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Published online before print October 4, 2005
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* Faculty of Health, School of Biomedical Sciences, University of Newcastle, and Hunter Medical Research Institute, New South Wales, Australia;
Immunology and
Genetics, Hunter Area Pathology Service, John Hunter Hospital, New Lambton, New South Wales, Australia; and
Medical Microbiology and
¶ Forensic Medicine Unit, University of Edinburgh, United Kingdom
1 Correspondence: HAPS Immunology, John Hunter Hospital, Lookout Road, New Lambton, NSW 2300, Australia. E-mail: Caroline.Blackwell{at}newcastle.edu.au
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ABSTRACT |
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Key Words: cot deaths • bacterial toxins • ethnicity • cigarette smoke • gene polymorphisms
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INTRODUCTION |
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The major risk factors for SIDS parallel those for serious bacterial infections in infants and young children, particularly infections of the respiratory tract (Table 1 ). These include genetic, developmental, and environmental factors, which could contribute to enhanced colonization of infants by potentially pathogenic microorganisms or severity of inflammatory responses to infection. The genetic and developmental factors are not modifiable; therefore, the campaigns to reduce the risks of SIDS have concentrated on environmental factors such as sleeping position, exposure to cigarette smoke, and prevention of overheating.
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EVIDENCE OF INFLAMMATORY RESPONSES IN SIDS |
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(TNF-) or other vasoactive compounds could contribute to anaphylactic-like responses. Identification of pyrogenic staphylococcal toxins in brain tissue has been proposed as one explanation for the brain edema noted in many SIDS infants [28
]. Evidence of immune/inflammatory activation in tissues and secretions of SIDS infants has been reported [27
, 28
, 31
, 34
].
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INFECTION AND SIDS—VIRUSES OR BACTERIA? |
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By definition, invasive bacterial infections are explainable causes of death and therefore, not involved in SIDS. Although virus infection might be an important cofactor in the series of events leading to death, there is little evidence that SIDS is a result of an unrecognized viral disease [49 ]. Toxigenic bacteria and/or their toxins have been identified in SIDS infants in studies from several different countries (Table 3 ). Many bacterial species express molecules that act as superantigens. The cytokines they induce, if not moderated, can cause tissue damage or death. They are responsible for the pathology of septic and toxic shock [82 ]. It has been suggested that SIDS is a result of rapid, uncontrolled release of inflammatory mediators in response to infectious agents or their toxins [83 ]. A survey of SIDS infants found little or negligible levels of antibodies to bacterial toxins [37 , 38 ]. In the absence of protective antitoxins, the inflammatory mediators induced by these toxins could produce significant changes in each of the physiological mechanisms proposed to explain these deaths— hypoxia, poor arousal, hypoglycaemia, vascular shock, cardiac arrythmias, hyperthermia, and anaphylaxis [84 , 85 ].
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Staphylococcal toxins can kill healthy adults or older children [89 , 90 ]. Staphylococcal enterotoxin A (SEA), B (SEB), C (SEC), or the toxic shock syndrome toxin (TSST) were identified in the tissues from over 50% of 105 SIDS cases from five countries (Table 4 ) [52 , 85 ]. Toxins produced by staphylococci isolated from SIDS infants varied by geographic areas. Isolates from Scottish infants predominantly produced SEB and SEC. Isolates from SIDS infants in Hungary predominantly produced SEA, and SEC was produced by only one isolate obtained from a healthy child [53 ]. TSST was identified in tissues of SIDS infants from Australia [52 ].
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A second common bacterial toxin is endotoxin of Gram-negative bacteria. These organisms are isolated frequently from the upper respiratory tract of infants who died of SIDS [19 , 30 ], and they are also found in significant numbers of older infants sleeping in the prone position [86 ]. Measurement of endotoxin in blood or tissues is controversial, even among live subjects [93 ]; however, in carefully designed animal studies, endotoxin levels in blood and a range of tissues were higher in rats injected with endotoxin immediately before death compared with control animals. The results were stable up to 4 days after death [94 ].
There were no significant differences in endotoxin levels in a study of blood and tissue samples of SIDS infants and controls; however, blood endotoxin levels were higher in SIDS infants in whom there was histological evidence of mild to moderate inflammation [95 ]. Experimental studies indicate that risk factors such as virus infection or presence of other bacterial toxins can potentiate the effects of endotoxin [96 , 97 ].
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ANALYSIS OF THE RISK FACTORS FOR SIDS IN RELATION TO SUSCEPTIBILITY TO INFECTION |
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STAGE 1. BACTERIAL COLONIZATION |
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Genetic risk factors
Ethnic group
Children in some Indigenous groups are colonized earlier and more heavily by respiratory pathogens than children of European origin [99
, 100
]. The basis for this is not known but might reflect differences in expression of human cell surface antigens, which act as receptors for microorganisms [101
], or environmental factors such as exposure to cigarette smoke or closer physical interactions with older siblings or other family members.
Gender
Male infants sleeping prone, with or without infection, had significantly higher counts of Gram-positive cocci (including S. aureus) compared with females [86
].
Developmental risk factors
Age range
During the 2- to 4-month age range, 80–90% of infants express the Lewisa antigen, and it was identified in respiratory secretions of 71% of SIDS infants examined in one study [102
]. This antigen is one of the epithelial cell receptors for three species of bacteria implicated in SIDS: S. aureus [102
103
104
]; B. pertussis [105
]; and C. perfringens [106
]. By 18–24 months, the antigen is usually found on red cells of 20–25% of children, a proportion similar to that observed in adults [107
]. The decline in expression of Lewisa parallels the decrease in frequency of isolation of S. aureus from healthy infants [102
].
Environmental risk factors
Prone sleeping position
Prone sleeping is a major risk factor for SIDS and implementation of "back to sleep" campaigns has contributed greatly to the worldwide reduction of these deaths. The prone position results in increased numbers of bacteria and an increase in the variety of species in nasal secretions of infants with respiratory virus infections. Increases in bacterial colonization might also be a result of decreased swallowing in the prone compared with the supine position. This is thought to contribute to the higher incidence of otitis media in infants who sleep prone compared with those who sleep in the supine position [108
]. The composition of the nasal flora of the infants sleeping prone resembled that identified in the upper respiratory tract of SIDS infants but was reduced in numbers later in the day when the infant had been upright [86
].
Exposure to cigarette smoke
"Passive" smoking implies a lower level of exposure to toxic components of cigarette smoke; however, some infants have levels of cotinine in their body fluids equivalent to those found in active smokers [109
].
Smokers are more frequently colonized by staphylococci [110 ]. In experimental models, buccal epithelial cells (BEC) from smokers bound significantly more S. aureus, B. pertussis, and several Gram-negative bacteria [67 ]. BEC treated with water-soluble extracts of cigarette smoke showed that increasing tar content was associated with increased binding of staphylococci [111 , 112 ], and the "sticky" effects of the extracts were present at dilutions as great as one in 300 [111 ].
Mild upper-respiratory tract infection
As noted above, inflammatory changes in the respiratory tract of SIDS infants are thought to reflect recent infections [113
]. Medical records for 31 SIDS deaths in a Canadian Aboriginal population indicated the majority had symptoms of colds, virus infections, or breathing difficulties [42
].
In an in vitro model using a human epithelial cell line, infection of the cells with respiratory syncytial virus (RSV; types A or B), influenza A, or influenza B significantly enhanced binding of S. aureus [102 ], B. pertussis [105 ], and a variety of other Gram-positive and Gram-negative species [114 115 116 ]. The changes in cell surface antigens, which can act as receptors for some bacterial species, could contribute to the increased binding observed [115 , 116 ].
Breastfeeding
In vitro experiments have demonstrated that glycoconjugates such as the Lewisa and Lewisb antigens in human milk significantly reduce binding of C. perfringens and S. aureus to epithelial cells. Breast milk contains IgA, which can aggregate bacteria, making them easier to expel in mucus. It also contains antibodies specific for some adhesins involved in binding to epithelial cells [104
, 106
].
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STAGE 2. INDUCTION OF TEMPERATURE-SENSITIVE TOXINS |
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Overheating
Other risk factors that could increase the temperature to the permissive range in which the toxins can be induced include viral infection, blockage of nostrils with secretions during respiratory infections, and covering the face with bedding or clothing.
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STAGE 3. RISK FACTORS AFFECTING INDUCTION OR CONTROL OF INFLAMMATION |
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Environmental risk factors
Respiratory viral infections
In model systems, induction of proinflammatory cytokines, which contribute to severity of the host’s responses to infectious agents or their products, can be enhanced greatly by coexisting virus infection [96
, 97
, 119
120
121
]. Priming with an asymptomatic virus infection can significantly reduce the concentration of bacterial toxins needed to induce death [97
, 121
].
Animal models have demonstrated that virus infection can change the cytokine response pattern following administration of sublethal doses of endotoxin, which results in dysregulation of the inflammatory responses. Morbidity and mortality were thought to be related to shock-like effects consistent with inflammatory cytokine responses and production of reactive nitrogen species. Usually, endotoxin induces a regulated series of events which result in a protective inflammatory response. In healthy human volunteers, serum levels of TNF- peak at 1 h after endotoxin administration; this is followed closely by IL-1ß, then IL-6 at 3 h, and IL-10 at 5 h [122
]. Alterations in the kinetics of these events can induce an exaggerated response often seen in septic shock in which proinflammatory cytokines (TNF-, IL-1ß, IL-6, and IFN-
) trigger a cascade of events leading to edema, systemic collapse, decreased blood volume, disseminated intravascular coagulation, organ failure, and death [123
].
Combinations of bacterial toxins
Some of the toxigenic species identified in SIDS have been tested in combination with in vitro models to demonstrate additive or synergistic effects between the toxins [124
].
Cigarette smoke
In an animal model, nicotine significantly enhanced the lethal effect of bacterial toxins [125
]. Cotinine, a metabolite of nicotine, enhanced production of some inflammatory mediators from human monocytes. In the same model system, a water-soluble cigarette smoke extract enhanced TNF- responses of human monocytes infected with RSV and enhanced nitric oxide (NO) production from monocytes exposed to TSST [126
]. Mononuclear cells from smokers showed increased production of proinflammatory cytokines IL-6, IL-1ß, and TNF-. They also had strong proliferative responses to mitogens compared with nonsmokers [127
]. Smokers had lower baseline levels of the anti-inflammatory cytokine IL-10 and lower levels of IL-10 in response to stimulation with TSST or endotoxin [85
]. The relevance of findings for smokers for the health of infants or children is supported by the findings of Daly and colleagues [109
], who reported that some infants have levels of cotinine similar to those found in adults.
Hyperthermia
The physiological effect of hyperthermia in relation to SIDS has been reported to be particularly significant in relation to infection [19
]. Hyperthermia significantly increased production of IL-6 but not IL-1ß in infant rats. In response to muramyl dipeptide (MDP), IL-1ß was increased significantly but not IL-6. MDP, in combination with hyperthermia, significantly increased mortality of the animals [128
]. These results suggest one possible mechanism underlying the protective effect of keeping infants cool, a recommendation of the Reduce the Risks campaigns.
Genetic risk factors
Ethnicity
Well before the campaigns to reduce the risk factors associated with SIDS, the incidence of SIDS among Indigenous groups was higher than those reported for other ethnic groups in the same country. Other groups such as Asian families in the United Sates or Britain had significantly lower incidences of SIDS compared with Caucasian families (Table 5)
. In Australia, there was no evidence to support criticisms that the higher incidence among Indigenous children was a result of bias in diagnosis [11
]. The higher risk of SIDS among Indigenous groups has not decreased as dramatically as those among populations of European origin. Among African American infants, it has been noted that the magnitudes of the differences in deaths as a result of respiratory infections were similar to those for SIDS [12
]. Although cultural and child-rearing practices and socioeconomic factors have been proposed to explain the differences between ethnic groups, there are no definitive data to account for the differences reported.
Among Indigenous groups and African Americans, there is a higher proportion of SNP associated with high levels of proinflammatory responses such as IL-6 and IFN-. There are also higher incidences of SNP associated with low levels of the anti-inflammatory cytokine IL-10 (Table 6
). Not all studies agree on the effects of the polymorphisms on levels of cytokine responses to various stimuli. This could be a result of differences in the model systems examined or other environmental factors. These will be explored further in the next section about control of inflammatory responses.
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) but not females [138
]. Inflammatory responses of rat ileal mucosal membranes exposed to normoxia were compared with responses elicited after 40 min of hypoxia and/or acidosis. Each of the conditions tested induced significant increases in proinflammatory responses by tissues from males compared with tissues from females. Female tissues produced higher levels of anti-inflammatory responses (NO and IL-10), and there was less evidence of mucosal injury. Estradial or testosterone receptor antagonist treatment of male rats decreased gut injury and IL-6 and macrophage inflammatory protein-2 responses [139
].
Control of inflammatory responses
Fatality of infection can be linked to high levels of proinflammatory cytokines; therefore, factors that affect their control need to be considered. In relation to infections and SIDS, there are three major categories to be considered: developmental stage, antibody levels, which are at their lowest during the 2- to 4-month age range and night-time cortisol levels that change dramatically during this period; genetic control of pro- and anti-inflammatory responses; and environmental factors, such as virus infection, overheating, or exposure to cigarette smoke.
Developmental factors
Antibody levels and the protective effects of immunization
As noted above, no, or negligible, levels of antibodies to common bacterial toxins have been detected in sera of SIDS infants compared with live, healthy control infants of the same age [37
, 38
]. In vitro experiments found IgA antibodies to TSST, SEC, and the enterotoxin A of C. perfringens present in human milk. These might neutralize the activities of the toxins before they could diffuse from mucosal surfaces. Pasteurized cow’s milk contains antibodies to the staphylococcal toxins, but infant formula preparations do not [140
]. Among women in the childbearing age range, British–Asian women had higher levels of total IgG and IgG specific for some of the staphylococcal toxins than women of European origin [141
, 142
]. Based on the predictions of the common bacterial toxin hypothesis, these higher levels of antibodies could contribute to low levels of SIDS among Asian infants in Britain. They start life with higher levels of maternal antibodies against toxigenic bacteria in their environment. Indigenous Australian infants also have significantly higher levels of IgG at birth compared with non-Indigenous infants [143
]. Antibodies specific for bacterial toxins implicated in SIDS in sera of Aboriginal Australian infants have not been assessed.
Careful epidemiological studies were carried out following suggestions in the 1980s that immunization triggered SIDS. Major studies in the United States and Britain found that immunization of infants against diphtheria, pertussis, and tetanus (DPT) is associated with protection against SIDS [22 , 23 ]. A year prior to the start of the national campaign in Britain to reduce the risk factors for SIDS in October 1991, there was a major change in infant care practices. In October 1990, childhood immunization, including DPT, was initiated at 2 months rather than 3 months of age for all British infants. Following the change in immunization schedules, there was a significant decrease in SIDS deaths among infants over 2 months of age. The greatest reduction in SIDS deaths in Scotland, England, and Wales was noted at 4 months of age, a pattern that might reflect a booster effect following primary immunization at 2 months of age, followed by further inoculations at 3 and 4 months [144 , 145 ]. A similar trend was observed in Hungary [146 ]. Another suggestion is that the protective effect of early immunization might be a result of earlier switches in the T helper cell type 1 (Th1)/Th2 T cell cytokine pattern of responses [147 ]. In rabbits, the DPT vaccine induced antibodies to the pertussis toxin and also IgG antibodies cross-reactive with some of the pyrogenic staphylococcal toxins identified in SIDS infants [144 ].
Development of circadian rhythm, cortisol levels, and the predominance of night-time SIDS deaths
The majority of SIDS deaths occurs at night or the early hours of the morning, especially those in which there is evidence of infection or exposure to cigarette smoke [19
]. The peak incidence of SIDS occurs during the 2- to 4-month age range, a period in which infants undergo the developmental switch to circadian rhythm, usually between 7 and 16 weeks of age. This physiological switch is detected in many studies by determination of the age at which the core body temperature of infants falls at night to 36.4°C, similar to that of sleeping adults. The period prior to the development of circadian rhythm is suggested to be an "immature" state, as infants who remain in this state for prolonged periods share many of risk factors with SIDS infants [148
]. Evidence against this hypothesis comes from later work. Asian infants stay in the immature state significantly longer than infants of European origin [149
], and Asian infants in Britain have a lower incidence of SIDS than infants of European origin [5
].
In conjunction with the change in body temperature rhythm, there is a dramatic drop in night-time, but not day-time, cortisol levels, the week following the temperature switch. Cortisol suppresses a broad range of inflammatory responses, and during the first 2 months of life, there is a steady decrease in plasma cortisol levels [150
]. Peak responses of TNF-, IL-1, IL-6, and IFN- to infectious agents occur during late evening or early morning when cortisol levels are lowest and the time during which most SIDS deaths occur [151
, 152
]. Cortisol levels similar to those present at night-time in infants following the developmental switch (<5 µg dl–1) had little or no effect on proinflammatory responses (IL-6 and TNF-) elicited from human leukocytes stimulated with TSST; however, levels >10 µg dl–1, found during the day or at night before the physiological changes, reduced proinflammatory responses [153
].
In infants, rectal temperature increased significantly the night following immunization for DPT and H. influenzae type b. Infants in the immature developmental state had a significant increase in urinary cortisol excretion at night and the morning after immunization. Once the circadian pattern had developed, immunization no longer caused an increase in cortisol output [154 ].
The period during which there are low levels of night-time cortisol could be a window of vulnerability for SIDS. If the low levels of cortisol occur when the infant has low levels of IgG, exposure to bacterial toxins with superantigen activities might result in high levels of proinflammatory responses. Remaining in the immature developmental stage for a longer period would have several advantages in relation to susceptibility to inflammatory responses as a result of what would normally be considered minor infections. The high levels of cortisol could contribute to control of inflammatory responses over a longer period, thereby allowing more time for the infant to produce active immunity to environmental bacteria and their products or to make antibodies in response to childhood immunizations, which commence at 6–8 weeks of age.
Interactions between genetic and environmental factors affecting inflammatory responses
For studies about the genetics of inflammation, the most serious confounding factor is ethnicity [155
]. The importance of matching cases and controls for ethnicity is essential to prevent false findings for epidemiological and experimental studies. Studies about the association between SNP and levels of cytokines induced by exposure to various stimuli have provided conflicting data. In experimental studies in which ethnicity has been matched carefully, it is not always possible to control for asymptomatic, chronic infection or the prodromal stage of an infection in which physiological changes have occurred that could alter cytokine responses before overt symptoms are apparent in the donor. Time of day during which blood is collected must be standardized to control for the effects of cortisol in relation to circadian rhythm. Exposure to environmental pollutants such as cigarette smoke also needs to be considered. For nonsmoking adults or young children, effects of passive exposure to cigarette can only be assessed accurately by estimation of cotinine in body fluids.
IL-1ß polymorphisms
IL-1ß has been implicated in the pathogenesis of SIDS in experimental studies in animal models [45
, 128
]. It is a powerful cytokine that can affect several of the physiological responses postulated to contribute to sudden infant death— vascular shock, hypoglycaemia, deep sleep and prolonged apnoea, cardiac irregularities, and fever [84
]. Parents of SIDS children were found to have significantly higher levels of IL-1ß in response to bacterial toxins [85
].
Among populations such as Aboriginal Australians, there is a higher incidence of SIDS and classical infections such as meningococcal disease and otitis media for which immunization is not available [156 ]. Fatal meningococcal infections have been associated with the IL-1B C-511T polymorphism TT genotype [157 ], which results in the overexpression of IL-1ß [158 ]. There were no differences in the distribution of the IL-1B C-511T polymorphism between Bangladeshi and Aboriginal Australian groups; however, both of these showed a significant difference in the distribution compared with Europeans (P=0.000; Table 6 ). The homozygote genotype (CC), predominant among Europeans, was rare among the other two ethnic groups. Leukocytes from European subjects with the TT polymorphism, who were smokers, produced the highest median IL-1ß responses to TSST and endotoxin; however, the numbers were too small for statistical analysis [134 ]. Other studies, which assessed the effect of smoking but not genotype, found enhanced IL-1ß responses to endotoxin among smokers [127 ].
IL-6 polymorphisms
In a Norwegian study, half of the SIDS victims had elevated levels of IL-6 in their CSF [36
]. The concentrations of IL-6 in SIDS infants were comparable with those found in infants dying from infectious diseases such as meningitis and septicaemia. The laryngeal mucosa in SIDS victims with high levels of IL-6 in the CSF also showed signs of immune stimulation with increased numbers of IgA immunocytes and increased expression of human leukocyte antigen-DR in the epithelium [159
]. Many of these infants also showed signs of infection prior to death and were found dead in a prone position.
The only SIDS group for whom we had reliable, local control data was the Australian population, in which the genotypes for SIDS infants were compared with those for parents who had not had a SIDS death in their immediate families. The allele frequencies for the IL-6 G-174C polymorphism for the Australian control population differed significantly from that observed for Australian SIDS infants (
2=8.6, df=2, P=0.02); only 24/63 (38%) controls had the high, proinflammatory GG genotype compared with 11/19 (58%) SIDS infants [135
]. For a second set of 47 SIDS infants from Germany, we compared the distribution of genotype frequencies with those for a healthy, control population for a study of the role of IL-6 polymorphisms in sepsis. The frequency of the GG genotypes for the 47 SIDS infants (17%) was intermediate between the control (32.4%) and sepsis (8%) groups; however, the differences were not significantly different {2=4.68, df=2, P<0.1; ref. [135
], unpublished results}. There were no differences in the distribution of the IL-6 G-174C polymorphism between Bangladeshi and Aboriginal Australian groups; however, both of these showed a significant difference in the distribution compared with Europeans (P=0.000; Table 6
).
There have been variable reports about the correlations between genotype and IL-6 responses. Cells from individuals with the GG genotype of the IL-6 G-174C SNP produced higher levels of IL-6 in vitro. Transfection of the IL-6-174C allele into HeLa cells resulted in lower levels of IL-6 compared with responses elicited by the IL-6-174G allele [160 ]. For leukocytes from cord blood of neonates, higher levels of IL-6 were associated with the CC genotype. No significant association between IL-6 responses and genotype was observed with leukocytes from adults [161 ]. In experiments with leukocytes from adults, risk factors for SIDS (e.g., cigarette smoke) might be confounding factors for some of these studies. To our knowledge, our studies are the first to assess cytokine responses in relation to smoking, gender, and genotype.
Cigarette smoke
In our recent studies, the highest median IL-6 responses to endotoxin were observed for smokers with the GG genotype. Higher median levels of IL-6 were not observed among nonsmokers for this genotype compared with those with the GC or CC genotypes. The median IL-6 responses to endotoxin for smokers with the GG genotype were significantly higher than those for nonsmokers with the same genotype (P<0.05) and for smokers of the other two genotypes (GG vs. GC, P=0.01; GC vs. CC, P=0.00). For nonsmokers, there were no differences between median IL-6 responses among the GG, GC, or CC genotypes [136
].
Gender
Male gender was associated with increased levels of IL-6 [134
]. The median IL-6 level for the 60 females tested was 4.9 ng ml–1 compared with 8 ng ml–1 for the 40 males; however, the difference was not significant. Smoking was noted to be a confounding factor. Median IL-6 levels for nonsmokers were significantly lower (P<0.03) for females (n=34, 5.2 ng ml–1) compared with males (n=24, 8.1 ng ml–1). Median IL-6 levels for smokers were not significantly lower for females (n=25, 4.6 ng ml–1) compared with males {n=15, 7.85 ng ml–1; ref. [135
], unpublished results}.
Hyperthermia
In an infant rat model, hyperthermia significantly increased production of IL-6. Increased temperature did not, however, further enhance IL-6 responses to MDP [127
].
IL-10 gene polymorphisms
IL-10 plays an important role in control of proinflammatory responses. The genetic background of an individual is thought to determine between 50% [162
] and 75% [163
] of IL-10 responses to endotoxin. In animal models, it reduces the lethality of staphylococcal toxins [165
]. With one exception [165
], the IL-10 G-1082A polymorphism in the promoter region has been associated with decreased IL-10 production [166
167
168
]. The differences between the genotypes were not always significant, but this might be a result of small numbers of subjects in most studies.
Evidence from studies about a small number of British SIDS infants suggested there was an excess of IL-10 polymorphisms associated with lower levels of IL-10, IL-10 G-1082A, and IL-10 C-592A [169
, 170
]. Another study about a larger sample of Scandinavian SIDS infants found no association with any IL-10 polymorphisms [171
, 172
]. Our studies, like those of the Scandinavian survey, found no significant differences in the distribution of these genotypes among SIDS infants compared with controls [132
]. There were no differences in the distribution of the IL-10 G-1082A polymorphism between Bangladeshi and Aboriginal Australian groups; however, both of these showed a significant difference in the distribution compared with Europeans (P=0.000; Table 6
). The proportion of individuals with the homozygous genotype (GG) prevalent among Europeans was significantly lower among Bangladeshis and Aboriginal Australians. The homozygous genotype (AA) found in 
30% of European populations was predominant in the other ethnic two groups (>80%).
In contrast to the predictions based on the British study, baseline levels of IL-10 of SIDS parents were increased compared with those of control parents. In addition, there were no significant differences between IL-10 responses of SIDS and control parents to TSST or endotoxin. The most important finding in these studies was that smokers had significantly lower levels of IL-10, baseline levels, and those measured in response to toxin stimulation [85 ]. When the genotypes were assessed in relation to smoking, leukocytes from Europeans with GA or AA genotypes showed significantly lower levels of IL-10 in response to low levels of endotoxin [132 ], which induced significantly lower median levels of IL-10 from leukocytes from smokers (25.6 ng ml–1, range 1–171.4 ng ml–1) than from nonsmokers (57.7 ng ml–1, range 1–1608.0 ng ml–1; P=0.00). There were no significant differences for IL-10 responses from leukocytes from nonsmokers to endotoxin for the three genotypes of the IL-10 G-1082A SNP. There were significant differences between smokers and nonsmokers for individuals with the GA genotype (P=0.04) and the AA genotype (P=0.01). The difference between smokers and nonsmokers for the GG genotype was not significant (P=0.09) [132 ].
If these responses are similar to those that occur in vivo, the differences in the lower proportions of Bangladeshi women who smoke (3%) [173 ] compared with Aboriginal Australian women (75%) [174 ] could be an important factor in explaining the differences in their respective SIDS rates and susceptibility to severe respiratory tract infections. This is particularly important, as it has been observed that some infants have cotinine levels equivalent to those found in active smokers [109 ]
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CONCLUSIONS |
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A summary of the risk factors for ethnic groups with low, medium, and high incidences of SIDS is provided in Table 7 . If cytokine gene polymorphisms were the main factor in susceptibility to SIDS, the incidence of these deaths should be similar for Aboriginal Australians and Bangladeshis. Genetic predisposition to strong proinflammatory responses is insufficient to explain the risk for SIDS; other genetic or environmental cofactors are required. Currently, the major modifiable risk factor for SIDS is exposure of infants to cigarette smoke. Among groups in which the incidence of SIDS is high, the proportion of mothers who smoke is higher than those groups in which there is a low incidence of SIDS and a low incidence of maternal smoking.
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Perhaps the most important results are those that indicate inflammatory responses of leukocytes from donors with different genotypes are affected to varying degrees by exposure to cigarette smoke. The models developed can be applied to testing the effects of other environmental factors which could affect pro- and anti-inflammatory responses associated with different gene polymorphisms, e.g., air pollutants and virus infections. Evaluation of the effects of smoking might help to explain discrepancies in results reported by different groups for cytokine responses associated with particular gene polymorphisms.
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ACKNOWLEDGEMENTS |
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Received May 9, 2005; revised June 1, 2005; accepted June 6, 2005.
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REFERENCES |
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interferon in SIDS J. Clin. Pathol. 45(Suppl.),25-28[Medline]
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ABSTRACT
INTRODUCTION