Animal models used to test the interactions between infectious agents and products of cigarette smoked implicated in sudden infant death syndrome

Animal test systems are reviewed that have relevance to sudden infant death syndrome (SIDS) are reviewed. These test interactions between infectious agents (or their toxins) and products of cigarette smoke. Infectious agents implicated in SIDS include members of the enterobacteria and clostridia, Staphylococcus aureus and Streptococcus pyogenes. Smoking is thought to be the single most preventable cause of SIDS. Tobacco smoke contains many extremely toxic products including cyanide and nicotine. Many animal test systems are available to examine the potency of bacterial toxins and smoke-derived components. These include mice, hamsters, rats and chick embryos. Such systems reveal synergy between bacterial toxins, especially endotoxin and superantigens. They have also demonstrated potentiation of low levels of bacterial toxin by low levels of both nicotine and its primary metabolite, cotinine. These findings suggest a possible causal explanation for the fact that passive exposure to cigarette smoke is a risk factor in sudden infant death syndrome.     

The common bacterial toxins hypothesis of sudden infant death syndrome

The background to the common bacterial toxin hypothesis of sudden infant death syndrome is presented. The idea is that some cases of sudden infant death syndrome are due to the lethal effects of nasopharyngeal bacterial toxins which can act synergistically to trigger the events leading to death. The concept is consistent with the age distribution of sudden infant death syndrome, the winter excess of cases and the role of prone sleeping and passive exposure to cigarette smoke. A number of laboratory-based investigations are described. There is an increased isolation of staphylococci and Gram-negative bacilli from sudden infant death syndrome infants compared with age- and season-matched healthy infants. Bacteria from sudden infant death syndrome infants interact synergistically to cause sudden death in gnotobiotic weanling rats. Bacterial toxins implicated in sudden infant death syndrome interact synergistically to cause death in chick embryos. Nicotine in very low doses potentiates the lethal effect of toxin combinations in chick embryos. Staphylococcal toxins and endotoxins have been demonstrated in sudden infant death syndrome tissues, antibodies to endotoxins are low in sudden infant death syndrome cases and the prone sleeping position leads to pooling of secretions in the upper airways, increasing the risk of bacterial growth and toxin production. If the hypothesis is correct, then there is the possibility of a further reduction in the incidence of sudden infant death syndrome based on immunisation against the toxins involved.     

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.     

The effect of prone posture on nasal temperature in children in relation to induction of staphylococcal toxins implicated in sudden infant death syndrome

The incidence of sudden infant death syndrome (SIDS) has declined in response to campaigns discouraging the prone sleeping position. Recent work suggests some SIDS death may be in response to bacterial toxins produced in the upper airway. A minimal temperature of 37 degrees C is required for induction of the pyrogenic toxins of Staphylococcus aureus identified in many SIDS infants. This aim of this study was to test the hypothesis that the prone position raises the temperature of the upper airways in children. A pilot study of 10 children (aged 3-8) and a main study of 30 children were carried out. Nasal septal temperatures were measured with an infra-red thermometer with the subjects in upright and prone positions under controlled conditions of ambient temperature and humidity. In both the pilot study and main study, nasal temperatures in the prone position were significantly higher (P < 0.01) Five subjects' prone readings were 37 degrees C or higher. These findings suggest that lying prone raises the upper airway surface temperature towards that required for toxin production. This could be one means by which the prone sleeping position contributes to the risk of SIDS.     

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.     

Used cot mattresses as potential reservoirs of bacterial infection: nutrient availability within polyurethane foam

Aim: To evaluate possible source of nutrients for bacterial growth within polyurethane (PU) foam of used cot mattresses as determinants of bacterial population density. Methods and Results: Used infant mattresses (n = 30) were analysed for bacteria capable of degrading colloidal PU and for aqueous soluble chemical components (aromatic amines, ammonium ions, phosphates and protein). Mattress type (waterproof cover vs exposed PU foam at the infant‐head region), mattress age and previous use by another child were evaluated as factors that could influence the measured parameters. The levels of protein extracted from PU foam were (i) significantly (P = 0·0019) higher for mattresses lacking a waterproof cover at the infant‐head region and (ii) positively correlated with both culturable bacterial population densities of the PU foams and extent of growth of Staphylococcus aureus on aqueous leachates. No statistically significant (P > 0·05) associations between other measured parameters and mattress type/use factors were identified. Conclusions: Infant use of cot mattresses with exposed PU foam leads to accumulation of proteins within the PU, which can promote bacterial growth. Significance and Impact of the Study: The study provides a mechanistic explanation for increased levels of bacteria associated with exposed PU of cot mattresses. In the context of the common bacterial toxins hypothesis for the sudden infant death syndrome (SIDS), this could explain the lowered risk of SIDS associated with use of a waterproof cover above the mattress.     

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.     

Endotoxin in blood and tissue in the sudden infant death syndrome

Although the explanation for sudden infant death syndrome (SIDS) remains unknown, an increasing body of evidence now exists to suggest a possible role for bacterial toxins in the aetiology, and a number of investigators have considered that endotoxaemia could explain some of the associated features. Following the development of an animal model which confirmed that endotoxaemia could be detected after death, we studied endotoxin levels in blood and tissue samples taken at autopsy from SIDS infants, child controls and adult controls. There were significant correlations between endotoxin levels in blood and the various organs sampled particularly in SIDS cases and child controls, and blood endotoxin levels in SIDS cases were higher in those infants where there was histological evidence of mild to moderate inflammation. However, overall no significant differences were found between endotoxin levels in blood or tissue in the three study groups. Further studies into possible actions or interactions of endotoxin in SIDS are required.     

Preliminary investigation of lethally toxic sera of sudden infant death syndrome victims and neutralisation by commercially available immunoglobulins and adult sera

The aim of the study was to test the hypotheses (i) that sudden infant death syndrome sera are toxic to 11-day old chick embryos and (ii) that such a toxicity can be counteracted by immunoglobulin or adult sera. Serum samples from 11 SIDS victims and five controls were tested for lethal toxicity in the chick embryo bioassay. Five serum samples were used to challenge chick embryos injected with the following: sudden infant death syndrome serum plus Hank's balanced salt solution; Hank's balanced salt solution alone; sudden infant death syndrome serum plus 3% w/v commercial immunoglobulin; sudden infant death syndrome serum plus 6% w/v immunoglobulin; sudden infant death syndrome serum plus pooled sera of 40 healthy adults. Results obtained revealed that Hank's balanced salt solution, the pooled adult serum and the commercial immunoglobulin were all non-lethal, in the chick embryo test system. By contrast. 10 sudden infant death syndrome victims yielded sera containing lethal levels of toxin(s) compared to 2/5 controls which was statistically significant (P < 0.05, Fischer's exact test). In the tests of sudden infant death syndrome serum plus immunoglobulin or pooled adult serum, the lethality of sudden infant death syndrome serum was abolished in all cases. The reduction in toxicity of individual sudden infant death syndrome serum plus immunoglobulin or pooled adult serum was often statistically significant (P<0.05-P<0.00005, Fischer's exact test). We conclude that lethal levels of toxin are present in sudden infant death syndrome sera and that they can be neutralised by normal immune serum. These results indicate that passive immunisation is a potential treatment to protect babies considered at risk from sudden infant death syndrome.     

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.     

Infection and food: a factor in sudden infant death syndrome?

Despite the identification of risk factors for sudden infant death syndrome (SIDS) and decreased SIDS rates in many countries, there is still no coherent, widely accepted, mechanistic explanation for SIDS. As an extension of our work on the infectious aetiology of SIDS, we have explored the prediction that infectious agents might reach susceptible infants and babies, via particular sources of food. In this ecological study, we demonstrated significant correlations between SIDS rates and exposure to meat from some sources, and we propose that more detailed studies be carried out.     

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.     

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.     

Sleeping position in infants over 6 months of age: implications for theories of sudden infant death syndrome

The aim of this study was to determine the prevalence of prone and supine sleeping in infants aged 0-12 months and relate this to changes in the number of cases of sudden infant death syndrome (SIDS) since 1985. Seventy-two babies, 38 male and 34 female, were followed for the first 18 months of life with regular home visits and sleeping position was recorded. In addition, data on the number of cases of SIDS in England and Wales between 1985 and 1995 were analysed. All babies slept supine for the first 5 months of life, but once they could turn over in their cots (mean age 7.34 months, range 5-11 months) the majority slept prone. By 11 months of age, 53 regularly slept prone (73%), 95% CI +/- 19.8%), while 11 slept supine, three adopted the side position and five varied from night to night. The number of cases of SIDS in infants aged 7-11 months has fallen significantly (P<0.0001) in a period in which the prevalence of prone sleeping, in that age group, has not changed. The most plausible explanation for this paradoxical result is that supine sleeping in the first 5 months of life reduces the absolute risk of SIDS in the second 6 months of life even though most babies are then sleeping prone. It is suggested that reduced exposure to nasopharyngeal bacterial superantigens in babies sleeping prone might explain this effect.     

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.     

Staphylococcal enterotoxin genes are common in Staphylococcus aureus intestinal flora in Sudden Infant Death Syndrome (SIDS) and live comparison infants

Pathological and epidemiological findings in sudden infant death syndrome (SIDS) suggest an infectious aetiology with indications of involvement of staphylococcal enterotoxins (SEs). While SEA, SEB and SEC have been found in the sera and tissues of SIDS cases, little is known about the role of intestinal Staphylococcus aureus or the roles of later-described toxins SEE, SEG, SEH, SEI and SEJ in SIDS. We used a molecular-based approach to define whether the intestinal tract could be a source of SEs to support the staphylococcal toxic shock hypothesis for SIDS. Intestinal contents from 57 SIDS infants and faeces from 79 age- and gender-matched live comparison infants were cultured and tested for S. aureus and sea-b-c-e-g-h-j and TSST using PCR. High proportions of infants in both groups carried toxigenic and nontoxigenic S. aureus . Significantly greater proportions of SIDS compared with comparison babies were positive for S. aureus (68.4% vs. 40.5%) and for SE genes (43.8% vs. 21.5%), suggesting a possible role in SIDS. The results indicate that colonization by S. aureus with SE genes is common in infants; however, their detection is unlikely to be a strong predictive tool for SIDS. Other factors (including immune response) may reveal a specific susceptibility to SEs in SIDS infants.     

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.     

Inflammatory responses in sudden infant death syndrome – past and present views

Sudden infant death syndrome (SIDS) is sudden unexpected death in infancy for which there is no explanation based on commonly accepted diagnostic criteria; however, half of the victims have had slight signs of infection prior to death. Such slight infection with fever is an important risk factor in combination with a prone sleeping position, especially in infants between 2 and 4 months of age. The purpose of this review is to summarise findings that support the theory that a significant part of cot deaths may be due to an overreaction to otherwise harmless infections. Such factors are mucosal immune stimulation, cytokines in the cerebrospinal fluid and hypoxanthine levels in vitreous humour. The review aims at explaining why we believe that a slight infection combined with a prone position, a warm environment and a vulnerable age period may trigger a vicious circle leading to death.