endotoxins, exotoxins or viruses might elicit inflammatory responses during a period when the infant's endocrine system is less able to 'damp down' the effects of powerful mediators such as tumour necrosis factor or to maintain glucose homoeostasis which is affected by these mediators. This hypothesis is discussed with reference to the recent decline in the number of cot deaths.     

Prenatal nicotine alters vigilance states and AchR gene expression in the neonatal rat: implications for SIDS

Maternal smoking is a major risk factor for sudden infant death syndrome (SIDS). The mechanisms by which cigarette smoke predisposes infants to SIDS are not known. We examined the effects of prenatal nicotine exposure on sleep/wake ontogenesis and central cholinergic receptor gene expression in the neonatal rat. Prenatal nicotine exposure transiently increased sleep continuity and accelerated sleep/wake ontogeny in the neonatal rat. Prenatal nicotine also upregulated nicotinic and muscarinic cholinergic receptor mRNAs in brain regions involved in regulating vigilance states. These findings suggest that the nicotine contained in cigarette smoke may predispose human infants to SIDS by interfering with the normal maturation of sleep and wake.     

The protective effect of breast feeding in relation to sudden infant death syndrome (SIDS): II. The effect of human milk and infant formula preparations on binding of Clostridium perfringens to epithelial cells

Breast feeding is known to protect an infant against gastrointestinal pathogens and epidemiological studies indicate that compared to breast fed infants, formula fed infants are at a greater risk of dying from sudden infant death syndrome (SIDS). Many SIDS infants have symptoms of gastrointestinal infections prior to death and one gastrointestinal pathogen associated with SIDS is Clostridium perfringens. Studies have found that a significantly higher number of formula fed SIDS infants have C perfringens and its enterotoxin in their faeces compared to breast fed infants. The aim of the study was to compare the effects of human milk and infant formula on binding of C perfringens to epithelial cells. Two protocols were used to assess the effect of human milk and infant formula to inhibit binding of C perfringens to epithelial cells. Binding was assessed by flow cytometry. For the in vivo protocol which more closely represents interactions on the mucosal surface, breast milk enhanced bacterial binding but infant formula caused inhibition of binding; however for the in vitro method, both human milk and infant formula resulted in consistent enhancement of binding. Flow cytometry studies indicated that enhancement of binding was due to the formation of bacterial aggregates. Lewis(a) and Lewis(b) antigens, found in both breast milk and infant formula, inhibited C. perfringens binding in a dose dependent manner. The Lewis(a) and Lewis(b) antigens in human milk and infant formula can inhibit C. perfringens binding to epithelial cells. While infant formula reduced binding of C. perfringens to epithelial cells in the experiments carried out with the in vivo protocol, the protective effects of breast feeding in relation to colonisation with C. perfringens are more likely to be due to formation of bacterial aggregates. These findings have implications for improving infant formula preparations.     

Maternal proximity and infant CO2 environment during bedsharing and possible implications for SIDS research

Sudden infant death syndrome (SIDS) is the leading cause of human infant mortality after the neonatal period in Western countries. Recently, child care practices have been shown to be important in determining infant vulnerability to SIDS. However, very little is known about the impact of parent-infant cosleeping on infant sleep physiology and behavior and SIDS risk. This reflects the failure of Western societal research paradigms to appreciate the human infant's evolutionary history of cosleeping, the recency of the emergence of solitary infant sleeping as a practice and the fact that parent-infant cosleeping is still the preferred sleeping arrangement for the majority of contemporary societies. Incorporating current hypotheses on the mechanisms of SIDS, we have hypothesized that the comparatively sensory-rich cosleeping environment might be protective against SIDS in some contexts. As a first step to characterize cosleeping environments, this investigation is aimed at assessing, in routinely bedsharing mothers and infants, their relative sleeping positions and the potential for sleeping in close face-to-face proximity and for infant exposure to increased environmental CO2 produced by maternal respiration. The latter is important in that breathing elevated levels of CO2 can have diverse effects, ranging from respiratory stimulation at low levels to suffocation at very high levels. Two related laboratory studies were performed. In the first, all-night videotapes of 12 healthy, routinely bedsharing mother-infant pairs were analyzed for sleeping positions and time spent in face-to-face orientation and distances separating their faces. Infants were 11–15 wk old. Mothers predominantly positioned themselves on their sides facing their infants, with the infants placed either supine or on their sides. Mothers and infants slept oriented face-to-face for 64 ± 27% (S.D.) of non-movement time, with distances less than 20 cm commonly separating their faces. In the second study, concentrations of CO2 in air were measured in six young women at distances of up to 21 cm from their nares. Peak expiratory CO2 concentrations remained above 1.0% at distances up to 9 cm and above 0.5% at 18 cm. Both baseline and peak CO2 levels were further increased at all distances when measured within a partial air pocket created to simulate a bedding environment sometimes seen during bedsharing. We conclude that during bedsharing there is potential for 1) a high degree of face-to-face orientation and close proximity and consequently 2) increased environmental CO2, as a result of maternal respiration, to non-lethal levels that might stimulate infant respiration. The close proximity would also maximize the sensory impact of the mother on the infant through other modalities. We also suggest that bedsharing may minimize prone infant positioning, a known risk factor for SIDS. Am J Phys Anthropol 103:315–328, 1997. © 1997 Wiley-Liss, Inc.