The role of bacterial toxins in sudden infant death syndrome (SIDS).

There is increasing evidence for the involvement of bacterial toxins in some cases of sudden infant death syndrome (SIDS), particularly the pyrogenic toxins of Staphylococcus aureus. This had led to the hypothesis that some SIDS deaths are due to induction of inflammatory mediators by infectious agents or their products during a period in which the infant is unable to control these normally protective responses. The genetic, developmental and environmental risk factors identified for SIDS are assessed in relation to frequency or density of mucosal colonisation by toxigenic bacteria and their effects on induction and control of inflammatory responses to the toxins.

Why is smoking a risk factor for sudden infant death syndrome?

Smoking is a major risk factor for both Sudden Infant Death Syndrome (SIDS) and respiratory tract infections. Such infections, both viral and bacterial, also increase the SIDS risk. This study investigated the effect of cigarette smoke at two stages of infection: 1) mucosal surface colonization; 2) induction and control of inflammatory responses. For colonization, RSV or influenza A infected cells bound several bacterial species in significantly higher numbers due to increased expression of host cell antigens. Buccal epithelial cells from smokers bound significantly more bacteria. For Staphylococcus aureus, this was associated with increased tar levels. Some SIDS deaths have been proposed to result from high levels of pro-inflammatory mediators elicited by infection and/or cigarette smoke during a developmental period when infants are less able to control inflammatory responses. Inflammatory reponses were compared between blood samples from smokers (n = 42) and non-smokers (n = 60) stimulated with TSST-1 or LPS. Non-smokers had significantly higher IL-6 (P = 0.011), IFN (P = 0.003) and IL-10 (P = 0.000) baseline levels. Non-smokers had higher IFN (P = 0.008) and IL-1 (P = 0.001, 0.007) responses to LPS and higher IL-10 responses to TSST-1 (P < 0.05) and LPS (P < 0.000). This study highlights that smoking increases the SIDS risk by greater susceptibility to viral and bacterial infections and enhanced bacterial binding after passive coating of mucosal surfaces with smoke components. In animal models, IL-10 reduced the lethal effect of staphylococcal toxins. In this study, smokers had lower IL-10 responses toTSST-1 and LPS. Dose response effects of cigarette smoke exposure needs to be established in relation to inflammatory response control and infantile infections.

Evidence for a genetic component in sudden infant death syndrome.

There is increasing evidence that inflammatory responses have been elicited in some Sudden Infant Death Syndrome (SIDS) infants and that these responses are under genetic control. The objective of this study was to investigate the hypothesis that the cytokine responses of SIDS parents (n = 41) differed significantly from control donors (n = 61). Blood samples were stimulated with the staphylococcal toxin TSST-1 and LPS from Eschericia coli and assessed for production of TNF, IL-1, IL-6, IFN and IL-10. In response toTSST-1 (P < 0.02) and LPS (P < 0.002), SIDS parents produced higher levels of IL-1 than the controls. SIDS parents produced higher levels of IFN in response to TSST-1 compared to LPS (P < 0.001) although in response to LPS, the IFN (P = 0.0008) and IL-6 (P < 0.0002) responses of the SIDS parents were lower than those of the controls. For TNF and IL-10, there was little difference between the two groups unless the effect of smoking was considered. As part of this work, a small pilot genotyping study was carried out using DNA from SIDS parents (n = 10), control donors (n = 10) and Bangladeshi subjects (n = 10). An IFN polymorphism (3/3) was found in 40%,15.4% and 0% of donors respectively. Staphylococcal toxins have been identified in SIDS infants therefore this study highlights the importance of assessing IL-1 levels. Determination of cytokine polymorphisms and consideration of interactions between these and environmental factors such as smoking in high, average and low risk ethnic groups will assist in establishing the contribution of these factors to an infant's susceptibility to 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.

Pyrogenic toxins of Staphylococcus aureus in sudden unexpected nocturnal deaths in adults and older children: factors influencing the control of inflammatory responses to toxic shock syndrome toxins.

Sudden unexpected nocturnal deaths (SUND) occur in young immigrant workers, mainly from south-east Asia, who are employed in countries such as Singapore and Saudi Arabia. Pyrogenic toxins of Staphylococcus aureus have been identified in two cases of sudden unexpected death in adults in the UK and it has been suggested that these or other toxins with superantigen properties might induce strong inflammatory responses leading to sudden unexpected nocturnal deaths. The objectives of the present study were (1) to assess the levels of antibodies to pyrogenic staphylococcal toxins in the general population, (2) to assess the levels of IgG to the toxins needed to reduce the production of inflammatory mediators by 50% in a model system, (3) to assess in a model system the effects on inflammatory responses to toxic shock syndrome toxin-1 (TSST) of cortisol levels present at night, during the day and under conditions of physiological stress. Enzyme linked immunosorbent assays were used to assess levels of IgG to TSST, staphylococcal enterotoxin A (SEA) and staphylococcal enterotoxin C (SEC). Human buffy coats were used to examine the effect of IgG to the toxins for neutralising activity and the effect of cortisol on induction of inflammatory mediators. Tumour necrosis factor alpha (TNF-alpha) was detected by a bioassay with L929 cells, interleukin-6 (IL-6) and interleukin-10 (IL-10) were measured by an enzyme linked immunosorbent assay. IL-6 and TNF-alpha levels elicited by the toxins were not reduced by night time levels of cortisol (5-10 microg dl(-1)) levels. Day time levels of cortisol (10-20 microg dl(-1)) significantly inhibited IL-6 production but not TNF-alpha in responses. Stress levels of cortisol (40 80 microg dl(-1)) significantly reduced all three cytokines earlier than the normal day time levels. The majority of the population tested had sufficient antibodies to reduce TNF-alpha and IL-6 responses elicited by TSST and SEC in the model system. In the age range in which most sudden unexpected nocturnal death cases occur (20-39 years), males had significantly lower levels of IgG to TSST compared with females. If these toxins play a role in precipitating the series of events leading to sudden unexpected nocturnal death, the higher levels of IgG to the toxins observed in females might explain partly the much higher prevalence of these deaths among men in this age range. If inflammatory responses play a role in sudden unexpected nocturnal death, the inability of the night time levels of cortisol to control IL-6 and TNF-alpha in the model system might reflect these interactions in vivo. The methods developed for detection of the toxins in tissue samples and the quantitative IgG assays for anti-toxins can be applied to investigation of SUND victims to test the hypothesis that some of these deaths are precipitated by pyrogenic staphylococcal toxins.