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.     

Immune and inflammatory responses in sudden infant death syndrome

Infancy is a time of unparalleled infection exposure. Coming from the privilege of the uterus, the newborn infant must make appropriate immune responses following infection that eliminates the infection but protects the host. There is evidence that in sudden infant death syndrome (SIDS) subjects there is a background of recent 'trivial' infection and immunological/inflammatory reactivity. This immunological/inflammatory reactivity is seen in enhanced pulmonary immunoglobulins and T-cell activation. It may be that in certain SIDS cases a trivial infection triggers an exaggerated inflammatory response, inducing cytokine cascades and eventual demise of the infant.     

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.     

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.     

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.     

Microbiology in sudden infant death syndrome (SIDS) and other childhood deaths

The usefulness of post-mortem microbiology in the assessment of sudden unexpected deaths in infants and children has been debated by many pathologists. In our centre, microbiological investigations have been part of the post-mortem protocol for investigation of sudden deaths in infants and children for the past 12 years. The objective of this study was to review the microbiological findings for infants and children examined by our unit during the past 4 years in relation to gross and histological findings of the autopsy and the medical and social histories of the children. We reviewed 57 consecutive sudden deaths in infants and children examined by our Referral Centre between November 1994 and October 1998. These 57 sudden deaths were aged from 1 day to 4 years and 9 months including 40 cases of sudden infant death syndrome (SIDS) and 17 non-SIDS deaths. Results of the microbiological investigations of tissues and body fluids were assessed during the case review with reference to histological shock signs, severe gastric aspiration, and signs of acute thymic involution. Bacteria alone or in association with viruses were identified in 45/57 (79%) cases including 34/40 (85%) SIDS. The most frequent bacterial isolate was Escherichia coli (27), and the virus identified most frequently was enterovirus (8). C-reactive protein was increased in 10 out of the 42 cases tested including 8/32 (25%) SIDS. Significant gastric content aspiration was found in 17/57 (29.8%) including 13/40 (32.5%) SIDS. Histological signs of shock were present in 33/55 (60%) cases including 22/39 SIDS (56.4%). The microbiological findings were positive for 27/33 (81.8%). We conclude that post-mortem microbiology is essential in sudden death investigation. The conclusion that a death is unexplained if no microbiology was done is not valid, even if in some cases it may be difficult to know precisely in what way the pathogen contributed to the death.     

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.     

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.     

Exposure to cigarette smoke, a major risk factor for sudden infant death syndrome: effects of cigarette smoke on inflammatory responses to viral infection and bacterial toxins

Exposure to cigarette smoke is a major risk factor for sudden infant death syndrome and also for respiratory infections in children. It has been suggested that toxigenic bacteria colonizing the respiratory tract might play a role in some cases of sudden infant death syndrome and nicotine has been demonstrated to enhance the lethality of bacterial toxins in a model system. Pyrogenic toxins of Staphylococcus aureus have been identified in tissues of infants who died of sudden infant death syndrome. It has been suggested that some of these deaths were due to induction of inflammatory mediators by infectious agents during a period when infants are less able to control these responses. The aim of this study was to assess the effects of a water-soluble cigarette smoke extract on the production of tumor necrosis factor alpha and nitric oxide from human monocytes in response to staphylococcal toxic shock syndrome toxin 1 or infection of the monocytes with respiratory syncytial virus. Cell culture supernatants were examined by a bioassay using mouse fibroblasts (L-929 cell line) for tumor necrosis factor alpha activity and by a spectrophotometric method for nitrite. Compared with monocytes incubated with medium only, monocytes incubated with any of the factors or their combinations tested in the study released higher levels of tumor necrosis factor alpha and lower levels of nitric oxide. Incubation with cigarette smoke extract increased tumor necrosis factor alpha from respiratory syncytial virus-infected cells while it decreased tumor necrosis factor alpha from cells incubated with toxic shock syndrome toxin. Incubation with cigarette smoke extract decreased the nitric oxide production from respiratory syncytial virus-infected cells while it increased the nitric oxide production from cells incubated with toxic shock syndrome toxin. Monocytes from a minority of individuals demonstrated extreme tumor necrosis factor alpha responses and/or very high or very low nitric oxide. The proportion of samples in which extreme responses with a very high tumor necrosis factor alpha and very low nitric oxide were detected was increased in the presence of the three agents to 20% compared with 0% observed with toxic shock syndrome toxin 1 or 4% observed with cigarette smoke extract or respiratory syncytial virus.     

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.     

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.     

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.     

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.     

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.     

Immunological evidence for a bacterial toxin aetiology in sudden infant death syndrome

Toxin-specific antibodies to clostridial, enterobacterial and staphylococcal toxins implicated in sudden infant death syndrome were studied in sera from sudden infant death syndrome infants and a comparison group of infants (babies with phenylketonuria). The results indicated a higher proportion of sera from sudden infant death syndrome infants contained IgA that bound to clostridial and enterobacterial toxins but a higher proportion of sera from the phenylketonuria comparison group contained IgA that bound staphylococcal toxins. The higher proportion of serum samples with IgG and IgM in the healthy comparison babies serum probably indicated immunity in this group of babies to these toxins. The effect of gender and age had a minimal effect on the incidence of these antibodies. The presence of toxin-specific antibodies in sudden infant death syndrome and the of comparison infants suggests that all infants are exposed to these toxins and most babies successfully overcome the toxic challenge. Some infants with predisposing risk factors (temperature change, smoking, infection, immune development, sleeping position, etc.) that could affect the baby's immune competency could succumb to these and possibly other toxins. This immunological evidence further strengthens the view that bacterial toxins are a significant cause of sudden infant death syndrome.     

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.     

Effect of time post mortem on the concentration of endotoxin in rat organs: implications for sudden infant death syndrome (SIDS)

The aim of the study was to test the following hypotheses: (i) that endotoxin injected 40 min prior to death can be detected in rat organs post mortem and (ii) that endotoxin levels do not change with increasing time post mortem. Rats were injected with or without endotoxin in buffered saline, 40 min prior to being killed. Endotoxin levels in rat organs were assessed using a Limulus amoebocyte assay. The effect of storage time post mortem was assessed by following various storage regimes at 25 degrees C and 8 degrees C. Significant differences (P = < 0.001) in endotoxin levels of all samples tested were found between rats injected with and without endotoxin. A significant increase in detectable endotoxin was observed between 0 h and 6 h post mortem in rats injected with or without endotoxin. No difference in detectable endotoxin levels in the kidney, liver and spleen was observed from 30 h to 102 h post mortem in rats injected with or without endotoxin. In rats injected with endotoxin, detectable endotoxin levels in the heart were raised between 0 h and 6 h, 6 h and 54 h, and 30 h and 78 h. Endotoxin injected into rats 40 min prior to death can be detected post mortem. For rats injected with saline or endotoxin prior to death levels in the kidney, liver and spleen were not affected by storage at 8 degrees C for 30-102 h, after initial storage at room temperature for 6 h. Levels of endotoxin detected in the hearts of rats injected with saline were not affected by storage up to 102 h. In rats injected with endotoxin prior to death, detectable levels in the heart were significantly affected by increasing time in storage.     

Detection of pyrogenic toxins of Staphylococcus aureus in sudden infant death syndrome

It has been suggested that pyrogenic toxins of Staphylococcus aureus are involved in the series of events leading to some cases of sudden infant death syndrome (SIDS). The objectives of the study were to screen tissues from SIDS infants for pyrogenic toxins and to compare incidence of identification of these toxins among these infants from different countries. An enzyme-linked immunosorbent assay (ELISA) and a flow cytometry method were used to screen body fluids and frozen or formalin-fixed tissues for pyrogenic toxins of S. aureus, toxic shock syndrome toxin 1 (TSST), staphylococcal enterotoxins A (SEA), B (SEB), and C1 (SEC). Toxins were identified in tissues of 33/62 (53%) SIDS infants from three different countries: Scotland (10/ 19, 56%); France (7/13, 55%); Australia (16/30, 53%). In the Australian series, toxins were identified in only 3/19 (16%) non-SIDS deaths (chi2 = 5.42, P < 0.02). The flow cytometry method was useful for toxin detection in both frozen and fixed tissues, but ELISA was suitable only for frozen tissues or those fixed for less than 12 months. Identification of pyrogenic toxins in > 50% of SIDS infants from three different countries indicated further investigation into the role the toxins play in cot deaths might result in development of additional measures to reduce further the incidence of these infant deaths.     

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.     

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.